Biotechnology Second Edition Volume12
Legal, Economic and Ethical Dimensions
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Biotechnology Second Edition Volume12
Legal, Economic and Ethical Dimensions
Biotechnology Second Edition Fundamentals
Special Topics
Volume I
Volume 9 Enzymes. B ioma ss
Biological Fundamentals
,
Food and Feed
Volume 2
Volume 10 Sp ecial Processes
Volume 3
Environmental Processes
Genetic Fundamentals and Genetic E ngi n eer i ng
Volume 1 1
Bioprocessing Volume4 Me a s u r ing Modelling and Control .
.
Volume 12 Legal, Economic and
Ethical Dimensions
Products Volume 5 Genetically En gi nee red Proteins and Monoclonal Antibodies Volume 6
Products of Primary Metabolism Volume
7 Products of Secondary Metabolism Volume H Biotransformations
© VCH Verlagsgesellschaft mbH. D-69451 Weinheim (Federal Republic of Germany). 1995 Distribution:
VCH. P. 0. Box 10 1161. D-69451 Weinheim (Federal Republic of Germany)
Switzerland: VCH. P. 0. Box. CH-4020 Basel (Switzerland) United Kingdom and Ireland: USA and Canada: Japan:
VCH (UK) Ltd . . 8 Wellington Court. Cambridge CBI 1HZ (England)
VCH. 220 East 23rd Street. New York. NY 10010-4606 (USA)
VCH. Eikow Building. 10-9 Hongo 1-chome. Bunkyo-ku. Tokyo 113 (Japan)
ISB'\ Vi27-2!!322-6 Set ISB'-i Vi27-2R310·2
A
Multi-Volume Comprehensive Treatise
Edited by H.-J. Rehm and G. Reed in cooperation with A. Piihler and P. Stadler
Volume12
Legal, Economic and Ethical Dimensions Edited by
D. Brauer
Weinheim New York Basel Cambridge Tokyo ·
·
·
Series Editors:
Prof. Dr. H.-J. Rehm lnstitut fiir Mikrobiologie Universitat Munster Corrensstra8e 3 D-48149 Munster Prof. Dr. A. PUhler
Biologie VI (Genetik)
Universitlit Bielefeld P. 0. Box 100131 D-33501 Bielefeld
Dr. G. Reed
2131 N. Summit Ave.
Apartment #304 Milwaukee, WI 53202-1347 USA
Vol ume Ed itor:
Dr. Dieter Brauer HoechstAG Head Office Corporate Res ea r ch and Development D-65926 Frankfurt am Main
Dr. P. J. W. Stadler BayerAG Verfahrensentwicklung Biochemic
Lei tung
Friedrich-Ebert-Stra8e 217
D-42096 Wuppertal
This book was carefully produced. Nevertheless. author s . editors and p ublisher do not war rant the information
contained therein to be free of errors. Readers are advised to kee p in min d that st at e me nts , data, ill ustr ations, pro cedural details or
other items may ina dvert entl y be inaccurate.
Published joint ly by VCH Verlagsgesellschaft mbH. Weinhei m (Federal Republic of G ermany) VCH Publishers Inc . . New York. NY (USA) Editorial Director: Dr. Hans-Joachim Kraus
Editorial M anager: Christa Maria Schultz Copy E ditor : Karin Dembowsky Production Manager: Di p l. Wirt.-lng. (FH) Hans-Jochen Schmitt
Library of Congress Card No.: ap pl i e d for British Library Cataloguing-in-Publication Data: A catalogue record for this book is available from the British Library Die Deuts che Bibliothek - Cl P-Einheitsaufnahme Biol�hnoloiY: a multi volume co m pr eh ensi v e treatise I ed. by H.-J. Rehm and G. R e e d . In c ooperation with A. Plihler and P. Stadler.- 2 .. co mpl e tel y rev. ed.- Weinheim; New York; Basel: Cambridge; Tokyo: VCH. ISBN J-527-28310-2
NE: Rehm. Han s J. [Hrsg.)
2 .. completely rev. ed. Vol. 12. Legal. Economic and E thi cal Dimensions I ed. by D. Brauer - 1995 ISBN 3-527-28322-6 NE: Brauer. Dieter [Hrsg.J
©VCH Verlagsgesellschaft mbH. D-69451 Weinheim (Federal R ep ubli c of G er many) , 1995 Pr inte d on aci d- free and chlorine-free paper. All rights reserved ( i nclu din g those of t r a nslati o n into other languages). No p ar t of this book may be reproduced in any form- by photoprinting. mi cro film . or any o ther means- nor transmitted or transla ted into a machine language without written p ermiss ion from the pu blishers . Registered names. trad emark s , etc. us ed in this book, even when not specifi cally marked as such, are not to be considered unprotected by law. Composition and Printing: Zechnersche Buchdruckerei, D-67330 Speyer. Bookbinding: Fik entscher GroBbuchbinderei. D-64205 Darmstadt. Printed in the Federal Rep ubl i c of G ermany
Preface
In recognition of the enormous advances in biotechnology in recent years, we are pleased to present this Second Edition of "Biotechno logy" relatively soon after the introduction of the First Edition of this multi-volume com prehensive treatise. Since this series was ex tremely well accepted by the scientific com munity, we have maintained the overall goal of creating a number of volumes, each de voted to a certain topic, which provide scien tists in academia, industry, and public institu tions with a well-balanced and comprehensive overview of this growing field. We have fully revised the Second Edition and expanded it from ten to twelve volumes in order to take all recent developments into account. These twelve volumes are organized into three sections. The first four volumes consid er the fundamentals of biotechnology from biological , biochemical, molecular biological, and chemical engineering perspectives. The next four volumes are devoted to products of industrial relevance. Special attention is given here to products derived from genetically en gineered microorganisms and mammalian cells. The last four volumes are dedicated to the description of special topics. The new "Biotechnology" is a reference work, a comprehensive description of the state-of-the-art, and a guide to the original literature. It is specifically directed to micro biologists , biochemists, molecular biologists, bioengineers, chemical engineers, and food and pharmaceutical chemists working in indus try, at universities or at public institutions.
A carefully selected and disti�ished Scientific Advisory Board stands behind the series. Its members come from key institu tions representing scientific input from about twenty countries. The volume editors and the authors of the individual chapters have been chosen for their recognized expertise and their contribu tions to the various fields of biotechnology. Their willingness to impart this knowledge to their colleagues forms the basis of "Biotech nology" and is gratefully acknowledged. Moreover, this work could not have been brought to fruition without the foresight and the constant and diligent support of the pub lisher. We are grateful to VCH for publishing "Biotechnology" with their customary excel lence . Special thanks are due to Dr. Hans Joachim Kraus and Christa Schultz, without whose constant efforts the series could not be published. Finally, the editors wish to thank the members of the Scientific Advisory Board for their encouragement, their helpful sugges tions, and their constructive criticism. H.-J. Rehm G. Reed A. Piihler P. Stadler
Scientific Advisory Board
Prof Dr. M. J. Beker
Prof Dr. T. K. Ghose
August Kirchenstein Institute of Microbiology Latvian Academy of Sciences Riga, Latvia
Biochemical Engineering Research Centre Indian Institute of Technology New Delhi, India
Prof Dr. J. D. Bu'Lock
Prof Dr. I. Goldberg
Weizmann Microbial Chemistry Laboratory Department of Chemistry University of Manchester Manchester, UK
Department of Applied Microbiology The Hebrew University Jerusalem, Israel
Prof Dr. C. L. Cooney
Prof Dr. G. Goma
Department of Chemical Engineering Massachusetts Institute of Technology Cambridge, MA, USA
Departement de Genie Biochimique et Alimentaire Institut National des Sciences Appliquees Toulouse, France
Prof Dr. H. W. Doelle
Prof Dr. D. A. Hopwood
Department of Microbiology University of Queensland St. Lucia, Australia
Department of Genetics John Innes Institute Norwich, UK
Prof Dr. J. Drews
Prof Dr. E. H. Houwink
F.
Hoffmann-La Roche AG Basel, Switzerland
Organon International bv Scientific Development Group Oss, The Netherlands
Prof Dr. A. Fiechter
Prof Dr. A. E. Humphrey
Institut ftir Biotechnologie Eidgenossische Technische Hochschule ZUrich, Switzerland
Center for Molecular Bioscience and B iotechnology Lehigh University Bethlehem, P A, USA
VIII
Scientific
Advisory Board
Prof Dr. I. Karube
Research Center and Technology
for Advanced Science
Tokyo. J apan
M. A. Lachance
Department of
Pl ant
Schugerl
I nstitu t fiir Technische Chemic
Universitat Hannover Hannover, Germany
University of Tokyo
Proj: Dr.
Prof Dr. K.
Sciences
University of Western Ontario London, Ontario. Canada
Prof Dr.
P. Sensi
Chair of Fermentation Chemistry and Industrial Microbiology
Lepetit Research Cen ter
G e re n zano I tal y ,
Prof Dr. Y. Liu
China National Center for Biotec hnology Development
Beijing, China
Prof Dr.
J. F. Martin
Department of Microbiology University of Leon
Prof Dr. Y. H. Tan
Institute of Molecular and Cell Biology National Universit y of Singapore Singapore
Prof Dr. D. Thomas
Laboratoire de Technologic Enzymatique
Un i v e rs it e de Compi eg n e
Leon. Spain
Compiegne, France
Prof Dr. B. Mattiasson Department of B i ot ech nology
Prof Dr. W. Verstraete Laboratory of Mic rob i al Ecol ogy
University of Lund
G e nt
Chemical Center
Lund. Sweden Prof
Dr.
M. Rohr
lnstitut fUr B i ochem i sche Technologic
und Mikrobiologie
Technische Universitat Wien Wien, Austri a
Prof Dr. H. Sahm lnstitut fUr Biotechnologie Forschungszentrum J i.il ich Jiilich, Germany
Rijksuniversiteit Gent ,
B el gium
Prof Dr. E.-L. Winnacker Insti t ut fi.ir Biochemic Universitat Mi.inchen M i.inchen , Ge rmany
Contents
Introduction
D.
1
Brauer
I. Modern Biotechnology - What Is New About It?
1 The Evaluation of Technology as an
Interactive Commitment-Building Process - The Failure of Technology Assessment 5 G. Van Steendam
2 Concepts of Risk Assessment: The "Process versus Product" Controversy Put to the Rest 39 H. I. Miller
3 Biosafety in rONA Research and Production 63 D. Brauer, M. Broker, C. Kellermann, E.-L. Winnacker
4 Biotechnology and Bioethics: What is
Ethical Biotechnology? D. R. J. Macer
1 15
7 Biomedicinal Product Development 213 J.-P. Gregersen 8 Regulations for Recombinant DNA Research, Product Development and Production in the US, Japan and Europe 239 D. Brauer, H. D. Schlumberger
III. Intellectual Property and Bioinformatics 9 Biotechnology and Intellectual
Property 281 J. Straus 10 Patent Applications for Biomedicinal Products 299 J.-P. Gregersen 1 1 Databases in Biotechnology 323 E.
Poetzsch
IV. Biotechnology in a Developing World II. Product Development and Legal Requirements
12 Commercial Biotechnology: Developing World Prospects 339 G. T. Tzotzos, M. Leopold
5 Structured Risk Assessment of rONA Products and Consumer Acceptance of These Products 157
13 Biotechnology in the Asian-Pacific Region 369 R. D. Schmid, B.-H. Chung, A. J. Jones,
6 Strategic Regulations for Safe Development of Transgenic Plants
14 Biotechnology and Biological Diversity 433
C. T. Verrips
T.
L. Medley, S. L. McCammon
S. Saono, J. Scriven,
197
M. Kawai
J. H. J. Tsai
X
Content.\
V. Public Attitudes and Political Responses I.S
Ih
··oui·· or ··Non'' to Biotechnology: The
Other French Refe rendum 449 A. Millet G ov er nm e nt Researchers and Activists: The Critical Public Policy Interface 459 S. L. Huttner .
17
18
Press Coverage of Genetic Engineering in Germany: Facts, Faults and Causes 495 H. M. Kepplinger, S. C. Ehmig The Regulation of Modern Biotechnology: A Historical and European Perspective 505 M. F. Cantley
Index
683
Contributors
Dr. Dieter Brauer
Dr. Simone Christine Ehmig
Hoechst AG Head Office Corporate Research and Development D-65926 Frankfurt am Main Federal Republic of Germany
Johannes Gutenberg-Universitii.t Institut fiir Publizistik Jakob-Welder-Weg 20 D-55128 Mainz Federal Republic of Germany
Dr. Michael Broker
Dr. Jens-Peter Gregersen
Behringwerke AG Emil-von-Behring-StraBe 76 D-35041 Marburg Federal Republic of Germany
Behringwerke AG Emil-von-Behring-StraBe 76 D-35041 Marburg Federal Republic of Germany
Dr. Mark F. Cant l ey
Dr. Susanne L. Huttner
OECD (Organisation for Economic Co-operation and Development) Head of Biotechnology Unit Directorate for Science, Technology and Industry 2, rue Andre Pascal F-75775 Paris Cedex 1 6 France
Director UCLA Systemwide Biotechnology Research and Education Program Molecular Biology Institute 405 Hilgard A venue Los Angeles, CA 90024-1570 U.S.A.
Dr. Bong-Hyun Chung
Dr. Alan J. Jones
Senior Research Scientist Genetic Engineering Research Institute of KIST Taeduk Science Town Taejon, South Korea
Counsellor (Industry, Science and Technology) Australian Embassy Godesberger Allee 106--107 D-53175 Bonn Federal Republic of Germany
Chapters 3 and 8
Chapter 3
Chapter 18
Chapter 13
Chapter 17
Chapters 7 and 10
Chapter
16
Chapter 13
XII
Contributors
Prof. Dr. Marion Leopold
Dr. Sally L. McCammon
Department of Sociology Universite du Quebec P-8888 Succ A Montreal, Quebec H3C 3P8 Canada
U.S. Departme nt of Agriculture APHIS Animal and Pl an t Health Service P.O. Box 96464 Washington. DC 20090-6464
Chapter 12
U.S.A.
Chapter
6
Dr. Terry L. Medley
Dr. Masao Kawai Director
of Agriculture APHIS A nimal and Plant Health Inspe ction Service P.O. Box 96464 Washington, DC 20090-6464 U.S. Department
Japan Monkey Center Chairman of the Commi ttee on Biodiversity Tokyo 105 Jap a n Chapter 14
U.S.A.
Chapter
6
Prof. Dr. Henry I. Miller
Dr. Cornelia Kellermann
Laboratori um fi.ir Molekulare Genzentrum Am Klopferspitz 18 D-82152 Martinsried Federal Republic of Germany Chapter 3
Biologie
Prof. Dr. Hans Mathias Kepplinger
Johannes Gutenberg-llniversitiit lnstitut fiir Publizistik
Stanford Unive rsity Hoover Institution and I nstitute for Interna tional Studies Stanford, CA 94305-6010 U.S.A . Chapter 2 Annette Millet Biofutur 29, rue Buffon
Jakob-Welder-Weg 20 D-55128 Mainz Federal Republic of Germany Chapter 17
F-75005 Paris France Chapter 15
Prof. Dr. Darryl R. J. Macer
Dr. Eleonore Poetzsch FIZ Chemie Berlin GmbH Fachinformationszentrum Post fach 12 60 50 D-1 0593 Berlin Federal Re p ubli c o f Germany Chapter 1 1
Institute of Biological Sciences University of Tsukuba Tsukuba Science Citv 305 Japan ·
and
Eubios Et hics Institute Colwyn Street Christchurch 5 New Zealand Chapter 4 31
Inspection
Dr. Susono Saono Research and Development Centre for
Biotechnology Ir. H. Juanda 18 P.O. Box 323 Bo go r 16122 Indonesia Chapter 13
Jl.
.
Contributors
Prof. Dr. Horst Dieter Schlumberger
Dr. George T. Tzotzos
B ayer AG Geschaftsbereich Pharma Forschung und Entwicklung Postfach 10 17 09 D-42096 Wuppertal Federal Republic of Germany Chapter 8
UNIDO United Nations Industrial Development Organization ICGEB Science Coordinator ( International Centre for Genetic Engineering and Biotechnology) Vienna Office P.O. Box 400 A-1400 Wien Austria Chapter 12
Prof. Dr. Rolf D. Schmid
XIII
Prof. Dr. Guido Van Steendam
Institut fiir Technische Biochemie Universitat Stuttgart Allmandring 31 D-70569 Stuttgart Federal Republic of Germany Chapter 13
ifb International Forum for Biophilosophy Director Craenendonck 15 B-3000 Leuven Belgium Chapter 1
Jeannie Scriven, B. A.
Prof. Dr. C. Theo Verrips
GBF Gesellschaft fiir Biotechnologische Forschung mbH Mascheroder Weg 1 D-38124 Braunschweig Federal Republic of Germany Chapter 13
Unilever Research Laboratorium P.O. Box 1 14 NL-3130 AC Vlaardingen The Netherlands Chapter 5
Prof. Dr. Joseph Straus Max-Planck-Institut fUr auslandisch e s und
Prof. Dr. Ernst-Ludwig Winnacker Laboratorium fur M olekular e Biologie
internationales Patent-, Urheber- und Wettbewerbsrecht SiebertstraBe 3 D-81675 Miinchen Federal Republic of Germany Chapter 9 Dr. Jane H. J. Tsai
Kurt-Schumacher-Weg 1 1 D-37073 Gottingen Federal Republic of Germany Chapter 13
Genzentrum Am Klopferspitz 1 8 D-82152 Martinsried Federal Republic of Germany Chapter 3
Biotec/11wlogy
Ed ited by ,H.-J. Rehm a nd G. Reed in coo p eration wi th A. Puhler and P. Stad ler C o p yright © VCH Verlagsgesellscnatt mbH,1995
Introduction
DIETER BRAUER Frankfurt am Main, Federal Republic of Germany
"Biotechnology" undoubtedly is a fascinat ing field with far-reaching legal, economic and ethical implications for mankind. In this Volume 12 of the Second Edition of "Bio technology" an experienced and diverse team of authors comprising scientists from academ ic research and industry. regulators and jour nalists examines the potential implications biotechnology may have from various angles. The perspective is thoroughly international and with many critical comparisons and views expressed. It is an indispensable reading for everyone seriously concerned with the poten tial risks and benefits of modern biotechnolo gy and the more general problems associated with the introduction of a new technology into society. From about 20 different technical and scientific disciplines including biochemistry. classical genetics. protein chemistry, micro biology etc .. further biologically derived tools such as genetic engineering and hybridoma technology have been developed. which are often referred to as "modern biotechnology" and which represent the most exciting ad vance in the biological sciences this century. However. there is evidence that this new technology is not understood by the public, that there is a tendency to think of biotechno logy as fundamentally different from other technologies. The speed of its introduction
seems to frighten some onlookers, and the sa fety of genetic modification is questioned. Hence the public demands regulation for its protection. Not surprisingly therefore, since the pio neering phase of modern biotechnology we have seen the production of an enormous quantity of political, scientific, socio-econom ic and ethical literature evaluating the differ ent aspects of biotechnology. There are also the questions of patenting "life''- needed for the protection of investments and rejected as ''unmoral" by other interests and fears with regard to biotechnology have to be linked to ambiguous attitudes towards technology in general. The contributions compiled in the five parts of this book are an attempt to cover the mainstream of thoughts and developments with respect to biotechnology from an inter national and multidisciplinary perspective: Part I guides the reader into biotechnology and starts with an introduction into technolo gy assessment in a fundamental way and not limited to biotechnology, only. The n the dif ferent concepts of risk assessment applied to day are discussed and evaluated and are fol lowed by a detailed introduction to biosafety issues in research and production. The intro duction to biotechnology is concluded by combining the terms "biotechnology" and
2
Introduction
"bioethics" and the development of thoughts about what ethical biotechnology might be. Part II focuses on the practical aspects of applying modern biotechnology in research and to the production of goods. It addresses the different expectations and needs of users of modern biotechnology, consumers and reg ulators who have to serve all interests appro priately. The topics range from structured risk assessment of rDNA products mainly in the food sector and the regulations applied to a safe development of transgenic plants to biomedicinal product development and a comparison of the different regulatory envi ronments for modern biotechnology in the US, Japan and Europe. Part Ill covers both intellectual property protection and bioinformatics. One chapter focuses on what "patent protection" actually is, and why lack of patent protection prevents investment into R & D confining activities to reengineering and copying. Only an effective use of intellectual property rights enables in dustry to recover the enormous costs involved in developing new products and processes. B ecause modern biotechnology is highly in formation-dependent, the availability of high quality, up-to-date and comprehensive infor mation is an important requirement on al most each level of R & D, production devel opment and in intellectual property protec tion. Therefore, databases are an essential tool in biotechnology. Part IV evaluates prospects for biotechnol ogy in the developing world and specifically in the Asian-Pacific region. It is discussed in detail, to which extent the disjunction of pri orities between the industrial and developing world influences the potential of biotechnolo gy to solve health- and food supply-related problems in the developing world. Many countries in the Asian-Pacific region are in a state of rapid transformation from agricultur al to industry- and service-based economies. The data available indicate that biotechnolo gy has achieved a high priority status in the whole region which has become a strong con tender to the development of biotechnology in North America and Europe.
Part V is an attempt to analyze the role of the public in the development of biotechnolo gy and to compare the differing views in some key countries like France, USA and Germa ny. The focus is put on the activities of inter est groups, the role of the media and the po litical responses. The concluding chapter in this book is a historical review of events and decisions in time relevant to the development of modern biotechnology with specific em phasis on the European perspective. Howev er, this chapter is not limited to but goes well beyond biotechnology. In a narrative form it represents a case study in how societies cope with new knowledge in the last quarter of the twentieth century. Everybody knows the fairy-tale of the in nocent maiden and the ugly and horrible beast which turned out to be something hon est and trustworthy after being treated with goodwill and trust rather than with fear and repulsion. But, unfortunately, there is no evi dence for who is the beauty and who is the beast. Is it the innocent and trusting public which is confronted with a flourishing science threatening human life, the environment and the integrity of God's creation? Or is it a pure and beneficial science promising progress in many human problems which is rejected by an ignorant and distrustful public? Hopefully, this comprehensive book will provide the interested reader with sufficient evidence to make him understand that bio technology is neither a beauty nor a beast, and that science and technology are not a subsystem of our society in the sense that they could be regarded separately from other subsystems. Understanding this and the points made in this book may help the reader to find his own views and positions based on an educated choice not only towards biotech nology but also to "technology" in a broader sense.
Frankfurt am Main, November 1994 Dieter Brauer
I. Modem Biotechnology What is New About It?
-
Biotec/uwlogy
Ed ited by .H.-J. Rehm a nd G. Reed in coo p eration w ith A. Puhler and P. Stadler Copyright © VCH Verlagsgesellschatt mbH, 1995
1 The Evaluation of Technology as an
Interactive Commitment-Building
Process - The Failure of Technology Assessment
GUIDO VAN STEENDAM Leuven, Be l gi um
1 Introduction 7 2 The Benefits of Technology 7 2.1 Growing Social and Economic Welfare 8 2.2 Maintaining Peace 9 2.3 Prestige 9 3 Technology under Attack 9 3.1 Doubts on the Socia l Relevance 10 3.1.1 Prestige 10 3.1.2 Maintaining Peace 10 3.1.3 Growing Social and Economic Welfare 3.2 The Hidden Costs 10 3.2.1 Cost to t h e Natural Environment 11 3.2.2 Cost to the Soc ial Environment 11 4 The Rise of Technology Assessment 11 4.1 The T A Methodology 12 4.2 The T A Office 13 4.2.1 A Congressional Ins t itution 13 4.2.2 A Strong Institution 14 5 The End of Technology Assessment 15 5.1 A Recognized Failure 15 5.2 An Inadequate View on Technology 16 5.2.1 Predictability 17 5.2.2 Controllability 17
10
1 The Evaluation of Technology as an interactive Commitment-Building Process
6
6
7
8
9 10
5.3 An Inadequate View of Assessment 18 5.3.1 Objective Overall Assessment 18 5.3.2 Subjective Overall Assessment 20 Lessons from TA 22 6.1 The Importance of Sound Interaction 22 6.1.1 Interaction with the Initiator 22 6.1.2 A Powerful and Committed Interaction 23 6.1.3 Informed Interaction 23 6.1.4 Properly Institutionalized Interaction 24 6.1.5 Interaction Among All Partners Involved 24 6.2 The Allurement of Objective Certainty 25 The Origins of Science and Technology Policy 26 7.1 Industrial Science and Technology Policy 26 7.1.1 The First Industrial Revolution 27 7.1.2 The Second Industrial Revolution 27 7.1.3 Later Revolutions 28 7.2 Early Governmental Science and Technology Policy 28 7.2.1 Prestige and Maintaining Peace 28 7.2.2 Growing Social and Economic Welfare 29 7.3 Spread of Governmental Science and Technology Policy 29 7.3.1 Science for Policy 30 7.3.2 Policy for Science 30 Making Science and Technology Policy Interactive 30 8.1 Making Existing Policy Interactive 31 8.2 Using All Possible Social Resources 33 8.3 An Information Process 33 8.4 A Process of Shared Commitment-Building 34 8.5 Decentralized and Multi-Form Institutionalization 35 TA after TA 37 References 38
2
1 Introduction Is Technology Assessment", or "TA", the magic brew which enables governments to guarantee the to tal quality and relevance of the technological developments they approve or stimulate? Can othe r initiators of technolo gies, such as biotech compa n ie s or academic research labs, make use of the same tool to convi nce the authorities of how well-pre pared, b e nefi c i al and safe thei r p l ans are? Or does T A provide activists and envir onmental ists with an infallible instrument to collect ir refutable evidence of the danger of speci fic developme nts which they had since long sus "
pected?
The answer to each of these question s is a disappointing but clear No : TA is not the panacea it is still often believed to be. While bein g prepared by t he American Con gress in the sixties as a method with capital T and capital A. to understand and assess all as pects of technological develop m e nts in real ity it never worked that way. and it never will. Both the conception of "technology" and the ideas on '"assessment" which underlie the T A approach appear to be exceedingly objective and therefore unrealistic. The T A experiment of the US Congre s s is an e x periment that failed and was doomed to fail. This is the first point we want to make in this chapt e r The second p o i n t is t h at the T A ideals are a permanent threat to any serious attempt to monitor the relevance and harmlessness of technological developments By holding up the prospect of providing a complete and ob jective analysi s TA play s a long with our de eply human but utopi a n craving for making infallible decisions. and in this way diverts our a ttent i on fro m mor e realistic appr oache s to e nhanci n g t h e quality of decision m a king
r ath er
"
"
,
.
7
The Benefits of Technology
well. They are important to the extent they succeed in developing activities that go beyond T A as designed by US Congress in the sixties, but contribute to reali z ing and sus taining a broader social process of informed, committed and interactive policy making This chapter begins with a description of the ambiguous situation of the "golden six ties" during which the American Congress conceived the idea of Technology Assessment and coined the term. The sixties were domi nated by technology which was first seen as the d riving force behind wealth and abun dance (Section 2) and later as a po tentia l dan ger and a major source of an irrelevant and degenerating lifestyle (Section 3). Next fol lows a p resentation of T A, as the attempt by US Congress to identify valuable technology and to sepa r ate the wheat from the chaff (Section 4). This outline is followed by an evaluation of this enterprise, expla ining the untenability of the approach (Section 5) and paying attention to the positive lessons we can learn from the T A experiment ( Se ction 6). The chapte r concludes with an overview of a more realistic and work able, though fallible, approach to monitor technological develop ments. It e x plains that such endeavor should be seen as a further step in the burgeoning science and technology policy ( Se ction 7) and that it takes account of our growi ng aware ness and inc reasing understandin g of the falli bility of human deci sion mak i ng in a perma nent situation of uncertainty (Section 8). -
.
-
.
.
2 The B e nefits of Technology
-
under uncertainty.
The most important point of this chapter is that proper ma na gement of te c h no l o gical de ve lopm en ts requires a great dive r sity of activ ities of a l ar ge variety of i nst i tutions linked to all formal and i n fo rmal social sectors. These institutions include res e arch units, advisory bodi e s discussion groups. international and interdisciplinary forums, and strategic grou ps - many of which al r eady exist and fu nct ion ,
In the 1 960s, few would have e x pect e d that anybody would ever seri ous l y endorse the idea that new technological deve lop m ents are in fact suspicious and in need of cr i t ic al as sessment before they be allowed to p roceed On the contrary, technological innovation was believed to be a good thing which should be stimulated by all means. Technology ap peared to have re vitaliz ed all important as pects of social life. .
8
1
The Evaluation of Technology as an Interactive Commitment-Building Process
2.1 Growing Social and Economic Welfare
The great affluence which so characterized the sixties was unrivalled by that of any other preceding period in the history of mankind. Never before had the people in Western in dustrialized countries experienced a similar wealth and comfort. Since World War II, the average productivity of human labor, the Gross National Product and the GNP per capita had steadily been increasing by about 3 to 4% per year. This trend of growing pros perity not only resulted in more dispensable income for the families and more money to invest for national states, but also in a de crease in the amount of working hours, which, in its turn, allowed for more time for leisure. Technological innovation, based on strong scientific research, manifested itself to be at the heart of this new social order. It appeared that four hundred years of modern science and two hundred years of modern technology had finally reached their stage of maturity. And, as the academic and industrial world were only at the beginning of the exploration and exploitation of promising fields and pow erful new technologies, much faith was placed in the fact that this process of increasing pros perity had been set into motion for good. Four fields were expected to lead to new rev olutions with breathtaking new possibilities. (1) The first one was the electronic revolu tion with the Integrated Circuit which at the time was still in its infancy. Despite its new ness, however, its application had already drastically heightened economic productivity. It was expected that by the year 2000, the computer would enhance the productive ca pacity of human labor by another 300% , al lowing every person to do the work - and to earn the income - of three. (2) The second field revolved around the development of new and cheaper sources of energy. Here the promising new technology would allow the unleashing of enormous amounts of energy stored in the inner core of highly energetic material, by converting this hidden energy into electricity for everyday use. This movement is also called the nuclear revolution.
(3) Thirdly, there was a similar hope that certain traditional basic materials, like steel, whose elemental properties were difficult to engineer, could be replaced by more flexible man-made materials such as plastics. The properties of plastics present the advantage that they can be designed in a research facility and specifically adapted to their planned use, and, at a later stage, they can easily be manu factured in chemical plants by employing sim ple readily available raw materials. (4) Finally, the sixties also announced a biological revolution. Genetics was believed to be the driving force behind this revolution. This discipline was seen as the study of the core elements of life, being genes and chro mosomes, which encoded the characteristics of the different species and forms of life and which are used by living organisms to trans mit hereditary traits to later generations. Re search increasingly succeeded in unravelling the basic mechanisms of those mysterious units, and subsequently opened up prospects for powerful technological applications not only in the field of human health care, but also in agriculture and other fields of human activities. By the end of the sixties, science had already succeeded in isolating the first gene, but it would take until the seventies be fore the first technological uses of those genes would become possible. These prospects, combined with the in sights into the driving forces behind them not only stimulated an increased respect for aca demic science and technology, but went on to nurture the growth of industrial companies. Only large companies could afford to be in volved in the basic research which was needed to guarantee ongoing economic growth. And it was only these same large companies that could afford to develop the mechanisms to turn these basic scientific dis coveries and technological developments into real industrial products to be distributed in society. In taking this beneficial effect of technolo gy on industry into account, we cannot forget that life and the happiness of individuals and families remained at the center of those de velopments. New machines helped to reduce burdensome work and to organize and enrich daily life. Washing machines, dishwashers, re-
3 Technology under Attack
frigerators and freezers became available and accessible to e ach house hold. Color television opened a more vivid window on the real world and provided a priva t e entertainment center for every l i vin g room. Communication was facilitated by a growing number of tele phones and cars. These were the golden six ties. filled with new m usic, wealth and hope.
2.2 Maintaining Peace Technology also left its mark on the wide spread belief that there would never be an other war like World War II which would be staged in the Western world. It was clear that war had not disappeared from the earth. But at the beginning of the sixties. massive war, with its atrocities and mise ry. did disappear from the daily life o f Westerners. War as a concept with a capital W had become humil iated to the abstract notion of a mere diplo matic tension between two blocks - the Cold War between the E ast and the West - or to the theoretical knowledge of smaller. local conflicts in "hidden parts" o f the world. There was a general faith that Western diplo mats. politicians and military forces could master all existing threats because the y could rely on t he most sophisticated arsenal of high tech weapons then known to man. which would easily be able to s t op all attacks from the outside. Furthermore. it was clear to many that these weapons. incl uding a whole battery of nuclear weapons. were so powerful that no other power would ever dare try to attack the West. because they realized that the West could immediately re ply to any at tack with the utter anni hilation of the attack ing force and indeed its entire nation by means of a series of atomic bombs many times more pow erf u l than the bomb which destroyed Hiroshima. In t he same way that large stone walls could protect the inhabitants of a medieval town or fortress. the shield of technology wa s believed to be protecting the modern Western world. Sophisticated weap ons re plac e d bow and arrow while radars and sa t e l l i tes replaced the watchers· ey e .
9
2.3 Prestige In the sixties. technology was not j ust ap preciated as the powerful engine of economic wealth and peace . It was also a deep source of human pride and a symbol of the unlimited possibilities of human rationality and of strong Western nations. Even the most unbe lievable adventures appeared to be possible now. The exploration of space was the show piece of this evolution. The manned landing on the moon was the first dream which be came true. On May 26, 1961 President KEN NEDY earned a long and thunderous applause while explaining his projects to the Con gress: "I believe that this nation should commit itself to achieving the goal, before this decade is out, of landing a man on the moon and re turning him safely to the earth. No single space project in this period will be more im pressive to mankind, or more important for the long-range exploration of space; none will be so difficult or expensive to accomplish." (JOHN F. KENNEDY, 1961). As we all know, this dream became reality. On July 21, 1969, NEIL ARMSTRONG and Buzz ALDRIN spent two hours walking on the moon. The l anding on the moon was transmitted live by television all around the world. This technical feat was experienced as the clear symbol of the unlimited power and possibilities of mankind. For many, the con viction prevailed that man had entered a new phase in his existence, or, as NEIL ARM STRONG expressed it, the very moment after putting the first human foot on the lunar soil: "That's one small step for man, one giant leap for mankind."
3 Technology under Attack
Being a major symbol of the successes of science and technology in t he sixties, the lu nar landing and space travel in general soon became a focal point in a growing movement of mistrust and critical reappraisal. Doubt was
10
1 The Evaluation of Technology as an Interactive Commitment-Building Process
cast on the social relevance of many splendid technological and industrial developments. Furthermore, it became clear that science and technology, functi oning as the engine of our increasing prosperity were accompanied by a host of social and environmental costs to which we had been blind for many years. Science and technology came under a grow ing attack in each of the domains in which they had proven so successful in the sixties. 3 . 1 D oubts on the Social Relevance 3 . 1 . 1 Prestige
The landing on the moon was soon fol lowed by a postnatal depression. For ten years there had been a concerted effort to put an American on the moon, and several scien tific, techno l ogical and industrial projects de rived their raison d'etre from this adventure. Now that the goal had been achieved, ques tions began to surface concerning the true na ture of the project. What was the real inten tion behind the space program? Was the nat ural next step to stage a s imilar landing on the planet Mars? What was the point of the American public authorities' incorporating space travel into their main technological pri orities? What had the nation - or mankind actu all y gained from its lunar expedition? Leading scientists had already considered these pr oblem s earlier. ALVIN WEINBERG, for example, a former member of the Ameri can President's Science Advisory Committee, wrote as early as 1 966: "A crisis of mission will face our space program during the middle seventies. The present scale and pace of our space enterprise is determined by our com mitment to send a man to the moon early in 1970. Now that this date is approaching, grave questions arise as to the next step. Should we go on to Mars; or should the space program revert to the scale it enjoyed before we de cided to send a manned expedition to the moon? The existence of a massive space es tablishment, including many fine laboratories, surely will tend to w eigh the balance stro n gly toward going to Mars after we have reached the moon. Yet I would hope that when the
time for this far-reaching decision comes, we shall have ready for this great scientific tech nical resource many other technical chal lenges that bear more directly on our human well-being than does a manned trip to Mars" (ALVI N M. WEINBERG, 1967). 3 . 1 .2 Maintaining Peace
The domain of military research, another priorities came under attack by the same school of criticism. After all, had not the Vietnam experience proved that the "American war machine" had not succeeded, even with the most sophisti cated weapons, in bringing the war to an end? This growing realization was linked to the general question as to why the Vietnam war had act u al ly been necessary. In addition, more and more members of the American Congress felt that the nation would be better served by a po li cy different from the mainte nance of a high-tech arms race. They also felt that research funds could be put to better use. of Americans technological
3 . 1 .3 Growing Social and Economic Welfare
Economic
growth had the history . While , in the sixties, few would deny that this growth had led to an increasing prosperity and general well-being, it also became gradually clear that it did not make sense to perceive unlimited growth as a goal in itself. These doubts dampened the evi dent relevance of the large investments in scientific and technological developments, de si gned to stimulate economic growth. and industrial
same ambiguous
3.2 The Hidden Costs There was another source of unrest and mistrust towards science and technology. The sixties marked the beginning of a growing awareness that some technologies, developed and applied with only the best of intentions, threatened our natural or cultural resources, long taken for granted.
4 The Rise of Technology Assessment
3.2. 1 Cost to the Natural Environment In 1 962 R A C H E L C A RSON publ i shed " Si lent Spring"' . In this dramatic and alarming report, she co nv i ncingly demonstrates how the increased use of pe s t i cide s is slowly but surely poisoning our biological environment. It is the first influential and well-documented admonition to s oc iety that. by undermining the environment. our technological civiliza tion could ultimately turn against humanity instead of promoting it. Her claim was fol lowed by many negative reports about the ef fects of motorways, jet aircrafts and airports, nuclear energy and many other phenomena of our modern culture. Until the beginning of the 1 960s it had always been naively pre sumed that the sea. rivers. groundwater, air, earth and the plant, animal and human king doms could withstand any conceivable shock that humans could deliver to them. Until that time, it had scarcely been thinkabl e that the increasing industrialization would ultimately lead to the w i des pread extinction of aquatic life, to heavily polluted coasts and beaches, or, inde e d to sickening and unhealthy air pol lution in the large cit i e s In the seventies. when biotechnological methodologies were revolutionized, the ve ry scien t ist s and tech nologists behind these breakthroughs had al ready expressed their deep concern for the potential hazards of the use and laboratory study of recombinant DNA molecules - haz ards to the human health as well as to the health of our environment. Leading molecu lar biologists even proclaimed a moratorium for all further research. This gesture of cau tion attracted the attention of the press and policy-makers and fue l led the widespread be lief that the potential dangers associated with biotechnology are of a very special nature. .
.
3 . 2 . 2 Cost to the Social
Envi ronm ent
Potential dangers, increasingly attributed to technological developments. were not lim ited to our natural environment. A great di-
11
versity of threats to the social enviro nment were also increasingly considered. U n employ ment was a manifest example of these social dangers. Less tangible perhaps was the dan ger that the ever-changing technologies in the workplace m i ght adversely influence the mo tivation of workers, as it could be feared that they would not want to constantly adapt to new procedures or to be i n need of perma nent education. Aside from the social environment in the workplace , the cultural and family-centered social environments were not spared from the technological implications of this new age. For example , it had been argued that televi sion had signified the death of social and cul tural life and even of family life. Also, the enormously increased mobility of the jet-age generation was described as a potential threat to family life. Questions also arose concerning the neces s i ty to adapt our legal and social mechanisms to the many new and powerful technologies, such as the broadened potentials of medicine in the fields of p renatal life and care of the elderly. Not everyone was convinced that the new social and legal order would ultimately bring out social optimal i ty in a better and more humane way than the old order did. Again the oncoming biotechnology and its multiple uses in agriculture , industry and health care stirred the imagination. What should we think e.g. about a society in which specific, newly designed, living beings obtain an economic value and are patented ? And how can our society survive in a situation where man can predefine the t raits of their own children or design "produce" and patent a genetically engineered worker or soldier?
,
4 The Rise of Technology Assessment
After years of economic growth and social euphoria, the 1 960s ended with a deep aware ness of crisis. The engine of our increasing prosperity, namely technological and indus trial de velop ment had p roved to be accom,
12
1
The Evaluation of Technology as a n lnteractive Commitment-Building Process
panied by a host of social and environmental costs to which we had been blind for many years. National governments, which were themselves systematically involved in large scale technological development programs, felt compelled to seriously examine and re consider their earlier carefree approach and their priorities. It was within the context of this reappraisal that the American Congress launched its own initiative, prepared by the subcommittee for "Science, Research and Development" of the "Science and Astronautics" Committee of the House of Representatives. The first report of this subcommittee, published on October 17, 1 966, described how Congress planned to deal with the growing conviction that it is ab solutely necessary to "keep [ . . ] tab on the potential dangers, as well as the benefits in herent in new technology" . Two major con cerns appear to form the basis of these Con gressional efforts. Their first objective was the ensuring of the attainability of in-depth knowledge into the potentially dangerous consequences of tech nologies like "technological unemployment, toxic pesticides, pollution, exhaustion of re sources, the disposal of radioactive wastes, and invasions of personal liberty by electronic snooping and computer data banks". They proposed reaching this objective by means of the development of a new, highly specific, scientific methodology to provide an all-en compassing assessment procedure of all that could be described as "technology". For this new discipline, the subcommittee coined the name "Technology Assessment" (TA). The second objective of the Congressional subcommittee was to make sure that such T A studies were actually carried out, and this in such a way that they would prevent the US Government from promoting and funding ir relevant or dangerous technological develop ments. This concern resulted in the firm belief that one had to establish some sort of institu tional mechanism which would organize the necessary "TA studies" on a systematic basis. Congress believed that this institution should be established within Congress itself. This clarifies why, in 1973, a new Congressional Office was established: the "Office for Tech nology Assessment" (OTA). .
The following sections will expose in greater detail the actual birth of both the T A methodology and the TA Office (see e.g., Sect. 6.1 .3).
4.1 The TA Methodology Unexpected troubles like the environmen tal crises of the 1960s had made Congress acutely aware of the importance of the ability of foresight. Only being able to recognize the destructive consequences of technological projects after they have been developed and widely used, was an embarrassing handicap Congress wanted to rid itself of. The alarming DDT experience should never happen again . Congressmen also staunchly opposed invest ing in the development of technological solu tions which afterwards would prove to be use less or socially irrelevant. They realized that they were in need of a methodology that could provide them with the accurate infor mation about future consequences of techno logical developments. The mechanism of foresight that was needed would have to be characterized by the following four elements: (a) Firstly, the mechanism should function as a "first alert" system which would sound the alarm bell before the hazardous technolo gy had gotten past the drawing board, or at least before the potential negative conse quences had the opportunity to take place. In other words, the information about future consequences would have to be provided when it was still possible to stop the planned technology from being implemented, or at least to redirect or restrain it. (b) Secondly, the early warning system should be systematic and exhaustive. Every consequence of the planned technologies should be explored including the "real and potential impacts of technology on social, economic, environmental, and political sys tems and processes" (VARY T. CoATES, 1 972). However, this analysis was not to con tent itself with the pure assessment of that trend or scenario, which at first glance ap pears to be the only or most evident one. Many technological developments can in fact follow several scenarios depending on the im-
4
pact of broad social or economic develop ments, specific human decisions or other ex ternal factors. In this case the consequences of each of these alternative scenarios should be studied. This included the special case of the consequences of the zero option . where it was decided not to i nitiate the technology at all. Finally, Congress wished that the scope of T A would be of such dimensions that all tech nological domains. harmless though they may appear to be, would be scrutinized . (c) Thirdly. the methodology should not just name the consequences, but also indicate to what extent and in what sense they are haz ardous. The methodology procedures should appraise the nature. significance and merits of the consequences. simultaneously providing a balanced appraisal of the technology under examination. B ased on the results of a T A analysis. the policy-makers should be able to understand what is really at stake when new technological programs are introduced. T A studies should become a powerful tool in pol icy-making. (d) Fourthly, the prognostications should not be the mere guesses of uninformed peo ple, or the work of lobbyists trying to stop or promote a specific technological develop ment. The forecast was to be reliable and ob jective for 1 00% and constitute an incontesta ble basis for sound and justified policy-mak ing. I n other words, the methodology of the investigations should follow some sort of ''scientific met hod '' and the result should be reliably scientific material. Congress was aware that no single e xisting scientific disci pline was able to deliver the required assess ment of all future conseq uences. So it be lieved that a great variety of existing analyti cal methods would have to be modified and combined to form a spanking brand-new dis cipline.
4.2 The TA Office l t was clear that the US Congress would al ready feel much more comfortable when a scientific methodology would be available for making complete and reliable predictions of the consequences of technological and indus trial developments. But the mere availability
The Rise of Technology
Assessment
13
o f a T A methodology could not completely reassure its members. Congress also wanted to regulate the institutional context of TA studies in such a way that they would be tak en seriously. A ccording to Congress, this would imply, first of all, that a new structure for T A studies should be created as an institu tionalized element of the Congressional work unto itself, and secondly, that this new struc ture should be given the necessary staff and funding to organize T A studies in a profes sional, systematic and consistent way.
4.2. 1 A Congressional Institution There are at least three reasons why Con gress wanted to develop the new TA i nstitu tion within Congress itself. ( 1 ) The basic reason is that , i n the US, it is the President and his administration who are the major initiators and promoters of national technological projects, while Congress asserts that it is the only institution that can effec tively put pressure on the President to stop or modify his technological proj ects, in the event the results of a T A study would have un masked their irrelevance or hazards. The most direct tool of Congress consisted in its power to control the budget of the President. In the United States, the White House can do relatively little without the consent of Con gress. which must approve the budget needed to carry out its plans. Thus the famous speech about man landing on the moon, delivered to the American Congress by President KENNE DY in 1 96 1 . was in fact not simply an expres sion of an undertaking by the President to his people . but was really a request to Congress to give financial support to his plans and to approve the budge t. As long as science and technology were generally considered to be beyond any suspicion, Congress did not feel the need for inte nsive and systematic assess ment studies. However, when the conviction grew that technological developments, and therefore also the technological policy of the government, might sometimes be hairy or even problematic, Congress wanted to give a clear sign to the American public that it was ready to shoulder its responsibility and to base its approval on a preliminary careful as-
14
1 The Evaluation of Technology
as
a n Interactive Commitment-Building Process
sessment of the technologies proposed. Con gress was naturally quite aware of the extent of the power of persuasion of public pressures (such as activists and lobbyists) in the White House. The tendencies towards a more direct democracy were understandably perceived as threatening by many members of Congress, who preferred to come up with a strong and potent plan to reassure the constituency that they were capable of and effective in fulfilling their mandate to control the executive pow er. (2) A second reason for Congress' desire to keep TA under its direct control, is that Con gress dwelt in the conviction that the impar tiality of the studies could only be guaranteed by relying on inhouse technical and scientific expertise. Congress did not go as far as to re quest that this inhouse Congressional office for TA studies be not allowed to subcontract minor or larger parts of the research needed. It felt, however, that working with external groups always carried the risk that such teams would include biased and partial experts, who might have an interest in giving an incom plete or distorted picture of the effects of a planned technology. In this sense it was felt that only the Congressional office itself could bear the responsibility for the final presenta tion of the results. (3) As a third important reason for having inhouse expertise available, Congress stressed that this method was the only means to avoid that certain studies which were relevant for policy-making would not be carried out be cause of lack of an interested external re search partner.
4.2.2 A Strong Institution There are also several reasons which help clarify why Congress was convinced that a proper functioning of TA required a strong, well-staffed and well-financed institute. The obvious reason is that the founding of such a well-established institution presents the only guarantee that technological initia tives funded or controlled by the US govern ment be assessed in a professional way. More specifically, Congress wanted to take advantage of the growing belief in the need of
TA, to strengthen its internal power and to counter the power of the White House. In fact, Congress had not (until then) ever been really involved in decision-making in the field of new technological developments. Setting the agenda for Government-funded technolo gy had always been the exclusive task of the President. The President had, of course, al ways been dependent on Congress for budget approvals, but Congress never commanded any serious means of discussing the proposals made by the President. Since the time of Pres ident ROOSEVELT, the White House had had the services of a special advisory body at its disposal. This body was led by the "Presi dential Science Advisor", and was utilized to determine the technological initiatives of the US Government. As a result, Presidential dossiers were usually well-prepared and con vincing. They were filled with tables, lists and figures, which authoritatively explained the supporting scientific evidence of the Presi dential initiatives and which illustrated the many benefits these new programs would bring to the American nation. Consequently, Congress did not see any necessity for engag ing in detailed discussions on the specific as pects of the plans of the President. Nor did it feel the need to, in doing so, prepare a tool of its own which would allow it to contest the conclusions of the Presidential experts. The result is that Congress did not dispose of the experience or expertise it required, when it gradually discovered the need to make its ap proval of the President's technology budget dependent upon the results of a serious as sessment of the long-term relevance, benefits and dangers of the new technological devel opments proposed by the President. On the other hand, the growing scepticism did, of course, also change the attitude of the sea soned Presidential advisors. They increased the strength of the scientific evidence endors ing their plans, they multiplied the number of pages of their reports, and they used ever more sophisticated strategies to convince Congress of the necessity of the technologi cal developments they proposed. R OB E RT McNAMARA, President JoHNSON's Defense Secretary, was notorious for his use of the computer in his attempts to silence members of Congress in debates and hearings. In this
5 co n t ext . Co n g r ess fe l t t he need for a s t r o n g counter-attack. which would lead to the es tablishment of a s t ro n g in-house office for the st ud y of te chn o logy . This is why. in 1 96 7 . re pr e s e n ta t i v e EMILIO Q. DADDARIO. chairman o f the subcommit tee which ex pl o re d the need for T A. i n t ro duced b ill H.R. 6698. which - be i n g the result of severa l hearings an d internal deliberations and e x t e rnal studies - fi n a ll y led i n 1 973 to the e s t abl i s h m e n t of a new Co ng res s i on a l Of fice . the " O ffi ce of Te c h n o l o gy Assessment"". or '' OTA "". di r ec t e d by E M I L I O Q. DADDA RIO. It is c l ea r t h a t t h e White H o use was not incl i n e d to favo r t h i s de v el op m e n t . On the contrary. the R e p ubli ca n President N IXON . during whose Pre s i de n t i a l term OT A w a s fi nally set u p . did his u t m ost to combat t h is i n t ern a l st re ngt h e n i ng of the t h e n pre d o m in a n t ly De mocrat i c Congress i n t h e area of s c ien ce policy . But w h e n President N IXON fi nally si gne d the bill, OT A became established as an autonomous Congress ional bod y. I t was founded on the idea t hat it sho uld not h a v e any other master than the obj ective re qu ire ments of its ne u tra l . scie n t i fic T A methodolo gy. which is a ble to monitor t he t e c h n o l og i cal i n i tiatives of the US Government. Conse qu e n t l y , it was accorded a l l kinds of r i ght s to guarantee its a u t o n o m y . also towards the power and influence of the P r esid e nt and his a d m i ni s tr a ti o n . It was give n the r ig h t to pub lish the resul t s of its s t u d ie s . w he ne ve r t h ese app e a r e d to make sense . albeit in the face of ex pl i c i t disapproval by t h e executive powers. This i s what h app e n ed in 1 988 when, under strong p ro t es t of the Pe n t a go n and the De pa rt m e n t of Defense . OT A p u bli sh e d its as sess ment of the S t ra te gi c Defense I n itiative under the title " S O l : Te c h n o l og y Survivabili ty and Software '". OTA was also given t he ri g ht to call w i tnesse s and to d em a nd a l l doc ume nts necessary for the success of its work. In this sense it h ad been given the power of a strong. p o lit i c a l . pa r l i a m e n t a r y c ommittee with the m a n date to tra ck and monitor t h e White Ho u se in its act ions.
The End of Technology Assessment
15
5 The End of Technology Assessment The T A experiment of the US Co n gress is more than 20 years u n d e rw a y b y now. OTA has b e com e a well-known a n d internationally respected body. It functions as a para d i g m for many w e ll - i n s p ired people all over the world, who are convinced t h a t technological devel opments re q u i re s t ri ct c o n t r o l and gu idance , but who fail to see how this ca n be d o n e . OT A gives them hope. For t h e m , OT A is a s y m bo l of success. It is the l i v in g evidence that it is n o t j u s t an unattainable dream to create an institution which can keep t e c h n olo gical de ve lop m e n t s on the ri g h t track. O T A. g iv e s them the courage t o fi gh t and lobby in o rd e r to introduce a si m il a r institution in their own coun t ry , all ow i ng the l ocal politi c ian s to differentiate be t wee n t e ch n o l o gie s which are i r r e l e va n t and hazardous and de ve lopme nt s which are relevant a nd sa fe . I n sho r t , the TA i n iti a ti v e of t h e U S Co n gre ss ga i n e d wide acce p ta nc e as the ap pro p riat e way to deal with social p r o b l ems linked to technology. Many people, w h e n t h ink i n g abo u t ha n d li n g te c hn o l o gical developments p rope r ly . do not fee l the need to go any fur ther t h a n s tu d yi ng an d im pl e m en t ing the same m e t h odolo gy which we described in the p re v io u s section and for which the US Con gress c o i ned t he s pecifi c name "TA " or " ' Tec h nol o g y Assessment . "
5 . 1 A Recognized Failure D e s p i t e its initial success a n d d es pi t e the fact that the TA me t h o do l o gy appears to be unquestionably co n v i ncing and self-evident, e v e ry bo d y who has a closer look at what h ap pe n ed in OT A can o nl y come to the conclu sion that T A. as created by the U S Co n gr e ss , did not work and never will. By t he e n d of t h e seventies. there existed a fa irly gene ral con s en t that OT A w a s not capable of ach i e v i n g the g o a l for which it had been founded. These ins i ghts were shared by scholars like VARY T. CO ATES . who at the beg i nni n g of the 1970s h ad worked enthusiastically on the de v el op-
16
1
The Evaluation of Technology as an Interactive Commitment-Building Process
ment of the theoretical structure of a scien tific "T A discipline". In 1 979 she writes: "Technology Assessment . . . had its day and has faded into the background along with planning by objectives, and Program-Plan ning and Budgetting Systems (PPBS), and other nonce phrases cum slogans recorded in the history of public administration" (VARY T. COATES, 1 979). Reports prepared by OTA virtually never achieved the level of scientific indisputability which had been envisaged. On the contrary, serious doubts arose at fairly regular intervals concerning the completeness or the "scien tific" nature of the studies carried out. Nor did OTA succeed in establishing an early warning system, coming up with wide-ranging and timely forecasts of potential social prob lems and environmental risks associated with the continued development of science and technology. Finally, OTA reports hardly ever affected actual policy-making. The influence of the studies on policy can in fact be de scribed as varying between minimal and non existent. For many analysts of technological devel opments, these rather negative observations did not come as a surprise. Even before OTA was established, as early as 1968, the National Academy of Sciences (NAS) in Washington, DC was asked by Congress to give it advice on how to organize an effective assessment of technological developments. This advice turned out to be a strong warning against any attempt to guarantee the relevance of tech nology by trying to install some type of agen cy which would function as a neutral j udge who is able to find out what is good for "so ciety" or for the "environment" and who is empowered to indicate which technological developments should be permitted and which prohibited. The NAS report clearly demon strates that this is not the way technology can develop or can be controlled. It concludes that it is simply an illusion to hope that a so called neutral and objective agency would be able to solve the problems linked to technolo gy. Proper decisions about technology require assessment procedures that differ completely from the creating of a centralized office of TA, and completely different studies than the all-encompassing TA studies OTA was
dreaming of. We will expand on this later. But first we want to analyze what exactly went wrong in the implementation of OT A. The problems appear to be very fundamental. It turns out that the concept of "Technology Assessment" as developed by the US Con gress was built on a complete misunderstand ing of what both "technology" and "assess ment" really are.
5.2 An Inadequate View on Technology
It is a common mistake to imagine science and technology as a totality of processes whose internal progress is determined by an implacable, strict, scientific method. In this view, technological developments can be compared to the movement of clocks which run according to their own dynamics. Once the process is started and its momentum kept up, its continued internal progress is regarded as being objectively fixed. According to this view, "external" institutions, such as public authorities, must refrain from any attempt to intervene in the "internal" dynamics of science and technology. Should they try to do this, the scientific quality of the processes can no longer be guaranteed. There is, however, another way for "external institutions" to in fluence the course of science and technology without endangering its internal logic. The basis of this type of interaction is the fact that many external conditions and bodies "from outside" are or can be involved in decisions about which scientific and technological pro cesses will be permitted, started, encouraged, held back or stopped. In all these "external interactions", the internal logic of the tech nological process is left untouched. This pos sibility formed the opportunity the US Con gress wanted to seize in order to prevent irrel evant or dangerous technological develop ments. This possibility was also the context for developing TA, which was believed to provide a solid basis for such "Go" or "No go" decisions by presenting a reliable and comprehensive analysis of what would really happen when a new technological process would be allowed to start.
5 The End
of Technology
17
Assessment
study does n o t attempt to forecast which of these scenarios will actually present itself at some time in the future. This, after all, will depend on the u n p re d i ct ab l e way in which the scientists, the decision-makers and the public will react at crucial moments in the fu ture. It is believed, however, that such a b roa d e r assessment of all scenarios, while be 5 . 2 . 1 Predictabi l ity ing of a less rigorously predictive nature, is still able to provide valuable insights in the possible future of a particular technology . Technol ogi cal d e v e l opments appear to The great problem with this "scenario have little in c o m m o n with the widespread thinking" is that it still c l i n gs to a classical idea that autonomous. homogeneous. p red i c t able processes are completely determined by view in which scientific and technological de some internal scientific logic. Instead, they velopments are rega rded as predictable pro appear to be complex social processes with cesses into which it is possible to have a con many poss i ble side-branches and alternatives. tinuous insi g h t. Although scenario a nalys t s I n designing and de v e lop i ng new technolo show themselves ready to take account of var gi e s scientists are continually faced by ious unpredictable in fl uences and all kinds of choices a n d are constantly forced to take social factors. they ultimately think it must be creative decisions concerning the di rection possible in principle to chart these influences th ey will follow in the fut ure. Many of these with reasonable clarity. This view, however. "internal" decisions a re co-determined by a makes no allowance for the individual nature multitude of "external" influences to which of the many conscious and unconscious con th e y are exposed. which feed and m on i tor trolling factors which are constantly at work their work and which are taken on board. It in scientific and technological d e v e l op m ent has been wid e ly demonstrated by now that This means that the sc e nar i o s described are the concrete form which a given scientific or those which t he client and the research group, technological development fi nally takes and possibly after wide consultation and study, the way i t is i m p l e mented in society. is not are willing and able to think of. The selection just the result of the internal logic of some of scenarios is therefore subject to their con clear methodology , hut also of a multitude of scious and unconscious preferences, and is individual and collective decisions and inter still far removed from the dreamed-of "objec ests. This concrete for m is anything but pre tive overview" of the future of a given tech dictable . due to t h e great number of variables nology. which a T A analysis promised to be. and the hig h measure of uncertainty inherent to t e ch no l ogic a l developments. A compre hensive analysis of the many types of conse 5 .2.2 Controllability quences of this technology for social life or the environment proves even less feasible. We have seen that the multifaceted com A proposed new way of avoiding this prob pl e x it y of real-life technological develop lem would be to ensure that an assessment ments precludes the possibility of providing a study does not s i m p l y entail an analysis of the ful l and reliable picture of their future conse co n s e q u e n ce s of a technology, but would also quences. Another aspect of this complexity is entail a whole decision-mak i n g and informa the impossibi l ity for outsiders, like TA an a t io n process which will accompany the devel lysts of the members of the US C o n gres s to opme n t of that technology. A good assess supervise the implementation of specific tech ment stu d y then does not t r y to come up with nological products by the sim p l e Go/No-go a clear "prognosis" of the future technology decision giving specific technological pro and its consequences. Instead. it aims at pre cesses the gree n light, while nipping others in senting the total picture of the various possi the bud. Could Congress really prevent some ble future developments (scenarios). The dangerous or undesirable future conse-
In real life technology, such solid TA p re appear to be unrealistic, just as much as the belief t ha t si mp le Go/No-go decisions bv external actors can determine whether or n o t spe c i fi c t echn o l ogica l developments will or wil l not he realized.
dictions
,
.
,
18
1 The Evaluation of Technology as an Interactive Commitment-Building Process
quences of a specific technological evolution by using all its power and authority to stop its development ? We have more reason to be pessimistic than optimistic concerning the power and the potential of such clear "No-go decisions". Obviously, it is possible for a financier to call a halt to a good many concrete research pro jects by turning off the flow of cash. An au thoritative government body can achieve the same effect in many other ways as well. And yet the influence of such decisions, even if they may be immediately successful, is always fairly limited and short-lived. Is it not suffi cient for the research group simply to find an other financial backer? Cannot the power of certain authorities be circumvented by con tinuing the same research in a location where the prohibiting authority has no say? There is a good chance that this could happen. After all, a decision to halt a scientific process al ways ends up in the midst of a complex force field in which a great number of other inter ests are already at work. The fact that one of the interested parties withdraws because he no longer finds the process interesting, or even feels it to be dangerous, does not neces sarily mean that the others will follow him and that the process will come to a standstill. It is more likely that the other partners will go in search of ways to continue the process and that they will if necessary seek out new interested partners. These are the sorts of considerations which regularly lead to the strange situation where by persons or institutions are genuinely con vinced that it would be better on the grounds of "higher motives" to halt an interesting de velopment, while they in reality simply carry on. The reason then given is that it is never possible to prevent the same work being done by others in another place, so that it is ulti mately felt to be better - if the work is to go ahead anyway - that those already involved should be the ones to reap the rewards. Moreover, scientific and technological de velopments do not simply follow a single straight line towards a certain goal, but rather seek their way through a multitude of pro cesses which in turn constantly branch out in various directions and cross each other again at various levels. In such a tangled web, an
"undesirable " effect which was revealed as a potential consequence of one specific devel opment may also come out of the blue as be ing the quasi-coincidental result of a whole series of completely unrelated technological developments.
5.3 An Inadequate View of Assessment
We mentioned that "Technology Assess ment", as created by the US Congress, is not only built on a completely inadequate view on technology, but also on a completely un workable view on assessment. In the previous section we explained that the sort of technol ogy the US Congress wanted to assess does not exist in real life. The manifest conclusion was that the TA methodology is totally un suitable for clarifying the possibilities, chal lenges and potential problems related to tech nological developments as they actually ex ist. We will now explain the problems of the TA methodology which are due to inadequa cies and ambiguities in its underlying concep tion of the general process of political assess ment. In fact, even if real-life technology proved to be the simple, straightforward and predictable process as TA assumes it to be, the TA methodology of the US Congress would still be doomed to failure. We will ex plain first the inadequacy of its theoretical view on assessment, and later the ambiguity of its practical view. 5 . 3 . 1 Obj ective Overall Assessment
The whole expected purpose of T A was to provide the members of Congress with an evaluation, an assessment of a specific tech nological project under discussion. This means that a TA report should contain the scientific evidence required to demonstrate to what extent the different facets, results and consequences of a specific technological pro ject will be dangerous or harmless, irrelevant or needed. EMILIO Q. DADDARIO, the driv-
5 The End
ing fo rc e beh i n d the establishment of OTA a n d its first director. put it as fo l l ows: "Technology a s sessm e n t is a fo r m of policy research w h i c h p ro v i de s a balanced appraisal to the p o Ji c y ma k e r ( E M I L I O Q. D A D D A R I O . ""
1 968 ).
This balanced evaluation is in fact why Congress o r i g i na l l y fel t t h e n e e d for c re ati n g a me c h a n i s m for obj ec t ive Tech n o l o g y As sessment. .. Co n gre s s created OT A i n 1 972 to meet its n e e d for a s o ur c e of technical infor mation that is nonpartisan. o bj ec t i v e and an t i c i p a t o r y . . . M e m bers of C o n g r e s s began to wonder whom to b e l i e ve as an expert because it a ppe ar ed that there were expe rt s 011 all s ides of an issue . I t b e c am e obvious that Con gress needed its own source of nonpartisan. in-house technical analytic help·· (CHR ISTINE LAWRENCE. 1985 ). C o n g re ss wanted to m a k e scie n tific e vide nce its only a d vi se r It was dis trustful of i n dust rial lo b b y i st s or P r esid ent i a l advisors who d we l l e d solely on t h e beneficial consequences of t he technology t h e y wanted to promote while d o w n p l a y in g p ote n t ial ris k s . Congress also looked w i t h distrust on activists a n d members of the a n t i t ec h n o log y lobby who come up with e n d l ess lists of r i s k y haz a r d o u s and bad c o n s e q u e n c es which are in v a r i ab l y prese n t e d as d a nge r s t o su c h i m p or tant goods as human health. the environment. the a i r , soci a l life . and many other elements. OTA was e s t a b l i s he d as a n ind e pen d e n t re source which w a s c a p a b l e of m a k i ng an o bj ec t i ve a ppra i s a l and allowing the m embe r s of Congress to make d ec i s i o n s based on facts. rather than on empty rhetoric. Th is is why Con g r ess wanted t h e reports of its T A o ffi ce to be explicit a n d e x h austive about a n t i c i pated problems and d a n ge rs as well as about e x p e c t e d ben e fi t s and p r o m i se s I n n u r t u r i n g these beliefs the U S Con gr es s is a chi l d of i t s time. It s h are s the e x pec t at io n s which have grad ual l y g a i n e d w i de sp re a d credibil ity since the e i g h t e e n t h c e n t ury. t h e age of the E n l i g h t e n m e n t . Keywords here are notions like h a r m o n y cert a in t y '"obj ec tive knowle dge . . . In fac t , the ideas of a homo ge n e o us and predictable sc ie n c e and tec h n o l ogy are part of a p a r t icul a r embodime nt of the Enlig h te nme n t ideals. which we will call the •·certainty-based" or '"completely-objec tivistic" E n l i ghte nm e n t v iew . Th is E n l i g h t en .
.
-
.
,
.
'"
".
..
".
-
of Technology
19
Assessment
ment view embraces t h e ideas that a balanced a pp ra i s al o f c o mp l ex human situations can be achieved t h rough the meticulous comp i l i ng d ed u ci ng a n d com p a ri n g of objective facts and that responsible de c i s i o n ma k i n g is une q u i v oca l l y determined by these o bj ect i v e and incontestable i ns i g h t s It is cl e a r that these types of E nl i g h tenm e n t beliefs have l eft t h e ir mark on every layer of our mo d er n culture and our modern b od y of t h o u g h t The idea of a purely l og i c a l and c o nt r o l la b le science and tech n o l og y which as we have seen is an un realistic myth, is in fa c t only one of the many traces of this s pec i fi c E n l ig h te n m e n t view. While the ce rt a i n t y b a s ed E n li g h te nm e n t p roj ec t has nev er been wit hout i ndividual critics and w h i l e its fa ilure a l re a d y gave rise to wid e sp rea d scept i c i sm and relativism, o nl y in t h e sixties d i d a powerful and sustained process of c r i t i q u e really break t hr o u gh It is n o t difficult to see t h a t its ideals per t ai n i n g to strong and certain assessment and d ec is ion m a k in g are as unrealistic a s i t s co n ce p t ion of science and t ech no l ogy Decisions on re sp on s i b le action and a gl ob a l assessment of a co m p l ex human situation are simply n ot as straightforward as we would h o pe and as the cert aint y -b a sed E nl ig h t e nme n t vision wants us to believe . We do not need a lot of theoretical a n a ly s i s to realize that there is something askew w i t h t h is pu re l y objectivistic view o n a ppra i s a l and decision-making. I t i s somewhat more difficult to grasp how a more rea l i s ti c u nders ta n d i n g of r a ti o n a l dec isi o n m a k i ng can be d e v e l ope d We will h a ve to c om e back to t h i s later. For the m o men t we can limit ourselves to unfo ld i n g the i de a that " pure fa c t s " and "an o bj e c t i ve analysis of a situation" ( s h ou l d they exist altogether) can i n no way present a balanced appraisal w h i c h could function as the uneq u i v o ca b l e guide to re s p o n s i b l e a c t i o n . We can illustrate this idea with an example from clinical g e n e t ic s where fu t u re parents sometimes seek t o d i s c over t h e r i s k s t h ey run of h a v i n g a child with a part i c u l a r disorder. N o-o n e will doubt that i g n oran ce on such q ue s t io n s is a great d i s a dv an t age . B ut the conscious o r un co n sc i o u s a p p re hens i o n s which people nurt ure conc e r n i n g p rec i se fig ures or a p rec i se des c r i p t i o n of the p oten t ial disorder are fre q u en t l y e x a gg era t ed . M a n y ,
-
.
.
.
-
.
-
.
.
.
,
20
1
The Evaluation of Technology as an Interactive Commitment-Building Process
secretly hope that they will ultimately know what to do when the objective figures are available, but these people tend to be cheated in their expectations. For example, there is absolutely no such objective guideline encom passed in the knowledge that there is a 25% risk of having a child with a given heart disor der, if there is no means of tracing or prevent ing this disorder before the birth. Should a couple give up a planned marriage in such a case ? Should all plans to have children be abandoned? Should the couple use one of the technologically aided forms of reproduction? Knowledge of obj ective figures and data gives no answer to these and other questions. Peo ple then usually want to hear more from the counsellor than statistics and objective prog noses. They hope the counsellor can also give them objective information about the best course of action left open to them at that point. They try to find out what the counsel lor would do in their situation. Counsellors are well-trained, however, not to answer these questions. They realize that any answer that they would give would go beyond the limits of the solid information they can pro vide and would simply be an expression of their subjective evaluation of the situation. They even know that their evaluation would be somewhat unrealistic and beside the point, because they are not in the exact same situa tion as their counsellees. The counsellors' subjective evaluation cannot take into ac count the complex mix of feelings they cannot possibly share with the counsellees. Counsel lors realize that even exact figures, trends and facts do not give us a complete picture of their acceptability or desirability. Having a balanced assessment of a situation is always something more than knowing and accepting the generally recognized facts about the situa tion. Facilities for genetic counseling have de veloped strategies for dealing with those un certainties. These strategies reflect the belief of these facilities that the information they can provide is of utmost importance as well as their understanding that this information has only a limited value. They know that they cannot provide a balanced appraisal of the situation of the counsellee and they are not in the position to tell them what their responsi ble decision should be.
The situation of policy-makers who deal with technological projects, is quite similar to the situation of parents. B oth have to make appropriate choices among different alterna tive actions with far-reaching consequences. Both try to gain a better understanding of their situation by obtaining scientific informa tion. In neither case, however, can a detailed report full of figures and data replace the bal anced appraisal of the decision-makers in volved. A major difference between the par ents and the policy-makers is that the institu tions which are created to help parents are well-aware of the difficult and complex na ture of the decisions to be made, while the of ficial ambition of OT A, as created by the US Congress, was to produce scientific informa tion which provides a balanced appraisal of the situation. It should have become obvious by now that "assessment" of, and " responsi ble decision-making" in a complex situation simply does not work this way.
5 . 3 . 2 Subj ective Overall Assessment
While absolute obedience to scientific ob jectivity is given lipservice in the official de scription of TA, experienced policy-makers like the members of the US Congress have al ways known better. In reality, they never be lieved that someone else could come up with a balanced appraisal of a situation where po litical decisions have to be made. It would have been consistent with the general ap proach of scientific neutrality to appoint a small group of authoritative, skilled research ers as staff members and to give them the re sponsibility for setting up the Congressional TA activity. This scientific group should then assume the responsibility of identifying the assessment studies to be done, for selecting, hiring and firing the scientific collaborators, for carrying out the research and for publish ing the policy-preparing TA reports which would contain the overall balanced apprais al. In practice, the members of Congress tried to be more closely involved in pulling the strings of OT A. In each and every step they
5 The End
embodied the idea that p o l icy- m a k i n g tran scends scientific a n a l ys i s . (a) Fi rs t of all, Cong r e ss u nd e n i ab l y con sidered the task of choosing the issues to be studied as a pol it i cal and not a scientific mat ter. Me m be r s of C o n gre s s wanted to retain the exclusive right to i ni ti at e T A s t u d i es . OT A could o n l y carry out those studies w h ic h were e x pl icit l y requested by t h e Congression al commi t te es and su bc om m i tt e e s. In t h e o ry . the director and the M a n age me nt Board of OT A (officially n a m e d the TAB or Te c h n olo gy Assessment Board ) . could also initiate studies. I n pra c t i c e . OT A m a de l ittle or no use of this p oss i bility . Be s i de s , i t would not really make much of a d i ffe re n c e if it did. EM I LI O D A D D A R IO . OT A's fi rs t director, was a former Congressman and could h ardly be c ons i d ered a n independent scientist. Fur thermore . the charter of OTA required that the twelve me m b er s of t h e Manage ment Board we re a l l e lected me mbers of Co ngre ss . six fro m e a c h po l i tic a l party. (b) Seco n d l y . Congress did not o n l y want to d e c i d e what was to be s t ud i ed . it al s o wanted to monitor the work of the sci e n ti s ts who were act u a l l y c a r ry i n g out the re se a rc h . So. it proved to be usual in D A D D A R I
of Technology
Assessment
21
· · A l though expert scientific advice had be come increasingly important to g oo d deci sion-making, C o n g re ss properly reserved to itself the responsibility to make policy" {JOHN H. G I B BONS, OTA di r e ct o r , 1 9791 992, a n d HOLLY L. GWIN, 1 985 ) . It should b e un ders t o od t h a t i n practice neither the members of Congress nor the OT A really expected that a n overall assess ment of te c h n o l ogy could be provided by scientific an a l ys i s . In reality, the ov e r al l as se s s m e n t of a t e c h no l og i c a l project was seen as an element of the broader proce ss o f p olit ical decision-making. In this context, a c l e a r distinction is m a de between the realm of science, wh i c h is r i go r o u s l y gov e r ne d by strict un a mb ig u o u s l o g i c and o bj e cti ve facts, and the realm of policy-making, which is charac terized by elements like opt i o n s , choices, in terests. n e go t iat i o n s and b a rgain i ng , and which are far more vague and subje.c tive . This realistic practical note does not, how ever, refute our earlier conclusion that the T A e x p eri m e n t . a s de s ig n e d and d e v e l o pe d by the US Congress, is b u i lt on a concept of assessment which is not practicable. Even when we take our practical q u a li fi ca t io n s into ac c ou n t . the l ea s t we can say is that the US Con g re s s holds a very a m bi g uo u s view on the relationship b e t wee n t h e a ss e s s m e nt of tech n ol o gy . ana l ysi s o f t e c h n ol ogy , and res p on s i ble d e c i s i o n s related to t e c h n o lo g y. Whereas in some contexts the rel atio ns h i p between those elements is seen as strictly o bj e cti ve , i n o t h e r contexts i t is seen as str i ct l y subjective. In the o bj e ct i v e approach, the key po s i t i on is held by the sci e n t ific a na l y s is of t ec h n o l og y , the T A study. This analysis is b e l ie v e d to in clude the overall assessment and to d e t e rm i n e the content of responsible d e c i s i o n-m a king . What is ex p e c ted from members of Congress is that t h e y use their political power and man date to g i v e a legal fo rc e to the conclusion w h i c h was obtained in a sc i e nti fi c T A study. In the s ubje c t i v e approach, on the other hand, e v e r yt h i n g revolves a ro u n d the com p l e x and multifaceted situation of poli tical de ci s i on - m a k i n g . In this view a sci e n t i fic TA re port on the consequences of a spec i fi c deci s i o n is on l y one as p e c t which the decision makers have to take into account. While they will r e a d i ly accept that a T A re po rt i s i m p o r -
22
1
The Evaluation of Technology as an Interactive Commitment-Building Process
tant, they are convinced that such a study does not entail the overall assessment of a sit uation, which can only be attained as the re sult of complicated subjective processes of p ol it ic al n e go ti a ti o n Our short description of these two approaches ought to have been suf ficient to illustrate why US Congress makes a proper mess of assessing technological pro jects instead of providing clear and workable guidelines. The situation is even worse. The problem with the subjective approach is not only that Congress is not consistent enough and is mixing this subjective approach with the remaining elements of an exaggerated ob jective approach; no, even taken by itself, the subj ective approach does not provide a clar ifying model of how a specific TA methodolo gy can contribute to keep the quality of tech nology in check. In a purely subjective con text we do not get the slightest hint of how to distinguish a responsible decision about tech nological developments from mere arbitrari ness, and the potential role of any policy-pre paring research is not clear at all. .
creation and development of many large tech nological projects. Over the years, members of Congress also gained an accurate and real istic insight in the way they could probably in fluence the quality of these technological de velopments. A deeper understanding of these backgrounds can help us to better grasp the real value of the Congressional T A initiative. Despite the complete failure of the TA ap proach in itself, the basic inspiration behind it is sound and extremely valuable. This school of thought rests upon the fundamental con viction that the monitoring of the quality and relevance of technological projects requires the reinforcement of an appropriate interac tion among all parties who have the power to influence the design of the project in ques tion. Five characteristics of this interaction appear to be of utmost importance. We will list them, and explain how an objectivist con ception of technology and assessment could deprive this sound approach of its strength.
6. 1 The Importance of Sound Interaction
6 Lessons from TA
6. 1 . 1 Interaction with the Initiator
Without downplaying the fact that the T A methodology, as designed by US Congress, is completely unworkable, unrealistic, naive, and doomed to fail, it would be too simple and unfair to blame the members of the US Congress for the weakness of their attempts to steer technological developments. Con gress failed to the extent its TA initiative is built on inadequate basic concepts which were widely accepted in the sixties, at least in Western culture. It did not invent the un workable concepts of technology and assess ment. Nor was it directly responsible for the ambiguous mixture of objectivity and subjec tivity which is so characteristic of contempo rary thought. All these are the common heri tage of the e nd l e ssl y objectifying Enlighten ment culture and the corresponding endlessly subjectifying reaction against it. It is wise not to underestimate the merits and strengths of the Congressional initiative. US Congress has long since been a privileged witness of the
Congress knew very well that real-life tech nological projects, especially the mega-pro jects like the development of an atomic bomb or sending a man to the moon, are rarely if ever unassessed. Every time Congress is asked to approve the budget of specific tech nological projects, its members know that those projects have already been evaluated and approved by the President. Congressmen know that Presidents are developing a struc tured and targeted science and technology policy. What they have to assess is not just an uninterpreted, merely logical scheme or plan, but a specific down-to-earth technological en terprise designed in a predefined context to achieve specific goals which are considered to be interesting or needed for political, military, economic or other reasons. Each of these large-scale technological undertakings has its own internal assessment procedures. The real lesson Congress learned in the sixties was not that there is an urgent need to start assessing
6
Lessons from
TA
23
makes
al of the pote ntials of the p roject. Congress
sense to imp ro ve existing assessment proce
also realized that its own input into the inter
dures by making them i nteract ive. Me mbers
action should be more than a mere token in
of Congress did not claim that the idea of
terest. Its input should be j us t as committed
evaluating and stre a m l i n i n g technological de
and powerful as the President's input. Con
velopments was t h e i r brainchi ld. They knew
fron ted with the problems which came about
they did not have to i nvent that idea.
i n t he sixt ies. members of Congress fe lt the
unassesse d technologies. but that
they
really
strengthe n
wanted
the
was
quality
to
it
and
strong need to provide a fi rm counter-voice
i n t e raction
to the Preside n t ' s tech nological plans. They
improve
of their
What
with the Preside n t 's scie nce and technology
realized that the President had his own priori
policy. Up to the
1 960s .
Congress had tended
ties and objectives and that he might not be
to view its con tribut i o n
Am erican science
critical or suspicious enough for a technologi
to
and tech n ology policy as m i n i m a l . I t was es
cal deve lopment which appears to be crucial
pecially the White H ouse administration that
for realizing his goals. Confronted with the
initiated the national technological proj ects
hidden impact of technologies on the e nviron
and that prepared t h e i r assessm e n t . More and
ment or on social l i fe . members of Congress
more , Congress wanted to be involved in this
developed t hei r own ideas on w hich technolo
process of assessing and directi n g tech nologi
gies or which aspects of those tech nologies
cal developments. A ssessing technology was
might require a n explicit and careful consid
seen as an interact ive process. A first funda
eration and fu rther study before declaring the
mental characteristic of this i n t e raction is that
proj ects desirable or acceptable. They knew
the i n i t iators and sponsors of technology , the
that i t was t h e i r task to challe nge the evalua
original assessors. should be i n volved . I t does
tions made by the Presidential advisors by
not make sense to establish a second circuit to
ope n i ng the
design an alterna tive science and technology
t hose aspects which the President would nev
policy. Such a second circuit will scarce ly un derstand what is really a t stake and will not have the power t o prevent or stimulate specif ic technological developments. The only way to effectively contribute to the quality of an existing scie nce and tech nology policy is to
e r have p l aced on the age nda. They were con
start an interaction with those who are al
sion
ready in charge and to e nrich their internal
lines. All too often the achievement of a con
assessm e n t procedures. Assessing technology
sen sus within Congress was a very difficult
is and remains primarily the task of the initia tors of technology . Any con t ribution to this
matter. given that poli tical power was divided betwe e n the two general asse mblies (House
assessm ent req u i re s an inte raction with those
initiators.
political d i scussion to include
vinced that they should take this task serious ly. and develop a prope r vision of the way a specific technology could promote or endan ger the quality
of
social life . They also real
ized that they had to stre ngthen their cohe
and
their internal consensus across party
and Senate) and the many committees and su bcommittees, were dominated by either of the two political parties. The fact that Con gress was often internally divided meant that
6. 1 . 2 A Powerful and Committed
Interaction
the President rarely came up against a strong unified opposition from Congress. In its
at
te mpts to answer this situation the keywords were " access to specialized information " and
We have described the link with the initia tor of a technological project as a first and cent ral fe ature of any workable i n te raction
req uired to assess and monitor the total qual ity of this project. Congress was very much
" the creation
of new structures".
6. 1 . 3 I nformed Interaction
aware of the fact that the perspectives and as
For years. Congress had looked on with
sessm ents which move the initiator constitute
envy at the way the President and his cabinet
a
fundamental
element of any global apprais-
were
able
to surround
themselves with
a
24
1
The Evaluation of Technology as an Interactive Commitment-Building Process
group of specialized science advisors, who have always been well-staffed and well-equip ped. Members of Congress knew that they would never be powerful partners in the in teraction with the President without being properly informed themselves about all as pects of a technology which were relevant to them. They realized that more was needed than general, informal or incidental informa tion. In the words of NANCY CARSON, an OTA program manager: "The tradition of high intelligence and informal decision-mak ing that characterized Congressional staff no longer seemed sufficient to deal with the com plexity of technology problems" and to reply to the well-prepared and cleverly presented "print-outs, calculations, and convincing pro jections" of the "executive branch witnesses" (NANCY CARSON, 1 989). What Congress needed now, was the possibility to initiate careful studies of its own.
6. 1 .4 Pro p e rl y Institutionalized
Interaction
Many elements of the interaction between Congress and the President are institutional ized. Their occurrence does not depend on a lucky coincidence, on the accidental initiative of one of the partners or the goodwill of both. In this broad context, there has always been a structural link between the Presidential science and technology policy and Congress. But, as we have seen, the way this interaction was institutionalized did not guarantee Con gress that it could remain as informed as the President, and, furthermore, due to its inter nal segmentation, Congress rarely came up with one, powerful voice in important matters like technology policy. When members of Congress realized that similar weaknesses were also present in several other domains of their interaction with the President, they de cided to combat the growing Presidential power by establishing appropriately institu tionalized structures. This resulted in the es tablishment in the 1 970s of a number of sup porting "offices" which contained members of both part;es and which were charged with preparing the way for a consensus in Con-
gress. In this manner, for example, a "Con gressional B udget Office" (CB O ) was set up to perform economic analyses, and a " Gener al Accounting Office" (GAO) was estab lished to carry out careful financial analyses of public programs. In addition, a well-equip ped parliamentary documentation center, the Congressional Research Service (CRS), was set up in the Library of Congress - the largest book collection in the world. This center maintains summaries and publishes short re ports on various complex political questions of the day. The Congressional Office of Technology Assessment (OTA) is another of the offices which was designed to strengthen the internal power of Congress and to counter the power of the White House. OTA is directed by a Technology Assessment Board (TAB), which consists of twelve members, six from each po litical party. Six members are appointed by the Chairman of the Senate and six by the Chairman of the House of Representatives. The TAB chooses its own Chairman and Vice-Chairman from among its members, with each political party taking at least one of these posts. The appointments of these posts alternate between the two parties every two years. Initially OTA could hire about 20 scientific collaborators to do the daily work. After some years this number had surpassed 1 50.
6. 1 .5 Interaction Among All Partners Involved
In the US, the official Science and Technol ogy Policy is designed by the Presidential ad ministration and in an increasing degree also by the Congress. So far we have focused on the interaction between these two political bodies and on the concrete measures taken by Congress to strengthen its role in this in teraction. By doing so, Congress not only wanted to exercise its democratic mandate of controlling the President. As we have seen, it also wanted "to provide a countervailing force to public pressures for more direct de mocracy" (K. GUILD NICHOLS, 1 978). This concern for its own position does not imply,
6
however, that Congress wanted to prevent other social partners from being i nvolved in the discussion and evaluation of technological projects. On the contrary, as a publicly ac countable body, Congress believed in the im portance of informing the public at large about new technological plans and their back grounds. This is why Congress decided that all T A reports should be made available to the public at large. Congress believed in the necessity to inform each relevant social actor, so that each was given the possibility to react using the appropriate channels at their dispo sal.
6.2 The Allurement of Obj ective Certainty
Even though until the dawn of the 1 960s, members of Congress had to content them selves with little more than a formal, symbolic and marginal input into the Governmental Science and Technology Policy, they were close enough to the decision-making process to be able to fully fathom its workings and how they could play a role in it. We can learn a lot from their sound intuition of the impor tance of an informed and committed interac tion among all partners involved. In spite of this solid point of departure, things went amiss during the process of fur ther elaboration of their basic vision. We have already seen how this failure was caused by unworkable and unrealistic conceptions of the technological processes themselves and on an ambiguous, at the same time over-ob jective and over-subjective, conception of as sessment processes. These weaknesses were identified as persistent remainders of a cer tainty-based Enlightenment view. A second lesson that we can derive from the TA experi ment is that we need be wary of the "fatal at traction " of this objectivist view - its disarm ing seductiveness to even fool one's better j udgement but also its power to kill viable and inspiring insights and beliefs. Congress often assumed that it could ob tain objective information about and an ob jective overall appraisal of technological pro j ects and their consequences. This under-
·
Lessons from TA
25
standing undermined any of the prerequisites of a serious and balanced interaction among all parties involved. To the extent that Con gress believed to be the neutral monitor and judge based on the "obj ective appraisal" pro vided by its T A Office, there was no longer any need to engage in interactive consulta tions with the Presidential Administration, which was then considered to be the merely subjective, politicized, "unreliable instigator" who cannot add anything to the insights of Congress (first characteristic). Secondly, this objective basis eroded the role of Congress it self, which was restricted now to be the serv ing-hatch of objective information - a role which in practice appeared to be ambiguous, because on top of its objective pretensions Congress still wanted to maintain the right of subjective interpretation of the so-called ob jective facts (second characteristic). Thirdly, a real contribution of other partners was seen as completely superfluous. The objective truth revealed by OTA was meant to serve Congress as well as President or any other so cial group (fifth characteristic). In this obj ec tive, positivistic approach, the central respon sibility for assessing technologies was passed on to one centralized, objective, impartial ar biter that was supposed to do the assessment job at the service of all parties involved. In this way, in the process of implementing OTA, an unworkable and objective method was adopted at the expense of a more promis ing, realistic and sound interactive approach. Fortunately, Congress and OTA soon un earthed these true underlying problems and, after some years of wandering and rambling in an impossible objective world, returned to their basic aspiration of reinforcing the inter active decision-making process. Congress was wise and judicious enough to learn in practice what it hadn't learned in theory. Even before the foundation of the OTA, as early as 1 968, the American National Academy of Sciences, in its very first recommendation written at the request of US Congress, had given an ex pressed and well-argued warning against an attitude where the responsibility to assess technological projects was to be placed in the hands of a single, so-called objective bureau which could directly influence policy. We quote from the report of the committee of the
1 The Em/uation
26
of Technology
as an Interactive Co m m itm ent-Building Process
N AS that dealt with the prob l em . and split up
the q uotation in five separate ones. because
ers of the sixties which can be regarded as forerunners i n this are a , had to wait until
each of them is still capable of giving food for
World War II before well-structured mecha
though t right up
nisms for scie nce policy were estab l i shed. The
to
the prese n t day.
'The panel would emphatically oppose any
sixties marked a pe riod of growi ng pains and
scheme t h at would e mpower a n agency to de
teething troubles. Dealing with the problems
cide on behalf of something called ' socie t y ' o r
of the sixties
' the e nvironme n t ' . w h i c h tech nological devel
mechanisms for science and technology policy
opments w i l l be permitted and which proh i
and exploring how they can be improved.
implies studying the existing
bite d . " "Selections am ong alternative tech nologies
require that choices be made among compet
ing
and conflicting interests. ··
'"To the exte n t that those choices are made
7 . 1 I ndustrial Scie nce and
Technology Policy
and enforced collective l y rather than individ ually. they are essentially political in charac
Nowadays everyone fi nds it self-evident
ter and must therefore be the responsibility of the politically responsive branches of govern
that fundamental scientific and technological research will sooner or later be translated
ment and of those publicly accountable bod
into the goods which can be mass-produced
ies that are speci fically entrusted with regula circum
and are of use to society. Thus, for example , research in electronics becomes visible after a
" Th e making of s u c h choices i s , in princi
more easily programmable dish-washing ma
ple , indistinguishable from the resolution of the many other conflicts that beset society . . .
chines or more sophisticated h i fi systems. I n
tory
responsibilities
in
n arrowly
time
scribed areas . · ·
"To e n t rust the resol ution of all those con tlicts to a
s i n g le
.
al l-encompassing aut hority
would be incompatible with represe n tative gove rnmen t " '
(NATION A L
SCI ENCES, 1 968 ) .
ACADEMY
OF
in
the
form
of improved computers,
the same way . fundamental biological re search is expected to lead to improve d health care and
increased
food
production .
Two
hundred years ago. even the most learned scient ist or the most skilled craftsman could not have imagined that his work would ever be
relevant for industrial production . The
scient ists of the 1 8th century were not con cerned with e n h ancing the productivity of the
7 The Origins of Science and Technology Poli cy While the sixt ies undeniably showed that
manufacturers, which were the industrial ists of the day. They identified their professional activi ties as the quest for and the discovery of the truth, and not as a contribution to
change
the world. Neither did artisans, craftsmen or tech nicians expect that their skills and tech
there is some thing wrong with the way tech
niques could ever be of any service to the ac
nologies were being planned and evaluated, it
tivity of large-scale productio n . Their arts a n d
would be n aive to i n fer from the growing
crafts w e r e n o t i nte nded to be practised b y
problems and doubts concerning technology
u n t r a i n e d workers. Man ufacturers, i n their
that no mechanisms for planning and evalua
turn. did not fee l this situation as a great lack.
tion existed and that there was a n urge n t
They took care of the e asy production of con
need to create t he m . I n fac t , most of the prob
sumables for the i nhabitants of their tow n .
lems with new technologies occurred precise
What t h e y n e e d e d w a s peop l e , time , r a w ma
ly because of
priorities forwarded by a de
terials. good eyes, good hands, and care for
v e l oping sci e n ce and technology policy. We h a v e to a dm i t that science policy was still re latively young and inexperienced. Even the
their work. Their work did not require so
Soviet Union, the two superpow-
methods of industrial production and their re-
US
and
the
the
phisticated skills or sci e ntific i nsights. The movem e n t which completely renewed the
7 The Origins of Science and Technology Policy lationship w i t h science a n d t e c h n o l ogy is cal l e d the ··industrial revolution " . which is usually subdivided i n t h ree or four waves ( s e e Fig. 1 ) .
were t h e
textile
m achin e ,
the
27
locomotive
( ST E P H E N S O N ) , and i m p ro v e m e n t s
in proce dures i n i ro n and steel p ro duc t i o n But t h es e are o n l y t h e most c o n s p i cu o u s examples of a g r o win g interaction between skilful craftsmen and m anu fa ct u re rs which even intensified around 1 800 and slowed down again towards the end of the first half of th e 1 9th century. When this first industrial revolution came to an end. the first modern "'industries" were de veloped. S op h i s ti cat ed mac h in e ry and tech ni q u es capa bl e of repe a t e d renewal and im provement. re p l ac e d the traditional pro d u c t i o n methods. An i nc r eas i n g p ro du c t i v i t y, a co n c entr at i on of workers in the n e i g h b o r hood of fa c t o ri es and grow i n g towns were some of t he consequences. This does not mean. though. that traditional manufactures ceased to exist as units of "industriar' produc tion. Near the middle of the 1 9th century, the industrialization was limited to England and Scotland, where the revolution began , and France and Belgium.
.
.
Production Too ls Manuflcturers
n
Ent�llll lndustrilllists
Craftsmen/ Artillns
Theory Philosophers
n
n
.
Scientists Engineellll Technologists
1 750
1 800
1 850
7 . 1 .2 The Second Industrial Revol ution
1 900
1 950
2000 Fig. I.
The I nd ustrial Revolution.
7 . 1 . 1 The Fi rst I n dustrial Revol ution
The f i rs t wave was put in motion by a com p l ex cluster of interacting social. demographic and technical processes. which started by the mi dd le of the 1 8 t h century. The introduction of the steam engine in the mining in d u st ry is i t s s h owp ie ce . Further i mportant innovations
The world of scie nce had not yet been sw ep t into this revolution. The primary in novations on which the revolution was based, like the steam e n gi n e or t h e locomotive were the work of i nve ntive craft sm e n a nd e x p e r i me n t i n g entrepreneurs. But while their crea tive intuition. inventiveness and practical un d e rs ta n d i n g sufficed to get the revolution off the ground, they were not sufficient to keep the inertial momentum going. More and more . technicians began to realize that the further i m prov e m e n t of their machineries and t oo ls required a real un de r sta n d i n g of un de r ly i n g scientific laws. They also exper i enced that several domains of industrial pro duction would pe r s i ste n t l y resist their efforts to d e s ign appropriate m e t h o d o l o gi e s and in struments. unless t h ey could base their at tempts on deeper scientific in si g h t s . I t took several years before the scientific world was ready to show some interest in helping to solve these tec h ni c al and industrial difficul ties. Bu t when this finally happened, after the
28
1
The Evaluation of Technology as an Interactive Commitment-Building Process
1870s, the Industrial Revolution gained speed again. A second wave began, resulting in the industrialization of most Western-European countries and the US. From this moment on, industrial compa nies were quite active in searching and creat ing possible links between industrial pro cesses, the technical infrastructure needed and "basic science". The German industry which specialized in the production of organic dyes was one of the earliest examples of a chemical industry founded on scientific re search. It erected in the very first years of the second industrial revolution (the last quarter of the 1 9th century). Similarly, at the very be ginning of the present century, scientific re search was adopted as the basis for the elec trical engineering industry in America. To guarantee a maximum of basic science which would explicitly serve the industrial objec tives of the company, both branches of indus try founded their own research laboratories from the start. 7 . L3 Later Revolutions
At the beginning of the 20th century, the second wave of the Industrial Revolution came to an end. It was succeeded by what is often called the Third Revolution, which transformed and revitalized industry by re placing steam with electricity and gas as the new sources of energy, and the fourth revolu tion, which introduced the automation and later the computerization of the production process and its administration. During all those years, industrial companies continued to manage their own Research and Develop ment budgets, which were far from inconsid erable. In most countries industrial compa nies spent more on R&D than the public au thorities. Only late in the sixties or even in the seventies did governmental science and technology policy become of equal impor tance.
7.2 Early Governmental Science and Technology Policy
7 .2. 1 Prestige and Maintaining Peace
JEAN-JACQUES SALOMON, former head of the Science Policy Division of the OECD, points out how contemporary governmental science policy found its roots in World War II. It is well known that wars can be a catalyst for governmental interests in science. Ever since the ancient times, generals and states men were eager to listen to the learned think ers and skilled craftsmen hoping that they would be able to invent a superb machinery that would help them capture a city, break through the enemy lines or simply win the war. This was true in Greek times, with the Trojan Horse and the inventions by ARCHI MEDES. It was still true during the First World War, when institutions were created whose aim it was to promote research into military and strategic applications of science. It is also true, however, that the state's inter est for science soon vanished once the war was over. Special war-oriented scientific en terprises were scrapped, following the conclu sion of peace. It is exactly in this respect that World War II was different, according to JEAN-JACQUES SALOMON. We know that during the war the familiar scenario reoccur red. The Manhattan project instituted by the American public authorities made history in this respect with the development of the atom bomb. The harsh reality of the bombs lay at the basis of many historical developments, of which the emergence of a systematic science policy is one example. There are two major underlying reasons. First of all, the bomb and the release of nearly unlimited amounts of atomic energy became a symbol of the great, nearly unlimited powers hidden in the prac tice of science. The bomb made it abundantly clear that modern science was capable of a great deal more than the theoretical explora tion of reality. The beginning of the Cold War was a second reason why, contrary to what normally happens at the end of a war, states did not simply send their scientists back to
7 The Origins of Science and Technology Policy
t h e ir ac a d e m i c labs and libraries. World War Il di d not really e n d . The tension which r e
mained between the great powers. a n d the e m er gi n g Cold War. s erv ed as the great stim ula t i n g force behind the superpowers t o keep their scie ntists m o b i li z e d and to institute large-scale coordinated scientific programs to serve the national i n t e re s t Th e publ i c author ities considered their pr i m a ry aim here to be the contin ued as s u ra nc e of national security and the streng t h e n i n g of national prestige. " Science policy d e v e l o ped . . . as a c on s e quence of the impossibility of establishing real peace at the end of World War I I '" (J .J. "
"
.
29
for s c i en t ifi c research which was thought increase the c o m pe t it i v e nes s of national
to in
dustries. In this way. the gold e n sixties'' b rough t not onl y grea t p ro s pe r i t y to the economies of th e industrialized nations. but also to sc i e n c e and technology. S c i e n t ist s and technologists. fr o m whatever research area. h a d q u i c k ly u n d e rst ood t h a t pu b li c authorities had the po tential to become goo d customers if they could c l ear ly see t h a t the research could con tribute to a m i li t a r y or ec onom i c break thro u g h . "
SALOMO N . 1 97 1 ) .
The A merican public au t ho r iti e s were forerunners in developing t he i r own sci e nce policy, and the w o r k in g model was set up in 1 945 at the re quest of President RoosE VELT by V A N N E V A R B l i S H . who during the War had bee n director of the U n i ted St ates Office for Scientific R e se a rc h and D eve l op m e nt The Soviet Union . the o t h e r superpower. took s im i lar initiatives. Other i ndustrialized countries followed suit . Jn t h i s light . priority in t h e U n i t e d States was given to three sectors: space travel re search. n uclear research and m i l i tary re search. The de v e l o pm en t of r a d a r . manned rockets. jet a ir cr a ft atomic e n e rgy . D DT a n d computers are all conse q u e nces of this po l i cy. The launch of t h e Sput n i k . t h e fi rs t manned space flight. and the l a n d i n g of the fi rs t man on t h e moon by the A m e ricans are clear symptoms of a fie rc e com p etit i ve race be twee n the sup e r po wers . a development which led to the enormous size and rapid g r owt h of the scientific d i sc i pl ine s concerned. .
.
7 . 3 Spread of Gove rnmental
Science and Technology Policy
The OECD ( O r g ani z a t ion for Economic Co-operation and D eve l op m e n t ) played an important role in the fu rt h e r development of science and technology policy. Th e OECD was founded in D e ce m b er 1 960 as t h e heir to the · · o rganization for European Economic C o ope r at i on ( O E E C ) . which was fo u n d ed in 1 948 i n the context of the p o st - war Marshall plan. The d e e d of fo undation was s i gned by 24 We s t er n i ndustri alized countries. The stim ulation of economic growth forms on e of the primary object ives with which the orga n iz a tion was e n tr u st e d . "The OECD is n o t a supra national o r g a n isation but a place where policy makers can meet and d i sc u ss their problems. where gov e r n m e n t s can compare t heir poi nts of view and their e xp e ri en ce . The secretariat is there to find and po i n t out the way to go. to a ct as a c a talys t Its role is not ac a d em i c ; nor does it have th e au tho r i t y to im pose i ts ideas. Its power lies in i t s ca p a c i t y for intellectual per "
.
7.2.2 Growing Social and
Econom ic Welfare
O n ce the public authori t i e s
saw how the in
j ection o f massive a m ounts of ca pit a l a n d the setting up of co or di na t e d sci e n t i fic p rog ra m s
had succeeded in cre a t i n g te chn o l o gi e s of na tional importance . a se c on d p h a s e in science policy was b o rn . in which an economic edge was added to t he old national go a l s . Enor mous research b ud ge t s were made available
suasion"
( J EA N - CLAUDE
PAYE,
Secretary
General of t h e O E C D ) . I t is clear that the OECD could not ignore the growing pot e n t i a l s of sci e n ce and t e chn o l ogy to stimulate economic growth and expan sion o n a global level. Within its s e cr et a r i a t it t h ere fo r e created a Scie nce Policy D ivision to s t ud y and monitor the possibilities of science p o l icy The OECD secretariat was convinced of the i m p o r ta nc e of a well-developed science p ol icy . It w an t ed to discuss the issues with its .
30
1
The Evaluation of Technology as an Interactive Commitment-Building Process
member countries. In 1 963 it convened a min isterial meeting between all the ministers re sponsible for science. In the majority of Euro pean countries this was the Minister of Cul tural Affairs. "When in 1963 the first Minis terial Meeting on science took place at the OECD, the Ministers specifically in charge of scientific affairs could still be counted on the fingers of one hand" (E. G. MESTHENE, 1 965) . During this meeting the representa tives from the various countries agreed that science is not merely a "cultural asset" to be protected and nurtured, but also an efficient provider of extremely valuable services for society. They concluded (a) that it was neces sary for the national states to develop a gov ernmental science policy and (b) that the states would have to create special organisms, advisory councils, secretariats and other insti tutional facilities in order to achieve this.
7.3 . 1 Science for Policy The core of contemporary involvement by public authorities in science was described at the OECD meeting as "Science for Policy", meaning "Science to serve Public Policy". The authorities had understood that science and technology could prove valuable aids in the achievement of the goals which the au thorities had set themselves. In fact, this comes down to the discovery that the scien tific world is the perfect provider of the high quality products which the authorities need. The only problem is that most of the products in which the public authorities show an inter est are so grandiose and special that they are not in stock as standard in the normal re search world, and are far from simple to man ufacture. If the authorities wish to enjoy the end products, then they must finance not only the marginal cost of the product itself, but also the costs of the scientific and technologi cal production mechanism. In this way, the authorities ended up as managers of extensive scientific and technological projects, in which they supported both "applied" and "funda mental" research.
7.3.2 Policy for Science This development enables us to understand why the OECD claims that involvement in science by the public authorities also contin ues to demonstrate a component which it names "Policy for Science" ("Public Policy at the Service of Science"). The authorities see themselves as a large, wealthy and patient customer of science. As such, the authorities are aware that it is necessary to allow the scientific tree to blossom in an ideal growing climate if they wish, sooner or later, to be able to pluck the technological fruits of that tree. In this sense, the authorities are ready to furnish an environment in which various re search activities are able to flourish undis turbed.
8 Making Science and
Technology Policy Interactive
A major point we have made is that the whole mechanism of TA, while self-evident, convincing and attractive at first sight, be comes unworkable and inadequate on further consideration. We explained that the TA ap proach, with its perceived objective methodo logy and institutions, does not provide an ap propriate way to deal with the growing and persisting doubts about the relevance and safety of technological developments. Both the conception of "technology" and the ideas on "assessment" which serve as the founda tions of the TA approach were described as exceedingly objective and therefore unrealis tic. In this concluding section we will illustrate how a workable alternative can be developed. We will expand on those ideas which have al ready been mentioned as sound elements of the basic inspiration of the members of the US Congress. The crucial point will be to de velop these ideas without allowing unrealistic conceptions of "technology" and "assess ment" to undermine their strength. Such an approach will be unworkable without explicit attention to the following five points.
8 Making Science and Technology Policy Interactive
8 . 1 Making Existing Policy
Interactive
When technology was gradually losi ng its a ura of being an i ncontrov e r t i b l e blessing for mankind. man had the opportunity to react in two different w ays The T A experiment is the most well-known example of t he first type of reac t i o n This response builds on t h e aware ness that c urre n t technology is not governed by an absol ute r a ti o n al i t y which is perfectly reliable in g u ar a n te e ing its total quality. I t co n c l u de s from this that it is t i m e to distance oneself from such a lack of c r i ti c a l ra t i o n a l ity and to active l y deve lop an o bj e ctiv e mecha nism which is able to b r i n g technological de velopments withi n the realm of reason. We h a v e see n . however. why this first type of reaction must be rejected. Its supposedly ob jective sol u t i o n i s onlv an i l l u sion Th is leads us to the second t y p e of reaction. which. like the first. recogn izes the lack of absolute ra tionality in the planning o f sci e nce and tech nology but which. unlike the first . a ccept s that this restrained rati onality. with its limited val ue, is all we have . The only thing left to do is to discover and maximize its resources. This is also what this second reaction plans to do with the way technological developments were drawn up in the sixties. It would be w rong to deny the l i m i t ation and short sightedness of these e a rl y science and tech nology policies. But it would be just as wrong to deny t h e ir e x i s t e nce and to think we have to reinvent the wheel. Instead of starting a se c o n d circu i t in dre a m -T A land. it is better to remain down-to-earth and to see how exist ing science and t e c h n o l o gy policy can be im proved. What is i n fa c t the problem of the science and technology policy as it existed in the six ties'? What can be done to improve it? Did governments, industrial companies or aca demic research institutions make mistak e s when they identified the proper technologies t o he developed'? Did t he initiators of n e w tech nologies act a g a i n s t the firmly established and u niversall y reco g n ize d standards of ra tionality ? The fundamental problem appears to be m uch d e e per and has to do with the standards of r a t i o n a l ity t h e m s e l v e s Accord.
.
.
.
.
.
31
ing to tr adit i o n a l stan dards, which were evi dent in the sixties. some action or plan can be considered " right" once you can provide one single proof that it is right. j ust l i k e one proof of guilt is enough to come to the conclusion that somebody is guilty. or j us t like you c a n rightly say that you have solved a mathemati cal problem once you have successfully fol lowed o n e p oss i ble strategy leading to the so lution. The events of the sixties, much more than theoretical works. were able to c o n v in c ingly argue that such '"one-dimensional" ra tionality was not always enough. We learned that an action which was rightly labeled as "good" was not n e ce ss a rily good, when seen from another point of view. Even when an ac tion is proven to be o f utmost importance for t h e best g o a l s - like maintaining peace, pro viding employment. destroying harm fu l in s e cts or promoting the w e al t h and happiness of many - no guarantee can be gi v en that sooner or later completely other considera tions. approaching t h e same action fr om dif ferent angles. will not strongly recommend us to raise doubts about its good quality or even to reject it. This situation m ight resemble the old wisdom that even the most desirable thing may have its drawbacks, as expressed in the p rov e r b ··No rose without a t horn". But the lesson of the sixties goes much further than that. The ne g at i ve aspects o f t e c h n ol ogy which were revealed were mu ch more than some minor drawbacks of something good and blessed. What we learned in the sixties is that the drawbacks may l a rge l y surpass the positive elements. What appeared to be a s i m ple rose migh t after all be m o re a t h or n . Furthermore . few would have expected t o find those negative aspects in such unsuspi cious reality as scientific and technological progress. which was the sacred cow of the six ties. We learned now that good. even w h e n said of the good beyond suspicion, is no long er simply good. The lesson of the sixties dictates that our one-dimensional. absolute conception of ra tionality does not hold water. The corre sponding challenge was to fee l the pressing need to develop a more appropriate concep tion of rational and wise decision-making; in other words. a conception of a rationality which allows room fo r uncertainty and tern
32
1
The Evaluation of Technology as an Interactive Commitment-Building Process
porariness and which accounts for the possi bility of different and sometimes conflicting approaches and evaluations - an "interactive rationality" which is not locked in its single minded logic and approach but which breaks out of the points of view it already acquired and is continually open to new evaluations which transcend its own logic. Much has been written about this new challenge to rationali ty. It is clear, however, that this new situation is in the first place a challenge for those who are involved in the practice of decision-mak ing. Developing ways of interactive rational decision-making are especially important for the founding of a sound science and technolo gy policy. The problems linked to large-scale technological projects were a major catalyst for opening the theoretical and practical de bate on interactive rationality. The OECD, in stimulating the develop ment of science and technology policies, has always underlined that this requires an in tense awareness of the complex interaction between all social actors involved. The need for a careful study of the interaction between science, technology and society was already one of the conclusions of the first meeting on science and technology policy in 1963. The OECD has held a leading position in prepar ing high-level studies about this relationship. These were closely linked with the general philosophical and sociological literature which was becoming increasingly critical of a one-dimensional understanding of scientific and technological rationality. In a series of shades and forms, the idea was developed that only an interactive decision-making pro cess could guarantee that science and technol ogy would genuinely evolve to serve society. According to the OECD , countries must work and experiment with various forms of active participation by the public in the deci sion-making process of the public authorities. From the very beginning, the OECD has also taken a critical stance towards the usefulness of the TA approach, as developed in the US. OECD studies have always pointed out that this American approach is too theoretical and too narrow and leaves no room for a real broadening of the decision-making process. The OECD has always refused to set up a for mal "TA program". It is convinced that the
problems linked to technology require an ongoing integration of policy-making on tech nology in the more general mechanisms of democratic decision-making. Dealing with the problems linked to technology is just one ele ment in the broader democratic experiment of the last centuries. We have already seen that the National Academy of Sciences in Washington shares this view, and states that solving problems linked to technology "is, in principle, indistin guishable . from the resolution of the many other conflicts that beset society. " Decisions about technologies are closely related to oth er social decisions, in that they do not require any more sophisticated treatment. Most gov ernments who were wise enough to ask for advice on how to deal with problems linked to technology received the similar advice not to narrow their decision-making basis by means of the establishment of some sup posedly neutral institution but, on the con trary, to broaden the basis of their decision making by stimulating all forms of social in teraction. In most countries, experiments for realizing this are still in their infancy. Even in very active countries like the US or the Neth erlands, there is still the strong temptation to turn back the clock and to reduce all demo cratic attempts at keeping up one, central, specialized research institution, linked to the parliament. Sweden has probably made the most deci sive advancements in developing workable experiments. It has a long tradition of ''con sensus democracy". This "ensured that even in the mid-1 960s much attention was devoted to the societal consequences of technology" (RUUD SMITS and Jos LEYTEN, 1988). Swe den also digested much of the talk about spe cialized TA, but it was not impressed by the so-called need for new methodologies and special institutions. It was evident for the Swedish that social evaluation of technology can only make sense when it "is considered to be an integral part of [ . . . ) societal decision making processes in which technology plays some role". It was also evident for them that the only way to enhance the quality of this evaluation consisted in "broadening and im proving public discussion" on all relevant fac tors. From this perspective "T A in Sweden
8
Making Science and Technology Policy
was never institutionalized in an independent organization". For this could do nothing bet ter than averting the attention from the real things to be done .
8.2 Using All Possible Social
Resources
It is good to warn against a potential mis understanding of our plea for an interactive technology policy. What we said is not that governments. industrial companies and aca demic engineers are professionally blind and helpless. and that the rationality of their ac tions and plans can only be warranted by forcing them to listen to ··society"' which is then taken to be the source and guard of true wisdom. Interpreting the value of alternative technological developme nts is as difficult for "society at large" as fo r the small group of in stitutional decision-makers. Problems linked to technological developments and inadequa cies in science and technology policy are caused by a lack of vision and consideration hy society as a whole . and not j ust by some alleged shortsightedness of tech nologists. scientists. industri alists or administrators. ··science policy is in disarray because socie ty itself is in disarray. partly for the very re a son that t h e power of modern science has en abled society to reach goals that were former ly only vague aspirations. but whose achieve ment has revealed their shallowness (OECD. The Brooks Report. 1 97 1 ) . Many. if not all. problems which are com monly believed to be "evoked"' by modern science and technology are. in fact . embodi ments of the underlying weaknesses in our cultural resources. By realizing our hollow and uncritical projects. scie nce and technolo gy often function a s a magnifying-glass of preexistent questionable ambitions or lack of interest. While it is true that many technologi cal developments need a broader vision of what is really relevant . meaningful or accepta ble for society. it would be naive to believe that the basic intuition of non-scientists or non-technologists could serve as a source of reference for this vision. The spontaneous as pirations of different social groups are not . . ...
Interactive
33
be tter off than those of institutional decision makers. The power of interactive technology policy does not resi de in the fact that the al leged shortsightedness of policy-makers is managed by the supposedly authentic aspira tions of society. It does not make sense to make science and technology even more de pendent upon the uncritical tendencies i n so ciety. The basic ideas behind interactive ra tionality are . in fact. primo, that no cultural or social sector can claim to possess absolute reason . and secunda. that the best we can do is to nurture and enrich our authentic cultural resources - i ndependent of the social sectors or social practices where they flourish . 8.3 An Information Process
The availability of appropriate i nformation is essential to high-quality i nteraction. Espe cially when dealing with complex technolo gies with far-reaching impact, critical reflec tion. intensive discussion and accurate re search are of utmost importance. The information needed is, however, much richer and far more diverse but also more vulnerable than the knowledge US Congress was looking for and T A research was be lieved to produce. The information should be appropriate to help us in answering the inter related questions about the interesting social activities and plans for us to realize and the interesting technologies for us to develop in this context. These questions are neither uni versal. e ternal nor general hut very specific and concrete. We arc not inquiring about the eternal good practice or social life. but about what would make sense for us. givi ng our past. our context and our possibilities. A great variety of information , a bout so ciety in general as well as about specific tech nological developme nts, can help us in this endeavor. More specifically it is re levant to gain a deeper practical and theoretical under standing of the original context and inspira tion behind the different traditions, institu tions, and practices which constitute our so cial life . There is of course no justification in using these dements as the absolute yardstick for our current or future plans. Those institu tions and practices only embody what was be-
34
1
The Evaluation of Technology as an Interactive Commitment-Building Process
lieved to be meaningful in the past. But to this extent, they at least offer a concrete point of departure for talking about relevant social projects. Furthermore, when we talk about social relevance, about improving or endan gering social structures, this is the only realis tic reference point we have. The only way to answer the question about our future, is to explore the best fut u re for our past. The study of scientific, technological and indus trial achievements and their impact on society and nature is simply part of this general at tempt to deepen our understanding of our cultural resources. We should not underestimate the degree of complexity of this intellectual enterprise. Contemporary society is a complicated web of a multitude of practices and traditions which in part conflict, overlap or evolve inde pendently. Additionally, several of these practices are strongly colored by science and technology and have intensified their private impact on the social and natural environment of all. But, as indicated by analysts, the greatest difficulty of understanding the cultu ral assets of our time might well be that for the last three centuries Western culture has neglected to update the understanding of its resources. This did not simply happen due to forgetfulness, laziness or lack of time but as a result of the basic belief in an absolutely ob jective reason, which we already mentioned above. When people believe that this univer sal rationality can and should guide all things in life, a careful understanding of the limited, contingent, present-day achievements and of their equally limited historical backgrounds becomes completely irrelevant and obsolete. This lack of interest and the absence of evalu ative discussion not only resulted in a gap in our understanding of several centuries of cul tural development, it also caused a strongly diminished integration of more recent achievements of Western culture, resulting in an increased number of internal conflicts and incompatibilities. Only a sustained effort of multidisciplinary research and multisectorial and cross-cultural discussion, proportional to the complexity of three centuries of intensi fied cultural developments and analytical standstill , can ever restore the basis which is needed in order to seriously assess technolo-
gical enterprises or other social projects. The success of this undertaking demands the col laboration of researchers like physicists, engi neers, biologists and physicians as well as thinkers like historians, psychologists, sociol ogists and philosophers. Furthermore, a close link with all social sectors is strictly neces sary. We are far away from the objectivist and narrow aims of the TA methodology US Con gress was dreaming about. The urgent need for this broad social research does not, how ever, mean that the detailed study of new technological projects is not equally impor tant. It remains a necessary component of our rational attitude towards technologies to con struct a realistic image, conveying as lucidly as possible the way we think the newly plan ned technology will function , how it will in fluence those activities we and others value, who will be able to influence the develop ment of the technology, and how further deci sions will be organized. But even this type of research is much broader than and different from the narrow predictive attempts of TA. It does not aspire to provide certain knowledge about an autonomous technological develop ment or to be a neutral and infallible guide for those who plan to become more closely involved with this technology. It only makes sense in the context of a broader and more permanent monitoring process of the technol ogy and not just as a red or green light at the so-called beginning of its development.
8.4 A Process of S hared Commitment-B uilding
Rational assessment of a technology, like any other social assessment, is not just an in tellectual exercise. It is much more than a process of information gathering, even though insight and knowledge play an impor tant role. It is also a social process of commit ment-building, of commonly accepting the re sponsibility for a social decision to be made. When we evaluate a specific development, we as a society decide whether and under what conditions this development can be seen as a further enrichment of our resources. We de-
8
Making Science and Technology Policy Interactive
cide whether and sometimes also under which conditions we prefer to live with it or without it.
This decision is never irreversible. New in sights may come up. The technology itself or ot her aspects of our society may have evolved in such a way that we believe it is better to retrace our steps and to reconsider earlier evaluations. We might decide to give a central place to a technology we earlier rejected, or we may become more hesitant towards a technology we us ed to endorse . Properly functioning social assessment pro cedures will, however. exclude that we blame let us say governments for not starting earlier with a specific type of new tech nology. or in dustries for producin g materials or tools with side-effects we dislike. To the extent that ap propriate assessment procedures are func tioning. we cannot be critical of every change and progress and blame our country for not being far-seeing or our health care for being old-fashioned. Just like we cannot simply ap plaud the fruits of economic development when everything appears to be all right and blame the initi ators in case unforeseen prob lems crop up. In short. assessing is more a well-understood political process. which builds shared subjective commitment, rather than a research methodology . which yields objective knowledge . When a decision needs to be modified or even turns out to be com pletely wrong. nobody can disclaim his share in the responsibility. The crucial importance o f the social pro cess. inhere nt in each rational assessment . does not diminish the significance of the role of information. A proper assessment is more than the accidental result of a discussion or political bargaining. J ustified assessmen t is not j ust a shared commitment. but an "in formed shared commitment". Decisions which are not founded upon the fullest possi ble practical and theoretical understanding of our cultural resources and of the technology to be evaluated. can hardly be called assess ments. whether they are made by dictatorial decree or by unanimous vote . This also im plies that even a complete consensus cannot make up for the necessarily i ncomplete and uncertain character of the available informa tion. Assessment remains a human and falli-
35
ble process. The many difficulties and weak nesses of the social process of shared commit ment-building still adds to the precarious na ture of assessment. Consensus will not always be achieved. In this case one has to take ref uge in systems like deciding by majority vote, which drastically reduces the level of commit ment of those involved. The fragmented char acter of our culture , and the fact that many decisions have to be made on a global scale still adds to this difficulty. Furthermore, it is impossible for anyone to spend time and at tention to each of the social problems in which he is directly or indirectly involved. In practice many decisions are taken on behalf of us, by people we give some sort of direct of indirect mandate. In short. the quality of our assessment depends on the general quality of the democratic and participatory structures we are developing. These structures are far from being perfect. but they are all we have. We can dream of a u niversal , theoretical, ab solute procedure which makes unequivocal , clear a n d infallible decisions. N o doubt that for many decisions we would be better off than now. But sheer dreaming does not make it reality.
8.5 Decentralized and Multi-Form
I n stitutionalization
Scientific and technological developments are occupying an ever more important place in our social and economic life. They have an increasing impact on society which is often welcome , sometimes regarded as suspicious, but occasionally hazardous or just irrelevant. There is a broad consensus that it would be unwise to leave their planning and follow-up to chance or to casual decisions. The conclusion we have to draw from this is that we need to institutionalize the plan ning mechanisms of technologies. Only in this way can we make sure that all relevant ele ments be included systematically in each planning process. O nly in this way can we guarantee that the necessary intellectual and practical resources are made available to those who need them. We are warned, how ever, that no institutionalization wil l be work-
36
1
The Evaluation of Technology as an Interactive Commitment-Building Process
able unless it is implemented in an interactive way. This is exactly what the OECD encour aged its member countries to do in the sixties: to institutionalize their own science and tech nology policy and to take the interaction with other social actors seriously. These recom mendations have laid the foundations, in the sixties, of the fledgling science policies of sev eral national governments, which are still in the process of further maturation. But what is needed in order to guarantee the total quality of technology is much more. The national governments, members of the OECD, are not the only actors involved in the planning and designing of technologies. Other social actors who are directly or indirectly involved include banks, consumer organizations, patient sup port groups or just plain users of technology. The total quality of technology can only be guaranteed to the extent that the impact on technology of each of these other actors is also properly institutionalized. As there is a great variety in the type of impact each of these actors may have on technological devel opments, there will also be a large diversity with respect to the proper way their involve ment should be properly institutionalized. This plea for far-going institutionalization of our concern for the relevance of technolo gy may appear strange. Didn't we strongly re ject the attempts of US Congress to create OTA, which is in fact nothing more than a highly specialized institution established for doing exactly what we wanted to institutional ize: to guarantee the total quality of technolo gy. It is not difficult to show that, despite these superfici al similarities, US Congress was dreaming of something completely differ ent than the type of institutionalized interac tion we advocate. Let us therefore recall what exactly OTA wanted to institutionalize. This will give us a last opportunity to reformulate the points we made in this text and to bring out the sharp contrast with the TA approach. The basic goal of OTA has been well sum marized by JOHN H . GIBBONS, director of OTA from 1 979 to 1 992: "If the national legislature were to act as 'all wise rulers must: cope not only with pres ent troubles, but also with ones likely to arise in the future, and assiduously forestall them ', it would need an institutional mechanism for
foresight, one that would make analysis of the consequences of technology a meth odical en terprise" (JOHN H. GIBBONS and HOLLY, L. GWIN, 1 985). The institutionalized mechanism which can realize this goal has three main characteris tics. ( 1 ) First of all: what is needed is a re search institution. What US Congress wanted was a methodological, scientific, objective analysis of the consequences of technology. At the institutional level this results in the es tablishment of a neutral research institution which can provide the necessary knowledge. (2) This first characteristic quite simply re sults in the second one: what is needed is one single institution. Once one institute has come up with the appropriate and objective results, a second institute can only reinvent the wheel. (3) This again results in the third characteristic: what is needed is a centralized institution. Only when the TA research is done under the direct control of the elected representatives of the people can its objectivi ty and neutrality be guaranteed. In contrast with this, we are talking about (a) multiform (b) many and (c) decentralized institutional elements. In an interactive ap proach the result of the evaluation process is not a report, but an informed shared commit ment. What is needed to realize and support this is much more than research but a variety of activities. It is impossible to indicate a gen eral structure and function for the various ac tors who are involved as formal and informal "decision centers" in the decision-making process with respect to technology. In prac tice, the actors display an enormous variety of forms and degrees of involvement, as well as an enormous variety of organizational forms, or the lack thereof. At an institutional level, promoting the total quality and relevance of technology implies the need for establishing a great variety of offices or bodies which pro vide support for enhancing the interactive quality of its own involvement in the social process of technology planning. Such "commitment and interaction-pro moting units" will differ for each type of ac tor. Their functioning and structure can only be determined as the result of a detailed anal ysis of the historical and sociological position of the actor involved, of his views on the fu-
9 TA after
ture , and of h i s
o n goi ng
or e x pe c t e d interac
37
TA
w ith the multidisciplinary , o rga nizati on al s u ppor t w h ic h
b y provi d in g him
tions with other actors. This requi res specific
scientific a nd
case studies and the pla nn i n g .
m i g ht help him to put his own resources to their best p ossibl e use and to s t ren gt he n his in p ut a n d contribution into the broader social re alit y. They cannot take away th e fallible and unce rtain nature of a l l human activities, i n c l ud i n g tech n olog ic a l proj ects. They can on l y contribute to make the human plans and choices re l a ted to tech nology a s responsible
performing and
t h oro ug h a n alyz in g of socia l ex p e ri m e n ts . It is clear though .
that
the dimensions of
such
be p r o po r t i o n a l to the in t ens it y of t he i nvolvement in t e c h n ol o gy planning. In
u nit s wil l t he
case of large and i m po r ta n t decision cen
ters, such as
governme n ts.
parl i a m e nt s . uni
versities . l a r g e e mp lo ye r s ' associations. such a
might de large group of full-time e m p l oye e s It cou ld also result in a standing c o n t r act with a p rop e r l y equipped and moti vated c o n s u l t a n cy or re s e a rch o rga n i z ati on . At the o th e r e xt re m e . that of a committed in "commitment a n d i n teraction unit"
a sm a l l
ve lop i n t o
or
.
dividual. the • · i nstit utional unit" to be estab
as possible.
Any attempt to create a central ized check p oin t i n the name of infallible obj ectivity, means a declaration of war to all serious and committed
att e m pt s
quality of our pr i va t e
t he t e c h n ol ogy
to enhance the total and social life and of
to make t h i s possible.
lished will be close r to m a k i ng a structural ar rangeme nt for the a llocation of time for re flection private terests
clude
on a re g u l a r basis about one 's own and soci al l i fe o n e ' s ach ievements. i n and p l a n n e d future . It m i gh t also in .
the establishment of s o m e li mited struc
tural link wi t h
m ore o perati o n a l
i nstitutions,
including becoming an active or passive mem
of
an a ss o c i a t i o n
or c l u b for reading or Whatever their o rga ni za t i o nal framework and in t e n si t y should prove to be. the basic fu n c t i on s of each "commitme nt a n d i n t e r act i on prom o t i n g u n i t ar e c lea r The y should help the actor ( a) t o maintain a c o n t i n ually updated u nd er s t a n d i n g and i n s p ir e d vi sion of its own past. po s si b l e futures, and cul tural resource s , ( b ) t o r e ma i n informed about be r
di scus s i o n.
"
.
the views and resources of other practice s .
(c)
9 TA after TA
to i n form other rel e v a nt actors a b o u t i t s
own ba ckg ro u n d s and s ta n d p oi nt s a n d ( d ) to part i ci p a t e in a n appropriate way in the social processes of shared d eci s ion - ma ki n g and commitment-b uilding. Even though t h e number of assessme nt-as s isti n g st ructures has been m ul t i p l ie d al l t h e se i nsti t u ti ons to ge t h e r cannot guarantee that new tech no l ogic a l d e v e lop m e n ts will be relevant and h a r m l e s s They do not provide socie ty with a n i n fa l l ible i ns ight into its pr e s ent state or w i t h a m e c h a n i s m for fo r esi gh t of t h e i m p act of 1ts future a c t i v i t ies i n clud i n g t h e d e v e l o pm e n t of t e ch no l o gi c al p roj e c t s These i n s t i t u t i o n s are m uc h more modest . They are att<�ched to one sp e c ifi c actor or type of actors and try to clari fy his s i tuati on .
.
.
.
The end of T A is
not the
end of the need to
plan a n d evaluate technologies. The failure of
does not necessarily mean t h at mankind monitor scien tific, tech n ol og ical and i n dustrial develop ments. Wha t we learned is t ha t such assess ment can not be achieved th ro u g h a s i n gl e , ob j ective , cool m e th o d ology or pe rfo r m ed i n some centralized , state-controlled a n d obj ec t ive institution . We know that the total a ss es s m e n t o f te c hn o lo gi ca l deve lop m e n t s is in the TA
should give up its atte mpts to
first place a broad , decentralized social pro cess. and that this process can be e ndorsed but
n ev er replaced
by
a g rea t v a ri e t y
of re
se arc h projects. Those i n te llectual efforts in cl u d e
"
fo reca s t i n g
t ec hn ique s
"
which extra
p o lat e curren t scientific and soci al trends i n order to const ruct a h y pothe t ical p i c t u r e of society within
20 or 50
years . Such a picture
can never be '·prove n " and is pr o babl y never true , but it he l ps
to understand and ev al ua te
curre nt tre nds and to see them in context. O t h e r pertin e n t research proj ect s i nclude the s ys t e mat ic
m a p pi n g o f kno wn
or e x pe c t e d
rel
evant consequences and aspects of o n g oi ng or pla nn e d tech no l o gi es . such as their
use
of en
e rgy. their expected c o n fl icts with e x is t i n g cial
or
so
le g a l institutions, and their impact on e nv i ron me n t a l eleme nts which our society
38
1
The Evaluation of Technology as an Interactive Commitment-Building Process
wants to protect. Many of these intellectual experiments existed before TA was born. The fact that it has proven to be impossible to use them as building blocks for some unified and infallible T A methodology, is no reason to cast doubt on their value as a resource in the process of assessing technological develop ments. Most pioneering TA institutions and thinkers have been wise enough to later make it quite explicit that they had abandoned the original TA inspiration. Some of them ex plain that they are working at implementing "TA in a broadened sense" which includes the development of high-level expertise for promoting social interaction and for perform ing some of the relevant types of research. Inadvertently, these attempts to give a second life to the concept of "Technology Assess ment" have fueled the naive illusion that "the old and powerful TA", which in fact was nev er more than a dream, is still alive. Many de cision-makers, inspired by the praiseworthy conviction that technology demands appro priate assessment, have been attracted and mislead by the false belief that the old "Tech nology Assessment" still exists and have es tablished TA initiatives in the old and com pletely inviable style. Much hope has been raised by and much credit been given to nu merous completely unrealistic initiatives, simply because they were believed to perform powerful, traditional TA studies. Much con fusion would have been avoided if those high quality institutions which developed TA in the sixties, only to abandon it in the seventies, would have circumnavigated the term TA en tirely, while persuing their mission of continu ing the development of interesting programs.
10 References (1989), Process, Prescience, and Prag matism: The Office of Technology Assessment (Internal Paper, prepared for the 1 1 th Annual Research Conference of the Association of Pub lic Policy Analysis and Management, November 2--4, 1989, Arlington, Virginia), OTA, Washing ton, DC. COATE S, V. T. ( 1 979), Technology Assessment in Federal Agencies. 1971-1976, George Washing ton University, Washington, DC. DADDARIO, E. Q. (1968), Technology Assessment. Statement of the Subcommittee on Science, Re search and Development (90th Congress, 1 st Ses sion), US Government Printing Office, Washing ton, DC. GIBBONS, J. H., GW I N , H. L. (1 985), Technology and Governance, in: Technology and Society, Vol. 7, pp. 333-352. LAWRENCE, C. ( 1 985), OTA: Technical G uidance for Congressional Decisions, in: EPRI 1. , Jan./ Feb., 34-38. MESTHENE, E. G. (1965), Ministers Talk about Science, OECD, Paris. NATIONAL A CA D E MY OF SC I E NC E S (1 968), Tech nology: Process of Assessment and Choice, Gov ernment Printing Office, Washington DC. NICHOLS, K. G. (1978), Technology on Trial, OECD, Paris. SALOMON, J.-J. ( 1971), Science Policy Studies and the Development of Science Policy, in: SPIEGEL ROS I N G, I. (1 977): Science, Technology and So ciety. A Cross-Disciplinary Perspective, pp. 4370, Sage, London. SMITS, R., LEYTEN, J. ( 1 988), Key Issues in the In stitutionalization of Technology Assessment, Fu tures, February, 19-36. WEINBERG, A. M . (1967), Reflections on Big Science, Cambridge, Massachusetts - London. CARSON, N.
Biotec/11wlogy
Ed i ted by , H . - J . Rehm a nd G. Reed in coo p eration wit h A. Puhler and P. S tadler C o p yright © VCH Verlagsgesellschatt mbH,1995
2 C oncepts of Risk Assessment:
The ''Process versus Product'' Controversy Put to Rest
HENRY I . MILLER Stanford . CA 94305-60 1 0, USA
1
Introduction 40 Myt h s of B i o t echn o l og y 41 2.1 M yth 1: Biotechnology is a Discrete New Technology 41 2.2 Myth 2: Biotechnology and G enetic Engineering are New 41 2.3 Myth 3: The Unknowns Outweigh the Knowns 43 2.4 M yth 4: Novel and Da n ge r ou s Organisms will be Created 44 2.5 Myth 5: N o n p a t h o g c n s will be Transformed int o P a t h ogen s 44 2.6 M yth 6: All Te ch n o l og y is Intrinsically Da nge ro u s 45 3 The Basis for Risk Assessment for the New Biotechnology: Product. Not Process 46 3.1 Broad Sctentific Consensus 46 3.2 A Useful S y l log i sm 49 4 The Status of R e g ula t i o n in the U n i te d States 5 1 5 Implications for Public Po l i c y 54 5. 1 Important Non-Scientific Issues 54 5.2 Re al W o r l d Effects o f Irrational or Excessive Re g u la t ion 55 5 . 2 . 1 Japan 55 5.2.2 Europe 56 5.2.3 The Developi ng World : Espe c ially at Risk 56
2 The
-
5.2.4 The U n ited States 5 7 5.2.5 Serious Flaws in a "'Horizontal"' A pp roach to Biotechnology Risk
o 7
5 . 2 . 6 A C 'm ·ea t
Concl usions References
60
61
for Policy Makers
59
58
40
2 Concepts of Risk Assessment: The "Process versus Product " Contro versy Put to Rest
1 Introduction The last two decades of regulation of prod ucts and processes of the "new biotechnolo gy" has seen much to praise and also much to criticize. On the positive side, oversight by the United States National Institutes of Health (NIH) has been relatively enlightened, with progressively decreasing stringency of their guidelines for laboratory research, and the de facto elimination of NIH approvals of field trials. The approach of the United States Food and Drug Administration (FDA) to the new products, overseeing them in the same way as similar products made in other ways, has been validated for a large number of products, with more than 800 (mostly diag nostics, plus approximately 20 therapeutics) approved for marketing and more than 1 500 clinical trials of drugs and biologics under way. On the negative side, good science and good sense have not always been well repre sented in the formulation of regulatory poli cy, and too often the burea ucracy b uilders have instituted burdensome, gratuitous regul ation or retained it long after its time. Plan ned introductions (field trials or "deliberate releases" ) in particular have frequently been overregulated. Several European countries and Japan have adopted a process-based ap proach to oversight and have been unneces sarily restrictive, and they have paid the price in di m i n ished research and development ac tivity. In the United States, an intermittently inhospitable regulatory climate and a lack of public understanding have discouraged re search and development in certain areas. In particular, academic and industrial research ers have been leery of field trials of recombi nant organisms - even in areas such as biore mediation and microbial biocontrol agents that were once highly touted - and inve sto r interest in sectors that require field trials has diminished. The emergence and perseverance of equi vocal or hostile regulatory climates for the new biotechnology can be traced in part to the propagation of various myths that have not been balanced by vigorous efforts at pub lic education. This disparity is unfortunate,
because the vast majority of applications of the new biotechnology are fundamentally similar, on both theoretical and empirical grounds, to well-accepted, ubiquitous applica tions of the "old biotechnology", and they are demonstrably safe. Treating "new biotechno logy" products as a discrete category that is haza rdous - or even poten tially h aza rdo u s is unjustified and leads to a number of unde sirable consequences, from holding super fluous conferences and doing the wrong risk assessment experiments to implementing flawed regulatory policies and creating disin centives to using the newest techniques. These outcomes will, in turn , cause the public ultimately to suffer from a failure or a delay i n the development of new prod ucts. A pivotal issue related to the destructive mythology attending new biotechnology is whether the trigger for regulatory jurisdiction or for a certain degree of regulatory scrutiny should be the use of a certain process of ge netic manipulation; or whether the character istics of the product (either a living organism or inert product) or its intended use should constitute the trigger. This co n u nd ru m has been referred to as the "process versus prod uct" debate, which has dragged on long after the issue should have been put to rest by in ternational scientific consensus. The goal of the United States govern ment's coordinated approach to the regula tion of biotechnology products has been to limit potential risks while encouraging the in n o vati o n, development , and availabil i ty of new products (Federal Register, 1986). How ever, not only must products be safe, but the public must have confidence in their safety. At the same time, public misapprehensions cannot be permitted to stimulate regressive policies. Thus, t he advent of the new biotech nology continues to pose a challenge that in volves perception as much as reality, and pub lic ed ucation as much as the presence of an effective and coherent regulatory framework. Only if we can correct the misconceptions and eliminate the harmful myths that have grown up around the buzzword "biotechnology" can its potential be realized.
2
2 The Myths of Biotechnology 2. 1 Myth 1 : Biotechnology is a Discrete New Technology
One m y t h i s t h a t biotechnology is s om e thing discrete or h o m oge n e ou s . a corollary of wh i ch is that t here e x i s t s a "biotechnology in dustry" that can or should be r i gi d ly con trolled. This view is facile and inaccurate. ·'Biotechnology .. i s mere l y a catch-all term for a broad group of useful. enabling technol ogies with wide and diverse applications i n in d u s t ry and com merce . This spectrum of tools has become so i n t e gr a t e d into the work of pr ac t i t i one rs such as plant breeders and mi crobiologists that it is difficult. and also po i n t less, to a t t em p t to dis t ing u i s h between "old" and "new". Thts theme i s enlarged upon in Sect . 2.2. A useful working definition of biotechno logy used by st·veral U . S . go v e r n me n t agen cies is ''the appl i c a t i on of b i o l ogi c a l systems and org an i sm s to technical and industrial processes". Th i!-. definition encompasses proc esses as different as fi s h farming. fo rest ry . the development of disease-resistant crop p la n ts . the production of e n zym e s for laundry deter gents. and the genetic engi nee r ing of bacteria to clean up oil s pills . kill insect larvae . or pro du ce in s u l i n . Biot e ch nol ogy thus encompasses m y r iad dissimilar processes. produci n g e v e n greater n u m bers of d i ss i m i l a r products for vastly di s similar applic a tions. These processes and prod u c t s are sc diverse and have so little in common w i t h o n e a n ot her that i t is difficult to construct valid generalizations about them. for wha t e v e r purpose ( see also S e c t . 5.2.5 ) . Be c a us e o f binl echnology·s lack o f systemat ic. uniform ch aracteristics. it cannot be effec tive l y legisl a t e d or ov e rs e e n in the uniform . all-inclusive ma nner that is possible. for ex a mp l e . for the unde r g r o u n d coal mining in dustry.
Biotech nolog y ' s
re gul ati on of
so
diversity dictates that the
many end u s e s must be ac complished by several governme nt agencies.
The Myths of Biotechnology
41
As the uses vary . so do agenc ie s '
j u r isd i ctio n and the nature of their evaluation of the p roduc ts . For example, a review by the U . S . Environmental Protection A g e n cy (EPA) of an e nzyme used as a d r a i n cleaner will be dif ferent from a review by t h e FDA of the same enzyme injected i nto patients to dissolve blood clots ( Federal Register. 1 984). The div ersi t y of products and the ir applications ar gues against the usefulness of legislation or re g u lat i ons that attempt to encompass unna tural groupings that would occur under gener al terms such as "biotechnology", " ge n etic a l l y ma n i pu lated org a ni sm s " , or "planned intro ductions" ( M I LLER , 1 986) .
2.2 Myth 2: Biotechnology and G e netic Engineering are New
A second m yt h is that biotech nology i s new. On the contrary, many forms of biotech nology have been widely us e d for millennia. Earlier than 6000 B.C. the Sumerians and the Babylonians e xpl o i t ed the ability of yeast to make alcohol by b re wi ng beer. A " p ict u re " of the ancients preparing and fermenting grain and storing the brew has actually been re tained for posterity in a h i e rog l y phi c (DE MAIN and SOLOMON, 1 981 ) . An even older subset of biotechnology is genetic en gine er i ng , the indirect manipulation of an organ ism's genes by the gu i d e d mating of animals or crop plants so as to enhance desired char acteristics. In this p ro c ess of domestication . changes are made at the level of the whole or ganism: that is. selection is made fo r desired phe notypes, and the genetic changes , oft e n poo rly characterized. occur concomitantly. The new technologies, i n contrast , enable ge netic material to b e modified at the cellular and molecular levels. These new techniques yield more p re c i se and deliberate variants of genetic engin eering, and the y c onse q ue n t ly produce better characterized and more p re dictable results: however. they retain the aims of classical domestication. Building on the domestication of microor ganisms for the modification of foods, indus try has used classical genetic methods to y iel d many valuable organisms. One examp l e is the
42
2
Concepts of Risk Assessment: The "Process versus Product" Controversy Put to Rest
genetic improvement of Penicillium chrysoge the mold that produces penicillin: by several methods including the screening of thousands of isolates and the use of mutagens to accelerate variation, penicillin yields have been increased more than a hundred-fold during the past several decades. There are many similar examples; microbial fermenta tion is employed throughout the world to pro duce a variety of other important substances, including industrial detergents, antibiotics, or ganic solvents, vitamins, amino acids, polysac charides, steroids, and vaccines (WHO, 1985). The value of these and similar products of conventional biotechnology is in excess of $ 100 billion annually. Today, with the iden tification of the genes responsible for the bio synthesis of various antibiotics, the empirical search for improved products or yields is be ing supplanted by the introduction of specific, directed genetic changes. In addition to such "contained" industrial applications, there have been many beneficial planned introductions of other organisms into the environment, including insects, bacteria, and viruses. Insect release was used success fully to control troublesome weeds in Hawaii in the early 20th century. Other examples are the successful program for the biological con trol of St. Johnswort ("Klamath weed") in California by insects in the 1 940s and 1 950s and the more recent use of an introduced rust pathogen to control rush skeletonweed in Australia. There have been hundreds of plan ned introductions of natural predators of in sect pests since the first such release of the Australian Vedalia beetle in California in 1 988. This area of research, the biological control of weeds, nematodes, insects, and dis eases, is actively promoted by the U.S. De partments of Interior and Agriculture (KLINGMAN and CO U LS ON , 1 982) . Currently, more than a dozen microbial biocontrol agents are approved and regis tered with the EPA, and these organisms are m arkete d in hundreds of different products for use in agriculture, forestry, and home gar dening (BETZ et al., 1 983). In another major area - growth promoters for plants - prepara tions containing the bacterium Rhizobium, which enhances the growth of leguminous plants such as soybeans, alfalfa, and beans, num,
have been sold in this country since the late nineteenth century. These products induce the development on plant roots of structures in which bacteria can convert nitrogen into compounds that can be used by plants and thereby decrease the need for chemical fertil izers. Some of the most ubiquitous planned in troductions of genetically modified organisms have involved the vaccination of human and animal populations with live , attenuated vi ruses. Live viruses modified by various tech niques and licensed in the United States com prise vaccines against mumps, measles, rubel la, poliomyelitis, and yellow fever. Inocula tion of a live viral vaccine entails not only "in fection" of the recipient (with minimal ad verse impact on health) but sometimes the possibility of further transmission of the virus in the community - with the presumed risk of serial propagation. Nevertheless, no vaccine virus has become established in the environ ment, despite the continual presence of vac cine viruses there. For example, studies in the United States and the United Kingdom have shown that vaccine strains of poliovirus are present in sewage, but this reflects the con tinuing administration and excretion of live virus vaccine rather than its serial propaga tion through human or animal hosts in the community (KILBOURNE, 1 985) . Viral vaccines produced with older genetic techniques for attenuating virulence have been remarkably effective throughout the world and have completely eradicated the dread smallpox virus. Despite rare adverse reactions, the beneficial impact of vaccines has been, to this point, superseded in impor tance as a promoter of human longevity and quality of life only by the agricultural "green revolution", which was mediated in part by genetically modified plants. Building on the successes of the past, the newest biotechnological techniques, including recombinant DNA, are already providing still more precise, b et t e r understood, and more predictable methods for manipulating the ge netic material of viruses and other microor ganisms for use as vaccines. The modification of crop plants has been performed ever since ancient agriculturists se lected for cultivation plants possessing desir-
2
able traits from domesticated relatives of wild species. The re d iscov er y in 1 900 o f MENDEL's co nc e p t s of inhl! ritance ushered in the scien tific ap p l ica tio n of genetic p ri nci p les to crop improvement. Since then, each scientific ad v an c e has incn!ased the ability to improve predictably the ge no t ype (and more impor tant for the consumer of the p rod uc t the phe notype); and now, a combination of several techniques is often used to improve pl a nt s. For example, an existing plant might have been modified hy many ge nerations of classi cal breeding and selection , and more recently by somaclonal variation and wide crosses with embryo resc ue (see below) . These plants are being further improved by the newer molecu lar tec hniq u e s (such as recombinant DNA) and can then he reintroduced into classical breedin g programs from which its descend ants will be re kase d i n t o c o mme rc e In t h i s cen tury , plant breeders have in creasingly used interspeci fic h y b ri d iz a t ion to transfer genes from c e rt ain non -cultivated p l ant species t o a variety of different ( b u t closely related) species. T he se interspecific transfers of trai ts from wild species to domes ticated relatives in the same genus stimulated attempts at e\·en wider crosses, including those between members of different genera. These "wide crosses" , transcending nat ura l barriers to m a t ing, have been facilitated by "embryo rescue'' - culture t e c h niq u es in which a sexual cross y i e ld i ng a viable e m bry o but abnormal e n d ospe rm is "rescued " by cul turing t h e e m b ry o This is a cco m pli s hed by pro vi d i n g the hybrid embryo with the l i fe support normally supplied in the early stages of de ve l opme n t by maternal tissue and the endosperm. A n u mbe r of plants resulting from wide cros�es have been used in further bre e di n g extensively field tested, and m a r keted i n the United States and elsewhere. These plants i n clude commonly available va rieties of tomat�)es. potatoes. corn. oats, sugar beets, rice , and bread a nd durum wheat. The molecular t e c h n i q ues for the genetic manipul ation of pla nts enable sci e n ti st s to move s p e c ifi c and useful segments of genetic material readily between unrelated organ isms. These t ech ni q ue s offer several advan tages and complement existing b reed i n g ef forts by in cre a s i n g the diversity of genes and ,
43
The Myths of Biotechnology
germ p l asm available for incorporation into crops. The n u m e ro u s molecular techniques for ge n e t ic ma n ipu l a tio n of p l a n ts can be div ided into two main t y pes - vectored and non vectored. Vectored m odifica t ions rely on the use of biologically active age nts such as p las mids and viruses, to facilitate t he e n try o f the foreign gene into the plant c ell N o n ve ctored m odi ficatio ns re l y on the foreign genes being physically inserted into the pl an t cell by s uc h methods as electroporation, mi croi nje ct i on or particle guns. Although in some respects the use of these molecular techniques is more complex than traditional plant breeding prac tices, it is likely to be at least as safe . In both kinds of approaches, new DNA e nters the plant's genome and is st a b l y maintained and expressed. ,
.
-
,
.
.
,
2.3 Myth 3 : The Unknowns Outweigh the Knowns
It is excessively neg a t i ve - and e v en mis to a rgue as some have that "as far as the ecological properties of microbes are con cerned, the unknowns far outweigh the knowns (SHARPLES, 1 987). In fact , it is not what is unknown , per se, th at is material, but what is unknown that relates to risk that is important. In the q u o t ati o n above, one could j ust as easily substitute "the functions of mu tations in live poliovi ru s vaccines" for "the ecological prope rt ies of microbes", but for four decades these uncharacterized genetic c hange s have not prevented our using e m piri cally developed, Jive, attenuated poliovirus vaccin e s The statement is particularly du bious for many microorganisms of commer cial interest, i n cl u d i n g several Pseudomonas s pe ci es (syringae, aureofaciens, fluorescens) , Thiobacillus s p e ci e s Bacillus thuringiensis, B. subtilis, Rhizobium , and b ac u l ovi ru se s as well as the microbes used in fermentation to produce bread , cheese, wine, beer, and yogh urt. In fact the majority of m icrob es are e s se n tial to ecosystem processes or otherwise beneficial to man, and only a minuscule frac tion are pathogenic or otherwise harmful. Until the recent furor over e n gi n e e re d (mea n i ng rONA-manipulated) organisms, l ea d in g
-
.
,
,
,
"
"
44
2 Concepts of Risk Assessment: The "Process versus Product" Controversy Put to Rest
small-scale field trials of native or non-pa thogenic microbes modified by classical tech niques were long exempt in the United States from both the pesticide and toxic substances regulations, and the safety record extending over more than half a century is admirable. The scientific method and prior experience, when applied logically to risk assessment, do enable us to make useful predictions.
2.4 Myth 4: Novel and Dan gerous Organisms will be Created
The degree of novelty of microorganisms or macroorganisms created by the new ge netic engineering techniques has been wildly exaggerated. A corn plant that has had newly incorporated into its genome the gene that synthesizes a Bacillus thuringiensis toxin is still, after all, a corn plant. Escherichia coli K12 which has been programmed to synthesize human alpha interferon by means of recombi nant DNA techniques differs very little from unmanipulated siblings that manufacture only bacterial molecules. Moreover, in nature, in numerable recombinations via several mecha nisms between even very distantly related or ganisms have likely occurred ( DAVIS, 1 976). Bacteria can take up naked DNA, though inefficiently, and in nature they have long been exposed to DNA from disintegrating mammalian cells, as in the gut, in decompos ing corpses, and in infected wounds. The hu man population alone excretes on the order of 1 0 22 bacteria per day; hence, over the past 106 years innumerable mammalian-bacterial hybrids are likely to have appeared and been tested and discarded by natural selection. An analogous argument can be made for recom bination among fungi, bacteria, viruses, and plants. Both genetic and ecological constraints op erate to prevent the emergence of exceeding ly pathogenic viral variants, though even a single point mutation can alter virulence (FIELDS and SPRIGGS, 1 982). And while the variations that continuously arise on an enor mous scale in nature do occasionally produce a modified pathogen, such as an influenza vi rus with increased virulence or the AIDS vi rus, it is hardly likely that they would produce
in one fell swoop a serious pathogen from a nonpathogen. Furthermore, the chances of such an event arising from the small-scale changes made by man do not compare with the tremendous background "noise" of re combination and selection in nature. It is pertinent that certain kinds of gene transfers thought until recently to be impossi ble in nature because of the phylogenetic dis tance between donor and recipient have now been shown to occur in the laboratory and may occur in nature as well. For example, B RISSON-NOEL et al. (1988) have demon strated that a gene or genes for erythromycin resistance was transferred between the Gram negative bacterium Campylobacter and unre lated Gram-positive bacteria. In recent labo ratory experiments, it was demonstrated that gene transfer can occur between E. coli and Streptomyces or yeast, and that the crown gall disease in plants results from a natural trans fer of DNA from a bacterial species (Agro bacterium) to plant cells (HEINEMANN and SPRAGUE, 1 989; MAZODIER et al. , 1 989). (Knowledge of the nature of this mechanism has already led to development of a highly ef fective means of developing transgenic plants without danger of disease induction, using DNA fragments from Agrobacterium.) Since evolution continually creates novelty, the distinction between "natural" and "unna tural" (or "novel") is not a clear one and is, arguably, irrelevant. Novel is not synonymous with dangerous, nor need it even imply uncer tainty.
2.5 Myth 5: Nonpathogens will be
Transformed into Patho gens
A frequently voiced concern is that genetic manipulation may inadvertently transform a nonpathogen into a pathogen. However, this view ignores the complexity and the multifac torial nature of pathogenicity. Pathogenicity is not a trait produced by some single omni potent gene; rather, it requires the evolution of a special set of properties that involve a number of genes whose functions control fac tors such as fitness, virulence, and adhesion. A pathogen must possess three general characteristics, which are themselves multi-
2 The Myths
factorial . First. i t must be able to metabolize and multiply in or upon host tissues : that is, the oxygen tension and pH must be sa t is fa c to ry, the temperature ( a nd . fo r pla n t p a tho ge n s . the tissue wat er p ot e n t i al ) suitable. and the nutritional milieu favorable. S econ d . a s s um i ng an acceptab l e range for all of the m a n y conditions necessary for metabolism and mul t i p lica ti on . the pathogen must be able to re sist or a vo id the host's defense mechanisms for a p e rio d of t im e sufficient to reach the numbers re quired actua ll y to p r oduc e disease. Third, a succes�ful pa t h ogen must be a bl e to surv i ve and be di ss e minat e d to new host or ganisms. The or g a n ism must be met i cu l o us l y ad apted to its p athogen i c l ife st y l e . Even a gene codin g for a pote n t toxin will no t convert a harmless bacterium into an effective source of ep i dem i c . or even l oc a li ze d , disease , unless many other r e q u i re d trai ts are pre s e n t . For h uman and animal p a t h og e n s , these include. at the l e ast . resistance to e n z y mes . antibodies. and p h agocytic cells in the host: the abili ty to adhere t o sp e c i fic surfaces: and the a b ilit y to th rive on avai l a ble nutrients provided by t h e host . No one of these t r aits confers p a th o g e n icit y , t hou gh a mutation that affects any es sential o n e can eliminate pathoge n ici ty. A nother i m p o r t a n t consideration is that se vere pathogen icity is more dem an din g of f a vorable conditions and therefore . much rare r in nature th a n are mild de gr ee s of pathoge nicity. H e nce , the probability of inadvertently creating a n o rga n i sm c a p ab l e of pr o du c in g a medical or agricultural cat a stro phe must be vanishin gly small. (This po int is impo r ta n t be cause of the claims of so me bi o t e c h n ology critics that while the likelihood of a mishap may be small, \\- he n one occurs. it will be ca t a clysmic. ) The record of t h e la bora t o ry use of rDNA tec h n i ques supports this p r e d i c ti o n . Despite the re!t:asc of t h e order of 1 0 7 r e com binant microorganisms per i nvestigator per year from the st a n d a rd B L I b i o sa fe ty level la boratory ( according to a 1 983 ana l y sis by LIN COLN et al. fu n de d by the U . S . E n v i r o n m e n tal Prot ection Agency under G ra n t No. R8083 1 7 -O J ) for more than 1 5 yea rs . not a sin gle adverse reaction has been observed in hu mans. animals . or the e n v i ron ment .
of Biotechnology
45
2.6 Myth 6: All Technology is Intrinsically Dangerous
Another myth is that th e app l icatio n of all t ec h no l ogy is dangerous. The basis of this view may be the at av i s t i c fear of d i s t u r b i n g th e natural order and of b r eak i n g pr i m i t i ve t a b oo s , co mbin e d wi t h un fami l i arit y with t h e statistical aspects of risk. Promulgators of this myth cite the hazards of toxic ch e m i cal waste dumps and the technical problems of the nuclear i n du s t r y ( w h i ch a r e of du b i ou s relev a n ce to b i ot echnolog y in a n y cas e ) , but they co n v e nie n t l y ignore the o v e rw h elmi n g successes of t e l epho n i c communication; vacci n a t i on ; blood transfusions; microchip circui try: and the im p rov e d p rod uctivi ty of pl a n ts , animals. and microbes wrought by gene t i c im prov ement . It is wo rt h r e membe rin g that crit ics p re d i ct e d electrocution from the first tele ph o n e s . the creation of h uman monsters by J ENNER's early attempts a t s ma l lp o x vaccina tion, the impossibility of ma tching blood for transfusions. and e pid e m i c s of uncontrollable "Andromeda st rain s " re su l ti n g from rDNA ma n i pula t i on of m i c robe s . They s a i d , in ef fect. "the costs will be too h i gh : there is no such t h i n g as a free l u n ch " . N o re sp o nsi b l e person would deny that c e r tai n of the p r a ctice s . processes, or p r o d uct s of b io t echn o lo gy a re p o t e n t ia ll y hazardous i n s o m e way. Some of these haza rd s a re a l ready we ll known: workers p u r i fy i n g a nt i b otics h a ve e x pe r i e n ce d a ll erg ic re a c t i o n s ; la b oratory wo rk e rs have bee n i n fe c t e d i n a d v e r t e n t l y by p a t h oge n ic bacteria: and vaccines have occa sionally elicited s er ious adverse reactions. In a ddi t i o n . introductions of exotic spe c i es , such as E n gl i s h spa rrows, gypsy moths, a nd kudzu ha ve had serious economic conse quences. An an a l og y is sometimes made be tween the introduct i o n of t h es e non-native ( a l i e n o r " e x o tic " ) o rgani s ms and the possib l e consequences of fie l d t r i a l s w i th o r gan i sm s modified by the n e w t e chn i ques. However. the co m p a r i so n is large l y sp e c i o u s , re l yi ng on the a ss u m p t i o n that recombinant DNA ma n i pula t ion can alter the pr o perties of an or g an i sm in a w hol l y unp redic tab l e way that will cause it to a ffec t the en v i ronm e n t ad v e r se l y . Both th e o r y a nd e xp e ri e nce make this o utc o me v e ry unlikely. Generally, intronew
46
2
Concepts of Risk Assessment: The "Process versus Product" Controversy Put to Rest
ductions will be of indigenous organisms changed minimally - often by only the inser tion or deletion of a single structural gene from organisms that are already present in the environment, and that will not enjoy a se lective advantage over their wild-type co horts. They will be subject to the same physi cal and biological limitations of their environ ments as their unmodified parents. Moreover, in the past, exotic pest organisms - whether introduced intentionally or inadvertently - ar rived in a new environment ecologically fit or adapted and with their undesirable properties present. In contrast, there is no evidence that any organism has been made a pest by breed ers' genetic manipulation of plants, animals, or microorganisms. Thus, for organisms mod ified by the techniques of the new biotechnol ogy, the older system of selective breeding, testing, and use of domesticated plants, ani mals and microbes, with its long history and admirable safety record, is a more applicable model than the introduction of exotic organ isms into environments in which a favorable niche existed. In any case, complex and comprehensive regulatory apparatuses based in numerous governmental agencies in the United States, European countries, Japan, and elsewhere, have long overseen the safety of food plants and animals, pharmaceuticals, pesticides, and other products that can be produced by bio technology. There is every reason to expect that for the products of new biotechnology these regulatory mechanisms will continue to be equal to the task and to perform in a way that does not stifle innovation. There may never be a "free lunch", but often we can make it an excellent value.
3 The B asis for Risk
Assessment for the New
B iotechnology: Product, Not Process Among those scientifically knowledgeable about the new methods of genetic manipula-
tion, there is wide consensus that existing risk assessment methods are applicable and suita ble for environmental applications of the new products; this is based on both the large body of knowledge about the biological world and evolutionary biology and from extensive ex perimentation using the newest techniques. Several kinds of procedures are available that make possible the assessment of risk in differ ent ways. And while it is true that risk assess ment for new and old biotechnology is not an exact, predictive discipline (any more than it is for other technologies or for making per sonal decisions about what automobile to buy or what foods to eat), the U.S. NATI ON A L SCIENCE FOUNDATION (1985) has concluded that available methods provide both a useful foundation and "a systematic means of organ izing a variety of relevant knowledge". In as sessing the potential risks of the new biotech nology, the need is not for new methods but rather for ways of ascertaining the correct un derlying assumptions. For risk assessment, as for many other aspects of the new biotechno logy, the new products manufactured with the new processes do not necessarily require new regulatory or scientific paradigms (see Sects. 3. 1 and 3.2). 3 . 1 Broad Scientific Consensus
International organizations and profession al groups have explored repeatedly the ques tion of what are the correct assumptions and whether the uses of the techniques of the new biotechnology are sufficient to elicit a new regulatory paradigm. Their conclusions have been remarkably congruent. A j oint statement from the International Council of Scientific Unions' (ICSU) Scien tific Committee on Problems of the Environ ment (SCOPE) and the Committee on Ge netic Experimentation (COGENE) (Bellagio, Italy 1 987) , concluded: " [t ] he properties of the introduced organ isms and its target environment are the key features in the assessment of risk. Such fac tors as the demographic characterization of the introduced organisms; genetic stability, including the potential for horizontal trans-
3
The Basis for Risk
Assessment for the New Biotechnology: Product, Not Process
outcrossing with weedy species: and
fe r
or
the
fit of
the
species
logical env ironme nt
t o t h e physical and bio
. . .
•
These considerations
apply equa l l y to bot h modified or unmodif ied organisms: and, in t h e case of mo difi e d
organ isms. t h ey
apply
technique� used to
i n depe n d e n t l y of t h e
•
achieve modifica tion.
That is. i t is the organism itself. and not how it
was
co n s t ru c te d . that is i mp o rt a nt ' " .
The report of a N ATO A D V A N C E D RE SEA RCH WORKSHOP ( 1 987 ) came to similar conclusions:
•
··Jn principle. the outcomes associated with
the introd uc tion i nto the e nv i ro n m e nt of or ganisms modified by rDNA techniques are l ik e ly to be the same in kind as those asso
ciated with : n t roduct ion of organisms modif
adve rse outcomes should be based on the nat ure of t he organism and of
the environ
ment into w h ic h it i s i n t roduced. and not on the method
(if
any ) of ge netic modification . "
Echoing these contemporaneous v i e w points. the UN IDO/W HO/UNEP Working G roup on Biotechnology Safety concluded (report of the t hird meeti n g of the Working Group. Par is 1 9 87) that "[ t] he level of risk assessment se lected for particular organisms should be based on the nature of the organism and the e nvironment i n t o which it is introd uced". Various national groups have both re flected and extl!nded these conclusions. The United States National Academy of Sciences (NAS) publisht·d in 1 987 a policy statement on the planned introduct ion of organisms into the environme n t , and it has had wide-ranging impacts in the United States and i nternation ally (NAS, 1 987) . Several of its most signifi cant conclusions and recommendations are : •
•
Recombinant DNA techn iques consti tute a powerful and safe new means for the modification of organisms Geneticall:v modified organisms will contribute substantially to improved health care , agricultural efficiency. and the amelioration of many pressing envi ronmental problems that have resulted from the e xte nsive reliance on chemi cals i n both agriculture and industry
There is no evidence of the existence of unique hazards either in the use of rONA techniques or in the movemen t of genes between unrelated organisms The risks associated with the introduc tion of rONA-engineered organ isms are the same in kind as those associated with the introduction of unmodified or ganisms and organisms modified by other methods The assessmen t of risks associated with introducing recombinant DNA organ isms into the environment should be based on t he nature of the organism and of the e nvironment into which the organism is to be introduced. and inde pendent of the method of engineering per se.
ied by oth e r methods. Therefore , ide n t i fica
t ion and ass.:ssmcnt of t he risk of possible
47
In an expansmn of this policy, the United States National Research Council (NRC) concluded in a landmark report that "no con ceptual distinction exists between genetic modification of plants and microorganisms by classical methods or by molecular techniques that modify D N A and transfer genes " , wheth er in the laboratory, in the field, or in large scale environmental i ntroductions. In order to leave no room for equivocation on this point, the N RC's report went on to reinforce it with related observations: •
•
•
"The committees [of experts commis sioned by the NRC] were guided by the conclusion (NAS, 1 987) that the p rod uct of genetic modification and selec tion should be the primary focus for making decisions about the environ mental introduction of a plant or mi croorganism and not the p rocess by which the products were obtained." (p. 1 4, bottom) " Information about the process used to produce a genetically modified organ ism is important in understanding the characteristics of the product. However, the nature of the process is not a useful criterion for determining whether the product requires less or more over sight." (p. 1 4 , bottom) "The same physical and biological l aws govern the response of organisms mod-
2
48
•
•
•
•
Concepts of Risk Assessment: The "Process versus Product" Controversy Put to Rest
ified by modern molecular and cellular methods and those produced by classi cal methods. " (p. 15, middle) . " Recombinant DNA methodology makes it possible to introduce pieces of DNA, consisting of either single or multiple genes, that can be defined in function and even in nucleotide se quence . With classical techniques of gene transfer, a variable number of genes can be transferred, the number depending on the mechanism of trans fer; but predicting the precise number of the traits that have been transferred is difficult, and we cannot always pre dict the phenotypic expression that will result. With organisms modified by mo lecular methods, we are in a better, if not perfect, position to predict the phe notypic expression." (p. 13, bottom) "With classical methods of mutagenesis, chemical mutagens such as alkylating agents modify DNA in essentially ran dom ways; it is not possible to direct a mutation to specific genes, much Jess to specific sites within a gene. Indeed, one common alkylating agent alters a num ber of different genes simultaneously. These mutations can go unnoticed un less they produce phenotypic changes that make them detectable in their en vironments. Many mutations go unde tected until the organisms are grown under conditions that support expres sion of the mutation." (p. 14, top) "Crops modified by molecular and cel lular methods should pose risks no dif ferent from those modified by classical genetic methods for similar traits. As the molecular methods are more specif ic, users of these methods will be more certain about the traits they introduce into the plants. " (p. 3, bottom) "The types of modifications that have been seen or anticipated with molecular techniques are similar to those that have been produced with classical tech niques. No new or inherently different hazards are associated with the molecu lar techniques. Therefore, any oversight of field tests should be based on the plant's phenotype and genotype and
•
not on how it was produced. " (p. 70, middle) "Established confinement options are as applicable to field introductions of plants modified by molecular and cellu lar methods as they are for plants mod ified by classical genetic methods. " ( p . 69, middle)
The NRC (1989) proposed that the evalua tion of experimental field testing be based on three considerations: familiarity, i.e ., the sum total of knowledge about the traits of the or ganism and the test environment; the ability to confine or control the spread of the organ ism; and the likelihood of harmful effects if the organism should escape control or con finement. The same principles were emphasized in an excellent and wide-ranging report by the U.S. NATIONAL BIOTECHNOLOGY POLICY BOARD (1 992), which was established by the Congress and is comprised of representatives from the public and private sector. The report concluded that " ( t ] h e risks associated with biotechnology
not unique, and tend to be associated with particular products and their applica tions, not with the prod uction process or the technology per se. In fact biotechnology processes tend to reduce ri sks because they are more pre c ise and predi ct ab l e . The health and environmental risks of no t pu rsu ing bio technology-based solutions to the nation ' s problems are likely to be greater than the risks of going forward." are
These conclusions were bolstered by the find ings and recommendations of the United Kingdom's House of Lords Select Committee on Regulation of the U.K. Biotechnology In dustry and Global Competitiveness ( WARD, 1993) , which are discussed below. The Paris-based Organization for Econom ic Cooperation and Development (OECD ) , approaching this question from a different di rection - the safety of new varieties of foods came to similar conclusions. OECD 's 1 993 re port "Concepts and Principles Underpinning Safety Evaluation of Foods Derived by Mod ern Biotechnology" described several con cepts related to food safety:
3 The Basis for •
•
Risk Assessment for
e r products resulting from new genetic e ngi
" I n princi p l e . food has been presumed to he safe unless a significant hazard . was ide nt i fi ed . .
pressed
" M odern b iotechnology broadens t h e
a n d safety of the newer techniques compared
scope of t h e ge netic changes t h a t can be made i n food organisms and broad ens the scope of possi ble sources of foods . Th is does not i n h e re n t l y lead to foods that are less safe than those de veloped by conventi onal techniques.
n e e ring techniques.
with
I
continue
to b e
im
the extraordi nary predictability
to t h e older. "'conventional'' ones; arguably, a n y disparity of regulatory treatment would logically propose lesser scrutiny of organisms crafted with the most precise and predictable techniques. other factors being equa l . ) The syllogism assume s. of cou rse , t h a t leav
The refore . evaluation of foods and
ing aside the new ge netic e ngineering, there
food com pone nts obtained from organ
e x ists adeq uate gove rnmental control over
isms deve lope d b y t h e application
•
49
the New Biotechnology: Product, Not Process
of
the testing and use of living organisms and
t h e n e w e r techniques d o e s n o t necessi
their products. This assumption is certainly
tate a fun damental change i n e stab
open t o question. particularly i n those coun
l ished pri nciples, nor does it require a different standard of safety . . . '"For foods a n d food compone nts from
tries where k nown da ngerous pathogens. chemicals . and similar products are largely unregulated or w h e re regulations are widely
organ isms Jeveloped by the application of mode rn biotechnology. the most pract i cal approach to the determin ation of safe t y i s to consider whether t h e y
ignore d . Nevert heless . throughout our pre-re combi nant-DNA history. i n the U nited S tates and elsewhere. sci e n t ists have had a high de gree of unencumbered fre edom of experi
are
m e ntation. with pathogens as well as nonpa
substan tially
equivalent to analogous
con ventional food prod uct ( s ) . if such
thoge n s . i n doors a n d out. The resulting harm
e x ist. · ·
ful i ncidents have been few . and t h e benefits, both intel lectual and com mercial. have far ex ceeded any detrimental effects. The syllogism can be illustrated graphical ly. I n Fig. la. the l arge triangle represe nts the
3.2 A U seful Syllogism
e n tire universe of field trials. The horizontal
A paradigm for regulation o f products of the new ge netic e n gi neering may be summar ized
in a syllogism. I nd ustry. government. and
lines divide the u n i v e rse into classes accord ing to the safe t y category of the experimental organism
(with
examples on t h e right side of
t h e public already possess considerable ex
the
perience with the planned introduction of tra
count the e ffect of ge netic changes, whether
ditional plants for
gene tically
agriculture
modified
organ isms:
figure ) . These cate gories can take i nto ac
they are a conseque nce of spontaneous muta
a n d microorganisms for
tion or of the use of conve n t ional or new
live attenuated vacci nes a n d for other uses
techniques of genetic manipulation. Such ge
such
netic changes can cause the organism to be shifted fro m one safe t y category to another. For example. i f one were to grow mutage
as se wage t reatment and mining. Exist
ing regulatory mech a n i sms have generally protected human health and t h e e n v i ron ment effectively without stifling industrial i nnova
t ion.
There is n o evidence that unique haz ards exist e i t h e r i n the use of recombinant
DNA techniq u�s or i n t h e movement of between u n re lated organisms. There j(ne. for recombinant D N A-manipulated or gene�
gani�ms. there i� no need for additional regul atory mechanisms to be superim posed o n ex isting regulation . (In fact . as a former regula tor who was involved for more t h a n a decade w i th the evalua t i o n of the organisms and oth-
nized cultures of
Neisseria gonorrhea or
Le
gionella pneum ophila i n t h e pre s e nce of in creasing conce n trations of a n t i biotics to select
for antibiotic-resistant mutants. the classifica tion could change from . say. Class
lii to Class
IV. Conversely. deletion of the e n tire botulin
tox i n gene from Clostridium b o tu linum could move the orga nism from Class I l l to Class I I
o r e v e n Class I . The obl i q ue lines divide t h e universe accord i n g t o t h e use o f various tech niques
(with
tech n i q u e s
becoming
newer,
50
2
Concepts of Risk Assessment: The "Process versus Product" Controversy Put to Rest
(a)
V IV
--""
Ill P . FLUOR ESCE N S ; DROSO P H I LA ;
II
SOYBEAN MOSAIC V I R U S
MAIZE ; R H IZOB I U M ; BOS TAUR U S ; MA R I G O LD ; P . AUR EOFAC IENS
CONVENTIONAL B R E E D I N G
M UTAGE N E S I S
SOMACLONAL
T I S S U E CULTU RE
CEU FUSION
VAR IATION
TRANSFORMATION
(b)
V IV
� ·
rONA
EM BRYO
TRANSDUCTION
RESCUE
CONJU GATION
F M DV; B. ANTHRAC I S
•.
�
I M PORTED F I R E ANT: A F R I CA N I Z E D H O N E Y BEE
Ill II
P. FLU O R E S C EN S : D R O S O P H I LA ; SOYBEAN M O S A I C V I R U S
MAIZE ; R H IZOBI U M : B O S TAU R U S ; M A R I G O L D ;
P. A U R EOFAC I E N S
CONVENTIONAL B R E E D I N G
TISSUE CULTURE
MUTAG E N E S I S
SOMACLO N A L
C E L L FUSION
VARIATION
TRANSFO R MATION TRANSDUCTION CONJUGATION
rONA
EMBRYO RESCUE
Fig. 1. Planned introductions into the environment. The large triangles represent the entire universe of
field trials of plants, animals, and microbes. The horizontal lines divide the universe into classes according to the safety category of the experimental organism and take into account the nature of a genetic mutation or genetic change. Examples of organisms within the categories are listed on the right. The oblique lines
divide the universe according to the use of various techniques (with techniques becoming more recent as one moves from left to right) .
4
The Status of Regulation in the United States
moving from left to ri ght) Consideration of the figure reveals that the use of various tech niques does not itself confer safety or risk (except insofar as a genetic change wrought with rDNA techniques is likely to be more precise, better characterized, and more pre dictable) . Rather, risk is primarily a function of the phenotype of an organism (whether the wild type or with traits newly i ntroduced or enhanced in some way) which . i n turn, is de termined by its genomic information: some organisms are destined primarily to exist sym biotically and in nocuously on the roots of leg u m e s (like the b acter iu m Rh izobium) and others to infect and kill mammals at low ino culum concentration ( Lassa fever virus). For an oversight scheme to be "risk based", the use of genetic manipulation tech niques generally or of certain te c h n i ques in particular should not . per s e . dictate the de gree of oversigh t r e q ui red ; rather. the trigger for oversight or for enhanced scrutiny should be a function of the characteristics of an or ganism - either as wild type or in any var iants. Therefore , t here is no coherent scien tific rationale for defining the scope of a regu l ator y net as, say, the "rONA" slice in Fig. 1 . though that approach has often been pro posed. Fig. l b differs from that in la by having Classes IV and V lifted off to illustrate that this. rather than th e "rONA slice " , might be an appropriate "scope" for a regulatory net. particularly if one were designing a regulatory scheme de nom. This suggestion is merely il lustrative: depending upon various considera tions such as the amount of scrutiny j udged to he appropriate and the regulatory burden on researchers and the government. what falls into the "net" could be stratified. For exam ple, Class IV and V organisms might be cir cumscribed for ·'case by case every case " re views by governmental agencies prior to field trials. Class II I organisms for onl y a notifica tion. with Class I and II o rga n i s m s exempt. Such a conceptual approach moves us away from discredited technique-based oversight toward more fruitful consideration of fac t ors relevant to cost -e ffective protection from risks. Why have I belabored these principles stated in almost t h e same words again and .
51
again by d istin g u ished national and interna tional scientific bodies and depicted in Fig. 1 ? There are two reasons. First, the principles are sound and their application can help to avoid false or shaky assumptions i n formulat ing public policy; they can help to avoid sub stituting value j udgements - especially those of new biotechnology's professional critics for science , in crafting regulatory policy. Sec ond. despite broad scientific consensus, the principles have not been u niversally applied. The flawed assumptions that h ave been ad opted in their stead have given rise to various kinds of mischief, from holding the wrong conferences and performing superfluous, wasteful risk assessment experiments, to im plementing regressive public policies (see be low) .
4 The Status of
Regulation in the United
States The overwhelming scientific consensus on the process versus product issue has inelucta bly influenced public policy in the United States. A watershed event for biotechnology regulatory policy was the release by the PRESIDENT's
COU N C I L
ON
COMPETITIVE
NESS ( 1 991 ) of the " Report on National Bio
tech nology Policy". The report described the basic tenets of official policy, including seek ing ''to eliminate unneeded regulatory burd ens for all phases of developing new biotech nology products - laboratory and field experi ments, product development, and eventual sale and use " . At least in theory, U.S. policy adheres to the principle that the extent of governmental oversight should be only that which is necessary and sufficient; or putting it another way. the object of regulation is not to regulate whenever possible, but only when there are unaddressed and unreasonable risks. The report also described principles of reg ulatory review that underpin regulatory poli cy in the United States. including:
52
2 Concepts of Risk Assessment: The "Process versus Product" Controversy Put to Rest
1 . "Federal government regulatory over
sight should focus on the characteristics and risks of the biotechnology product - not the process by which it is created." This principle echoes the ma jor conclusions of U.S. and internation al scientific panels (see above) and should be reflected in future refine ments of U.S. agencies' policies. 2. "For biotechnology products that re quire review, regulatory review should be designed to minimize regulatory burden while assuring protection of public health and welfare. " 3 . "Regulatory programs should b e de signed to accommodate the rapid ad vances in biotechnology. Performance based standards are, therefore, general ly preferred over design standards. " Another important milestone was the an nouncement in early 1 992 of the U.S. policy, "Exercise of Federal Oversight Within Scope of Statutory Authority: Planned Introduc tions of Biotechnology Products into the En vironment" , the so-called Scope Announce ment. It described "a risk-based, scientifically sound approach
to the oversight of planned introductions of biotechnology products into the environment that focuses on the characteristics of the bio technology product and the environment into which it is being introduced, not the process by which the product is created. Ex ercise of oversight in the scope of discretion afforded by statute should be based on the risk posed by the introduction and should not turn on the fact that an organism has been modified by a particular process or technique" (Federal Register, 1 992b).
All federal agencies' regulations and guide lines were then expected to move toward con formance with these principles. However, the requirements of U.S. regulatory agencies are currently in various stages of readiness - and conformance. The last major coordinated statement of policy by the federal agencies was published in 1 986 (Federal Register, 1986}. The presence of a new administration makes future developments and directions
difficult to predict, but there is little reason to expect progressive policies. In 1 987, USDA's APHIS (Animal and Plant Health Inspection Service) promulgated Plant Pest Act regulations specifically for or ganisms that have been manipulated with re combinant DNA (rDNA) techniques and that contain any amount of DNA from a plant pest. Organisms were covered even in the face of compelling evidence of the extremely low probability of transforming a benign or ganism into a pest (MILLER, 1 991; HUITN ER et al., 1992; HUTINER, 1 993) , and field trials or even the transport (say, from one laborato ry building to another) of organisms were subjected to a federal permitting process that included a comprehensive (and expensive) environmental assessment. In fact, all of the more than 1400 permits for field trials or trans port issued under these regulations have been for organisms of negligible risk. In late 1992, with this realization (and also in order to im plement the intent of the "scope" principles), the B ush administration sought to rationalize the APHIS rules. Accordingly, APHIS drafted a proposal to substitute notification to USDA to replace a permit under certain lim ited circumstances. The circumstances were so narrowly defined, however, that only a very few companies and almost no academic researchers would have benefitted. The ef fects of this proposal would have been merely the illusion of regulatory reform, the plight of researchers largely unchanged, and the vast regulatory bureaucracy undiminished. White House officials despaired early on of removing completely the rDNA focus of the regulations and eventually settled for small but significant changes that made the propo sal somewhat more risk-based and scientifi cally defensible, applicable to more research trials with more different species of plants, and that would have better encouraged in novative research. This proposal was pub lished on November 6, 1 992 (Federal Register, 1992a}. After the comments on the proposal were received and analyzed, the Clinton adminis tration had its chance to correct the half measures of the November 6 notice. But not only did they not correct the deficiencies in the proposal, they removed the improve-
4 The Status of Regulation in the
ments that had bee n wrought. O n March 30, 1 993 , the final rule was published ( Federal Register. 1 993a ) .
Regulation by the E PA has been in a mud dle for almost a decade . Manifestations of these problems i nclude the decision to classify as a pesticide the ubiquitous and innocuous ''ice-minus" Pseudomonas syringae. the one rous review to which it was subj ected ( K E Y STO N E NATION A L B I OTECHNOLOGY Fo R U M . 1 989) , and also the agency 's proposed policies. The E PA has put forth proposal after pro posal in which the scope of regulation - that is. whether or not a product fell into the regu latory net - has turned on the use of the new est and most precise genetic manipulation techniques (HoYLE. 1 993 ). This has occurred notwithstanding the wide scientific consensus and the official U. S . government "scope " pol icy to the contrary. and in the face of severe criticism of EPA 's policies i n separate reports by the U . S. N ATION A L B I OTECHNOLOG Y PO LICY BOAR D ( 1 992) and by the agency's own blue-ribbon panel ( E PA . 1 992) . EPA has seemed determined to eschew bona fide r i s k considerations i n favor of focusing on tech niques. Eventually. forced to a compromise by the Bush administration 's Office of Man agement and Budget. EPA did offer one ex plicitly risk-base d alternative (of three ) in its January 22. 1 993. proposed FIFRA (Federal Insecticide , Fungicide. and Rode nticide Act) rule (Federal Register. 1 993b ) . Predictably. EPA's preferred approach was not the expli citly risk-based alternative but one that fo cuses on organi�ms whose pestic i dal proper Lies have been imparted or enhanced "by the introduction of genetic m a teria l that has been deliberately modified " (emphasis added). In practice, this latter element is virtually syno nymous with "manipulated with recombinant DNA techniques" because organisms created with chemical or other mutagenesis would not be captured (gt·netic material is not consid ered to be introduced) and other classical techniques such as conj ugation or transforma tion are now seldom use d . A s poi nted out by DUDLEY ( 1 993 ) t h e re are also important pro cedural differences between the different al ternatives. and it should come as no surprise that EPA's preference is for a centralized ap-
United States
53
proach; that is. for essentially all rONA-ma nipulated biocontrol agents, the EPA would perform a review and decide on the applica bility of the burdensome experimental use permit ( E U P ) regulations. In contrast, the risk-based alternative is at the same time more scientific and more de centralized: the need for involvement of the EPA before a field trial depends on a variety of factors that are actually related to the risk of the product i n the environment in which it will be tested. The researcher, after consider ing EPA's risk guidance, is assumed to be in an appropriate position to judge whether the experiment meets the criteria that cause it to require a permit from the EPA (DUDLEY . 1 993).
The FIFRA rule represents another oppor tunity for scientific principles to determine public policy. but it seems a foregone conclu sion that in the final rule, the EPA will be permitted to adopt their preferred, central ized. technique-based approach. The research side of the Department of Agriculture appears to have abandoned its earlier intention to implement guidelines for field research ( Federal Register, 1 989). This leaves intact a "vertical" mechanism for over sight of research, with field trials subject to the jurisdiction of various agencies, according to the characteristics of the organism or its in tended use. For example. veterinary vaccines and plant pests would be subject to U S DA/ A PH I S , human vaccines to FDA, microbial _pesticides to EPA. and so forth. The FDA has imposed no new procedures or requirements for products made with the new biotechnology (MILLER and YouNG , 1 988) . For more than a decade. FDA has re garded the techniques of new biotechnology as an extension. or refinement, of older ge netic manipulation techniques; and the prod ucts of new biotechnology, therefore, have been subject to the same regulatory require ments and procedures as other products. In May 1 992. F D A published a statement of pol icy on the oversight of new varieties of food plants. FDA's regulatory approach identifies scientific and regulatory issues for which the developers of the new variety may need to consult with the agency. These issues are re lated to characteristics of foods that raise sa-
54
2 Concepts of Risk Assessment: The "Process versus Product" Controversy Put to Rest
fety questions and that elicit a higher level of FDA review. Such characteristics include the presence in the new variety of a substance that is completely new to the food supply, the presence of an allergen in an unusual or un expected milieu, changes in levels of a major nutrient, or increased levels of toxins that are normally found in foods. New food varieties without such potentially worrisome character istics are subject to an appropriately lower level of governmental scrutiny. The use of one or another technique of genetic manipu lation does not in itself determine the need for or the level of governmental review.
5 Implications for Public Policy
5 . 1 Important Non-Scientific Issues
Of concern to many practitioners, regula tors, and observers of biotechnology are four non-scientific issues that could play a pivotal role in the future of the new biotechnology's development and use in the United States and elsewhere. First, the regulatory climate could, if irrational or inappropriately risk-a verse, impede industry's eventual introduc tion of products now being developed. This obstacle could lead to future withdrawal or diminution of new product development, with continued reliance on less sophisticated, and often more hazardous, alternative technolo gies. Second, concerns within the financial com munity about the long-term stability and suc cess of companies doing business in environ mentally (over)regulated fields could depress the values of those companies, drying up cap ital for the continued development and test ing necessary to satisfy regulatory require ments (KINGSBURY, 1 986). Third, the genetic approach to crop im provement has resulted in tens of thousands of individual improvements in plants in order to overcome locally important constraints on crop production. These are typically "deliv-
ered" into practice in the form of locally ad apted crop varieties, an approach that will be not available to new biotechnology if the newer molecular methods of manipulation are subjected to an assortment of "case by case every case" regulatory disincentives. Fourth, the continued antagonism of a handful of well-organized and vocal oppo nents of biotechnology (a term that seems an oxymoron, like "opponents of antibiotics" or "opponents of tangelos") has had some ef fect. Their efforts have confused and misled the public, and diverted government agencies from their more constructive bureaucratic pursuits by forcing them to contend with nui sance lawsuits, petitions, and the like. Those who are responsible for regulatory policy toward biotechnology have a critical responsibility to act quickly and definitively to weigh the arguments and evidence - and to make those policy decisions that remain. With the accumulated wisdom of the analyses of the NAS, NRC, House of Lords Select Committee, and others (see Sect. 3 . 1 ) , the broad scientific questions have been resolved and the correct assumptions identified. The notion that the products derived from the new biotechnology defy useful, accurate risk assessment or are too dangerous to introduce into the environment is without merit: both theory and experience repudiate this asser tion. Policy must be guided in part by an un derstanding that there are genuine costs of overly risk-averse regulatory policies that prevent the testing and approval of new prod ucts. Real-world examples of these costs in clude the destruction of crops by frost while field trials of the obviously innocuous "ice minus" bacteria were debated endlessly; the continued application of chemical pesticides while new biological control agents lan guished untested for years (and some were abandoned completely in the face of regulato ry uncertainty or hostility); and the sluggish pace of development of rONA-modified oil degrading organisms, largely because of its overregulation. BENGT JONSSON is correct in stating that safety can only be bought at a cost (JONSSON, 1986), but one must wonder at the appropriateness of any "cost" - that is, whether we buy any true increment in "safe ty" - when regulators' resources are ex-
5
pcn d ed on such things as the
e n vi ron men t a l
Pseudomonas syrin gae, exte n d e d shclf-lit"c t o m a t o e s and petu nias of a n e w color. e ffects of the i c c -m i nu s
5.2 Real -World Effects o f Irrational or Excessive Regu la ti o n Conce rns about ove rregulation arc m o re than
theoretica l .
I n tern a t i onally.
h as been a h odge - p od ge ,
regula tion
and often excessiv e . A lthou g h J a p a n ' s r eg u l a t ory approach has been i ll ogi cal and p r oc ess- b ased . its restric tions on p h arma ce u t i ca l p r oduc t s made with the n ewest t e c h n ique s have seemed m e re l y annoying to i n d u s try rather than de b ili ta t i n g , and the new bio t ec h n ol og y applied t o phar maceuticals t h e r e h as s u s t ai n e d si gni fi can t progress. B ut some are as h av e u n do ubt e d l y been impeded by the g o ver n m e n t ' s convic tion that the ust· of rDN A t e c h n iques , per se, r a i se s new s afe t y issues. For example , d es p i t e a
medi cal and scientific i n frastructure that
could support cl i n ical trials of h uman ge n e th e r a py , no J a p a n e s e group is close t o m ovi ng into the cl i n i c, a n d n o t a s i n g l e company has been
created t h ere
with gene
therapy as
its
goal. By co n t rast . gene therapy tri al s are al ready un de r way i n the U ni ted States. Italy, France, the Netherlands. a n d China. with more t h a n 200 p a t i e n t s having been treated and t he nu mbe r s risi n g e x pone ntially.
5.2. 1 J apan Jap an ' s nology is
st i gm a t iza t i o n of the new bi ot e c h s i milarl y reflected in a gri c ul t u ral
biotechnology. O n l y three fie ld trials in J apan of re comb i n a n t DN A-manipulated p l a n ts (but no n e of m i croorganisms) have been car an d J a panese r e se a rc h
and d e v e l op be h in d what one would expect. The J a p a ne s e government has provided l i t tl e e ncouragement i n the fo rm of clear, p re d i ct a bl e , ris k-base d re gu l a ti on to those cont e m pl a t i n g fie l d tr i al s . M o re o v e r , ried out.
ment in t his
area
is far
t h e Jap a nese MIN ISTRY OF H E A LTH AND
WELFA R E
has i m p o se d a strict re g u l a tory re g i m e specific to foods a n d food addi
Implications for Public Policy
55
5 .2 . 2 Europe Den mark . t h e Federal Republic of G e rm a
ny. and the E ur ope a n Union (EU), for m e rly t he European Community (EC), are w i del y
perceived as h av i n g cre at ed po te n t re g ula to ry disincentives to the use of new biotechnology (European BioNews, 1 992) . Denmark's Novo/ N o rd i sk Industri, the world's largest p ro d uce r of enzymes, has th reat e n e d to move its re search a n d developm ent to Japan , and Ger many h as e x pe ri e n ce d a veritable hemorr
of research a n d d eve l o pm ent ( RAuCoN , 1 989). B a y e r AG h as co n ti n u e d to e stab l i s h research and d e v e l opme n t faci l i t i e s a bro ad , es pe c i a l l y in the U nited States and recently a l so in Japan ( Ba y er announced in Fe b ru a ry 1 993 its int e n t i o n to establish a Ce nte r for Al l e rgy Rese arch in Kansai Sc i e nce City that wou l d create 400-450 j o bs ) . BASF h a s s h e lved i n v e s t m e n t pl a ns for a $ 70 mil lio n re search a n d d e v e l op m e n t facility i n Ludwi gs hafe n and has e rected it n e a r Boston instead. Hoechst has d isc o n t i n ue d investments i n G er many an d expa n d e d their facilities in Austra lia, Japan and in the United States. A m i d sized co m p a ny , Wiemer P ha rm aze utisc h hage
Chemische Fabri k ,
has abandoned its bi o
pro d uct i o n a n d l iqu i d a t e d its e q u i p m e n t : Abbott Diagnostics in W i esb a d e n has p os t po n e d in d e fi n i t e ly its b i o technol ogy plans (RAUCON, 1 989) . The EU h as be g u n the i m p l em e n ta t i o n o f ex t r e m e l y regr e ss i v e d i r ect iv e s ( t h e e qu i v a l e n t of regulations in the U ni t e d States) for both contained uses an d plan n e d introduc tions of ge net i ca l ly modified o rgan i sm s into the environment (Nature, 1 990 ) . Str on gl y p roce ss-based , t h e d ire cti ve s' unde rl yi n g pre mises are scie ntifically flawed; they are ex pected to h i n d e r research and development activities t h r o u gh ou t t h e sc i e n t i fi c al l y and ec o n om i c a l l y advanced EU co un t ri e s ; and the d ir ec t i ve s ' pro v i s i o n s c o u l d po t e nt ia l l y be used to e rect non-tariff t ra d e barriers to for e i g n p rod ucts ( W A R D 1 993; YOUNG and MI LLER, 1 989) . The United States C o ngre s s' O ffi ce o f Te c h n o l ogy A s se s s m e nt rece n tl y t e c h n olo gy
publishe d this analysis:
{1 992)
tives m anu fa ct u r e d
with rDNA t e c h n iq ues.
'" I n enacting d i rectives that specifically regul ate genetically m od i fie d organisms, the EC
56
2
Concepts of Risk Assessment: The "Process versus Product" Controversy Put to Rest
has established a regulatory procedure that is significantly different from that of the United States. In the EC, regulation is expli citly based on the method by which the or ganism has been produced, rather than on the intended use of the product. This implies that the products of biotechnology are inher ently risky, a view that has been rejected by regulatory authorities in the United States . In addition, manufacturers are concerned that their new biotechnology-derived prod ucts may face additional barriers before they can be marketed, for the product may also be subject to further regulations based on its intended use" ( U. S . CoNGRESS, 1991).
For evidence of the wide-ranging, real-world impact of the EU's regulatory philosophy and directives, it is instructive to consider three news articles on a single page (page 684) of the 21 October 1993 issue of Nature. One arti cle, "German changes face opposition", de scribes the futile struggle of Germany, with one of the most restrictive rONA regulatory regimes in Europe, to liberalize its law even in small ways. (However, many observers be lieve that even if this attempt were successful, it would be too little, too late for German bio technology.) A second article, "Biotechnolo gy rules: Spain falls into line," describes Spain's attempts to discharge its responsibili ties to the EU directives by crafting a new law focused on rONA. These attempts seem to have alienated vi r t ua lly every part of the gov ernment and society that is involved. Finally, "UK report criticizes EC directives" describes the recommendation of the House of Lords Select Committee on Science and Technology for essential and fundamental changes in the "excessive regulation" that emanates from the EU directives (see below). Responding to widespread criticism of the biotechnology directives from both outside and within Europe, the EU established in March 1 991 a new high-level "interservice group" , the Biotechnology Coordination Committee (BCC) , to oversee EU biotechno logy policy. According to an EU press release (number 1P(91) 277 , March 1991) , the main tasks of the committee will be three-fold: to examine new initiatives made by the Commis sion's services and to prepare the Commis sion's final decisions; to convene, as neces-
sary, discussions among the Commission, in dustry, and other interested parties; and to "evaluate the existing Community policy on biotechnology " (emphasis added). The ac tions of the B CC may mitigate to some de gree the full potential negative impact of the directives, but there has been little evidence of its influence. Another spur to needed changes in the EU directives may be the October 1 993 report of the UK House of Lords Select Committee on Science and Technology, "Regulation of the United Kingdom Biotechnology Industry and Global Competitiveness". Echoing other as sessments of the EU's approach to biotechno logy, the report excoriated the EU's regulato ry approach to both contained uses and field trials of organisms and recommended re d uced and rationalized regu l at i on (WARD, 1 993): "As a matter of principle, GMO-derived products should be regulated according to the same criteria as any other product . . . U.K. regulation of the new biotechnology of genetic modification is excessively precau tionary, obsolescent, and unscientific. The resulting bureaucracy, cost, and delay im pose an unnecessary burden to academic re searchers and industry alike."
5.2.3 The D eveloping World: Especially at Risk
The prospect of gratuitous or excessive reg ulation of the new biotechnology is especially ominous for the developing world. As de structive as overregulation and specious ap pro a ch e s to oversi gh t have been to technolo gically advanced countries (see above) , lesser developed countries, which often lack ade quate resources for the regulation even of products that are known to be hazardous, are less able to absorb such excesses. If they are compelled (or feel compelled, which is much the same thing) to establish a regulatory ap paratus specifically for "GMOs" (genetically modified organisms, i.e., defined as those ma nipulated with rONA techniques), such coun tries are likely to have greatly reduced access to such products. A reduced array of techno!-
5 Implications for Public Policy
ogies or products for local producers and con sumers spells more limited environmental and social opt ions. Proposals such as the UNIDO ··code of conduct'" ( Biotech Forum Europe. 1 992) for field trials of G M Os and the .. safety provisions·· in Article 19 of the Convention on Biological diversity - if they are focused on GMOs - are a lose-lose-lose proposition, particularly for those whose re sources are meagre: they waste resources di rectly on gratuitous bureaucracy: provide dis incentives to developing countries· perform ing R & D the mselves: prevent developing countries from becoming real partners in the commercial ent erprise : and send inaccurate messages to the i r public and their politicians about risk and. most especially. about relative or al ternative risks. In view of the scientific consensus that "' GMOs'" are not conceptually distinct from ot her organisms, whether wild type or manipulated with other techniques (NRC, 1989). it is difficult to defend the es tablishment of elaborate regulatory mecha nisms to evaluate ..case by case every case" the field trials of GMOs in countries that lack
57
adequate oversight of vaccines, pesticides, toxic chemicals, plant pests and other patho gens. For example , one difficult-to-reconcile outcome of a process-based regulatory ap proach could well be a regulatory net that re quires governmental risk assessments of ev ery rONA-manipulated plant but omits scru tiny of field trials with "natural " organisms such as Bacillus an thracis, foot and mouth dis ease virus (FMDV), or an invasive plant such as bamboo or kudzu, even if these have been genetically manipulated with older, cruder techniques.
5 .2.4 The U nited States Investor confidence in two of the sectors of U.S. industry that use the new biotechnology,
namely biopharmaceuticals and agriculture, provides a measure of the effect of excessive regulation (see Fig. 2). Over the period 1 9831 992 investor interest in the biopharmaceuti cal sector was strong, outperforming the mar ket by about 200% . By contrast, the agricul-
Biotech nology Biopharmaceutical & Agricultu re Segments Relative Performance vs . S & P 500 I ndex �-------.---,�� 360
Jan 1 983
=
1 00
l-----!11----+ 340 1--IIH---+ 320 1---t-++--+ 300
1--++t-....-iH- 280 1-++-t�H- 260
1--1-+----+ 240
1--f-+----+ 220
Fig. 2. Relative perform
tf---+----+ 200
ance of two sec t o rs of U . S.
industry using t h e new bio
11----+-----+ 1 80
technology. The �hare
weighted stock performa nce of companies n or m a l ized to Standard and Poor 's 500 I n d e x is grouped by biophar maceuticals (98 com panies). and agriculwre ( I I compa· nics). The i ndice�- were set at 100 for J a n u a r y 1 983. ( D ata from L . I. \f i LLER. PaineWebber. I n..: . ) .
1-----1---+ 1 60 �--+---+ 1 40 1--+---+ 1 20
1--+---+ 1 00
.......-:=:-:=-.
1-----4.::-----1- 80
L....o<.-'-+_.;.;.-'-' 1---F-t�-=-+ 60 \.-JI"L---+----+ 40 ��������mmffiffi� 2o 1 983
1 984
1 985
1 986
1 987
1 988
1 989
1 990
1 99 1
1 992
58
2
Concepts of Risk Assessment: The "Process versus Product " Controversy Put to Rest
tural biotechnology sector performed dismal ly and, despite stunning breakthroughs in the relevant basic science, actually underper formed the marked by about 20% . One reason for this disparity is certainly the marked difference in the regulatory mil ieus. The FDA adopted a scientifically rea soned policy that regulates new biotechnolo gy-derived products no differently from other products, approved approximately 20 drugs and biologics in significantly less than the usual approval times, and permitted more than 1 500 clinical trials of such products. By contrast, field testing of new biocontrol and other agricultural products have faced addi tional regulatory requirements because rDNA techniques were employed, as well as much-publicized regulatory and judicial de lays. Not surprisingly, private sector investors have shown reluctance to gamble funds on re search and development in an area where the climate is inhospitable - where it could take years as well as millions of dollars simply to perform a single field test, let alone meet the requirements for marketing approval down the road, and where virtually every experi ment requires government intervention and unnecessary delays. Another U.S. example of the problems of overregulation is to be found in the state of Wisconsin, where by 1988 the prospect of months of regulatory paperwork to obtain ap proval for a single field trial was causing in vestigators, especially young untenured aca demic researchers, to shy away from research areas that require field testing ( The Capital Times, 1 988). A 1989 survey of agricultural research in the public and private sectors un covered a similar problem. Approximately 1 0 percent of the researchers i n the public sector (nonprofit institutions, including universities) and 20 percent in the private sector had ac tually developed organisms with the new bio technology but had elected not to proceed with field trials; three-quarters of these re searchers cited reasons related to governmen tal re g ula ti on as the reason for not proceed ing (RATNER, 1 990) . Thus, whole areas of research that could ultimately provide useful products, ranging from growth promotants to microbial biocon trol agents and biological treatments for toxic
wastes, are being systematically avoided . In addition, some companies have felt com pelled to eschew the newest and most precise techniques of molecular genetic engineering in favor of scien tifically inferior b u t bureau cratically favored - in other words, less strin gently regulated - techniques for constructing organisms for agricultural applications (U.S. BIOTECHNOLOGY NATIONAL POLICY BOARD, 1 992 ; Wall Street Journal, 1 989). These are the fruits of disincentives to the ap plication of the new biotechnology.
5.2.5 Serious Flaws in a
" Horizontal" Approach to
B iotechnology Risk
Irrational regulatory policies are not the only unfortunate legacy of what has been termed a "horizontal" approach to biotechno logy risk - that is, "a fallacy based on scan ning across experiments whose only common element is the use of the same genetic modifi cation technique " (MILLER a n d GUNARY, 1 993) . This misconception has, in recent years, dictated the theme of major confer ences and a survey of field trials of rDNA modified organisms commissioned by the Or ganization for Economic Cooperation and Development (OECD). More such dubious exercises are planned. However, given the kinds of organisms that have been modified and the traits introduced, one might as well survey all experiments that were performed using plastic, as opposed to glass, pipettes; or ones that were begun on certain days of the week. In addition to stimulating irrational public policies and superfluous conferences and sur veys, there is evidence that the horizontal ap proach to biotechnology risk also encourages the wrong kinds of risk assessment experi ments. Consider, for example , the elaborate risk assessment experiment performed by CRAWLEY et al. (1 993), "to fi n d out how eco logical performance is affected by genetic en gineering". Conducted in three climatically distinct sites and four habitats, the experiment com pared the invasiveness of an "unmodified"
5 Implications for
variety of oilseed rape with two variants of the plant manipulated with rONA techniques to confer herbicide or antibiotic resistance. Some of the significant limitations of this well executed but poorly designed experiment were described in a commentary i n the same issue of Nature ( K A RE I V A . 1 993 ) . Indeed, there is little reason to anticipate that. in the absence of the herbicide or antibiotic to which the modified plants were made resist ant, selection pressure would favor the rONA-modified forms. And one observed difference, reductions in s ee d survival in the modified plants. cannot be at tr i b u ted unequi vocally to the genetic modification, because of the presence of maternal effec t s and other variables. The absence of unexpected persistence . in v asive n e s s , or ge n e transfer in field trials with rDN A-modificd plants that have been pro t ect e d against interpolhnation with related crop or wild plants does not indicate that an incorporated trait may not under specific cir cumstances be hazardous. A rigorous demon stration that an rONA-modified plant pre sents a different degree of hazard from a new non-rONA-modified variety of that species ( or plan t s of that species in regular use) must entail experime nts that provide reasonable opportunities for the manifestation of identif ied hazards. The performance of such a well executed but poorly designed risk assessment experi ment, "one of the most comprehensive popu lation studies ever undertake n in plant ecolo gy " ( K A REIV A. 1 993). makes one wonder whether the real purpose of the study was more ecological public relations than scien tific enquiry. I n any case . i t seems unlikely that an experiment of this design and magni tude could have been performed in the ab sence of confusion over whether to focus on the traits newl} introduced into t he plant or the technique used for genetic manipulation. Additional. second-order effects of inaccu rate and over\} risk-averse messages extend more broadly to science and technology. Do N A LU K E N N E D Y ( 1 987) has warned that vital research is already curtailed in research insti tutions in parts of the United States. He pointed out that the anti-research m o v e m e n t whether from c o nce rn for laboratory animals .
Public
Policy
59
or from fear of scientific experimentation, had delayed the opening of Stanford's com pleted $ 1 3 million biomedical research facili ty and had declared war on others planned at the U niversity of California and elsewhere. K E N N E D Y asked rhetorically where this op position expects society, without such facili ties, to find cures for AIDS and other scourges.
5 .2.6 A Ca veat for Policy Makers FREEMAN DYSON ( 1 975) has observed as tutely that resisting a new technology is gen erally safer for regulators than embracing it, but that this course often has larger costs for society. Ultimately there is no real alternative but to try to channel and control new technol ogies, with only that amount of governmental intervention that is necessary and sufficient. One cannot attempt to avoid problems with new technology by resisting it, by trying to stuff the genie back into the bottle. For these reasons. the professional practi tioners and regulators of t h e new biotechnol ogy must strive to demystify it and to provide an accurate perspective for the public, be cause it is the public who will benefit most. The stakes are high in terms of both econom ic and social be n e fi t In recent years the FDA has approved several products of new bio technology that are medical milestones. These include alpha-interferons for the treat ment of a lethal leukemia, beta-interferon for multiple sclerosis, a monoclonal antibody pre paration for preventing the reje c t i o n of kid ney transplants, a new-generation vaccine for the prevention of hepatitis, a hormone that reduces the blood transfusion requirements for kidney dialysis patients, and a growth fac tor that is an important adjunct to cancer che motherapy. Among myriad other applica tions. biotechnology promises improved diag nostic devices for detection of harmful che m i cals and pathogens; vaccines against scourges such as malaria, schistosomiasis, and AIDS; as well as new therapies that could ameliorate or cure for the first time such genetic diseases as cystic fibrosis and certain inherited im mune deficiencies. Used for new generations of medicines and food plants and animals, .
60
2
Concepts of Risk Assessment: The "Process versus Product" Controversy Put to Rest
biotechnology could provide partial solutions to the trinity of despair - hunger, disease, and the growing mismatch between material re sources and population. Finally, far from constituting an imminent threat to the environment, application of the new biotechnology may well provide solu tions to existing environmental problems. For example, more efficient crop plants require a smaller commitment of land to agriculture, freeing it for recreation or for a return to wilderness; plants can be engineered that diminish the overall need for chemical pesti cides and fertilizers; herbicide-resistant plants can offer farmers more choices, favoring the use of herbicides that are less suspect than those used now with some crops; microorgan isms can be engineered to degrade toxic com pounds; and biological control agents are likely to reduce costs and to be more predict able and safer than many chemicals.
6 Conclusions Biotechnology has been widely applied for millennia, including many successful and ben eficial uses that require introductions into the environment. In recent decades, the precision and power of the genetic manipulation of both macroorganisms and microorganisms have greatly increased with the development of molecular genetics. The techniques of the new biotechnology are best viewed as exten sions, or refinements, of older techniques for genetic manipulation and domestication. For these reasons, there exists a broad scientific consensus that current risk assessment meth ods are suitable and applicable for the fore seeable applications of the new biotechnolo gy, and that new products manufactured with the new processes do not necessarily require new regulatory paradigms. There is no scien tific rationale for fear or avoidance of the ne west techniques of genetic engineering or, in deed, of nonpathogenic, nontoxigenic organ isms that have been modified by any tech nique. Likewise, there is no rationale for pub lic policies that create disincentives to re search and development using the newest,
most precise techniques; or that send inaccu rate messages to the public via discriminatory regulation, product labeling or other means. Moreover, there are genuine costs of over ly risk-averse regulatory policies that impede or prevent the testing and approval of new products. Such policies are anti-innovative, and they delay the benefits of new products to the public. These policies both emanate from and feed into a pernicious anti-science movement that threatens basic as well as ap plied scientific research. Much of the anti science and anti-technology movement has less to do with concerns about safety than about attempting to arrogate control over re search and development strategies and over consumers' choices. The long-term antidote to both the public misapprehensions about biotechnology and to the ( modest ) successes of the antagonists of science and technology has two parts: first, improved education of consumers and, espe cially, public opinion leaders, about science, technology, and the basic aspects of risk anal ysis; and second, the establishment of rational public policies that are consistent with sound science. MAX PLANCK said more than half a cen tury ago that an important scientific innova tion rarely makes its way by gradually win ning over and converting its opponents; rath er, its opponents gradually die out and the succeeding generation is familiarized with the idea from the beginning. It would be tragic if this were the fate of the new biotechnology, for it would result in prolonged delays in the widespread testing and use of valuable new products. Acknowledgements This chapter is dedicated to the memory of Professor BERNARD D. DAVIS. The author would like to thank Professors JAMES CooK and ARTHUR KELMAN for their comments on this manuscript.
7
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BioteclllloloKJ
Ed i ted by ,H.-J. Rehm and G. Reed i n coo p eration w i th A. Puhle r and P. Stadler Copyri�ht © VCH Verla� s�esellschatt mbH,1995
3 Biosafety in rDNA Research and Production
DIETER B RAUER Frankfurt am Main. Federal Republic o f G erm a n y
MICHAEL B ROKER Marb urg.
Federal Republic of
Germany
CORNELIA KELLERMANN Martinsried. F e der a l Republic of Germany
ERNST-LUDWIG WINNACKER Martinsried. Federal Re p u bl i c
1 I ntroduction 65 The Development of Molecular Biology 3 Determinants of Pathoge nicity 66 4 Pathogenic M icroorgan isms 7 1 4 . 1 B acteria 73
2
4.2
Viruses
74
Fungi and Parasites 7 6 5 General A ssessme nt of B i o s a fe t y 77 6 Species-Specificity of G e ne s 7 '13 7 Gene Tran s fer Mechanisms '130 8 The Escherich ia coli Bacteria '134 '13. 1 Pathoge n i c i t y of Escherichia coli 4.3
65
'134 '13.2 Escherichia coli in the Environme nt 86
of
G e rma n y
64
3 Biosafety in rDNA Research and Production
9 Risk Assessment of Recombinant Saccharomyces cerevisiae 86 9.1 Survival in the Environment 87 9.2 Saccharomyces cerevisiae A Non-Pathogen 88 9.2.1 Colonization of the Human Gut 88 9.2.2 Possible Signs of Pathogenicity 89 9.2.3 Allergy 90 9.3 Plasmids and Gene Transfer 91 9.3. 1 Expression Plasmids 91 9.3.2 Gene Transfer 93 10 Biosafety Aspects of Animal Cell Cultures 94 10. 1 Risks Associated with the Transformed Character of Tissue Culture Cells 10.2 Contamination of Cell Lines with Viruses 97 1 0.3 Safety Aspects of Viral Vectors Used in Eukaryotic Tissue Culture 98 10.3 . 1 Vectors Derived from Poxvirus 98 1 0.3.2 Vectors Derived from Retroviruses 98 10.3.3 Vectors Derived from Adenoviruses 99 10.3.4 Adena-Associated Viruses 100 1 0.3.5 Vectors Derived from Herpes Viruses 1 00 1 0.3.6 Vectors Derived from Bovine Papilloma Virus 100 1 1 Risks of Genetic Engineering: Facts and Fiction 101 12 Conclusions 104 1 3 References 1 04 -
95
2 The
1 Introduction M ode rn bi ot e c hnology represents the most e x citi n g
advance in the biologi c al sciences this century. Particularly genetic engineeri n g opened up compl e tely new horizons for gen eral basic research in biological systems which subseque n t l y are bound to be followed by new prospects for medical . agricultural and industrial app l i c at io n s . However. biotechnol ogy is not in itself a science . an i ndu s try nor a product but a powerful set of tools which is in cre asi n gl y used to d e v e lop processes and to manufacture many pr o d u c ts for every-day use or consumption as we l l as for industrial uses. Much of the current confusion and lack of policy cohe r en c e arises from the tendency to think of biotechnology as fundamentally dif ferent from other t e ch n olog ie s and therefore requiring special rules pa r ticula rl y with re spect to biosafety issues. This equal l y con cerns the han d l i n g of recombinant o rga n i s ms in the laboratory and production fac i l i t y . con sumption or use of products from such pro cesses and the d e l i bera t e re lease of o r ga n i s ms into the environment with the obj ective of their survival therein. While al l regulat i o ns of modern biotechnology worldwide differen tiate and ther e by exclude a pp l i c at io n s of non recombinant methods like d iagno s is "in vi rro" fertilization o r e m bry o s plitting correctly. the interest groups profoundly host ile to bio t ec h n ology continue to scramble up all appli c atio n s and construct horror scenarios well received by parts of the media. This chapte r will focus on biosafety issues which are relevant to the handling of micro organisms in "'contained use·· and t h e re by re view the experience accumulated in bot h mi crobi o l o gy and molecular biology which is the basis for the a ss e ssm e n t of b iologica l risks o f organisms co n t a in i ng recombinant D N A mol ecules ( the widely u sed t e rm · · recombinant orga nism is ac tu al l y misl eading a n d should only be used fo r organisms p ro d uced by cell fusion techno l o gy ) While for "'naturally·· oc cu rr i n g organisms. and particularly pathogen ic m icroo r gani s m s much scientific knowledge has accumulated si nce the end of la st century. the ··safety issues·· of the debate on '"recombi nant DNA technology·· ( to be differentiated .
Development of Molecular Biology
65
from t he '"socio-economic" issues) was and still is largely based on the presumption th a t recombinant organisms are "unique " . While the scientific com m u n i t y in vain tried to falsi fy t h is view. it w as taken up by the media and particularly by the European environmental agen ci e s and the E u ro pean political establish ment re s u l t i ng in regula t i o n s specific for the application of recombinant DNA t ec hn ology instead of more appropriately int roducing regulat i on s for operations with pathogenic or ga n i s ms and biological e ntities potent i al l y harmful t o parts of the environment as well as product approval systems evaluating the safe ty of biological products primarily by their properties and not by the methods they are manufactured. Consequently. ass e s s m e n t pro cedures were int rodu ced which allow the comparison of a recombi nant o rga n ism with its non-recombinant wild type or comparable non-recombinant organisms. This leads to a classification of the re co mbinant organism either to be harmless or to be classified into one out of the three risk groups (three is the highe s t risk group) which are used for the classification of na t u r a ll y occurring pathogenic m i croo rga m sm s S a fety issues related to food and p h arm a ceutical products and the deliberate release of G M Os are treated in different chapters in this volume.
.
-
..
.
.
2 The D evelopment
of Molecular Biology
Biotechnology is best characterized as a n interdisciplinary issue and can be defined as fol lows (SAG B. 1 990): B io tec hn o logy· refers to the applica of l i v i n g organisms and their ce ll u l a r . subcellular or molecular compo nents to create p r oducts and p r o cesses
'"
·
tion
.
Modern b i o t echn o log y and i n pa rt i c u l a r genetic enginee ri ng stems from k n o wledge and methods developed in different areas of research like m icrobiology (bacteriology and .
,
66
3 Biosafety in rDNA Research and Production
virology), cell biology, biochemistry and oth er specialist fields. Since GREGOR MENDEL discovered the basic principles of the laws of heredity in 1866 (published under the title "Experiments with Plant Hybrids") and DARWIN's discovery of the evolution of organisms, the prime goal of basic research in biological science has been to find out what these hereditary characteris tics and their relation to the evolution of or ganisms actually are and how they work. Ulti mately, this scientific quest aims to under stand life; at least its biological basis. Although deoxyribonucleic acid (DNA) was discovered by MrESCHER long ago in 1 869, it still took another 75 years for detect ing the functional relationship between DNA and the genetic properties of living organisms by AvERY (1944). Once it had been demon strated that the chromosomes located in the cell nuclei are the carriers of hereditary infor mation, WATSON and CRICK succeeded in 1 953 in making the pioneering discovery that DNA consists of two molecular chains in the form of strands which are arranged in a heli cal structure as a double strand. Since JACK SON, SYMONS and BERG (1972) first con structed a DNA molecule which was capable of multiplication ("recombinant" plasmid) , genetic engineering i s the major contributor to the dramatic progress in understanding biological systems in molecular terms and for unique applications from industrial processes to medical therapy. As the genetic engineering methods can be rapidly understood, learnt and put to practi cal application using excellent manuals (Aus UBEL et al. , 1 989) , they will not be presented here.
3 Determinants
of Pathogenicity
Before organisms and the work to be con ducted with them are allocated to a safety lev el, a risk evaluation must be conducted. This implies that it is necessary to define exactly what actually a pathogenic microorganism is: namely an organisms which is known to be
able to cause a disease (or diseases) in hu mans, animals or plants or for which there is a well-founded suspicion that this may be the case. An important subject in this context is the measurement of pathogenicity because, in a strict sense, the term pathogenicity has only a comparative and no absolute meaning. Therefore, because one microbial population can be more pathogenic than another and standard species or strains are not defined (nor seriously can), pathogenicity often can be compared only by inoculating animals with graded doses of the respective strains until a disease is detected. However, species differ ences, location of (primary) infection and the general health "status" of the animals are dif ficult to compare. Not surprisingly therefore, reliable methods for growing and quantifying the pathogens or valid animal models often are not available. For the classification of pa thogens, some general aspects need to be con sidered for the evaluation and in this context are: - The quantification of the inoculum (in fectious dosis) which is relatively simple to determine for many bacteria but less satisfactory for viruses and fungi. Addi tionally, the route of inoculation (e.g., by aerosol or intraperitonial) often af fects both the necessary dosage and vi rulence itself. - The comparison of pathogenicity be tween species is almost impossible in quantitative and qualitative terms, when, e.g., the influenza virus causes a respiratory disease in ferrets and the Iassa virus produces a hemorrhagic fev er in mice or rabbits (these are the standard animal models). - The ideal test animal is a natural host, which essentially only applies to veteri nary diseases. The choice of experimen tal animals with similar disease syn dromes is often difficult to achieve, and primates are usually not available for many studies: while there is no good animal model available for human mea sles, the aerosol infection of guinea pigs with Legionella pneumophilia is a good model of the respective human pneu monia (regarded as zoonosis), and the
3 Determinants of Pathogenicity
oral infection of primates with Shigella spp. mimics the human bacillary dysen tery (shigellosis). - The in-depth analysis of the multifacto rial nature of pathogenicity, e.g., with respect to mucosal infection and inva sion, multiplication in or outside cells, evasion of host defenses like phagocy tosis or complement action, immunopa thology etc. has progressed much fur ther with bacteria than with viruses, fungi or parasites. - Pathogenic determinants can be identif ied by either chemical mutation and biochemical purification or by genetic modification. However, with respect to the isolation of surface markers it must be kept in mind that such markers are not necessarily identical with the deter minant(s) of pathogenicity. Only the use of the recently developed genetic engineering methods allows the analysis of individual pathogenic determinants, e.g., by cloning a determinant from a pathogenic strain into Escherichia coli and subsequently reintroducing the de terminant into a deficient strain thereby eventually reestablishing "natural" pa thogenicity. In addition, for the demon stration of its biological significance, the cloned determinant can be easily mutated in vitro with a concomitant loss of its biological properties. During the last 20 to 30 years much knowl edge for many pathogenic species has accu mulated on the multifactorial nature of parti cularly bacterial pathogenicity, and numerous components of pathogenicity have been iden tified and probed. A good example may be the following collection of pathogenic deter minants of Vibrio cholerae, which may not even be comprehensive (MDLLER, 1 992) : •
•
• • •
•
one heat-labile and one heat-stable toxin one hemolysine one N-acetylhexose aminase one neuraminidase one nicotinamide-adenine dinucleoti dase several proteases
• •
•
67
fucose- and mannose-sensible hemag glutinins "outer-membrane" proteins and motile flagellae.
Since these pathogenic determinants will not have developed to have pathogenic ef fects on the human intestine, their natural and ecological functions have to be inter preted with respect to the natural niche of Vi brio cholerae, which is the colon and exoskel eton of crab species. This means that this hu man pathogen may be a harmless facultative or even obligate parasite in lower crustacea (Huo et al., 1 986) and underlines the intro ductory remark that pathogenicity is not a strict but relative term. It remains to be seen what the functions of such determinants in their normal niches real ly are. For legionellas it was found that the normal ecology as well as pathogenicity coin cide: Namely the ability to multiply intracellu larly within free-living amoebas in the same manner as in human leukocytes within the human lung causing pneumonia. Insofar, lis terias and "atypical" mycobacteria may exhi bit similar patterns. With respect to an understanding of patho genicity it is certainly helpful to distinguish "obligate" pathogens such as Vibrio cholerae, Shigella spp. or Salmonella typhi (each carry ing specific pathogenic determinants) from "facultative" pathogenic organisms such as Pseudomonas aeruginosa, certain streptococci or E. coli. While the presence of the classical pathogenic agents in water, food or even in feces may present a high risk for the commu nity, the latter " intestinal " organisms belong to the natural flora of the human body or to those microorganis�ns which are typically found in the environment. Furthermore, it must be kept in mind that particularly feces may contain microorganisms which can be highly pathogenic to the host if introduced parentally into the host (e.g. , Clostridium te tani via injury). These ubiquitous "faculta tive" pathogenic organisms only rarely devel op strains with pathogenic determinants and mostly may cause mild infections only under certain unusual conditions. Well known are also "opportunistic" ente ropathogenic bacterial strains which usually
68
3
Biosafety in rDNA Research and Production
do not cause infections except in. e.g . . immu no logi ca l l y co mpro m i se d HIV patients (RuF and PoH LE, 1 989). Ubiquitous microorgan i s m s, such as some " a t y p ica l '' strains of Myco bacterium. Salmonella. Sh ig ella. Campylo bacter, Clostridium . and some fu n g i . which
were re po r t e d to use the o p po rtu n ity to colo nize and propagate in the immunocomprom ised body w h at they can no t in he a l t h y pa tients. While these i n fe c t i o n s usually a re ac cessible to, e.g .. an t i b i o t i c th e rapy , infections recur frequently. H ow ev er , it must be stressed that wh i l e such "se c ond a rv" infec tions with opportunistic pathogens can be ob served, th e often lethal infections in HIV pa tients are not caused by t hese opportunistic patho ge n s but by s i mul tan e o us infections with pathogenic organisms ( e . g . . cau s in g pn eum o n i a or i n fl u e nza ) . It is n ot ewort h y to m e n t i o n , t hat E. coli . which may cause g a s troi ntesti n a l i n fections in h e a l t h y p at i ent s . are not sig n i fi c a n t in such o pp or t un i st i c infec tions, and that microorganisms s uc h as Sac charomyces cerevisiae. Bacillus subtilis and others, which are classified as non-pathogens. ha v e not been i d e n ti fi e d as oppo rt u n i s t s i n these i m m u n o c o m p r o m i s ed p a t i e n ts. Last but not least the infectious d o s is . i.e . . the number o f pa t hoge n i c organisms neces sary to e st a b l i s h a disease. is re l ev an t for the classification of pa th ogeni c it y . which r ange s from about 3 cells for Rickettsia tsutsugamu shi or 1 80 cells for Sh igella jlexneri to lOx cells for Vibrio r.holerae. For further d et a i l s con c e r n i n g issues re l e vant to pathogenicity. the interested reader is re fe rre d to the literature {SMITH. 1 988; F I N LAY a n d FALKOW. 1 989 ). In conc l us ion , the feasi b l e but difficult task is to c lassify pa t h oge n icity via the observation of prevalence. du r ati on and severety of the di se ase prod u ce d by t he different species in man and comparing this w it h the i nfectious dosis determined i n a ni ma l models. With re spect to risk assessme nt, bey o n d the classifi cation of pa thog e n i c organ i s m s additional cri teria like the a v ai l a bi l i t y of cures (e . g . . a nti bio ti cs ) or p re v e nti ve measures (e.g . . vaccina tion) need to be i n s pe c t e d and valued. While t h e criteria and a spe c t s outlined a b o v e apply to p a th o gens o n l y. more than 80% of the res e arch work conducted world-
us e s n o n - pat hoge n ic o rgan i s m s such as K 1 2 . S. cerevisiae, B. s u b tilis or Strep tomyces spp. For production purposes there is a clear priority to use non-pathogenic o rgan isms be c a u s e of the safety for workers c ons id erations. investment costs and p rod uc t safety validation. However. there exists am p l e e x pe ri e nc e with "classical" prod uct ion s using pathogenic microorganisms for tox i n prod uc tion (e.g., pe rt us s i s t o x oid p r od u ce d by Bor detella pertussis ) or the p ro d uc t i on of " ina ct i vated" v ac c in es (e.g .. rabies) with excellent safety records for both workers and the popu lation (Tab. 1 ). In July 1 97 4 . a comm i t t e e of p rom i ne n t scientists i nvol v e d in r ON A research called for a temporary worldwide mo ra tori um on certain types of recombinant experime n t s and also called for an int er n a t io n a l conference on potential biohazards { fo r review see OT A R E PORT. 1 98 1 ) . In response to this in iti a t i ve of the involved scientists. t h e NIH established the rONA Ad v i s o ry Committee ( RAC) on 7 October 1 974. and an international c on fe r ence was h e l d at the Asilomar Conference Center. Pacific G rove . California, in Fe b ru ary 1 975. As a consequence of these activities, the NIH G U I D E L I N ES FOR RESEARCH INVOLV ING RECOMBINANT DNA MOLECULES w e re established in 1 976, revised in 1 986 and ex panded for large-scale uses in 1 991 . It sho ul d be noted that t he N I H Guidelines r egu l a t e a p p l ic at i on s with " recombinant molecules" and " o r g a n i sms c o nta i ni n g recombinant DNA molecules" i n s te ad of us i n g the rather inaccurate or vague term " ge ne t i c all y modif ied org a nism " used by the EU D I R E<.TIVES wide
E. coli
( 1 990).
As ti me p a ss ed , it be ca m e clear that the in itial worries about certain risks of rONA re search were greatly overstated, and in p a rt i cular no evidence has been brought forward u nt i l t oda y which would support the early risk scenarios. While this a s s e ssm en t is based on general experience. this v ie w was further sup ported by ex p e ri m e n t s designed to e xp lo r e risks of rONA ex pe r i m e n t s ( I S R A E L et a!. , 1 979; C H A N et al ., 1 979): In a series of e xp e ri ments polyoma virus DNA was cloned into b ac t e ri al vectors. Neither the recombinant DNA molecules ( "' naked DNA'') nor E. coli K 1 2 ce ll s carrying t h e s e v ec t ors c a u sed v i r a l
3 Determinants of Pathogenicity Tab. 1. V accines for I n fect ious D iseases
in
H u m a n s and Fermenter
V o l um es
Used
in
69
Indust rial
Fe rmenta tions
Bacterial Diseases Diphtheria
Tetan us
Pertussis
Typhoid fever
Pa ratyphoid fever
Cholera
Plague Tube rculosis
Meningitis Bacterial
pneum o n i a
Typhus fever
Leprae
Ferrnenter Volume (L)
Toxoid Toxoid
300 700 600
Killed Bordetel/a pertussis
Killed Sa lm o n ella typhi
Killed Salmonella paratyphi
K i l le d/ext racts Vibrio clwlerae Killed/ext racts Yersinia pestis
Attenuated Mycobacterium tuberculosis Polysaccharide fr o m Neisseria meningitidis
Polysacch aride from Haemophilus influen z a e
Polysaccharide from Streptococcus pneu m o n iae
4000 4000 300 < 300 < 300 1 000 300 1 00
Killed Rickettsia prowazeki
e gg armad illo
Killed Mycobacterium leprae
Viral Diseases A t t e n uated virus
calf
Yellow fever
same
e gg cell c ultu re
M umps
same
cell culture
same
cell culture cell culture
A t t e n uated or inactivated virus ( Salk }
e gg cell culture
Smallpox Measles
Rube lla Polio I nfluenza Rabies
same
A t t e n uated ( Sa b i n ) or inact ivated virus
I n activated virus
infections nor tumors in mice. Mos t s i g n ifi cantly, while it has long be e n known that mammalian ce lls can take u p DNA ( G R O N EN BERG et al.. 1 975 ) . b io l o gi c a l effe c t s d e pe n d on the n a t ure of t h e transmitted DNA: baculovirus DNA is not transcribed and rap idly eliminated from mammalian cells (CA R BON ELL and M I LL E R , 1 9 8 7 ) . while the i njec tion of v-onc DNA into a n i mals ( B U R N S et al., 1 99 1 ) may induce tumors similar t o natu rally occurring infections w i t h o nco ge n i c vi ruses . Th ese observations have led to recom mendations for the p r ot e c t i o n of l ab o r at o ry p e rsonn el to apply certain laboratory prac tices w h i le ha n dl i n g potentially o nco ge n i c DNA (ADVISORY COM M I TTEE ON G EN ETIC MOD IFICATI O N . United Kingdom. 1 990). Howeve r , the accumulated know le dge clearly indicates that cloned pat h og e n i c viral D N A bears no increased hazards in com p a riso n to the uncloned viral DNA i t self. Any number of s c i e ntifi c e x pe r im e nts may prove that no ge n e r a l or u n i qu e b i o l o gi c a l risks are associated wi t h rONA e x pe ri me n t s . neverthe less. by definition a final risk in indi
vidual cases cannot be excluded. With res p ect to the classification of rONA work into Good Laboratory Practice ( GLP) or one out of three risk categories, the so-called "additive model" has proved to be a useful and re l iab l e tool for ass e ssi n g p ot en t i a l risks. This mode l is a p pl ie d worldwide and basically assumes that re c o m b i n a n t DNA expe r im ents can be classified by i n sp e c t in g the properties of the host o rgan is m . the o r gan i s m the DNA frag ment is derived from and the vector to be us e d . In ad d i t io n to this it is assumed that the introduction of DNA s e gme n t s from a non p at h o ge n i c o rg a n is m into another non-pa t h o ge ni c organism (host) does not result in a p at h o ge n ic o rg anis m . With respect to the de terminants re sp on si ble for pathogenicity, as outlined before, this a s s u m p t i o n appears both reasonable and pract i c a l . Moreover. even the i n t r oduc t ion of pathogenic de t e r m i n a n ts (like the ones from Vibrio cholerae) into a non-pa t h o gen i c host such as E. coli K 1 2 or yeast is no t sufficient to convert the hosts into pa th o gen i c o r g a n isms . O n the ot he r hand, it is obv i o u s that the cl o n i n g of pathogenic deter-
70
3 Biosafety in rDNA Research and Production
minants from, e.g., Yersinia pestis into Vibrio cholerae needs the appropriate safety precau tions, firstly because the host is pathogenic, and secondly such a modification may (or may not) increase the pathogenicity of the re combinant host in comparison to the wild type organism. However, if such a modifica tion would be beneficial to the host, it is high ly probable that such a modified organism would have established itself by means of a "natural" gene flow which is known to exist among microorganisms (LORENZ and WACK ERNAGEL, 1 994). In practical evaluations, the different bio logical backgrounds into which a certain gene (or set of genes) is cloned and potential "sy nergistic effects" originating thereof are not fully predictable in any case but not necessar ily new or ignored. At the genetic level, an example for such effects is the activation of recombinational events leading to genomic rearrangements in developing lymphocytes by two adjacent genes (OEITINGER et al., 1 990). Similar effects are known from a variety of biological systems, e.g. , Drosophila, the acti vation of oncogenes (positioning effects) or recombinational events during embryogene sis. Altogether, while such effects may ampli fy or weaken certain properties of an organ ism or result in modified properties or sub stances being synthesized, it is hard to imag ine that such effects could convert a non-pa thogenic organism into one with unique prop erties and risks. The vast experience accumu lated in rONA R & D and particularly its ex cellent safety record support this estimation and champion the additive assessment model as an adequate and pragmatic tool. In conclusion, the knowledge accumulated in biological and genetic sciences is a sound basis for the evaluation of potential risks as sociated with the genetic modification of mi croorganisms. This applies to both classical and recombinant methods used for modifying microorganisms genetically. Beyond the safe handling of non-pathogenic microorganisms, the risk evaluation concerning the use of bac teria, viruses, fungi and parasites which are pathogenic to man principally has to take into account the following criteria:
•
•
•
• •
Virulence and/or pathogenicity of the organism, i.e., whether in fact an infec tion is caused and the severity of its course Route of infection: aerosols, direct or indirect contact, injuries, vectors, etc. Epidemiological behavior: incidence and distribution of a pathogenic organ ism, immune state of the host organism, role of vectors and possible reservoirs Survival conditions in the laboratory Ability to survive outside the laborato ry/production facility
If a microorganism is classified pathogenic according to the above criteria, several factors should be considered which could be relevant to any kind of work which might change the pathogenic profile and especially increase the pathogenicity of a microorganism. This in cludes possible effects of the vector(s) being used: • •
• •
•
•
• •
• •
• •
• •
• • •
Production of one or more toxins Transfer of genetic elements which have an invasive effect (this may main tain the infection and could be neces sary for multiplication) Infectiousness Pathogenic mechanisms Infection dose to establish a disease Invasiveness Change in host specificity Ability to survive outside the host Mechanism for the transfer of genetic elements Biological stability Antibiotic resistance Toxicology Antiphagocytic factors Organotropisms Triggering of allergies Expression rate of the product (pro tein) Biological properties of the product.
Because this Jist does not claim to be com plete, and particularly with respect to the ad ministrative biosafety regulations, the reader is referred to the specific literature (SIMON and FROMMER, 1 992) or the requirements ac cording to, e.g., the EU Directives 90/21 9/
4 Pathogen ic Microorganisms
EEC
( conta i n e d "
use " )
( '" deliberate release ' ' )
and
or the
90/220/EEC
NIH G uide
lines. The " contained use "
of m icroorgani sms i n
classified fac i l i t i e s means t h a t t h e technical measures taken are a lowe r or hig h e r h urdle for the microorgani sms to escape a giv e n con tainment. Therefore . a 1 00% containm e n t is
both not possi b l e and not necessa ry .
I nstead .
t he e ffici e n c y of c on t a i n m e nt must be both v alidated and a pp r opriate for the microor ga n isms to be con t a i n e d . While
most
tions deal survive i n
of t h e con t a i n e d u s e applica
with microorga nisms th e e nv i ronment . the
71
4 Pathogenic
Microorganisms M icroorga nisms such as bacteria, viruses. parasites and fungi are available i n large amounts ( D A V I S e t at., 1 985) in soil, water and air, and only v e ry few of them are pa
thoge n s . In fact, the great m ajority of micro o rganisms i s harmless. and many are ben efi cial for an i mals as well as plants. M icroorgan isms pat hoge nic for man usually occur as a few types in species which mostly contai n
which do not
many non-pathoge n i c membe rs
deliberate re
N O SS E N SC H A IT
DER
(BER U FSGE
C' H E M I S C H E N
I N D US
lease of organ i sm s into the e nvironme nt with t h e purpose of their survi v a l t h e re i n . a t least for a ce rta i n t i me period . raises differe n t
TR I E .
question s. Eval uations h a v e to con s ider t h e fact t h a t possibl e adve rse consequences as a result of the release of a naturally occurring
" G olden Era" of medical bacteriology, non pat hoge nic and particularly h ighly pathogen i c
exotic organism into a fore i gn and perhaps fa vora ble environment
REPORT. 1 993)
is
( for review see OT A
to
be
e xpected
much
greater than the re l ease of an or g a nism which h as been modifi e d by ge n e t i c en gi nee r i ng and
which
originates from a known. harmle ss or
ganism with resp e c t to the e nviron ment it is r e lease d into. This e q ually applies to plants. animals and mi croorganisms which may be harmful to the e n vi ronme nt or no t . Th ere fore. in regard to both t h e contained use an d
the deliberate rele ase of or g a nisms. the over all properties of the organ i sm i n question
should be assc s�ed when eval uating the risk met hods used to obta i n the " modification ··. A wi d e-ran g i ng discussion o f i s s u e s w h i c h a rose in connection with t h e delibe rate r e l e ase of ge n e t i c a l l y mod i fie d orga nisms i n t o the e nvironme n l i s n o t subj e c t of this chapte r . b u t i s reviewed a n d well docume n t e d i n the scientifi c l i ter a t u re ( DOMSCH e t al.. 1 987: TIEDJE et al . . 1 989) and i s treated bv M E n 1. E Y a n d McC A \1 M O N i n t h is vol um e and not the
.'
1 992) a nd can oft e n be further divided into v i ru l e nt and aviru l e n t strains. Since the e n d of the last century, the
mi croorganisms h a v e been investigated i n b a s i c research - safely for the resear c h ers a n d
workers conce rned. t h e g eneral population and t h e environ ment. With respect to i n dus trial applications i t must be st ressed t h at par t icularl y the fermentat i on of pathoge nic bac
teria. e.g .. for the production of vacci nes has proved t o be ve ry safe ( K O ENZI et a t . , 1 985: Tl J IJ N E N B U RG . 1 987). Re garding legal aspects. i t m us t be noted that i nternationa l cooperation i n the control of epi d emics h as h ad a legal basis since the begi n ning of the century ( I nternational Agre e m e n t on Sanitation. 2 1 June, 1 926). Since the i n t roduction of the I m per i a l Epi dem ics Law and. e.g . . t h e G e rman Epidemics Law of 1 962. i n fectious di seases caused by more than 50 pathogen i c microorganisms have to be reported an d are the r e fo r e subj ect to administrative control . Furthermore , the G e rman Epidemics Law controls not only the handling of sick patients or animals, but also rules that an auth orization is required for the hand l i n g of pat hoge nic microor anisms. e . g . , for research purposes. i n clinica l and bio chemi cal laboratories. S imilar regu l ations are i n place i n m o st O ECD countries. I mport ant con t ributions to the u nderstand ing of biolo g ica l processes stem from the analysis of t h e D a rw i n i a n p rocess o f genetic adaptat i on of orga nisms to various ecological niches. Such evol ution occurs r ap i d l y with mi-
g
3
72
Biosafety in rDNA Research and Production
croorganisms. A well known practical exam ple is the introduction of the myxomatose vi rus to Australia in order to reduce the crop destructions caused by rabbits. Initially, this lethal and easily communicable disease was very effective and reduced the rabbit popula tion d ramaticall y. However, within a few years the rabbit population returned to ap proximately the number before the introduc ti on of the virus because of the survival of re sistant rabbit strains and the outgrowth of less virulent myxomatose strains which evidently had better opportunities to spread. This ex ample addresses various factors which are in volved in infectious diseases, namely pathoge nicity or virulence, infectivity and communi cability of a pathogen, while the immunologi cal defense mechanisms are necessary for sur vival or resistance of the host. Pathogenicity and virulence, which is a synonymous term, is the capacity of some microorganisms to pro duce a disease. It is convenient to distinguish pathogenicity from virulence: for example, Bacillus anthracis is more pathogenic than E. coli, but the Vollum strain of B. anthracis is more virulent than the H M strain . Microor ganisms vary enormously in their pathogenic ity: from those which may infect humans with o ut being pathogenic ( i ndigenous bacte ria of the pharynx , lower intestine or genitals) through those which coexist with the host in a "truce" (like staphylococci and herpes sim plex virus) that is only occasionally broken up to those microorganisms which are usually er adicated after causing an acute disease (like thyphoid bacilli or the measles virus). To trigger off a disease, a microorganism must be both infectious and pathogenic. This implies that the microorganism may have to overcome several hurdles, namely: • • • •
be communicated to the host attach itself in or on the host, resist host defenses, penetrate into its tissue via the n at u ral entry points and through mucous sur faces or via tissue injuries,
•
multiply within the tissue and
•
cause damage.
The molecular basis of the biological requi rements for pathogenicity are the determi-
nants of pathogenicity. Any microbial factor and specifically surface components and ex tracellular products such as bacterial capsular materials, toxins and viral envelope compo nents can be the respective molecules. In vivo, host factors like nutrients or tempera ture are also important, because they contri bute to the growth of the pathogens and play a major role in the differing susceptibility of animal species to various diseases. Each of the requirements mentioned above is com plex involving many facets of pathogen-host interaction, and many different determinants are needed for a pathogen to successfully ac complish survival and multiplication. Patho genicity therefore is a multifactorial property. Depending on the pathogen in question, the loss of only one of the required properties listed above may result in a complete loss of pathogenicity or may lead to reduced patho genic potential (FRETER, 1 978). For the investigation of the genetics of mi croorganisms, their properties u s u a l ly have been changed by mutagenesis, i.e., modifica tion of the hereditary material by irradiation or with mutagenic substances. The pa thog e n i c potential of the mutants obtained was often lower or higher than that of the respective wild types. Nevertheless, the safety record de monstrates that it was possible to work very safely with these mutants simply by using hy gienic procedures and technical measures (COLLINS, 1 990) . However, laboratory infec tions may occur caused by injuries with, e.g., syringes irrespective of the nature of a pa thogen - mutated or not. Thus, numerous safe working methods are available today, which are based on about a centuries' experi ence of working with pathogens and which permit the safe handling of all kinds of differ ent organisms if applied appropriately, in cluding those that have been modified by ge netic engineering. Principally, the technical measures taken to contain the different pa t h oge nic organi s ms are designed to red uce the number of bacteria escaping the contain ment to a level which does not pose a hazard to workers or the protective goals in general. Such "primary containment" measures are the use of sterile work benches (lamina flows) and technical measures to prevent aerosols escaping from, e.g., centrifuges. It should be
4 Pathogenic Microorganisms
73
Tab. 2. Comparison of the M ajor Con t a i n m t: n t Measures G LP/G I LS P "
Cl assification
R i sk G rou ps
Air filters
+
+
(shit:lded)
(separate building)
closed . scaled, locked
closed
closed
Doors, windows
Reduced
+
+
Separated area
+
air press u re
+
+
Waste inactivat i o n Waste water inact iv a t i o n coats
( -I+ )
+
+ + +
( -/+ ) +
or
II)
( -/+ )
Good Laboratory Practice: G I LSP.
the
key technical d e s ign dif
level I a nd safety lev els 2 a nd 3 are additional measures like re d uced pre s s u re a imi n g to prevent pathogens from escaping t he ··secondary" co nta i n m e n t (Tab. 2). Such tech nical m e a s ur es do not add •· safe ty " to t hose wo r ki n g inside the "second ary" containment area. H owever. such t e c hni cal methods are n e ith e r ap plic a ble in keeping and t re a t ing in fect e d p a t i en t s nor in routine work in medical laboratories - n ot s urp ri s i ng ly i n fections o c cur a cc i d e nt a l l y ( HU NTE R . 1 993 ). The follow ing d e sc rip t io n of t h e different risk groups of b a ct e ria . viruses. fungi and pa rasites is mainlv based o n t h e assessments published by th e German B E R U FSG E N OSSEN SCHA Fr DER C H E M ISCHEN I N DUSTR I E ( 1 99 1 1 992). Howe ve r . in t h e fo llow i n g the classifi cation system re com m e n d e d by t h e OECD and upon which t h e E U D i r ec tiv e 90/2 1 9 EEC "contained use " i s b a se d . will b e used. This system distinguishes h a rml e ss microor ganisms (group I o r ga n isms in the EU Di re c tive) to be h a n dl e d following t h e rules of " Good Labor a tory Practice ( G L P ) " a n d I ndustrial
Large
Scale
Practice
from harmful patho genic orga ni sm s classified into the ri s k groups I , 2 and 3 (group II orga n i s ms in the EU Di rective ) w hich may b e only worked with in ( G ILSP ) " , respe c t i v e l y .
filters)
+
(class Ill) +
+ +
(extra cloth i ng)
+
Good I n d ustrial Large Scal e Practice
ferences betwe e n safety
" Good
I
+ +
Emergency power
unde rstood t h at
(double +
+ (class
" GLP,
+
+
Safety hood
Lab
C3
C2
Cl
r es pe cti ve
con t a i n m e n t level Cl , C2 an d facilities. Unfortunately, other sy s tems have been i mpl e m e n t ed like in the German Ge n e Technology Act , which classifies organ isms into four risk groups a n d therefore does not r eall y d i s ting u i s h harmless from patho genic o rg an i sm s . th e C3
4. 1 B acteria I n c ontra s t to m a n y other microorganisms, bacteria are morphologically differentiated i n to only a few forms. These are s ph e ric a l or straig h t . bent or spiral forms. At prese n t , more t h a n 3000 bacterial s pecies are known , and about 1 50 new species are d i scov ered eac h year. The ratio of th e large surface area to t h e small volume of bacteria leads to a v e ry effici e nt metabolic rate. B acte r i a can meta bolize up to 1 0 000 ti mes their own weig h t in sugar per h o ur. The h uman bo dy would re quire about 30 y e a rs in order to achieve the same t urn o ve r . Bacteria with a g e n e r a ti on time of 30 min utes. could grow from one cell to 1 0 1 4 cells we i gh ing about 100 g within 24 h ou rs and co uld t heoretically m u l tipl y to 10211 cells the next 24 hours and a tt a in a weight of 1 00 000 000 000 to n s . I n re a l ity, b ac teri a l
74
3 Biosafety in rDNA Research and Production
"growth" is soon halted by nutritional and other environmental restrictions. Up to 109 bacteria are contained in 1 g of soil, and the approximately 400 bacterial spe cies colonizing the human body on the skin and in the intestinal tract amount to about 1 0 14 cells, that is mo re than the number of cells of a human body, which is approximately 1 0 13 cells. While environmental bacteria usually are saprophytes, i.e., they grow on "non-living" organic material and often are also capable of using nutrients directly from living organisms like plants or animals, most bacteria are not capable of piercing the me chanical, chemical, cellular and immunologi cal defense mechanisms of other organism. Overall, there is a great variety of bacteria rang i ng from saprophytes to obligate parasitic bacteria b e i ng classified into three risk groups (or classes) according to their pathogenic properties initially only to men but mean while also to animals and plants (e.g., Ger man Gene Technology Act) . Comprehensive lists have been compiled in many countries worldwide, and the experience reflected in these lists is the basis for the risk assessment introduced for genetic engineering. Group I bacteria compromise those organ isms where "no" risk is known to exist for man and vertebrates (therefore, there is no need to label such organisms with the prefix "risk"). There are several groups of bacteria which have no relevance as pathogens be cause of their specific properties: • • • • • • • • •
psychrophilic bacteria multiply only be low 20 °C thermophilic bacteria multiply only above 50 °C acidophilic bacteria grow only below pH 4 alkaliphilic bacteria grow only above pH 8.5 obligate phototrophic bacteria ob l iga t e chemolit hot rop h ic bacteria bacteria with a safe history of industrial use, e.g., Bacillus subtilis saprophytes bacterial strains which have completely lost their virulence and therefore are used as live vaccines (e.g., Salmonella typhi 21a) .
Group II, Risk Group 1 bacteria comprise those organisms which may cause a disease in workers, but with respect to infectivi ty, pa thogenicity and the availability of prophylac tic and/or therapeutic measures (for both workers concerned and the general popula tion) on l y low risks are to be expe cted. This group also contains organisms which are pa thogenic only to vertebrates (but not to man) . Typical organisms are: •
•
•
Streptococcus mutans, colonizes the mu cous surface of the mouth and is in volved in the development of caries. It is a facultative pathogen and only rare ly causes endocarditis. Clostridium tetani, develops spores ubi quitous particularly in rural areas. Even in the absence of a vaccination, the reg ular contact with these spores is not sufficient to cause a disease. Vibrio cholerae, needs a high infection dosis. The infection occurs almost ex cl usively with "drinking" water, and in fections do not occur via air or body contacts.
Group II Risk Group 2 comprises organ isms which may cause a serious disease but pose a moderate risk only considering the cri teria described for Risk Group 2 . Typical ex amples are: •
•
Mycobacterium tuberculosis , causes a serious disease with a lengthy thera peutic treatment. Vaccination is possi ble. Yersinia pestis, can be transmitted by flea-bites and via air, then causing a very serious infection. Vaccination is possible.
There are no bacteria known which need to be classified into Group I I Risk Group 3. This high risk group contains viruses only.
4.2 Viruses Viruses display unique features not found in other microorganisms. These primarily
4 Pathogenic Microorganisms
concern the inabi l ity of v i r uses for self-multi plicatio n . i.e., they infect a host first and t h en use t h e rep li ca ti o n machinery p r o v i d e d by the
host
stage
of lat e ncy i t
75
is often ex tre m e l y difficult
to de t ec t viral p a rticles.
Various criteria need to be considered for
for amplification. H ence i t i s not surpris
th a t no chemotherapy has been developed compar able to the effi c ie n t t re a t m e n t o f b ac terial i n fections wi t h a n t ibiotics. The genom e of v i r use s consists of eithe r DNA or ing
the classification of viru se s i n t o the fou r risk groups which are ma i n l y :
so far
RN A with
the
• virulence of the pathogen • seriousness of the i n fe c t i on
transcribed i n to D N A . before repl ica tion of the vi ral genome can occur. V i ruses a re spe cialized to certai n pe r mi ss ive cell types and
• transmission pat hw a y
can be found as ce l l par as ite s and/or patho gens fo r almost all k i n d s of cells i n c luding bacteria. V i ruses can be t r a n s m i tt ed horizon
•
··
"
t al l y between hosts and v e r t ica l l y betwe e n successive generations of permissive hosts.
Similar
to
bac t er i al i n fect ions. the horizontal
transmission of vi r uses may occur via: •
certain blood
transmitted
c e l l types
by
•
and rhi noviruse s ) digestive t rac t ( po l iovirus)
"no"
to l ow
•
perinatal
G roup 1). mod e ra t e to un
I co m pr i se s v i ruses which are com
to
h um a n s (and most ,
occur
cause diseases ( under cer t a i n conditions, i . e . , only i f re v ers e mu t at i o n s o cc u r a n d ve ry
via:
.
•
s l e s , parv nvirus-B- 1 9 )
ranges from
.
ra r e l y ) ge rmline ( re t rov iruse s ) • hematoge n-diapl ace ntal
and
risk ( G roup I ) . low to mod e ra t e
v e rt ebrates ) , such as bacterial p h a g e s p l an t viruses and l i ve v accines ( e . g . poliomye l itis type 1 . 2 and 3). even t h ough t h e l a tter may
vi ruses or mea
Vertical transmissions may
• genital i n fec t i o n s
v i r u s e s resembles the
of bacteria
p l e t e l y non-pathogenic
• skin ( p api llo m a v i ruse s )
sles)
The classification of classification
Group
• w a t e r ( enterovi ruse s )
( h e rpe s
dosis availability of vaccines
man/animal vi ruses. which are not foun d in Europe and for which the refore the epiz o otic be havior is not k n own.
.
fluenza-
• direct contacts
infection
•
pathogens and dual human/animal pathogens.
e tc ) aerosols. dust ( in.
(immunity,
The term " u nknown" risk for Risk G ro up 2 v i ruses refers to "exotic" a n i m a l and dual hu
• vectors in ge ne ral ( i nj uries. i nj e ct i o n
food . i n fects . tick s
situation
w i t h i n one risk gro up r e l a t e t o t h e s l igh t ly d i f ferent properties of human pathogens, animal
2. e t c . ) ( ra b 1 e s )
needles,
• epide miological reservoirs. e tc . )
( G roup I I . Risk
• bi t e s
• respiratory t ract by
fre
k nown ( G roup I I . Risk G roup 2) to high risk ( G ro u p I I . Risk Group 3). These variations
inj ections. transfusion or se xual inte r course (hepatitis B and C virus. H I V I and
and i t s
quency
latter usually being reve rse
( herpes
It must be
n ot e d
w h i c h m ultiply i n . e.g ..
( G e rm a n mea
and 2 )
that
live
vaccines
trans into revertants. Group II Risk Group 1 co mp ri s e s a very b r o a d spectrum of v i ru se s rangin g from spu ma v i r u ses ( human diseases are not d ocu m e n te d ) h e p a titi s B v i r u s to h u m a n herpes v i r use s like HSV 1 a n d c y t omeg al o virus. For t he se human herpes vi ruses in more t h a n mitted and m ay
v i ruse s )
transmissi ons ( H I V 1
.
humans can be
propagate
,
I n ge neral. v i r a l infections e ralized
.
v ar y from gen
loca l . persisting. c h ron i c
.
latent to
"slow·· forms with very d i ffe r e n t symptoms. even
serious viral infections wi t h e .g hepatitis B virus may take a chronic form with almost n o cl i n ica l symptoms. Nearly all h e rp e s viruses tend to c a use latent diseases with reactivations of the v i r u s e s aft e r . e.g . stress or part i a l immunodeficie ncies. At the Moreov er.
.
..
.
80% of t h e a d u l ts tested a n ti bodi es a re foun d .
i.e.
.
one or t h e
other
form of p ri m ar y
i n fec
t ion ( mos t ly i nappare n t ) must have occurred. E v e n i n the prese nce of h i g h t iter s o f neutr a l izing a n t i bodies a substantial fr act i o n of the
population is s u bj ec t to
re c u rre n t herpes.
76
3 Biosafety in rDNA Research and Production
Group II Risk Group 2 contains viruses which are characterized by diseases with up to 1 00% both manifestation and lethality and for which often neither therapies nor prophy lactic vaccination are available. While the hu man immunodeficiency viruses (HIV 1 and 2) are transmitted only via the transfer of body fluids, yellow fever presents a complex eco logical situation with two distinct epidemio logical types and is only transmitted by in sects which do not exist in Europe ( vaccina tion is possible) . The herpes B virus of mon keys may infect man only accidentally but can be transmitted via air (laboratory infections have been reported). Group II Risk Group 3 comprises those vi ruses which are highly contagious with almost 1 00% manifestation and lethality of the dis ease. These viruses have a high probability to cause pandemics and can be transmitted even by vaccinated individuals. Examples are lassa virus, variola major/minor and marburg virus, which need specific precautions to be taken if they are subject to diagnostic or research op erations. With respect to their genetic contents, vi ruses vary considerably in size from small RNA tumor viruses with only 4 genes (e.g., Rous sarcoma virus with the gag, pol, env and src gene) to herpes viruses, pox viruses or in sect viruses with up to more than hundreds of genes and genome sizes up to 300 000 nucleo tides. By now, several thousands of animal vi rus isolates have been analyzed which could be classified into a reasonably small number of virus families. The accumulated genetic knowledge clearly indicates that the replica tion mechanisms of viruses rely on complex interactions with the host, which leads to the conclusion, that the evolution of a successful virus type must be a very rare event. For more than 100 years viruses have been the object of intensive research. Following the introduction of genetic engineering, major discoveries about the genetics of higher cells came from first studying their viruses. If the necessary technical precautions are taken for containment, even the viruses of the highest risk group can be handled safely for both re search and industrial operations as the practi cal experience proves.
4.3 Fungi and Parasites Fungi are abundant in soil and on plants and are found in all climate zones. They have traditionally been regarded as plantlike or ganisms, grow either as single cells (yeasts) or as multicellular filamentous colonies (molds and mushrooms) and produ,ce ubiquitous air borne spores. It is difficult to define fungi comprehensively and unambiguously because there are at least 1 00 000 fungi with an enor mous diversity (HA WKSWORTH et al. , 1 983). While only few fungi cause diseases in man, other pathogenic fungi have serious impacts on human welfare as causes of plant diseases destroying harvests or by toxic or carcinogen ic metabolic byproducts such as aflatoxins and ochratoxins from aspergilli. Fungi repro duce by both sexual and asexual cycles as well as by a parasexual process, and most of the fungi that are pathogenic for man lack sexual ity. Fungi pathogenic to man usually are clas sified with respect to healthy workers and therefore do not include serious immunodefi ciencies or other diseases like tuberculosis, AIDS or diabetes with respect to fungal infec tions. Parasites are organisms which live either on or in the body of other organisms (ectopa rasites and endoparasites, respectively) and may cause parasitoses. The most frequent dis ease is caused by Malaria tropica with cur rently more than 300 millions of new infec tions annually with more than one million le thal cases (mostly children). Beyond the indi vidual health problems caused by parasites, the economic costs for health care in both hu man and production losses with domestic ani mals are considerable. Most parasites have complicated life cycles with usually more than one host being involved. Differing from the classification schemes used for bacteria, for viruses and fungi a different and more indi vidual classification approach is necessary . With respect to parasites it is important, whether vectors and/or intermediate hosts are used in the respective work. The examples given are restricted to fungi. Generally, fungi and parasites are classified by definitions similar to those used for vi ruses. There are no fungi and parasites
5 General A ssessment of Biosa.fety
k nown . which need to be classifi e d int o G roup l I Ris k Group 3 . Grozip I fungi c o mp r i s e t h o s e organisms
where no d ange rs for man a r e associated with ( Saccharomyces cerevisiae ) and t hose which m ay be o pp o r t u n i s t i c path o g e n s i n sev e re ly immunocompromised pat i e nts o n l y
( e . g ..
As
pergillus
niger u b i q u i tous in nature . and Mal assezia furfur. \\> hi c h co lo n i z e s t h e h e a l t hy h u ma n skin b u t may cause s y stemic i n fections i n se ve re l y immunocompromised childre n ) . Group II Risk Group I contains fu ngi
which may cause in fecti o ns i n case of minor disturbances of t h e i m m u ne system and for
which effective t h e r a p y
is a v a i l a bl e Ex a m p l e s are Candida albicans (which is found in the mouth and the intestinal t ract and only in .
c ase s like diabetes or c h e m o th e r a p y may c a use systemic candidosi s ) . and Trichophyton mentagrophytes w h i c h is t h e age n t causing common athle t e ' s fo o t und e r c e r tain c o ndi
ti ons. Group
myc o ti c d i sea ses as is t h e
case
dioides
se v e re
with Cocci
immitis which is fo u n d in ce rtain areas i n s o ut h w e s t USA and which m a y . via an in fection of the lung. cause fu rther i n fections of
other organs. Several fu n gi
a re
non- p a t h o g e n s by d e fi n i
tion but may cause d a m a g e by the p ro d ucti o n of mycotoxins which may even pa s s the skin
like trichothece ne from spect
to t he
Fusarium
sp. W i t h
re
inactivation of fu ngi including
their spores. toxins may s u rvive t h e treatme n t and therefore s om e t i mes afford extra atten
t ion
ment ( e g . . for agricultural uses or re se ar ch p u r p o s e s) have shown that the number of live microorganisms usually d e cr e a s e s very rap idly by s e v e r a l powers of t e n ( A RMSTRONG et a ! . . 1 987) whi c h ma i n l y d e p e n ds on the nu trients available ( D E V A N A S e t a ! . , 1 986) . The cl assification of mi c r o o rg a nisms into three risk groups and accordingly the use of d i ffe rent technical safety m e asures in three .
"safety" levels ( b e y o nd G LP) have a s oun d a nd d e p e n d on the p r o p e r t i es of t h e relevant orga nisms. Thus, for exam pl e E. coli K 1 2 laboratory strains a nd baker's yeast are comple t e l y h ar m l e ss to humans, a n i ma l s p la n t s a n d the e nvironment ( Group I ; G LP and G I LSP. respe c t i v e l y ) Polio vi ruses ( w i ld s t rains ) are harmless to animals and the e nvironment but c o ns t i t ut e a s e ri o us risk for i n dividuals who have not been vaccinated ( Risk G r o up 2: S a fe t y level 2). S i mi l arly. s m al lpo x viruses represent a le t h a l r i s k o n l y
scientific basis
,
,
.
not infect animals), and c o n st it u te s a s e rious risk only to ca t t l e ( bo t h are classified i n to R i s k Group 3: S afe ty level 3), but c a rr i e s for humans
II Risk Group 2 may cause
.
5 General Assessment
of Biosafety
With about l0 7 to lOx ce lls per gr a m of soil and thousands of different species/subspecies. mi c r oo rg a ni s ms a re i n a fie rce c o m p e t i t i ve s t r u ggl e . Th e y have to e s t a blish t he mselves i n
the face of n umerous s t r e ss fact o r s a n d co m pe ti tors ( ALEX A N D E R . 1 98 1 ) . Cou ntless i n vestigations with l a b o ratory or w i l d strains which had been re l e ased into t h e e n v i r o n
-
77
( but
do
the foot-and-mouth disease v irus
no ris k s to humans a n d p l an t s Based on the organism. v e ct o r and ge netic .
material used fo r g e n e t i c e ng i n e e rin g work ,
such work too is cl assifi e d into one out of the fou r c at e g orie s and allocated to either GLP/
G J LSP or
the
re sp e c ti v e
containment level
with the appropriate technical safe ty meas ures (SINGER and SoLL, 1 97 3 ) . This system has a proven s a fe t y record and p e rm it s risk m i n i m ized h a nd li ng of p at h o ge n ic o rg an i sms under appropriate containment. In pr a c t ic al terms . t echnical m e a su re s extend, for e x am p l e . from the use of glove s ( G LP) t o lamina flow work benches. autoclave s and laboratory exhaust air fi lters to sp eci a l facilities in the co n tainm e nt level 3. which must be kept com p l et e l y under reduced air pressure i n or d e r to p re vent the e sc a pe of m icroo r g a n isms from the c o n t ro l led area. These techn i cal safety m e a s u r e s do not ap ply s o l el y to genetic e ng i n e e r ing work. how ever. The conventional g e n e t i c and b i oc h e m i cal i nvestigation of all k i nds o f pat h og e n i c m i
cr o org a n isms a re of course also carried out u n d e r sim i l a rly grad e d co ndit i o ns Only with the introduction of g e n e ti c eng i n e e r i n g t e c h ni q ues t h e tec h n i c a l s a fe t y m e as .
-
78
3 Biosafety in rDNA Research and Production
ures applied to the safe handling of microor ganisms could be supplemented and extended by biological safety measures. Using certain combinations of safe microorganisms and vec tors, dual host/vector systems were developed which allow to classify certain genetic engi neering work into the lowest safety level or even exempt them from regulatory overview. The exempt category, as defined in the NIH G U I DELINES ( 1 984) , covers approximately 80-90% of all rDNA experiments , whereby most work is conducted with E. coli K12, S. cerevisiae and asporogenic B. sub tilis host vector systems. Theoretically, an additional safety system could be established if microorganisms could be constructed which, if they escape from the laboratory, would produce a factor that re sulted in immediate death of the respective cell (suicide system) . Naturally, tests would have to be carried out in order to establish how reliable such a system would be. What does the introduction of biological safety measures additionally to technical safe ty measures mean in practical terms? First, a certain combination of technical sa fety measures must be applied to the multipli cation and subsequent research conducted on infectious pathogenic organisms such as HIV, hepatitis C or Bacillus anthracis (which are all classified into Risk Group 2). Such bacterio logical or virological research, recombinant or not, is subject to safety provisions as manda tory according to the rDNA rules for contain ment level 2 for rDNA research. Second, the analysis of individual genes and the respective gene products of such pa thogenic organisms, once they are introduced into safe host/vector systems like E. coli Kl2 in conjunction with certain conjugation-nega tive plasmids, usually can be carried out un der GLP/G ILSP conditions. The background is that a "safe" non-pathogenic organism like E. coli Kl2 cannot be transformed into a pa thogenic one by the transfer of any combina tion of genes, because pathogenicity is a too highly specific and multifactorial phenome non. Additionally, it should be kept in mind, that DNA from eukaryotic cells (including vi ruses) usually cannot be expressed in proka ryotic cells, e.g., E. coli, and vice versa. Conse-
quently, eukaryotic proteins will not be syn thesized, and hence no biological risks devel op. In this context, it must be borne in mind that patients infected with the naturally oc curring microorganisms quoted above , of course are not subject to the technical safety measures applicable to containment level 2 as applied in the laboratory, even though the count of infectious particles released by pa tients may be significant. Using the dual system of technical and bio logical safety measures described above, the pathogenicity factors of virtually all (micro) organisms can be easily and safely investi gated in the low safety levels. The introduc tion of genetic engineering methods into medical, bacteriological, virological and eco logical research and for biotechnical produc tion processes therefore has led, in many re spects, to a marked increase in safety at the workplace for the researchers and other per sonnel concerned and for the environment.
6 Species-Specificity of Genes
The genes (DNA) transferred from one species to another (for example, between mammals, microorganisms, and plants) can not, with a few exceptions, be directly used by other species. This is due to the great specific ity of the regulatory structures (promoters) and the specific mechanisms of protein bio synthesis at the ribosomes which control the transformation of the information stored in the genes into the relevant gene products (i.e. , protein molecules). The relevant proc esses, named "transcription" and "transla tion", are highly specific and can utilize DNA only from organisms which are genetically compatible. As a consequence of the genetic differences mentioned above, a large part of the application-oriented genetic engineering research and process development work deals with the exchange and improvement of such regulatory structures in order to achieve max-
6
imum expression rates of the cloned coding sequences in prokaryotic or eukaryotic cells. In addition to the non-compatibility of the promoters, chromosomal eukaryotic genes usually are structured into intron and exon regions, which is not the case for bacterial genes (only the fused exon regions are finally used in eukaryotic protein biosynthesis). Not surprisingly, bacteria are not able to remove the intron regions from the original "euka ryotic" mRNA transcript (which is an exact copy of the coding DNA strand) into the "fi nal mRNA", which in eukaryotic cells finally is translated by the ribosomes into the respec tive protein(s). Therefore, prokaryotes usually are not cap able of expressing chromosomal eukaryotic genes into biologically relevant amounts of functional proteins (and vice versa) because: • •
the regulatory structures are not com patible and because of the intron/exon structures.
This inability also applies to the few known cases of eukaryotic gene sequences which do not contain introns. For details on the molec ular mechanisms of gene expression and oth er related issues the reader is referred to the literature, e.g., WATSON et al. ( 1 987). As, for example, the human proinsulin gene is associated with the typical properties described for eukaryotic cells, it cannot be di rectly used for production purposes in bacte rial cells. Therefore, instead of using the chro mosomal insulin gene, firstly the "final mRNA" is isolated from tissue and reverse transcribed into the corresponding DNA structure using the appropriate experimental procedures. Secondly, a suitable bacterial promoter is fused to this DNA structure re sulting in an artificial gene now composed of both a promoter and coding region. Thirdly, this gene is integrated into an appropriate vector and transformed into, e.g., E. coli K12 cells which only under appropriate nutritional conditions can synthesize the proinsulin mol ecule. This hybrid gene constructed in vitro from the bacterial promoter and the section of DNA determining the proinsulin protein structure can, however, only be used in bacte-
Species-Specificity of Genes
79
ria after the modification. It can no longer be activated in mammalian cells because these conversely cannot use the bacterial promot er. The transfer of DNA segments between organisms using similar DNA transcription and message-processing mechanisms auto matically results in the transfer of genes, be cause these can principally be expressed by the recipient cell. This usually applies to the cloning of bacterial DNA, e.g., into E. coli cells and is similar to natural processes which are known to occur in nature (TREVORS et al., 1987). Different to this, the DNA trans ferred between organisms using different DNA transcription and message-processing mechanisms usually cannot be processed by the recipient cell and therefore cannot be considered as transfer of genes but of non functional DNA only. This applies to, e.g., the construction of eukaryotic gene libraries in E. coli cells. The basis of this distinction is, that a gene in fact only exists, when a cell is able to ex press it into a biological function - otherwise the DNA sequence in question must be con sidered as non-coding DNA only. Whether or not such a sequence can be activated by cellu lar mechanisms like recombination (or oth ers) , would be an event which is not unique to genetic engineering and comparable to effects caused by, e.g., transposons, retroviruses and, more generally, by repair mechanisms. For the reasons described, it is impossible to construct a "super-gene" (and hence a su per-enzyme) that could simultaneously be: • •
expressed in all species, biologically active in all species with a multitude of biological properties.
The fundamental differences between pro karyotic and eukaryotic life forms with re spect to gene expression have been identified at the molecular level (hence molecular biolo gy) and constitute a highly relevant and in trinsic aspect of biosafety. After successful completion of the "con struction" work at the DNA level, as de scribed, no further genetic or genetically engi neered changes need to be carried out for the production of proteins for research and com-
�0
3
Biosaf"ety in
rDNA Research and Production
mercia! purposes ( e . g . . for crystallization ex periments and as pharmace uticals. respective ly). Genetic engineering in the narrower sense is therefore restricted to the laborato ry . All further measures a re identical to the conventional fermentation methods and have to be ap proac he d . e.g . . with respect t o t he p rod uct ion of substances for clinical testing. in terms of process and facility validation as usual.
7 Gene Transfer Mechanisms
In ge n e tic engi n eer i n g DNA is u su a l l y transferred by means of vec t o rs . i . e . , plasmids (WINNACKER. 1 987) or viruses. and multi p lie d together with these. Naturally occurring vectors can be transmitted between different cells via three different mechanisms: conjuga tion (an d m o b i l iza t ion) . transduction a nd t r a n s fo rm at i on ( A R B E R , 1 987; STRAUSS et a!., 1 986; ROSZ A K an d COLWELL, 1 987; STE WART and CARLSON, 1 986: MORR ISON e t a l . . 1 978) .
For "conj ugation " a c onj ug a ti v e plasmid is required which m us t fi rst multiply i n the do nor cell so that it can be transferred to a reci p ient cell. For mobilization, a helper plasmid must make the necessary enzymes available . "Transduction" is based on viral D N A mole cules wh i c h are i nte gra te d into the genome of a cell and multiplied by cell division. Such p roviruses are activated by a wide range of in fluences and fi nal ly are packaged i n t o infec tious v iral p a r ticl e s . During this process host genes located next to the p roviru s can be " i nadvertently included". In contrast to the two "biological" mecha nisms m e n t io n e d . "transformation " is a pas sive process in which the n ucleic acid is t rans po r t ed into the cell through the cell wall/ me m b r ane by unspecific means. Subsequent ly. t ra n s for m e d DNA is multiplied like plas mids or can be integrated i nto the cells' chro mosome by recombination o r re p air mecha nisms.
E. coli cells require chemical pretreatment to make them ·•competent" for a transforma tion as described. U nl i k e t he n atu r a ll y occurring bacterial p l as m i d s (CouTURIER et a!., 1 988) , most vec tors (i.e .. s afe t y p la s m id s or p hage s ) used in genetic engineering fo r the multiplication of DNA fragments cannot be transferred to oth er bacteria by conjugation or transduction be cause . particu larly in the case of plasmids, the ge net ic elements necessary for the transfer have been removed. In the case of phages fre quently used in addition to p la smi ds , the host specificity is restricted almost exclusively to the E. coli K l 2 J abor atory strains (BLATINER et al.. 1 977: D E N H A RDT et al., 1 978) . The transfer of plasmids between different bacteria fol lows certain biochemical rules and requires the plasmids to carry s p ec ial struc tures from which the "transfer mechanisms" can proceed (B ASTIA, 1 978) . The transfer genes (at least 1 2 tra genes; W I L LETS , 1 988) n ee de d for transfer, the genes of the re spec tive enzymes (mob; BoYD e t a!. , 1 989) and the mobilization site (niclbom; FINNEGAN and S H ERRATI, 1 982) are not present on the s afet y p l a smid s employed today. For t hi s rea son, safety plasmids of this type cannot be transfe rred with helper functions from other plasmids (TWIGG and SH ERRATr, 1 980). E v en n at u ra l ly occurring broad-host-range plasmids (such as RP4 and others) which can multiply in many bacterial species from E. coli t o Alcaligenes strains and Agrobacterium tllmefaciens ( S A Y L E R and STACEY, 1 986; EL SAS et a!. . 1 990) do not mu l t ip ly uncontrolled in all possible bacteria, as is sometimes claimed even of the safety pl asmid s . If this were the case. it would never have been possible to develop antibiotic therapy for b acterial infections with compounds such as penicillin, tet racycline, cephalosporin o r st re pto m y cin , because antibiotic resistance is known to be passed on by plasmi d s, and con sequently all existing bacteria would be bound to be resistant ( KELCH and LEE, 1 978). The molecular genetic p r in c i p l es for the widely va ry i ng and often very limited a bi l i t y of naturally occ urr ing plasmids to mul ti pl y have been investigated in depth ( e . g . . for Co! E l derivatives) and are ba s e d on n umer ous ge n e t i c properties:
7
- For their stabilization in bacteria plas mids require a section located in the vi cinity of the "origin of replication" which is known as par (from partition) (MEACOCK and COHEN, 1 980). This section interacts with certain cellular components which bring about uniform distribution of the plasmids on the daughter cells during division. If this section is removed from the plasmid or if the section is biologically inactive (as a result of mutations) , the plasmid is slowly lost in a growing bacterial cul ture (JoNES et al., 1 980). If, however, a plasmid of this type contains an anti biotic resistance gene, it can be stabil ized in a growing bacterial culture as a result of the selection pressure exerted by, e.g. , adding the appropriate anti biotic. Only bacteria containing the plasmid can survive under these selec tion conditions. Therefore, care must be taken in R & D in order to ensure that the plasmids are stabilized by se lection pressure in the host bacteria used and that they are not lost as a re sult of carelessness. - Naturally occurring plasmids are div ided into more than 30 different "in compatibility groups" (N ovi C K , 1 987; THOMAS and SMITH, 1987) . This classi fication is necessary because genetically similar plasmids cannot multiply at the same time in the same bacterium. One type of plasmid is rapidly eliminated. This genetic property also contributes to the fact that plasmids do not multi ply in all bacteria occurring in nature. - Restriction enzymes are isolated from microorganisms and used to break down DNA into defined fragments. To day, more than 200 different enzymes from differing bacteria are known (Ro BERTS and MACELIS, 1 992) . Many of the commercially available restriction enzymes are obtained by genetic engi neering techniques. The restriction coenzymes are one part of the "restric tion-modification system" of bacteria whose effect can be interpreted as an "immune system". Its aim is to protect bacteria from penetrating "foreign
Gene Transfer Mechanisms
81
DNA". This is achieved by the foreign DNA being digested by the cell-specific restriction enzymes, while the host DNA first is changed chemically by the cells' modification enzyme (methyla tion) to such an extent that it is pro tected against the cell-specific restric tion enzymes. Naturally occurring bac teria possess further effective mecha nisms which can restrict the invasion and spread of DNA (RA YSSIGUIER et al. , 1 989). - As mentioned above, the vast majority of plasmids that are used for genetic engineering are derived from the natu rally occurring plasmid ColE1 (HERSH FIELD et al., 1974). This plasmid is rela tively small and carries the genetic in formation for a protein molecule de scribed as "colicine E 1 " . (Colicines are proteins which help bacteria to destroy competitors; KoNISKY, 1 978.) Because of the properties of its very thoroughly investigated "origin of replication" ( K O ES and STAHL, 1 989), the ColE1 plasmid has an extremely narrow host spectrum and can only be fermented in coliform enterobacteria, but not, for ex ample, in bacilli or pseudomonads. The reasons for this specificity are the se quences and enzymes needed for multi plication which are largely host-specific. Since the naturally occurring ColE1 plas mid does not multiply in non-enteric bacteria, its origin of replication proved eminently suit able for the construction of the various plas mids in use today. The DNA transfers between Gram-nega tive and Gram-positive microorganisms (M A ZODIER et al. , 1989), bacteria and yeast cells (HEINEMANN and SPRAGUE, 1 989) and be tween bacteria and plants (BucHANAN-WOL LASTON et al., 1987} described in the litera ture show that a slight horizontal gene trans fer can be detected under artificial conditions. Usually special selection procedures precede the detection, and the following conditions have to be considered:
3 Biosafety
82 •
•
•
in
rDNA Research and Production
ject of
specu lation , because t h ere is too little k nowledge at the molecu l a r level and particu larly no well-founded suspicion that this might be relevant. Depending on the genetic relationship be
no safety plasmids should be used. the recipient cells must be made com petent or experi ments must be carried out with high cell de n s i t ie s sterilized soi ls or water s a mp l es must be used. special buffers. plasmid concentrations and temperatures are r e qui re d .
•
•
tween
.
There are so far no reports of conj ugation . transduction or mobilization p r oce sses which did not employ one or the other of the above experimental conditions. Horizontal gene transfer (or the supposed ly uncontrollable spread of ge nes) is an often discussed topic and has already been ad dressed to the definition of g e n e s a n d the question when they are merely to be consid ered non-coding DNA. In respect of safety to humans and to the environment. such r e flec tions can be based on broad practical expe r i ence and o n the biol ogical mechanisms th a t are widely encountered in nature . M any organisms are bound to take in. with their food, large amounts of DNA from the cells of plants or meat. This means. that DNA is an important part of the diet and that not only the h uman body has learned to break down and ut ilize orally i ngested DNA. irres p e ct ive of its origin. This a ppli e s equally to DNA w h i c h is prese nt in the microorganisms ingested every day with the food and from t h e environment. These microorganisms may have been capable of causing even fatal dis eases in individual cases over thousands of years . but they have not been '"transmitted"' to mammals and have therefore never caused hereditary genetic problems. A prereq uisite for any stable uptake of DNA would be that certain sections of the DNA. which can e x ert spe c i fi c e n z y mati c functions i n the re c i p i e nt organism. must be incorporated i n to the o rga n i s m s chromo some (for microorganisms) or the germline (e.g. , for mammals). Thereby the n e w ge ne t i c trait would be made available to the heredita ry and evolutionary processes the individuals in question u n de r ly Irrespective of the fact that this is not bound to be disadvantageous per se to the species concerned. such events a nd m e c h a n i s m s today can o n l y be the sub
'
.
the donor and
t h e recipient,
the DNA
naturally transferred between species may be immediately usable by the recipient. In such a case. phenotypical p ro p e r tie s may be added and could be detected immediately by bio chemical methods - irrespective of whether the DNA becomes integrated into a chromo some or is maintai ned in extrachromosomal dements like plasmids or viruses. Otherwise, if the DNA is not usable because of genetic incompatibility between donor and recipient, the DN A will have no generic biologic effect except for possible indirect effects on neigh boring genetic elements. Therefore, biochem ical effects are not detectable in such cases, and the DNA segment in question may have effects o n l y after accu mulating mutational events. S i n c e evolution i s not target-oriented, i.e does not aim for a certain property of a DNA segment or even the properties of a gene product. the long-term effect cannot be estimated. I t is questionable whether this scenario has any relevance at all, a s a simple ..
comparison (ZIN K E , 1 990) of the first 90 nu
cleotides of
al . , 1 980) with {3- /a cta m ase from E. coli (pB R 322; S UTCLI FFE, 1 978) glycogen synthetase from E. coli (Ku M A R e t aJ., 1 986) tetanus toxin from Clostridium tetani ( FA I R W E ATH E R and LYNESS, 1 986) and a statistically compiled ra n do m se quence
• human preproinsu/in ( B E LL et • •
• •
indicates. which show a similarity between 20 and 37% of absolute identity: Similarity in % {3-lact.
glyc.
s.
random s.
tetanus t.
22.5
20 27
36 . 6
18
22
21 22 33 30 insulin {3-lact. g/yc. s. random s.
7 Gene Transfer Mechanisms
This simple co mp a ri son shows that a "new" r a n d o m sequence or any other se
quence can p ri nc i pa l ly be derived by a com p a r able number of su cc e ss i ve mutations from many other DNA sequences. Because of t h e properties of t he gene tic c od e ( th e first nu cleotide i n a codon is more '' s pe c i fi c '' than t h e t h ird n ucleotide ) even l e s s mutations will be necessary for the d e v e lop m en t of the respec tive b i o l og i ca l activity (e.g .. peptide or p ro tein) . Irrespect i ve of whether thi s c o m p a r i so n has a m i nor or major s i g ni fi c an c e . it can be co nc l ud e d t h a t by i n t r od uc i n g e u k a r y ot ic D N A ( v i sible a n d non-visible ge n e s ) into pro karyotic hosts, no " new type " of potential risk i s b e i n g formed. S i n c e there are no b ioc h em ic a l differences between coding DNA. n on -co din g DNA and re com b i n a n t D N A . the s a m e b io l o g i c a l laws apply. There fore. both t h e o retica l l y a n d a c c ord ing to the e m piri c a l experience with clas sical mutage n e s i s and se lect i o n pr oc e d u r es . short - a n d lo n g - te r m e ffe c t s bot h po s it i v e a n d neg a t i v e (how to defi n e ? ) by "modified" or ganisms only can occur. if: •
•
col lective p ro p e r t i e s of an o rg a n i s m allow its long-term survival and positive o r neg a ti ve effects ac t u a lly de
the
velop .
Howe v e r . t h e s e two
es s e n tia l properties, the capacity of s urv i v i ng and a c e r tain p o t e n t i a l fo r m e a s u rab le effects. are diffi cult t o obtain with no n - en v i ro n m e n t a l organ is ms . such as F. coli K 1 2. S. cerevisiae and eu karyotic cells. and h a v e not been observed w it h recombinant DNA te c hno l o g y since its invention. Thi s is d ue to the fa c t that the typ ical properties of a " s a fe " organism ( e .g .. non pathoge nic. no environmental germ. de pe n d ence on certa i n nutrients and te m per a t u re s , non-competitive in its s p ec i e s · eco l o gica l niche ) c a n n o t he c ha n ge d by i n t rod uc in g a couple of fore ign genes or by m ut a tion s of a recombinant gene. Therefore , even t h e intro d u ctio n of recombinant ge n e s used in prod u c tion processes i nto other bacteria can be as sessed as not r e le v a n t in biol o g ica l terms. Thus. in more ge n e r a l terms. there is no unique risk pot e n t i a l associated with the transfer of Dl\ A sequences by r O N A beyond namely .
what
83
h a p pen s with microbes anyway. Instead, a pote nti a l risk arises s o l e l y from the function of a DNA se q u e n ce or, more specifically, of the c o r respo nd i ng gene p ro d u ct (R A M A GH A DRAN, 1 987). This applies, for instance, to the m an ufact u r i n g of toxins in, e.g., E. coli K12, which doe s not raise problems of b acte r ial pa thogenicity b u t those of product tox icit y . Nu m e rou s v acc i n es , es p ecia l ly live vac cines, contain nucleic acids, i.e., DNA and/or R N A . S i n ce the last century, these nucleic acids have been inj ec t ed as constituents of the ac t ual vaccines or administered o r a ll y , w ith o u t ca us ing a n y fund a m e n t a l p ro bl e m s . Even the cases described (WHO, 1987) of vaccines i n a d v e rt e n tl y contaminated w i t h viruses that are pathogenic to animals ( ye l low fever vac cine contaminated wi th avian leucosis virus and polio v accine contaminated with SV 40 v i r u s ) have had no adverse effect on the vac cinated persons. The side e ffects of vaccines that can be observed from time to time are not due to the nucleic acids (DN A/RNA) but to other causes, mostly to fa i l u r es of t h e im mune system, a n d chimeras or superorgan isms t ha t might jeop a rd iz e m ankin d h av e of co u rse n ot o cc u rre d. The above evaluations are consistent with the observations that DNA is c on st a ntl y re leased from carcasses of mammals and asso ci a t e d m i cr oo rg a n i sm s . from pl an t s , plankton (PAUL et a!., 1 987) and from bac t e r i a (MuTo and GoTo, 1 98 7) and the therefore p e r ma n e n t av a i l a b i l i ty of DNA ( "gene po o l " ) for ex ch a n ge withi n the microflora of the soil ( LORENZ an d WACKERNAGEL, 1 994) . Last but not least, since i n n u me rou s spe cies of m icroo rga n ism s . often in very similar but distinguishable s u b fo rm s , have deve l o pe d and s t a b i l i ze d, there is no reason to pursue the v ie w that a unique role should be as s i gn e d to the tr a nsfe r of recombinant ON A between different s pe cie s different from the role t h e transfer of non-recombinant D N A p l a ys in nature (VIDAVER, 1 985 ) .
84
3
Biosafety in rDNA Research and Production
8 The Escherichia coli
B acteria
Since the turn of the century, and particu larly from the work of THEODOR ESCHE RICH, it is has been well established that the "bacterium coli communalis" is part of the natural intestinal microbial flora of humans and animals, and that it may be a causative agent for intestinal and extraintestinal infec tions. These pathogenic Escherichia coli (E. coli ) bacteria are characterized by carrying pathogenic determinants which are not found in the laboratory strain E. coli K12. "Normal" intestinal bacteria of the genus E. coli repre sent up to 5% of the over 400 different spe cies of bacteria (in addition to fungi) compris ing the normal flora in the human and animal intestine (LINZENMEIER, 1989; DANCYGIER, 1989) where they feed on organic substrates (LEVINE, 1 984; LEE, 1985). As the compre hensive literature proves (GLANTZ and JACKS, 1967), they are harmless and in tem perate latitudes do not survive outside their host. As E. coli bacteria are easily detectable, they are often determined as a "fecal indica tor" representative for cholera and typhoid pathogens. Whereas tropical warm waters usually contain little oxygen and therefore are low in nutrients (e.g., contain small amounts of plankton), the determination of coliform bacteria may temporarily be necessary in oth er waters which are heavily charged with or ganic material (LOPEZ-TORRES et al. , 1988; BERMUDEZ and HAZEN, 1 988). The family of E. coli K12 bacteria differs markedly from the naturally occurring E. coli wild strains and has been widely used since 1922. Meanwhile, several hundred variants have been developed from the original K12 bacteria. E. coli K12 has been very closely in vestigated as model organism for a wide vari ety of genetic, medical and biochemical inves tigations, and at present it is the best studied organism in biochemical and particularly in genetic terms (BACHMANN, 1 990) . By international agreement E. coli K12 is regarded, both by the scientific community and by the authorities (e.g., see Recombinant DNA Technical Bulletin 10, 1 987) , as harm-
less to humans, animals, plants and the envi ronment. Therefore, in genetic engineering E. coli K12 serves as host for cloning and expres sion of both prokaryotic and eukaryotic genes. This is one of the reasons, why the ear ly biosafety studies in the mid seventies were conducted with this bacterial strain. 8 . 1 Pathogenicity of Escherichia
coli
E. coli bacteria belong to the group of fac ultative pathogenic microorganisms with more than 90% of the variants characterized as completely non-pathogenic. The following pathogenic variants may cause intestinal in fections, i.e. , different forms of diarrhea: • • • •
enterotoxic E. coli (with cholera-like symptoms) enteropathogenic variants (infections in newborns) enterohemorrhagic E. coli (hemorrhagic colitis) enteroinvasive E. coli (dysenteric symp toms).
Extraintestinal infections are mainly those of the • • • •
urinary tract (uropathogenic variants) very rarely meningitis of newborns or septic infections, bovine mastitis and newborn chicken sepsis or enterotoxemic infections in pigs.
In contrast to the rare E. coli strains that are pathogenic to humans and which can cause the infections listed above, the labora tory strain K12 is not pathogenic (HACK ER et al., 1 991). Moreover, because of numerous genetic differences, it is even less harmful than the vital non-pathogenic wild strains of the genus E. coli which occur naturally in the human or animal intestine. In particular, E. coli K12 cannot form colo nies on the skin (ROMERO-STEINER et a l . , 1 990), on the nasal mucous membrane (WINKLER and HoeKSTRA, 1 985) nor in the
8 The Escherichia coli Bacteria or a n i m a l intestine ( A N D E RSON , 1 975 ). since it has lost the properties neces sary to adhere t o the intestinal cells. K l 2 has
h uman
lost the adhesive factors (fimbriae-adhesins) the reco g n i t i o n of oligosaccharide recep tors at the e u k a ryotic cell surfaces, it misses the K antigens n e c e ssary for pathogenicity. and the normal " smoot h·· lipopolysaccharide with the 0 antige n side-chains ( O RSKOV et al., 1 977 ) i s re d uced. No E. coli K I 2 bacteria have been detected in the feces of volunteers later t h a n 6 days aft e r oral administration ( LEVY e t al. . 1 980). and the lethal dose ( LD;;u) in mice IS 10 2 to 1 0 1 -fold compared to pathogenic wild strains. A b se n t . too. are v ir u l e nc e determinants such as the capsule antigens which are located at several sites of the bacterial chromosome (KL E M M . 1 985 ) a s well as the toxins necessary for pathogen icity ( L U PSKI and FEIGIN.
for
1 988) : • • •
enterotoxk ( heat-labile and/or heat-sta ble ) toxi n s . enteroinvasive t o x i n s . e n te ropa t h ogenic toxins.
E. coli K l 2 i � se nsitive to the acidic condi tions prevailing i n the stomach. a n d some la boratory strains are extremely sensitive to bile acids because of numerous mutations which cause � t r u c t u ral changes i n the outer cell mem brane ( WA L LACE et al . . 1 989). Whe n present in the tissue or in the blood s tre a m . t h i s la boratory s t r ai n is very sensitive to defe nse m e c h a n i sms ( HA H N and B R A N D E I S . 1 988) s u c h a s l ysozyme (TAYLOR and KROLL 1 983 ) and t h e immune response by a ntibod i e s or t he very effective bactericidal pr i n c ip les w h i c h are mediated by T-lympho cytes. granulocytes and macrophages (phago cy t os i s ) as w e l l as comple ment (TA Y L O R . 1 983 ) . Th e re a r e also no indications t h a t E. coli K l 2 wou l d cause autoimmune diseases. a nd even in the case of immunocompromised H I V patients no s p e c i fic gastrointestinal i n fe ct i ons h ave b e e n observed ( R u F and PO H L E. As
1 989) .
t he
p a t h ogenicity
o f microorganisms the specific t r ansfe r of oth t.: r v i r ul en ce factors such as col ici n e V o r h e m o l ysi n is not sufficient to trans-
d e p t.: n d � on a ' a riety of fa cto r s .
85
form E. coli K 1 2 i nto a virulent strain ( MIN SHEW et al., 1 978). Even the transfer of viru lence factors from Shigella jlexneri 2 a (SAN SON ETII et al. . 1 983) or from Yersinia strains ( lsBERG, 1 989 ) into E. coli K l 2 did not r e
store in vivo pathogenicity. The many functions described above which are missing in E. coli K l 2 are typical for wild type E. coli and are independent of each oth er. The many genes involved in the pathoge nicity of the facultative pathogen E. coli are distributed over the entire bacterial genome , and there appears to exist no means in nature to transfer these genes to E. coli K 1 2, which misses them. Hence the assessment that the introduction of foreign DNA into E. coli K 1 2 is safe as well. This classification o f E. coli K 1 2 has been practically proven by a study which was car ried out for a period of 12 months in a pro duction plant for recombinant interferon al pha-2a (WEIBEL a n d SEIFFERT, 1 993), that asked the questions: Can we observe changes in the anti biotic resistance of the gut flora of the staff? 2. Ca n we find the production organism or rONA in the gut flora of the person nel? 3 . Can we efficiently destroy the rDNA and resistance genes in the process? 4. Can we find anti-product antibodies in the serum of the employees? I.
Using various analytical
methods, includ
ing t h e polymerase chain reaction , no change
of the antibiotic resistance pattern nor rDNA was found in the gut flora, no anti-product antibodies were found, and the r O N A was completely destroyed in the process. These findings are in accordance with the data col lected and published in a report by the FO N D S DER I N DUSTR I E C H E M I SCHEN ( 1 993 ) . I n summary, E.
coli K 1 2 represents a com pletely non -pathoge n i c strain of the E. coli species. and the properties described above are the basis for the classification of E. coli K 1 2 as a biological safety measure in addition to technical safety measures as included in most regulations for gen et i c engineering.
86
3
Biosafety in rDNA Research and Production
8.2 Escherichia coli
in the Environment
E. coli bacteria disappear from the environ ment within a very short time, as they are sen sitive to dryness and react with UV light (E. coli K12 to an even greater extent) and can not demonstrably survive neither by a cryptic (non-discoverable) state of dormancy (DEVA NAS and STOTZKY, 1986) nor by drifting into deeper layers of soil (CoKER, 1983). No cases of transfer to birds ( GLANTZ and JACKS, 1 967) or long-term survival in sterile soils, in which neither competing microorganisms nor predatory protozoa or nematodes are present (ScHILF and KLINGMULLER, 1 983) , have been observed. Moreover, it has long been known that "the environment" is not "toxic" nor "lethal" to normal intestinal bacteria such as E. coli, but they cannot compete with "environmen tal" organisms and hence do not survive. E. coli bacteria are no environmental bacteria, but instead are adapted to the intestines of some mammals. As one gram of human feces contains about 10 6 E. coli bacteria out of a total of about 10 1 1 microorganisms (HOBSON and POOLE, 1988) , the approximately two million people living in the Rhein/Main dis trict in Germany alone produce 6--8 tons E. coli bacteria per day (other pathogenic micro organisms from hospital effluent and the bac teria liberated by domestic animals not taken into account) . The intestinal microorganisms are efficiently removed by competing micro organisms in sewage treatment plants, or they are removed from the environment within a very short time after soil fertilizing with man ure or sewage. The environmental problems sometimes associated with the latter examples resulted from the introduction of too large amo b nts of organic compounds like urea (over-fertilizing) but were not related to the release of enteric microorganisms. Thus "nor mal" E. coli bacteria, even in large quantities, do not represent any hazard to humans or the environment. This applies to an even greater extent to the comparatively less viable labora tory strain K12 whose chances of survival in nature are still further reduced, as has been demonstrated by many experiments and a
wealth of data. E. coli K12 therefore is classif ied as a safety strain and has a wide range of applications throughout the world.
9 Risk Assessment of Recombinant
Saccharomyces cerevisiae Strains
The generic name Saccharomyces cerevisiae was introduced by MEYEN in 1 838 for brew er's yeast. In 1 870, REESS distinguished be tween the beer yeast S. cerevisiae and S. ellip soideus, which also fermented fruit juices. Later on, S. cerevisiae was described by HANSEN as forming large spheroidal cells measuring 5-1 1 �m and as to be found in the sediment in hopped wort. VAN DER W A LT ( 1 970) classified more than 41 species within the genus Saccharomyces, the most important of which is S. cerevisiae for wine, beer and bread production, production of vitamins, en zymes, nucleic acids and their components, coenzymes, lipids as well as a live therapeutic agent itself. At present, only ten species within the gen us Saccharomyces are accepted (BARNETT, 1 992). Many well-known and long established yeast names (specific epithets) , though be longing to the genus Saccharomyces, are no longer.accepted as those in current taxonomy. Background of this is that no "correct" clas sification system for Saccharomyces species exists and the rules vary with the techniques used and the prejudices of taxonomists. Apart from E. coli, S. cerevisiae is one of the best studied organisms in the fields of cell biology, physiology, biochemistry and classi cal and molecular genetics. S. cerevisiae does not produce any toxins and is widely accepted for human consumption by both the consum ers and the authorities. With the advent of re combinant DNA technology, it was soon real ized that the new technique offered an enor mous potential for producing proteins of high commercial value. E. coli is not the ideal host,
9 Risk A ssessment of Recombinant Saccharomyces cerevisiae Strains
since this prokaryote l acks many post transla
•
t i on a l
•
modificat ion
systems. does not exhibit
S. cerevisiae S. cerevisiae
in
cannot assimilate nitrate tolerates high concentra
tions of sugars and a lcohol
the cell ular environment to express any euka ryotic prot ein
87
•
t h e correct folding and gen
S.
cerevisiae tolerates low p H values.
erally does not secrete prote ins into the cul
ture fl u id
Higher eukaryotic cells like animal tissue
.
The yeast S. cerevisiae has unequivocally bee n s h own to be an ideal host for modern
cult ure cells are highly restricted to specific media and growth conditions, which can only
biotech n o l o gy One of the first recombinant prote ins used in h u man medicine . the hepati tis B vi r u s surface antigen ( HBsAg), was ex p r ess ed in S. Cl.'revisiae. This recombinant an tigen has been proven to be highly immuno genic. and the s u b u n i t v ac ci n e is safe and in use worldwide ( STEPHENNE, 1 990). A n u m ber of heterologous proteins have also been
be
more , they are less demanding as regards nu
expresse d in S. cerevisiae. including lympho
ture and concentration of gas ) , and some of
.
kines, hormon e s and enzymes. Many of them
can now
be
produced in sufficient quantities
with appr op ri a t e
provided
in
laboratories.
Without any
doubt, t hese cells die immediately upon being set fre e into the environment. This is
general
ly not the case with m icroorganisms, since these in general exhibit a cell wall which pro tects the
cells
against physical stress. Further
trition and culture conditions (e.g., tempera them can develop cell forms like spores (ba
cil l i ) . which enable the cell to survive under
biological activities. A dd i tionally. an area of major interest is the strain i mprove ment of S. cerevisiae by genetic engi neering for its use in the food industry, e . g .. for the manufacturing of food i ng red i ents es pecially for b a k i n g distilling, beer- and wine making ( LA I' C i -H I N RICHS and HINRICHS,
disadvantageous conditions.
1 992 ) .
such investigations have been made . LIANG
,
So
far, many experiments have been car
ried out on the survival of bacteria, especially
E. coli,
in their natural environment as well as
under laboratory conditions resembling the natural
For
S.
ones ( DEVANAS
and
STOTZKY , 1 986).
cerevisiae, only a l imited number of
et al. ( 1 982) studied the survival of S. cerevi
9 . 1 Surviva l in t h e Environment The
n a t u ral habitats of S. cerevisiae are ripe
cerevisia e is
fruit and exudates
of tree
n ot foun d in the
atmosphere nor in aquatic
bark.
S.
habi t ats . m ari n e and river sediments, and was
siae laboratory strain G RF104
(not
trans
formed with any plasmid) and observed a de crease in living
cells
under various, non-ster
ile conditions. In a comparative study
KER,
(BRO
1 990) , the survival of a prototrophic iso
late of
S.
ce
revisiae
was compared with an
auxotrophic l aboratory strain and the labora
only occasiona l l y and temporally detected in
tory strai n transformed with a plasmid which
The yeast is trans
confers the expression of a h uman protein un
ferred from the fru i t to insects - mainly bees,
der sterile and non-sterile conditions. The
soil (DI MENI' A, 1 957).
wasps and flies like
Drosophila. A
number of
number of yeast cells declined slowly and
inve st ig a ti o ns ( B E N D A , 1 964) indicate that S.
continuously i n sterile water and sterile soil/
c
water s uspensions, whereas the yeasts died
ere v isia e
does not survive in the soil during
the winter. and that bees rather than wind
may p l a y
a
dominant role in the survival of
rapidly under non-sterile conditions
-
inde
pendent of the strain and whether the cells
yeasts and their distribution .
carried a plasmid or
This ecological niche is d u e to the fol low ing b i ol o g ic al fea tures of S. cerevisiae:
cerevisiae cells decay even faster than the
•
S. cere l 'isiae
s u ch
mainly
not. In a similar study, JENSEN ( 1 986) re port e d that recombinant S. wild-type strai n .
me tabolizes sugars
as gl ucose and galactose . but not pentoses like ribose and xylose nor po lysacc h arides l i k e starch. many fruit acids and s ugar alcohols
These studies indicate t h a t prototrophic
as
well as the auxotrophic laboratory strains of
S.
cerevisiae can survive in sterile medium for
a rather long time
(several
weeks), but that
they are el iminated quickly (within some days
88
3
Biosafety in rDNA Research and Production
or
less) upon introduction into the natural en vironment, because they are susceptible to predation, parasitism, lytic enzymes and tox ins produced by the indigenous microbial community. Up to now, no invasion of recom binant S. cerevisiae into the indigenous micro flora is expected in the case of an accidental release of yeast cells from a production plant, and no or only a limited interference with the existing community of organisms is expected. Since the essential factors such as the su gar-containing environment of grapes and berries would be lacking in the case of an ac cidental release of recombinant yeast and due to the specialized eco-niche of S. cerevisiae, a heterologous gene expression with respect to risk assessment has no relevance.
9.2 Saccharomyces cerevisiae
A Non-Pathogen
9.2. 1 Colonization of the Human Gut
The human gastrointestinal tract is colo nized with about 10 times more microorgan isms (10 14) than the human body consists of cells (10 13). The habitats of the microorgan isms are the ileum, the caecum, the colon as cendens and colon transversum. In addition, bacteria can be found in the duodenum and the jejunum in healthy humans, although they are normally not found in these regions. About 90 to 99% of all microbial flora are bacteria belonging to the Bifidus group, the Bacteroides group, streptococci, lactobacilli and the coli group. Only about 1 % or less of the microorganisms include aerobic spore forming bacteria, clostridia, staphylococci, pseudomonads and yeasts. S. cerevisiae does not belong to the normal flora of the gut in contrast to some other yeast species, e.g., the
genus Candida (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, C. pseu dotropicalis). These species belong to the commensal flora of the gastrointestinal tract, and more than 75% of the central-European people carry these yeast species. Candida cell numbers of 104 per gram of feces seem to be
without any clinical relevance, whereas higher numbers indicate immunological or vascular disorders. Mycological studies of feces iso lated from cats and dogs have shown that yeast can frequently be isolated (WEBER and ScHAFER, 1 993 ). In most cases, C. albicans was the yeast species found, but S. cerevisiae was also isolated. Nevertheless, there is no in dication that cats and dogs serve as a reser voir for infections of humans with yeast. For the treatment of functional disorders of the intestine such as colitis or diarrhea, commercial preparations (Perenterol®) of live S. cerevisiae Hansen CB S 5926 (synonym: S. boulardii) are available. More than 60 years ago it was shown that yeast can passage the human stomach without relevant loss in via bility ( MoNTGOMERY et al. , 1 930). This has been confirmed for S. cerevisiae by experi ments on the survival of the yeast in artificial stomach juice (GEDEK and HAGENHOFF, 1 988) and by several in vivo pharmacokinetic experiments in healthy volunteers ( KAPPE and MOLLER, 1 987 ) . When baker's yeast cells are introduced into the gastrointestinal tract of mice, nude mice, rats, cynomolgus mon keys or man, they do not multiply, but are eliminated with the feces either live or dead within a few days (PACQUET et al. , 1 991 ). The authors could not find any evidence for the passage from the intestinal lumen to any oth er part of the body. However, in the hypo thetic case that S. cerevisiae cells would pass from the intestine to the lymphatic system, the majority of the cells would probably be persorbed in the liver and would therefore never reach the peripheral sites, due to man nose receptors of the liver macrophages clear ing the yeast cells effectively from the circula tion. In the early stage of infection, the man nan-binding protein (MBP) found in the se rum may play a role prior to the generation of the specific humoral and cellular defense sys tem directed against yeasts. The MBP is a se rum lectin, which can act as an activator of the classical pathway of complement after binding to the suitable carbohydrate ligands (THIEL, 1 992) .
9 Risk Assessment of Recombinant
9.2.2 Possi b l e Signs
S. cerevisiue
of Pathogenicity
M a n y myce l ial fungi and yeast. which are non-pathogenic for healthy humans or which even belong to the normal commensal flora of the human skin or the gut, such as Candida or Torulopsis. emerge as major nosocomial pathogens in �eriously weakened patients. These opportu nistic microorganisms include seve ral species of t he ge nus Candida , Fusar ium a n d Trich os1wron as well as Malassezia filrfur (MARC< lN and POWELL. 1 992), Crypto coccus neoformans and Torulopsis glabrata. H igh - ri s k patie n ts include those with leukem ia. s o l id tumors and leukopenia, bone marrow transplant reci pients. patients with gastroin testinal disease�. burn patients. HIV patients and premature infants ( PFALLER and WEN
1 91J2 ) . Desp i te considerable human oral uptake of foods produced by means of adding live S. ZEL.
cerevisiue
and t h e occasional presence of this yeast in normal oral and gastrointestinal tract flora . S. cern isiue is generally regarded as non-p athogenic. F u r t he rmore , live S. ce re v i siae CBS 5926 ( Perenterol®) has been orally adm i n istered as a prophylaxis and therapy for diarrhea. enteritidis and colitis for many years to both adults and children with good results
(RIECKHOF, 1 �43 ) .
There are o n l y very fe w case reports o n S. cere visiue as a human pathogen. The first re port concerned
a septicamia
probably caused
( ESCHETE a n d BURTON, 1 980) nosoco mially i n a hyperalimented burned man . Fungemias caused by S. cerevi siae have bee n described in immunocom by
S.
Saccharomyces cerevisiae Strains
cerevisiae
promised patients with chronic renal failure ( CIMOLAI et a l . . 1 987 ) . mi tral prosthetic valve ( R u BINSTEIN et a l . . 1 974). postoperative peri not itis ( Douc i H ERTY and SIMMONS, 1 982) . leukemia ( E N n et a l . . 1 984) and in a patient with A I D S (SLTI-! IA and M ANDELL, 1 988) . Vulvovaginal i nfections have also been de s c r i be d ( N ICO L . ! e t a l . , 1 974 ) . This list is of course not complete. and the number of cases will i ncrease with the number of immunocom promised humans studied. especially tumor and A I D S patients. However, it must be em phasized that t h ere is no indication classifying
89
as a potential pathogen for heal thy persons. The interconversion of a yeast form to a fil amentous form is typical of many pathogenic fungi, e.g., Candida albicans and Malassezia furfur. GIMENO et al. ( 1 992) reported on a di morphic transition of S. cerevisiae which in volved changes in cell shape and resulted in invasive filamentous growth under nitrogen limiting conditions. Thus, the genetic poten tial of S. cerevisiae in its filamentous state has yet to be established. McCUSKER and DAVIS ( 1 991 ) have char acterized an S. cerevisiae strain isolated from an AIDS patient. This clinical isolate has some unusual properties, as it can grow at 43 °C, a temperature at which laboratory strains are completely unable to grow. Fur thermore . the isolate is able to secrete a pro tease as determined by liquefaction of gelatin. I n this context i t is interesting to note that protease secretion is thought to be a virulence factor in pathogenic fungi. In addition, the authors found that the cell and colony mor phology can switch between multiple colony and cell-type forms. So far, there is no evi dence of S. cerevisiae causing disease , and no death has been observed, when clinical S. cer e visia e isolates were tested in experimental animal infections. These results were ob served despite the fact that large numbers of cells ( 1 06-107 colony-forming units) were in jected intravenously into mice. It is very unlikely that clinical strains could cause problems for healthy persons. The "vir ulence " of the clinical S. cerevisiae isolates ap pears to be a quantitative trait polygenic with complex additive and epistatic effects. Realis tically, a person who is so debiliated as to har bor S. cerevisiae, is at a far greater risk of in fection from commensal yeast (e.g. , Candida albicans) or other opportunistic or pathogenic microorganisms found in the environment. There have been reports of patients suffer ing from repeated attacks of alcoholic intoxi cation without any prior intake of alcohol. This is called "intragastrointestinal alcohol fermentation syndrome" or " autobrewery syndrome" (KAJI et al., 1 984). This syndrome can be caused by yeast, mainly those species belonging to the Candida group, but also by S. cerevisiae. if they have proliferated abnor-
3
90
Biosafety in rDNA Research and Production
mally in the gastrointestinal tract. This rare syndrome consists of the following essential factors: •
•
• •
parasitism and abnormal proliferation of the causative agent (yeast), which is capable of alcohol fermentation in the alimentary tract, abnormal stagnation of foods caused by organic or functional disorders of the alimentary tract, intake of a carbohydrate diet as the substrate for the alcohol fermentation, a low threshold of the host patient to alcohol.
High ethanol concentrations of up to 19.7 mgldL blood in a patient have been re ported among a group of patients with a vari ety of disorders and clinically suspected yeast fermentation who had been orally loaded with large amounts of glucose after an over night fast (HUNNISETI et al., 1990). The autobrewery syndrome has also been discussed as playing a role in the etiology of "sudden infant death". BININ and HEINEN (1985) studied the ethanol production of some yeast species including S. cerevisiae, when grown on infant food formulas and sup plements or Coca Cola. The highest alcohol production was determined, when S. cerevi siae was cultivated in infant food prepara tions, but additional studies are needed to de termine if there is a relationship between ethanol production in the gastrointestinal sys tem and of "sudden infant death".
9.2.3 Allergy Allergies to fungi are an increasing prob lem and are correlated to the increase of tech nically produced hydrolytic enzymes from fungi for industrial purposes or as compo nents of food. Furthermore, hydrolases are added to creams, perfumes, toothpastes, etc. and are used in the production of textiles. Several hundred tons of glucoamylase from Aspergillus or Rhizopus are produced every year, and hydrolases, beta-amylase from As pergillus, cellulase from Penicillium or inver tase from Saccharomyces are produced and
used in high amounts in various industrial productions (SCHATA and JORDE, 1 988). In contrast to many other mycelial fungi and yeasts (e.g., Candida ) (GuMOWSKI et al. , 1 991), S . cerevisiae does not seem t o b e a cau sative agent of allergic reactions. Even after more than 35 years of Perenterol® produc tion, no allergies have been observed in the workers of the respective production facilities (GEDEK and AMSELGRUBER, 1 990). When ever allergic reactions to beer have been ac counted to S. cerevisiae, thorough investiga tions led to the conclusion that the allergens originated from the Fusarium species which enters the beer via the hop ( J OR DE , personal communication). Besides this assessment, the following two observations need to be dis cussed: BALDO and BAKER ( 1 988) reported on all ergic reactions to enolase from yeast and showed a high cross-reactivity between the enolases from S. cerevisiae and from Candida albicans. Recently, the eDNA of the enolase from C. albicans has been cloned (SUND STROM and ALIAGA, 1 992) . The analysis of the predicted amino acid sequence of the C. albicans enolase showed strong conservation structure with the enzyme from S. cerevisiae. The enolase is a major circulating antigen in patients with disseminated candidiasis, al though the enzyme is not present on the sur face of C. albicans. Regardless of the true source of the fungal hypersensitivity, the au thors conclude that S. cerevisiae enolase may prove to be useful for diagnosis of fungal hy persensitivity in at least a population of sub jects showing symptoms of inhalation of molds. Raised levels of antibodies to S. cerevisiae have been found in patients with Crohn's dis ease, but not in patients with ulcerative colitis when compared with normal controls (McKENZIE et al. , 1 990; LINDBERG et al. , 1 992) . The patient sera reacted preferentially to a cell wall-associated, water-soluble and heat-stable glycoprotein of S. cerevisiae (HEELAN et al., 1991 ). It has been suggested that the immunological sensitization can oc cur in man through ingestion of products from brewing and baking. Recently, GIAFFER et al. ( 1 992) concluded from their findings that the presence of IgG antibodies to S. cere-
9 Risk Assessment of Recombinant Saccharomyces cerevisiae Strains
vlsta e i s chara.:teristic but not specific to Crohn's disease . Nonetheless. the immuno logical basis for the association of an immune re sp o ns e to this S. cerevisiae ant igen in Crohn's disease a n d th e p a th ogenic i mp o r tance of raised l gA antibody levels in Crohn's disease remain to be explained. R e c e nt l y , SA VOLA I N EN et al . ( 1 992) a nd KORTEKANG AS SAVOLA I N EN e t al. ( 1 993) r e p or ted that the severity of a t o p i c dermatitis. studied in a pop ulation of more than 200 patie n t s . correlated with the skin prick test response to S. cerevi siae. The correlation in turn correlated with serum t ota l lgE and s k i n pr ic k test response to other yeast spe ci e s studied, e.g., C. albi cans . Crypotococcus albidus and Pityrospo r u m ovate. B e c a use there was a skin r esp o n s e to a l l yeast sp ec i e s tested, one m ay conclude that the causative agent was not S. cerevisiae but a no t her yeast sp ecies with c ro ss - re ac t i n g antige n ( s ) . e.g . . t he eno l a s e . One of the m o s t c o m mo nl y used re c o m b i nant protein i so la t ed from S. cerevisiae may be the surface a nt ige n of the h epa t i t i s B virus (HBsAg). Intensive studies on the immuno genicity and the r e a cto ge nici ty of the yeast derived hepatitis B v accin e have shown that t he re were no s i g n i fic a n t differences in the immunogenicity and re a c t o genicity when com pari ng the recombinant and the plasma derived vaccine . I n ad d i t i o n . no signs of vac cine-induced hypersensitivity were o bse rv ed ( WIEDERMAN N et a l . . 1987 ) . No significant c ha nge s i n t h e levels of a nt i yeast lgG or l g E a nd no new species of a nti yeast antibodies were observed after vaccina tion with the r ec o mb i n a nt h ep at itis B vacc i ne (WIEDERMANN et al.. 1 988 ; ANDRE, 1 987 : DENTICO et al ., 1 992). This indicates that pu ta t i ve yeast contaminants a ppa re n t l y play no major ro l e aft e r i mmun i z a t i o n with the re combinant h e p a ti t i s B vaccines. C ompa r ative ly good toleration should be e xpe cted when other re com b i n a nt pro tein s isolated from S. cerevisiae come into clinical use. which have been highly p u r ifi e d .
91
9.3 Plasmids and Gene Transfer
9.3.1 Expression Plasmids vectors which are used to n orm all y E. coli/S. cerevisiae shuttle vectors. T he p r o k a ry o ti c part u su a lly originates from pBR322 or deri vatives t here o f and therefore contains the Coi E 1 type of o ri g i n of replication, the a mp i cillin res i s ta nce marker and/or the t e t r acy cline resistance marker. This arrangement al lows E. c oli to be used as a p ri m ary host cell for v ar io us m a nipul a ti o ns associated with DNA. The eukaryotic part of the shuttle vec tors is b a sed o n t wo t ypes o f re pl i c a ti on sys tems. The fi rs t is dependent on chromosomal DNA fr a gm ents isolated from S. cerevisiae and contains auton o m o u s ly rep l ica t ing se quences ( A RSs). The second type of shuttle vectors is based on elements derived from the e ndogenous ye a st 2 J..L m p l a s mid . The A R S- b a se d vectors can transform S. cerevisiae e ffi ci e ntly and can replicate to a high copy n u m b e r within th e nucleus of the c e l l s , but they are m i t o ti call y very un stable under non-se lective and even under selective conditions. Therefore , A RS-based vectors are cu rren t ly of limited use for biotechnological purposes . Th e ins t a b i lity of the ARS vectors can be over come by the add i t i on of a segment of DNA o rigina t i n g from the yeast ce ntro mere . These CEN v ect o rs also transform S. cerevisiae w it h high effi c a cy , are almost en tirely st a bl e and are maintained at a cop y number of 1 -2 per cel l . This low co py number is of di sadv a n ta g e in m ost biotechnical pro cesses. be c a use the c l o n e d gene of interest consequently has the same low copy n u mb er . Hence the p ro duc t ion yields are relatively low. Most of the expression vectors are based on the 2 J..L m pl asm id . T hi s pl a smid is present in most lab orat ory strains of S. cerevisiae at a copy n u mb e r r a nging from 20 t o 200 per cell. It is a c i rc u la r molecule of 63 1 8 bp c ont ai nin g two inverted repeats of 599 bp, and the repli cation o f t h is pl a sm i d and its maintenance in the cell are dep e nde nt on two cis- ac ting ele ments ( o r i gin of r eplicati o n and REP3 or STB ) and two tra ns - ac t ing elements (REP1 and REP2 ) . In addition, there is a major codThe
pla smid
t r a n sfo rm S. cerevisiae are
92
3
Biosafety in rDNA Research and Production
ing sequence, the FLP gene , encoding a re combinase which mediates site-specific re combination between the inverted repeats (MEACOCK et al., 1989). Vectors based on the essential function of the natural 2 1-1m plasmid can be used to transform S. cerevisiae at high frequencies and are maintained at copy num bers ranging from 20 to 400 per cell. The expression plasmids are generally transformed into laboratory strains which are auxotrophic for amino acids (e.g. , leucine, tryptophan) or bases (e.g., uracil, adenine), and the selection is carried out by the respec tive functional genes cloned into the plasmid. That means, a yeast strain which has the ge netic markers leu2 or ura3 can be trans formed with a plasmid which harbors the LEU2 gene coding ,8-isopropyl malate dehy drogenase or which carries the URA3 gene coding for orotidine 5-decarboxylase. Strains with double or triple markers (e.g., leu2, ura3, trp1) and which are transformed with an ex pression plasmid that carries only one selec tion marker (e.g., LEU2) are still auxotrophic for the other marker(s); in this case: ura3 and trp l . Therefore, the transformants have to be supplemented with the amino acids or bases which they cannot synthesize when grown in minimal media; but these transformants usually have no markedly retarded growth rate or other disadvantages under laboratory conditions. Besides the selection of transformants by means of complementation of defects in en zymes of the biosynthetic pathway, vectors have been developed with dominant selection markers. These plasmids confer, e.g., resist ance against antibiotics like G418 or heavy metals like copper. Nevertheless, such selec tion systems are only rarely used, and such plasmids are mainly introduced when proto trophic strains have to be transformed where no selection based on complementation of basal enzymatic activities is possible. When yeast strains are transformed with plasmid to express heterologous proteins either on labo ratory or industrial scale, this is normally not the case. Besides the essential sequences which are needed for the selection and propagation in E. coli and S. cerevisiae, these shuttle vectors contain yeast-specific promoters (transcrip-
tion IDltiatwn elements) and transcription termination elements. These DNA elements are in nearly all cases derived from genes of S. cerevisiae to fulfill optimal expression. It is unusual to observe transcription of a hetero logous gene in S. cerevisiae because baker's yeast is usually unable to accurately initiate transcription on a heterologous promoter even when it originates from a eukaryotic cell. In most cases, either no transcription takes place or an aberrant transcription, e.g., from the promoter of the Dictyostelium dis coidin I gene (JELLINGHAUS et al. , 1 982) and the bean phaseolin gene (CRAMER et al. , 1 985), can b e obtained. Although promoters of S. cerevisiae are highly efficient only in this species, there are examples of S. cerevisiae genes being ex pressed in other yeast species. These include genes from the biosynthetic pathway, e.g. , the L E U2 gene and the URA3 gene which are ac tive in the fission yeast Schizosaccharomyces pombe and can complement leu1 and ura4 auxotrophies in this species. Constitutive pro moters from the S. cerevisiae ADC I gene (al cohol dehydrogenase I) and CYC I gene (iso1 -cytochrome c) have even been used to allow the expression of heterologous proteins in S. pombe under the control of these transcrip tion initiation elements (B R O KER et al., 1987) . Although S. cerevisiae promoters are normally not functional in prokaryotes, it cannot be totally excluded that certain yeast DNA sequences may have promoter activity in bacteria. KoRMANEC ( 1 991), e.g., identif ied a DNA fragment from S. cerevisiae by chance which acts as a promoter in E. coli. This DNA sequence, part of the S. cerevisiae POP/ gene, exhibits the optimal promoter consensus structure ( - 35)TTGACA - 1 7 ± 1 bp - ( - 10)TATAAT. This may be interest ing in evolutionary terms. Yeast promoters contain many of the ca nonical sequences common to higher euka ryotic promoters, although the locations of these sequences, namely the "TATA" box and the "CAAT" box, are more heterogene ous than observed in higher eukaryotes with respect to the mRNA start site(s). Yeast genes also contain upstream cis -acting ele ments (upstream activator sequences; VAS) , which modulate transcription.
9 Risk A ssessment
of Recombinant Saccharomyces
The GA L l and GA L l O divergent promot ers contain a UA S sequence at which the G AL4-e ncoded protein binds for optimal transcription. In 5. cerevisiae. the GA Ll and GA L l O promoters are repressed in the pres ence of glucose . but are induced when glucose i s replaced by galactose . This is regulated by the binding of the GA L4-encoded protein at th e VA S of the GA L J I GA L JO promoter re gion (JOHNSTON. 1 987). Whenever this posi tive regulator protein interferes with the GAL80 e ncoded regulated protein in the presence of glucose or when the GAL4 pro tein is absent. n o transcription of the GA Ll or GA L l O promoter-controlled expression can be observed. This explains why promot ers like the CiA L l / GA L J O are much more species-specific than constitutive promoters from glycolytic genes. I n fact. the GA L l i GA L l O promoter is not even active in the fis sion yeast S. pomhe (which does not synthe size a protein functionally related to the S. cere1·isiae GAlA encoded protein). unless the S. cerevisiae GA L4 gene is cloned in addition into the GA L / iGA L / 0 promoter containing plasmid ( B RO K F R. 1 990) .
9.3.2 Gene Transfer Gene transfer between microorganisms has been investigated intensively since the discov ery of the phenomena of bacterial transfor mation, conjugation and transduction in the 1 950s and 1 960s. The frequency of gene trans fer and its implication for risk assessment. es pecially in resp..:ct of ge n e transfer between bacteria. has been discussed in Sect. 7 . Among the possible gene transfer mecha nisms within yeast . no transduction has been detected so far. and no yeast viruses have been identified. Rctrotransposons (or virus like particles, V PL) are well known in yeast and have been intensively characterized. but these VPLs are non-infectious. and no hori zontal transfer has been detected ( WICKN E R . 1 992 ) .
Transformatilm o f S. ce re vis iae with plas mid DN A is routinely- carried out in molecu lar biology laboratori es. S. cerevisiae cells are not competent t o pick up DNA during certain stages of their li fe cycles as, e.g., Bacillus sub-
cerevisiae Strains
93
tilis is. On the contrary, tedious procedures
have to be carried out in order to transform S. by plasmid DNA. To make S. cere visiae cells competent, they have to be grown under special conditions, the cells are then treated in special buffers, containing lithium salts and/or polyethyleneglycol and are heat shocked. By improvements of this transfor mation protocol, up to 1011 transformants/,_.,g plasmid DNA can be obtained. Alternative transformation procedures are either the elec troporation (DELORME, 1 989) or the transfer of DNA into cells which have been converted into protoplasts upon digestion of the cell wall with lytic enzymes (HUBBERSTEY and WIDEMAN, 1 99 1 ) . A n inspection of the trans formation protocols published by the above mentioned authors makes evident that the transformation of S. cerevisiae cells by the mechanism of transformation needs special requirements. These can only be provided un der artificial laboratory conditions. No DNA transformation of S. cerevisiae cells has been reported so far where the cells have not been made competent. Conjugations between bacteria and yeast h av e been observed recently under experi mental conditions, between E. coli and S. cer evisiae (HEINEMANN and SPRAGUE, 1 989} and Schizosaccharomyces p om b e (SIKORSKY et al., 1 990) . The DNA transmission mecha nism from E. coli to yeast is physically and ge netically comparable to a conjugal DNA transfer between bacteria. The frequency at which DNA is experimentally transmitted to yeast by bacterial conjugation is similar to the frequency of transmission observed in crosses between bacteria. D uring the conjugational event, the thick yeast cell wall must be by passed to allow productive cell to cell contact. This might occur during a discrete stage of the cell cycle. The transfer and the establish ment of the plasmid in S. cerevisiae does not need yeast-specific ars sequences for stable replication of the incoming DNA. N ISHIKA WA et al. ( 1 992) have shown that foreign plas mid DNA can integrate into the recipient host chromosome by recombination e vents. However. integration is rare, probably be cause, like E. coli, S. cerevisiae demands ex tensive sequence homology between mole cules before it permits their recombination. cerevisiae
3
94
Biosafety in rDNA Research and Production
Bacteria-yeast conjugation is a laboratory phenomenon of horizontal gene transfer. At present, this process is of uncertain biological significance. In the natural environments of S. cerevisiae, e.g., in ripening fruit, many bacte ria are found which carry conjugal plasmids. In the case of such a conjugal DNA transfer from prokaryotes to yeast, the foreign DNA must enter the nucleus and must be replicated in order to be passed onto the yeast daughter cell(s). There are some examples known from the literature that prokaryotic sequences can be replicated in S. cerevisiae, e.g., broad host plasmids like RP4 and staphylococcal plas mids (GouRSOT et al., 1 982). However, such DNA sequences are unstable, replicate only transiently and are not established in the new host cell. Conjugational transfer of genes from yeast to bacteria or from one yeast to another have not been reported so far. By means of plas mids with the right choice of replicons and se lection markers such an event should be eas ily detectable under laboratory conditions if it occurred.
1 0 B iosafety Aspects of
Animal Cell Cultures
The use of animal cells in tissue culture for the production of pharmaceuticals and as a tool of biomedical research has a history which dates back at least five decades. Issues of biological safety pertaining to the use of tissue culture are therefore not new (PETRIC CIANI, 1 987). The recent introduction of re combinant DNA techniques, however, has broadened and widened the scope of tissue culture applications to such an extent that safety questions must be reconsidered in the light of these developments. Mammalian cells in culture are currently employed for the following purposes: • •
propagation of viruses for vaccines pro duction, tools for biomedical research, i.e. , for the study of transcription and replica-
•
• •
tion patterns as well as mechanisms of growth control, sources of nucleic acids for the prepara tion of genomic and eDNA libraries, sources of proteins, sources of recombinant eukaryotic pro teins which cannot be expressed in bac teria, i.e., proteins of high molecular weight and with extensive posttransla tional modifications.
The safe handling of mammalian cells criti cally depends on the origin and the status of the cells in question. In tissue culture we dis tinguish between primary cell culture and es tablished permanent cell lines. Primary cul tures are obtained from explants of tissue or from organs. They can be propagated only for a very limited number of passages and have been used to produce the early polio vaccines (summarized by HILLEMAN, 1 990). The use of such cells may be quite hazardous because, if prepared from free-living animals, they may be contaminated with pathogenic viruses, bacteria, mycoplasms, fungi, and other para sites of the donor organism. There are only very few instances of laboratory infections, however, which could be traced back to con taminated cell cultures. Among these are the outbreaks of Marburg virus infections in the sixties as well as the contamination of polio vaccines with the oncogenic Simian virus SV40. Such infections can arise in animals even after long periods of quarantine and are particularly disturbing in view of the constant danger of unknown and therefore non-detect able viruses. Primary cells, if kept in culture for ex tended periods of time, undergo a "crisis" from which they may recover as permanent cultures that can be cultured almost indefin itely. This is true for cell lines derived from the Syrian hamster, the Chinese hamster, and the mouse. Cells, however, derived from hu mans and chicken, invariably fail to survive cell culture conditions and thus do not give rise to non-malignant continuous cell lines. In these cases, primary cell cultures can be im mortalized and thus developed into contin uous cell lines by transformation with tumor viruses or oncogenes. Immortalized cells can be obtained also directly from tumors and
10
de velop into perma nent malignant cell lines. Hybridomas. which are h y b ri ds of nor mal and transformed lym p hoc y t e s . also be lo ng to t h is category. Most permanent and m a l i gn a nt ce ll lines are a ne uplo id i.e .. they do not contain the proper d iplo id set of chro m oso me s M a ligna nt as w e l l as n o n mal i g n a n t continuous cell lines possess features that are pa rt i c u l ar l y relevant to t h e i s s u e of b iolog i c al safe t y :
often
,
.
•
-
t h e transformed character of some of t hese cells.
• •
the possi b l e contamination w i t h viruses and t h e risks associated with the use of viral vectors.
1 0. 1 Risks Associated with the
Transformed Characte r o f Tissue Culture Ce lls Protooncoge nes are n o rma l const ituents of tissue c u ltu r e ce l l s The y are part of endoge nous r e t ro v i r a l genomes present in birds and .
m am m al s i.e i n many. if n ot all. tissue cul ture lines de r i ve d thereof. Germ line DNA from all inbred strains of mice c ont a in s about 50 copies of murine leukemia virus-related se quences (STOVE a n d Co FFI N . 1 988) . Among the n o n - de fect i v e p ro v i r us e s we dist ing uish e cotro p i c xe no t ro pi c and polytropic viruses. Ecot rop ic viruses can re p l i c a te on ly within their host cells. x en o tro p ic viruses replicate only on non-host cells. while polyt ropic vi ruses in general have a very b ro ad host range . It is th ou gh t that most . if not all. inbred strains of m i c e share a s in g l e female ancestor (FERR I S et a l . . 1 982 ) . The observed differ ences in the p rovi ra l content of d iffe ren t inbred strains wh ic h ha v e con s is t en t l y been observed and docume nted thus must arise b y (a) the m o b il i t y of some of the prov i ru se s and (b) by the d i fferential fix a t ion of the provi ruses dur i n g different i nbreedi n g s t r a teg i e s There is no doubt t h a t the horizontal transfer of x e n o t ropic provi ruses can cause i n sert i o na l m u tag e n e s i s a n d that these viruses can b e c o m e p ar t n e rs i n recomhinational processes .
..
.
.
Biosafety Aspects of Animal Cell
Cultures
95
leading to novel types of retroviruses, i.e., variants with a different host range. The human genome con t a in s thousands of endogenous r etro v ira l copies. As far as we know t h e y are all defective , i . e . , they contain only pse u do ge ne s or lack parts of the ele me nt s re q ui red fo r p rovi ra l activation and re p l ic ati on . Their ancestry has been studied in considerable detail (MARIANI-CONSTANTIN I e t a l . , 1 989) . Some a r e related to rodent intra cisternal A-particle genes (ONO, 1 986) , s om e to simian sarcoma v i r u s sequences. Re ce ntly it was shown that some even are related to human i mm u no defi c i en c y virus type 1 (HoR WITZ e t a l 1 992 ) . Two of these e n doge n o u s sequences. named EHS-1 and EHS-2, d i s pl ay sequence s im i l ari ty with the domain of t h e enve l ope protease cleavage site of HIV-1 and with the overlapping reading frame for Rev and gp41 . A va r i et y of reports have demonstrated that e n doge nous prov i ru s es can be expressed in both normal and m ali g n a n t human cells ( re v i ew e d in LA RSSON e t al. , 1 989) . Expres sion o f e n dogen ou s retrovirus genes can also be induced by X-ray irradiation and cer tai n mutagens. e.g . . 5 - a zacy t i di n e ( H S I A O e t al . . 1 986) . a l t hou g h i n human cells many i f not most of the p r o v i ral genomes are unavailable for e x p re s s io n Infectious r e t rov ir u ses corre s p o n d in g t o en do ge no u s proviral genomes t h u s are probably quite rare and therefore do not pose health hazards to anyone wo rk i n g with human t i s s ue c u l t ure ce l l s . The situation is quite different in the rodent system. Here e n doge no us p r o vi ru se s can be readily in duced a n d activated (STO Y L E and COFFIN . 1 987) . U s i n g RNA fingerp r in t i n g t e c h n i q u e s and PC R m e t h od o lo gi es they can be easily identified and followed anal yt i ca l l y (SHIH et al.. 1 991 ). ..
.
.
The transformed character of tissue culture cel l s can a lso be in duced by DNA tumor vi r u s es e.g .. papil loma a n d certain herpes v i ruses. P a p i l l oma viruses cannot be propa ga t ed in most tiss u e culture cells (zuR HAu SEN, 1 98 1 . 1 99 1 ) e x c ept i n k e r a tinocyt es (MuNGAL et al.. 1 992 ) . Bovine papilloma v i .
rus. however, is able to transform bovine and m ur in e cells in c u l t u r e . The transformed cells ge n e ra lly carry the viral genome in an e pi so mal form . In humans, common skin warts do
96
3 Biosafety in rDNA Research and Production
not convert into malignant tumors while some papillomas, e.g., certain types of genital warts, have strong tendencies to undergo malignant conversion. Tissue culture cells derived from these tumors, for example, HeLa and their derivatives, but also primary cells derived from cervical carcinomas, contain human pa pilloma virus genomes in both integrated and episomal forms (ScHWARZ et al., 1 985; BEAUDENON et al., 1 986). Some human tumors, for example, Burkitts lymphoma and human nasopharyngeal carci noma, are thought to be connected with a hu man herpes virus, the Epstein-Barr virus (EBV) (MARX, 1989). Cancerous cells de rived from these tumors, for example, B- and T-lymphocytes, harbor the EBV genome in a circular form. EBV infection is often used to immortalize human B-cells and to establish continuous B-cell lines. A well known exam ple of such a cell line is the Namalva line which is widely used in vaccine production. It is transformed by EBV and carries an EBV genome which, however, is thought to be de fective. Since EBV is also the cause of infec tious mononucleosis in man, cell lines derived from EBV-derived tumors must be treated under the biosafety level conditions required for experiments with EBV virus (biosafety level 2). There is little doubt then that genomic DNA from tumor cell lines carrying non-de fective endogenous retroviruses and/or on cogenic papilloma viruses or EBV genomes must be treated with considerable caution. An immediate skin contact certainly must be avoided. Several reports in the literature at test to these difficulties. DNA derived from the cloned viral gene v-src, if infected into chicken, can induce tumors at the site of in jection (FuNG et al. , 1 983), and human T24 H-ras gene preparations induce tumors when rubbed onto the surface of the skin of mice (Bu RNS et al., 1 991 ). In these cases, however, homogeneous oncogene preparations were used, while genomic DNA would contain eight orders of magnitude less of a particular oncogene at a given DNA concentration (LOWER, 1990). In addition, oncogenesis is a multistep process both in vitro and in vivo. The risk of developing tumors by working
with genomic DNA even from malignant cell lines must be regarded as remote. Nevertheless, the "Pasteur incident" is not forgotten. It relates to the observation of five fatal rare cancers in 1986 at the Institut Pas teur, Paris, among workers younger than 50. The matter has never been fully elucidated, although a mortality study among 3765 peo ple who had worked for at least 6 months in the Institut Pasteur between 1 971 and 1 986 was initiated following these incidences (CORDIER, 1 990). The study showed that the total mortality was less than expected com pared with national rates, but that certain groups of people working mostly in bacteriol ogy laboratories had an excess risk of death from bone, brain and pancreatic cancer. No connection was found as to the suspicion that some of the observed cases might be linked to chemical carcinogenesis. Nevertheless, both British and German authorities have recently given a strong advisory to avoid the simulta neous use of oncogenic nucleic acids and chemical or physical carcinogenic agents. In this context it may be reassuring to know that DNA from tumor samples of two molecular biologists who had died from malignant lym phoma and adenocarcinoma of the colon, re spectively, and who had worked with SV40 vi rus as well as SV40 transformed cells did not contain SV40 DNA, even when assayed with PCR techniques. Since transformation with DNA tumor viruses requires the viral genome to be present in the transformed cells, SV40 cannot have played a part in these tragic inci dences (HowLEY et al. , 1 991 ) . Direct contact should also b e avoided with intact, full-length proviral DNA from retrovi ruses. In a recent study, recombinant bacte riophage lambda DNA containing SlY-provi ral DNA was injected intramuscularly into M. fascicularis monkeys (LETVIN et al. , 1 991 ) . All animals not only seroconverted within several weeks of inoculation, but also intact SIV particles could be isolated from peripher al blood lymphocytes of most of the trans fected animals. The study suggests that viral nucleic acids are not only infectious in tissue culture but also in vivo in their permissive hosts.
10
1 0.2 Contami nation of Cell Lines with Viruses Con t a m i n a t i o n s o f t i s s u e culture cells with v i r us e s may have various or ig i n s . They may be the results of acute o r latent infections of the donor. a n d hence cells and o r ga n s taken from such donors are mos t l i kel y a l so infected with these a g e n t s . Other pot e ntial sources fo r contaminations are me dium additives. for ex ample .
seru m .
hormon es.
growth
factors.
from other sources with in the la b orat o ry may also be a facto r to b e con s i d er e d . T h e p o t e n t i a l h azards of p r i m a ry h uman cell lines a r e mainly associated with human i mmunodeficiency virus ( H I V ) . he pa t i t i s B ( H B V ) and h e p a t i t i s C virus. PCR technology and sensitive i m m u no ass a ys can be e mployed to readily ascertain whether such infec t ions are to be e x p e ct e d in material d e rived from pa r t ic ula r donors. P r i m a r y cells from non - h u m a n p r i m at e s can be co n t a m i na t e d by simian foamy virus ( S FV ) ( T E I C H . 1 984 ) and s i m i a n immunodefi ciency virus ( S I V ) ( D A N I E L e t a l . . 1 985 ) . Most A frica n gre e n monkeys kep t i n c a p t i v i t y are i nfected w i t h these viruses ( K A N K I et a l . . 1 985 ) . although t h e y d o not show a n y symp toms of disease . When transferred to ma caques. an Asian old world p ri m a te . t he l e n Cross-contami n a t i o n
t ivirus S I V . howe ver. i nd uces H I V-Iike symp toms in these a n i m a l s . W h i l e foamy viruses are not k nown to i n d u c e d i seases in natural herds as we l l as i n l a b o r a tory a n i m als ( C o F FI N , 1990 ) . S I V - re l a lt:d l e n t i v i ruses h av e bee n
isolated from h u m a n s i n We s t Afri ca. In
or der to minimize hazards associated with the use of p ri m a ry cult ures derived from non-hu man p ri m a t e s. these cells should be kept i n biosafe t y level 2 co n t a i n m e n t fa ci l i t i e s . A m o n g the r i s k s of t i ssue c u l t ure asso ciated w i t h e xoge n o us s o urce s looms the specter
of contamination
from se r u m . I n m ost
cases i t s s o u rce is fr o m c a t t l e . as fe tal calf or calf s e r u m . While m a n y of t he more com mon bov i n e virus d i s e a s e age n t s can be a ss a y ed
read i l y and t h e re fore a v o i d e d . a major
cern
ciated
co n p o t e n t i a l risk asso s p on g i fo rm e ncepha lopa
remains with the w i t h bov i n e
thy ( B S E ) . one
of fo u r prion diseases recog-
Biosafety Aspects of A nimal
Cell Cultures
97
nized in animals. The disease was first identif ied in Britain i n November 1 986 and is thought to be caused by cattle feed containing ground offal from scrapie-infected s h ee p car casses. The incubation time of BSE r a n g e s from 2 to 8 years. Since the British govern
m e n t banned the feeding of meat and bone to
J u l y 1 988, it may take until the the century until it d i sapp e ars , unless it becomes e n d e mi c . as scrapie in sheep. The origin of the p ri o n diseases is co n t rov ersi a l ( PA B LOS- MENDEZ et al., 1 9 9 3 ) . In the ab se nce of di a gn o st i c tests, contamination of tis sue culture can only be avoided by relying on sera from herds with no k n ow n history of B S E or on se r u m - fre e media (KIMBERLI N , ruminants in
turn of
1 990: HODGSON, 1 993) . A fi nal source o f concern i s cross-contami nation with v i r uses within the laboratory. The most rece n t and conspicuous e x a m p l e s con
cern th e re l a tio n s h i p between different HIV isolates. some of which having been identified as laboratory contaminations ( M U LDER,
1 988: ALDHOlJ S. 1 991 ) . Such contaminations are d ifficult to avoid, especi ally when han
dling new isolates. which can r e a di l y be out grown by contaminating viruses pres e n t i n the l ab o r a to ry a n d al re ad y adapted to tissue cul t u re
conditions. Viruses can survive in aerosol
d r o plet s as well as in glass-ware. Rigorous ru l e s and schedules thus h ave to be estab lished in isolates.
laboratories working with
novel viral
Fi n a lly . the issue of accide ntal infection of laboratory workers e x p o se d to contagious vi ruses remains e n ig ma tic . It is n ot new b u t has re c e n tly been revived due to the ex p a n d in g i n t e n s it y o f l a bor ato ry work with H I V . A re ce n t s t u d y as se ss i n g such risks concludes that strict obse rvance of b iosafety level 3 contain ment as well as c on s t a nt refi n e m e n t of proce dures should be a b l e t o contain the problem (US
DEPARTMENT O F H E A LTH AND H U M A N 1 988: W E I SS et a J . . 1 988; M I LM A N
SE RVICES.
a n d D'SouzA. 1 990).
98
3 Biosafety in rDNA Research and Production
1 0.3 Safety Aspects of Viral Vectors Used in Eukaryotic Tissu� Culture
Vectors are vehicles used in recombinant DNA technology to transfer genes into reci pient cells. They are thus necessary prerequi sites for the establishment of cell lines pro ducing recombinant proteins including vac cines, as well as for somatic gene therapy (MILLER, 1 992). In mammalian systems these vectors are mainly based on viral genomes. These include DNA viruses such as adeno-as sociated viruses, papova- and herpes viruses, but also poxviruses and retroviruses. In most cases these viral genomes are used in a form which lacks possible virulence factors and thus makes them considerably safer to use than the corresponding viruses themselves. Due to the different strategies these viruses use to invade their host cells, these virulence factors may be oncogenes, enzymes of nucleo tide metabolism, DNA sequences serving as targets for homologous recombination with endogenous host cell sequences, and others. More often than not, vectors contain anti biotic resistance genes. Such genes when present, for example, as DNA impurities in proteins prepared from recombinant cells, could potentially be transferred to a patient and/or his/her bacterial flora. This chain of events not only has to be considered as highly improbable , it can and will be efficiently avoided by adhering to WHO or even better standards as to the amount of DNA impuri ties permitted in drugs. Nevertheless, the problem is not negligible because of the cur rent medical crisis spawned by the spread of drug resistance following an uncontrolled use of antibiotics in the past decades (NEU, 1 992). It would certainly be advisable not to aggra vate the problem and to avoid the use of re sistance markers whenever possible. 10.3 . 1 Vectors Derived from Poxvirus
Poxviruses, in particular vacctma virus, have recently enjoyed a growing interest as efficient vectors to express foreign genes for
the production of functional and posttransla tionally modified proteins, often from other viruses (SPEHNER et al. , 1 991 ; MORRISON et al., 1 991). Recombinant poxviruses are gener ated by in vivo homologous recombination of the insertion vector with an appropriate virus strain, e.g., the WR (Western Reserve) strain of vaccinia virus. The general enthusiasm about the success of these vectors, however, has been tempered by safety questions re garding vaccinia virus. Although the chances of accidental infections with recombinant vac cinia virus under biosafety level 2 conditions can be regarded as low, such infections can occur and have occurred in the past. As in smallpox vaccination such infections may re sult in adverse reactions, e.g., encephalopathy or exanthematous disease. Efforts have thus been undertaken recently to develop highly attenuated vaccinia strains which have lost their virulence. This was achieved by deleting 18 genes from the viral genome, including some genes involved in nucleotide metabol ism, the thymidine kinase gene and the gene for ribonucleotide reductase (TARTAGLI A et al., 1 992). This will prevent replication of the virus in the quiescent cells of the nervous sys tem which do not express the corresponding cellular enzymes. It has also been proposed to use non-replicating poxviruses as vectors, e.g., canary poxvirus (CAooz et al., 1992) . Since, however, these grow quite inefficiently on their permissive host cells, chicken embryo fi broblasts, it remains to be seen whether this particular approach will eventually prevail. In summary, it can be stated that the use of the highly attenuated vaccinia strains as ex pression vectors will reduce the hazards asso ciated with the use of vaccinia virus and thus should be strongly recommended and encour aged. This is particularly true because many countries do not preserve registered smallpox vaccines anymore since the WHO has de clared smallpox as eradicated from the globe in 1 980. 10.3.2 Vectors Derived from Retroviruses
Recombinant retroviruses are widely used as vectors in human somatic gene therapy.
10 Biosafety Aspects of Animal Cell Cultures
The current strategies employ defective ge nomes from which all viral genes have been removed. They cannot replicate in their re spective target cells and simply serve as one way vehicles to transfer a foreign gene into a desired genome. Potential risks associated with these vectors are of two kinds: insertion al mutagenesis and helper-virus production. Retroviruses integrate at random chromo somal sites. The integration event therefore may interrupt important genes or may lead to the undesired activation of neighboring genes, i.e., cellular oncogenes (CULLEN et al. , 1 984) . This has been observed in mice in the course of infection with replication-compe tent retrovirus, but never during work with replication-deficient genomes. Nevertheless, the problem cannot be avoided as a matter of principle and will only be eliminated if retro viruses were to be designed which integrate preferentially at known and specific chromo somal sites. The problem of helper virus production re lates to the difficulty of having to propagate and package defective viral genomes which themselves lack the viral genes and their products required for packing into viral par ticles and for their propagation. In principle, these functions can be provided by coinfec tion with appropriate helper viruses. Since this is undesirable , the problem has been cir cumvented by using "packaging" cell lines. These produce all of the viral protein but not infectious virus, because the corresponding infected viral genome lacks a packaging signal required for packaging of viral RNA into vir ions. Transfer of a retroviral vector into such a cell line thus produces vector RNA contain ing virions which can "infect" an appropriate target cell. This system unfortunately carries with it self the potential of helper-virus formation through homologous recombination between the vector genome and the endogenous ge nome in the packaging cell. Homologous re combination in retroviruses is an efficient process. It has been well documented (Lusso et al. , 1 990) and studied in detail (STU HL MANN and B ERG, 1 992) . In this particular sit uation it can be minimized by the use of vec tors with little or no overlap with the viral se quences in the packaging cell line.
99
By employing the most advanced vectors currently available and approved by the FDA as well as the appropriate cell lines (MILLER and B urn M O RE , 1 986) recombinated helper virus production has been virtually eliminated even by the most stringent assay standards (MILLER and R O S M A N , 1 989; LYNCH and MILLER , 1 991 ) . Nevertheless, a "break through " event, i.e., the generation of a repli cation-competent helper virus has recently been described in a commercial production facility for retroviral vectors (Fox, 1 993) . Whether this rare recombination event hap pened with the most advanced vector technol ogy or with less advanced systems is not known. Nevertheless, the incident reinforces the need for both improvements in vector technology and possibly improvements in the tests for the absence of helper virus.
1 0 . 3 . 3 Vectors Derived from Adenoviruses
Adenovirus-derived vectors - unlike retro viral vectors - have the advantage of being capable of delivering recombinant genes into non-proliferating cells ( B E RKNER, 1 988). Since they are tropic for the respiratory epi thelium, they have been used to transfer the human at-antitrypsin gene as well as the hu man cystic fibrosis transmembrane conduc tance regulator gene to the respiratory epi thelium of experimental animals (RosEN FELD et al. , 1 991 , 1 9 92 ) . Adenovirus vectors are even considered as recombinant virus vac cines. A construct expressing herpes simplex virus (HSY ) glycoproteins, for example, has been used to protect mice from lethal chal lenges with HSV (JOHNSON, 1 991 ). With re gard to the safety of such vectors, it must be realized that while human adenoviruses are widely spread in the general production, some serotypes are known to be ( a ) involved in respiratory diseases and ( b ) to be oncogen ic in newborn rodents. The serotypes 2 and 5, however, which are currently used as the ba sis for vector constructions, are non-oncogen ic. In addition, they are constructed to be re plication-defective by removal of at least two early region genes, the El a and El b structur-
100
3 Biosafety in rDNA Research and Production
al genes. A major negative manifestation of an adenoviral infection, the lytic infection re sulting eventually in cell death, thus can be avoided. Potentially it could be envisaged that certain host cells could overcome this re plication defect by providing the missing Ela function in trans or that a wild-type adenovi rus infection, latent or acute, could induce re plication of the recombinant virus by recom bination or complementation ( RosENFELD et al. , 1 992) . Wheth er such events turn into sig nificant risk factors, may depend on the im mune st a t u s of the patients. Many adenovirus vectors not only contain deletion of the Ela/Elb regions but also of early region E3. This region is non-essential in tissue culture but codes for a number of proteins which modulate and influence immu n osurveillance in the infected host (WO LD and GooDING, 199 1 ) . One of the E3-protei ns down-regulates the level of class I MHC poly pe p tide heavy chains on the plasma mem brane and thus reduces the number of targets for rec og ni t i on of infected cell antigens by cy totoxic T-lymphocytes. Another protein pre vents cytolysis by tu mo r necrosis factor. Dele tions in this gene markedly increase the in flammatory responses in experimental ani mals ( GINSBERG et af. , 1989"j. ft tftus nas to be kept in mind that even the avirulent sera types 2, 4, 5 and 7 may become virulent strains when used as vectors with E3 dele tions. 10.3.4 Adeno-Associated Viruses
Adenovirus-associated virus ( A A V) is a non-pathogenic parvovirus which has poten tial for certain application in human gene therapy. It requires a human adenovirus as helper virus for its propagation. In the ab sence of helper virus the parvovirus genome integrates into a single chromosomal site in the long arm of human chromosome 19 (SA MULSKI et al. , 1991). While an integrated viral genome is rescued by adenovirus superinfec tion, vector DNAs remain stabiy integrated and do not replicate under such conditions (MURO-CACHO et al., 1 992). AAV-derived transducing thus appears to be both a highly efficient and safe delivering s ys tem for h uma n
gene therapy and is being considered for the treatment of hemoglobinopa thies (WALSH et al., 1992) as well as in gene transfer strategies directed towards the respiratory tract (FLOITE et al., 1 992); 10.3.5 Vectors Derived from Herpes Viruses
Herpes simplex virus (HSV-1 )-derived vec tors are only beginning to be considered as gene transfer vehicles. In particular, due to t h e known neurotropism of this virus they are envisaged to provide useful tools for gene transfer to cells of the mammalian nervous system. Nevertheless, vector development is only in an early state. So far, the replication defective vectors which lack the essential reg ulatory gene IE3 are toxic to cultured CNS neurons and glias (JOHNSON et al. , 1 992; HUANG et al., 1 992) . This problem eventually will have to be solved. In addition, herpes vi ruses may be explored for their tropism to o th e r cell types, e.g. , H. saimiri for the gene transfer into human T-cells (BI ESINGER et al., 1 992).
1 0.3 .6 Vectors D erived from Bovine Papilloma Virus
BPV-1 viral DNA can transform rodent cells in culture. Although there are reports which describe the identification of B P V - 1 DNA integrated into host chromosomal se quences (ALLSHIRE and B OSTOCK, 1986) , it generally persists in an unintegrated episomal form in the transformed cells. Since it cou l d be shown that the latter is also true for B P V -1 D NA cloned in to the E. coli plasmid pBR322 ( HowLEY et al., 1 980), the potential of B P V 1 DNA as a shuttle vector for the expression of foreign proteins in transformed mouse cells has been recognized and even commercially exploited ( WURM and ZETTLMEISSL, 1 989). Hazards associated with such vector con structs relate either to the malignant potential of the transforming DNA or the potential spread of shuttle vectors based on B PV -1 and
I I Risks of Genetic Engineering: Facts and Fiction
E. coli plasmid sequences into the environ
ment. I f th is should be a problem. it can be el i mi n a t ed by avoiding the use of shuttle vec tors. As to the malignant pot e n t i a l of B PV- 1 -de rived vector D N A . it can be argued that BPV l only i nd uc es benign tumors in its natural host, t h e cattle. Nevertheless. there are indi cations that B PV-derived malignant tumors c an arise in cattle under circumstances of co carcinogenesis with environmental carci no gens (JA R R ElT et al 1 978). BPV- 1 D N A has been isolated from equine sarcoids ( A MT MANN e t a l 1 980 ) . A l t h ough a clearcut cause/effect relationship has not yet been es tabl ish ed PCR-studies with a B PV- 1 - and BPV-2-derived set of primers indicate that BPV play an important role in the develop ment of eq u i ne sarcoids (TEIFKE and W E I SS. 1 99 1 ) . There is no evidence t h at h u m a n tu mors are caused h y BPV - 1 o r have ever been found to contain BPV- 1 DNA. Humans working with BPV -1 infected cattle can devel op benign skin warts but not tumors. Exten sive studies on warts in butchers and fish merchants have co nvin c ing ly demonstrated that they contain only h u m a n p a p i llo ma virus DNA. i.e . . HPV-7 (JABLONSKA e t al.. 1 988: RuouN G E R e t at.. 1 989). There is no doubt. howe ver. that the issue of t umorige nicity of B PV-1 DNA containing cell lines and protein p roducts derived thereof has to be addressed carefully pr i o r to the licensing of such pro cesses and products.
. .
..
.
modifications in their genome and have to be u n d e r safe ty conditions. A s a result of all the genetic modifications successively collected. the penicillin yield from culture me dium. for example. has b e e n increased from 7 1-1-g per liter with the wi ld strain Penicillium chrysogenum to over 30 g per liter with the p ro d uct io n strains used today. In the initial p h a se of genetic en gi ne er i n g and th e development of recombinant organ isms, the scientists a s ke d themselves the im portant question . whether conj ectual risks could arise with the new tech nique. The focal point of consideration wa s whether the trans fer of sections of DNA of foreign origin, w h ich themselves con tain n o pathogenicity genes. into n o n p ath oge ni c organisms could poss i b ly create pathogenic o rg an i sm s by "sy n e rg is ti c e ffects. I f this were possible, "new ty pe s of r i sk s could occur which would have to be assessed differently or more se ve rely than the hazards already known from the work with pathoge nic (and hence hazardous) bacteria and viruses (and their hereditary ma
handled
.
-
"
"
terial ) .
This q u e s ti o n ( B E R G e t al. , 1 974) was posed i m med i at e ly after the first gen e t i c engi neering experiments between 1 972 and 1 974 and led to the co ngress in Asilomar (USA) in 1 975 ( B ERG et a l 1 975; G R O BSTE I N , 1 977) at which the fi rst guidelines were drafted and experiments to answer this question w e r e pl a nn e d I n re tros pe ct i v e it is fair to state that t h e issues and motives for the biosafety debate initiated by the inventors of genetic e n gi neering i . e . . PAUL BERG and co ll eag ues never have been understood by the public and instead have triggered the regul ation s s pec ifi c for genetic eng i ne e r i ng. Public debate still speculates on the .. chances and risks" of modern biotechn o logy particularly of genetic eng i neer i ng , which are said to be associated with these new methods of modifying the genetic composition of or ganisms. In fact , such d i sc u s s i on s are found with respect to almost a n y issue. albeit in dif fering magni tude s These debates usually mi x the terms "risk" and "hazard" r a t h e r unspe ci fic a l ly. which therefore need some reflec tion . Th is a pp l i es also to the term c ha nce s often used in conj unction with "risk" and "hazard". .,
.
,
,
1 1 Risks of Genetic
Engineering: Facts and Fiction For more than 4 0 years enzymes, amino acids. an tibiotics. vaccines and other sub stances have been produced by fermen t ati o n with numerous mic r oorgan i sms (including pa th ogen ic organisms ) . often on a very large 3 scale ( up to 250 m ) . Comp are d with the wild s t ra in s isolated from nature. the high-per formance strains obtained by m u ta ge n e s i s and selection ca r ry nu m e rou s u n ide nti fie d
101
,
,
.
"
"
1 02
3 Biosafety in rDNA Research and Production
A "hazard" exists, if a microorganism threatens the host's health and thereby causes damage. The extent of the damage caused, and therefore the severety of the disease, are directly related to the hazard posed by the microorganism. With respect to "risk", in ad dition to the magnitude of the damage caused, the dimension of "probability" needs to be considered (risk equals the product of probability x damage caused). For practical evaluations, this means that very different scenarios can be drawn, and that the term "risk" needs to be used rather carefully because it can easily be misinter preted, misunderstood or misused: - The probability of microorganisms to escape from facilities applying GLP or GILSP is rather high, but the probability of these apa thogenic microorganism to cause any dam age is extremely low. - The probability of a microorganism to es cape from a containment level 2 or 3 facility is rather low, but the probability to cause damage is rather high for a certified host e.g., hepatitis viruses for humans and foot and mouth disease virus for cattle - not vice versa and both not for plants or insects nor other species. - The probability of a recombinant cow, pro ducing a pharmaceutically relevant protein in the milk, to escape from the stable, to dis appear in the environment and to cause a damage therein, is rather low. But there is a high probability that this animal might be a competitive economic threat to classical in dustrial facilities worldwide which produce the same protein by conventional cell cul ture techniques in a less efficient way. - A transgenic crop plant with higher nutri tional value is no threat to the environment but probably to the balance of the EU bud get from which 60% are spent for agricultur al subsidies. In other world areas such a plant will not be considered a "risk" and be welcomed instead.
There should be no illusions: as with any innovative technology, biotechnology will change economic and competitive conditions on the market. Indeed, economic renewal through innovation is the motor force of dem ocratic societies. In respect of (not only) ge netic engineering it is therefore necessary to identify issues and not to mix terms which do
not belong together. Therefore, the assess ment of whether a microorganism is harmful or not, cannot be made by sociological, legal or ethical arguments, and social or ethical questions which arise in prenatal diagnostics (e.g., using DNA probes) cannot be answered by biosafety assessments (modified organisms are not created nor involved). Unfortunately, the scientific contexts usually are not inter pretable by the general public, and it seems not possible to comprehensively present the scientific issues in a simple fashion - hence uneasiness remains in the public, which can be exploited for various purposes not neces sarily related to the science in question. Since about 1976 it has been repeatedly es tablished and confirmed (PROCEEDINGS FROM A WORKSHOP HELD AT FALMOUTH, MA, 1 978; UNIDO, 1 989) that no "new types of risk" are involved and no specific accidents or damages have been reported. For this rea son, the safety requirements of the safety guidelines which had been introduced in many countries since about 1 978, have been continuously relaxed (LEVIN, 1 984). This also applies to the "Guidelines for the protection against risks constituted by in-vitro recombi nant nucleic acids" (BMFf, 1 986) which were valid in Germany in its fifth amended version until the Gene Technology Act came into force on 1 July 1 990. As in the US, the Ger man chemical industry had voluntarily agreed to abide by these guidelines which were man datory for government-sponsored projects only (PHARMA-KODEX ZUR GENTECHNO LOGIE, 1 988) . In addition, since 1 988 the Ac cident Prevention Regulations for Biotechno logy have been in force which control the handling of biological material to protect workers and environment (BERUFSGENOS SENSCHAFT DER CHEMISCHEN INDUSTRIE, 1988). In contrast to the different classical meth ods used in animal and plant breeding which employ the entire genetic information (the DNA of all chromosomes) of the organisms cultivated, genetic engineering work is re stricted to the handling of relatively small sec tions of DNA compared to the size of chro mosomal DNA. This is because of the physi cochemical properties of DNA and is basical ly limited by the fragility of DNA. The effi-
1 1 Risks of Genetic Engineering: Facts and Fiction
ciency of the genetic engineering methods must therefore not be unrealistically overesti mated as it often is by the general public. An assessment corresponding to the inter national evaluation of genetic engineering was also made by the "Enquiry Committee of the German Parliament: Chances and Risks of Genetic Engineering" in their report to the Parliament (CATENHUSEN and NEUMEISTER, 1 987): "Ten years' intensive fundamental re search with these systems in which countless gene transfer experiments were carried out worldwide showed no indication of hypothetical new risks. This research , which was conducted with special precautions, had implicitly the function of safety research. It is moreover likely that the risks would have been identified if there were any. "
vantageous or dangerous. Applied to genetic engineering, this means that it is not the method of genetic engineering i tself or the handling of nucleic acids (DNA or RNA ) that involves risks, but that in individual cases a recombinant organism, protein molecule or a secondary metabolite may be associated with a certain hazard to man, animals or local envi ronments. As outlined above, it might be ad vantageous to address "hazards" instead of "risks" in order to separate scientific issues from sociopolitical scenarios. Above and beyond the known risks involved in the han dling of non-pathogenic, pathogenic and oth er harmful organisms, no "unique risk" has been observed with organisms modified by genetic engineering. This assessment was already filed i n 1 987, e.g., by the U.S. National Academy of Science (KELMAN et aJ. , 1987): •
A wholesale "no" to genetic engineering research or products manufactured by recom binant methods as stated by the German B .U.N. D . (Association for Environment and Protection of Nature) is basically a nonsensi cal and irrational assessment (BUND, 1 988):
•
•
"The BUND demands a prohibition of any genetic manipulation of life forms and viruses. This prohibition i ncludes any research, production and use in this area." •
Interestingly, this much publicized declara tion has partly been overruled by an almost unpublicized declaration ( B U ND, 1 990) : "The necessary_ medical/pharmaceutical research and applications without rea sonable alternatives can - case by case and including a risk assessment - be ex cluded from this prohibition. " The fundamental misconception in such statements is that a technology can never be dangerous in itself. B asically, only the ingre dients used in a certain production process or a certain product manufactured by means of certain methods, alone or in combination with other substances or factors, can be ad-
1 03
rDNA techniques constitute a powerful and safe means for the modification of organisms. There is no evidence that unique haz ards exist either in the use of rONA techniques or in the movement of genes between unrelated species. The risks associated with the i ntroduc tion of rONA-engineered organisms are the same in kind as those associated with the i ntroduction of unmodified or ganisms and organisms modified by other methods. The assessment of risks associated with introducing rDNA organisms into the environment should be based on the nature of the organism; based on the environment into which the organism is to be introduced; and independently of the method of engineering per se.
Meanwhile, this view repeatedly was con firmed, e.g. , by a review of the drugs and di agnostic products approved by the FDA and at a public hearing in the German Parliament on experiences with the Gene Technology Act (CATENH USEN et al. , 1 992), where the chairman of the German ZKBS (rDNA Advi sory Committee) and the representative of the Berufsgenossenschaft der chemischen In dustrie (professional cooperative of the
1 04
3
Biosafety in rDNA Research and Production
chemical industry) reported that they were not aware of any single event that would indi cate specific hazards or safety concerns with recombinant DNA technology.
1 2 Conclusions Genetic engineering has become a normal and often essential feature of research, tech nical application and student training on both international (BAP, 1 982-1 986; BRIDGE, 1 990-1 994) and national scale (IN D EVE LOP MENT: BIOTECHNOLOGY MEDICINE, 1 990). Many diseases and in particular epidemics have posed a threat to mankind since prime val times. These risks have initially been countered by the introduction of hygienic measures or quarantine, although the scien tific principles on which these initiatives were based had not been researched or under stood. This was followed by vaccination and by antibiotic treatment. Nowadays many details are known of the wide variety of organisms that are used with good effect in traditional biotechnology, both in research and in industrial applications, in cluding, of course, organisms obtained by mu tagenesis or cell fusion. "' The new genetic engineering methods are being used intensively in more than 20000 la boratories worldwide, and in almost 20 years innumerous different microorganisms have been modified and constructed by genetic en gineering, with their behavior being moni tored and their properties being analyzed. Based on these findings and the microbio logical knowledge accumulated, a reliable risk evaluation can be carried out. Based on this, further studies pointing the way forward are envisaged which will give further insights into biological processes. These are then bound to give rise to new questions in a never ending process. Reviewing the available data and the prac tical experience gained from different branches of biological research, the conclu sion is that microorganisms - modified with out and with recombinant methods - have been handled extremely safely as a result of
technical measures alone. This applies to both the people working with these organisms and to the plants, animals and the remainder of the environment indirectly affected. Only with the new methods of molecular biology an additional safety level has become availa ble which was described as a biological safety measure. The risk which an "organism" can consti tute for scientists, the general population, ani mals, plants or the environment is always in terrelated with its specific properties and in dependent of the kind of its manufacture. The views of biological safety discussed here have carefully been developed and investigated by competent scientists in worldwide collabora tion. As knowledge increased, this gave rise to the international agreement that no "new" risks are associated with genetic engineering methods, that biological risks are clearly re cognizable and that they can be particularly well controlled when the dual concept of technical and biological safety measures is ad hered to in both research and production.
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E . , D E N I STON -THOMPSON, K., F A B E R , H . E . , FU RLONG, L. A . , G R U NWALD, D . J . , KIEFER, D . 0 . , MOORE, D . D . , SCHU M M , J . W . , S H E LDON , E. L., S M I TH I ES, 0. ( 1 977), Charon phages: Saf er derivatives of b a cte r i op h age lambda for D N A c l on i ng , Science 196, 1 61 -1 69.
( B u ndes m i n i s t e r fiir Fo r sch u ng und Tech no l o g ic) ( 1 986) , Richtlinien zum Schutz vor Ge fahren durch in-vitro neukombinierte Nuklein siiuren ( G u i d e l in e s for Protection against Risks C a us ed by in vitro Recombinant N ucleic Acids), 5 t h revised Ed., 5/1 986, B o n n : B M FT. B O Y D, A. C., A R CH E R , J. A. K . , S H E R R ATT, D. J. ( 1 989), Characterization of the Coi E 1 mobiliza t io n region and its p rotei n prod u ct s , Mol. Gen. Genet. 217, 488-498. BRIDGE ( 1 990--1 994) , Biotechnology Research for Innovation, Development and Gro wth in Europe, P ro gra m m e z u r F o rd e r u ng u n d E n t w i ck l u ng der G e n t e c h ni k ( Programs for Promotion and De v e lop me n t of Gene Technology ) , B russe l s : Com m is s i o n of the E uropean C o m m un i ty ( G D XII). B R O K E R , M . ( 1 990) , A s t u d y on t h e survival of wild-type , laboratory and re c o mb i n a n t strains of th e baker ye a st Saccharomyces cerevisiae under sterile and nonsterile c on d i t i on s , Zbl. Hyg. 190, 547-557. BROKER, M . , RAGG, H . , K A R G E S , H. E . ( 1 987), E x pr e s s ion of h u m a n antithromb i n III in Sac charomyces cerevisiae and Schizosaccharomyces pombe, Biochim. Biophys. A cta 908, 203-213. B U ND ( B u n d fiir Um w e l t und Naturschutz Deutschland e.V.) ( 1 988) . Decision of the dele gates at the annual assembly in Laneburg. BMFT
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Bioteclrtwlogy
Ed ited by , H . - J . Rehm a nd G. Reed in coo p eration w i t h A. Puhler and P. Stadler Co p yright © VCH Verla gsgesellschatt mbH,1995
4 Biotechnology and Bioethics: What is Ethical Biotechnology?
DARRYL R . J . MACER Tsukuba Science City, Japan, Christchurch, New Zealand
Biotechnology and Bioethics 1 1 7 Bioethics 1 1 7 2 . 1 Autonomy 1 1 7 2.2 Rights 1 1 8 2.3 B eneficence 1 1 8 2.4 Do No Harm 119 2.5 Justice 1 1 9 2.6 Confidentiality 1 20 2.7 Animal Rights 1 20 2.8 Environmental Ethics 1 2 1 2 . 9 Decision-Making 1 2 1 3 Cross-Cultural Bioethics 122 4 Perceptions of Ethical B iotechnology 1 23 4. 1 "Moral" is Not the Same as Ethical 1 23 4.2 Mixed Perception of Benefit and Risk 1 24 4.3 Reasoning Behind Acceptance or Rejection of Genetic Manipulation 4.4 Concerns about Consuming Products of GMOs 1 35 5 Past and Present " Bioethical Conflicts" in Biotechnology 1 35 5 . 1 Interference with Nature or "Playing God" 1 37 5 . 2 Fear of Unknown 1 37 5 . 2 . 1 Health Concerns 1 3 8 5.2.2 Environmental and Ecological Risks 1 38 5 . 3 Regulatory Concerns 138 5.4 Human Misuse 1 39 6 Future " Bioethical Conflicts" in Biotechnology 1 3 9 6. 1 Changing Perceptions of Nature 1 39 6.2 Pursuit of Perfection - a Social Goal 1 40
1 2
·
1 28
1 16
4 Biotechnology and Bioethics: What is Ethical Biotechnology?
6.3 6.4
Limitation of Individual Autonomy 1 4 1 Human Genetic Engineering 1 4 1 1 42 7 B ioethics versus Business: A Conflict? 7.1 Intellectual Property Protection 1 42 7.2 Global Issues of Technology Transfer 1 43 7.3 Short-Term versus Long-Term Perspectives 1 44 7.4 Safety versus Costs 1 45 7.5 Is New Technology Better? 1 45 8 Resolution of Conflicts 146 8 . 1 Who Can be Trusted? 1 46 8.2 Provision of Information May Obtain Higher Public Approval 1 47 8.3 Public Education Not Propaganda 1 48 8.4 Sufficient Regulations 1 49 8.4 . 1 Regulation of Environmental Risk 1 49 8.4.2 Product Safety 149 8.5 Public I nvolvement in Regulatory Processes 150 9 Ethical Limits of Biotechnology 150 9. 1 Absolute or Relative? 150 151 9.2 Timeless or Transient? 9 . 3 Scientific Responsibility for Ethical Applications 1 5 1 10 Criteria to Assess Whether Biotechnology Research i s Ethical 151 1 1 Conclusion 1 5 2 1 2 References 1 52
2 Bioethics
1 Biotechnology and
1 17
community and individual issues. We can think of ethical i ssues raised by biotechnology
Bioethics
that
involve
the
whole
world ,
and
issues
which involve a single person. A global prob lem such as global warming may be aided by
As has been described in other volumes of
global applications of biotechnology, for ex
this series , modern biotechnology has had a
ample ,
great impact on medicine and agriculture. It
dioxide increase by reducing e missions or in
to reduce
net
atmospheric carbon
can only be expected to have an even more dominating impact on future science and technology. It's impact is not limited to the
creasing biomass, however, excess consump
technical impact that these advances have
tion and energy use can only be solved by in dividual action, to reduce energy use. A re gional issue is the risk prese nted by the intro
upon industry, medicine and agriculture, any technology influe nces society, and one can
duction of new organisms or of an unstable genetically modified organism (GMO) i n to
it
expect that life science technology potentially
the environment, but
has the greatest impact.
al responsibility to ensure that sufficient care
Biotechnology
has
the
and monitoring of the release is made. Other
thinking of society. as will be discussed in this chapter, and we can expect further paradigm shifts to occur. These paradigm shifts include
ethical issues arising from biotechnology that
the switch to biodegradable products, indus trial pressures to re structure scientific infor mation sharing. the paradigm of sustainable
societal implications.
and limited economic growth, and the para digm of intervention in nature rather than ob
tors are crucial for guiding decision-making, especially over such a diverse spectrum of is
servation and participation in it. Biotechnolo
sues. Medical et hics involves decision-making
gy has also been a catalyst to the considera and
on a personal leve l , it concerns the patient and the health care professional, especially
the two words, biotechnology and bioethics,
the physician. At a further level away may be
have coevolved. Before extending discussion it is essential
many others who will be indirectly affected by such questions as the cost of very expensive
to define what is meant by the words , biotech nology and bioethics . This in itself i s no easy task because different people with different
treatment that takes funds away from other patients. At this level higher policy-making is required as in the case of issues such as envi
interests can broaden or n arrow these con cepts In this chapter a broad meaning of bio
ronmental risk , or intellectual property pro tection policy.
tion of bioethical issues
also
influenced
also involves individu
(MACER, 1 990),
.
are thought of as individual issues such as ge netic testing, or use of gene therapy, also have We hardly need to ask why we need ethics, rather we need to ask what principles and fac
,
technology is taken: the use or development
Some key principles of ethics are outlined
of techniques using organisms (or parts of or
below, with brief discussion of their relevance
ganisms) to provide or improve goods or ser
to biotechnology issues. We should balance
associated with life , including medical and en vironmental ethics. Both of these words are
the implications that arise from each principle to arrive at more ethical decisions. We may need to develop further principles and bio
vices. Bioe thics is the s tudy of ethica l issues
recent terms, but both topics throughout human history .
are
found
,
ethics is still being developed
(MACER, 1 990,
1 994). 2 . 1 Autonomy
2 Bioethics There are l arge and small problems in ethics; there are global, regional, national,
All people are different. This is easy to see, if we look at our faces, sizes and the clothes that we chose to wear. This is also true of the choices that we make. We may decide to play
1 18
4 Biotechnology and Bioethics: What is Ethical Biotechnology?
tennis, or golf, or chess, read a book, or watch television. These are all personal choices. In a democratic society we recognize that we have a duty to let people make their own choices. Above the challenges of new technologies, and increasing knowledge, the challenge of respecting people as equal persons with their own set of values is a challenge for all. This is also expressed in the language of rights, by recognizing the right of individuals to make choices.
2 .2 Rights Legal rights are claims that would be cur rently backed by the law if the case went to court, while human rights are critical to main taining human dignity but may not have yet attained legal recognition. The recognition of human rights has changed the situation in many countries, and many countries in the world have signed the U.N. Declaration of Human Rights (SIEGHART, 1 985) , or one of the regional versions of this. This can be ap plied to many situations, for example, we all have a right to be involved in decisions about our country, the freedom of religion, or speech, to raise a family, to share in the bene fits arising from scientific advances, and a right to a reasonable future. Some of these rights are difficult to define, as human "rights" have always been. Respect for per sonal rights should change the nature of rela tionships between people in power and peo ple without power from being characterized by authoritarianism or paternalism to becom ing a partnership. Ethics is not the same as law. Ethics is a higher pursuit, doing more than the law re quires. The law is needed to protect people and to set a minimum standard, but you can not determine good moral behavior by set tling cases in a court of law. We only need to think of medical litigation or environmental damage penalties, which can lead to huge sums of money being paid for accidents (or negligence) which cannot really by compen sated by monetary reimbursement. The solu tion is to have more careful and moral physi cians, companies, lawyers, and politicians, and the replacement of monetary balance
sheets by ethical values, as the primary mo tive of decision-making. 2.3 B eneficence
One of the underlying philosophical ideas of society is to pursue progress. The most cited justification for this is the pursuit of im proved medicines and health. It has often been assumed that it is better to attempt to do good than to try not to do harm. A failure to attempt to do good, working for people's best interests, is taken to be a sin of omission. Beneficence is the impetus for further re search into ways of improving health and ag riculture, and for protecting the environment. B eneficence supports the concept of experi mentation, if it is performed to lead to possi ble benefits. The term beneficence suggests more than actions of mercy, for which charity would be a better term. The principle of beneficence as serts an obligation to help others further their important and legitimate interests. It means that if you see someone drowning, providing you can swim, you have to try to help by jumping in the water with him/her. It also in cludes the weighing of risks, to avoid doing harm. Governments have a duty to offer their cit izens the opportunity to use new technology, providing it does not violate other fundamen tal ethical principles. Just the definition of what fundamental ethical principles are, may be culturally and religiously dependent, espe cially in the way that they are balanced when opposing principles conflict (see Sect. 3). Al though different cultures vary, they all share some concepts of beneficence and do no harm. People should be offered the option of using new technology in medicine and agri culture, and such applications should be made, providing internationally accepted ethical and safety standards are applied. Beneficence also asserts an obligation upon those who possess life-saving technolo gy, in medicine or agriculture, to share their technology with others who need it. This is relevant to biotechnology companies also, who may hold patent rights on particular processes, beneficence would assert that they
2
must share it with others, even if they cannot pay for it. This may mean that companies share developments with developing coun tries, or give new drugs to individuals too poor to purchase them, and may conflict with so-called business ethics. 2.4 Do No Harm
The laws of society generally attempt to penalize people who do harm, even if the mo tive was to do good. There needs to be a bal ance between these two principles, and it is very relevant to areas of science and technol ogy where we can expect both benefits and risks. Importantly, we must balance risks ver sus benefits of different and often alternative technologies, then apply these comparisons to our own behavior, as well as in determining government policy. Do no harm is a very broad term, but is the basis for the principles of justice and confi dentiality, and philantropy. It can also be ex pressed as respect for human life and integri ty. This feature is found in the Hippocratic tradition and all other traditions of medical and general ethics. To do no harm is ex pressed more at an individual level, whereas justice is the expression of this concept at a societal level. Do no harm has been called the principle of non-maleficence. Biotechnology and genetic engineering are providing many benefits, but there are also many risks. It is also unclear who will really benefit the most. It is important to see these benefits and risks in an international way be cause the world is becoming smaller and ever more interdependent. Biotechnology affects the lives of people throughout the world (WALGATE, 1990) . All people of the world can benefit if it is used well, through medi cines, and more environmentally sustainable agriculture. However, biotechnological inven tions that allow industrialized countries to be come self-sufficient in many products will change the international trade balances and prosperity of people in developing and indus trialized countries. If developing countries cannot export products because of product substitution, the result may be political insta bility and war. This may in the end become
Bioethics
119
the biggest risk. For example, the use o f en zymic conversion of corn starch into high fructose corn syrup causes serious damage to the economies of sugar exporting nations (SASSON, 1 988), and may already have caused political instability there. We need to remem ber national and international issues. Although we will continue to enjoy the many benefits to humanity, and we may hope for environmental benefits, the price of the new technology is that it may make us think about our decisions more than in the past. This is long overdue! International food safe ty and environmental standards should be speedily developed to ensure that all people of the world share their protection, and no country becomes a testing ground for new ap plications.
2.5 Justice
Those who claim that individual autonomy comes above societal interests need to re member that the reason for protecting society is because it involves many human lives, which must all be respected. Individual free dom is limited by respect for the autonomy of all other individuals in society and the world. People's well-being should be promoted, and their values and choices respected, but equal ly, which places limits on the pursuit of indi vidual autonomy. We also need to consider interests of future generations which places limits on this generation's autonomy. We also need to apply this principle globally, as dis cussed above; no single country should pur sue policies which harm people of any coun try. The key principle arising from the high val ue of human life is respect for autonomy of each individual human being. This means they should have the freedom to decide major issues regarding their life, and is behind the idea of human rights. This idea is found in many religions also. Part of autonomy is some freedom to decide what to do, as long as it does not- harm others, also called individual liberty or privacy. Well-being includes the principle of "do no harm" to people, and to work for people's best interests.
1 20
4 Biotechnology and Bioethics: What is Ethical Biotechnology?
I n te rnat ionally. the area of biotechnology patent pol icy should be examined in light of public opi nion and the principle of j ustice. Naturally occurring genetic resources should not be able to be owned by any one individu al or company. rather they should be com mon . At the same time, some patent protec tion for speci fic applications involving bio technology need to be protected to encourage further rese arch , and to make the results of such resea rch immediately open for further scientific research (see Sect. 7).
2.6 Confidentiality The emphasis on confidentiality is very im portant. Personal information should be pri vate. There may be some exceptions when criminal activity is involved or when third parties ar e at direct risk of avoidable harm. It i s very difficult to develop good criteria for exceptions . and they wi l l remain rare. We must be careful when using computer data banks that contain personal information, and i f they ca n n o t be kept confidential, the infor mation should not be entered into such a
ban k .
A feature of t h e ethical use of new genetics the privacy o f genetic information. This is one of the residual features of the existing medical tradition that needs to be reinforced. I t is not only because of respect or people's autonomy. but it is also needed to retain trust with peop le. [f we break a person's confi dences. then we cannot be trusted. If medical i nsurance companies try to take only low risk clients by prescreening the applicants, there should be the right to refuse such questions (HO LTZM A � , 1 989) . The only way to ensure prope r and j ust health care is to enforce this on employers and insurance companies, or what is a hetter solution. a national health care system allowing all access to free and equal necessary medical treatment. We need to protect i ndi v i d u a l s from discrimination that may come in an imperfect world. one that does not hold j ustice as its pinnacle. is
2.7 Animal Rights
These above principles apply to human in teractions with other h umans. However, we also interact with animals, and the environ ment.
The moral status of animals, and decisions about whether it is ethical for humans to use them, depe nds on several key internal attri butes of animals; the ability to think, the abil ity to be aware of family members, the ability to feel pain (at different levels), and the state of being alive. All will recognize, inflicting pain is bad, so if we do use animals we should avoid pain ( S I N G E R , 1 976) . If we believe that we evolved from animals we should think that some of the attributes that we believe humans have, which confer moral value on humans, may also be present in some animals ( RA CHELS, 1 990 ) . Although we cannot draw black and white lines, we could say that be cause some primates or whales and dolphins appear to possess similar brain features, simi lar family behavior and grief over the loss of family members to humans, they possess higher moral status than animals that do not exhibit these. Therefore, if we can achieve the same e nd by using animals that are more " primitive" than these, such as other mam mals, or animals more primitive than mam mals, then we should use the ani mals at the lowest evolutionary level suitable for such an experiment, or for food production (which i s by far the greatest use of animals). I f we take this line of reasoning further, we conclude that we should use animal cells rather than whole animals, or use plants or microorgan isms for experiments, or for testing the safety of food. Animals are being used for genetic engi neering, for use &s models of human disease, for use in the production of useful substances such as proteins for medical use, and in the more traditional uses in agriculture. Some of these uses, such as the production of muta tions in strains of animals to study human dis ease will have human benefit, but are more ethically challenging because some of these strains may be deliberately made sick and will therefore probably feel pain (MACER, 1 989, 1 991 a).
2
2.8 Environmental Ethics Humans also have interactions with the en vironment . and in fact depend upon the health of the e n vironment for life . The easiest way to argue for the protection of the envi ronment is to appeal to the human depend ence upon it. There are also human benefits that come from products we find in nature. from a v ari e t y of species we obtain food. clothing , housing, fuel and medicine. The va riety of uses also supports the preservation of the diversity of living organisms, biodiversity. As we have le arnt. the ecosystem is delicately balanced, and the d ange r of introducing new organisms into the e nvironment is that this may upset that balance. This is another key issue raised by genetic engineering. However, we have been using agricultural selection for 10 000 years. so the introduction and selection of i mproved and useful microorganisms, plants and an imals is nothing new. and we should learn from mistakes of the past. The above arguments should convince peo ple of the value of the environment. and that is a first stage . However. it appeals to our sense of values based on human utility. There is a further wa} to argue for the protection of nature and the environment, and it is a more worthy paradigm. It i s that nature has value in itself because, it is there . We should not damage other species. unless it is absolutely necessary for the survival of human beings (not the luxury of human life). Nature has l ife, thus it has som e value. A nother para digm for looking at the world is a religious view, that God made the world so the world has value, and we are stewards of the planet, not owners. This paradigm can make people live in a better way than if they look at the world only wit h the pa r a digm of human bene fit. There needs to be examination of the view of nature that different people have, so that w e can find w hat the commonly acceptable li m i t s to modification of nature, plant and an imal varieties. and human beings are. I n the modern world any new science can easily spread, so researchers are accountable to all peoples of the world. There will be future possible
Bioethics
121
against "common morality" . We need to know what these perceived limits of changing nature are, before we grossly change the char acters of individual organisms, or make irrev ersible changes to the ecosystem and human society. A study on the images revealed in open questions about "life" and "nature" in different countries of an International Rio ethics Survey showed universality of thinking about these concepts (MACER, 1 994) . Microorganisms are generally placed at the lowest end of the "scale" of ethical status, be cause the only internal character they have is the state of being alive. External factors from a human esthetic viewpoint mean that the only argument usually applied to them is hu man utility. Biodiversity may have some value in itself, though it is yet to be defined in non-religious terms. If we want to preserve biodiversity, it is essential that we separate parts of nature on land and ocean as nature reserves or parks, away from the parts of nature which are agricultural areas. However, while we separate these areas physically we should not separate them psychologically as areas which we can abuse and areas which we protect. This applies both in terms of sustainable envi ronment protection and animal rights. In fact, agricultural biodiversity is of direct human utility, and we should attempt to stop its con tinued loss (FOWLER and MOONEY, 1 990) . 2.9 Decision-Making
To anyone who starts to try to apply these principles in his/her daily life or to decisions concerning biotechnology, it will very soon be apparent that there needs to be a balancing of conflicting principles of ethics. Different in terests will conflict, so, for example, there are exceptions to the maintenance of privacy and confidentiality if many people or large envi ronmental damage, are threatened. How do we balance protecting one person's autonomy with the principle of j ustice , that is protecting all people 's autonomy. Many medical and scientific procedures are challenging because they involve technology with which both ben efits and risks are associated, and will always be associated.
122
4
Biotechnology and Bioethics: What is Ethical Biotechnology?
Human beings are challenged to make ethical decisions, and to balance the benefits and risks of alternatives, they have to. The benefits are great, but there are many possi ble risks. In this regard utilitarianism, that we should attempt to produce the most happi ness and benefit, will always have some place, though it is very difficult to assign values to different interests and to the degree of "hap piness" or "harm". Although our life may be come easier due to technological advances, so that it may appear that we do not need to make so many decisions, we are challenged to make more decisions than in the past. The more possibilities we have, the more deci sions we make (MACER, 1990). Standards of education are increasing, but it is another thing whether people are edu cated for decision-making. People need to be taught more about how to make decisions, and the education system should accommo date this need of modern life. Even if they are, this may still be no guarantee that the right decisions will be made.
3 Cross- Cultural Bioethics Any attempt to develop international bio ethical approaches must involve considera tion of the values of all peoples. We could call this cross-cultural bioethics. This means something different from universalism - at tempts to define an international ethical code of what is ethical and what is not, or a table of acceptable and unacceptable risks based on consideration of ethical principles. Universal ethics (MACER, 1994) may be possible to a significant degree, however, we even have difficulty in universal recognition of basic laws such as those respecting human rights. The existence of international environ mental laws, e.g., The Law of the Sea, and charters of human rights (SIEGHART, 1985) , is some encouragement for the future progress of limited universalism. We also see attempts within regions, such as by the Council of Eu rope, to devise a European Convention on Bioethics (EP, 1991 ; MUNDELL, 1992; HOLM, 1 992).
Cross-cultural bioethics involves mutual understanding of various cultural, religious, political and individual views that people have. The diversity of individual viewpoints in any one culture appears to exceed the dif ferences between any two. For example, in any culture one can find people fervently op posed to induced abortion and those who support it as a "right" for women's choice. The opinions expressed in the responses to an International Bioethics Survey, conducted in Australia, Hong Kong, India, Israel, Japan, New Zealand, The Philippines, Russia, Singa pore and Thailand in 1 993, suggest that peo ple in these diverse countries have a similar variety of reasoning (MACER, 1 992a, 1 994). This type of research provides to better un derstand the reasoning of people. People in many countries do share the same hopes and fears, which strengthens the call for interna tional standards. If we look at declarations of ethical codes made by different religious groups, profes sional groups, and among different nations, we can see the principles of bioethics that were outlined in the above section in most. A key question in cross-cultural bioethics is how the concept of do no harm should be applied, and to what beings it applies. For example: At what stage of development should human em bryos be legally protected, for in vitro re search or abortion decisions? Which animals should be protected from which research or use? How do we balance justice within na tional boundaries with global distributive jus tice, and justice to future generations? How much individual liberty do we allow when in dividual choices affect society values and op tions for other people or beings? What is ne cessity and what is human desire or luxury? What is the level of acceptable risk of harm? These are wide questions, and this chapter will discuss some of them. For the purposes of this volume the discussion will be focused around the question of what ethical biotech nology is, and developing approaches that may allow us to better answer this question for policy development.
4 Perceptions of Ethical
123
Biotechnology
4 Perceptions of Ethical
still
4. 1 " Morar· is Not the S ame as
will sustain the people in power in those
Biotechnology
posi
tions . Usually appeals are made to the selfish side
we ca ll
We cannot say that
rather they are sustained by groups of people pursuing their own interests who can lead the public into following the pattern of living that
Ethical What
continues today.
these abuses are always based on ignorance ,
of human
personality, that we a l l possess.
Rather, we should b e concerned with global
" e t h ical biotechnology''
can
not be decided j ust by public opinion. How
sustainability and protection of the a ll people .
rights
of
We m u s t remember t h i s distinction be
ever, something which is morally offensive to the maj ority of people in a country , or region,
tween ethica l and moral when we look
or world-wide . is j udged to be immoral and is likely to be outlawed. What i s seen as immo
public opinion. Law is often based on the so called common morality of a country , and in
ral i s oft e n also une thicaL though unethical
at
the are a of biotechnology we can see varyi ng
practices are often tolerated by a society and
laws established by different countries, and
thus our definition of moral would say that
even within Europe there are conflicting laws,
they are "morally acceptable... because it is
for example, in the area of assisted reproduc
"common
tion and the use of human embryo experi
ing in
ments for research. Germany prohibits re
morality"'. For example. people liv industrialized co unt r i es enjoy the fruits
of an economic system t h a t is disruptive to
search
people l iving in developing countries and the
1 992),
as a criminal offense (DEUTSCH, a n d Britain permits approved research
envi ronme nt. B y use of basic ethical princi
until the embryo is
ples of distrib u tive j ustice , and j ustice to fu
al.,
t ure ge ne r a t i on s who will h ave to live in a poll uted and ch anged world,
we
would say i t
i s unethical. However, t h i s situation i s "com mon
mora li ty ··
to
a
majority of the people liv
isms v ary betwe e n different countries, due partly
be
falling, and
it
is morally un ac
to
different
public
perceptions
of
risks. Whenever we consider the results of opin
ing in the rich cou ntries, though the propor
tion may
14 days old ( B oLTON et
1 992) . The laws on the contained use or release of genetically engineered microorgan
ion
su rve y s , we
n ee d to
remember
the axiom
ceptable to the poor of developing countries.
" Lies, damn lies and statistics " . N evertheless,
we drew our definition of morality at na
they are an i mportant gauge of public opin
If
tional
or
regional borders, we would see this
mixed moralit y standard , but if
morality from it as im moral.
a
we
drew our
global majority we would see
rights
conse nsus supports
a
of minori ty groups are
it makes
methods
of
that allow the thinking behind such
results to be determined, they are important in sociological study. Governments and com
Decisions may be made democratically in a
country if
io n , and when combined with the results
t h e m , if
the
respected, and if
sense in the long term, both nation
a lly and internationally. However, not all de
cisions made this way will be ethica l , society
panies
involved
in
biotechnology
research
have become careful in their monitoring of public opinion , for in
the
case of governments
it can mean they are not reelected , and public opposition to companies can be expensive
in
terms of time delays and lost sales.
can make unethical majority decisions and
Most people receive information via the
will continue to do so. In the area of biology
m ass media , especially the newspaper and
and gen e t ics, we should never forget the un
television. The media have a l arge responsi
world in the
scientists should also inform people about science. The media have a responsibility to
ethical compul sory e ugenics that swept the
half of this century, when more t h an 40 countries made l aws to enforce
mandatory
fi rst
sterilization and selective immi
gration polici e � ( KELVES.
we forget
the
1 985 ) , nor should envi ronmental destruction that
bility to comm unicate science issues well, and
present balance d information , on the benefits and risks of alternative technologies and to
do
this
independently of commercial inter-
124
4
Biotechnology and Bioethics: What is Ethical Biotechnology?
ests. Public opinion can be influenced by groups who have a special interest, such as political groups, and other groups, whose members spend time to publicize their opin ions, and who can get media coverage of their views. The media may also have their own special interests.
4.2 Mixed Perception of Benefit
and Risk
There have been some opinion polls con ducted on the topics of biotechnology, and these are the subject of other chapters. Many of these opinion polls have limited meaning because they ask set questions with set re sponses, allowing little room for free re sponse. The responses are often suggestive, and cannot give us the real picture of what the public is thinking. The extra time spent in analysis of free response questions may be well worth the investment if the underlying reasoning is to be determined. Even the use of questions looking at the balance of benefit and risk are more useful than asking single questions (MACER, 1 992a, 1993, 1 994). In August-October 1 991 , a series of public opinion surveys were conducted in Japan (MACER, 1 992a). Mailed nationwide opinion surveys on attitudes of biotechnology were conducted in Japan, among randomly se lected samples of the public (N = 551), high school biology teachers (N = 228) and scien tists (N = 555). The results of several of the 20 questions are summarized in this chapter, as they are useful in examining what are seen as "bioethical" conflicts of biotechnology, that will be examined in Sect. 5. The results were compared with the results of the same ques tions used in New Zealand in May 1990 (COUCHMAN and FINK-JENSEN, 1990), among samples of the public (N = 2034 ) , high school biology teachers (N = 277) and scien tists (N = 258). People were first asked about their aware ness of eight developments of science and technology (Q5a), then asked whether they thought each development would have a ben efit for Japan or not (Q5b) . Q5c and Q5d ex amined their perceptions about the risks of
technology by asking them how worried they were about each development. The questions were: QS. We will ask you about some particular scien tific discoveries and developments. Can you tell me how much you have heard or read about each of these. Please answer from this scale. 1 I have not heard of this. 2 I have heard of this, but know very little/nothing about it. 3 I have heard of this to the point I could explain it to a friend. How much have you heard or read about? Silicon chips B iological pest control Biotechnology Fiber optics in vitro Fertilization Agricultural pesticides Superconductors (IVF) Genetic engineering QSb. For each of these developments that you
have heard of, do you personally believe (DEVEL OPMENT) would be a worthwhile area for scien tific research in Japan (NZ)? 1 Yes 2 No 3 Don't know QSc. In the area of (DEVELOPMENT) do you
have any worries about the impact of research or its applications? 1 Yes 2 No 3 Don't know QSd. For e ac h development where you are wor
ried, could you please tell me how worried you are, using this scale . . . about the impacts of (DEVEL OPMENT)? 1 I am slightly worried about this. 2 I am somewhat worried about this. 3 I am very worried about this. 4 I am extremely worried about this.
Japanese have a very high awareness of biotechnology, 97% saying that they had heard of the word (Tab. 1 ) . They also have a high level of awareness of in vitro fertilization (IVF) and genetic engineering. In New Zea land only 57% said they had heard of biotech nology. These results were confirmed with other surveys in Japan, and in the 1 993 Inter national Bioethics survey (MACER, 1994) . In a 1988 survey of 2000 public in the U .K. only 38% of respondents said they had heard of biotechnology (RSGB, 1 988), considerably less than in New Zealand, and compared to 97% in Japan in this survey in 1 991 . The re sult of Q5 suggests that the Japanese public is
4 Perceptions Tab. l. Attitude s to
Developments
in
S am p l e
of Ethical
1 25
Biotechnology
Science and Technology
J apan
NZ
High School B iology Teachers NZ Japan
403 84. 1 43.7 14.1 1 6.9 10.9 4.2 26.0
1 668
211
5 16 84.9 38.2 1 4. 1 16.9 1 3 .0
1 15 1 7 1 .7 68.4 2.5
217 93 . 5
6.0
22.6 20 . 7 8.3
Public
Scientists Japan
NZ
511 96.3 60.3 7.2 1 1 .4 8.4 2.2
256 96.9 32.4 48.4 12.5 3.9
0
3.7
2.0
253
542 97.4 53 . 7 1 1 .4
Biological Pest Control He a rd of
(N)
Worthwhile
Not worried Slightly worried
Somewhat worr i e d
Very wor r ie d
Extreme ly worr i e d Don 't know Biotechnology
He a rd of (iV) Worthwhile
Not worried Slightly worried Somewhat worrie d Very worried
Extremely worr i e d Don 't k n o w
Pesticides Heard of ( N) Worthwhile Not worried
Slightly worried Somewhat worried Vel)' w o rr i ed Extreme ly worrie d
D on ' t know
8.5 2 1 .5
509 89.2
27 . 1 7.9 14.9
25 . 1 1 8. 1 1 6. 1
85.8
49 . 7
6.0 1 1 .3 22.2 9.6 0. 7
1 4.3 7 .2
94.8
45 .4 1 2 .8
20.9 1 2.3 4.7
8. 2
35.0 8.3
1 .6
6.9
1 86 1 84 . 5 38.9 1 4.2 18.1 22. 1 6.3
217 87.6
0.4
24.0
6.0 1 3.4 29.0
22.6 7 .3
Genetic Engineering
He a r d
of
(N)
Worthwhile Not worried
Slightly worried
Somewhat worried Very w o rr i e d
Extremely worri e d Don 't know
495 76.2 19.4 11.1 1 8.2
2 1 .4
1 492 57.4 43.8 14.6
1 3 .8 1 8.6
1 9.8
8.2
19.8
0.9
214
9 1 .6 1 6.4 7.9 1 4.5 3 1 .3 25.2 7.9
276 99.3 34 . 1 47 .8 9.4
3.6
0.7
84.6 42.3 39.5 6.7
1 6.4
2.0
1 1 .6 6.1
0.4
0.8
225 81.3 46.2
39.1 6.2 0.4 0 8.0
9. 1
4.4
259 79.2 7.7 2 2.4 32.4 18.9 13.1
533 94.7 43.9 7.1 16.7 20.6 1 1.1 2.6
241 82.2 15.4 30.7 28.6
540 94.4 43.3 11.3 1 6.5 1 7. 2 12.8 3.2
247 79 . 8 14.2 39.3 22.3 1 3.8 8.9 1 .6
0
273 85.7 10.6 37.4
3 1 .9 1 0.6 8.4
1.1
13.3
8.3 3.7
The values are exp res s e d as % of the number of respondents to 05 who had heard of, or could explain. each developme n t ( N) . Results from Japan are from MACER ( 1 992a ) . and New Zealand results are from the survey of COUCHMAN and FtNK-J ENSEN ( 1 990) comparatively very well exposed to the word
·biotechnology· . with 33% (29% in 1 993) say ing they could explai n it. compared to only 8% ( 1 5 % in 1 993) in New Zealand. The responses revealed that there are mixed perceptions of benefit and risk from
the use of these technologies (Fig. 1 ) . Bio technology was seen to be worthwhile by 85% of the public, while 40% were worried about research . Genetic engineering was said to be a worthwhile research area for J ap an by 76% , while 58% perceived research on IVF
1 26
4 Biotechnology and Bioethics: What is Ethical Biotechnology?
Public pe rception of scie nce developments In Japan
1 00
Biological p e s t con trol
l Fibe r
80
o p t 1 cs
1
"j
•
a
• Pesticides Biote chnology
S u p e r conductor s
•
• Silicon chips
60
Genetic engineering
• IVF•
neering when compared to other develop ments of science and technology (Fig. 2). These results were also confirmed in 1 993, us ing extra research area of "computers", and "nuclear power" (MACER, 1 994). Nuclear power gathered significantly more and greater concern than other areas, in all coun tries. The later survey also included open questions on the reasoning for both the plus and minus side of each area which is reported fully elsewhere (MACER, 1994 ) From the results of this question it appears that people had a mixed view of the benefits of science. The attitudes to biotechnology vary even within Europe (EB , 1 993). A fol lowing question in these surveys asked them "Overall do you think science and technology do more harm than good, more good than harm, or about the same of each?" This looked at their general attitude to the benefit and/or harm perceived to be done from science in general. The Japanese high school biology teachers and the public gave similar responses in 1 991 (MACER, 1 992a) with 58% and 56% , respectively, thinking that they did more good than harm. Only 6% of the public and 3% of the teachers thought that science and technology did more harm. Scientists had a more optimistic picture, with 78% saying science and technology did more good and only 2% saying it did more harm than good. In a 1 989 public survey in the U.K., (N = 1020) for the same question, only 44% answered "more good", 37% said "about the same", 9% said "more harm", and 10% "didn't know" (KENWARD, 1989). These re sults were similar to the U.K. in 1 985. In Aus tralia, in 1989, 757 public were asked the same question, and 56% said "more good", 26% said "about the same", and 10% said "more harm", with 2% saying they "didn't know" (ANDERSON, 1989). In 1993 in Austra lia 66% were found who said "more good", 27% said "about the same", and 4% said "more harm", with 3% saying "don't know", but in Japan reduced support with 42% say ing "more good", 45% "about the same", 5 % "more harm", and 8% "don't known" (MAc ER, 1994). Australians were the most optimis tic of all respondents in the International Bioethics Survey for the broad question, but not for specific questions about different .
40
20
60
80
1 00
% of those who hod heard of the developments who were worried a bout their impact ( O c t o ber 1991, Macer , 1992 a )
Publ i c p erceptions of s c i en ce developments I n New Zealand
1 00
..
£
Biological pest control
- o
0£
80
.., _ � .c 0 0> ..
.c
-o 0 .J:
0
� =
�
.. Ill
"'
:1' c ..
� .r:.
111 � "'0 •
P e s ticides
IVF0
m
a
Genetic engin e e ring
40
.,
o E � .. .J: a. - o �
0�
s
Superconductors
:1'
_g 'i 1:0
•
11 m Silicon c hi p s
60
•
Biotechnology
op tics
"
0 :E
.
Fiber
20 0
0
20
40
60
80
1 00
% of those who had heard of the dev elopments who were worried about their impact (Couchman and Fink-Jensen , M a y 1990)
Fig. 1. Comparative perceptions of science develop
ments between Japan and New Zealand. The re sults are based on the number of respondents who said that they had heard of each development (QSa), and are presented as scattergrams, with number of respondents who thought each develop ment was worthwhile for their country versus the number of respondents who were worried about the impact of the developments.
as being worthwhile; however, 61% were worried about research on IVF or genetic en gineering (Tab. 1 ) . Japanese expressed more concern about IVF and genetic engineering than New Zealanders. People of all groups expressed a relatively high degree of worry about biotechnology, IVF and genetic engi-
4
Perceptions of Ethical Biotechnology
1 27
The deg ree of worry about the Impact of science
developments I n J apan
Genetic
e n gin e e ring
S uperconductors In
vitro fertilization IZJ slightly
Pesticides
r:lil s o m e w h a t
Fiber optics
B very
Biotechnology
B
Silicon chips
extremely
Biological p est co n t r o l 0
20
40
60
80
% of those who had h e a r d o f the
were w orried about their impact (Macer . 1992a)
dev elopments w h o
The degree of worry about the Impact of science developments In New Zealand
IZI slightly
r:lJ somewhat B very B extremely
0
20
40
60
80
% of those who had heard of the developments who were worried about the i m p a c t ( d a t a from Couchman a n d Fink-Jensen . 1990)
Fig. 2. Comparative public concern about the impact of developments in science and technology between
Japan and New Zealand. The results are based on the number of respondents who said that they had heard of each development (Q5a), and the degree of worry about the impact of the developments (Q5d) is plotted. * IVF, in vitro fertilization.
areas of technology. Internationally, the most optimistic respondents to this question were respondents to a 1989 survey in Beijing, Chi na {N = 491 1 ), where 82% said more good, 2% said more harm, 12% said the same and 5% said "don't know" (ZHANG, 1991 ). In most countries science and technology have been promoted as being of benefit to people, by government and industry. Aware ness of the developments of science and tech nology in 05 was not directly correlated with
the perception of these technologies. The re sponses are more complex than 06 may indi cate, for example, New Zealand scientists and high school teachers expressed more general concern about the impact of all developments in 05 than their peers in Japan, whereas the New Zealand public expressed less concern about all these developments than the Japa nese public! B ioethically, a more mature group may express most selectivity in concern between different applications of technology.
1 28
4 Biotechnology and Bioethics: What is Ethical Biotechnology?
4.3 Reasonin g Behind Acceptance
or Rej ection of Genetic Manipulation
It is apparent that people do, on balance. see more benefits coming from science than harm. However. at the same time people also perceive risks, such as human misuse of tech nology . We need to determine more about these perceptions. More specific questions than those asked in 05, were used in 07 (MACER, 1 992a). Rather than testing con cerns about the techniques included by the broad term •·genetic engineering" , the views of genetic manipulation on four types of or ganisms w e re examined: humans, animals. plants and microbes. with room for free re sponse to list reasons for acceptance , benefits and risks pe rceived. The questions were: Q7a. Can you te l l me how m uch you have heard or
read about
. . .
'!
genetic material in human ce lls genetic material in microbes Manipulating genetic material in plants Mani pulating genetic material i n a n imals U se this scale . . . I I h ave not heard of this. 2 I have heard t he words but no more. 3 I h ave heard the words and have some under st a n d ing of the idea behind it .
Manipulating Manipulating
Q7b. Please answer the questions below: Which. if any, of those biological methods you've heard of are acceptable to you for any reasons? I Acceptable 2 U nacceptahle ( If unacceptable write why each one is not accl!ptable to you) Q7c. Which of t hose biological methods, if any. of those you've heard of could provide benefits for Ja pan? I No benefit 2 Benefit (If a benefit. what benefits do you be lieve each one could produce? ) Q7d. Which. if any. o f t hose biological methods
could p rese nt serious risks or hazards in Japan? I Risk 2 N o risk ( If a risk. what serious risks or hazards do you b e l ieve each one could present in Ja pan ? )
ln
both J apan and N e w Zealand. genetic
manipulation of plants is the most acceptable type , followed by genetic manipulation of mi crobes, animals and humans, in order of de creasing acceptability (Tab. 2). About half of the teacher and scientist samples think that human genetic manipulation (human cells) is acceptable , in both countries. This preference order is the same as that obtained in the USA in November 1986 (OTA, 1987). This could represent two major thoughts, a scale of bio logical complexity associated with increasing ethical 'status' from microbes to plants to ani mals to humans. This is complicated by the higher perceived danger of genetic manipula tion using microbes, which are associated with disease and which are environmentally more mobile , and animals which are mobile. The results of questions on the benefits and risks (07c, d) found most people perceived both benefit and risk, as in 05. The results for public and scientists are schematically repre sented in Fig. 3. The reasons for unacceptability, benefit or risk perception were asked, and they are per haps the most interesting result. For different organisms they were different, reflecting real ity. This is particularly useful for those work ing on an organism such as microorganisms, the focus of this book series, for the percep tions will vary greatly from those associated with human genetic manipulation. The meth od used to analyze the reasoning was to as sign the comments to categories. A total of 38 different categories were used in the comput er data analysis, some of which were later combined in data presentation. Although a variety of comments were written, generally they could eas!ly be assigned to categories. For each distinct reason given in the com ment. a count of 1 was scored in one of the categories of the data sheet in the computer. The most reasons given for a single comment were 3, but generally there were only 1 or 2 reasons. Also, a high proportion did not write any comment. A summary of the reasoning is presented in Tabs. 2, 3 and 4. U niversity students and academics in social sciences were also surveyed in Japan; for the results and many examples of the actual com ments, see MACER (1992a). I nterestingly, more public wrote comments for reasons for acceptability than scientists.
4
Tab. l. Reasons
Given for
Un acceptability of Genetic M a n ip ul at i o n
Orga nism
Group
% who said it wa� acce p t a ble
p
T
s
Unacceptable for Interfe ring
the fo l l ow i n g reasons
with n at ure, unnatural
p s
p
T
s
U net hical
p
T
D isa�ter, out of cont rol
Fear of unknow n
s
p
T
s
p
T
H um a n i t y chang.:d I nsufficie nt con t ro l s
D a nger of human misuse
E uge nics, cloning
Deformities, m u t a tions
H uman health e ffect
Not stated
26.0
80.9 87.8
46.6 54.6
92.5
12.3
3.6 2.8
1 0.8 5.0
4.7
2.2 1 .1
2.3
M
A
H
72.8
54. 2 75.6 24.4 9. 5
82 .4 89. 9
4.1
2.2
1 .3 2. 0
0.9
0.9
4.5
0
4.9
9.4
0.2 0.4
6.0
0.2
5. 1 2.2 1 .9
0.6
1 .8
0.4 0.1 0.5 0 1 .2 4.5
0 .6
6.1 7.2
1 .8
p
6.5 5.7 1 .4
New Zealand
p
M
A
42.5 48.7 53.8
85 . 4 87.3 82.7
71.1 7 2 .2 75.2
56.4 81.6 77.4
s
0.8
0.9
T
4.9 0.5
1.8 0
1 .9
0.2
p
3.1
0
1 .8
0
s
1 .9
3.6 2.4
1 6. 1
5.1
6. 4
9.6 3.0
2.6
1 .0 2.0
0
0
1 .7
3.5
5.1
3.7
1 .5 3.0
9. 2
2.4 2.2
22.1
2.6
2. 3
9. 2 6 .2
1 .7
1.5
6.5
3 .6
\ .5
4.7
4.6
1 .6
1 .8
2.7
3.7
0
0
3 .6
1.5
0.5
3.1 3.2
0
0.5 1 .0
4.0 9.8 9.7
1 .2 1 .4 4.8
2.9 2.6
0.4 0.5 3.0 4.4
7.7
6.1
1.2
0.2
3.8 1.8
2.6 1 .3
4.7
2.7
0
0
0
0 0
0
2.8 5 .0
0.2
0.1
9.0
2.2
0.4
3.1 0.2
T
3 .0 2.2
0.4 2.3
2.3
5.2 6.2
p
4. 1
0.6 1 .7
0.7
0.6
1 .5
5.1
3.7
0 0
0.2 0
0 0 0 0
s
s
4.5
0 0
s
2.2
0
T
1 .7 1 .4
0 .2 0.4
0
p T s
1 .2
0. 8 0.9 0.8
0 0.4
T
1 9. 5 0.9 1 2. 7
T
p s
p s
0 49 2.7 3.7 .
0.8
0.2 1.2 3.2 2.2 1.7
0.6 0.6 0.9 0.2
0.2 0.5
7.3
1 3.6 6.8 7.7
3.9
4.2
5 .2
1 .5
1 .4 0.6 3.6
3.5 3.3 4. 1
0.5
0. 1 0 0
p
3.3
4.5
0
1 .9 3. 1 0.5
p
4.6 1.5
3.9
1 .7 0.9
1 .3 1 .8 0 0.4
T
5 .4 8. 7
1 .2 2.2
6.5 3.2
T
1.1
1 5.2 6. 1 2. 7
5.6 4. 6
2.4
s
3.2
1 .3
1 .7
p
1 .4
4.9
3.8 1 .8
T
Feeling
p
0. 9 1.1 5.1 2.2
s
Ecologica l e ffect s
Japan
H
( % t ot a l respondents): T
Playi ng G od
1 29
Perceptions of Ethical Biotechnology
2 .9 5.1
1 .7
2.3 1.7 1.1
0.9
0.5
5 .2
3.6
0 0.9 2.6 0.5 9.5
1 .4
0.5
1 .0
0.9 2.9 1 .5
0.4
0 0.5
0.4 1 .4 0.4 0.9 4.4 0.9
The values are expressed as % of the total respondents who answered 07; in Japan, public N = 509, teachers N = 222, scientists V = 535 ( MACER. 1 992a): and New Ze a l an d , public N = 2034, teachers N = 277, scientists N = 258 (CouCHMAN and FIN K-JENSEN, 1 990). Organism: H , hu m an cells: P. p l a n t s : M. m i c ro b es ; A, animals. Grou p: P. p u b l ic : T. high school biology teacher; S, scientist. The a bse nce of data is indicated by '-'
1 30
4 Biotechnology and Bioethics: What
is Ethical Biotechnology? N ew Z e a l a n d p u b l i c : b e n e l l l
J a p a n es e p u b l i c : ben e l l l
H u man cel l s .';r :; , s P iJ,'ih!!"\
Plant cel l s
" >
-··
·.
P
,;, . ; ); -.•. :•"''; < -·�:_.,;./r
Microbes
-
c.: :>'j "2;.? " J
A n i ma l s
0
20 4 0
60
0
80 I 0 0
H u m a n cel l s
Plant cells
Plants
Microbes
Microbes
A n i ma l s
Anim als
Plant cel l s M i c robes A n i mals
0
2 0 40 60 80 I 00
J a pa n e s e s c i e n t i s t s :
be ne fits
20 40
60 80 I 0 0
New Z e a l a n d p u b l i c : r i s k
H u m a n cells
Human cel l s
. . . · · .: -'� >" /·:n::� p
Animals
Japanese p u bl i c : risk
0
. . . . . ,_,,, ,,.,.• •r>·• · • · · - 1
Mi crobes
2 0 4 0 60 80 1 00
New Z e a l a n d s c i e n t i s t s : benel l l s
K====" =�j.f lz.:;::::;:::::=�J� �-�-,=·�==�·-1,.·
, . , , . ,·.
·· r
t===r::� :=;::: ;._,
0
0
20 4 0 6 0 80 I 00
New Zea l a n d s c i e n t i st s : r i s k
Japanese scientists: risk
H u m a n cells
Human cells
Plant cells
Plants
M ic r o bes
Microbes
A n i ma l s
A n i mals
0
2 0 4 0 6 0 80 1 00
2 0 4 0 60 80 I 00
0
20 4 0
60 80 1 00
Fig. 3 . Comparative perceptions o f the benefits a n d risks o f genetic manipulation i n Japan and N e w Zea
land by public and scientists. Results from Japan are from Q7 of MACER (1992a), and New Zealand results are from the survey of COUCHMAN and FINK-JENSEN (1990).
The major reasons cited for the unaccepta bility of genetic manipulation (Tab. 2) can be grouped into categories:
1. 2.
Unnatural, playing God, unethical, feeling Disaster, fear of unknown, ecological and environmental effects
3. 4. 5.
Human misuse, insufficient controls, eugenics, cloning, humanity changed Health effects, mutations Not stated.
Group 1 concerns may persist with devel opment of the technology, but group 2 and 4
4
131
Perceptions of Ethical Biotechnology
Tab. 3. Benefits n f Genetic Ma nipulation Cited b y Respondents Japan Orga nism
% who
saw a
be nefit
New Zealand M p
Group
H
p
M
A
H
p
37.7 5 3 .5
78. 9 86.8
6 8.5 80. 5
53 . 1 7 1 .0 74.3
48.4 59.8 55.0
87.5 96.6 94.2
0.2 0.5
10.6 29.9 20.9
0 0
T
60.8
88.0
p
8.3
T s
24.4
0.4 0
24. 1
0
0.2 0 0
s
86.5
62 . 7 8 1 .2
8 1 .9
A 66.4 8 1 .6
8 1 .6
Reasons c ited as b e ndits ( % total respond e n t s ) :
Cure or p revent g•: n e t i c disease
0
1 .6
0
Disease con trol
p T s
5 .-t 10.0 1 1 .8
2.7 5.2 6.4
2.3
1 .2
3.6
4 2 .5
2.7
1 5 .0 7.2 1 1 .0
35.8
1 6.9 13.8 7.4
Medical a d v a nce . cancer cure
1 .8 1 .9
p T s
5.4 9. 1 7.0
1 .9 2.2 1 .7
1 0. 1 10.9
2.7 5 .9 4 .4
1 .7 19.3 2.8
3.2 1 8 .8
Make medicines
p
() 0.5
0.2 0 0.6
8.7 1 6. 7 31 .9
p T s
0.2 0 0.6
1 .3 2.2
p
0.6 3.2 3.1
Make use ful subst :mces. industry
Scien tific knowledge
T s
T
s
Agricultural adva nce
T
() 0
p
0.4
p
s
Increased yield.
to
m a k e m o r e food
Different varieties
T
0
0
s
0
p
0
T
0
s
Incre ased q ualit�
0.2
0
7. 1
4.4
23 . 1
9.3
2.3
14.8
()
0.8
20.5
0.2 3.0 3.3
1 .4 4.5 4.6
1 .8 6.8 8. 1
2.0
1 .0
0.4
6.7 3.8
3.1
4.5 2.7
1 9.2 23.2 20.7
16.9 1 8 .8 23.0
4.7 7.2
8.0 1 1 .8 1 3 .5
0
1 1 .5 27 . 6 22.4
20. 1 40 .6 4 4 .3
1 .9 3. 6 5.8
6.8 1 9. 9 1 6.4
1 7 .5 29.0 22 .6
0
2 .5
5.0 6. 7 3. 5
33.2 2 1 .3 24.5
4.3
1 .6 9. 1
1 .9 0
s
0.8
Exports increase . ..:conomics
3.8 3.5
p T s
0.5 0.9
0.4 3.8
Env i ronmental advan tage
p T s
0
3.6 1 .5 5.3
4.9
Ul
0.5
5.4
1 .0
p
5.1
T
1 .8
8.0 4.2
6.6 7.2 6.0
()
H u m a nity benefi t� - whole world be nefits
Doubtful benefit
B.:ncfit
not
stakd
0
9.7
3.5
0 1.7
3.7 0.5
4.6
s
5 .4
6. 1
7.4 6.8 6.9
p T s
0. 4 0.9 0.8
0.6 0.7 0.8
0.4 0.9 0.8
p
1 2.8 8.6 1 4. 1
30. 1 1 5 .0 26.3
25.8 1 7. 2 26. 1
T s
2.0 6.5 4.9
2.0
1 .8 5.2
p
0
8.2
10.6
26.9 22.0
0.5 1 .9
T
2.3
1.7
0 0
3.5
0.5 2.9
47 . 1 37.7 3.4
0.6 1.1
1 .9 0 1 .1
1 .4
3.9
1 .9
7. 9 2.9 1 0 .4
6.3 0.8 6.6
4.0 1.6 2.4
8.2 20 . 3
6.6 1 1 .4 8.2
24.6
1 0.6 3 1 .8 3 1 .0 12.2 1 0 .6
3 2. 5
32.6 36.7
1 .3
7.3 4. 1
7.3
7.3
1 1 .4
6.9
1 0.6 2.4 6 .0
2.6 0
5.6 0 4. 9
4.0 0
9.7
7.0
1 8.8
9.3
1 .6
3.8
4.9
2.4
0.9
1 .6
0.5 0.6 1 9. 4
20.5 22.0
The v a l u e s a r e expressed as % of t h e total respondents w h o an swere d Q7: in Japan, p ub li c N = 485 , teachers N = 2 2 1 . scientists N = 5 1 8 ( MA C E R . 1 992a ) ; and New Zealand. p u b l ic N = 2034, teachers N = 2 77 , sc ie n t ists !\' = 2 5 8 ( Co u cH '-l A r>; and FINK-JENSEN. 1 990) . Organism: H. human cells; P. plants; M. microbes; A, animals. Group: P . public : T . high school biology teacher; S. scientist . The absence of data is indicated by ·-·
132
4 Biotechnology and Bioethics: What is Ethical Biotechnology?
Tab. 4. Risks of Genetic Manipulation Cited by Respondents
Organism % total who saw risk
Japan M
Group
H
p
p
83.3 85.6 70.8
39.5 54.7 42.9
3.9 10.4 7.1 7.2
0 0
T
s
A
H
53.6 69.6 5 1 .7
6 1 .3 68.7 54.3
74.4 43. 9 56.7
0 0 0.4 3.1 0.9 1 .5 3.7 7.7 3.3 7.8 9.0
1 .0 1 .4 2.3 4.9 2.2 2.7 3.7 5.0 3.9 8.5 9.5 7.9 12.1 1 5.4 10.6 1 .5 1 2.7 2.5 4.9 6.4 1 1 .0 0.4 0.9 0.6 0 0 0 0.4 0 1 .2 2.1 5.0 2.1 3.3 3. 1 6.2 1 .0 0.5 1 .2 24.7
3.7 12.3
New Zealand p A M 42.4 25.6 38.9
67.4 57.5 56.1
58.4 25.0
0 0.5 5.5 4. 1
0 0 4.7 2.3 1.7 16.8 25.3 26 . 9
4.5 3.5 5.3 3.8
43.3
Reasons cited as risks (% total respondents): Unethical, ethical abuse
p T s
Playing God, unnatural
p T
Disaster, out of control
p T
s
s
Fear of unknown
p T
s
Ecological effects
p T
s
Biohazard, spread of genes
p T
s
Danger o f human misuse, biowarfare
p T
s
Eugenics
p T
s
Cloning, human reproduction abused
p T
Humanity changed
p
s
T s
Deformities, mutations
p
T s
Insufficient controls, need public discussion
p
T
s
Economic corruption of safety standards
p T
Not stated
p T
s
s
2.5 4.1 0.9 17 2.7 5.3 2.3 2.7 5.9 4.2 2.5 9.7 6.8 10.4 8.2 10.2 7.5 7.9 8.9 9.1 7.4 5.4 14.5 1 4.0 7.3 3.4 10.0 1.9 0.6 2.9 9.5 1 .8 5.9 3.3 3.7 1 .7 4.1 6.6 8.4 1 1 .7 5.5 9.5 15.8 9.9 1 1 .8 0 3.5 0 8.2 0 0 5.0 0 0 2.2 0 0 0 0 3.2 1.9 0 0 0 5.2 0 2.7 0 0 0.6 6.8 0.8 1 .5 0.4 4.9 2.3 10.0 2.7 1 .5 4.2 1 .7 2.2 4.5 2.2 3.6 3.2 3.2 5.6 7.0 5.6 1 .0 0.8 0.8 0 0.4 0.5 1 .2 1.1 1.2 33.2 13.8 1 9.8 23.6 13.6 15.8 22.0 12.1 1 5 . 2 .
13.6
6.0 3.5 1.1
5.1
18.6
1 0.6
6.6
4.6 1 1 .3 5.1 3. 1 9.3 5.1 10.2 5. 1
12.5 9.7 4.4
10.2 0 0
7.4 4 .6
8.0 3 .4 6. 3 7.4
5.1
1.8 8.2 7.5 9.1
0.5
1 8.4
4.6
3.4 2.3 5.7
5.1 6.7 2.9 7.4
0 0
0.6 0
3.5
4.3
1 2 .3
5.0 1 1 .7 7.6 2.0 9.5 6.4 45 .
6.9 3.5 1 .3
5 .3
3.0 4.8
7.0 3.5
2.8 17.1 4.8 1.1
8.2 4.4 1 0.8
0 0 6.4 3.8
0 0 15.5
10.8
10.4
0.8 0.9 6.4 2.0 0.4 7.0
4.6
4.0
9.1
8.7
1 4.8
10.5
2.3
2.6
16.7
17.4
5.1
3.1
The values are expressed as % of the total respondents who answered 07; in Japan, public N = 485, teachers N = 221, scientists N = 518 (MACER, 1992a); and New Zealand, public N = 2034, teachers N = 277, scientists N = 258 (CouCHMAN and FINK-JENSEN, 1 990). Organism: H, human cells; P, plants; M, microbes; A, animals. Group: P, public; T, high school biology teacher; S, scientist. The absence of data is indicated by '-'
4
concerns may he le sse ned by develop m e n t of technology. G roup 3 concerns can be les se n e d by regulations. as will discussed in Se ct . 8. People who d id not cite a reason may feel less strongly about the issue. but there is no real indication of what concerns they had. We should also note that many people expressed r e asoni ng across several of these types of con cern. The most common response in both coun tries for a ben t.: fit from ge netic m anipu l a t i on of human cells were medical reasons, as from microbes w he r e the benefit of making useful substances was also often cited ( Ta b . 3 ) . E co nomic benefits were not cit e d much. with more re spondents in New Zealand listing these benefits, pe r ha p s because the economy is so de p e n de n t upo n b io te c h n o l o gy . in te rm s of agriculture . and the economic recession has been much harder there. In the reasons cited for gen e ti c manipulation of a n i mals. many more New Zealanders cited disease control of animals. as a reason. I n both coun tries sim i lar p rop o r t i o ns cited ··new varieties'' or "increased p r odu c tio n and food'' as the main benefits of ge netic manipulation of plants and an i m als. with a trend for more New Ze alander� to cite the latter. There was a lso a w i de diversity of re sponses to the reasons why people pe rc eiv ed risks from ge n e t ic manipulation (Tab. 4). The frequency of the common responses to Q7d did n ot differ greatly from those given to Q7b. tho u g h many respondents listed differ e n t reasons in response to th e se two ques tions. The risks were in general m ore involv ing h uman misuse . and activity. rather than abstract concerns such as ·· inter fering with nature". They were also more specific. so that more responde nts listed deformities and mu t a t io ns as a problem. In addition to ecological and environme n tal concerns. t h e r e were also substantial numbers who cited a risk con nected with the sp re a d of genes. vi ruses. and genetica l l y modi fied o r g a n i s m s (GMOs). ge n e rally labelled · · biohazard " in the categories in Tab . 4 . A fe w said that sci e n c e was always assoc i a t e d with danger. In a recent E u ro pean p u b lic opinion poll in t h e U.K . . France . Italy and Germany (per formed in 1 990 by G a l l u p for Eli L i ly . N = 3 l 56 . DIX O N. 199 1 ) . the respondents
Perceptions of Ethical Biotechnology
133
were asked to choose the largest benefit that they saw coming from biotechnology, be tween one of four possible be n efits from bio technology. Over half rated cures for serious diseases as the most important benefit. An other option was reducing our dependence upon pesticides and chemical fertilizers, which 26% of Italians, 24 % of Fre n ch , 22% of British and 1 6% of Germans, chose as the largest benefi t . The European re s p o n dents were asked a similar q u e st i on about their largest concern. Potential health hazards from laboratory ge netic research were named by 29% i n Italy. 1 7 % in France, 1 1 % in Britain and 10% in Germany. 40% of French, 35% of Germans, and 25% of B r it i sh and Italian respondents chose e ugenics , and slightly l owe r propor tions overall chose environmental harm, 34% in Britain, 33% in France, 22% in Italy and 2 1 % in Ge r m any . In the European survey, overall one third of respondents feel that biotechnology is ethi cal. and one third feel that it is unethical, and one t h ird think i t is i n be tw e e n, "neither". This compares to a more favorable accepta b i l it y of ge ne t ic manipulation in Japan and New Zealand, especially for n on - hu m an ap plications ( Tab . 2). In the USA w h e n people (N 1 273) were asked whether they thought that human gene t h e r apy was morally wrong, 42% said it was. and 52% said it was not, with 6% unsure (OTA , 1 987). However, o n l y 24% of the USA sample said t h at cr e a ti ng hybrid plants or animals by genetic manipul ation was morally wrong. but 68% said it w as not, 4% said it depends, and 4% said they were un sure. The peop le who found it morally unac ceptable were asked for reasons, and t h es e reasons can be compared to those given i n Tab. 2 from Japan and N e w Zealand. The US r esu l t s , expressed as % of the total sample. were that 3.1 % said that it was interfering with nature. 2.8% said it was playing God, and about 1% said they were afraid of u n known results, 0.6% said it was mo rally wrong and d i d not cite a reason, and another 2-3 % had other reasons. It does re i nfo rc e the idea that abstract reasons are a major conce rn about genetic manipulation . but further data are needed. In the European survey, e u ge n i cs was the =
134
4
Biotechnology and Bioethics: What is Ethical Biotechnology?
major concern (DIXON, 1991). However, in the Japanese survey and in the New Zealand survey, the proportion of people who cited eugenic concerns from genetic manipulation of humans was equivalent to about 4% of the total respondents, half of the proportion who expressed concern because of environmental reasons, and much lower than the number of respondents who cited reasons related to per ceived interference with nature, playing God, ethics, or fear of the unknown (Tabs. 2 and 4). In 1993 surveys in response to the above question Q5d (Sect. 4.2) people were asked to give their reason for concern about "genetic engineering". In New Zealand and Australia 7% of the total expressed eugenic concerns, while only 0.6% of Japanese did (MACER, 1 994 ) . Because free response questionnaire data are unavailable from Europe, we cannot directly compare the apparently higher con cern about eugenics in Europe as opposed to New Zealand or Japan. One could speculate that it may be related to self-acknowledge ment of t he past e uge ni c abuses in Europe, and due to media coverage of the eugenic concerns raised by organized feminist and Green groups in Europe. Free response ques tions may provide a better estimate of peo ple's opinions and provide a better picture of actual perceptions than agreement with sug gestive concerns. Another feature of the free response sur veys was the low proportion of respondents
who cited environmental benefits (Tab. 3). In the European survey, discussed above, the choice of the benefit of reduced pesticide use and environmental benefits was popular. In Japan and New Zealand further questions concerning science were included in 016. Q16. To what extent do you agree or di sagree with the follow i ng statements that other people have
made? 1 strongly disagree 3 neither agree nor disagree
2 disagree
4 agree
5 agree
stron g ly
Q16f. Gen e t i cally modified plants and animals will
help Japanese agriculture become less dependent on chemical pesticides.
The response to Q16f, which asked if peo ple thought GMOs would have an environ mental advantage, was quite supportive (Fig. 4 ). The 1993 survey found the same values in New Zealand and Japanese public as 1991 , with similar values in Australia (MACER, 1994). The free response questions (Q7c, Tab. 3), however, suggest that it may not actually be a common feeling. Environmental benefits of biotechnology may be very unfamiliar, de spite the high level of concern expressed in Q5 about pesticides (Figs. 1 and 2). In both New Zealand and Japan, there should be more publicity associated with this environ mental benefit, though the chemical compa nies who make pesticides may have different
Public J • S t ro n g l y d1sag ree • 0 1 s a g ree
NZ
Teachers J
• Neither 0 A g re e
NZ
D S t r o n g l y a g re e
Scient i sts J
0
20
40
60
80
1 00
% of re sponde nts Fig. 4. Pe rce p tion of environmental benefits from applications of genetic e n gineering in agriculture in Japan (J) and New Zealand (NZ). Results from Japan are from Q16f of MACER (1992a), and New Zealand results are from the survey of CoucHMAN and FINK-JENSEN (1990).
5 Past and Present "Bioethica/ " Conflicts in Biotechnology
priorities ( see Sect. 7 ). As in the risk of euge nics discussed above, we see clearly the lack of reliable dat a about public perceptions. at least. among what has been published.
4.4 Concerns about Consuming Products of GMOs Products produced by genetically engi neered microorganisms, such as human in sulin or growth hormone . have been ap proved for medical use for over a decade . The first food products for human consumption have been approved for consumption. and it i s expected th at v e g e t a b l e products derived from G M Os will be approved in 1 994. We can expect many products t o be approved as safe for human con sumption in the next few years. so a pressing q uestion is what concerns the public has that could result i n conflict. The views o n t h e safety of products made by genetic manipulation were examined by Q8b (MACER. 1 992a) . as had also been used by COUCH M A t\ and FIN K-JENSEN ( 1 990). 75% of the J apanese public said that they were aware that G M Os could be used to pro duce food and medicines. similar to 73% of the public in .1\ew Zeal a n d . and in both coun tries. 97 % of s.cie ntists said that they were aware of t h i s Free response was requested of the concerns people had:
135
l ogy teachers. which are very concerned in Ja pan. Scientists in Japan are also more con cerned than their peers in New Zealand. though many Japanese company scientists showed less concern t h a n government scien tists (MACER. 1 992a). The concerns included significant numbers who saw the products as unnatural (see Sect. 5 . 1 ), and who had health concerns. Similar reasons were cited in the 1 993 International B ioethics Survey (MACER, 1 994 ). There appears to be joint perception of benefits and risks as for genetic manipulation. In a European-wide survey (N 1 2 800. MACKENZI E. 1 99 1 ) . 65% of people approved of genetic engineering to i mprove food and drink quality. but 72% said that it was "ris ky In an earlier US survey (OTA, 1 987) , 80% had not heard o f risks associated with genetically engineered products while only 1 9% had. However. since the time of that sur vey . we can expect that many people have heard of concerns about consuming products of genetic engineering. A related issue has been continued controversy about the use of genetically engineered bovine somatotropin, despite evidence that it is safe for human con sumption. These concerns will be considered in Sect. 7. =
".
.
Q8b. [f any of the following w e r e t o be produced from ge n e t ically modified orga nisms . would y o u
have any concern' a bout using them ? 1 No concern 2 Conce rn For each product that you are concerned about. what concerns wuuld vou have about u s i n -g i t ? Vegetables Dairy prod ucts Medicines M eat
The results a re l i sted in Tab. 5. Vegetables were of less concern . especially among the p u blic. and meat was the product with the highest concern. Dairy products were of inter medi ate conce rn. Medicines were still of con siderable concern. New Zealanders appear to be somewhat le-;s concerned about consuming products containing GMOs or made from them. than are the Japanese . The biggest dif ference is in the opinions of high school bio-
5 Past and Present
" B i oethical " Conflicts in
B iotechnology From the results of the above public opin ion surveys. and other data, we can see which issues among the variety that have been ex pressed by academics and protest groups in the decades of debate on biotechnology, are common and which are not. In this section we will consider the m ajor reasons cited for re jection of genetic manipulation research . The emotions concerning these technologies are complex, and we should avoid using simplistic public opinion data as measures of public per ceptions, rather we need to address the ex pressed concerns and apply policy measures
1 36
4
Biotechnology and Bioethics: What is Ethical Biotechnology?
Tab. 5. Concerns about Consuming Products Made from GMOs Product % total with concern
Group
Dairy
Japan Veget. Meat
p
5 1 .6 34.9 36.1
41.0 3 1 .5 32.3
T
s
Med.
Dairy
New Zealand Veget . Meat
55.4 36. 1 38.0
50.5 35.5 28.8
42.8 1 3.0 24.0
38.4 9.7 21.7
48.3 13.7 24.4
34. 1
7.2
Med.
9.7 19.8
Concerns cited about consuming such products (% total): Unnatural, will taste bad
p
T
s Don't know what we are consuming Unknown health effect
p
T
s
p
T
s
Long-term risk
p
T
s
New disease
Side effects
Because it is food, daily use
12.3 1 .5 2.8
7.8 1.1 2.7
2.0
0.4 1.4 0
0.6 1 .3 0
0.7 1 .4 0
0.4 1.4 0
6.0 1 .0 0.7
4.6 0.7 0.9
7.2 0.7 0.7
3 .4 0.4 0.4
8.9 7.2 5.5
7.4 6.3 5.5
9.5 7.7 5.7
7.8 7.7 5.2
9.4 4.0 4.3
7.7 2.9 3.5
10.1 4.7 5.1
7.8 0.4 4.0
2.3 0.9 2.0
2.4 0.4 2.2
2.6 1 .4 2.2
1.9 0.9 1 .8
1.5
1 .1
1 .3
0.8
1 .4
s
0.3 0.4
3.3
p
2.1 1 .8 0.7
0.6 1.3 0.6
1.9 3.2 0.8
5.9 5.5 1.3
3.0 3.2 3.6
2.5 3.0
1.9
2.4 3.4 3.4
4.1 3.6 3.2
6.1 9.5 9.4
5.3
9.1
9.6
5.9 9.0 9.9
5.5 9.5 8.5
5.1 1.8 8.7
3.8 1.9 7.8
4.3 1 .8 7.1
5.1 1 .5 8. 1
0.7 1 .8 1.1
0.6 0.9 0.9
0.7 0.9 1.1
1 .0 0.9 1 .0
1 .7 0.8 1.2
1 .5 0.7 1.1
1.9 0.7 1.2
1 .7 0.7 0.4
1 .3 1 .8 4.6
1.3 2.2 3.3
1.1
1 .3 2.3 3.3
1 .3
1.5
1 .9
0.3
2.3 4.6
1 .5 0 0.2
1 .5 0.4 0.2
1 .9 0.4 0.2
1.1 0 0
0.7 1 .4 0.7
0.7 1.8 0.7
0.7 2.3 0.7
0.8 0.9 0.6
0.9 0.9 0
0 0 0
0 0 0
0.4 0.5 0. 1
3.2 1 .8
3.4 1 .8 1 .9
2.9 1 .4 1.7
4.7 0.8 0.7
3.8 0.7 0.9
4.3 1.1
1 .8
3.0 1.8 1.8
0.7
4.1 0.7
0.4
0.7 1 .4 0.7
0.7 1.3 0.7
0.9 1.4 0.7
1.1 1.4 0.7
17.7 8.6 8.8
12.1 7.7 9.6
19.6 9.0 9.7
15.9 8. 1
4.7 0.8 2.6
4.2 0.4 2.8
5.8 0.4 3 .2
4.8 0.4 1.6
T p
T
p
T p
T
s
p
T p
T
s
p
s
Lack information, information is hidden
T
T p s
Not stated
1 .4 2.4
2. 1 2.3 1 .7
Other reasons: Medicines patients are weak; dairy - given to children
Economic corruption of safety standards, ethical concerns
1 1 .1
1 .8 1 .4 3.3
s Environmental effects
5.7 3.1 3.0
0.6 1.3 2.2
s No guarantee of purity or quality
8.5 4.5 4.2
1 .8
p
s Unknown research area
6.1 4.5 3.7
T
s Safety doubts, need to test properly
6.8 5.0 4. 1
p
T
s
p
T s
7.2
The values are expressed as % o f t h e total respondents who answered Q 8 ; i n Japan , public N = 527, teachers N = 22 1 , scientists N = 543 (MA CER, 1 992a); and New Zealand, public N = 2034, teachers N = 277, scientists N = 258 ( CoucHMAN and FINK-JENSEN , 1 990) . Group: P. public; T, high school biology teacher; S, scientist. Absence of data is indicated by '-'
5 Past and
Present " Bioethica/" Conflicts in Biotechnology
to lesse n the conflict that people find with biotechnology. Because be neficence is a basic ethical principle, we can assume that there are important grounds for pursuing research and apply i n g t echnology. providing we are consistent in re-;pecting the other ethical prin ciples. s uc h as 10 do no harm.
5 . 1 I n terfe re nce with Nature or
"Playing God"
There were also significant proportions of respondents who thought that genetic manip ulation was ink rferi n g with nature . or that it was p rofa ni ty to God . or said that t h e y had a bad feeling about it. Also many saw genetic manipulation. e spe c i ally of humans and ani mals, as unet hical (Tab. 2 . Sect. 4.3). These respondents m ay see these techniques as unacceptable . regardless of the state of tech nology and regulation. In the US survey. 46% said that we have no business med d l i ng with nature . while 52% disa g reed ( OTA. 1 987 ) . Although many scientists react t o people with these views as i rrationaL it is noteworthy that about 1 6% of the scientists and teachers in New Zealand and Japan who found these techniques u nacceptable also shared these views, and these reasons were also cited re garding genetic m anipul a tion of microbes. The questions about food also illustrate this con ce r n . I n J apan 12-1 6% of the public who were concerned about consuming prod ucts made from GMOs, said that such food stuffs or medici nes would be unnatural . while in N e w Zealand the values were much higher (Tab. 5 ) . These results were confirmed in the 1 993 International Bioethics Survey (MACER. 1 994). Australians were similar to New Zea landers. with other Asians expressing this idea less. like .J apanese. While rationally we can say such foods are j ust as natural as foods made from a n y modern crop or animal breed, I 0- 1 2 % of scie n t i s t s also said this. In a 1 988 public o p i n io n survey in B r itai n . 70% agreed that "natural vitamins are better for us than l ab o rat ory - ma de ones··. while only 1 8% disa greed ( D U R A '
1 37
therlands ( H A M STRA, 1 993) . In fact the use of varieties bred using genetic engineering should allow the avoidance of chemical pesti cides and preservatives during crop growth, food storage and processing, which could ac tually make such foods "more natural". We have yet to understand what people believe nature really is. It is a changing con cept and varies between individuals, religions and cultures. As societies become urbanized t hey lose touch with nature. However, there is also a rec en t trend to buy products from "or ganic farming" , or preferences for "free-range eggs'' over eggs from battery farmed chick ens. All people have some limit in the extent to which they support changing nature , or the application of technology. Bioethics still needs to be developed in order to approach this abstract area of thinking. In the mean time , scientists as well as the public perceive limits to what is acceptable. or ''ethical" , bio technology. and fur t he r research is needed to determine what these limits are. By reducing the use of chemicals in agricul ture . food processing, and medicine, biotech nology may actually be able to make these ar eas more ''natural". Also, if e ffici e n cy of agri culture is increased, and genetic diversity in creased, biotechnology may allow some agri cultural land to revert to more random natu ral vegetation. The potential is there, if socie ty demands it. However, increased use of mi croorganisms for industrial and environmen tal processes may lessen the use of chemicals in these applications, would this also lessen people's co n cern - or raise it? 5.2 Fear of U nknown
In general the other frequently cited com ments in all sample groups for all organisms w e re connected with the unknown nature or danger of the results of genetic manipulation. S o m e people s aw this in terms o f a disaster, while others have less dramatic concerns. There is also fear associated with unknown research fields, which is true of any area. We could subdivide this concern into health and ecological concerns.
1 38
4
Biotechnology and Bioethics: What is Ethical Biotechnology?
5 .2.1 Health Concerns Fear of the unknown was found to be a common concern that people had about ge netic engineering (Tabs. 2 and 4). Fear of health effects are related to this, and were also common. When asked a later question concerning food safety, the principal concern was regarding health effects, including side ef fects (Tab. 5). Food safety represents the principle, to do no harm. It is a responsibility of developers and marketers of new varieties of GMOs and products from GMOs. Suffi cient regulatory procedures should be in place already as for existing products, and further regulations have been added in some countries (like Japan or the European Com munity) but not in others (like the USA) (see Sects. 5.3 and 8. 1 ) .
5 . 2 . 2 Environmental and Ecological Risks
There is growing concern about environ mental issues, which must be welcome to all who are concerned about environmental ethics and j ustice to current and future gener ations. Part of the reason for the increased concern has been recognition of global pollu tion that human activity has caused, and a fear for the survival of the planet (WRI, 1 992) . The phrase "sustainable technology" has been added as an ethical criterion of tech nology. Clearly, with the changed UV light and predicted increased temperature and cli mate change, the current conditions are not sustainable - rather we need to look at the steady state that may be possible to stabilize in another century. Nevertheless, the earlier we act, the less different the future world will be, and sustai nability has become recognized as an ethical criterion of technology. Any biotechnology which is in conflict with this principle will be called "unethical". As discussed in Sect. 5.1 , biotechnology has potential for ecological im provement, if applications are targeted with that objective. The ecological concern that many people have, refers to the introduction of new organisms into the environment, in-
eluding GMOs. Ecological studies are needed, and monitoring of releases of GMOs, to gain data to allow prediction of the ecolog ical impact of such introductions. Some data are already available, after over 1 000 field tests of GMOs already performed, but until safety has been demonstrated for each type and species of GMO in question we should not have commercial introduction on a large scale. We should support programs such as the PROSAMO study in the U.K. which are designed to provide methods to monitor the release and survival of GMOs (KrLLHAM, 1992). In the cases where safety has been shown, and in cases where the GMO presents less ecological risk than the current varieties, we should use the GMO. It is basic risk man agement. It is the topic of other chapters of this volume. 5.3 Regulatory Concerns
There was also much concern expressed in Japan and New Zealand about insufficient controls, especially by teachers and scientists. If what are seen to be safe and adequate con trols are established, the people who had these reasons for objecting to genetic manipu lation, may accept it. It is up to the research ers to prove that the results represent an ac ceptable level of risk, and to adjust regulatory procedures to those that are seen to be ade quate. A discussion of the regulation of bio technology is in Sect. 8, and biosafety is dis cussed in Chapter 3 of this volume. There was also qualified acceptability by some respondents, depending on the intro duction of appropriate control measures. About 7% of scientists and teachers, and 2% of the public, wrote such comments for plants and microbe applications, and 1 9-25 % of all respondents in Japan who said that these techniques were acceptable wrote such com ments for genetic manipulation of human cells (MACER, 1 992a). The actual number of respondents who were concerned about con trols should include these respondents in ad dition to those who said that the area was unacceptable because of insufficient controls. It may be significant that such a high propor tion of respondents who said that the tech-
6 Future
n i q u e s were ac c e pt able did spontaneously write down some qualification to their re sponse choice . Field release� of G MOs are regulated in all countries of t h e world . officially . as they should be (MACER. 1 990: Chapter 6). The procedures var:-· . as does t h e public satisfac tion with such procedures. They are also sub j ect to politica l climate . a nd bureaucratic reg ul ations conflict with industry and with the p rin c i p l e of b e n e fi ce n ce whereas inadequate regulations risk harm. as discussed above . Most countries are shifting to a product-based system. which i� more sci en t i fi c than a system o f exclusion or inclusion based on production method. Howe\ er. the ex c l us i o n categories of o rganisms from regulations may be broad ened so m uch as to conflict wi t h suffi cient prot e c ti on of h u m a n and e co l ogic a l s a fe t y In 1 992 the US F D A s a i d that they would not impose any special re g ula t i o ns on G M O food prod uc t s ( K ESSL E R e t a l . . 1 992) . This has pleased ind ustry ( Fox. 1 992 ) . bu t it may lead to more people having fear of what they perceive are u n known food products. I n the European Com m u n ity a nd Japan, a comm i t tee will e x ami n e each case. to determine whether extra safety tests are required ( M A c ER, 1 992a ) . H e re we see different balancing of ethical principles. benefice nce versus do no harm . It remains to b e s een how much con flict there is in the acceptance of food made from varieties bred using genetic engineering. it may depend on po s s i ble future cases if harm is related to such p rod u c ts .
.
.
.
5 . 4 H uman Misuse There
also concern about human mis techniques, which again. could be eased by further guarantees over who uses these techniques. For human beings. another m ajor re s po n se was concerns about eugenics. and c l on i n g These fears may be eased by the introduction of laws. but we should note t h a t in E urope where there are some l aw s to pre ve nt such abuses. there is still much concern with e ug e n ic s (�ee Sects. 4.3 and 8.2). I t may he go o d to mai ntain a hig h level of such fears i n society as the most effective met hod to pre vent future abu�es of biotechnology from bewas
"Bioerhica/ " Conflicts in Biotechnology
1 39
ing made. However. it is important that peo ple learn to distinguish medical uses of ge netics from racia l applications that are asso ciated with the word eugenics. They can al ready distinguish between applications in volving different organisms. A related issue. and one more relevant to microbial biotechnology, is the use o f b io technology in biowarfare research. Biotech nol o gy is being applied to mili tary research, to develop biose nsors t o detect poisons, and to improve immunity (NRC, 1 992) . If the mo tive i s defensive, and the results are distri buted to the general public, globally, we could find e thical justification for such re search. However, such research would con flict with ethics if it is not shared with all peo ple . and if there is any p os si ble escalation of offensive biological warfare research . W e c a nnot e liminate the pos s i b ili ty that biotech nology will be applied to biowarfare develop ment by individual terrorists, so such defen sive research could have benefit. Additional ly. any research to improve immunity will be u s e ful as we face infectious diseases, and i n the future as the increased incidence of U V l i g h t ma y decrease our immunity. We can only attempt to ensure that biotechnology is not misused.
6 Future " Bioethical "
Conflicts in B iotechnology
6. 1 Changing Perceptions of Nature
use of t he se
.
As discussed i n Sect. 5.1 . a significant pro portion of people. including scientists, see ge netic m a nipul a t i on as i n t e rfe ri n g with nature. As will be discussed in Sect. 8.2, people who said ge netic manipulation of human c el l s is playing G od may still support medical use of human gene therapy. or environmental appli cations of GMOs ( M ACER, 1 992a, c). This represents the most common reason why peo ple may overcome their fear of playing God, to treat disease. Disease is natural in the ,
140
4
Biotechnology and Bioethics: What is Ethical Biotechnology ?
sense that it may not involve human action, but it can be perceived as unnatural when it is curable. There are of course limits to this change, as we will all die - death is natural. What is thus important is not whether it is natural or not, but whether we should treat it or not. In medicine, there are other words which distinguish these concepts, ordinary treatment and extraordinary treatment. This already presents conflicts to the un limited use of biotechnology, such as life sup port technology used in intensive care. We can expect these conflicts to become more fa miliar and more common, in questions such as which genes do we consider important to "fix" in gene therapy?, which genes do we perform genetic screening for?, what is dis ease?, how far do we genetically engineer an imals as transgenic production systems for pharmaceuticals? , and how far do we trans form our environment with genetically modif ied plants for agriculture and ornaments?, and should we introduce genetically engi neered microorganisms into the wide envi ronment in efforts to clean up pollution, by removing or degrading toxic chemicals or heavy metals? The list of questions is enormous. Biotech nology may not have a fundamental conflict with nature, and many would see new tech nology as a gift from God; however, we must not confuse ourselves with God. We are likely to make mistakes in the future, and apply technology too far. One basic criterion for ex amination of the extent to which we should proceed and what is ethical application of technology is that we should not use technol ogy which will mean that future generations lose the possibility of reverting back to social and environmental conditions that existed in our generation. This may mean that we limit the introduction of genetically engineered mi croorganisms into the wider environment, though many may arise via the selective pres sures present in polluted environments. Are these selected organisms different from speci fically designed ones?, are they any safer?, we would say in general no. However, elimination of disease is ethical biotechnology; there should be no objection to the elimination of human diseases, such as smallpox. There may be more debate about
the elimination of recessive disease-causing alleles, that may have some unknown advan tage, like the sickle cell anemia trait which of fers improved protection against malaria, but no baby should be denied the possibility of therapy for the disease, be it by safe gene therapy or other options. However, carriers may want to eliminate their risk of transmit ting a harmful allele to their offspring - what is called germ-line gene therapy. This is an other future conflict that faces us, even if some countries enact regulations that prohibit germ-line gene therapy for the present, we cannot escape the question.
6.2 Pursuit of Perfection - a Social
Goal
The paradigm of beneficence argues that we should pursue benefit. This is sometimes confused with pursuit of perfection. As any human being carries 1 0-20 lethal recessive al leles, no one is perfect, and we can never ex pect to become "perfect" genetically. Because social standards also differ, no one will be so cially "perfect" to all. Thus the pursuit of per fection is impossible. There is also no perfect environment, or food, we all have different preferences, and we must also weigh the ethi cal interests of other organisms. However, ideals of phenotype are not im possible. A recent example illustrates this, the case of using recombinant human growth hor mone to make short children, without a growth hormone gene defect, tall (DIEKEMA, 1 990). Such a study was supported by the NIH in the USA, and is under some ethical review (STONE, 1992). Is this ethical biotech nology? Support for it only comes from the recognition of parents autonomy - however, we already limit this when it may damage the child or society. Is it a waste of resources? It is a waste of health care res o urce s , but is it any worse than spending large sums of money on luxury pursuits? The principal objection must come from the social effect of allowing parents to make their children taller by extraordinary methods (though good food may have an equal effect), which is consistent with a social ideal that tall
6 Future '' Bioethical"
children are
better - which
is i nco ns i s t e nt
with human e q u a l i t y and could have harmful
social conseque nces. It also has harmful envi ro n men t al con�equences. as big pe op l e use more re so urce s . Above all. such treatme n t r e cog n i ze s a fai l u r e of s o c i e t y to t o le ra t e differ e n c e s , and i f i t i s app rov ed , s u g ge sts soci ety has give n - up. I f this is so, we can expect fur ther discrimination a ga i n s t those who are dif fe re n t from a n arr o w i n g social norm . This argum e n t applies to all c a ses o f t re a t i n g a b n onn a l i ty - however. the crucial e t h ical
factor t h at m e a ns t h at i t is e t hical
to t re a t som e on e w i t h a serious g e ne t i c dise ase and it is not ethical to pe r for m c o s me t i c t h e rapy like that example . i s that t h e p r i nc ipl e of benefi cence d e ma n d s us to a s s i s t th ose who suffer from disease , be it me n t a l or p h y s i c al , b u t t h e pr i n cipl e of do no harm to s oc i e t y asserts that we do not d e ve lo p a so ci e t y less tolerant of abnormality. We b a l a n c e these two p ri nc i pl e s in favor of i nd i v id ua l beneficence when the dise ase is seri ous. Another example o f t h i s is the p u rs ui t of efficiency in agriculture . Ba tt e r y fa rm in g of chic kens may have been somewhat chea pe r than free-range fa r m i n g . however, in Switzer land and Sweden it i s be i ng r ej e c t e d due to e thi cal reasons. As a g r i cul t ura l systems to more e ffi c i e n t l y feed a n i ma l s are d e ve lope d . peo p le ma y say t hat t he s e are une thical. a nd p refe r to pay a l i t t l e e x t r a pr i c e fo r h a vin g free - ran ge a n i m a l s . P e rh a ps the e co nom ists may even redo their eq u a t i o n s and fi nd that the tourist income from g r a z i ng s h e e p scenes more than com pe n s a t e s for a po ss i bl e hi gh er production cost c o m p are d to factory fa rmi n g . If we h ave suffici e n t prod u c t i o n capa c i t y . a n d some w ou l d Sa) e v e n if not. there is no e t hi c a l excuse for animal c r ue l t y . Biotechnology has t h e po t e n t ia l to i n cr e a s e p r od u c t i o n e ffi ci e n c y so that m o r e fr e e - r a n g e animal systems can be used. The 4uestion of w h e t h e r this wi ll h ap p e n . is a d d r e s s e d i n Se c t . 7. 6.3 Li mitation of I ndividual A utonomy The above e x ample about growth ho r m o n e i l l ust rates the c o nflict between i n d i v i d u a l a u -
Conflicts
in
Biotechnology
141
tonomy and s oc iety . A u t o n om y must be lim i ted b y soc i e ty i n order to preserve the auton omy of all i n di v i d u a l s to an e qu al de gree . E t h i c a l l y . we should ap p ly this gl oba l l y , based on j ustice and equali t y o f h u m a n ri g h t s , so that individual a u to n o my sh o u l d b e l i m ite d . A clear contradiction t o this comes in the po li c i e s on e n vi ronmental use. C u rr e n t l y , in dustrialized c o u n tr i e s p r o d uc e mu c h mo re p o l l u t io n . and use much more e n vi ro n m e n t a l resources than d e v e l opi n g countries. Should
any person use more than hi s/ he r share of communal e nv i ro n m e n t al resources or p r o
duce too much p o l l u tion ? Yet, societies who like to claim high value on liberty, claim that individuals can use their money to s a t i sfy their desires, without referen ce to these fac tors. The on l y way to co mb at this selfish g re e d , that most of us p oss e s s , would be to i n t ro d u c e fai r e nvironm e ntal quo t a s . A d i ffe re nt issue is whether we sho u l d p r e v e n t i n d iv i d u a ls fr om e x p os i ng themselves to risky be h a v i o r . We allow individuals to p l ay d a n gerous sports, but we i m p os e stricter lim its o n o cc up a tio n a l heal t h . A l r e a d y t h e re a r e s o m e g e n e ti c risk factors identified that cou l d be used to screen out workers at high ri sk i n pa rti c u l a r e nviron ments ( D RAPER, 1 991 ) . Should socie ty be paternalistic, or s hould it
let
i n dividuals
h ave
freedom. As further g e ne t i c p r e d i s p osi tions, we will have more issues at stake .
ge n e s are identified
for
6.4 Human Genetic Engineering I n the future when t e c h n iqu e s for t a r ge te d gene insertion become safe to use on humans, t re a t me n t of n o n - d i se a se conditi ons will b e called for. It is a fu r ther issue
whether
it is
e t h ical to attempt to improve the genes of h u mans as we m a y do w i t h a gri cu l tu r al o rg a n
i sms.
A l t hough
such
ge n e t i c
en g i n e e r i n g
would be co n s i d e r e d unethical by many peo today, it is l i k e l y that t h i s conflict will ar ise w h e n i n c re as i n g numbers of pe o p l e want to i m p r o ve characters such as i m m u n i ty to disease , i m p r o v e the e ffi ci e nc y o f digestion of fo o ds t u ffs . or numerous p s yc h ological or so c i a l traits. I m m u n izat i o n by gene therapy e n tered a cl ini c al trial in 1 992 ( A N D E RSON , 1 992b) . so i t may be a more immediate p ro s -
ple
142
4
Biotechnology and Bioethics: What is Ethical Biotechnology?
pect. These applications will cause future con flict, and it is also related to the above ques tion of when individual autonomy should be restricted.
7 Bioethics versus B usiness : A Conflict? In short, the answer is yes, the reason is that ethical concerns rely on principles such as just distribution of wealth and equality, and on factors such as beneficence. However, the goal of business is to make profit, and many businesses aim at economic growth and high profits. Biotechnology may allow pro duction of consumer goods from renewable biomass sources, however, energy is still re quired to transform raw materials into fin ished products, thus economic growth re quires continual energy input. The economic policies, based on Schumpter Dynamics, are not compatible with sustainable development (KRUPP, 1 992) , therefore if biotechnology aims to be ethical it must use a different eco nomic theory. When businesses consider raw materials, they may attempt to use the lowest cost materials, which may mean that interna tional common assets such as environmental resources are used, the so-called problem of the commons. They may also ignore the fu ture costs of pollution caused by the produc tion and use of technology. Much of the new wave in biotechnology re search is being performed by private compa nies. These companies are being encouraged to perform research in their countries' nation al interests, including the hope of more ex port earnings from the sale of products and/or technology (OTA, 1 991c). Some of the con flicts relevant to ethical biotechnology are discussed below. 7 . 1 Intellectual Property Protection
There are several forms of intellectual property protection, and they are outlined in
Chapter 10 of this volume. There continues to be much controversy regarding the patenting of plants and animals, and of genetic material from living organisms, especially humans. There is less controversy regarding patenting of microorganisms. Patents and variety rights are supported to act as incentives for technology development (LESSER, 1991), consistent with beneficence. However, should there be subject matter which is exempted from patent protection, such as plant and animal varieties are ex empted in the clause 53 (b) of the European Patent Convention? There is also a question of what is novel, when gene sequences consist of information that is already existing in na ture - even though this information can be shuffled into new vectors. Another question that is important for the future of biotechno logy patents and for gene sequencing patents is whether the application of robotic sequenc ing methods is non-obvious. The policy should be made considering all the economic, environmental, ethical and social implica tions, and it should be internationally consis tent. In 1991 a controversy arose when a single patent application for 337 human genes was made in the USA, and in February 1 992 a fur ther application for patents on another 2375 genes was also made by the NIH (MACER, 1 992a) . Modern technology has the ability to sequence all of the 1 00 000 human genes with in several years, and the company The Insti tute for Genomic Research has promised to publish most human gene (eDNA) sequences by early 1 995. There is no demonstrated utili ty, so this type of broad application is ex pected to fail, regardless of ethical or policy issues. The patents were applied for on behalf of the US National Institutes of Health, though many inside the NIH are against it (ROBERTS, 1992). This government body wanted to sublicense particular US compa nies to pursue research on these genes in an attempt to "protect" the US biotechnology industry from international competition. Researchers in Britain, France and Japan are also obtaining many gene sequences (in cluding some of the same genes and se quences), so a patent war was threatened which would damage international scientific
7
Tab. 6.
A tt i t u d e: �
Towards Patenting by
Company,
Gove rnme nt and U n i ve r s i ty Government
Company
Item
I nventions
Books
Plants Animals Plant and animal genetic material Human ge netic material
Yes
No
ON
Yes
No
ON
4 8
97
2
1
93
3
80 88 84
13 5 7
7
9
7 9
83 76 73
62
21
17
35
52
32
16
143
Bioethics versus Business: A Conflict?
24
8
11
30 41
14 16 35
35
Scientists in
J apan Total
U n ive rsity Yes
No
ON
92 83 71
4 11 11
4
67 45 34
12 31 37
6 18 21 24 29
Yes
94 82 78 74 46 35
No
ON
3
3
11
8 10 28 37
7
14 16 26
28
Responde nts w e r e asked the q u e stion . .. In your opi nion. fo r which of the following should people be able obtain p a t e n ts and copyright ?" . R e s po n se s : Yes = approve . No = d isapprove , ON = don't k n ow (from MACER. 1 992a ) to
cooperation in the h u ma n gen om e proj ec t . The US Pate n t Office made a re lat i v el y quick decision r ej e c t in g the initial applications. Government action to pre v en t such patents on random eDNA fra g m e nt s has be e n widely c al l e d for ( K I L E Y . 1 992 ) . The French g ove r n ment, and J a p a n e s e ge nome researchers (SWINBANKS. 1 99 2 ) . have announced t hat t h e y will n ot apply for similar patents because of ethical reasons. England 's M e di c a l Re search Council ( M RC) app l i e d for a similar patent on more than 1000 ge n e s . but in 1 993 wit hdre w the ap p l ic a t i o n . I n t he end. t h e rap id progr e s s in sequencing t h e human ge nes. as r e fe r red to just above. has defused t h e i s s u e . The human genome is comm o n property of all human bei ngs . and no one should be able to pa te n t i t ( M ACER. 1 991 b). Public opinion could fo rc e a policy c h a n ge regarding th e pa tenting of ge n e t i c material . even if it is jud ge d to be l e g a ll y va lid. People in Japan a n d New Zealand were asked if t he y agreed whether pate n t s should be o bt a i n a ble for different subject m a tt e r ( M ACER. 1 992a . b ) . 90-94% of all groups agre e d with the p a t e nt i n g of i n ve n tions in general . such as consumer p rod u ct s . There was less consensus on the paten t in g of other items. tho ugh the same relative order of items was followed in a l l groups in Japan and New Zealand. There was less ac cep t a nce of p a te n t i n g new plant or animal varieties than of inventions in ge n e ra l . Only 5 1 % of the p ub l ic agreed v. ith p aten t ing of "g e n e ti c ma terial extracted from plants and animals" in New Zealand, hut even less, 38% . in Japan. There was eve n lower acceptance of patent-
" g e n e tic material extracted from hu mans" . in Japan only 29% of the public agreed. w h i l e 34% d i s a gree d . I n all groups more p e op l e disagreed with the pat e n t i n g of ge n e ti c material extracted from humans than those who a g ree d with it. Among scientists, however, company scientists were much more s upporti v e of pat ent s than government scien tists, as can be seen in Tab. 6. The rej e ct io n of patents on human g e n e t ic material was also seen in the International B ioet h i cs S urv e y ( MACER. 1 994) .
ing
7.2 Global Issues o f Technology
Transfer
Most research is c onduct ed in "rich" ind u s of their resources and company base. Genes c an be d e rive d from one country. which may be a d e v e l opin g country. and the rese a rch conducted in an o t h e r country. Th e re fore . a patent may be ap plied for b y the researchers who by virtue of their mon e y could invest tim e into sequencing a gene associated with a us e fu l property. In 1 992 a Biodiversity Treaty was s i g ned by m os t countries of the world at the World Environ ment and De velop m e n t Summit in Rio de Ja neiro, w h i ch would offer some protection to developing cou n t r ie s against such oppor tu n i s tic in ve st m ent . They may argue that a l re ady the rich countries are ga i n i ng m uch advantage from fre e transfer of a g ric u l t u ra l crops that o ri g i n a t e d in d e v e l op i n g c ou n t r i e s , d e v e l op e d tria lized coun trie s because
1 44
4
Biotechnology and Bioethics: What is Ethical Biotechnology?
by old biotechnology, so the developing coun tries should be able to at least share equally, or even gain some compensation, for future uses of genetic resources by rich countries who apply new biotechnology. The question is whether old biotechnology is so different from new biotechnology, and what is justice. We can only expect this conflict to continue, as the Biodiversity Treaty is applied to patent policy and law. There is still no reward given to the farm ers who for millenia have established crop va rieties, which plant breeders use as starting materials. It is ironic that small farmers con tinue to lose their farms in the development of commercial biotechnology. In 1 983, at a UN Food and Agriculture Organization con ference, representatives from 156 countries recognized that "plant resources were part of the common heritage of mankind an should be respected without any restriction" (JUMA, 1 989). Since then an international network of gene banks has begun to be established, which will provide genetic material world wide. These also preserve genetic material from species that are becoming extinct be cause of environmental destruction. All people should share in the benefits of biotechnology. There is ethical and religious support for this, such as "love thy neighbour as thyself" , and the utilitarian ideal that we should try to benefit as many people as possi ble, and from the ethical/legal principle of jus tice. In the United Nations Declaration of Human Rights, Article 27 (1 ) , is a basic com mitment that many countries in the world have agreed to observe (in their regional ver sions of this declaration, SIEGHA RT, 1 985). These are "(1) Everyone has the right freely to participate in the cultural life of the com munity, to enjoy the arts and to share in scien tific advancement and its benefits" (italics ad ded for emphasis) . The common claims to share in the benefits of technology should be considered in all aspects of biotechnology, also including the questions of who should make decisions concerning its applications. This question is important for the sharing of technology.
7.3 Short-Term versus Long-Term Perspectives
Most businesses, and governments, are run on short-term windows, rather than long-term perspectives. Until long-term perspectives are adopted, sustainable technology is likely to be considered too expensive to compete with short-term resources. We only need to think of the price of petroleum for energy use and transport to see a key example. Biomass-de rived energy sources, which are based on re newable solar energy, may not be adopted until they can compete economically. Because pollution damage from petroleum emissions is not included into their cost analysis, they are seen as cheaper energy sources. There is thus an economic conflict, which prevents the rapid introduction of biotechnology-derived energy sources. There has been much controversy regard ing the use and FDA approval for sale of re combinant bovine somatotropin (BST) to in crease milk production in the dairy industry. The major concern is not the safety of the product (KESSLER et al., 1 992), but the socio economic impact on farming communities (OTA, 1991a). Although BST increases milk yield, it may accentuate the current trend for small dairy farmers to go out of business, and for larger farms, which are more economically efficient, to succeed. Here we have a short term economic view versus a long-term per spective related to social issues or urbaniza tion, and secondary economic issues about the creation of new employment. This is not unique to agricultural biotechnology, and other factors such as nutrition of feed can al ter milk production, but it is a question that requires a long-term perspective to answer in an ethical way. Societal change as a result of international trade and changing agricultural practice has occurred increasingly in recent decades. This challenges the lack of forward planning in free market economics, however, the eco nomic failure of most centrally planned com munist economies illustrates the dangers of unrealistic plans. Although GATT was agreed at the end of 1993, a number of ethi cal, social and environmental questions re-
7 Bioethics �-ersus Business: A Conflict?
main with the ac ce p te d e c o n om ic fr e edo m t o purs u e n ew tec h n o l o gy adop t ed by short term economic and social views. 7.4 Safety
v e rsus
Costs
S uc h a hea d i n g may be p ro vo c at i ve . but it a real co nfl ict. More t i m e spent in t e sting t h e s a fe ty of a new d r ug or foodst uffs. or t h e environme ntal safety of a new o rga nis m . means more money is i n ves t ed . Ethically. we m a y say do no harm h a s pr i or i ty . a nd re q u i r e long pe riods for te st i ng of new produc t s . However. this m e a n s th a t the average cost s for developme n t of new drugs are so la rge that only l a rge c o m p a n i es can t ak e a p roduc t th ro ug h to the market. after sa fet y a pp rov a l. S ocie ty allow i n g p r i v a t e in dustry appears to succeed better. as shown fro m the rece nt experiments with communism in the 20th cen tury, so socie t y wants to promote industry as a me an s to co m pe t i t i v e a nd mo r e effi c i e n t prod uc ti o n of dmgs o r foods. It is t o the ben efit of so c i e ty to s u p p or t s ome ind u s t ry . t ho ug h t h e y must be c a re fu l w h e n giant mo n opo l ies are for m e d . Therefore . there is a conflict betw een safety and de ve lop m e n t costs. This con flict led to the use of specia l measures such as the O rpha n Drug Act in t he USA. which a l l ows the earlier use of ne w drugs if there i� a strong medical need. e n couraging i ndust ry t o spend time d ev e l o ping them. Ne v e r thel es s. s oc i e ty d o e s imp os e safety standards to pro tect h u man and environmen tal health. An o t he r method of a t t emp tin g to ensure safety is to allow l iabi li t y suits i n courts, w hich i s a n additio n al prote ct i on . However. t here also need t o be limits o n lia bility c l aims, ot h erwise research into such ar eas as c o nt racep tiv e s. or v ac c ine s. may be in hibited. due to company fears of future li t i g a t ion for unrea l i stic monetary sums in such is
sensitive areas.
1 99 I . t h e US government a t restrict regulations on bio t ec h no l ogy p r od uct s (PC C. 1 99 1 ) . such as food s t u ffs . as an i nc e n ti v e to e n co ur a ge further industrial investment. We w i l l not k no w whether this compromises h uman or e n v i ron m e n t a l health until the fu ture if mi s h a p s occur. La r ge in du s -
In early
tempted
to
145
try m a y be cautious a bou t liabil i ty suits, and better ensure safety of products , but it has b e e n su gg e s t ed that a llowi ng i n d u st ry the op tion of n o t asking for independent re v iew of prod uct sa fety . risks exposing the public t o un t e s ted p rod ucts marketed by sm a ll compa nies tryin g to m a ke a quick pr ofi t .
7.5 Is New Technology B e tter? Com p a ni es naturally h av e a d e si re to re cover d e v e lo p m e n t costs of new p rod u c t s , so t h ey will attempt to market their p r o d u ct s once they are ap pro v ed . There has bee n re cent controversy over the use of several prod u c t s of geneti c engineering in mic r oo r ga n i s m s that are examples of the t y pe of ethical con flict th a t can arise if these p rod u cts may not be the most clinically suitable or cheapest. Recombinant human insulin has been as so ciated with unaware ness of hypoglycemia, un l i k e porcine insulin, and there are grow i n g calls to examin e its effects (EGGER et a!., 1 992) . Human insulin w as s pe e d il y adopted in most countries of t h e world as a re pl aceme n t for porcine insulin, a decade ago; w h e n new data come to ha n d r egardi ng adverse effects, we need to reexamine its use. An example in volving much more economic interest re g a r d s t he repo rted lower effectiveness of tissue pl a sm i n o gen activator (TPA) in s ome medi cal applic ati on s c omp a red t o s t re pto ki n ase (ISIS-3, 1 992). TPA is much mo r e exp ens i v e t h a n s tre p t o ki n a s e. so t h at even if their e ffec tiveness is equal, we s h o uld use t h e ch e a p e r product. according to just distribution of health care money. However, commercial i n terests want TP A to succeed. One c a n even see the i n famo u s case of the apparent French delay i n u se of HIV -tests u nt i l a French-pro duced kit wa s available, to p rotect national i n dust ria l interests ( A N D ERSON, 1 992a ) . A n other area of economic benefit to phar ma ce u tical companies is development of new broad spectrum a n t ib io t i cs , yet th e s e can b e li n ked to i n cr e as i ng he a lth p roblem s caused by anti biotic-resistant m i c roorg a nis m s (NEU, 1 992) . There are cle a rly many con fl ict s raised by co m merc ia l i n t e rests and mar ket i ng . Ethical biotechnology is often under challenge, and will be su bo rd i n a te to commercial biotechnol-
146
4
Biotechnology and Bioethics: What is Ethical Biotechnology?
ogy interests. There may even be unethical calls for patronage of research areas made by scientists who want to develop new technolo gy, when older techniques are available, as in the case of calls for a malaria vaccine versus use of the money in vector control (GAJDU SEK, 1 992). The public may sustain this by be lief that new technology is better - it is not always.
8 Resolution of Conflicts 8 . 1 Who Can be Trusted? Scientists will win more public support for research by involving the public in decision making, and being open. If it is ethical bio technology, then the public may, by a large majority, support such an application. The public has a high level of suspicion of safety statements made by scientists, especially those involving commercial decisions. In sur veys conducted in Japan (MACER, 1992a) and New Zealand (CoucHMAN and FINK-JENS EN , 1 990), high school biology teachers and government scientists were even more suspi cious than the public, when asked the follow ing questions: Q16. To what extent do you agree or disagree with
the following statements that other people have made? 1 strongly disagree 2 disagree 3 neither agree 4 agree 5 agree strongly nor disagree Ql6b. If a scientist working in a government de
partment made a statement about the safety of a research project, I would believe it. Q16c. I would usually believe statements made by a company about the safety of a new p roduct it had
released. Ql6d. The activities of scientists in Japan should
be more closely regulated to protect public safety.
In Q16b, 35% of the public said that they would believe a statement made by a scientist
working in a government department about product safety, and 21 % said that they would not, and 44% said that they would not be sure (Fig. 5). Q16c asked about the credibility of company statements about product safety, and there was less trust of such statements, with 17% of the public saying that they would believe such statements and a greater propor tion, 36% , saying that they would not believe it, and half, 46% , said that they would neither agree nor disagree. The responses to Q 1 6c clearly show how company safety statements are not trusted by people, even by company scientists. Only 12% of scientists said that they would usually believe a statement made by a company about the safety of a product it had released. Only 6% of government scientists would usually believe company safety statements, but 24% of company scientists said they would believe them, whereas 26% of govern ment scientists, and 35% of company scien tists, said they would believe safety state ments by government scientists (MACER, 1992a). In the USA, people were also asked whether they would believe statements made about the risks of products by different groups (OTA, 1987), and companies were less trusted than government agencies, with uni versity scientists being the most trusted. Only 6% said that they would definitely believe a statement made by a company about its prod uct, and 15 % said they would not believe, with 37% inclined not to believe and 39% in clined to believe. Similar distrust of compa nies was found in the International Bioethics Survey (MACER, 1 994), and in Europe (EB , 1 993). Committee meetings involved in the regu lation of biotechnology and genetic engineer ing should be open to the public. Such open decision-making would gain more public sup port than closed meetings, and openness would improve public confidence in regula tors. It may also result in better safety than regulations which put industry on the defen sive and result in closed-door discussions. Moreover, an open approach may be better at winning public support than the current ap proach of spending money on advertising campaigns that could be seen as pro-biotech nology "propaganda" campaigns. Most peo-
8
N� ;;;;�����S
" T h e act i v i t e s of sc1 e n t i st s s h o u l d be m o re closely
scientists
Teachers NZ P u b l i c N�
147
Resolution of Conflicts
IIi���
regu latsd"
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• I would u s u a l l y beheve stat e m e n t s m ade b y a c o m p a n y
a b o u t t h e safety of a new product i t had r e l e as ed "
Scientists N� Teachers NZ
• Stro n g l y d i sagree • Disagree 0 Neither
J
D Ag ree
P u b l i c NZ
0 Strongly agree
J
"If a sci e n t i st
workmg m
a gove r n m e n t d e p a rt m e n t made a
stat e m e n t about t h e safety of a rese arch proJect . I would beheve
0
20
%
40
60
of respo n d e n t s
80
1
11"
00
Fig. 5. Comparative a t t itudes towards scient ists i n Japan (J) and New Zealand (NZ). Results from J&pan Q l6b. c . d of MACER ( 1 992a). and New Zealand results a re from the survey of CoucHMAN and
are from
fiNK-JEN SEN ( 1 990 ) .
ple were already aware of the benefits of bio
W h e n people were asked whether they
technology, but they will remain concerned
would use gene therapy to cure serious ge
about
netic diseases, the maj ority in all countries overwhelmingly accept (80--90% ) the use of h uman genetic manipulation for curing seri ous genetic diseases (MACER, 1 992c, 1 994; OTA , 1 987 ) . 07 was a general question and was expected to show lower approval of ge
decision -making that is hidden.
8.2 Provision of Information May Obtain High er Public Approval cations of genetic e ngineering than there was
netic manipulation on h umans than the spe cific questions (Tab . 2). A similar effect is seen regarding the ap
for general research , suggesting that the pub
proval for e nvironmental release of
lic
(MACER, 1 992a, 1 994; and KENDALL, 1 992).
There was h i gher support for specific appli
will
better support worthy applications of
technology if they are told the details of them . I n the resul ts of the opinion surveys con
ducted in manv countries (MACER, 1 992a, 1 994 ) , a n d the i JSA ( OTA, 1 987 ) , higher ac ceptance with bi otechnological techniques was found when specific i nformation was giv en.
QI9.
If
there
OTA , 1 987 ;
was no direct risk to
very remote risks to
the
GMOs HOBAN
humans a n d
only
e nvironment, would you
approve or disapprove of the environmental use of genetically engineered organisms
duce . . ? .
designed
to
pro
148
4
��iilili���
Biotechnology and Bioethics: What is Ethical Biotechnology?
Japanese public o p i n i o n about enviro n me ntal uses of G MOs with remote risk Larger game fish Disease - resistant crops
Bacteria to clean
oil spills
More effective pesticides
Frost-resistant
plants
• a p prove
li':l disa pprove [] d on't know
0
1 00 40 20 80 60 o/o of total respondents I N = 529 , data from Macer. 1992al
u . s. o p i n i o n s a b o u t envi ronmental u s e s o f GMOs w i t h remote risks Larger game fish Di sease- resistant
Bacteria to clean
crops
oil spills
More effective pesticides Frost-resistant plants
�· ,.__._, �· ,.__._, W?'h%0. �-� �· �-/ '9'� r=:=�=�==;== �=�1 0
1
Approve
40
20
60
80
0 appr ove
m disa pp rove • don't know
1 00
o/o of total res p ondents IN= 1273 , data from OTA , 1987)
2 Disapprove
3
Don't know
Frost-resistant crops
More effective pesticides
Fig. 6. Attitudes to envi ronmental release of
GMOs (genetically modi
fied organisms ) in Japan and the USA.
8.3 Public Education Not Propaganda
Bacteria to clean up oil spills
Disease-resistant crops Larger game fish
The results from the 1991 Japanese and 1 986 US surveys are shown in Fig. 6. There was clear approval for environmental release of disease or frost-resistant crops, with less approval for bacteria to help fight oil spills. There was lower acceptance of developing better pesticides, though still a majority of all groups supported this. There was rejection of the idea of making big game fish in all coun tries, with least rejection in the USA. A sur vey in the U.K. (MARTIN and TAIT, 1992) found a similar differentiation by British peo ple. These survey results are a clear mandate for further research to develop some products involving G M O s , and to have further field re leases of new varieties of plants to test their performance, prior to farmer's use. They also clearly illustrate that the public can differen tiate their support depending on the per ceived benefits or risks, and the information they receive.
There is a significant public policy decision to be made regarding public education pro grams. There has been an information cam paign underway for a decade in Japan sup ported by members of the Japan Bioindustry Association, involving government and indus try, to promote biotechnology. It appears to have resulted in high awareness of bio technology, with mixed perceptions. There are also calls in Europe by industry groups to promote biotechnology, with the goal of re ducing what is seen as a high level of concern about the technology. Such campaigns can in clude publication of books, which can also be useful to promote discussion of ethical issues (BMA, 1992). Some US companies have also had large public relations campaigns, such as Monsanto. Recently, following a survey of scientists in the USA engaged in recombinant DNA research, which found that more saw public attention on genetic engineering re search as beneficial than harmful to their re search, public education programs to stress
8 Resolution of Conflicts
the ben e fi ts of biotechnology have been called for (RA BINO, 1 991 ), though some are underway al re a dy in t he USA. A similar sur vey and concl u si o n was made a m ong Euro pean scientists ( RABINO, 1 992). The results of the surveys described i n MACER ( 1 992a. 1 994) question the effective ness of such p ro g ra m s and also whether their goal is desirable . Rather than attempting to dismiss feelings of concern. soc i e t y should value and debate these concerns to improve the bioethical maturity of society. However. media responsibility is c r uci a l ( see Chapter .
1 7).
8.4 S u ffi cient Regulations 8.4. 1 R e g ul a tio n of Environmental Risk Regulations for the environmental release of G M O s have been enacted in many coun tries of the world. some being statutory and others guidelines. The Eu r opean Parliament set minimum legal standards for European Community countries. though regulations vary between strict. as in Germany, and non existent in other co u n t ries - which rely on the default European regulations. In the U S A a variety of agencies have taken responsibility for different areas of biotechnology applica tions, and the guid e l i n es are evolving into product-based r e gul a t io ns with exemptions (OTA, l 99 l c) . The USDA has approved many releases of G M Os (see Chapter 6). In Japan, each of the major mini s t r ies have their own regulations. and there has been only one field release of a G M O (M ACER, 1 992a) . Islands may develop particularly different regu latio ns and enforce them, but regions, such as Europe, need common minimum reg ulations, as neighboring countries are at risk. Conversely. any country which imposes extra regulations must s u ffe r the low e r industrial d e v e l op m e n t of their ne i ghb o rs without a significant reduction in risk. We m ust also g a t her information from past releases of new organisms and their ecologi cal consequences. We can ho p e that the i nfo r mation i s shared globally, to avoid others ,
149
making the same m istak es and to e nsure that all countries have a similar minimum stand ard of protection. It is clear that the authori ,
ties and committees that have the most ex perience with releases should have developed the most skill in assessing the ecological risk. Review should of course be independent, to avoid conflict of interests. There may be beneficial environmental consequences of biotechnology, as discussed in Sect. 4.3. There may also be less risk asso ciated with using living organisms to produ c e raw materials for industries, such as the chemical industry (OTA, 1 991b). We only need to think of accidents like Bhopal in In dia, where a disaster was caused by dangerous chemical intermediates. Biotechnology using safer intermediates and raw materials may not only be m o r e sustainable but also safer.
8.4.2 Product Safety I nde p e n den t clinical r e vi ew of drug safety is already standard in most countries, and to be ethical, we must ensure that all people of the world share its protection. S uch protec tion should be standardized, but it is a more difficult question when a country wants to im pose stricter standards. A go v ern m ent has a duty to allow beneficial products and technol ogies to be used by its citizens, including un conventional treatments such as somatic cell gene therapy. We should ensure that all p e ople of the world enjoy the protection of similarly high safety standards, and that they are k ept in formed of the content of their food. We may not need to apply any additional regulations to food, unless novel components are intro duced to the food (WHO, 1991). The p oli cy has recently been formulated in several coun tries. In a rapidly m ovin g and new area, an independent committee approach to regula tion is the only way to efficiently and safely examine food safety. The Japa n e se M i n i st ry of Health and Welfare has published bilin gual guidel i nes for foods and food additives produced by recombinant DNA techniques (MHW. 1 992). They exclude organisms that have gen e deletions from these guidelines, only including organisms which contain "re-
1 50
4
Biotechnology and Bioethics: What is Ethical Biotechnology?
combinant DNA" sequences or parts of vec tors. The "expert committee" of the Ministry will review all cases "to ensure and sustain reasonable criteria", and they can decide whether to insist on additional data from sa fety tests or not. The data presented must be published in peer reviewed journals. The key question is whether they decide the foods are novel or not, because if they are novel, exten sive safety tests must be performed. The guidelines state "the novelty depends upon comparison of identity and promotion of product with existing foods or food addi tives". The test of the guidelines will be how the committee works, whether , they make their proceedings public, and where it draws the line of novelty. It is certainly safer to force a committee examination, than to ex empt that as has been adopted in the USA.
8.5 Public Involvement in Regulatory Processes
In some democracies the public has a clear role in the process of regulation, and clear op portunities to voice concerns. This opportuni ty to voice concerns is important to gain pub lic trust, especially considering the lack of trust (see Sect. 8.1). In some countries hear ings are conducted in public, as in the RAC committee hearings on human gene therapy in the USA. This may have lowered public concern in a controversial area, though com panies do not require RAC approval, only FDA review which is private (ANDERSON, 1 992b). In other countries there is almost no openness to the public, as in Japan. In the above mentioned survey responses (MACER, 1 992a), the public, high school bio logy teachers and academics gave very similar depth of responses to many questions, sug gesting that the public can make well rea soned arguments concerning biotechnology risk and benefit. The public should be in volved more in committees making science policy and regulating applications of science. This requires more public willingness to be involved, and the scientists and bureaucrats should allow third party and public entry to committees. As a minimum standard for en-
suring ethical biotechnology, decisions should be made in forums open to public knowl edge.
9 Ethical Limits of B iotechnology 9.1 Absolute or Relative? We can ask whether there should be an ab solute ban on certain applications, such as sex selection, or germ-line gene therapy. Such bans are only justified when there is a clear risk of social harm. There are other areas of biotechnology where there clearly should not be an absolute ban, as in the use of genetic engineering on any organism. There are some conditional bans imposed, such as the guide lines to protect human subjects from uncon sented experimentation or dangerous experi mentation. Some would call for a ban on ex perimentation using animals, and the propor tion supporting such a ban on primates as sig nificant. Laws may be introduced to impose absolute or conditional bans on some re search, and this is needed, at least in some ar eas. Everyone is subject to laws, and scientists should not expect to be exempt. Laws, as said above may not always be ethical, they may be relative, as public opinion is not always re flecting an ethical view - and there may not even be an absolute ethically correct answer. Is there a clear distinction between disease and non-disease, which may determine whether prenatal genetic screening and selec tive abortion is ethical or not? At the ex tremes there is, but there are gray areas in the middle, and we must ask how to regulate this - do we impose absolute limits, or do we take up the principle of autonomy and allow wo men to decide what is a disease or not. The ideal would be to allow women a completely free choice in the adoption of the disease markers they want to use, and that they would responsibly do this. However, abuses may occur, sometimes due to social forces upon the women - such as a medial insurance companies refusal to provide medical care to
10
Criteria to Assess Whether Biotechnology Research is Ethical
children suffering from di se ase w h o had a '·preventable birth''. S u ch a discussion will be s hocking to some peo p l e . but i n other cu l tures a majority may be more pra gmat ic , and it would not be seen as im mo ra l . Can we have ab solute limits '? Another example is w h e t he r we s ho uld have absolute exclusions on subj e ct matter for patents. Should we m ak e e x cept ion s in ar eas of important b e n e fi t , or t o encourage ben eficial re s earch that would not otherw ise be performed. The a n s wer is th e r e may b e ex ceptions, a n d a response to the demand for flexibility is t h e use of i n d ep e n d en t commit tees for decision-making.
9.2 Timeless or Transien t ?
A s disc u ss e d above i n Sect. 6, t he re will be future conflicts i n de te rmi n i ng what is ethical b i o techn ol og y . Our concep ts will change, and there is no guarantee that unethical applica tions will be made. and ev e n s u pporte d , by fu ture public majorities. We need to remember history, and also may need to introduce some internati o n a l laws which m ake it more diffi cu lt for future unethical us e s to occur. How ever, we nee d to be flexi ble , as we gat h er ex perience we may need less strin gent regul a tions, as in the case of release of GMOs or gene t h e rap y . B iot ech n ology has had a p os iti v e effect on the d eba t e or bioethics, and we must ensure that the debate matures and is applied more wide ly to other tech n o lo gies , old and new. The i ntroduct ion of new techni q ue s may even be necessary t o c h a n ge gene ra l patterns of eth ical and social thi n k i n g , for e x a mpl e , the i ntro duction of nondirective genetic co u n se l ing that is associate d with ge net i c scre e n i ng could h as ten the introduction of the c o ncept of informed co n s ent in to general medica l pr a ctice .
9 .3 Sci entific Responsibility for Ethical Applications
Sci entists are called up o n to take re spo ns i bility for the social con se q uence s of their re-
151
s e arc h . Rece n tl y we can see the growth of ELSI (ethical, legal and social impa ct ) grants from human genome research programs, so that the NIH in the USA is spendi n g over 5 % o f t h e h um a n genom e p roject grants o n ELSI issue research. We c an also see the emer gence of movement s such as the Universal Movement fo r Scie ntifi c R espons i b i li ty (MURS). MURS is a t te m p ti n g to introduce articles into the UN Charter of Human Rights (MELANCON, 1 992) , and such moves repre se n t i mp o rt ant steps in the growi n g mat urity of scientists. These may illustrate a p aradi gm shift am o ng scientists to co ncentr ate more at tention on the soci al impacts of the ir re search, especially i n areas such as biotechnol ogy and genetics.
10 Criteria to Assess
Whether B iotechnology Research is Ethical We can think of some summary cri te r i a which may be useful in determin ing whether any give n application of bi otechn ol ogy is ethi cal. A lthough it is possible to d e ve lop useful numerical scoring systems, as has been at tempted for animal exp eri m ent s (PoRTER, 1 992) , th ey are still o nl y gu id es and may be more useful in directing attention to t h e bet ter and more ethical design of experiments. Therefore , o n ly some criteri a imp ort ant to as sess the eth icity of an expe ri m en t or applica tion are give n b elow :
1. What is the ben efi t ? To whom? Is it life -s avi ng ? Human benefit is greater th an m one tary be n efit . 2. Do no harm to humans. What is an ac ceptable level of risk? Foll ow ethical codes on free a n d informed consent for human e xp erim e ntat i on . 3. Do not cause p a in . P rot ect a nim a l ri ghts as much as p ossib le , use less sen tient animals for research, a nd d e velo p no n - a n im al a lt er nati ve s .
1 52
4
Biotechnology and Bioethics: What is Ethical Biotechnology?
4. Do no harm to the environment. Use the technology that is most environ mentally sustainable over the long term. Minimize consumption, may need to introduce environmental quotas to do this according to just distribution of global assets and introduce maximum levels for individual production of pol lution. 5 . Protect biodiversity. Protect endan gered species. Allow farmers affordable or free access to breeding stock, and encourage planting of diverse crops. 6. Justice to all people, and future genera tions. Share benefits and risks. 7. Independent open decision-making on safety questions, consider ethical and social impact. 8. Inform and educate the public and scientists about all dimensions of the projects, scientific, social, economic and ethical, using third-party media.
1 1 Conclusion We need to understand that perceptions of the impacts of technology are more complex than simple perception of benefit or risk, as they should be. The capacity to balance bene fit and risk of alternative technologies, while respecting human autonomy and justice and the environment, while simultaneously being under the continual influence of commercial advertisements and media stories of varying quality and persuasion, may prove to be an important indicator of the social and bioethi cal maturity of a society. In addition, to devel op the bioethical maturity of society, global human rights need to be increasingly re spected so that we get social progress as well as scientific progress. All people should equally share both the benefits of new tech nology and the risks of its development.
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RACHELS, J.
(1 990), Created from Animals, Ox ford: Oxford University Press. RoBERTS, L. (1992) , NIH gene patents, round two, Science 251, 912-913. RSGB (Research Surveys of Great Britain) ( 1 988), Public Perceptions of Biotechnology: Interpreta tive Report, UK: RSGB Ref. 4780. SASSON, A. (1988), Biotechnologies and Develop ment, Paris: UNESCO. SIEGHART, P. (1985), The Lawful Rights of Man kind, Oxford: Oxford University Press. SINGER, P. (1976), Animal Liberation, London: Jonathan Cape.
STONE, R. ( 1 992) , NIH to size up growth hormone trials, Science 257, 739. SwiNBANKS, D. (1 992), Japanese researchers rule out gene patents, Nature 356, 1 8 1 . WALGATE, R . ( 1990), Miracle or Menace? Biotech nology and the Third World, London: Panos In stitute. WHO (World Health Organization) ( 19 9 1 ), Report of a Joint FA OIWHO Consultation, Strategies for Assessing the Safety of Foods Produced by Bio technology, Geneva: WHO. WRI (World Resources Institute) ( 1 992), World Resources 1 992-93, Oxford: Oxford University Press. ZHANG, Z. (1991 ) , People and science: Public atti tudes in China toward science and technology, Sci. Publ. Pol. 18, 31 1-317.
H. Product Development and Legal Requirements
Biotecllllology
Ed i ted by , H . - J . Rehm and G. Reed in coo p e ration w i th A. Puhle r and P. Stadler Copyright © VCH Verlagsgesellschatt mbH, 1 995
5 Structured Risk Assessment of
rDNA Products and Consumer Acceptance of These Products
C. THEO VERRIPS Vlaardingen, The Nethe rlands
1 General Introduction 1 58 2 Introduction into Some Technical A s pe cts of rDNA 159 2 . 1 Defini t i o n of Hazard and Risk 1 60 2.2 Ev e nts Resulting in Ch a n g es in DNA 1 61 2.2 . 1 Vertical Flux of G e n es 1 6 1 2.2 . 2 H o rizon t a l Flux o f Genes 1 61 2.3 RNA S p l ici n g and mRNAs Derived from S y n thet i c Genes 164 2.4 Re li a b il i t y of Tr a n s l a t i o n Processes and Post- Translational Modifications 1 65 2.5 R andom and Site-Directed Mutated Genes 1 67 2.6 Protein Folding 1 67 2.7 Choice of Host Str a i n/ V a r i ety for Fore ign DNA 168 2.8 Plasmid St a b il i ty and S t a bil it y of I n t eg r a ted Foreign DNA 170 2.9 Reprogramming of Metabolic P a t hw a y s in Cell s Hosting Foreign DNA 1 7 2 3 Various S t a ges in the Development of an rDNA Process or Product 173 4 D ecisi o n Schemes for Various Types of rDNA Products and Various Applications of These Products 1 75 4.1 G eneral 1 75 4.2 Decision Tree Derived from "Guidelines on the Assessment of Novel Foods and
Processes''
175
4 . 3 Decision Scheme for ''Foods Derived from New Plant Varieties" as Applied by the
FDA
1 76 Schemes Developed for the Dutch Government for Foods Co n t a i n ing rONA-Encoded M a t er ials 1 77 4.5 Decision Scheme for the Ap p rov a l of GMOs 1 83 4.6 I nte gr a ted Scheme to Evaluate A n y rDNA Product 1 89 5 Some Ethical Aspects and Acceptance of rONA Products by C o n s um ers 1 89 6 Co n cl usio n s 1 94 7 References 1 95 4.4
Decision
158
5
Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products
1 General Introduction Biotechnological products based on recom binant DNA have been a subject of debate at many levels since the Asilomar Conference in 1 975. It started as a debate among conscien tious scientists who wanted to think about the consequences of new techniques in molecular biology before applying these in the construc tion of new combinations of DNA. Already during the Asilomar Conference this debate became clouded by a number of unscientific arguments and personal interests (CAMP BELL, 19 90 ) Some journalists started to de scribe this technology in the media as a mod ern version of Cerberus or the molecular ver sion of the monster of Frankenstein. Unfortu nately, the scientific community was not very well prepared for this debate and did not react uniformly. Moreover, the scientific com munity started to compare the risk related to rDNA technology to other risks, e.g., the risk of spontaneous or deliberate mutations or classical breeding resulting in dangerous com binations of DNA. These types of compari sons were scientifically incorrect and led to further confusion among the public. Most unfortunately, rDNA technology has often been compared with nuclear energy technology. This comparison is extremely misleading, as for nuclear energy the intrinsic hazard is certain (in the language of this chap ter "1 .00"), and its effects may be very large and will affect all living species. Therefore, the probability of such a hazard occurring should be extremely small, and the debate on nuclear energy always focuses on the aspect whether physical containment can ensure this extreme low probability. For rDNA technolo gy the intrinsic hazard was often unknown. In general this hazard will depend on the nature of the foreign gene, the host cell and various other factors, and it will range from zero to one (e.g., in case of the transfer of a gene cod ing for a toxic protein to human cells). During the initial discussions it was assumed that in general the hazard of rDNA products was not zero, and therefore, the debate concentrated on the physical and biological containment of the experiments to reduce the risk. .
Soon after the Asilomar Conference in most countries committees were formed to set up rules to ensure that the intrinsic hazard of the foreign genetic property was low and that biological and physical containment would guarantee that the probability that the hazard would become manifest outside the laborato ry would be extremely small. The arguments of certain individual manufacturers that the rules proposed to evaluate hazards and risks related to rDNA could jeopardize their fu ture, were not correct and contributed to a further polarization of views. This all resulted in a delay of the acceptance or even in a re jection of rDNA technology outside the area of health care by the public. It is beyond any doubt that the application of rDNA technology to elucidate fundamen tal questions in biology has contributed enor mously to our understanding of the basic bio logical processes. After just 20 years it can be concluded that PAUL BERG (1 974) and others who organized the Asilomar Conference were absolutely right in that rDNA technolo gy would have an enormous impact on man kind and in their plea for a careful evaluation of this technology, since so little was known about it. A large number of discoveries that have been made since 1 975 such as the exis tence of introns, the role of transposons in many species, RNA as enzyme, the repro gramming of transcriptional competence, a number of translation processes that deviate from the general rules for translation, some preliminary rules for protein folding and var ious processes resulting in horizontal fluxes of genes DNA between species, the influence of ecological pressure on the selection of species created by the horizontal and vertical fluxes of genes, demonstrate that in fact proper risk assessment of rDNA processes or products was not possible at that time. Although at present still much more has to be learned, the results of millions of rDNA experiments show that indeed there i s unity in biology and therefore rDNA technology is as such not intrinsically dangerous. Moreover, there is now sufficient understanding of basic processes in biology to allow a rational ap proach of the evaluation of hazards and risks related to rDNA technology. This knowledge of molecular biology together with a struc-
2
Introduction into Some Technical Aspects of rDNA
tured approach to evaluate the various as pects of rON A technology separately can contribute to end the confusion about real or perceived hazards and risks related to rONA technology. Whether after careful evaluation of these factors rONA products other than pharma ceuticals will be accepted by society is a com pletely different story. However, as will be discussed later. a risk assessment showing that the risk is very low will increase the ac ceptance of the product by the public (see Sect. 5, Tab. 1 5 ) . It is the aim of this chapter to discuss the various technical aspects of hazard analysis and risk assessment of rONA products and to indicate briefly the complex but extremely important aspects such as ethics. labeling and consumer acceptance. As in most countries the area of hazard analysis and risk assess ment and the legislation of rONA products are far from established. no definitive view can be given. H owever, a decision scheme to analyze hazards and risks containing the most useful elements of a number of national guidelines will be presented. I mplementation of a decision scheme in line with the proposed one m igh t facil itate the approval of rONA products in many countries. To structure the discussion it may be worthwhile to put these aspects in a frame work comprisin g all aspects related to rONA technology: I.
2.
3.
4.
5.
Technical aspects a) Intrinsic hazards of recombinant DNA b) Risk of creation of intrinsic hazard in the recombinant DNA c) Risk of accidental release of rONA modified microorganisms during pro cessing d ) Risks associated with cell-free rONA products e) Risks associated with the deliberate release of microorganisms Structured methods to control intrinsic hazard and risk of DNA processes and products Benefits versus real and perceived risks Ethical aspects Consumer acceptance .
159
The first two items concern matters be tween regulatory bodies and scientists in academia and industry. The aspects 3 and 4 have much more players, like consumers and consumer organizations, retailers, religious groups, politicians, pressure or action groups. health authorities, regulatory bodies and manufacturers. Moreover. the risk/benefit analysis cannot be generalized, as the risk/ benefit ratio for rONA products that inhibit processes related to AIDS, like inhibition of reverse transcriptase, RNase H, protease or the regulatory protein TAT of the HIV virus, will differ substantially from that of frost-re sistant strawberries or from a microorganism capable of degrading halogenated benzene. Moreover, it should be borne i n mind that to cure certain diseases highly specific inhibitors will be required and that only rONA technol ogy will be able to produce molecules having t he required specificity. Also consumer acceptance cannot be simp ly defined, as it will be a function of the reli gious, cultural and educational background of the consumers as well as of their economic situation. This was demonstrated clearly dur ing a discussion on this subject at the Third International Congress of Plant Molecular Biology in Tucson in 1 99 1 . After listening to several speakers from the Western societies, a representative of China stated that he consid ered the whole discussion on the application of rONA technology to improve yields of crops as a luxury problem of Western society and that his government and fellow scientists considered it their duty to use rONA technol ogies, e.g., to develop new rice varieties that can be cultivated on land that cannot be used at present.
2 Introduction into Some
Technical As p ects of rDNA
If one wishes to carry out a hazard analysis and risk assessment of an rONA process or product, it is essential to take into account all aspects that may infl uence these analyses.
160
5 Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products
This seems to be an obvious statement, but unfortunately, too often the terms hazard analysis and risk assessment have been used for improper analysis. Therefore, in this chap ter the terms hazard and risk will be defined and the biological processes that may in fluence these analyses will be discussed brief ly. In Sect. 4 the hazards and risks related to the construction of rDNA molecules in re search and development stages will be ana lyzed taking into account the following bio logical processes: 1 . Errors introduced during DNA duplica tion and other events on DNA level 2. Errors in transcription and translation 3. Stability of episomal vectors and inte grated foreign DNA 4. Reprogramming of metabolic pathways in the host cell 5. Transfer of the foreign genes from se lected hosts to unknown recipient cells. 2 . 1 Definition of Hazard and Risk
Before starting any discussion on rDNA technology it is essential to define the words hazard and risk. In this chapter hazard is de fined as the potential (toxicological or eco toxicological) harmful intrinsic property of the product encoded by the newly con structed genetic material or by the host carry ing this genetic material or its translation product. Risk is the probability of the hazard occurring. rDNA technology can be used to construct genetic material that is potentially harmful, and in fact this possibility was one of the ma jor concerns in the early days of rDNA tech nology. Potentially harmful means that when this genetic material is transcribed and trans lated into a protein, that protein is either by itself harmful or the protein (enzyme) is able to catalyze (a) reaction(s) that directly or in directly produce a harmful compound. As the rDNA technology has been developed using Escherichia coli as host for the foreign DNA, in the discussion on the hazards of this tech nology the intrinsic harmful properties of E. coli, e.g., their production of endotoxins and the potential of certain E. coli strains to pro-
duce enterotoxins have played an important role. Therefore, at the start of rDNA technol ogy it was advocated to use only certain strains of E. coli K12 or to use other microor ganisms, e.g., Bacillus or Saccharomyces cere visiae (baker's yeast) as hosts for genes trans ferred by rDNA technology. Unfortunately, compared to E. coli, insufficient understand ing of the molecular biology, especially regul ation of transcription and translation pro cesses of Bacillus and S. cerevisiae existed in the mid seventies. For the transformation of plants an intrin sic hazardous plasmid was used, and for the expression in certain hosts promoters were used originating from viruses (e.g., CaMV for plants and SV40 for mammalian cells). To gether with the lack of understanding of the basic principles of biology by the public, the use of biological material that is intrinsically harmful or was perceived to be harmful has contributed largely to the confusion about the hazards and risks related to rDNA technolo gy. If vectors are used that do not contain un known sequences or known sequences that can code {directly or indirectly) for harmful products or genes that can give an ecological advantage to a second generation of recipient cells, one may define such vectors as safe. If one knows that the gene transferred by rDNA technology has been sequenced and proved to contain only the intended informa tion, this then guarantees the absence of the hazard that the foreign gene will code for a protein different from the intended protein. However, all this does not guarantee the ab sence of any intrinsic hazard. Firstly, the for eign gene will be subject to normal vertical flux of genes (see Sect. 2.2. 1 ) . Secondly, there is a small, but not negligible probability that the foreign genetic material will be tran scribed or translated differently from the nor mal transcription and translation processes (see Sects. 2.3 and 2.4) . Finally a gene not coding for a potential harmful property in a certain host cell may in the second generation of recipients of the new genetic combination code for a protein that contributes indirectly to a hazard. The probability of such events occurring should be assessed (compare Sect. 4.5) .
2
Introduction into Some Technical Aspects of rDNA
Often opponents of rONA technology use "unforeseeable synergistic effects" as an argu ment against this technology. Although enor mous progress has been made in our under standing of cel l biology. it is certainly true that we do not understand cell biology in all its d etails One aspect . feedback control mech a nisms has been analyzed in detail in various systems. and from these studies it can be concluded that it is extremely unlikely that transfer into a new host cell of a gene not coding for proteins involved in signal trans duction or tran scription. will result in un fore se e able syn e rgistic effects··. Moreover, if one requires that new food products can only be introduced into the marke t if one can gua rantee that no ··unforeseeable synergistic ef fects" will occur, this would mean that we have to block the introduction of any new food product. In fact. no existing food prod uct will com p l y with such a requirement. Moreover, food products derived from re combinant orga ni s ms will be analyzed in much more detail than any other food prod uct, and not just for the " known effects but also for unexpected effects. e.g. , by the appli cation of the technique recen tly developed by the group of A RTH U R PARDEE that can de tect differences in the expression of ··un known" genes ( LIANG and P A R D E E , 1 992 ) . A l so the ''90 days feeding trial"" required in most countries wi l l reduce the probability of "unforeseeable synergistic effects". .
,
"
"",
2.2 Events Resulting in Changes
in DNA 2.2. 1 Vertical Flux of Genes
Even before 1 975 it was known that recom bination on the DNA leve l was a common process i n E. coli . In fact, recombination is an important fact or in generat i ng genetic diversi t y . and recombination is involved in the re pair of chromosome breakage and other DNA damage . and according to S M ITH ( 1 988 ) m ultiple pathways of homologous recombina tion for multiple reasons exist. This clear ly in dicates that DNA is not the inert genetic blueprint of the living ce ll as was thou ght be fore 1 970.
161
Although the reliability of DNA duplica tion is very high and the few mistakes are oft en corrected by i ngenious mechanisms and counterbalanced by back-mutations, DNA duplication is not an errorless process. For eign DNA will, therefore, also be a subj ect of these e r rors and constitute a factor that should be included in the hazard analysis and risk assessment of rONA products. However, the mutations are not directed towards a cer tain property or function of the gene product, but occur j ust by chance. This means that for genes introduced by rONA technology the mutation frequency will be equal to or less than that for endogenous genes. Recently W. ARBER (1 990) has described the events that may change DNA: 1.
Fidelity of DNA replication Mutagenesis induced by external fac tors 3. Reco mbination processes a) General genetic recombination b) Transposition c) S i te speci f i c recombination d) Illegitimate recombination.
2.
-
The probability of a mutation in a certain gene in cells, growing under conditions that do not stimulate mutations , is low (about w - 5 per bacterial genome per generation) but it cannot be excluded. So also mutation i n foreign genes can occur. The probability th a t a mutation may render the gene p r oduct from an intrinsically innocent into a h a z ardou s pro tein is very small. Moreover, as outlined in some more detail in Sects. 2.4 and 2.9, tech niques are available which can be incorpo rated into the normal QA/QC procedure of manufacturers of food enzymes or starter cul tures (these procedures should be followed also for endogenous gene products). These procedures will eliminate the possibility that products encoded by mutated fo reign genes will pose a hazard. 2.2.2 Horizontal Flux of Genes
It is difficult to define which disc overy ini tiated the development of modern biotechnol ogy. The work by AVERY et a!. (1 944), using
5
1 62
Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products
transformation experiments with S and R type pneumococci resulted in the conclusion "that a nucleic acid of the deoxyribose type (DNA) is the fundamental unit of the trans forming principle of Pneumococcus" could certainly be considered as a landmark in bio technology. Transformation requires that the recipient cells are competent (i.e., able to take up DNA from the environment). Com petence is part of the normal physiology of many species and can also be induced artifi cially by chemical and physical treatments. In fact transformation proved to be a biological process that has played an important role in biological evolution (Fig. 1 ) . ,
l
Ve rtica l flux of genes (genomes)
- - - - - - • Horizontal flux of genes (DNA segments)
e Todays diversity of microorganisms Fig. 1.
Flux of
genes in biological evolution.
The frequency of transformations in Na ture is not very well known, but it has been reported that rONA microorganisms intro duced in soil could transform Bacillus subtilis present in that soil (GRAHAM and !STOCK, 1978) . Therefore, transformation of rONA
from the selected host into new recipients in the environment cannot be excluded and should be considered in the risk assessment. Numerous experiments have been performed to determine the probability that genetic ma terial will be transferred from the host strain to a recipient cell. One of the most convi ncing
experiments was done by IsRAEL et al. (1979). The complete genome of Polyoma vi rus was transferred into E. coli K 1 2 and 5 · 10 9 transformed cells were inj ected into mice In control experiments the virus itself, naked vi ral DNA either in the single-strand or dou ble-strand forms, integrated in a bacterial plasmid as such or treated with a restriction enzyme were used. The outcome of these ex periments was that the rONA construct was more than 1 0 000 times safer than the naked genome and more than 1010 safer than the vi rus itself (note: no tumor formation with the rONA construct could be detected). In an other experiment the guts of 100 mice were colonized by transformed E. coli for 6 weeks. No tumor formation was found which means that the probability of transfer must be less than 1 in 2 · 10 13 per day. In fact these ex tremely low values mean that in a risk assess ment this probability can be considered as zero. The above results may be explained by the lack of competence of epit hel ial cells to take up DNA or an extremely well developed sys tem of the epithelial cells to destroy foreign DNA or that DNA in the hostile condition of the gut is not very stable. Another matter of concern was the transfer of rDNA from the host cell to cells of the gut flora. LEVINE et al. (1983) carried out extensive studies with E. coli that hosted a self-transmissible plasmid and a poorly transmissible plasmid pBR325 containing a gene resulting in tetracycline re sistance. LEVINE was unable to detect pBR325 in the E. coli cells belonging to the gut flora. From his experiments it can be esti mated that transfer of DNA between related species in high-density populations as exist in the gut, is extremely rare. Bacilli used in com mon fermentation processes, Saccharomyces sp., Kluyveromyces sp., or Aspergillus niger or A. awamori are unable to colonize the gut and, therefore, the probability that these mi croorganisms will transfer rONA to microbial cells of the gut flora is even lower than for E. coli and can therefore be considered as zero in risk assessments. Transduction (the exchange of genetic ma terial mediated by bacteriophages or viruses) is another method to transfer DNA from one species into another. This is of direct rele.
2 Introduction into Some Techn ical
vance, if the fo re i g n DNA is located on a p h age or virus, however. this is an unusual procedure and should not be applied on an industrial scale. However. as a risk factor transduction cannot be excluded completely, if plasmi ds or integration vectors are used as vehicles for rON A . In aquatic a nd terrestrial ecosystems q uit e high titers of temperate and lytic bacteriophages have been determined. If an rONA containing bacterium enters this en vironment, it is possible t h at one of these phages recognizes this bacterium and occa sionally plasmid or even ch romosomal DNA can be packed into the ca p s id s prod uc i ng a transducing panicle that may contain rONA (SAYE et a!.. 1987 ) . However. the probability of such events i s very low. Conj ugation ( the parasexual transfer of plasmids and/or c h romos o m a l DNA) of bac teria or mating of lower eukaryotes is the m os t important mechanism to transfer genetic material between related species. There is overwhelming e vi d e nce that if sufficiently high numbers of antibiotic-resistant cells are present in nature and sufficient selection
A spects
163
of rDNA
pressure exists, transfer of genetic material , even between very distinct species occurs, as is proven by the widespread antibiotic resist ance among e n t eric bacteria. Tab. 1 shows some figures for the horizontal flux between related microorganisms, however, a consider able amount of evidence exists that also be tween unrelated species like E. coli a nd S. cerevisiae conj ugational transfer of genetic in formation can occur (HEINEMANN and SPRA GUE. 1 989). Mating between lower eukaryotes seems to be restricted to the members of the same gen us due to t h e role of s p eci fic p h e r omon e s and receptors for the mating factors in t h is pro cess (SPRAGUE. 1 991). In production pro cesses the probability of conjugation or mat i ng can be eliminated by proper strain selec tion, and therefore it is n o t necessary to in clude these aspects in the risk assessment. However. conjugation and mating should be included in the risk assessment of emitted rDNA organisms from production processes. Conjugation of deliberately released microor ganisms with microorganisms in the environ-
Tab. 1 . Horizontal Flux of Genes Be tween Bacteria Plasmid
Donor
p B C 1 6 (Tra + ) R P4 ( Tra + ) R68.45 (Tra
+
__,
Rate "
Recipient
Bacillus subtilis
__,
B.
B. subtilis
B. megaterium
->
10 - 5-to - z
B. subtilis
B . subtilis ->
licheniformis
Escherichia coli .... Thiobacillus no vel/us
)
Pseudomonas aeruginosa ->
P.
aeruginosa
aeruginosa .... P. aeruginosa
PMQl (Tra + )
P.
pBR325 (Tra - Mob + )
E. coli .... E. coli
pFTIO (Tra + )
B.
w -3 t o -6
w-o
w-4 w -5 w -z to -R w - l (R) w - z (R) t o - 4 (R) w -7
R Plasmids (Tra pBC l o (Tra + )
+
)
p DN705 (Tra - Mob +
piJ673 (Tra + )
cereus .... B. subtilis
Transconjugant
(R)
w -7 to -6
E coli -> A lcaligenes emrophus
w -6 w-' w - 6-w - 5 w - 4_wo
Streptomyces /ividans -> S. lividans
w - z_w - 1
Klebsiella sp . .... Klebsiella sp. thuringiensis .... B. thuringiensis
B.
B. thuringiensis ....
S. violaceolatus •
w -s
->
Soil bacteria
S. lividans
pe r donor cell. or transconj ugant per recipient ce ll ( R )
w - 6- 1 0° w-
'
1 64
5 Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products
ment cannot be excluded and, therefore, should form part of the risk assessment. Mat ing in the environment outside the produc tion facilities can be excluded, because in the environment the concentrations of wild-type and rDNA microorganisms of the opposite mating type will be very low. Besides the horizontal flow of genetic ma terial between microorganisms and in rare cases between microorganisms and plants, this flow also exists between plants by pollen exchange. Whereas new traits of commercial crops introduced via classical breeding are often not of any use for their wild relatives, transgenic plants will often be equipped with new properties like salt and drought tolerance and herbicide or insecticide resistance, and these properties may be beneficial to the wild relatives as well. ELLSTRAND (1 988) has sum marized the probability of horizontal flow of genes via either wind or insect transferred pollen as a function of the distance between the donor and recipient plant (see Tab. 2). These data clearly show that a horizontal flow of genes (also rDNA) can occur with a rather high probability when wild relatives are present within 1000 meters, and therefore this should be included in risk assessment of transgenic plants, in particular if the foreign gene codes for properties that provide the re cipient with a clear ecological advantage. Tab. 2. Gene Flow by Pollen
Species
Isolation
Gene Flow
100-1000 m 8 km 5{}-100 m
>1
(% )
Herbs
Raphanus sativus Agrostis tenuis Phlox drummondii
4.5-18.0 8
Trees
Gleditsia triacanthos Pinus taeda Pseudotsuga menziesii
200 m
1 22 m 161 m
5.8 36 20.4-26.6
The available data demonstrate that pollen can act as a vehicle for the transfer of engineered genes from crops to their wild relatives. The spread of these genes into natural populations will probably be rapid even if the wild relatives occur 1000 m from the crop and if the engineered gene confers an advantage to the wild species.
In the event that by one of the above de scribed mechanisms for horizontal flow of genes, genes have been transferred, this does not mean that the gene will be expressed in the recipient cell. Even between relatively closely related species as E. coli and Pseudo monas aeruginosa many genes are not tran scribed because of inefficient promoters. It is important to keep this in mind when reading publications on horizontal flows of genes based on the PCR methodology, as this meth odology does not give any indication of gene expression. Fig. 2 summarizes experimental evidence of transfer of genetic information between unrelated species. The barrier between var ious species is clearly not as absolute as was thought in the early seventies, and the argu ment that rDNA technology is hazardous only because it surpasses natural barriers is at least disputable.
2.3 RNA Splicing and mRNAs Derived from Synthetic Genes
RNA splicing can be considered as a com mon process in eukaryotes and soon after the discovery of this phenomenon, DARNELL and DOOLITTLE (1986) proposed that RNA splic ing has played an important role in evolution. The nucleotide sequences of 5 1 and 3 I splice sites are well known and reasonably con served, although differences in nucleotide are permitted. Even taking into account that the sequences are not conserved absolutely, it is not too difficult to scan foreign genes for the potential that they may contain RNA splice sites that may result in a completely different ly processed mRNA and consequently in a completely different protein. Especially if chimeric genes are constructed and these con structs are transferred to eukaryotic hosts, it is essential to check for the creation of splice sites to eliminate unintended splicing as a hazard. For prokaryotes splicing is not a fac tor of the hazard analysis. To improve the translation rate of foreign genes they are quite often synthesized chemi cally in the codons preferred by the new host (ANDERSON and KURLAND, 1990). Also
2 Introduction into Some Technical Aspects of rDNA
1 65
Archaea
6
: Euryarchaeota
2
Fig. 2. Transfer of genetic information between unrelated species. Bacteria: 1. Thermotogales; 2, flavobac teria and relatives; 3. cyanobacteria; 4, purple bacteria; 5. Gram-positive bacteria; 6, green nonsulfur bac teria. Arcbea: kingdom Crenarchaeota: 7, genus Pyrodictium ; 8, genus Thermoproteus; and kingdom Eu ryarchaeota: 9. Thermococca les; 10, Methanococcales: 11. Methanobacteriales; 12, Methanomicrobiales; 13, extreme halophiles. Eucarya: 14, animals; 15, ciliates; 16, gree n plants: 17, fungi; 18, flagellates; 19, microsporidia (from D A V I ES. 1 990; WOESE et al.. 1 990).
genes coding f or enzymes that have to be modified to improve their usefulness in cer tain application (e.g .. detergents) are often synthesized as a modular system containing different DNA cassettes. Normally each cas sette is flanked by a unique restriction site enabling the r apid exchange of such a cassette by another carrying the modified genetic code. The introduction of restriction sites quite often requires silent mutations. Finally genes are often ( partly) synthesized chemical ly to improve the stability of the mRNA or their rate of translation. although general models that describe the stability of mRNA hardly e x i s t (BAlM and SHERMAN, 1 988). Synthetic genes that have new nucleotide se quences should be screened for frameshift mutations, splicing and premature termina tion as all these p roc e ss e s may result in the synthesis of unknown proteins. Consequently they can contribute to the intrinsic hazard of rONA products. Careful analysis of the tran scription products of the foreign (synthetic) gene can reduce largely the above mentioned phenomena as a source of hazard related to the rONA technology.
2.4 Reliability of Translation
Processes and Post-Translational Modifications
Although gene expression is mainly regul ated at the transcriptional level, there are a number of ingenious regulation mechanisms that have been developed on a translational level. Some of these mechanisms involve frameshifting or initiation of the translation at a site different from the normal start codon. These frameshifts result in proteins that differ from the protein derived from the nucleotide sequence, and therefore this phenomenon is important in the discussion on the intrinsic hazard of foreign genes. Various mechanisms of recoding the message of an mRNA have been discovered: 1. Plus-one frameshifts. One of the best studied e x am p le s of + 1 frameshifts is the release factor 2 (RF2). In RF2 a stop co don (UGA) is located in position 26 (CRAIGEN et al., 1 985). However, with a probability of about 50% a + 1 frameshift
1 66
2.
3.
4.
5.
5 Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products
(UGA --+ G AC) occurs resulting in the biosynthesis of RS2 (CRAIGEN and CAs KEY, 1 986). This type of frameshifts is only possible, if a certain sequence in the mRNA, called stimulator, is present to which the 16S RNA of the ribosome can bind. Recently also for the eukaryotic chromosomal gene involved in the post translational modification of ornithine de carboxylase, a + 1 frameshifting has been discovered (GESTELAND et al., 1992). Minus-one frameshifts occur quite fre quently in the translation of retroviruses. The stimulator is a stem-loop structure lo cated downstream of the place of frame shift (BRIERLEY et al., 1989). Minus-one frameshifts are not restricted to retrovi ruses, but occur also in E. coli (TsuCHI HASHI and KORNBERG, 1990). Hopping is another translation phenome non that can cause the synthesis of a pro tein different from the protein expected on the basis of the nucleotide sequence of the gene. This phenomenon is quite well documented for bacteriophage T4. At a certain sequence the ribosome leaves the mRNA molecule and rejoins it about 50 bases later (HUANG et al., 1 988). In the genetic information of certain re troviruses and some plant and bacterial viruses, codons are encoding amino acids differently from the codon table as estab lished by NIRENBERG and others. For in stance, in certain mRNAs that contain particular sequences (ZINONI et al. , 1 990), the stop codon UGA encodes selenocys teine (HILL et al., 1 991). Although in higher eukaryotes also UGA is used to incorporate selenocysteine in proteins, the mechanism in these cells is less well known, but it is likely that again down stream sequences play an important role (BERRY et al., 1 991). Normally translation starts at the triplet ATG. However, at a low probability translation starts at GUG (8% ) and even more rarely at UUG or CUG (KOZAK, 1983). This may occur also in the transla tion of an rDNA gene encoded product.
Although recoding of the genetic informa tion is a rare event and mainly restricted to
viruses and bacteriophages, it has been de tected in normal mRNAs of bacteria, lower and higher eukaryotes and, therefore, it is es sential that for each gene transferred into a new host at least a theoretical evaluation is made whether recoding can occur. This is of particular relevance, if the transferred gene is chemically synthesized to adapt the codons or to design a gene that is very suitable for pro tein engineering, as there is a small probabili ty that a stimulator sequence has been intro duced. On top of theoretical analysis, careful inspection of the proteins produced by the rDNA strain by 2D electrophoresis and West ern blotting and in cases of any doubt deter mination of the C- and N-terminal amino acids can eliminate recoding as a hazard. Besides recoding of the mRNA, foreign genes may be translated into a protein differ ent from the protein in the original host by differences in post-translational modification. The best studied difference in post-transla tional modification is glycosylation. A euka ryotic gene carrying the amino acid sequences Asn X Thr or Ser that serve as a recognition site for glycosylation in the endoplasmic reti culum and Golgi apparatus, will when trans ferred into a prokaryotic host not be glycosy lated. Alternatively, if the gene is transferred from one eukaryote to another, e.g., from a plant to a yeast or mold, the N-glycosylation site will be recognized by the new host, but the type of glycosylation will be different. Be sides N-glycosylation also 0-glycosylation ex ists, but the exact mechanism by which 0-gly cosylation takes place is not fully known and is consequently an uncertainty in rONA tech nology. Moreover, in addition to glycosyla tion, other hardly known post-translational modifications, such as N- or C-terminal pro cessing resulting in smaller proteins, phos phorylation, farnesylation, etc. can occur. All these changes will be noticed already in the initial research phase and when observed, the choice of host should be reconsidered (with the exception of differences in N-glycosyla tion) to eliminate the biosynthesis of a pro tein of which the intrinsic property is un known. With respect to N-glycosylation the situation is different. Firstly, the degree of glycosylation is not constant but seems to vary with cultivation conditions. Secondly,
2 Introduction into Some
quite a number of pro tein s have been made via rONA techn ology that have the same am ino acid sequence b u t d i ffe rent g ly c osylation The e nz ymic pr op e r t ies of t h ese enzymes are very similar as. e.g has been p rov en for the tt-galactosidase fr o m Cyam opsis tetragonolo ba when ex p re s sed in various hosts (OvER BEEKE et aL 1 990 ) . A l tho u gh any change in N-glycosylation ma y in pr i n c iple create an in trinsic hazardous p r o t ein the absence of any indication for this until n ow proves that it is e x t re mely unlikdy that this will really occur. However. the a llergic pro pertie s of an en zyme produced i n a new host may differ from those of the original enzyme. In most decision schemes for the appr ov a l of rONA produ c ts for food applications. the pro t ein will be tested in fe eding trials. If the results of these tests are sim i l a r to those for t h e natural pro tein, no hazard has been introduced by the transfer of the gene from the original source to the new host. .
..
.
2.5 Random and Site-Directed
Technical Aspects of rDNA
1 67
In most of the decision trees for approval of new food products no attention is paid to genes that have been modified in a well known way and on applying the schemes very s t r i ctly modified genes have to be rejected or will at least require much more testing as they a re not originating from, or are not (yet) found in a naturaL appro ve d source. Provided t hat all the test procedures for the wild typ e gene product have been carried out and the gene pr odu ct has been app r oved a si m ple scheme to cope with this p r ob l em for en zymes used in food or chemical processes, o r i n food s or in personal car e or detergen t products is proposed (Fig. 3, Tab. 3). This scheme takes into account the possibility that the modified gene product will have different immunological or enzymi c prope rties If the modified gene product deviates in significant aspects from the wild-type gene product then a completely new approval procedure has to be followed. On the other hand, if in all but a few. from a safety point of view secondary as pects, the modified g en e product is equal to the wild-type gene product a more simple ap p ro v al procedure is proposed. .
-
,
.
,
,
Mutated Genes
One of the great prom is es of rONA tech n ology is t ha t enzymes can be obtained that
can c a ta lyze reactions under non-physiologi cal c o ndi t i ons This is of particular relevance to the chemical indu s try with respect to the de ve lopment of processes in which e nzymes are used as catalysts. T h ese processes are more e nvironmentally friendly than most of the pre se n tly used processes in the c he mic al i n du s try Also for t he development of en zymes for cleaning products random or site d ir ec t ed mut a ge nesis is very important ( WELLS and E"TELL. 1 988). Bot h random and site-directed mutagenesis w i l l create en zymes that most pr o bably do not exist in na ture. Arguments t h a t nature has had four bil lion years to t ry out all possible combinations are n o t v a l i d be c a use firstly it h a s been c al c u l ated that by far not all poss i b le combinations h ave bee n made ( MANFRED EIGEN , personal communication ) and secondly. there has not been any e nvironmental pressure in nature to select those enz ymes the chemical or deter gent industry i s interested in. .
2.6 Protein Foldin g I n most cases the transcription and transla tion of the rONA gene will be performed without any fa i l ure Still this does not guaran.
.
.
Fig.
3. Decision scheme to evaluate the hazard of
proteins derived from site-directed or randomly mutagen ized ge n e s .
5
1 68
Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products
Tab. 3. Proposed Approval Scheme for Mutagen
ized Proteins
2.7 Choice of Host Strain/Variety for Foreign DNA
Entry, Actions and Results
A.
B.
C. D.
Mutagenized gene Start complete approval procedure Determine nucleotide sequence of the gene(s) Gene(s) or gene product(s) do (does) not pose a hazard
Questions
Q 1. Q 2.
Q 3.
Q 4.
Q 5.
Has the non-modified gene product been ap proved by an official body? Has the modification been done using site directed mutagenesis? Has (have) the gene(s) due to the modifica tion any new sequence that may result in re coding phenomena or has (have) the modif ied gene product(s) a new stretch of at least 6 amino acids identical to another class of proteins? Has (have) the gene product(s) encoded by the modified gene(s) essentially the same im munological, physical and enzymic proper ties? Has (have) the nucleotide sequence(s) of the modified gene(s) been determined?
tee that the rONA product will be folded cor rectly. Intrinsically protein folding is a very complex phenomenon, moreover, it depends among other things on the translocation pro cesses and the redox potential in various cell compartments or organelles (HwANG et al. , 1992) and with a relative low probability this may result in (partially) improperly folded proteins. Sometimes very specific helper pro teins are required for the correct folding. If this helper protein is absent, improper folding occurs (e.g. , FRENKEN et al., 1993a, b). Al though our understanding of protein folding is rapidly increasing, it is still impossible to predict folding of rONA proteins in new hosts. For enzymes the specific activity (kcat per mass, determined by enzymic and immu nological methods) is a very accurate meas urement of proper folding. For non-enzymic proteins it is more difficult to determine whether the protein is folded correctly, but a combination of physical and immunological measurements can reduce this probability of an unexpected hazard due to improper fold ing considerably.
Directly after the discovery that between evolutionary unrelated species genetic mate rial could be transferred, the discussion about the safety of the host strain started. This was mainly due to the fact that the gut bacterium E. coli had become the work horse of the mo lecular biologists. To decrease the probability of a pathogenic strain being used as host in rONA technology, the strain E. coli K12 has been selected. This strain, originally isolated in 1 922, has lost during the many generations of cultivation on rich laboratory media four of the five essential properties to be a patho genic bacterium, notably the property of ad hesion in the gut, the production of entero toxins, its resistance against phagocytosis. Moreover, E. coli K12 became sensitive to the human immune system and lost its property to penetrate through the epithelial wall of the gut. The production of endotoxin was re duced largely but not completely lost (BERG MANS et al., 1 992). An important lesson can be learned from this. Microorganisms maintained for a large number of generations on rich laboratory me dia will with a high probability lose some of the capabilities they have acquired during evolution. This is not only valid for E. coli K12, but for many other strains selected on their performance in this type of media. Con sequently this means that strains, optimized to perform under standard conditions in a fer mentation process will have a largely reduced capability to survive under the severe condi tions outside the fermentation process. The other lesson E. coli K12 taught us is that pathogenicity is quite a complex proper ty. Experiments of GurNEE ( 1 977) to recon struct the pathogenicity of E. coli K12 by transferring the genetic material coding for the adhesion factor and the enterotoxin pro duction failed. Similar results were obtained by ISBERG and FALKOW (1985) who trans ferred the adhesion factors back into E. coli K12. When microorganisms used as host for rONA technology are functional microorgan isms in fermented food products (Tab. 4) and
2 Introduction into Some Technical Aspects of rDNA
169
Tab. 4. Main Functional Microorga nisms in E uropean Fe rmented Foods Microorganisms
Foods
Baked G oods
Lactobacillus
Molds
Ye asts
Bacteria
farciminus
p lan tarum
acidophilus
l ru eck ii
de h
Saccharomyces
cere�·isiae
xi
ri
Pich ia
e gu e s inusitus saitoi
Candida
vini
bre�·is buchneri
fe rmen tu m san
Wine and B randy
Leuconostoc
francisco
gracile venos
Hanseniaspora u varum
casei
Saccharomyces cerevisiae
t ru m
p la n a
fructiocrans
Kluyveromyces apicu/ata
rosei uvarum oviformis
des idiosus hilgardii
·
brevis Pediococcus
cerevisiae
Beer
Saccharomyces cerevisiae �� �·arum
Cheese a nd Dairy Products
Brevibacterium lin en s
Lacrococcus
Klu.v�·eromvces lactis
/actis c
.
rem o ris
fragilis
casei helveticus
bulgaricus
Leuconostoc
reuteri plantarum
cremoris
Pediococcus
acidilactici
Streptococcus
pentosaceum e rm op il
th
faecum Cabbage and
Cucumbers
Olives
Lactobacillus
h us
breds
plantarum
Pediococcus
meretoroides cerevisiae
L.. a ctobacil/us
p lama ru m
Sacch a ro my ces sp.
delbrueckii
Ha nsen u la sp.
Leu conostoc
hre�·is
Streptococcus sp. Pe diu cocc us sp. Leuconostoc sp. Meat
Laccobacillus Pediococcus A1icrococcus
Kluyveromyces sp.
De ba ryomyces sp.
plallfamm
Debaryomyces hansenii
lactis
Saccharomyces cannosus
acidilactici
pentosaceum caseo/yticus va rians
De ducted from Biotechnology 1 st Ed. Vol. 5 Chapters 1-8
Penicillum camemberti caseicolum roqu efo rtii
170
5
Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products
have a long safety record, the probability that such a strain becomes pathogenic through the transfer of one or a few well defined genes that code(s) for intrinsically safe proteins is extremely small. To put it in perspective, this risk is consid erably lower than the famous 12 D concept (the probability that less than one tin can in 10 12 will be contaminated with Clostridium botulinum and that this will result in the for mation of a detectable amount of toxin) which is used successfully in the food industry to ensure the safety of canned foods (SMELT, 1980).
Moreover, the probability that strains se lected for their performance in a fermenta tion process will survive in the environment will be very small. 2.8 Plasmid Stability and Stability of Integrated Foreign DNA
Stability of the plasmids or transposons carrying the foreign gene was a matter of great concern in the early days of rONA tech nology, and this concern is depicted in Fig. 4 (SAYRE and MILLER, 1991 ).
Concerns
Concern due to mobility
Concern for inserted structural genes
I
Transponson
------
.. � Frequency of insertionA·� etc. in host DNA .,.. _
•
-
-
'
Site-specific insertion
Concern for MGE genes not involved i n transfer
-
.
� _
_ _ _ _
_
'
- - Plasmid
-
--------
--
Transfer rate of transposon to plasmid
•
'
Non site-specific insertion
Rate of loss of MGE from cell and rate of uptake by. . . . .
•
Same species
�
i tor'""""""'
' '"'"'
Dlffe"'
Conjugation I Transduction I Transformation ami ,...,.
Medi u m : soi l , sediment, water, waste water, ground water
Frequency of phenotypic alteration in original host
''----
+
Frequency of phenotypic alteration in new host
___.
... ... •Adverse effect ..,. ,... ___
Fig. 4. Concerns about plasmid and transposon carrying rDNA genes.
2
Introduction
The s t abi l i ty of plasmi d s derived from pBR322 i n E. coli o r A RS - o r 2 ILm derived vectors in Saccha romyces cerevisiae h as been described in numerous papers. However. the reason for concern in relation to risk assess ment of rONA was not very clear. It can be argued that if a p lasmi d is unstabl e , m a n y pe digrees of the transformed c e l l will not carry the foreign ge ne(s ) and. therefore. the s e pedi grees are of n o con c er n in th e risk assess ment. Nearly al w a y s selection pressure is re quired for good stabi l i t y of vectors. Often a n tibiotics are used for the selection pressure . A n tibiotics will not be p re sent in the e n vi r on ment in sufficient quantities . and c o n seq u e n t ly t h e fate of the plasmid in the transformed host in the environment will be even worse than t h e fate o f p l asmid s unde r sele c tion p ressure . w h ich alre ady is not very good (e.g., s e e for yeast vectors M u RRAY and SzosTAK. 1 983). This diminishes the p r ob a bility of transfer of the pl asm i d to unknown recipie nts considerably.
M ore recently, so-cal led food
into
Some
Technical
Aspects of rDNA
171
host. These i nte g r at ion vectors are very stable (stability most often identical to that of the chromosome ) . but the draw backs are that the vector is not always integrated at the selected site ( i lle gi timate in t e g ration ) and t h e number of gene copie s is qu i te low. R ecently these disadvantages have been overcome in an ele gant way by constructing an inte g ratio n vec tor that contains upstream of a gene ( encod ing an enzyme essential for the anabolism of t h e host) a defective promoter and part of the genes coding for ribosomal RNA ( UNILEV ER, pate n t
application, 1 989).
In
this way the
vector is inte g r ated in a multimeric form p re ci s ely at a prede fin e d locus in the chromo some of the host. The advantage of inte gra tion vectors is that the probability of horizon tal flow is extremely low an d may be ne glected in risk assessments. Vectors used to tra n sform plants are nearly all based on the tumor-induci n g plas m i d of Agrobacterium tumefaciens
(SCHELL, 1 987) .
From these vectors onl y that p a rt is main tained which i s esse n tial for integ r a t ion into the chromosome of the host plant. The disad vantage of this procedure is that the site of inte gration is not known beforehand and is difficult to determine. This means that a cer tain met a bol ic function can be da m aged in the host cell and that is a h azard. T h e a tt rac tive ness of u sing Ti- p lasm i d to transform p lants is that the forei g n gene is st a b ly inte grated in the chromosome of the host and that the probability of horizontal flux of the foreign gene is ex t re m ely low. More rece n tly other vectors and methods to transform p lan ts have been developed, but all res u lt in stab l e, site -unspecific inte gration, although
grade vectors ( fully c h a rac t eri ze d vectors that contain, wit h the ex ce p ti o n of the fore ign gene , on ly homologous seque nces and these sequences should only code for normal ana bolic fu n ctions in the h ost cell) have been de veloped both for proka ryotes and eukaryotes. These vectors are maintained in t h e host, be c ause they cont a i n a gen e e ncodi n g an essen tial enzyme of t he an abolism of the host, e.g. , an en zyme of the biosynthesis of an amino acid. In principle this sele ction pre ssure will be mai n t ai n ed i n the enviro n m e n t. however. these host cells are in general quite fast i dious. Therefore, the host cells will not survive very well in the e n v i ronment, and this will red uce very rece ntly i ndications have been obtained the risk of horizontal flow of g ene to un that site -s pecifi c integration in plants is possi known recipients. M oreov e r. the recipient ble (P. HooiJKAAS, personal communica will have i ts own gen e for that anabolic func tion). Transformation of plants always me ans in tion which most likely is more effective in the te gratio n of rON A into the ch romosom e of recipie n t than in the foreign gene. In fermentation processes stability of vec the pla n t. This is also the ca se in t h e often tors c on t aining t h e gene of in terest is of major used anti-sense technology to repress the i mportance . as t he y i e l d of the g e n e product translation of m RNA. During the anti-sense i s often dire c t ly related to the number of gene studies quite often effects o f the posit i on of copies. E ve n ve ctors t h at are maintained by integration are observed as well as the rather se lection press ure are not c o m pletely stable. surpri s i ng result that also sense genes can re and therefore ,·ectors h ave been developed press translation (GRIERSON e t al. , 1 991 ) . which integrate into the c h r o m osom e of the These unexpected results sh ow o n ce m or e
172
5
Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products
that it is important to determine the place of integration and the effects on the metabolism of the host cell that integration can have.
2.9 Reprogramming of Metabolic
Pathways in Cells Hosting Foreign DNA
One of the targets for rONA technology will be the reprogramming of the metabolic pathway of the host cell. Intended reprogram ming of metabolic fluxes can be illustrated with four examples: (1) Anti-sense polygalacturonase (PG) in to matoes. In these tomatoes a gene coding for the endogenous PG gene is introduced but in the anti-sense direction ( S M ITH et al., 1 988). Although the anti-sense mechanism is not completely understood (GRIERSON et al., 1991 ) , one explanation is that the sense and anti-sense mRNAs "coding" for PG recognize each other and form a complex that cannot be transcribed. In this way the amount of PG is reduced, and this will decrease the cell wall degradation, and consequently the shelf life of the tomato is extended. (2) Using the same principles Calgene Inc. has developed rapeseeds in which the conver sion of stearic acid into oleic acid by a desatu rase is blocked by anti-sense 8-C9-stearoyl desaturase. This results in a higher level of stearic acid in rapeseeds, which is of advan tage for certain industrial applications ( CA L GENE, 1 991). (3) To improve the gassing power of baker's yeasts, GIST-BROCADES has developed a yeast strain in which maltose permease and maltase are expressed constitutively, thereby avoiding glucose repression of the endoge nous genes. Indeed this resulted in an in crease in the gassing power of about 25% (GIST-BROCADES, 1 987). (4) To improve the ethanol production rate of yeasts all genes of the glycolysis have been cloned and over-expressed. However, due to extensive feedback control mechanisms the ethanol production rate increased only by about 5% (SCHAAFF et al., 1 989). Whereas in the first example only a minor pathway in the metabolism was reprogram-
med, the rapeseed and baker's yeast exam ples are examples of a change of one particu lar step in a main metabolic route. Both ap proaches were very successful. However, the reprogramming of a whole main metabolic route in brewer's yeast was unsuccessful, be cause cells have many feedback inhibitions and other control mechanisms of main meta bolic routes. The above examples deal with intended reprogramming of the metabolism, thereby creating cells that may differ consid erably from the original host and should therefore be tested according to the full safety scheme. In most rONA projects metabolic repro gramming is not planned, but may be caused by intended or illegitimate integration (Sect. 2.8) . Moreover, change in metabolism can be caused by the intrinsic property of the intro duced foreign gene or by a helper gene, if the maintenance of the vector is based on the anabolic function of the helper gene product. Therefore, in the hazard analysis the possibil ity that the normal fluxes of metabolites in the host strain will be changed by the intro duction of foreign genes encoding enzymes should be considered. Using molecular bio logical techniques the occurrence of meta bolic reprogramming could be determined. Using Southern blotting coupled with RFLP/ RAPID analysis the site of integration could be determined, and if this integration resulted in disruption of a structural gene, the function of this gene should be determined. Alterna tively, by very sensitive analysis differences in the mRNA, profiles between wild-type and transformed cells can be determined (LIANG and PARDEE, 1992) . Also with enzymic or im munological methods the translation products of these mRNAs can be determined. Know ing or calculating the levels of enzymes it is possible to estimate the difference in fluxes of substrate conversions due to these changed levels (PosTMA, 1 990) and therefore the im portance of unexpected aspects of metabolic reprogramming.
3 Various
Stages in the Development of an rDNA Process
3 Va rious Stages in t he Development of an rONA Process or Product Soon after the Asilomar Conference in a number of countries committees were estab lished to develop guid e lines to evaluate the s afety of rON A experiments in the l aborato ries. These committees focused their effort on cre a ting frameworks for the catego r izati on of rONA experi m e nt s on the basis of intrinsic h azard of the foreign gene. nat ure of the vec tor u sed in the transfor m ation p r ocedures , pe rc ei v ed hazard based on the o r i gin of the fore ign gene, possib l e errors in the cloning proce dures and the intrinsic hazard of the host cell. I n i tially there were man y differences in the views of these committees, but after a number of years in nearly all Western cou n t rie s and Japan more or less the s ame rules for the evaluation of the sa fet y of l aboratory exper i m e n ts were ap p l i e d . At the end of t h e se venties the fi rs t gu i de lines for exper i m e nts exce eding the 10 l i t er scale were e s ta b l i s h e d , and again these rules were quite similar in various countries. Early 1 980 r ules for pilot-plant and large-scale pro duction were for m u lated . I n mo st countries for e ac h containment level general approval for the facilities can be obtained, however, for each new type of process or product approval of the used strain. equipment and proces s ing are n ecessar y. The volume of I 0 liters for which an addi tional approval p roced ur e must be started is qui te arbitrary . Additional approval for pilot pla n t or large-scale production does in gener al not pose a problem to manufacturers, as transfer from lab-scale to pilot plant and from pilot pla n t to la rg e scal e i s always a point of careful evaluation of all a s pec t s of any new process/product. Although ofte n the ap p roval of p i lo t and production facilitie s and the pro cess has been rather t im e -co nsum i ng with a few ex cepti on s. e.g . . of the rONA pr od u ction of human insulin by Hoechst in Germany, ap prov al w as obtained. However, app r ov a l to produce an rONA product does not mean
or
Product
173
that a new product can be market e d . For pha rmaceutical products the procedures for approval of new p roducts , including rO N A products are quite clear. For rONA products in food proc e ssing or for their use in food or dete rgent prod ucts or in other consumer products. unclear procedures varying from country to co u ntry exist or even no proce dures are in place at aiL The absence of clear and uniform guidelines in Western Europe ( EE C ) , USA and Japan has c lear l y contrib uted to a considerable delay in the introduc tion of rONA products and resulted in cer t a i n companies reducing or even losing their inter est in rONA tech n ology . For companies it is e x treme l y i mportant that it is clear alr e ady at the start of a n e w research and development program what the approval procedures for the e n d product will be. I f a company knows the approval proce dure s , a sche m e for the development of an r O N A process/product, i nc l u d i ng the approv al procedures and an estimated time scale, can be set up. A typ i cal exam pl e of such a sch e me is g i ven in Fig . 5 . In sp i te of the many approval procedures, the de v e lopment of rONA processes and products by a co m pa n y that uses such an integrated development/ap proval scheme will in general not be slowed down by these procedures. Many of the q uestions of the decision sche mes can already be answered at the moment the project reaches the state of transfer from shaking flask to fermentation or small-scale gl ass ho u se exper i ment s . Approval of the fa cilities can be obtained, even if the project is still i n it s research phase , altho u gh in mos t countries approval for pilot-plant and large scale production per project is necessary. However, this approval is normally not a problem. If necessary, the feeding and toxico l ogical studies can start as soon as the outline of the process on p i lot - plant scale has been e s tabl i shed . The e x tens i ve trials to get ap proval for pharmace utical products will take more time: however, also for new pharmaceu ticals produced via conventional techniques these tri a l s determine largely the ti me of in troduction. Such an app r oach also implies that d u ring the actua l research s t age of the development of a new rONA product the various steps in
174
5
Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products
Phase in project:
Idea Start
p roject 1 -2 year
Completion of molecular biology in lab. strain/variety
,,
1 -2 year
Decision point to
,
go from lab to pilot p la nt scale; Fillin g patents;
Dec isi on po i nts! actions
Checks
Completion of
of opti mization of production system
2 ye ar
,
Transfer to
pro ducti o n ,
,
Decision point to transfer proj ect from R&D to com pany
I
Start ( inte rnal) clearance procedure
I
discusion retailers and consumer
Start
organizations
Start consumer 1 trials 1 I I
Approvals
Laboratory facilities;
New project
lab scale
Process/Product
Pilot plant facilities; Ne w project pilot plant scale
clearance by authorities
Acceptance consumers
by
Fig. S. Different phases in the development of an rDNA product.
the construction of the new gene and its ex pression are carried out in such a way that the probability that approval will be obtained is optimal. In Sect. 2 the possible sources or er rors in the rONA technology that can render an intrinsically safe gene or gene product present in an intrinsically safe host organism into an intrinsically hazardous product have been discussed. Most of these sources can be detected during the research stage, and their absence should be checked by independent external experts. Spontaneous mutations can occur after completion of the laboratory ex periments and even during actual use of the transgenic organism in production processes or in agriculture. By applying common quali ty assurance/control protocols spontaneous mutations of the gene resulting in a change of catalytic or antigenic properties or molecular mass or physical characteristics or in a differ ent restriction pattern of the foreign gene and its flanking regions can be detected. Sponta neous mutations that are silent in all these as pects can be considered as safe (as the expres-
sion products are identical to the original products) . Larger rearrangements at DNA level will be detected by Southern blotting of microorganisms or RFLP or RAPID analysis of plant DNA. Both sets of techniques are (should be) standard procedures in fermenta tion or seed breeding industries, respectively, as such rearrangements may have an in fluence on other quality traits of the organ isms as well. Consequently there is no techni cal reason not to know for certain whether a transgenic organism carries a hazard. An im portant feature of the proposed scheme is (Fig. 5) that discussions with consumer organ izations and others start soon after filing pa tents bu t certainly long before the new pro cess is transferred to a production facility. In this way sufficient time is created to discuss the risk/benefit ratio of the new rONA prod uct with consumer organizations and others, and this may increase significantly the proba bility of acceptance of the rONA product by consumers.
4 Decision Schemes for Various Types of rDNA Products and Various Applications
4 De c is i o n Schemes for Various Types of rDNA Products and Various Applications of These Products 4 . 1 General
A number of committees ( have ) develop for t h e approval of be a p p l ied in various types of products. e.g .. pharmaceutical. per sonal care products. cleaning products. and in the food and process industry. This section will focus on decision schemes for food prod ucts. As no uniform gui d el i nes for these deci sion schemes exist worldwide ( KoK et a!.. 1993), it was necessary to start with different schemes devel op e d by universities or govern mental institutes, several national or intern a tional g uidelines and to develop these schemes. In Tab. 5 a number of guidelines and their main characteristics are summar ized. (ed) decision �chemes rONA p r od u c ts that will
In this section the guidelines proposed by the Department of Health of the U.K. for novel foods serve as a starting point. This choice was made because t he scheme includes all types of novel foods i nc l u d i n g foods de rived from biological species obtained via classical breeding and chem i ca l ly or enzyma tically m o d i fi e d foods or food ingredients. Moreover. the proposed decision scheme could be connected easily to the schemes pro posed in the Statement of Policy of the FDA on ··foods Derived From New Plant Varie ties'' and to recent proposals of t he GEZOND H EIDSRAAD ( 1 992) and the VOEDINGSRAAD ( 1 993) to t h e Dutch government which fit quite well within the EEC directives and may together with the U .K. guidelines serve as a framework for E E C decision schemes. 4.2 Decision Tree D erived from ' ' G uidelines on the Assessment of
Novel Foods and Processes"
In 1 99 1 the Department of Health in the issued a report in which the Advisory Committee on Novel Foods and Processes gives " G uidelines on the Assessment of Nov el Foods and Processes" (ACNFP, 1 991). In this report a decision tree for all novel foods is gi v e n and this tree includes also foods de rived from genetically modified organisms. Although it is called a decision tree, it does not end in qualifications like "approved" or "not allowed", but in a large number of ac tions. Unfortunately, the necessary act i on s to ob ta i n approval are not always clearly defined in this report. However, as the decision tree includes all foods, it is a good scheme to start with. Fig. 6 and Tab. 6 show t h a t part of the decisio n tree for novel foods derived from ge neti c ally modified organisms which is rele vant in the framework of this chapte r . U.K.
.
Tab. S. Comparison Between M ajor Characterist ics of Various G uide l i n e s for Food Products Made by. or Containing rDN A Material ( KoK e t al.. 1 993) Reference
A
B
IFB C ( 1 990) NNT (1991 )
+
+ +
-
ACNFP ( 1 99 1 ) WHO/FAO ( 1 99 1 )
Voedingsra ad
( 1 993 )
EEC ( 1 990 a. h ) OECD ( 1 99 1 ) FDA ( 1 992)
A,
uses
+
-
+
) +
'
+
+
+ +
+ +
c
D
'? -
+
E
F
-
+ -
+I-
+
+ + +
•)
•)
-
+
+
-
-
decision trees
B, case -by-case approach
+
'?
C. new regulation necessary D. risk assessm ent i n v olves animal fee ding trials E, allergy is co n s id e r e d as a n i m p o r t a n t factor F. m a nufacture r i s fully responsible + I - in certain but not all cases required
?
+
175
176
5
Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products NOVEL FOODS
Tab. 6. (Continued) Questions 1. Novel material? 2.
3. 4.
5. 6.
7. 8. 10. 11.
12. 13. 14. 15. 16.
Naturally occurring strain? Genetic change? Classical breeding? Significant change in genetic material? Human exposure? GMO? GMO? Does the food product contain genetic material? Human exposure? Human exposure? GMO? GMO a seed? GMO? GMO a seed?
The numbers I-XV above refer to the information requirements listed below I. II. III. IV. V. VI.
Fig. 6. Guidelines on the assessment of novel foods and processes. Truncated decision tree.
VII. VIII. IX. X.
Tab. 6. Guidelines on the Assessment of Novel Foods and Processes (Truncated Decision Tree)
Entry, Actions and Results
A.
This is not a novel food Exit point: Information requirements:
G. H.
I, II, III, V, VI, VII
I.
J. K. L. M. N. 0. P.
Q.
R.
Z.
I, II, III, IV, V, VI, VII I, III, V, VI, VII , VIII, IX I , III, IV, V, VI, VII, VIII, IX I , II, III, IV, V, VI,
VII,
VIII, X, XII
XI.
XII. XIII. XIV. XV.
Instructions for use Evidence of previous human exposure Intake/extent of use Technical details of processing and product specifications Nutritional studies History of organism Characterization of derived strain Toxicological assessment Human studies Assessment of a genetic modification proce dure Effect of a genetic modification procedure on the known properties of the parent organ ism Genetic stability of a modified organism Si te of expression of any novel gene t ic mate rial Transfer of the novel genetic material Assessment of a modified organism for survi vability, colonization and replication/amplifi cation in the human gut
I , III, IV, V, VI, VII, VIII , IX, X, XII I , III, V, VI, VII, VIII, X, XI, XII, XIII
I,
I I I , V, VI, VII, VIII, X, XI, XII, XIII,
XIV I , III, VI, VII, VIII, X, XI, XII, XIII, XIV,
XV l , III, V, VI, VII, VIII, IX, X, XI, XII, XII I
I , III, V, VI, VII, VIII, IX, X, XI, XII, XIII,
XIV I , III, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV
The food material must be genetically modi
fied
4.3 Decision Scheme for "Foods Derived from New Plant Varieties " as Applied by the FDA
The FDA issued a Statement of Policy on foods derived from new plant varieties (FDA, 1992). The various decision schemes given in this statement have been integrated into one
4
Decision Schemes for Various Types of rDNA Products and Various Applications
1 77
Fig. 7. FDA Statement of Policy on "Foods derived from new plant varieties" . Integration of their decision schemes into one decision tree.
scheme (Fig. 7, Tab. 7). This scheme can quite easily be connected to the general scheme that covers all types of novel foods. Com pared with the scheme proposed in the U.K. (see Sect. 4 .2) and the Dutch schemes (see Sect. 4.4) it is remarkable that the FDA schemes include a number of questions on the (expected) allergic properties of the new vari eties. This is in contrast with the two Euro pean schemes. On the other hand, the FDA schemes do not ask many details on DNA constructions. This is consistent with their view that it is not the way by which the intrin sic properties of a product are obtained, but the intrinsic properties as such that matter.
4.4 Decision Schemes Developed
for the D utch Government for Foods Containing rDNA-Encoded Materials
The guidelines produced in The Nether lands are largely based on the rules proposed initially by PARIZA and FOSTER (1983) . Dif ferent decision schemes have been developed for four food product categories (G EZO ND HEIDSRAAD , 1992; VOEDINGSRAAD , 1 993):
a ) Single chemicals or well defined mixtures of chemicals produced by biological sys tems modified by rDNA technology (deci sion scheme given in Fig. 8, questions in Tab. 8) b) Foods derived from transgenic plants (Fig. 9, Tab. 9) c) Foods derived from transgenic animals (Fig. 10, Tab. 10) d) Foods or food ingredients made by rDNA-modified microorganisms (Fig. 1 1 , Tab. 1 1 ) .
The Dutch schemes are the outcome o f a number of discussions between consumer or ganizations, governmental and academic ex perts on rDNA technology, toxicology and communication and industry and cover the whole range of food products. During the dis cussions it became clear that the traditional 90 days feeding trials are not (always) appro priate for the evaluation of food products made by rDNA technology. Therefore, much attention has been paid to find molecular bio logical approaches to guarantee the safety of these products. As not very much experience in this area exists, it was decided to use the traditional feeding trials and the molecular approaches simultaneously and to decide aft er a period of at least three years whether in-
5 Structured Risk
1 78
A ssessment of rDNA Products and Consumer Acceptance of These Products
Tab. 7. Foods Derived fro m New Plant V a r ie t i e s Decision Tree B ased on FDA S t a t e m e n t o f P o licy . M a y 1 992 Entry, Actions and Results Food derived fr o m a new (via rON A technology modified) p l ant variety? A. B.
Assess th e s a fe t y of t h e host pla nt and the donor of th e D N A (gene)
v a rie t y is
C.
New
E. F.
Consuh F D A
n o t a c c e pt ab
le
D.
No concern
G.
The p ro d uc t does n o t fit i n t h i s d e c isi o n s c he m e
Cons u h
FDA
for
a dd i t i o na l
or alternative test ing
Questions 0 1 . Will the modification re s ul t i n nu tritional e ffects ? 0 2. Does the host s pec i e s have a hist o ry of safe use ? 0 3. Do characterist ics of t h e host species. related spe cies 0 4.
c o l og i ca l tests? Do
.
or p r oge n i to r l i nes
w a r ren t
an alyti ca l
or
toxi
test result p rovide e v i d e nce that tox ica nt l ev el s in the new pla n t v a ri e ty do not prese nt a safet y
conce r n ?
0 8.
Is t h e conce ntration and bio-availability of i m portant n u t rie n t s in the new var i e t y within the r a n ge in t h e host sp e c ies? Is food from the donor c om m o n ly a ller ge n ic ? Can i t b e d e monstrated t h a t the a l l e rg e n i c determinant has n o t b e e n transferre d to the n e w v a r i e t y of host'' Do c h a r ac t e r i st i c s of t h e donor species. re l at e d species. or p r oge n i t or lines warrent analytical or
0 9.
Will the
0 5. 0 6. 0 7.
ord ina ri l y observed
toxicological tests''
modification result in
the e xp re s s i o n of
pro t e in (s ) in
t he
new variety?
0 1 0. Is t h e newly introduced pr ot e i n prese nt i n food de ri v ed from the p l a n t ?
0 1 1 . Is the protein derived from a food so urc e sub sta n ti a ll y. or simi l ar to an edible pr ote i n ?
0 1 2. Is food from t he donor co m m o nl y a l l e rge n i c? 0 1 3. Is the i ntrod uce d p rot e i n re por t e d to be toxic?
0 14. Can it be d e mon st r a t e d that t h e a l l e rge n ic determinant has n ot been transfe rred to the new variety
of
host ?
0 1 5. Does
the biological funct i on of the i ntro d uce d pro te i n raise any safety co nc e r n ,
protein r e p o rted
or i s
the introduced
to be tox i c?
0 1 6. I s the i n tro d u c e d prote i n li ke l y to be a m acr oco n s t i t u e n t of the human or animal diet? 1 7 . Will the i nta k e of t h e donor prot e i n i n the n e w va rie t y be ge ner a l ly c o m p a ra bl e to the intake o f the
0
s am e or s i m i l a r pr o t e i n in t he donor or other fo o d ? 0 1 8 . Will the mo d i f ica t i on res u l t in the bi o sy nt hes i s of new or modified carbohydrates i n the n e w varie
ty?
0 1 9. Has t h e re been a n intent ional alteration in the struc t u re . composit ion or level of ca rbohydrates in ,
the
new variety?
Q 20.
Have any structural fe a t u re s or function a l groups been i n t roduced i nt o t h e carbo h y d r a t e that do n ot
021.
Have t here been any a l t e rations that c o u ld a ffe ct d ige stibi li ty or n u t r i ti on al quality in a
normally occur i n food c a r b o hydrates? t h a t is l i k e l y to be a macroconstituent
of
ca r boh ydrate
the d i e t ?
0 22. 0 23.
Will the m od i fi c a t i o n r e s u l t i n the biosynthesis of
0 24.
Have the intentional alte rations b e e n i n a fat or o i l that w i l l be a
new o r modified fats or o i l s in the new va ri e t y ? structure, or co mposi t io n of fats or oils in the
Has t h e r e hee n an inte n tional altera t ion in the i d e nt i ty ,
ne w varie t y ?
0 25 . A re any unusual or toxic fa t t y a c i d s produ ced in the new va ri e t y?
m ac roc o ns ti tue nt
of the
diet?
4
Decision Schemes for Various Types of rDNA Products and Various Applications
179
Ftg. 8. Decision tree for well-defined s i n gle food components.
Tab. 8. Decision Tree for Well Defined Single Food Components Entry, Actions and Results A. Carry out evaluation studies to determine the safety of the product and make specifications C. Make new specifications D. Apply a process to reduce t he l e v e l of undesirable components E. Carry out a 90-day feeding trial X. It is not allowed to bring the component on the market Z. The component is a ppr o v e d for use in foods Questions
1 . Is the use of the component in foods allowed at this moment? 2. Does the component comply with e x is t ing specifications on ide n t it y and puri t y? 3. Are the existing specifications sufficient to control the presence of undesirable site components or too high levels of the i n te nde d component? 4. Are the levels of known components w ithi n the safety specifications? 5 . Is it possible t o reduce the level of undesirable components during processing in order to comply with the existing specifications? 6. Is it possible that the product con t a i n s unknown components? 7 . If the intended or assumed consumption of the component results in a change in eating habits will the new habit still be considered as safe? B . Does the eval uation show that the component is safe? F. Does the 90-day fe e d ing trial show that the component is safe?
Note: Q uestions B and F are not (yet) included in the Dutch decision trees as separate questions but form part of action A and question 5. respectively
deed the molecular biological methods are better than the traditional methods (see Fig. 8). Chymosin is most probably the first and most widely applied rONA enzyme in the foods area. The gene coding for preprochy mosin has been cloned (UNILEVER, 1981 ) and
expressed in the GRAS yeast Kluyveromyces lactis (GIST-B ROCADES, 1 982). Many publica tions on the properties, safety evaluation and production of chymosin have been issued, and therefore chymosin can serve as a mod el.
180
5 Structured Risk Assessment of rDNA Products and Consumer A cceptance of These Products
Fig. 9. Decision tree for foods de rived from transgenic plants.
Tab. 9. Foods Derived from Transgenic Plants
Entry, Actions and Results
A. Start a procedure for novel foods
B. Carry out evaluation studies and determine the safety of the product
C. Do these evaluation studies show that the expression product(s) is (are) safe? D. Apply a process to reduce the endogenous or new components to an acceptable level E. Carry out a 90-day feeding trial X. It is not allowed to bring products derived from this plant on the market Z. Products derived from this plant are approved for use in foods Questions
1. Is there sufficient know-how on host organism and donor DNA to start the approval procedure? 2. Are the components of the food only of an endogenous nature? 3 . (Are) is the expression product(s) of the donor DNA an endogenous expression product(s) of a/ another food? 4. Is there a possibility that consumption of the new component in the intended or assumed quantities will affect the health of the consumer negatively? 5 . Is it possible to reduce the (active) components to the allowed level during processing? 6. Is (are) the site(s) of integration of the donor DNA on the plant chromosome(s) exactly known? 7. Is that knowledge sufficient to conclude that the metabolism of the plant is not changed or are the changes within the naturally occurring variations? 8. Does the 90-day feeding trial show that the component is safe?
Fig. 12 shows a flowsheet of the rDNA chy mosin production process developed by GIST BROCADES. The flowsheet demonstrates clearly that the probability that genetically modified organisms (GMOs) that have pro duced chymosin will be present in the end product is practically zero. Firstly, the fermen tation liquid is filtered twice to separate the
GMOs from the enzyme, secondly, the liquid containing the enzyme is acidified with a solu tion containing about 200 mglkg benzoic acid (pH 2). The latter is necessary to transform prochymosin into the active enzyme chymosin and provides an additional guarantee that the end product is free of GMOs. Finally, in a lat er stage of the process an ultrafiltration step
4
Decision Schemes for Various Types of rDNA Products and Various Applications
181
Fig. 10. D eci s i o n tret! for foods d e rived from animals t re at e d with prod ucts made by modern biotech nology or obtained from transgenic animals.
Tab. 10. Foods Dt!rivt� d from Animals Treated with Products Obtained by Means of Modern B iotechnol ogy or from Transgenic Animals Actions and Results A. Start a procedure for B. Evaluate tht! prod u c t C.
D.
E. F.
G.
X. Z.
novel food s
in accordance with the national/international legislation for veterinary p ro d ucts This p rod uct should be analyzed as a no vel food Evaluate the safety of the new com ponents Does the e v a l uat i o n of the new component show its safety? Develop a procedure/process to reduce the level of the endogenous or new component Does the evaluation of t he p roce dure or proce ss to reduce the level of the e ndoge nous or new compo nent show that the level is acce p tah le ? It is not allov.:ed to bring p roducts derived from this animal on t h e market Products derived from this animal a re approved for use in foods
Questions 1.
2. 3.
4. 5. 6.
Is the food or food prod u c t derived from a transgenic animal? Is the food or food pr od u c t derived from an an imal treated or fed with a product made via rON A tech n ology ? Has the a n i m a l been treated w i t h a veterinary p roduct? Is there sufficient k n owl e dge and docu menta t ion about the host animal and the gene t ic donor material to start t he a pprov al p roced ures ? Are the components of the food or food product de ri ved from the tr an s ge n ic animal e nd oge no us? Is ( are ) the expression p roduct(s) encoded by the genetic donor material endogenous in other foods·�·
a possib i l i t y that consumption of the endogenous or new components in the inte nded or as quan ti ties will affect the health of the consumer negat ively? R. Is it possible to redu c e the endogenous or new components to an acce p t ab le level'?
7.
Is there
su m e d
1 82
5 Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products (ingredients) produced by GMO
Food
5
>--TN'--_.� y
y
N
N
y
Fig. 11. Decision tree for foods or food ingredients derived from GMO.
1
INOCULUM CULTURE
8
STERILE FILTRATE TANK
Fig.
2
INOCULUM FERMENTOR
9
3
FERMENTOR
ULTRA·FILTER FEED TANK
4
5
FILTER PRESS
MASH TREATMENT TANK
10
ULTRA· FILTER
12. Production of chymosin by rDNA
11
UF.CONCEN· TRATETANK
12
FORMULATION BLENDING TANK
Kluyveromyces.
6
FILTRATE
7
STERILE FILTER PRESS
13 STERILE FILTER PRESS
14 STERILE TANK
15
PACKAGING
4 Decision Schemes for Various Types of rDNA Products and
Va rio us Applications
1 83
Foods or Food Ingredients Produced with the Aid of Genetically Modified Microorganisms ( see also Fig. 1 1 )
Tab. ll.
Actions and Results
C. X.
Thi s product should be analyzed as a novel food It is not allowed to bring food products containing i ngredie n ts produced with this GMO on the mar
Z.
Food product� co n t a i n i n g ingred ien t s produce d with this GMO are ap p roved
ket
Questions
unmodified mic roo rga n i sm have a record of safe use in food p roducts? Can on the basis of feeding and/or toxicological studies t he unmodified microorganism be considered as safe in food products? Is there sufficient k now ledge and documentation that the new gen e ti c material codes for (a) pr od uct(s) that is (are) acce pt a bl e in food prod ucts ? Does the G M O or an inherent part of it or the product(s) encoded by the new genetic material remain in the food product? It is intended that t h e modified microorganism fulfills a fu nctio n al role in the gastrointestinal tract of the consumer'' Has t he intended functionality been demonstrated? Is the modified microorganism free of genes encoding antibiotic resistance ? May the consumption of the food, in particular t he GMO or an inherent part of it, or the product(s) encoded by the new genetic material in the intended or expected consumed qu a nti tie s result in any n ega tive aspect on the health of the consumer? Is it possibl e to reduce the quantity of the GMO or an inherent part of it or the product(s) encoded by the ne w genetic m a teri al to an a cce pt a b le level? Is the p hysic a l state or the i nte gr ation into the chromosome of the host of the new genetic m at e ria l fully known? Does the integration of the new genetic material d i st u rb the metabolism of the ho st in such a way that hazardous p roducts may be formed? Does a 90-day feeding trial with the food product con t a in i n g the GMO or an inherent part of it show that the introduction of the new ge n et ic material into the host does not have an effect on the metabol ism of the host cell resulting in (a) hazardous compou nd( s ) ?
1 . Does the
2.
3.
4.
5. 6. 7.
8. 9.
10. 11. 12.
is
included to concentrate the chymosin. The
probability that a GMO will escape from the
process upstream of the first filtration unit is low, but certainly not zero. Naturally the fer mentation unit h as been designed to exclude the possibility that microorganisms from out side will penetrate the fermentation un it . However, the equipment is not aseptic and due to the high number of yeast cells in the fermentation unit . there is a probability that from time to time the rONA yeasts will es cape and enter the environment. However, as explained in Sect. 2.7, the probab i li ty that the _production microor_ganism. in this case Kluy veromyces lactis, will survive the conditions present in the environment is extremely low. TEUBER ( 1 990) described the safety evalua tion of chymosi n process and product. In this paper the chymos in gene is still assumed to be
located on a plasmid containing an antibiotic resistance marker. When a pplying the scheme of Fig. 8 for approval of this product, this is not allowed. At present, the construct carry ing the chymosin gene is integrated into the chromosome and does not carry an antibiotic resistance marker (GIST-BROCADES, person al communication).
4.5 Decision Scheme for the Approval of the Release of GMOs
It is likely that foods c o nt a ini n g pl an ts or microorganisms derived from genetic a lly modified organisms will be the first GMOs that will enter the market. Normally foods de rived from plant material will not be used to
184
5 Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products
(re)generate plants; however, food products like bread or yoghurt may contain rONA mi croorganisms that are still alive and are able to grow out. It is the release of this category of rONA organisms that is still a matter of much debate. Although certainly more com plex than dead material derived from GMOs there is no fundamental difference between
the approaches to assess the risk of these products. In Figs. 13 and 14 and in Tab. 12, a rational approach to assess the risk of living lactic acid bacteria in a dairy product is giv en. An important question in this type of risk assessment is whether one should stop with the transfer of genetic material from the host
Fig. 13. Decision tree for the risk assessment of the release of genetically modified microorganisms present
in food products for human consumption.
Fig. 14. Decision tree for
the risk assessment of the release of genetically modified microorganisms present in food products into the environment.
4 Decision Schemes for
Various Types of rDNA Products and Various Applications
185
Tab.
U. A Proposal for a Structured Assessment of the Risk Related to th e Introduction of Genetically Modified Micro o r ga n i s m s (GMOs) in (or as) Food Products
Entry, Questions, Actions and Results Food Products 1 (E). 2 (Q). 3 (R). 4 (0). 5 (A).
Genetical ly modified microorganism ( GMO) Has the product containing the GMO formal clearance based on animal feeding trials? The release of this GMO cannot be evaluated before it has this formal clearance Is this GMO produced as a mixed culture? Determine the probabilit y P (a) that the genetic information will be transferred to (one of) the other microorganisms present in the mixed culture
6 (0). ls P (a) > a'? (Note : in the research phase attention should have been pa id to minimizing the probability of such a transfer) 7 (A). This secondary transformed microorganism (STO) should be cleared in the same way as the GMO (compare qu estion 2 ) 8 (0). Official clearance obtained? 9 (A ) . Go to action 1 0 1 0 (A). Determine the amount of product that comes into the environment ( into the sewage system e ith er from factorie� or households or directly in the soil) before consumption ( = spilled product) 1 1 (0). Is V (spilled) > b V ( p ro d uc ed )? 1 2 (A). Go to action 40 to evaluate the behavior of GMO (and if appropriate the STO) in spilled products and continue with question 13 for consumed product 13 (Q). Will the product containing the GMO receive a physical/chemical treatment before consumption and will that treatment result in an inactivation of GMO by a factor > c? 14 (A). Determine the distribution of the residence times of GMO in the gastro/intestinal (gli) tract of the consumers. Take the time corresponding w i th 95% of this distribution curve as t (r) 15 {Q). Will the GMO lyse with a probability > d i n the gli tract? 16 (A). Although the correct procedure will be the determination where lysis will occur and the determi nation of the distribution of the time of intact cells in the gli tract, a worst-case scenario is used assuming the concentration of intact cells is not changed by the lysis and that the intact cells can transfer their genetic information during t (r) to other microorganisms in the gli tract 17 (A). De t erm i n e the probability P (e) that intact cells of the GMO transfer genetic information to nor mal inhabitants of the g/i tract. Use in these studies t (r) as contact time and the conditions of the gli tract. Determine also the probability P (f) that the GMO w i ll be transformed by genetic mate rial originating from the common gli tract microorganisms ( = modified GMO) 1 8 (Q). ls P (e) > e? 1 9 (A). D e t erm i n e whether the transformed inhabitants (or STO) obta in an advantage over untrans formed inhabitants in the g/i tra ct : A (i) Define A (i) in either faster growth rates t' (g); better adhesion h ' ; or higher production of certain metabolites {p (x) x = 1, } 20 (A). Determine the p robabi li t y P (g) that any of the events described under action 19 will result in the formation of a h a zar d ous microorganism (producing toxins) or that the STO will replace benefi cial microorganisms in the g/i tract) microorganisms 2 1 (Q). I s {P (e) + P (l)} · P (g) > g or P (m ) · P (g) > g? 22 (A). This risk is unacceptable and the GMO should not be released 23 (Q). Is the number of STOs larger than h per volume unit gli tract (compare action 19)? 24 (A). Determine the proba bi l i ty P ( i), that the STO can transfer that part of its genetic content that contains the genetic i nformati o n from the GMO to another microorganism of the g/i tract result ing in a tertiary transformed microorganism (ITO) 25 (0). I s {P (e) + P (i)} · P (i) > i or P ( m ) · P ( i) > i'? 26 (A) . Determin� whether the TIOs have an ad v antage over untransformed cells in the gli tra ct (com pare action /9) 2 7 (A). Determine the probability P (j) that any event described in action 2 6 will result in a hazardous microorganism 28 (Q). Is P (e ) ·P ( i) · P (j) > j or P (m) · P (i) · P (i ) >j? 29 (0). Is P (f) > f'! ' ,
. . .
1 86
5 Structured Risk Assessment of rDNA Products and Consumer Acceptance of These Products
Tab. U. (Continued)
30 (A). Determine whether the modified GMO gains an advantage over untransformed GMOs: B (i). De fine B ( i) in either faster growth rates t" (g); better adhesion h ; or higher production of certain metabolites {p (x) " , x = l , . . . } 31 (A). Determine the probability P (k) that any of the events described under action 30 will result in the formation of an hazardous GMO 32 (Q). Is P (fl P (k) > k? 33 ( A ) . · As described in action 16 a worst-case scenario is used to determine the probability that DNA of lysed GMO cells transforms other microorganisms of the gli tract. (Use for these studies t (r) as contact time and the gli tract conditions) 34 (A). Determine the probability P (l) that DNA originating from lysed GMO transforms normal inhabi tants of the gli tract (resulting in STO) 35 (Q). Is P (/) > 1? 36 (A). Determine the probability P (m) that DNA originating from the inactivated GMOs transforms normal inhabitants of the gli tract (resulting in STO). (Use for these studies t (r) as contact time and the gli tract conditions) 37 (Q). Is P (m) > m? "
·
38 (R). The GMO
can be released This is the end of the risk assessment in the g1i tract. The next phase will be the risk assessment of GMOs, modified GMOs and STOs in the en'rironment ("Sewage System").
39.
"Sewage System" (This scheme products) 40
(A).
41 (Q). 42 (Q). 43 (A).
44 (0). 45 (A).
46 (A). 47 (Q). 48 (A).
49 (Q). 50 (Q). 51 ( A ) . 52 (Q). 53 (A ) .
can
also be used for the release of microorganisms in the environment for non-foods
This decision tree deals with genetically modified microorganisms (GMOs), or modified GMOs and secondary transformed microorganisms (STOs) Determine the average residence times of the GMOs or modified GMOs and STOs in sewage (t (r2), t (r3) and t (r4), respectively) Is the microorganism considered STO? Will the GMO or modified GMO lyse with a probability of > n in the "sewage system" ( s system)? Determine the probability P (o ) that the GMO or modified GMO will transfer its genetic informa tion to other inhabitants of the s-system. Use in these studies t (r2) and t (r3), respectively, as contact time and the various s-system conditions to determine P (o) ls P (o) > o? Determine whether the transformed inhabitants gain an advantage (or new property) over un transformed inhabitants of the s-system: C (i) Define C (i) in either faster growth rates t"' (g); better survival s "' or higher production of certain metabolites {p (x) "' , x = 1, . . . } Determine the probability P (p) that any of the events described under action 45 will result in the formation of a hazardous microorganism Is {P(o) + P (u)} · P (p) >p? Determine the probability P (q) that a transformed hazardous microorganism in the s-system (STO) will enter the food chain Is {P (o) + P (u)} · P (p) · P (q) > q? Will the STO change the ecosystem considerably, e.g., replace the natural microflora? Determine the probability P (r) that the GMO will be transformed by DNA of the normal inhabi tants of the s-system Is P (r) > r? Determine whether the transformed GMO gains an advantage or new property over untrans formed GMO in the s-system: D (i) Define D (i) in either faster growth rates: t " " (g), better survival: s " " , or higher production of certain metabolites {p (x) " , x = l , . . .} Determine the probability P (s) that any of the events described under action 53 will result in the formation of a hazardous modified GMO Is P (r) · P (s) > s? "
54 (A). 55 (Q).
4 Decision Schemes for Various Types of rDNA Products and Various Applications
187
Tab. 12. ( Continue d )
56 (A). Determine the possibilit y P (t) that the modified GMO will e n t e r the food chain 57 (Q). Is P (r) P (s) P (t) > t? 58 (A). D e t e rm i n e the poss i b i lity P (u ) that the DNA origi na t i n g from the GMO transforms the normal inhabitants of the s-system 59 (Q). Is P (u) > u? 60 (Q). Will the STO lyse w i t h a probability > v in the s s y st e m ? 61 (A). Determine the probability P ( w ) that the STO wi l l transfer its genetic information to the normal inhabitants of the s-svstem 62 (Q). Is { P ( o ) + P (u)} · P ( �) > w? 63 (R). The GMO can be released if the "right band tree" starting with question 42 leads to result 72 64 (A). Determine whether the transformed inhabitants (TfO) gain an advantage (or new property ) over the normal i nhabitants of the s-system: E (i) Define E (i) i n either fas t er growth rat e s : t " " ' (g); better survival s ' " " or higher p ro d uc tio n of ce rtain metabolites ( P " " ' (x), x = l , . . . ) 65 (A). Determine the pro b ab i l i t y P (y) that any of the events described under action 64 w il l result in the formation of a hazardous TIO 66 (Q). I s {P(o) + P ( u)} · P ( w ) P (y ) > y or {P (o) + P (u)} · v · P (a ) P (y ) > y? 67 (A). Determine the probability P ( z ) that the hazardous TIO will enter the food chain 68 ( Q ). Is {P(o) + P ( u)} · P ( w) P (y) P ( z ) > z or {P (o) + P (u)} · v · P (a) · P (y) P(z) > z? 69 (Q) . Will the te rtiary t r a n s forme d microorganism (TIO) change the ecosystem considerably? 70 (A). Determine the pos si b ili t y P ( a ) that the DNA originating from the GMO via STO transforms the normal inhabitants of the s-system 7 1 (Q) . Is {P (o) + P ( u )} · v · P (a) > a? ·
·
-
·
·
·
·
·
72 (R). Provided that the new genetic information of the (surviving) GMO still has its original configura tion, the
GMO can be released
strain to the pri mary recipient, or eve n whether it should include the proba b i lity that the primary r e cipi e nt will pass its n e wly ac quire d genetic i n form at ion to a se con da ry re c ip i ent Other im po rtant but difficult ques tions to be answered are the accep ta bl e prob abilities of the transfer of this genetic mate ri al and how to e v a luat e these criteria. In t he ad ditional Tab. 13 very pre l im i n a ry proposals for the various criteria are give n Many of the p rob a b i lit i e s and numbers p r opos e d in Ta b 1 3 are not based on experimental data. It i s obvious that before GMOs in food products can be int roduced these proposed p rob a b i li ties and numbers should be confirmed and, whenever the proposals are not correct, be re placed. However. in an attempt to s t ru c ture the re search in this area and to avoid "political" in te rpr e tat i on s of the research data ob t ai ne d this scheme and the corresponding prob a bili ties a nd numbers are proposed. .
.
.
.
,
4.6 Integrated Scheme to Evaluate Any rDNA Product
Based on the various d e ci s ion schemes giv e n above, a general ize d decision scheme for all rONA prod uc ts has b e en d e ve loped (Fig. 1 5 , Tab. 14). This scheme divides the va rious types of products into groups, and for each group one of the previously discussed schemes can be followed. A lt hough this scheme has not been aut h or ized, it is useful d uring the d e v e l o pme n t phase of an rON A product as it po i nts out q uest ions t ha t m os t prob ab l y will have to be answered to obtain the approval of official bodies. This will guid e the research work in such a way that most of the questions c an be answered straight away.
Events Result
Probability Function
Probability
Donor
Recipient
P (a) > a P ( e} > e P (f) >f {P (e) + P (l)} · P (g) > g or P (m ) · P (g) > g {P ( e ) + P (/)} · P (i) > i or P (m) · P (i) > i P ( e) · P (i) · P (j) >j or P (m) · P (i) · P (j) >j P (f) · P (k) > k P (l) > l P (m ) > m P (o ) > o {P (o) + P (u)} · P (p) >p {P ( o) + P (u)} · P (p) · P (q) > q P (r) > r P (r) · P (s) > s P (r) · P (s) P (t) > t
a e f g i j
= 1 0 - 16 = 1 0 - 16 = 10 - 10 = 10 - 23 = 10 - 1 9 = 10 - 23 k = 10 - 19 l = 10 - 16 m = 1 0 - 16 - 16 0 = 10 9 p = 10 - 1 2 q = 1Q - 3 r = 10 - 10 s = 1Q - 19 t = 10 - 23 u = 1 0 - 16 w = 10 - 1 1
GMO GMO G/i tract cell
Co-ferment cell G/i tract cell GMO
P (u) > u
·
{P (o) + P (u)} · P (w) > w {P (o) + P (u)} · P (w) · P (y) > y or {P (o) + P (u)} · v · P (a) · P (y) > y {P (o) + P (u)} · P ( w) · P (y) P (z) > z or {P (o) + P (u)} · v P (a) · P (y) P (z ) > z {P (o ) + P (u)} · v · P (a) > a ·
·
·
STO STO Modified GMO STO Hazardous STO TTO TTO ---> Hazardous ITO Mod. GMO Hazardous GMO STO STO STO STO --> Hazardous STO Haz. STO Food chain Mod. GMO Mod. GMO --> Hazardous GMO Haz. mod. GMO --+ Food chain STO TTO --->
STO
G/i tract cell
--->
Lysed GMO Inactivated GMO GMO
G/i
Sewage cell
GMO
tract cell G/i tract cell Sewage cell
-->
Lysed GMO STO
Sewage cell
Sewage cell
y = 1 Q - 19
TTO
z = 10 -23 11 a = 10 b = 10 -2 d = 10 - 1 n = 10 - 1
Others
Lysed STO 11 c = 10 h = 1 0 - 14 1 v = 10 -
Sewage cell
Haz. TTO TTO
--+
Hazardous ITO
--+
Food chain
...,
� I: "'
!: �
$;:>,.
:::tl !;j ·
;.;-
). 1:! ., 1:! ::! ., :a.
�
t,
� '""c
�
$;:>,. I: "'
!;;'
1:1 ;::s $;:>,.
� ;:s '"' I:
::! ., .., ). R
5 Some Ethical Aspects and Acceptance of rDNA Products by Consumers
Fig. 15. Decision scheme
any rDNA product .
to ev aluate
5 Some Ethical Aspects
and Acceptance of r DNA Products by Consumers
One cannot d i scuss accep tan ce of rONA prod u cts without taking moral or ethical as pects into acc o u nt . In contrast to moral con siderations which are often based on emo tions, ethicists try to a na lyz e in a sc i en ti fic way the moral questions in detail and to for mulate standards for societies to re gula te their be h a vior . In a recent report for ICI STRAUGHAN ( 1 992) divided ethical concern towards 1 992 rONA technology in three groups: Modern biotechnology is blasp h e mous, unnatural and di sre s p ectfu l . The b l asp h e m ou s arguments are based on the view ·'God has created a perfect, natural order: for mankind to impro v e that orde r by manipulating DNA, the basic in gredi e n t of all
189
co life, t hereb y cro s sing species boundaries insti tu t ed by God, is not merel y presumptuous but sinful " . An a l yzing rONA t e ch nol ogy it is d iffi c ult to conclude that rDNA technology is b l asp h emou s as it is a careful and very limited imitation of what has been used by Nature to deve lop the richness of biological diversity we know at prese nt. Applying th e laws of ther m o d yn ami cs t o the tot a lity of living systems on ear t h , it can be forecasted that at l e ast as long as the so l a r energy s uppl y exceeds the energy necessary for maintenance of t h e t o t a l ity of living systems, new (higher) ordered structures will be created (MOROWITZ, 1 978) . Moreover , the horizontal and vertical fluxes of genes have created and will continue to c re a te novel forms of life. The most st ri k i n g ex a mple of a h o ri zon t a l gene flux in evol ut i o n is w it ho ut any doubt the transfer of gene t i c systems of archaebacteria i nto sp i ro c haete t h ere by formin g primitive e uk ary oti c cells having organelles like mitochondria (Fig. 1 6).
5 Structured Risk Assessment of rDNA Products and Consumer Accep tance of These Products
1 90
Tab. 14. Integrated Scheme to Evaluate Any rDNA Product
Entry, Actions and Results
A Not relevant to this scheme B. Evaluate the safety of the non-modified product
C. Stop evaluation procedure because evidence is insufficient D. Use approval systems for traditionally modified products E. Use adapted form of the scheme for newly defined chemicals (Fig. 8) F. Use normal approval systems for new pharmaceuticals G. Follow scheme for newly defined chemicals and the normal procedures for the approval of personal care products H. Use scheme for newly defined single food component (Fig. 8) J. Not relevant to this scheme K. Use scheme for products derived from animals (Fig. 9) L. Use one of the schemes for products derived from plants (Fig. 10) M. Use scheme for microbial products (Fig. 1 1 ) Questions
1. Is the product new or modified or does it contain a new or modified compound?
2. Is the product derived from a source (strain, variety, cultivar) or bred from an approved source?
3. Does the source contain a new trait ( = well defined genetic property/properties) obtained by rDNA
techniques?
4. Has the product or the new or modified compound been produced by a process that involves products 5.
6.
7.
8.
9.
10. 11.
produced by rDNA techniques? Is the product used as a pharmaceutical? Is the product used as a food? Is the product used for personal care? Is the product a single well defined compound? Is the product derived from animals? Is the product derived from plants? Has the non-modified product been approved?
�
Horizontal flux of genes --.
�
Protists
/
Primitive
t
Vertical flux of genes (genomes)
Fungi
Animals
Plants
Cyanobacteria
�
Spirochaete
Archaebacteria
Eubacteria
Fig. 16. Fluxes of genes and genomes during the evolution of Nature (L. MARGULIS, personal com munication).
Also external factors have influenced the creation of the present living systems as do
boundaries between species is weak. Al though the exact processes that resulted in
rONA technology in living systems, enzyme
most probably will remain obscure, circum stantial evidence is available that "natural
external
factors
at
present.
Without
any
systems have been created to adapt these cells
to the xenobiotics introduced by mankind (ALEXANDER, 198 1 ) . Finally the argument of
the formation of eukaryotes and eubacteria
boundaries" are rather a kinetic than a ther modynamic barrier. S ince evolution has been
5 Some Ethical
Aspects and Acceptance of rDNA Products by Consumers
going on for billions of years under quite varying conditions. even slow processes of transfer of genetic material from unrelated species will have occurred (see Figs. 2 and 16). Therefore. so-called natural boundaries can be considered more as an invention of biologists to divide the present biological world into often quite arbitrary groups. The second concern in ethical discussions is the "unnaturalness" of rONA technology. However, rONA technology is just applying enzymes deve loped during evolution for the purpose of changing DNA. The immune sys tem in mammals would not have been able to cope with the enormous number of foreign molecules, if it had not been based on cutting, joining and mutation of DNA sequences, in a superior but in principle similar way as mo lecular biologists do. It is very likely that in the near future it will be found that the im mune system is not the only system using in vivo methods similar to rONA technology. A candidate is the olfactory receptor system (R. AXEL, personal communication). In discussions rONA technology is often called disrespectfuL because it is perceived as "not to abide by the law as set (or perhaps as seen to be used) by Nature itself" . Another aspect of disrespect is that ··even if no rules as set by Nature are violated, it cannot be de nied that Nature has never been in the posi tion to organize itself against the interests of mankind on purpose and consciously, rONA technology enables man to do just that" . As such the argument that "Nature has never been in the position to organize itself on pur pose" is correct. However, it is not correct to introduce in the discussion on rONA technol ogy the argument that this technology will be used against the interests of mankind on pur pose and consciously. What is in the interest of mankind is a different discussion. The concern that rONA technology as such is "disrespectful"' cannot be counteracted by straight scientific arguments. STRAUGHAN ( 1 992) quoted the German philosopher KANT, who argued that "respect required treating others as ends, never only as means " . Accepting this view opens a rational way to discuss rONA t echnology. Applying rONA technology to c o r r ec t genetic diseases falls certainly within the category "ends"; howev-
191
er, using animals j ust as a means to produce rONA products is in KANT's view "disres pectful" . Until recently there has been no de bate on "ends" and "means" for plants and microorganisms. In fact, in ancient times the precursor form of our present civilization started with the cul tivation of plants and the use of microorgan isms to ferment many of these agricultural products to prolong the shelf life of these products. Since that time plant varieties have been selected and crossed to improve yield, to become resistant to certain harsh environ mental conditions, etc. Similar procedures have been followed to select the most appro priate microbial strains for fermentation pro cesses. Never in human history these proce dures (changes of the genetic makeup of these organisms) have been a subject of ethi cal discussions. Also in more recent times the work of MENDEL and PASTEUR on these pro cedures have in spite of tremendous influence on human life not been regarded by the pub lic as disrespectful. Of course they did not have any idea that in principle their work was based on manipulation of DNA. According to the criteria of KANT, the re sults of classical breeding can be seen as "end" and in line with that view no debates on the ethical aspects of traditional breeding have been held and traditional breeding is widely accepted in all societies. It is very diffi cult to understand that traditional breeding techniques are accepted as "respectful" and the much more precise rONA technology is considered as disrespectful. Having been in volved in various aspects of rONA technolo gy for nearly 20 years, I have noticed that mo lecular biologists are deeply impressed by the elegance of the solutions Nature has found to solve problems, and the vast majority of mo lecular biologists are very respectful to living systems. This respect is the driving force of numerous molecular biologists to unravel the way Nature works and to use this knowledge to find very specific and effective medicines, to ensure that agriculture will provide safe, nutritious and affordable food supplies for the ever growing population of this world and to ensure that the environmental problems created by this increase in population and the desire for a higher quality of life for the pop-
192
5
Structured
Risk
Assessment of rDNA Products and Consumer Acceptance of These Products
ulation of the developing countries can be met. Respect also means that certain types of rDNA experiments with animals and certain ly with humans will not be carried out. Often discussions on the ethical aspects of rDNA technology are blurred by risk aspects. As explained in the previous sections, this should be discussed separately. Provided that the necessary control experiments are done carefully (which should be checked by inde pendent bodies ) for nearly all approved ap plications of rDNA technology, it can be proved that the hazard is so small that it can be considered as zero as can the risk. For the average consumer to accept modern biotech nology it is very important that the risk is very low. In a recent survey in the U.K. the influence of the risk on the public acceptance of rDNA technology has been meas ured (Tab. 15). Tab. 15. Public Acceptability of Risks from the Re lease into the Environment of Genetically Engi neered Organisms
Risk Level Unknown 1:100 Unknown, but very remote 1:1000 1:10000
1: 100000 1:1000000
Approve (%)
Do Not Approve (%)
31
65
40
51
45
46
55 65 71
37 27 21 18
74
The prosperity of the present societies of Western Europe, USA, Canada and Japan are mainly based on the exploitation of scien tific discoveries and technological break throughs. However, besides these positive as pects the consumers in these societies have been confronted with a large number of un foreseen or neglected negative consequences of the application of these developments. Any discussion about the public acceptance of rDNA technology should take these posi tive and negative feelings of consumers into account. Therefore, it is essential that manu facturers estimate the benefits ve rs us ri sks for
new technologies or even for new products. In the case of rDNA products, it is obvious that the benefit of this technology for the de velopment of a new generation of very effec tive, precise medicines with minimal side ef fects is enormous. Nevertheless, the applica tion of rDNA technology for the develop ment of new medicines has not been accep t e d in all its aspects (e.g., gene therapy) , mainly because the communication with the consum ers has been insufficient and inadequate. The author is not aware of any systematic nation wide education program to teach students or consumers the benefits and risks of the var ious aspects of the application of rDNA tech nology. In an extensive analysis of the Dutch Institute for Consumer Research (HAMSTRA and FEENSTRA, 1989) only 57% of 1729 inter viewed persons knew the word "biotechnolo gy", and even of this 57% only 45% knew that insulin was made via biotechnology, whereas fewer than 10% of all interviewed persons knew that experiments are in pro gress on rDNA cells modified in such a way that they can inhibit certain forms of cancer. In a recent analysis done by the University of Strathclyde (U.K.) the p ublic was divided into seven specifically targeted subgroups. The attitude of the various subgroups towards biotechnology is extremely variable. As could be expected, certain applications of rDNA technology are not or hardly acceptable for the public: biological warfare (95% ) , chang ing the human physical appearance (84% ), cloning prize cattle (72% ), using viruses to at tack crop pests ( 49% ) and improving milk yield (47% ) . Medical applications are consid ered by most of the groups as acceptable (Tab. 16). Similar results were obtained in a Dutch investigation, although the acceptance of products made via rDNA te chn o l ogy that can contribute to an improvement of the envi ronment scores higher (HEIJS and MIDDEN, 1993). Labeling of products is only relevant if consumers are able to understand the infor mation on the label. According to the view of the FDA, labeling should not be based on the way a certain product is obtained. This is or should be part of normal approval for agricul tural practice or industrial processes, and if approved then labelin g is unnecessary. This is
6 Conclusions
193
Tab.l6. Attitudes to Applications of Genetic Manipulation Adapted from (A) MARTIN and TAIT (1992) and (B) HE!JS and MIDDEN (1993) Comfortable
Neutral
Uncomfortable
Microbial production of bio-plastics
(B)
91
6
3
Cell fusion to improve crops
Curing diseases such as cancer
(B)
81
10
10
(A)
71
17
Extension shelf life tomatoes
(B)
71
11
19
Cleaning up oil slicks
(A)
65
20
13
Detoxifying industrial waste
(A)
65
20
Anti blood clotting enzymes produced by rats
(B)
65
13 22
9.5
Medical research
(A)
59
14 23
Making medicines
(A)
57
26
(A)
54
25
13 19
Mastitis-resistant cows by genetic modification of cows
(B)
52
Producing disease-resistant crops
(A)
46
16 29
23
Chymosin production by yeast
(B)
43
30
27
39
31
29
(A)
23
26
49
Improving milk yields
(A)
22
Cloning prize cattle
(A)
30 18
47 72
(A)
4.5
(A)
1.9
9.5 12 2.7
84
Producing hybrid animals
Making crops to grow in the Third World
( A)
Improving crop yields
Using viruses to a\tack crop pests Changing human physical appearance
( A)
Biological warfare
common practice for near ly all food products, e.g., the label on a can of meat or fish never mentions that the
product
has received a heat
treatment equivalent to Fn of at least 5 (to en sure 12 decima l reduction of the risk of botu
lism), but the consumers trust the government to check the manufacturer of these cans. An argument against the view of t he FDA is that certain consumers are in
princi ple
against
a
certain technique and these consumers have the ri ght to know which technology has been
applied gy, but
a product. However, this is not restricted to rONA technolo
to produce
argument
applies to all types of technologies.
Without any doubt the label should contain
information on the contents of the produc t in order to inform the consumer. Therefore. it seems l ogica l that if a product still contains a foreign gene or gene product, it should be la beled. Accepting this view it is clear that also products derived from plants obtained via classical b re edi n g or products containing mu tated organ i s ms should be labeled. However. in view of the general ignorance of the public about biotechnology it is dangerous to label products containing rONA-derived products. Such labeling can repel consumers unneces-
7.2 4.5
sarily and can
15
31
82
95
therefore slow down considera
bly the introduction of this technology even for applications that
are
considered by the
public as desirable, such as reduction of the amount of chemicals used to protect crops.
6 Conclusions It is v ery
likely
the
most
become
that rONA technology will
important
technology
in the
first part of the 21st century, because this
technology will help us to unravel the secrets of Nature, and by doing so we can learn from Nature how to cope with diseases and large ecological problems, for Nature has frequent ly faced these problems and found magnifi cent solutions. Also for food products rONA wil l become an i mportant tool to reduce the use of chemicals in agriculture and energy and production of waste during processing. Moreover. rONA
will provide techniques
to
opt i m ize the quality of food products and in crease the naturalness of food products (VER RIPS, 1991 ) .
194
5
Structured
Risk
Assessment of rDNA Products and Consumer Acceptance of These Products
The risk related to the introduction of new rONA products should be assessed carefully. Always two aspects should be assessed sepa rately. Firstly, the intrinsic toxicological or eco-toxicological hazard of the foreign gene( s) and the construction methods should be determined. If the foreign gene codes for a harmless protein and the host organism is safe (recognized as functional organism in fermented food; see , e.g., Tab. 4 of DFG Mit teilung XI, 1 987) and all the aspects men tioned in Sects. 2.3, 2.4, 2.6-2.9 are carefully analyzed and no mistakes or unexpected events have been found, then the hazard of this transgenic organism can be considered as zero. In that case an assessment of the proba bility that the foreign gene present in the transgenic organism will be transferred into a wild organism is not necessary because what ever that probability is the hazard is zero, so the product of hazard· probability (=risk) is zero. Nevertheless, a risk assessment for the eco-toxicological consequence will have to be made. If the hazard analysis shows that the haz ard is not zero, e.g., in case of a pharmaceuti cal product that encodes for an inhibitor of an enzymic reaction in malignant cells of a cer tain tissue but this inhibitor will also be able to block this reaction in healthy cells of other tissues or even other species, a full risk assess ment should be carried out. The open ques tion is then what will be an acceptable risk. No definitive answers to this question can be given. In the food industry the acceptable risk of microbial spoila�e (in the order of one product unit in 10- ) is much larger than the acceptable risk of microbial poisoning (rang ing between about 10-6 for relative innocent poisonings to 10 -Iz for poisoning by botulin um toxin). Also the kind of hazard related to rONA products and the acceptable risk will be related to each other. Moreover, as was explained earlier in this chapter, the risk as sessment of GMOs will be more complicated than that of cell-free rDNA products, but the approaches are not fundamentally different. For medicines made via rDNA technology, even a third factor will become important in this risk assessment, notably the benefit of the rDNA product to cure severely ill people.
The most important aspect of legislation of new scientific developments is clarity. Only if clear legislation is in place, will the manufac turers or seed companies know exactly under which conditions a new discovery can be com mercialized and can they calculate whether their benefit versus cost ratio will be positive. Although improvements of the present legis lation are certainly possible and harmoniza tion of the legislation between the various countries is of great importance, in most countries there is legislation of sufficient clar ity to enable introduction of this technology. However, nearly all these legislations are based on the assumption that rDNA technol ogy is an intrinsically hazardous technology and, as described above, this cannot be justi fied by scientific data. Governments should educate their citizens (especially pupils at schools) to ensure that they really understand this new technology and are. able to make real choices. This is im portant for all new technologies but especially for rONA technology, as this technology is closely related to the most fundamental pro cesses of life. A better understanding of biol ogy will certainly result in a better acceptance by the consumers. Acknowledgement The author is grateful for the contribution of ESTHER KoK (Rijks-Kwaliteitsinstituut voor Land- en Tuinbouwprodukten (RI KILT-DLO), Wageningen, The Netherlands) for preparation of Table 8 and W. HoEKSTRA (Rijksuniversiteit Utrecht, The Netherlands), E . KoK (RIKILT-DLO), 0 . K O RVE R , W. MusTERS (Unilever Research, Vlaardingen), D. ToET (Gist-Brocades; at present Hercules, Rijswijk, The Netherlands), B. DE VET (Uni lever, Rotterdam) and A. WEERKAMP (NIZO, Ede) for the valuable comments on the manuscript.
7
FDA (Food and D r u g Administration) eral Register 57, No. 104, M ay 29.
7 References ACNFP (Advisory Committee on Novel Foods and
Processes) ( 1991 ) . in: Guidelines and the Assess ment of Novel Fo ods and Processes. Department
of Health, Re port 38. London : Department of
Health.
ALEXANDER, M.
(1981). Sci en c e 211, 132-138. G. E., KURLAND, C. G. (1990), Mi 54, 198--210. (1990). in: Introduction of Genetically
ANDERSSON. S. crobia/. Rev. ARBER, W.
O rganis m s
the Environment (MOONEY, H. A., BERN ARDI . G. . Eds.), pp. 1726, Scop e 44, New York: J. W i l ey & Sons. Modified
into
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Biotecllllology
Edited by ,H.-J. Rehm and G. Reed i n cooperation w ith A. Pu hle r and P. S tadler Copyright © VCH Verlagsgesellschatt m b H , 1 995
6 Strategic Regulations for Safe Development of Transgenic Plants
L. MEDLEY SALLY L. McCAMMON TERRY
Washington, DC 20090-6464, USA
I
Introduction I 98 Ch allenge 198 3 Identifiable Science-B ased Triggers 199 3.1 Policy 199 3.2 Science 200 3.3 Transparent Triggers 201 4 Effective and Responsive Regulations 203 5 Meeting Domestic and International Needs 207 5.1 Domestic Needs 207 5.2 International N eeds 207 6 Conclusion 209 7 References 210
2 The
1 98
6
Strategic Regulations for Safe Development of Transgenic Plants
1 Introduction In business, a strategic plan determines where an organization should be going. It is also used to assure that all organizational ef forts are pointed in that same direction. There is an old saying that "if you don't know where you are going, any road will take you there" (BELOW, 1 987}. For agricultural bio technology, strategic regulations are regula tions which provide a framework or process for actions that lead to consistent and plan ned results. Therefore, they are regulations that are developed and applied in a strategic manner. Strategic regulations are developed and applied in a comprehensive manner to avoid being one-dimensional or limited to a single issue focus. Although consideration of risk versus safety is of paramount importance, the regulations should also consider their im pact on other concerns such as product verifi cation/utilization, safe technology transfer, economic competitiveness, international har monization, and global needs/acceptance. Consequently, strategic regulations have a multi-dimensional focus. In our opinion, to ensure the best likelihood of success, strategic regulations should: (1) have identifiable science-based triggers that are consistent, eas ily understood, and transparent; (2} be effec tive and responsive as well as flexible and dy namic; and (3) meet domestic and interna tional needs.
2 The Challenge Biotechnology is an enabling technology with broad application to many different ar eas of industry and commerce. A recent re port by the Committee on Life Sciences and Health of the Federal Coordinating Council for Science, Engineering, and Technology, Biotechnology for the 21st Century: Realizing the Promise, Washington, DC., June 30, 1992, broadly defines biotechnology to "include any technique that uses living organisms (or parts of organisms) to make or modify prod ucts to improve plants or animals or to devel-
·
op microorganisms for specific use." The re port further predicts that, "by the year 2000, the biotechnology industry is projected to have sales reaching$ 50 billion in the United States." For American agriculture, biotechnology has the potential to increase productivity, en hance the environment, improve food safety and quality, and bolster US agricultural com petitiveness (OTA, 1 992}. However, if bio technology's vast potential, which is an out growth of substantial public and private in vestment, is to be of the greatest benefit, the development of appropriate and effective reg ulatory structures is a necessity. The 1970s and 1 980s in the United States have come to be associated with certain regu latory policy milestones for the development of modern biotechnology. The 1970s were as sociated with the concern over the safety of conducting experiments with recombinant DNA under conditions of adequate laborato ry containment. This led to issuance of the National Institutes' of Health guidelines for research involving recombinant molecules (NIH, 1976). The 1980s have been associated with concern over the safety of conducting ex periments using genetically modified organ isms outside of a laboratory in the environ ment. This led to issuance of the Federal Coordinated Framework for the Regulation of Biotechnology (OSTP, 1 986}. If the first three years are any kind of indi cator, the 1990s promise to be no less signifi cant in terms of their association with bio technology regulatory policy milestones. At the United States Department of Agriculture (USDA), a petition process has been final ized for removing transgenic plants from fur ther regulation (USDA/APHIS, 1 993}. The Food and Drug Administration (FDA) pub lished its policy statement on food derived from transgenic plants (FDA, 1992). The En vironmental Protection Agency (EPA} held an open meeting of the agency's Scientific Advisory Panel to assist in developing regula tory policy for plants genetically engineered to express pesticides (EPA, 1 992). Many of these new plant varieties will be available in the 1 990s. But their introductions will be un der circumstances unlike any met by other new plant varieties because of the technology
3
used to develop them. "Uncertainties over these new technologies raise questions of po tential impacts on food safety and the envi ronment, and possible economic and social costs. Nevertheless. there will be a push for . . . biotechnology .. . to be used commercially, adopted by industry. and accepted by the public .... The challenge. however, will be whether government, industry, and the public can strike the proper balance of direction, oversight and allow these technologies to flourish." (OT A. 1992. emphasis added). In ou r opinion. strategic regulations have the greatest potential for creating a frame work or process to meet this challenge. The following is a discussion of the Animal and Plant Health Inspection Service (APHIS), USDA. regulations for transgenic plants in such a strategic context.
3 Identifiable Science-Based Triggers One of the most critical and controversial decisions associated with the development of regulations is identification of scope. In other words, what organisms will be covered or what are the •·triggers·· for inclusion. We must guard against di fferent approaches to this is sue being inaccurately characterized as a con tinuation of the process-versus-product de bate. It is more appropriately characterized as a commitment by regulatory officials to the development of regulations that neither over regulate nor under-regulate. In the United States we do not know of any Federal agency which seeks to regulate based upon process only, independent of risk or uncertainty (MEDLEY, 1990). For biotechnology in the United States. this issue is best demonstrated by the publication of a proposed scope docu ment for regulation of biotechnology in 1990 and a very different final scope policy docu ment in 1992. (OSTP, 1 990. 1992). These two documents were very different and did little to resolve the scope debate or determine nec essary triggers for inclusion. Regulations which are strategic in their development can avoid this initial barrier by using triggers for
Identifiable Science-Based Triggers
1 99
inclusion that are consistent with adopted regulatory policies, based on sound science, and in themselves transparent.
3.1 Policy Industry analysts as well as academic scien tists have stressed the importance of US Fed eral programs and policies for the future of US biotechnology. particularly US Federal support for basic and applied research funda mental to the biotechnology industry (O L SON. 1986; ERNST & YOUNG, 1 992). The US Federal investment in biotechnology research for Fiscal Year 1994 is approximately 4.3 bil lion US dollars. An adjunct to the US Federal investment in biotechnology is the Federal commitment to promote the safe develop ment of products of biotechnology. Such a commitment requires that each Federal agen cy with authority to regulate such organisms and products implement risk-based regulato ry requirements. These regulatory require ments should assure safety and facilitate tech nology development and utilization by re moving regulatory uncertainty. The Federal policy for the regulation of biotechnology was proposed on December 3 1 ,1984 (OSTP, 1 984), and published in final form on June 26, 1986 by the US Office of Science and Technology Policy (OSTP 1986) . The Federal policy is referred to as the "Coordinated Framework for Regulation of Biotechnology." The OSTP concluded that products of recombinant DNA technology will not differ fundamentally from unmodif ied organisms or from conventional products. Therefore, existing laws and programs are considered adequate for regulating the organ isms and products developed by biotechnolo gy. The USDA policy on biotechnology was consistent with the policy established by the OSTP. USDA's policy document of Decem ber 1 984 stated that existing statutes were ad equate for regulating the products of agricul tural biotechnology, and further, that USDA did not anticipate that such products would differ fundamentally from those produced by conventional techniques (OSTP, 1 984, p. 50896). This position was reaffirmed in the fi,
200
6 Strategic Regulations for Safe Development of Transgenic Plants
nal policy document of June 26, 1986 (OSTP, 1 986, p. 23345). The current Administration has framed its policy objectives in President CLINTON's and Vice President GoRE's initiative, Technology for America's Economic Growth, A New Di rection to Build Economic Strength, February 22, 1993, White House, Washington, DC. In this document, the Administration stated, in relevant part, the following objectives: ( 1 ) We must ... turn . . . to a regulatory policy that encourages innovation and achieves so cial objectives efficiently; (2) We can promote technology as a catalyst for economic growth by . . . directly support ing the development, commercialization, and deployment of new technology; [and] (3) To improve the environment for private sector investment and create jobs, we will: en sure that Federal regulatory policy encour ages investment in innovation and technology development that achieve the purposes of the regulation at the lowest possible cost. These policy objectives are reinforced by Executive Order 12866 (Fed. Reg. 58, 5173551744, October 4, 1993) which states, in rele vant part: (4) In setting regulatory priorities, each agen cy shall consider to the extent reasonable, the degree and nature of the risks posed by var ious substances or activities within its jurisdic tion. (10) Each agency shall avoid regulations that are inconsistent, incompatible, or duplicative with its other regulations or those of other Federal agencies. ( 1 1 ) Each agency shall tailor its regulations to impose the least burden on society, includ ing individuals, businesses of differing size, and other entities (including small communi ties and governmental entities), consistent with obtaining the regulatory objectives, tak ing into account, among other things, and to the extent practicable, the cost of cumulative regulations. However, one of the most prominent and essential aspects of the Clinton Administra tion's biotechnology policy is the requirement that there be more public access to the Feder al decision-making process or as GREG SI MON, Domestic Policy Advisor to Vice Presi dent GORE, states "the importance of a regul-
atory system for biotechnology that operates in an open and fair way" (BROWNING, 1 993) .
3.2
Science
Strategic regulations for biotechnology should be developed and applied using sound science as a cornerstone. However, moving genes across natural barriers creates uncer tainty for some scientists as well as for society in general. A major question is: what consti tutes an "unreasonable" risk? Such risks nor mally fall into categories of risks to the food supply, human health, and the environment. Plant and animal pathogens are included as well as carcinogens. Thus, uncertainty is created in new cases or situations in which pa thogens are used as part of the process of de velopment and genes for pathogenesis are in serted into an organism. The scientific community itself does not appear to be of a single mind as to the rami fications to the environment of moving genes from non-sexually compatible species and from pathogens into plants. In particular, the scientific establishment does not agree on the types of risk and what is low risk. For exam ple, in 1 989, the report by the National Re search Council, Field Testing Genetically Modified Organisms: Framework for Deci sions, emphasized familiarity with the "prop erties of the organism and the environment" in order to make a determination of risk (NRC, 1989). The Council stated that "(f]a miliar does not necessarily mean safe. Rather, to be familiar with the elements of an intro duction means to have enough information to be able to judge the introduction's safety or risk." Enhanced weediness was cited as the major environmental issue with plants. With the addition of traits for herbicide tolerance or pest resistance, it was felt that crop plants would be unlikely to become weedy. Howev er, the report also stated that "genetic modifi cations of only a few genes can produce a modified plant with significant, ecologically important alterations". They stated that, for initial tests, confinement was the "key to min imizing the environmental impact to nontar get species" (NRC, 1989).
3 Identifiable Science-Based Triggers
In the same year. the Ecolog i c al S ociet y o f A me rica publish ed a p aper entitled ·The Planned I ntrod uct ion of G ene t i cally E ngi ne e red Or ganisms: E colo gical Considerations and Recommendations"' in which several fac
tors were rated for t heir level of concern in a risk evaluation (TIEDJE et al.. 1989). These included factors r e l a t ing to the ge n e tic altera tion. the p are ntal organism . and the p heno type of the altered organism. Factors such as a new gene function b e i ng introduced to the parent o rg a nis m . the source of the gene being from an un rela te d organ ism, the vector being fro m an unrelated spe cies or pathogen, and the p are n t be ing self propagating all wa rran ted scientific evalua tion. Other s c i e ntis t s have ra is ed concerns over the effects of i n troduc ing genes from plant path ogens into the plants themselves; espe ci ally . concerns about viral coat protein gene s and vi ra l nucleic acid recombination have been discussed (HULL, 1990; DE ZoET EN, 1991). It a l so appears to us t ha t the view that one ge ne change cannot cause a change in pa thogen e sis is an oversimplification. g iven reports in the literature (PAYNE et al . . 1987; WHEELER,
1975).
Therefore. strategic regul ations for bio technology biosafety reviews sh o u ld focus o n the scientific ques tions and the most efficient way of doi ng the re v ie w in the context of fa cilitating the safe application of t he biotech nologies. Thus. a cer t ifica t i on system for eval uating any safety issues wh ile the v a rie t y is being developed, preferably at the initial field te sting stage. is most appropriate (CooK. 1993). Science must be the basis of the decisions th a t address the concerns asso cia te d wit h t h e application of b i ot e ch n o lo gy to agri c u lture . A n e cess a ry role for re gu l a to ry officials is to frame the qu es tio n s and issues t h at science must answer. Science is t h e base by which regul a tory officials can as s u re and build upon cre d i bi l ity , remain cu r re n t . and assure a ra tional ba s is for decision-making. Science and process are in ext rica bly linked for stra te gic r e g ula tio ns that evaluate bi o l o gic al programs and p rod ucts . In the area of b i o tech n o l o gy re gu l a tio n. science without the process to frame the is sues becomes ov e rwh e l m i n g and m i s le adi n g .
201
while process w i th ou t science is r educed to being bureauc ra tic , self-serving, and ineffec tive . Neither science nor regul ation can afford to be in an all or none category. To a d apt to new i nfo rm at ion and new needs, both types of systems need t o work together to fr am e and address the c o n cerns and requirements of the many co m po ne nts of our society.
3.3
Transparent Triggers
It is not e no u g h that the triggers for stra tegic r e g ulat i ons be co n s istent with na t i onal bio tech nolog y po licies and are science-based, they m us t also be e asy to understand and id enti fy (transparent). S uch transparency is necessary to enable those r e gul a ted to clearly understand the r e gula tory requirements. Tra nspa rent regulations should remove re gul atory u n ce rtain t y , e s ta b lish p r edictable stand ards and a l l o w sa fe tech n o l ogy utilization and expanded development. For those that have concerns about the biotechnology activities b e i n g re g u la te d , it should provide a clear or t ranspa re n t window to observe and evaluate gove rnmen t a l o v e r si ght . A PH I S re gulations , which were promul gated pursuant to authority g rant e d by the Federal Plant Pest Act (FPPA), (7 U . S . C. 150aa-150jj) as amended, a n d the Plant Qua rant i ne Act (PQA), (7 U.S.C. 151-164a, 166167) as a mende d , re gula te the introduction (impo rt a tion , interstate movement, or release i nt o th e en vironment) of certain g ene ti cal ly e ngi nee re d organisms and products. A geneti cally e ngine e re d organism is deemed a regul ated article if eith e r t he don or or ganis m, re c i pi e n t o r ga nism, vector or vector agent used in e ngine ering the o r g anis m be lo ngs to one of the taxa listed in se c t io n 340.2 of the regula tions a nd is also a pl an t pest; if it is unclassif ie d ; or. if APHIS has reason to believe that th e gen e tic a l l y e nginee re d o r ga nism p re se n ts a plant pest risk . (7 CFR par t 340; see a l s o McCAMMON and MEDLEY, 1990). Prior to the introduction of a regu l ated ar ticle, a person is require d under section 340.1 of the re gula tion s to either (I) notify APHIS in accordance with se ct i on 340.3 or (2) ob tain a pe rm i t in accordance with section 340.4. Under sec tio n 340.4, a p e rm it is g ra n ted for a
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Strategic Regulations for Safe Development of Transgenic Plants
field trial when APHIS has determined that the conduct of the field trial, under the condi tions specified by the applicant or stipulated by APHIS, does not pose a plant pest risk. The FPPA gives USDA authority to regul ate plant pests and other articles to prevent direct or indirect injury, disease, or damage to plants, plant products, and crops. The PQA provides an additional level of protection by enabling USDA to regulate the importation and movement of nursery stock and other plants which may harbor inj urious pests or diseases, and requires that they be grown un der certain conditions after importation. For certain genetically engineered organisms, field testing may be required to verify that they exhibit the expected biological proper ties, and to demonstrate that although de rived using components from plant pests, they do not possess plant pest characteristics. An organism is not subject to the regulato ry requirements of 7 CFR part 340 when it is demonstrated not to present a plant pest risk (SCHECHTMAN, 1 994). A plant developed from a plant pest, using genetic engineering, is not called a plant pest, but rather a "regulated article". There has been misunderstanding as to the basic as sumption of APHIS regulations. The regula tions do not imply that part of a plant pest makes a plant pest or that plants or genes are pathogenic. The regulations instead have as a trigger that when plants are developed using biological vectors from pathogenic sources, use material from pathogenic sources, or pa thogens are used as vector agents, that they should be evaluated to assure that there is not a plant pest risk. For example, APHIS does accept that Ti plasmids used to transform plants have been disarmed. APHIS does a re view that allows a verification of the biology and procedures used; assesses the degree of uncertainty and familiarity, and allows the identification of any risks, should they be present and predictable. Vectors are evaluated because plant pa thogens are used to move genetic material into the plant (genetic materials from viruses and pathogens are used as promoters, termi nators, polyadenylation signals, and enhanc ers; and genes from plant pathogens are in serted to obtain resistance to these patho-
gens). Evaluation includes the verification of the removal of plant pathogenic potential of biological vectors so that pathogenic proper ties do not become part of the heritable char acteristics of new crop varieties. Strictly inter preted, concern is not over the use of viral promoters or disarmed Ti plasmids but over the elimination of genes for pathogenesis or unknown/non-characterized DNA. APHIS regulations do not assert that genetic traits would cause a plant to exhibit plant pest char acteristics unless the plant itself was already a pest to other plants. However, they do allow verification that (1) a disarmed plasmid was used, (2) genes implicated in plant pathogen esis did not become part of the heritable char acteristics of the plant, and (3) the introduced genetic material is inherited as a single Men delian trait, or lack of genetic stability of the new plant variety is not expressed by the plants in the field. APHIS has issued permits for field tests for plants containing various genes for insect to lerance, virus tolerance, fungal tolerance, her bicide tolerance, nutritional and value factors, heavy metal sequestration, pharmaceutical products, and selective markers. There are di rect implications of genetic factors on plant health and the effects of toxicants on benefi cial insect populations that are important to consider in evaluating impact on plants and the environment. The regulations would not be based on sound science if assertions rather than evi dence, or laboratory data alone, without field confirmation were used as the sole basis of decisions under the regulations. Molecular se quence information does not preclude the need for appropriate scientific evaluation and data collection in various environments in the field. The use of the technology itself poses no unique hazards, i.e., genetic material inserted into a plant via this technology will behave no differently than genetic material inserted via any other technology. The risks in the envi ronment will be the same; there is no evi dence that unique hazards in the use of rDNA techniques are present. The risk is in the genes interacting in a new genetic back ground and with an organism in a new envi ronment. In the case of the use of pathogenic
4
material that has been reviewed under the FPPA and the PQA. pathogenic genes could not be introduced into the heritable charac teristics of the plant without the use of the technique. Th e plant pest source of the genetic
material, not the techn ique. is the major basis for regulation .
4 Effective and Responsive Regulations The baseline for strategic regulations, simi lar to the baseline for a ny business. is whether the system is productive. i.e . . does it work. When applied. regulations should not only address any safety concerns raised about the use of the tech nology but also meet the needs of those being regulated. Some members of the academic research community had the following to say to fellow researchers about the effectiveness of the APHIS biotechnology regulations: .. our experiences with the permit process have been positive . We are all in agreement that the existent system is fast, friendly. and efficient. allowing us to concen trate our energy on experimentation rather than paperwork" (SHAW. 1 992 ) . I n addition t o being effective a n d respon sive, oversight in an area such as biotechnolo gy must be dynamic. flexible . and constantly evolving. Th is flexible and dynamic focus is needed because the technologies and their applications are rapidly evolving. The struc ture of regulations should assure safety and facilitate technology development and utiliza tion. Although regulations should be risk based, the purpose of regulation itself can be multifold and include: ( 1 ) safety: (2) product verification ; and ( 3 ) quality assurance. Regul ation is at the intersection of scientific risk as sessment and product evaluation and, in a new area like biotechnology. necessarily has to adjust and change rapidly with advances in both. AP H I S . like other U S Federal agencies . regulates the products of biotechnology un der i ts existing statutory authority. APHIS' broad historic authority to protect plant
Effective
and Responsive Regulations
203
health is applicable to the regulation of cer tain plants as well as microorganisms devel oped through biotechnological processes. Equally as important is the statutory and leg islative intent to empower APHIS (via the Secretary of Agriculture) to be the first line of defense in protecting US plant health. Hence , the statutes have built in flexibility to take those measures necessary to prevent di rect or indirect risks to plants (7 U.S.C. 150aa-jj ) . Almost s i x years have elapsed since APHIS first established regulations for cer tain transgenic plants. We are committed to assuring that our regulations are flexible and modified when appropriate to remove unne cessary restrictions or. if necessary, to add ad ditional ones. Flexibility of the system to ad apt based upon experience is essential for strategic regulations that enable the structure/ operation of the regulations to be most effec tive and responsive. Such regulatory systems should evolve and be well-designed. Thereby, strategic regula tions stimulate rather than frustrate or inhibit innovation. Strategic regulations provide op tions for the safe introduction and commer cialization of products of new technologies. They can stimulate private sector investment and innovation, while at the same time, re ducing regulatory costs and complying with environmental/safety concerns and man dates. APH IS, through strategic regulations, has attempted to develop a flexible regulatory structure that ( 1 ) evaluates on the basis of risk; (2) provides a means of specifying per formance standards as far as criteria for ex emption; (3) defines and documents risk or lack of risk; and (4) exempts regulated mate rial from oversight efficiently once evidence of lack of risk is presented. All procedures followed depend upon the i ndividual propo sal itself which the applicant submits and APHIS reviews. Therefore , this regulatory structure is applicant-driven which assures that design standards (rigid protocols) are avoided and performance standards empha sized. Our responsibility is to identify the risks and to make a decision as to their signifi cance. We have attempted to design a system
204
6 Strategic Regulations for Safe Development of Transgenic Plants
that evaluates the molecular biology and practices and knowledge from traditional ag riculture in order to document conclusions of safety or acceptable uncertainty. Under the APHIS regulations, our analysis compares the new plant line with previous varieties and crops in evaluating hazards. The initial stage of testing gives the most valuable information on the interaction of a gene in a new organism. The plant itself is the most sensitive test for the effects of a new gene in a new organism (e.g., assessing the in teraction of the trait, the plant, and the envi ronment). From 1 987 to 1 992, the primary regulatory option for the planned introduction of a transgenic plant was the permit. The regula tions stipulate that, once a complete permit request has been submitted, APHIS has 120 days in which to reach a decision whether to issue or deny a permit. The five major steps APHIS takes in this process are to: ( 1 ) evalu ate relevant information (both that submitted by the permit applicant and that gathered by APHIS from other primary and secondary sources); (2) notify and consult with regulato ry officials in States where the applicant pro poses to field test; (3) provide, through a gen eral announcement, an opportunity for public comment; (4) prepare a site-specific environ mental assessment; and (5) reach a decision as to whether to issue or deny the permit (McCAMMON and MEDLEY, 1 992). APHIS considers a broad range of infor mation for an environmental assessment, in cluding details of the biology and characteris tics of both the parent organism and the or ganism that provides the exogenous genetic material; factors associated with the modifica tion itself, such as whether or not gene se quences from a plant pest are used, and if so, how they have been modified to ensure they pose no risk of plant disease; the expected characteristics and behavior of the modified organism; and data concerning the environ ment in which it would be field-tested. Such information includes, for example, the loca tion and size of test plots, numbers of test or ganisms, nature of the nearby environment including the presence or absence of sexually compatible relatives, or the presence in the same county of threatened or endangered
species that could be impacted. On the basis of this analysis, APHIS decides whether or not to issue a Finding of No Significant Im pact (FONSI). If a FONSI is reached, a per mit is issued. If a FONSI is not reached, then the permit is denied, or issuance would be de ferred pending results of a more extensive analysis, known as an Environmental Impact Statement (EIS). APHIS has not yet declined to issue a permit for a field test because of failure to reach a FONSI. However, we have had applicants to either withdraw a submis sion for a permit based upon initial review by APHIS or not submit a permit request based upon pre-submission discussions with the APHIS scientific reviewers. After almost six years evaluating permits and considering the results of field trials un der permit, experience demonstrated that ca tegories could be defined for certain field tests that do not present plant pest risks, un certainty or significant agricultural safety is sues. Therefore, the type of regulatory analy sis described above for the issuance of a per mit was demonstrated to be unnecessary for such categories. General procedures already existed for ex emption of broad categories of organisms from regulation based upon scientific data, consistent with the internationally accepted definition for "case-by-case". That definition was adopted by the United States and other members of the Organization for Economic Cooperation and Development (OECD), and explicitly allows for exemptions based upon scientific data. "Case-by-case means an indi vidual review of a proposal against assess ment criteria which are relevant to the parti cular proposal; this is not intended to imply that every case will require review by a na tional or other authority since various classes of proposals may be excluded" (OECD, 1986). Many cases reviewed by APHIS are categorically excluded from coverage by the regulations. Some field tests are not reviewed or are reviewed only upon request. The increase in field trials in the United States of transgenic plants or plant-associated microbes in recent years has been explosive. In anticipation of dramatic increases, on March 31, 1 993, APHIS put in place two addi tional regulatory options, notification and pe-
4
became e ffectiv e on April 30. 1993. APHIS now has four options to facili tate the safe introduction of trans ge nic plants du ring research, development. and commer cialization : the organism is not a regulated ar ticle, a permit for movement or re lease, notif ication for mo vem e n t or release. and petition for removal from further regulation (USDA/ APHIS. 1 993). "Notification " and p e t i t io n o p tions pro vide for what a m o unts to s t rea m l ined re v iew o r e xe m pt i on from fu r th e r regu l ato ry review by APHIS. respectively. A field test con ducted under notification allows the appli cant. with A P H I S acknowledgement, to com mence a fi e l d trial wit h i n thirt y days instead of the 1 20 days re q u i re d under permit. Intro duction under notification ( section 340.3) re qui res that the introduction meets spec i fied eligi bi l i t y criteria and pe rfo rmance standards. The eligibility cr it e ri a impose limitations on the types of ge netic m od i fi c a t i on that qu a l ify for not i fi ca t i o n . and the p erfo rm an ce stand ards impose li m i t a t i ons on how the introduc tion may be c o nduc t ed The notification op tion is p re sen t l y restricted to fiel d tests of new varieties of six c ro ps : corn . potato. cotton . to mato, soy be a n and tobacco. A lthou g h it is expected that other crops will become e ligib l e for field tes t in g under the no tifi c a t ion option in the future, at the t ime t h is o p tion was ini tially ado pted these six crops captured ap proximately 85% of the field test permits be ing issue d The n otification o ption is further limited by p r e c l udin g certain ty p e s of modifi cations (e.g., those enc oding genes for phar maceutical co m po u n ds or from human or ani mal pathoge n s ) a n d re quiri ng field tests un der notification to be co nd u c t e d under speci-
tltJOn . which
"
··
.
.
.
.
Effective
and Responsive Regulations
205
fi e d p e rfo rm a n c e standards that am o un t to g eneti c containment (MEDLEY, 1 993) . Field tests not falli ng within these constraints may still be conducted under permit, as before. The petition option . for which the full term of art is "petition for determination of non re g ulat e d status.·· allows an applicant to re quest that APHIS decides whether a given transgenic plant or microbe should no longer be considered a regulated article. The dete r mination is, as with a permit, based on infor mation provided by the app l ica n t which is considered with other information collected by APHIS. Once a p e ti t ion is ap p rove d by APHIS there is no lon ger any need for APHIS review or approval for in t roduct ion of the article into American a gricu l t ure or com merce (MEDLEY, 1 993). If food safety, pesti cide or other regulatory questions remain, however, the man d a to ry requirements of rel evant regulatory agencies, such as the FDA, EPA. and USDA's Food Safe t y a n d I nsp e c tion Service, must be met. From 1 987 through 1 993, there h ave been 674 field tests of tra n s geni c plants or plant associated microbes approved by APHIS in the United States. Of these field tests 47 1 were conducted under permit, and 203 under n oti fication at 1 739 sites. These sites have been located in 42 of the 50 States (most oft en in California, Illinois, and Iowa) , and Puerto Rico. These n umbers reveal a substantial amount of research and de ve l opm e n t activity. The vast majority (85% ) of activities are being carried out by commercial entities Academia ranks second, with 1 1 % and the Agricultural Research Service (ARS) of the USDA third with 4% (see Fi g. 1 ) . ,
.
,
= 27 (4. 0%) ,- LJinfvl!rs/,Ues = 72 ( 1 0. 7%)
' "'""' ' u"''-'"'
Fig. 1. Source of applicants for biotechnology re lease permits 1 987- 1 943.
Commercial
=
575
206
6 Strategic Regulations for Safe Development of Transgenic Plants
Of the 34 crops or plant-associated mi crobes that have been field tested, by far the largest category has been new varieties of maize (corn), at 1 67. Soybeans and tomatoes are second and third, with about one hundred each, followed by the other crops presently eligible for field tests under notification, to bacco being lowest, at 35. The next two crops most often field-tested in the United States are cucurbits (melons or squash) and rape seed, at 28 and 20, respectively (see Fig. 2).
The largest category is for crops with im proved weed management qualities based on herbicide tolerance, comprising 32% of all field tests. This is followed by crops variously mod ified to resist losses to insect pests (most often by addition of the gene encoding the insectici dal protein derived from Bacillus thuringien sis), a category that embraces 21% of crops field tested. Modifications for resistance to vi ral diseases follow at 19% , and improvements to product quality at 16 percent (see Fig. 3).
Com Soybean Tomato Potato Cotton Tobacco
Melon & Squash
==-79 0
Rapeseed
Alfalfa
8
5
Clavlbacter
Rice
Pseudomonas Cucumber Xanthomonas Walnut Sunflower
F"iJ:. 2. l " y p l' ' ol p l a n t s a n d
Lettuce Sugarbeet
m i noorga n i s m s a n d n u m b e r
Apple
Poplar
o l p � r m i l s i " u l' d a n d o f no
0
Herbicide Tolerance = 1 7&
50
100
150
200
t i fi c a t ions a .: k nowll'dgcd l lJl\7 - l lJlJ_� _
(32.5�
*
Fig. 3. Gene-phenotype summary of permits issued and notifications acknowledged 1 987-1993. *
**
Metabolic characteristics, modified ripening, oil modification, seed protein starch/solid increase, wheat germ aggl utinate. Markers, male sterility, chiA, chicken lysozyme, DHDPAS, Rhyzobium R and C1 transcript activator (courtesy), tn5 (marker), tmr, transposable elements, pharmaceutical products, plant stress tolerance.
5
5 Meeting Domestic and International Needs Strategic regulations should provide a pro cess by which domestic and international needs are met. A coordinated procedural and scientific review of field testing and develop ment assures that plant products are develop ed, commercialized, and accepted. Regula tions must not only assure safety, they also must provide a framework for evaluation and technology transfer. This framework includes the initial phases of testing, the developmen tal phases, commercialization, and interna tional harmonization of evaluation. This will contribute to flourishing industries, global ac ceptance and use, and creation of jobs.
5 . 1 Domestic Needs To meet the domestic challenge, regula tions must take into account needs of the States, other Federal agencies such as the EPA and the FDA, as well as those of the public, including academic, consumer, envi ronmental, and industry groups. The regula tions must remove uncertainty and allow de velopment and utilization through document ing informed decisions and evolution based upon experience. The notification and peti tion regulations evolved because of docu mented experience with the field testing of certain crops. Domestic needs have been served through several avenues. USDA has developed a user-friendly system through publishing a User's Guide (USDA/APHIS, 1991), giving examples of applications for importation, movement, and release. Applications can now be submitted as well as processed, and per mits issued, via computer technology. Deci sions for release are based on information from workshops bringing together experts from various fields and affiliations (McCAM MON and DWYER, 1990; KEYSTONE, 1990). Federal Register notices alert the public to op portunities to comment on specific decisions. For example, prior to the decision to propose the notification and petition amendments to
Meeting Domestic and International Needs
207
the APHIS regulations, the Agricultural Bio technology Research Advisory Committee (ABRAC), in an open forum, reviewed the scientific basis for proceeding with a notifica tion and petition process based upon docu mented experience with traditional and gene tically engineered crops. Additionally, prior to the adoption of the rule amendments, com ments were solicited from the general public (FDA, 1992). Coordination across agencies is a necessity as agricultural, environmental, and food safe ty issues arise and as products develop. The decisions by one agency should support and build upon the decisions required by other agencies. The decisions required by the im plementation of these biotechnologies cut across the traditional responsibilities of sev eral regulatory jurisdictions. This requires an unprecedented integration of the entire deci sion-making process in order to assure that safety is assured, duplication is avoided, and the entire infrastructure is effective. In a democracy, multipartisan support must be achieved in order to proceed wisely. Thus, industry, the scientific community, domestic regulatory groups, non-governmen tal organizations and other public interest groups, all need to be involved as systems and policies evolve (OTA, 1 992). Regulations should allow decisions to be made in a trans parent manner and these decisions must be informed. Data and input must come from many perspectives. The questions do not eas ily distill into "either/or", "right/wrong", "yes/ no". Decisions of safety will not necessarily be the final answer, but these informed choices will be made on the basis of the best science available, and the process will be car ried out in the open.
5.2 International Needs The types of domestic concerns associated with the development of transgenic plants will most likely be the same types of concerns identified internationally. Due to the univer sal nature of such questions and concerns, products approved under strategic regulations should be generally accepted internationally. International harmonization will occur
208
6 Strategic Regulations for Safe Development of Transgenic Plants
through compatible regulatory systems that allow reciprocity of evaluations of safety. In ternational harmonization of approaches to commercialization means that ''equivalent"" approaches will be use d i n different countries. In this context . equivalent means "equal"' . not "the same ··. Facilitation of international trade , the prevention of trade barriers, and harmonization of international systems are all important results of a coordinated agreement as to approaches to review. Therefore . the strategic application of our USDA regula tions has required that we focus on ( 1 ) inte gration of compatible national approaches; (2) coordination of national approaches; and (3) assurance that scientific principles are used for evaluation of organisms (MEDLEY. 1 99 1 ) . A general process that can cover the needs of all countries for the use and regulation of biotechnologies ba se d upon the technique or the final product alone is unlikely. The infra structure . legal systems, types of products and testing, and other specific issues will be differ ent for each country and region. The biotech nologies will i m ple m e n t already e x i s t i n g needs, conventional goals, and production re quirements. The biotechnologies will affect agriculture in various ways through plant products that enter or are tested i n develop ing countries; through technologies that are used to develop products and commodities for local consumption or export: through ex port of products and commodities from the country; and through using the technologies to identify genetic resources and understand biological and ecological systems. The appro priate application of the biotechnologies will vary from country to country. Thus . internationally it would be difficult to develop a general document addressing procedures for e v a l u a ting the se products. Such a document would most likely result in the least common denominator being accept ed and would be the most restrictive. Thus. international agreement on the general issues for prod ucts has been and will continue to be the most useful approach. International agreement on consistent and compatible approaches for review should fo cus on the scientific questions and the most efficient way of doing the review. I nternation-
al agreement on the general issues for evalua tion is essential for transfer of the technology to developing countries and for acceptance of commodities and products in international trade. In the Americas. the I n ter-American I nstitute for Cooperation in Agriculture and the North American Plant Protection Organi zation have been forums for discussion of a wide range of issues relating to biotechnolo gy. The United Nations Organizations have also hosted many discussions. Recently, the scientific approaches to the evaluation of plants. and especially transgenic plants, have been developed internationally in the Organi zation for Economic Cooperation and Devel opment (OEC D ) I nternationally, several different venues h ave looked at and coordinated the ap proaches developed in each country based on scientifically identified issues. The United States frequently meets in bila teral discus sions with its t r ad i n g partners, Canada and Mexico, as well as with the European Com munity ( n o w : European Union, E U ) The de cisions and experience developed by one country should support and build upon the decisions required by other countries. Re cently, the USDA published its notification and petition procedures (USDA/APHIS, 1 993). This was followed soon after by the EU Simplified Procedures (EEC, 1 993) and the U nited Kingdom's " Fast Track Guide lines" (DOE/ACRE, 1 994). Each of these documents uses information that builds upon both local and international experience. These procedures will facilitate international harmonization based upon experience. Within the OECD, several documents re lating to the scientific principles underlying the safe use of genetically modified organisms have been developed. These have included documents on en vironmental testing of plants and microorganisms, the industrial use of mi croorganisms, food safety, and monitoring of these organisms in the environment. The process of developing these documents re quires the consensus of the member govern ments at each stage in the development of a document. Evaluation of initial field tests of transgen ic plants was treated by the O ECD in "Good Developmental Pr inci ples (GOP): Guidance .
.
6
for the Design of Small-Scale Field Research with Genetically Modified Plants and Micro organisms" (OECD, 1 992). GDP showed the rationale by which initial field tests could be evaluated and carried out safely. This deter mination is based on evaluating the plant, the site , and the agricultural practices. The next document, treating the develop mental testing of a potential new plant varie ty, is called "Scientific Considerations Per taining to the Environmental Safety of the Scale-up of Crop Plants Developed by Bio technology" (OECD, 1 993a). Scale-up in cludes performance trials, advanced tests, demonstration trials, yield trials, and seed in crease. The "scale-up" document shows how an evaluation is made to move from small scale tests to developmental-scale tests for crop plants for traditional uses such as food, feed, fiber and flowers. The emphasis shifts from containment to identification of envi ronmental issues. The environmental issues for crop plants can be framed, defined, and analyzed using the combined expertise and approaches of breeders, agricultural scien tists, and regulatory scientists. These environ mental issues are relevant at any scale. The issues will be the same no matter what the stage of the planting, whether initial tests, de velopmental tests, or commercial plantings. However, their probability of occurrence in creases with increasing scale. Familiarity with the host plant, the environment, and the trait is the basis for this analysis. When transgenic plants were first being reviewed, they were being defined as exotic organisms in some countries. This document provides the basis for viewing transgenic plants as familiar or ganisms with a new trait. Essentially, the basic premise of the "scale up" document is that plant breeders have a tremendous amount of knowledge about how crop plants behave in the environments in which they are grown and also can identify is sues of concern to agriculture, the agricultural environment, and the surrounding environ ments. However, plant breeders have not documented this knowledge previously in terms of safety. The "scale-up" document and the companion document "Traditional Crop Breeding Practices: A Historical Review to Serve as a Baseline for Assessing the Role of
Conclusion
209
Modern Biotechnology" (OECD, 1993b), which describes the characteristics of and ag ricultural practices used with 17 agricultural crop plants, treats the issues of safety on the basis of our familiarity with these crop plants. The commercialization phase of transgenic plants is now occurring. To assist in address ing commercialization issues, the USDA has funded a position for a consultant to work with the Environment and Agriculture Direc torates in OECD. The consultant is working on a project which will compare the different policies of the OECD member countries to wards development and commercialization of transgenic plants. The project will also ex plore ways that these new varieties will move into the traditional systems of seed certifica tion and variety registration. The point at which food safety issues are evaluated will also be compared.
6 Conclusion President CLINTON's technology initiative, articulated in the February 22, 1 993, Report Technology for America's Economic Growth, A New Direction to Build Economic Strength stated that investing in technology was neces sary for progress into the future and that this investment would require several compo nents. The report emphasized that although the transitional Federal role in technology de velopment has been limited to research initia tives, Government can play a key role in helping private firms. This can be accom plished while assuring a Government that is more productive and more responsive to the needs of its citizens. The report further stated that "regulatory policy can have a significant impact on the rate of technology develop ment in energy, biotechnology . . . regulatory agencies can affect the international competi tiveness of the industries they oversee . . . skillful support of new technologies can help businesses reduce costs while complying with ambitious environmental regulations". After the seemingly endless debates of the 80s, the Clinton Administration hopes to use
210
6 Strategic Reg u la tio ns for Safe
De�·elopment of Tran sgenic
the 90s to deve lop a regime for commercializ ing biotechnology products. a regime that is reassuring to the public. predictable and ex peditious for industry and free of unnecessary political h u rdles (SIMON . 1 993). Strategic reg ulations can assist i n achieving these goals by (1) having identifiable science-based triggers that are consiste nt, e asily understood. and transparent: (2) being effective and respon sive as well as flexible and dynamic: and (3) meeting domestic and international needs. Ack nowled gements
To Dr. VAL GIDDINGS for analysis of data on field tests. and Mr. CLAYTON G I V E N S for preparation of charts. Disclaimer
93/584/EEC. Commission Decision of 22 Octo ber 1 993 establishing the criteria for simpli fied procedures concerning the deliberate release into the environment for genetically modified plants pursuant to Article 6(5) of Co u ncil Direc tive 901220/EEC, Off 1. Eur. Commun. L279, 42-43.
( 1 992), Su bpan el on Plant Pesticides. Fed. Reg. 57, 55531 . E R N ST & YouNG. San Francisco ( 1 992), Biotech
EPA ( Environmental Protection Agency)
FJFRA Scientific
Admi nistrator
a nd Science Advisor. respec tively. APHIS. USDA. The views expressed in this chapter are those of the authors and do not necessarily represe n t those of the Uni ted States Government.
A dvisory Panel -
'93: A ccelerating Commercializ ation , September
1 992: and Biotech tember 1 99 1 .
'92:
Promise
to
Reality,
Se p
and D r u g Administration) ( 1 992), Policy: Foods De ri ved from New Plant Varieties: notice, Fed. Reg. 57, 22984-
FDA ( Food Statement
of
23005 . HULL R.
(1990) ,
The use and misuse of viruses in
cloning a nd expression i n p l ants , NA TO A S/
Ser. 41,
TERRY L. MEDLEY . J . D .. and SALLY L. McCAMMON . PH .D. . are Acting Associate
Plants
443.
Keystone , Colorado. ( 1 990) . Workshop on Safe guards for Planned Introduction of Tran sgen ic
Corn
and Wheat,
Confe rence Report.
McCA M M O N , S . L. . DwYER, S. G. (Eds . )
(1 990), Workshop on Safeguards for the Planned Intro duction of Oilseed Cru cifers , Proceedings, Cor n e l l U niversity, I t haca, NY, 33 pp. McCAMMON, S . L., MED LEY T. L. (1 990), C e r t ifi cation for the planned introduction of transgenic plants into the environment, in: The Molecular and Cellular Biology of the Potato (VAYDA, M . E . . PA R K W . D . • Eds . ) , p p . 233-250, Walling ford, UK: CAB I nternat ional.
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Hooso N . R .. L E N S K I , R. E .• M A c K , N . , REGAL,
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WH E E L E R , H . ( 1 975 ) , Pla n t Pathogenesis, New York-Heidelberg-Berlin: S pringe r - Verlag, 106 pp.
Industry
National Academy of Sciences.
Washington. DC: N a t i onal Acade my Press.
OSTP ( O ffice of Science and Tech nology Policy)
( 1 984). Proposa/ .fiJr
produci ng
cient in PLe. J.
OECD ( Organ ization for Economic Cooperation and Development ) ( 1 992 ) . Good Dn·elopmental
cations
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National
Recombinant DNA
Safety Considerations. 69 pp .. Paris:
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plant tissues of
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H . ScHOEDEL. C.. K E E N , N. T., COLL A . ( 1 987) , M u ltiplication and virulence i n
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pectate lyase isozymes PLb and PLe a t high lev
Washington. DC: Nat ional
Acade m y P re ss 1 70 pp. OECD ( Organization for
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Pl a n t Health I nspection Se rv ice ( 1 987), Introduction of Orga n ism s and Products
A ltered or Produced through Generic Engin ee r ing which are Plant Pests or which there is Rea son to Believe are Pla nt Pests, Fed. Reg. 52,
of Science and Technology Policy)
22892-229 1 5 . U S D A/APH I S ( U S Department o f Agriculture/
( 1 986) . Coordinated Framework for Regulation of Biotechnology: A nnouncement of Policy and Notice for Pu blic Comment. Fed. Reg. 51, 23302-
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o l Science and Technology Policy )
Exercise of Federal Oversight wirlrin Scope of Sraw rorv A u thority: Planned lntroduc thms of Biotechnolog v Products imo the En l'i ron mem. Fed. Rt.•g 57. 6753--6762. ( 1 992 ) .
OT A (US Congre ss. Office of Technology A ssess me n t ) ( 1 992 ) . A New Technological Era .for A m erican A griculture, O TA -F--174. Washington. DC: US Government Printing Office .
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and
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Department of Agricult ure/
Animal and Plant H e alth I nspection Service ) ( 1 993 ) Genetically Engineered Orga n isms and .
Products: Notification Procedures for the Intro duction of Certain Regulated A rticles; and Peti tion for Nonreg u la ted Status: Final Rule, Fed. Reg. 58, 1 7044-- 1 7059.
BioteclltloloKJ'
Ed ited by .H. -J. Rehm and G. Reed i n coop eration wit h A. P u h l e r and P. Stad ler Copyri�ht © VCH Verla�s�esellschatt m b H , 1 995
7 Biomedicinical Product Development
}ENS-PETER GREGERSEN Marburg, Federal Republic of Germany
General and Commercial Aspects of Biomedicinal Product Development 2 1 4 1 . 1 Product Development Follows Different Rules than Research 2 1 4 1 . 2 Commercial Chances a n d Risks of Pharmaceutical Development 2 1 4 2 Market Research 2 1 6 2 . 1 Creative Market Research and Other Valuable B ackground Information 2 1 6 2.2 The Product Profile 2 1 8 3 Registration Requirements 221 3.1 Three B asic Elements 221 3 . 1 . 1 Quality 222 3 . 1 . 2 Safety 222 3 . 1 .3 Efficacy 223 4 Tech nical Aspects of Product Development 224 4.1 Process Dev e lo p me nt and M an ufacturi ng 224 4.2 Analytical Development and Quality Assurance 226 5 Planning and Managing Product Development 228 5 . 1 Risk-Oriented Planning 229 5 . 2 Product Development Phases 230 5 . 3 Decision Making 232 5.4 The Project Manager 234 5.5 Organizational Structures and Motivation 235 6 References 236
214
7 Biomedicinical Product Development
1 General and Commercial Aspects of B iomedicinal Product D evelopment 1.1
Product D evelopment Follows
Different Rules than Research
Product development for biological phar maceuticals might appear as a simple contin uation of a research project after a sufficiently effective compound has been identified. From a scientific point of view there is no clear dis tinction between research and development. Until the clinical phase, product development utilizes the same basic skills and methods and - to a great extent - the experience of the same people who did the research. However, the rules change considerably as soon as in novative research turns into conservative test ing of quality, safety, efficacy and into analyti cal and process development. The decision to develop a pharmaceutical product transfers an active principle or com pound from the resource-limited research la boratory into a new environment, the stage of development. In a multi-disciplinary ap proach the compound is subject to a variety of analytical, pharmacological, toxicological, and clinical tests and trials. From now on methods, results, documentation and the ma terials created are under strict scrutiny ex erted by the developing organization itself and finally by several authorities. Research activities are hardly ever subject to such sur veillance and control concerning, for exam ple, the precision and consistency of methods and results. It usually takes time for a re searcher to fully acknowlewdge and accept this fact. Since there is no clear distinction between the research and development phase, projects frequently move into development while the people involved are unaware of the changed rules. This may result in neglecting essential aspects, in extra cost for the repetition of crit ical studies and in a considerable loss of time.
In larger organizations research and prod uct development are usually separated in dif ferent units because of the fundamental dif ferences between creative research and syste matic, goal-oriented development and be cause development requires special knowl edge and experience. In the field of biological pharmaceuticals, however, most companies and organizations are relatively small, since they traditionally operate on a national scale. They do not have several products under de velopment which are subject to a similar de velopment scheme. The methods are more complex, and the materials created in the re search phase are directly passed on for devel opment. Furthermore , biotechnological prod ucts are still in their infancy, and pharmaceu ticals from biotechnological processes are not yet routine products. Thus, there are many reasons why researchers in these areas in in dustrial and non-industrial research organiza tions contribute to or perform product devel opment. These scientists need to know more than j ust their science to understand their new task. The general aspects of biomedicinal prod uct development presented in this chapter are meant for researchers and scientists who are less experienced in product development. This chapter is also meant to prevent the oft en observed overly ambitious ideas about the commercialization of research results. Un realistic expectations about the simplicity and duration of development may lead to inap propriate management decisions, which may even endanger the future of research oriented enterprises. The success of biotech nology ventures does not only depend on good research but also on a realistic assess ment of the potential products and on the ability to adopt the required skills to effec tively develop research results into commer cial products.
1 .2 Commercial Chances and Risks of Pharmaceutical Development
Pharmaceutical development is expensive , and the risk that the project fails during this
1 General and Commercial A spects of Biomedicinal Product Development
process i s high . T h e following facts a n d fig ures may illustrate the costs and risks that may be expected. Although these figures do not differentiate between research and devel opment and are not specific for biological pharmaceuticals (they represent mainly chemical entities for human drugs ) , the gener al picture is similar for all types of pharma ceuticals, and the i mplications for product de velopment are essentially the same. The average capitalized cost to develop a human pharmaceutical product in the USA amount to US $ 231 million ( D I M A S I et al., 1 99 1 ) . Comparable figures for 1 982 are US $ 9 1 million (LANGLE and 0CCELL I , 1 983) and for the time between 1 963 and 1 975 US $ 54 million (HAN S E N , 1 979). On one hand, these considerable increases in cost, which tended to double within ten years, reflect the increas ing difficulties to find new and commercially attractive drugs, since these figures include the cost of aborted projects. On the other hand, a substantial part of the rising cost is due to the increasing regulatory demands which must be met to achieve marketing ap proval. The average time to develop a newly dis covered compound i ncreased continuously over the past decades from less than 4 years in 1 960 to more than 1 0 years in 1 989 (KARIA et al . , 1 992). A s a consequence, the average effective patent protection for human and an imal health products approved i n the USA between 1 984 and 1 989 was only 10 years and 7 months, including the possibility of restora tion of patent terms for medicinal products of up to 5 years (V A N G ELOS, 1 99 1 ) . Longer de velopment times automatically reduce the ef fective patent protection period and thus sig nificantly influence the revenue expectations. Despite the sharp increase i n development cost, the number of new products launched and their sales expectations remained fairly constant (LU MLEY and W A L K E R , 1 992). It has been calculated that i n the UK even the best selling 1 0% new drugs require longer than the effective life-span of their patents to recover the research and development cost; the majority of new pharmaceuticals cannot recoup these cost even after more than 20 years (PRENTIS et al., 1 988) .
215
Comparable figures with reasonable validi ty for animal health products are not availa ble. Veterinary product development cost are definitely lower, but the revenues are also much lower. Due to rising registration de mands, influenced by both the pharmaceuti cal and the agricultural sector, veterinary product development cost follow the same trend as human health products. In general the animal health market has stagnated since 1 980. The international com petition has increased, and the more produc ers of biologicals and vacci nes try to interna tionalize their products and sales in order to outbalance the price erosions by growth in sales volume. Whereas vaccine producers in the USA have been rather successful to pene trate European markets, European vaccines were prevented from access to the lucrative US market due to concerns about potential adventitious agents i n these vaccines (e.g., FMD , BSE). At the same time European vet erinary vaccines have to comply with increas ing regulatory demands and the introduction of GMP (Good Manufacturing Practice) standards. Relatively few really new and attractive products have been introduced in the animal health care market. The recently developed new and expensive human therapeutics do not play a major role in animal health care. Prophylactic vaccines against the major en demic diseases are already avai lable and are difficult to improve for a competitive price . Several other interesting vaccine candidates are stuck in the research phase due to unsur passable difficulties to achieve sufficient effi cacy. The contin uing high interest and invest ment in pharmaceutical research cannot be attributed to guaranteed high revenues. Re turn on assets - a commonly used measure of industrial profitability - for the eight most successful health care companies in the USA in 1989 was approximately 16% , or 1 1 % if re search and development expenditures are in cluded as gross assets for better comparability with other, less research-intensive industries ( V A N G ELOS, 1 991 ) . It seems that the general perception of high profits is strongly influenced by the com mercial success of a few ''blockbuster" prod-
216
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Biomedicinica/ Product Development
ucts such as the H2-receptor antagonists, iver mectin or the recently launched erythropoei tin. These are the exceptions, whereas ex tremely hopeful candidates, rendering very moderate success, seem to be more the rule. The pharmaceutical industry is much more research-oriented than other industries and has to cope with higher risks. Due to the high development cost and long development times, risks must be eliminated as early and consequently as possible. Risk elimination must already start in the research phase and before the expensive industrial development commences. High-risk research projects need much time, thus they must be kept small and have to focus only on the major risk factors. Research projects should be clearly separated - if not physically, at least in mind - from the more rigid and much more expensive devel opment. Once an attractive product has been iden tified, the time factor becomes extremely im portant; risk and cost are no longer the only relevant criteria. From now on speed and effi ciency are of paramount importance. A minor planning error which results in a delay of a task on the critical path for only one month can delay the entire project by one month. Almost inevitably it also adds 1/12 of the an nual budget to the development cost. Thus, in a project with an average annual budget of $ 2.5 million, a delay like this can cost more than $ 200 000. Apart from these direct cost, later access to the market can cause much higher losses.
2 Market Research 2.1 Creative Market Research and Other Valuable Background Information
According to a study Management of New Products by Booz, ALLEN and HAMILTON conducted in 1 968, on average about 70-90% of the money spent in research and develop ment of new products is used for products which are failures. No industrial organization
would commit itself to an applied research or development project without investigating the general and market situation to reduce this failure rate. There is no reason why publicly funded research projects should not do the same. Starting a project without such an as sessment means being more concerned about doing the project right than doing the right project. Researchers (in academic institutes as well as in industry) tend to view market research in a very narrow sense. They do not perceive the potential of the approach, thus missing in novative ideas. Market research may, in fact, bring research ideas back to the earth and help avoid major mistakes. If used with a wider perspective and by a creative mind, it can help identify interesting options. Market research should add information and use it for a better assessment of chances, risks and options. It should not be used to reduce the project idea to a few simple figures. The use fulness of market research depends a good deal on intensive interaction between re search and marketing and information ex change in both directions. A basic assessment of important market and other environmental factors does not neccessarily require marketing experts. But if their advice is sought, it should be by an inter active process, not by presenting the idea for a verdict. During this process the marketing expert will probably identify the weak spots of the researcher's proposal. With reasonable background information the researcher (who else?) should also be able to recognize and understand the subjective assumptions (i.e., weaknesses) of the marketing expert's assess ment and to challenge them where adequate. The problem is that the additional informa tion usually requires changes of the direction or the priorities of the project. Unless there are very convincing arguments, a researcher who is convinced of an idea is unlikely to con sider such changes. The most convincing ar guments are those which are developed from one's own considerations. Thus, researchers should do their own market assessment to de velop an opinion about the chances, risks and best applications of their approach. (If they don't like the term market assessment, they
2 Mark et Research
may call it "SPA for "strategic project as sessment'' if this sounds more rep � table . ) One needs n o special skills t o identify the ma jor threats to and opportunities for a project. These are usually rather obvious. if some ba sic i nformation is available and i s considered critically. At the beginning it must be kept in mind that it is very easy to define an "ideal prod uct" . B ut this ideal product is probably the most difficult one to develop or may be an unrealistic development target. Sooner or lat er it pays off to have identified all the options, including the lesser ones with a higher proba bility of success. Of course , the optimal prod uct may be chosen as the aim of the project, but minor options should be included in the planning as a fall back position. The more detailed the collected informa tion is, the better it serves its purpose. Ac quitting oneself of the task by only quoting a figure about the (ill-defined) "market poten tial" of a product (usually followed by a sum of some hundred millions or even some bil lions) obscures the matter rather than illumi nating it. In many cases this figure i s so mean ingless that it would not result in any conse quences for the proj ect, if somebody simply changes the currency unit from B ritish Pounds to Italian Lira. Creative market research should initially collect a few basic figures on the occurrence of the disease or condition to be treated. Scientific review articles and epidemiological investigations as well as disease statistics may serve to provide these. As a next step infor mation should be collected about current methods to diagnose and treat the disease or condition. This includes the products or com pounds used, the frequency of their applica tion, cost of the products used and the overall cost of the treatment. Most of this informa tion can be obtained by a specific l iterature search i n the medicinal field or from physi cians and clinicians. Clinicians should also be asked for deficiencies in the current products or treatment schemes, such as side-reactions, lack of efficacy (in general or under certain conditions) and for other medicinal treat ments (e.g., prevention or surgical tech niques) which have an impact on pharmaceu tical products in this area. ..
2I7
This background information should be used to ide ntify the needs of the "market " . i . e . . o f patients a n d physici ans. o f veterinar ians and their clients or of diagnostic labora tories. I t also serves the purpose of checking whether the proj ect in mind has the required potential to i mprove the existing situation. A simple assessment of the likely cost of the new or improved product, compared to the benefits that it provides. can be very illu minating, even if the figures are only rough estimates. Acceptable costs for the new prod uct may be ded uced from prices of compara ble product classes or from specific products which are currently used to treat the disease in question. These prices are likely to give a reasonable estimate. Depending upon the es timated value of additional benefits of the new product, a premium can be added to the basic figure. This sort of simple calculation and estimate is particularly warranted for vet erinary products and for products which will compete with already existing and established products. If the existing products or prophy lactic treatment schemes cost only a few dol lars, the active ingredient is only worth a few cents. To get a rough idea about the upper limit for the cost of the active component in these cases, the market price of the existing product may be split up by the following "rule of thumb calculation": about 40-50% for cost of sales and a profit margin (before tax), 2030% for quality control, packaging and label ing and 10% for formulation. For lower priced products in a competitive environment the active ingredient may account for only about 1 0-30% of the market price. If it is believed that the proposed new product can compete in terms of cost of man ufacturing despite a more demanding process, or that the product offers significant advan tages which j ustify a higher price , it will be necessary to present evidence for a high-yield system or to focus on a proof of the claimed advantages. Live and vector vaccine approaches should take into account the epidemiological situa tion and health care schemes in the target countries. The efficacy of live vaccines and vectors may be affected by a pre-existing im munity in the population. Live vaccines can also interfere with screening tests, e . g . , for sal-
218
7 Biomedicinical Product Development
monellosis in people who handle food or for bovine leukosis in eradication schemes. Diagnostic tests may be rather useless, if the test result does not lead to any conse quences, for example, when no effective treatment is available or because the test pro cedure takes too long to influence the choice of therapeutic options. In the latter case a much faster and simpler "bed-side test" (or cow-side test for veterinarians) may be the better solution. The use of medicinal products and thera pies in man is more driven by ethical and less by economic considerations. Direct commer cial aspects such as cost of the product may be less critical. Instead, the assessment should concentrate more on safety and quality as pects and their scientific and economic ramifi cations. Which safety standards must be met by the product? Does it contain components with an unknown safety profile or a poor tol erance at the application site? What are the chances of replacing these and getting access to better components? Are adequate safety tests for attenuated or genetically modified microorganisms available or must/can these be established and will these tests give suffi cient confidence in the safety of the product to justify later trials in human beings? Who would be interested and could contribute to address the safety issues, e.g., by characteriza tion of the strain of microorganism used, by developing adequate models and tests? How early should these activities start or how long should the project proceed without address ing these very critical issues? Not only live vaccines, but also therapeutic polypeptides and subunit vaccines have to meet very demanding safety requirements, before they can be tested in humans. As soon as a protein with potential as a vaccine com ponent or a therapeutic drug has been identif ied, the questions arise of which systems and methods should be used to produce the active component, how to separate it from potential ly harmful components and how to purify it to the required degree. Assuming that a purity of at least 95% and only a very limited num ber of known and defined impurities will be allowed for a human medicinal product, the expression and purification systems and yields warrant some careful considerations at
a very early stage. The wrong choice or taking what is readily available, instead of using the best option, can result in a loss of time, im practical patent applications and a loss of the competitive edge of one's research. A list of aspects to be examined as part of a creative market research and far-sighted pro ject planning is given in Tab. 1 . Depending on the maturity of the project, it may not be nec essary or possible to cover all aspects. How ever, the attitude should prevail that it is bet ter to gather as much information as possible and then decide whether a specific piece of information is useful or not. Information nev er comes too early, but frequently too late ! Based upon this background information a thorough market assessment for a product to be developed identifies the potential strength and weaknesses of a new product as well as those of competitive programs or therapeutic schemes. This assessment should include the patent situation and the competitiveness of the organization in terms of the skills and re sources to develop, manufacture and sell the product when assessing the chances and risks of the intended development product. From this information one or a series of potential products can be identified, defined by their key characteristics (their product profile) and can be compared.
2.2 The Product Profile A product profile should be established for each development product or candidate . The product profile describes essential product qualities such as the indication, form of pre sentation, intended application and use pat tern, efficacy, safety, and other critical as pects, e.g., patent restrictions and cost limita tions for the compound or for the formulated product. The expected date of product launch and sales expectations as well as the expected development cost are important elements of the product profile. Tab. 2 summarizes and explains the aspects which should be covered by a product profile. Based on the product profile a cost-benefit analysis can be calculated. Such an analysis helps in deciding whether, under the given circumstances, a potential product is suffi-
2 Market Research
21 9
Tab. l. Points to Consider in Stra tegic a n d M arket-Orie nt e d P l a n n i n g of Research and Deve lopment for Bio l o gical M e d i ci n a l P rod ucts
General Aspects Occurrence of the d isease or c ond i t ion : ge og ra ph ic d ist ri but ion a nd fre q uenc y Curre nt d i a g n ost ic and th e r ape u t ic measures De ficiencies of current treat m e n t : effic acy . side-effects. cost. practicability
Potential im p ro ve m e nt s of existing met hods Acce p t a nce of p o t e nti a l i m p rove m e nt s: safety . cost . practicabi lity
I n ter a ct io n with health care and e radication schemes
Efficacy Aspects Potential indications. sci e ntifi c feasibility and risks
De gre e of e fficacy req u ired Systems a n d models to demonst rate e fficacy
Safety Aspects Pott:ntially harmful e ffects of the p ro p ose d p rodu c t
Safety requirements: s i m i l a r or better than existing p rod uct s Systems and m ode l s to assess safety
Commercial Aspects
Product p r i ce s and cost of current t reat m e nt
Fre q ue ncy of
a p pl ic a t i on
of existing p rod u c ts
Likely cost of the p ropose d new p rod u c t and treatment Cost/be nefit re lationship
Patent Aspects
Existing pate n t s and appl ications in the fi e ld Gaps and ch a nce s for an own patent app li c ati o n Availability a nd costs of patent support Cost/benefit of patenting
Project-Related Aspects
O t h e r research and d ev e l o p m e nt projects in this area: scientific competitiveness of t he own p roje c t S pec i fi c skills and methods re qu i red
Collaborators for specific proble ms ot to extend the scope of the proj ect
Who would be interested in the project/product and p ro v i de pract i ca l or financial
s upport ?
Funding organizations to be approached: interest and u se r groups. government and speci a l res ea rch funds. supranat ional fu ndin g org a nizations. industry
ci e nt ly at t ract i ve to d e v e l o p and w h ich indica tio n for the new co m pou nd is m o re or less at t ract ive . It is m ai n l y a m e a n s to p rioritize and to compare the par t ic ular develop m e n t prod uct with other products under dev e l op men t
or under consi deration. This may be neces
sary
since
seve ral
development ca nd i da te s may compete fo r the same resources such as perso n n e l . d evel op m e n t bu dge t capital in vestment, and prod uc t io n cap a ci t y It should be noted that c o st b e n e fit calcu l ations for the same d e velop m e n t p r oduc t may vary conside rably b e tw e e n different or.
.
-
ganizations ( H ODDER and RIGGS, 1 991). First. t h e calculation methods m a y b e differ ent. Second. the assu m ptio n s that go into these calculations. e.g., t h e expect ed sales of a certa i n product. may vary considerably.
These figures depend on company-specific factors such as avai lable sales force a n d pres
e nce on relevant markets, as well as on cer tain personal o p i n ion s and other s ubj ective j udgeme nts. Apart from this. it is obvious that already e x i s ti n g man ufactu ring facilities with out the need for a maj or i n ve s t me n t can sig nificantly influence the result of a cost-bene-
220 Tab. 2.
7
Biomedicinical Product Development
Contents of a Development Product Profile •
I. Essential Product Characteristics
Indication Presentation
Application/use pattern Efficacy Safety/tolerability
Condition or disease to be treated. Target species for veterinary products Type of product and formulation, e.g., live or inactivated vaccine, vector vac cine, type of vector, liquid or lyophilized product, adjuvant, special formula tions Mode and frequency of application, e.g., route of application, single or re peated use, duration of use, booster intervals Specified or in comparison to other products or treatment schemes Specific demands, e.g., standards set by other products or treatments
II. Commercial Aspects
Cost of development Cost of product Investment costs Sales expectations Expected date of launch Patent protection Major product advantages Major development risks Cost-benefit
analysis
Per year until product launch, updated during development Active ingredient, formulation and packaging, cost limitations Manufacturing plant and equipment Differentiated by medicinal indications, by major countries Month and year for major countries Duration in major countries, quality of patent protection Major selling arguments, strategic importance Reasons for failure, e.g., efficacy, safety, regulatory risks, competing prod ucts or developments With annotations on critical limitations and including the important assump tions upon which the analysis is based
• The product profile should address all essential aspects of the product and the development. It describes the agreed development task and assists in management decisions.
fit analysis. Thus, a cost-benefit analysis is a scenario and the assumptions that formed the basis of the described situation should be specified and carefully taken into account, be fore general conclusions are drawn. Besides the aspect of providing informa tion to assist in decision making, a precise product profile has several other benefits. It creates a common vision about the direction of the development by defining the aim un mistakably to all people involved, thus assist ing in tight proj ect planning without the need for endless discussions about the goals. (About the importance of a common vision
for projects see also HARDAKER and WARD,
1 991 . ) Critical aspects of the project are ex posed at the beginning, and measures to solve these problems can be included in the devel opment plan at the best, most convenient and cost-effective time. Defining the product pro file helps to recognize changes in critical pa rameters (e.g., in efficacy) and deviation from
the decided development route earlier, so that counter-measures can be initiated before these become too costly. The later changes are initiated, the more expensive they are. Product profiles frequently tend to de scribe an ideal or almost ideal product be cause this is much easier and less controver sial to define. In order to become a meaning ful base for planning and decision making, the essential product characteristics in a prod uct profile should be described as minimum criteria which define what must be achieved and where the product must not fall short. Only minimum criteria are useful to define pote n ti al milestones for the development plan which in turn are used as an objective guide for decisions to continue a project or to abandon it, if the milestones cannot be achieved. Desirable goals for further improvements can be added where appro priate.
3
Of co u rs e a p r od u ct p r o fil e is not a one sided instruction. It re q uires input from re se arch , p re c l ini c a l a n d c l i ni c al d e v elopme n t m ar k e t in g a nd s ale s dep a r t m e nts and is de vel ope d by an iterative. st t:pwi se p roce d u re .
Registration Requirements
221
W h a t i s p oss i ble and achievable soon be comes a standard by which sub se q ue nt p ro d ucts w i l l be measured. This leads t o contin uous a nd des irab l e i m p rove m e n t s and re q ui re s continuous attention of those who de velop and r e g i st e r pr oduc ts Since there is no limit. very c os t l y and u ndes ir ab l e extremes may be anot h e r con seque n ce A ccord i ng to today·s standards . the most successful a n d b ene fic ia l p h arm aceu t ic a l prod uct s such as the vaccinia virus vaccine, live po lio vi ru s vac c i n e and other live vaccines, wo ul d pr ob a bly not be r e gi s t rabl e for a wide-spread use in hu mans. The fo l l ow i n g section gives on ly a basic u n ders t a n d i n g of regu la tory re q uirements by p o i n t i n g out the common and e sse n t i a l ele ments whi c h a r e ap p li c able to most produ c ts For a more p rofo und but r e a son ab l y short overview wit h s p ec i a l emph asi s on th e techni cal rather than the formal requirements and for information about the spec ifi c g ui d e l ine s cove rin g biomedicines. t h e i n t e r e ste d reader is re fe r re d to G R EGE RSEN ( 1 994) .
.
.
.
.
3 Registration Requirements
,
R e g i s tr a t i on regu la t i o n s for medicinal product s d e sc r i b e th e q u al i ty safety. e fficacy and formal req u i rements for m a r k et approv al. D u r i ng the last few decades p ha rma ce u t i c a l re g u l ati o n s i n the w e st e r n world have be c ome so c om p le x a n d s p e c i fi c t ha t t he tas k o f ob s ervi ng them cannot s imp l y b e d e le gated t o re gi s tra t i on s p ecia l i s ts Registration sp e c ia l ists should be consulted alre a d y d u r ing t he p la n n i n g phase of a d e v el op m en t p roj e ct and should be able to give advice which laws. di rectives and gui d e l ines ap p ly in a s peci fic c ase an d t o wh a t de gree guidelines must be ad hered to. Everybody involved i n pro d uc t de velopment who develops a n a l y ti ca l m e th o d s a n d p ro c e sse s or c o n t ri but e s data on the q ual ity. safety and e ffi c a c y of the pr od u c t candi date needs to know the sp e c i fi c directives a n d g ui d e li n e s c o ncer n i n g her or h i s field of ex pertise. For effective d e v e l opme n t one has to consider the details of reg i st r a ti o n r e q ui r e me n t s al re ad y du r i n g th e p la nnin g of all ma jor ta sk s Otherwise months and years can be lost b ec au s e t ri al s a n d e x p eri m e n ts have to be a dd ed or r e p e ated after the d e v elop m e n t has a l ready been fi n i s h e d and the re g i st ratio n dossiers were handed i n . The re g istra t ion of m e d ici n a l products is governed by relative values which cannot be c le a rl y d e fi n ed or l i m i te d . for e x a mpl e by e t h i c a l con siderations and the e ndeavor to ensure t h e best poss i b l e quality and s a fe ty of pharmaceut icals. As a consequence. one can not expect that r e g is t ra t i on g u id e li nes give definite s pe c i fi ca t i o n s for all m aj o r p roduc t characteristics and define exactly what must be d o ne or - which is p ro bab l y m o r e impo r tant needs not to be done. R e g i st rati o n re quirements are flexible and ch a nge wi t h t i me .
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3 . 1 Three Basic Elements Market app r ov a l or re gistrati on of a p h ar m ace u t i cal p ro d uct depends on the fu lfill ment of three main requi rem e n t s:
•
•
•
Q ua l i t y S a fet y E ffi c a c y
This sounds fa i r l y simple. but these three basic terms must be i n te rp r e t ed in a very wide sense; every s i ng l e aspect within these catego ries must be sub sta n t i a ted and proven under p ract i cal conditions. The scope and defini tio ns c h a nge with time and wi th scientific, pharmaceutical , and m e th o d o l og i cal progress. The d e fi n i t i o n s fo r qua li t y sa fe t y and efficacy vary between product g rou ps countries, au thorities and between people within a u t ho ri ties. In fact. there are no e x a c t definitions at all. Q ua l ity - as far as it can be j udg e d inde pendently of sa fe t y and efficacy - is in p rin ci ple assessed by a comparison w i t h the state of ,
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Biomedicinical Product Development
the art, i.e., with similar products. Products with inferior quality than other products may need improvements before they can be regis tered; products which surpass current stand ards will raise the general standards. Safety and efficacy, too, are no absolute values which can be easily defined. Market approval depends on a reasonable relationship be tween safety and efficacy, between risks and benefits. Quality, safety and efficacy are no indepen dent criteria. The quality can significantly af fect the safety and efficacy. A highly effica cious and beneficial product may be accepta ble, even if it has serious side-effects. Keeping these interdependencies in mind, product de velopment must address and emphasize the three basic registration requirements in the same order as listed above, starting with the product quality, although project risks suggest a different strategy which concentrates more on efficacy. Without a defined quality, all safety and efficacy tests may be irrelevant, and without an adequate safety, efficacy trials under natural conditions cannot be carried out. 3 . 1 . 1 Quality
Quality does not only comprise the final product itself and its attributes that can be tested. The high variability, in particular of biological products, demands that all varia bles of the manufacturing process are evalu ated. Product quality commences with the starting materials and their attributes, runs through the entire manufacturing process and extends to the manufacturing facility and its infrastructure. Everything that can affect the product quality must be assessed, tested and documented. For example, if one intends to harvest a product continuously from a cul ture, it must be specified what "continuously" means. If it is intended to harvest a hundred times over a hundred days, one has to prove that the product is still the same after the hundredth harvest - and probably even beyond that limit - to add some safety mar gin. Of course, it is necessary to validate all in process control and product quality control
tests, i.e., to substantiate that the tests really measure what they are supposed to do and within which limits. All claims on product safety and efficacy depend on the specified quality; if the quality is not consistent, safety and efficacy may not be the same. Safety and efficacy data for the product are only valid if they were estab lished with material of the specified quality. The practical implications are that test mate rial must meet the relevant specifications of the final product before safety and efficacy data can be generated. For biological prod ucts, this means that the test substances have to be made by a process which must not de viate from the final manufacturing process in essential elements. If the manufacturing pro cess is changed during the development, all previous data with earlier material may be worthless, unless bioequivalence can be prov en. 3 . 1 .2 Safety
Safety of a product comprises any aspect of its production, use and disposal. This includes the manufacturing premises and their envi ronments, starting materials (especially cells and microorganisms), the active component of the product as well as metabolites, impuri ties and the excipients. Excipients are compo nents which are added to the product, for ex ample, preservatives, vaccine adjuvants, sta bilizers, emulsifiers and release controlling substances. Safety of the manufacturing process and the facilities is covered by a variety of regula tions concerning the layout of facilities, work organization, procedures and related controls and inspections. General national regulations on work safety and biohazard control meas ures, specific regulations for manufacturing pharmaceutical products and quasi-legal GMP requirements have to be applied. These are an inherent part of the registration dos sier and market approval to ensure consistent quality and safety of the product and its man ufacturing. Safety of the product itself for the target organism, the user (who applies it) or the en vironment is addressed by a range of preclini-
3 Registration Requirements
cal and clinical assessments which depend on the product and its use p at t e rn . The range of sa fe t y fe a t u res t o be a ss e s se d includes local and systemic tolerance . acute and chronic t o x icity, im m uno t oxic i t y and. for vet e ri n a r y me dicinal prod uc t s . also the e cot o x i c i ty . Tests for m u t age n i city . tu mor ige ni city and repro duc ti ve t ox ici ty may also be requ ire d for ce r t a in pro d ucts or indications. For s afe ty a sse s sm e nt of a pharmaceutical produ c t i n the ta rge t organi s m it is necessary to know the action and fate o f t h e pr o du c t and its compone nts within the body. after it has been ad m i n i s t ered . This knowledge de rives from pharmacodynamic and pharmaco ki n etic studies. the re su l ts of w h i c h will in fluence the c h o i ce and s e t u p of sa fety tests to be conducted. Pharmacodynamic studies in vestigate the in fl u e nce of p harm a ce ut ica l sub stances on the human or animal organism.
such as their mode of a c ti o n and mechanism of side e ffe ct s a l o n g w ith d os e - e ffe c t re la t i on s h ip s . Pharmacokinetic studies address the influe nce of the o rg a n i sm on absorption. distribution , metabol ism. and elimination (A DM£) of pharmaceutical pr oduc t s in ade quate models and in the target spe ci es . Phar maco ki net i c studies for biomedicines ( espe c ial l y metabolism and e l i m i nation st ud i e s ) are usual l y less intensive than fo r chemical drugs. For b i o log i cal p ro duc t s the ( c h e m i c a l ) e x c i p i e nt s are often o v e r l oo ke d . T hey . too. may have effects or side-effects a n d can leave resi dues in animals tha t e n d up in human food. Their choice for a d e v e lo pme n t p rod u c t must be considered c ar e fu l l y . Eit h e r one uses in gredients with a well established quality and safety profi le or a v a ri e t y of a n al y t i cal and safety data have to be e st ab l i sh ed for these excipients. Safety studies fo r n e w e x c i p i e n ts may cost more than the safety assessment of the biological p ro du ct i t se l f . It is e s sent i al to d e m on st r a t e that p ha rma ceuticals for food - p ro d u c i n g animals do not have harmful effects on humans. pa rti c ul arl y if residues of the active co m p o n e nt or of exci pi en t s and of their metabolites may occu r in m e a t . milk or eggs. Th is means that e x t e nsi v e studies regarding the safety for humans and res id ue depletion s tudi e s m ust be p erform ed with t hese p rodu ct s .
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As a ge nera l rule , p r od u c t s that are used once or a fe w times have to u n d e rgo few er safety tests than products which will ad mi nistered regularly or over a longer time. Less - if any - side-reactions are tolerated for p rod u c ts intended to be used in hea l thy indi viduals (e.g.. v ac c i ne s ) than for p rod uc t s which are used in diseased individuals. In any case t he benefits must c learl y outre ach any po tent i al si de - e ffe c t s. on l y
3.1 .3
Efficacy
A p h a r ma c eu t i c al product m u s t fulfill its p u rp o s e under all recommended conditions and it m ust do so reproducibly. E xpe r i en c e shows that efficacy in controlled e x pe ri m e nt s does not guarantee that the product does the same and t o the sa me degree u nd e r p rac t ica l conditions. Pharmaceuticals for h u m a ns must be te s ted i n human beings for their pharma codynamic and pharmacokinetic characteris tics to prove their effectiveness and safety . These clinical trials are normally carri ed out i n t hree stages. each p h ase invol v i ng an i n creased number of patients (see Tab. 4 be l ow ) . Clinical trials in humans are u s u ally the most critical, most e xp e n s ive , and mo st time co nsu m ing developmental step and can ac count for more than o n e half of the deve l op ment costs. Concerning the proof of e fficacy fo r animal health p rod u ct s . there is o fte n the misconcep tion that controlled e x p e r ime n t s in the target spe c i e s (pen tr i a l s o r a challenge e x peri m en t under controlled c o nd i t ion s ) which show that the product is efficacious. are sufficient to register a product. Animal health products also have to undergo cli nical or fi e l d trials to prove their efficacy and s a fe ty u n der p ract ic al conditions. Quite often, these trials reveal several hitherto unrecognized we akn e s s e s of t h e product. However. c l i n ical trials for vete r in ary med ici nal p roducts are much less c ri t i ca l. le ss e x p ens iv e , and usually less t i m e - co n su m i n g than hu m an clinical trials. Due to the p re cli n ical pharmacological, efficacy and safe ty tests p e r for med in the target species, the cli nical trials are mainly designed to confirm p re clinical e fficacy data and to provide a b roa d e r basis for the safety evaluation.
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7 Biomedicinical Product Development
Clinical trials are an important base of effi cacy claims for the product. As a logical con sequence, all indications for which the prod uct is recommended, all proposed routes of application, treatment schemes, doses, rele vant age groups and, in the case of veterinary products, all recommended species must be tested. For an effective development it is of ten better to initially concentrate on only one or a few of the potential indications to reduce the risk and to get the product on the market earlier, than to follow up all variants at the same time.
4 Technical Aspects of Product D evelopment Medicinal products must have a consistent quality in order to be reliably effective and safe. Achieving consistency in all aspects is a cumbersome technical and analytical task which takes much time and which is usually not the main virtue of research work. Scien tists without experience in product develop ment tend to neglect the technical aspects which lead to a consistent product quality. Increasing registration requirements for the product and the production process as well as environmental issues also add a signif icant technical and analytical dimension to the development. This particularly applies to products derived from biotechnology. Com pared to conventional biological products, the final product is usually much better defined and its manufacturing process can be better controlled. But it requires the application of a variety of quite sophisticated techniques to do so.
For most new biotechnological products, processes and analytical methods have to be newly established. This represents a major and costly part of product development. In newly founded biotechnology firms pertinent technical experience and practical knowledge about the application of regulatory require ments is usually missing and must be develop ed. Early information and consideration of these aspects may considerably shorten this learning process.
4 . 1 Process Development and Manufacturing
The active ingredient of a potential prod uct, as it was identified in research, is initially produced in minute amounts and by a process which in most cases is not acceptable for a pharmaceutical product or for large-scale pro duction. Process development represents a link between research and manufacturing and adapts the research methods to the needs of production or develops new methods where necessary. Process developers must take mul tiple aspects into consideration (Tab. 3). Their task would be much easier, if research ers were aware of these aspects. In the worst case process development can imply that an entirely new procedure to ob tain the active ingredient must be found and established. Frequently master seed stocks (cells, viruses, bacteria) must be newly gener ated and tested, since those from research are not suitable because of their quality (contami nants, inhomogeneity) or unclear history and documentation. Unacceptable starting materials used in re search must be replaced by those which meet the regulatory quality and safety criteria. Ref erence to standard volumes of pharmaceutical ingredients and excipients should be made to decide whether a certain ingredient can be used. Standards are described in the pharma copoeias of relevant countries, in The Extra Pharmacopoeia ( MARTINDALE, 1993) and in the Handbook of Pharmaceutical Excipients (AMERICAN PHARMACEUTICAL ASSOCI A TI O N/THE PHARMACEUTICAL SOCIETY OF GREAT BRITAIN, 1986). The German Lexi kon der Hi/fsstoffe ( FIEDLER, 1989) also pro vides many useful informations about accept able excipients and about their applications and safety. Components used and approved for human food may also be considered as po tential ingredients for certain applications. Hazardous components cannot be used at all or have to be removed during the process. Special conditions apply to the use of starting material of human or animal origin to avoid the presence of adventitious agents in the fi nal product.
4 Technical
Aspects of Prod11ct Development
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3. Process Deve lopment for B iological Pharmaceuticals: Major Points to Conside r in Process Development
Tab.
I. Starting Materials and Excipients
Availability: appropriate quantities. regular supply Quality: specifications and consistency (compliance with pharmacopoeia speci ficat ions if these exist ) Safety acceptable for a pharmaceutical product and freedom of adventitious agents. e.g human serum components. bovine serum! Masters seed cultures: quality. documentation. suitability ..
II. Safety and Environmental Aspects
Work safety. e .g .. organic solvents, aerosols containing microorganisms Contamination from the e nvironment Contamination of the environment Cross-con tamination and separation of activities Waste material decontamination and disposal Ill. Legal and Regulatory Aspects
Registration requirements for product and process Lice ncing of facilities Good Manufact uring Practice ( G M P ) I nfri ngement o f existing patents? IV. Economical Aspects
Cost of goods Y ie lds
Recovery rates I nvest ment into equipment/facility
Process developers should check existing patents and patent applications in order to avoid patent infri ngement with any use or process patent. On the other hand. there may be possibilities t o pate nt the particular pro cess newly developed or critical elements of it. Economic aspects such as yields from cell culture or fermentation. product recovery af ter purification and cost of materials and equipment need constant attention. Produc tion cost forecasts should be calculated and updated regularly. A variety of product safe t y . work safety. environmental safety aspects and other legal aspects m ust be taken into consideration when a process is designed. Good Manufac turing P ractice standards for facilities, equip ment. and working procedures must be met. GMP approval is subject to inspection a nd re quires constant attention and updating. Ex tensive documentation must be provided to comply with these requirements.
Manufacturing facilities are approved for their specific purpose , e.g., for the manufac turing of one particular product. If it is in tended to manufacture another product in the same facilities, this must also be approved and requires very strict measures to avoid any cross-contamination and mix-ups. Either the facilities have to be separated, or production runs for different products have to be per formed at different times with intensive cleaning and decontamination in between. The preferred option is of course to devel op a manufacturing process for an already ex isting manufacturing plant. If adequate and approved facilities are not available , the pos sibility should be considered to develop the product in cooperation with somebody who has free capacities in a suitable plant. ( Many conventional vaccine producers have more capacities than they need.) If this alternative is unacceptable, considerable investment and time will be required to establish manufactur ing facilities. They have to be planned, built,
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equipped and approved first, and it will be necessary to gain sufficient experience with the new plant and the manufacturing process in these facilities. The use of existing manufacturing facilities also overcomes another common limiting fac tor in product development: the availability of product for test purposes and clinical trials. All critical tests must be done with a product which is essentially the same as the final prod uct, if the data from these tests are to be used for the registration application. Research ma terial of d ubious quality is definitely not ap propriate. It may take months or years to develop a controlled process which reproducibly gives a product with adequate quality. As a conse quence, process development must start very early in the development phase. The product specifications should not simply evolve from the process; the main parameters should be fixed beforehand. This does not only provide clear objectives for process development, it also makes sure that no time is wasted .by test ing products of inadequate quality which may render the data obtained useless for registra tion purposes. In some cases it may be unavoidable to change relevant product specifications. If ma jor pharmacological and safety tests have al ready been done, it may not be necessary to repeat all of these. Comparative tests (bio equivalence studies) with the earlier and the new product should be performed to check whether both are equivalent in all critical as pects. In the case of higher standatds, (e.g., for purity) this may be relatively simple, low ering these standards, however, will be diffi cult to justify and requires thorough studies about the nature and the effect of the addi tional impurities.
4.2 Analytical Development and Quality Assurance
Quality assurance schemes for medicinal products have evolved mainly from experi ence. Whereas initial quality controls were carried out only with the final product - with elimination of batches which did not pass the
test - nowadays quality assurance covers the entire manufacturing process and continuous ly develops towards a more holistic system. Presently quality standards cover everything that goes into the product (starting materials, excipients, the active ingredient and its by products) , everything that could come into contact with the product (e.g., air, water to clean vessels, packaging materials) or has the potential to influence product quality without being noticed by the usual checks (e.g., per sonal qualification, management responsibili ties, the validity of methods, documentation). The given examples may illustrate the general scope of modern quality assurance for phar maceutical products. Analytical procedures have to be develop ed for the active ingredient as well as for starting materials and the excipients used in the final formulation. These tests should be able to specify and confirm the identity, puri ty, potency, stability and consistency of these materials. If significant impurities, degrada tion products or critical metabolites occur, analytical methods for these will also be re quired. In-process control methods must be de vised and developed to observe all relevant steps of the manufacturing process in order to have adequate control over the inherent var iants and to detect potentially harmful con taminants at a stl\ge where they may be easier to trace. The spectrum of tests to be employed com prises methods from microbiology, immunol ogy, protein and peptide biochemistry, ge netic engineering and physico-chemical meth ods as well as animal experimentation. If these exist, for example, in pharmacopoeias, standard method descriptions have to be fol lowed. Critical steps of the manufacturing process and analytical methods have to be validated carefully. Process validation will be required, for example, for the inactivation or elimina tion of potentially pathogenic microorganisms (e.g., viruses in transformed cell cultures) from the product. This can be done by run ning spiked samples through the process or through a smaller laboratory version of the process which exactly mimics all relevant pa rameters. Volumes, tests, and test sensitivity
4 Technical Aspects of Product Development
must be considered carefully and statistically for such experiments. Analytical methods a re validated by inves tigating specificity . sensitivity, detection lim its. quantification limits. accuracy (of the indi vidual r e sult) precision ( variation between different tests ) . applicability and practicability under laboratory conditions and the robust ness (susceptibility to interference) of the method. This enables t h e organization itself to employ these tests much more consciously and with bet t e r res ult s . but it also serves the purpose of enabling the registration authori ties to use these tests for the regular batch control tests. Official guidelines by the regulatory au thorities for the validation of analytical meth ods and processes are available for consulta tion. Good Manufacturing Practice ( G M P ) standards arc a further step towards the con cept of "total quality". Implementing and maintaining a G M P status requires commit ment of the e n t i re organization and special and constant attention by those who are in charge of qualit y assurance. Because of the complexity and wide scope of the subject and the amount of paperwork (some translate GMP as "Give M e Paper " ) extra personnel or external consultants will most likely be required. GMP includes for example: .
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•
•
•
• •
The organization . management struc ture. personal qualifications and train mg Standard Operating Procedures (SOPs) with appropriate documentation and implementation systems ensuring their effective application Production. packagi ng. labeling. han dling. testing and approval of starting materials. i n te r m ed i a t e and final prod uct
Construction. infrastructure and main tenance of buildings and equipment Regular inspections and self-inspections and many more details.
Whereas GMP
as well as GLP (Good La
bora tory Practice ) and GCP (Good Clinical Practice ) arc m a in ly acti ng on the operational
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or technical level. other quality assurance standards have been established by the Inter national Organization of Standardization ( ISO) to assure quality at the organizational level. I nadequate organizations with unclear tasks and responsibilities can severely in fluence the quality of products and services. In the near future further quality assurance elements as recommended by the quality guidelines ISO 9000- 9004 will certainly also be applied to pharmaceutical developers. manufacturers and to sales organizations. A formal accreditation of compliance with these standards requires the implementation of quality assurance schemes covering. for ex ample, the following aspects of a business: • • •
• •
•
Management responsibility and com mitment Organizational structures with explicitly defined and delegated responsibilities Quality assurance systems covering all functions in procurement, production, control of production, handling, stor age . product identification, packaging, delivery . marketing, afte r-sales servic ing. product supervision and "design " (design res ea rch and development) Identification of non-conformity and corrective actions Means to ensure product traceability, facilitating recall and planned investiga tion of products or services suspected of having unsafe features U se of statistical methods to enhance and maintain quality at all stages and of all activities in the product cycle. =
It is to be expected that by the year 2000 or earlier compliance with ISO quality manage ment standards will be obligatory for staying in business. The personnel cost of implement ing and maintaining these q uality assurance systems should not be underestimated.
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5 Planning and Managing Product D evelopment The development of a modern pharmaceu tical product is a complex task which is fur ther complicated for biological or biotechno logical products by the potential variabilities of the biological production system and the resulting consequences. Therefore, apart from considerations of adequate skills and re sources, careful and very detailed planning and controlling is imperative for the success of development. Those who are unexperienced with the tools of project planning and managing may refer to one of the numerous books about project managing. Although these books are usually aiming at more technical applications, the basic techniques do not differ and are of course also applicable to other areas. Alter natively one can buy a project management software package and learn the application of these tools directly by using it in the planning process. Knowledge of the essential registration re quirements is mandatory for the planning of a pharmaceutical development project. If these are neglected, the development process will be like navigation in unknown waters without a compass or a map. The risk of a shipwreck is high, in any case the j ourney will take much longer and will cost more. Provided that a reasonable and useful product profile (see Tab. 2) has been estab lished, the general aim of the project and the most relevant objectives have already been decided. The objectives which serve as orien tation points in the project will most likely address the exact indication, efficacy, the type of product, its formulation and application scheme. Another important general objective in the product profile may be the expected price limit for the production of the active in gredient or the formulated product. Specific tasks and measurable success criteria for process development and manufacturing, e.g. , in terms of yields and recovery after purifica tion, can be deduced from this price limit. Other very specific objectives and the majori ty of project tasks relate to specific registra tion requirements.
It may take several months to establish a workable development plan, and most of this time will be required to collect the neccessary information. At the beginning the project plan will probably be a rather simple outline which then grows continuously while the pro j ect progresses. A project master plan which covers the major sections, milestones and de cision points can be established far ahead and - if prepared thoroughly - will remain essen tially unchanged from then on. More specific and detailed planning and updating is done in subordinated plans for the individual sections and must be performed continuously. Development plans must be much more detailed than research plans. The simple rea son for this is that the commercial environ ment in which development takes place re quires a much stricter planning, use and con trol of time, budgets, and manpower. Significant time savings can, for example, be achieved by preparing tasks and trials ear ly and by careful and extensive evaluation of trials. Often time is lost, since in negligent project plans resources for the planning and evaluation phase of larger studies as well as certain aspects, which can be tested simulta neously and do not require separate experi ments, are ignored. This applies especially to clinical trials which need considerable time to get started and where it is possible to collect data on efficacy, pharmacology, safety and tolerability aspects at the same time. Many tasks have to be performed accord ing to very detailed legal and quasi-legal standards which may differ from country to country. Relevant countries' guidelines must be checked and considered in planning the in dividual tasks. Studies performed according to GLP standards, animal trials and clinical studies can only be performed, after internal or external examinations of protocols or ap proval procedures have been passed. In this situation it is essential that all people in volved start their activities with precise and detailed instruction and are given sufficient time for a careful preparation of their tasks. Good project plans include the preparation of relevant studies and trials as specific tasks in order to avoid delays. Effective project controlling also needs de tailed planning. Under normal circumstances
5
Planning and Managing Product Development
the p l a n s must be exact e n ou gh to allow p r o gress to be m on i t ore d a t i n t e rv a l s of 2--4 weeks. ( Some industries and c o m p a ni e s have much t i gh t er sche mes! ) I n cr i tica l situations or for activities on the c ri t i c al pa th (if de laye d, activi ties on the cri t i cal path de l a y the entire p roj e c t ) . more frequent ch e c ks and cor rections may be necessary. Where possible, progress should be m oni t o red before a task is finished. Requesting i n fo rm a t i o n abou t the pr ogres s halfway t h ro ugh a j ob can also create a better a w are n e ss for time limits a n d ta rg e t dates. If p ro b l e m s are li kely. m e a n s to solve them can be pl an ne d a nd i m p le m e n t e d before these problems cause m aj or co ncer n .
5. 1 Risk-Oriented Planning The most di fficult a n d controversial part in planning and m anagi n g of a de v e l op m ent process is to k ee p t h e r i g h t balance between the t h ree cor n e rst ones cost . r i s k . and time. Using more time r e d u c e s the risk b u t i n creases the cost and d elay s t h e p rod uc t launch. Con troller and m a rk e t i n g manager will raise t h e i r pro t e st . Taki n g more ris k s in cr e a se s the po ssi b i l i t y o f n o t m e e t i ng the mi lestones. and eve ry body is concer ne d . There is no way to do it r i g ht fo r e v e ryo ne ! The willingness to t a k e risks can be a key element for a r ap id and cost-effective devel op m e nt prog r a m . M a k ing a ssum p t ion s about the likely outcome of a piece of work and commencing the next step w h i c h depends on a particular resu l t be fo re i t is av a i l able . does increase the risk, but it also permits to short en the d e ve l op m e n t time considerably . The most rele v a n t risk to be co nsi d e re d during the d ev el o p m e n t of a b i ol ogical phar maceutical is the efficac y and sa fe t y in t h e tar get organism. De s p it e exte n s i ve p re c l i n i c a l tests, m a n y product c a ndi dates are aban doned after first tests i n h u ma n s . Th e p rob lems e nc o un te re d at this stage a re o fte n due to pharmacological or immunological d i ffer e n ce s he tween t h e model used in the preclini cal tests and humans. T h us . it is ne ce ssary to plan P h a se I c l i n i c a l trials as e arly as possible. S i m i l a rly m o s t ve t e r i n a ry development pro jects fai l due t o a lack of efficacy and unex pected <Jdverse e ffects w hich remain unno
229
ticed until the p rod u c t is tested in the target species. Ve t e r i n a ry p rodu c ts should be tested i n t h e t a r get s pe c i es as soon as sufficient p rod uc t is a v a ilab l e . Tests under p r act i c a l conditions s h ou l d follow as soon as possible. Quite often m ajor progress, but also unex pected n eg a t i ve results. come from experi me nts in humans (or pr im a tes) or in target animal sp e cies . Besides the al r eady emphasized i mpo r tance of tests in the target or ga nism , the im portance of animal and in vitro models for pharmace u tical pro d u c t development h a ve to be p oin ted out. In most cases the available range of models a n d in vitro t e st s needs to be extended for t h e d e v el opm en t phase , because the models used in research are not adequate n or sufficie n t . Considering the fact that all p o t e n ti a l facets and variations of a new act ive co m pone n t (different conformations, concen t rati o ns . formulations the mode of action, im m u n o l o gy , p h a r m aco k i n e ti c a n d s a fety a n d e ffi c acy under various conditions) should b e studied , the availability of models can be an im porta n t asset for a fast and cost-effective prod uc t deve l opme n t . Models allow certain aspects to be investi gat e d i n m ore d ep th , but t h e y r e fle ct o n ly a part of the entire situation. The refore, they need to be v a l i d a t e d by c o m pa r i n g their re sults with t h o se in the t a rget o rg a ni sm . Mod els should be considered as a v al ua ble addi t ion. not as a replacement fo r tests in t h e tar
ge t organism. The eco n o m i c feasibility of a p r oduct ca n be a n othe r m ajor risk which n e ed s contin uous attention dur i n g t he d ev el o p m en t . This is e sp eci a l ly true for animal health projects a n d for all the products which will compete with simpl e and effective alternative treat me nts. for example, with e x i s tin g vaccines. Fa c t o r s d i re c t l y affe c ting the economic assess ment a r e t hose l isted i n the prod u c t pr ofi l e u nd e r " co m mercial aspe c ts " (cf. Tab. 2). A p roj e ct manager will have to control t he de velopment cost a n d pa y spe c i a l attention to details like yields and recovery rates d uring t h e proce s s de v e lop m e n t . Critical l i mi ts fo r t he m a n u fa ctu r in g should be addressed by s e t ting s p e cific objectives. One should not forge t that the economic
aspects of a project depend on the underlying
7
230
Biomedicinical Product Development
assumptions about the product's characteris tics. Less efficacy than assumed or a slightly compromised tolerability may seriously affect a product's performance and viability on the market. 5 .2 Product Development Phases
As a starting point for the planning of a de velopment project, Tabs. 4 and 5 propose and summarize a phased scheme of a risk oriented development plan. Several impor tant milestones and decision points have al ready been included. Each phase must fulfill certain criteria in order to be accomplished before the next phase may start. Management decides whether a project is advanced enough Tab. 4.
to proceed to the next phase, since this deci sion is usually associated with the involve ment of more people in different departments or of external participants and has significant financial implications. The data and informa tion needed for an assessment of progress and criteria for the decision should be known be forehand. Most of these criteria, which are in cluded in Tab. 5 as proposed milestones (which need to be specified in detail for a giv en project), address the critical aspects of the project and the question what should be done to reduce these risks and to allow the project to enter the next phase. The first management decision will be to forward a research proposal and component to development. This decision should not be made if the active principle (substance) is not
Product Development Phases, Main Risks and Tasks
Project Phase
Main Risks
Main Project Tasks
Research
Scientific feasibility, efficacy
Proof of a reproducible active principle Achievement of sufficient efficacy
Pre development
Efficacy, safety, economic feasibility
Confirmation of efficacy in best available models or in tar get species Limited, orientating safety studies Establishment of a small-scale process, scaleable and with acceptable quality Calculation of economic parameters
Preclinical development
Efficaccy, safety
Evaluation of efficacy for all indications Full pharmacological, immunological and safety evaluation Process development and validation Analytical development and validation
Clinical development
Efficacy, safety and tolerability
Registration
Formalities, safety, quality
Updating/improvement of dossier Additional safety studies Additional quality assurance tests of validations
Postmarketing development
Safety, acceptance and practicability
Drug monitoringlpharmacovigilance Further safety assessment Postmarketing trials
•
Phase 1: Dose-finding, pharmacologic action, metabolism, side-effects: Intensive studies in patients or healthy individu als, usually 20--80 subjects • Phase II: Controlled studies on effectiveness and on side-ef fects: usually no more than several hundred subjects• Phase III: Expanded, controlled and uncontrolled trials on efficacy, safety, risk-benefit relationship, practicability: usually several hundred to several thousand subjects•
Numbers quoted from 21 CFR 312.21 {USA)
5 Planning and Managing Product
Tab. 5.
Development
231
Prod uct Developm e n t Phases, Milestones and Decisions
Milestones
M ajor Decisions
Research
Active component characterized
Effi cacy
pr ove n
;&>
Decision to enter pre-developme n t Decision on indications
Pre-development Effi c a cy confirmed in re l i able m od e l ( s ) or in the target species for veterinary products No s afet v risk i d e n t i fied Scal e a b l � process av a i l able: yields. cost and quality acceptable Favorab l e economic fe asibility s t u d y
;&>
Decision to enter preclinical development Decision on t a rget countries Decision on ( preliminary) product specifications Decision on man ufacturing site and method
Preclinical development
Proven
effi c ac y for all i ndications
Acceptable safe t y/tolerability for all i ndica
tions/condition�
Process d et a i ls according to plan : scale. y i e l ds . cos t . product specifications
;&>
Decision on p roduct specifications Decision on fi nal production process
Decision o n i n dications t o be pursued
Decision to enter clinical development Preliccncing serials passed quality cont rols; trial material a v a i l a b l e
;&>
Decision to s t a rt clinical trials
;&>
Decision to file registration
;&>
Decision
Clinical development Successful co m p l e t io n of Phase I S ucce s sfu l completion of Phase I I Successful
completion of
Phase I I I
Registration
Obtain market approv a l
Decisions afte r completion of a phase should not exclude
to
m a r k e t product
that preparations
for later activities can be made
before that decision . The act u a l ac ti v i ty i n question (e.g . . clinical trials. p roduct sales), may only start with full approv a l .
or insufficiently d e fine d. A re combinant antigen which is incompletely characterized most likely needs much more research before it can be considered a devel opme n t candidate. I t should stay in the less costly research l a bor a t o ry until sufficient effi cacy wit h a clearly cha r a ct erize d antigen is
yet av a i la b l e
achieved. There would be no point in testing s afety features or to develop a process for a component if its essential fe a t u re s are still u n known. The ability to complete the product profile to a reasonable degree could serve as a pre re qui s ite for a decision to enter develop ment.
232
7 Biomedicinical Product Development
An important element, which is frequently used in drug development, is the introduction of a pre-development phase which serves the purpose of reducing major project risks be fore the full development commences and be fore extensive resources are allocated to the project. It can also serve as a time buffer to complete missing points of the product pro file. In order not to delay the project too much, this project phase must have a limited duration of usually one year, but not more than two years. As far as possible, the crucial risk factors efficacy, safety, and economical risks should be investigated, e.g., by perform ing efficacy trials under the best available conditions. These could be target species ex periments for veterinary indications and a range of animal model studies or perhaps even a small study in primates for human in dications. Short-term safety tests can be per formed to indicate where potential problems may be and which range of toxicity tests will address them. Most likely the methods used in research to generate the active component are unsuitable for later production, and the pre-development phase may be used to iden tify, investigate, and calculate better options. The introduction of defined project phases and management decisions before each new phase mainly intends to create a clear basis and an overall agreement before major new activities are initiated. These management tools should be h andled pragmatically in or der not to cause unnecessary complications and time delays. For example, it could be nec essary to approve preparations for clinical trials months before the preclinical develop ment has been finished and before the formal decision to enter clinical trials is envisaged. The planning of such trials and the recruit ment of trial cooperators and trial subjects can take a long time, which would be lost if decision procedures were not flexible enough. 5 . 3 Decision Making
Decisions are only the visible result of a process which is preceded by the generation of data, writing of reports and statements, ex change of information, meetings, and discus-
sions. For larger development projects, in which many people are involved and deci sions imply significant expenses and invest ment, this process can take a considerable time. If decisions are well planned and pre pared, they represent an important element of stability and support. If applied in the wrong way, they may severely hamper the progress of a project. A well-founded decision to enter the devel opment phase of a product usually takes sev eral months. Often delays occur because the decision is not anticipated and the necessary facts, figures, and reports are not collected in advance. But also if the decision-making indi viduals are not prepared and do not indicate early enough what kind of information and prerequisites they need to make the decision, months could be lost. For example, the exis tence of an acceptable product profile ( cf. Tab. 2) including the required information and evaluations may be used as a basis for a development decision. Major decisions can and must be antici pated and prepared by both the decision makers and by those who's further work de pends on the decision. The major decisions for a development project, as proposed in Tab. 5, should be integrated in the project plan along with the necessary tasks for their preparation. Management should provide guidance on the information needed for such decisions. Most larger companies have estab lished routine schemes for the major project decisions and for the necessary documenta tion. If applied pragmatically, such schemes can shorten decision procedures considera bly. Minor decisions should not be made by the top management. Considering the number of people who are directly or indirectly in volved, the time spent and the cost of this time at work, a decision can be more expen sive than the expenditure for the object of the decision (WITIE, 1 969). If the suspicion arises that this could be the case, the project organi zation is probably top-heavy, and delegation is done without giving appropriate authority. Delegating responsibility to a proj ect man ager and to project team members also in cludes the delegation of decisions to them. Extent and limits of the delegated responsi-
5 Planning and Managing
bility and authority should be defined in the job descriptions. Only if there is trust and confidence in their capabilities. responsibility and decision making can be delegated. Unless there are important and very con vincing arguments which have not been taken into account. the subordinate's decision should be respected. Accepting a subordi nate 's decision can sometimes be very diffi cult for the superior manager, particularly if (s)he would have decided differently and the decision is cri ticized and must be defended. Overruling decisions of subordinates or fac ing them with already made decisions which would have fallen into their direct responsi bility can seriously affect the working rela tionship. Approval of a project requires the consent of many people, but a single "no" can cause the project to collapse. This mechanism has the potential of being misused by individuals to undermine projects they personally do not like. Risky projects (projects are by definition risky) are frequently surrounded by people who question the entire project by emphasiz ing one or the other inherent risk. If their concern has bee n recognized before and was considered during previous decisions, such criticism seems inappropriate and the critics should be requested to provide more con structive proposals. Decisions to s t o p a project are the most difficult decisions. Although perseverance and full support by everybod y are essential for the success of any project. there is a point where "the plug must be pulled''. A feeling of personal failure if the proj ect fails. selective perception and reporting of information , ma jor setbacks being considered as temporary problems and the hope to recoup at least part of the investment are strong forces which hinder a reasonable decision at the right time. STAW and Ross ( 1 99 1 ) have discussed the personal intere sts of people involved in such situations in more detail. Simple recipes do not exist to prevent the project dragging on in a hopeless situation. But things can be done to make decisions to stop a project more rationally and less pain fully for those affected by it. First . the fee ling of personal failure must be eliminated. Many organizations still con,
Product Development
233
sider the fear of failure and direct or indirect punishment (status, sala ry no further promo tion) as an important driving force - accord ing to the "carrot and stick" method to keep a donkey moving. This method seems hardly adequate for the needs of project work with responsible and highly skilled individuals. Proj ect groups and their managers need recognition of their work and praise if they did a good job. This also applies to a project group which could not solve the scientific or economic problems of the proj ect despite all reasonable efforts. The only reason to blame somebody personally would be if she or he refused to do what could have been done. In this case the person needs to be retrained to solve the problem. Second, honest reporting also of negative results must be encouraged. The best encour agement is a modest, rational response and the offer of active help if unexpected prob lems arise . Finally, one must not accept the argument that too much money and effort already went into the project and that it needs only some further investment to rescue it. Decisions must be based on the future perspective of the project. The past, including all money spent, does not count. The project should be evaluated in exactly the same way as a new project proposal and using the same kind of information. I f in the new scenario, chances and risks, cost and time to develop the prod uct do not justify the continuation of the pro ject it should be stopped based upon objec tive and rational arguments, but not because someone failed. Project decisions tend to take a long time and even proj ects which eventually finish up successfully are sometimes subject to several critical decisions during their life-span. In these times the individuals in the project group may frequently ask themselves, wheth er their efforts are worth it. The rule should be that as long as there is no official decision to discontinue a project, everyone should continue unharmed by the ongoi ng discus sion. ,
.
,
7
234
Biomedicinical Product Development
5 .4 The Proj ect Manager
The success of any larger and complex pro ject depends to a great extent upon an effec tive project management. Development pro jects for medicinal products need project managers with a variety of skills and personal qualities to cope with the very demanding job (see Tab. 6). A good working knowledge in different scientific fields (e.g. , medicine, mi crobiology, immunology, protein biochemis try, pharmacology, toxicology) as well as in technical subjects (e.g., biotechnology, pro cess development, analytical methods, formu lation, manufacturing) are valuable assets for the planning and management of a project. Project managers must be prepared to contin uously learn about these aspects. It is not sufTab. 6.
Responsibilities of a Project Manager
Planning
Development of a project concept Definition of objectives, milestones, and deci sion points Definition of project tasks Scheduling of project tasks Planning of resources Replanning and updating of plans Coordination
Identification of shortages Reallocation of resources Negotiation of use of resources versus time performance Preparation and initiation of major decisions Organization and chairing of project meetings Special tasks as required ("putting out fires") Development and provision of missing skills Controlling
Cost monitoring Compliance with time frames (milestones) Compliance with quality criteria (objectives) Effective use of resources Adequacy of documentation Information
Effective communication among project group members Initiation of scientific and technical reports and documentation Progress reports Project presentation and justification to the management
ficient to rely entirely on the specialists, since good decisions and judgement need overview. Furthermore, it could be helpful to know the subject in detail, if resources and time per formances have to be negotiated. Management skills, certain personal char acteristics and psychological knowledge are required to coordinate and control the project and to maintain progress despite the unevita ble setbacks. Project managers must always think ahead, sense potential problems before they actually appear and devise measure to avoid them. Nevertheless, they must be pre pared to spend much of their time by solving unexpected problems and conf!icts and de fending their project against criticism which is raised from various sides as soon as a proj ect does not proceed smoothly. Project managers are always in the most prominent position when problems are tackled. They are the scapegoat and need a high level of resistance against frustration. Success will be claimed by everyone. Project managers need clear and adequate organizational structures with delegation of defined duties and authority. Delegating the responsibility for a project to the project manager means that the "ability to respond" (in French: responsabilite) must be given. Re sources and authority should be at the project manager's disposition to react according to the needs of a situation. For the benefit of the project, this must include the full authority to use the planned and agreed resources plus a certain degree of flexibility in special cases without the need for extensive discussions, negotiation, and approval procedures. The assistance and support of all proj ect group members is essential for a project man ager. Considering the fact that project manag ers have to impose very unpopular time, cost and quality control measures on their work, some individuals in the group may have diffi culties with accepting this. Project managers can fulfill their task only by delegating work to other members of the project group. (There will always be enough left for them to do. ) The presence of unqual ified or less agile project team members re veals itself by the repeated inability of certain individuals to achieve agreed objectives and milestones or much earlier by the fact that
5 Planning and Managing Product Development
others ( usually the p roj e c t managers) have to do essential parts of t h eir job. Another indi cation for weak s po t s in the project group a re peo p le w h o ' s p l a n n i ng an d re p o rti n g needs constant assistance and who do not actively and in time collect the information w hich they need for t he i r work. If pe r m anen t pressure mu s t be applied to ensure that o bj ec t i v es are met completely and in time . this c ou l d either indicate that neces s ary skills are missing or that the p roj e c t p la n was too ambitious and u na ch ie v a b le . Since the individuals should know best what they can or cannot achieve in a certain time. this can be av oid e d by a delegation of the pl a n ning of details ( and provi si o n of assistance where necessary ) to the funct i o n a l groups and to the individual project members. If the problems remain the same . the project man ager faces the very difficult task of c h a n gi n g the g ene r al attit ude and mo t i va t io n of the proj e c t g roup . B ut who motivates th e p roj e ct manager? For further re ad i n g about this su bjec t the classic a rt i c le The Project Manager by PAUL GADDIS ( 1 991 ) as well as the Harvard Busi ness Review. v o l u me Motivation a re recom mended (see References) .
5 . 5 Organizational Structures and Motivation An organization w h ich focuses enti rely on only one project should not h ave m aj o r i nter nal co nfl i c ts aoout resou rces. Such a '·task force " represents a largel y i nd e pe nden t group
within an organization with far-reaching com peten ce s . which is created tem p orarily and in e xcep t ional situations to solve a critical p rob lem or for v e r y large proj ects. Under normal circumstances different de partments
or groups
with d i fferen t
skills
con
trib u t e to one or several p r oj ect s besides their o w n r o ut i n e work, e.g.. in research. Some bod y within these departments is nom ina t ed as p roj e c t leader a n d continues to report to the head of his department. Qu i te often the differe n t leaders of these functional de p ar t m e n t s a c t u a lly lead the p r oje c t , each of them with a particular personal o p i ni on a n d p refe r -
235
ence . An overall responsibility and a coordi nating pe rson with a d equa t e a u t h ori ty is miss ing. A common solution to accomodate the needs of de v elo p m e nt projects is the creation of a matrix management structure. In a matrix orga nization a project ma n a ger is appointed, who reports d i rect l y to the h i g h e r manage ment and. as far as it concerns the p roject , is usually on an equal le ve l with the functional managers who control t h e resources. The au t ho r i t y of the p roj e ct manager reaches across the functional dep a r t me n t s . A matrix organization cle a rl y puts more emphasis on project work. Since in a commer cia l ly oriente d organiz at ion research p roj ects
with a higher p riori ty than develop ment pro j ec t s rare ly exist. it also stre n gt h e n s de velop
ment activities. In other words, if the func tion al d e par t m e nts conduct research and de v e l opment , conflicts between t h e se two activi ties are usually re so l v ed by giving the higher prior i ty to the d evelo p ment proj e ct . The matrix orga n izatio n does not abolish resource a n d p r iority conflicts between differ ent
projects
t h e se
and their managers. If
necessary,
conflicts have to be resolved on a higher level, either b y t he upper management or by a project s t ee ri n g committee. This s teeri n g committee acts as project mandator . ap p roves p roje ct plans . decides in case of conflicts and has the overall responsibility for product de v elo p ment . Th e p r oject managers should be members of the s t ee r i n g comm i t tee .
Matrix organ izations p rovide for an effi c ien t use of resources and a better coordina
tion across the functional departments (BARTLElT and G HOSHAL, 1 990). However, much t ime must be sp e n t on proper pl a nnin g, coord inat i on , ne go ti a tion a n d fi nd i n g agree ments about details. Pr oj e c t team members report at least to two bosses and have t o or ganize, n egoti a te and pri or i t i ze their work be tween their functional manager and one or several p roj e c t managers. The individual i n a matrix organization can be caught in a difficult situation and bears the u n p le as an t consequences if the structure does not function properly. This, as well as the in heren t ins tabil i ty of the system, may result in a situation where the individuals d i sre ga rd proj e c ts and set their own p rioritie s .
236
7
Biomedicinical Product Development
Tab. 7.
Main Motivation and Dissatisfaction Fac tors on the Job " Motivation results from: 1. Achievement
2.
Recognition 3 . Work itself 4. Responsibility 5. Advancement � Motivation is achieved on the individual level! Dissatisfaction results from:
1 . Company policy and administration 2. Supervision 3. Relationship with supervisor 4. Work conditions 5. Salary � Dissatisfaction must be avoided on the organi zational level !
The five most important factors on the job which motivate or lead to dissatisfaction, ranked accord ing to their importance. •
Organizational structures and administra tion have a significant potential for dissatis faction among the staff and thus may severely influence the overall performance of the or ganization. Tab. 7 lists the five major factors which can result in positive motivation or dis satisfaction at work. It was summarized from 1 2 different investigations and covers all hier archical levels and jobs in various organiza tions (HERZBERG, 1 986) . The message given by this table is rather clear: Dissatisfaction seems to be caused mainly by internal struc tures, supervisors, and general work condi tions. Discontent about the salary ranks rela tively low on this negative side of the list (and does not appear among the motivating fac tors ! ) . Changing the dissatisfaction factors which are criticized only by an individual per son seems difficult because this would in most cases affect the entire organization. If, howev er, the majority of staff complains about such aspects, changes must be considered serious ly. Motivation can quite simply and effectively be created by the delegation of recognizable sections of work or independent parts of a project along with adequate authority to make own decisions concerning these parts. This allows the individual to assume responsi bility, creates more interest in a given job and
makes sure that the individual 's achievements become visible and are recognized. Motivation appears to resemble biotechno logical products: they both have a tremen dous potential and are inexpensive and highly effective. In practice, however, their availa blility is rather limited because their applica tion is more difficult than expected. Acknowledgements I owe special thanks to GARY COBON and
JIM HUNGERFORD who critically reviewed
draft versions of this chapter and made many important suggestions for its improvement. My colleagues at Behringwerke AG, Bio tech Australia Pty. Ltd., and Hoechst AG contributed greatly to this work by providing good practical examples and competent ad vice at many occasions. At this place I wish to thank all those who shared their experience with me and who's cooperation I enjoyed during the past decade as an i mportant source of learning and motivation. The responsibility for the content of this chapter lies entirely with the author. The views and opinions expressed are those of the author and are not necessarily those of the persons and companies mentioned above.
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si t y of Belfast.
MARTINDALE ( 1 993), The Extra Pharmacopoeia, 30th E d . , London: The Pharmaceutical P r ess .
E., W I RTZ, T. ( 1 992), Effizientes Pro jektmanagement. D Ussel dorf: ECON V er l a g .
MEHRMANN, PRENT I S ,
R.A.,
WALK E R ,
TuCKER, A . M .
( 1 988 ),
S.R.,
HEA R D,
D.D.,
R & D investment a n d
p har m ace u t i ca l i n novation in t h e U K , Manageri al and Decision Economics 9, 1 97-203 . STAW, B . M . , Ross, J. ( 1 9 9 1 ) , K no w i n g when to pull the plug, in: Project Management, H B R 90053 , p p . 57-6 3 , Boston: H arvard B usiness School Press.
P . R . ( 1 991 ) , Are prescription drug high? Science 252, t 080-1 084. WITTE, E. ( 1969), Mikroskopie einer unternehme rischen Entscheidung, I B M 1 9 ( 1 93 ) , 490 (quoted
VANG ELOS,
p r ice s
a ft e r MEHRMANN and WIRTZ ) .
Bioteclrtwlog}'
E d i ted by , H . -J . Rehm a nd G. Reed in coop eration wit h A. Puhler and P. S tadler Co p yright © VCH Verlagsgesellschatt m b H , 1 995
Regulations for Recombinant DNA Research, Product D evelopment and Production in the US, Japan and Europe
8
- Analogies, Disparities, Competitiveness -
D IETER B RAUER Fran k furt a m Main , Fe deral R e pu b l i c
of
Germany
HORST DIETER SCHLUMBERGER Wuppe rtal .
I Introduction
2
USA
242
2 . 1 The N I H
Fed e ral Re public
of
G e rm a n y
24 1 G u id e l i n e s
242
R e v i ew Processes 243 D i re ct o r of the N I H . Recom b i n a n t DNA Advisory Committee O ffice of Re com b i n a n t DNA Activities ( ORDA) 243
2 . 2 Committees a nd Offices I nvolved i n 2.2. 1
2 . 2 . 2 I n stitutional Biosafety Committee ( I B C )
( RA C )
244
2.3 B i osafety L e v e l s . Cl assification and Re v i ew of Ex p e rime n t s
2 . 4 Large - Scale Uses of O rganisms C o n ta i n i n g
a n d Prod uction )
2.5 Construction
246
of B u i l d i n gs
2 44 Recombinant DNA Molecules ( Res e a rch
for Recombinant DNA Operations
248
2.6 P ro d uc t Approval and Production Facility 248 2 . 7 Sh i p me n t and T r an sp o rt o f Or ga n i sm s Con t a i n i n g rONA M a t e r i a l s 2.8 Field Test ing of Recombinant Organisms
and NIH
250
249
240
8
Regulations for Recombinant DNA Research, Product Development and Production
3 Japan 253 3.1 Introduction 253 3.2 Recombinant DNA Technology in Research, Product Development and Production 255 3.2.1 Containment Categories, Classification and Assessment of Experiments 256 3.2.2 Construction of Facilities for Research (STA and MHW Guidelines) 259 3.2.3 Construction of Facilities for Production (MHW and MITI Guidelines) 259 3.2.4 Field Trials (MAFF Guidelines) 260 4 European Union 264 4.1 Directive 90/219/EEC on the "Contained Use of Genetically Modified Microorganisms" 266 4. 1 . 1 Scope of the Directive 266 4.1.2 Classification of Microorganisms and Operations 267 4. 1 .3 Procedures and Duration of Obtaining a Permit 267 4.2 Directive 90/220 EEC on the "Deliberate Release into the Environment of Genetically Modified Organisms" 269 4.2. 1 Procedures and Duration of Obtaining a Permit for the 'Deliberate Release ' of GMOs 269 4.2.2 Procedure and Duration of 'Placing on the Market' of Products Containing or Consisting of GMOs 270 4.3 Directive 90/679/EEC on the "Protection of Workers from Risks Related to Exposure to Biological Agents at Work" 271 5 Concluding Remarks 271 6 References 276 ·
I Introduction
1 Introduction Th i s
ch apte r
compares
reg ul ation s of re
ope ra t i ons i n re p rod uct development and prod u ct ion of th e United States of America and of J a p an with t h ose of t h e E u r ope a n U nion. The Euro pean regulations are enacted in two rONA spe c i fi c EC Council D ire ct i ve s. 90/2 1 9/EEC and 90/220/E EC ( E E C . 1 990a . b ) . The de sc r i p t i o n of the U S a n d Ja pan e s e r e gul a ti o n s are base d on t h e respective g u i d e l ines , i n t e r vie w s a n d mat e ri al p r o vid e d by v ar io u s insti tutions such as u n i v ers i ti e s . government agen cies and i n d ust ry . The obj e ct i ve of this report is to p o i n t to the differe nces in re g u l a tion s for recombinant D N A ( rONA ) o pe r a t ions with respect to research. large-scale research. d e v e l op m e n t . p rod u ct ion and to t he deliberate release of re co m b i n a nt organisms. Proce dures for the approval of products and l ic ens ing ( e . g . . fo r drugs. d i ag n os tic s . foo d s an d seed s ) are not considere d . T h e United States did not adopt any specif ic l eg i sl atio n to r e g u late genetically modified o r ga n i s m s ( G M O ) or t h e i r prod uct s . The ha n dli n g o f G M Os is cont rol l e d by guidelines issued by the N ational Institutes of Health ( N I H ) w h i c h have be e n continuously ad juste d to scienti fic exp er ie nc e and progress. The government p o l i c y to s u p e rv i s e rONA activities and t h e i r prod u ct s applies existing l e gis la t i o n t h r o ugh three government agen cies: the Food a n d D r u g Admin istration (FDA ) . the A nimal and Plant Health I n s p ec tion Service (APH I S ) of the U S Department o f Agriculture ( C SD A ) a n d t h e E n v ir o n me n tal Protection Age n cy ( EPA ) . I n recent meas ures to furt h e r simplify the a pp l ica tio n of bio technology. t h e US government has d eci ded to a dh e re to a r i s k- ba s ed a p p r o a ch to guide review . This risk-based a pp ro a c h o f re g ul a to ry con t r ol i s scie n t i fica l l y sound an d pro pe r ly protects p u b l i c health and the e n v iro n m e n t a ga i n s t p o t e n t i a l h azards. and moreover. it avoids obstruc t i n g safe in n ov atio n s . Japan has extensive e x pe r i en ce in handl i n g micr o or g a n is m s i n biotechnological proce d u re s a s w e l l as i n m o n i tor i n g biot e ch n o logi c al production processe s. In th i s conte xt, the long-standing p r actic e has proven the value of combinant DNA ( r ON A ) search.
241
e m p loy i ng flexib le gui del ines i nstead of ri g i d l aws w h i ch - as a rule - are difficult to adapt to scientific progress. Japan has developed a review sy st e m for recombinant DNA technol ogy w h i c h can be eas i l y h andled and which is h ighly flex i b le. I t i s based on guideli ne s and has been si m pli fie d d u r in g the past years. Ja pan very c l o s e ly follows th e OECD recom m e n da t i on s. The OECD emp h as i ze d as early as 1 986 . on the basis of worldwide e x p e ri e nce . that novel risks are not i n vo l ved in experi ments a n d op e r at i o n s with ge netically modif ied organisms. D ep e nding on the na t u r e of t he recombinant DNA experimentation a n d the p r ope rties of the product. a v a ri e ty of g u i d e l i ne s issued by different ministries are to be considered. In the core areas - i.e., with r e ga rd to c las s ifi c a tio n and e va l u a tion of re combinant DNA o p e r a t ion s. as well as to the r esu ltin g conta inment leve l s - the diffe r ent guidelines are i de ntica l . De s pite the worldwide sa fe t y record of re c o mb i nant DNA t e ch n o lo gy , i.e., no rONA s pe c i fi c accidents have been rep or te d al though many t h ous a nd s of experiments have be e n carried out in thousands of l abor a t o ries and p ro d u ct i on p l a n t s , the Eu ropean Unio n ( E U ) has chosen a technology-specific ap pr oa c h for the regulation of recombi nant DNA t e c h n ol o gy . In co ntr a s t to the U nited States and Japan. it i s not the product and its application . that is primarily reg a r de d as a risk. but the methods by which p ro ducts are derived. This legal approach i s t e ch ni cally de s c r ibe d as "horizontal " as opposed to a "ver t ical ' ' . pro duc t -oriented re g u lato ry system. This leads to an o v e r l ap of s ev eral a pp r ov a l procedures for any biotechnological p r o d u ct; it is t i m e - co n s um i n g and expensive and hampe rs Eu rope a n competitiveness. The Eu ro pea n regulations a r e also extremely un usual i n that they a re de s igne d to re g u l a te i m a gin e d rather tha n real risks. At the time o f generat i on of th e r es p e ctive EC C ou n c i l Di rectives in 1 98 7 . the responsibility for the reg ulation o f b i ote ch no l o gy shifted from the ex perienced Di rec t o r at e General XII (Re search) and D ir e c tora t e General I I I (Econo my and Dr u g Approva l ) to the D i rectorat e General XI (Environment). In E u ro p e , the Directives disregarded the int e rn at i o n a l e x pe r i e nc e which h a d led 1 986 to the statement
242
8 Regulations for Recombinant DNA Research, Product Development and Production
of the OECD that "it is expected that any risk associated with the application of rONA or ganisms may be assessed in generally the same way as those with non-rONA modified organisms." In Europe, universities, research institutions as well as industry repeatedly ar gued in vain that there is no scientific evi dence that recombinant DNA technology would pose unique risks to human health or to the environment.
2 USA Biotechnology consists o f a set o f different processes and methods of which the most powerful tool is gene technology. The pro duction of organisms with new molecular techniques may or may not pose risks, de pending on the characteristics of the modified organism and the type of application. The Na tional Research Council (NRC, 1 989; OSTP, 1992a) has extensively reviewed the potential risks of introducing genetically modified or ganisms into the environment. The Council reached the general conclusion that organ isms, that have been genetically modified, are not per se of inherently greater risk than un modified organisms. In August 1 990, President BusH approved 'Four Principles of Regulatory Review for Biotechnology' (OSTP, 1 992b) which can be applied as general rule of regulatory review, as follows: 1. Federal government regulatory oversight
should focus on the characteristics and risks of the biotechnology product - not the process by which it is created. 2. For biotechnology products that require review, regulatory review should be de signed to minimize regulatory burden while assuring protection of public health and welfare. 3. Regulatory programs should be designed to accommodate the rapid advances in bio technology. Performance-based standards are , therefore, generally preferred over de sign standards.
A "performance-based standard" sets the ends or goals to be achieved, rather than specifying the means to achieve it, e.g., through a design standard. For example, a performance-based standard for contain ment would permit alternative biological approaches for assuring containment in place of a design-based standard requiring specific physical barriers. 4. In order to create opportunities for the ap plication of innovative new biotechnology products, all regulations in environmental and health areas - whether or not they ad dress biotechnology - should use perform ance standards rather than specifying rigid controls or specific designs for com pliance.
"Design-based" requirement may preclude use of biotechnology products even when such approaches may be less costly or more effective. For example, a require ment to employ specific pollution control equipment would prevent the use of inno vative biotechnology pollution remedia tion or control techniques. The new administration is continuing this policy. According to a policy statement by President CLINTON and Vice-President GoRE (1 993), "regulatory policy can have a signifi cant impact on the rate of technology devel opment in energy, biotechnology, pharmaceu ticals, telecommunications, and many other areas. " Therefore, the US regulatory policy will be reviewed in order to "ensure, that un necessary obstacles to technical innovation are removed and that priorities are attached to programs introducing technology to help reduce the cost of regulatory compliance. " 2 . 1 The NIH Guidelines
After the moratorium of Asilomar in 1 975, the "Guidelines for Research Involving Re combinant DNA Molecules" were promul gated by the National Institutes of Health (NIH) in June 1 976. These guidelines were revised several times whereby some relaxa tion of primarily restrictive provisions were achieved according to the state of science and
2
technology. The latest complete version of the NIH Guidelines was published on May 7 . 1 986 (NIH, 1 986a). On J uly 1 8, 1 99 1 t h e ap pendix K of the NIH Guidelines was intro duced addressing " Physical Containment for Large-Scale Uses of O rgan i sms Containing Recombinant DNA Molecules'' (N I H . 1 99 1 ) . Based o n the Biological Control Act ( 1 902), the original Food and Drugs Act ( 1 906) and the Federal Food, Drug and Cos metic A ct (F D CA) ( 1 938) , the Food and Drug Administration (FDA) is the regulatory agency which approves rO NA products. ex cept recombinant pesticides plants and ani mals. The NIH Guidelines apply to all rONA re search conducted at or sponsored by any in stitution recei v ing financial support from the Federal government. Alth o ugh the NIH Guidel ines are not binding for private compa nies, they have created a mechanism of com pliance for the private industrial sector. Fur thermore. indus try is required to comply with gener al safe ty standards issued by the Occu pational Safety and Health A dministra tion (OSHA) of the US D epart me n t of Labor. Appendix K of the N IH Guidelines which concerns the large-scale use of rONA organ ism s is particularly relevant to the private sector (NIH, 1 99 1 ) . Some cities such as Cam bridge and Worcester, Massachusetts. and Berkeley, California, have introduced local ordinances that require universities and in dustry to ob s erve the N I H Guidelines. There is no evidence that private companies in the United States did not follow and comply wi th the NIH Guidelines.
USA
243
B. Experiments which require I B C approval before initiation of the experiment C. Ex perimen ts which require IBC notifica tion at the time of i nitiation of the experi ment D. Expe riments which are exempt from the procedure of the NIH Guidelines .
To determine the different types of rONA experiments with respect to safety classifica tion and safety measures, different commit tees, offices and serv ices are a s signed for re view.
.
,
2.2 Committees and Offices
Involved in Review Processes A ccording to the NIH Guide l ines rONA experiments are divided into four classes: ,
A . E xperime nts
w h i ch re q ui r e specific " Re combinant DNA A dviso ry Committee (RAC)" review and app ro val by the "In stitutional Bi osafety Committee (IBC)" and the Director, NIH. before initiation of the experi m e n t
2.2. 1 Director of the NIH,
Recombinant DNA Advisory Committee ( RAC ) and NIH Office of Recombinant DNA Activities ( ORDA ) U nder the N I H Guidelines, the D irector is the final decision maker. He can over rule the advice of the RAC, as was th e case with the first somatic gene the rapy expe ri ments. Every action t a k en by the Director must meet the goal of achieving "no signifi cant ris k to health or the environment" by any rONA experiment. The Recombinant DNA Advisory Com mittee ( RA C) advises the Directo r NIH, concerning rONA research and meets three to four times a year. The committee consists of 25 members appointed by the Secretary, Health and Human Serv ices including the chair. At least 14 members are selected from auth o ri ti es knowledgeable in the fields of mo lecular biology or rONA or other scientific fields. At least six members shall be knowl edgeable in applicable law, standards of pro fessional conduct, the environment, public and occupational health or related fields. Representatives of Federal agenci e s shall serve as non-voting members. The chairman can install subcommittees w ith additional ex perts in order to investigate issues further. RAC meetings, including the agenda, are an nounced in the Federal Register and are open to public comment. The meetings are open to the public. The specific funct i on s and opera,
NIH,
,
,
244
8 Regulations for Recombinant DNA Research, Product Development and
tion procedures of the RAC are defined in the NIH Guidelines. The Office of Recombinant DNA Activi ties (ORDA) serves as a focal point for infor mation on rDNA activities and provides ad vice to all within or outside NIH including scientific and industrial institutions, Biosafety Officers, Principal Investigators, Federal agencies, State and local governments and the private sector. In the case of experiments that require both IBC approval and RAC review, the IBC has to submit the necessary informa tion to the ORDA which decides, whether RAC review is to be initiated or not. ORDA is responsible for reviewing and approving IBC membership. The Federal Interagency Advisory Com mittee on Recombinant DNA Research (In teragency Committee) is composed of repre sentatives from approximately 20 agencies, provides additional oversight and coordinates all federal rDNA activities. Its members are non-voting members of the RAC.
2.2.2 Institutional Biosafety Committee
( IBC)
The IBC supervises all rDNA work of an individual institution that is involved in rDNA research, development or production and often also assumes the function as a gen eral safety committee including general occu pational safety and health, and environmental protection. The IBC shall comprise no fewer than five members, so selected that they col lectively have experience and expertise to as sess the safety of rDNA experiments and any potential risk to public health or the environ ment. Large organizations usually establish an IBC with more than five members. The biological safety officer (BSO) is mandatory when research is conducted at the Biosafety level 3 (BL3), Biosafety level 4 (BL4), and at all large-scale operations. The BSO serves as a member of the IBC. For institutions that have to comply with the NIH Guidelines, two members shall represent interests of the com munity with respect to health and protection of the environment and shall not be affiliated with the institution. At federally funded insti-
Production
tutions, these non-affiliated members are usually appointed by the local Board of Health. Commonly, private companies have established an IBC and usually appoint two additional members from the community or experts from other public non-affiliated or ganizations (e.g. , universities). In the few sites with specific city ordinances (i.e., Cambridge, Worcester, Berkeley) and/or State laws that regulate rDNA operation, private companies are obliged to establish an IBC as requested by the NIH Guidelines. Except for experiments which require re view by the Federal Recombinant DNA Ad visory Committee, only the IBC reviews and approves experiments or must be notified of rDNA projects. The IBC has the competence to deal with all safety issues under the NIH Guidelines. The IBC meets regularly and has to submit an annual report to ORDA con taining a list of the IBC members and back ground information of each member on the request of ORDA. The registration docu ments submitted to the IBC for review are, however, not communicated to ORDA and, thus, remain confidential. Upon request, only those documents on research projects must be released under the Freedom of Information Act which are submitted to or received from Federal funding agencies. On request of the applicant, data involving important intellec tual property rights or production know-how are kept confidential.
2.3 Biosafety Levels, Classification and Review of Experiments
The NIH Guidelines introduced four biosa fety levels (BL1-BL4) which consist of com binations of laboratory techniques and prac tices and safety equipment appropriate to the potential hazards derived from the organisms used. Based on the "Classification of Etiolog ical Agents on the Basis of Hazard" pub lished by the Center for Disease Control (CDC) in 1974, a list of classified microorgan isms is included in the NIH Guidelines. These organisms are divided into five classes where by non-pathogenic organisms are in Class 1 and pathogenic agents are in Classes 2, 3, and 4. Class 5 agents comprise disease agents
2 USA
which are forbidden entry into the US by law. by US Department of Agriculture policy or which may not be studied in the US except at specified facilities ( N I H Guidelines Appendix B-III - Classification of Microorganisms on the Basis of Hazard ) . e.g .. the WHO Collabo rating Center for Smallpox Research in At lanta. It must be emphasized that the N I H Guidelines are based on existing experie nce and established approaches to the contain ment of pathogenic organisms. In addition. two levels of biological containment were in troduced which limit the survival of a host vector system and its dissemination in the en vironment. Recombinant DNA experiments are classified into four categories initially as sessed, judged and based on the experience obtained with similar non-modified organ isms. Meanwhile. a substantial amount of ex perience with organisms containing rONA molecules has accumulated. In addition to the NIH Guidelines. the National Cancer I nsti tutes recommend three safety levels for re search with oncogenic viruses which corre spond to the categories B L2 . BL3 and B L4. A
Experime nts that require review of the Recombinant DNA Advisory Committee. approval hy the IBC and the Director . N I H . before initiation are: A-1 Deliberate formation of recombinant DNAs containing genes for the biosyn thesis of toxic molecules.
A-3 Deliberate transfer of a drug-resistance trait to microorganisms that are not known to acquire it naturally, if such ac quisition could compromise the use of the drug to control disease agents in hu man or veterinary medicine or agricul ture. A-4 Deliberate transfer of recombinant DNA or DNA or RNA derived from re combinant DNA into human subjects. The requirement for RAC review should not be considered to preempt any other review of experiments with human sub jects. I nstitutional Review Board (IRB) review of the proposal should be com pleted before submission to NIH. This approval procedure of the RAC thus applies only to new types and certain speci fied experiments, e.g., with highly toxic mole cules or the deliberate transfer of recombi nant molecules into h uman subj ects (e.g., so matic gene therapy). Such experiments may only be initiated after review by the RAC and approval of both the Director, NIH. and the I B C.
B
Le t h a l it y for ve rtebr a t e s a t an LD;o o f less 100 na n o g r a m s pe r ki logra m body weight. e . g .. microb i a l toxins such as the bot u l i n u m toxin. t e t a n u s t ox i n . Shigella dysenter iae ne urotox i n . Specific approval has b e e n g i v e n for t he c l o n i n g i n E. coli K 1 2 D N A s con taining ge nes coding for the biosynt hesis of t oxic molecules w h i c h a re lethal to verte brates at 1 00 n a nograms to 100 m i c rogr a m s p e r kilogram body weigh t . Con t a i n m e n t lev els for t hese e x perime nts are also sp e c i fi e d in Appendix F of t h e NIH Guidelines (NIH. than
1 986h ).
A-2
Deliberate release into the environment any orga nism containing recombinant DN A . except certain plants, as specified i n Appendix L of the N I H Guidelines
of
( N I H . 1 986b ) .
245
C
Experiments that require IBC approval before initiation For experiments that require IBC ap proval before initiation, a short registra tion document must be submitted to the IBC which contains a description of: (i) the source (s) of DNA (ii) the nature of the inserted DNA; (iii) the hosts and vectors to be used; (iv) w hether a delib erate attempt will be made to obtain ex pression of a gene, and what protein will be produced; and (v) the containment conditions specified in the NIH Guide lines. The I B C has to review and ap prove the proposal before the experi ment is initiated. Experiments which fall under this procedure can be carried out at B L2 , B L3 and B L4 containment. For work with Class 5 agents an additional permit must be obtai ned from the US Department of Agriculture (USDA). Experiments that require I B C notifica tion simultaneously with the initiation of experiments
246
D
8
Regulations for Recombinant DNA Research, Product Development and Production
A registration document containing the information listed under B must be sub mitted to the IBC, which in turn shall re view the proposal. However, review pri or to initiation is not needed. The ex periments which fall into this category can be carried out at containment level BLl and comprise those in which all components derive from non-pathogenic prokaryotes and non-pathogenic lower eukaryotes. Exempt experiments Certain rONA molecules are exempt from registration and approval by the IBC. Examples are listed in the NIH Guidelines, e.g., DNA molecules which consist entirely of DNA segments from different species that exchange DNA by known physiological processes or DNA from a prokaryotic host when propa gated only in the same host organism (self-cloning).
It is estimated that approximately 80% of experiments reviewed by the RAC are de voted to the application of rONA technology to humans, e.g., by gene transfer protocols and somatic gene therapy. More than 99% of the experiments are classified into categories B, C and D. While experiments falling into category C can be initiated at the time of fil ing the notification, experiments classified into category B usually can be initiated within a few days after filing the registration form to the IBC. IBCs from universities and private companies are not required to send copies of the registration documents to ORDA, thus rONA experiments classified into the catego ries B, C and D are not published, as is often assumed and incorrectly stated by European regulatory authorities and politicians. Experiments that require BL4 containment can be reviewed and approved by the IBC. Such experiments are - unique in the United States - prohibited by ordinance in the city of Cambridge, MA. It is probably noteworthy that the NIH Guidelines reflect the "state of the art" and can be rapidly adapted to scientific progress and are considered "never (to) be complete or final, since all conceivable experiments in volving recombinant DNA cannot be fore-
seen. Therefore, it is the responsibility of the institution and those associated with it to ad here to the intent of the NIH Guidelines as well as to their specifics".
2 . 4 Large-Scale Uses of Organisms Containing Recombinant D NA Molecules (Research and Production)
Appendix K of the NIH Guidelines (NIH, 1991) specifies physical containment guidance for large-scale research or production involv ing viable organisms containing DNA mole cules ( > 10 liters of culture fluid). This ap plies to both large-scale research and produc tion activities, and addresses potential haz ards that may be associated with rONA or ganisms. Other potential hazards accompany ing large-scale cultivation of genetically mod ified organisms such as toxic properties of the products, physical, mechanical or chemical as pects of downstream processing must be con sidered separately. For large-scale operations, the NIH Guidelines apply with the following minor additions: •
•
The institution shall appoint a Biologi cal Safety Officer (BSO) with duties specified in the NIH Guidelin es (sec tion IV-B-4). The institution shall establish and main tain a health surveillance program for personnel engaged in activities that re quire BL2 and BL3 containment.
For large-scale operations four physical containment levels are established which are referred to as Good Large Scale Practice {GLSP) , BLl -LS, BL2-LS and BL3-LS. No provisions are made for large-scale research or production requiring BL4 containment. If necessary, the requirements will be estab lished by the NIH on an individual basis. Depending on the containment level •
discharges containing viable recombi nant organisms may be handled accord ing to governmental environmental reg-
247
2 USA
Organizational and technical safety specifi cations are provided in the N I H Guidelines and are summarized in Ta b 1 . To qualify for GLSP, an organism must meet certain criteria such as non-pathogenici ty and built-in environmental limitations, and must have an extended history of safe large scale use (OECD, 1 986) . With respect to
ulations (GLSP) or need to be inacti vated by a validated inactivation proce d u re (BL I -LS to BL3-LS). containment e q u ipment has t o reduce the potential for escape of viable or ganisms (BL I -LS) or to prevent the es cape of viable organisms ( B L2-LS and BU-LS).
•
.
Tab. 1. C.omparison of Te ch n ic a l and Organizational Measures of D i ffe re nt B iosafety Levels a t Large Scale Pract ices ( a dapted from NIH Guideline s • according to M E AGHER, 1 992)
Criterion
GLSP
B L l -LS
B L2-LS
B L3-LS
duce exposure to biological. chemical, or physical agents
•
•
•
•
clothing
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Provide written i nst ruction and training of personnel to re Provid e changing and h andwashing facili t ies and protec t ive Prohibit eati ng. drink ing. smoking, mouth pipet t i ng and ap plying cosmetics in the facility Develop e m e rgency pla ns for handling large spills Inactivate waste solut ions and m a terial in accordance with their biohazard pote n t i a l Use
a
validated prot ocol to ste r i l i ze closed vessels
•
Operate i n closed systems
Control aerosols by e ngineering or p roced u ral controls to prevent or minimize re lease of organisms during sampling, addition of materials. transfer of c u l tured cells, and remov
•
•
•
•
•
•
al of materials. products. and effluents from system to
•
•
Ensure med ica l surve i l l ance
•
•
Treat exhaust gases from a closed syste m c
Rotate seals and other penetrations into a closed syste m
•
•
desig ne d to prev e n t or m i n i m i ze leakage
•
•
tegrity of containment
•
•
Ensure permanent identification of closed systems
•
•
Incorporate monitoring or se nsing devices to mon i to r in Validate i ntegrity t e s t i ng of closed systems Post
a
•
universal biohazard sign on e ach closed syste m
Require controlled access t o facility ( double doo rs , a i r
•
• •
lock)
•
ensure in tegrity of con t a i n m e n t fe atures
•
and decontam i n a t i o n
•
Maintain closed syst e m at as low a pressure as possible to Design walls. cei l i ng. and floors to permit re ady cleaning
Protect u t il i t i e s and services against contamination
•
into the e nvi ron ment in the event of an accident
•
Design controlled area to precl ude release of culture fluid
d
Appe ndix K-1 - V, N I H G ui d e l ines ,
" In
,-
Fed. Reg.
56, 33. 1 78 ( 1 99 1 )
GLSP, m i n i m ize b y procedure ; i n B L l -LS, minimize b y engineering
In B L t - L S . m i n i m ize
248
8 Regulations for Recombinant DNA Research, Product Development and Production
practical applications of large-scale opera tions, this means that the construction of fa cilities is conducted according to the permit system outlined in Sect. 2.6 and that the IBC assesses the potential risks and determines the measures necessary to ensure occupation al and public safety. It is the IBC that deter mines the procedures to be followed in the case of an accident, e.g., containment and measures to handle a large spill. At the few city sites (Cambridge and Wor cester, Massachusetts) where local ordinances are in place, additional permits for rDNA large-scale operations must be obtained. The permit requires compliance with the NIH Guidelines and is issued commonly on an an nual basis and, usually, is renewed automati cally. In an amendment of the Municipal Code of the City of Cambridge such permits can since February 22, 1993 be obtained with out a public hearing.
2.5 Construction of Buildings for Recombinant DNA Operations
There are no regulations specific for this rDNA technology at Federal and State level with regard to construction of buildings, i.e., laboratories, pilot (up-scaling) and produc tion plants, to conduct research, product de velopment and production. In general, any building owner has to acquire a variety of permits from the competent State or city au thorities according to respective Federal and State laws and city ordinances. These permits include safety issues with regard to construc tion, fire prevention, electricity, waste and waste water management. At this level, there are no specific requirements for technical construction of laboratories or other facilities, e.g., specific containment requirements, equipment or even specific demands for the intended use of the building. It is, however, required that the characteristics and the ex pected amount of waste water are outlined in order to obtain the necessary permit for the connection to public waste water processing plants. A certified architect, the construction com pany and representatives of the owner submit
a construction plan of the building, and plans for technical installations, i.e., electricity, plumbing etc., to the competent city depart ment in order to obtain the permits. The building permit is usually granted within 1 to 3 weeks so that construction work can start immediately. For obtaining other permits at State or Federal level, e.g., FDA approval for experimental animal facilities, more time may be needed. However, these permits are usual ly obtained at the time when the construction work is concluded. Partial permits can be ob tained for construction work, electrical instal lations, plumbing, etc. This speeds up con struction work and helps to reduce costs. During the different stages of construction the progress of construction is supervised by inspectors from the respective State or city authorities. After completion of the building, the occupation and the use of the building is granted by issue of the "Certificate of Occu pancy". There are no differences in the administra tive approval procedures for setting up facili ties for chemical, bacteriological, immunolog ical or recombinant DNA operations, in al most all locations in the US. Cities like Cam bridge and Worcester (Massachusetts), and Berkeley (California), require an additional permit f