Wandering in the Gardens of the Mind: Peter Mitchell and the Making of Glynn

Wa n d e r i n g i n t h e g a r d e n s o f t h e m i n d

John Prebble Bruce Weber Foreword by Sir Tom Blundell

Wandering in the

1 2003

peter mitchell and the making of glynn

Gardens of the Mind

1 Oxford New York Auckland Bangkok Buenos Aires Cape Town Chennai Dar es Salaam Delhi Hong Kong Istanbul Karachi Kolkata Kuala Lumpur Madrid Melbourne Mexico City Mumbai Nairobi São Paulo Shanghai Taipei Tokyo Toronto

Copyright © 2003 by Oxford University Press, Inc. Published by Oxford University Press, Inc. 198 Madison Avenue, New York, New York 10016 www.oup.com Oxford is a registered trademark of Oxford University Press All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of Oxford University Press. Library of Congress Cataloging-in-Publication Data Prebble, John, 1944– Wandering in the gardens of the mind : Peter Mitchell and the making of Glynn / John Prebble, Bruce Weber. p. cm. Includes bibliographical references and index. ISBN 0-19-514266-7 1. Mitchell Peter Dennis. 2. Glynn Research Institute. 3. Biochemists— England—Biography. I. Weber, Bruce, 1941— II. Title. QP511.8.M58 P73 2002 572′.092—dc21 2002075411 [B]

9 8 7 6 5 4 3 2 1 Printed in the United States of America on acid-free paper




To Pat and Kathy

Preface




In many ways, biological science came of age in the twentieth century. Among the large number of scientists who brought about the new understanding of living things was Peter Mitchell (1920–1992). Mitchell is important in twentieth-century biology because he was the major figure responsible for bringing about a paradigm change in biochemical thinking about metabolic energy and discovering the link between metabolic energy and the transfer of substances across membranes. He himself undertook something of a crusade in the 1950s in trying to bring together thinking about physiological transport across membranes and thinking about the general metabolism of cells largely conceived as taking place in undifferentiated solution. While Mitchell regarded his ideas on the relation between transport and metabolism as his major contribution, the world remembers him for a derivative of these ideas—the chemiosmotic theory developed in the 1960s and 1970s. This theory explained a phenomenon, which had baffled biochemists since Engelhardt, Kalckar, Ochoa, and others first described the process of oxidative phosphorylation, whereby metabolic energy of oxidation is conserved as ATP (adenosine triphosphate), the energy currency of the cell. There are other reasons for writing a biography of Mitchell. Apart from developing the chemiosmotic theory, which solved a long-standing problem, he engaged in other creative activities. Endowed with family money, he set out to prove that it was still possible to set up and run a small independent research institute, the Glynn Research Institute. This he did with his lifelong associate, Jennifer Moyle. The award of the Nobel Prize in Chemistry to Mitchell in 1978 not only provided recognition of his contribution to biochemistry but also, at least in his

eyes, justified the existence of the institute. To date, there have been two biographies of Mitchell: a short authoritative Royal Society biographical memoir by Bill Slater and a short unpublished manuscript by Milton Saier. Essentially, Mitchell is that rare breed of scientist, a theoretical biologist. He believed in thinking about science almost as an activity in its own right, and, unlike his older contemporary Hans Krebs, Mitchell proposed complex theories before proceeding to test them. The words of our title appear on a plaque in the garden of remembrance created by Helen Mitchell and reflect the spirit with which Peter Mitchell approached biology. All of these aspects of Mitchell’s life, and many others, are why we feel a life of Peter Mitchell is needed. The history of the remarkable achievements of twentieth-century biochemistry is only beginning to be written, with but a few biographies so far published. It is our intention that this biography of Peter Mitchell will tell one important story of this stream of human endeavor. One of us (J. P.) first heard Peter Mitchell lecture in 1956 and was fascinated by his approach to biological thinking. Although he heard him lecture many times over the years, he did not get to know Mitchell until late in his life. The other (B. W.) first interviewed Mitchell in 1979 and carried out many more interviews over the ensuing years. Both of us have interviewed, and corresponded with, many biologists and members of the family over recent years. We owe a great debt to those who had the patience and were prepared to give time to answering our questions and telling us about Mitchell. We are especially indebted to Mrs. Helen Mitchell for her interest, encouragement, and help and to Dr. Jennifer Moyle for her help. We would also like to record our appreciation of the advice offered by Professor Mårten Wikström (University of Helsinki) on chapters 9 and 11 and to Dr. Harmke Kamminga (University of Cambridge) on chapters 3 and 4. The biography is based primarily on interviews with Mitchell himself, discussions with scientists who knew him, and his published papers, but particularly on the extensive files of letters and other papers he left when he died. While this work has been proceeding, Mitchell’s papers have now been catalogued and are housed in the library of the University of Cambridge. The letters are mostly from the Glynn period (1964–1992), although there are some from earlier years. Thus the major resource for the early period has been interviews, while the later years have relied heavily on archives, principally Mitchell’s archives, but we have also drawn to a

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limited extent from Professor E. C. Slater’s archives at Haarlem in the Netherlands. Wherever possible, significant points have been confirmed from more than one source, and we have consulted published records such as the Cambridge University Reporter for the Cambridge period (1939–1955). Mitchell was a very complex person, and we have discovered people’s memories of events in which he was involved, and their feelings about him, vary widely. We offer this biography as our best interpretation of his life on the basis of the material available to us, but we are aware that some of his contemporaries will have different views. Mitchell left relatively few laboratory notes, and the ones we found are almost exclusively from the Edinburgh period (1956–1963). He did not keep good records of his experiments, and those that have survived are sketchy; they can be interpreted only with difficulty and some uncertainty. They were originally housed in binders, but by the time we saw them in the last days of the Glynn Research Institute, they were almost all loose and mostly undated. During the Glynn period, the laboratory notes were probably kept exclusively by Jennifer Moyle, who, regrettably, has forbidden access during her lifetime. There are special problems about writing a scientific biography of a twentieth-century scientist, which relate to the nature of the science. While the central reason for writing about Mitchell is the achievement of his science, the essential character of that science itself is not easily conveyed to the reader because of its extremely technical nature. We have endeavored to simplify the biochemistry but realize that, to biochemists, we will be seen to have glossed over, and on occasions misrepresented, important details of Mitchell’s and also other scientists’ work. We also appreciate that our attempts to eliminate the technical detail may not have gone far enough for some readers, and, to give some assistance to them, we have added an appendix on the theories of oxidative phosphorylation. We would like to acknowledge the help of Dr. Peter Rich, who succeeded Peter Mitchell as director of the Glynn Research Institute and who gave us access to Mitchell’s papers before they were transferred to Cambridge. The many others who have given us their time, advice, and support are listed in the acknowledgments. Their generosity and friendship are greatly appreciated. We are indebted to our editor, Kirk Jensen, and his colleagues at Oxford University Press for their help. Finally we are most grateful to Professor Sir Tom Blundell for

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agreeing to write the foreword to this work in which he has shown interest and given encouragement. Royal Holloway, University of London California State University, Fullerton and Bennington College, Vermont October 2001

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J. P. B. W.

Ac k n o w l e d g m e n t s




We express our appreciation to the following for giving us interviews: Angelo Azzi Giovanni Azzone Harold Baum Paul Boyer Martin Brand Marie Cassidy Britton Chance Brian Chappell Tony Crofts James Danielli Mary Danielli Helen Davies Robert Davies David Deamer Lars Ernster Peter Garland Keith Garlid David Green Edward F. Hartree Y. Hatefi Julia Heffer (née Mitchell) Peter Hinkle Eva Ibbotson Baz Jackson André Jagendorf Hermann Kalckar

Douglas Kell Sir John Kendrew Arnost Kleinzeller Margot Kogut C. P. Lee Albert Lehninger Alan Maddy Aubry Manning Vanessa Martin Eileen McNeil (formerly Eileen Mitchell) Helen Mitchell Jeremy Mitchell Peter Mitchell Murdoch Mitchison Harold Morowitz Jennifer Moyle Don Northcote Sam Perry Max Perutz Lord George Porter Ef Racker Bob Reid Bryan Robertson Daniel Robertson Sir Rutherford Robertson

Fred Sanger Vladimir Skulachev Bill (E. C.) Slater Jui Wang

Ian West Mårten Wikström Bob Williams John Wrigglesworth

We would also like to acknowledge those who corresponded with us about Peter Mitchell: Ernest Gale, Eva Ibbotson, Yasuo Kagawa, Joan Keilin-Whiteley, James Moore, Harold Morowitz, Jennifer Moyle, Sandy (A. G.) Ogston, Sir Rudolph Peters, Sir Rutherford Robertson, Bill (E. C.) Slater, Nobuhito Sone, Ian West, and Mårten Wikström. We wish to acknowledge financial support from the American Philosophical Society (B. W.), Burroughs-Wellcome (B. W.), the National Science Foundation (B. W.), and the Wellcome Trust (J. P.). We express our appreciation to those who kindly read all or part of the manuscript: David Depew, Chuck Dyke, Ann Marshall, Gideon Mitchell, Harold Morowitz, Jack Pridham, and Peter Rich. However, any errors are solely our responsibility. We are grateful to those who have given permission to reproduce material from their published work or letters to Mitchell or others: Helmut Beinert, Paul Boyer, Britton Chance, Brian Chappell, Michael Gordon, Franklin Harold, Peter Hinkle, Andre Jagendorf, Jennifer Moyle, Sergio Papa, Gottfried Schatz, Bill (E. C.) Slater, Ian West, Mårten Wikström, and Bob (R. J. P.) Williams. We acknowledge the permission of the Cambridge University Library to reproduce material from Peter Mitchell’s letters and unpublished material. Finally, we wish to thank Professor Britton Chance and Dr. Helen Davies for copies of letters and Mrs. Helen Mitchell for her diary of the Nobel Prize celebrations and Peter Mitchell’s diary for the refurbishment of Glynn.

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acknowledgments

Contents




Foreword, by Sir Tom Blundell Chronology

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1

Prologue: Who Was Peter Mitchell?

2

Early Years and Education: 1920–1939

3

The Early Cambridge Years: 1939–1947

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Research at Cambridge: 1947–1955

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Edinburgh: 1955–1963

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The Creation of Glynn: 1962–1965

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Testing the Theory: 1965–1968

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Exploring the Implications of the Theory: 1969–1973

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Getting the Arithmetic Right: 1974–1976

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From Review to Nobel Prize: 1977–1978

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11

The Cytochrome Oxidase Controversy: 1977–1986

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Science for Humanity: 1985–1992

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Epilogue: Mitchell and Glynn

3 10 24 44

64 96 115

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Index

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248 269

Appendix: Theories of Oxidative Phosphorylation Notes

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278

Foreword




The popular image of science bears little relationship to what most innovative scientists do. Stories in the newspapers often depict science as strong on authority, reinforcing the image of the scientist as an expert who can reveal truths that are unassailable and unalterable.1 Science writers who use a detective story approach to scientific explanation reinforce the same sense of certainty. Many science students consider scientific theories to be unchanging and offer exact predictions. Scientific experiments are often considered exercises that have a right answer that students fail to deliver most of the time.2 Science is characterized as from unanswered questions to unquestioned answers. For those who have such views of science, this biography will come as a shock. Peter Mitchell was a larger-than-life individual who changed the way we think about the key processes of energy metabolism and membrane transport in living organisms. His work was surrounded by controversy and uncertainty. For several decades two theories—or perhaps more correctly, hypotheses—competed with his for recognition, in what was known as the “ox phos wars.” Mitchell and his talented experimentalist coworker, Jennifer Moyle, had to repeat many of the experiments on which they had based their theory as they were challenged elsewhere in Europe and in the United States. Even when Mitchell had received the Nobel Prize for his work, there was still uncertainty and controversy about detailed mechanisms. Of course, Mitchell was an unusual scientist. He was brought up in upper-middle-class affluence, with money from one of the U.K.’s most successful builders, which was run by his uncle. Not too many research students could afford a Rolls Royce in Cambridge in the 1940s. By in-

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stinct he was nonideological; he despised what he characterized as the hothouse atmosphere of Marxism that he found in the department of biochemistry in Cambridge. Those who knew him in Cambridge at that time found that he had an assurance and ruthlessness found amongst the rich. He dressed flamboyantly and wore his hair long, looking like Beethoven. His natural independence of mind was reinforced by the confidence of his class. But Mitchell did not have things all his own way. His undergraduate exams were not a success; he gained only a third-class pass in his first year at Cambridge University. His Ph.D. dissertation was a mixture of theory and somewhat unrelated experiment; he was asked to resubmit by his examiners. Indeed, even at this early stage in his career, his main interest was to establish a theoretical framework, devising experiments only thereafter. Whereas this approach was accepted as necessary in some areas of theoretical physics and astronomy, where experiments are difficult and expensive, it was certainly unconventional in the life sciences. For a community that was used to devising experiments in a series of careful steps, each arising out of the previous, this approach raised eyebrows. It also led to the appearance, and probably to the practice, that experiments needed as controls had not been done appropriately. Indeed, this was the view of Hans Krebs, another Nobel Prize winner, on listening to one of Mitchell’s early talks. Biochemistry in Cambridge is now a large department with over four hundred researchers. In the 1940s, when Mitchell started his research, it was known as the Dunn Institute of Biochemistry and was much smaller. It occupied less than a quarter of the present space, but with a cabin annex and space made available in the neighboring Molteno Institute. It had been established twenty years earlier by Frederick Gowland Hopkins, who won the Nobel Prize for his work on vitamins and who advised the U.K. government on nutrition during the First World War. It had become the center of biochemistry in the United Kingdom during the 1930s, welcoming many who were fleeing from Nazi Germany, including Hans Krebs, but also including major figures like J. B. S. Haldane and Joseph and Dorothy Needham. Contemporary with Mitchell were other future Nobel Prize winners, Fred Sanger and Rodney Porter. The department was clearly a very exciting place where scientific history was being made by many talented researchers working cheek to jowl. When challenged by my colleagues now about the insufficient space they have for their experiments in the present department of biochemistry, I have occasionally remarked that it is presently

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much greater than that allocated to Mitchell, Porter, and Sanger fifty years ago, and they all got Nobel Prizes! But in reality, space seems to have been as much an issue then as now. Mitchell was a controversial figure in many ways. His unusual methods of approaching his science clearly contributed to his success in pursuing his ideas, but these approaches were often seen as weaknesses by his peers. His preference for working things out from first principles was certainly a strength when a shift in paradigm thinking was required, but it was often perceived as a failure to review the literature carefully as a first step. Moreover, he did not seem to like reading, a feature evident from his school days. The authors often refer to his interest in philosophy, but chiefly to his reading of Ogden and Richards’s Meaning of Meaning, and also to Popper and Heraclitus. And he clearly did not join the many others who listened to the influential lectures of Wittgenstein, Ayer, Russell, and others in Cambridge at the time. Later, he did realize that he had not read around his subject properly, and only then spent time reviewing the complex biochemistry of oxidative phosphorylation. Mitchell had a very focused approach to supervision of research. He was reprimanded early in his career at Cambridge for setting goals that were too well defined for the research student whose work he was supervising. One wonders whether his approach was appropriate for research training. But his interaction with Jennifer Moyle through several decades of collaboration was remarkably successful. He was also appreciated by his technical staff at Glynn. And of course it worked: he developed a new area of science, with a relatively small team, and without much of the infrastructure on which other institutions depended. In reading this biography, I found myself often asking whether Mitchell needed to be so uncompromising about his science. Perhaps it was necessary to sustain his more holistic approach in terms of the strong theoretical framework of the chemiosmotic theory. But perhaps it was more his nervousness about having his theory diluted and his ideas lost in the process. I still find his treatment of the debate with Bob Williams, the very imaginative and original Oxford chemist, quite extraordinary. An open publication of their extensive correspondence in the 1960s, together with a recognition that it had taken place, would have allowed a more balanced assessment of the development of the theory and would have been a fair response to Williams’s generosity in discussing his ideas earlier. Mitchell’s reactions to the conformational model of Paul Boyer are also difficult to understand, especially with the advantage of the sub-

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sequent work of Boyer, John Walker, and others. It is clear that conformational change does play a major role in coupling transport and metabolism and in many of the concepts complementary to those of the chemiosmotic theory. But then it does take an extraordinary person to secure a paradigm shift in scientific thinking. This biography makes it clear that Peter Mitchell was such an extraordinary person. Cambridge August 2001

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Tom Blundell

Chronology




1920 Mitchell born in Mitcham, Surrey, England 1931 Entered Queen’s College, Taunton 1939 Entered Jesus College, Cambridge 1942 Graduated in biochemistry with upper second class honors 1944 Married Eileen Rollo 1948 Collaboration with Jennifer Moyle commenced 1951 Awarded the Ph.D. degree 1954 First marriage ended 1955 Moved to Edinburgh University to set up the chemical biology unit in the zoology department 1958 Married Helen Robertson First published use of the term chemiosmotic 1961 Published the first version of the chemiosmotic hypothesis 1963 Resigned from appointment at Edinburgh University 1964 Established with Moyle Glynn Research Ltd. and the Glynn Research Laboratories at Bodmin, Cornwall, England Beginning of the further evaluation of the chemiosmotic hypothesis 1966 The revised version of the chemiosmotic theory published 1972 Failed ear operation renders Mitchell almost completely deaf 1975 Publication of the Q cycle 1977 Nervous breakdown

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1978 Awarded the Nobel Prize for Chemistry Name of the laboratories changed to Glynn Research Institute 1981 Awarded the Copley Medal of the Royal Society 1983 Retirement of Jennifer Moyle 1985 Glynn Research Ltd. renamed Glynn Research Foundation Ltd 1986 Conclusion of the disputes on the arithmetic of proton translocation 1987 Mitchell retired 1990 Celebration of Glynn’s silver jubilee 1992 Death of Peter Mitchell 1996 Glynn Research Institute closed 1998 Glynn Laboratory of Bioenergetics opened at University College, London

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Wa n d e r i n g i n t h e g a r d e n s o f t h e m i n d

1
Prologue Who Was Peter Mitchell?

The life of Peter Dennis Mitchell (1920–1992), like that of most people, is characterized by complexities, contradictions, and paradoxes. Biographers, to the extent that they succeed, can capture only partially the richness of the phenomenon of another human being and his or her action in the world. Our knowledge is limited, no matter how much detailed information is available. Thus this biography inevitably represents an interpretation of Mitchell’s life from several of the numerous perspectives possible. This problem is compounded by the fact that the subject was a scientist, and much of Mitchell’s creativity and passion were engaged in activities that required both a technical and a specialist knowledge. Hence, there is a need to balance the personal and the scientific, as well as to endeavor to make the science as accessible as possible to a broader audience. Moreover, in this book we deal with an additional factor, the “life” of Mitchell’s private, independent research institute, the Glynn Research Foundation. Peter Mitchell, British biochemist and Nobel laureate, brought about a paradigm shift in one area of biology—bioenergetics, the field that looks at obtaining and using energy in cells. Although initially an academic in Cambridge and Edinburgh Universities, he became disillusioned with university life and set up his own research institute at Glynn near Bodmin in Cornwall, England. To house his institute satisfactorily, Mitchell bought a derelict Georgian manor house, which he renovated, giving part to the institute and keeping part for a family home. While the roots of Mitchell’s science are in his education and experiences at Cambridge and early career at Edinburgh, it was at the Glynn Research Institute that Mitchell developed, deployed, tested, and

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argued for his ideas about energy transformation in living cells. When he founded Glynn in the early 1960s, Mitchell consciously undertook a double experimental program. First, he set out to test his theory (originally formulated while he was in Edinburgh); second, he sought to find out whether world-class science could be accomplished in a small institute, remote from the usual pressures of university life, but also without the supportive environment of academic science. In both of these he was successful. Peter Mitchell’s life spanned much of the twentieth century. His formal education was drawn from the ethos that prevailed in England up to the Second World War. His initial head of department at Cambridge, Sir Frederick Gowland Hopkins, had fashioned the department at Cambridge in the prewar years, and his ideas had dominated the field far beyond. Mitchell was nurtured in the intellectual milieu of that period. However, he made his contribution to biological thinking in the second half of the twentieth century, which was a very different world. His major contribution—the theory for which he is most remembered, the chemiosmotic theory—was not formulated until 1961 and was not properly understood in the field until the 1970s. It was in this latter decade that the bioenergetic community finally felt the full force of his ideas.



Mitchell’s Achievement, Contributions, and Controversies

Mitchell’s two major contributions to biology, well documented in contemporary textbooks of biochemistry, concern the link between the oxidation of foodstuffs by oxygen and the conservation of energy as ATP (adenosine triphosphate). ATP is the energy currency of the cell and is formed in the small particles (organelles) in the cell that are known as mitochondria. The link between ATP formation and the oxidation of foodstuffs had been a mystery that puzzled biochemists for some thirty years. To try to solve the puzzle, a hypothetical chemical intermediate had been proposed, but despite enormous effort and expenditure of money, particularly in Europe and North America, such intermediates could not be found. One philosopher regarded the field as having reached a state little short of crisis. It was against this background that Mitchell proposed his chemiosmotic theory in 1961, his first major contribution, which described the link between oxidation (cellular respiration) and ATP synthesis (phosphorylation) as a gradient of protons

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(with an accompanying electrical potential) across a biological membrane. Oxidation (respiration) would create the gradient; the gradient would be used to drive ATP synthesis. Therefore, while his contemporaries saw the link as a chemical substance, Mitchell saw it as a gradient of protons (with an accompanying electrical potential). Such a fundamental change in thinking was not easily accepted, and it took at least a further fifteen years for most of the field to accept Mitchell’s proposals, a period of much debate that often became contentious. Mitchell’s second major contribution, in 1975, was to propose a mechanism whereby some of the protons were moved across the membrane; this became known as the Q cycle. While the Q-cycle proposal can be seen as an adventurous and imaginative interpretation of the available experimental evidence, the original chemiosmotic theory lacked any direct evidence when it was formulated. It is true that there was circumstantial evidence, mainly drawn from other fields of research, but the question arises for the chemiosmotic theory: Where did it come from? Such a question is best answered within a consideration of Mitchell’s life and thought. Mitchell was endowed with a strong personality, and without it he might never have emerged as one of the significant figures of twentiethcentury biology. At a cursory glance, his life might seem to be a series of disputes that commence as early as the Cambridge period. The most important controversy concerned the mechanism for gaining energy from the oxidation of foodstuffs, the chemiosmotic theory. Here he eventually surmounted initial hostility to his ideas from the leaders of the research community, whose views he sought to change. In 1978 he was the sole recipient of the Nobel Prize in Chemistry. This award reflected Mitchell’s achievement not only in solving a major problem in twentieth-century biochemistry and cell biology but also in unifying several areas of research within a common conceptual framework. Further, it confirmed that significant research could be conducted at a small institute, such as Glynn. As often happens with the Nobel Prize, there was controversy in some quarters about Mitchell’s selection and a dispute over the originality and priority of his theory, which continues to this day. Even as Mitchell triumphed in getting the qualitative aspects of his theory accepted by most of his peers, new disputes broke out. The controversies that emerged in the mid-1970s concerned the quantitative aspects of his proposals and lasted for a further decade. They involved both the detailed mechanisms for moving protons across membranes, as proposed

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by Mitchell, and the quantitative results obtained in Mitchell’s and other laboratories. This second round of controversies mostly went against Mitchell. Mitchell’s last years were spent reformulating aspects of his theory to bring it into accord with experimental findings and attempting to secure funding and a stable future for the Glynn Research Institute as an independent entity. Glynn did survive Mitchell’s death in 1992, but only for a few years. Mitchell is regarded as one of the “superstars” of biochemistry. His picture is included in many contemporary textbooks of biochemistry, where the basic insights of his chemiosmotic theory are presented as a central and unifying conceptual framework, tying together what had previously appeared to be disparate phenomena. Indeed, Mitchell was featured in a millennium essay in Nature, where his contribution was compared with that of Darwin and Einstein.1 This echoed earlier appraisals that likened Mitchell’s contribution in cell bioenergetics to a paradigm change comparable to the Copernican,2 although it is too early to know whether such views are justified.



Mitchell the Man

Anyone who met and interacted with Peter Mitchell was impressed by the originality and force of his intellect and personality. They usually also responded to an impishness and youthful demeanor and to the energy and enthusiasm of his wide-ranging interests. He could be formidable and playful, simultaneously or by turns. He valued gentleness, but he could be as aggressive as any scientist who competes at the highest levels. People were drawn to his elfin looks and to his charm. Mitchell’s last days were characterized by both an élan and grace, according to one eyewitness, that reflected his life. But what of Mitchell the man who left an indelible mark on the history of twentieth-century biology? Through most of his life Mitchell had no shortage of money. His parents lived a very comfortable but not ostentatious life. It was his uncle, Godfrey Mitchell, known as “Uncle G,” who was a very successful businessman and who endowed Peter Mitchell with both money and a window into the commercial world. This family background instilled in Mitchell a confidence and entrepreneurial sensibility that marked him throughout his life.

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Indeed, it was Mitchell’s supreme confidence and fierce independence that characterized his approach to science, coupled with an ability to figure out things on his own. He possessed a self-assurance about the correctness of his insights into nature that almost, but not quite, bordered on arrogance. He preferred learning something new by thinking about it from first principles rather than reading accounts in standard textbooks, a habit started in his schooldays that continued throughout his career. Early in his life, his artistic temperament expressed itself in a deep love of Romantic music and visual art, and as a student he affected the hairstyle and general demeanor of Beethoven, as is evidenced in the sketch of him at that time by the artist Elizabeth Vellacott. Later in his life, deafness severely hampered his ability to enjoy music. He was a colorful and somewhat eccentric dresser. There was a flamboyant aspect to Mitchell, certainly in his younger days, when he wore vibrant coats and pants; later, after he received the Nobel Prize, he sported an earring. The choice of the fine Georgian house at Glynn, in which he accommodated his family and the institute, was consistent with this aspect of Mitchell’s self-image. Through the formality of the institute’s founding and management, he sought to give his institute an administration comparable to that of much larger bodies. Mitchell’s confidence, creativity, and love of independent action shaped his approach to science and to much else. He had no hesitation in extensively remodeling the first two homes he owned, and, moving on from that experience, he enthusiastically undertook the two-year restoration of Glynn House by directing the work. Subsequently, he restored a number of ancient buildings in Cornwall. Mitchell, a city boy and academic, took on running a dairy farm that was initially part of the Glynn House complex of buildings, and he won awards for the quality of the cream. He also engaged in various quixotic activities such as minting his own silver “Glynn pieces”; he initiated schemes, which did not come to fruition, for bottling and selling spring water from the estate, and he designed a windmill for electricity generation.



Mitchell the Scientist

Much of Mitchell’s approach to science can be understood in terms of his personality. He had a passionate, creative, confident, and imaginative engagement in his research. His strength lay more in the development of theory rather than in the life and work of the laboratory. His

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highly imaginative mind, coupled with his artistic temperament, gave him the ability to develop a unique approach to the study of living things. Although his work centered on the study of cell membranes and membranes in small particles within cells (mitochondria and chloroplasts), it was derived from a consideration of the basic properties of living things. In contrast to most biochemists of his generation, Mitchell felt that understanding the molecular basis of life was best accomplished by an intense formulation of theory, which became the driving force for experiment, rather than the empirically driven experimental approach of most biochemists of his day. Mitchell had a deeply intuitive sense of how chemical processes in living beings were organized, which grew out of his own philosophy. He developed a way of thinking about the relationship of static biological structures with dynamic processes; he felt such ideas were supported in the work of the pre-Socratic philosopher Heraclitus. Thus his abiding metaphor for a living system was the flame, which is sustained as molecules pass into it, undergo reactions (burning), and pass out again as the products of combustion. This gave him a three-dimensional view of molecules passing into a cell and undergoing metabolic reactions, then the products leaving the cell. He saw the membrane as controlling these processes, and the study of movement of substances across membranes linked to metabolism gave him his insights into how biological systems worked. This represented a type of personal knowledge and an interpretative principle that was foundational to his creative scientific thought. The principle was one source of his successful insights, as well as a possible reason for his reluctance to give up aspects of his mechanism in the face of contrary evidence in the post-Nobel period.



Glynn

Mitchell had difficulty working within systems and in particular with authority when it impinged on his freedom of thought and action. This trait limited his academic career in the department of biochemistry at Cambridge in the early 1950s, leading him to seek the somewhat more open structure of the department of zoology at Edinburgh. Ultimately, his efforts to work even within this more congenial environment were frustrated; he found university life too onerous, and this led to a deterioration of his health and to his resignation from Edinburgh.

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He was fortunate to have considerable money available from his family, such that, in 1964, he was able to fund Glynn Research Limited as an independent, private research organization that managed the Glynn Research Laboratories. At Glynn, Mitchell finally had the scope to work unfettered by the usual constraints and demands of academic life. It took great confidence and independence to weather the firestorm of controversy that greeted his efforts to support his theoretical claims during the “heroic” phase of his work at Glynn. It was during this period (1964–1977) that he moved most of the field to accept the phenomena his theory predicted. However, the personal traits and the seclusion and academic isolation of Glynn that served him so well in his battle with the scientific establishment also proved to be a limitation in some of the subsequent controversies over the quantitative evidence. These later debates, which took place during the period 1975–1985, seriously threatened the mechanisms Mitchell had proposed as elucidations of his chemiosmotic theory. By the end of this time, he was forced to concede the correctness of his critics’ experimental data. However, rather than countenancing the widely accepted mechanistic schemes of his opponents, he reformulated some of his mechanisms within his general conceptual framework of vectorial (directional) chemistry. Consequently, he sought to preserve what he regarded as his fundamental insight into biological processes. It was only in the special environment of Glynn that Mitchell was able to give full rein to his creativity and to his uniquely idiosyncratic approach. Since Glynn did not exist, he had to invent it. There was no institutional structure at universities or government laboratories that could give Mitchell such independence and autonomy and, because of its small scale, the focus and lack of bureaucracy that Glynn afforded. If he had not founded Glynn, it is not clear how Mitchell and his ideas would have fared. Glynn was probably essential to Mitchell’s survival and success as a scientist, and the story of Mitchell’s life after 1963 and the history of Glynn are almost synonymous.

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2
Early Years and Education 1920–1939



Origins

Peter Dennis Mitchell was born on 29 September 1920 in a two-story semi-detached house at 19 Rustic Avenue in the middle-class London suburb of Mitcham, Surrey. His father, Christopher Gibbs Mitchell, was 31 and his mother, Kate Beatrice Dorothy (née Taplin) Mitchell, was 27. They had married in 1914 just before World War I broke out. An older son, Christopher John (Bill) Mitchell, was born in 1916. The Mitchell family was from Dorset, but it is not clear how many generations may have lived there or what occupation they followed. Family lore was that they were descended from seventeenth-century French Huguenot immigrants named Michelle and the name had been anglicized to Mitchell. Although some of the family suspect that a few of their ancestors were engaged in smuggling,1 Peter Mitchell liked to think that at least some of his forebears had been pirates in the English Channel.2 What is certain is that Peter Mitchell’s grandfather, Christopher Mitchell, was trained as a stone mason but rose to be manager of a quarry in Portland, the Portland Stone Works. Christopher Mitchell was ambitious and an able businessman whose investments included the firm Minimax, which made fire extinguishers and of which he later became director. Probably in the 1880s he moved to Peckham, London, and became a clerk of works employed by the London County Council. His quarrying expertise led to his forming a partnership with Matthew Ascot Rowe, who had made his fortune in the United States. The firm Rowe and Mitchell brought granite from quarries in Alderney to London to make road surfacing for the various London boroughs. Christopher Mitchell married Margaret Way of Weymouth and had two sons, Christopher Gibbs Mitchell, born in 1889, and Godfrey Way Mitchell, born in 1891. Of particular significance to Peter Mitchell was his father’s younger

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brother, Godfrey, Peter’s “Uncle G.” Godfrey attended the academically excellent Haberdashers’ Aske’s School at Hatcham where he shone in mathematics and science. On leaving school at 16, he went into his father’s business rather than further his formal education. Because of the wartime increase of shipping rates and the death of Rowe, coupled with serious illnesses of both father and son, the Mitchells sold their business, and Christopher Mitchell retired. During the war, Godfrey served as a captain in the Royal Engineers, running quarries in the Pas de Calais using German prisoners as his workforce. In 1919, shortly after returning from the war, with his father’s help, he purchased a small, insolvent construction company, George Wimpey and Company Ltd. The firm had been founded in 1880 and had a good reputation until it fell on hard times after the death of George Wimpey in 1913. By 1927, Godfrey Mitchell had expanded the activities of the company into private home building, and more than 300,000 homes had been built in England by the time of Godfrey’s death in 1982. During World War II, Wimpey Construction built ninety-eight airfields, as well as balloon stations, docks, and army camps, for which activities Godfrey was knighted in 1948. After the war, he further expanded the company’s operations, building Heathrow Airport and many other major projects in England and overseas. In 1934 Wimpey went public, but Godfrey and his father retained 57 percent of the ordinary shares.3 Wimpey has subsequently become one of the largest contractors in Europe. Gifts of shares of this stock became a major factor in Peter Mitchell’s later life, allowing him not only considerable economic freedom but also funding his research and research institute. Peter Mitchell felt he knew the reason for his uncle’s great success: “He had an idea that a good business is like a living organism and that there should be a strong devolution of responsibility for the different kinds of activities.”4 Peter Mitchell always enjoyed visits to Uncle G’s because his conversation reflected a keen and nimble intellect interested in social, economic, philosophical, and religious matters. These, apart from the last, were to become abiding concerns of Peter’s, too.



Father

Godfrey’s older brother, Peter Mitchell’s father, Christopher, who also showed a strong aptitude in mathematics and science, received a B.Sc. in engineering from the University of London. Peter Mitchell recalled

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that the basic personalities of his father and his uncle were very different; whereas Godfrey was confident, Christopher was diffident. During World War I Christopher served as a captain in the army, although the family, especially his wife, did not consider that he had distinguished himself for bravery. After the war, he took a position as an engineering inspector at the National Ministry of Transport. He had a responsible job and came to supervise over seventy staff members. He designed and oversaw the construction of roads for about a fifth of the country, mainly the Midlands, and he was responsible for the controversial innovation of one-way streets. He received an Order of the British Empire (OBE) for his services, a not uncommon award for a successful civil servant of his standing. Peter remembered his father as a slight and short man with a limited sense of humor, although he referred to his OBE as his “Old Boiled Egg.” He also had a short temper and brought home the stress of his workplace. He was able in mathematics and was an avid bridge, golf, and tennis player, but he had little interest in art or music. Nor was he particularly interested in philosophy or religion, and he did not attend church. In general, he was viewed by his wife and sons as not being interested in much other than his job; he relaxed by playing games. Although he was clearly concerned with providing for his family and giving his sons a good education, he was not successful to the degree that his younger brother Godfrey was. He did not form a strong emotional bond with his boys, especially in the case of Peter, a situation that worsened as Christopher’s marriage began to unravel. Later, he committed suicide, an event that had an impact on Peter. In fact, Peter was much more influenced by his mother, but he also seemed to look for a father substitute. This role was soon to be filled by his headmaster at Queen’s College, Christopher Luke Wiseman, and later by the eminent biochemist, David Keilin.



Mother

Peter Mitchell’s mother, Kate Beatrice Dorothy Taplin, was born in 1892. She was the daughter of William George Taplin and Rosetta (née King) Taplin, who lived in a relatively less affluent section of Fulham, London. Late in his life, Peter Mitchell asserted that William Taplin’s mother had been Jewish and his wife was of Polish Jewish extraction. It is not clear if this was indeed so, but it is interesting that Mitchell’s selfimage was that of being of partial Jewish descent. Indeed, Mitchell

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seems to have regarded the only interesting people in England as “the Celts, the foreigners and the Jews.”5 In any event, it appears that the Taplins, like the Mitchells, were conventionally observant of the religious practice of the day, although Peter Mitchell could not recall any time when either set of grandparents ever talked about religion or God. William Taplin was a commercial traveler and wholesaler who sold to small-town grocers and was only modestly successful. However, he valued education highly and encouraged his daughters’ academic efforts. Kate received a scholarship to attend the Haberdashers’ Aske’s School (for girls); Christopher Mitchell had attended the boys’ school. Upon completion of her course of study, Kate was sent for a year to a finishing school in Switzerland to increase her knowledge of literature and arts, as well as to improve her French. Peter Mitchell recalled that his mother was a tall woman (over five foot ten, and taller than her husband) and was very beautiful with dark hair and eyes. She was a gentle, shy person but of firm will and independent thought and action. She had strong artistic perceptiveness and an abiding interest in visual arts and music, but unlike her husband she disliked any form of games or sports.6 Her face reflected her seriousness and moral earnestness, but she could break into a most charming smile with ease. Kate was a talented amateur musician who made certain that her sons’ environment at home reflected her interests. She took her young sons regularly to the promenade concerts at the Queen’s Hall, thus helping to inculcate in them a lifelong love of classical music. She was a rationalistic atheist, whom Peter Mitchell characterized as nonaggressive and whose deep concern about philosophical issues and questions of morality reflected an innate religious nature put off by dogma. Among Kate’s favorite authors were Marcus Aurelius and Bertrand Russell. Christopher Mitchell and Kate Taplin apparently met during their school days, although the nature and duration of their courtship and decision to marry seem not to have become part of the family lore. They were married on 3 July 1914 in the Wesleyan Methodist Church on Kitto Street, Nunhead, in Greenwich, London. Christopher was then a first lieutenant in the Royal Infantry and reportedly cut a dashing figure in his uniform. Pictures of Kate at that time suggest both intelligence and shyness. However long they had known each other, it is likely that they had married primarily because of a physical attraction and in haste because of the possibility of war. The Mitchell family considered the Taplins to be social inferiors, which was to become one source of strain on

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the marriage of Kate and Christopher Mitchell. Unfortunately for the durability of their marriage, Kate and Christopher Mitchell were of different temperaments and interests in ways that clashed rather than complemented.



Growing Up in the Family

One of Peter Mitchell’s earlier memories was of a fierce row between his parents concerning the day maid, after which he recalls that his parents seemed increasingly estranged. Shortly afterward, Kate Mitchell began to behave more independently, learning to drive and purchasing a car of her own. The bickering between Kate and her husband intensified. Eventually Peter’s father came to feel the object of a family conspiracy against him since the boys tended to side with their mother. Other early memories of Peter Mitchell were of visits to his grandparents, usually on Sundays, about once a month to each family. By then his paternal grandparents, Christopher and Margaret Mitchell, had moved to a grand house in the upper-middle-class neighborhood of Ealing, complete with several servants. The visits there were stiff, formal, and boring for young boys. The only compensation was that as they left, Grandfather Mitchell gave the boys a ten-shilling note each, a considerable sum at that time. In contrast, the boys looked forward to visits with William and Rosetta Taplin, who lived in a modest home in Fulham, an area Peter Mitchell regarded as Jewish. Visits there were informal and relaxed; the boys were encouraged to play in the garden, and no concern was shown if they got their clothes dirty. Peter Mitchell recalled especially the odors in the Taplin home, of pipe tobacco, herbs, spices, and in the cellar an aroma of wood from his grandfather’s woodcarving hobby. In recollection in 1991, Peter Mitchell recalled this home as having a slightly exotic, Middle Eastern or Jewish character. He also recalled visits to another of his mother’s relatives, an “Uncle Hinkle” who seemed even more Jewish and whose home was filled with even more exotic odors. The contrast of the family traditions left Peter feeling even closer to his mother. Kate Mitchell was not one to enforce rules for their own sake or to treat children as other than personalities of their own. When Peter was about 1 or 2 years old, his older brother came in from playing and announced that henceforth he was to be known as “Bill” and not as Christopher John. He had met a friendly workman down the street who

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seemed to be just the sort of chap he would like to be, and the workman’s name was Bill. Kate respected her son’s wish and henceforth he was Bill. Bill’s father was not pleased, but he finally accepted the name change. As a young boy, Peter brought home all sorts of junk from which he would construct various mechanical devices. Kate’s response would be, “Oh, Peter, what a dirty old rusty thing. Well, come on, put it in the kitchen.” The fact that she let him keep such things and even helped him clean them further cemented the relationship between them. Kate also helped Peter with his collection of different-colored birds’ eggs collected on Peter’s many sojourns in the nearby woods. Later she tolerated his and Bill’s experiments making gunpowder and other explosives. After a particularly loud report, she reacted by saying, “Oh, yes, Bill and Pete, I did hear a rather big bang. If you do something stupid you’ll hurt yourself. But you take whatever risks you want to take, and if you kill yourselves, well, that’s pretty stupid.” Kate constantly reinforced her notion of personal responsibility even as she acted as a coconspirator in their less paternally approved activities. A few years later, Peter was making hydrogen from zinc and hydrochloric acid in a flask that exploded, glass fragments entering Peter’s legs. Peter rushed down the stairs pulling off his trousers, to which his mother responded, “Oh, what have you done now? This is silly. Get the tweezers. I’ll pull out the pieces of glass.” Peter later commented, “I suppose all that was a very good training for an adventurous person, never to be forbidden to do something stupid. But of course, we had one or two accidents, fortunately nothing fatal. We learned by our own mistakes and became really quite sensible and responsible people.”7



Early Schooling

Peter Mitchell entered Streatham Grammar School in the autumn of 1926, a small, one-room school with twenty students of all levels. At this time he was more interested in exploring woods or participating in track events, for which he had considerable ability. A year later, Peter and his brother, Bill, were transferred to Barrow Hedges School in Carshalton. Christopher Mitchell, who was now earning more money, built a new, larger home for his family, Mayfield House, on West Way, in the more salubrious neighborhood of Carshalton Beeches. The school was not particularly distinguished, and, although Bill was happy enough

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there, Peter hated it, except for the instruction in mathematics. He recalled that he frequently feigned illness and stayed at home in order to have time on his own in the well-equipped workshop. This had been established above the garage for Bill and Peter and included a metalworking lathe. There he made various devices. In addition to several radios, he constructed a camera of his own design with which he photographed the view of the London skyline from a viewpoint in the attic. Otherwise, he spent long hours exploring the woods next to the house. Bill, who later received a degree in engineering from Cambridge, became increasingly bookish, whereas Peter at this stage was much more practically minded. However, they collaborated in exploring the chemistry of explosives and in various building projects. In 1931 their grandfather Mitchell purchased an old Wolsey automobile so that they could take it apart to see how an internal combustion engine worked. Their first attempt to start the rebuilt engine resulted in a fire because they had incorrectly fitted a valve. They were able to discover their error and correct it, from which Peter again took the lesson that making mistakes was part of learning. A few years earlier, their grandfather had set up both boys with their own bank accounts at Lloyd’s Bank, which they were to use for such things as school payments, in order that they learn how to manage money properly; he also gave them shares in Wimpey.



Queen’s College, Taunton

In 1931, Bill and Peter were sent to Queen’s College, Taunton, by their parents to further their education, provide them with a healthier environment in the country, and correct the Cockney accent that the boys had picked up from their mother. The Mitchell family physician, Dr. Cameron, had had an affiliation with the college and recommended it to the Mitchells as a place where the boys would be taught to be polite and would not learn to swear. An additional reason may well have been to remove Bill and Peter from the parents’ deteriorating marriage. Since 1929 both brothers had been boarders during the week at Barrow Hedges School, and when they were home on weekends their father was often absent. Indeed, from about 1931 on, Christopher Mitchell lived in Birmingham most of the time in order to be near his work. He and Kate were effectively though informally separated. Peter Mitchell maintained an independent if emotionally distant relationship with his

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father, especially after moving to Cambridge in 1939, until his father’s suicide in 1951. It was only much later that Peter began to appreciate the qualities of his father that made him a success in his work, respected and liked by his peers and subordinates. Queen’s College was established by the Wesleyan Methodist Church in 1843; it was designed to provide secondary education for middle-class boys from the Methodist school of Kingswood, for ministers’ children, and for overseas students, especially from West Africa. It was regarded in its time as the premier Methodist school.8 Queen’s College was located about one mile outside of Taunton (in southwest England) in a specifically built structure (1846) in a late Domestic Tudor style. The school’s motto non scholae sed vitae discimus, “we learn not for scholarship but for life,” reflected the goal of providing more than academic learning to the students. The Mitchells chose Queen’s because of its scholarly reputation rather than for its religious affiliation, as they had never bothered to have either boy baptized. Christopher Mitchell was not particularly interested in religion, whereas Kate Mitchell was a self-defined atheist. The headmaster, Mr. Christopher Luke Wiseman, was a deeply religious person of a liberal and pacifist persuasion. His brother F. Luke Wiseman was general secretary for home missions of the Methodist Church. Headmaster Wiseman became a major influence on Peter Mitchell’s life, if not on his religious beliefs. Bill went to the main school, which at that time accommodated about two hundred boys (although this number fell substantially during the depression), whereas Peter went to the junior school of about thirty boys that was located in a separate building on the grounds. Except for holidays at home, the brothers saw each other for only one hour a week. In addition to daily Bible readings and hymns, Peter Mitchell’s curriculum consisted of scripture, English, Latin, French, geography, history, mathematics, and physical training. When he went to the senior school he dropped Latin and added physics and chemistry, since by then he knew that he wanted to study engineering or science. Each Sunday, regardless of weather, the entire school would walk the mile to Taunton in a long line to attend chapel, a distance that in 1991 Mitchell remembered as three miles. Peter Mitchell would recall that the religious instruction and devotion taught him a great deal about Christianity but did not have the intended effect. When at home on vacation, he talked to his mother extensively about his reactions to the religious teachings and the problems he had with dogma. She did not try to persuade him but was a good sounding board. By the time he was 15, Peter

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decided that he was an atheist like his mother. Later in life he would incorporate into this worldview notions he learned from Confucianism and Taoism. In 1932 Kate Mitchell took both boys to be tested by the National Institute of Industrial Psychology in London. Peter Mitchell was assessed as having an above-average intelligence and an exceptional ability in problem solving and in mechanical aptitude. The assessment statement concluded that Peter had a pleasant personality, and this, combined with his talents, suggested that he would have a successful educational and professional career.9 During the same year, Kate Mitchell, who had been a friend of the aviatrix Amy Johnson, obtained her pilot’s license and taught both of her sons to fly. Because Peter was not yet 14, he could not qualify for a license, but Bill could and did. Although Peter never went back to flying, Bill continued and during the war was a flight instructor for the Royal Navy. Music had always been important to Peter, an interest that his mother strongly encouraged. Since Peter was away from ready access to concerts and because of his desire to play a musical instrument, Kate arranged for Peter to get violin lessons from a Miss King, a professional violinist, who came to Queen’s once a week for the lesson. Peter played in the school orchestra and also sang in both the choir and the more advanced and demanding madrigal consort. Mr. Wiseman, in addition to being a skilled mathematician and mathematics teacher, with first-class degrees in mathematics and physics from Peterhouse College, Cambridge University,10 was also a first-rate amateur pianist. He provided informal musical education for those boys who were seriously interested in supplementing their musical education. Each Sunday night after the normal bedtime, Peter and six or seven others would go in their pajamas to Wiseman’s room where he would play classical music from his extensive record collection on a mechanical gramophone that one of the boys had to wind up. Wiseman would then illustrate points about the music on his fine Bechstein piano and do improvisations on key passages. In this fashion Wiseman not only taught music appreciation but also basic music theory. These evenings were among Peter Mitchell’s fondest memories of his time at Queen’s. Wiseman was important to Peter Mitchell beyond enriching his musical education: “It was not just the influence of these studies, but it was Wiseman’s personality, which was very gentle, civilized and refined, that affected the way I wanted to live.”11 In later life Mitchell would use terms

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to describe his self-ideal that were very similar to those he used to describe Wiseman. If Mitchell responded to Wiseman’s character and saw him as a role model and a father substitute, Wiseman apparently responded to his student’s serious musical interests, as well as his considerable mathematical ability. Wiseman accorded Mitchell some special privileges. Because he craved some time alone (“I didn’t find it easy to exist in a crowd, although I liked other individual boys”12), Mitchell was allowed to rise an hour or so before the other boys and to leave the school grounds so that he could have a walk in the countryside and enjoy some solitary time. In inclement weather he could find a quiet corner in the reference room to read or to let his mind wander in contemplation. These became habits that lasted Mitchell’s lifetime. Mitchell looked forward to the holidays when he would have time at home and the opportunity to use the workshop. When he expressed to Wiseman how much he missed the times he spent making things with his hands, Wiseman arranged for a basement room, complete with lock, personal key, and some tools. The room was made available to Mitchell during the term so that he could construct his gadgets during free time. This was time that Mitchell treasured, not only because he enjoyed the opportunity of being alone but also because he was increasingly applying what he was learning in his science and mathematics classes to help his designs and constructions. Mitchell was especially proud of a primitive, but functioning, sound-recording machine that he made. He employed the technology of a recording head involving a little armature moving the steel stylus to cut a groove in a soft plastic disc that could be subsequently hardened. As he did not have any batteries, he had to make do with a large, old transformer. Considering the materials and tools available, the gramophone recorder gave surprisingly good results. He used it as a way to record music and some of his “meditations” as he let his mind wander. However, it was the actual making of something that was most satisfying for him. Mitchell had strongly disliked the tradition of hazing and bullying that he had encountered when he arrived at Queen’s, as well as a number of rules that struck him as silly. Initially, there was little that he could do except chafe under the system and miss the freedom and selfresponsibility that his mother had established at home. When he became a house prefect, he tried with some success to relax some of the more stringent rules that seemed unreasonable or unproductive. Then, in his last year, when he was school prefect, he worked strenuously to abolish hazing, which he was able to do with Wiseman’s support.

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Given Mitchell’s love of solitude and aversion to group activities, it is not surprising that, although a natural athlete, he did not particularly enjoy the school’s strong rugby tradition. Along with gymnastics, he much preferred individual track activities, such as running and jumping, in all of which he excelled; indeed, his name appears several times on the athletics honors boards at Queen’s. Because he was somewhat small for his age, he was intimidated by the physical roughness of rugby and sought to avoid it. The physical training instructor, Mr. Ward, encouraged Mitchell to participate enough to show that he was not afraid but realized that Mitchell’s true skills lay elsewhere. However, it turned out that Mitchell played well and was respected by the other boys for his courage, and for a time he was even the captain of the team. Mitchell remained grateful for Ward’s advice and sought to recall it when he felt inclined to avoid something he did not like. Ward and an academic teacher, Mr. Spencer, who was also an excellent athlete, took the boys on three-week camp outings to North Devon each year. Before Bill went to Cambridge it was about the only opportunity, other than holidays, for the brothers to spend much time together. Both enjoyed the more relaxed and informal atmosphere this event provided. Ward also taught a course in basic mechanics that Peter Mitchell found especially interesting. Mitchell discovered, however, that he did not feel he really understood what Ward was teaching until he wrote out the basic principles in the form of a short textbook using his own examples. This became a habitual form of learning and exploring a subject for Mitchell. In youthful exuberance, Mitchell was in the habit of jumping down half a flight of stairs in the school each day on his way to classes. On one occasion, however, he misjudged and hit his head, resulting in an abnormal landing that badly broke his right ankle. For a while the surgeon thought that Mitchell would lose the use of his leg, but in the end he only had a lifelong deformity in his ankle. However, this did mean that he could no longer participate in the athletics he enjoyed so much. Ultimately, this would mean that Mitchell would spend more time on his studies. In order to recover from his injury, he was laid up on his back for three weeks, during which time he wrote an essay/text on heat engines and turbines to keep himself occupied. I remember being quite pleased by being able to calculate quite simply from first principles that the best speed for a primitive turbine blade would be half the velocity of the steam jet that was

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driving it. I didn’t get that out of a textbook. I just got it out of the top of my head, which was quite fun. I was a bit surprised that one’s knowledge of maths was adequate to do something quite practical like that.13 Mitchell increasingly found that he preferred to work things out from first principles rather than starting from a textbook. Instead, he would think his own way through something and then check what he had deduced against the textbook. The lack of appeal of standard textbooks and modes of teaching made it difficult for Mitchell in areas other than the sciences and mathematics. Whereas he was at or near the top of his class in these subjects, as well as in physical training, he was only average or below average in scripture and languages. In history and geography, however, he was consistently at the bottom of his class. He earned such low marks in these two subjects that on one occasion when he obtained 3 out of 100, he was detained from going on holiday for three days because the instructor thought that this poor performance was deliberate. Retesting showed that he just had not mastered the material because of a combination of lack of interest and confusion about details due to his inattention to the textbooks. Some of the problem was more than lack of interest and reveals something of how Mitchell’s mind worked. History was almost entirely made up of battles, and people like Newton didn’t exist in history at all. It was all English history. And then you had geography. I always used to get muddled up because all the maps in the atlas were the same size and so the map of Africa was the same size as England. It was all very silly and boring.14 It seemed to Mitchell that such subjects and approaches were not serious in their content or manner of presentation, and, further, it was not possible to reason from first principles in these disciplines. In general, Mitchell was also put off by literature. An evaluation by his English teacher was that he “did not understand the raison d’être of English literature.”15 It was not just the required reading, but literature in general that did not interest him, in spite of the fact that he had a strong imagination himself. Literature seemed artificial and abstract compared with the real things discussed in science or which could be described by mathematics. Later in life he wrote quite a bit about what he saw as the conflict of the “word” and the “world” and how words could lead to mischief in the world. However, in addition to reading

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considerable reference material on music, he later recalled that he did respond to poetry and read extensively Donne, Hardy, Eliot, and Spender, of whom he liked Eliot best. He did read Brave New World and Eyeless in Gaza when they were published since there was so much discussion about them among his friends. Nevertheless, Mitchell responded to the imaginativeness of the language of Shakespeare and his strongly drawn characters. One of his happiest memories was of playing Lady Macbeth in the school’s production; the play was covered in The Daily Mail of 29 June 1934, including a picture of Mitchell in his role. Wiseman taught the sixth-form class in calculus. Since there was a small number of students, he taught it in an informal tutorial mode using many practical problems from Newtonian mechanics. From this Mitchell felt that he gained a surer sense of the principles of calculus and also deepened his understanding of physics. This further contact with Wiseman reinforced Mitchell’s respect for him. He saw in Wiseman’s approach to both intellectual and administrative problems the importance of imagination combined with analysis. Most of all, Mitchell felt that through Wiseman and his mother he experienced and learned the most important of human virtues: tolerance. Mitchell also had coursework in electricity and magnetism, as well as in inorganic, organic, and analytical chemistry. He did not particularly like the way that chemistry was taught since it seemed to be presented as a mass of unconnected empirical observations that in the worst case was reminiscent of history. He much preferred the conceptual structure of physics and those parts of chemistry that were presented in the same spirit. He felt empowered by being able to reason from first principles to get the answers that interested him, or which had some practical application. When asked much later why he had become a chemist, Mitchell responded that he did not know—certainly it was not based on his experience at Queen’s. He went on to say that while in school he expected to become an engineer, like his brother. In fact, he mused that he felt still more of an engineer in spirit than a chemist. However, he learned to think biologically as a physiologist when he went to Cambridge. Mitchell expected to follow Bill to Cambridge. Because he did not care for Latin and since it seemed likely that Latin would be dropped as a requirement for admission to Cambridge science curricula, he had stopped taking Latin quite early. It came as a shock in his final year at Queen’s to learn that passing an examination in Latin was still a Cambridge requirement. He presented his dilemma to Wiseman, who came

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up with a creative and effective solution. Mitchell was to spend two to three months (it turned out to be nine weeks) following the Latin teacher, Mr. Kingdom, through all his classes from the introductory second-form through the advanced sixth-form classes doing all the work. As it turned out, they spent additional time together in private tutorial and in speaking in Latin. Mitchell found out that although Kingdom was a strict disciplinarian, he had a great love of the Latin language and was a gifted and creative teacher. Mitchell found that he could learn more quickly by this total immersion approach. In particular, he made rapid strides when exposed to the more complex sentence structures of the advanced classes, since there he was looking at patterns and structure of the language rather than at individual words. Mitchell not only gained a pass grade at the entrance examination in Latin but also came to appreciate Latin for itself. Although Latin was a success, Mitchell did not do well on the Cambridge scholarship examination, for which he sat but failed, and he was rejected. He had chosen the more difficult scholarship examination rather than the regular entrance examination because he hoped to save his family the cost of tuition. Wiseman again intervened and wrote to those responsible for admissions at Jesus College that Mitchell’s examination performance should be ignored since it did not reflect his true ability and accomplishments, especially in mathematics and the physical sciences. Based on this recommendation, Mitchell was accepted by Jesus College, Cambridge, to start in October 1939. There was a summer break between completion of his work at Queen’s and the start of the Michaelmas term, however. With war imminent, a number of preparations were under way. With the expectation of a German blockade of England, the government undertook to expand the agricultural capacity of the island. Mitchell became involved in this during the summer of 1939, working with the Boy Scouts who were clearing thistles and bracken from Bodmin Moor in Cornwall. Nearly a quarter of a century later he returned to Bodmin and lived and worked there for three decades. Later in the summer, while staying at a cottage his mother had acquired in Exmoor, he joined the Home Guard and was given rudimentary training in the use of firearms. There were no rifles available since these had all gone to the Army. Members had to procure their own weapons. Mitchell was able to acquire a heavy-gauge shotgun and a Colt revolver. He took the revolver with him when he left in October, driving the Morgan fourwheeler car that his mother had just given him.

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3
The Early Cambridge Years 1939–1947



Jesus College

Peter Mitchell arrived, loaded Home Guard revolver in pocket, in time for the Michaelmas (first of three) term at Jesus College to a Cambridge1 already altered by the war. Although the colleges were still functioning, there was a reduction in numbers of both staff and students, while portions of the colleges and other facilities had been requisitioned for warrelated use. A part of Jesus College was used for pilot training, for instance. Although only one minor air raid actually occurred, the town lived under blackout conditions. Mitchell took up residence at the college and joined an ambulance service, spending one night a week on duty. Partway through the first year, Mitchell moved from the college to a rented room nearby in a quiet terrace house, built in 1810, at 58 Jesus Lane to enjoy a less communal lifestyle. Music was still an important aspect of his life. He played the violin unaccompanied, as well as with Maurice Sugden, whom he met at Jesus and who lived just around the corner in Malcolm Lane. Sugden, a chemist, went on to become a fellow of the Royal Society and was ultimately knighted. Together they played through the Bach, Mozart, and Beethoven violin sonatas. One of Mitchell’s zoology instructors, Cyril Smith, also accompanied him and introduced him to Brahms and the late Romantics, as well as teaching him more advanced interpretation. Quin Geering, a zoology student at Jesus, became a frequent visitor to 58 Jesus Lane. Geering, a quiet, gentle Quaker and a registered conscientious objector, shared many of Mitchell’s perspectives on life. However, they agreed to disagree about

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the existence of God. They enjoyed a lifelong friendship, and later Mitchell asked Geering to be one of four directors of the Glynn Research Foundation. Another science student at Jesus, John Gayer Anderson, although very different from Geering, also became a lifelong friend. Gayer Anderson was much more flamboyant and was strongly interested in the arts. Indeed, after completing his science education and military service, Gayer Anderson returned to Cambridge to take an arts degree in preparation for a writing career that was only partially realized. Later Mitchell recalled that as their friendship deepened, he and Gayer Anderson converged in habits and mannerisms. These three friends frequently attended concerts and plays together. Once, when Mitchell and Gayer Anderson went to see Olivier’s film version of Hamlet, Mitchell became so intensely emotionally involved that he blacked out for five minutes. Gayer Anderson recalled that such experiences happened on several occasions. Subsequently, Mitchell avoided movies and later even television. Many of his friends remember Mitchell during his years in Cambridge for his flamboyant dress: a burgundy purple jacket, shirt open sometimes as far as the waist, long hair almost to his shoulders. Indeed, his visage bore a remarkable resemblance to his bust of Beethoven. In Cambridge, especially in wartime, Mitchell “stood out in a somewhat dingy crowd.”2 Rather than eat in the dining hall or at one of the pubs frequented by scientists, such as the Eagle, he tended to dine at the Peacock. This small restaurant, which no longer exists, was situated on All Saints’ Passage and was run by a Jewish Czechoslovakian refugee. The Peacock was a favorite of foreigners in Cambridge, as well as of artists and musicians. Even as he became more deeply involved in science, Mitchell continued to prefer to associate with artists. In the Cambridge system, each student was assigned to one of the college tutors who advised on personal matters, whereas several supervisors were assigned to each student to deal with academic issues. Mitchell recalled two of his supervisors. For physiology, he had William Rushton, who also was a superb violinist. When Mitchell came for his session, he often found Rushton playing and would spend his hour just listening to him. However, he remembered that his biochemistry supervisor at Jesus was very helpful. Hugh King, who left in the fall of 1941, oversaw Mitchell’s part I biochemistry: “As a supervisor he was very good because he noticed your failings and he was capable of urging you to do more. He criticized in a way that was very constructive and helpful.”3 The professor of physiology, Edgar Douglas Adrian, Nobel laure-

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ate, gave lectures that “switched on” Mitchell, not only because of their quality and use of demonstrations but also because of their focus on understanding nerve physiology in terms of biochemistry and membrane physiology. Another physiology instructor, Francis J. W. Roughton, gave memorable lectures on the physico-chemical aspects of physiology. Although he was not a compelling lecturer and spoke largely about his own research, Roughton taught the importance of adding a time dimension to the space dimensions when thinking of events at the molecular level. While appreciating the power of the reductionist approach, Roughton exemplified, Mitchell was left with an intuition that a more holistic perspective was needed to understand how a living system differed from an artifact, a concern that manifested itself in the philosophy of his first thesis. For all his involvement with music, his interest in the theater and visual arts, and his continued reading of Shakespeare and of modern poets, Mitchell was a serious and thoughtful science student. His typical day in term consisted of a morning lecture followed by a two-hour practical, with the same pattern in the afternoon. He would copy over his notes in the evening and compare them with several textbooks. He frequently found that he got interested in some aspect, such as electrochemistry, and would explore the advanced textbooks available in the university library or in Heffer’s Bookstore, where a tolerant management would allow him to browse for sufficiently long periods that he could read whole books. Mitchell was interested in more than mastering the curriculum. He sought to understand fundamental principles of biochemistry and physiology that could be used to explore living systems. This became a deepening interest as he moved from undergraduate to graduate work and was noted by his friend Maurice Sugden, who was a member of the Cambridge University natural sciences club. The regulations of the club limited membership to twenty, of whom no more than eight could be undergraduates. Members were the elite of the science students at Cambridge.4 Mitchell was elected to the club on 6 November 1941. He gave his first talk to the members on 6 February 1942, on “Enzymes and Our Conception of Life.”5 His next presentation, “Meaning,” given on 12 March 1943, reflected how his interest in fundamental principles of biological sciences related to his broader philosophical concerns. During his first year he had picked up at Heffer’s a copy of C. K. Ogden and I. A. Richards’s Meaning of Meaning, which got him thinking seriously about how words are used and what the relationship is between

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“words” and the “world” they represent. At the same time, he was reading Norman W. Pirie’s article on “The Meaninglessness of the Terms Life and Living” in the volume Perspectives in Biochemistry, edited by Joseph Needham and David Green of the Cambridge biochemistry department. Pirie warned about the confusion that can be caused by not carefully relating words, and mathematical symbols, to what they stand for in the natural world.6 Mitchell’s interest in philosophical aspects of science did not entice him to attend lectures in philosophy. Indeed, although both Bertrand Russell and Ludwig Wittgenstein gave lectures during the period Mitchell was in Cambridge, he never seems to have attended any of them. Mitchell’s future collaborator, Jennifer Moyle, who was a student at Girton during the same period, attended many of these, as well as the public lectures on the history of Western philosophy given by Russell, which were published in 1946; she recalled that she never saw Mitchell at any of these lectures. Mitchell preferred to explore such subjects on his own and through discussions with friends. He shared some of his early speculations on general properties of living systems with one of his instructors, Ernst Friedmann, who taught the course on steroids in the Lent (second) term in 1942. Mitchell explored these ideas in two natural science club talks in 1943: “The Living Cell” given on 9 July and “Things Seen in Cells” given on 28 July. Friedmann, who was well versed in Greek philosophy, mentioned that Mitchell’s ideas bore some resemblance to those of Heraclitus. This comment led Mitchell to read not only the early Greek philosophers but also Plato and Aristotle. His personal copy of Burnett’s Early Greek Philosophy (fourth edition, 1945) seems to have been purchased when he was working on his first doctoral thesis project in 1945–1948. As will be seen later in this chapter, in this work Mitchell was seriously exploring the implications of mathematical descriptions of matter and energy flows in living cells, as part of his broader philosophical conception of dynamic processes. Initially, however, he seems to have been more attracted to the honest, probing questioning of Socrates about how one should conduct one’s life. Mitchell found the political climate of Cambridge, particularly in the natural science club and the department of biochemistry, to have a “hothouse” atmosphere of Marxism. Mitchell by instinct was nonideological but tended to reflect the assumptions of his class; those who knew him well during his Cambridge years found that he had an “assurance and ruthlessness often found among the rich.”7 Although Mitchell had no formal training in economics, he read widely on his

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own, discerned what he perceived to be the fundamental principles, and developed carefully thought-out positions on economics and politics. These remained abiding interests throughout his life. He was particularly fascinated by the role of money: “It became clear to me when I was quite a small boy that there was something very special about money.”8 What particularly caught Mitchell’s interest was the communication aspect of money. He perceived some similarity of flows of goods and money to flows of matter and energy in living systems. As he became more confident of a worldview informed by his reading of Greek philosophy, he saw his approach as based on scientific principles and individual responsibility, whereas he felt that the Marxists had a pseudo-science based on fallacious assumptions. From the mid-1970s onward he increasingly considered shifting his research focus from biochemistry to studying communication and political economy. During Mitchell’s final year as an undergraduate, he received a gift of a very fine Bechstein baby grand piano from his mother. Mitchell taught himself to play and soon was performing Bach preludes and the Goldberg Variations, early Beethoven sonatas, Chopin, and Satie. As Mitchell became more involved in laboratory research as a graduate student, he found that playing the violin seemed to be more like work and playing the piano was more relaxing. Within a couple of years, he had almost set aside the violin for the piano. It was through Quin Geering that Mitchell met his first serious love. Geering’s girlfriend at that time was Brenda Roberts, an architectural student at the University of London, who had come to Cambridge when her college had been moved because of the war. Brenda was slim and very beautiful with long, dark hair. Peter is described in this period as having “charisma, a pan-like look, and great sexual allure.”9 The two were quickly and strongly attracted to each other. Geering graciously stepped aside. Mitchell and Roberts began an eighteen-month-long relationship. It was a platonic but emotionally deep experience for them both, as they shared common musical and artistic interests. They found that they truly enjoyed spending considerable time in each other’s company. Some months after Mitchell started his time-consuming graduate studies and his war research with Jim Danielli, Roberts began to drift away from Mitchell. Shortly thereafter she met and went off with a poet, whom she eventually married. Later in life she became a successful architect. Mitchell was devastated by the loss of Roberts, and many years later he still felt the pain. Danielli, who did not approve of Brenda Roberts, warned Mitchell that he would have to choose between marry-

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ing a beautiful woman or an intelligent woman, to which Mitchell replied that if he had to make a choice, he would choose a beautiful one.



“Hopkins’s Wrecking Crew”: The Department of Biochemistry at Cambridge

Although his friends and his social life in general formed an important part of Mitchell’s postadolescent development, there is little doubt that the biochemistry department played the major formative role. Such a role was played out not only in terms of positive influences but also in providing views of the subject to which Mitchell could object. It was partly the shortcomings of contemporary biochemistry that stimulated Mitchell to seek over the ensuing years more intellectually satisfying views of living organisms. The staff imparted conceptual frameworks for the discipline, but some also provided role models in the scientific sense. Perhaps the most significant of these was Frederick Gowland Hopkins. The department itself contained several brilliant biochemists who were or who became international leaders in their respective fields. When Mitchell arrived in Cambridge, the head of the department was the much revered Sir Frederick Gowland Hopkins, whose intellect, vision, efforts, and character had made the department one of the best, if not the foremost, biochemistry departments in the world. Hopkins had been recruited by Michael Foster, professor of physiology, in 1898 in order to lecture and do research in physiological chemistry. In 1914, Hopkins was appointed the first professor of biochemistry in Cambridge, and in 1920 he became the Sir William Dunn Professor of Biochemistry. The chair had been endowed by the Dunn Board of Trustees, who had also provided a new building (opened in 1924) for research and teaching. Hopkins remained head of biochemistry until 1943, and shortly after his death in 1947, the first International Congress of Biochemistry was held at the department in Cambridge (in 1949), reflecting the worldwide high regard in which both Hopkins and the department of biochemistry at Cambridge were held.10 Hopkins’s initial research was in nutritional biochemistry. In 1901 he discovered the amino acid tryptophan, essential in the human diet and one of twenty amino acids found in proteins. In 1929 he shared the Nobel Prize in Physiology or Medicine for work on the discovery of vitamins. Hopkins was knighted in 1925 and was awarded the Order of

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Merit in 1935. As significant as his empirical findings were, his great contribution was conceptual. As he shifted from physiological and nutritional chemistry to fundamental biochemistry, he helped define the focus and range of the subject. Indeed, nearly half of his publications are theoretical and philosophical. Such an interest certainly correlated with the approach to biochemistry to which Mitchell aspired, and it is difficult to think that Hopkins failed to influence Mitchell in this respect. In his seminal address to the British Association for the Advancement of Science in 1913, Hopkins argued against the crypto-vitalism of many physiologists, who saw the protoplasm of the cell as a living entity that could not be chemically defined. He also objected to the simple-minded reductionism of organic chemists, who thought reactions that could be demonstrated in the test tube had to be those operating in living systems. Instead, Hopkins presented a vision of the cell as a chemical machine subject to the laws of thermodynamics and physical chemistry, but which exhibited organized behavior. He stressed the importance of the protein catalysts, the enzymes, and the fact that metabolism would consist of many enzyme-catalyzed steps involving small changes in the structure and energy of chemically well-defined intermediates. He also stressed that the cellular processes were dynamic and that biochemists needed to go beyond just knowledge of molecular structures. For Hopkins, the living cell is “not a mass of matter composed of a congregation of like molecules, but a highly differentiated system: the cell, in the modern phraseology of physical chemistry, is a system of co-existing phases of different constitutions.”11 While expecting to find an underlying simplicity, he viewed life as “a property of the cell as a whole, because it depends upon the organization of processes.”12 Such a philosophy was attractive to Mitchell, and in his personal copy of Hopkins and Biochemistry he marked a passage from one of Hopkins’s addresses. This referred to the need to analyze events in the cell and not just substances, to which Mitchell had added a handwritten comment that Hopkins was putting in the time dimension in addition to the spatial ones. Joseph and Dorothy Needham recalled that as important as these ideas were to Hopkins, he never lost his respect for data: Inspired by his intuitive understanding of the living cell, Hopkins stood self-forgetful in front of the facts. One can see him now, at the top of the stairs, coat open and hands in pockets, . . . with

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cigarette drooping over the centrifuge tubes; head quizzically slightly at an angle, benignly smiling, inquiring about the latest results. One never came across anybody at all like him.13 Hopkins’s personal character, as well as his vision, helped mold the special ethos that existed in the biochemistry department at Cambridge up to about 1950: “Hopkins’ outstanding personal characteristic was a universal courtesy, even a capacity to suffer fools gladly (knowing that some fools may change into wise men in the process).”14 Perhaps the best summary of the impact of Hopkins was written by Marjory Stephenson: “There comes a time in the life of every science when it requires a midwife before it can emerge and start an independent existence. What Lyell did for geology and Claude Bernard for physiology Hopkins did for biochemistry.”15 Such a man could scarcely fail to have a major effect on his students, and Mitchell was no exception. Over the years Hopkins assembled in his department a talented group of staff who developed his broadly conceived research program and created a curriculum based on the assumption that biochemistry was a fundamental and unique discipline. Malcolm Dixon became a demonstrator (a junior, untenured academic post) in 1921, rising to the rank of reader (the most senior academic tenured post below the rank of professor) in the subdepartment of enzymes by the time Mitchell joined the department. Dixon’s work on enzymology reflected the fundamental importance Hopkins placed on understanding how enzymes control metabolism that became one of the foundations of biochemical thinking; his book Multienzyme Systems (1949) summarized this approach. His later book with Mitchell’s contemporary Edwin Webb, Enzymes, became a standard text for a number of years, going through three editions. While Dixon’s approach to enzymology undoubtedly provided Mitchell with a firm basis in this aspect of the discipline, in time he came to see what for him were its shortcomings. Hopkins was ahead of his time in encouraging the careers of women scientists. In 1919 he recruited Marjory Stephenson from University College London to join the department. Subsequently, he encouraged Stephenson to shift her studies from animal nutrition to microbial biochemistry. She had no training in bacteriology and had to acquire the methods and learn microbial taxonomy. She developed many new techniques and ultimately emerged as a leading authority in bacterial metabolism. She published the very influential and innovative

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textbook Bacterial Metabolism, which went through three editions over twenty years and in which the importance of the enzymological approach to metabolism was communicated to a wide audience. In turn, Hopkins came to lean on the advice and insights of Stephenson, who was appointed the reader in chemical microbiology and put in charge of a subdepartment on microbiology.16 Together, they demonstrated the importance of studying the biochemistry of all organisms and not just that of animals of commercial or medical value. Stephenson helped found the Society for General Microbiology in 1944 and was serving as its president at the time of her death in 1948. In recognition of her substantial contribution to science, Marjory Stephenson was elected a fellow of the Royal Society in 1945, along with Kathleen Lonsdale, the first year any women were so honored. Ernest Gale, who did his doctoral research with Stephenson, rejoined the department after the war and became Stephenson’s successor in 1949. He was elected a fellow of the Royal Society in 1953 and ultimately became the first professor of chemical microbiology in 1960. It was this group devoted to microbial biochemistry to which Mitchell belonged and where he eventually developed many of his initial ideas on bacterial biochemistry. Joseph Needham joined the department in 1922 as a demonstrator and later became the second Sir William Dunn reader in biochemistry. He succeeded J. B. S. Haldane, who had developed mathematical methods for analyzing enzyme data and for population genetics and, in addition, had promoted a program of putting genetics on a biochemical basis.17 Haldane is also considered to be one of the founders of the modern evolutionary synthesis. Needham extended the range of biochemistry to developmental biology and published monographs on chemical embryology and morphogenesis and on the history of embryology during the 1930s and 1940s. His Terry Lectures at Yale, published in 1936 as Order and Life, were an important influence on the development of Mitchell’s ideas about fluctoids (see chapter 4 in this volume). Although Needham’s course of lectures at Cambridge do not seem to have inspired Mitchell, his writings did. Ernest Baldwin joined the department in 1931, first as a graduate student, then as a demonstrator, and subsequently as a lecturer in biochemistry, until he took a professorship of biochemistry at University College London in 1950. Baldwin developed Needham’s comparative biochemical approach and wrote the volume An Introduction to Comparative Biochemistry, first published in 1937. He was one of a number of the biochemistry teaching staff who helped shape Mitchell’s approach

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to the subject. His introductory biochemistry lectures were outstanding and vividly reflected Hopkins’s vision of enzyme-catalyzed metabolic dynamics as fundamental to all living systems and of biochemistry as a distinct and basic science. Such a view was attractive to a great many students but particularly to Mitchell. Indeed, in his opinion, Baldwin was simply the best and most engaging lecturer at Cambridge. These lectures formed the basis of the influential and widely used textbook Dynamic Aspects of Biochemistry, first published in 1947, and dedicated to Hopkins; four further editions appeared over the next twenty years. Baldwin’s approach to biochemistry was marked by an enthusiasm for metabolic reactions and the role of coenzymes but ignored the enzymes other than to note their role as catalysts of the reaction. Brian Chappell, who also took these lectures, felt that this left students without a feel for proteins in dynamic aspects of biochemistry. Indeed, Mitchell’s approach during the whole of his life was to concentrate on the role of small molecules (such as ubiquinone) and groups such as the hemes but to minimize the role of proteins. For Mitchell, another important figure in the department was Robin Hill, who had earlier made significant contributions to the study of hemoglobin. Later Hill extended Hopkins’s approach to plants, making fundamental contributions to our understanding of photosynthesis by pioneering the biochemical study of chloroplasts. Hill was influenced by Keilin at the Molteno Institute and, like others, carried out some of his work there. He demonstrated in 1937 the reaction, now known as the Hill reaction, in which light-driven evolution of oxygen is linked to an artificial electron acceptor; the reaction is independent of carbon dioxide fixation. Among his later studies were his descriptions of cytochromes in chloroplasts and the formulation of the first full scheme (known as the Z-scheme) for photosynthesis. Hill was independently wealthy and hence did not need a formal appointment in the department, or a salary, but he was a full participant lecturing on plant biochemistry. Mitchell remembered him as an excruciatingly shy person who would flatten his back to the wall in a hallway when he encountered someone. A bond of sympathy developed between Hill and Mitchell, so that later Mitchell sought Hill’s advice, particularly when formulating the chemiosmotic theory. This then, in brief, gives an overview of the department into which Peter Mitchell entered as an undergraduate in 1939 and in which he worked as a graduate student up to 1950. Many who knew the department at that time noted that Hopkins had fostered a strong sense of

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community in which individuality and creativity were encouraged and treasured. David Green, who was a graduate student in the department in the 1930s, recalled that Hopkins would “accept a young person like myself as a colleague in the fullest sense of the word. . . . It was his way of elevating you and making you confident in yourself.”18 The university administration, although supportive of the academic excellence of the department, regarded it as not easy to deal with—as one official put it to Hopkins, it was “that wrecking crew of yours.”19 By 1943 Hopkins’s health had declined such that he decided to retire. A. C. Chibnall, a protein and lipid chemist, was selected to be the successor. Chibnall had been educated at Imperial College and in the United States and had been professor of biochemistry at Imperial College London since 1929. He instituted some changes but found that the administrative responsibilities distracted him from his primary interests in teaching and research. In 1948 Chibnall resigned due to a dispute with the university administration over basic policy, but he agreed to stay on until after the International Congress of Biochemistry meeting in August 1949, of which he was president. Two internal candidates, Dixon and Needham, were seriously considered to replace Chibnall. Among the external candidates was Hans Krebs, then professor of biochemistry at Sheffield and who later became professor of biochemistry at Oxford and won a Nobel Prize; he had worked for two years in the department immediately after he had been forced to leave Germany in 1933. After all, Frank G. Young, then professor of biochemistry at University College London was appointed, and he took over by Michaelmas term in 1949. Young dropped the name of the Dunn Institute of Biochemistry and the annual Dunn dinner and worked to shift the emphasis of the department back to the more traditional focus of physiological and medical biochemistry. He remained the head until 1970. Like many of his colleagues, Mitchell never felt comfortable in his relationship with Young.



Peter Mitchell’s Biochemical Education

Mitchell took the natural science tripos (course of study), studying chemistry (inorganic, organic, and physical chemistry), physics, physiology, and biochemistry for part I (first two years of the program). At the end of the first year, he took the preliminary examination for part I and only achieved a third-class pass (pass lists are divided into four categories—first, second, third, fourth—in rank order). The next year he

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improved to a second-class pass in part I. Mitchell chose biochemistry as the subject for part II and was awarded upper second-class honors. Only one of the other three biochemistry graduates in 1942 received a first-class degree, Edwin C. Webb; Webb joined the staff of the department of biochemistry in due course. Mitchell later commented about these examination results, “I’ve never been any good at examinations. My problem in exams has always been that I start to think, which is fatal during an examination.”20 The biochemistry courses for part II (starting in the Michaelmas term in 1941) included comparative biochemistry from Baldwin; physical biochemistry from Danielli; enzymes, cell respiration, and biological oxidations from Dixon; plant biochemistry from Hill; biochemistry of carbohydrates from Mann; and protein chemistry from Neuberger. Mitchell recalled that Dixon looked at biochemical processes as molecular events; at the time, he was starting to write about multienzyme systems and emphasized the importance of coupling of enzyme-catalyzed reactions in metabolism. When Dixon drew diagrams of enzymes during his lectures, he presented the notion of group transfer so that it was accidentally presented as a spatial migration of a chemical group form, or donor group, to an acceptor group. He would often draw an enzyme molecule as a square on the blackboard. Then he would draw a little line from the box which went to the group that was being transferred. Then, he would draw, say the group-donor on the left and the group-acceptor on the right. Thus, the chemical transformation was already indicated by an arrow which showed you the migration of the group. I think that tended to suggest, although Dixon himself didn’t intend, . . . that there were vectors in his diagram. It interested me to think that if you imagine the catalytic center in the middle of the enzyme, then the vectors in the diagram would be a vectorial representation of group translocation. I think that probably was quite important for the evolution of my ideas about vectorial chemistry.21 Possibly Mitchell’s interest in painting, and the visual arts generally, helped him interpret Dixon’s lectures in such spatial terms. This approach is reflected in his personal copy of Perspectives in Biochemistry that he had purchased a year or so before, where his handwritten notations on the article by Haldane interpret some comments as evidence of “position effects.”

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Danielli’s physical biochemistry course focused on the membrane as a structure and on the directionality implied in the movement of metabolites across the membrane. In the practical, Danielli had the students work with monomolecular layers in Langmuir troughs. The measurement of surface layer forces made Mitchell appreciate that strong forces could operate between molecules, and in his mind he saw these as Newtonian, and hence vectorial, forces; ever since his exposure to Newtonian mechanics by Wiseman, Mitchell felt comfortable when he could formulate a system in those terms. In lectures, Danielli, “who liked to introduce you to some fundamental thermodynamics, gave us this little book by Guggenheim as a set book to read, and having done a bit of mathematics, I was fairly well able to understand it, whereas many biochemistry students found thermodynamics rather difficult.”22 Reading Guggenheim at the same time as studying enzymology reinforced the picture of spatial organization and vectorial motion that he had been developing from his interpretation of Dixon’s lectures. “I realized in that context that there is a fundamental difference between free energies, which are the scalar products of two vectors . . . and entropic energies . . . which are the scalar product of two scalars which did not have any vectorial content.”23 In other words, when chemists dealt with energies rather than chemical forces, they were losing important information about the spatial directionality of chemical reactions. Mitchell had an intuition that in this lay a clue to a deep connection between the scalar chemical transformations of enzyme-catalyzed metabolism and the directional transport across membranes, but such notions would be inchoate for a while. Later this insight informed Mitchell’s first graduate thesis project (withdrawn) and subsequently formed the basis of his research program. Hill’s lectures on the role of membrane-bound pigments in photosynthesis suggested that, indeed, important metabolism could occur in membranes and not just across them. In the Lent term of 1942 Ernest Baldwin continued his lectures on comparative biochemistry, Ernst Friedmann lectured on steroids, Leslie Harris on vitamins, Dorothy Needham on muscle biochemistry, Joseph Needham on chemical embryology, and Marjorie Stephenson on the biochemistry of microorganisms. Mitchell’s main recollection of these courses was the encyclopedic approach of Joseph Needham, which summarized a vast amount of experimental detail but did not provide any principles with which to think about the phenomena. It seemed too much like history and thus was dismissed by Mitchell. He was not sur-

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prised when Needham decided to change his field of interest to the history of science. Stephenson’s course on chemical microbiology introduced Mitchell to what would become his principal area of research in subsequent years. Most important, it brought Mitchell to the attention of Stephenson, who came to play a crucial role in the development of his career. The Easter term was given over to doing research with Danielli.



War Research

On its own initiative, the biochemistry department drafted proposals for possible research projects that the staff and graduate students might undertake to contribute to the war effort. After graduation, Mitchell began work in 1942 on determining the mode of action of poisonous gases and searching for possible antidotes, which had been approved and funded by the Chemical Defence Research section of the Ministry of Supply. Dixon was appointed the head of the team that included Danielli, Hill, Mitchell, Dorothy Needham, and Webb. A parallel group under the direction of Stephenson worked on pathogenic bacteria. Mitchell worked directly under Danielli and became his sole Ph.D. student at the time. Danielli had previously developed a model of membrane structure with Hugh Davson and had written The Permeability of Natural Membranes published in 1943, so it was natural for his subgroup to look for possible damage to membranes, such as those of capillary walls, caused by the poisons. Mitchell synthesized two dye molecules, one of which is known as “Peter’s Blue.” These were used to “tag” serum protein molecules to assess if the arsenic-containing poison gas lewisite acted by causing damage to capillaries, resulting in leakage of serum.24 The effective antidote, British anti-lewisite (BAL), was developed by a team of Oxford biochemists led by Rudolph Peters, so the Danielli group shifted to working on BAL. They developed a modified version, a glucoside derivative, that could be intravenously delivered to protect against lewisite or any other arsenicals.25 Until penicillin was widely employed, arsenicals were used to treat soldiers with syphilis, but this treatment often had side effects that were ameliorated by the compound developed by Danielli’s team. Brief notes appeared in Nature in 1944 and 1946 on some aspects of this work, and a fuller report was published in the Biochemical Journal in 1947. These constitute Peter Mitchell’s first publications.26

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Mitchell liked working in Danielli’s laboratory because of its relaxed atmosphere and the amount of freedom that he was given. In private, he found Danielli easy to work with and a considerate mentor who would gently suggest improvements or missing information. However, in public, Danielli could be quite aggressive, especially if he was challenged in any manner. Mitchell had to learn to avoid public confrontations with Danielli and to defuse such situations when they interacted with others outside the group. Although on paper he remained Mitchell’s Ph.D. supervisor, Danielli moved to a position in London at King’s College in 1946.



Loves and Marriage

When Mitchell began his work with Danielli, he was still in a relationship with Brenda Roberts, of whom Jim and Mary Danielli did not approve. They were pleased when she broke off her relationship with Mitchell. Although distraught at the loss of Brenda, Mitchell continued to have many friends in artistic circles and still frequented the Peacock. There he met Helen Bremner, who became his second love. Mitchell recalled that “although not as striking in coloring as Brenda Roberts, she had a beautiful physiognomy and the figure of a classic artist’s model.”27 She was highly imaginative and had an emotional intensity about her. This relationship was also platonic, and it ended in Bremner leaving Mitchell and marrying the artist Vladimir Daskal, also a frequent patron of the Peacock and characterized by Mitchell as a derivative cubist painter and a notorious womanizer. According to Mitchell, Bremner tamed Daskal but joined him in “smuggling” toward the end of the war. Somewhat later, Mitchell saw a woman at the Peacock who had a “Mona Lisa” type face in the company of a young man who subsequently disappeared. Mitchell introduced himself to this woman, Eileen Rollo, and they began seeing each other. She lived near the Peacock with her father, who was a civil servant; her mother had recently died after a bout of mental illness. Eileen worked at a nursing home for servicemen, Silbury, at 60 Grange Road that had been requisitioned from its owner for the duration of the war. They enjoyed going to concerts together, although there was less emotional intensity on either side than there had been in Mitchell’s previous relationships. Eileen was struck by an automobile while cycling and was seriously injured. When

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Mitchell heard of her accident, he rushed to her bedside. Eileen took this as serious interest on Peter’s part and was soon asking him when they would “cement this thing.” Although he had misgivings about marrying, even a beautiful woman, Mitchell later recalled that he seemed to be on a type of “auto-pilot” and did not have the will to alter course. The atheist, Mitchell, and the lapsed Catholic, Rollo, were married in an Anglican ceremony at the small and historic St. Edward’s Church in St. Edward’s Passage, on 11 December 1944. Quin Geering was the best man, and Eileen’s bridesmaid was Juliet Barker-Starkey, who later married Geering. Twins, Jeremy and Julia, were born to Peter and Eileen Mitchell on 10 December 1945. With the expanded family, Peter sought more comfortable lodging, particularly since Eileen’s father, who had just retired, also lived with them. Silbury, which was leased from St. John’s College, was likely to be derequisitioned. Mitchell contacted the leaseholder, a clergyman who lived in Malvern and who was interested in selling the fifty years left to run on the lease. Mitchell took a chance that derequisitioning would soon occur and purchased the lease for £7500, a very considerable sum in those days. In due course, Silbury became available and the Mitchell family moved in. Silbury had been built near the turn of the century by a professor, and the house came complete with a large garden, including flower and vegetable areas, together with chickens. At the back of the house there was a room that had been a private laboratory. This annex Mitchell remodeled into an independent flat for his father-in-law, complete with a bathroom and kitchen. He also considerably remodeled the main house in order that he, Eileen, and the children could live on the ground floor and the two upper floors could be rented out to boarders. Quin Geering and his wife, Ted Cranshaw (a physicist, pianist, and the curator of the new Heffer’s Art Gallery), and Bryan Robertson (later a well-known art critic and curator of major galleries in London and New York) lived on the second floor. Peter Sterne, already a distinguished journalist, and his wife lived on the third floor with their children. Not long after the birth of the twins, Peter and Eileen started to grow apart emotionally. In many respects the differences in temperament and personality resembled those which had caused so much pain in Mitchell’s parents’ marriage. However, unlike his parents, who never legally separated, Mitchell’s marriage ultimately ended in divorce in 1954. In spite of, or perhaps because of, the problems in the marriage, Peter and Eileen Mitchell led very active social lives. They were seen

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frequently at concerts and plays and driving about town in a 1926 Rolls Royce that Mitchell had restored. Eileen was a superb cook and liked having frequent small dinner parties. Peter helped and learned quite a bit about good cooking, which he put to use a few years later. In spite of his previous preference for solitude, he engaged himself in these social activities and with Eileen hosted a number of large parties that became legendary in Cambridge at the time. On one occasion, men were invited to come disguised as clergymen and women as goddesses. Francis Crick and E. M. Forster were among the frequent guests, in addition to Mitchell’s previous circle of friends that included many artistic types. However, Eileen did not like Crick’s continual advances or the Bohemian nature of some of Peter’s friends, such as Gayer Anderson, who on return from the war and completing a literature tripos, took up writing while running a pig and chicken farm. For Mitchell, music remained an important activity and the basis of a number of friendships. Although he had given up playing the violin, he continued to play the piano frequently. When not actually making music, he and his friends would listen to recordings of Brahms and Schubert chamber music with candlelight and wine. He also spent much time discussing economics and political theory, as well as the social responsibilities of scientists, especially with Bryan Robertson. Peter was concerned that there should be a popularization of science so that it could be more a part of the general culture, although this was not something he wished to do himself. Mitchell saw himself, and scientists generally, as like artists and composers who needed a similar freedom for their creative work. Robertson and Mitchell often talked about books they were both reading, by authors such as Anthony Powell and Iris Murdoch; Mitchell used to read in bed each night. Robertson recalled Mitchell “as being a man of passionate convictions, a sensual man, like Picasso, who occupied the center of his universe and thus did not fully think of others.”28 Mitchell was also disarmingly tenderhearted, trustful but very unsentimental, even steely; he had sentiment but loathed sentimentality. To Robertson, Mitchell was also one of the most interesting people in Cambridge, very much alive with an “amused intelligence”; he was warm, open, and generous, with a strong sense of the absurdities of life and an excellent teller of dirty stories. Robertson and Mitchell became firm friends. Mitchell did not get on well with the authorities at the university, and this further endeared him to Robertson. As committed as Mitchell was to opposing the Marxists in the department, he was bothered by the treatment that Joseph Needham

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received when, in 1946, he returned from China where he had been science officer at the British embassy in Chungking (Chongqing). By then the political atmosphere had calmed down somewhat, but when Needham wished to talk about his experiences and the current revolutionary situation in China, Chibnall declined to allow him to use the department’s lecture theater on the grounds that such a presentation was “too political.” Immediately upon learning about this, Mitchell arranged to have the talk at Silbury and invited the department to it. Mitchell was quite knowledgeable about art, especially modern art, which was Bryan Robertson’s area of expertise. Mitchell knew the contents of the Fitzwilliam Museum well and showed a good sense of quality in the work of contemporary artists he admired, such as Cecil Collins. Both Mitchell and Robertson became friends with the Cambridge artist Elizabeth Vellacott. She made a sketch of Peter at this time in which he looks remarkably like the later Beethoven. Mitchell purchased some Vellacott paintings and drawings before she was widely recognized. The friendship with Vellacott and Robertson would lead to a major change in Mitchell’s life in 1951, shortly after he completed his Ph.D. degree.



David Keilin and the Molteno Institute

In some ways, perhaps, the major influence on Mitchell at Cambridge was David Keilin, the director of the Molteno Institute. Keilin, son of a Polish businessman living in Moscow, was born in 1887. He was educated in Warsaw at the Górski Gymnasium. He started studies for medicine at the University of Liège but because of health problems decided on a less arduous program of study in biology, specifically entomology with Maurice Caullery at the Laboratoire d’Évolution des Êtres Organisés in Paris, receiving his D.Sc. from the Sorbonne in 1914. He moved to Cambridge in 1915, where he joined the new Molteno Institute, funded by Mr. and Mrs. Percy Molteno to promote research in parasitology under the direction of Professor George Henry Nuttall. In 1925 Keilin was made lecturer in parasitology, and in 1931 he succeeded Nuttall as the Quick Professor of Biology and director of the Molteno Institute. Keilin was a quiet, shy person who disliked administration but who had the courage of his convictions and a dislike of authority. He kept his operation in the Molteno small. Although he never had a secre-

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tary of his own, he had a small but skilled technical staff, including Edwin Francis Hartree. This was augmented by occasional postdoctoral researchers, including E. C. (Bill) Slater. Keilin’s research program on cytochromes and the respiratory chain was very productive, making major discoveries about the heme proteins of biological membranes that are involved in cellular respiration. Up to the end of World War II more than 40 percent of the biochemistry papers published in Britain came from either the Dunn Institute of Biochemistry or the Molteno Institute. Although Keilin lectured occasionally in the third and final year of the biochemistry curriculum, he kept a separate identity from the department. When Hopkins retired in 1943, Joseph Needham sent a telegram to Keilin from China, where Needham was acting consul, begging Keilin to apply for the professorship of biochemistry. A number of members of the biochemistry department walked the hundred or so yards to the Molteno to second the request in person. His daughter recalled: My father would not consider this for a moment. He had no wish for a large department, no matter how prestigious, with its load of administration. Above all, he did NOT want to found a “school.” . . . If anyone from the Biochemistry lab or any other lab wished to talk things over with my father, they were always welcome just to knock on his door—there were no secretarial barriers—and he never begrudged giving time to anyone, no matter how junior, so they felt at ease with him. 29 Keilin provided laboratory bench space not only to formal visitors to the laboratory, but also to members of the Cambridge research community when they needed it. Thus he allowed Max Perutz and John Kendrew to grow crystals of hemoglobin and myoglobin in the Molteno since there was no room at the Cavendish Laboratory for biochemical work during the 1940s. Although Perutz had for a time an official affiliation with the Molteno, Hartree recalls that there were many individuals who were unofficially provided temporary “parking spaces in the Molteno laboratories, among whom was Peter Mitchell.”30 Thus when Peter Mitchell was reintroduced to David Keilin in late 1945 or early 1946 (they had met when Keilin had visited Danielli’s laboratory briefly one summer when Joan Keilin was doing a short research project there), he found someone who was available and open to discuss ideas about biological phenomena and someone whose personality was reminiscent of Wiseman’s. Shortly after they met, Mitchell and

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Keilin were both invited to a formal party of the biochemistry community of Cambridge given by Chibnall. Mitchell and Keilin were eating olives while talking: I was only a young student and we were eating these olives, and after a bit Keilin put one of the olive stones on his thumbnail and flipped it across the room and laughed when it pinged somewhere. I was not accustomed to a professor behaving that way, so I was absolutely delighted. He maybe even did it because he knew I was an outsider and would be pleased, wishing I could do it myself.31 An impish antiauthoritarian streak in Mitchell was often noted by those who knew him, and it is not surprising that finding this trait in someone else his senior would have helped put Mitchell at ease.

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4
Research at Cambridge 1947–1955



Promise but Not Fulfillment

Mitchell’s experimental research work at Cambridge, although productive, was relatively undistinguished. Of rather greater interest were his initial theoretical writings, but even these might be lightly passed over if they were not seen in the light of his later achievements. The Cambridge period was not one of academic success for Mitchell; it was, rather, a time when ideas began to take root in his mind, ideas whose great potential he himself could scarcely have foreseen at that time. But for the brilliance of the Edinburgh and early Glynn periods, much of his work such as his first thesis might be passed off as of a dilettante nature. Indeed, the first thesis for his Ph.D. was referred (rejected but could be resubmitted after revision). But the Cambridge research period is of great interest because it sowed seeds for his later creativity. Mitchell’s promise does seem to have been appreciated by some of his contemporaries, particularly Marjory Stephenson and also David Keilin. Certainly some regarded him as a very clever scientist, but others were less certain. In the end, the department did not offer him a permanent position. In the normal course of events, Mitchell should have received his Ph.D. degree by 1945, but the war research prevented him from starting his doctoral research. Shortly after the war ended, Danielli moved from Cambridge, and Mitchell was largely on his own. Eventually, Chibnall asked Ernest Gale, who had returned to Cambridge to join his former mentor Marjory Stephenson, to act unofficially as Mitchell’s supervisor, although the Cambridge University Reporter shows that Chibnall was the

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official supervisor to the end of 1948. Mitchell pursued some laboratory research on amino acid transport into bacteria with Gale, while he was developing a theoretical framework for his approach to biochemistry. This encompassed Danielli’s understanding of membranes and Mitchell’s intuitions about the biochemical dynamics of the cell. The latter were influenced by Hopkins’s ideas of dynamic biochemistry. Thus Mitchell developed a unique blend of empirical and theoretical work.



Jennifer Moyle

One of the most significant events in Mitchell’s career occurred almost by chance and was brought about by Marjory Stephenson, who seems to have initiated the link between Mitchell and her assistant, Jennifer Moyle. Moyle became a close collaborator through almost the whole of Mitchell’s scientific career until her retirement in 1983. Jennifer Moyle was one of two daughters of S. H. Leonard Moyle, son of a farmer from Helston in Cornwall, and Olive M. Dakin; Leonard and Olive were married in 1919. Olive was the only child of John Howard Dakin, a tea and coffee merchant in Norwich. The family business had been founded in 1857, and Jennifer’s great grandfather was the mayor of Norwich in 1889. Leonard Moyle became a partner in the business after his marriage, and eventually he ran it alone. Jennifer was born in 1921 and started her education at Norwich High School (a day school for girls) in 1926, where she remained until she went to Cambridge in 1939. Both parents were accomplished amateur musicians, and Jennifer, together with her younger sister, Vivien, maintained lifelong musical activity. Jennifer sang in various choirs in Cambridge and later in Cornwall and Norwich. In 1939 Moyle went to Girton College, one of the women’s colleges at Cambridge, and chose to read (take the courses in) a natural sciences tripos (course of study) because of her interest in natural history and the exciting manner in which science classes had been taught in her school. She read biochemistry, chemistry, botany, and zoology. She recalled that Ernest Baldwin was the lecturer who most impressed her and whose teaching inspired her to pursue biochemistry professionally. She also attended a number of lectures in philosophy. At that time, Cambridge University did not award degrees to women but only gave a “title of a degree.” Moyle received her title in 1942 and joined the Auxiliary Territorial Service. From there she went straight into military intelligence,

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becoming an intelligence officer in MI8 (a branch of military intelligence) and second in command of her section that analyzed intelligence obtained from cipher breaking of the German codes by the British. After the war she continued in the service for a further year, participating in a teaching unit that helped prepare servicemen to return to civilian life. Moyle’s sister, Vivien, who was a research assistant to Ernest Baldwin, told Jennifer of a research assistantship open with Marjory Stephenson. Moyle applied and was accepted. She recalled Stephenson as “a lovely person, caring very much for the well-being of all her colleagues. Her devotion to thorough-going and down-to-earth research was very persuasive.”1 Moyle’s first recollection of meeting Peter Mitchell was in February 1947 at a departmental tea. She recalled that Mitchell stood out in the department, both in terms of appearance and as having a keen intellect with wide-ranging interests. By Christmas 1947, Stephenson knew that she had terminal breast cancer and started to make arrangements for her laboratory and subdepartment. She had already selected Gale to be her successor, but she expressed concern to Moyle that she did not always see eye to eye with Gale and that she felt Moyle might be happier working with Peter Mitchell, who was very clever. She approached Mitchell, as well as Chibnall, and Moyle’s placement with Mitchell was agreed. Both Mitchell and Moyle felt in retrospect that Marjory Stephenson possessed great insight into both of their personalities and abilities and foresaw how they could complement each other. Moyle was a superb, precise, and orderly experimentalist with a keen analytical mind, whereas Mitchell had a creative vision and instinct for asking fundamental questions. Together they became a formidable collaborative team, and during the 1948 to 1952 period, Mitchell and Moyle worked together very closely. Their relationship was from the outset of an entirely professional nature. Moyle’s personality and skills seemed to complement Mitchell’s in a way that proved highly creative for thirty years.



Life and Work in the Department

Mitchell and Moyle shared a single bay of a four-bay lab on the first floor on the south end of the biochemistry building. The other bays were occupied by Don Northcote, working on plant development, R. K. Morton, an Australian student of Dixon’s, and Joan Keilin (David Keilin’s daughter), who was working for Robin Hill on heme proteins

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and who was recalled as being almost as shy as her mentor, Hill. Other laboratories on this floor housed the groups of Robin Hill, Malcolm Dixon, and Dorothy Needham, among others. The large four-bay laboratory across the north end of the floor was occupied by members of the enzymology subdepartment until 1950; afterward it was used by the group belonging to the new head of department, Professor Young. The top floor was used for instruction. The ground floor had the departmental offices, including that for the head of department, Guy Greville’s laboratory, the lecture theater, the library, and the all-important tea room where staff met in the afternoon to discuss their research informally. The basement housed workshops and storage, as well as one research laboratory, which had been used by Danielli’s group up to 1946. Just after the war, two temporary laboratories or “huts” were built with funds from the Rockefeller Foundation. There was a “bug” hut, where the bulk of the microbiological work of Gale and his group was housed, with the exception of Mitchell and Moyle, who were formally in this subdepartment. There was also a “protein” hut occupied by Chibnall, Kenneth Bailey, Rodney Porter, Sam Perry, and Fred Sanger. Sanger, who became the only scientist to win two Nobel Prizes in the sciences—first for methods to determine the linear sequence of amino acids in proteins and later the linear sequence of nucleotides in DNA—was only a few years older than Mitchell. They developed a strong friendship. Both remembered an incident from this period when they used to go ice-skating together on the sewage farm outside Cambridge, where the ice was quite smooth. One day Sanger stuck his foot through the ice into the mire beneath, much to Mitchell’s amusement. An hour later Mitchell was skating with daring but insufficient caution and fell totally into the muck, coming up covered and reporting that it was rather warm. Sanger had the last laugh, and their friendship was cemented. Mitchell greatly liked Sanger but thought that his research was not imaginatively exciting. When Sanger received his first Nobel Prize in 1958 for the structure of insulin, Mitchell commented to Gregorio Weber that he was surprised because he did not think that Sanger was that smart. To this Weber responded that of course Sanger was not smart to have stayed so long with a problem that nobody thought could be solved. Mitchell was seen by his contemporaries as a fairly formidable character. He was hardworking and serious about his research, going into the laboratory well before eight in the morning well ahead of others. He was conscientious about making certain that Moyle had plans

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and materials for her work each day. Don Northcote and Bryan Robertson saw Mitchell as exceptional among Cambridge intellectuals, most of whom they felt were lazy. Mitchell was passionate about biochemistry, very thoughtful about how data related to larger theoretical concerns, and willing to help others interpret difficult results, but he was also intellectually aggressive. Although he was an active participant in the department, he longed for some space for solitary thinking. Such an opportunity became available through his interaction with David Keilin.



Shelter in the Molteno Institute

When Mitchell’s relationship with the authorities in the biochemistry department became seriously strained, Keilin provided space for Mitchell to work in the Molteno. Mitchell found Keilin, a senior scientist, to be someone with whom he could relate easily and discuss his ideas. After Danielli’s departure in 1946, his supervision became somewhat uncertain while his relationship with Gale (his de facto supervisor) was not always easy. Under the circumstances, Mitchell found the Molteno Institute a haven in the storm. As Mitchell developed ideas for his first doctoral dissertation, he was seeking to find a way to unify membrane phenomena with metabolic phenomena. Keilin’s approach to such questions was more that of a physiologist than a biochemist, and he was willing to entertain Mitchell’s ideas even if they were short on specific mechanisms. For Mitchell, Keilin’s “attitude strongly suggested that he had a feeling that what I was trying to do at that time was in principle a good idea, even if I had not made much progress, it might come to something.”2 Indeed, the relationship with Keilin was perhaps the most important experience of Mitchell’s later years at Cambridge. Not only did he [Keilin] offer encouraging, humorous, and wise advice. He also provided me with a small research room on the ground floor of the Molteno Institute, where I could have some privacy and set up some simple experiments to test some of my ideas. My work produced no obviously useful results . . . but David Keilin did not seem to expect anything tangible, and never quizzed me about the progress I might (or might not) be making. This was an invaluable time of mental exploration and slow and

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painful enlightenment for me, and I shall never forget the debt that I owe to David Keilin for appreciating what was going on, and generously and altruistically offering his personal blessing and friendship to a young student who was struggling to do something creative in the scientific wilderness.3 More important, Keilin was a role model who exemplified the ideals to which Mitchell aspired: He was a very remarkable and gentle kind of person, so I was soon attracted to him, and felt that if I could be the sort of scientist, the sort of person that he was, that would be pleasing to me. So that was one thing I made up my mind to do, to be unaggressive and not to imagine I knew things that I did not know. Although I do not think I have ever managed to get very near it.4 In 1978 Mitchell entitled his Nobel lecture “David Keilin’s Respiratory Chain Concept and Its Chemiosmotic Consequences.” In his opening comments he referred to Keilin as being not only one of the greatest of biochemists but the kindest of men and the scientist who had the greatest impact on him.



Devising a Relevant Philosophy: Fluctoids

Although Mitchell seems to have had little contact with the philosophy department or to have attended its lectures, he was reading books on philosophy such as Ogden and Richards’s Meaning of Meaning, and he began to devise a philosophical system of his own. While the point in time at which he started this endeavor is uncertain, it may nevertheless be as early as his undergraduate period. However, around 1945 he began drafting, in mostly undated manuscripts, ideas that he eventually applied to biological systems. The proposed system analyzed the world in terms of statids, objects composed of statistically organized atoms and molecules that are likely to be unstable or destroyed by interactions with their environments, and fluctids, objects that are part of the environment that is flowing through a defined space. A statid has a fixed structure and composition, whereas a fluctid is drawing its matter from the environment and passing its components back to the environment. An example of a statid would be a crystal; an example of a fluctid would be a flame. Unlike

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fluctids, statids cannot renew themselves and in time become disorganized. Mitchell’s simple example of the statid was a teacup whose form could be lost if the cup broke. A Bunsen burner with a flame constitutes a flowing (fluctid) element associated with a static (statid) element, the two together being a fluctoid in Mitchell’s terminology. A river flowing between its banks would be another example of a fluctoid. Mitchell noted that the most complex example of the fluctoid is the living cell. He published this system on only one occasion, in the proceedings of a symposium on the origin of life held in Moscow in 1957, where he had considered the importance of membranes in the evolution of primitive forms.5 At an early stage Mitchell seems to have mentioned his ideas to Ernst Friedmann, one of his lecturers, who had pointed out that his system was closely related to that of the pre-Socratic philosopher, Heraclitus. On Friedmann’s advice he purchased a copy of Burnett’s Early Greek Philosophy, apparently in 1945, although he was possibly aware of it several years before.6 What Mitchell found striking in Burnett’s discussion of Heraclitus was that he saw fire as the primary substance because a flame appears to remain the same even as its substance is continually changing. Heraclitus came to see all things as flowing; Plato saw the world of nature as one of becoming, not being. Mitchell recalled feeling some satisfaction that in his system only some things flowed. As part of the development of his philosophy, he included in his notes material entitled “Heraclitus on the Fluctoid.” In the heat of developing this worldview that had such a clear resonance with some aspects of Greek philosophy, Mitchell sought the professional opinions of the philosophy department at Cambridge, “where there was a man called Wisdom in those days who more or less told me I was a nit.”7 Mitchell was not deterred. From an early stage he appears to have had a confidence in his ability to work out the implications of what he took to be fundamental principles. Indeed, the drafts he developed from sometime in 1945 up to at least that of his first dissertation are reminiscent of his way of studying when he was at Queen’s. The significance of the fluctoid lies in providing a way in which living systems can be viewed and analyzed. Thus Mitchell explored various contemporary writers to relate and develop the concept of the fluctoid in relation to major issues in biology. He prepared papers containing quotations from D’Arcy Thompson, Joseph Woodger, and Joseph Needham under headings of “fluctoids” and the “living organism as a fluctoid.” Of particular interest to Mitchell were Needham’s

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concept of the cytoskeleton, developing ideas of Rudolph Peters, and issues concerned with concentration gradients and diffusion. A few more fully articulated drafts that include some mathematical analysis and are more complete are dated in September 1946. In addition, there was a full draft manuscript of a paper that was never published, “Studies in the Distribution of Substances in Systems with Continuous Inhomogeneity Relevant to the Organisation of Biological Systems.”8 There is little doubt that the work on fluctoids was a significant means of resolving and expanding Mitchell’s ideas about living systems. Although the fluctoid notion might seem a very primitive philosophical idea and even rather naïve, it had at least three essential consequences. First, it provided Mitchell with a model for a thoroughgoing holistic approach to living systems, which distinguished him from many of his generation of biochemists who were increasingly focused on partial processes. Second, it centered on a consideration of reactions within the spatial and temporal organization of living systems. Third, by focusing on the flowing aspects of biological activities, Mitchell set himself a distinctive path of thought and also experiment. The fluctoid concept was a highly creative force in Mitchell’s thinking and can readily be traced as a covert theme through much of his writings at least up to the early 1960s.9 The fluctoid notion was highly speculative and idiosyncratic, yet it reflects the particular intellectual milieu of the Cambridge biochemistry department in which Mitchell was nurtured. The general tenor of the concepts of dynamic biochemistry set by Hopkins and the emphasis on spatial and temporal aspects of biological phenomena in Needham’s thought provided fertile ground for the seeds of Mitchell’s intuitions. The theoretical biology club, with its ethos of scientific discourse with philosophical speculation, was still likely to be an influence because of the Needhams’ presence. This environment undoubtedly encouraged Mitchell to elaborate his ideas and to apply them to biochemical problems. The exploration of the fluctoid idea characterized Mitchell’s general approach to biological problems, where he usually generated a well-developed theoretical framework before he considered carrying out experiments. Such an approach proved an outstanding strength and underlies almost all of his significant creative work. It also proved a serious weakness when theory seemed to prevent his seeing experimental evidence in a new light, such as occurred in the cytochrome oxidase controversy.

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The First Doctoral Dissertation

It appears that as Mitchell began to develop specific plans for his doctoral thesis, ideas that had been inchoate from his undergraduate days now—informed by some actual research experience—began to surface for clearer analysis. The primary impetus seems to have come from his fluctoid idea. The thesis, which was not submitted until 1948, had the title, “The Distribution of Freely Diffusing Substances in Solution of Graded Composition, with Special reference to the Biological Systems.” It was in three parts with an introduction, but only a three-page portion of the introduction has survived. This begins: The practical and theoretical work described in this dissertation was the direct outcome of certain general considerations of the properties of living biological systems which distinguishes them from dead things. These general considerations are of little consequence to the appraisal of the more specialised work which is described; but, whether valid or not, useful or otherwise, to other workers, they serve as a legitimate introduction to this work for which they have provided a stimulating background.10 In the second paragraph Mitchell cites Heraclitus, along with Seneca’s comments on Heraclitus’s famous dictum that one cannot step into the same river twice. He notes that the same is true of a human, whose identity persists but whose substance is constantly being changed. In the same paragraph he cites Walter de la Mare’s little verse about Miss T. that includes the lines “Whatever Miss T. eats, Turns into Miss T.” In the next paragraph he moves to a quotation from Woodger that some things are not damaged by interacting with the environment but “manifest a new type of persistence.” The final sentence of this fragment gives definitions of statids and fluctids but breaks off before the definition of fluctoid. From Mitchell’s recollections, as well as those of his examiners Ernest Gale and Sandy (A. G.) Ogston, this introduction was followed by a section on a mathematical theory of diffusion and distribution of substances within cells, including some experiments illustrating aspects of these notions (probably done at the Molteno). This first section, which expanded on the fluctoid idea, appears to have been presented as the most important part of the thesis. The second section dealt with the absence of a gel coat when bacteria were subjected to electrophoresis and sought to address the nature of the bacterial cell surface. The final

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section presented some solid but preliminary experimental results on the uptake of amino acids by bacteria. This was clearly an unconventional structure for a formal academic thesis. The external examiner was Sandy Ogston, a physical chemist from Oxford who later moved to Australia. The examiners felt that Mitchell had cast his net too wide, that the thesis was too speculative, and that he had not worked out any one theme sufficiently to a logical conclusion. In particular, Ogston felt that “the set-out of Mitchell’s work and his attitude to it in discussion seemed to be silly, not a presentation.” Ogston “insisted on its ‘referral’ for re-presentation.” Subsequently, he remarked, “I think now that this was too hard.”11 The comments on fluctoids were not appreciated, and Mitchell was advised to omit them in his resubmission, as well as in his theoretical discussion of intracellular diffusion. A deadline of 30 September 1950 was set for the submission of the second dissertation. Mitchell was very angry, not only because he felt that he was already behind the normal timetable of professional development but also because of the rejection of his approach to biochemistry. Keilin shared Mitchell’s upset; Keilin’s daughter recalled, “I remember clearly how disappointed he [Keilin] was, indeed angry, when Peter was asked to resubmit his Ph.D. thesis.”12 Keilin remarked, “The trouble is that Peter is too original for his examiners.”13 Mitchell was tempted not to make any revisions, but friends, such as Don Northcote, persuaded him to do as the examiners had requested.



Research on Penicillin and the Second Doctoral Dissertation

At that time in Cambridge, doctoral research students were expected to develop their own problems and work on them independently, with only modest supervision from the Ph.D. supervisor. Gale, probably the most appropriate supervisor for Mitchell, had considered him to be really Danielli’s graduate student, even though Danielli was no longer in Cambridge. Hence he had not paid attention to the project Mitchell had developed for his first dissertation. Indeed, even in 1950 the Cambridge University Reporter still showed Chibnall rather than Gale as the official supervisor. This was only a formality, however, left over from when Chibnall was head of department; Gale became the de facto supervisor. Gale, who was less interested in theory, liked to ask specific questions

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for which precise experimental answers could be obtained. He did in fact interact with Mitchell to request his assistance in interpreting results on amino acid transport in bacteria. Gale suggested that Mitchell address the problem of the mode of action of penicillin as the subject for his second dissertation. In the end, Mitchell did a workmanlike job, but his heart was not in the project. He explored the role of penicillin in altering nucleic acid synthesis in bacteria, later publishing three articles arising from his unpublished dissertation.14 In addition, three articles about improved experimental techniques were also published.15 On 6 December 1950 Peter Mitchell’s second thesis, “The Rates of Synthesis and Proportions by Weight of Nucleic Acid Components of Micrococcus during Growth in Normal and in Penicillin-Containing Media, with Reference to the Bactericidal Action of Penicillin,” was officially accepted, and the Ph.D. degree was conferred. The mechanism Mitchell proposed for the action of penicillin, however, proved to be incorrect. He did make an observation about an alteration in nucleotide composition in the presence of low levels of penicillin that held the clue to the eventual elucidation of the true mechanism. Gale later criticized Mitchell for not following this up. However, in retrospect, Mitchell viewed this work as unexciting: The work that I did on penicillin did indicate the existence of a nucleotide that accumulated and was a precursor of cell wall material. I suppose if we had spent another five years fiddling away at that problem we might have found the mode of action of penicillin. So what? Even when they knew the mode of action, it led to no better antibiotics and what was learned was a rather minor part of metabolism.16 Nevertheless, Mitchell’s work on these bacterial systems was not without some consequence. Sometime thereafter, an observation of an “X-P” component in gram-negative bacteria was probably the first indication of the presence of teichoic acids, but a larger group, which became aware of Mitchell’s results, was able to move faster to publication. In any event, Mitchell regarded such work as a distraction from his main interest. Subsequently, Gale described Mitchell’s approach to this research in the following terms: He would carry out a large number of small, rather inconclusive experiments which enabled him to develop his theory of what was

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occurring. Then he would design one massive all-inclusive experiment based on the results of all the preliminary tests—and that, if it worked, was that. To anyone outside the department, much of his early work seemed to be incomplete because he left out those tests or controls which were discarded during the preliminary work. I well remember sitting next to Hans Krebs at a meeting of the Biochemical Society when Peter first gave a major paper on his work on energy transfer and ionic changes. Krebs steadily became more and more incensed and muttered “But he hasn’t done the controls.”17 Although Mitchell no longer made any public mention of fluctoids or of intracellular gradients after the experience of the disaster of his first dissertation (except in the Moscow paper of 1957), he was still preoccupied by the search for general theories of biological phenomena. He came to focus more on the membrane as the site of interplay of metabolism and transport where spatial effects might well be important.



The Society for General Microbiology Meeting

Despite Mitchell’s problems with his first dissertation, he was well regarded as a bright and promising microbiologist. He taught full courses on microbial physiology in the biochemistry department during the Michaelmas terms of both 1948 and 1949. He was invited to participate in a symposium by A. A. Miles and Norman Pirie (both formerly of the department during the 1930s), probably on Stephenson’s recommendation. The subject was the nature of the bacterial surface and was arranged by the Society for General Microbiology, which met at the Royal Institution in April 1949. Mitchell’s lecture, his first at a major meeting, was entitled “The Osmotic Barrier in Bacteria.” The term “osmotic barrier” was probably first used in this paper, and, although he was very cautious, he appeared to identify this with the bacterial cytoplasmic membrane, a step which was a logical outgrowth of his work with Danielli and Gale. Another issue discussed, which anticipated some of his later work, was the uptake of glutamate. Here he suggested that an enzyme on the outside of the membrane converted glutamate to glutamine, which could traverse the barrier and be converted back to glutamate by an enzyme on the inside of the membrane. This conception implied that the mem-

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brane played a part in metabolic events and that some of its proteins were enzymes rather than serving simply as a coating, as Danielli had envisaged. A number of these ideas also arose from the thoughts that he was formulating about the cell surface in the second part of his first dissertation. The paper concluded: To summarize, the evidence suggests that Claude Bernard’s concept that all free living organisms must possess a relatively isolated internal environment is true for the bacteria. As well as offering passive resistance to the movement of substances into and out of the cell, the osmotic barrier is the seat of processes of active transfer which maintain the differences of composition of the internal and external environments in actively metabolizing or in growing cells; and the steady concentrations of the substances within the cell generally represent steady state conditions and not equilibria.18 He concluded his paper by outlining the need to undertake research about the structure and function of the osmotic barrier. During the 1950s, Mitchell’s research program was based on working out and articulating the implications of the ideas explicitly or implicitly presented in this symposium presentation. This meeting was memorable to Mitchell for another reason. Sir Alexander Fleming, the discoverer of penicillin and Nobel laureate, gave a demonstration of the action of light on the motility of Proteus vulgaris treated with low levels of penicillin. The main point was that Fleming was able to see the flagella of the bacteria under a phasecontrast microscope and was able to demonstrate their function in bacterial motility. However, work in Fleming’s laboratory early in 1949 convinced him that the bacteria responded to light when the mirror under the microscope was tilted to ensure that more intense light shone on a bacterium. Fleming even speculated that the bacteria seemed to have a primitive nervous system.19 When Mitchell witnessed the demonstration of the light effect he noticed that there was a lag time before the bacteria became motile. He asked Fleming if he had ever tried using a heat filter that would allow the light energy through but prevent a heating of the medium. Fleming said that they had not. Mitchell then suggested using a flask of water as a heat filter, which Fleming tried on the spot and the light effect totally disappeared. When the paper about the motility of bacteria in the presence of low levels of penicillin appeared in 1950 (manuscript received 21 October 1949), there was no mention of any light effect but, rather, of a heat effect that

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had a lag time and that could be blocked by heat filters; there was no acknowledgment of Mitchell’s suggestion.20 Mitchell was “a bit chagrined that Fleming never mentioned that it was I who suggested that he alter his experiment. That was one of my first experiences of finding that sometimes something you suggest gets swiped.”21



Employment in the Biochemistry Department

Shortly after Mitchell completed his requirements for the Ph.D. degree, Gale considered Mitchell for an open demonstratorship (a junior academic appointment) in the microbiology subdepartment of the biochemistry department. Such appointments were for five years, with promotion to a tenured lectureship if all went well and if a vacancy were available. Demonstrators were expected to carry out research, supervise research students, give a limited number of lectures, and mainly run practical classes for science and medical part I students. Gale decided not to offer Mitchell a demonstratorship because of doubts about his suitability as a supervisor of research students: Peter was then working on a research grant and I asked him to supervise one of our research students to see how he managed. As the weeks went by I became aware that the research student (who eventually became a research scientist in his own right) was not happy. I then found that Peter had a meeting with his student each morning, discussed his work in detail and outlined to him the precise experiments he was to carry out that day. The young man was given no opportunity to explore his own ideas or plan his own experiments. I took Peter aside and asked him why he was treating his “student” as an assistant and was told “Oh—he hasn’t any ideas of his own and I want him to get the answer.” So I had no alternative but to change the young man to another supervisor. And I decided that, especially in the situation we then were in trying to develop a new subject, we could not offer a demonstratorship to Peter.22 As Gale observed, Mitchell was happier directing others to work on his ideas than on encouraging the young to develop independence. However, there was a vacancy that arose in the department shortly thereafter, and Young appointed Mitchell to a three-year term that expired in summer 1953, renewable for two more years, at an annual salary of £738–15s.

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Most of Mitchell’s teaching responsibilities were in conducting practicals for part I students and just four lectures in physical microbiology in 1953 and 1954. For two years he was able to work closely with Jennifer Moyle, but in 1952 Gale decided not to renew the research support for Moyle, urging her to move on to another researcher. Dixon, who was then in the throes of writing his massive book on enzymology with Webb, had need of a research assistant and hired Moyle to work on isocitrate dehydrogenase. Moyle did help Mitchell finish some of their joint projects on the side, and she often turned to Mitchell for advice about her research as Dixon was usually not available for consultation. Young asked Mitchell to organize the weekly seminar series for the department, known as the Tea Club meetings. This gave Mitchell an opportunity to become aware of the current work of his colleagues. For example, Fred Sanger presented the first accounts of his insulin sequencing to the Tea Club. However, Young’s administrative style was virtually the opposite of Hopkins’s and Chibnall’s. This began to make life miserable for Mitchell and also for many others in the department. Young instituted a new policy that required that he review all papers before they were submitted for publication. Resistance quickly mounted. Hill put a paper in an envelope addressed to the journal with a note on it so that all the department could see: “Young, Please post. Hill.”23 Northcote, when asked publicly by Young what he was currently doing, replied, “Professor, I gave you my most recent paper a month ago.” Young went blank. Whereupon Northcote said, “But Professor, don’t you even remember the pictures?”24 Mitchell had a more serious confrontation with Young. In late 1952 or early 1953 he requested the purchase of a spectrophotometer that had recently become available. After discussing the cost and possible budgetary support, Young said, “But Mitchell, you said you thought it’d take about a nine-month delivery time. How do you know you will be here when it arrives?” Mitchell recalled that “of course a hole formed in the floor, and I went straight down.”25 Shortly thereafter Mitchell, along with Northcote and Gregorio Weber, formed the SFDWSP club (Society for Doing without Some People). Since Young had insisted that all staff wear laboratory coats, the club members all wore black laboratory coats, a gesture noted but not appreciated by Young. By 1955 Mitchell’s future in the department was murky at best. Despite Mitchell’s difficulties with Young, others at Cambridge

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held Mitchell in high regard. He was a member of the select group of junior faculty who belonged to the Hardy Club, devoted to discussion of biophysical subjects.26



Helen Robertson and the Dissolution of the Mitchells’ Marriage

In 1951 Bryan Robertson suggested that he, John McNeil, and the Mitchells, who had a wonderful touring car, all drive through France to a large villa in Monaco that Elizabeth Vellacott and two students were renting. He also suggested including Pat and Helen Robertson, no relation. Pat Robertson had painted the sets that Peter had admired in a recent production of Purcell’s King Arthur. Given their impoverished circumstances, the Robertsons eagerly agreed to an almost cost-free holiday in the south of France. There was an instant, strong, and obvious attraction between Peter and Helen. A photograph of the group in the car on the drive through France shows Peter and Helen seated close together and oblivious of the uneasy looks of the rest of the passengers. Helen (née ffrench [sic]) Robertson was born in 1924. Her father Raymont ffrench, the son of a small land-holding Irish Catholic family in Galway, was a lieutenant colonel and served in the Middle East in World War I and in India. He married Dorothy Pittman, and they set up house in India. When Helen and her brothers reached the age of 10, they were sent to England to boarding school. When she was 16, she moved to Cambridge, where she had a job as a waitress at a café called the Whim and lived on her own until she married an architecture student, Pat Robertson, in 1946. The Robertsons had a daughter, Vanessa, born 6 March 1948, and a son, Daniel, born 15 June 1949. They had very little money, subsisting on a small and inadequate grant. They resided in a small Jacobean house called the Oysters, the name coming from the time when it had been a pub serving freshwater oysters, the shells of which piled up around the exterior. The Oysters had no running water or facilities, but the rent was only 7s 6p a week. Helen’s friend Eva Ibbotson commented that Pat Robertson was a nice and easygoing sort of person, although the relationship seemed to have lacked passion. He decided that rather than pursue a career in architecture, he would prefer to work in the theater, designing and painting sets. At that time, Helen was not an active artist, as she later became, but she did pose for artists and developed friendships with them. She be-

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came close to Betty Reed and Nan Youngman, sculptress and painter, respectively, who lived in a Georgian house called Paper Mill. They helped Helen with childcare, and it was there that Helen met her first scientist, J. D. Bernal, or “Sage,” who was one of Betty’s lovers. As Helen remembered, “I knew Sage because he was a great chaser of women, and he used to chase me around the playroom. I tried to avoid this as much as possible.”27 Peter Mitchell recalled the sojourn in France as a very romantic time, but also relaxing as they spent hours sunbathing. Mitchell liked to think that his ease of tanning and his “Mediterranean” appearance, about which many people commented, were the result of his “Jewish genes.” A romance between Helen and Mitchell quickly developed into a physical relationship upon their return to England, and Mitchell moved out of Silbury into the annex with his father-in-law. He soon bought a house in Lavenham, some thirty miles east of Cambridge, for his fatherin-law and took sole possession of the annex. Pat Robertson was understandably upset about the attraction between Peter and Helen. However, shortly after their return, Pat had to leave Cambridge, since he had taken a job at the Old Vic in Bristol and needed to find accommodations for the family. On his return, Pat discovered, in a rather dramatic fashion, that Peter and Helen had become lovers, and he gave Helen an ultimatum: either she stayed with him to be with the children, or she left him for Peter and lost the children. Helen went to Bristol with Pat and the children. However, Peter arranged through his old friend, John Gayer Anderson, who was living on a farm outside Cambridge, to send eggs, generally unavailable at that time, to the Robertsons in Bristol, hiding letters in the cartons. Gayer Anderson helped arrange a meeting between Peter and Helen, and Peter went to Bristol “in disguise.” After this intimate liaison, Helen decided that this just could not go on, as she was being torn apart by her love for Peter and that for her children. As she could see no way to leave Pat and take the children with her, she made a decision and wrote to Mitchell: “Dearest Pete, I can’t do two things at once and therefore mustn’t ever see you again. Good-bye for ever. Love, Helen.”28 They did not contact each other for nearly four years. Jason Robertson was born on 16 August 1952. Helen claimed that Jason was Peter’s son, although a blood test conducted some years later proved inconclusive, given the technology then available. Peter Mitchell later adopted Jason as Jason Mitchell. In early 1953 Mitchell met the actress Ann Salisbury, who operated

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a restaurant in Cambridge called the Soup Kitchen. Mitchell soon moved out of the annex at Silbury and in with Ann. He helped with the cooking at the Soup Kitchen, drawing on the culinary skills he had learned from Eileen. Peter and Eileen Mitchell had their divorce finalized in 1954; later Eileen married John McNeil. Peter and Ann took trips to Greece and to Italy together, riding on Mitchell’s recently acquired motor scooter. The relationship lasted until Mitchell moved to Edinburgh but did not survive the separation.



Developing a Research Program

In the work on the possible mechanism of penicillin, Mitchell and Moyle had observed that there was a phosphate complex in the cellular envelope of the bacterium they were studying. This complex contained about a quarter of the phosphate of the cell.29 Sometime in 1952 they embarked on a series of experiments designed to find the pathway for the entry of phosphate. In a 1953 article, Mitchell and Moyle presented a series of carefully designed and executed experiments that elegantly established an osmotic barrier to the entry of phosphate, as Mitchell had postulated in general terms in 1949. He also showed that phosphate crossed this barrier by interaction with a molecule that mediated its transport.30 In an accompanying, more theoretical article, Mitchell argued for a model of the membrane as the osmotic barrier, with some form of mediated transport of low-molecular-weight substances across it, as opposed to an alternative hypothesis based on adsorption properties of surfaces.31 In 1954, Mitchell demonstrated that the phosphate transport system was highly specific. He suggested that the transport was like an enzyme-catalyzed reaction in which the transport protein provided a way through the osmotic barrier analogous to the way that enzymes lower the energy barrier to chemical reactions.32 Calculations suggested to Mitchell that there was a major reorganization in the membrane of the protein responsible for the transport of phosphate. These papers were carefully conceived and thought through, and they were written with an assurance not previously seen in Mitchell’s publications about penicillin. He had clearly found the basis for a productive research program that linked his previous experience and education with his deeply held intuitions about the nature of the processes of living systems as a whole.

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In a pattern that Mitchell followed in subsequent years, he presented his results and ideas in several symposia, where he could reach a broader audience, as well as have greater editorial freedom to pursue his theoretical speculations. Mitchell admitted he appreciated the “poetic license” that an unrefereed symposium presentation afforded him. At a symposium of the Society for Experimental Biology on active transport and secretion, Mitchell generalized his findings, arguing that the processes of transport across the membranes of cells were like those of coupled enzyme reactions of metabolism. He went on to speculate that “in complex biochemical systems, such as those carrying out oxidative phosphorylation . . . the osmotic and enzymic specificities appear to be equally important and may be practically synonymous.”33 This comment reveals that Mitchell was not unaware of the problem of how energy was captured and transduced in mitochondrial and bacterial oxidative phosphorylation. It also shows that Mitchell was allowing his intuitive vision to broaden so that he could speculate on how metabolism and transport might be fundamentally linked. Mitchell’s recollection of writing that paper was that I was thinking at that time, as I had been tending to think for quite some time before, that there was no reason why the notions of metabolism shouldn’t be entirely compatible with the notions of transport or why there shouldn’t be a branch of biochemistry which dealt with both as a unitary process that wouldn’t distinguish the edge of one from the edge of the other.34 The final article that Mitchell wrote from Cambridge was presented at the Sixth Symposium of the Society for General Microbiology, which was held at the Royal Institution in April 1956. It should be noted that at that time the nature of the bacterial plasma membrane was by no means fully established. Thus another contributor to the same symposium could write, “In electron micrographs . . . the cytoplasmic membrane is embarrassingly difficult to see.”35 Hence Mitchell and Moyle reinforced their argument for the osmotic barrier (assumed to be the plasma membrane), particularly since alternative views suggested that the cytoplasm behaved like a sponge surrounded by a net structure that allowed free passage of small molecules. Mitchell and Moyle also summarized some of their earlier work from 1953 in which they were able to estimate the permeability of the bacterial membrane to phosphate and other metabolites and ions. They repeated their generalization that transport is like an enzyme-catalyzed metabolic process:

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the plasma membrane [is] not only a static barrier to the free diffusion of small molecular weight solutes, but also a mosaic of specific carriers which may allow the free movement of certain solutes with a specificity equal to that of enzyme-substrate combination— some of the carriers being enzymes themselves. . . . We propose the hypothesis that the permeability of bacteria to many of their nutrients and waste products is a specific one, dependent upon the presence of enzymes which absorb the nutrients and desorb the end-products of metabolism in the surface of the plasma membrane.36 By 1955 Mitchell was ready to move forward with a well-conceived research program. He was also open to the possibility of physically moving from a department where he increasingly disliked the administration and where he felt neither understood nor appreciated. Indeed, as his demonstratorship expired in 1955, it was not clear what his role or future in the department at Cambridge would be. His divorce and the situation of his personal life also made the prospect of relocation attractive. Thus when he heard from Michael Swann about a possible position at the University of Edinburgh, he was receptive.

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5
Edinburgh 1955–1963



A Creative Period

Probably the most creative period in Mitchell’s life was the years spent in Edinburgh from 1955 to 1963. It was here that the ideas on vectorial metabolism took a defined form and the expression of Mitchell’s concept of the fluctoid, although rarely referred to, achieved its full expression in his philosophy of living systems. While the notion of vectorial metabolism did not greatly influence his contemporaries, it was the specific application of these ideas to the problem of oxidative phosphorylation that did. The chemiosmotic hypothesis proposed by Mitchell in 1961 while he was at Edinburgh not only created a unique approach to a major problem of biological science but also placed Mitchell in the center of scientific debate for the rest of his life. A key question, therefore, is how Mitchell came to propose the chemiosmotic theory that undoubtedly constituted a classical paradigm shift for cell bioenergetics.



A New Opportunity

Michael Swann, a cell biologist, was the same age as Mitchell and had been a university demonstrator in zoology at Cambridge over the period 1946–1952, where he was certainly aware of Mitchell. Swann had moved to take the chair of natural history at Edinburgh, where he sought to develop the zoology department. In due course he became principal (equivalent to president) of the university and later, as Lord

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Swann, became chairman of the British Broadcasting Corporation Board of Governors. In 1954 he attracted Mitchell to Edinburgh to a lectureship. The new post was coupled with the title of director of the Chemical Biology Unit, which Mitchell was to create. Swann agreed with Mitchell that Jennifer Moyle should accompany him so they might continue their collaboration. However, it was the Scottish Hospital Endowments Research Trust that funded Mitchell’s research from 1955 to 1959. Later Swann wrote: Both Murdoch Mitchison (now Professor of Zoology) and I had known Mitchell well in our Cambridge days, and had a very high regard for his ability. When therefore we heard that he would like to leave Cambridge and find a more congenial environment, we set about getting him to Edinburgh. The University provided a lectureship, but he had a very able colleague, Dr Jennifer Moyle, whom he wanted to bring with him, and he had ambitious plans for research that needed money. . . . Sometime in 1954 I think, we put in a large and I suppose audacious application, to set Dr. Mitchell up as Director of a Chemical Biology Unit within the Department of Zoology.1 Mitchell had many reasons for accepting the offer from Swann. The opportunities arising from having his own research unit were certainly an attraction. He had been at Cambridge for sixteen years, and some visible sign of academic progress was now desirable. Edinburgh was regarded as the premier Scottish university, and although not in the same rank as Cambridge, it was clearly an intellectual center of high caliber. If there were reasons to pursue new opportunities at Edinburgh, there were also good reasons for leaving Cambridge, including personal ones. Cambridge was the city where his marriage had been unsuccessful and where his first wife still lived. A move away from Cambridge would certainly make life easier. The biochemistry department was another reason. Mitchell’s time in the department had not been without problems. He had gained much from working in one of the finest biochemical intellectual environments, initially under the benevolent leadership of Hopkins, regarded as the father of English biochemistry. However, a later professor, Frank Young, had introduced many changes in the department, several of which Mitchell, among others, had not liked. All in all, it was time for a change.

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Edinburgh Is Not Like Cambridge

Mitchell found Edinburgh very different to Cambridge, and he was disappointed by the absence of anything equivalent to Oxbridge college life. The student body was distributed into the general life of the large city, and the whole ambience was not that of an academic community to which Mitchell had been accustomed. The zoology department was located in the King’s Buildings, some distance from the center of the city where the biochemistry department was still housed. In particular, he missed the social life he enjoyed in Cambridge and spent much more of his time at home. The regular and frequent visits to concerts were no longer possible except during the Edinburgh Festival, when the effort of trying to keep up with everything that was happening was positively exhausting. In due course, however, there were skating parties that also included Audrey Manning from the department and a friendship with the zoologist Bryn Jones and his wife. Bryn Jones was also a talented painter admired by Mitchell; indeed, Mitchell felt that perhaps in temperament Bryn Jones was more an artist than a zoologist, a quality that endeared him to Peter and in due course to Helen. Another colleague who proved a friend to Mitchell was Jack Dainty, who headed a small biophysics unit and worked on transport across plant cell membranes. They discussed the intricacies of electrochemical potentials and electrochemical activities, which Dainty helped Mitchell master. Dainty recalled: Peter would often come (at one period, every day) and discuss his ideas with me; in a sense he was “using me” to sound out and sharpen his ideas. I think he expected from me, who am trained in the physical sciences, a check on whether any of his notions were physically nonsensical. This was particularly so in respect to the thermodynamic aspects of his model(s). . . . I remember that he seemed obsessed by physical models of vectorial transport coupled to ATP synthesis. He would build them from plywood (~1 cm thick) and each model would consist of several pieces articulated together and able to swivel in various ways. He would produce a new plywood model every week or so at one stage and he would try them all out on me—demonstrating exactly what he thought was happening with the ADP, Pi, ATP, H2O, H+ and so on. He was very very dedicated and obsessed with them.2

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Among others who discussed ideas with Mitchell was the developmental biologist Conrad Waddington, who had also been in the biochemistry department at Cambridge (but left before Mitchell arrived) and shared Mitchell’s passion for theoretical biology. On arrival at Edinburgh, Mitchell acquired from a departing member of the university an upstairs flat with its own private access through an outside staircase, on a road leading directly to the King’s Buildings. The King’s Buildings housed a number of scientific departments, including the department of zoology, where Mitchell had his laboratory, a big room with low benches (used for microscopy but not really suitable for chemical work) in a rather dingy basement. In due course, Mitchell felt he needed an office and decided, rashly without reference to the university administration, to build one himself. He duly went in his Landrover to acquire the materials and erected it in the corner of the laboratory. It had a remarkably narrow door and when asked by a research student why the door was so narrow, Mitchell replied, “That, my boy, is to put the professors at a psychological disadvantage when they come to see me.”3 At the time Mitchell was very slim, whereas both Swann and Mitchison were quite large, rotund men. There were desks in the corridor for his coworkers. His colleagues found him an admirable and charming person, although rather difficult to understand in scientific discussions. In contrast, his set-piece lectures, of which there were twelve devoted to chemical biology, were both inspiring and lucid. In the departmental research seminars, he appeared to be several jumps ahead of the lecturer. His students saw him as a brilliant, eccentric, and gentle anarchist. He never tried to put anyone down but built them up; in contrast, those who tried to grind him down got a formidable response. His appearance helped reinforce his eccentricity. His hair was long, down to his collar, and one of his colleagues here, like some at Cambridge, remembered his appearance as like that of the later Beethoven with his heavy face and long hair.4 From the flat to the laboratory was an easy walk, enabling Mitchell to travel between the two at any time. The furnishing was sparse, as Mitchell had brought little with him from Cambridge, although he had brought his piano. The arrangement did not prove totally satisfactory. The man living in the ground floor flat complained that Mitchell’s walking about in the middle of the night and sometimes playing the piano created a disturbance. Both for this reason and that the flat was rather limiting, Mitchell concluded that it was not a suitable place to live; in due course he would need to find somewhere else.

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Marriage

Mitchell had not lost his interest in Helen Robertson (still living in Bristol), nor had Helen lost her interest in him. It was over four years since they had seen each other, however, a situation brought about in part by Helen’s loyalty to Pat Robertson and also the possibility that Pat would keep the children if Helen left him. An invitation to lecture in Bristol provided Mitchell with an opportunity to visit Helen, and on her part she was keen to make Peter welcome and invited him to stay the night. The ultimate outcome of this visit was that Helen took her children to her mother’s and departed for Edinburgh to live with Peter. In due course, Pat agreed to divorce proceedings, and Peter married Helen in 1958. Their younger child, Gideon, was born the same year. Jason joined the Mitchells in Edinburgh and was formally adopted. Mitchell showed a keen interest in the upbringing of his sons and involved himself fully in parenthood.



Carrington

Mitchell had arrived in Edinburgh with his Rolls Royce, but in time he had found it rather expensive to run. Accordingly, he had disposed of the car and acquired a motor scooter, later to be replaced by a “Bubble” car and, after that skidded on ice, a Landrover. It was the scooter that he used at weekends to tour the surrounding countryside, however. On one such day out, he visited the ancient villages of Carrington and Temple some ten miles to the south of Edinburgh. At the top of the hill in Carrington, he noticed the old manse, a typically Scottish building with small windows and massive stone walls. Inquiries locally indicated that the parishes of Temple and Carrington were being merged and that the Carrington manse would no longer be required for its original purpose. On the advice of Murdoch Mitchison, Mitchell wrote to the church elders inquiring whether the building was for sale. After some delays he was invited to enter a bid for the house. He offered £920, and this was ultimately accepted. It was to this house that Peter brought Helen. Despite its primitive condition at the beginning—it had no electricity, no hot water, only one cold water tap downstairs and surprisingly no drainage—Helen felt that this was her first real home. She remembered the first sight of the building surrounded by dark yew and laurel. It was early Georgian and

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had very few windows, and there was little light inside. She also remembered the first night when they slept on a mattress on the living room floor while, unknown to them, a rat ate a hole in the blankets that covered them. Mitchell set about dealing with the vermin and renovating the house. With Helen’s advice, he turned it into a comfortable home for her and the children. Mitchell organized a number of changes in the house, including taking out half a floor so that the very dark kitchen was open to the room above, which then became a balcony. The modification also provided a place for the piano. Since a general building firm could not be found for the renovations, Mitchell employed the various trades individually as necessary: slaters for the roof, carpenters and joiners for the woodwork, and stone masons, for example. There were no planning regulations at the time, so Mitchell was able to make all the plans himself and to organize the craftsmen, a situation that gave him great satisfaction and enjoyment. It was an experience that would prepare him well for events that followed. When finally the Mitchells left Carrington, Helen felt it was a beautiful house. The Mitchells were not particularly sociable; neither of them liked the cocktail parties that were a major social activity in Edinburgh. They did relatively little entertaining themselves, although Jennifer Moyle visited the house quite frequently and Peter and Jennifer would discuss research and write papers in the garden. Close friends of the Mitchells were John Gayer Anderson from Cambridge days and Eva Ibbotson, the author, from Helen’s time at Bristol.



Mechanisms for Active Transport

The move to Edinburgh seems to have been associated with a redefinition of Mitchell’s scientific interests. The Cambridge period had been primarily concerned with transport across the bacterial plasma membrane as a physical phenomenon and the membrane itself as the osmotic barrier, culminating in a review that focused on the osmotic function of the bacterial membrane. In contrast, the Edinburgh period addressed the relationship of membrane transport to the proteins of the membrane and particularly to the membrane-bound enzymes, leading to the concept of vectorial metabolism. For Mitchell, transport across biological membranes became associated intimately with the chemical reactions located in these membranes and the extent to which such reac-

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tions could account for the process of “active transport” (see appendix to this volume). These were not the only issues pursued, but they were the focus of his work.5 The collaboration with Moyle established itself firmly during this period, and she completed her Ph.D. thesis under Mitchell’s supervision. Her superb technical and experimental ability, coupled with her patience and attention to detail, was very valuable and probably essential for Mitchell’s success. Her skills complemented his very well: he had the ideas, while she was the person he tested them against first. He was very able with his hands, a skilled glass blower, and at this stage a competent, though not brilliant, experimentalist. The laboratory work advanced as a result of acquiring the ability to prepare bacterial membranes. Thus in a paper given to the Biochemical Society,6 Mitchell and Moyle showed experimentally that the location of the cytochrome system of the respiratory chain was in the cell membrane of a bacterium and drew attention to the possible involvement of respiration in ion transport. Life in the department was not without its tensions. Swann, whom Mitchell respected and liked, apparently wanted the Chemical Biology Unit to solve the biochemical problems raised by other projects being pursued in the department. In contrast, Mitchell felt that for a tiny unit to be effective on a global scale (perhaps a pious hope, he later admitted), it would have to concentrate on certain fundamental biochemical problems. In general, Mitchell and Moyle seem to have got their way most of the time, although later, when money was short, they had to accept a grant from the Nuffield Foundation for work on rheumatism, which led to Mitchell giving a short series of radio talks on the subject.7 Mitchell interpreted the purposes of this grant broadly, arguing that in order to understand the abnormal systems, one would need to understand the normal first! This view justified work on Mitchell’s real interests that were proceeding alongside the work on rheumatism. During this period, Mitchell’s early philosophical considerations still proved to be influential. In response to an invitation to contribute to a symposium on the origin of life in Moscow in 1957, he chose to discuss the organizing functions of natural membranes. The original notions of statid, fluctid, and fluctoid are here defined and presented as a logical extension of the ideas of Schrödinger and Haldane. It was Schrödinger the physicist who had addressed the question, “How can the events in space and time which take place within the spatial boundary of the living organism be accounted for by physics and chem-

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istry?”8 Mitchell pointed out that “the importance of the spatial distribution of the substances in such systems has not however generally been considered.”9 It is the spatial relationships that characterize most of Mitchell’s concerns in the late 1950s. Thus the fluctoid idea (outlined in chapter 4) was developed here in relation to the need for a semipermeable membrane to enclose the various cellular processes in order for life to develop.



Linking Metabolism and Transport

During his formative years at Cambridge, Mitchell had felt that the research group devoted to membranes (Danielli’s group) had little connection with the group working on enzymes (Dixon’s group). He felt that this was a serious defect in the contemporary approach to biochemistry. It is true that Keilin’s work on the membrane-bound respiratory chain did, to some extent, bridge the gap between enzymes and membranes, but Keilin was in the Molteno Institute and not part of the biochemistry department. Membrane biochemistry became important to Mitchell because it was here that directionality of biochemical systems could most readily manifest itself. The immediate question that concerned Mitchell was how metabolism, which provided the energy for transport across membranes, could actually be linked to this transport process. In a paper given to a Faraday Society meeting that discussed “Membrane Phenomena,” Mitchell and Moyle presented a review of experimental studies on transport of sugars and inorganic ions across the bacterial membrane and included their own work on phosphate. They commented on the possibility that membrane-bound enzymes might catalyze a reaction and simultaneously provide the mechanism (and specificity) of transport across the membrane: Since the end products of metabolism of this organism are lactic, formic and succinic acids, it seems legitimate to suggest that the corresponding dehydrogenases which are concentrated in the membrane may be concerned with the movement of their substrates outwards through the cell membrane. The presence of the cytochrome system in the membrane also lends some support to hypotheses in which the cytochrome system is supposed to be implicated in the movements of ions across the membrane, and in the last analysis to provide the source of the membrane potential.10

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Mitchell felt the recent studies by Monod at the Institut Pasteur on “permeases” (proteins located in the bacterial cell membrane, which are responsible for very specific transport) supported his view. Later, he disputed whether the permease was simply a sugar carrier or, rather, an enzyme in the membrane. In July 1957, drawing on work of Davies and Ogston and of Ussing, Mitchell published a general theory of membrane transport in bacteria. While he considered transport of sugars as studied by Monod and the earlier studies of Gale on amino acid metabolism (to which Mitchell had contributed), his experimental work on phosphate took center stage. At the outset, Mitchell wished to direct attention to biochemical group transfer reactions—that is, reactions that transfer a group, such as phosphate, from one molecule to another. He also wished to draw attention to biophysical membrane transport reactions rather than the contemporary preoccupation with ion movements and associated electric potentials. His experimental results from studies in bacteria, together with a growing confidence in formulating biological theory, led him to describe a scheme for phosphate uptake. He suggested that a membrane protein could covalently bind phosphate externally and then rotate in the membrane so that the bound phosphate now faced inward. The phosphate could then be transferred to another molecule, R, on the inside of the membrane to form R-phosphate (see fig. 5.1). Thus external phosphate would be transferred as a group across the membrane to form a phosphorylated compound inside the organism. Mitchell suggested that “enzymes are the conductors of bacterial membrane transport—that metabolic energy is generally converted to osmotic work by the formation and opening of covalent links between translocators in the membrane and the carried molecules exactly as in enzymecatalyzed group-transfer reactions.”11 The idea was hardly revolutionary, but it made a direct structural link between transport and metabolism. It also resolved the anomaly (as the permease proposal had done) that there was low physical permeability of the membrane even though there was comparatively easy access for nutrients outside the cell to metabolic systems inside. There was little experimental evidence, however, and most of the argument was concerned with the feasibility of the proposal. Concurrently, Mitchell contributed a paper to a symposium on structure and function in microorganisms. While he gave a general review of structural aspects, he concentrated on a much fuller discussion

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Figure 5.1 The uptake of phosphate (represented as P-OH) across the plasma membane by a phosphate carrier protein that also acts as an enzyme: (left) External phosphate is bound to the membrane protein; (right) The bound phosphate is moved through the protein and then transferred to an internal molecule, R-H. R-H + carrier-P + carrier-OH ➝ R-P + H-OH + carrier. Based on P. Mitchell, “A General Theory of Membrane Transport from Studies of Bacteria,” Nature 180 (1957): 134–136.

of the ideas. Again he argued that the conversion of chemical energy to osmotic energy involved the formation and breaking of covalent links between translocators in the membrane and the carried molecules as in enzyme-catalyzed group transfer reactions. This review also contains the first use of the word chemiosmotic. Mitchell discusses the word rather than defining it. Chemiosmotic processes are seen in terms of the bacterial membrane, which is an osmotic link (concerned with the transport of a compound or an ion) between the media to either side of it and also a chemical link that allows for one covalently linked group to be exchanged for another. In concluding, Mitchell wrote: The research that I have described indicates that by containing the requisite enzymes and carrier systems, the plasma [cell] membrane of bacteria may not only cause active transport in the accepted sense (the solute being free in the solutions on either side of the membrane), but may cause the entry of nutrients such as amino acids from the external medium into covalent intermediates with translocators in the membrane and thence direct into covalent compounds in the protoplasm. . . . In view of certain similarities between mitochondrial membranes and the plasma membranes of bacteria, I would venture to suggest that the function of the membranes of mitochondria and of the endoplasmic reticulum may be,

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like that of the plasma [cell] membrane, to act as chemiosmotic links between the media that they separate.12 Through much of the 1950s, Mitchell was intrigued by the problem of oxidative phosphorylation but very rarely made reference to it. He felt unable to make any contribution to the subject. However, the “idea of covalent chemical changes being concurrent with transport took a terrible grip on Mitchell’s mind.”13 Over the Edinburgh period particularly (but also through the rest of his life), Mitchell sought a holistic theoretical understanding of living systems. Such understanding involved conceptions developed well ahead of the experimental evidence. These proposals put forward in the early Edinburgh years led naturally to his major theoretical concept, vectorial metabolism, and ultimately to the chemiosmotic theory that forms the basis of modern bioenergetics.



Vectorial Processes

Two issues concerned Mitchell about contemporary approaches where active transport across membranes was seen as independent of metabolic processes but nevertheless using metabolic energy. First, “active transport” was regarded as a pump. So, for example, a biologist of the day could argue that a pump would be a system capable of passing an ion across a membrane against an electrochemical gradient. To this Mitchell would reply (in summary) that no chemical component could travel up an electrochemical gradient; it could appear to, but in reality it must travel down. Second and more important, biologists viewed transport and metabolism as essentially independent processes. Mitchell challenged this notion by proposing that transport and enzyme reactions were linked and could be part of the same molecular process. In support of this, the growing evidence that kinetics of transport had considerable similarities to kinetics of enzyme-catalyzed reactions proved a further spur to the formulation of transport mechanisms based on group transfer reactions. Thus Mitchell proposed a number of ingenious schemes, including those for glutamate and succinate transport, as well as that already outlined for phosphate. A corollary of this approach was the notion that enzyme reactions themselves involved a directional transport activity, as discussed in a

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paper in 1958. A fuller version of this article had been earlier rejected by Nature and was then published elsewhere, with the acknowledgment “We would like to thank . . . Mr. A. J. V. Gale of ‘Nature’ for rejecting an earlier version of this paper.”14 Mitchell realized that his proposals on transport through a membrane could also be applied to transfer of a group directionally through a single enzyme molecule (fig. 5.2). It was argued that particularly in group-transfer reactions, the group would be transferred from one substrate to the other at the active site of the enzyme in a specific directional movement in relation to the enzyme molecule. The two substrates would approach the active site from different directions in order for the transfer to take place. Such a proposal would have little value for understanding the mechanism where the enzyme was free to rotate in solution. However, for an enzyme fixed in the membrane, the groups being transferred could approach, and leave, the enzyme active site on different sides of the membrane, thus achieving both the enzyme-catalyzed reaction and transport across the membrane. Such an approach became the basis for the chemiosmotic theory. These views also anticipated the discovery in the 1960s of the bacterial phosphotransferase systems, where sugar transport and phosphorylation were shown to be aspects of the same vectorial process. The discovery of the phosphotransferase system, however, owed little if anything to the ideas of Mitchell. In May 1959, Mitchell and Moyle contributed a paper and introduction to a symposium on the cell surface organized by the Royal Physical Society of Edinburgh in which they discussed the coupling of metabolism and transport. The biological argument is essentially the same; the

Figure 5.2 Transfer of a phosphate group vectorially through an enzyme. Reproduced from P. Mitchell and J. Moyle, “Group-Translocation: A Consequence of Enzyme-Catalysed Group-Transfer,” Nature 182 (1958): 372–373, figure 2, with permission from Nature, © 1958, Macmillan Magazines Limited.

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cell membranes of bacteria contain many enzymes, whose role could be both a metabolic one and a translocational one. There is no new experimental information from Mitchell’s laboratory in the article, but it is a synthesis of his earlier work and ideas of others. The opening paragraphs, after a general statement reflecting Mitchell’s early ideas on fluctoids, raised a key factor in the history of bioenergetics. This is the intellectual separation of biochemists, usually with strong backgrounds in chemistry working on metabolism, from physiologists who concentrated on the transport aspects but not on the related metabolism. This science [metabolism] was largely nourished from the domain of chemistry, and being mainly dependent on the language and symbolism of “homogeneous” chemical reactions. It was not adapted to take account of, let alone describe, the organization of the chemical processes in space. Conversely . . . our conception of the processes by which solutes pass across the cell surface stems, to a great extent, from the studies of the physiology of excitable cells such as nerve, and of the cells of specialized organs of secretion (stomach) and absorption (intestine and kidney), special consideration being given to the movement of stable ions and of water, but not to the metabolic processes accompanying these movements at the molecular level.15 This concern ultimately lay at the heart of Mitchell’s approach to oxidative phosphorylation where he parted strongly from the general chemical approach pursued for more than fifteen years and espoused his chemiosmotic approach, integrating both transport and chemical metabolism. He felt he had a mission to integrate the physiological approach with the chemical and wrote, “Perhaps the belief in the necessity of coupling separate membrane-transport systems and metabolic systems has partly been a reflection of the necessity for coupling physiologists to biochemists.”16



The Prague Symposium

Most of the leading authorities on active transport met in August 1960 in Prague. This symposium devoted to “Membrane Transport and Metabolism” has been seen as the moment of birth of the modern era of the biochemistry of membrane transport. For Mitchell personally it was also a significant event. On returning to Edinburgh, he was very

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enthusiastic and felt that his ideas on group translocation had been consolidated. Mitchell presented the first paper at Prague, outlining the relationships of transport and metabolism incorporating his current thinking. He particularly stressed the importance of diffusion and drew on Lipmann’s idea of the escaping tendency of chemical groups: “The prime mover of chemical transformation and transport is diffusion. The process of metabolism consists of alternating phases of substrate and group diffusion, and the chemical and spatial pathway of this process is channeled by enzymes and catalytic carriers.”17 Later, in analyzing the paper, Weber noted that there was an explicit attempt to connect transport phenomena and enzymology and also that the paper provided the theoretical basis for the chemiosmotic theory of oxidative phosphorylation.18 During the symposium, Mitchell noted that “the use of the phrase ‘active transport’ can thus be equivalent to a confession of ignorance (or indifference to) the molecular mechanism of the transport process.”19 Notwithstanding this ignorance, it was the meeting where Robert Crane and colleagues put forward an innovative mechanism coupling sodium ions with the active transport of glucose into brush border cells of the lining of the small intestine.20 Essentially, the glucose would cross the cell membrane on a carrier. The sodium ions would diffuse across the membrane on the same carrier down a concentration gradient (high sodium outside in the intestine and low sodium inside the cells), but the transfer of a sodium ion across the membrane would occur concurrently with the transfer of a glucose molecule. The sodium gradient would thus enable the glucose to be accumulated within the cells. Other mechanisms maintain the sodium gradient. Crane described what happened at the end of his talk on 24 August in which he outlined this mechanism: I gave my talk. At the end of it, Peter Mitchell cried out “You’ve got it.” He then hurried to the table I shared with Aharon Katchalsky and I re-explained the model to them both. I had proposed Na+-coupling. Together with what Mitchell surely had in mind, H+-coupling, the generalization was, on the instant, made.21 From this outburst, Crane assumed that Mitchell already had in mind proton coupling, but it is not clear whether this was actually the case. Certainly the involvement of transport with an ion gradient was in itself a very major advance in thinking about active transport. As Crane himself points out, at Prague Mitchell did “consider the possibility that

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the movement of ions can actually take place through a chemical reaction, which is being catalyzed by an enzyme, such as an ATPase.”22 However this statement was made in relation to experiments that Lowenstein had recently carried out, showing that ions promoted phosphoryl transfer. The questions that arise from these discussions are, first, how clear was the chemiosmotic theory in Mitchell’s mind in the summer of 1960 and, second, to what extent did Crane’s model for glucose transport influence Mitchell’s thinking? The partial answer to these questions, but only the partial answer, emerged a few weeks later at another symposium.



The Stockholm Meeting

A symposium on “Biological Structure and Function” was held in Stockholm on 12–17 September with several sections, including those devoted to “Mitochondrial Structure and Function,” “Structure and Function of Chloroplasts and Chromatophores,” and a small section devoted to “Specific Membrane Transport and Its Adaptation.” Mitchell was the first main speaker in the latter section. He also contributed to the discussions in the mitochondrial section. Before attending this meeting, Mitchell had discussed his ideas on oxidative phosphorylation with David Keilin. Keilin’s advice had been to take great care not to discuss these ideas before Mitchell had them reasonably well formulated and clear in his mind. While in general he followed this advice, Mitchell did have long and confidential discussions about his ideas with F. A. Holton from the Royal Veterinary College, University of London. Holton contributed a paper on structural and osmotic properties of mitochondria to the meeting. Mitchell’s paper, the final version of which was submitted for publication shortly after the meeting, was devoted to general issues about transport in bacteria, with a discussion of the enzyme glucose-6phosphatase in Escherichia coli that had been studied by his student B. P. Stephen. There was also a further development on his views relating to the role of enzymes as uptake catalysts in bacterial cells. At the end of the paper, Mitchell turned again to glucose-6-phosphatase, although what followed, a description of chemiosmotic coupling, showed little relationship to the experiments on this enzyme described earlier in the paper. This seems to have confused some in the audience, and

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André Jagendorf wondered “why would they let a physiologist in to talk about biochemical processes.”23 The discussion on the enzyme was the first demonstration of the principles of the chemiosmotic theory and centered on how the energy from a proton gradient could drive a chemical reaction. Having made this statement of chemiosmotic coupling in principle, Mitchell then added a statement that amounts to the first published reference to the chemiosmotic theory of oxidative phosphorylation itself: I need hardly point out that a similar, but greater asymmetry of electrochemical hydrogen ion [proton] activity to that considered in the above example, could be responsible for converting the ATPases of the particulate systems of photosynthetic and oxidative phosphorylation into the ATP-synthesizing catalysts. I hope to develop this interesting and important aspect of translocation catalysis on another occasion.24 Thus the chemiosmotic theory for oxidative phosphorylation appears to be almost complete in Mitchell’s mind at Stockholm, and this view was shared by Mitchell himself during discussions in 1991. It is clear that he had been considering the mechanism of oxidative phosphorylation for some time. Thus in the summer of 1959 he had written to Slater, “I wanted to ask you a number of things about the present position in oxidative phosphorylation, especially the possible involvement of quinol/quinone systems.”25 The interest in quinones is significant since the 1961 chemiosmotic hypothesis involves them in contributing to the proton (pH) gradient. Because the idea of creating a proton (pH) gradient by electron and hydrogen transport had already been explored in the thinking of Bob Davies, R. N. Robertson, and H. Lundegårdh,26 and that substrate transport driven by ion gradients had been clarified by Robert Crane, the theory appears complete. The symposium also allowed Mitchell to consult on the state of existing theories of oxidative and photosynthetic phosphorylation and obliquely to test out his ideas: Last September I had occasion to discuss the orthodox hypotheses of oxidative and photosynthetic phosphorylation at some length with Dr. Slater, Dr. Chance, Dr. Lehninger and Dr. Arnon during the IUB/IUBS Symposium on Structure and Function at the Wenner Gren Institute in Stockholm, and I was very impressed by the

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general admission of the weakness of the orthodox conceptions involving the hypothetical “energy rich” intermediates, X~I etc., none of which has yet been identified, although they have been assumed to exist for many years. The general climate of opinion during our discussions was quite favorably disposed towards considering alternative hypotheses, if such hypotheses could be formulated—especially if they would include a closer connection between the supramolecular structure and chemical function. In my formal contribution to the Symposium I made a general suggestion along the lines of the enclosed paper, but without giving details, and this aroused considerable interest, particularly from Dr. Lehninger, with whom I had further private discussion.27 Why did Mitchell wait until late April 1961 before sending his revolutionary paper to the journal Nature? It is possible that, in part, he was delayed because of another article published by Bob Williams that may have caused him to hesitate. More significant, the theory was probably not complete in Mitchell’s mind until early in 1961, when he gave a brief account of it to the Biochemical Society in March (with an abstract submitted in mid-February). As he wrote in April 1961: Earlier this year, having formulated the chemiosmotic conception much as it appears in the enclosed paper, I spent several days in Cambridge discussing its main features privately with Prof. D. Keilin, Sir Rudolph Peters, and Dr. Robin Hill, and they were all favorably disposed towards it. Six weeks ago [March 1961] I described the hypothesis in bare outline in a ten-minute paper to the Biochemical Society, and again it was well received, and aroused the interest of Dr. G. D. Greville who is an authority on “uncoupling.”28 These consultations with senior scientists in the field appear to have started at the end of 1960 and to have been accompanied by some experimental information, which was no doubt that given to the Biochemical Society in July 1961 and discussed later in this chapter. Thus Rudolph Peters wrote in December 1960: “It seems that you have some important new evidence and ideas. I hope that I may keep it [the manuscript] a few more days before sending it to Keilin.”29 The manuscript appears to have been that for the Stockholm paper.30

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A further problem for Mitchell was to acquire a detailed working knowledge of oxidative phosphorylation. As he wrote to Slater in July 1961: I expect that you can well imagine how very difficult it has been for me to try to obtain a broad knowledge of the background and the current facts and theories in the field of oxidative phosphorylation, and it has only been with considerable heart searchings that I have dared to venture into it.31 Above all, it was probably the advice from Keilin to think through his proposals carefully before committing them to print that weighed with him. As he wrote to Albert Lehninger, enclosing a copy of the March 1961 abstract of his theory: You may remember that I was trying to sort out a structural conception of oxidative phosphorylation, and I have been waiting for this to crystallize in my mind so that I could write to you explicitly about it. . . . Now, at last, the gestation period seems to be more or less over and I have given birth—I hope not too prematurely— to a chemiosmotic infant. I really do not know whether it will survive the rigors of scientific scrutiny and criticism.32



An Alternative Proton-Based Hypothesis of Oxidative Phosphorylation

In 1959, R. J. P. (Bob) Williams, an Oxford inorganic chemist, gave a first indication of his thinking about a proton-driven synthesis of ATP in oxidative phosphorylation. The respiratory chain was known in principle to generate at least one proton per electron during oxidation. It was this proton that Williams felt could create inside the membrane the right conditions for ATP synthesis: “We further consider that the intermediate transport along the chain of catalysis is carried out by the transport of H atoms . . . and in its oxidized state hydrogen as the proton can bring about condensed polymerization such as polyphosphate formation [ATP formation].”33 At the very beginning of 1961, Williams—who had worked with the Swedish protein chemist Arne Tiselius on metal-protein combinations that eventually led him to consider electron transfer in biological systems including the respiratory chain—published a full article (with a

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second one a year later).34 This might have been published earlier had he not received a rather discouraging comment from Krebs, to whom he had shown the manuscript. As Williams later wrote: Late in 1959 I had shown the precursor of my paper to Prof. Krebs and asked for an opinion. He wrote saying that he did not think such hypotheses should be published. . . . In writing to me Krebs did not mention his earlier paper with Davies which had outlined chemiosmosis. I have to conclude that Davies was largely the influence behind the paper.35 Williams considered the chain of catalysts in the respiratory chain where protons could be derived from the dehydrogenase reactions creating local concentrations of protons that would drive ATP synthesis in the anhydrous membrane. The proposal had some similarities to that of Mitchell. It differed primarily in the fact that the proton gradient remained within the membrane, whereas in Mitchell’s proposal the proton gradient was across the membrane in the aqueous phases. Probably almost immediately after seeing a copy of Williams’s paper, Mitchell wrote on 24 February 1961 to seek further clarification. He gave his reason for writing in a postscript to the letter saying that he was “writing a review on the organization of enzyme systems and this is partly why I would like to make sure that I have got your conception right.”36 At some later date Mitchell wrote on his copy of this letter that the review “was the Biochem. Soc. Symposium review.”37 This defensive comment was probably an error, possibly occasioned by complaints from Williams about the way Mitchell had misled him, even though Mitchell states that the review is only part of the reason for writing. However, the Biochemical Society paper (which makes no reference to Williams’s theory) was not really a review. There was another review in progress at exactly that time for the International Reviews of Cytology with a provisional title “Cytological Organisation and Anisotropic Properties of Enzyme Systems,” which was due for submission in May 1961 but was never completed because of work on his new theory and his deteriorating health. In 1961 Mitchell wrote to the editor, Danielli, that Some six months or so ago I had my review for International Reviews of Cytology well under control and rather ahead of schedule. Unfortunately I have suddenly been landed with an unexpected baby in the form of a new hypothesis of oxidative phosphorylation and this ravenous infant had gobbled up a great

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deal of time and energy lately. It has caused me to wish to revise my review in a number of ways.38 Williams subsequently published the letter of 24 February after Mitchell’s death, commenting on the postscript that it was at best “untrue and deceitful.” He also felt as “incorrectly described”39 Weber’s comment that “Mitchell’s hypothesis . . . is quite distinct from Williams’s.”40 The letter of 24 February 1961 sought clarification on two issues to which Williams replied on 27 February with detailed answers. The correspondence continued through to the 25th of April, by which time eleven letters had been exchanged in a little over eight weeks, and it had become acrimonious. Mitchell delayed replying to the letter of 25 April for a month and dispatched the Nature paper a few days later. Of the points raised by Mitchell in the correspondence, it is worth noting that he saw Williams’s hypothesis as having “very close similarities in broad outline to the mechanism given in a review by Robertson.”41 He also added that he was attempting to show a separation of protons and hydroxyl ions by the respiratory system in the mitochondrial membrane. He made it clear that he was developing his own theories and, indeed, gave a description of his proposals to the Biochemical Society meeting at University College London on 29 March, although Williams was not aware of the meeting and was not present. Mitchell wrote: Your description of “dislocated reactions” interested me particularly, because it is related to the conception of group translocation and chemiosmotic coupling that we have been developing here for some years. . . . But your view differs from ours in an important respect. As you have explained in your recent paper and in your letters, you consider the reactions as occurring in microscopic dislocated phases . . . while we consider the reactions as occurring across the regions between the dislocated phases. Thus our conception is explicitly a vectorial (or transport) one, while yours is, like orthodox chemistry, a scalar conception. This contrast is represented in our nomenclature; yours, dislocation; ours, translocation. I think you will agree that this shows an interesting relationship between our respective conceptions of the metabolic processes catalyzed by organized multi-enzyme systems.42 Mitchell’s final letter in the series (running to eight typed pages) summarized the correspondence to date. Much of the summary was

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concerned more with Mitchell’s vectorial chemiosmotic system than with Williams’s proposals. The second half of the letter dealt with issues raised by Williams in a previous letter. But it is the opening paragraph that gave some indication of Mitchell’s position: I do not think that your endogenous ideas about electron- and hydrogen-transfer phosphorylation are as similar to the ideas that I have been developing during the last few years as your most recent letter seems to suggest, and I am somewhat concerned in case our exchanges of views should develop into a kind of lifemanship—the capacity for fair comparison and comprehension being displaced by the competitive instinct! You will, perhaps, recall that I opened this correspondence with you in order to assess your views on multienzyme systems fairly in relation to those of others; and this you had made rather difficult by omitting to refer to much of the relevant literature in your paper.43 The tone of these paragraphs, together with other factors mentioned later in this chapter, especially Mitchell’s own failure to refer subsequently to relevant literature, in particular the paper by Williams and also the correspondence, created a permanently strained relationship. The absence of any reference to Williams’s work left open the question of how much it had influenced Mitchell’s final formulation of his theory; this uncertainty created a situation that did not help Mitchell’s reputation. Williams’s comment when reviewing the history of the correspondence is worth noting: “I hope that in the hurly-burly of rough exchanges of scientists, others can see that we must be able to write to one another in a spirit of trust, otherwise science becomes warfare.”44 The arguments initiated in 1961 continued to the end of Mitchell’s life and beyond. The two theories were distinct, but since both depended on protons (in the case of Mitchell’s theory, clearly so only after 1966), their similarities could easily be stressed. However, Mitchell had arrived at his theory from his consideration of the movement of molecules across membranes and the transmembrane gradient was of the greatest importance to him, a point not appreciated by Williams. Alternatively, Williams had developed his theory from a consideration of the role of the proton in the chemistry of polyphosphate synthesis and, hence, ATP synthesis. Thus Williams viewed the proton itself as of prime importance, and in this respect he could claim priority over Mitchell. In contrast, it was the osmotic gradient rather than the proton itself that was important to Mitchell, and he felt that his theory there-

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fore owed nothing to Williams. Given the personality clash between the two and the complicated relationship of their theories, a dispute was almost inevitable. There is another aspect of Mitchell’s personality that no doubt contributed to this dispute. Jack Dainty, a physicist who became a plant biophysicist, knew Mitchell at Cambridge but particularly at Edinburgh, where he had a strong recollection of the “intensity of feeling Mitchell had for his ideas.”45 This passion for his theories was important for their development and advocacy, but it was undoubtedly a cause of some grief for those working in the same field, who did not see issues in the same way as Mitchell did. Although Mitchell’s apparent purpose in pursuing the correspondence was to ensure that he understood Williams’s proposals, it was probably much more to establish the independent identity of his own theory. Satisfied with his position, Mitchell sent off to the editor of Nature his paper, giving the first full account of the chemiosmotic theory. In the covering letter he made no reference to Williams but referred to conversations (already noted) with other scientists in Stockholm and later ones in Cambridge. In support of publication, apart from justifying its length, he wrote: The conception of the phosphorylation mechanism contained in this article has mainly been developed in the last year, although the general principle on which it is based is a good deal older. . . . I thought, therefore, that I should now describe this conception in more detail and give it a wide circulation with as little further delay as possible. . . . You will notice that I have presented the new conception so as to show that, not only does it explain many of the established facts which were not satisfactorily explained by the orthodox conception, but it also has the virtue of suggesting new and more crucial experiments.46 The paper was published on 8 July 1961.47 

The Chemiosmotic Theory of 1961

Mitchell’s case for his hypothesis was based in part on the failure of the previous approach. Both the ATPase and the respiratory chain could function separately, but in oxidative phosphorylation the two systems are coupled. Fritz Lipmann had been the first to propose a mechanism for coupling the two processes, but it was Bill Slater who outlined a set

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of reactions that formed the basis for research over the next two decades. This mechanism predicted unidentified phosphorylated substances that would be formed by the reactions of the respiratory chain and which would provide the phosphate and the energy for the synthesis of ATP. The failure to find this phosphorylated high-energy intermediate, Mitchell suggested, would justify his new approach. The novel part of Mitchell’s proposal was the mechanism for the synthesis of ATP by the ATPase (fig. 5.3), which was a development of his ideas on vectorial processes and in principle the same as his proposals for the glucose-6-phosphatase outlined the previous summer in Stockholm. The energy for an energy-requiring reaction, ATP synthesis, is provided by a proton gradient (see the appendix to this volume). In essence, Mitchell proposed that the high-energy intermediate (the phosphorylated intermediate) of the chemical theory was now replaced by a proton gradient (and membrane potential) formed by the respiratory chain and used to drive ATP synthesis. In this version of his theory, which was revised subsequently, Mitchell assumed that a single proton/hydroxyl would be sufficient for the synthesis of one ATP. In effect, the respiratory chain would transfer three protons (and/or hydroxyl ions) per oxygen atom reduced. Thus there would be three ATPs synthesized per oxygen atom reduced, a figure that matched the thenaccepted estimate of ATP synthesis. Mitchell also estimated the proton gradient necessary for the synthesis of ATP. The figure obtained was high but at that stage did not seem unrealistic to him. Although the mechanism of the theory was described in terms of mitochondrial oxidative phosphorylation, Mitchell noted that it could also be applied to photosynthetic phosphorylation (as was the chemical theory) and the oxidative phosphorylation of the bacterial cell membrane. Figure 5.3 The synthesis of ATP by the mitochondrial ATPase. The reaction is driven by the removal of water as OH– and H+, the ions being removed to opposite sides of the membrane. Based on P. Mitchell, “Coupling of Phosphorylation to Electron and Hydrogen Transfer by a Chemi-osmotic Type of Mechanism,” Nature 191 (1961): 144–148.

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The ATPase proposal was novel, being based on Mitchell’s theorizing on vectorial processes as discussed in this chapter. The movement of protons by the respiratory chain was not in itself new. Davies and Ogston had discussed the possible role of the respiratory chain in translocation of protons (or hydrogen ions) in acid secretion in the stomach; Lundegårdh had seen a similar process driving ion uptake in roots, while Conway was interested in the general issue of ion pumps. (Mitchell later admitted to finding Conway’s papers difficult.) Robertson had reviewed the relationship between respiration and the active transport of ions. He believed that there was a close link between ion transport and respiration. He noted that “understanding of the mechanism of oxidative phosphorylation might lead to understanding active transport, but knowledge about active transport may also contribute to understanding oxidative phosphorylation.”48 Thus there was a body of both experimental work and theory to support the view that the respiratory chain might pump ions and particularly protons, but this could not be considered as more than circumstantial evidence for Mitchell’s proposals. By contrast, those working within the field of oxidative phosphorylation tended to regard ion transport, particularly in mitochondria, as a secondary consideration, with the result that the chemiosmotic theory was for them very problematic. The theory did answer a number of problems about the then-current understanding of oxidative phosphorylation, however. Besides avoiding the problem of the high-energy phosphorylated intermediate, it explained why there was a structural requirement. Oxidative phosphorylation (and also photophosphorylation) was always associated with a membrane system. The effect of uncouplers was explained in terms of equilibrating the concentrations of protons across the membrane, ultimately in terms of transporting protons across the membrane. The publication of the theory in Nature did cause some ripples. Many felt that Mitchell did not communicate his hypothesis in as simple a way as he might; they found it almost metaphysical and difficult to understand. Williams described his reaction on reading it in August 1961: “I was never more put out in my life. I did not and still do not understand what motivated him.” The upset was caused by the fact that Williams felt Mitchell had told him nothing of his ideas during the correspondence. This was further exacerbated by Mitchell’s failure to refer in his paper to the correspondence or to Williams’s theory. As Williams has written, “Mitchell’s failure to refer to earlier literature, to state clearly the origins of ideas he uses and his avoidance of reference to ex-

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changes of information by correspondence with others have confused [those writing histories of the subject].”49 Following the appearance of the article in Nature, Davies wrote to Mitchell: You suggest that the concept of the anisotropic ATPase is new. I wonder whether you forgot or missed a paper of Prof. Krebs and myself presented nearly ten years ago to the Biochemical Society which contains just this idea which was also mentioned in brief by Davies and Ogston.50 The paper to which Davies referred did include elements of the chemiosmotic proposal. As already pointed out by Prebble, “Thus, in essence, they proposed a proton translocating ATPase although in the absence of any understanding of the enzyme or of structure the concept was inevitably primitive.”51 Mitchell replied to both Bob Davies and Sir Hans Krebs. To the latter he wrote: I would like to take this opportunity to apologize directly to you for having been ignorant of the interesting suggestion that you made in your paper nearly ten years ago. I am not quite sure that I can agree with some of the implications of the remark in Bob Davies’s letter, a propos the anisotropic “ATPase,” that your paper contains “just this idea”; but at all events there is no doubt that I should have referred specifically to your suggestion that osmotic energy may be a link in oxidative phosphorylation.52 Indeed, it is possible to see the basic principles of the chemiosmotic theory in a very few lines close to the end of the Davies and Krebs paper. Krebs replied: It had never occurred to me that it was of any importance that Ogston, Davies and I had entertained an idea of the possible role of osmotic energy in oxidative phosphorylation. After all, it was no more than an idea—hardly a hypothesis—and did not lead directly to any useful experiments. Unless an idea is a guide to experimentation, its value, I feel, is very limited.53 Mitchell also wrote to his former Ph.D. examiner, Sandy Ogston, now in Australia, apologizing for “being ignorant of the interesting suggestion that osmotic energy may be a link in oxidative phosphorylation” made by Davies and Ogston in the 1950 paper.54 Ogston was very

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relaxed about the issue and in his reply invited Mitchell to join him at the John Curtin School of Medical Research, Australian National University, Canberra, as there were posts available. Ogston later believed Mitchell had asked for such an invitation,55 although this is unsupported by surviving letters. Mitchell considered the matter very carefully. The good research facilities and absence of teaching with few research students to supervise was attractive. The prospect of a readership at Edinburgh, the Chemical Biology Unit, and the happy department where he had a good relationship with Swann were arguments for staying. However, much of the work of the unit (with six research workers, six technicians, and a secretary) was devoted to the fibroblast work for the rheumatism project, whereas Mitchell felt his first interest was in the biochemical basis of transport processes. The education of his children was a further problem. The strong discipline of the Scottish system where creative thought and activity seemed to be placed second had made the “children rebellious and then submissive at school and beastly at home!”56 Would education in Australia be better? In the end, Mitchell, with deteriorating health, did not pursue the matter. There were two significant positive responses to Mitchell’s chemiosmotic theory. The first came from Bill (E. C.) Slater. At the beginning of 1962 he wrote: To summarize, I find your theory most stimulating. It has many attractive features, especially with the stoichiometry. There are a number of “facts” about oxidative phosphorylation which I think it might have difficulty in explaining, but I should prefer to write again about these. One of its great virtues to my mind is that it is the first theory described in concrete terms in which there is one mechanism for all three phosphorylation steps in the respiratory chain. Many people, including Lipmann, have from time to time wondered if that might be the case, but I could never picture such a theory.57 In addition to Slater, Albert Lehninger from Johns Hopkins University also reacted positively to the article in Nature, giving it the first review. He corresponded with Mitchell about the theory, although it is not clear that he fully understood Mitchell’s proposals. He seemed to view the theory as a means of accounting for ion transport by mitochondria, a subject in which Lehninger was particularly interested at the time. He therefore warmed to a new theory of oxidative phosphorylation that was based on ion movements. In a review published in 1962

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Lehninger and C. L. Wadkins outlined the principles of the chemiosmotic hypothesis, and in another review, Lehninger considered its advantages and shortcomings. He noted: Of great interest also is the fact that the hypothesis can explain the occurrence of selective ion accumulations in the mitochondria as well as conformational changes in the membranes. . . . [After considering his objections, he continued.] However despite these and other possible objections, the chemi-osmotic hypothesis demands the closest scrutiny and experimental tests since it, together with the ideas of Lundegårdh and Davies & Ogston provides chemically realistic ways of accounting for the ion distributions which accompany oxidative phosphorylation.58 The theory was discussed in a number of places, for instance, in the enzyme club in the Cambridge biochemistry department meeting on a Saturday morning around the end of November 1961. Subsequently, Greville wrote to Mitchell: “No startling suggestions for further work emerged.”59 Although from the events at Prague, Crane appears to have influenced Mitchell’s thinking, no reference was made to his work in the article in Nature. However, reference to ion and substrate movements across membranes in that article is absolutely minimal. A consideration of the issue of transport in light of Mitchell’s rapidly developing ideas came in a symposium on translocation through natural membranes held in the spring of 1962.



Translocation Systems

Mitchell’s contribution to the Biochemical Society’s symposium in 1962 dealt with molecule, group, and electron translocation through membranes—in summary, it was a survey of vectorial processes in cells. The inclusion of electron translocation allowed him to expand on his ideas on oxidative phosphorylation, particularly the role of the respiratory chain and his proposed movement of ions in the ATPase reaction. The discussion of molecule and group translocation gave him the opportunity to exercise his passion for words and language (although it has to be admitted that generally he was not a lucid writer). He introduced into the language of biological science new words that continue in use. Monoport (later to become uniport), symport, and antiport defined molecular mem-

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brane translocation systems. The monoport was applied to noncoupled translocation of ions and groups in distinction to those cases where a molecule or ion was translocated coupled to the movement of another substance. The translocation of a substance in exchange for another was an antiport, while the translocation of a substance in association with another was a symport. The implications of these systems were explored. Of particular significance was the symport, as described by Crane and coworkers at Prague and discussed earlier in this chapter, where glucose was translocated in association with a sodium ion (Na+). Such gradients could thus be seen as a driving force for active transport, giving rise to the prediction (later demonstrated) that the permease described by Monod might be a symport for galactoside and the proton. In concluding his article, Mitchell raised another issue: so that enzyme molecules located in membranes would be able to function asymmetrically, they would need to be specifically located. Since it seems unlikely that most of the catalytic components of the spatially organized membranes and other catalytic complexes of living cells could be synthesized at the points where they are found to reside, we must presume that these catalytic components possess not only substrate specificities but also locational specificities that will allow them to diffuse from their sites of synthesis and to become anchored at their proper sites of activity.60



Evidence for the Chemiosmotic Theory

At the time the theory was put forward there was, in Slater’s words, “not a shred of experimental evidence in its favour.”61 In fact, Mitchell had started experiments sometime in the spring (his notebooks show intense work in May and June 1961, possibly earlier), which demonstrated that the bacterial membrane was impermeable to protons and that uncouplers (see the appendix to this volume) increased proton permeability. These were fundamental requirements of his theory. His research student at the time, Bob Reid, remembered Mitchell crouched over an old pH meter taking readings of the proton concentration every fifteen seconds or so. On several occasions he was elated.62 The results, which also included experiments on mitochondria, were described at a meeting of the Biochemical Society in Oxford in July 1961.63 In his talk, he concluded:

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There seems to be little doubt that the membranes of mitochondria and bacteria have a low proton permeability and that certain classical uncouplers of oxidative phosphorylation catalyze the movement of the protons through them. The questions we must now ask are whether this catalytic action is relevant to the uncoupling action, and how the conduction of protons comes about.64 Rather more significantly, at a meeting of the American Society of Cell Biology in the autumn of 1961, Mitchell described experiments where respiration in bacteria was found to lead to acidification of the medium (indicative of the ejection of protons). It could also be shown that if the membrane was made proton permeable with uncouplers, then the protons returned inside.65 After Mitchell had attended a Gordon conference in 1962, where he was able to outline his theory to an American audience, Lehninger advised him: “I gather that on this side most people have aligned themselves in favor of chemical mechanisms. . . . For the first time a number of people have taken the trouble to think about your idea and give it serious attention.”66 Clearly, the theory was being considered seriously but was hardly making a major impact on the biochemical community. The experiments with bacteria referred to earlier in this chapter were also carried out with mitochondria, and similar results were obtained. These were independently confirmed by Guy Greville. In fact, Mitchell had visited the Institute of Animal Physiology, Babraham, where Greville worked at the beginning of July 1961, to discuss mitochondrial experiments, of which Mitchell did not have much previous experience. However, Greville was able to write to Mitchell: “It is quite amazing how you managed to get the mitochondria to work in such a short time.”67 Greville himself undertook experiments on mitochondria, as he reported to Mitchell: “This is to assure you that work on the Mitchell phenomenon has been relentlessly and continuously pursued over the past few weeks. Of course, we have confirmed your findings in essence.”68 Early in the course of his experiments Mitchell realized that the chemiosmotic theory as propounded in the Nature article needed modification. Originally, the scheme proposed a release of protons inside the mitochondrion and hydroxyl ions outside. However, Mitchell discovered that protons were ejected from the mitochondrion as a result of respiration. In other words, the system as originally proposed was inside out. The experimental support for the theory was at this stage ex-

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tremely fragile. The movement of protons was consistent with Mitchell’s theory, but it could not be regarded in any sense as providing proof. What had been shown was simply that protons were ejected when respiration took place, without in any way showing that such a process was a key part of the mechanism of oxidative phosphorylation. It was at this point that Mitchell’s health began to impede further work and, indeed, no further significant progress was made at Edinburgh.



Reviewing Vectorial Metabolism

Mitchell’s work throughout the Edinburgh period shows the influence of his early philosophical ideas on fluctoids, which formed the rationale for the rejected and abandoned thesis but remained a tacit force within his thinking over these productive years.69 Not only were they formerly defined in the Moscow paper published in 1957, but also they can be traced in many of his papers. Nowhere is it more obvious than in the abstract for his paper to the Biochemical Society Symposium in 1962 where, without using his terms, the statid and fluctoid are defined: Crystals or molecules tend to persist for a time, and can remain recognizable because they consist of sets of atoms that are bonded together in certain relative positions in space. As the knowledge of the structure and function of deoxyribonucleic acid has shown, . . . the stability of living organisms depends on the stability of molecular structure. Nevertheless, the persistence in time and the continued recognizability of living things are not entirely determined by the factors governing crystal and molecular stability; for living cells are partly composed of electrons and atomic nuclei undergoing spontaneous rearrangement as they diffuse to and from the environment through catalytic parts of the cells.70 The symbol of the statid is the crystal. The fluctoid is composed of a static element (or statid) and a flowing element and is clearly described in the foregoing quotation; its symbol is the flame associated with a static burner. Thus elsewhere Mitchell talked about the “flame-like properties of living things.”71 One of the last papers to be published from Edinburgh was a further consideration of the relationship between transport and metabolism and given as a lecture to a symposium on bacterial structure and

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activity held at Oxford in September 1961. Although generally speculative, the paper also contains some experimental results on proton transport across bacterial membranes. During the lecture (although not in the published version), Mitchell suggested that we would come back to Liebig’s more advanced “view where the momenta in chemistry were more important than the energies, because the momenta still retain a vectorial significance.”72 After the lecture and in relation to these remarks, Krebs, who was in the audience, accused Mitchell of advocating a retrograde step. As Mitchell recalled: I actually did not resent the great Krebs saying that, I think I said “it’s quite right, it does represent a retrograde step in a way.” I meant looking at it in the way he did because, after all, his ability to make progress with metabolism—bag of enzymes metabolism almost entirely—was exceedingly important. So there was a very valid point of view for which this attitude of mine would be a retrograde step.73 The purpose of Mitchell’s paper to the 1961 Oxford symposium is explicitly stated: My aim has been to draw your attention to the spatial asymmetry of the individual catalysts and the spatial asymmetry of the organized polymolecular systems in which they reside. For this spatial asymmetry can properly be regarded as a primary cause (or specification) of the vectorial diffusion processes of organised metabolism and growth.74 Mitchell considered the movement of molecules from their site of synthesis to their ultimate location in the plasma membrane or cell wall. He invoked from David Green the idea that enzymes must have locational specificity, as well as substrate specificity. Molecules concerned with transport are not only an integral part of metabolism but also an integral part of morphogenesis. Thus the vectorial idea is extended to embrace a view of the cell as a whole: Thus it emerges that the activities of biological transport represent the elusive directiveness of the phenomena of life. Scalar (or directionless) biochemistry is a subject of dead things, like crystals. To describe the flame-like properties of living things, we have to rep-

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resent the metabolic processes as projections in space as well as in time. This requires the recognition and development of a new subject: the subject of vectorial chemistry. Perhaps, once again, the exact sciences are to receive inspiration from biology!75 In essence this article summarizes Mitchell’s thought of the Edinburgh years; it also expresses his holistic approach to living processes: “Transport processes in biology are integral with the activities of growth and survival.”76 Metabolic processes should not be seen as scalar processes but as having a directional or vectorial element. Central to this is an understanding of a respiratory chain in which protons and hydroxyl ions form a gradient and where the synthesis of ATP is driven by the migration of hydroxyl ions and protons in specific directions. The 1961 formulation of the chemiosmotic theory would need further revision, but its basic tenets were established. Indeed, Mitchell gained confidence from his initial experiments described earlier so that he could write in 1962: While the chemiosmotic idea is, I think, still only at the stage of a hypothesis, our quite determined efforts to disprove it have so far failed, and it does in fact seem to be quite a promising departure from the more orthodox mechanisms. . . . We are actively working on systems which may help us to decide between the orthodox view and the chemiosmotic view of coupling in mitochondrial systems and in bacteria.77 Illness terminated Mitchell’s scientific activities at Edinburgh around 1962. This work was to remain dormant for over two years, until new possibilities arose at Glynn. For the time being, Mitchell expressed his other talents in a rural existence.

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6
The Creation of Glynn 1962–1965



A Holiday Home

Both Helen and Peter had a desire for a retreat further south. At Carrington they found the autumn and winter very lovely, Carrington being above the snow line for some three months in the year. However, they felt that there was no spring: winter simply dissolved into summer. More seriously, Helen feared that Pat Robertson might not allow Daniel and Vanessa, the children from her first marriage, to travel to Scotland, where the legal system is slightly different. In October 1961, while Peter was in the United States for a meeting of the Society for Cell Biology, Helen saw an advertisement in the Sunday Times offering two cottages for sale in Cornwall—Glynn Mill and Glynn Mill Cottage. The price was very reasonable, and she rang Peter in the United States for advice. He told her to go to Cornwall to see the properties, which she did. She thought them enchanting. A few days later on Peter’s return, they both travelled to Cornwall; Peter also liked the properties, and they were duly purchased. The Glynn area is some three miles southeast of the center of Bodmin in north Cornwall, close to the route of the A38 road and a half a mile north of Bodmin Parkway Station (formerly Bodmin Road Station). It is a heavily wooded agricultural area and has been classified as an area of outstanding natural beauty.



Glynn House

While the estate agent, Donald Weekes, was showing the Mitchells over the cottages, he discovered Peter’s interest in old houses. He mentioned that Glynn House itself was for sale and suggested that they walk up

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the drive to the house that had long been empty and was now in a very dilapidated state. In fact, it had been on the market for some years at a price around £6,000 to £7,000 without finding a buyer. Mitchell remembered thinking as he walked up the hill that it would make a beautiful research institute. Later he wrote: I was delighted by its unpretentious Regency style and by its perfect setting on the southern slope of the valley—fixed, I dare say, as the site for the much earlier dwelling of Osferd, who is recorded in the Domesday book as living thereabouts in 1086, when he must have had all the valley to choose from.1 The house was in an advanced state of decay and riddled with dry rot so that Mitchell concluded, “only a lunatic would want to become involved with it.”2 Despite this assessment, on his return to Edinburgh, Mitchell wrote to Weekes expressing an interest in the house and hoping that something could be done to save it from ruin. His expression of interest did not fail to draw a response. However, Mitchell felt the owner, Claude Selleck, was asking too high a sum for the property. As a result of a further visit in January 1962, when he made a thorough inspection of the property, Mitchell reluctantly concluded that he must forget Glynn House: “It was difficult to imagine any financially viable future for this architecturally and historically interesting house.”3 At Edinburgh the demands of teaching and of his research were placing a heavy strain on Mitchell, and he felt he could not cope with the extra constraints that Glynn House would place on his time and energy. In the early spring of 1962 Selleck died, and Weekes was now looking for reasonable offers for Glynn House, which had three acres of land associated with it. By the summer of 1962 Mitchell had bought Glynn House, with the simple intention of restoring the property as a useful and beautiful building. The purchase was completed on 9 August 1962, at a price of £2,817–10–0, the sum being less than Mitchell’s offer and reduced by Mrs. Selleck for taxation reasons. Mitchell later gave his thoughts behind the purchase: The original impulse which led me to purchase the house was motivated simply by a desire to save a fine old building from destruction, and I do not believe I would have purchased the house if I had been thinking of it as a business proposition. . . . The cost of restoring the house has been very much greater than I expected (in

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fact it has cost me about twice what I expected) and I do not think I would have undertaken the work if I had known at the outset how expensive it would turn out to be.4 Nevertheless, Mitchell acquired substantial additional land at Glynn during the ensuing years. The manor of Glynn had for many generations belonged to an ancient family of that name but had eventually gone out of the family through lack of male heirs. Sometime before the reign of Charles I, it had been purchased by another branch of the Glynn family. At the beginning of the nineteenth century, F. Hitchins and S. Drew recorded that Glynn, the delightful mansion of Edmund John Glynn, Esq. is situated on a gentle eminence that commands an extensive portion of that lovely vale through which the river Foy flows towards Lostwithiel and from thence to the sea. Connected with its surrounding scenery, it justifies the import of its name, which . . . is taken from the natural circumstances of the place where lakes, pools, and rivers of water abound and where groves of trees or coppices grow and flourish.5 The current house at Glynn dates from the beginning of the nineteenth century, when it was rebuilt following a major fire in November 1819. At that stage, it was itself a newly built house and the interior had not been completed. The owner was Edmund J. Glynn, a partner in the North Cornwall Bank, which collapsed in 1822, rendering him bankrupt. He sold Glynn in 1825 as the much admired Demesne of Glynn on the river Fowey with the shell of the mansion, most substantially built with choice Stone in the chastest style of Grecian Architecture, situate on a verdant lawn, commanding the most interesting scenery, and tastefully ornamented with fine timber, and thriving plantations, walled gardens, stabling, and convenient offices designed for a residence of superior order.6 The purchaser, General Sir Hussey Vivian, was one of Wellington’s generals at Waterloo and performed with great distinction at that battle. Vivian restored the property, incorporating fine plaster moldings, including those based on the designs of his medals. It remained in the Vivian family for several generations and was eventually sold by the trustees of the 4th Lord in July 1947. The house was allowed to decay,

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and it was then bought by Selleck, no doubt with the intention of refurbishing it. Mitchell’s original plan was to sell Glynn House after the restoration to someone who could make good use of it. However, he did consider the possibility of retiring from Edinburgh and setting up a small independent research institute in the house. The advice he obtained suggested that the financial and legal problems were too formidable, and he abandoned the idea.



Dry Rot

The work on Glynn House proceeded while Mitchell lived in Glynn Mill during his occasional visits to Cornwall. He had considerable previous experience of restoration work at Carrington, which was also in a very poor condition when he acquired it from the Church of Scotland. Even so, this was hardly an adequate preparation for the gigantic task that faced him at Glynn. The initial and urgent problem was to try to stop the dry rot, which was due to a fungus. The fungus was producing its fruiting bodies almost everywhere, and these were spreading spores throughout the house, while in many places the weather was penetrating the building so that the woodwork was damp enough to provide ideal conditions for its growth. Immediately after purchase of the property, toward the end of August 1962, Mitchell started work by trying to track down the main centers of fungal infection. He found two very bad patches in the roof and many others throughout the house. When he pressed a windowpane, the center of the frame fell right out. He decided to dismantle a “leanto” portion of the house that was a very serious source of damp and infection and which when removed improved ventilation. Part of the roof had to be removed in one corner because of the danger of falling slates. His initial approach was to try to dry out the house. A grain-drying fan heater was obtained from the electricity board and run on cheap, off-peak electricity between 11 P.M. and 7.30 A.M. A quantity of antidry-rot fluid (forty-five gallons) was obtained and applied to infected areas. This amount proved too little, and in the end some four hundred gallons were used. The drying out involved opening up areas and removing badly infected timber. Meanwhile, Mitchell invited the local authority planning officer to send a representative to visit the house—an invitation at first

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resisted but eventually acceded to. Mitchell wished to make it clear to the authorities that the state of the building was not due to his neglect and therefore sought an early meeting to demonstrate the point. In general, this meeting was successful and the urgency of action was agreed. He then approached Dudley Coles, a Plymouth firm, which sent a surveyor on the 11th of September to discuss the approach that would be taken to restoration. The seriousness of the situation was underlined by the fact that much of the interior of the building was a timber frame that was filled with stone and a lime-based cement. While Mitchell opened up floors, removed panels, and tried to kill off the infection, Helen cleared the conservatory of wood and weeds. Some two to three weeks after work started, Helen and Peter had almost made up their minds to live in the house themselves. During this period, John Gayer Anderson stayed with the Mitchells and also became involved in helping with the work. Mitchell returned to Edinburgh in the autumn of 1962 but made several visits to Cornwall over the autumn and winter. There was some good news about Glynn House. He made a visit with an electrician to check the wiring. This was said to be in quite good order and would be perfectly satisfactory if it was tidied up in the places where it had been cut, exposed, or shifted. The visit revealed further incursion of rainwater, and polythene was attached to prevent this. In one of his visits to Glynn House during the early winter of 1962, Mitchell concluded: The house is much drier but there is still a good deal of active rot. I discovered two leaks in the roof and did my best to stop them up and in the process of scouting about inside the roof I came across a new seat of dry rot infection. . . . It is rather disheartening to think of the decay steadily going on while I am still, as it were, trying to muster some forces to give battle.7 The forces were essentially those of the builder Dudley Coles, who had failed to supply estimates after the survey in September, thus delaying the start of refurbishment. Mitchell also wrote to his accountants to seek advice on forming a charitable trust in case this might be the best plan for the future of Glynn House. Mitchell spent three vacations away from Edinburgh, progressively bringing Glynn House under control, an activity that he regarded not as a chore but as a pleasure. Unfortunately, gastric ulcers caused Mitchell to rethink his whole future. At this stage, he was faced with choices on a range of fronts, including whether to continue in university life,

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whether to relocate his main home from Scotland to Cornwall, and even whether to continue in science.



Farewell to Edinburgh

During the early 1960s Mitchell began to be affected by gastric ulcers, and his health began to deteriorate. As he wrote to a friend in March 1961, “I have been rather unwell and have had to cancel many of my engagements during the next two months.”8 By late 1962 the problem was becoming acute; he was in pain, and he stopped smoking cigars temporarily. The medical treatment suggested was a major operation to remove the ulcer, and the outcome was not guaranteed. The alternative was a complete rest and avoidance of the stress of university work. Mitchell chose the latter course. It is ironic that Mitchell’s illness coincided with his promotion within the university to a secure position. In October 1961 after Bryn Jones had vacated his senior lectureship, the court (governing body) of the university allowed the department to keep the post and appointed Mitchell. The following July the court conferred the title of reader on Mitchell at a salary of £2,325. Thus Mitchell was now on a track that could lead in due course to a professorship. However, the growing problems with ulcers intervened severely. The court of the university granted three months leave of absence on full salary from mid-March 1963 “to enable him to undertake private study.” However, they considered the possibility that sick leave might be more appropriate and deferred any decision, pending the receipt of a medical certificate. In July 1963 the court recorded the termination of the appointment of “P. D. Mitchell Ph.D., FRPS, Reader from 30 September 1963.”9 Looking back on his time at Edinburgh, Mitchell realized that he lacked the ability to switch his mind off problems that were bothersome to him. The situation at Edinburgh had become uncongenial; the work on rheumatic disease was a distraction from his main interest, and his inability to relax brought the inevitable result. To the end of his life he remained very skeptical about whether universities were an appropriate place to carry out creative work. Thus Peter and Helen left Edinburgh in 1963 and made Glynn Mill Cottage the family home. Had Mitchell planned to leave Edinburgh before such a move was dictated by his health? When discussing whether

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he planned to create an institute when he started work on Glynn, he commented that he did and he didn’t. In fact, it appears that his approach had initially been ambivalent and that the issue was probably settled by his deteriorating health. Nevertheless, it is very questionable whether he could have launched a research institute without a considerable recovery of health. In any event, he was not sorry to leave Edinburgh. The lack of cultural life except during the Edinburgh Festival had been a disappointment, and he had found the requirements and prejudices of university life, whether at Cambridge or Edinburgh, somewhat restricting. Indeed, when Juda Quastel had written to him complaining that he had received a lot of opposition to his work at Cambridge (particularly from Marjory Stephenson), Mitchell had replied, “I became aware . . . of the stolid opposition which it [Quastel’s work] had received from certain members of the Biochemistry Department. Perhaps my own departure from university life . . . is connected with rather similar experiences to your own.”10 A similar view was reiterated many years later when Mitchell remarked that “David Keilin was one of the few people who treated my efforts seriously and encouraged me to persevere.”11 Helen, too, welcomed a move to the southwest of England, where she felt there was a real spring, a season that seemed absent in Carrington.



Farming

At about this time, Mitchell realized that possessing the house but not Glynn Farm was a major drawback since the farmhouse was closely associated physically with the main house. More especially, the long entrance drive, the local water supply system, and the drainage system (there was no water supply or drainage) were part of the farm property and the rights of use were not well defined. In addition, the drive itself, which was in an appalling state suitable only for tractors, was certainly inadequate for a research institute. Mitchell therefore somewhat reluctantly purchased the farm property. This not only gave him a large acreage but also made him the owner of eight Jersey cows that required hand-milking morning and evening. Mitchell placed on the main road at the end of the drive a plaque showing the head of a Jersey cow with “Glynn Farm” and “Peter Mitchell” at both the top and the bottom! Mitchell seems to have enjoyed this type of work, although he pursued

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it for only a year or two; he also found life as a farmer, particularly the milking, did wonders for curing his ulcers. Subsequently, the pedigree herd increased significantly in size, and although eventually he appointed a farm manager to handle this side of his activities, he retained a personal interest in the farm until, very much later, in the 1980s, he sold the farmland but retained the farmhouse.



Restoration of Glynn

Restoration of Glynn started in 1963 and continued until late in 1964. For the first few months Mitchell kept a detailed and illustrated diary of the work. Early during this period Mitchell wrote to Jennifer Moyle at Edinburgh and asked her whether she would be interested in joining in an enterprise to create a research institute at Glynn House. Mitchell felt some concern over the risk involved since there could be no guarantee of success. On her part Moyle was excited by the prospect: I decided to join Peter in the Glynn venture because I felt, in spite of it obviously being a gamble, that it would be most exciting if it succeeded. He told me his plans and asked me to join him—and I felt that nothing would be lost and possibly a lot would be gained by my saying “yes.”12 Meanwhile, Mitchell agreed on the arrangements for the work to proceed on refurbishing Glynn House with the builders, Dudley Coles. There was to be no architect; Mitchell would fill this role himself. The various craftsmen and laborers supplied by Dudley Coles would be under the control of a foreman, who turned out to be a carpenter. Mitchell would work full-time with the foreman on the project doing the surveying and everything else that was necessary to administer the job; Jennifer Moyle acted as Mitchell’s assistant. Similarly, the financial arrangements reflected the method of working. Dudley Coles was to charge only 15 percent over cost for the materials on the grounds that it was a prestigious job. There was no absolute estimate for the work, but the charges were to be based on time and materials. Moyle recalled that they spent much time checking invoices against material supplied. Mitchell himself hired a local plumber from Wadebridge. The arrangement with the builders did run into a problem when Mitchell decided to install a steel spiral staircase in the main entrance lobby. The cost was going to be in the region of £500, and Dudley Coles wished to

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add 15 percent to the cost for ordering it. Mitchell talked to the plumber, who told him about a firm in Wadebridge, which would supply the staircase direct, consequently making a significant saving. Mitchell found that the design of spiral (helical) staircases was an unexpectedly complex issue that had to be mastered. The outcome was successful, and the final price was only £140! Similarly, Mitchell found that he could reduce the price of a vibration-proof bench by two-thirds by having it made in a local granite quarry. The workforce (carpenters, masons, plasterers, and, later, painters) was drawn from the Plymouth area and brought the thirty or so miles to Glynn daily by bus. The gang was a very mixed group, including an elderly carpenter (aged about 75), who did excellent work. Two of them had recently been in prison, while a third was an ex-wrestler. Mitchell recalled: Len was a super foreman . . . and we were on the job all day everyday and that had a remarkable effect and the men weren’t used to the person controlling the job actually being in dirty jeans, grubbing about trying to decide what was the best way to tackle the next job. So we really became a sort of happy family.13 By the spring of 1964, the vision of Glynn House was beginning to take shape. As Mitchell wrote to Bill (E. C.) Slater: I am trying to establish this place as a quiet haven for untrammeled scientific work and thought. And I would feel especially happy if we could arrange for you to come and relax here for a few days later this year. . . . At present the sum total of the staff is Dr Moyle and a secretary and myself and we expect a technician to join us in October—so it is quiet and there are few distractions.14 Toward the end of 1964, Glynn was close to completion. On 7 October 1964, Mitchell wrote, “we have only just established this laboratory and have not yet begun experimental work, but the builders and decorators will be out in a few days.”15 At Christmas 1964, Mitchell presented each of the men working on the project with a copy of a nineteenth-century engraving of Glynn, a gift that was much appreciated. The cost of the work on restoring Glynn is unclear; Mitchell felt that he had spent twice what he expected and that the institute section had cost around £9,000 to refurbish. The refurbishment of the whole house would then have cost a figure in the region of £30,000.

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A Private Research Institute

The idea of a research institute had been in Mitchell’s mind for some time. At the end of 1962, when he was still trying to dry Glynn out and to prevent the spread of dry rot, his mind was already seriously toying with the idea of a research institute. He wrote from Carrington to solicitors in Bodmin: I would be grateful if . . . you could seek the relevant factors relating to qualifications required of charitable institutions and the formation and operation of charitable trusts. I would particularly like you to explore the possibility that the Association could take the form of a limited liability company for which the memorandum of association states that the only objects are to carry out research and to promote education by the sale of books, papers and by broadcasting, and expressly forbids the application of income or profits for any purpose other than its own purposes of research and liberal education, in the interests of humanity.16 Discussions on setting up the company continued during the whole of 1963. At the same time, financing of such an institute by Mitchell’s brother (Bill Mitchell) was explored, and legal advice was sought for establishing the best method of transferring money. In the summer of 1963, Mitchell prepared plans of Glynn for submission to the North Cornwall Planning Authority, with a view to change part of the building from residential to laboratory use. After discussions with the authority, planning permission was granted in November 1963. Although the greater part of Glynn remained residential for Mitchell’s personal use, 4,300 square feet were allocated to the Glynn Research Laboratories (later the Glynn Research Institute), which were located in the south-facing wing. While Glynn became the Mitchell family home, Moyle lived in Bodmin. The laboratory accommodation designed for the institute was essentially self-contained (see fig. 6.1). On entering the main door under the small portico, one came on the room containing the spiral staircase. Later, a divider was added behind the staircase to cut off a general preparation area to the rear. To the left of this room was the library, which in due course became a good collection of journals and books in the field of bioenergetics. Indeed, within a couple of years it was valued (at cost) at about £2,500 and subscriptions to journals and information services were running at over £400 per annum, which was sufficient to

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(a)

(b) Figure 6.1 (a) Plan of the ground floor of the main house. The front entrance (marked by four columns) is located in the middle at the bottom edge of the plan. The main rooms occupied by the institute (not necessarily immediately) are labeled I. L1 is the original library and L2 the library established in the 1980s. P is the prayer room used as a seminar room in later years. (b) Plan of the upper floor of the main house. The main rooms occupied by the institute (not necessarily immediately) are labeled I. F is the flat, later used for visiting scientists, and C the common room.

take a good range of journals in those days. To the right of the entrance there were two laboratories with a preparation room. The spiral staircase led into an office and thence to a corridor with three spacious research rooms. This area of the building was leased by Mitchell to Glynn Research Limited (later the Glynn Research Foundation) initially at a nominal rent of £1 per annum, pending the fixing of a realistic figure, which was to be equal to the gross annual value. Later, the valuation officer fixed the gross annual value at £400, but everyone seems to have concluded that this was too high and the annual rental was agreed at £250 per annum for a period of seven years. The annual costs of the institute also included supplementary payments, amounting to some £50 per annum, as well as maintenance and repairs. While the refurbishment of Glynn House was still fully under way, work on setting up Glynn Research Limited was completed with the incorporation of the company on 21April 1964 with its registered offices at Glynn House. The objects of the company, defined as charitable, were broadly drawn: To promote and carry out scientific research, in particular in the field of fundamental molecular and behavioral biology, with a view to the development and spread of scientific knowledge, in particular of the causes of disease. There were a number of ancillary objects, among which were the following: 









To establish and maintain a scientific research unit, in particular for doing original scientific research and for collecting and exchanging scientific information. To promote and organize scientific conferences, and to establish and maintain appropriate facilities for such conferences. To promote scientific research in places other than the company’s own research unit, and to provide financial assistance for the promotion of such extramural research. To publish, report on, and disseminate the results of the work of the company or other scientific information. To borrow or raise any monies for the furtherance of the primary object of the company.17

There was to be a council of management of the company, which would hold an annual general meeting. The council was to be composed of not fewer than two members and not more than five. At the

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outset, the members were Peter Dennis Mitchell and Jennifer Marice Moyle. A company secretary was appointed, Miss S. C. Lomax of Bodmin. There was provision for an honorary director of the foundation who would be chairman of the council, and this position was occupied by Mitchell until his death. There would be one or more directors of research; there was only one, however, Peter Mitchell, until his formal retirement when Peter Rich took on the title. There were the usual financial provisions requiring the keeping of books of account, the production of an annual balance sheet, and the appointment of auditors, who in the early years normally attended meetings. The company’s solicitor was also often in attendance. The council of management composed of Mitchell, Moyle, and the secretary first met on 30 April 1964. At this meeting Peter Mitchell was formally appointed as director of research at a salary of £2,100 per annum and Jennifer Moyle as research fellow at a salary of £1,500 per annum. It was noted that office accommodation was already available and that the laboratories should be completed before the end of the year. The council accepted a gift of 40,000 fully paid £1 ordinary shares in Messrs. George Wimpey and Company from Mitchell’s brother, C. J. (Bill) Mitchell, with a value in the region of £250,000. The council agreed to seek approval of the company as a charity in view of the tax advantages. A few months later at the fifth meeting of the council, it was reported that Mitchell was asking the company to accept as a gift from himself the laboratory furnishings, including the cold room, warm room, dark room, benching with services, and other special laboratory facilities, which at that time (July 1964) were partly installed. At this early stage Mitchell considered the financial position of the company. The investments were capable of providing, potentially, £10,000 per annum, and advice was being taken about diversifying the portfolio, since initially the holding was exclusively in Wimpey shares. The expenditure of the company (which excluded all the work carried out on Glynn House paid by Mitchell personally) was estimated at £6,000. This purchased the basic laboratory equipment necessary to enable the experimental work, begun at Edinburgh, to continue at Glynn. The provision was minimal but adequate. Running expenditure was estimated at £7,800 thus presenting the council with a small deficit. The following year saw a marked drop in capital expenditure but a rise in general costs and in salaries as staff were taken on. This led to further deficits in the region of £2,000 to £3,000.

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Attempts to compare the costs of supporting the research workers at Glynn with those in university departments were undertaken with the help of Michael Swann at Edinburgh. However, there was always a problem obtaining comparable figures. Moreover, as the solicitor repeatedly pointed out, salaries paid to Mitchell and Moyle were unduly low. Mitchell seems to have drawn the conclusion that the costs at Glynn were comparable, although the figures used showed that, in fact, running the institute was marginally more expensive than running a university department. Certainly, the endowment proved inadequate to provide interest sufficient to finance the institute’s work over the years. Thus a slow erosion of capital was an almost permanent situation for Glynn over the whole of its life. Overall, these provisions allowed for the development of Glynn as a research institute. They also provided for a number of other developments, which Mitchell saw as possibilities but which never actually occurred. The inclusion of behavioral biology would enable Mitchell to consider other research areas when and if the study of bioenergetics was exhausted, and Mitchell explored this proposition on more than one occasion. It is also clear that Mitchell intended an organization that would be financially much more successful that it turned out to be. The inclusion in the objectives for which the institute was established of the promotion of research outside Glynn is an example of this. While a small number of scientists have set up research activities privately, few, if any, have done it with the professional approach and thoroughness that Mitchell undertook when setting up Glynn. Annual reports both of work carried out and of accounts provided a formal framework for monitoring progress and development, and although Mitchell and Moyle constituted the council initially, others from outside Glynn joined them later.



Initiating Research at Glynn

As already noted, the objectives of Glynn Research Limited were broad. Nevertheless, there was a need to develop specific and focused lines of research. In Edinburgh, Mitchell had pursued his ideas on vectorial metabolism and the transport of substances across membranes, particularly bacterial plasma membranes. It was only in the last year or two that he had begun to consider oxidative phosphorylation seriously and to try some experiments with mitochondria. An indication of Mitchell’s

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thinking on the selection of a research problem for Glynn was given in a report he made to the annual general meeting of the council in 1966: In a small research organization it is not, of course, possible to work on a wide range of research problems. Sound economic and intellectual considerations show that it is necessary to concentrate upon a limited range of experimental techniques (thus minimizing expenditure on expensive specialized equipment), and to focus attention upon a limited area of the intellectual field in which the research workers have competent knowledge and experience. The fact that the research problem is selected within a limited experimental and intellectual field does not, however, necessarily mean that the solution of the problem will have a correspondingly limited application. In practice, according to the best traditions of research strategy, one attempts to select small-scale problems, the solutions to which will have large-scale applications. . . . The research activities of our company have been focused upon the “mechanism of oxidative and photosynthetic phosphorylation.”18 Therefore, Glynn was to continue interests first publicly explored at the Stockholm meeting in September 1960 and developed from 1961, along with experimental work on bacteria and mitochondria. But the key question was to be the veracity of the chemiosmotic theory. As Mitchell reported, the first months of the institute’s life were devoted to setting up laboratories while the builders finished work on the refurbishment: For the first five months of the life of the company, most of our time was occupied with planning the layout of the furnishings of the laboratories in the best possible way to enable us, with a capital expenditure of only some £7,000 to produce some useful research results. Dr. Moyle and I had earlier decided, as a matter of general policy that the Company should launch into a suitable research project during the first year of its activities, and that there should be no attempt to enlist outside financial help either from the official grant giving Bodies, or from private sources until the Company’s research project was yielding a reasonably good return of results.19 Although Mitchell and Moyle felt that external funding should be delayed until experimental work was proving fruitful, there were discus-

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sions from a very early stage about how to raise extra income, particularly in view of the predicted deficits. The solicitor suggested that a campaign should be launched for raising money, possibly enlisting the help of the local Member of Parliament who could write to potential donors on behalf of the institute. Mitchell did not like the idea, and the question of raising money was discussed over the first years but without significant action. Serious laboratory work started in October 1964 in an institute still incomplete but with the main laboratory now equipped and working. Mitchell and Moyle had not engaged in significant experimental investigation since sometime in 1962 or early 1963 when their studies had been cut short by Mitchell’s developing illness. In the meantime, Mitchell had been giving further thought to his chemiosmotic theory and engaging in correspondence with several bioenergeticists, especially Slater. He now felt well enough to travel and participate in international meetings on oxidative phosphorylation and closely related issues. Consequently, work continued on searching for support for the chemiosmotic theory. Hence Mitchell reported toward the end of the first year of operation: In the last 3 months of 1964, we undertook a short program of experiments—partly designed to round off some work that we had been doing in Edinburgh University on the organization of enzyme systems in the membranes of bacteria and partly designed in the hope that we might find an experimental opening into the study of the mechanism of respiratory chain phosphorylation. I had previously been involved in theoretical essays on the mechanism of respiratory chain phosphorylation, and, largely owing to encouraging correspondence with Professor EC Slater of the University of Amsterdam, we prepared the way for a more thoroughgoing involvement with this much studied and difficult problem. Our preliminary experimental studies with bacteria and with rat liver mitochondria were surprisingly successful and by the beginning of this year we were fully committed to a program of theoretical and experimental work on the mechanism of respiratory chain phosphorylation. The work has gone forward in an unusually orderly and promising way. Part of the theoretical work has been described in a paper read at a symposium on “The Regulation of Metabolic Processes in Mitochondria” held in Bari, Southern Italy in May and this work was also the subject of a full day’s discussion

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at the research laboratories of Messrs. Phillips Limited in Eindhoven, Holland. A preliminary account of the first phase of our experimental work has just been completed and it is hoped that this will be published in ‘Nature’ within the next few weeks.20 Importantly, Mitchell was not only communicating research results supporting the chemiosmotic theory, but he was also publicizing the existence of his research institute. This he did both at the conferences mentioned, at a Gordon Conference held in Andover, New Hampshire, and at a meeting of the American Society for Cell Biology held in Philadelphia in 1965.



Neighbors

A potential drawback of creating an institute in the far southwest of England was its remoteness. Despite this apparent isolation, Mitchell succeeded in making Glynn known to the scientific world partly through work and publications but particularly through personal contacts and correspondence. The nearest research group in bioenergetics was at the University of Bristol, not the nearest university to Bodmin, being some 130 miles away but with a direct rail link. The interest of the group led by Brian Chappell lay particularly in transport across the mitochondrial membrane and therefore an area close to an aspect of the chemiosmotic hypothesis. Chappell had been in the next room to Mitchell in Cambridge in the early 1950s, when he first became interested in mitochondria, but at that time Mitchell himself was working on phosphate uptake in bacteria and there was little contact. Later, after working with Britton Chance, Chappell returned to collaborate on mitochondrial questions with Guy Greville in Cambridge before moving to Bristol. Mitchell wrote to Chappell as soon as research at Glynn was under way, pointing out that in terms of the international bioenergetics community they were near neighbors and suggesting a meeting. Mitchell visited Bristol in January 1965 and discussed a range of issues, including the state of the chemical theory. At the time, Chappell, like almost all biochemists, seems to have been fully wedded to the chemical theory. A few days later, Mitchell wrote to him about a remark made at the meeting that referred to yet another putative high-energy intermediate: “I have been pondering seriously over your remark that the orthodox chemical theory of oxidative phosphorylation is now well

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established by the isolation of undoubted intermediates such as the cytochrome c~ derivative.”21 Nevertheless, there were signs that Chappell was becoming seriously interested in the chemiosmotic theory. It showed in his reactions to Chance, who was inclined to reject respiration-driven proton translocation: I am getting rather cross with Chance. He keeps saying that the idea of a proton pump is untenable because under certain conditions protons don’t appear. He says this in your letter and he said it to me in Oxford. We know there are conditions, e.g. Ca++ plus acetate accumulation where this is not so—but then one would not expect it to be so. He agreed with this but then said there were other cases and refused to say what they were!22 Indeed, Chappell early became convinced of the value of the chemiosmotic approach. As he later expressed it, “I’ve always liked simplifying notions. And it seems to me that there was a tremendous economy of explanation of all these transport phenomena in terms of the chemiosmotic hypothesis.”23 Thus the relationship with the Bristol group remained a valuable link for Mitchell, although the number of people who visited Glynn ensured it was one among several.



A Center for Bioenergetics

Glynn now became a place where bioenergeticists could come to discuss theory and experiments and, on occasion, to carry out experiments. The first scientific visitor appears to have been Robert Crane, who had discussed ion-linked glucose transport with Mitchell at the Prague symposium and was now chairman of his department in Chicago. Many leaders in the field visited Glynn in the first year or so, and the flow of visitors continued throughout the institute’s life. So Mitchell reported the following: In May we invited Dr. André Jagendorf of the McCollum-Pratt Institute, Baltimore, USA to come to our laboratories for a mutual exchange of theoretical and practical information on the problem of photosynthetic phosphorylation—which is closely related to that of respiratory chain phosphorylation. Dr. Jagendorf is one of the leading American experimentalists in this field and we wished

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to arrange a meeting with him because his work had been confirming the predictions of our theory, and because, in correspondence with us, he had asked for more clarification of theoretical points that would have been difficult to deal with except by means of several days of thorough going discussion. Dr. Jagendorf spent a very productive week with us at the beginning of June.24 By early in 1965 the builders were gone, and the laboratories were working. In January 1965 Roy Mitchell (no relation to Peter Mitchell) was appointed as the first technician. Both Mitchell and Moyle had feared that in rural Cornwall it would be difficult to find suitably trained technical staff, but they were delighted with Roy, who was the best technician they had seen in twenty years. Later, in September 1966, a second technician, Robert Harper, joined the staff. Glynn had been set up with the intention that visiting workers could carry out research at the institute. During a visit to Dartmouth Medical School in late 1965, Mitchell met Peter B. Scholes, a British scientist who was a graduate of Liverpool University and was working with Lucille Smith. Scholes had been awarded a research fellowship by the Science Research Council that was designed to entice British scientists abroad to return home. He chose to work at Glynn, where he arrived in late 1966. He continued at Glynn, obtaining a further fellowship administered by the Royal Society. He helped with various aspects of the work and later published on photosynthetic bacteria. Thus, after little more than two years of research, the staff of the institute comprised three scientists, two technicians, and the secretary. This team of six focused on the central problems of bioenergetics. “The atmosphere in this isolated place could hardly be more congenial for scientific discussion,” wrote Mitchell.25

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7
Testing the Theory 1965–1968



A New Life in Cornwall

The period starting in 1965 marks a point when Mitchell’s life became dominated by the need to explore the chemiosmotic theory. In addition, putting Mitchell’s concept of the private research institute into effect in the second half of the twentieth century was a formidable task. He had made a massive investment of time, money, and personal energy in Glynn. Could such a small institute operate successfully in a world in which science was increasingly carried out in large university departments and research institutes many times the size of Glynn? The prospect does not seem to have daunted Mitchell, who appears to have had total confidence in his ability to make the project succeed. It is true he regarded it as somewhat of an experiment—nevertheless, an experiment with an anticipated positive outcome. Among Mitchell’s interests, which still included farming, was the refurbishment of old houses. He had carried out a major refurbishment of Carrington while at Edinburgh and then had undertaken the restoration of Glynn. These refurbishments seem to have given him an enthusiasm for this type of work, and he wanted another property to support this enthusiasm. He acquired Blisland Manor (now Blisland Mansion), where reputedly Queen Elizabeth I had stayed. The village of Blisland is some ten miles or so from Glynn on the western edge of Bodmin Moor. The property was in need of major renovation, which Mitchell undertook over a period approaching ten years, using some of the craftsmen employed on Glynn. On completion it was sold, although not without some difficulty. Mitchell’s concern was to restore the building

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to its original state as much as possible. The front porch, originally two stories high, had been reduced to a single story when Mitchell acquired it. Local people showed Mitchell where the stones from the upper part of the porch had been discarded in a field. Mitchell rebuilt the porch in its original form with the help of a picture provided by John Betjeman (poet laureate) who earlier had photographed the manor. In addition to Blisland Manor, there were other properties in Cornwall refurbished by Mitchell. One of the last was Cuilan, a fine bungalow, which Mitchell had almost completely rebuilt, overlooking the creek opposite St. Mawes on the south Cornish coast. Mitchell had an affection for old buildings and was fond of Winston Churchill’s statement that we shape our buildings, but thereafter they shape us. He was attracted by their history, but more particularly he exhibited a passion for restoring them to their former glory. When Blisland was sold (at a substantial loss to Mitchell), he provided the new owner with a history of the building and a diary of the refurbishment. Although such work also appealed to his entrepreneurial side, profit was not the motive and, indeed, almost all these activities made a loss financially. Mitchell was interested in craftsmanship and in methods used in earlier times in the building trade, which were applied in the process of restoration. Detailed supervision of building work gave expression to that side of his character that in his school days expressed itself in making things in the workshop.



Starting Research Again

When it became possible for research to start late in 1964, the subject to be pursued was not a difficult decision. Mitchell was confident that the chemiosmotic hypothesis was sufficiently robust to merit full experimental testing. This is not to say that it solved the quest for the mechanism for oxidative phosphorylation, only that it merited serious attention as a possible mechanism. In late 1964 very few laboratories, if any, were giving such consideration to the hypothesis. Mitchell approached the problem in three ways. First, the intervening years since 1961 had given him the opportunity to reflect on the chemiosmotic process. He had been able to explore much more fully the implications of his earlier ideas, which, in any case, had not been readily understood by others. There was a need therefore to expound the hypothesis, both fully and clearly. Second, the hypothesis needed

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experimental evidence to support it. When it was originally proposed, the hypothesis lacked direct evidence. In the last year or so at Edinburgh, Mitchell had obtained some results consistent with his proposals. That experimental work required completion, but, above all, a new, more rigorous research program was needed to test the hypothesis. However, important as experimental evidence is, laboratory results do not in themselves necessarily persuade scientists of the veracity of a theory. Thus, third, there was a need for advocacy to convince workers in the field that the hypothesis should be given credence. Mitchell was becoming keenly aware of the importance of effectively and persuasively presenting his arguments.1



Networking

Mitchell had not previously participated in the community of scientists working on oxidative phosphorylation, and at the time he launched the chemiosmotic theory, he was essentially an outsider. He needed to make contacts and also discuss relevant issues to enlarge and develop his understanding of the field. Although this had started in Edinburgh with Albert Lehninger and to some extent Bill (E. C.) Slater, it was rapidly curtailed by Mitchell’s impending illness. During the first year of operation at Glynn, Mitchell made a number of personal links. In May 1965 he attended the meeting held at Bari in southern Italy, where there were more than sixty European biochemists. The subject of the meeting was the regulation of metabolic processes in mitochondria, and Mitchell presented an account of the chemiosmotic theory. He was clearly encouraged by the meeting and “got the impression that the orthodox hypothesis [the chemical theory] of oxidative phosphorylation was not as secure as it was a year or two ago.”2 On the way home, he stopped in at Eindhoven in Holland, where his work was the subject of a full day’s discussion with Bill (E. C.) Slater and with his research group. Slater had graduated from Melbourne University and in 1946 had come to England to work at the Molteno Institute at Cambridge under David Keilin; he stayed at Molteno until 1955, although he also spent some time in the United States. In 1955 Slater moved to Amsterdam, where he remained for the rest of his career. One of his most significant contributions was the formulation of the chemical theory of oxidative phosphorylation in 1953. By the mid-

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1960s Slater had become one of the recognized authorities in the oxidative phosphorylation field. In late 1964 Slater wrote to Mitchell that it might be “most instructive . . . if we could invite you for a further discussion of your theory of oxidative phosphorylation.”3 The invitation was occasioned by the problems the group was having, both in relation to the work of an American biochemist, André Jagendorf, on photosynthetic phosphorylation and in understanding Mitchell’s theory. For his part, Mitchell found the meeting in Slater’s laboratory a valuable opportunity “to see the current knowledge of oxidative phosphorylation in a satisfactory and interesting light.”4 At this stage, Mitchell was becoming acutely conscious of the deficiencies in his knowledge of the field. In August he visited Andover, New Hampshire, for the Gordon Conference on “Energy-Coupling Mechanisms”; a general account of the chemiosmotic hypothesis was given, partly in support of Jagendorf’s work, which appeared to support Mitchell’s hypothesis. In November Mitchell again visited the United States to attend the meeting of the American Society of Cell Biology held in Philadelphia. During this trip, at the invitation of Lehninger, Mitchell gave lectures on his work at the Johns Hopkins School of Medicine and to Efraim Racker’s group at the Public Health Research Institute, New York City. Other invitations were also forthcoming but had to be declined for lack of time. Links with other workers were also strengthened by inviting them to Glynn. Jagendorf, Slater, Robert Crane, Brian Chappell, Britton Chance, and Chuan-Pu Lee from Lars Ernster’s group in Stockholm, among several others, were early visitors. Mitchell felt that the value of Glynn’s isolation was that visitors only came for serious scientific conversation. He remarked in his 1968 report that “a number of . . . scientists, mostly from abroad, have visited our laboratories for discussion and exchange of scientific information. In our opinion, such visits are often more productive, taking into consideration the expenditure of time and money involved, than large scientific conferences.”5 The relative isolation of Glynn was seen by Mitchell as an advantage rather than a drawback.



Competing Theories

It would be wrong to assume that Mitchell was operating on a level playing field, where the hypothesis would be sympathetically examined. The biochemical world had long worked with the theory pro-

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posed by Slater for the mechanism of oxidative phosphorylation, the chemical theory, based on classical biochemical principles. This theory proposed that a chemical substance, the “high-energy intermediate,” was formed during the oxidation of cell substances by the respiratory chain and was used for the synthesis of ATP, the energy currency of the living cell (see appendix to this volume). However, as Mitchell pointed out repeatedly, a long search for such a high-energy intermediate had failed to discover it. This had been a costly search, as he pointed out: “Several million dollars have been expended in the USA alone in past attempts to solve the problem of the mechanism of oxidative and photosynthetic phosphorylation.”6 Such a situation had an inevitable consequence: those who believed in the chemical theory, and had sought to support it experimentally, had acquired a personal commitment to it, espousing it ever more passionately. Indeed, as Mitchell described the approach: “This particular field has long been afflicted with various sorts of religious fervor.”7 That fervor had resulted in several claims that the elusive intermediate had been found. The philosopher of biology Douglas Allchin noted the regular pattern of claims to have discovered such an intermediate followed by its withdrawal: At least sixteen different claims were published, each offering evidence for a separate intermediate molecule or isolate. Furthermore most such claims were presented not just once but in a series of successive papers or research reports. . . . None of the intermediate claims, however, ever survived in the long run.8 This fascination with the chemical theory meant that the chemiosmotic theory at best got only modest attention, a situation exacerbated by the fact that it required a different mind-set than that of most workers in the field of oxidative phosphorylation. Most workers had been trained as chemists, whereas the chemiosmotic theory required a more physiological approach. However, the search for the predicted high-energy intermediate gradually decreased beginning in the mid-1960s, although new proposals continued to appear occasionally. There were other theories, including those of Bob Williams, Paul Boyer, and David Green, but at this stage, none of them dominated the field like the chemical theory. Within a few years the theory of Boyer became the refuge of chemical theorists, who began to find their theory no longer tenable.

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Mitchell’s Theory Is Beautiful

We have already noted that while Mitchell was still at Edinburgh, Lehninger had shown significant interest in the chemiosmotic theory, writing, “this extremely interesting hypothesis . . . is worthy of the closest scrutiny.”9 This interest was partly stimulated by Lehninger’s work on the osmotic properties of mitochondria, the particles where oxidative phosphorylation occurs. As work was starting at Glynn, Lehninger published a book in which he noted, in relation to the chemiosmotic theory, that “the idea provides some rationale for the fact that the respiratory and phosphorylating enzymes are located in the membrane, rather than in granules or in solution in the matrix.”10 Lehninger felt, however, that the theory did not account for the number of ATPs synthesized in oxidative phosphorylation, an issue that Mitchell subsequently took up. Slater in Holland also felt that the chemiosmotic hypothesis was worthy of serious and detailed consideration. He had been in communication with Mitchell since 1959 and had given him help with understanding the contemporary research in oxidative phosphorylation. Although he was the author of the chemical theory, Slater sought to tease out the nature of the chemiosmotic theory and to reexpress it in his own terms. In 1964, he was preparing a review on oxidative phosphorylation, which gave prominence to the chemiosmotic concept. A considerable amount of correspondence passed between Mitchell and Slater, as the latter sought to ensure that this section of the review, which occupied several pages, fairly reflected Mitchell’s position. During this discussion, in part to place his ideas in the mainstream of biochemical thinking, Mitchell invoked ideas of the Nobel laureate Fritz Lipmann. These related to the way the structure of the ATP molecule was viewed chemically, concepts that he felt aided the appreciation of his own position on the mechanism of ATP synthesis in the chemiosmotic theory. Much of the material from this correspondence found its way into Slater’s review, and Mitchell wrote, “I have now been through the part of your review dealing with my theory very carefully, and I think it coincides with what I was trying to say in my ‘Nature‘ paper about as nearly as any review can be expected to do.”11 For his part, Slater commented: Mitchell’s theory is beautifully simple, and as we have seen it explains all the experimental findings concerning oxidative phospho-

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rylation which we have discussed to date. We shall see below that it also explains in a simple way many other findings. There are however a number of observations which are more easily explained on the basis of discrete phosphorylation steps [chemical theory]. In general oxidative phosphorylation appears to be more complicated than envisaged by the Mitchell theory.12 Sympathetic treatment by Slater and to a lesser extent by Lehninger certainly did not imply acceptance of the chemiosmotic proposition. Indeed, in a symposium in 1965, Slater himself pointed out that “most workers in the field accept as a working hypothesis that . . . the energy of oxido-reduction reactions in the respiratory chain is conserved in the form of high energy compounds [the chemical theory].”13 Ernster, probably the leading European worker (other than Slater) in the field at the time, all but ignored the theory in an article published in the Annual Review of Biochemistry. Thus at the outset of work at Glynn, Mitchell was faced with a problem of persuading the bioenergetic community to take his theory seriously as a realistic explanation of the mechanism of oxidative phosphorylation. This could only be done by obtaining convincing experimental evidence.



Putting the Theory to the Test

Mitchell had made initial attempts at testing some of the implications of the theory while he was still in Edinburgh. Three tentative conclusions, all positive support for the proposal, had emerged from experiments on bacterial membranes and also some on mitochondria. First, membranes concerned with oxidative phosphorylation were themselves relatively impermeable to protons so that a proton gradient could be created across them. Second, uncouplers that broke the link between respiration (oxidation of foodstuffs) and phosphorylation (the synthesis of ATP) appeared to render the membrane permeable to protons, thus collapsing the proton gradient. Third, respiration of mitochondria resulted in an increase in the proton concentration of the medium, suggesting that these particles were ejecting protons, a finding which, as noted earlier, was independently confirmed by Guy Greville. However, the latter result implied that the polarity of the membrane was the reverse of that set out in the 1961 paper, and the theory therefore required amendment. Thus, from his experiments, Mitchell had encouraging evi-

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dence that was at least consistent with his proposals. Such evidence was not strong enough to sway his fellow bioenergeticists, however. It would be wrong to suggest that, at this time, Mitchell felt that the chemiosmotic theory was a true reflection of the process of oxidative phosphorylation. Rather, he had a commitment to testing the proposal experimentally. Accordingly, he preferred to describe the chemiosmotic proposal as a hypothesis. Thus to Slater he explained: I have no preconceived ideas at present as to which of the alternative conceptions is the more likely to fit all the facts, and so I look forward very much to being able to discuss the whole question with you in an entirely open-minded way. We have done a number of experiments here aimed at disproving the feasibility of the chemiosmotic conception, but so far without success.14 In his 1962 review, Lehninger had raised two major criticisms of Mitchell’s proposal. First, he felt that the proposals failed “to account for the more or less exact” number of ATPs synthesized in oxidative phosphorylation.” Work in the late 1940s and 1950s had concluded that three ATPs were synthesized per oxygen atom reduced by the respiratory chain. Second, “occurrence of oxidative phosphorylation in submitochondrial systems, with badly damaged membranes, would be unexpected according to the mechanism.”15 At that time, fragments of mitochondria (submitochondrial particles) that were capable of carrying out oxidative phosphorylation were thought to lack intact membranes and therefore should be incapable of forming a proton gradient. Mitchell and Moyle addressed both of these issues. First, they found that close to six protons were pumped out of the mitochondrion when oxidizing a normal substrate (NADH; nicotinamide adenine dinucleotide). Second, they tested the splitting of ATP (the reverse of ATP synthesis) and found that two protons were translocated. They assumed that if two protons were translocated when ATP was split, the same number would be translocated in the opposite direction when ATP was synthesized. Thus, with NADH as the substrate, six protons ejected outward would be sufficient to provide for uptake inward of three pairs of protons for the synthesis of three ATPs, the experimentally anticipated number. Mitchell and Moyle concluded this paper by noting that “the chemiosmotic hypothesis is now able to provide as realistic a model of oxidative phosphorylation as the more fashionable chemical hypothesis, and in particular it affords a very simple explanation of the action of classical uncoupling agents such as dinitrophenol,

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of mitochondrial swelling phenomena.”16 It should be noted that these results simply met Lehninger’s objection; they did not distinguish Mitchell’s theory from the chemical theory. Even so, others, particularly Britton Chance, had difficulty in confirming these measurements, and Mitchell and Moyle improved the conditions for and precision of these measurements in a later article.17 Mitchell and Moyle dealt with Lehninger’s second objection in a further article.18 Here they showed that mitochondrial fragments (mitochondrial sonic particles), which were able to carry out oxidative phosphorylation, contained intact membranes although they were turned inside out. The evidence impressed Slater: You have provided good evidence in support of the view that submitochondrial particles are turned inside out, a view which I have long favoured but for which I have never had any experimental support. I agree, also, that your hypothesis has survived this hurdle. Your experiments provide nice evidence in favour of the vectorial nature of ion transport.19 Thus the argument that such particles should not be able to carry out oxidative phosphorylation if the process proceeded by a chemiosmotic mechanism was untenable. Mitchell and Moyle also felt their experiments supported the chemiosmotic theory and not the chemical theory, a view that did not find favor elsewhere. In these experiments Mitchell was essentially supporting the argument that the chemiosmotic theory was as satisfactory an explanation of the mechanism of oxidative phosphorylation as was the chemical theory. The latter theory also had no difficulty in accounting for ion movements, including those of protons, as a side reaction in oxidative phosphorylation.



Support from Studies in Photosynthesis

For Mitchell there was an encouraging development on the other side of the Atlantic in the laboratory of André Jagendorf at the McCollum Institute in Johns Hopkins University. Even before experimental work started at Glynn, Jagendorf wrote to Mitchell, who reported to Slater: I had an interesting note from Jagendorf today saying that his work on phosphorylation and a non-phosphorylated “intermedi-

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ate” in chloroplasts . . . seemed to be quite consistent with the build-up of a pH [proton] gradient and the driving of phosphorylation by my chemi-osmotic mechanism. As you know I have always been rather skeptical about my theory, and so one feels all the more appreciative when the odds seem to be so interestingly poised.20 Mitchell’s chemiosmotic proposals were intended to explain not only the mechanism of oxidative phosphorylation in mitochondria and bacterial membranes but also the mechanism for the conversion of light energy into chemical energy in photosynthesis carried out in green plant chloroplasts. This involved the synthesis of ATP in a manner similar to that in the mitochondrion (see appendix to this volume). Jagendorf obtained evidence for an intermediate in ATP formation in the light during photosynthesis. The intermediate continued to exist transitorily after the light was switched off. Initially he interpreted this finding in terms of the high-energy intermediate of the chemical theory, but later he regarded it as a proton gradient. He wrote to Mitchell: I have been meaning for some time to write to let you know how much our current research efforts are influenced by the concepts of the mechanism of phosphorylation expressed in your article in Nature in 1961. Specifically, in the chloroplast phosphorylating system we have discovered the existence of a pool of high energy, non-phosphorylated “intermediate”; and all of our data so far seem to be consistent with its being a pH [proton] gradient, as you predicted. Furthermore, after reading your article we thought that the pH [proton] gradient might be observable as an increase of pH [decrease of proton concentration] in the medium, at a time when the intermediate accumulates. This has turned out to be the case and we have yet to find any discrepancies in the correlation between the observable pH rise [decrease of proton concentration] and the existence or kinetics of the intermediate. While I do not think that these phenomena actually prove your concepts to be true in a completely rigorous fashion, I do think that everything falls into line so far.21 In fact, it was Geoffrey Hind, working in Jagendorf’s laboratory, who had drawn his senior colleague’s attention to Mitchell’s 1961 paper, and the two had discussed it at length. Curiously, the letter to Mitchell, perhaps one of the most important

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he ever received, did not draw an immediate response. Some six months later he wrote excusing the delay, saying that he had been convalescing under doctor’s orders and was just beginning to work again. He commented that Jagendorf’s results were “in accord with the chemiosmotic theory” but could also be interpreted in terms of the chemical theory. He added that such a result was “of great interest to me and has encouraged me to take a somewhat more aggressive approach towards the orthodox theory.”22 Following this promising research, further correspondence revealed that some experiments raised questions about whether a proton gradient was the intermediate in chloroplast photophosphorylation. There seemed to be too many protons translocated. In June 1965 Jagendorf visited Glynn for a week of discussions and some experiments, an experience he thoroughly enjoyed. He wrote: I don’t know how to express my appreciation strongly enough, for your marvelous hospitality last week, or for the generosity of the Glynn Research Foundation. I had a truly wonderful time; I feel ever so much more like a traveled man of the world now that I have been to England, eaten Cornish cream, and seen Glynn House.23 An even more significant experimental result was to come from Jagendorf’s laboratory. In the summer of 1965, he wrote to Mitchell saying that he was successfully carrying out experiments in which he was applying a proton gradient to chloroplasts in the dark, which resulted in the synthesis of ATP. Mitchell’s theory predicted that an artificial proton gradient should induce the synthesis of ATP in the dark. Jagendorf found that by first treating his chloroplasts with an acid and then decreasing the external proton concentration of the organelles with alkali, he was able to demonstrate ATP synthesis.24 Such a result was certainly a strong support for the chemiosmotic theory, although other interpretations were possible. Mitchell, Jagendorf, and Slater remained fully in touch over these developments. In March 1966 Slater wrote to Mitchell, explaining that in his laboratory Jagendorf’s early findings had been confirmed even though similar experiments with mitochondria had failed. Mitchell himself was clearly encouraged by the overall situation. It is true he had a little difficulty in understanding how Jagendorf’s experiment worked since no steps had been taken to make the electrical membrane potential favorable. Thus with his own experiments on pro-

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ton translocation in mitochondria and Jagendorf’s on ATP synthesis in chloroplasts, Mitchell felt that “experiments have been steadily pushing me towards accepting the chemiosmotic hypothesis and I think I shall feel inclined presently to regard it as a theory.”25



Revising the Theory

Nevertheless, the theory needed revision and elucidation. As he remarked to Slater in February 1962, “there are a number of possible modifications of my general chemiosmotic scheme that I must soon describe to you, for my paper in Nature was only intended to set out the general principles of the chemi-osmotic coupling conception.”26 Thus even before he left Edinburgh, a restatement of the theory was in Mitchell’s mind. Further, the serious interest of Slater—especially the searching questions raised in his letters, stimulated in part by the preparation of his review—had caused Mitchell to think more deeply about the chemiosmotic theory. There were major factual changes required. The number of protons translocated had to be doubled throughout, and the polarity of the membrane had to be reversed. A revision was thus essential and would have the added advantage of promoting and clarifying the theory that was not well understood among fellow biochemists. A particular problem for many biochemists—including Slater, who sought advice from Williams—was the role of the membrane potential (see appendix to this volume). After visiting Slater’s laboratory at Eindhoven, Mitchell had written: “I have continued to ponder over your difficulties concerning the electrical potential part of the driving force in the chemi-osmotic conception, and have been wondering what is the simplest way of grasping the idea of electrical potential driving forces in chemical processes.”27 In fact, the amendment of the chemiosmotic theory occurred by stages: initially in 1962, then in a further paper to a meeting in 1965 of European bioenergeticists in southern Italy at Bari, as already noted. Here, in an attempt to link the theory into the mainstream of biochemical thinking, Mitchell had presented the chemiosmotic theory “using the conventions and outlook of the recent lucid review by Ernster and Lee.”28 The theory was discussed in more detail than previously. Mitchell concluded: “The chemi-osmotic theory differs, perhaps most of all, from the chemical theory, in that, without additional assumptions, it can offer simple explanations for the rather dramatic swelling and

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shrinkage and other osmotic effects that have been found to accompany respiration and ATPase activities in mitochondria.” He went on to note that the chemical theorists were now being forced to propose a number of hypothetical high-energy intermediates to account for ion transport, swelling, and contraction phenomena. He continued: “I began by referring to the chemiosmotic hypothesis but have ended by discussing the chemiosmotic theory. This was not entirely unconscious, for I have noticed that the proponents of the chemical hypothesis of oxidative phosphorylation refer to it as a theory all the time.”29 The article also includes a comment, also made elsewhere in relation to amendments to the theory, that “it should perhaps be emphasized that these corrections apply only to the quantitative considerations, and involve no change of general principle.”30 Possibly, Mitchell was concerned about maintaining priority for his theory, particularly after arguments with Williams and Davies, among others. It was the Bari symposium, however, that provided the trigger for his preparation of a full review of the theory. Mitchell felt that his presentation to the symposium had been very unsatisfactory in a number of ways. More particularly, it was in the discussions with other biochemists that Mitchell became aware of his own weaknesses. He recalled: Although the discussion was extremely fruitful to me it was the first time I had really been thinking hard amongst the ox-phos people and had been able to discuss with them in detail the different ideas that I had about the system. I felt that my own ignorance was so profound, it really worried me very much.31 It should not be thought that the field of oxidative phosphorylation was in any way easy to grasp at this time. As Racker and Conover had remarked, “Anyone who is not thoroughly confused just does not understand the situation.”32 On his return, Mitchell resolved to take drastic action about his lack of knowledge and began to read the literature very extensively, using as his guide the recently published review by Ernster and Lee. Although based on the chemical theory, Mitchell found the review an extremely valuable source of information. It was the result of this extensive reading, inspired by the Lee and Ernster review, that resulted in Mitchell’s wish to write a full review of his own theory. The opportunity to set out the chemiosmotic theory in some detail had actually arisen back in 1962. At the suggestion of Michael Swann and Sir James Gray, Mitchell had been invited by the editor of Biological

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Reviews, H. Munro Fox, to “write a review article on some topic of your own choice.”33 Mitchell at the time felt that he would like very much to write a review article for Biological Reviews but as I have so many commitments at present I cannot honestly see any likelihood of completing a suitable article in less than eighteen months from now . . . I would be very happy to receive your notice to contributors, and will give some sort of instruction to my sub-conscience to start the wheels turning.34 The review, stimulated by his experiences at Bari and the writing of Ernster and Lee, got “longer and longer.” Inevitably, the editor of Biological Reviews wanted a shorter document. In the end, a shorter review entitled “Chemiosmotic Coupling in Oxidative and Photosynthetic Phosphorylation” was sent to Biological Reviews, whereas the full version was published by Glynn and became known as the first “Grey Book”35 because the covers were gray in color.



The First “Grey Book”

It was Mitchell’s view that a full account of the chemiosmotic theory was required. The “Grey Book” published by Glynn Research Limited in 1966, was described as “a shortened version of Publication No 66/1 of Glynn Research Ltd.” Private publication also avoided the complications arising from the “monopolistic” activities of editors to which Mitchell was definitely allergic. Mitchell gave his reasons for the Grey Book in its introduction, a statement missing from the introduction to the shorter review. The statement reflects Mitchell’s view that although the evidence for the chemiosmotic hypothesis was still limited, the evidence for the chemical theory was much weaker. Further, the latter theory had suffered increasing elaboration in order to accommodate experimental evidence. He could then commend the chemiosmotic theory on the grounds of simplicity: the study of the question of the coupling mechanism has continued to be ruled by the well-trodden and familiar tenets of the chemical coupling conception, no matter how fantastic the resulting tissue of hypothesis. The object of the present review is to overlook this customary restriction of perspective and to pose the cen-

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tral question of electron transport phosphorylation in the elementary form: How are the flows in the oxido-reduction [respiratory chain] and hydro-dehydration [ATP synthesis] pathways coupled to each other? In answer to this question I shall develop the view that coupling may occur through a chemiosmotic type of mechanism that does not require chemical intermediates common to oxidoreduction and phosphorylation.36 It was from this account, in fact, that many biochemists, particularly the rising generation, acquired their understanding of the chemiosmotic hypothesis. The institute arranged for one thousand copies to be printed and sold initially at a price of 7 shillings ($1) each; when Glynn closed in the late 1990s, some copies were still available. Nevertheless, the book had a wide circulation among biochemists who were interested in the field, and its modest cost made it available to students. Chappell at Bristol bought several for his department. In essence, the first Grey Book marked the point from which a real interest in the theory developed. As Ernster and Schatz later wrote: The official debut of the chemiosmotic hypothesis took place in a short paper in Nature in July 1961. . . . However the real breakthrough of the hypothesis did not begin until 1966 when Mitchell published a book entitled Chemiosmotic Coupling in Oxidative and Photosynthetic Phosphorylation. In this book he outlined his hypothesis in detail, specifying its basic postulates and defining the protonmotive force. . . . At the same time experimental evidence for these concepts began to appear [referring to work of Mitchell and Jagendorf]. As a result work was initiated in many laboratories in order to evaluate Mitchell’s hypothesis, and constituted the principal task in bioenergetics for the next decade.37 Thus the Grey Book provided a full and complete description of the theory and examined the evidence in its support. It had other functions. It was a means of persuading fellow scientists that the chemiosmotic theory was a credible explanation of the process of oxidative phosphorylation and that it should be taken at least as seriously as the chemical theory. As we have already noted, there was also a need to render the theory more comprehensible. As Mitchell maintained, the theory outlined in the Grey Book was unchanged in principle, although some of his contemporaries argued that this was not the case and that the 1966 version contained a new approach. Indeed, Slater felt that

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“Mitchell’s hypothesis changes with a time constant shorter than that necessary for people to understand him.”38



The 1966 Version of the Chemiosmotic Theory

What then were the differences from the original version of the chemiosmotic theory published in Nature in 1961? In the first version, Mitchell dealt only with principles. He considered both protons and hydroxyl ions, which may or may not have actually migrated across the membrane, but now protons alone migrated across the membrane (see fig. 7.1). He also proposed detailed molecular mechanisms for proton transport (his proton conducting loops). In addition, he discussed the available experimental evidence that had brought about a refinement of his views, particularly reversing the polarity of the membrane and doubling the number of protons translocated. The theory was summarized as four postulates. In fact, the revision did slightly simplify the basic concept, thus making it more comprehensible. It can be summarized as the translocation of protons (six per oxygen atom) outward across the mitochondrial inner membrane by the respiratory chain (see fig. 7.2). This translocation of protons created the proton motive force (a new term), which was

Figure 7.1 Diagram of the chemiosmotic hypothesis. The respiratory chain is represented simply as the means whereby protons (H+) are transported from the inside (matrix) to the outside (intermembrane space, IMS). The active part of the ATPase is shaded and is responsible for ATP synthesis, driven by the translocation of protons inward. The membrane potential is shown as positive outside and negative inside. It will be dissipated by transfer of positive ions (H+) inward and created by the reverse.

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Figure 7.2 Diagram of the electron transport chain showing the loops for transporting protons. The scheme does not put the components of the electron transport chain in the contemporary conventional sequence but does give three proton translocating loops. The protons are transferred across the membrane by NAD (nicotinamide adenine dinucleotide), FMN (flavin mononucleotide), and CoQ (coenzyme Q, or ubiquinone). Electrons are transferred across the membrane in the opposite direction by Fe-S (iron sulfur proteins) and cytochromes. Adapted from P. Mitchell, Chemiosmotic Coupling in Oxidative and Photosynthetic Phosphorylation (Bodmin, Cornwall: Glynn Research Ltd., 1966).

composed of the proton gradient and the accompanying membrane potential (Mitchell’s first postulate). The protons returned across the membrane through the ATPase enzyme, synthesizing ATP. The proton gradient and the membrane potential would drive the return of the protons (the second postulate). The remaining two postulates concerned the movement of other ions and the impermeability of the membrane itself to ions that included protons. Although in the 1961 article there was no room to do other than

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note that the proposals would apply to photosynthetic systems, in the 1966 book Mitchell gave these systems a similar treatment, supported, in particular, by the experiments of Jagendorf’s group, which were discussed in some detail (see appendix to this volume). It has to be admitted that Mitchell’s version of the respiratory chain was unorthodox at the time (as it had been in the 1961 version). He placed one component, ubiquinone, in an unusual position in order to create his loops (contemporary schemes normally placed ubiquinone before cytochrome b rather than after; see fig. 7.2). Later, Mitchell commented: As you know I have always thought that there was a good deal of circumstantial evidence indicating that ubiquinone may, indeed, be involved in coupling oxidoreduction specifically between cytochromes b and c1. I notice, incidentally, that a number of new communications have appeared in the literature during the last few months which tend to support my contention.39 There were also unusual aspects about Mitchell’s view of the ATPase. In the intervening years since 1961, work in several laboratories had located the active site of the enzyme on the inside face of the membrane and projecting into the mitochondrial matrix. This location of the active site created problems for Mitchell. In the earlier version the enzyme could be located in the membrane, just as the respiratory system was, and could react with hydroxyl ions on one side and protons on the other. To accommodate a role for protons in an active site no longer embedded in the membrane, Mitchell needed to make the energy of the gradient across the membrane accessible to the place where the reaction occurred. He chose to use the terminology of the chemical theorists and use a “high-energy” compound (denoted X~I) to do this, a course of action which somewhat blurred the distinction between the chemical and chemiosmotic theories. However, Mitchell never saw this compound as in any way equivalent to the high-energy intermediates of the chemical theorists because it was only in the ATPase and not intermediate between the respiratory chain and the ATPase. Mitchell sent a copy of the Grey Book to Lipmann, whom he greatly respected. Lipmann responded: “In general, your recent contact with the professionals has given you the opportunity to expand. Yet, the extensions and modifications seem, at least to a somewhat uncommitted reader, to have weakened the exuberance and indeed brilliance of your original papers.”40 Mitchell interpreted these somewhat enigmatic com-

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ments to refer to his revised view of the ATPase. He wrote: “I feel, that, as you are perhaps hinting, the more detailed mechanism that I recently proposed for [the ATPase] conceded too much to the orthodox homogeneous phase concepts, involving X~I [the high-energy compound] etc., and was in danger of taking too little account of the anisotropic situation in the membrane.”41 A further issue explored in the Grey Book was the energetics of the chemiosmotic hypothesis. The doubling of the number of protons translocated by the respiratory chain and those used in ATP synthesis made plausible energetic proposals easier since both the predicted size of the proton gradient and the membrane potential necessary for ATP synthesis were halved.



Distributing the Grey Book

Copies of the Grey Book were distributed to scientists working in the field of bioenergetics across the world. Among those who received a copy was Bob Williams, who had been a correspondent in 1961 when the tone of letters had progressively deteriorated. This revived the correspondence. Williams wrote: Thank you very much indeed for your booklet. Reading it, especially the introduction, it seems to me that your views and my views are a little nearer together than they were in 1961. By the way, it is a pity that you do not refer to our previous exchange of letters and to the similarity between our thoughts in this matter. You will notice that I do refer to your work and to our exchange of letters.42 Mitchell responded by saying that Williams had suggested that the letters should not be referred to in publications. He went on to argue that his hypothesis and that of Williams were quite distinct, and he developed his argument with a number of specific points: “It seems that our views were completely opposed on these fundamental points and that your theory was not concerned with the type of chemiosmotic coupling conception that I have been developing.”43 Mitchell had understood from Slater that Williams regarded the chemiosmotic hypothesis as “unworkable.” Later, however, Mitchell apologized for not referring to Williams’s papers but pointed out that Williams’s own reference list failed to quote relevant papers. However,

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Mitchell hardly ever cited Williams. The correspondence, which terminated in discord after some five or so letters, shows evidence of an underlying concern about the priority to be attributed to their respective theories and the concern that Williams might have influenced Mitchell in formulating his theory.



Acid Baptism

Jagendorf’s experiments in which chloroplasts were shown to synthesize ATP in the dark after an acid-alkali bath were a strong support for the theory. If they had been correctly interpreted, then a similar effect should be seen in mitochondria. In these organelles, however, the polarity of the membrane is the reverse of that in the chloroplast, so that an acid bath should be effective. Slater wrote to Mitchell, Jagendorf, and Chance outlining such experiments: As a result of Dr Jagendorf’s demonstrating that chloroplasts can synthesize ATP when they are brought from a low to a high pH [high to low proton concentration; i.e., acid to alkali], and Dr. Mitchell’s remark that, if a similar process occurs in mitochondria, it would be expected to occur when the mitochondria are brought from a high to a low pH [alkali to acid], Dr. Koivusalo has carried out the following experiment in our laboratory. . . . It must be concluded that no ATP formation by mitochondria can be demonstrated when they are brought from pH 9.3 to 6.5 [alkali to acid].44 Similar tests were carried out in Racker’s laboratory, where much work on the ATPase enzyme had been done and where Jagendorf’s experiment had been repeated successfully. Racker wrote: “Acid baptism has not progressed much around Christmas time. One attempt was made to demonstrate it in yeast submitochondrial particles. . . . Neither acid baptism . . . nor alkaline baptism worked.”45 In September 1966, Bob Reid of the University of York, who had earlier worked with Mitchell in Edinburgh, visited Glynn. This provided an opportunity for further work on acid treatment of mitochondria. Mitchell and Moyle, together with Reid, did manage to obtain a synthesis of ATP in mitochondria, albeit transient, and they felt that this finding promoted the position of the chemiosmotic theory.46

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Disputes, Experimental Verification, and Strained Relationships

Mitchell’s idealism during this period was summed up in a letter to Harold Baum. In attempting to make the chemiosmotic hypothesis explain as many of the experimental facts as possible, I was subjecting it to a very rigorous test—but that, after all, is the only way in which a hypothesis can be dealt with, if one wishes to discover, without bias, whether it may later be eligible to become a theory.47 Such a cool objective approach was not the whole story. Others saw Mitchell as doggedly defending his theory. Deciding between the theories was not easy. Thus the chemical theory was adapted to accommodate observations on proton movements. These and other ion movements were seen as a side reaction of the high-energy chemical intermediate. The ejection of protons when mitochondria respired was regarded by chemical theorists as a secondary event and should be slightly delayed when respiration occurred while the intermediate was formed. In contrast, a simple prediction that could be made from the chemiosmotic theory was that when oxidation reduction took place in the respiratory chain of the mitochondrion, the protons should simultaneously appear in the surrounding medium. One of the leading American bioenergeticists, Britton Chance, at the University of Pennsylvania, possessed the type of equipment that made it possible for him to check this prediction. He observed a lag between the respiratory process and proton ejection of the order of 1 sec. In contrast, when he repeated the test using his own methods, Mitchell found the proton ejection to be synchronous. Further, much to the exasperation of his colleagues, Mitchell suggested that in some experiments synchrony would not occur. Numerous tests devised to disprove the chemiosmotic hypothesis (or, indeed, the chemical theory) turned out to be capable of other interpretations, thus leaving the field in a state of uncertainty. Such a situation was bound to create tensions. While Mitchell saw increased evidence for his theory, Slater felt “at about this time the chemical hypothesis seemed to receive [experimental] support.”48 Our experiments on the Mitchell theory have left me more and more convinced of the correctness of the [chemical theory], but I

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admit that this is only conviction and that the theory (or hypothesis—I always seem to get bogged down in a useless discussion with Mitchell on the difference between a theory and hypothesis) is far from proven.49 Slater had given pride of place to Mitchell’s theory in his review prepared around 1964, but the cordial relationship that existed then began to deteriorate in the mid-1960s. “My early enthusiasm evaporated when Mitchell . . . proposed a looped respiratory chain which I found difficult to reconcile with what I knew of the respiratory chain.”50 Indeed, by the time Slater read the first Grey Book, relations with Mitchell had almost collapsed: I have only just got around to reading Mitchell’s privately produced testament, and it has made me mad. . . . In fact, I am at the moment not answering Mitchell’s letters, since I see no profit in discussion with someone who is so obsessed with his theory that he only considers as established data that [which] fits his theory, dismissing other data as trivial.51 Such tension came out into the open at a meeting in Warsaw in 1966, where there was a heated debate about Mitchell’s experiments and their interpretation. Slater remarked, “I cannot accept the experiments of Mitchell as evidence in favor of his theory,” while Mitchell summarized his and Moyle’s measurements of protons as in accordance with his theories.52 As Mitchell wrote to Jagendorf, “Bill Slater seems to have declared war on some of our experiments recently.”53 Many participants recalled this meeting as being particularly rancorous. One participant, Brian Chappell, recalled seeing Slater and Mitchell in heated conversation, where the former was so furious that he was hopping around on one foot! Chappell felt that he now knew what “hopping mad” meant. A year later the situation had not improved. Slater wrote: Frankly I do not wish to become involved in further discussion with Peter. . . . Peter has never once conceded a point which I have made in voluminous correspondence, but patiently explained how I had not understood his theory. I believed this for a long time, because I am rather stupid, until I discovered that he would not listen to any interpretations of his experiments that do not fit with his theory, and he began to answer my more quantitative criticisms with fine-sounding but to me meaningless jargon, such as ‘backlash’.

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I found the earlier discussion with him very stimulating but I believe that the chemiosmotic theory is at the moment very harmful. The theory and the predictions that flow from it are being confused in the minds of many with fact. He is leading many able people like André, and many younger, astray. Peter’s little grey book is becoming like Mao’s red book. I expect to be greeted in England with students reciting the three postulates of the chemiosmotic hypothesis!54 Slater’s dispute with Mitchell was typical of other people’s concerns. Williams noted “Mitchell’s polemic is wild and has changed character so as to be very unlike his original position.”55 He also noted that “it is a pity that he [Mitchell] is such a difficult man to deal with for some parts of the arguments he uses are very instructive.”56 Such disputes with Mitchell also arose in the photosynthetic field. Norman Good at Michigan State University started a debate over what he saw as too easy an acceptance of the chemiosmotic theory: “I cannot yet accept that proton translocation is the prime mover in ion transport, neither as a proven fact nor as the best hypothesis.”57 This dispute involved André Jagendorf, Geoffrey Hind, and Robin Hill, among others. Good felt that “the tendency to swallow large doses of Peter Mitchell without chewing does seem to be the current fad. . . . Small amounts of Peter are stimulating but after a time one begins to sicken of grand phrases and pine for verifiable specifics.”58 The more Mitchell enhanced his theory, the tougher the debate became. The world of bioenergetics was now in disarray.



The Second Grey Book

Undoubtedly the success of the first Grey Book encouraged Mitchell to contemplate a sequel. Such a publication could not be expected to have the same effect as the first book with its much-needed full account of the chemiosmotic hypothesis. But Mitchell had set up Glynn Research Limited with the specific intention that it would “publish, report on and disseminate the results of the work of the Company or other scientific information.” The object of the second Grey Book was to make available to research biochemists and university teachers and students some recent developments in the concept of chemiosmotic coupling, and to describe some aspects of recent progress in

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the application of the concept of chemiosmotic coupling to the central question of energy transduction through the channels of photosynthetic phosphorylation and oxidative phosphorylation in the plant and animal kingdoms.59 Like its predecessor, the core of the material was published elsewhere,60 and clearly the delay in publication of this material had been a further stimulus to the preparation of this Grey Book. A considerable amount of the second Grey Book was given to discussion of transport across membranes of protons and other inorganic and organic ions. Mitchell liked inventing words for specific systems. He proposed again here, as he had done in his Edinburgh days, terms for various types of membrane transport systems such as uniport, symport, and antiport, which are defined and discussed. These words remain in use, although at the time some regarded their invention as acts of imperialism. The “proton motive force,” which mathematically combines the membrane potential and the proton gradient, was also defined and discussed.



Problems with Protons

A major conceptual difficulty during this period was a misunderstanding of the basis of the chemiosmotic theory as a result of confusing protons with the proton motive force. Thus Mitchell wrote: Unfortunately, however, much of the recent discussion about the mechanism of coupling in oxidative and photosynthetic phosphorylation (e.g. papers by Lehninger’s group, Chance’s group, Vernon’s group, Pressman and Harris, and by Slater) has been based on a misconception about the identity of ∆pH [proton gradient] and ∆p [proton motive force]. As this misconception has led to erroneous and time wasting arguments about the merits of different hypotheses (dogmas?).61 It was natural for those who had worked with the chemical theory predicting a high-energy intermediate to replace that intermediate with the proton gradient. Such a view tended to ignore the importance of the membrane potential, and this led to a number of problems since it was this electrical potential that Mitchell regarded as the major component of the proton motive force in mitochondria. Indeed, as late as 1977

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Slater was still having trouble with understanding the theory, particularly the membrane potential, and seeking advice from Williams. Lehninger also noted the problem of misunderstanding the proton motive force and wrote to Mitchell, “Even Britton Chance, with his very highly developed feel for the kinetics of complex systems, seems to be missing the point when he concludes that there is no chemi-osmotic coupling. . . . Anyway, I don’t think he is really measuring what he thinks he is measuring.”62 Chance’s group was using a dye (bromthymol blue) to estimate the proton gradient across the membrane. They found that the gradient was dependent on the presence of calcium ions and that the proton gradient itself was extremely small. They concluded, “No experimental evidence exists for the establishment of a measurable pH [proton] gradient in calcium deficient rat liver mitochondria.”63 Subsequently, Mitchell and Moyle, together with Lucille Smith, who was visiting the institute, showed that the dye was not a reliable indicator of proton concentrations in mitochondria, thus invalidating some of Chance’s conclusions. The calcium ions themselves were dissipating the membrane potential, allowing further protons to be transported by the respiratory chain; this explanation was derived from the chemiosmotic theory.64 Mitchell’s ability to counter the criticisms of Chance by using the chemiosmotic theory undoubtedly enhanced his personal position in the field. In the same issue of Nature that Chance and Mela published their findings, Slater’s group showed results that were at odds with Mitchell’s demonstration of proton pumping by mitochondria. They concluded that “the arguments developed in this paper are directed against the interpretation of their experiments by Mitchell and Moyle rather than against the chemiosmotic theory itself.”65 Mitchell and Moyle repeated experiments similar to those of Slater but were unable to confirm the latter’s results.66 Harold Baum in London, who had seen an account of the Jagendorf and Uribe experiments in a copy of Information Exchange Group [IEG] Bulletin, was also concerned about whether protons could act in oxidative phosphorylation. The IEG described itself as “a continuing international congress by mail” and included articles that had not yet been published. It was a means of circulating information rapidly among those actively working in the field, including Mitchell. Baum raised a question, eventually referred to Mitchell, about the meaning of proton concentrations in very small volumes such as mitochondria. McCabe

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also raised similar concerns in Nature but here, using Chance’s estimate of the proton gradient across the mitochondrial membrane, he noted “the number of hydrogen ions [protons] involved . . . would be too small to have any significance.”67 Thus he apparently undermined the chemiosmotic hypothesis. In a letter to Nature, Mitchell responded to McCabe and pointed out that the notion of proton concentration needed a time dimension. In a second letter, responding to Baum, he drew attention to the fact that in rapidly respiring and phosphorylating mitochondria, the proton gradient might be very small, as observed in Britton Chance’s laboratory. Thus the proton motive force was primarily in the form of the membrane potential rather than a proton gradient.68 The arguments over protons highlight the genuine difficulties many workers, who had lived for years with the chemical theory, had in understanding the chemiosmotic theory, in particular the implications of the concept of the proton motive force. By concentrating on protons, rather than on the proton motive force, they were frequently driven to the conclusion that observable proton gradients were inadequate for the role assigned to them by the chemiosmotic theory.



Successful Collaboration

The first years at Glynn successfully took Mitchell’s work a significant step forward. The Glynn Research Laboratories were moving along as he had intended, and the collaboration with Moyle was proving fruitful. An effective rhythm of work at Glynn had been established. Each day Mitchell and Moyle discussed for some hours the latest experimental results, a discussion which not infrequently generated new theoretical points. Such discussions also generated ideas for new experiments. Experiments were then carried out in the second half of the day. While initially both engaged in the experimental work, the demands of theoretical work, writing papers, and the Grey Books meant that Mitchell increasingly had to leave the laboratory work to Moyle, assisted by the technicians, although the daily discussions ensured that Mitchell remained in close contact with the experimentation. Thus theory developed alongside practice. Mitchell and Moyle felt that this was a significant improvement over the situation in universities where the leading scientist, taken up with other duties, tended to become separated from laboratory work, with the result that experiments were often not rigor-

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ously designed and carried out. Equally, the development of theory remained in close contact with experimentation.



Mitchell’s Interpreters

The chemiosmotic theory was not an easy concept for orthodox biochemists to grasp. Guy Greville, who had collaborated with Mitchell over the first demonstrations of proton translocation, was asked to prepare a review that would scrutinize the theory for the serial Current Topics in Bioenergetics. Greville’s main research interest had been in the field of mitochondrial metabolism. He was head of the department of biochemistry and deputy director of the Agricultural Research Council’s Institute of Animal Physiology at Babraham near Cambridge. It was Greville’s review that certainly helped many biochemists appreciate the nature and implications of the chemiosmotic hypothesis. It benefited from the fact that Greville had not been a major protagonist in the field. Somewhat in jest he had earlier remarked to Mitchell, “I do not understand a word of the chemiosmotic hypothesis.”69 In the introduction to the review, he described the position in the field as he saw it: Workers who are inclined to be critical of the Mitchell hypothesis and to accept the chemical intermediate alternative include Britton Chance, EC Slater, L. Ernster, BC Pressman and M. Avron, while those who tend to explain their experimental findings in terms of the chemiosmotic hypothesis may be mentioned: JB Chappell, AR Crofts, AT Jagendorf, B. Rumberg and HT Witt. Prominent workers in the field who seem to have adopted a notably neutral attitude include M. Klingenberg, AL Lehninger, L. Packer, and E. Racker. The present writer when asked for a bird’s eye appraisal of the Mitchell hypothesis felt that the wrong phylum had been selected and he offers instead a worm’s eye scrutiny. His chief qualifications are that he is completely uncommitted.70 Mitchell responded encouragingly to the draft that Greville sent him: “It has been very interesting reading for me, and I think you have made a very erudite and fair scrutition [sic]. . . . As you will see none of the points that I have raised are of more than minor significance.71 Whether of minor significance or not, they involved a good deal of further discussion, much of it over the telephone. At last Mitchell

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seemed satisfied: “It now seems to me to be very lucid and impeccably fair.”72 In summarizing the situation as he saw it, Greville commented in relation to the chemiosmotic hypothesis: We may expect that acceptance would derive from gradually accumulating evidence in its favour. Experimental evidence has been obtained for its chief requirements—proton translocation by the respiratory and photochemical electron transport chains, ATP synthesis driven by a pH gradient and low electron and proton conductivity in the coupling membrane—but there are workers who maintain that these experimental findings are equivocal in spite of Mitchell’s arguments.73 He also noted the survival capacity of the chemical theory: “However, the versatility of the chemical hypothesis permits in most instances an alternative explanation to observations consistent with the Mitchell hypothesis.” Mitchell felt that the review was helpful in almost every possible way. . . . I think it was helpful in so many different ways, in that he used the language of the present experts, which I was not very well able to do. . . . He was able to act as the interpreter using the language of the existing ox-phos people and explaining to them in their language what it was that I was trying to say in my language.74 In fact, there is little doubt that Greville’s review was published at the point when it was most needed for those in the field who now needed to consider the chemiosmotic hypothesis as a plausible explanation of the mechanism of oxidative phosphorylation. Sadly, Greville died in December 1969, shortly after the review was published. Chappell felt that Greville’s life should be marked in some way. He wrote to Mitchell for advice. Mitchell’s reply reveals something about Mitchell’s nature: I have been trying to sort out my feelings about your suggestion that some sort of meeting should be organized next spring as an appreciation of Guy Greville. I shall certainly miss him a lot, but I expect you will feel it even more as you knew him so much better that I did—and I feel very sympathetic with you about that. But I am not able to feel enthusiastic myself about any public demonstration of our love for Guy.

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So, while I would be quite willing to participate in some scientific meeting associated with the name of Guy Greville, if I could make some useful contribution to it, I do not feel that I would want to be involved in the emotional by-products. I hope that this will not seem to be too insular an attitude. Really that is not the motivation.75 In the same year as Greville’s review was published, David Deamer provided a comparable interpretation for many American workers in the Journal of Chemical Education. He concluded that “there is presently no evidence which demolishes the chemiosmotic hypothesis and, in fact, that a great deal of evidence supports it.”76



Discussions at Prague

By July 1968 when Mitchell attended the meeting of the Federation of European Biochemical Societies in Prague, the theoretical view of oxidative phosphorylation had become even more complex. Paul Boyer had recently proposed a different approach to the mechanism, based on the ability of proteins to change shape (conformation) and in so doing to change their energy. Boyer suggested that, in the process of oxidation in the respiratory chain, the energy arising from the oxidation could be stored in the conformation of the component of the respiratory chain. The energy could then be transferred to an adjacent ATPase enzyme. This ATPase could then use this conformational energy in the synthesis of ATP. Thus the need for a high-energy intermediate chemical substance is avoided, but otherwise the proposal shared many aspects of the chemical theory. The view was supported by a number of the properties of mitochondria, which could be shown to undergo changes in shape when carrying out energy-dependent reactions. It was also supported by some aspects of Boyer’s studies on the ATPase, which ultimately proved of great significance. At Prague, Slater reviewed the energy conservation mechanisms of oxidative phosphorylation and concluded in relation to the now three contending theories: There are at present three hypotheses concerning the nature of the primary energy-conserving process. I still favor the chemical hypothesis although . . . it does not give a satisfactory explanation

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for the multi-component respiratory chain. Mitchell’s chemiosmotic hypothesis is in many ways attractive and it has stimulated much discussion. In my opinion, however, the experimental evidence is against the basic postulates of the hypothesis, and the thermodynamic difficulties are even greater than with the chemical hypothesis. The conformational hypothesis first proposed by Boyer and recently supported by Green et al., is formally rather similar to the chemical hypothesis. . . . At present the hypothesis . . . is an attractive speculation without much experimental support.77 The Swedish biochemist, Lars Ernster, in his opening remarks at the symposium, noted that “the chemiosmotic hypothesis of Peter Mitchell . . . has stimulated a great deal of experimentation and discussion— perhaps more than any other hypothesis has done in this field of biochemistry.”78 Clearly, Mitchell had succeeded by a variety of means in focusing attention on his proposals. For all his undoubted success as an advocate for the hypothesis, he had still failed to persuade the majority of bioenergeticists that this was more than an interesting, albeit stimulating, proposal. Nevertheless, as Ernster and Schatz later viewed it, the “chemiosmotic decade” had now begun. Such activity had begun to take its toll on Mitchell’s health. As he remarked: “The fact is that I have to be a little careful about my health when I am travelling abroad—otherwise I would be more able to enjoy, and stand up to the wear and tear that necessarily accompanies travelling schedules with lectures etc.”79 It was not only a matter of health and the strain of traveling. What some members of the field have regarded as “lively debate” was sometimes a personal attack. Others also noted Mitchell’s treatment on some occasions. After a meeting in Chicago in 1967, Lipmann had written to Mitchell, “I was appalled by the treatment some of our colleagues gave you at the luncheon.”80 The advocacy of the chemiosmotic theory was not without its cost. Mitchell felt unable to attend the International Congress of Biochemistry to be held in Tokyo in August 1967 and wrote to Greville: Tragedy of tragedies—I am sorry to tell you that I shall not be going to Tokyo after all. Pressure of work, a wish to avoid mud slung from various directions (not to mention the low countries), ulcerous grumblings, and general harassment have unfortunately led to this decision. Needless to say, I shall greatly miss our projected oriental tour.81

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In fact, ill health dogged Mitchell’s life over the whole of his time at Glynn. Nevertheless, Mitchell did happily travel for pleasure. From about 1966, together with Helen and the children, he took holidays in Greece in the island of Skiathos during the summer for periods of about eight weeks. In 1968 Mitchell, who loved Greece and its people, bought a house on the island and renovated it by adding a large terrace that gave a fine view of the Aegean Sea. If conferences occurred during these vacations, he flew from Athens and returned to Greece.



A Successful Period

In the five or so years since Mitchell and Moyle had initiated experiments at Glynn, the institute had established itself on the international scene. Biochemists working in, or simply interested in, the field of oxidative phosphorylation, including biochemistry undergraduates, had become aware of Mitchell’s work. Although it was relatively remote, Glynn had attracted many visitors for discussions and, in some cases, for joint experimental work. The collaboration between Mitchell and Moyle was also clearly a success, with Mitchell leading on theory and to a large extent Moyle leading on experimental work. In June 1969 it was noted that no fewer than twenty-two articles from the institute had been published. Mitchell was able to report that “he felt that the Company could claim credit for revolutionizing the field of oxidative and photosynthetic phosphorylation within the short space of five years.”82 Although such a positive conclusion was fully justified, there were other less satisfactory aspects. Several very senior workers in the field were totally unconvinced by Mitchell’s hypothesis, including, notably, Chance, Ernster, and Slater. Another problem was the institute’s finances, which were not seen by Mitchell himself as a serious problem but were nevertheless somewhat unsatisfactory. In most years during this period the income from investments and other sources (including a grant from the Royal Society for a double beam spectrophotometer) rose but less than the rise in expenditure. An appeal for funds posted in the Times of London had failed to produce results. However, a substantial rise in the stock market during this period led to a healthy increase in the value of investments. All in all, Glynn Research Limited and Peter Mitchell in particular were now fully established and recognized internationally.

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8
Exploring the Implications of the Theory 1969–1973



Facing the Opposition

While Mitchell had put forward his chemiosmotic theory with a feeling that it could well be proved wrong, by 1969 he had acquired a certain amount of confidence in its validity. It is true that in conversation with others he openly discussed the importance of finding experiments that might prove the theory wrong. Nevertheless, there were indications at the annual general meeting of Glynn Research Limited in June 1969 that he believed he had solved the central issue of oxidative phosphorylation. These became much clearer at the New Year 1970 meeting of the council of management, a formal meeting between Mitchell, Moyle, and the company secretary. It was recorded: The Chairman [Mitchell] reported on the success of the organization’s research policy: the concentration of attention on a limited but fundamental area of biological research, namely the problem of oxidative and photosynthetic phosphorylation. He now considered it likely that the organization’s useful participation in this field of activity would naturally come to an end in the next few years.1 A termination date of 1 October 1972 was suggested, at which point the company would formally turn its attention to another problem. While Mitchell was confident in his theory, most of the rest of the field were not. Certainly, the theory was now being taken very seriously by those working in oxidative phosphorylation, and particularly those in photosynthesis, but there was nevertheless a strong affection for the chemical theory and a distrust of the physiological principles underly-

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ing the chemiosmotic theory. As Guy Greville had outlined in his review, the leaders of the field were not prepared to do more than discuss the proton motive force and its shortcomings. Mitchell’s confidence led him to face the problem of convincing his colleagues that the central mechanism of oxidative phosphorylation involved the translocation of protons across the mitochondrial membrane and their return through the ATPase. He published a number of papers during the period, expounding different aspects of the theory, particularly the ATPase. However, converting his fellow bioenergeticists proved no easy task. Indeed, the controversy has been described as the “ox phos wars” in which the debate was often heated and sometimes acrimonious. Efraim Racker gently commented, “Peter’s ideas have not been treated too kindly by the investigators in the field.”2 Numerous articles were published by others, describing experiments that were claimed to be in conflict with Mitchell’s hypothesis. Generally, Mitchell was able to interpret these results in terms consistent with his theory. This battle continued during the late 1960s and most of the 1970s, with Mitchell and Moyle adding experimental evidence to support and strengthen their position. Thus, in a major review from Slater’s laboratory, Karel van Dam and Alfred Meyer noted that, despite an enormous number of articles published between 1968 and 1970, it was “not possible to make a more definite choice between the different theories than it was two years ago.” The field was progressively becoming bogged down in an increasingly personalized battle about the mechanism of oxidative phosphorylation. At the end of their review, van Dam and Meyer sounded a warning note, quoting the Greek philosopher Myson: “It should not be our aim to explain facts in the light of arguments but to argue on the basis of facts.”3 By contrast, a contemporary review of photosynthesis concluded that a proton gradient was the most likely candidate for the link between electron transport and phosphorylation. This was “based on the experimental successes and the predictive value of Mitchell’s chemiosmotic hypothesis.”4 Indeed, the photosynthesis field was from the time of André Jagendorf’s acid bath experiments much more relaxed about accepting Mitchell’s theory; of course, these researchers did have more problems to concern them, particularly the mechanisms by which light energy could effect electron transport. In addition, almost all those in the photosynthetic field did not have the same personal commitment to the chemical theory as did those who were working in the oxidative phosphorylation field.

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Mitchell’s personal reaction to the situation was twofold. On the one hand, he deplored the failure of his colleagues to proceed by cool rational argument and their tendency to personalize situations, a position that caused him to think hard and deep about the nature of communication between scientists and between humans generally. On the other hand, his robust intellect made him on occasions condescending, and there was an aspect of his character that relished an argument in which he himself could become quite aggressive. This latter trait did nothing to cool situations that were already tending to become somewhat passionate. In an answer to a request that he should contribute a chapter to a book, Mitchell expressed some of his impatience about the way in which he felt the field was flawed, especially in the underlying theoretical approach of his fellow workers. He agreed to write the chapter, “provided that there seems to be a reasonable chance that the volume will actually help to clarify some of the fundamental issues which have tended to remain clouded by silly squabbles and idiotic misrepresentations of the simple facts in the past.”5 Mitchell’s new confidence in his theory also led him to look more seriously at the wider implication of the chemiosmotic principles, which he had earlier predicted might have a major role in transport across cell membranes, particularly transport of foodstuffs into cells.



The Bari Conferences

Beginning in 1965, bioenergeticists from around the world gathered annually in southern Italy for a meeting to discuss problems in the fields of mitochondrial metabolism, oxidative phosphorylation, and photophosphorylation. Mitchell attended some of these meetings but by no means all of them. In 1969 he attended the conference that met at Fasano south of Bari. The introductory paper was given by Bill (E. C.) Slater and colleagues, who noted how difficult the problem of oxidative phosphorylation had proved: One of the major unsolved problems of biochemistry—and one that has been with us for a long time—is the mechanism by which energy made available by oxido-reductions in the mitochondria of animals and plants, the chloroplasts of green plants . . . is conserved in a utilizable form. For many years it was customary at opening sessions of International Congresses of Biochemistry to

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predict that this problem would be solved before the next congress. No one made this prediction at the last International Congress in Tokyo. Apparently the problem is more difficult than originally envisaged.6 Slater et al. reflected on the nature of the high-energy intermediate in oxidative phosphorylation, which they termed “energy pressure.” This might be a chemical substance, a proton gradient, or a conformational change in a protein. They admitted that there was a distinct weakness in the chemical theory and that the total failure of experiments designed to find the chemical intermediate was turning people away from the theory that he himself had proposed in 1953. Referring to this theory, they commented: Spectacular claims to have isolated the corresponding intermediate of NAD and cytochrome c, soon followed by the withdrawal of these claims, have led to a swing of the pendulum away from this hypothesis, and have focussed attention on others, at first the chemiosmotic hypothesis initially proposed in 1961. A third working hypothesis, favored at present by many workers in the field, is that the energy of redox reactions is primarily conserved in a conformational change of a respiratory protein.7 Thus the conformational theory was proving particularly attractive during this period. It should be noted that both the chemical theory and the conformational theory had no difficulty in accounting for the pumping of protons across the membrane as a side reaction in oxidative phosphorylation. Indeed, any theory had to account for the pumping of ions such as calcium into mammalian mitochondria, which was generally seen as a secondary process to that of oxidative phosphorylation. It was not difficult also to regard proton movements as secondary to the process of oxidative phosphorylation, rather than as the core of the mechanism as Mitchell had proposed. The opening session of the conference in 1969 was chaired by Mitchell. In the first paper, Bob (R. J. P.) Williams gave a version of his theory in which protons played the central role but in which conformational changes, chemical intermediates, and proton gradients had a place. Compromise proposals such as this rarely made much headway in the field. Elsewhere in the conference Williams pointed out the similarities of his proposals to those of Mitchell but stressed their differences. Mitchell and Moyle considered aspects of their theory in a

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single paper that concentrated on the process of proton transfer by the cytochrome oxidase, which would require an additional hydrogen carrier.8 Overall, the conference did not give too much support to protonbased theories. Williams recalled that at one session the principal workers in the field occupied the front row of the lecture hall and totally monopolized the discussion. Both he and Mitchell were farther back. Williams eventually intervened to say that there were many other people in the hall who might have valuable contributions to make but were unable to get a hearing. The intervention did not seem to have a great effect. While Mitchell and Williams were able to make common cause in such meetings, which tended to be dominated by those supporting chemical and conformational theories, they tended to part company rather easily when considering details of their proton-based theories.



Peter Hinkle

The younger generation of biochemists interested in mitochondria and oxidative phosphorylation tended to be very much less antagonistic to Mitchell’s theory. They lacked the personal investment in the chemical theory that characterized many of the older generation and were prepared to think new thoughts. One such was a young graduate student, Peter Hinkle, in Racker’s laboratory in the Public Health Research Institute of the City of New York. Hinkle had met Mitchell, and been impressed by him, when the latter had visited Racker’s laboratory in late 1965. Hinkle wrote to Mitchell early in 1966, no doubt with Racker’s encouragement, inquiring about the possibility of working at Glynn and about the facilities that would be available. He explained that he had been an undergraduate at Harvard, where he had written a thesis on osmotic properties of the erythrocyte; he was married to an electrophysiologist. He had then worked with Racker on the mitochondrial ATPase, the enzyme carrying out phosphorylation in oxidative phosphorylation. Thus his background made him naturally sympathetic to chemiosmotic ideas. He suggested that at Glynn he might work on measuring the membrane potential directly. He obtained a National Institutes of Health Fellowship to work with Mitchell for a year and arrived at Glynn in October 1968 to join Mitchell, Moyle, and research fellow Peter Scholes;

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Robert Reid from York also worked at Glynn during this period but only on an occasional basis. Hinkle’s view of Glynn showed both its strengths and its weaknesses. He found Glynn very isolated but enjoyed his time there. Life appeared to proceed at a slower pace than in the laboratories he was familiar with in the United States; indeed, Mitchell discouraged work over the weekend. Rat liver mitochondria, the main material used for experiments, were prepared only twice or possibly three times each week, and a whole day was devoted to analyzing and discussing the previous day’s experiment. The laboratory was well equipped for studying proton and other ion movements. Mitchell had specialized in acquiring ion-specific electrodes in order to facilitate such studies. There was also everything necessary for growing bacteria and preparing mitochondria. Hinkle felt that the absence of facilities for the use of radioisotopes was a major limitation, however. Hinkle found Mitchell rather an isolationist, although perfectly capable of being very sociable and hospitable. He observed the close collaboration between Moyle and Mitchell. Moyle carried out the routine experiments, while Mitchell maintained equipment and also made instruments. During 1968 Mitchell built a double-beam spectrophotometer that worked satisfactorily but not very well. However, a new machine arrived during the final stages of construction of Mitchell’s machine, which he finished to satisfy himself that it would work. Experiments and work generally were discussed in detail by Mitchell and Moyle regularly. Hinkle was a particularly significant visitor to Glynn. Although he published an article on the effect of the membrane potential on cytochrome oxidase, of more consequence was the relationship he made with Mitchell. Thus, he became a much-needed interpreter of the chemiosmotic theory in the United States following his appointment at Cornell, where Racker and also Jagendorf were now working. Another significance of Hinkle’s visit was his interest in the philosophy of Karl Popper. From his undergraduate days Mitchell had developed a keen interest in philosophy and had been strongly influenced in his early years by Ogden and Richards’s The Meaning of Meaning. Hitherto Mitchell had been unaware of Popper, but on Hinkle’s recommendation he read the key books and eventually probably almost all of Popper’s published work. Mitchell was already by nature a Popperian in that, for some years previously, he had considered the chemiosmotic theory in terms of it being falsified rather than proved positively; that

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is, the theory might stand until it could be shown by experiments to be wrong. He therefore warmed to Popper’s writing, being particularly impressed by the notion of the three worlds—the physical world, the mental world, and the world of ideas in the objective sense; these concepts still fascinated him at the end of his life. He later placed his own gloss on these notions in “Culture of the Imagination,”9 a lecture given locally in Cornwall. However, several of his later works make reference to Popper’s Objective Knowledge: An Evolutionary Approach, which was originally published in 1972. In due course Popper joined David Keilin as the two men whom Mitchell most admired. Later Mitchell joined a group, which included Krebs and the economist Hayek, who unsuccessfully nominated Popper for a Nobel Prize.



Exploring the Implications of the Chemiosmotic Theory

The chemiosmotic theory arose out of the theoretical consideration of vectorial metabolism. In essence, its provenance was associated with the problems of transport through biological membranes. While oxidative phosphorylation and photophosphorylation were the initial areas of his interest, by the end of the 1960s Mitchell was returning to the consideration of the basic vectorial issues. Thus he turned to questions of transport of substances across plasma membranes into the cell and across the mitochondrial membranes into the mitochondrion. In 1963 he had indicated the association between chemiosmotic oxidative phosphorylation and transport across membranes. This he expanded in the 1968 Grey Book. Now he examined these processes from both a mathematical and a biochemical perspective, particularly group transfer reactions.10 By 1970 he was advancing on a broad front in cell bioenergetics. He demonstrated proton transport by two membranebound enzymes—the transhydrogenase11 in the mitochondrial inner membrane and the pyrophosphatase12 in photosynthetic bacteria. The process of active transport remained a concern. He considered the conservation of energy in oxidation and photosynthesis as a proton gradient and the use of that gradient to move substances across membranes. With Moyle, he was looking for experimental evidence for the arrangement of the respiratory chain into a series of three loops, as required by the 1966 formulation of the theory. At the annual Bari meeting in 1971, Mitchell discussed the position-

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ing of the components of the respiratory chain in and across the mitochondrial inner membrane. To account for the mechanisms he had proposed for the transfer of protons across the membrane by the chain, it was necessary that they were positioned to form the suggested loops.13 Another implication of the chemiosmotic proposals that Mitchell considered was whether protons might drive the motion of the bacterial flagellum. While he was correct in principle, the suggested mechanism fell well wide of the mark. He viewed the flagellum as functioning by a whiplike motion, the contemporary view, and proposed that it was a tube flexing under the influence of protons (or possibly sodium ions), which passed into the cell under the influence of the proton motive force.14 A little later, when the flagellum was seen as functioning by rotation, an American group demonstrated experimentally that the motion was due to the proton motive force.15 Mitchell returned to the subject in 1984, proposing a protonic motor in which protons would drive the rotation of the flagellum.16 Again, he pointed out that essentially the same mechanism could be adapted for sodium ions that by this time were known to drive flagella motion in some organisms.



The Third Grey Book

With the success of the first and second Grey Books well established, Mitchell turned to the production of a third in 1969. Like the previous one, it was intended “to make available . . . some useful recent developments in the knowledge of chemiosmotically coupled systems.” It concerned itself with a “biochemical description of coupling between oxidoreduction and phosphorylation by means of a proton current” and with “solute porters,” systems for transport of substances across cell membranes. It was dedicated to “my friend Guy Greville.”17 However, this third Grey Book, which was completed in December 1969, was never published, and the manuscript, prepared in clean copy, was filed away. Mitchell felt that “by then everything was moving so fast that I became very dissatisfied every time I wrote another part of it. It seemed to me to fall between two stools. It was trying to be too authoritative, and yet it would take too long to make it sufficiently compendious.”18 Nevertheless, with an average of about six publications a year over this period, Mitchell had adequate opportunity to expound his ideas in print.

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West and the Uptake of Sugars into Bacteria

Another young biochemist who had become fascinated by Mitchell’s robust intellectual style and particularly his views on bioenergetics was Ian West. West had obtained his doctorate from Oxford for research on phosphate uptake into a single-cell alga; he had found that one of the two authorities on phosphate uptake in the literature was Mitchell, who had worked on this problem in the early 1950s in Cambridge. On completion of his thesis, and on the suggestion of his aunt, who had known Mitchell in Edinburgh, West considered the possibility of working at Glynn. After a visit to Bodmin, both Mitchell and West concluded that it would not be right for him to join the institute. After a short period in London, West went to work with Wilfred Stein in Manchester. West’s intention had been to test Mitchell’s theory about sugar uptake in bacteria. In 1962 Mitchell had expanded on the implications of the chemiosmotic theory in a paper to a symposium of the Biochemical Society. He had argued that the uptake of sugars such as lactose, on which extensive work had been carried out in the Institut Pasteur, was driven by the proton motive force. The proposed mechanism was simply the transport of one proton into the cell with each molecule of lactose taken up. On arriving at Manchester, West was confronted with Stein’s claim that he had tested the theory and found it wrong. In fact, he had tested whether a sodium ion rather than a proton was transported. Later, while still at Manchester, West demonstrated that protons were taken up with the sugar. In 1970 he gave an account of this work to the Society for Experimental Biology, of which Mitchell was a member. Mitchell contacted him and invited him to Glynn to work on aspects of the chemiosmotic theory in bacteria, an invitation which West accepted. In the autumn of 1970, as Peter Scholes departed, West arrived in Glynn. West’s impressions differed slightly from Hinkle’s a year or two earlier. The farm was still operational, but Mitchell had handed over the running to a farm manager installed in the farmhouse attached to Glynn House. Now Moyle ran a mitochondrial experiment almost every day in which the mitochondria were prepared during the morning by her technician, Robert Harper. This preparation was allowed to stand over lunch, and the experiments were done in the afternoon. Moyle used the morning for analyzing and reviewing the previous day’s work. The reproducibility of Moyle’s experiments was one of the remarkable aspects of the institute’s work, although with hindsight this may have been due in part to the very regular timing of the day’s ac-

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tivities—the ability of mitochondria to transport protons declining progressively with time. At this stage, tea was a formal affair. The institute obtained boxes of Earl Grey tea from Fortnum and Mason, a leading London supplier, which also supplied the royal family. The milk was very rich, coming from the Jersey herd on the farm. During this period Mitchell realized that employees could be given luncheon vouchers for a sum of two shillings and sixpence, a significant sum at the time. This sum was not taxable, and Mitchell, disliking tax in principle, made vouchers available. Since Glynn was isolated, he also provided in the institute’s kitchen a variety of food on which the vouchers could be spent. Thus the staff made their own lunch but at the institute’s expense. West stayed until 1973, working mainly on the question of sugar uptake into bacteria but also looking at the bacterial ATPase. In bacteria, West and Mitchell confirmed Mitchell’s original suggestion of 1963 that the proton gradient would drive the uptake of sugars into bacteria. They found that a single proton passed into the cell with a molecule of the sugar, lactose. This finding resolved the puzzle of how cellular energy was used to drive the uptake of the sugar that was known to be strongly accumulated by the bacterium under suitable conditions. Indeed, it was already known that lactose could be concentrated in bacterial cells up to one thousand times the external concentration. Subsequently, the mechanism was found to operate in the transport of a number of sugars and other substances across bacterial plasma membranes. This research represented a valuable working out of the chemiosmotic theory in terms of transport of molecules into cells. It should be noted, however, that the mechanism is similar in principle to that proposed by Robert Crane for the transport of glucose, albeit with sodium ions across the mucosal cells of the intestine. Crane first outlined his mechanism at the Prague symposium in 1960 (see earlier discussion in chapter 5).



The Chemiosmotic Processes and Transport across Membranes

In the Bari conference in 1972 held at Pugnochiuso under the title “Mechanisms in Bioenergetics,” Mitchell returned to the discussion of transport systems. These he considered to have been his main field of interest and the chemiosmotic theory a by-product:

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The chemiosmotic hypothesis of the coupling mechanism in systems catalyzing oxidative and photosynthetic phosphorylation, with which my work has tended to be associated in recent years, was really an accident that occurred while I was endeavoring to develop a general theory of the mechanism of coupling between metabolism and transport in fundamentally orthodox biochemical terms.19 In contemporary biochemistry, Mitchell distinguished two theoretical approaches to the process of active transport across cell membranes. In the first, chemical processes of metabolism were considered separately from the osmotic (transport) processes of metabolism. Energy in some form was regarded as the means of coupling the energy-yielding reactions of metabolism to the energy-consuming processes of active transport. This approach, he noted, tended to emphasize a role for highenergy intermediates or high-energy conformational states that were associated with membrane proteins responsible for transport. In other words, transport was explained in terms of the ideas of the chemical or conformational theories of energy conservation. The alternative approach, which Mitchell had proposed in the years immediately after the first formulation of the chemiosmotic hypothesis, involved “downhill” diffusion (diffusion down an electrochemical potential gradient) of the substances transported. In the case of the transport of sugars like lactose into bacteria (e.g., Escherichia coli) by coupling the sugar to a proton, the proton gradient ensured that the sugar passed across the membrane. Indeed, Mitchell made his point by contrasting his work on sugar transport driven by a proton gradient to that of Adam Kepes, who had explained the energetics of this sugar transport system in terms of high-energy chemical intermediates. Mitchell’s chemiosmotic approach had provided a clear and relatively simple means of explaining how molecules might be transported in an energy-dependent way across membranes. These views had been supported by Brian Chappell at Bristol in a number of studies of transport of molecules into and out of mitochondria that had confirmed the existence of proton-linked transport systems. In bacteria, however, Mitchell felt that up to the early 1970s, these possibilities had been ignored until the work of Franklin Harold in the United States and William Hamilton in the United Kingdom.20 In consideration of transport across membranes, Mitchell also turned his attention to the cation-translocating ATPases and suggested

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schemes for the transport of ions such as calcium and sodium/potassium. He considered that the positively charged cation might be associated with the migration of the negatively charged adenine nucleotide in the membrane during the ATPase reaction. Overall, Mitchell was able to develop a variety of proposals based on the mechanisms inherent in his chemiosmotic theory. While some did not stand up to detailed examination, others, like those demonstrated experimentally by Chappell, have proved to have a more lasting value. A sodium/proton exchange (antiport) system that transported sodium out of bacterial cells was demonstrated by West and Mitchell and also proved to have a long-term significance.21



Personal Problems

Mitchell’s health remained a serious problem for him. In 1970 he suffered a recurrence of the ulcer problems that had caused him to leave Edinburgh. As he wrote to Racker, “I have been having a lot of trouble with my ulcers again, and I do not think it likely that I can continue with so many commitments in the future without more serious trouble.”22 On this occasion he was forced to cancel a trip to the United States where the International Congress of Pure and Applied Chemistry was to be held. Nevertheless, despite problems with his health, Mitchell continued to enjoy a variety of pursuits, including the restoration of old houses in Cornwall. He also took up sailing: “Recently we got involved in becoming the proud possessor of a thirty foot boat, and it looks as if we may get a bit hooked on sailing once the addiction has had time to set in.”23 Indeed, during this period the boat became a good distraction from the demands of the institute and his scientific work, and on occasion he spent a significant amount of time on it. The boat was kept at Cuilan, the bungalow refurbished by Mitchell on the south Cornish coast. This retreat with the opportunity for sailing provided a valuable means of spending time with the children. Eventually, the boat was sold and a larger boat acquired, but this second boat seems to have spent all its time on the grass at Glynn, where Mitchell would occasionally work on it. The second boat was sold in the late 1980s when Mitchell needed money. In the summer of 1972 Mitchell suffered a serious personal setback. For some time his hearing had been impaired, and he was wearing a

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hearing aid. The warm summer weather made his ears damp from perspiration, which resulted in an infection. Mitchell was almost completely deaf, and he sought medical treatment as a matter of urgency. He discovered that treatment locally in Cornwall would involve a substantial wait, and he therefore turned to a private clinic in London, where he could receive almost immediate attention. The experience turned out to be a nightmare for him. His relationship with the nurses was catastrophic, and he felt the standard of nursing to be abysmal. Much more seriously, the operation on his ear was a total failure: it not only destroyed his auditory system but also seriously damaged his semicircular canals. The result was traumatic: a serious infection followed, he found balance difficult and would occasionally appear drunk, he had noises in his ears that often made sleep difficult, and his vision was somewhat impaired so that he would walk into objects such as branches of trees. With time, he adapted to his new condition and the noises became less serious, but he remained seriously deaf for the rest of his life. He commented to Racker more than six months later, “I have recently become further incapacitated by the results of the bungled operation that destroyed my right labyrinth system and thoroughly traumatized my cerebral system last November. I am expecting to have to lay off intellectual work for a number of months.”24 Further periods of stress aggravated the condition, leading to terrible noises in his head that made it impossible to concentrate and forced him to take periods of rest. He considered taking legal action against the surgeon and was advised that he could sue for a large sum of money and would probably win. However, he was also advised against such a course because it would take a very long time to complete, it would cause him great inconvenience, and it would be costly. Mitchell accepted the latter advice. The effect of his condition did create a number of problems. Among these was an inability to participate in and appreciate music. While he was in scientific conferences, he could hear the main speaker possibly in part by lip reading, a skill that he acquired at least to some extent. The problem became serious during the ensuing discussion when contributions from those in the audience were frequently made with their backs to Mitchell. Nevertheless, he learned to cope with the situation, although his enjoyment of scientific meetings was now much reduced. Reading became even more important, and he found he could assimilate very thoroughly the contents of published papers. He also relied increasingly on letters that he felt had a value over

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direct face-to-face discussion. Because he had more time to compose questions and to make suggestions, the recipient also had time to consider what had been written. In any case, the relative isolation of Glynn meant that communication by letter was a valuable means of keeping in touch. However, there were times when his correspondence had a negative effect. Slater, for example, commented, “I am also becoming very fed-up with the discussion by correspondence that Peter seems to be able to devote so much time to. I can scarcely find time to read it, let alone sit down and write the sort of letter required to refute statements made by such a redoubtable debater.”25 The loss of his hearing was a very severe blow to Mitchell and seriously increased his fits of depression. He commented that he would have preferred to have gone blind rather than deaf. He deeply felt the impairment of his physical condition that curtailed his enjoyment of many activities such as music and water skiing.



Things Greek

During the 1960s Mitchell had acquired a house on the Greek island of Skiathos, where he used to retreat with the family for a month or so in the summer. This provided him with a necessary rest from the tensions and stresses of his work and the strenuous and often factious debates that were now taking place in the field of bioenergetics. Mitchell liked the Greeks and, as one colleague remarked, all things Greek. He admired the ancient Greek intellectual legacy; after all, he had benefited from that inheritance in his Cambridge days when he had discovered the work of Heraclitus, which fertilized and authenticated his own philosophical development associated with the notion of the fluctoid. He was also captivated by the charm and hospitality of the modern Greeks whom he met on Skiathos. Nevertheless, strains could occur. About a year after the ear operation, he learned that his neighbor in Skiathos had for some reason used explosives in carrying out some renovations of his property and that this was damaging Mitchell’s property. As a consequence, Mitchell decided he would need to journey to Greece. He booked himself through to Athens on the Orient Express, resulting in a journey that had significant problems arising from his deafness, particularly at night when he took off his hearing aid. One time he only realized that customs officials were banging on the door of his couchette because everything seemed

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to be bouncing about—he simply heard nothing. He soon learned the phrase “I am very deaf” in several European languages. In Skiathos he found that the neighbor was now using Mitchell’s water supply for the construction work. Worse, Mitchell found that the damage to his house was continuing. He knew that Greeks were not very susceptible to quiet persuasion, and therefore early in the morning he turned off the water supply to his neighbor and sat on the cover over the tap to await developments. In due course the builder arrived and tried to physically remove Mitchell. To Mitchell’s delight, the builder proved not strong enough to do so. Having won the first round, Mitchell and the builder went off in a car to talk about the situation. Initially, the conversation proceeded in English, but Mitchell insisted that it be continued in Greek and persuaded the builder to sign a paper agreeing to repair all the damage to his house. The event had for Mitchell a personal significance well beyond his property interests. It was an antidote to the depression that he had felt after the unsuccessful ear operation. It convinced him that he had at least partially recovered his physical capabilities and that he could continue to lead an almost normal life. Even so, as he wrote to Slater at the beginning of 1974, “I have difficulty now keeping up with the pressure of work that I used to find quite manageable.”26 Mitchell was, after all approaching his mid-50s.



The Phosphorylating Enzyme

One of the significant areas of interest in the early 1970s was the enzyme responsible for phosphorylation, a central component in the chemiosmotic theory. In oxidative phosphorylation (and photosynthetic phosphorylation), the phosphorylation itself, the synthesis of ATP from ADP and inorganic phosphate, is carried out by the ATPase (ATP synthase) enzyme. When formulating his theory in 1961, Mitchell had proposed that the extraction of elements of water (H+ and OH–) to opposite sides of the membrane would drive the synthesis of ATP. Later in 1966, he had formulated a more complex and sophisticated mechanism involving a high-energy intermediate (formed by the proton gradient), which would then be used for the synthesis of ATP. The proposal suffered from the inclusion of this high-energy intermediate, which seemed to

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resemble the compound suggested by the chemical theorists, although Mitchell himself insisted it was quite different. As already noted, Lipmann wrote to Mitchell suggesting he had taken a backward step in making these proposals. No doubt in part as a consequence of the criticism of Lipmann and in part because Mitchell was occupied with other predictions of his theory, he remained relatively silent in public on the mechanism of the ATPase for a few years. In 1970, as he told Paul Boyer, he had started a new paper on this aspect of the enzyme. In fact, a series of papers emerged during the early 1970s as Mitchell explored the mechanism of the ATPase. In the early 1970s, serious attention was being given to Boyer’s proposals that the link between the respiratory chain and phosphorylation was not a chemical intermediate and not an electrochemical proton gradient but protein conformational energy. Boyer was suggesting that the oxidations in the respiratory chain produced a conformational change in those proteins, and this conformational change stored the energy. Essentially, it was like winding up a spring (the protein), and the energy in the spring could be used to wind up another spring (the ATPase). The ATPase could then use its energy to form ATP. Mitchell’s response to these proposals was to accept the importance of conformational changes but to argue that they were not the means whereby energy was transferred. However, Mitchell was largely blind to the possibilities of a significant role for proteins, probably as a consequence of his Cambridge training. He expressed his view a year or two later: “As Vladimir Skulachev once said, one can explain biochemistry on the basis that ‘proteins can do anything’—hence the magical significance that has tended to be attached to ‘conformational’ notions.”27 Mitchell appears to have been inherently incapable of understanding Boyer’s viewpoint. At a meeting in Bristol in September 1973 on “Phosphorylation Reactions in Cell Metabolism,” both Boyer and Mitchell presented their views on the ATPase. Subsequently, Boyer took a conciliatory view of the meeting: I did feel some concern that the audience may have felt there was more conflict between your and our approaches than might prove to be the case. Your persuasive work and that of others you have stimulated does appear to make membrane potential deserve con-

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sideration as a precursor to conformational changes driving ATP synthesis.28 Such a gentle and conciliatory tone did not seem to find favor with Mitchell: I did not think that the audience at the Bristol meeting were at all misled about the fundamental differences between our points of view. Presumably it is incumbent upon us to present hypotheses of the coupling mechanism involved in the reversal of the ATPase without blurring the edges—otherwise the process of groping towards the most faithful model of reality would become even more uncertain and even more open to misunderstanding.29 The comment was followed by a statement of the characteristics of Boyer’s hypothesis compared with Mitchell’s own. Mitchell was now clarifying his position on the ATPase and differentiating his views from those of Boyer and also of Williams. Early in 1973 he had submitted a paper to FEBS Letters in which he had amended his views as set out in 1966.30 Returning to the original view expressed in 1961, he wanted to involve the proton directly in the process of ATP synthesis. Following work in Racker’s laboratory and elsewhere, the ATPase was now seen clearly as an enzyme in two parts, F0 and F1, each part having its own distinct function (see fig. 8.1). Mitchell saw the F0 part as allowing the proton to pass through the membrane to reach F1. In F1 the proton must in some way be involved in the synthesis of ATP. At this stage he retained his hypothetical intermediates, as set out in the 1966 account, as an optional mechanism for transporting protons across the membrane in F0. A year later he set out his full mechanism for the ATPase involving the proton directly in the reaction and abandoning any hypothetical intermediates. He now referred to the views of Williams and noted that the “lowering of pH in equilibrium with the reaction domain would

Figure 8.1 Mitochondrial ATPase. F0 transports protons across the membrane, and F1 synthesizes ATP.

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not, as originally suggested by Williams, cause ATP synthesis.”31 The 1974 article establishes the general form of Mitchell’s approach to the ATPase for the rest of his life. Not only is the ATPase a proton-translocating enzyme, but also the protons actually participate directly in the reaction. It left Mitchell in opposition to Boyer, who was now becoming prepared to allow for a role for protons in driving the synthesis of ATP but not to involve protons in the reactions at the catalytic site of the enzyme. For Boyer, the driving force for ATP synthesis was the conformation of the enzyme, although he would accept that the conformational changes could be brought about by an electrochemical gradient of protons. As Mitchell wrote to Boyer in 1973: I agree with your notion concerning the probable involvement of conformational changes in the action of the ATPase during ATP synthesis—but, as first indicated explicitly in the paper that I gave to a Biochemical Society symposium ten years ago, my view differs from yours in that I regard the conformational changes as a result of cooperative interactions with the enzyme-substrate complex between H+ ions that pass through the complex under the influence of a proton motive force.32 Boyer’s own view was more relaxed. He saw a possibility of combining Mitchell’s overall proton electrochemical gradient approach with his own conformational approach to the enzyme itself. As he wrote a little later in reply to Mitchell’s approach, quoted above: Our results are not necessarily in conflict with the concept of the chemiosmotic model that a potential gradient might be the energy conserving mechanism. There may be a number of ways in which membrane potential could induce conformational change. However if ATP is made with little energy input but is tightly bound at the catalytic site, it does not appear as appropriate to suggest mechanisms in which the passage of protons induces formation of the covalent structure of ATP.33 For most workers in the field, the choice was between Boyer’s view and that of Mitchell. Those who had long espoused the chemical theory and were suspicious of the chemiosmotic theory tended to shift their allegiance to the conformational views of Boyer, which conceptually was closer to the old chemical approach and easier for most biochemists to appreciate.

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Correspondence with Williams

The reference to the work of Williams, noted earlier in this chapter, was long ignored by Mitchell in his published work, and this fueled the dispute between the two. The correspondence in 1961, which had ended in discord, has already been discussed in chapter 5. There was also a short exchange in 1966 about the ATPase after Mitchell had sent Williams a copy of the first Grey Book. Then Williams had responded by noting that Mitchell’s views were now nearer his own and regretting that Mitchell had not made reference to the earlier correspondence. The discussion resurfaced after the publication of Mitchell’s 1973 article on the ATPase. Mitchell’s view of the discussion is represented by a comment in a letter to Williams: “Basically I don’t understand why you feel that my hypothesis is indebted to your notions, when we have generally found ourselves during public discussion taking up quite different positions.”34 Williams felt that the correspondence in 1961 had contributed to Mitchell’s development of the chemiosmotic theory and that Mitchell had never been willing to admit the point. Thus much of the argument in 1973 was about Williams’s wish to publish the 1961 correspondence, a step to which Mitchell was unwilling to accede. Williams’s feelings are perhaps represented by the following note to Mitchell: I do not claim chemi-osmosis as my idea. (I happened to think it up independently of you. I discussed the placing of enzymes in membranes with you freely . . .). The reason I am teased by you (and always will be) is that I regard your publication in 1961 as a dishonorable act (that is a personal judgement). I was prepared to forget it—eventually—as I regard your work with esteem and learn from it. However when you have in your possession all my letters and know my work and when you write “history” as you do, you re-open my old wounds. I cannot let such a mash of halftruth about my work stand without a fight. . . . Just publish all our letters and let the world decide between us.35 However, Mitchell persisted in being unwilling to publish the letters and, in effect, blocked an attempt at publication during the 1980s, although Williams did publish some material after Mitchell’s death. In an article published in 1975, Williams explained that the letters of 1961 and his paper were written before Mitchell had published his chemiosmotic theory. Williams then wrote:

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It is important now to see how an apparent extension to a theory based on osmotic energies [Mitchell’s 1961 paper] has come to resemble . . . a theory based upon a high local concentration of protons in a membrane [Williams’s 1961 paper], for throughout the debate I have pointed out that even if osmosis were involved it is necessary to pass the proton at high effective pH back through the ATPase.36 Thus the position adopted by Mitchell in the mid-1970s appeared to Williams to be essentially that outlined in Williams’s theory of 1961 and discussed at length in the extensive correspondence of 1961. Such a view was always unacceptable to Mitchell. However, Slater pointed out that while Williams “and Mitchell both brought forward the idea of the involvement of protons in 1961, . . . it was Mitchell who developed it in 1966 as a coherent theory.”37 In any event, neither Mitchell’s nor Williams’s views on the mechanism of the ATPase have stood the test of time.



The Turning Tide

In the year 1973 there was growing evidence that the tide of biochemical thinking was now beginning to move strongly in Mitchell’s direction. The number of requests for Mitchell to attend international meetings as a key lecturer was increasing. Racker put extensive pressure on Mitchell to contribute to a book on bioenergetics and was willing to accept more or less anything that Mitchell was prepared to write. David Green planned a symposium at New York and not only sought Mitchell as a participant but also as a co-organizer. Indeed, the symposium was advertised as jointly organized by Green and Mitchell. In the end, Mitchell did not feel able to attend or to contribute to the organization. Hinkle, who did attend the conference, felt that the meeting was not a success due to Mitchell’s absence, which disappointed many participants. Another event to influence the field occurred in 1973. A protein from bacteria (bacteriorhodopsin) had been shown by Walther Stoeckenius to pump protons when activated by light. Racker and Stoeckenius succeeded in combining this protein with the ATPase in a vesicle so that they could obtain ATP synthesis when illuminated by light, thus demonstrating the operation of the chemiosmotic process. This impressive experiment influenced many, particularly outside the immediate

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field, in favor of the chemiosmotic theory, although those directly involved in mitochondrial work were more resistant. As Mitchell wrote to Stoeckenius: I feel your work will do much to help promote interest in the chemiosmotic type of coupling mechanism outside the classical arena of oxidative and photosynthetic phosphorylation where the simple scientific realities still tend to be rather obscured by the dust and smoke of ancient battles, and the young warrior fears to enter the arena because of the general din and unpleasantness of it all.38 The year 1973 was also a time when Mitchell was considered very seriously for election as a fellow of the Royal Society, although his name may have arisen earlier in this context. On this occasion one fellow consulted on the matter wrote: I have thought very hard about your request concerning him [Mitchell] and believe that election would be premature at this time. He did not initiate the chemiosmotic theory, see for example, Comprehensive Biochemistry, 22, Bioenergetics, p. 189. Nor has he shown conclusively that it is the explanation for situations such as oxidative phosphorylation, photosynthesis, etc. In the absence of a major theoretical or experimental finding which could be uniquely associated with his name, I feel that election would be inappropriate at this time, although I profoundly hope that this will change in the future.39 The article quoted was written by Mitchell himself, and on p. 189 he referred to the work of Davies, Krebs, Conway, and Robertson. As already discussed, at the time of the first formulation of the theory there was some dispute about its originality. Such disputes were not easily forgotten. One year later, at the end of 1973, the same fellow responded to a similar inquiry, indicating that he had changed his mind: What every one now calls the “chemiosmotic hypotheses of oxidative phosphorylation” is central both to the way ATP is made and also to the mechanism of ion transport across membranes. Whereas the idea of this did not originate with him, he has done so much work himself and has stimulated so much work in others, that I now support his election. The recent international Congress

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of Biochemistry at Stockholm showed clearly that his work has had a very major effect on developments in this field.40 Mitchell’s election to the Royal Society, the principal accolade for a British scientist, was announced in 1974. Another fellow felt in retrospect (after the award of the Nobel Prize) that the election had become rather urgent, lest Mitchell’s work would be recognized by the Nobel Committee before it was recognized by the Royal Society. Despite Mitchell’s undoubted rise to scientific respectability on the basis of his proposal of the chemiosmotic theory, the field still remained uncertain about whether the theory really did represent the mechanism for oxidative phosphorylation. In the Biochemical Society’s Sixth Keilin Lecture delivered by Bill Slater in 1974, there was still uncertainty about the chemiosmotic theory, although Slater, the principal proposer of the chemical theory, was prepared to allow his own hypothesis to fall into oblivion: The gathering conviction that the high-energy intermediates in the sense envisaged in my 1953 hypothesis do not exist and the intellectually satisfying structure built up, with great brilliance and originality, by Peter Mitchell around the basic concepts of the hypothesis have persuaded many of its fundamental correctness. . . . We should at least keep open an alternative view. Implicit in my 1953 hypothesis is the formation of a covalent bond between a component of the electron transfer chain and a ligand. In 1964 Paul Boyer proposed that the energy is conserved in a conformational change of the protein of the electron carrier, without formation of a covalent bond. As a matter of fact there are sufficient common features of the chemiosmotic and conformational hypotheses, and also of an earlier one by the last Keilin lecturer, R. J. P. Williams to warrant an attempt at a unitary hypothesis which I have made elsewhere.41 Many of the chemical theorists had, like Slater, felt that the conformational theory had experimental support, at least in terms of the mechanism of the ATPase. Impressed as some of them had become with Mitchell’s views, they felt that the conformational theory had to receive at least as much serious consideration as the chemiosmotic theory. As far as unitary hypotheses were concerned, Mitchell simply did not like hybrid theories that he felt obscured the key issues.

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New Fields for Glynn?

The future of work at Glynn remained an open question. Mitchell felt that the central problem of oxidative phosphorylation had now been solved by the chemiosmotic theory. The evidence for the theory had been gathered, and the original problem selected for the work of the institute must therefore shortly be concluded. In 1970 it was thought that work on the chemiosmotic theory might be closed in October 1972. This date was later adjusted to September 1975. In the early 1970s there remained the question of what problem or even problems should be pursued. Were there other issues in the general field of biochemistry that should be tackled, or should a different field within human affairs be selected? Mitchell regarded the term biology, as used in the memorandum and articles of incorporation of Glynn Research Limited, as covering most activities involving Homo sapiens. Certainly, this included human relations, human communication, and aspects of economics. He even toyed with the possibility of running a biochemical study alongside one of the studies of humanity (his terminology). Other aspects of the institute’s life were also subject to review during the early 1970s. Mitchell had leased part of Glynn to Glynn Research Limited to accommodate its work. The original seven-year lease was due for renewal in 1971. At this stage, the council of management, consisting of Mitchell, Moyle, and the secretary, Stephanie Key (née Phillips), considered the possibility of finding alternative accommodation. A new factory unit owned by the Bodmin Borough Council on the Walker Lines estate was discussed and costs were determined. It was concluded that, despite the many costs of upkeep, including that of the very long drive to the institute, the costs at Glynn were lower than those that would be incurred if the institute moved to a new site. Costs remained a matter of concern. Even so, the total endowment of the company had increased during the nine years 1964–1973 by 133%, from £240,000 to almost £560,000, as a result of the rise of the stock market. Indeed, the endowment increase would have been greater had not a considerable portion of the funds been invested in equipment so that it was no longer capable of earning interest. Nevertheless, expenditure exceeded income. Annual deficits were beginning to rise to levels that gave some concern to Mitchell and also to the financial adviser. From 1970 to 1973 the recorded deficits at the annual general meeting of Glynn Research Limited were £4,000, £7,000, £8,350, and £10,054, respectively. Discussions took place regularly about ways of at-

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tracting more money. The company’s portfolio of investments was rearranged to obtain more income, particularly as it was felt that potential donors could be very critical of a failure to manage the investments to maximum advantage. In 1974 salary costs were in the region of £15,000, covering Mitchell, Moyle, and Key, together with technicians Roy Mitchell, Robert Harper, and Alan Jeal. Library costs were tending to soar, and subscriptions to journals were being cut as a part of the attempt to contain expenditures. Despite the problems of finance, money was not a major preoccupation during this period. West, who left in 1973 to take a post at Cambridge, had been supported on a Science Research Council grant. The remainder of the grant was transferred to David Osselton, who came to Glynn in October 1974 from Harold Baum’s department at Chelsea College, London. Glynn continued to have a steady run of visitors from abroad and frequent visits from the bioenergetics group at Bristol University. Mitchell felt concerned to maintain links between the institute and the rest of the bioenergetics community. Thus a threat of cuts to the rail service to the local station (Bodmin Road, later Bodmin Parkway) produced a protracted correspondence between the institute and British Rail, and the institute appeared to be successful in their lobbying. A problem of a different sort was the threat to route a new trunk road through Glynn valley, and this was strongly opposed by Mitchell and Moyle; eventually that threat also receded. Such problems were minor. Research was proceeding with considerable success. Overall, Glynn was now regarded around the world as an important center for the study of bioenergetics.

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9
Getting the Arithmetic Right 1974–1976



Recognition

The year 1974 marked the recognition of Peter Mitchell as a leading scientist who had made a significant contribution to his field of interest. No particular event seems to have triggered this. Simply, the scientific world had become conscious that, at the very least, Mitchell might be right about the mechanism of oxidative phosphorylation. Even if this were not true, he could still be credited both with stimulating the debate on the subject and with promoting a good deal of experimentation. In addition, he had contributed significantly to the field of active transport across membranes. It was also true that an increasing number of scientists were convinced of the validity of the chemiosmotic theory. The championing of his chemiosmotic theory, together with the extensive experimental evidence he had gathered with Jennifer Moyle, was now paying dividends. In the spring of 1974 Mitchell’s election as a fellow of the Royal Society was announced, and he was formally admitted in April of that year. The British Biochemical Society also felt that his work should be recognized and awarded him the society’s CIBA medal and prize given “for outstanding research” and endowed by the Ciba research laboratories in 1964. These marks of success seem to have created something of a feeling of euphoria at Glynn. Mitchell felt that the awards were in part a consequence of the loyal work of the staff, and almost everyone was promoted: Moyle to a senior research fellow, Roy Mitchell from technician to research assistant, Harper to chief technician, and Jeal to technical assistant. Stephanie Key was promoted from secretary to secretary

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and research director’s assistant. All of these promotions were associated with a salary increase.



Electrical Independence

The year 1974 saw an unexpected problem for Glynn. Industrial unrest in the United Kingdom led to severe power shortages, and the government instituted a three-day workweek to conserve power. Work at the institute continued, but under some difficulty. Perhaps more serious was Mitchell’s farm, where there were one hundred cattle, with a requirement to milk sixty cows twice a day. Although a farm manager was employed to care for the farm, Mitchell continued to take a very close interest in the agricultural side of his activities. Power shortages were a problem for the farm. Probably stimulated by this situation, Mitchell considered the possibility of generating his own electricity. Earlier he had attempted to use the stream near Glynn for a waterdriven generator. Now he explored the technicalities of wind-driven generation. A suitable wind-driven generator would require a tall structure located in a prominent place to catch the wind. Thus planning permission would be needed from the local authority. Mitchell planned a windmill and paid particular attention to the design of the sails, and he felt he had devised a new and efficient shape. However, his brother, an engineer, pointed out that, although the design was indeed efficient, it had originated in Victorian times. This event illustrates Mitchell’s tendency to solve a problem without first finding out if solutions already existed. With the help of a Bodmin surveyor, Mitchell applied for permission to build a “traditional Dutch-type windmill for generating electricity (approximately 50 kW) for dairy farm and agricultural storage purposes.” The parish council supported the application, noting that “this is in the nature of an experiment for the production of electricity.” He wrote to a fellow scientist in Australia: I have just managed to obtain an indication from the Planning Authority that planning approval may be forthcoming for a 50-foot high windmill on the farm here. The mills of the local authority grind rather slowly, so formal Planning Consent if we get it, is not expected in under three months. . . . I am expecting to obtain up to about 50 kVA during the windier part of the season.1

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The North Cornwall District Council approved the application, although the project never seems to have proceeded. It is noteworthy, however, that this development preceded commercial wind-driven power generation, which later became a serious activity in Cornwall.



Charting Success

The Biochemical Society’s award was associated with a lecture, and Mitchell delivered the ninth CIBA Medal Lecture at the society’s meeting in London in December 1974. He drew attention to the Curie principle that had fascinated him in the early 1970s. In Mitchell’s terms, the principle was expressed as “effects cannot be less symmetric than their causes” and was derived from the discovery of the piezoelectric effect by Pierre Curie and his brother Jacques around 1880. For Mitchell, the significance of the principle related to the fact that the asymmetric proton gradient across the membrane should reflect an asymmetry in the arrangement of the respiratory chain in the membrane, since the chain was responsible for forming the gradient. The lecture dealt with group translocation and vectorial issues that had occupied him in the late 1950s and an account of the chemiosmotic theory. Inserted into the middle of the lecture was a diagram (see fig. 9.1, where the final version is shown, including later additions), which set out the growing acceptance of the theory as Mitchell saw it. Referring to the diagram he wrote, “I have plotted an assessment of the attitudes of some of the principal protagonists based on that given by the late Guy Greville in his excellent scrutiny of the chemiosmotic hypothesis.”2 Mitchell recalled: When I first began to develop and advocate the chemiosmotic view of oxidative and photosynthetic phosphorylation in the early 1960s, the four fundamental postulates were almost entirely hypothetical, [and] many of my most distinguished and respected colleagues . . . were persuasive supporters of coupling through energy-rich chemical intermediates and coupling factors. . . . However although there is now a relatively widespread acceptance of the chemiosmotic rationale in the field of photosynthetic phosphorylation, where there is a strong biophysical tradition, there has been more resistance in the field of oxidative phosphorylation.3

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Figure 9.1 Mitchell’s diagram showing the acceptance of the chemiosmotic theory among a selection of senior bioenergeticists. The position of Williams in this diagram probably reflects the antagonism between the two. From P. Mitchell, “Bioenergetic Aspects of Unity in Biochemistry: Evolution of the Concept of Ligand Conduction in Chemical, Osmotic, and Chemiosmotic Reaction Mechanisms,” in Of Oxygen, Fuels and Living Matter Part 1, ed. G. Semenza (New York: John Wiley & Sons, Ltd.). Reproduced with permission of John Wiley & Sons Limited ©1981.

The diagram showed the conversion, in Mitchell’s view, of four biochemists over the previous four years, including Efraim Racker, Sergio Papa, and Vladimir Skulachev, and, in the photosynthetic field, Mordhay Avron. More significant, by 1973, seven of the most senior leading workers in the field of oxidative phosphorylation still supported other theories. However, the chart did not include a number of younger bioenergeticists, particularly in the U.K., who found the

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chemiosmotic theory an entirely reasonable approach to oxidative phosphorylation. There are problems with the chart. It implies a switch from the chemical theory or “direct interaction coupling” to the chemiosmotic viewpoint representing a simple choice made by workers. However, the proposal of a conformational theory by Boyer, originally in 1964, had found progressive acceptance among many. This was particularly true of those who were forced to abandon the chemical theory but felt unable to ally themselves with the physiologically based chemiosmotic approach. It is primarily the conformational theory that is covered by the term “direct interaction coupling.” Indeed, by the mid-1970s the conformational theory had become the principal haven for the antichemiosmoticists. It would also be an error to regard the acceptance of the chemiosmotic theory as marking the total demise of its competitors. The conformational theory certainly lived on, forming the basis for the understanding of the function of the ATPase, a contribution recognized by the award of a Nobel Prize to Paul Boyer in 1997 (shared with Jens Skou and John Walker). Douglas Allchin, the philosopher of biology, also felt that “there was no single solution to the problem(s) of ox phos; there was only resolution among originally competing, over-lapping explanations. One must jettison the either-or, or winner-take-all terms of most models of theory-choice.”4 Even so, it is difficult to see that the chemical theory made a significant contribution to the understanding of oxidative phosphorylation that emerged at the end of the twentieth century other than providing perhaps the greatest stimulant for experimentation over the 1950s, 1960s, and early 1970s. There is some evidence that the diagram was an oversimplification of the situation in another respect. When the sociologists Nigel Gilbert and Michael Mulkay looked at the movement toward the acceptance of the chemiosmotic theory by interviewing a range of participants in bioenergetics research, they obtained a more complex picture. They felt that in presenting the steady upward curve of acceptance of the theory, Mitchell had, in fact, simplified the true picture. A rather different picture would be obtained if those working on photosynthesis were separated from those in oxidative phosphorylation. Further, researchers’ positions were much more complex and “the identification of individual scientists’ views by other participants is a complex and potentially variable interpretative achievement.”5 In contrast, Mitchell’s own views on

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the work of the sociologists were, like those of most scientists, somewhat critical. Although he strongly favored such interest, he felt that they were “not well-informed” and gave far too little weight to experimental evidence in their considerations. Mitchell’s diagram also seemed to cause some offense. The personal identification of those for and against the chemiosmotic rationale was not altogether welcome among Mitchell’s fellow workers. At least one senior bioenergeticist felt that it was in “bad taste.”



Efraim Racker

The conversion of one of the senior American bioenergeticists, Ef Racker from Cornell University, to the chemiosmotic approach was a significant development. In the earlier years the Americans had been less influenced by Mitchell’s ideas than those working in bioenergetics in the United Kingdom. In 1975, Racker was invited to deliver the ninth Hopkins Memorial Lecture to the Biochemical Society meeting in Liverpool. Although the title of his lecture was “Reconstitution, Mechanism of Action and Control of Ion Pumps,” Racker initially considered the history of oxidative phosphorylation from Keilin through to Mitchell (see fig. 9.2). He recalled the early formulation of the chemiosmotic hypothesis and somewhat tongue in cheek commented that Mitchell had denounced proposals for the existence of intermediates that couple oxidation to phosphorylation, and replaced them by a proton motive force, which consists of two components, a hypothetical proton gradient and an imaginary membrane potential. Given the general attitude of the establishment, these formulations sounded like the pronouncements of a court jester or of a prophet of doom.6 He went on to note that there had been a number of published experiments that were claimed to disprove the chemiosmotic hypothesis and which could not be repeated in other laboratories: “On the other hand, the chemiosmotic hypothesis rose from each of these burnings like phoenix with increasing strength, and soon it became a favorite tool in the design of experiments.”7 The lecture concluded with a comment on the scene as it was in 1975. Racker felt that not only was it difficult to decide on theories but also it was difficult to determine what were the facts about oxidative phosphorylation. He quoted the physical chemist George Scatchard:

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Figure 9.2 Efraim Racker’s cartoon of key persons in the history of bioenergetics. David Keilin rediscovered cytochromes and developed an understanding of the respiratory chain. He was an important influence on Mitchell. Vladimir Engelhardt is credited with the discovery of oxidative phosphorylation. Severo Ochoa measured the number of ATP molecules synthesized when two electrons pass along the respiratory chain. Albert Lehninger is credited here for his demonstration of the number of phosphorylations associated with NADH oxidation, while Bill (E. C.) Slater proposed the chemical theory that introduced the high-energy intermediates, A~X and X~P. Finally, Peter Mitchell proposed the proton motive force as the energy source for ATP synthesis rather than A~X. Reproduced with permission from E. Racker (1975), “Reconstitution, Mechanism of Action and Control of Ion Pumps,” Biochem Soc. Trans. 3: 785–802, © the Biochemical Society.

For many years I was troubled by a statement attributed to Faraday, . . . that he held his theories by his finger-tips so that the least breeze of fact might blow them away. I was troubled because it seemed to me that some theories are more trustworthy and tenable than many facts. When I realized that a fact to Faraday . . . was something he had observed in the laboratory, and that Fara-

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day was an exceptionally able observer, my troubles stopped until I began to study membranes. Now I need two handfuls of fingertips: one for alleged theories and one for alleged facts. Racker concluded that “I have tried to show in my lecture how an important hypothesis such as that advanced by Mitchell has revolutionized our thinking and guided our experimental approach.”8 Scatchard’s statement would certainly have been viewed with some sympathy by Mitchell.



More Recognition

It was a happy state of affairs that Mitchell also received positive recognition abroad, particularly in the United States, where he shared the Warren Triennial prize with Racker. Mitchell felt that these honors should be regarded as tokens of the success of our small and congenial research organisation as a whole. We should justly regard them as a vindication of the notion that, given the chance, small organisations can compete very effectively with large ones and may even manage to be more productive as well, and more congenial to work in, than their larger and reputedly more streamlined and high-powered counterparts.9 In 1974, with such successes Mitchell felt certain that the work he had set out to do on the mechanism of oxidative phosphorylation was now almost complete and would be wound up in October 1975. Twelve months later, the annual general meeting of Glynn Research Limited could record that more honors had been conferred. Mitchell was awarded the Wilhelm Feldberg Foundation prize for outstanding work in biochemistry. He was elected a foreign member of the American Academy of Arts and Sciences, and he was given the Louis and Bert Freedman Foundation Award by the New York Academy of Sciences for research in biochemistry. The nomination for this award came from outside the bioenergetics community—in fact, from Phil Siekevitz of the Rockefeller University, New York, who was known especially for work on ribosomes. But just as Mitchell began to feel that he had completed his contribution to the field of oxidative phosphorylation and could consider fresh fields, new problems came over the horizon. The annual general meeting of Glynn Research Limited recorded that

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with regard to future research plans, we have reconsidered the decision, announced in my previous report, to wind up the present research project on the mechanism of oxidative and photosynthetic phosphorylation from October 1975. The reason for this reconsideration is that new difficulties have come to light in the interpretation of the detailed mechanisms of the redox chain and ATPase . . . which our organisation appears to be especially competent to study.10 Indeed, just as it seemed that Mitchell’s work was being accepted, the chemiosmotic theory came under severe attack yet again. The source of the problem lay in measurements of the number of protons translocated out of the mitochondrion per oxygen atom reduced.



Problems with the Arithmetic

When Mitchell and Moyle had measured proton movements across mitochondrial membranes in the late 1960s, the ensuing simple arithmetic (stoichiometry) had proved very satisfying. The prevailing view at the time was that three ATPs were synthesized (one at each of three coupling sites) when two electrons passed down the respiratory chain (from NADH) to reduce an atom of oxygen. The Glynn group had found that the reduction of an atom of oxygen by the respiratory chain was associated with the ejection of six protons. These six protons were made up of two at each of the three coupling sites where ATP was synthesized. It was also found that when the ATPase synthesized or hydrolyzed a molecule of ATP, two protons crossed the membrane. Thus the six protons translocated during respiration (as shown by Mitchell and Moyle’s experiments) was the appropriate number for the synthesis of three ATPs. Although Giovanni Azzone and others had earlier queried the proton numbers, this became contentious when Albert Lehninger challenged Mitchell’s data at the Bari meeting of 1975. Lehninger had taken up studies on calcium transport first developed in the early 1960s in his laboratory and elsewhere. Now, on the basis of the calcium work, he concluded that four protons were ejected at each coupling site. This would be equivalent to twelve protons per oxygen atom reduced (twice Mitchell’s figure). These results were to some extent reinforced by a paper from Karel van Dam in Amsterdam, who also attended the Bari

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meeting. A robust discussion over the problem of the arithmetic had taken place. Lehninger’s results were aggressively challenged by Mitchell, who suggested that experiments supporting the higher proton numbers were being wrongly interpreted. In the enthusiastic defense of his position, Mitchell seems to have unintentionally offended Lehninger. Subsequently, he wrote: I was all the more sorry that you were offended by my remarks about the need to distinguish between facts and opinions in the matter of the →H+/O or →H+/2e– stoichiometry of respiratory chain systems and the →H+/P stoichiometry of ATPase systems. Certainly no offence was meant, especially since having dabbled in theoretical matters a good deal, it may be suggested with some force that I myself may be especially susceptible to the trouble that comes from mistaking opinions for facts!11 Mitchell went on to hope that the differences between himself and Lehninger could be discussed privately through the mail. Lehninger accepted the conciliatory tone of the letter and the suggestion for ongoing discussion by post but not the proposal for privacy—he agreed to send to Mitchell copies of papers already submitted to journals. The problem for Mitchell arising out of the challenge from Lehninger and van Dam was twofold. First, the careful experimentation done at Glynn in the 1960s and supported by work elsewhere was being subjected to serious criticism, implying that Mitchell had got it wrong. Second and much more significant was the fact that Mitchell saw these results as a direct challenge to the chemiosmotic theory itself, although some others regarded the issue as less serious. Mitchell had proposed that the transport of protons was brought about by electrons that passed through loops in the respiratory chain. Each pair of electrons passing through a loop at a coupling site would transport a pair of protons. If the number of protons transported were doubled, this mechanism could not work, and Mitchell felt that this situation undermined the chemiosmotic theory itself. As he commented to Lehninger: You may recall that Lasse [Lars Ernster] asked me at Fasano whether I thought the chemiosmotic hypothesis would be invalidated if our value of 2 for the →H+/~ quotient in the respiratory chain were found to be wrong. I replied that, if I were frivolous, I would say “no”, but that, as I was serious about trying to develop a useful chemiosmotic rationale, I would answer “yes”. When I

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went on to agree with Lasse that, in abstract principle, the chemiosmotic coupling concept was not wedded to any particular →H+/2e– value, Bill Slater expressed concern that one seemed to be ready to consider shrugging off the serious consequences that would ensue if our →H+/2e– values were indeed found to be contrary to the facts. Although this seems to me to be somewhat of an academic question at present, I must say that my sympathies are very much with Bill’s point of view. In practice I think it would be hard for the chemiosmotic hypothesis to survive if your contention were found to be correct that the →H+/2e– quotient per “site” in the respiratory chain is 4 and not 2. This means . . . that your interpretation of the experimental data would not be seen as supporting the chemiosmotic hypothesis.12



Fighting Back

Undoubtedly, some would have argued that the chemiosmotic theory was not dependent on any particular stoichiometry and was capable, like most good theories, of being adjusted to accommodate the results of new experimental evidence. Such a situation had certainly applied to the chemical theory that underwent a great many adjustments, one by Racker even as late as 1970. But there was in Mitchell, particularly in his later years, a basic unwillingness to attempt any revision of his theory in the light of experimental evidence unless such a revision was absolutely necessary. Thus, he would seek alternative interpretations of the experimental results so that the theory could remain inviolate. He had a remarkable confidence in his theoretical constructions, which meant that theory tended to have primacy over experimentation. Nevertheless, Mitchell’s approach was often a source of considerable irritation to other workers in the field, especially as Mitchell was particularly adept at providing alternative interpretations of the results obtained by others. But as has been noted in other chapters of this volume, facts unambiguously supported by adequate experimentation were thin on the ground in oxidative phosphorylation. As one researcher put it in conversation at the time, “You cannot make any statement in oxidative phosphorylation that will not be disputed by someone somewhere in the world.” The exchange with Lehninger continued. The letters contained a great deal of detailed technical argument on the interpretation of experi-

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ments carried out by Lehninger’s group and also those performed by the Glynn team. As Mitchell commented: leaving aside your reductant-pulse experiments (which I do not understand), I am not questioning your experimental observations, but only the interpretations that you place upon them. . . . Generally speaking, I would not want to dispute your suggestion that we would get much the same results as you do if we were to repeat your experiments under substantially similar conditions.13 Lehninger sent Mitchell a copy of an article in which his group directly measured the translocation of protons associated with respiration.14 This time they concluded that three protons (which Lehninger regarded as a minimum number) were translocated for every pair of electrons passing through a coupling site equivalent to a →H+/O ratio of 9. He demonstrated that Mitchell’s results (→H+/O = 6) could be obtained if phosphate was present. Lehninger concluded that the reason for these discrepancies lay with the phosphate present in the mitochondrial preparations used at Glynn. Phosphate could reenter the mitochondria, taking protons with it. Thus the number of ejected protons actually observed was less than the real number because some of them had immediately reentered the mitochondrion with phosphate. He sought comment from Mitchell on this paper over a number of letters but never felt that he obtained the response he was looking for. On the surface Mitchell was apparently undisturbed by these new results, but in reality Glynn was working hard to reexamine the data and in a new program of research to establish the true proton numbers. However, Lehninger felt that Mitchell was ignoring his work. Eventually Mitchell wrote: I heard from Ef. [Racker] that you feel that I have ignored your data. May I assure you that this is really not the case—indeed, it could hardly be so, since your data and our data do not seem to me to be in conflict (except, perhaps, in a few minor respects). Jennifer Moyle and I are now going back over some of our earlier proton-pulse work and repeating and extending appropriate experiments with the idea of testing your contention that our →H+/2e– and →H+/O quotients should have been 3 or 4 per “site” rather than 2. We continue to find it hard to accept your view that we did not take account of or allow for movements of phosphate and other anions.15

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Mitchell did obtain higher numbers of protons similar to those seen by Lehninger, but he felt that these results were suspect and did not measure the true →H+/O ratio. It was a question of interpretation of the data, as he indicated to Lehninger: It is not over the raw experimental data that we disagree, but over the interpretations that we put on them. I hope this letter will help to explain the basis of my opinion that the oxygen-pulse experiments done in my laboratory, and confirmed and extended in a number of other laboratories, represent the most reliable method of estimating →H+/O quotients. . . . And that the observed value of 2H+ per ~ that we have found experimentally has not yet seriously been undermined by other more reliable or relatively more extensive experimental data.16 However, perhaps his true feelings about the situation are those expressed in an outburst to Sergio Papa: I have been rather depressed by what you refer to as the “controversial experiments”. My general impression is that the technical quality of the work of these experiments is second-rate—mostly, I guess, done by students with little experience, or because they spend so much time talking, and so little time listening or thinking or working studiously! Please forgive that outburst but it is loaded with sadness, and comes straight from the heart.17 Mitchell was not prepared to accept the higher proton numbers of Lehninger and van Dam until there really was no other alternative. Yet it should not be thought that, in his better moments, Mitchell did not welcome the issues raised by Lehninger’s work: “We have often wished, in my lab, that more biochemists would take an active interest in the precise stoichiometry of proton translocation in the respiratory chain and ATPase systems involved in oxidative phosphorylation.”18 On the issue of the high proton-oxygen ratios, however, the stakes for Mitchell were high. As he wrote some four years later as the argument continued to rumble on: It would have been good to have you persuade me to accept the big stoichiometries and overturn the current development of knowledge of direct ligand conduction mechanisms19 in the protonmotive cytochrome system. The evidence as I have seen it so far, has been urging me steadily the other way. . . . But I am always open to persuasion.20

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In other words, Mitchell felt that the higher proton numbers did undermine his conception of the mechanisms that he had developed for the transfer of protons across the membrane. It is difficult not to believe that deep inside Mitchell there was a requirement that experimental observation could only be valid if it supported theory. Thus he continued to provide logical arguments to undermine the interpretation put on observations by his fellow bioenergeticists but formally remained open to a change of view.



A Protracted Debate

As time progressed, the importance of the argument on proton numbers (stoichiometry) escalated, thereby justifying the description of these episodes as part of the “ox phos wars.” Mitchell’s simple arithmetic was now threatened in various ways. In 1976 Lehninger’s group summarized these problems.21 First, if one assumed Mitchell’s simple arithmetic, six protons ejected per oxygen atom reduced, then there was not sufficient energy in the measured electrochemical gradient of protons to provide for ATP synthesis. Second, studies on the uptake of calcium ions into mitochondria suggested that instead of six protons per oxygen atom reduced, the figure should be nearer twelve. Third, studies with the ATPase in chloroplasts suggested that at least three protons were associated with the synthesis/hydrolysis of ATP. All in all, it appeared that Mitchell’s measurements of proton ejection in mitochondria in 1967 produced estimates that were far too low. Lehninger’s group repeated the measurements by various methods and concluded that about nine protons per atom of oxygen reduced, possibly more, was the appropriate figure. After three years of debate with Lehninger, Moyle and Mitchell published the results of their extensive experimental program to remeasure the proton-oxygen ratio.22 They concluded that their original numbers of protons were correct and that the phosphate movement was adequately controlled in their experiments. Further, the calcium work required a different interpretation to that applied by Lehninger’s group. The issue was given further consideration in later publications. Even in 1982, Mitchell, whose position in the bioenergetics community had, by then, been much enhanced by the award of a Nobel Prize, concluded that

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on close examination, the criticisms of the respiratory pulse method of estimating . . . ratios do not appear to be well founded either theoretically or experimentally. It is understandable that the big protonmotive stoichiometry school should have been applauded by the seekers after . . . conformationally coupled proton pumps. That, however, is not justification enough for rejecting the evidence in favor of the relatively experimentally consistent low stoichiometries yielding a . . . value close to 2 in the hands of the majority of workers.23 This comment again reinforces Mitchell’s determination to maintain the purity of his chemiosmotic theory. Thus he felt that those who supported higher proton numbers must be doing so because they were looking toward the conformational theory. This loss of ground by the chemiosmotic theory was noticed by others, including the Finnish biochemist Mårten Wikström, who wrote to Mitchell: I would like to tell you rather confidentially that in the opinion of quite a few people the recent meetings, particularly the last one on mechanism of calcium and proton pumps in Padova, have been rather disastrous due to your absence, although some of us . . . tried hard to minimize the dogmatism that again burst into flowering. It seems to be quite clear that after the door of high stoichiometries was opened as an apparent escape from the chemiosmotic principles; it became quickly crowded by those who had waited for the opportunity for years.24 Although the chemiosmotic theory might have been modified to accommodate higher proton numbers, it is clear that they threatened the standing of the theory itself. Perhaps Mitchell had no viable alternative but to defend his original position that six protons were translocated per oxygen atom reduced. There was another reason why Mitchell felt bound to stick to his position. The alternative approach, the conformational theory now espoused by many of those who earlier supported the chemical theory, could accommodate a great variety of interpretations. He wrote, “As the exclusively conformational mechanisms can accommodate any stoichiometry, they encourage sloppy experiments.”25 A further defense produced by Mitchell was to attack the work on

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calcium. Here the argument was that two Ca2+ ions were transported per coupling site. This would amount to four positive charges transported, equivalent to four protons, each carrying a single charge. But, suggested Mitchell (with Moyle), calcium might be transported with a single charge per atom if it were linked to phosphate, and he proposed a calcium phosphate transport system that was consistent with a significant part of the evidence on calcium transport.26 After a few years, Mitchell began losing confidence in his calcium proposals. As he wrote: “The experimental evidence for the existence of the calcium phosphate and calcium ß-hydroxybutyrate symport systems . . . is not very substantial.”27



Surrender

The debate over the number of protons translocated by the respiratory chain continued during the 1980s with little further advance. However, by this time Mitchell had become involved in another argument about whether the cytochrome oxidase pumped protons. It was not until 1986, when the outcome of the cytochrome oxidase debate had gone against Mitchell and undermined his fundamental arithmetic, that he returned to the original question of the →H+/O ratio; but now Mitchell and colleagues concluded that the value was not six but at least eight.28 Concurrently, Mitchell also withdrew the calcium-anion symport concept that had been used to undermine arguments based on calcium transport into mitochondria.29 It should not be thought that the change of view was presented simply as a retraction. Rather, new evidence was presented in both articles indicating that the earlier interpretation was not justified. In the view of one of Mitchell’s collaborators, the critical experiments had simply not been done until that date. The stoichiometry debate had been robust and at times acrimonious. Although Mitchell was viewed as the object of a variety of attacks, often personal, there is little doubt that the forthright defense of his position and his effective criticism of the work of others stimulated aggressive argument and debate that could become rancorous. However, concurrent with the long debate about the number of protons was a much more positive and creative activity that had only an oblique bearing on the issues just discussed. This was the highly imaginative proposal on how one part of the respiratory chain actually translocated protons across the membrane, the Q cycle.

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Sleeplessness

Mitchell had never slept easily at night; frequently he rose very early and did some work. Even in his Edinburgh days he had upset his neighbor by playing his piano in the middle of the night. It was during these periods of wakefulness that he puzzled over the problems of oxidative phosphorylation. One of those problems in the early 1970s was to understand the mechanisms whereby the electrons passing down the respiratory chain in the membrane could transfer protons across that membrane. He had developed the basic model of the simple loops in the chain. But such mechanisms did not satisfactorily match up to some of the experimental evidence and did not provide an adequate explanation in all cases. Thus he endeavored to develop a loop for the first section of the respiratory chain, the NADH dehydrogenase, which possessed flavin mononucleotide (FMN) as a potential hydrogen carrier, but there was insufficient knowledge about the properties of this flavin. Thus he wrote to Tsoo King: The trouble is that I wake up in the middle of the night and think that I should speak to you about this, but, for some reason, it seems too ordinary or self-evident in the cold light of day. The question is, do you think that perhaps the FMN of the NADH dehydrogenase may possibly have a mid-point potential that is considerably more positive than most people have expected it to be? . . . No doubt, you realize that my interest in the flavin component of the NADH dehydrogenase stems from the fact that the first step towards understanding the topology of the reaction lies in establishing the sequence of the electron transfer and hydrogen transfer processes.30 However the NADH complex, the first segment of the respiratory chain, continued to be an inscrutable system. But the mechanisms within the first complex of the respiratory chain were by no means the only ones to concern Mitchell in the 1970s. The third complex (the cytochrome b–c1 complex; see appendix to this volume) was a major puzzle that occupied Mitchell’s mind, especially in the early hours. Here he did gain a major insight into the mechanisms of electron transport and proton conduction across the membrane on a night in 1975, and this led to the proposal of the Q cycle. Not only did the Q cycle explain much about proton translocation across the

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membrane, it also resolved a long-standing issue about the location of ubiquinone in the sequence of the respiratory chain.



Where Does Ubquinone Belong in the Sequence of the Respiratory Chain?

Conventionally, the quinone was placed relatively early in the respiratory chain (between the dehydrogenase complexes and the b-cytochrome complex). Even in the early formulations of the chemiosmotic theory, Mitchell had placed ubiquinone in the middle of the b-cytochrome complex because he needed a hydrogen carrier to transport protons across the membrane in that region of the respiratory chain. Ubiquinone was the only component of the chain available for that function. This positioning of the quinone certainly attracted criticism from others in the field. In 1970 he had asked Tsoo King, an expert on the respiratory chain itself (rather than oxidative phosphorylation overall), for help with this problem. Can you help me with the problem of the position of coenzyme Q [ubiquinone] in the respiratory chain relative to cytochrome b? In spite of what most authors say—especially Chance, Klingenberg and Ernster—I think the experimental evidence strongly indicates that coenzyme Q reacts between cytochromes b and cytochrome c1.31 In fact, he did not get much help from King, who responded, “I don’t know where Q should be. Indeed I am more confused after talking with Klingenberg last week.”32 There were a number of other problems about the process of electron transport in the cytochrome b–c1 complex. These included the way the b-cytochrome in particular underwent oxidation reduction. The conventional formulations of the respiratory chain were not effective in interpreting results of a number of experiments carried out in a variety of laboratories. Even the b-cytochromes themselves had curious properties, which provided a basis for Slater to propose another mechanism for oxidative phosphorylation. This was met with some disparagement by Mitchell, who, when replying to a letter from A. S. Cearns, commented:

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I liked your discussion of Slater’s theory about what I like to call the “bumbling bees”. Frankly I do not think that Slater’s very vague notion about energy conservation through the cytochrome b system is at all realistic. One of the main difficulties is that this theory has almost no experimental facts to support it. . . . It may also be relevant to remark that Slater has now withdrawn the detailed theory that you mentioned and prefers to describe the energy transducing system as a kind of “black box”. I am not quite sure what he means by this, but I assume he thinks that work is directly transferred somehow from the b-cytochromes to the reversible ATPase by a direct interaction, but he is not prepared to hazard a guess as to how this actually happens.33 For Mitchell, however, there was a much more serious problem. If six protons were translocated by the respiratory chain (oxidizing NADH), then two would be due to the NADH dehydrogenase complex and the remaining four must be in some way due to the b-cytochrome complex since the last complex, cytochrome oxidase, lacked a proton carrier. Mitchell therefore assumed that there would be two places in the third, b-cytochrome complex, where protons were translocated.



The Q Cycle

As already noted, the solution to the problems that Mitchell was trying to resolve suddenly came to him in the middle of a sleepless night. The traditional sequence of members of the respiratory chain (including the quinone) was a linear one. Branched schemes with quinone reducing both the b- and c-cytochromes were conceived in 1972 by both Mitchell and Wikström independently (Wikström provided supporting experimental evidence),34 and these can be seen as the first step in the evolution of the Q cycle. Mitchell now saw a cycle involving ubiquinone reactions. This he realized could resolve a variety of questions about electron transport and energy conservation in complex III. Later he recalled the event: It was clear that one couldn’t think how to place the ubiquinoneubiquinol couple in the chain. Well, I had been wrestling with that, and feeling more and more that this might well be a point where we could succeed in falsifying the chemiosmotic hypothesis. Then

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. . . on the 20th May 1975, I wasn’t sleeping well. I had in my mind’s eye loops 2 and 3, and I put in my mind’s eye . . . ubiquinone couples. . . . I was more inclined to put the Q/QH couple in loop 3 and the QH2/QH couple in loop 2. Being in bed with my eyes shut, it was easy to visualize the thing, as it were, in front of me, and suddenly, as I was visualizing it, I noticed what hadn’t been noticed before. In these two loops, drawn like that, QH was going one way across the membrane in one loop and the other way across the membrane in the other loop. . . . In my mind’s eye, I could see you could allow the QH to go along the surface of the osmotic barrier, formally speaking on each side, and you could have a cyclic arrangement of the two couples. And that of course was the Q cycle. . . . Well, of course, I didn’t sleep for the rest of the night. In fact I got dressed and started doodling and drawing diagrams.35 The cycle solved the vexed problem of location of ubiquinone in the respiratory chain, it explained a number of apparently anomalous results, but, in particular, it released not two but four protons per pair of electrons. Mitchell’s arithmetic remained secure. The six protons that he had measured were translocated as follows: two by the first complex, four by the third b-cytochrome complex, and none by the last cytochrome oxidase complex. As he wrote to Wikström, who had already proposed a relevant arrangement of the b-cytochromes: I have had further thoughts on the general organization of the cytochrome system in the context of proton translocation mechanisms, and I have attempted a more frontal (and, I hope, more biochemically orthodox) attack than before—trying . . . to save an otherwise unsatisfactory conceptual situation.36 This was one of a great many schemes produced by Mitchell over the years, almost all of which were very ingenious but which were soon discarded. The Q cycle had a lasting value and proved to be capable of development. It was presented to the Bari meeting in 1975 where Mitchell used a hand-cranked model to demonstrate the working of his new cycle. The scheme was published in outline in August 1975 with a more detailed consideration in November of that year.37 The Q cycle was also found to be operative in photosynthetic systems and, in due course, in bacteria. Indeed, Mitchell’s major theoretical contributions to the field of oxidative phosphorylation and photosynthetic phosphoryla-

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tion were the overarching chemiosmotic theory and the Q cycle that showed how protons were translocated across the membrane in the one very important case.



Justifying the Q Cycle

In general, the Q cycle was well received as an interesting and useful contribution. Lars Ernster noted that the protonmotive Q cycle had “already elicited a great deal of discussion—e.g., at a meeting in Italy in September.”38 Perhaps the views of many bioenergeticists at the time were summed up in a note by the Italian bioenergeticist Sergio Papa, who wrote that “I find your cycle extremely ingenious as well as attractive, although too speculative.”39 Although the Q cycle helped explain what appeared to be anomalous results, it rested, like the newly formulated chemiosmotic theory, on very slender experimental evidence. Following a meeting between Harold Baum and Mitchell in October 1975, Baum wrote to John Rieske to inquire what modifications of the cycle might be necessary to accommodate all the experimental evidence and also how the scheme might be tested experimentally. Rieske, an expert on the cytochrome b–c1 complex, felt generally positive about the Q cycle, although on some issues he had reservations. Attempts by various workers to test some of the cycle’s predictions met with mixed results. Some experiments appeared to support the cycle, while others appeared to show that it was wrong. After ten years, one reviewer could only regard it as a possible mechanism for electron transport: “The mechanisms of electron transfer and proton translocation by complex III are not clear. A possible mechanism considered best to fit the available information is that known as the Q cycle.”40 An alternative scheme, the b-cycle, had been proposed and was considered on equal terms with the Q cycle. Almost a further ten years had to elapse before consensus on the veracity of the Q cycle was achieved. However, in the late 1970s Mitchell himself found other values in his proposal. He felt that it helped bridge the communication gap between those who promoted the chemiosmotic theory with its strong physiological bias and the traditional biochemists: My own liking for the Q cycle is to a great extent social rather than scientific; because I think it has a chance of helping to give a more metabolic feel to the protonmotive cytochrome system—and so en-

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able the metabolic enzymologists to realize that the chemiosmoticists have not really spoiled their classical (and rightly beloved) biochemistry.41



Economics

Certainly as far back as his Cambridge days Mitchell had been interested in economics. During his time at Glynn he developed a strong interest in the economist Friedrich August von Hayek, reading most of his books. In 1974, he became a member of the Economic Research Council, an independent body (with no links to a political party) whose prime object was to promote education in economics, particularly monetary practice. Its principal activity was to hold meetings in London, which included lectures by distinguished speakers on an economic issue of the day. In addition, the council produced a journal and occasional papers, and from time to time it commissioned research. Mitchell valued his membership in this body, and he included it in his Who’s Who entry. More particularly, it brought him into contact with those in business, politics, and commerce who were interested in economics. In the 1970s, this interest was stimulated by the very real economic problems facing the institute. Glynn had been founded with a fixed endowment derived from the success of Sir Godfrey’s construction company, George Wimpey Ltd. The value of that endowment was now threatened by the high inflation rate experienced in the United Kingdom during this period. Mitchell also felt strongly about the levying of tax on profit that in real terms represented a loss. Mitchell’s views were succinctly expressed in a letter to the press: Is it not a scandal that when the annual rate of inflationary depreciation of the £ is around 20 per cent, and nominal interest rates are around 10 per cent, the real rate is around –10 per cent, and the banks and monetary system are thus permitted to milk away the real value of depositors’ money at a rate of some 10 per cent per annum; and, furthermore the Inland Revenue is permitted to levy tax as though this 10 per cent loss were a 10 per cent gain? What of the responsibility of the banks and monetary institutions for safeguarding the savings of ordinary people?42 Mitchell went on to argue that there was a need for an inflation-proof unit, for which he suggested the name pax, “after the Roman per-

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sonification of peace, associated by Augustus with the aim of establishing political and social harmony.”43 He defined the British Pax as the purchasing power of the pound on January 1, 1974. Indeed, during the 1970s Mitchell wrote a large number of letters to the Financial Times on the general theme of inflation and problems associated with it. In particular, he repeatedly extolled the merits of his proposal for the pax. Inevitably, only a few of these letters were published. In December 1981, an article by Sir Jeremy Morse entitled “Don’t Blame the Banks,” dealing with lending policies, was published by the Times. This article stimulated Mitchell to draft an open letter, dated 1 January 1982, to Sir Jeremy Morse, chairman of the Committee of London Clearing Bankers, which neither the Times nor the Financial Times was ultimately willing to publish, in part, because of its considerable length. Again, the core subject was inflation, and Mitchell distinguished between money (which, he argued, most people closely linked with a stable unit of account) and currency (which has a variable and usually diminishing purchasing power): Would it be entirely unfair if bankers were held partly responsible for the fact that, over a long period of history, the confusion of currency with money has worked to the advantage of those heads of state, central governments and financial institutions that have been involved in the debasement or inflation of currencies at the expense of the general users, including industrialists, who were inevitably (and legally?) robbed of part of the monetary worth of their debased or inflated currency?44 The letter concluded with advocating the use of the pax as a British standard money unit. The letter was circulated widely, including to the chancellor of the Exchequer, and received a somewhat defensive response on behalf of the government from the chief secretary to the Treasury. A more sympathetic response, indicating some of the problems with Mitchell’s views, came from the chief adviser to the Bank of England, who suggested further reading. The prime minister’s office, on behalf of Margaret Thatcher, provided a fairly lengthy reply. Sir Jeremy Morse replied briefly but made it clear that he did not wish to prolong the correspondence. With a lack of interest from Morse, the Times lost interest in Mitchell’s letter or even a possible article by Mitchell. Overall, the response was sympathetic and also respectful that a distinguished scientist should interest himself to such an extent in the serious national problems associated with inflation. But it also carried a

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strong undertone that Mitchell needed to be much more conversant with the history of, and background to, the issues he was addressing.



The Entrepreneurial Spirit

There was always in Mitchell a strong entrepreneurial spirit that led him to plan a variety of enterprises. These included the generation of his own electricity, the sale of bottled spring water from the estate (for which he designed and printed labels and purchased large numbers of bottles in the early 1980s), and the renovation and sale of old buildings. Only the last of these was carried to completion, and none of them proved profitable. A further project was the minting and sale of silver Glynns. The issue of maintaining the real value of the institute’s endowment had concerned Mitchell increasingly from the late 1960s onward. In the early 1970s, Glynn Research Limited had made a significant investment in silver bullion, a move that did prove, certainly in the short term, a hedge against inflation. In the late 1970s, independently of the institute, Mitchell conceived the idea of marketing silver medallions or coins as an investment opportunity. Together with his old friend Will Coutts, originally an Edinburgh antique dealer, who had also helped with renovation of Glynn House, Mitchell traveled to the East End of London to view and then to purchase an old machine capable of cold pressing silver coins. This was transported back to Glynn, and, since it was too tall (some ten feet or so) to be housed in any of the buildings, a shed was erected in one of the courtyards to house it. It was christened by Coutts as Rameses II. Mitchell recalled that My machine for striking Glynn silver pieces (they were pieces of silver bullion weighing 1 Troy ounce) was a kind of experiment and a demonstration against inflation of the pound sterling at a rate of 25% (which seemed a lot at the time!). However people were so convinced that there must be a catch in it that my silver pieces did not sell, although they were much better value (in silver) than the Jubilee crown. Latterly the silver market was bugged with problems.45 Mitchell had molds made with his own design and produced the coins known as Glynns. The inscriptions reflected some of Mitchell’s personal beliefs: on the one side, freedom to save liberty to

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earn; on the other, one troy ounce 999 fine silver glynn bullion piece 1977. When it was suggested that these were for commemorative purposes, he responded, “As it happened, I did put a pleasant design and other lettering on my bullion pieces for purposes of identification, and to indicate the weight and purity of the silver, but these bullion pieces were in no way intended as commemoratory medallions.”46 Although they were a commercial failure, silver Glynns were presented to the king of Sweden on the occasion of the Nobel Prize award. Subsequently, when Mitchell and his wife were entertained at the palace after the award ceremony, Mitchell gave one to Queen Elizabeth II, who placed it in her handbag along with the dog biscuits—or so the family story goes. He also gave Glynns to his colleagues, including the Finnish biochemist Mårten Wikström and several American biochemists including Britton Chance. On a later occasion, when Mitchell sent out a letter seeking funds for the foundation, Chance donated his silver Glynn to the appeal!



Winning and Losing

The mid-1970s were somewhat of a roller-coaster experience for Mitchell. On the one hand he himself had now been recognized as a leading international scientist in the field of bioenergetics. On the other hand, just as the chemiosmotic theory was gaining widespread support, particularly in the United Kingdom, it ran into a fresh wave of opposition and uncertainty over questions about the number of protons translocated. True, many of the most senior workers in bioenergetics had not yet been converted to the chemiosmotic theory, but many of the younger generation now understood and accepted Mitchell’s theory. Despite this acceptance, Mitchell himself was questioning whether the theory might yet be falsified as a result of the work on stoichiometry coming from Lehninger’s laboratory and elsewhere. The Q cycle, which was consistent with Mitchell’s own view of the arithmetic, was in 1976 only an intriguing and ingenious idea as it lacked any significant experimental support. Nevertheless, there were other events occurring concurrently with the issues described in this chapter. These certainly served to focus both the opposition’s mind and Mitchell’s own approach to the field.

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10
From Review to Nobel Prize 1977–1978



Reviewing the State of Bioenergetics

The arguments on the mechanism of oxidative phosphorylation became increasingly like set pieces, with various workers having adopted entrenched positions between the chemiosmotic viewpoint and the conformational viewpoint. Although the chemical theory had never quite died, it was now a minor part of the debate. Some in the field felt unable to accept the physiological concepts underlying the chemiosmotic theory, concepts that had not been part of mainstream biochemical thinking. The importance of the debate was not just a question of understanding the mechanism of oxidative phosphorylation; in many cases it was the driving force for the design of experiments. Inevitably, Mitchell was in the center of the debate. He adopted a stance of forthright defense of the chemiosmotic theory on the ground that no experiment had yet falsified it even though it had been put to the test extensively. Those outside the field of oxidative phosphorylation saw this area of research in a state of chaos. While the situation did nothing to enhance the scientific standing of the workers in bioenergetics, the real problem came over funding. Questions began to be asked about the wisdom of putting money into an area of research that appeared to have reached stalemate. This was particularly true in the United States, where extramural funding was at the core of scientific survival. In the middle 1970s, an attempt to present a united front was made by publishing a joint review of oxidative phosphorylation in the Annual Review of Biochemistry for 1977. The Annual Review, which had charted

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progress in biochemistry with volumes since 1932, was accustomed to presenting a review on an area of the discipline with one or a small number of authors. In 1977 the review of oxidative phosphorylation was unique in being composed of a series of independent parts, each by a different author expressing his view on the subject. Many have regarded the review as marking the point when the field came to a resolution of its problems, although the differences of opinion, albeit considerably muted, can still be seen. The origins of this unusual set of contributions lay in a letter sent by Efraim Racker to senior workers in the field in 1974.



Stirring the Field

Racker’s letter was addressed to the leaders of the oxidative phosphorylation field and did not address those who specialized in photosynthetic phosphorylation. It was sent to Mitchell and also to Paul Boyer, Britton Chance, Lars Ernster, David Green, Tsoo King, Henry Lardy, Albert Lehninger, Rao Sanadi, and Bill Slater. It started with an assessment of the situation as Racker saw it: Many investigators in bioenergetics have felt for some time that our field has not received the appreciation it deserves. This has led to problems with the funding of grants and it has been particularly difficult for young scientists to write applications that impressed study sections that often don’t even include a biochemist working in bioenergetics. I understand that some highly respected members in the field have discussed this problem with representatives of NIH [National Institutes of Health, a major funding body for the field] but I do not think that the situation has markedly changed. It is my impression that among the major reasons for the unfavorable image are the rather confusing controversies which have dominated some sessions at the Federation meetings as well as published records of contradictory data and conclusions. Although we all know that this happens in other areas of science also, it is the consensus of our biochemical colleagues that we have had a rather excessive share of it. Since the polemics and controversies of this kind neither help the progress of science nor the well-being of the scientists involved, I have always made an attempt when confronted with

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such a problem, to contact the person with whom I disagreed and to resolve the discrepancies by collaboration before going into publication.1 Racker went on to illustrate his point and then to recommend collaboration between laboratories, particularly those with opposing viewpoints. He would have liked to see joint publications and gave examples, including those from Chance and Mitchell. He went on to propose “a note signed by an international group of bioenergeticists describing in broad terms the present state of our knowledge, the areas of uncertainties and disagreements and a statement to the effect that collaboration of the type proposed above is being planned.”2 The reference to what happened at federation meetings seems almost to be an understatement in view of the way some bioenergeticists described them. Nigel Gilbert and Michael Mulkay cite one worker, who referred to a slightly earlier period: “the oxidative phosphorylation field had the reputation that if you went to a Federation meeting, all the meetings were crowded because everybody went along because they knew there would be a damned good fight there.”3



Answering Racker

As might be expected, the letter drew a variety of responses. While Mitchell agreed with Racker’s analysis of the situation and with attempting to improve relations in the field, he did not approve of what he felt was papering over the cracks. His letter to Racker was forthright and reflects Mitchell’s self-assessment as being outside the scientific establishment: I agree, of course, that it would be helpful if differences of opinion or interpretation of experimental data could be resolved by improvements in the quality of our scientific dialogue. But the best will in the world cannot bring sweetness and light into the scientific dialogue in the absence of a fundamentally sound conceptual framework and rationale through which we can communicate conveniently and unambiguously. It is my impression that many of the difficulties that have been experienced in bioenergetics were created not by lack of collaboration or lack of agreed policies between highly respected members in the field, as your letter seems to imply; but rather certain acci-

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dents of biochemical history led to a widely agreed research policy that turned out to be ill-founded. Therefore I doubt now the wisdom of endeavoring to formulate a new agreed policy to be signed by “an international group of bioenergeticists” that may turn out to be as ill-founded as the earlier policy. In my view we need less authoritarian attitudes, decreed from the centre, and more liberalism in the field of bioenergetics; and I would have thought that the necessary changes can best be allowed to arise spontaneously, I mean by unforced mutual consent between most of the participants, if and when the appropriate scientific developments take place. Indeed it may be that, after the turmoil of the last few years, we may be moving into a more rational and more congenial phase of development in bioenergetics. If that were to happen, it would not be unusual in the history of science, but we should be careful not to risk strangling the delicate growth of scientific enlightenment by issuing directives from the centre or smoothing over the subtle implications of scientific dissent in shotgun marriages between the better-known protagonists. Mitchell concluded his letter on a friendly and relaxed note. Let me say again, I welcome your suggestion that we try to improve the quality of the scientific dialogue. . . . Incidentally, although I hardly recognized you at first in the disguise of your letter, I noticed as I read on, that you were wearing your lab-coat under your diplomatic robes. May your beautiful research work prosper!4 Slater’s response was more measured. He agreed that the field of bioenergetics “did not possess a good image with some of our most distinguished colleagues,” although he did not feel that this had led to funding problems in Europe. Part of the reason for the poor image was the inherent difficulty of the field and a part was due to a failure “in ‘selling’ our achievements.” However, he felt that “the special difficulties of the field have attracted to it highly intelligent and competent but impatient scientists, who . . . tend to concentrate on the unsolved problems instead of talking about the field as a whole.” He felt that the solution lay (a) in doing good science and (b) in improved presentation of the field, taking the opportunity to emphasize the positive and undisputed findings of recent years. He supported Racker’s suggestion for improved collaboration between laboratories. He agreed with

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Mitchell that “we must not give the impression that the establishment is laying down the gospel” He also felt that it would be wrong to attempt to eliminate controversy.5 The distinguished Swedish bioenergeticist Lars Ernster was much more positive, welcoming Racker’s suggestions and pointing out that he had made essentially the same proposal for a note signed by an international group some eighteen months earlier. He suggested a workshop in which a statement might be prepared. Of the Americans, Paul Boyer, then associate editor for the Annual Review of Biochemistry, noted that the editorial committee had already discussed “how to adequately assess and present advancements in the field.”6 He supported the idea of a document produced in Ernster’s proposed workshop that could then be published in the Annual Review. Chance agreed warmly with Racker’s proposals. However, in considering the issue, he thought that “one of the basic problems has been Peter Mitchell’s inability over the past year or so to visit among us as he used to do. . . . Perhaps we should make a point of getting us all together in a felicitous manner to discuss implementation of your suggestions.”7 Elsewhere, he noted that “one of our problems is the isolation of Bodmin. It is hard to get to, and Peter has been unable to travel.”8 King also agreed more or less entirely with Racker, but wished to add that not only were scientists in other fields confused, so also were the students.



Producing a Statement

This rather mixed set of responses to his letter nevertheless seemed to persuade Racker that he should continue with his proposals. Accordingly, he prepared a statement which he suggested should be published in one of the weekly science journals, Science or Nature. His short statement began as follows: “After years in stormy weather, the ship of oxidative phosphorylation has entered calmer waters and land appears to be in sight. As usual, no one was completely right in his prediction, and it is likely that the final solution will include elements of several hypotheses.” He then went on to set out an account of oxidative phosphorylation that included proton movements, conformational changes, and a high-energy phosphorylated intermediate. He seemed not to appreciate that such a hybrid statement was an invitation for a further storm. However, he concluded the statement by noting that there was an “exchange of collaborators and students between various laborato-

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ries even across the oceans.”9 Mitchell’s copy was sent with a covering letter urging him to come to the United States. Mitchell’s response could have been anticipated. He supported Racker’s attempt to improve dialogue in the field, but he felt that adding names to the statement would not help: Such authoritarian techniques belong (perhaps unhappily) to politics and not to western science, which (at its best) takes an experimental view of scientific truth. It is, I suppose, the scientific factual and conceptual content that matters and not the names of those who subscribe to it. Therefore, the omission of my name should detract nothing from any scientifically valuable statement that you make. You imply in your “statement” that the signatories have suddenly become much more chummy, sending collaborators and students across the wide oceans. But is this really true? And if so, is it because we have made some scientific progress?10 He went on to consider what progress might have been made asking three questions: Is the respiratory chain an electrogenic proton pump or not? Is the ATPase a reversible electrogenic proton pump or not? Is energy transduced from the respiratory chain to the ATPase by direct interaction through the conformational type of coupling mechanism, as proposed by Paul [Boyer], David [Green], Bill [Slater], Lars [Ernster] and others or not?11 Mitchell felt that Racker’s compromise statement would simply serve to confuse the general biological public rather than clarifying the situation. He recalled a statement he made at a federation meeting when he argued that the chemiosmotic theory should be tested to destruction. He concluded (no doubt remembering that Chance and Slater were yachtsmen): I do hope these remarks will not have the effect of rocking the ship of “oxidative phosphorylation”. But if anyone is worried about the possibility of stormy weather ahead, I would strongly recommend putting one’s trust in the compact and sturdy chemiosmotic lifeboat which has been tested very stringently for more than a decade, and in which, I can say from practical experience, one can brave the oceans, even single-handed, in pretty terrible weather.12

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Mitchell added one other significant point. He wished to circulate the correspondence to a much wider group of bioenergeticists, many of whom were younger scientists and a significant proportion of whom appear to have supported the chemiosmotic approach. Racker saw no problem in this development, which served to make a much wider group immediately aware of the emerging debate. Slater also responded to Racker rather negatively. He agreed with the points in Mitchell’s letter and addressed Mitchell’s three questions. He answered “yes” to the first two and to the third, “rather likely.” He felt that Mitchell had missed the key question, which was, “Is energy transduced from the respiratory chain to the ATPase by way of a pH [proton] gradient across the membrane?”13 His answer to this question was that it was rather unlikely; Slater still did not like the chemiosmotic theory. Lars Ernster’s response was to produce a modified statement that Slater felt he could support. Racker felt that a statement without Mitchell’s signature would be of little value, and he would therefore discontinue his “peace efforts.” He felt that a new confrontation between the conformational and the chemiosmotic hypotheses was inevitable, but he would support the idea of Lars Ernster in bringing bioenergeticists together in a workshop the following year. The workshop would form the basis for a chapter in the annual reviews, at this stage planned for 1976. The situation was further improved by a visit of Mitchell to Boston and Cornell (where Racker worked) in the autumn of 1974.



A Joint Review

Lars Ernster and Paul Boyer met in the early summer of 1974 to develop the idea of a multiauthor article for the Annual Review. They discussed their ideas with Chance and Slater at a Gordon Conference and also consulted Racker. In general, Boyer felt that, despite some apprehensions, there was a definite consensus that “the venture appears to have sufficient potential to warrant undertaking.”14 The plan was to have short articles prepared by Boyer, Chance, Ernster, Mitchell, Racker, and Slater. Curiously, Lehninger and Green were omitted, and a later attempt to include the former failed. Chance said that he would include Lehninger’s views in his own statement. Boyer and Slater would act as editors. The articles would be circulated among a proposed list of between thirty and forty discussants, whose brief comments would be re-

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turned to the primary authors, who would modify their statements as deemed appropriate. Finally, a workshop (conference) would be held in July 1975 when the final primary statements and appended discussant statements would be finalized. On behalf of the others, Boyer wrote to Mitchell expressing the hope that he would participate in the project. Mitchell replied to Ernster as the prime mover (although copying the letter to the others), expressing his objections to the project. He felt that this proposal still had the same problems as the “agreed statement” suggested by Racker: In my opinion your proposals for a “group review” are open to much the same criticisms as Ef’s proposals, because they hinge upon personalities and not upon the fundamental scientific issues. The circular enclosed with Paul’s letter . . . did not even mention the main scientific issues to be discussed.15 Mitchell felt that the proposals would give too much prominence to the confrontation between the chemiosmotic and conformational theories (the latter being covered below by the term direct-interaction coupling). He noted that the other contributors are (or were until very recently) supporters of direct-interaction coupling, and have not made use of the new conceptual perspectives and research opportunities opened up by the chemiosmotic rationale. This is the main reason why I am not prepared to become involved in your proposed “group review”, at least in its present form.16 While this lengthy and logically argued communication expressed Mitchell’s position formally, a more private note to Racker reveals his feelings on the matter: “Whatever you do, don’t go back on your agreement with me to avoid getting bogged down with the pot-pourri review intended by Lars and Paul to produce a perfumed account of the lovely relationships in oxphos!”17 Indeed, Mitchell felt that a review by Paul Boyer alone would serve the field much better. Boyer responded by asking Mitchell to reconsider the matter and providing further explanations on a number of issues. He also took exception to one of Mitchell’s points, thus adding a little tension to an already difficult debate. Mitchell agreed to delay coming to a decision on the matter until after he had seen Ef Racker in Boston in October

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1974. That meeting seems to have resulted in a more cooperative approach on Mitchell’s part. At that stage, he appeared to be willing to consider taking part in the project, although formally he did not commit himself. In the latter part of 1974 extensive and very detailed discussions took place by post between Mitchell and various of the contributors to the review, but particularly Paul Boyer, Ef Racker, and, to a lesser extent, Bill Slater. Such correspondence undoubtedly served to increase understanding of opposing views and to bring the field closer together. This was one of the very positive results of Racker’s initiative. However, it did not resolve the fundamental differences between the various viewpoints. Mitchell’s correspondence with Boyer became somewhat strained by the summer of 1975, and Boyer terminated it. Much of this concerned questions of the mechanism of the ATPase, which now became the focus of the differences between Mitchell and most of the others. For Boyer, as for most of the others, ATP was synthesized by conformational changes in the enzyme, and such changes could be brought about by a proton gradient. For Mitchell (as for Williams), the proton was intimately involved in the process of ATP synthesis itself, although Mitchell fully accepted that conformational changes could occur, but these would be secondary phenomena. Thus, while Boyer could at least contemplate a marriage of the two theories, Mitchell felt that there was no justification for such an approach. Indeed, he regarded Boyer as attempting to confuse the difference between chemiosmotic and conformational coupling. He went on to argue that Racker had fallen into this trap when the latter had written, “I see a merger of the chemiosmotic, conformational and chemical hypotheses in a compromise formulation that proposes that the proton gradient and membrane potential formed during oxidation is responsible for conformational change in the ATPase.”18 Subsequently, Racker pleaded guilty to aiming at “a gentlemen’s political compromise. From my early childhood, I had wanted to live in a peaceful world. Although I have always enjoyed friendly controversy and arguments, I have been most uncomfortable during the bitter polemics in our field in the last decade.”19 Chance observed these discussions in a more detached way, regarding himself more as “a fly on the wall.” He noted what he considered to be the apostolic names of the main protagonists, Paul and Peter. Mitchell responded with some doggerel based on a children’s rhyme:

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Brit is the name of the fly on the wall With two little dicky birds, Peter and Paul Fly away Peter, fly away Paul, Come back Peter, come back Paul, Brit says the gospel according to St. Paul Is different from the gospel of St. Peter on the wall. What motivation is behind this call For a different conformation from that described by Paul? Translocate Peter, transformate Paul, Phosphorylate the ADP or everyone will fall. Come back Peter, come back Paul,

Brit says Peter must explain to Paul. Protonmotivation is the secret of it all.20



Mitchell Withdraws (Again)

In a letter to Boyer dated March 1975 Mitchell decided again to withdraw from the group review. The tone of the letter showed some irritation, a quality that seemed progressively to enter into this correspondence. Part of the reason was a continual feeling by Mitchell that the Americans, particularly, were to some extent conspiring against him. Another part of the reason was probably poor health. He wrote: Different scientists obviously have different ways of appreciating and comprehending the things and phenomena of the physical world, and the latest turn of this correspondence has reinforced my earlier misgivings about my ability to contribute usefully to the group review on oxidative phosphorylation and related energy transductions mentioned in your letter, for which you earlier proposed that the joint authors should be: Boyer, Chance, Ernster, Racker, Slater and me. In view of your wish to encourage a resurgence of interest in the conformational coupling conception, I think it would be appropriate to include David Green in your group of joint authors. As you know, David has been the most active supporter of the notion of electromechanicochemical coupling in oxidative phosphorylation, and he has had the courage and enterprise to develop his ideas in some theoretical detail and has endeavored to back them up with experiments designed to show that coupling between the redox chain system and the reversible ATPase system

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is direct and that it is independent of intermediary osmotic energy transduction. Under the circumstances I have definitely decided to step down from your joint review, and I recommend that you invite David to participate in my place.21 Green’s theory was not broadly supported within the bioenergetics community but was regarded as related in concept to the conformational theory. At the time the letter was written, Green had claimed to have disproved the chemiosmotic theory by demonstrating oxidative phosphorylation in a system devoid of any osmotic coupling, a claim which later could not be substantiated and was retracted. Boyer wondered whether they should seek another author to present the chemiosmotic viewpoint, or should they hope that Peter would reconsider? At this stage, Boyer still proposed to continue with the review, even if it meant that there would be no contribution from the chemiosmotic camp. This seemed to reflect the confidence of at least some of the leading American bioenergeticists in their position. It was now agreed that manuscripts would be circulated by mid-July, in time for some consideration at the Bari meeting to be held in early September 1975. The withdrawal of Mitchell had further repercussions. It had originally been agreed that there would be an introduction to the “group review” provided by Boyer or Boyer and Ernster. In a letter in October 1974, while Mitchell was at Cornell, Racker had said that the introduction should be withdrawn in favor of a signed statement by all contributors stating how the review came about. Now Racker noted that this request had not been granted, and he too withdrew.



Mitchell Joins the Group (Again)

Racker visited Mitchell in Bodmin in July 1975 and discussed the proposed review at some length. He wrote to Boyer from Bodmin, suggesting that Mitchell might be prepared to consider contributing to the proposed review if the publication was moved back by twelve months to 1977. Mitchell was simply too pressed to write a review, even a short one in 1975. Were Boyer, Slater, Chance, and Ernster to agree to such a proposal, Racker would also rejoin the group. Mitchell also wrote in similar terms, stressing that a further year could produce a much better situation in the field:

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The correspondence sparked off by Ef’s initiative has already clarified several important points at issue, and I would have thought that a good deal more could be achieved in this direction by further discussion between the experts. . . . The present rapidly evolving climate of opinion amongst experimentalists in our field would be likely to bring us closer together.22 The final arrangements for the review were agreed at the Bari conference held in Fasano in September 1975. At that meeting, a short title for the review and the length of the contributions were agreed on. Racker was to draft the short introduction that would then be accepted by the six authors, but there would be no general conclusion. Within the editorial conventions of the Annual Review, each author would be free to determine the general style of his contribution. Boyer subsequently endeavored to obtain a greater uniformity between authors, but this was rejected, particularly by Racker and Mitchell. Racker and Mitchell exchanged drafts of their contributions to the review, but even by April 1976 Mitchell had received no comments on his draft nor had he seen drafts of the others except Slater’s. However, some discussion of drafts did take place before the submission date of 1 September 1976, which was adjusted to 1 October 1976 in the late summer. Nevertheless, Mitchell remained skeptical about the value of his contribution to the review. When he received Chance’s contribution just before the submission date, he felt that there was no time to comment and threatened to withdraw yet again, particularly because Chance seemed to be suggesting that Lehninger would now become a seventh author. This drew an unreserved apology from Chance and a categorical denial that Lehninger was to be involved.



Publication at Last

The review—consisting of six independent contributions with an introduction coauthored by all six—finally appeared in the 1977 Annual Review of Biochemistry.23 It was entitled “Oxidative Phosphorylation and Photophosphorylation,” although none of the authors belonged to the photosynthetic subset of bioenergeticists. In the joint introduction, they noted that they were presenting an appraisal of recent advances, together with the current status of the field. They hoped that by the multiauthor approach they could provide a broadly based appraisal and give

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a sharper focus to differences of opinion, as well as to areas that required clarification and further research. Of course, no reference was made to the original purposes of improving the image of bioenergeticists and enhancing funding prospects. In his contribution, Mitchell noted the following: As van’t Hoff pointed out in a delightful lecture almost a century ago, imagination and shrewd guesswork are powerful instruments for acquiring scientific knowledge quickly and inexpensively—a view brilliantly elaborated by Popper. According to this view there are few, if any, certainties in science; we build up our knowledge by testing preconceived models experimentally, thus detecting and testing the concepts that are false and retaining the concepts that show by their survival that they are factually serviceable because they represent reality as far as it is known.24 He went on to argue that the chemiosmotic hypothesis could be so described. He outlined the hypothesis, briefly giving his reasons for discarding the chemical and conformational theories, together with those of Williams and some others. He considered various aspects of the mechanism, including that in the ATPase, where he reiterated his views about the direct involvement of the proton in the synthesis of ATP. The other contributors all seemed to view the ATPase as synthesizing ATP by a conformational process in which the proton gradient and membrane potential brought about the conformational change. However, these authors, with the probable exception of Racker, felt that they could not be certain whether the energy transferred from the respiratory chain to the ATPase was passed through the formation of a proton gradient and membrane potential or by some more direct (conformational) process. They did not doubt, however, that the respiratory chain (and the ATPase) could create a proton gradient. Slater specifically reiterated that the chemical theory was no longer tenable. Racker seemed to support the view that the proton motive force mediated the transfer of energy from the respiratory chain to the ATPase. Thus, while nobody supported Mitchell’s view of the functioning of the ATPase, only Racker seems to have accepted the chemiosmotic theory in principle. Boyer, Chance, Ernster, and Slater were basically agnostic about the mechanism of oxidative phosphorylation. However, all authors, to a greater or lesser extent, accepted that the chemiosmotic theory was a potentially viable explanation of the mechanism of oxidative phosphorylation. Boyer was not necessarily enamored of the final

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outcome. He contemplated adding a limerick to his contribution that perhaps summarized the whole project: The very fine field of ox phos Has been blest with a lot of chaos Then all agreed nicely To state it precisely The result was some gain but more loss.25 Racker’s initiative had achieved in many ways its original goals. It had enabled the senior protagonists in the field to focus their debate much more sharply, and it had stimulated the search for a shared understanding of differences of approach. It did not totally resolve the question of oxidative phosphorylation, but it defined the issues much more clearly. It might even have paved the way for the Nobel committee to consider the claims of Mitchell’s chemiosmotic theory seriously.



Personal Crisis

The notion of a midlife crisis, particularly in men, is often treated with amusement. For Mitchell, a personal crisis in his mid-50s was an unhappy fact. In his case, a number of pressures conspired to generate a situation that finally overwhelmed him. His poor health had been a continual burden against which he battled—sometimes successfully, sometimes unsuccessfully. The problems resulting from the ear operation remained but could be controlled most, but not all, of the time. Ulcers, which originally forced him to leave Edinburgh, could also on occasion be troublesome, while fits of depression could be more serious. None of these problems were made any easier by the social forces operating in the bioenergetics community and by his own robust way of tackling those who did not agree with him; indeed, Mitchell returned from scientific conferences emotionally drained. To this was added increasing concerns about the financial security of Glynn. These issues came to a head in the mid-1970s. The crisis for Mitchell developed around the time when he was 56 years old. From his Cambridge days on, he had enjoyed the company of women, and he seems to have been the sort of man who was generally attractive to most women. In Greece, he had met a German girl, younger than himself, with whom he had a lasting but apparently platonic friendship. A more serious and disruptive relationship arose

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through a meeting of the Biochemical Society. At a dinner during the meeting, he had met and been attracted to the wife of another biochemist. The attraction seemed to catch Mitchell off balance. Before long, he had arranged for the two of them to move into the bungalow, Cuilan, that Mitchell had restored on the South Cornwall coast some thirty miles from Bodmin. The partnership in Cuilan lasted less than a week, and Mitchell’s lover left him. Perhaps she discovered that, despite his great personal charm and wit, she could not live with his strong and dominant personality. Mitchell returned home contrite, and, although Helen forgave him, their marriage never quite resumed its previous warmth and affection. For his part, Mitchell chose, in his phrase, to put the whole incident in his “forgettory.” In fact, by not facing up to the crisis in his marriage, he no doubt heightened the effect of this event on his health. However, in a curious way, Mitchell did have the ability to put matters out of his mind. Some ten years after his divorce from Eileen, he attended the wedding of their daughter, Julia, and noticed that the woman sitting opposite to him looked familiar. He asked her whether he knew her, and she replied, “Yes, I was your first wife!” Shortly after these events, in the summer of 1977, Mitchell had a nervous breakdown and was very strongly advised by his doctors to take a complete rest. To what extent the nervous breakdown was a consequence of the failed relationship is not clear. It is possible that Mitchell’s general emotional state had led to both events. He wrote to Hinkle, “I was smitten by something known to the head-shrinkers by the uncomplimentary name of hysterical dissociation. It has been taking some time to recover—as much from the causes of it as from the h.d. itself.”26 By September 1977, he felt that “the worst of the agony of opposing impulses and passions and ideals is over.”27 The events at Cuilan and the nervous breakdown that followed almost seem to be a fulcral point in his life. He had unquestionably been deeply creative in the three decades up to this point. In contrast, his later years involved the perpetuation of several unsuccessful controversies (mostly started before 1977), in which he seems to have lost his ability to be flexible. These included the mechanism of the ATPase, whether cytochrome oxidase pumped protons, and how many protons in total were translocated by the respiratory chain. In the two latter cases, he ultimately had to retract his position after a major international debate, while in the first he was left in an isolated position at the end of his life. In the early years, he had subtly adjusted his chemios-

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motic theory in the face of new facts to maintain its viability, and he had modified the simple loop concept to create the Q cycle. Now he seemed unable to modify his views in a positive fashion in order to accommodate the new experimental findings. In this later period, he certainly did not lose his creative genius, but it was now largely employed in defending his position and approach rather than in formulating new ideas. A particular problem was his dogged adherence to the view that conformational changes were the refuge of those who lacked proper mechanistic explanations. Nevertheless, there were undoubtedly flashes of brilliance, but these mainly, though not exclusively, concerned alternative interpretations of other people’s experiments to protect his earlier formulations. Another possible consequence of this change in Mitchell’s personality was to bring new people into the management of Glynn. Since the foundation’s creation in 1965, Mitchell and Moyle alone had managed Glynn. Now he felt able to widen the responsibility for leading the institute. In addition, there was now a strong attempt to escape bioenergetics and move into another field. Thus the events around 1977 can be seen as marking a significant point in Mitchell’s life. The underlying causes of these events were probably also at work in Mitchell’s new determination to abandon bioenergetics.



A French Retreat

The affair with the wife of a fellow biochemist and Mitchell’s nervous breakdown also had a significant effect on Helen. She now took up painting; she also felt she needed more security and acquired a cottage at St. Pons-de-Mauchiens, not far from Montpelier in France. Despite the events just described, Helen had been, and remained, an essential support for Peter Mitchell. The cottage in France was built into the walls of the ancient village. Initially, Peter would have nothing to do with this property, but as relations progressively improved, he eventually joined Helen there. His interest in old buildings inevitably took over, and he acquired a neighboring property and refurbished the two cottages as a single, very delightful, holiday retreat. In the ensuing years, Peter and Helen spent summer holidays there and also used it as a retreat at other times of the year. They entertained friends there, such as Eva Ibbotson. She remembered Mitchell as a superb craftsman with a strong sense of perfection,

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who had used his skills, together with Helen’s design ability, to create a most delightful retreat with no expense spared. Here Mitchell would also on occasion do the cooking, an art he had mastered in earlier years. With increasing health problems, the residence at St. Pons-de-Mauchiens became an important part of Mitchell’s life, enabling him to relax away from strains of life at Glynn.



Reviewing Glynn

When Mitchell moved from Edinburgh to Bodmin and decided to set up his private research institute in the early 1960s, he realized that such a creation was essentially just as experimental as his attempt to explore the newly proposed chemiosmotic theory. By the mid-1970s Mitchell was convinced he had succeeded in both projects. In his statement to the annual general meeting of Glynn Research Limited, he noted: The work of our small research organization in the field of bioenergetics, which is now coming to a close, has been remarkably successful. To some extent this success may be attributed to accidents of history or pure chance. But the fact that we have sustained a successful and highly innovative research programme fairly continuously for some thirteen years indicates that factors other than pure chance have played a part in enabling us to be so productive. I suspect that not least of these factors is the small size and independence of our organization, which has permitted us to react relatively quickly, spontaneously and effectively to changing knowledge, and to the changing demands of our problems.28 In truth, the real value of Glynn with its small size was to provide Mitchell himself with a congenial research environment where he could think creatively. It was also a place where he could express his dominant personality without irksome contradictions and constraints. The people nearest to him were both women who sought to support him as strongly as possible. Moyle was able to act as an invaluable discussant of his ideas and to provide strong experimental support, while Helen Mitchell provided an emotionally secure home and a window onto a nonscientific world. His small staff recognized his ability and greatly respected him, even if they did find some amusement in his more outlandish ideas. Mitchell also felt that there were disadvantages to a small group.

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The year before, he had considered the need to move on to fresh areas of study. He had doubts about the ability of our small group to continue to operate usefully in the field of oxidative and photosynthetic phosphorylation now that our initiative has led to an understanding of the general principle of the mechanisms of these processes. Larger groups of research workers are often better adapted than small groups to deal with working out the details of processes of which the general principles are already understood. However our decision last year to continue to study key obscurities in the field of oxidative and photosynthetic phosphorylation has fortunately been vindicated by the general enthusiastic reception and experimental confirmation of our concept of the protonmotive Q cycle, which we introduced to explain many puzzling features of the detailed behavior of the cytochrome systems of animal, microbial and plant cells.29 While this view was almost certainly correct, there were possibly other reasons for Mitchell’s wish to change direction. It was not the experimental work that was the prime quality of Glynn as a research institution; it was the theoretical conceptions that had emerged over the thirteen years of its existence. It is true that some of those conceptions had required experimental justification and some proved to have no future. However, without the experiments, progress in understanding the chemiosmotic theory would have been very much slower. But it was the theoretical work that seemed to Mitchell to be complete. Perhaps the real reason Mitchell wanted to leave the field of oxidative phosphorylation was that he did not relish long drawn-out arguments over experiments that were designed to measure specific quantities in relation to the chemiosmotic process. Since the late 1960s he had wanted to look forward to a change of intellectual milieu from the chemiosmotic theory. He wished to work in a field where he could apply fundamental principles to the development of theoretical ideas, particularly where the outcome could be helpful in meeting the needs of humanity. Now, with advancing years, the matter was becoming pressing. The decision to cease biochemical research at Glynn was taken by the council of management in October 1976. From “1st October 1977, attention would be concentrated on the problems of the social behavior of Homo sapiens that were relevant to the current devastating social diseases which had reached frightening proportions for very many peo-

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ple.”30 This was the outcome of extensive discussions by Mitchell and Moyle on the future of the institute. A variety of possible projects for Glynn had been considered. Significant among these was a study of the enzyme responsible for fixation of atmospheric nitrogen. Although this was considered a worthy project, Mitchell and Moyle anticipated that the cost of the necessary equipment ruled out such a proposal as a practical alternative to the work on bioenergetics. Similarly, they considered the possibility that biochemical activities might have continued while at the same time starting up a parallel project in the field of social behavior. But at this stage they felt the lack of available funds made that possibility undesirable. Mitchell and Moyle had given much consideration to the wisdom of this total change of activity. They had entertained misgivings about moving into such a new field of study, but “in several respects the control of the interaction of individual people and of groups of people by the mediation of money was like the energetic inter-relationships between physical systems.”31 Three members of the staff—Roy Mitchell, Robert Harper, and Alan Jeal—were felt to be appropriate only to scientific work, and it was agreed that, in due course, redundancy notices (a legal requirement leading to dismissal) would have to be served. At the time Cornwall was not an area with a high demand for scientific personnel, and a year later the three men were still looking for alternative employment.



Developing a New Image for Glynn

Thus the work of Glynn Research Limited was now to take a totally new course. Such news was communicated to others in the field of bioenergetics, but some of those closest to Glynn saw this as a very undesirable step. Although Mitchell was resolute in deciding to change his subject, he did have serious misgivings about taking such a major and dramatic step. In a letter to Racker, he noted: It feels strange to be coming to the end of my time as a biochemist. The effects in anticipation are more disturbing than I expected. Rather like the terror of the ream of clean white paper that waits for one’s hesitant pen, when you know how to write but not what to write—only more so!32 As it became known progressively that Glynn was to pull out of work on bioenergetics, there were significant repercussions among his

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colleagues. Mitchell identified two responses: First, “There was a strong movement among the antagonists of the general chemiosmotic theory . . . to take advantage of our withdrawal and to press new, but illfounded research claims, the effect of which was to undermine the consensus of opinion which we had been working to promote.”33 Second, others brought pressure on Mitchell not to leave the field, a response which he had expected, but he was surprised by the intensity of the feeling. In particular, Lars Ernster from Stockholm, while on a visit to England, made a special visit to Glynn to persuade Mitchell and Moyle to continue with bioenergetic studies. It was probably Ernster who really influenced Mitchell to continue, as Mitchell subsequently wrote: “I thought you might like to know that your very kind and powerfully persuasive efforts last September were instrumental in causing Jennifer and me to change our decision about giving up the studies of bioenergetics at Glynn.”34 Thus at the formal meeting of Glynn Research Limited, it was agreed not to cease bioenergetic work at the end of September 1978. Rather, they would continue for a few more years with bioenergetics (now titled molecular biology) and, at the same time, would initiate a new project in behavioral biology. There is no doubt that Mitchell (and to some extent, Moyle) had undergone considerable strain during this period. As Mitchell wrote to Hinkle, referring possibly, in part, to his unsuccessful affair but more probably to his attempt to totally change the direction of Glynn: After an unsuccessful and rather traumatic attempt to escape from the biochemical treadmill, I am back in harness and am facing two tasks in which I would be extremely grateful to have your help. One is the writing of a book on chemiosmotic processes. The other is the expansion of the activities of Glynn Research Ltd., which is dependent on increasing our financial endowment.35 However, the book was never written. Mitchell saw two immediate consequences of his decision. First, the projects to be undertaken by the institute would need to be defined. Second, the membership of the management committee of the institute needed to be expanded. Since the institute’s creation, the annual general meeting had been a discussion between Mitchell and Moyle in consultation with their advisers, the solicitor and the auditor. The council of management engaged in a similar set of discussions, but without advisers. Thus the main difference between the almost daily discussions

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between Mitchell and Moyle and those of the formal meetings was that at the AGM and at the council, the discussions were recorded by the secretary (since 1969, Stephanie Key née Phillips) as minutes and that at the AGM advisers were present. Mitchell and Moyle decided on inviting Geering and Baum to become directors, making a total of four. Dr. Quin Geering, a long-standing friend of Mitchell, was a member of the research staff of Fisons Ltd., Cambridge. Professor Harold Baum was the head of the biochemistry department of Chelsea College, University of London, and had been engaged in bioenergetics for some time; he knew both Mitchell and Glynn relatively well. Both accepted the invitation and joined the annual general meeting and the council of management as directors of Glynn Research Limited beginning in June 1978. Their presence certainly served to restrain some of Mitchell’s wilder impulses. The possible projects were discussed in the summer of 1978. The molecular biology (bioenergetics) proposals were defined in general terms: “The molecular biology studies are concerned with the molecular mechanisms by which the chemical reactions of metabolism are coupled to the motion or transport of specific chemicals from one place or compartment to another within living organisms or between living organisms and their environment.”36 This formulation covered work currently in progress at Glynn and was sufficiently broad to allow for all likely developments. The reference to molecular biology showed a development in Mitchell’s thinking that became a reality at Glynn when Peter Rich became research director almost ten years later. The behavioral biology studies, which were never clearly formulated, were described as being “concerned with the recognition of the failure of communication between people that has resulted in the alarming increase in human destructiveness and aggressiveness, which most authorities regard as so serious as to endanger the survival of civilization. These problems have been outlined by Erich Fromm.”37 Reference was also made to the views of Popper and the Austrian economist Hayek, both of whom had much interested Mitchell. He wished to lead the behavioral biology project, while a senior research fellow could be brought in to lead the work on molecular biology. Mitchell did not see the new area of study as independent of the old. He felt that there were common principles that would enable the two fields cross-fertilize each other. More particularly, he felt that the science that had been so successfully pursued at Glynn could provide important insights for behavioral biology: “These studies involve two aspects of communication:

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the transmission of energy or power; and the transmission of chemical substances (nutrients, metabolites, ions, waste products).”38 Such developments required additional funding. The directors agreed that an additional endowment of £2 million was required and felt that the institute should now seek to raise such a sum. A general fund-raising campaign was felt to be too intrusive on the work of the institute, and it would therefore be better to persuade a few individuals to subscribe. The new directors would assist in making direct approaches to suitable trusts. A further issue raised at this time was the lease, which was due to expire in 1978. The directors considered that it might be time for the institute to seek the security of owning its own premises. They sought a valuation and advice from a firm of surveyors, and appointed Moyle to negotiate with the landlord, Mitchell. Thereafter, the lease was renewed at a more realistic (substantially higher) rent, and some additional accommodation was made available to the institute. In practice, the work of the institute continued along the lines already set. Fortunately for Mitchell and Moyle, the staff had still failed to find alternative employment and therefore continued at Glynn. The behavioral biology project was not started immediately and awaited both more definition by Mitchell but especially further funding. In fact, the required additional funding was never obtained, and other than a few essays Mitchell’s ambitions in this area were never realized.



Good News

News that Mitchell had been awarded the Nobel Prize in Chemistry for 1978 reached Glynn, not from Stockholm and the Nobel committee but from the news agency Reuters. Mitchell had been taking a late lunch after a morning’s work when his secretary (Stephanie Key) burst in, saying that he had won the Nobel Prize and that Reuters wished to speak to him on the telephone. Reuters wanted Mitchell’s reaction, to which he could only respond, “Astonishment.” Obviously, Mitchell had been aware of rumors and also realized that such an event was conceivable, but he certainly had not been awaiting the annual announcement of the prizes. In due course, the official announcement arrived. The secretary of the Royal Swedish Academy of Sciences wrote to confirm the award of the prize for chemistry on 17 October: “for your contribution to the understanding of biological energy transfer through the

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formulation of the chemiosmotic theory.” The prize would be worth £84,000. There are two interesting aspects of the award. First, it was not for the theory itself but, rather, for Mitchell’s contribution to an understanding of the process of energy transfer. As the chairman of the Nobel Committee for Chemistry wrote sometime later, “the committee was well aware of the fact that Mitchell was wrong about how the proton gradient is created (proton pumps rather than redox loops) and how it is utilized to make ATP. . . . That is why the academy’s citation read rather vaguely.”39 Such a view did not do justice to the Q cycle,40 but it must be remembered that the Q cycle was largely an unsupported hypothesis when the committee had its deliberations. Second, the award was the prize for chemistry. In view of the strong link of the theory with the process of transport of molecules in cells, and that Mitchell’s work served to unify aspects of metabolism and transport, the prize in physiology might have seemed more appropriate. Again, the award was made for the understanding of energy transfer rather than for the more physiological aspects of the work. From the moment of the announcement and for several months, the phone seemed to ring incessantly, and Mitchell received numerous telegrams and letters of congratulation. These included one from the chairman of Lloyds Bank, where Mitchell had banked for many years. In due course he responded, suggesting that the bank might consider providing some funding for Glynn. Unfortunately, the bank did not feel able to respond positively! Some were more lighthearted. Rufus Lumry at the University of Minnesota wrote: “My congratulations. Your success is just one more proof that popular acceptance of an idea generally means the idea must be wrong.”41 Mitchell felt that in many ways he did not approve of prizes in an area where he felt the work itself was its own reward. Nevertheless, he had to admit that the money was very valuable, coming at a time when he “had an enormous bank overdraft which had been partly created by the fact that a large part of my family money had been put into the Foundation.”42 He also felt that the prize was somewhat of a handicap. He liked being provocative and making remarks during discussions that were not well thought through, all of which seemed to be good fun. However, now as a Nobel laureate he found that people took his remarks rather seriously, making the prize something of a liability. It is not uncommon for Nobel Prizes to be shared between two or three people who have contributed significantly to the field. Indeed, J.

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B. Hanson from the University of Illinois some eighteen months earlier had asked in informal discussions at a bioenergetics conference why Mitchell had not received a Nobel Prize. He found no one was surprised at the question, but among the answers was the suggestion that adequate proof of Mitchell’s hypothesis was still lacking. Another was that a delicate problem exists: contributions such as those of Britton Chance toward understanding the electron transport chain and those of Efraim Racker in showing the properties of the coupling ATPase cannot be ignored. No award has ever been made for membrane coupling mechanisms, and after such a cautious delay any Nobel Prize would have to carefully recognize the accumulated contributions of many.43 Mitchell’s prize was not shared. While most scientists felt in 1978 that he deserved the prize, some felt it was premature and some voiced the view that the Nobel committee would have egg on their faces when the chemiosmotic theory was demonstrated to be untrue. However, the positive view was well expressed by Helmut Beinert, who wrote to Mitchell congratulating him: Many colleagues who do not necessarily agree with some of your more detailed schemes and interpretations, ratios and numbers, nevertheless feel that your basic ideas and your insistence on them have been the most influential factors in the development of bioenergetics in the past four decades and that this is justly recognized by the award.44 Some scientists felt that there were strong grounds for sharing the prize. This was a view held by some of the leading American bioenergeticists—certainly they had contributed greatly to the general understanding of bioenergetics. For example, such a view was expressed by one of the most significant contributors to the field: “I am glad that Peter was awarded the Nobel Prize—it certainly gives proper attention to a very useful hypothesis. I am very sorry, however, that those who labored so hard to bring substance to its shadow should not have been similarly recognized.”45 Indeed, many thought that Racker should have shared the prize. On the eastern side of the Atlantic, there were also scientists who had made major contributions. Certainly, one candidate for recognition would have been Bob Williams, the Oxford inorganic

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chemist who had fought hard to have recognized the importance of the proton in oxidative phosphorylation. Thus the award of the prize to Mitchell, while generally producing a lot of pleasure (for example, Mitchell received news of a party held at Sydney University to celebrate the award), also brought some disappointment and possibly a feeling of injustice in some areas.



Collecting the Award

In December, Peter and Helen, together with Jennifer Moyle, set off for Stockholm to receive Peter’s Nobel Prize. Initially, they traveled to London to have dinner with the Swedish ambassador, a tall imposing man with, as Helen put it, a delicious sense of humor. Their friends Prakash and Naomi Datta were also guests. Prakash Datta, the editor of FEBS Letters, was regarded by Mitchell as being outstandingly civilized in the way in which he ran the journal where Mitchell had published a great deal of his work. The following day they flew to Stockholm, where they were met by Professor Bernhard, president of the Swedish Academy. Avoiding customs, they were taken to the VIP lounge, where photographers awaited them. There they met their personal amanuensis, who looked after them for the week. From there they were taken to the Palace Hotel opposite the Royal Palace. In the evening they attended a reception for Nobel laureates, where Peter was able to talk to the Russian low temperature physicist, Piotr Leonidovich Kapitsa, then in his 80s. Although Peter wanted to talk philosophy, Kapitsa regarded the subject as irrelevant to the needs of the world. The round of social engagements continued, with a reception by Professor Bernhard, a tour of museums for Helen and Jennifer, a dinner given by Lars Ernster especially for Mitchell, a lunch given by the British ambassador, and dinner with the amanuensis, himself a nobleman. During the week, Mitchell gave his lecture at 3:00 in the afternoon. It was entitled “David Keilin’s Respiratory Chain Concept and Its Chemiosmotic Consequences.” As noted earlier, it was Keilin who had befriended Mitchell when he had been at a low ebb in Cambridge and to some extent had been a father figure for him. More particularly, Mitchell felt that the transport of protons across the membrane that he had explored was a property of Keilin’s respiratory chain. Keilin, whose work had established the respiratory chain, was not himself awarded a Nobel Prize. As Mitchell said,

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My immediate and deepest impulse is to celebrate the fruition of the creative work and benevolent influence of the late David Keilin, one of the greatest biochemists—to me, at least—the kindest of men whose marvelously simple studies of the cytochrome system, in animals, plants and microorganisms led to the original fundamental idea of aerobic energy metabolism: the concept of the respiratory chain.46 He referred to his early life at Cambridge and to his supervisor, Jim Danielli, from whom he had learned “the techniques and concepts of the membranologists.” He recalled that the general outlook of the department was “that of classical homogeneous solution metabolic enzymology.” He thought Keilin occupied a conceptual position between these two approaches to biochemistry. It was the great divergence of outlook of the two extreme views, membranes and solution enzymology, and the antagonism between them that persuaded Mitchell to seek a way of bringing them together. By contrast, any influences of the department of the University of Edinburgh did not feature in the lecture, although much of the work carried out at Edinburgh was discussed. In general, the lecture reviewed Mitchell’s life’s work around the chemiosmotic theme. He concluded that “with few dissenters, we have successfully reached a consensus in favor of the chemiosmotic theory,” and he paid tribute to his former adversaries, including Bill Slater, who had persuaded him in 1965 to become more involved in the field of oxidative phosphorylation. On Sunday afternoon, the ceremony took place; Mitchell himself looking quite relaxed. As Helen recalled, “Pete had half a smile on his face and didn’t look a bit nervous.”47 At the dinner afterward, Helen sat between the prime minister, whom she found dreary, and the controller of the royal household, whom she found intelligent and humorous. When Helen admired the jewels worn by the queen, the controller told her that they were only lent to her for the occasion. The social round continued during the early part of the next week and included dinner with the king and queen, when Mitchell presented the king with a silver Glynn piece. There was a visit to Gothenburg and dinner with Bo Malmström, who had chaired the chemistry committee. The award of the Nobel Prize in many ways changed Mitchell’s life. In a sense, it canonized him for the field of bioenergetics so that his views now had a weight that they had not had previously. While this appealed to a part of his personality, he often found the seriousness

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with which he was treated irksome and sometimes embarrassing. This was particularly so when his sense of humor got the better of him. Mitchell, although somewhat aristocratic in style, was not a member of the establishment, he never had been, and he thrived on being totally independent and able to view the world from a slightly detached vantage point. Essentially, Mitchell had made his great contribution to science by developing his ideas on linking metabolism vectorially with membrane biochemistry. As Ernster and Schatz noted in 1981 when considering the way in which an understanding of oxidative phosphorylation was developing, the baton was passing from the membranologist to the protein chemist.48 History has justified such a view. The next Nobel Prize to be awarded in the field went to those, particularly Paul Boyer and John Walker, who had concentrated on the protein chemistry.

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11
The Cytochrome Oxidase Controversy 1977–1986



An Argument

Mitchell was involved in many controversies. That concerning the cytochrome oxidase was certainly a major one and throws light on his personality and on his approach to science. It also provides a window on the nature of scientific debate. In the late 1970s, a major public argument with a Finnish biochemist developed over an aspect of the chemiosmotic theory. The question under debate, whether or not protons were pumped by the cytochrome oxidase (the terminal enzyme of the respiratory chain that reduces oxygen to water), was related to the more diffuse argument over the number of protons pumped by the respiratory chain, as discussed here earlier. It was an issue that was to be debated for eight years and in which many of the leaders in the bioenergetics field became involved. For Mitchell personally the underlying basis of the chemiosmotic theory was at stake.



The Origins of Mitchell’s View of the Oxidase

When Mitchell developed his original theory in the Grey Books of 1966 and 1968, he specifically considered the question of how the passage of electrons down the respiratory chain would move protons across the mitochondrial membrane. This led him to propose a molecular mechanism in which the respiratory chain was folded in three loops across the mitochondrion’s inner membrane. Each loop conveyed electrons in-

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ward and hydrogens (protons plus electrons) outward. Thus the loop in one direction was composed of electron carriers and in the other direction consisted of hydrogen carriers. The consequence of this approach was that the cytochrome oxidase complex itself (complex IV) should be unable to translocate protons since it possessed electron carriers but lacked proton carriers. Mitchell’s approach was to assume that the protons, which moved out of the mitochondrion (six per oxygen atom reduced), were all associated with the earlier part of the respiratory chain (see fig. 11.1). Thus he developed a theoretical position that denied any proton translocation by the cytochrome oxidase, the terminal enzyme. This

Figure 11.1 Mitchell’s proton pumping respiratory chain, 1966. The quinone (ubiquinone, coenzyme Q, CoQ) transports two protons outward, and the oxidase, composed of cytochromes a, a3, and copper (Cu), conveys electrons inward to reduce oxygen to water on the inside of the membrane. Cytochrome b conveys electrons inward. The transfer of electrons from cytochrome c to oxygen is not associated with proton transfer across the membrane. Adapted from P. Mitchell, Chemiosmotic Coupling in Oxidative and Photosynthetic Phosphorylation (Bodmin, Cornwall: Glynn Research Ltd., 1966).

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was strengthened by the formulation of the Q cycle in 1975. The six protons per oxygen atom reduced could be readily accounted for: four were translocated by the Q cycle in complex III, and two were translocated by the NADH dehydrogenase (complex I). Thus his arithmetic was sound even if, during the late 1970s, it had been challenged by Lehninger, whose proton measurements gave not six but nine to twelve protons per oxygen atom. However, in the late 1970s Mitchell’s view, that the cytochrome oxidase did not translocate protons, was challenged by the Finnish biochemist Mårten Wikström.



The Challenge to Mitchell’s View

Mårten Wikström initially worked with Nils-Erik Saris in the 1960s in the University of Helsinki on mitochondrial studies. After holding a fellowship from the European Molecular Biology Organisation in the early 1970s in Bill Slater’s laboratory in Amsterdam, he had returned to the University of Helsinki as assistant professor and later as professor of medical chemistry. He had also spent a year working with Chance. An association between Mitchell and Wikström had been initiated mainly through correspondence at the end of the 1960s. Over the succeeding years the relationship had become increasingly cordial, partly because Wikström recognized the rightness of the chemiosmotic hypothesis. His respect for the author of the chemiosmotic theory is perhaps best summarized by the remark that Mitchell “was a genius, there is no other word for it.”1 In March 1977 Wikström published in Nature an article in which he claimed to demonstrate the translocation of protons across the inner mitochondrial membrane by cytochrome oxidase.2 Before the article appeared, he wrote to Mitchell, enclosing a copy of the manuscript and inviting him to comment. A month later Mitchell responded that Moyle had followed up Wikström’s experiments in the laboratory at Glynn, but that they were “quite unconvinced by the experimental evidence” that Wikström had provided in support of his argument. “We are practically convinced that the proton translocation that you see arises not from cytochrome oxidase activity but from the oxidation of NADH or other endogenous hydrogenated substrates.”3 In other words, Wikström’s observations were an artifact of the experiment that had therefore been misinterpreted. However, Mitchell concluded with an invitation to visit Glynn at the earliest opportunity.

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Mitchell’s letter had little effect since Wikström, writing to Peter Hinkle at Cornell a little later and copying the correspondence to Mitchell, Slater, and others, expressed his confidence in proton pumping by the oxidase.4 Meanwhile, in December Mitchell wrote to Slater, stating categorically that “the activity of cytochrome c oxidase is accompanied by net electron translocation but not by net proton pumping.”5 In his experiments Wikström had used an artificial electron donor (ferrocyanide) to feed electrons to the enzyme (see fig. 11.2) and claimed that a pair of protons were pumped across the membrane for every two electrons from the ferrocyanide used by the oxidase to reduce oxygen. The issue of electron donors to the oxidase was to prove a crucial question. Cytochrome c is the natural donor, but experiments with this protein were technically difficult. Thus most work was done with artificial donors, but the experiments were open to the criticism that they did not reflect the true reaction of the oxidase in the intact mitochondrion. A further issue that affected the dispute was that the two groups routinely used different methods to prepare their mitochondria. Nevertheless, in due course Wikström did show that cytochrome c oxidation by the oxidase was linked to proton translocation under his

Figure 11.2 Measurement of cytochrome oxidase activity using ferrocyanide as a source of electrons. Ferrocyanide and other electron acceptors are used to reduce cytochrome c in the membrane. Electrons then pass from cytochrome c to the oxidase, which uses them to reduce oxygen to water (four electrons are necessary to reduce an oxygen molecule to two molecules of water). Ferrocyanide replaces complex III (the cytochrome c reductase) as a source of electrons, but in order to be certain that all electrons come from the ferrocyanide and that complex III is not active, it is inhibited. Inhibitors of complex III include antimycin and myxothiazol.

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experimental conditions. However, this was not confirmed under the experimental conditions used by the Glynn group. Hence a new ox phos war began. In November 1977 Wikström reinforced his argument that the oxidase pumped protons in a more detailed article (coauthored with Herkko Saari).6 If cytochrome oxidase pumped protons, then Wikström felt this supported the chemiosmotic theory. In contrast, Mitchell felt that since mechanisms he had proposed for proton translocation could not operate in the oxidase, these results opposed his theory. Wikström’s solution to the problem was to suggest that proton pumping was driven by a conformational change in the oxidase. In contrast to Mitchell’s theory with its well-defined proton transport mechanisms, such a change in conformation could not be readily defined and, hence, was regarded by Mitchell as “black box” biochemistry. It also suggested to him that Wikström’s views were supporting the conformational theory of Paul Boyer rather than his own theory. Indeed, Mitchell wrote to Wikström: I think we should maintain a sense of proportion about exclusively conformational types of coupling mechanism, because not a single case of this is known in the coupling of one chemical reaction to another by enzymes or enzyme complexes. . . . As the exclusively conformational mechanisms can accommodate any stoichiometry [number], they encourage sloppy experiments.7 In December 1977, Wikström enthusiastically accepted the invitation to Glynn, also in this letter. He stayed in the house with Peter and Helen with the institute meeting his expenses. A former colleague of Wikström’s, Slater, joined them for part of the time. It is interesting to compare the differing expectations for this meeting. Wikström told Mitchell that his “foremost aim will be to try to convince you and Dr. Moyle of the proton-translocating properties of the cytochrome oxidase.”8 Mitchell clearly had the reverse view: in a letter to Hinkle, he commented that he hoped “to lay some of the ghosts of conformationally magical proton pumping by cytochrome oxidase. We hope that Mårten may be induced to retract some of his recent claims after his visit.”9 The visit was certainly a social success, and Wikström described his time with the Mitchells as a most wonderful four days. The time was spent mainly in discussion of issues rather than in carrying out experiments, but it is questionable whether the occasion was a scien-

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tific success. Two months later Mitchell expressed his view of the matter in a letter to Slater: “Wikström has been misled by an unfortunate set of artifacts. It is a pity that he published his observations before doing more careful experimental controls to verify his rather speculative interpretations.”10 A more serious issue that damaged, albeit temporarily, the relationship between Wikström and Mitchell was a patronizing postscript to a letter sent to Wikström toward the end of January 1978. Although it includes technical issues, Mitchell’s concerns are clear: Jennifer and I feel sad that we have to disagree so flatly with your new interpretation of the action of cytochrome c oxidase. We really are sorry about that. But we do attach great importance to the stoichiometric data, and to the wise use of reagents like NEM in studies of oxidative phosphorylation. As we explained, during your visit last year, we have been much exercised by the recent effects of the conformational and NEM bandwagons in the field of bioenergetics—which has never been famous for the quality of the dialogue at the strictly scientific level. We are still struggling to try to achieve a more analytically simple (group- and electron-translocation) rationale, for the sake of the more analytically-minded students that we would like to help to recruit into this fascinating and important field of study. We think imagination is very important; but we would like to encourage people to use less imagination in the interpretation of individual experiments. That is why we were inclined to emphasize so much, during our conversations with you here, the importance of sabotaging one’s own native disturbances by means of numerous control experiments.11 This comment was not well received by Wikström, who found it difficult to reply. He objected to Mitchell’s flat disagreement on the substantive issue; to Mitchell’s claim that he had shown unequivocally that the oxidase did not pump protons; and, most particularly, to the postscript, which implied such heavy criticism of Wikström’s work as a scientist. Mitchell apologized for the offense but still tried to defend his statement. The damage was done, and Wikström stated that he would have to defend himself in public. Nevertheless, serious correspondence continued; at the end of March in a postscript, Wikström invited Mitchell to “accept a bet of a 25 box of Partagas cigars about whether cytochrome oxidase pumped protons or not.”12

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Mitchell’s Defense

Mitchell replied immediately with a counterproposal in a letter otherwise devoted to arguing about the positions adopted by Wikström and himself. Perhaps in part to make amends for the rather carping tone of the earlier part of the letter, he concluded: It seems to me to be interesting (and perhaps good) that the same data can give rise to such diametrically opposed interpretations and views even in comparatively exact science. Obviously we disagree—but don’t let’s quarrel about it. Our fellow scientists (for whom we write our papers) will eventually help us to discover which of us is mistaken. I will lay a bet with you on the basis that I will give you a box of 25 Partagas cigars if it turns out that Jennifer and I (and Peter Hinkle and Sergio Papa) are right in our interpretation that cytochrome c oxidase does not normally have the function of pumping protons across the mitochondrial cristae membrane as you have claimed.13 Wikström replied in respect of the first part of Mitchell’s letter that he did not mind being attacked but accepted the bet with the added condition that he would give Mitchell the cigars if he (Mitchell) were wrong. Concurrently, Moyle and Mitchell responded with an article, “Cytochrome Oxidase Is Not a Proton Pump,”14 a title suggested by the editor of the journal. A copy of the manuscript was sent to Wikström and to several others. In the article, Mitchell claimed that his view that cytochrome c oxidase only translocated electrons, not protons, was supported by Hinkle, Papa, and Racker. He concluded from experiments done at Glynn that the oxidase did not pump protons and explained Wikström’s results as due to an unidentified electron donor. In essence, Mitchell argued that such proton pumping as people observed in whole mitochondria was due to other concurrent reactions. In August 1978 Wikström wrote a tense letter to Mitchell. The reason for writing was “to try sincerely once more to make you realize (perhaps through some extra experimentation of your own) that you are incorrect vis-à-vis the cytochrome problem.” After an extensive discussion of experimental results and their interpretation, Wikström wrote that he was by now absolutely sick and tired of this controversy . . . and I very much hope that the two of us can settle it before the end of

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the year (in time for Christmas cigars!). So can’t we now agree on a simplification of the controversy (to prevent confusing discussion on all the different experimental steps) and decide that [your] O2 pulse experiment with cytochrome c++ as substrate (which seems to have a minimum of complications) is The Decisive Issue? . . . I therefore kindly ask you to do this experiment again under your kind of conditions and then tell me what was wrong with it. All right? Please!15 The award of the Nobel Prize to Mitchell, on which Wikström sent a congratulatory cable, inhibited further discussion. In fact, the correspondence was not taken up until May 1981 when Wikström fruitfully reopened the discussion. During 1981 Mitchell responded to Wikström’s 1978 letter quoted above and agreed on the significance of experiments with cytochrome c. However, further results obtained at Glynn from similar, although not necessarily identical, experiments did not match those from Helsinki. Despite the closeness of Mitchell and Hinkle, it was from Wikström that Mitchell heard about Hinkle’s confirmation of proton pumping by the oxidase with cytochrome c. Mitchell immediately wrote to Hinkle to clarify the position. In reply, Hinkle admitted to Mitchell that although relations with Wikström were strained, nevertheless experiments at Cornell were beginning to give support to Wikström’s position and the cytochrome oxidase “looked more and more like a proton pump.”16 However, later, when Mitchell visited Hinkle, he was unmoved by the latter’s experimental demonstration of the oxidase pumping protons. In the same letter, Hinkle tried to persuade Mitchell to soften the language in his papers. He advised Mitchell, “I think the tone is so strong that the neutral reader and your opponents are turned off and don’t take your arguments as seriously as they should.” Mitchell replied, “Don’t you think it is good, sometimes, to call a spade a spade or an artifact an artifact?”17 Despite this negative response, Mitchell took Hinkle’s advice seriously but perhaps without too much effect. It is doubtful whether many others apart from Hinkle could have made Mitchell seriously consider the matter. The overall position was now complex. At an international symposium in Japan, Wikström reinforced his position that the oxidase translocated two protons per oxygen atom reduced. He found himself in a middle position, being strongly opposed by the Glynn team on the one side (who claimed no protons were translocated) and now on the other

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side by Lehninger’s group and Azzone’s group (who claimed four protons). Meanwhile, Mitchell and Moyle responded vigorously in lectures and conferences to these attacks as they saw it, on the chemiosmotic rationale as developed at Glynn.18 They reinforced their view that protons were transported across the mitochondrial membrane only by variations of Mitchell’s proton-conducting loop mechanism. The results of experiments showing proton translocation by the cytochrome oxidase were attributed to two types of artifact. The first was other independent proton translocation reactions taking place concurrently with the oxidase reaction. The second arose from release of protons during other reactions with cytochrome c. If these artifacts were taken into account, then cytochrome oxidase did not translocate protons. These controversies, together with the excitement of formal and informal celebrations resulting from the award of the Nobel Prize, inevitably took their toll. Toward the end of 1979 and again at the end of 1980 and the beginning of 1981, Mitchell experienced a serious recurrence of his problems arising from the unsuccessful ear operation in 1972—intense hallucinatory noises accompanied by vertigo and nausea, which caused him to cancel engagements and writing assignments.



A Birthday Celebration

In 1980 Mitchell celebrated his sixtieth birthday. Leaders in the bioenergetic field decided to publish a book in his honor. Peter Hinkle and Vladimir Skulachev (from Moscow) edited the volume, but not without difficulties. According to Hinkle, the Russians apparently were not allowed to use glue on their envelopes, with the result that one from Skulachev had arrived in Cornell empty! The threat of a possible invasion of Poland by the Soviet Union also threatened the satisfactory completion of the project. After consultation with Mitchell, Hinkle and Skulachev agreed on the title: “Chemiosmotic Proton Circuits in Biological Membranes.” In their preface, the editors noted that “the chemiosmotic theory explains a broad range of phenomena in transport and coupling of biochemical reactions so that the electrochemical proton gradient across the membrane is now regarded as a central energy currency equal in importance to ATP.”19 Over fifty workers in the field contributed papers, and Mitchell accepted an invitation from Hinkle to write the final chapter, possibly on ”some theoretical bit.” In the end, he wrote a broad-ranging

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article, particularly stressing vectorial principles that he felt had to some extent been ignored. The formal presentation was made at a Gordon Conference held at Plymouth, Massachusetts, in the summer of 1981, while a special leather-bound edition was sent to Mitchell later. Subsequently, Mitchell commented that the “celebration was done pleasantly, and with a lightness of touch that I really appreciated and enjoyed.”20 Among the articles in the book were two of relevance to the cytochrome oxidase controversy. Wikström contributed a further paper in support of his notion of the proton pumping oxidase. However, a second contribution on oxidases, this time in a bacterium known as PS3, was contributed by the Japanese biochemist Nobuhito Sone. This also supported the view of proton pumping by oxidases. Subsequently, Sone published work with Hinkle that further strengthened the notion of a proton translocating oxidase for the biochemists in general, if not for Mitchell.



The Field Resolves Itself into Two Opposing Camps

In the summer of 1981, Mitchell and Moyle traveled to the University of Bern, Switzerland, to discuss the oxidase issue with Angelo Azzi. In preparation for the trip, Mitchell reconsidered the evidence for proton pumping yet again. He concluded in a letter to Hinkle that the evidence for the proton pump “has a very uncanny resemblance to the type of evidence that was supposed to show the existence of energy-rich intermediates [in oxidative phosphorylation] of twenty years ago,”21 when Mitchell first put forward the chemiosmotic hypothesis. Mitchell continued to advance alternative explanations for the results obtained in other laboratories. For example, in the case of proton pumping observed by purified preparations of the oxidase inserted into vesicles, he argued that protons released were due to a reaction of cytochrome c with the lipid of the vesicles. They were not pumped across the membrane. The field was now effectively divided into two camps. Mitchell, arguably the most senior scientist, together with Moyle and supported by the Italian biochemist Papa, firmly believed that the cytochrome oxidase did not pump protons and that observations of proton pumping made by other workers were artifacts. The other camp, now becoming much the larger, was led by Wikström and was supported by an impressive international group composed of Hinkle, Azzone, Lehninger,

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Slater, and Sone, among others. It is perhaps misleading to describe those who believed in proton pumping by the oxidase as a single camp. Wikström observed that “it is amusing, almost tragicomic, that I now receive letters from you [Mitchell] and from Al [Lehninger] both telling me that I am wrong.”22 Mitchell argued that no protons were pumped by the oxidase, while Lehninger argued for four protons per oxygen atom reduced. Indeed, Lehninger wrote to Mitchell and argued that the problems arose from poor experimental technique: “We believe that the low H+/O ratios obtained in many laboratories are the result of incomplete or defective reconstitution of the enzyme, because lipid mixtures that do not resemble those of the inner membrane were used.”23 The field was now in a state of confusion. In March 1982 Franklin Harold from Denver, an early supporter of the chemiosmotic theory, visited Glynn while on an extended stay at the University of Aberdeen. The oxidase issue was discussed among many others. At a colloquium devoted to microbial bioenergetics that was organized by the Biochemical Society in April 1982, Harold informally discussed the issues surrounding the oxidase. He wrote to Mitchell later that at the meeting there was a fair cross-section of Britain’s bioenergetics community. . . . To a man, they have accepted the proposition that the oxidase pumps protons, and were rather surprised to learn that you maintain otherwise. In truth, I also had felt that Wikström’s case was solid and probably correct; and it is only your and Jennifer’s forceful arguments that have made me reopen the issue.24 Mitchell was not surprised by the news but felt “that the problem is not unlike that of the UFO! Once you postulate it, people are inclined to see it.”25 Clearly Mitchell was isolated but nevertheless still felt he was right. At about this time, he and Moyle commenced experiments with purified cytochrome oxidase incorporated into lipid vesicles. Mitchell turned to Tsoo King at the State University of New York at Albany for suitable preparations of the enzyme for such experiments and to John Wrigglesworth at Chelsea College (later King’s College London). Such experiments had the advantage that other complexes of the respiratory chain were absent and other substrates should not interfere with the observations. However, at an early date Mitchell and Moyle observed proton release from lipid vesicles treated with cytochrome c but lacking any oxidase!

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Resolving the Future of Glynn

Mitchell continued to receive honors from various organizations and universities. In 1981 he received the Copley Medal of the Royal Society, perhaps its most prestigious award. Those previously honored in this way had included Keilin, Perutz, and Sanger, but there were those who felt that Mitchell did not have the stature appropriate to the award. Early in 1982, as the cytochrome oxidase controversy continued, Mitchell applied for a Royal Society professorship for which he was short-listed but did not get. No doubt the main reason for the application was a financial one, but other factors now began to arise for the future of Glynn. Moyle’s retirement was becoming imminent. Mitchell himself was involved in several disputes, and, in addition, he had several times considered a change in direction. On this occasion, he developed a specific new research strategy for the institute and consulted Slater. The major issues were numerical. How many molecules of ATP were synthesized per atom of oxygen reduced to water by the respiratory chain? How many protons were transferred across the membrane per atom of oxygen reduced? Particularly, how many protons were pumped by the cytochrome oxidase? This latter number was still regarded by Mitchell as zero. To answer these questions, Mitchell felt a new research team would be appropriate: himself with four experienced research workers supported by four technicians. Of the research workers, he hoped that two could be obtained on leave of absence from a university for a period of three to five years. He would need to secure funding for the project, which should be for five years in the first place and if work was successful should be renewable. Slater was not impressed. He agreed that there was a need to tackle the numerical problems. He discussed a variety of issues themselves before coming to “the difficult part.” I do not think that you are the person to lead a team of 4 experienced research workers plus 4 technicians (and it makes no difference if someone else is formally the principal investigator) tackling this problem. You have never had a large team: your strength has been to be tucked away in Cornwall with Jennifer and one or two others, free from distractions and the teaching responsibilities (including training future senior investigators) that others have had. You have been able to lead the field by your writings and your interpretations of other people’s experiments, many of which have

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been inspired by your ideas. This has been your “thing” to use a modern phrase. You have received the highest honours that exist in science as recognition of your contributions.26 Slater concluded that Mitchell had many more years before him, but he should not now be looking for new ways—he should stick to the old. Why not, said Slater (an enthusiastic sailor), do something else, like sailing? Finally Slater admitted that the advice he had been asked for and given would not be liked. Mitchell responded positively, although he was not daunted by Slater’s view of him as a kind of “Cornish gnome,” who was not a person to help implement the solid research program he had put forward. “Perhaps it is the ‘something else’ that is waiting for me to do! Only time can tell.”27 Despite Slater’s cold response, Mitchell still needed to resolve the issue of Glynn’s future and its research. Moyle would retire in 1983 having worked with Mitchell for about 35 years. This association had been initiated in Cambridge, she had moved with him to Edinburgh, and with Mitchell she had been a cofounder of Glynn. She had spearheaded the experimental work in the laboratory; she had been a continual support to Mitchell, the person with whom he discussed his scientific ideas on an almost daily basis. With so much support from Moyle, Mitchell felt slightly guilty that she had not received more recognition for her contribution. In 1982 he had sought a public honor for her. Accordingly, he had asked Lord Swann to put her name forward, but he also wrote to the permanent secretary of the department of education and science in support of Swann’s recommendation: Dr. Moyle was co-founder with me of the Glynn Research Institute from which I write this letter as Director of Research. Dr. Moyle and I have worked together for more than a third of a century, and I would like to put it on record that without Dr. Moyle’s outstanding contribution to the work of this Institute, I think it is most unlikely that we would have achieved our present position as an internationally recognised centre of excellence in research on biological aspects of energy conservation. Dr. Moyle is a uniquely talented experimentalist. Indeed, I would say that I know no other biochemist whose experimental skill and judgement is superior to that of Dr. Moyle. I feel particularly strongly that Dr. Moyle’s contribution to British Biochemistry deserves more explicit recognition than it has so far received. Dr. Moyle has been my chief collaborator, and has

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done the greater part of the experimental work at the bench, which has been instrumental in obtaining the new knowledge and developing the new biochemical and bioenergetic theory for which I, as the leader of our small research group, have received many honours, including the Nobel Prize for Chemistry in 1978. The part that I have played in the new theoretical developments has tended to overshadow the immensely important role of Dr. Moyle’s experimental contributions to our joint efforts—to my mind, quite unfairly. It would indeed be good if the balance could be redressed.28 However, Mitchell’s efforts were not rewarded, nor were his attempts to obtain an honorary degree for Moyle. Even if he could not get Slater’s support for the new grand design, Mitchell needed to solve the question of replacing Moyle and managing the laboratory. He therefore approached Ian West, whose earlier work at Glynn had impressed Mitchell. West was now offered a research readership (a senior research position) at Glynn for a period of five years, his role to be essentially that of Moyle—to run the laboratories and do the experiments. However, the finances of Glynn could only support West for two to three years, and thereafter external funding would be necessary. West felt that with his family responsibilities, which included three children, he could not surrender the security of a permanent lectureship at the University of Newcastle for a short-term appointment at Glynn. In the end, West negotiated a five-year leave from the university, thus keeping his post open for his return. On West’s arrival, discussions about funding his work were continued. After an abortive attempt, a successful application was made to the medical research council, with West listed as principal investigator. It was for a period of three years but was subsequently extended for a further year, which by that time covered the remainder of West’s time at Glynn. West remembers the early part of his appointment at Glynn as very enjoyable. There were four scientific members of the team: Peter Mitchell; Roy Mitchell (no relation to Peter), now a full scientist rather than a technician; John Moody, who had recently come from York where he had completed a Ph.D. with Bob Reid on the transhydrogenase; and West himself. This group would meet every Monday morning to review the previous week’s work and to plan that week’s experiments. Roy Mitchell, Moody, and West worked closely together and also discussed

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a variety of problems in the field of bioenergetics. Much of the experimental work was concerned with resolving the various numerical problems. The scientists were supported by three technicians and three fulltime and one part-time support staff.



Issues of Communication between Scientists

The several controversies in which Mitchell had been involved led him to consider the basic questions about the way in which scientists make choices between differing theoretical positions. From the late 1970s Mitchell had developed a strong interest in the question of human communication—in particular, communication between scientists. Thus he had tried to steer the institute toward the study of what he described as “behavioral biology.” At the heart of this was the question of relationships and communication between people. When Slater had complained about being imprisoned in his office at the University of Amsterdam by paperwork, Mitchell had sympathized with him. He felt that bureaucracy sapped one’s vitality. The root cause seemed to be a failure in human communication and relationships. In 1982 when the crisis over proton translocation by the cytochrome oxidase was at its height, Mitchell had published some of his views on the subject of scientific communication, views clearly influenced by the particular problems he was having over the cytochrome oxidase issue.29 He considered the irrational (as well as the rational) aspect of the evolution of ideas. His argument started with the inaugural lecture of the nineteenth-century chemist, van’t Hoff, who had himself been caught up in a major scientific dispute in Germany and who gave to his inaugural lecture for his professorship at Amsterdam the title “Imagination in Science.” Mitchell went on to consider ideas of the philosophers Ogden, Richards, Popper, and Holton, outlining the relationships between the worlds of real things, the mind, and symbolic models that equate to theories. Mitchell developed these ideas to include the conjectural foundations of theoretical positions (not a dissimilar notion to that of Kuhn’s paradigms). The particular issue of interest to Mitchell was the change in conjectural foundation, a change of theoretical position that he felt was “more like a leap in the dark, the consequences of which cannot be adequately appreciated until after a good deal of experimental testing and conceptual familiarization.”30 Where there was a choice of theory, there were two distinct methods for making the choice.

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The first method was “analytic and involves quantitative or observational tests of the predictive capability of hypotheses.”31 While this method is very powerful, it can be undermined by experimental or observational imprecision; it also suffers from the possibility of selecting the experiments that seem to show what a given hypothesis predicts one should observe. Thus the very prediction of a phenomenon or entity may temporarily give rise to its apparent observation: “Consequently it may take some time to settle even such a simple scientific question as: Does the hypothetical proton pump of cytochrome oxidase exist or not?”32 The second method of deciding between hypotheses is based on the question “which theory does the scientific fraternity prefer to use, which has the greater generality and which is the most attractive and convenient?”33 It was these two methods of resolving issues, particularly the second, that lay behind the meeting that Mitchell planned for the early spring of 1983. It was reinforced by an underlying conviction that “the peaceful and largely amicable evolution of objective science by the fraternity of subjective often very individualistic and idiosyncratic scientists is an achievement of humanity not science.”34



The Octavian Meeting, or the Battle of Bodmin

To help resolve the situation, Mitchell decided to convene a “Collaborative Consultation on Electron Translocation and Proton Ejection by Cytochrome Oxidase Vesicles” on 22–24 March 1983 at Glynn. In addition to this primary purpose, there was a significant secondary purpose; he wished to put to the test some of his ideas about scientific communication partly based on issues just described. Comments made later, when considering the outcome of the meeting, give an indication of Mitchell’s thinking: I continue to think that there is much that can be done to enable the standards of collective scientific enquiry to be improved. . . . I admit that it is difficult to judge at all accurately just how effective scientific communication may be in a given context: but I think, nevertheless, that it is possible to see, in the historical development of scientific enquiry, how progress in building up a body of practically applicable scientific knowledge (the crucial test of

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good science being that the knowledge actually works, whereas incantations do not) has accelerated as reliance on authority and the acceptance of the views of potentates or physically powerful masses of people, or the acceptance of God-given inspiration (Einstein’s “God doesn’t play dice”) has given place to reliance on rational open-minded discussion, and the willingness to re-examine the experimental basis of accepted ideas.35 Thus the meeting was intended “to improve the effectiveness of the scientific communication system,” and within this Mitchell hoped to encourage collaborative and open-minded discussion, which would consider the evidence for the positions held. Specifically, the three main aims were identified as: 1. To exchange and discuss information about experiments on cytochrome oxidase vesicles 2. To help resolve the existing division of opinion about proton pumping by cytochrome c oxidase 3. To assess the performance of such a consultation in facilitating the first two aims and in providing a forum for communication.36 The meeting took a form quite unlike that of a normal scientific meeting and was designed for the discussion of issues rather than the presentation of results. Mitchell invited the participants with the intention of having twenty present; in fact, nineteen attended. The meeting was to be a set piece held in the lofty “Prayer Room” at Glynn complete with its gallery. Into the center of the room, observed from above, Mitchell placed a specially made octagonal table with eight seats that became the focal point. Rules were established whereby only those at the table were able to speak and enter into the discussion. Those at the table not involved in the discussion were expected to surrender their seats to others who wished to contribute. Discussions were timed for thirty minutes on a specific topic following a precise program. This approach successfully ordered the discussion and appears to have enhanced its quality. The gallery was occupied by those who wished to observe the meeting, particularly those who were interested in the issue of communication and who therefore had an excellent vantage point. Two sociologists from the University of Leicester were present for the occasion and subsequently presented a report on the meeting. Despite the formality, the occasion was generally regarded as a success as far as communication was concerned. Those wishing to con-

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tribute gained access to the table, and in general those at the table surrendered their seats when necessary. The same conclusion could not be drawn about the other major purpose of the meeting. While the two camps may have understood each other better, they nevertheless retained their own views about the question of proton pumping by the oxidase. From the gallery it appeared that the “pumpers came to the meeting confident if not convinced that they were right. They viewed the meeting as a battle,” and one of them was observed to draw a cartoon entitled “The Battle of Bodmin.” Their “expectation was that in the cut and thrust of the engagement they would vanquish the opposition.” The anti-pumpers were similarly confident “that the pumpers were wrong, and if only in this respect, that they were right. They (the antipumpers) eschewed the conventional adversarialism of scientific debate and sought to establish the validity of their skepticism through a collaborative and self-critical examination of experimental evidence and theory.”37 Mitchell felt that the “meeting worked remarkably well technically,” but he was “much less happy about its effectiveness in assisting the evolution of scientific comprehension.”38 Not everybody present at the meeting was committed to one view or the other. Ian West took a neutral view at the outset. Having heard the claims of both sides, he concluded that, while the evidence for pumping was strong, the counterarguments of Mitchell and his allies could not be dismissed or ignored. Perhaps the most interesting observation on the meeting came from Michael Gordon of the Primary Communications Research Centre of the University of Leicester. He told Mitchell: By virtue of your standing in the field of chemiosmotic theory, you appear to have almost a veto on the acceptance of the pump model as established “knowledge.” So although by the rules of political democracy, the pumpers won over the floating voters at Bodmin, and can claim a clear overall majority, this represents only a partial victory. For yours is the vote they seek.39 Wikström certainly did not regard the meeting as an unqualified success. On arrival back in Helsinki, he wrote to Mitchell, expressing his pleasure at the hospitality he had received but complaining that people had unreasonably selected their data to support their arguments. Those he cited were in the Mitchell camp, mainly Mitchell and Moyle. Mitchell did not reply, and their correspondence only resumed

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more than six months later when Wikström wrote to Mitchell about quite different issues.



Interpretation of Experiments

Mitchell and Moyle carried on with new experimental approaches. Meanwhile Mitchell continued to provide further explanations as to why proton pumping was an artifact. In part, he was prompted by the fact that in most cases when protons were pumped—apparently by the oxidase—the decay of the proton gradient did not follow the expected course but returned to the baseline. This suggested to Mitchell that the protons had come from another source, possibly from a reagent. However, the principal problem was that in mitochondria prepared in sucrose (a generally accepted method for preparing good mitochondria, and the one used at Glynn), proton translocation could not be observed when the natural substrate cytochrome c was added, even though it was clearly oxidized; however, mitochondria prepared in high salt (an alternative method, and the preferred method used in Helsinki) did pump protons when cytochrome c was oxidized. Mitchell regarded the sucrose-prepared mitochondria as the test case and felt that any proton pumping observed was due to other oxidations taking place in the mitochondria. Much time at Glynn was spent with purified cytochrome oxidase incorporated into vesicles that did appear to pump protons when cytochrome c was the substrate for oxidation. Here Mitchell felt that the observations could be accounted for by reactions of cytochrome c with the lipid in the vesicle. Cytochrome c binds membrane surfaces differently in the oxidized and reduced states. Mitchell suggested that, when cytochrome c was oxidized, a change in binding brought about a release of the protons from the surface of the vesicles. Thus the protons appeared in the medium when cytochrome c was oxidized, but these had not been pumped across the membrane by the oxidase. This argument was supported by ingenious alternative explanations for other experiments that were supposed to show proton pumping.40 Mitchell’s ability to propose plausible alternative explanations of experimental results that had not occurred to others helped to sustain his position based on his own version of the chemiosmotic rationale. However, some felt that he ignored control experiments done by others that negated his explanations. In March 1984 Wikström visited Glynn again when Mitchell, Roy

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Mitchell, John Wrigglesworth (King’s College, London), and Ian West were all present. It had been agreed that experiments performed in Helsinki, which demonstrated proton pumping, should be carried out at Glynn. Wrigglesworth recalls that the proton gradient obtained was not quite as large as Wikström normally obtained but larger than that obtained at Glynn. The Glynn team attributed discrepancies to the strangeness of the rats used to prepare the mitochondria! Wikström recalls that when he was shown the results, Mitchell responded, “We sometimes get this artifact too.” Mitchell’s diary records that “little progress was made . . . still rather a mess.” Wikström recalled that Mitchell seemed to lose interest when the results were obtained and changed the subject of discussion to other issues. However, by May 1984, Mitchell seems to have begun to give up the fight. To King, he gave an account of a meeting he attended that month in Dortmund at which the Swedish bioenergeticist Bo Malmström gave a talk on the mechanism for proton pumping by the oxidase. Mårten Wikström commented in the discussion that the existence of the proton pump is now virtually certain, and implied that we have now reached the stage where it is unreasonable to doubt the strength of the evidence for it. That now seems to be the conventional wisdom. It seems best to remain silent. But I could not help feeling a bit sad—not for myself, but over the state of affairs.41 The biochemical world was moving against Mitchell. In a review of proton pumping by the oxidase, Malmström wrote in the late summer of 1984 that he would “start from the explicit assumption that the protonpump activity is a reality.”42



Resolution of the Controversy

Formally, the point at which Mitchell admitted that he had been wrong came with the publication of a new theoretical chemiosmotic mechanism for the operation of the cytochrome oxidase. This showed how the protons could be conducted across the membrane by the oxidase. It was submitted to FEBS Letters at the end of May 1985 and published in the August issue for that year.43 The change of mind came in early 1985 with news from Wikström, but in the previous autumn the Japanese biochemist Sone seems to have begun to convince Mitchell of the weakness of his position.

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In October 1984, Mitchell visited Japan at the invitation of Yasuo Kagawa at the Jichi Medical School. He found the Japanese very hospitable and, as he expected, very disciplined and diligent but very charming. The laboratory was like one anywhere else in the world, but the atmosphere in the laboratory he felt was very good. Like other Westerners making their first visit to Japan, Mitchell initially found Japanese faces difficult to interpret and disconcerting; however, he found himself quite at home with his new friends after five days. During his stay he was particularly impressed by a ceremony that Mitchell believed to be Buddhist, presided over by an elderly priest in “gaudy” robes, to say thank you to the animals used in experimentation. As a penance, the president of the university had to read a very long sentence without drawing breath, which left him looking very white and caused Mitchell some concern. Nevertheless, Mitchell felt this was appropriate, since the animals had given life through research but had paid for that by their own lives; all in all it seemed a good way of dealing with an awkward psychological situation. He also felt that such contrition by the Buddhist intellectuals might avoid problems with animal rights groups. During his time at the medical school, he watched experiments by Nobuhito Sone, who was measuring protons pumped by vesicles containing a bacterial oxidase. Mitchell was very impressed by Sone’s very gentle, quiet approach and unassuming manner, together with his excellent demonstration of proton pumping. He commented to Sone, “It is natural for you to think the oxidase is proton pumping.”44 Mitchell noticed that the vesicles gave an ideal ratio of protons to oxygen and a proper exponential decay of the pulse. In fact, he was almost persuaded to change his mind and admitted that in the light of this demonstration he would find it difficult to maintain his opposition to proton pumping by the oxidase. Later he wrote to Hinkle of this experience: It has been good from my point of view that I have turned out to be wrong in my interpretation of the experimental data relevant to the proton translocating function of cytochrome oxidase; and, of course, I regret not having been persuaded earlier of the merits of the case that you, amongst others, advocated quite eloquently. I think the turning point came when I was in Japan and spent some days with Nobi Sone. His experiments worked so beautifully, and his persuasiveness came mostly from what he didn’t say!45

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Mitchell wrote to Sone in early June 1985, pointing out that the Glynn group had now accepted the view that cytochrome oxidase pumped protons. He explained, “Your gentle persuasiveness and beautiful experiments have played an important part in getting us to change our minds. Now we are, of course, greatly interested in the question: How does it do it?”46 It was this letter that announced Mitchell’s conversion to the scientific world at large, but not in a way Mitchell had intended. At a Gordon Conference in July 1985 that was attended by most of the leaders in the field, but not Mitchell, Sone, before giving his own paper, read his letter from Mitchell—it was greeted by gasps and applause! To Wikström, Mitchell wrote shortly after his visit to Japan about Sone’s work: “These experiments looked much more convincing than any I have seen before. But I am still not quite convinced.”47 Such a comment was hardly likely to be well received by the worker who had pioneered the evidence for the proton pumping oxidase. And it was not. Yet, Sone’s influence should not be regarded as the ultimate turning point. Even in January 1985 at a symposium organized by Mitchell and Anthony Crofts in Paris, Mitchell and Wikström continued their debate. Again Mitchell (with Moyle, West, and Roy Mitchell) described experiments in which cytochrome oxidase with cytochrome c as substrate gave a proton pulse that collapsed immediately, so that the experiments were interpreted as not supporting proton pumping; the abstract does have a less dogmatic feel about it, however.48 In a letter to Hinkle, Mitchell admitted that “the experiments of Bob Casey and Mårten Wikström . . . pulled the rug from under Jennifer’s and my feet.”49 Rather than a new, more persuasive experiment on proton pumping, the Helsinki group had demonstrated that cytochrome c was not oxidized by the oxidase in intact mitochondria but only by the small proportion of damaged ones. This explained why Mitchell did not obtain the results he expected if protons were pumped. In midJanuary 1985 Wikström wrote twice, advising Mitchell of the results of his experiments. On receiving the second letter, Mitchell’s immediate reaction was that Wikström must be wrong, but later the same day Mitchell recorded in his diary that “it looks quite a convincing case.” Within hours of receipt of the letter at Glynn, Roy Mitchell and Ian West had repeated Wikström’s experiment and concluded that the Finnish group was right. Peter Mitchell, however, continued to consider the

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matter for some days, particularly consulting the laboratory’s experimental notebooks. In early February Mitchell wrote to Wikström about these experiments: We think you are right. We also agree that this may explain a number of the peculiarities of experiments on the protonmotive stoichiometry using ferrocytochrome c as reductant. I think it is too early to say yet whether this important finding will enable us to convince ourselves that protons are pumped by cytochrome oxidase during oxidation of ferrocytochrome c. But it certainly affects our view of the overall weight of evidence for and against the pump.50 Mitchell’s major supporter at the time was still Papa. Finally, in July he wrote to him from the family retreat in the south of France, where he had gone to recover from a further period of poor health. He regretted that at the Gordon Conference, Sone had made public Mitchell’s change of view and that this had initiated a premature discussion of the position of the Glynn group. Mitchell enclosed a prepublication copy of the paper on the O cycle, which showed how the oxidase might pump protons and which drew attention to the Wikström and Casey paper, the conclusions of which the Glynn group had been able to confirm. Mitchell concluded that the oxidase does translocate one proton per electron across the membrane. Some four months later Papa replied, mildly protesting that Wikström’s paper did not demonstrate that the oxidase pumped protons. Papa was correct, of course. Wikström and Casey’s recent article51 explained why, with cytochrome c as substrate, a good mitochondrial preparation will only show weak and atypical proton pumping, and this situation caused Mitchell to attribute the result to an artifact. In intact mitochondria, cytochrome c (unlike ferrocyanide) cannot penetrate the outer membrane to reach the oxidase on the inner membrane. The observed proton pumping with cytochrome c as substrate came from only a fraction of the mitochondria that had damaged outer membranes. Thus the proton pumping and particularly the membrane potential (in the functioning mitochondria) was many times higher than the results appeared to suggest. Consequently, the system did not behave like other systems that Mitchell had measured. It was the failure to get the typical curve during pulse experiments that led him to suspect the results with cytochrome c, the natural substrate for the oxidase. Thus for Mitchell, the failure of the native mitochondrial oxidase to

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pump protons in a predictable way when oxidizing cytochrome c was the principal experimental reason for his opposition to the notion of a proton-pumping oxidase. In October 1985 the end of the controversy was marked by Wikström in a letter to Mitchell: “I guess that I lost our bet and now owe you a box of Havanas.”52 Later in a letter accompanying the cigars, Wikström said: Please find enclosed the payment for losing our bet. . . . You probably understand that this is the very first time I enjoy losing a bet. But more seriously, the settlement of our difference in opinion has been a great relief to me. As I recall having told you earlier, it meant relatively little to me that a majority of workers in the field seemed to accept the proton pump already for some time. The fact that you disagreed brought a lot of good with it, as judged now afterwards. There are in fact very few transport systems that have been studied from so many different aspects and with so many different independent techniques, as the cytochrome oxidase system.53



The Basis of Mitchell’s Position

Mitchell had sustained his position with considerable brilliance on logical grounds. However, his change of mind appeared to come not from an improved demonstration of proton pumping but from work that undermined his reliance on cytochrome c oxidation by mitochondria prepared in sucrose. It has to be admitted that Mitchell showed a strong bias in his judgments against pumping by the oxidase; indeed, there were many reasons why he had proved so stubborn. As noted earlier, when he had elaborated the chemiosmotic theory in the Grey Books, the oxidase was not seen to possess hydrogen carriers in the sense that ubiquinone could be so described. For Mitchell, therefore, on theoretical grounds, the oxidase could not pump protons. A related issue, noted earlier, was the total number of protons pumped by the respiratory chain, as determined by Mitchell. Since the Q cycle, together with complex I, accounted for this number, additional proton pumping by the oxidase would undermine Mitchell’s position on the arithmetic. Most workers, including Wikström, regarded their results as pro-

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viding a basis for adjusting the chemiosmotic theory and giving further support to it. Mitchell, in contrast, felt the theory to be threatened by such attacks on the concept as he had originally formulated it. A similar problem had arisen in the late 1970s with the total number of protons per oxygen atom reduced. Again, he argued that if his numbers were invalidated, then the theory itself was at stake. Mitchell admitted that, in principle, the chemiosmotic coupling concept was not wedded to a precise mechanism. However, in practice, he felt that any attack on his formulation was an attack on the theory itself. Mitchell was a convinced Popperian and felt that theories had to be formulated with sufficient precision that they could be falsified. On this basis, the process of proton transport by small molecules (ligand conduction) was integral to the theory. In considering Mitchell’s lengthy resistance to Wikström’s proposals, it must be borne in mind that Mitchell had long fought for the chemiosmotic theory in the 1960s and 1970s and on occasion had suffered verbal abuse for his position, but in the end he had won, very strongly endorsed by the award of the Nobel Prize. The stubbornness that had earlier been a strength now became a flaw, particularly after his illness in 1977. Indeed, Wikström raised a question at the beginning of 1985: “Don’t you think that it may be about time for Peter to accept the pump in the oxidase?”54 A member of the Glynn team responded: “Peter will believe in the pump when he absolutely has to, but not before. Any ambiguity or problem will be exploited to put off that evil hour.”55 Mitchell’s response to the situation was not to abandon the original argument about hydrogen carriers and electron carriers. Instead, he proposed that oxygen, as well as being reduced to water, might act as a proton carrier across the membrane. His immediate public response to Wikström’s paper was therefore to propose an O cycle, thus maintaining his commitment to his chemiosmotic mechanisms. This idea was developed privately during February and March and then in collaboration with Baum and Wrigglesworth during April 1985; it was sent for publication not long after. While it preserved Mitchell’s theory of proton pumping by the respiratory chain, the proposal constitutes a public retraction of his opposition, even though he did not actually admit to changing his mind about the oxidase. The proposal was not well received for technical reasons, however. It was replaced by the copper loop theory,56 but that also failed to survive examination. Mitchell then left Peter Rich, the new research director, to lead the institute’s attack on the problem of the mechanisms of cytochrome oxidase.

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A letter to Michael Mulkay, professor of sociology at York in England, with whom Mitchell had discussed sociological aspects of scientific development and communication, has a direct bearing on the foregoing analysis of Mitchell’s thinking. It refers to a concern about the experimental work, a concern shared by at least one other member of the Glynn team: My recognition that I have been wrong about the proton translocating function of the oxidase, which is a factual matter (i.e., it refers to what is going on in experiments designed to establish what the oxidase really does), was brought home to me by the demonstration that our experiments (especially using cytochrome c as a reductant in whole mitochondria) were badly designed and gave misleading results. My objections to accepting other evidence appear to have carried more weight (I mean I had thought, partly subconsciously, that it could be legitimate to attach more significance to them) because there were theoretical reasons for thinking that the proton translocation mechanisms were likely to be direct, and it had been supposed (mistakenly) that proton translocation by cytochrome oxidase would have to be indirect since the enzyme “contained only formal electron carriers”. Now that it has been appreciated that direct mechanisms are possible, I have naturally come to see the evidence with different confidence.57 The fact that this admission was made to a nonbiochemist is perhaps symptomatic of the embarrassment that Mitchell felt over this issue, one on which he was ultimately shown, publicly, to be wrong. In retrospect, his view of the situation was ambivalent. On the one hand, he regretted that he had argued so long against proton pumping by the oxidase; on the other hand, he felt the data were soft and his objections to the interpretations put on experiments by others might have been valid. He consoled himself with the thought that the scientific method had triumphed in the end, and that the dispute had “been resolved because experiments really work.”58 Such consolation did not altogether make up for the personal hurt that Mitchell felt; his wife remembered how upset her husband became over the question of “the pumps.”

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12
Science for Humanity 1985–1992



The Motto

Shortly after the foundation of Glynn, Mitchell had a brass plate fixed outside the front door with the inscription “Founded to Promote Fundamental Biological Research for the Benefit of Humanity.” In the late 1980s a new panel was mounted in the entrance hall of Glynn. It carried the heading, which he afterward referred to as the institute’s motto, “Science for Humanity.” It expressed one of his major concerns of later life that the purpose of science is for the good of humanity. Mitchell explained: In that motto the word Humanity has two meanings. On the one hand it means humankind, and on the other hand it refers to that special quality of sympathy and understanding that we associate with people’s love for one another and for other creatures with whom we share the natural world.1 Mitchell shared with many of his scientific contemporaries a feeling that the general public should see science as one of the great benefits of the age. He also shared their disappointment, not only at the indifference of much of the general public but also at the deep suspicion of what science was doing, leading to the view that science was alien and dangerous. He sought to address this problem in various ways, including inviting schools to send parties to Glynn, where he had prepared some exhibits. The motto also expressed another aspect of Mitchell’s character. He saw his interests in bioenergetics and his interest in social issues as re-

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lated; in Mitchell’s view, after all, they were both aspects of biology. This was expressed in the purposes for which Glynn had been founded. At the beginning of 1964 Mitchell had defined the objects of the foundation as promoting research in “the field of fundamental molecular and behavioral biology.” In the late 1970s he had endeavored to launch a research program in the behavioral area. He felt a concern that humanity suffered from a number of social diseases that needed to be researched and understood to secure a future for the race. Although a formal research program was never launched, Mitchell himself pursued questions in this area to the end of his life, and the council of management eventually appointed him as director of behavioral research in late 1986. Some of his views were expressed in an essay published in 1983 entitled “Science and Humanity” that was discussed in chapter 11 since it was heavily influenced by the controversy over the cytochrome oxidase. Probably the best expression of Mitchell’s thinking in this area came in a paper requested by a journal of the Japanese Chemical Society and published only in Japanese—but an unpublished English version exists (see note 2, this chapter). It was entitled “Aspects of Chemical Philosophy: Science as a Pursuit of Humanity.” In this paper he started by noting two different aspects of the way in which the word science was used. One aspect is the personal activity of the imaginative and speculative pursuit of new knowledge: “science-in-the-making,” which resembles problem solving in everyday life. The other aspect is the agreed codified concepts and factual information: “science as an institution.” Science-in-the-making was illustrated initially by reference to a nineteenth-century dispute involving van’t Hoff’s publication of the booklet “La chimie dans l’espace” and then by Mitchell’s own story of vectorial metabolism and the chemiosmotic theory. Mitchell felt that this “provided useful material for studies of the scientific cultural system in action.” He noted “that different workers judged the same experimental information differently, and opinions changed gradually as time allowed improvement of comprehension and accumulation of knowledge.” He noted that it was difficult for those working with a chemical view to adjust to the more biophysical view of membrane transport required for the chemiosmotic theory of oxidative and photosynthetic phosphorylation. He was “deeply impressed by the difficulty of effective communication and co-operative action between opposing conceptual schools, and by the need to make special efforts of appreciative understanding.” He recalled from his recent experiences as

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a result of the cytochrome oxidase controversy in which he was wrong, that it could “be very painful and temporarily destructive to self confidence at the time of collapse of one’s carefully chosen interpretative assumptions.” The link between science and humanity is briefly explored by Mitchell in terms of the work of the painter. He had an interest in art, at least as far back as his Cambridge days, and this was no doubt further stimulated by Helen Mitchell, who had a keen interest in art and became a serious painter in her later years. He saw distinct similarities between the work of the scientist and that of the painter. Based on the views of E. H. Gombrich, the art historian, he noted that portrait painters have some conception of the sitter, formed in their imagination. This is tentatively conveyed to the canvas. The creation of the final portrait depends on acceptance or rejection of the match that has been obtained, as the painting proceeds, between the look of the picture . . . when compared with the look of the sitter. . . . The creative process in painting has a fundamental resemblance to that in science. The creative process is basically evolutionary. It begins with inductive acts of imagination, and continues with the submission of the conjectures, so produced, to acts of critical comparison that the conjectures may or may not survive.2 Mitchell saw the process of development of science as somewhat more complex, and he analyzed his experiences in philosophical terms. At Cambridge, he had been interested in the ideas of Ogden and Richards, but these ideas had been largely replaced in Mitchell’s mind by the work of the philosopher Karl Popper, with whom Mitchell spent whole days in his last years. As noted before in this volume, it was Popper’s three worlds that interested him so much: the physical world, the mental world, and the world of ideas in the objective sense.3 Mitchell felt that on occasion people found difficulty in distinguishing the important differences between these worlds. Referring to work of Gilbert and Mulkay on the evolution of knowledge, he asked Joseph Robinson, “Do you think they have a problem of communication in that they have never witnessed (from the inside as we have done) how the detailed information of World I [the real world] is distinguishable from the ideas in the mind and codified theoretical descriptions of World II [the mental world] and World III [the world of theories and models]?”4 From his experiences, Mitchell concluded that there were two separate sets of criteria for deciding between alternative hypotheses, theo-

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ries, or views of nature. The first depends on experimental or observational tests, which are essentially a quantitative comparison between worlds I and III through the human mind. In connection with these tests, he wryly noted, as he had done before, that “the very prediction of a phenomenon or entity may temporarily give rise to its apparent observation” in the way that chemical intermediates in oxidative phosphorylation had been “discovered and partly characterized, before they were found not to exist!” The second method was “appreciative” and reflected Mitchell’s experiences with the chemiosmotic theory (where he was right) and with the proton translocation by the cytochrome oxidase (where he was wrong): In this case, the question is: Which theory or view of nature does the scientific community prefer to use, which has the greater generality, and which is the most attractive and convenient? There is no final arbiter other than the scientific community, dependent for such decisions on a highly complex cultural system.5 The conclusion to Mitchell’s essay comes back to the motto and explains something of his understanding of the importance of science to humanity: The gentle art of open-minded enquiry, otherwise known as scientific research, may well help us to improve the processes of human communication across barriers of dogmatism and passionate unreason, and may make it less difficult to substitute the habits of appreciative consultation and consensus for the adversary attitudes that cause widespread suffering in the world today.6 Such a comment also explains something of what Mitchell meant when he referred to “social diseases,” about which his behavioral research would be concerned.



Education and Research

In the late 1980s, Mitchell became interested in university research and the welfare of the universities. Although he had turned his back on the higher education system more than twenty years earlier, he now began to feel strongly about the increasing central control of research and research funding in the university system. He expressed his views in a letter to his favorite paper, the Financial Times:

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If I had allowed my research decisions to be swayed by the central authorities in the 1960s, instead of establishing an independent charitable foundation with its own research institute—where work could be pursued by those most closely in touch with events at the frontiers of knowledge—it is very unlikely that the results would have merited the Nobel Prize for Chemistry in 1978.7 In fact, Mitchell deeply distrusted any attempt to direct scientific research. Mitchell was deeply opposed to the development of a coherent science policy in the 1980s. His opposition reflected his conviction that Glynn had sought to test the feasibility of research that could be carried out in a way that would “avoid the stultifying effects of central planning and control.” On government policy he felt that the idea that we can plan our way into a more productive period in Britain’s scientific research performance on inadequate resources of finance and public enthusiasm by centrally organised crystal gazing that will concentrate funds in selective areas of supposedly “productive” research can hardly be consistent with the improvement in the scope and creativeness that is required of our scientific cultural activity.8 Mitchell did not accept the prevailing government view that research funding had to be selectively targeted to nationally advantageous projects. His belief in the independence and freedom of the scientist made him distrust any attempt at planning.



Keeping Glynn Solvent

In 1978 when Mitchell had augmented the council and the annual general meeting of the foundation with two extra directors, Harold Baum and Quin Geering, he considerably sharpened the management of the institute. Baum and Geering asked questions and made a variety of suggestions that enhanced the approach of Mitchell, Moyle, and others in the local team to problems facing the institute. On occasion they also acted on the institute’s behalf. In addition to significant discussions on the employment and remuneration of the institute’s staff, including both Mitchell and Moyle, together with property matters, the particular issue that they addressed was the state of the institute’s finances.

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In earlier years, Mitchell had raised the issue of how much longer the institute should devote its work to oxidative phosphorylation and the evidence for the chemiosmotic theory. In the mid-1970s, this was to some extent replaced by the question, how long could Glynn Research Limited maintain its activities? Thus at the beginning of 1981, Stephanie Key, the secretary, had estimated that the institute could continue at its current rate of income (supplemented by sale of endowment investments) and expenditure for approximately thirty months, by which time all of the endowment would have been used up. However, at this time a two-year contract gained from the U.S. Office of Naval Research paid Moyle’s salary and that of a technician, thus extending the active life of the institute. At the end of 1981 some other donations enabled an optimistic meeting of the council to see a future as far as 1986. Later, another calculation from Key suggested that the funds would be exhausted by the end of September 1985. The threat of closure continued to hang over Glynn, so that in March 1988 the foundation (Glynn Research Limited having changed its name in 1985 to the Glynn Research Foundation Ltd.) could see a future until the end of November 1989. Estimates for future life by the council of the institute seemed to vary. However, by 1989 Mitchell noted that for some time they had been able to see a future of about three years, a view based on the premise that when the endowment fell to £100,000, the council would need to arrange closure. It is remarkable that the continued threat of closure apparently did nothing to dampen the enthusiasm and entrepreneurial spirit of Mitchell, Baum, Geering, and Moyle. Over this period the institute expanded its activities, planned for a long future, hired more staff, expanded into new space, and even purchased the freehold of its premises from Mitchell. Papers continued to flow from its research laboratories and from its director. The confidence shown by the council was paying dividends; grants and donations were being received, although the much-desired enhancement of the endowment itself proved elusive. It was in any case necessary to assure potential donors that Glynn was a going concern. The responsibility for fund-raising was shouldered primarily by Mitchell himself, although a great deal of work was carried out by the secretary and a further member of staff who was hired for the purpose. A brochure was produced at the end of 1980, but initial responses were very disappointing. From the first seventy-one companies approached, only one small donation was received. However, Mitchell and his team

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were learning from their experiences. By the late 1980s, significant sums were being received by the foundation, particularly from the Tudor Trust, which originally had been established by Sir Godfrey Mitchell. Various commercial companies and an anonymous donor contributed sums, and there were also a number of smaller donations and a steady run of research grants. In the early stages of the fundraising, a significant boost came from Mitchell’s brother, Christopher Mitchell, who donated 100,000 Wimpey shares. Such successes maintained morale and ensured temporary financial stability, but the council, determined to present a thriving face to the public, inevitably increased expenditures.



Expanding Glynn

In 1986, in keeping with the positive and optimistic approach of Mitchell and his council, the institute acquired further premises. Mitchell reported to the annual general meeting on these developments: “The acquisition of the freehold of Glynn House, which includes premises at the back of the main house that were not previously available for use by the Foundation, will enable us to improve our research, consultation, workshop and other facilities.” However, he was apologetic that the institute, which had paid £175,000 for the property (the lower of two professional estimates of its value), had not received it as a gift: Since my late brother and I made donations to the Foundation totaling a value greater than £1.5 million in terms of present-day currency, I was not in a position to give Glynn House to the Foundation, gratis, though I would have liked very much to have been able to do so. However, I am fairly hopeful that other personal and corporate benefactors, who share my family’s desire to promote the enlightening humanitarian objects of this Research Foundation, may be willing to restore to our income-earning endowment the effective cost of the purchase of our premises. I am also optimistic that, in view of the architectural virtues of Glynn House, and the place of Glynn in the history of Cornwall, our Foundation may receive quite generous help in our role as custodians of Glynn House.9 Mitchell maintained a keen interest in Cornwall, its economics, its history, and its language. In later years he was learning the Cornish language, a Celtic language that is now virtually extinct.

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Glynn had cost Mitchell personally a great deal. Toward the end of his life, the effect was felt. In 1991 he explained to Moyle that he had not had to sell the house in France but that Cuilan, the restored bungalow on a south Cornish creek, had been sold rapidly—“that was a great relief, as our cash flow problems had become sufficiently acute to make me sell my Shogun car and my grandfather clock, amongst other things.”10 At this stage, aware of his deteriorating health, Mitchell was incurring significant personal expenditure in refurbishing for Helen the “Farmers House” behind and somewhat above Glynn itself. This step proved necessary since the part of Glynn that Mitchell occupied had been sold to the institute and, in the event of Mitchell’s death, would be required for the next director.



Staffing of the Institute

Following Moyle’s retirement from research work in 1983, West was appointed to a research readership at Glynn but later was funded by a Research Council grant, returning to Newcastle in 1988. Moyle herself continued as a director of Glynn until its final closure. Although there had been some mention of West becoming the director of research, Mitchell did not proceed with this. Roy Mitchell, no relation to Peter Mitchell, had been the institute’s first technician and over the years had become one of the scientists. Now Peter Mitchell, through Baum’s good offices, arranged for Roy Mitchell to be registered for the degree of Ph.D. in the University of London, even though he had no first degree. The doctorate was awarded in 1991, thus recognizing his significant contribution to science at Glynn. Mitchell wished to strengthen the scientific team at Glynn and suggested to the council that Peter Rich, then at Cambridge, might be willing to relocate his research group funded by the British Petroleum Venture Research Unit. The council asked to meet Rich, and in due course it was agreed that he should transfer to Glynn around the end of 1985. Mitchell had first met Rich at Cambridge in 1979, when the latter was working on the chemistry of quinones. He had shown considerable interest in Rich’s work, particularly since the Q cycle (where quinone occupied a central role) was still very much a hypothesis for which evidence was required. During the 1980s Rich had made one or two visits to Glynn for discussions with Mitchell. Now it was suggested that Rich might come to Glynn as a research fellow, with the strong prospect

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of becoming a director of research. At the end of 1985, Mitchell wished to plan the termination of his role as director of research and was looking for a younger person. The 1980s had not been an unqualified success for Mitchell, and his time had been eroded significantly by the need to work on fund-raising for Glynn. Rich had been a postgraduate student at Cambridge, then had worked in Philadelphia and returned to Cambridge, where he was not a permanent member of the department but did have a large grant. The opportunity to work in an environment dedicated solely to research was attractive to him. The council concluded that it wished to invite Rich to Glynn, where he would continue on his grant and when that terminated the council would give serious consideration to his appointment as director of research in June 1987. He brought with him his assistant, David Moss, who remained at Glynn to the end of the BP grant. Rich himself lived initially at Glynn, but then moved to his own property in the area. Rich was appointed director of molecular research from the beginning of 1987, although he did not become a director of the foundation and hence did not attend council meetings. Concurrently, the council appointed Mitchell as director of behavioral research and director of the foundation, the duties of each of these appointments being defined by the council. However, the arrangements for Mitchell did not last long. As he wrote to Keith Garlid, “Unfortunately I have not been at all well for some time, partly because of an excessive amount of work and perpetual worries over the financial problems of this research organization. There came a point when it was essential to slow up to avoid something irreversible happening.”11 In fact, the previous year Mitchell had spent some time in the hospital undergoing surgery. Early in 1987 Mitchell indicated that he would wish to formally retire on his sixty-seventh birthday, 29 September 1987, but he intended to continue as a member of the council. The council agreed to appoint him honorary director of the foundation, and in this capacity he continued to spearhead the fund-raising for the institute and also continued to chair the council and the annual general meeting. He noted in the summer of 1987: “My role at this institute is now rapidly changing from one in which I was actively involved in the molecular research to one in which I will be acting as public relations officer and fund raiser.”12 However, he did not find the new role altogether easy. He wrote to Gebhard von Jagow in Munich, with whom the institute was now cooperating with European Community funding:

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My new role as communicator and fundraiser has got me very disorganized, as I do not seem to have been able to get a feel for the proper priorities and strategies for each day’s work. That has been making me feel a bit tired and old. But I am hoping things will improve with familiarity. 13 Although the council noted that it would need to attend to the appointment of a director of behavioral research, no such appointment was ever made. Rich brought a new and now much needed fresh approach to experimental work at Glynn. Mitchell and Moyle, as Rich remarked, had performed extremely clever and very simple experiments with modest equipment. Biochemistry had now become much more equipment based, and Rich felt that the institute’s greatest need was not further staff but more modern, complex laboratory equipment. Rich pioneered new, more sophisticated experimental approaches at Glynn, concentrating particularly, but not exclusively, on the mechanisms operating in the cytochrome oxidase. Initially, he shared Mitchell’s approach, concentrating on the role of the main electron-conducting components and treating the proteins as simply providing the milieu for the various reactions; later, Rich broadened his views to consider the role of proteins. Another change that occurred during 1987 was the appointment of Maurice Williams as a director. Williams was an accountant and had been Mitchell’s personal accountant. His addition to the council strengthened its handling of the financial and legal issues facing the foundation; he was later appointed honorary treasurer.



Patrons

Early in 1987, Mitchell considered the advantages for the foundation of having patrons. Unquestionably, such a move would enhance the image of the foundation as seen by potential donors. Having referred the council to the Oxford English Dictionary definition of patrons, Mitchell suggested Lord Swann (his head of department in Edinburgh), Dr. Frederick Sanger (a distinguished biochemist at the Cambridge department and one of the rare scientists who had won two Nobel Prizes), Sir John Kendrew (also of Cambridge and a Nobel Laureate), Sir George Porter (later Lord Porter, Nobel laureate and president of the Royal Society), and Professor Herbert Simon (the American economist, com-

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puter expert, and Nobel laureate). Mitchell approached the five proposed patrons, and all accepted, being allotted one share each in the Glynn Research Foundation Ltd. and becoming voting members at the annual general meeting. In fact, they attended only the jubilee annual general meeting, and otherwise they authorized Moyle and other members to vote on their behalf. Later, when Mitchell came to know Sir James Black (Nobel laureate) and after the death of Lord Swann in 1990, Black also became a patron of Glynn. Thus by the late 1980s, the foundation had five directors, including Mitchell, and five patrons.



Mitchell’s Biochemistry

The mid-1980s had been a rather humiliating time for Mitchell. Early in 1985, he had realized he was wrong (and Wikström was right) in supposing that the cytochrome oxidase could not translocate protons across the membrane. Almost immediately, he realized that his arithmetic on the total number of protons (per oxygen atom reduced) translocated by the respiratory chain was also wrong and that Lehninger’s estimates were nearer the true value. However, there were areas of bioenergetics that were still moving Mitchell’s way, and research was still successfully proceeding, with seven articles published during the year 1984– 1985, for example. The Q cycle had been formulated in 1975 on absolutely minimal evidence and a great deal of conjecture. Now this well-conceived proposal appeared to be winning wide acceptance. Mitchell wrote in his report to the council in 1985: During the year, our research has made good progress across a wide range of topics in the field of bioenergetics. Amongst other things, it is gratifying to note that there is now general acceptance of the so-called Q cycle mechanism. . . . This achievement is one of the first in which the general principle of the molecular mechanism of a chemically-driven transport process has been explained in sufficient detail to enable one to appreciate, in the mind’s eye how it actually works.14 In the last seven years of Mitchell’s life, the two main bioenergetic issues to concern him were the mechanism of proton translocation by the cytochrome oxidase, and the mechanism of action of the ATPase. In the oxidase, where he had been forced to accept that the enzyme translocated protons, he had initially proposed the “O” cycle (compara-

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ble in some ways to the Q cycle) based on oxygen and water. However, this was heavily criticized by others in the field, and in effect Mitchell withdrew it by publishing a mechanism based on the possible role of copper atoms in the enzyme.15 This appeared in October 1987, but toward the end of this month Mitchell submitted to the same journal, FEBS Letters, a modification of the proposal that he felt was “a particularly subtle and nice example of the development of the redox loop idea.”16 In less than three weeks it was rejected, provoking some fury in Mitchell, although he subsequently wrote to the editor, “I am not at all offended by the rejection of my recent CuB loop paper (which, incidentally, has delighted Britton Chance).”17 He then published the paper himself.18 Slater provided some comfort: First, let me congratulate you on joining the perhaps not-so-small but in some ways select club whose submissions have been found wanting by the Editors of the FEBS Journal. I claim the distinction twice. . . . I think that your CuB hypothesis is ingenious and it should not have been rejected by FEBS Letters.19 However, this event seems to have marked the end of Mitchell’s original theoretical papers, although he contributed a paper to the New York Academy of Sciences symposium on cytochrome oxidase the following year20 and continued to make many contributions as coauthor of papers on the oxidase. Mitchell also continued to develop his ideas on the ATPase, although here he remained convinced that the proton should pass through the active site of the enzyme, whereas the prevailing view saw protons inducing conformational changes in the enzyme, which then brought about the synthesis of ATP. The latter view was now being developed in many laboratories on the basis of the ideas of Paul Boyer. On this issue Mitchell never seems to have changed his mind. Thus in an unpublished lecture given at an international meeting in Moscow in 1989 and at the jubilee meeting at Glynn, Mitchell remained committed to his interpretation, although outlining the conformational model of Boyer as an alternative. One of his main objections to conformational models was that, in his view, they were vague and did not imply a specific number of protons to be translocated (stoichiometry) for each ATP synthesized: “The stoichiometry is of no consequence for the conformational mechanism . . . because the actual molecular mechanism of coupling is not specified.”21 He expressed his concern to a colleague, although he accepted that some transport processes might be explained

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by conformational changes: “I share your concern about the tendency of biochemists to invoke protein conformational changes to explain a variety of bioenergetic phenomena when more direct, explicitly definable chemical and/or physical interactions may provide a simpler and more easily testable mechanism.”22 However, Mitchell reminded his listeners that it was he who had “invented” the proton-coupled reversible (F0F1) ATPases when he originally formulated the chemiosmotic theory in 1961. Mitchell continued to think almost daily about the mechanism for the ATPase up until the last month of his life. In the summer and fall of 1991, in an echo of his earlier efforts to work through his basic notions of chemiosmotic coupling and later the Q cycle, Mitchell built plastic models of the ATPase. These contained small, embedded magnets that allowed the subunits to swivel. Frequent entries in his diary tracked further ideas by which he might save a direct role for protons in the active site of the ATPase rather than accept the now widely held conformational view. Even when he became very seriously ill in early 1992, Mitchell interspersed notes about his pain and treatment with comments on how the enzyme might work. Indeed, after being told on 5 March that he had only about a month to live, he wrote in his diary ideas for a review that he hoped he might last to complete. However, this was the penultimate reference to the ATPase in his diary as his attention turned to his final council meeting on 13 March.



The Gardens of the Mind

Mitchell’s view of biochemical science was that the development of theory and the design of models were valuable means of both generating and interpreting experiments, and for this imagination was important. In 1988 he remarked on the usefulness of trying deliberately to evolve the conceptual devices that we can use, both as navigational aids for exploring the experimental realities about which we aim to learn, and for building and shaping the theoretical models that we need in order to systematize and describe our knowledge. It is a particularly fortunate characteristic of the present stage of the growth of knowledge and understanding in biochemistry that the models are rapidly becoming more realistic

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and (in a holistic sense) simpler, as the factual information accumulates and offers itself for appropriate arrangement according to the systems of rules, or general concepts, that we have discovered.23 For Mitchell, science was a proper activity for a human being with the inherent quality of imagination, even though only a few human beings would actually engage in it: “We don’t do science because we are scientists, because of science—we do it because we are human beings. It is a most wonderful romantic, cultural activity, just as much as being a sculptor. . . . It’s problem solving.”24 It was in the same discussion, with Lewis Wolpert, that Mitchell gave a description of how he saw his odyssey in bioenergetics: Most people, who try to be creative, I think, have found that they’ve got to become crafts people as well as art people. You have to go through the, dare I say, dreary business of school, and in my case, of learning chemistry out of the textbook. There is a huge amount of information you have to absorb before you can start walking about in it, as it were. I’ve often thought that the human mind is a bit like a garden. You prepare this garden, and you plant things there, and it’s a sort of garden partly of facts, and partly of ideas, and you keep re-arranging it, and that’s really quite hard work, but at the same time, its well worth it because you can go for a lot of walks, especially if you don’t sleep very well.25 Mitchell did not seem to see a division between the arts and science. Wolpert and Richards entitled this interview broadcast on BBC radio as “Gardens of the Mind.” Following Mitchell’s death in 1992, Helen Mitchell created a garden behind the Farmer’s House at Glynn with a plaque (which at the time of writing is still there) inscribed “Remembering Peter Mitchell in whose gardens of the mind we wander in joy and gratitude.” Such an epithet aptly described the man whose approach to his subject, as to life in general, was an imaginative intellectual activity and whose biochemistry was as much an art as a science.



A Healthy and Productive Institute

Glynn remained an international center for bioenergetics, marked, for example, by the election of Mitchell as an honorary member of the Biochemical Society of the Soviet Union. A snapshot of the work of Glynn

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in the late 1980s can be gained from a report to the council in September 1989. At this stage, six projects were in hand. Three were devoted to the cytochrome oxidase, with Roy Mitchell and Rich working on the proton translocation by the oxidase, John Moody working on structural aspects of the enzyme, and Helen Lyons and John Moody looking at the enzyme that had lost its copper atoms. Peter Rich was also working on a complex in the photosynthetic system and, together with Sally Madgwick, on the mechanism of proton transport in complex III (the cytochrome b-c1 complex) of the respiratory chain. Finally, assisted by Robert Harper, Rich was working on the chemistry of quinone. There was also a good deal of work by Harper and Jeal, the technicians, in building specialized spectrophotometric equipment under the direction of Rich. Although Mitchell was not directly involved in the projects, he discussed scientific issues extensively, kept up with the literature in bioenergetics, and continued to influence science at Glynn. By September, seventeen articles were published, in press, or submitted to journals since March 1989. Clearly, the institute under its revised leadership was proving highly successful and productive. The cash value of the endowment was remaining approximately constant at around £500,000, but annual expenditure was around £200,000. Significant sums were being received in grants and donations, but inevitably small sums were drawn from the endowment to cover income shortfalls. In addition, plans were in hand for a new library and a new workshop.



Celebrating Twenty-Five Years

The Glynn Research Institute started some experimentation in the autumn of 1964, but at that stage the builders were still completing their work so that the institute did not become fully operational until the beginning of 1965. Thus 1989 or 1990 could have been the time to celebrate twenty-five years. Initially, in December 1988, the council favored a symposium with twenty to thirty active participants, including the patrons, to be held in conjunction with the annual general meeting in September 1989. However, this proposal collapsed and was replaced by a plan for a full symposium, initially for forty people, in October 1990, close to Mitchell’s seventieth birthday. Mitchell also hoped to launch a book of essays under the title “Science and Humanity.” The plan for this

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project was very ambitious; among the sixteen authors to be approached were Sir Walter Bodmer, Richard Dawkins, Karl Popper, and Andre Sakharov. Unfortunately, the book did not proceed, as many of the invited authors were unable to contribute, and the project was dropped. In any event, the symposium was held at Glynn and in many ways was its finest hour. It was entitled “Perspectives in Vectorial Metabolism and Osmochemistry.” Six main papers on aspects of chemiosmotic systems were presented, by Mitchell, Franklin Harold, Vladimir Skulachev, Peter Garland, Peter Henderson, and Peter Rich. Opening and closing remarks were provided by Moyle and Charles Pasternak, respectively, while Bruce Weber provided a lecture on the history of Glynn and the chemiosmotic hypothesis. Moyle described the symposium as developing several interwoven themes: The most general and esoteric theme is the interaction between the evolution of fundamental theory and the winning of experimentally based knowledge. More specific themes, implicit in the titles of the contributions, are developed in the fields of vectorial chemistry, vectorial physiology and morphogenesis, energy transmission and storage, medical practice, protein dynamics, and the dynamic vectorial molecular mechanisms of ligand conduction.26 Around ninety people attended, drawn from around the globe, including most of the patrons. Mitchell had a tent erected in a courtyard so that all participants could have their meals together, which were prepared by a local chef. Richard Gregory, a psychologist from the University of Bristol, provided an after-dinner talk on paradoxes of perception, a topic that Mitchell found not only intriguing but also full of clues to the creativity of scientists as they recognize patterns in nature. Overall, the symposium was judged a major success, and full-page reports appeared in Nature and New Scientist. The presented papers were subsequently published in Bioscience Reports. The set of papers was also made available by the Glynn Research Foundation as a celebratory book in a gray hardcover becoming known as “the Silver-Grey Book.” For the symposium itself, Mitchell raised significant funds, so that the cost to the foundation was reduced to about £19,000. It was a just and fitting occasion to mark both the success of the research institute and the success of Mitchell’s ideas of vectorial metabolism, chemiosmotic coupling, as well as the influence of these ideas on the field of bioenergetics.

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Last Days

In October 1990 Quin Geering died. His contribution to the council of Glynn had been substantial, and after the November 1990 meeting of the council, Mitchell invited as a successor Peter Henderson from Cambridge, who accepted. At the same meeting, the council considered the question of a successor to Mitchell as chairman of the foundation. No decisions were made, but it was felt that the advice of Sir John Kendrew and Lord Porter should be obtained. For his part, Mitchell stated that he would be most unhappy if an administrator were appointed; he felt the chairman should be an experienced scientist. However, Mitchell as chairman continued with his science, and a part-time research assistant was appointed in 1991; in particular, he was still continuing to work hard on fund-raising for the institute, which now survived only by virtue of the steady stream of donations and grants. Even so, these were rarely sufficient to meet the full cost of running Glynn. It was in 1991 that Mitchell was invited to become chairman of the advisory committee for a research unit in Cambridge. This was established to study the development of infants and children to determine how environmental influences and interpersonal relationships, in interaction with the genetic endowment, influence individual characteristics, personality, and vulnerability to physical and psychiatric disorder. Mitchell relished the prospect of this role, despite his deteriorating health. It was around Christmas 1991 that Mitchell became convinced he was dying. He advised friends that they should come to see him soon. He was complaining about a pain in his collarbone. The local medical practitioners did not seem to be able to help, and the pain was getting worse. Initially he saw a London general practitioner: I have been incapacitated by a nasty and now extremely painful illness that seems to have been gaining ground for six months or more. I am writing this on the way back from a rather agonizing visit to my London GP who has been investigating the problem very thoroughly; and it seems quite likely that it can be treated successfully. Basically it seems to be a severe form of polymyalgia arthritica, but with some atypical accompaniments. Anyway I am hoping to be feeling a good deal better by the time of our Council Meeting.27

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Helen now arranged for him to see a London doctor who was also a friend and who had a private practice in Knightsbridge. After a day of tests, Peter and Helen were told that Mitchell had only about a month to live. Cancer had started in the liver but had spread everywhere. He returned home and continued to work for as long as he could, completing the editing of the Glynn jubilee volume. After his death, the articles in the symposium volume were dedicated by Mitchell’s scientific colleagues to Helen Mitchell, who had done a great deal to make the jubilee meeting a success. Mitchell chaired the council meeting on 13 March 1992, when he gave notice of his intention to retire imminently and asked the council to accept his resignation as honorary director and chairman of the foundation. Mitchell indicated that, if asked, Peter Rich would be prepared to become the new chairman, an appointment that Mitchell clearly favored and a proposal that the council formally accepted. Mitchell showed his confidence in a letter to Sir David Phillips, describing Rich as having “quite outstanding promise as a world leader in Biochemistry.”28 Mitchell died on 10 April, at home in Glynn, the institute that he had created, in the house that he had restored from a ruin. At the end, Mitchell’s bed was moved down to the main living area to receive visitors and for him to say his farewells. The family was present, as well as Jennifer Moyle and a long-time friend and frequent visitor to Glynn, Keith Garlid—a fitting conclusion for a man who listed as the first of his interests in Who’s Who “the enjoyment of family life.”



Remembering Peter Mitchell

There were a number of memorial activities instigated by the council but also by others. Part of the Second International Union of Biochemistry and Molecular Biology Conference held at Bari was dedicated to the memory of Peter Mitchell, and Peter Rich appropriately gave a lecture. In July 1992 the summer studentships available for a student to work at Glynn were renamed Peter Mitchell Summer Studentships. The Biochemist gave over a significant part of one issue in Mitchell’s honor. As a lasting tribute, the European Bioenergetics Conference instituted a Mitchell biennial lecture, with the award of a bronze medal. The first Peter Mitchell memorial lecture was given by Les Dutton from Philadelphia at the 1994 meeting held in Valencia, Spain.

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The Institute Lives On

There were two major experiments in Mitchell’s life. The first was to test whether the chemiosmotic hypothesis was a realistic model for the cellular process of oxidative and photosynthetic phosphorylation. This had clearly been successful. The second was to see whether a small institute could flourish. As Moyle had written in 1990: When Peter Mitchell and I set up the Glynn Research Foundation and Institute in 1963–4, both of us hoped, of course, that the venture would be a success scientifically in the years ahead, although we were perfectly well aware that we were taking a considerable risk, because part of our aim was to discover whether small could be effective as well as beautiful in the case of an organization pursuing fundamental research.29 In part, in this second experiment, Mitchell had already been vindicated; Glynn was well recognized internationally as a center for bioenergetics. Nevertheless, Mitchell had in his later years sought to place Glynn on a secure financial footing with a strong council and with the prospect of a long and productive future. Thus it fell to Peter Rich to endeavor to give that dream a reality. At the council meeting in July 1992, Rich assumed the chair, and business continued as usual. In addition to the many detailed issues concerning Glynn, Rich initiated a discussion on fund-raising, and plans were laid for new initiatives. In particular, Rich proposed “to form a body of advisers, possibly including some of our patrons, to help advise on new directions and new ideas, which would be coordinated by our fund manager.”30 This body came into existence in 1993 and continued to meet for the remaining years of Glynn’s life. Sir John Kendrew was the chairman, and the members were Professor Sir David Phillips, Professor Bill (E. C.) Slater, Professor Sir Philip Randle, Professor Sir Hans Kornberg, Professor Franklin M. Harold, Sir James Gowans, and Lord Porter. At some stage, Sir James Black and Dr. Trevor Jones, director of research for Wellcome PLC, also became members. Several members, particularly the chairman of the board of trustees gave considerable time to helping and supporting the institute. In the ensuing months and years, Rich himself, with the advice of the board, spared no effort to raise core funding for Glynn. In particular, the big foundations were approached one by one, but one by one, they felt unable to provide the core funding Glynn needed. Research grants could be obtained

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from research councils, the European Union, and foundations such as the Wellcome Trust. But research grants in themselves, while funding the direct costs of the work itself, did not fund the indirect costs and were a financial liability. Fundamental research in the United Kingdom is almost all carried out in universities, with some in a dwindling number of research institutes. This research is mostly funded by research councils, the Wellcome Trust, and, increasingly, European Union money. To a greater or lesser extent, all these sources have assumed that universities are funded centrally to maintain a research base. While this funding has become increasingly selective, it is assumed that research is supported by a dualfunding principle: part through the direct funding of universities through the Higher Education Funding Councils, and part primarily from the research councils. For Glynn, such a policy created an almost impossible situation of finding that money for research that universities receive from their funding councils. A further factor in research policy in the United Kingdom was a wish to centralize fundamental research in the universities so that small research activities were becoming attached to universities. Several universities held discussions with Glynn, including the nearest neighbors Exeter and Plymouth, but these led nowhere since universities themselves were under severe financial pressure at the time. An independent research institute (which did not undertake teaching) came to be regarded as an ineffective way to pursue research and did not fit the national policy. The fact that Glynn provided a cost-effective and productive approach to research, that its managing body included as voting members its patrons, who were some of the most respected scientists in the land, did not seem to affect the situation. If Glynn could provide its own core funds well and good, but the established bodies would not provide them. Its new director, while being able to raise all the research grants he needed, did not have the charisma and standing of his predecessor; Mitchell’s Nobel Prize was certainly worth more than its original cash value. However, even Mitchell himself had major difficulties in attracting core funding and had failed to stop the erosion of the institute’s endowment. Over the years from 1992, Rich continued to run a highly productive institute with a steady flow of publications on a variety of aspects of bioenergetics. The staff continued to number three leading scientists—Rich, Roy Mitchell, and Moody—while there were always two or three research fellows and some two or three technicians. The atmo-

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sphere continued to be one of serious dedication to scientific research and loyalty to the purposes for which Mitchell created Glynn. However, annual expenditure continued to exceed income from the endowment, research grants, and donations by a significant amount. In October 1995 the council considered its options. First, it might sell teaching and research expertise to a university in return for core finance. Second, it might allow Glynn to be taken over by a university, with the institute remaining a going concern. However, if neither of these options proved possible, the institute would have to be closed down and the research team could be moved to a university. As it turned out, it was only the last option that proved feasible. Notices of dismissal were served to the staff for 30 April 1996. On 1 March 1996 the council resolved to advise an extraordinary general meeting of the Glynn Research Foundation that the foundation be wound up and dissolved. The director’s letter to the shareholders contained a brief statement by Moyle: As co-founder of the Glynn Research Foundation with Peter Mitchell in 1964, I am saddened that financial considerations have required the dissolution of the Foundation; particularly when Peter Rich and the present team are doing such good work and have enhanced the international reputation of Glynn in the bioenergetics field over the last nine years.31 Rich successfully negotiated a transfer of the research group to the biology department of University College London. Roy Mitchell retired, and John Moody, wishing to remain in the southwest, transferred to the University of Plymouth. At University College, Rich set up the Glynn Laboratory of Bioenergetics to which the remaining resources, including the proceeds of the sale of Glynn House itself, were transferred. Now that the Glynn laboratory was in a university setting, the very foundations who had refused to support Glynn were happy to invest generously in the new laboratories. On 24 September 1998, in a manner Mitchell would have approved of, the opening of the Glynn laboratories was celebrated with a symposium, “The Molecular Machinery of Bioenergetics.” The speakers reflected the international tradition of Glynn: Rich; Wikström from Finland; Les Dutton from Philadelphia; John Walker, Nobel laureate from Cambridge; and Wolfgang Junge from Germany. The phoenix had risen from the ashes. Ironically, Glynn’s research activity was finally absorbed into the university system from which Mitchell had sought to escape.

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13
Epilogue Mitchell and Glynn



Envoi

At the time of Mitchell’s death a number of the obituaries and appreciations attempted to express the special quality of both Mitchell as a person and his approach to, and achievements in, science. Keith Garlid, who was with Mitchell during his last days, wrote, “My sense of impending loss was continually interrupted by joyful memories of his generous and youthful spirit. Pete was not afraid of death and was grateful for having lived such a full and happy life.”1 Various tributes mentioned Mitchell’s joie de vivre, his élan, and his gentle, good humor. Mitchell was described as “modest, approachable and humorous”2 by one colleague, and yet another recalled that he “was very competitive and relished controversy, but he was also very appreciative of . . . people, of the humane; even if he occasionally found these feelings had to be subordinated.”3 But all agreed about the very special intellectual power and brilliant intuition Mitchell possessed: he was “a man who had great intellectual gifts of memory and tenacity, great creative gifts of imagination, originality and energy, and great human gifts of zest, humour and charm.”4 It is not surprising for a scientist’s intellect to be so described, but rather unusual to have his intuition highlighted. A particular feature of Mitchell’s Nobel Prize was identified in an article by Garlid, who noted that the award was “for a pure act of the imagination”5 rather than for the more usual experimental discovery or development of a valuable new technique. As noted earlier, Mitchell had felt that he had a mission to unify the previously disparate fields of membrane transport and metabolism, and Garlid judged that this had been one of his significant achievements. Peter Hinkle and Keith Garlid later wrote that “only rarely do indi-

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vidual scientists leave an indelible mark on a field. Peter Mitchell made such a mark when he proposed and then developed and defended the chemiosmotic theory of energy coupling in oxidation phosphorylation, photophosphorylation and active transport systems.”6 In fact, his theory was developed in a way that made it readily susceptible to refutation by experiment. Ultimately, Mitchell’s mark was to bring about a considerable conceptual unification that bridged gaps between a number of fields of research to forge the discipline of bioenergetics. Two examples may serve to illustrate the breadth and significance of Mitchell’s influence as the turn of the century approached. In a multiauthor work, Frontiers of Cellular Bioenergetics, most contributions either cited Mitchell directly or built upon his notions, such as the Q cycle, without citation, since Mitchell’s ideas had become an accepted part of the intellectual furniture of the field. In the foreword, Slater referred to “the innovative proposal by Mitchell on the fundamental role of the translocation of protons across membranes, which revolutionized the way in which the mechanism of energy transduction was envisaged.”7 In the introduction to a symposium volume entitled Bacterial Responses to pH, Robert Poole wrote: Undoubtedly, the most profound impact on our appreciation of the role of the proton in biology has come from Mitchell’s chemiosmotic theory. According to this theory (Mitchell 1966) the energycoupling cytoplasmic membranes of bacteria are topologically closed structures that are essentially impermeable to protons (as well as to ions generally). Energy-conserving metabolic highways are arranged so that during operation (e.g. respiration or photosynthesis) protons are translocated (either directly or indirectly) to generate an electrochemical gradient. It is this potential, and not a chemical intermediate, that is the driving force for energy-requiring processes such as ATP synthesis, solute transport and motility. The impact of these ideas on all areas of biology, and on bacterial energy transduction and metabolism in particular, is inestimable. The search for proton-driven mechanisms has inspired the work that has led to at least two Nobel Prizes in the past few years. The conceptual framework of many experiments and ideas presented in this symposium is that of chemiosmosis.8 Indeed, electrochemical proton gradients have come to be viewed as a major component of cellular energy “currency,” along with ATP. The principles developed and enunciated by Mitchell underlie much

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current research in bioenergetics, even if he was incorrect in some of his mechanistic details. While Mitchell continues to be honored for the unification that resulted from his paradigm change, and is so acknowledged widely in contemporary biochemistry textbooks, his ideas of vectorial chemistry have been used by only a rather small number of followers.9 Mitchell felt that his vectorial ideas were his most fundamental contribution to biochemistry, but the field has not generally been directly influenced by these ideas. In practice, it appears that the principles about which Mitchell was so concerned have been unconsciously absorbed by the discipline from a number of sources, but not uniquely from Mitchell. For biology more generally, Franklin Harold has argued that Mitchell’s “most profound contribution may have been to introduce the spatial direction into biochemistry and thereby transform our perception of the relationship between molecules and cells . . . we are all chemiosmoticists now.”10 In the end, the principal benefit of the concept of vectorial metabolism has been the special case of the chemiosmotic theory. It is the chemiosmotic concepts that have become the foundation of contemporary bioenergetics. Indeed, this field is emerging as a valuable case study for historians and philosophers of science.11 Further, controversy continues to characterize this area. The authors have recently heard that there is a proposal to rename Mitchell’s chemiosmotic theory as the Davies-WilliamsMitchell theory. While we believe we understand the motive behind such a proposal, which has much to do with Mitchell’s unjust treatment of the work of Davies and, particularly, Williams, we feel that such a move would not right previous injustices and would confuse both the historical and the biochemical facts. Davies’s proposals can only be properly understood in the light of Mitchell’s own thinking, while Williams’s proposals, albeit concerned with protons, are distinct from those of Mitchell. Although we would certainly not advocate it, we believe a better case could be made for naming the current theory the Mitchell-Boyer theory since Boyer’s later proposals combined his own views on the ATPase with Mitchell’s on the role of protons in energy transfer.



Contradictions in Mitchell’s Personality

Mitchell’s personality was complex in that certain aspects were in conflict. Mitchell was passionate and imaginative in all aspects of his life and work, yet he was drawn strongly to the Enlightenment project of

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the primacy of reason, particularly as instantiated by his scientific heroes and by his view of Karl Popper. Mitchell was an introvert who was happiest “wandering in the gardens of his mind,” yet he had a deep and abiding concern about social issues and about making institutions more humane. There was a genuine humility in his appreciation and study of natural systems, yet he was ambitious to be successful in science as measured by the acceptance of his ideas by his peers. Gentleness was an ideal learned from his mother, as well as from his headmaster Wiseman, and was a trait present in many of his interactions with others. Yet, clearly, there was a tension between this humility and gentleness on the one hand and the strong, aggressive part of his nature on the other. In some respects, the polarities of Mitchell’s personality reflect the differences between those of his parents. Their strained relationship was also a likely source of his emotional aversion to conflict and preference for solitude. He had his father’s abilities with mathematics and fascination with problem solving together, in youth, with his love of and ability in athletics. The artistic temperament and engagement with art and music were obviously cultivated by Mitchell’s mother. It is significant that most of the women in Mitchell’s life were artists or very interested in art. Mitchell’s strongly emotional and artistic personality often made difficulties in his dealings with other scientists but was an important aspect of his social interactions and in his relationships with women. It is this artistic aspect of his character that is probably connected to his strong reliance on intuition in his approach to scientific problems. He sought to comprehend patterns rather than particulars. His imagination, particularly in relation to science, reflected the spatial concerns of the artist and the mathematical proportions of the musician. He also had the artisan’s love of crafting things. Although he was not a great experimentalist, Mitchell took pride in his glassblowing abilities to fabricate apparatus, and throughout his career he made models with which to explore the dynamic and structural aspects of his theorizing. This side of his character also expressed itself in the very practical activities associated with refurbishing and restoring old and practically derelict buildings. Although Mitchell had a palpable aversion to discord, he did not draw back from scientific controversy. Indeed, he was eager to assert his ideas against the opposition of the leaders of the field, even though it took an emotional toll on him. He had great confidence in his abilities

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and, at the end of the day, did not believe that his opponents could be right. Knowing that he was likely to win added savor to the contest. His plan for the Octavian meeting format, used for discussion in the cytochrome oxidase controversy, was a reflection of his rational self. However, his emotional self did not give any ground in this more relaxed and civil discourse, and he was deeply disappointed that the Octavian sessions did not change his opponents’ minds.



Mitchell’s Science

One of the major characteristics of Mitchell’s scientific work was his intuitive thinking. Thus he was able to speculate about biological systems in a rational and creative way, which produced an understanding that often turned out to be close to reality. This gave him confidence to use his imagination, to build on hints from empirical evidence, to develop general explanations, and to generate a theory-driven research program. As he deepened his ideas about the fundamental relationship of metabolism and transport, he increasingly became convinced that he had an insight into basic principles that were congruent with the way nature was. Consequently, the chemiosmotic hypothesis was propounded with virtually no experimental basis, and the Q cycle with only slight empirical support. He felt sufficiently sure of the basic correctness of his approach that when theory and experimental data were in conflict, he immediately suspected problems with the experiment or its interpretation. Further, he felt that his ideas, as embodied in his chemiosmotic theory, had been vindicated by the unsuccessful efforts of his many critics to falsify them. This reinforced his determination not to give in to his opponents about the details of his theory, such as notions of how protons are translocated across membranes. These mechanisms were deeply integrated into what he regarded as his fundamental insights. The depth of this commitment is captured by an incident during the week of celebrations of the Nobel Prize in Stockholm. Lars Ernster, who had served on the Nobel selection committee, talked privately to Mitchell concerning the controversies about the proton arithmetic. Ernster was concerned that Mitchell was spoiling the beauty of his theory by adherence to specific mechanistic details and predictions that Ernster regarded as superfluous to the chemiosmotic rationale. Mitchell responded that the general notion of a proton-motive force in coupling

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oxidation and phosphorylation depended on the principles upon which his mechanisms were based; if the mechanisms were rejected, the theory would also be rejected. Ernster replied with a parable about an Indian prince whose fiancée died the night before their wedding. The grief-stricken prince vowed to build the most perfect mausoleum to honor her memory. Twenty years were required for completion, and when the prince walked in he realized that indeed all was perfection except for the sarcophagus, which spoiled the effect. He ordered it to be removed. Ernster underlined the moral that how something comes to be is not as important as what it is. Mitchell replied that he disagreed and that the prince was an immoral man since, but for the sarcophagus, the building would never have been built. Mitchell added that for him the sarcophagus contained David Keilin, for whom he had great respect and affection. The meaning of this is perhaps best understood by reading the first part of Mitchell’s Nobel lecture, in which he expressed his personal and scientific indebtedness to Keilin. Despite his interest in the nature of communication and an ability to be a deft rhetorician in debate (especially in letters, as has been analyzed by Michael Mulkay),12 Mitchell did not often get his message across successfully to his biochemical audiences. The supreme example of this was his 1961 paper. One source of this difficulty was his great care to state things precisely, which often led him to write very complex sentences, as well as to create new terminology. The latter practice was interpreted by some as imperialistic. To a greater extent, the problem lay with the way that Mitchell thought; what was intuitive to Mitchell was often counterintuitive to most biochemists of his time. The very concepts themselves seemed strange to biochemists and often puzzled them. This was particularly so for various aspects of what Mitchell referred to as “vectorial metabolism.” It was not until Guy Greville published his review in 1969 that Mitchell’s theory was presented in a form that could be understood by most biochemists.13 Although he learned to use less philosophical language in putting forward his ideas, Mitchell continued to think creatively within a philosophical context; possibly he never fully realized that he needed to translate his insights into a formulation that was closer to the conventional norm. In his later years, part of the problem may also have arisen from his lack of interest in the new understanding of molecular mechanisms provided by protein chemistry. These newer insights did not become incorporated into his theoretical thinking. This is particularly apparent in his approach to the mechanism of the ATPase.

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Because he started with a theoretical premise, Mitchell often confused his audiences and readers, who tended to assume that biochemistry was an empirically driven enterprise. Whereas most biochemists worked from experimental results to theoretical interpretation, Mitchell worked from theory to experimental design. Nevertheless, he failed to make the case for a theoretical biology. This was mostly likely because this need was self-evident to him.



Moyle

It is very questionable whether Mitchell would have made significant progress in his research program if he had not had the support of Jennifer Moyle. This entirely professional relationship made an essential contribution to Mitchell’s success. First, Moyle was an able experimenter, whereas Mitchell, despite his undoubted technical and engineering ability, was not. Although almost all of Mitchell’s theoretical papers did not include Moyle, virtually all of his later experimental papers featured Moyle as coauthor. Her carefully crafted experiments were essential for the campaign to persuade biochemists of the veracity of the chemiosmotic theory. Second, and less obviously, she was the person with whom Mitchell could discuss his imaginative ideas and who could help him distinguish the good from the bad. Such a role was all the more important because of the isolation of Glynn. The experimental work from the first two decades of Glynn provided crucial qualitative and quantitative support for the theory, as well as an essential input to sustain Mitchell’s further theorizing. Ultimately, however, valuable as this work was in the 1960s and 1970s, many of the quantitative elements have not stood the test of time. This is hardly the first time that experiments, which ultimately prove incorrect in detail or which have been misinterpreted, have helped sustain an investigative pathway. There have been a number of long-term collaborations in science, but probably none that quite equal that of Mitchell and Moyle.



Glynn as an Experiment in “Small Science”

Mitchell’s dislike of working within larger organizations was greater than that of the typical introvert. He needed a degree of autonomy of action that was not feasible in traditional academic settings. Glynn al-

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lowed him to express fully his personality and, in a world that he controlled, his creativity was given full rein. From 1964 to 1978 the council of management of Glynn consisted only of Mitchell and Moyle. Not until 1978, after recovering from his breakdown of the previous year, did Mitchell decide to expand the membership of the council by the addition of Quin Geering and Harold Baum. At that time, he was seeking to change and expand the direction of research and to obtain external funding. The financial cost of Glynn to Mitchell was very substantial and in the end threatened to make him insolvent. He developed a series of schemes to raise personal money, which included the minting and marketing of the silver Glynns and the projected sale of bottled water from the estate. A similar motivation seems to lie behind the project to develop a windmill on the property to generate electricity. While these activities were an expression of his entrepreneurial streak, nevertheless, there may be in these efforts an element of his desire for independence and autonomy. Glynn offered solitude and a barrier from the pressures, distractions, and demands of the academic and scientific world. Not only did Glynn provide a venue for doing science with a Zen-like clarity and intensity (Mitchell’s own characterization), but it allowed him to choose when to go out to meetings. Mitchell felt that the isolation of Glynn ensured that those scientists who came to visit him were serious about discussing bioenergetics. Moreover, from Mitchell’s point of view, the meeting was held on his own ground. The isolation and simplicity of life at Glynn, as well as its beautiful setting, encouraged a deeper exploration of Mitchell’s theories and experiments in a less stressful manner than was obtained at most scientific conferences. In an era of big science, Mitchell was successful with his dual experiment. This was to explore the implications and evidence for his chemiosmotic proposal and to create a small, private, and independent institute that could have significant effects on international science. Although the basic notion of the chemiosmotic theory was developed in Edinburgh, with deeper roots traceable back to Cambridge, the bulk of the experimental evaluation and the refinement of the theory were achieved at Glynn. Mitchell may have needed Glynn, which was ideally suited to his theoretical approach to biology and his personality. Without doubt, the success of Glynn depended on Mitchell’s collaboration with Moyle and the good fortune that significant results could be obtained from relatively simple and inexpensive equipment and technology.

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The Glynn Research Institute laboratories were modern and staffed with professional scientists and technicians; this was no gentlemanscientist’s home laboratory, although it was certainly not equipped in lavish style. Over the years the staff grew to about a dozen individuals, including visiting postdoctoral fellows. Throughout its lifetime, the Glynn Research Institute was operated according to the rules governing private organizations and charitable trusts, with all appropriate records legally kept. Indeed, Glynn was unique. As Lord Swann remarked, “There can be few such organizations in the world, set up and endowed by a practicing scientist, and none, I am sure, set up by a scientist who went on to win the Nobel Prize.”14 In its first decade of existence, Glynn was highly successful as an institution in which world-class science could be done. In its second decade, financial problems began to plague its operation. During its third decade, Mitchell was spending most of his time trying to obtain sufficient funding to secure its future. Even so his chosen successor as research director, Peter Rich, continued to produce a stream of important papers, albeit with a much more sophisticated instrumental base. Only a few years after Mitchell’s death it became clear that, although funding was available to support the research, there were no agencies or individuals willing to provide funds to maintain such a small, independent operation. However, as soon as Rich moved to University College London, where he established the Glynn Laboratories of Bioenergetics, the funding agencies that had denied support to an independent Glynn institute now provided support for the laboratory. It appears unlikely that we will see another Glynn. We cannot but feel that something special has been lost to science with its demise.

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Appendix
Theories of Oxidative Phosphorylation



The Background

The oxidation of foodstuffs in cells proceeds by a series of steps, which terminate in a chain of reactions leading to the reduction of oxygen to water. Almost all the energy made available to the cell from this process comes from this terminal chain, which synthesizes ATP (adenosine triphosphate), the energy currency of the cell. Most cells (animal including human, plant, yeast, and many bacterial cells) that use oxygen carry out these reactions. This terminal part of the oxidation of foodstuffs, the respiratory chain, consists of a sequence of reactions in which electrons from the oxidation of foodstuffs (held in a substance known as NADH, reduced nicotinamide adenine dinucleotide) are passed to oxygen. The respiratory chain consists of a sequence of different compounds that include flavoproteins, cytochromes (which are proteins), and a relatively small compound, ubiquinone (also known as quinone, UQ, and Q). The compounds are clustered in three main complexes. NADH ➝ [Complex I] ➝ [Complex III] ➝ [Complex IV] ➝ O2

The first complex oxidizes NADH (NADH dehydrogenase, complex I) and reduces the middle complex (known as complex III, ubiquinonecytochrome c reductase). Complex III transfers electrons from the first complex to the last. The last complex, the cytochrome oxidase (complex IV) receives electrons from complex III and reduces oxygen to water. Each of these three complexes is linked to the synthesis of ATP from ADP

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(adenosine diphosphate), which is catalyzed by the enzyme ATPase (ATP synthase). Thus when two electrons pass from NADH to reduce an atom of oxygen, ATP is synthesized at three points in the process. Note: There is also a complex II that oxidizes succinate and passes electrons to complex III. It is not coupled to ATP synthesis, nor does it translocate protons.



Mitochondria and Chloroplasts

Almost all cells, other than bacteria, possess small particles (organelles) within them known as mitochondria. These are the organelles responsible for the final stages of oxidation of foodstuffs. They have two membranes, which surround an inner aqueous part. The outer membrane is freely permeable to small molecules but not proteins. The inner membrane is itself impermeable to most molecules (except, for example, oxygen and water) but contains a number of proteins that carry specific molecules across the membrane. The respiratory chain and the enzymesynthesizing ATP are found in the inner membrane. Chloroplasts, where photosynthesis occurs, are organelles found in green plant cells. They have a double membrane surrounding the organelle and contain a number of internal membranes. These internal membranes possess an electron transport chain (similar to the respiratory chain) and also an ATPase-synthesizing ATP. Bacteria lack mitochondria but possess a cell membrane (plasma membrane) surrounding the internal part of the cell. This membrane possesses the ATPase, the respiratory chain, and proteins for transporting molecules across the membrane into the cell.



Coupling and Uncoupling

Although knowledge accumulated about the respiratory chain from 1925 onward, the way in which that chain reacted in order to synthesize ATP was not easily understood. Carefully prepared mitochondria could be shown to synthesize ATP during respiration, but the ability to synthesize ATP was easily lost. Aged or slightly damaged mitochondria readily carried out respiration but were unable to synthesize ATP. Thus mitochondria and similar systems were described as coupled when the

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respiratory chain was linked to ATP synthesis, and uncoupled when the respiratory chain functioned without being associated with ATP synthesis. Beginning in the early 1950s, biochemists became aware that there were a number of substances that could break the link between the activity of the respiratory chain and the synthesis of ATP. These substances became known as uncouplers. The first uncoupler to be readily characterized was dinitrophenol (DNP), which was widely used until more potent uncouplers became available.



Oxidative Phosphorylation and Photosynthetic Phosphorylation

The process of respiration coupled to the synthesis of ATP and leading to oxygen reduction to water became known as oxidative phosphorylation. This distinguished it from another type of phosphorylation (substratelevel phosphorylation), where the ATP synthesis is linked to straightforward chemical reactions in the process of sugar breakdown in cells. Oxidative phosphorylation could be measured in terms of the ratio of the number of ATP molecules synthesized to the number of atoms of oxygen reduced, the P/O ratio. The value of this ratio was considered to be an integer, 3 during most of Mitchell’s lifetime (later it was realized that it was less than 3.0). This meant that there would be one ATP molecule synthesized in each complex of the respiratory chain when a pair of electrons passed through the complex on their way to reduce an atom of oxygen. Photosynthesis occurs in the chloroplast. The process involves the light-driven transfer of electrons from water through complexes in a manner similar to that of respiration in the mitochondrion. The transfer of electrons is coupled to the synthesis of ATP from ADP, as in the process of oxidative phosphorylation. The process of ATP synthesis in chloroplasts is known as photosynthetic phosphorylation or photophosphorylation. It was long assumed that the mechanism of synthesis of ATP coupled to electron transport would be the same in the mitochondrion and chloroplast. However, understanding the mechanism whereby the transfer of electrons through the complexes (oxidation reduction) was coupled to ATP synthesis proved a major problem for biochemists. Many theories were proposed, although for most purposes three major theories only need be considered.

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The Chemical Theory of Oxidative (and Photosynthetic) Phosphorylation

The chemical theory was proposed by E. C. (Bill) Slater in 1953 and was a development of a proposal by Fritz Lipmann in 1946. In essence, Slater had assumed that biological synthesis of ATP must proceed by similar sets of reactions and, therefore, oxidative phosphorylation must be very similar to substrate-level phosphorylation. He looked at the reactions where ATP was synthesized during the breakdown of sugars and suggested similar reactions for the respiratory chain. Thus it was necessary to propose an intermediate substance (or substances) formed during oxidation reduction in the complexes and used for ATP synthesis. Such a substance would possess the energy available from oxidation in the complexes, and this would be used for ATP formation. The intermediate was therefore termed the “high-energy intermediate.” Thus the link between respiration and the synthesis of ATP was a chemical substance(s). It was necessary to suggest that in some way uncouplers brought about the breakdown of the high-energy intermediate. Following Slater’s proposal of the chemical theory, a major (and unsuccessful) search for a high-energy intermediate was initiated and lasted some twenty years.



The Conformational Theory of Oxidative (and Photosynthetic) Phosphorylation

The way in which the polypeptide chain is folded to form a protein is called its conformation. Ideas about the way in which proteins can change their conformations developed during the 1960s. It was appreciated that different conformations would have different energies. Thus a conformational change would be associated with an increase or decrease in the energy of the protein. Paul Boyer proposed in 1964 (and developed the idea thereafter) that the process of oxidation in the complexes of the respiratory chain could be associated with storing the energy in the proteins of the complex as energy-rich conformations. He suggested that in some way the energy from the respiratory chain could be transferred to create a highenergy conformation of the ATPase (the enzyme responsible for ATP synthesis in oxidative phosphorylation). The enzyme would then pos-

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sess the energy for the synthesis of ATP from ADP and inorganic phosphate. While conformational changes could themselves not readily be measured, Boyer succeeded, in due course, in demonstrating that conformational changes (involving energy transfer) must occur in the ATPase. Later, Boyer accepted that the respiratory chain might create a gradient of protons across the mitochondrial membrane (as Mitchell had suggested). This proton gradient could bring about the conformational changes in the ATPase necessary for ATP synthesis. Boyer’s understanding of the ATPase itself progressively gained wide acceptance (although not by Mitchell), and he shared in the Nobel Prize for Chemistry in 1997 for this work.



The Chemiosmotic Theory of Oxidative (and Photosynthetic) Phosphorylation

In 1961, aware of the failure to find the high-energy intermediate of the chemical theory, Peter Mitchell proposed his chemiosmotic theory. The initial version differed from the mature theory proposed in 1966, which was substantially elaborated in later years. The synthesis of ATP involves the removal of water from inorganic phosphate and ADP, resulting in ATP. Water could be considered as composed of two components, the proton (a charged hydrogen atom, H+) and a negatively charged hydroxyl ion (OH–). In his original version, Mitchell considered that ATP might be formed by the membranebound ATPase through removal of a proton to one side of the membrane and the removal of the hydroxyl ion to the other side. This could happen if there were a gradient across the membrane with high OH– on one side (attracting the H+ from the ATPase) and high H+ (attracting OH– from the ATPase) on the other. The gradient with high H+ on the one side and high OH– on the other would be formed by the functioning of the respiratory chain. The later version is very similar but simpler. The proton now passes through the ATPase, driving the synthesis of ATP. The respiratory chain sets up a gradient of protons by pumping protons from one side of the membrane to the other (the membrane itself is impermeable to protons). In either the early or later versions, the movement of the charged ions in relation to the membrane sets up an electrical potential. (When an electrically charged particle such as a proton passes across a

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membrane, it establishes an electrical potential.) This potential encourages the ions to return. Thus the mechanism for oxidative phosphorylation is explained in terms of proton movement by the respiratory chain forming a gradient of protons and a potential, both of which encourage the proton to return through any available pathway. The principal pathway is the ATPase where ATP is synthesized. In summary, a proton gradient and the accompanying membrane potential replace the highenergy intermediate of the chemical theory. A key question for this theory is how protons are transported across the membrane by the respiratory chain. Mitchell proposed that they were carried by molecules which, when reduced, required both an electron and a proton and, when oxidized by removal of the electron, released a proton. If the reduction of such a molecule occurred on one side of the membrane, a proton would be taken up; if the oxidation occurred on the other side, the proton would be released on that side, thus forming a proton gradient. The most obvious molecule in the respiratory chain to carry out such a process is ubiquinone. This molecule had a key role in the theory at the outset and later was the basis for Mitchell’s Q cycle. The way in which the proton drove ATP synthesis was a complex question that Mitchell discussed for the rest of his life but never satisfactorily solved. In this theory, uncouplers are substances that dissipate the proton gradient by rendering the membrane permeable to protons. Bob Williams also proposed a theory, slightly before Mitchell’s 1961 paper, which was based on protons, but the mechanistic principles were different.



Explanatory Notes

Stoichiometry The word stoichiometry is used to describe the measurements of the ratios of, for example, ATP synthesized to oxygen atoms reduced (P/O ratio) or the numbers of protons transferred across the membrane per oxygen atom reduced (H+/O ratio or ←H+/O ratio). Transport The word transport is used to cover the transfer of substances across membranes. In the case of the chemiosmotic theory, this is the transport of protons. However other substances may also be

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transported in exchange for protons, such as sodium ions (the system was described by Mitchell as an antiport). Some are transported with protons such as phosphate or sugars (where Mitchell used the term symport). Some may be transported on their own (uniport) such as calcium in response to the membrane potential. The term active transport was used to denote uptake of a substance against a concentration gradient, the process requiring metabolic energy. Transport of most substances across mitochondrial, chloroplast, or bacterial membranes normally requires a carrier, but oxygen and carbon dioxide can diffuse across membranes.

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Notes




The letters quoted below from and to Peter Mitchell are held in the Cambridge University Library P. D. Mitchell Archive. Files of letters are listed in a published index (National Cataloguing Unit for the Archives of Contemporary Scientists, University of Bath, England, 1997). Unpublished essays, notes, etc., by Mitchell are also held in the P. D. Mitchell Archive at Cambridge. Letters to and from Bill (E. C.) Slater are held in the North Holland State Archives (E. C. Slater archive), Haarlem, The Netherlands. A few letters not in the above archives have been made available to us privately, and we hold copies. The minute books from Glynn are currently held by Peter Rich at University College London but are expected to be transferred to Cambridge. Peter Mitchell’s diaries are held by the family. Tapes, transcripts of interviews, and other correspondence are held by the authors. a b b r e v i at i o n s BW, Bruce Weber JP, John Prebble PM, Peter Mitchell foreword 1. R. Curtis, “Narrative Form and Normative Force: Baconian Storytelling in Popular Science,” Social Studies of Science 24 (1994): 419–461. 2. K. Edmondson and J. Novak, “The Interplay of Scientific Epistemological Views, Learning Strategies, and Attitudes of College Students,” J. Res. Sci. Teaching 30 (1993): 547–559.

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chapter 1 1. Leslie E. Orgel, “Are You Serious, Dr. Mitchell?” Nature 402 (1999): 17. 2. Anthony R. Crofts, “Peter Mitchell and the Chemiosmotic Hypothesis,” Biochem. Soc. Bull. 1 (1979): 4–7. chapter 2 1. Interview, Helen Dunwell (née Mitchell) with BW, 1991. 2. This and other information in this chapter is based partly on interviews of PM with BW, 1980, 1982, and 1991. 3. See David J. Jeremy, “Sir Godfrey Way Mitchell,” in Dictionary of Business Biography, ed. David J. Jeremy (London: Butterworths, 1985), 4: 256–261. 4. Interview, PM with BW, 1991. 5. Interview, Bryan Robertson with BW, 1991. 6. “Peter Mitchell,” Preface to P. Mitchell, “David Keilin’s Respiratory Chain Concept and Its Chemiosmotic Consequences,” in Les Prix Nobel en 1978 (Stockholm: Nobel Foundation, 1979), 135. 7. Interview, PM with BW, 1991. 8. John Morel Gibbs, Methodist Residential Schools: A Conflict of Attitudes (London: Board of Management for Methodist Residential Schools, 1989). 9. Milton S. Saier Jr., Peter Mitchell and the Vital Force (unpublished biography, 1991). 10. H. J. Channon, History of Queen’s College Taunton (Taunton: Old Queenians Association, ca. 1957), 114. 11. Interview, PM with BW, 1980. 12. Interview, PM with BW, 1991. 13. Ibid. 14. Ibid. 15. Ibid. chapter 3 1. Mitchell’s matriculation was recorded in the Cambridge University Reporter, 28 November 1939, p. 207. In the Cambridge University Reporter of 22 December 1939, p. 377, it was noted that Mitchell had been exempted from the qualifying examinations except for Latin, which was the only one he had passed. 2. Letter, Joan Keilin Whiteley to BW, 5 July 1992. 3. Interview, PM with BW, 1991. 4. Of the fifty-three individuals who were members during the years that Mitchell belonged (1941–1949), eighteen went on to become fellows of the Royal Society (F.R.S.), and most had significant academic appointments. 5. Cambridge University Natural Science Club 1872–1982 (Cambridge University, 1982), 77. 6. Peter Mitchell’s personal copy of the 1939 reprinting of Perspectives in

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Biochemistry, with his annotations, appears to have been purchased in 1939 or 1940, as was his personal copy of the fifth edition of The Meaning of Meaning, which was reprinted in 1938. 7. Interview, Bryan Robertson with BW, 1991. 8. Interview, PM with BW, 1991. 9. Interview, Bryan Robertson with BW, 1991. 10. For a history of the biochemistry department at Cambridge, see Mark Weatherall and Harmke Kamminga, Dynamic Science: Biochemistry in Cambridge 1898–1949 (Cambridge: Wellcome Unit for the History of Medicine, 1992); Mark Weatherall and Harmke Kamminga, “The Making of a Biochemist. I: Frederick Gowland Hopkins’ Construction of Dynamic Biochemistry; II: The Construction of Frederick Gowland Hopkins’ Reputation,” Med. Hist. 40 (1996): 269–292, 415–436; Joseph Needham and Ernest Baldwin, Hopkins and Biochemistry: 1861–1947 (Cambridge: Heffer, 1949). 11. Frederick G. Hopkins, 1913, as reprinted in Needham and Baldwin, Hopkins and Biochemistry, 151. 12. Ibid., 152. 13. Joseph Needham and Dorothy Needham, “Sir F. G. Hopkins’ Personal Influence and Characteristics,” in Needham and Baldwin, Hopkins and Biochemistry, 119. 14. Ibid., 116. 15. Marjory Stephenson, 1949, “Sir F. G. Hopkins’ Teaching and Scientific Influence,” in Needham and Baldwin, Hopkins and Biochemistry, 37. 16. Sidney R. Elsden and Norman W. Pirie, “Obituary Notice: Marjory Stephenson 1885–1948,” J. Gen. Microbiol. 3 (1949): 329–339. 17. Haldane wrote two seminal books during his time at Cambridge, one on enzymology—Enzymes (1930)—and one on evolutionary theory: The Causes of Evolution (1932); both were widely used for many years and are considered foundational in their respective disciplines. See Ronald Clark, J. B. S.: The Life and Work of J. B. S. Haldane (London: Hodder and Stoughton, 1968), and David J. Depew and Bruce H. Weber, Darwinism Evolving: Natural Selection and the Genealogy of Natural Selection (Cambridge, MA: MIT Press, 1995). 18. Interview, David Green with BW, 1981. 19. Elsden and Pirie, “Obituary Notice: Marjory Stephenson,” 329. 20. Interview, PM with BW, 1991. 21. Interview, PM with BW, 1980. 22. Interview, PM with BW, 1979. 23. Interview, PM with BW, 1980. 24. G. D. Cameron, R. H. D. Short, P. D. Mitchell, and J. F. Danielli, “Interim Report on the Study of Capillary Permeability to Protein in Lewisite Poisoning,” Ministry of Supply Report No. 20 (Y.8855) (London: The War Office, 1943); P. D. Mitchell, J. F. Danielli, and R. D. H. Short, “Local and Systematic Plasma Albumin Exchange in Lewisite Poisoning with Special Reference to Therapeutic Measures,” Ministry of Supply Report No. 25 (Z.1304) (London: The War Office, 1944). 25. J. F. Danielli, M. Danielli, P. D. Mitchell, L. N. Owen, and G. Shaw,

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“BAL INTRAV: A New Nontoxic Thiol for Intravenous Injection in Arsenical Poisoning,” Ministry of Supply Report No. 26 (Z.1576) (London: The War Office, 1944). 26. J. Barcroft, J. F. Danielli, W. F. Harper, and P. D. Mitchell, “Wharton’s Jelly Considered as a Conducting Path,” Nature 154 (1944): 667; J. F. Danielli, M. Danielli, P. D. Mitchell, L. N. Owen, and G. Shaw, “Development of a Chemotherapy for Systematic Arsenical Poisoning,” Nature 157 (1946): 217–218; J. F. Danielli, M. Danielli, J. B. Fraser, and P. D. Mitchell, “BAL-INTRAV: A New Non-toxic Thiol for Intravenous Injection in Arsenical Poisoning,” Biochem. J. 41 (1947): 325–333. 27. Interview, PM with BW, 1991. 28. Interview, Bryan Robertson with BW, 1991. 29. Letter, Joan Keilin Whiteley to BW, 5 July 1992. 30. Letter, E. F. Hartree to BW, 24 November 1982. 31. Interview, PM with BW, 1991. chapter 4 1. Letter, Jennifer Moyle to BW, 20 August 1991. 2. Interview, PM with BW, 1979. 3. Letter, PM to R.A. Klein and B. Schmitz, 28 July 1987. 4. Interview, PM with BW, 1980. 5. Peter D. Mitchell, “The Origin of Life and the Formation and Organising Functions of Natural Membranes,” in International Symposium on the Origin of Life, ed. A. Oparin (Moscow: Ho. Acad. Sci. USSR, 1957), 229–234. 6. Mitchell’s personal copy was printed in 1945 and has his signature in the “copperplate” style he used up to about 1946. 7. Interview, PM with JP, 1991. 8. Unpublished manuscripts in the Cambridge University Library, P. D. Mitchell Archive, File C-13. Other manuscripts in this file are based on extracts from Joseph H. Woodger, Biological Principles: A Critical Study (London: Kegan, Paul, Trench, Trubner, 1929); Joseph Needham, Order and Life: The Terry Lectures, Yale (Cambridge: Cambridge University Press, 1936); D’Arcy W. Thompson, Growth and Form (Cambridge: Cambridge University Press, 1942). 9. See John N. Prebble, “The Philosophical Origins of Mitchell’s Chemiosmotic Concepts,” J. His. Biol. 34 (2001): 433–460. Also, Milton Saier, “Peter Mitchell and His Chemiosmotic Theories,” ASN News 63 (1997): 13–21. 10. Manuscript, Cambridge University Library, P. D. Mitchell Archive, File A-48. 11. Letter, Sandy (A. G.) Ogston to BW, 3 March 1993. 12. Letter, Joan Keilin Whiteley to BW, 5 July 1992. 13. Ibid. 14. Peter Mitchell, “Some Observations on the Mode of Action of Penicillin,” Nature 164 (1949): 259–262; Peter Mitchell and Jennifer Moyle, “Occurrence of a Phosphoric Ester in Certain Bacteria: Its Relationship to Gram

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Staining and Penicillin Sensitivity,” Nature 166 (1950): 218–220; Peter Mitchell and Jennifer Moyle, “Relationships between Cell Growth, Surface Properties and Nucleic Acid Production in Normal and Penicillin-Treated Micrococcus pyogenes,” J. Gen. Microbiol. 5 (1951): 421–438. 15. Peter Mitchell, “A New Technique for Stirred Aerated Culture,” Nature 164 (1949): 846–847; Peter Mitchell, “Spectrophotometric Estimation of Nucleic Acid in Bacterial Suspensions,” J. Gen. Microbiol. 4 (1950): 399–409; Peter Mitchell, “A Micro Lipid Extractor,” Nature 172 (1953): 124. 16. Interview, PM with BW, 1991. 17. Letter, Ernest Gale to BW, 9 August 1991. 18. Peter Mitchell, “The Osmotic Barrier in Bacteria,” in The Nature of the Bacterial Surface, ed. A. A. Miles and N. W. Pirie (Oxford: Blackwell Scientific, 1949), 55–71. 19. André Maurois [translated by Gerard Hopkins], The Life of Sir Alexander Fleming (New York: Dutton, 1959), 236. 20. A. Voureka, I. R. H. Kramer, W. H. Hughes, and A. Fleming, “The Morphology and Motility of Proteus vulgaris and Other Microorganisms Cultured in the Presence of Penicillin,” J. Gen. Microbiol. 4 (1950): 257– 269. 21. Interview, PM with BW, 1991. 22. Letter, Ernest Gale to BW, 9 August 1991. 23. Interview, PM with BW, 1991. 24. Interview, Donald Northcote with BW, 1982. 25. Interview, PM with BW, 1991. 26. Soraya de Chadarevian, Designs for Life: Molecular Biology after World War II (Cambridge: Cambridge University Press, 2002), 91. 27. Interview, Helen Mitchell with BW, 1991. 28. Ibid. 29. Peter Mitchell and Jennifer Moyle, “The Glycerophospho-Protein Complex Envelope of Micrococcus pyogenes,” J. Gen. Microbiol. 5 (1951): 981–992. 30. Peter Mitchell and Jennifer Moyle, “Paths of Phosphate Transfer in Micrococcus pyogenes: Phosphate Turnover in Nucleic Acids and Other Fractions,” J. Gen. Microbiol. 9 (1953): 257–272. 31. Peter Mitchell, “Transport of Phosphate across the Surface of Micrococcus pyogenes: Nature of the Cell Inorganic Phosphate,” J. Gen. Microbiol. 9 (1953): 272–287. 32. Peter Mitchell, “Transport of Phosphate across the Osmotic Barrier of Micrococcus pyogenes: Specificity and Kinetics,” J. Gen. Microbiol. 11 (1954): 73–82. 33. Peter Mitchell, “Transport of Phosphate through an Osmotic Barrier,” Symposia of the Society for Experimental Biology 8 (1954): 254–261; see p. 254. 34. Interview, PM with BW, 1982. 35. J. R. G. Bradfield, “Organisation of Bacterial Cytoplasm,” in Bacterial Anatomy, ed. E. T. C. Spooner and B. A. D. Stocker (Cambridge: Cambridge University Press, 1956), 296–317; see p. 306. 36. Peter Mitchell and Jennifer Moyle, “Osmotic Function and Structure

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in Bacteria,” in Bacterial Anatomy, ed. E. T. C. Spooner and B. A. D. Stocker (Cambridge: Cambridge University Press, 1956), 150–180; see pp. 175–176. chapter 5 1. Michael Swann, in J. Dundas, Scottish Hospital Endowments Research Trust: The First Thirty Years (Edinburgh: SHERT, 1984), 79–80. 2. Letter, Jack Dainty to BW, 18 August 1987. 3. Interview, Robert Reid with BW, 12 October 1982. Letter, John M. Mitchison to BW, 12 August 1991. 4. Interview, Robert Reid with BW, 12 October 1982. 5. See, for example: Peter Mitchell, “Hypothetical Thermokinetic and Electrokinetic Mechanisms of Locomotion in Micro-organisms,” Proc. Roy. Phys. Soc. Edin. 25 (1956): 32–34; Peter Mitchell, “A Hypothesis of Cell Division without Discontinuity of Growth Rates,” Proc. Roy. Phys. Soc. Edin. 25 (1956): 10–12. 6. Peter Mitchell and Jennifer Moyle, “The Cytochrome System in the Plasma Membrane of Staphylococcus aureus,” Biochem. J. 64 (1956): 1–19P. 7. R. Sinclair, Robert A. Reid, and Peter Mitchell, “Culture of Strain L Cells in Suspension: Replacement of Polymer by Traces of Trypsin in a Defined Medium,” Nature 197 (1963): 982–984; Peter Mitchell, “The Causes of Rheumatism,” in The Listener for 17 and 24 November 1960. 8. Erwin Schrödinger, What Is Life? (Cambridge: Cambridge University Press, 1944; reprinted 1992), 3 [emphasis in original]. 9. Peter Mitchell, “The Origin of Life and the Formation and Organising Functions of Natural Membranes,” in International Symposium on the Origin of Life, ed. A. Oparin (Moscow: Academy of Sciences, 1957), 229–234. 10. Peter Mitchell and Jennifer Moyle, “Permeation Mechanisms in Bacterial Membranes,” Faraday Society Discussions 21 (1956): 258–265, 278–279, and 282–284; see p. 283. (Reproduced by permission of the Royal Society of Chemistry.) 11. Peter Mitchell, “A General Theory of Membrane Transport from Studies of Bacteria,” Nature 180 (1957): 134–136; see p. 136. 12. Peter Mitchell, “Structure and Function in Micro-organisms,” Biochem. Soc. Symp. 16 (1959): 73–93; see p. 91. 13. Ian West, “In Memoriam: Peter Mitchell, 1920–1992,” Mol. Microbiol. 6 (1992): 3623–3625; see p. 3624. 14. Peter Mitchell and Jennifer Moyle, “Enzyme Catalysis and Group Translocation,” Proc. Roy. Phys. Soc. Edin. 27 (1958): 61–71; see p. 70. 15. Peter Mitchell and Jennifer Moyle, “Coupling of Metabolism and Transport by Enzymic Translocation of Substrates through Membranes,” Proc. Roy. Phys. Soc. Edin. 28 (1959): 19–27; see p. 19. (Reproduced by permission of the Royal Physical Society of Edinburgh.) 16. Ibid.; see p. 24. 17. Peter Mitchell, “Biological Transport Phenomena and the Spatially Anisotropic Characteristics of Enzyme Systems Causing a Vector Component of Metabolism,” in Membrane Transport and Metabolism, ed. Arnost

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Kleinzeller and A. Kotyk (Prague: Czechoslovak Academy of Sciences), 22–34; see p. 33. 18. Bruce H. Weber, “The Impact of the Prague Symposium on the Conceptual Development of Bioenergetics: A Retrospective and Prospective View,” in Ion Gradient-Coupled Transport, INSERM Symposium 26, ed. F. Alvarado and C. H. van Os (Amsterdam: Elsevier, 1986), 1–9. 19. Mitchell in “Biological Transport Phenomena,” Membrane Transport and Metabolism, 100. 20. Robert K. Crane, D. Miller, and I. Bihler, “The Restrictions on Possible Mechanisms of Intestinal Active Transport of Sugars,” in Membrane Transport and Metabolism, ed. Arnost Kleinzeller and A. Kotyk (Prague: Czechoslovak Academy of Sciences), 439–449. 21. Robert K. Crane, “The Road to Ion-Coupled Membrane Processes,” Comprehensive Biochemistry 35 (1983): 43–69; see p. 67. 22. Ibid., 67. 23. Interview, Andre Jagendorf with BW, 1979. 24. Peter Mitchell, “Approaches to the Analysis of Specific Membrane Transport,” in Biological Structure and Function, vol. 2, ed. Trevor W. Goodwin (London: Academic Press, 1961), 581–603; see pp. 597–598. 25. Letter, PM to E. C. Slater, 8 July 1959. 26. These issues were fully reviewed by Robert N. Robertson, “Ion Transport and Respiration,” Biol. Rev. 35 (1960): 231–264. 27. Letter, PM to the editor of Nature, 28 April 1961. 28. Ibid. 29. Letter, R. A. Peters to PM, 4 December 1960. 30. A letter from PM to Malcolm Dixon, 14 February 1961, notes that “I am enclosing a manuscript of a paper which I read at a symposium in Stockholm last September as this contains the gist of my idea, and I would be most grateful to have your criticisms and comments upon it.” Thus Mitchell may have used the Stockholm manuscript to seek advice from various friends, including Keilin and Peters, rather than a draft of the Nature paper. 31. Letter, PM to Slater, 24 July 1961. 32. Letter, PM to Albert Lehninger, 27 March 1961. 33. Robert J. P. Williams, “Co-ordination, Chelation and Catalysis,” in The Enzymes, 2d ed., ed. Paul D. Boyer, Henry Lardy, and Karl Myrbäck (New York: Academic Press, 1959), Vol. 1, 399–441; see p. 436. 34. Robert J. P. Williams, “Possible Functions of Chains of Catalysts,” J. Theoret. Biol. 1 (1961): 1–17; Robert J. P. Williams, “Possible Functions of Chains of Catalysts II,” J. Theoret. Biol. 3 (1962): 209–229. 35. Robert J. P. Williams, “The History of Proton-Driven ATP Formation,” Biosci. Rep. 13 (1993): 191–212; see p. 199. 36. Letter, PM to Williams, 24 February 1961. 37. This refers to Peter Mitchell, “Molecule, Group and Electron Translocation through Natural Membranes,” Biochem. Soc. Symp. 22 (1963): 141–168. 38. Letter, PM to Danielli, 20 July 1961. 39. Williams, “The History of Proton-Driven ATP Formation,” see p. 204.

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40. B. H. Weber, “Glynn and the Conceptual Development of the Chemiosmotic Theory: A Retrospective and Prospective View,” Bioscience Reports 11 (1991): 577–617; see p. 587. 41. Robertson, “Ion Transport and Respiration.” Quoted in a letter PM to R. J. P. Williams, 8 March 1961. 42. Letter, PM to Williams, 8 March 1961. 43. Letter, PM to Williams, 19 April 1961. 44. Williams, “The History of Proton-Driven ATP Formation.” 45. Letter, Jack Dainty to BW, 18 December 1992. 46. Letter, PM to the editor of Nature, 28 April 1961. 47. Peter Mitchell, “Coupling of Phosphorylation to Electron and Hydrogen Transfer by a Chemi-osmotic Type of Mechanism,” Nature 191 (1961): 144–148. 48. Robertson, “Ion Transport and Respiration,” see p. 258. 49. Williams, “The History of Proton-Driven ATP Formation,” see pp. 203 and 193. 50. Letter, Davies to PM, 14 September 1961. 51. John Prebble, “Successful Theory Development in Biology: A Consideration of the Theories of Oxidative Phosphorylation Proposed by Davies and Krebs, Williams and Mitchell,” Biosci. Rep. 16 (1996): 207–215; see p. 211. See also Robert E. Davies and Hans A. Krebs, “The Biochemical Aspects of the Transport of Ions by Nervous Tissue,” Biochem. Soc. Symp. 8 (1952): 77–92. 52. Letter, PM to Krebs, 10 Oct 1961. 53. Letter, Krebs to PM, 13 Oct 1961. 54. Letter, PM to A. G. Ogston, 18 October 1961. 55. Letter, Ogston to BW, 3 March 1993. 56. Draft letter, PM to Ogston, undated. 57. Letter: E. C. Slater to PM, 4 January 1962. 58. Albert L. Lehninger and C. L. Wadkins, “Oxidative Phosphorylation,” Ann. Rev. Biochem. 31 (1962): 47–78; see p. 52; see also Albert L. Lehninger, “Water Uptake and Extrusion by Mitochondria in Relation to Oxidative Phosphorylation,” Physiol. Rev. 42 (1962): 467–517. 59. Letter, G. Greville to PM, 6 December 1961. 60. Mitchell, “Molecule, Group and Electron Translocation through Natural Membranes,” 165. 61. Edward C. Slater, “Peter Dennis Mitchell, 29 September 1920–10 April 1992,” Biographical Memoirs of Fellows of the Royal Society 40 (1994): 282–305; see p. 294. 62. Interview, Reid with BW, 12 October 1982. 63. Laboratory notes, Cambridge University Library, P. D. Mitchell Archive, Files C83–C91; Peter Mitchell, “Conduction of Protons through the Membranes of Mitochondria and Bacteria by Uncouplers of Oxidative Phosphorylation,” Biochem. J. 81 (1961): 24P. 64. Peter Mitchell, “Conduction of Protons through the Membranes.” Manuscript notes for the lecture. 65. See Peter Mitchell, “The Chemical Asymmetry of Membrane Trans-

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port Processes,” in Cell Interface Reactions, ed. H. D. Brown (New York: Scholar’s Library, 1963), 33–56. 66. Letter, Lehninger to PM, 5 December 1962. 67. Letter, Guy Greville to PM, 19 June 1961. 68. Letter, Greville to PM, 21 November 1961. 69. See John Prebble, “The Philosophical Origins of Mitchell’s Chemiosmotic Concepts,” J. His. Biol. 34 (2001): 430–460. 70. Peter Mitchell, “Molecule, Group and Electron Translocation through Natural Membranes,” Biochem. J. 83 (1962): 22P–23P. (Reproduced with permission, © the Biochemical Society.) 71. Peter Mitchell, “Metabolism, Transport and Morphogenesis: Which Drives Which?” J. Gen. Microbiol. 29 (1962): 25–37; see p. 35. (Reproduced by permission of the Society for General Microbiology.) 72. These comments were omitted from the version of the lecture published later (see note 70). 73. Interview, PM with BW, May 1980. 74. Mitchell, “Metabolism, Transport and Morphogenesis,” 29. 75. Ibid., 35. 76. Ibid. 77. Letter, PM to W. W. Anderson, 15 March 1962. chapter 6 1. Peter Mitchell, “The Culture of Imagination,” J. Roy. Inst. Cornwall, New Ser. 8 (1980): 173–190; see p. 174. (Reproduced with permission of the Royal Institution of Cornwall.) 2. Ibid., 174. 3. Ibid. 4. Letter, PM to Valuation Officer, 4 June 1964. 5. F. Hitchins and S. Drew, The History of Cornwall (W. Penaluna: Helston, 1824), 150. 6. Royal Cornwall Gazette, 2 July 1825. 7. Mitchell kept a diary illustrated with photographs of his work from the beginning of September to the end of November 1962; see entry for 9 November 1962. 8. Letter, PM to Erich Heinz, 21 March 1961. 9. Minutes of the Court of the University of Edinburgh, July 1963. 10. Letter, PM to Juda H. Quastel, July 1964. 11. Letter, PM to Roger A. Klein and B. Schmitz, 28 July 1987. 12. Letter, Jennifer Moyle to BW, August 1991. 13. Interview, PM with BW, August 1991. 14. Letter, PM to E. C. Slater, 16 April 1964. 15. Letter, PM to Lars Ernster, 7 October 1964. 16. Letter, PM to J. A. F. Harvey, 28 December 1962. 17. Memorandum and Articles of Association, Glynn Research Limited. 18. Minutes, Annual General Meeting, Glynn Research Limited, 13 June 1966.

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19. 20. 21. 22. 23. 24. 25.

Minutes, Annual General Meeting, 26 July 1965. Ibid. Letter, PM to Brian Chappell, 8 February 1965. Letter, Chappell to PM, 28 June 1965. Interview, Chappell with BW, 19 May 1980. Minutes, Annual General Meeting, 26 July 1965. Letter, PM to Howard Rasmussen, 1 April 1964.

chapter 7 1. For a study of Mitchell’s rhetorical strategies, see Michael Mulkay, The Word and the World (London: George Allen and Unwin, 1985). 2. Letter, PM to Albert Lehninger, 26 May 1965. 3. Letter, E. C. Slater to PM, 8 December 1964. 4. Letter, PM to Slater, 13 May 1965. 5. Minutes, Annual General Meeting, Glynn Research Limited, 18 June 1968. 6. Minutes, Annual General Meeting, Glynn Research Limited, 12 June 1967. 7. Letter, PM to Burton Guttman, 26 April 1966. 8. Douglas Allchin, “A Twentieth Century Phlogiston: Constructing Error and Differentiating Domains,” Persp. Sci. 5 (1997): 81–127; see p. 96. 9. See Albert L. Lehninger, “Water Uptake and Extrusion by Mitochondria in Relation to Oxidative Phosphorylation,” Physiol. Rev. 42 (1962): 467–517. 10. Albert L. Lehninger, The Mitochondrion (New York: Benjamin, 1965); see 127–129. 11. Letter, PM to Slater, 8 January 1965. 12. Edward C. Slater, “Oxidative Phosphorylation,” Comprehensive Biochemistry 14: 327–396; see p. 355. 13. Edward C. Slater, “Mechanism of Energy Conservation in Mitochondrial Oxido-reductions,” in Regulation of Metabolic Processes in Mitochondria, ed. J. M. Tager, S. Papa, E. Quagliariello, and E. C. Slater (Amsterdam: Elsevier, 1966), 166–179; see p. 169. 14. Letter, PM to Slater, 14 February 1962. 15. Albert L. Lehninger and C. L. Wadkins, “Oxidative Phosphorylation,” Ann. Rev. Biochem. 31 (1962): 47–78; see p. 52. 16. Peter Mitchell and Jennifer Moyle, “Stoichiometry of Proton Translocation through the Respiratory Chain and Adenosine Triphosphatase Systems of Rat Liver Mitochondria,” Nature 208 (1965): 147–151; see p. 151. 17. Peter Mitchell and Jennifer Moyle, “Respiration-Driven Proton Translocation in Rat Liver Mitochondria,” Biochem. J. 105 (1967): 1147–1162. 18. Peter Mitchell and Jennifer Moyle, “Evidence Discriminating between the Chemical and the Chemiosmotic Mechanisms of Electron-Transport Phosphorylation,” Nature 208 (1965): 1205–1206. 19. Letter, Slater to PM, 6 December 1965. 20. Letter, PM to Slater, 3 June 1964.

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21. Letter, André Jagendorf to PM, 25 May 1964. 22. Letter, PM to Jagendorf, 6 February 1965. 23. Letter, Jagendorf to PM, 15 June 1965. 24. A.T. Jagendorf and E. Uribe, “ATP Formation Caused by Acid–Base Transition of Spinach Chloroplasts,” Proc. Natl. Acad. Sci. USA 55 (1966): 170–177. 25. Letter, PM to Slater, 2 November 1965. 26. Letter, PM to Slater, 26 February 1962. 27. Letter, PM to Slater, 13 May 1965. 28. Peter Mitchell, “Metabolic Flow in the Mitochondrial Multiphase System: An Appraisal of the Chemi-osmotic Theory of Oxidative Phosphorylation,” in Regulation of Metabolic Processes in Mitochondria, ed. J. M. Tager, S. Papa, E. Quagliariello, and E. C. Slater (Amsterdam: Elsevier, 1966), 65–85; see p. 65. The review referred to is Lars Ernster and C. P. Lee, “Biological Oxidations,” Ann. Rev. Biochem. 33 (1964): 729–788. 29. Mitchell, “Metabolic Flow in the Mitochondrial Multiphase System,” 82. 30. Ibid., 83. 31. Interview, PM with BW, May 1980. 32. Efraim Racker and T. E. Conover, “Multiple Coupling Factors in Oxidative Phosphorylation,” Federation Proc. 22 (1963): 1088–1091; see p. 1088. 33. Letter, Munro Fox to PM, 15 January 1962. 34. Letter, PM to Munro Fox, 16 February 1962. 35. Peter Mitchell, “Chemiosmotic Coupling in Oxidative and Photosynthetic Phosphorylation,” Biol. Rev. 41 (1966): 445–502; Peter Mitchell, Chemiosmotic Coupling in Oxidative and Photosynthetic Phosphorylation (Bodmin: Glynn Research Ltd., 1966). 36. Mitchell, Chemiosmotic Coupling in Oxidative and Photosynthetic Phosphorylation; see pp. 2 and 3. 37. Lars Ernster and Gottfried Schatz, “Mitochondria: A Historical Review,” J. Cell Biol. 91 (1981): 227s–255s; see p. 244s. (Reproduced by copyright permission of The Rockefeller University Press.) 38. Letter, Slater to Daniel Dervartanian, 4 February 1969. 39. Letter, PM to Harold Baum, 13 October 1971. 40. Letter, Fritz Lipmann to PM, 19 August 1966. 41. Letter, PM to Lipmann, 5 October 1966. 42. Letter, Robert J. P. Williams to PM, 29 July 1966. 43. Letter, PM to Williams, 31 July 1966. 44. Letter, Slater to Britton Chance, Jagendorf, and PM, 3 November 1965. 45. Letter, Efraim Racker to PM, 30 December 1965. 46. Robert A. Reid, Jennifer Moyle, and Peter Mitchell, “Synthesis of Adenosine Triphosphate by a Proton-Motive Force in Rat Liver Mitochondria,” Nature 212 (1966): 257–258. 47. Letter, PM to Harold Baum, 18 January 1967. 48. Edward C. Slater, “An Australian Biochemist in Four Countries,” Comprehensive Biochemistry 40: 69–203; see p. 176.

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49. Letter, Slater to Williams, 22 April 1966. 50. Slater, “An Australian Biochemist in Four Countries,” 175–176. 51. Letter, Slater to Williams, 5 December 1966. 52. Edward C. Slater, “The Respiratory Chain and Oxidative Phosphorylation: Some of the Unsolved Problems,” in Biochemistry of Mitochondria, ed. E. C. Slater, Z. Kaniuga, and L. Wojtczak (London: Academic Press, 1966), 1–10; see p. 8; Peter Mitchell and Jennifer Moyle, “Proton-Transport Phosphorylation: Some Experimental Tests,” in Biochemistry of Mitochondria, ed. E. C. Slater, Z. Kaniuga, and L. Wojtczak (London: Academic Press, 1966), 53–74. 53. Letter, PM to Jagendorf, 21 June 1966. 54. Letter, Slater to Norman Good, 30 June 1967. 55. Letter, Williams to Slater, 20 December 1966. 56. Letter, Williams to Slater, 28 February 1967. 57. Letter, Good to PM and Jagendorf, 16 June 1967. 58. Letter, Good to Slater, 26 July 1967. 59. Peter Mitchell, Chemiosmotic Coupling and Energy Transduction (Bodmin: Glynn Research Limited , 1968), iii. 60. Peter Mitchell, “Chemiosmotic Coupling and Energy Transduction,” Theoretical and Experimental Biophysics 2 (1969): 159–216; Peter Mitchell, “Proton-Translocation Phosphorylation in Mitochondria, Chloroplasts and Bacteria: Natural Fuel Cells and Solar Cells,” Federation Proc. 26 (1967): 1370–1379. 61. Letter, PM to Joe Wiskich, 17 January 1968. 62. Letter, Lehninger to PM, 14 August 1967. 63. Britton Chance and L. Mela, “Proton Movements in Mitochondrial Membranes,” Nature 212 (1966): 372–376; see p. 376. 64. Peter Mitchell, Jennifer Moyle, and Lucille Smith, “Bromthymol Blue as a pH Indicator in Mitochondrial Suspensions,” Eur. J. Biochem. 4 (1968): 9–19. Peter Mitchell, “Oriented Chemical Reactions and Ion Movements in Membranes,” in The Molecular Basis of Membrane Functions, ed. T. C. Tosteson (Englewood Cliffs, NJ: Prentice-Hall, 1969). 65. J. M. Tager, R. D. Veldsema-Currie, and E. C. Slater, “Chemiosmotic Theory of Phosphorylation,” Nature 212 (1966): 376–379; see p. 379. 66. Peter Mitchell and Jennifer Moyle, “Chemiosmotic Hypothesis of Oxidative Phosphorylation,” Nature 213: 137–139. 67. M. McCabe, “Mitochondria and pH,” Nature 213 (1967): 280–281. 68. Peter Mitchell, “Intramitochondrial pH: A Statistical Question of Hydrogen lon Concentration in a Small Element of Space-time,” Nature 214 (1967): 400; Peter Mitchell, “Proton Current Flow in Mitochondrial Systems,” Nature 214 (1967): 1327–1328. 69. Letter, Greville to PM, 24 January 1967. 70. Guy D. Greville, “A Scrutiny of Mitchell’s Chemiosmotic Hypothesis of Respiratory Chain and Photosynthetic Phosphorylation,” Curr. Topics Bioenergetics 3 (1969): 1–78; see p. 2. 71. Letter, PM to Greville, 5 November 1968. 72. Letter, PM to Greville, 6 December 1968.

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73. Greville, “A Scrutiny of Mitchell’s Chemiosmotic Hypothesis,” see p. 71. 74. Interview, PM with BW, 23 May 1980. 75. Letter, PM to Chappell, 23 December 1969. 76. David W. Deamer, “ATP Synthesis: The Current Controversy” J. Chem. Educ. 46 (1969): 198–206; see p. 206. 77. Edward C. Slater, “Energy Conservation Mechanisms of Mitochondria,” in Mitochondria: Structure and Function, ed. L. Ernster and Z. Drahota, FEBS Symposium 17 (London: Academic Press, 1969): 205–217. 78. Lars Ernster, “Opening Remarks,” in Ernster and Drahota, Mitochondria, 1–4; see p. 3. 79. Letter, PM to Tsoo King, 28 March 1967. 80. Letter, Lipmann to PM, 27 July 1967. 81. Letter, PM to Greville, 6 July 1969. 82. Minutes, Annual General Meeting, Glynn Research Limited, 26 June 1969. chapter 8 1. Minutes, Council of Management, Glynn Research Limited, 8 January 1970. 2. Letter, Efraim Racker to E. C. Slater, 7 August 1973. 3. Karel van Dam and A. J. Meyer, “Oxidation and Energy Conservation by Mitochondria,” Ann. Rev. Biochem. 40 (1971): 115–160; see pp. 116 and 151. 4. M. Schwartz, “The Relation of Ion Transport to Phosphorylation,” Ann. Rev. Plant Physiol. 22 (1971): 469–484; see p. 482. 5. Letter, PM to Efraim Racker, 19 September 1972. 6. E. C. Slater, E. Quagliariello, S. Papa, and J. M. Tager, “Introduction,” in Electron Transport and Energy Conservation, ed. J. M. Tager, S. Papa, E. Quagliariello, and E. C. Slater (Bari: Adriatica Editrice, 1970), 1–4; see p. 1. 7. Ibid., 2. 8. Robert J. P. Williams, “Energy Pressure Expressed as Changes in Concentration Terms and Changes in Standard Rates,” in Tager, Papa, Quagliariello, and Slater, Electron Transport and Energy Conservation, 373–378; Peter Mitchell and Jennifer Moyle, “The Intrinsic Anisotropy of the Cytochrome Oxidase Region of the Mitochondrial Respiratory Chain and the Consequent Vectorial Property of Respiration,” in Electron Transport and Energy Conservation, 575–587. 9 Peter Mitchell, “The Culture of Imagination,” J. Roy. Inst. Cornwall 8, New Ser. (1980): 173–190. 10. Peter Mitchell, “Chemiosmotic Coupling and Energy Transduction,” Theoret. Exp. Biophys. 2 (1969): 159–216. 11. Jennifer Moyle and Peter Mitchell, “The Proton-Translocating Nicotinamide Adenine Dinucleotide (Phosphate) Transhydrogenase of Rat Liver Mitochondria,” Biochem. J. 132 (1973): 571–585. 12. Jennifer Moyle, Roy Mitchell, and Peter Mitchell, “Proton Translocat-

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ing Pyrophosphatase of Rhodospirillum rubrum,” FEBS Lett. 23 (1972): 233–236. 13. Peter Mitchell, “Energy Transduction in Respiration and Photosynthesis,” in Structure and Function of the Respiratory Chain of Mitochondria and Bacteria, ed. E. Quagliariello, S. Papa, and C. S. Rossi (Bari: Adriatica Editrice, 1971), 123–152. 14. Peter Mitchell, “Self-electrophoretic Locomotion in Microorganisms: Bacterial Flagella as Giant Ionophores,” FEBS Lett. 28 (1972): 1–4. 15. M. D. Manson, P. Tedesco, H. C. Berg, F. D. Harold, and C. van der Drift, “A Protonmotive Force Drives Bacterial Flagella,” Proc. Natl. Acad. Sci. USA 74 (1977): 3060–3064. 16. Peter Mitchell, “Bacterial Flagellar Motors and Osmoelectric Molecular Rotation by an Axially Transmembrane Well and Turnstile Mechanism,” FEBS Lett. 176 (1984): 287–294. 17. Manuscript in Cambridge University Library, P. D. Mitchell Archive, File D 60. 18. Interview, PM with BW, 23 May 1980. 19. Peter Mitchell, “The Chemiosmotic Theory of Transport and Metabolism,” in Mechanisms in Bioenergetics, ed. G. F. Azzone, L. Ernster, S. Papa, E. Quagliariello, and N. Siliprandi (New York: Academic Press, 1973), 177–201; see p. 177. 20. Peter Mitchell, “Performance and Conservation of Osmotic Work by Proton-Coupled Solute Porter Systems,” Bioenergetics 4 (1973): 63–91. 21. Ian C. West and Peter Mitchell, “Proton/Sodium Ion Antiport in Escherichia coli,” Biochem. J. 144 (1974): 87–90. 22. Letter, PM to Racker, 26 November 1970. 23. Letter, PM to Peter Hinkle, 13 October 1971. 24. Letter, PM to Racker, 10 July 1973. 25. Letter, Slater to Paul Boyer, 1 April 1975. 26. Letter, PM to Slater, 22 January 1974. 27. Letter, PM to William Jencks, 26 May 1977. 28. Letter, Boyer to PM, 9 October 1973. 29. Letter, PM to Boyer, 22 October 1973. 30. Peter Mitchell, “Cation-Translocating Adenosine Triphosphate Models: How Direct Is the Participation of Adenosine Triphosphate and Its Hydrolysis Products in Cation Translocation?” FEBS Lett. 33 (1973): 267–274. 31. Peter Mitchell, “A Chemiosmotic Molecular Mechanism for ProtonTranslocating Adenosine Triphosphatases,” FEBS Lett. 43 (1974): 189–194; see p. 190. 32. Letter, PM to Boyer, 25 June 1973. 33. Letter, Boyer to PM, 28 November 1973. 34. Letter, PM to Robert J. P. Williams, 18 October 1973. 35. Letter, Williams to PM, 17 November 1973. 36. Robert J. P. Williams, “Proton-Driven Phosphorylation Reactions in Mitochondrial and Chloroplast Membranes,” FEBS Lett. 53 (1975): 123–125; see p. 124.

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37. Letter, Slater to Williams, 8 December 1976. 38. Letter, PM to Walther Stoeckenius, 11 June 1973. 39. Letter dated 8 November 1972. 40. Letter dated 2 December 1973. 41. Edward C. Slater, “From Cytochrome to Adenosine Triphosphate and Back: The Sixth Keilin Memorial Lecture,” Biochem. Soc. Trans. 2 (1974): 1149–1163; see p. 1153. (Reproduced with permission, © the Biochemical Society.) chapter 9 1. Letter, PM to N. Alan Walker, 1 August 1974. 2. See chapter 7 in this volume. 3. Peter Mitchell, “Vectorial Chemistry and the Molecular Mechanics of Chemiosmotic Coupling: Power Transmission by Proticity,” Biochem. Soc. Trans. 4 (1976): 399–430; see p. 412. (Reproduced with permission, © the Biochemical Society.) 4. Douglas Allchin, “How Do You Falsify a Question? Crucial Tests versus Crucial Demonstrations,” in PSA 1992, Vol. 1, ed. D. Hull, M. Forbes, and K. Okruhlik (East Lansing, MI: Philosophy of Science Association, 1992), 74–88; see p. 81. 5. G. Nigel Gilbert and Michael Mulkay, Opening Pandora’s Box (Cambridge: Cambridge University Press, 1984), 127. See chapter 6 in this volume. 6. Efraim Racker, “Reconstitution, Mechanism of Action and Control of Ion Pumps,” Biochem. Soc. Trans. 3 (1975): 785–802; see p. 787. (Reproduced with permission, © the Biochemical Society.) 7. Ibid., 788. 8. Ibid., 801. 9. Minutes, Annual General Meeting, Glynn Research Limited, 25 June 1974. 10. Minutes, Annual General Meeting, Glynn Research Limited, 19 June 1975. 11. Letter, PM to Albert Lehninger, 30 September 1975. 12. Letter, PM to Lehninger, 17 November 1975. 13. Letter, PM to Lehninger, 30 December 1975. 14. Martin D. Brand, B. Reynafarje, and Albert L. Lehninger, “Re-evaluation of the H+/Site Ratio of Mitochondrial Electron Transport with the Oxygen Pulse Technique,” J. Biol. Chem. 251 (1976): 5670–5679. 15. Letter, PM to Lehninger, 4 June 1976. 16. Letter, PM to Lehninger, 30 December 1975. 17. Letter, PM to Sergio Papa, 29 November 1977. 18. Letter, PM to Lehninger, 30 December 1975. 19. The reference to “ligand conduction” refers to Mitchell’s proposed loops in the respiratory chain of hydrogen carriers that would transport the proton across the membrane. 20. Letter, PM to Lehninger, 26 April 1979.

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21. Brand, Reynafarje, and Lehninger, “Re-evaluation of the H+/Site Ratio.” 22. Jennifer Moyle and Peter Mitchell, “Measurements of Mitochondrial ←H+/O quotients: Effects of Phosphate and N-ethylmaleimide. FEBS Lett. 90 (1978): 361–365. 23. Peter Mitchell, “A Critique of ←H+/2e– and →e–/2e– Measurements,” in Oxidases and Related Redox Systems, ed. Tsoo E. King, H. S. Mason, and M. Morrison (Oxford: Pergamon Press, 1982), 1247–1263, 1260. 24. Letter, Märten Wikström to PM, 16 September 1977. 25. Letter, PM to Wikström, 13 October 1977. 26. Jennifer Moyle and Peter Mitchell, “Electric Charge Stoichiometry of Calcium Translocation in Rat Liver Mitochondria,” FEBS Lett. 73 (1977): 131–136; Jennifer Moyle and Peter Mitchell, “The Lanthanide Sensitive Calcium Phosphate Porter of Rat Liver Mitochondria,” FEBS Lett. 77 (1977): 136–140; Jennifer Moyle and Peter Mitchell, “Lanthanide-Sensitive Calcium-Monocarboxylate Symport in Rat Liver Mitochondria,” FEBS Lett. 84 (1977): 135–140; Peter Mitchell and Jennifer Moyle, “Calcium-Anion Symport Systems in Mitochondria,” in Frontiers of Biological Energetics, ed. P. L. Dutton, J. S. Leigh, and A. Scarpa (New York: Academic Press, 1978), 2: 1171–1178. 27. Letter, PM to Helmut Acker, 31 May 1984. 28. Roy Mitchell, Ian C. West, A. John Moody, and Peter Mitchell, “Measurement of the Proton-Motive Stoichiometry of the Respiratory Chain of Rat Liver Mitochondria: The Effect of Ethylmaleimide,” Biochim. Biophys. Acta 849 (1986): 229–235. 29. A. John Moody, Ian C. West, Roy Mitchell, and Peter Mitchell, “Is There Ca2+(Sr2+)-3-hydroxybutyrate Symport in Rat Liver Mitochondria?” Eur. J. Biochem. 157 (1986): 243–249. 30. Letter, PM to King, 25 October 1972. 31. Letter, PM to King, 6 January 1970. 32. Letter, King to PM, 4 May 1970. 33. Letter, PM to A. S. Cearns, 13 March 1973. 34. Letter, Wikström to PM, 10 June 1972. 35. Interview, PM with BW, May 1980. Quoted in B. H. Weber, “Glynn and the Conceptual Development of the Chemiosmotic Theory: A Retrospective and Prospective View,” Biosci. Rep. 11 (1991): 577–617; see p. 601. 36. Letter, PM to Wikström, 15 July 1975. 37. Peter Mitchell, “Protonmotive Redox Mechanism of the Cytochrome b–c1 Complex in the Respiratory Chain: Protonmotive Ubiquinone Cycle,” FEBS Lett. 56 (1975): 1–6; Peter Mitchell, “The Protonmotive Q Cycle: A General Formulation,” FEBS Lett. 59 (1975): 137–139; Peter Mitchell, “Protonmotive Function of Cytochrome Systems,” in Electron Transfer Chains and Oxidative Phosphorylation, ed. E. Quagliariello, S. Papa, F. Palmieri, E. C. Slater, and N. Siliprandi (Amsterdam and New York: North Holland and American Elsevier, 1975), 305–316. 38. Letter, Ernster to Karl Folkers, 13 January 1976. 39. Letter, Papa to PM, 16 October 1975.

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40. Youssef Hatefi, “The Mitochondrial Electron Transport and Oxidative Phosphorylation System,” Ann. Rev. Biochem. 54 (1985): 1015–1069; see p. 1035. 41. Letter, PM to Harold Baum, 12 April 1977. 42. PM, letter to the editor, Financial Times, Monday, 12 January 1976. 43. PM, letter to the editor, Financial Times, Friday, 23 January 1976. 44. Unpublished open letter to Sir Jeremy Morse, dated 1 January 1982. 45. Letter, PM to L. M. Rinaldini, 21 August 1985. 46. Letter, PM to Denis Uttley, 15 May 1979. c h a p t e r 10 1. Letter, Efraim Racker to PM and others, 11 March 1974. 2. Ibid. 3. G. Nigel Gilbert and Michael Mulkay, Opening Pandora’s Box (Cambridge: Cambridge University Press, 1984), 36. 4. Letter, PM to Racker (copied to others), 18 March 1974. 5. Letter, E. C. Slater to Racker (copied to others), 16 April 1974. 6. Letter, Paul Boyer to Lars Ernster, 23 April 1974. 7. Letter, Britton Chance to Racker (copied to others), 31 March 1974. 8. Letter, Chance to Slater, 25 April 1974. (Courtesy of Professor Chance.) 9. Attached to letter, Racker to PM, 2 May 1974. 10. Letter, PM to Racker (copied to others), 16 May 1974. 11. Ibid. 12. Ibid. 13. Letter, Slater to Racker (copied to others), 14 June 1974. 14. Letter, Boyer to PM, 15 July 1974. 15. Letter, PM to Ernster (copied to others), 12 August 1974. 16. Ibid. 17. Letter, PM to Racker, 26 September 1974. 18. Quoted in letter, PM to Boyer (copied to others), 22 January 1975. 19. Letter, Racker to PM, 29 January 1975. 20. Enclosed with a letter, PM to Chance and Boyer, 7 February 1975. See P. D. Mitchell archive file G123, Cambridge University Library. 21. Letter, PM to Boyer (copied to others), 6 March 1975. 22. Letter, PM to Boyer, 21 July 1975. 23. Paul D. Boyer, Britton Chance, Lars Ernster, Peter Mitchell, Efraim Racker, and Edward C. Slater, “Oxidative Phosphorylation and Photophosphorylation,” Ann. Rev. Biochem. 46 (1977): 955–1026. 24. Peter Mitchell, “Vectorial Chemiosmotic Processes,” Ann. Rev. Biochem. 46 (1977): 996–1005; see p. 996. 25. Letter, Boyer to PM, 28 April 1977. 26. Letter, PM to Peter Hinkle, 9 September 1977. 27. Letter, PM to Tsoo King, 14 September 1977. 28. Minutes, Annual General Meeting, Glynn Research Limited, 23 June 1977.

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29. Minutes, Annual General Meeting, Glynn Research Limited, 24 June 1976. 30. Minutes, Council of Management, Glynn Research Limited, 8 October 1976. 31. Ibid. 32. Letter, PM to Racker, 1 February 1977. 33. Minutes, Annual General Meeting, Glynn Research Limited, 8 June 1978. 34. Letter, PM to Ernster, 25 January 1978. 35. Letter, PM to Hinkle, 28 October 1977. 36. Minutes, Annual General Meeting, Glynn Research Limited, 8 June 1978. 37. Ibid. 38. Ibid. 39. Bo G. Malmström, “Mitchell Saw the New Vista, If Not the Details,” Nature 403 (2000): 356. 40. See John Prebble, “The Lasting Value of Mitchell’s Mechanisms,” Nature 404 (2000): 330. 41. Letter, Rufus Lumry to PM, 24 October 1978. 42. Interview, BW with PM, September 1991. 43. Jack B. Hanson in a paper sent to PM in 1976, “Who Is Peter Mitchell, Anyway?” Cambridge University Library, P. D. Mitchell Archive, File G357. 44. Letter, Helmut Beinert to PM, 27 October 1978. 45. Letter, Chance to Racker, 30 October 1978. (Courtesy of Professor Chance.) 46. Peter Mitchell, “David Keilin’s Respiratory Chain Concept and Its Chemiosmotic Consequences,” in Les Prix Nobel en 1978 (Stockholm: Nobel Foundation, 1979), 137–172; see p. 137. 47. Helen Mitchell, Personal Journal of Nobel Week, December 1978 (unpublished). 48. Lars Ernster and Gottfried Schatz, “Mitochondria: A Historical Review,” J. Cell Biol. 91 (1981): 227s–255s. c h a p t e r 11 1. Interview, Mårten Wikström with JP, August 1997. 2. Mårten K. F. Wikström, “Proton Pump Coupled to Cytochrome c Oxidase in Mitochondria,” Nature 266 (1977): 271–273. 3. Letter, PM to Wikström, 13 October 1977. 4. Letter, Wikström to Peter Hinkle, 17 October 1977. 5. Letter, PM to E. C. Slater, 24 January 1978. 6. Mårten K. F. Wikström and Herkko T. Saari, “The Mechanism of Energy Conservation and Transduction by Mitochondrial Cytochrome c Oxidase,” Biochim. Biophys. Acta 462 (1977): 347–361. 7. Letter, PM to Wikström, 13 October 1977.

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8. Letter, Wikström to PM, 21 November 1977. 9. Letter, PM to Hinkle, 10 November 1977. 10. Letter, PM to Slater, 21 February 1978. 11. Letter, PM to Wikström, 25 January 1978. 12. Letter, Wikström to PM, 30 March 1978. 13. Letter, PM to Wikström, 5 April 1978. 14. Jennifer Moyle and Peter Mitchell, “Cytochrome Oxidase Is Not a Proton Pump,” FEBS Lett. 88 (1978): 268–272. 15. Letter, Wikström to PM, 17 August 1978. 16. Letter, Hinkle to PM, 11 May 1979. 17. Letter, PM to Hinkle, 18 May 1979. 18. Peter Mitchell and Jennifer Moyle, “Electronmotive Function of Cytochrome Oxidase,” in Cytochrome Oxidase, ed. Tsoo E. King, Y. Orii, B. Chance, and K. Okunuki (Amsterdam: Elsevier/North Holland, 1979), 361–372; Peter Mitchell, “Direct Chemiosmotic Ligand Conduction Mechanisms in Protonmotive Complexes,” in Membrane Bioenergetics, ed. C. P. Lee, Gottfried Schatz, and Lars Ernster (Reading, MA: Addison-Wesley, 1979), 361–372. 19. Vladimir P. Skulachev and Peter Hinkle (eds.), Chemiosmotic Proton Circuits in Biological Membranes in Honor of Peter Mitchell (Reading, MA: Addison-Wesley, 1981). 20. Letter, PM to Tsoo King, 24 August 1981. 21. Letter, PM to Hinkle, 21 May 1981. 22. Letter, Wikström to PM, 22 February 1983. 23. Letter, Albert Lehninger to PM, 12 March 1984. 24. Letter, Franklin Harold to PM, 8 April 1982. 25. Letter, PM to Harold, 26 April 1982. 26. Letter, Slater to PM, 15 September 1982. 27. Letter, PM to Slater, 21 September 1982. 28. Letter, PM to Sir James Hamilton, 9 March 1982. 29. Peter Mitchell, “Science and Humanity: An Essay on Analytic and Appreciative Communication,” in Cell Function and Differentiation (New York: A. R. Liss, 1982), 1–10. Some of these ideas appeared earlier in: Peter Mitchell, “The Culture of Imagination,” J. Roy. Inst. Cornwall 8, New Ser. (1980): 173–190. 30. Mitchell, “Science and Humanity,” 7. 31. Ibid. 32. Ibid. 33. Ibid. 34. Ibid., 8. 35. Letter, PM to Michael Gordon, 16 December 1983. 36. Michael D. Gordon and Pauline K. Marstrand, Report on a Collaborative Consultation Held at Glynn Research Institute, Bodmin: “Electron Translocation and Proton Ejection by Cytochrome Oxodase Vesicles, 22–25 March 1983, Primary Communications Research Centre, University of Leicester (July 1983).

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37. Letter, Gordon to PM, 25 November 1983. 38. Letter, PM to Gordon, 22 November 1983. 39. Letter, Gordon to PM, 25 November 1983. 40. For an indication of Mitchell’s approach, see Peter Mitchell and Jennifer Moyle, “Alternative Hypotheses of Proton Ejection in Cytochrome Oxidase Vesicles: Transmembrane Proton Pumping or Redox-linked Deprotonation of Phospholipid-Cytochrome c Complex(es),” FEBS Lett. 151 (1983): 167–178. 41. Letter, PM to Tsoo King, 31 May 1984. 42. Bo G. Malmström, “Cytochrome c Oxidase as a Proton Pump,” Biochim. Biophys. Acta 811 (1985): 1–12; see p. 2. 43. Peter Mitchell, Roy Mitchell, John A. Moody, Ian C. West, Harold Baum, and John M. Wrigglesworth, “Chemiosmotic Coupling in Cytochrome Oxidase: Possible Protonmotive O Loop and O Cycle Mechanisms,” FEBS Lett. 188 (1985): 1–7. 44. Letter, Nobuhito Sone to JP, 1 August 1996. 45. Letter, PM to Hinkle, 13 February 1986. 46. Letter, PM to Sone, 6 June 1985. 47. Letter, PM to Wikström, 5 February 1985. 48. Peter Mitchell, Jennifer Moyle, Ian West, and Roy Mitchell, “Chemiosmotic Stoichiometry of Cytochrome Oxidase in Rat Liver Mitochondria,” abstracts in Cambridge University Library, P. D. Mitchell Archive, Files F 190–195. 49. Letter, PM to Hinkle, 13 February 1986. 50. Letter, PM to Wikström, 5 February 1985. 51. Mårten Wikström and Robert Casey, “The Oxidation of Exogenous Cytochrome c by Mitochondria: Resolution of a Long Standing Controversy,” FEBS Lett. 183 (1985): 293–298. 52. Letter, Wikström to PM, 17 October 1985. 53. Letter, Wikström to PM, 14 February 1986. 54. Letter, Wikström to West, 2 January 1985. 55. Letter, West to Wikström, 25 January 1985. 56. Peter Mitchell, “A New Redox Loop Formality Involving MetalCatalysed Hydroxide-Ion Translocation, FEBS Lett. 222 (1987): 235–245. 57. Letter, PM to Michael Mulkay, 3 September 1985. 58. Interview, PM with BW, 1991. c h a p t e r 12 1. Letter, PM to C. M. Aldhouse (Dragons Lair Animal Aid), 20 July 1990. 2. Peter D. Mitchell, “Aspects of Chemical Philosophy: Science as a Pursuit of Humanity” Kagaku to Kogyo [Chemistry and Chemical Industry] 42 (1989): 60–69. The article is published only in Japanese. The comments and quotations here are based on Mitchell’s original manuscript (no page numbers); in University of Cambridge Library, P. D. Mitchell Archive, File D 186.

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3. See Karl R. Popper, Objective Knowledge (Oxford: Oxford University Press, rev. ed., 1979), 154. 4. Letter, PM to Joseph Robinson, 7 January 1987. 5. Mitchell, “Aspects of Chemical Philosophy.” 6. Ibid. 7. Letter to the editor of the Financial Times, 7 April 1987. 8. Letter to the editor of the Financial Times, 25 January 1986. 9. Minutes, Annual General Meeting, Glynn Research Foundation Ltd., 13 June 1986. 10. Letter, PM to Jennifer Moyle, 21 October 1991. 11. Letter, PM to Keith Garlid, 30 March 1987. 12. Letter, PM to A.-M. Colson-Corbisier, 28 July 1987. 13. Letter, PM to G. von Jagow, 29 April 1988. 14. Minutes, Annual General Meeting, Glynn Research Limited, 31 March 1985. 15. Peter Mitchell “A New Redox Loop Formality Involving MetalCatalysed Hydroxide-Ion Translocation,” FEBS Lett. 222 (1987): 235–245. 16. Letter, PM to Matti Saraste, 3 December 1987. 17. Letter, PM to Giorgio Semenza, 15 December 1987. 18. Peter Mitchell, “CuB Loop Mechanisms for Cytochrome Oxidase using a Hydroxide or Oxide e–/H+ Antiport Gate,” Glynn Biological Research Reports 3 (1987): 1–7. 19. Letter, E. C. Slater to PM, 5 April 1988. 20. Peter Mitchell, “Possible Protonmotive Osmochemistry in Cytochrome Oxidase,” Ann. N. Y. Acad. Sci. 550 (1988): 185–198. 21. Peter Mitchell, “Foundations of Vectorial Metabolism and Osmochemistry,” Bioscience Reports 11 (1991): 297–346; see p. 332. 22. Letter, PM to Gerald Elliott, 18 December 1990. 23. Peter Mitchell, “Respiratory Chain Systems in Theory and Practice,” in Advances in Membrane Biochemistry and Bioenergetics, ed. Chong H. Kim, Henry Tedeschi, Joyce J. Diwan, and John C. Salerno (New York: Plenum, 1988), 25–52; see p. 48. 24. Lewis Wolpert and Alison Richards, “Passionate Minds,” (Oxford: Oxford University Press, 1997), 83–90; see p. 87. 25. Ibid., 87. 26. Jennifer Moyle, “Opening Symposium Remarks” for “Perspectives in Vectorial Metabolism and Osmochemistry,” Biosci. Rep. 11 (1991): 293–617; see p. 295. (Reproduced with permission from Kluwer Academic/Plenum Publisher.) 27. Letter, PM to Peter Henderson, 20 February 1992. 28. Letter, PM to Sir David Phillips, 1990. 29. Moyle, “Opening Symposium Remarks.” 30. Minutes, Council of Management, Glynn Research Foundation, 6 November 1992. 31. Minutes, Council of Management, Glynn Research Foundation, 1 March 1996.

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c h a p t e r 13 1. Keith Garlid, “Dr. Peter Mitchell,” Times (London), 21 April 1992. 2. Peter Garland, “Peter Mitchell (1920–1992),” Nature 356 (1992): 747. 3. Ian C. West, “In Memoriam: Peter Mitchell, 1920–1992,” Mol. Microbiol. 6 (1992): 3623–3625; see p. 3625. (Reproduced with permission from Blackwell Science Limited.) 4. Ibid. 5. Garlid, “Dr. Peter Mitchell.” 6. Peter C. Hinkle and Keith D. Garlid, “Peter Mitchell 1920–1992,” Trends Biochem. Sci. (August 1992): 304–305. 7. Edward C. Slater, “Foreword,” in Frontiers of Cellular Bioenergetics: Molecular Biology, Biochemistry and Physiopathology, ed. Sergio Papa, Ferruccio Guerrieri, and Joseph M. Tager (New York: Kluwer Academic/Plenum, 1999), xi. 8. Robert K. Poole, “Introduction,” in Bacterial Responses to pH, ed. Derek J Chadwick and Gail Cardew (Chichester: John Wiley and Sons, 1999), 2. 9. See Milton Saier, “Vectorial Metabolism and the Evolution of Transport Systems,” J. Bacteriol. 182 (2000): 5029–5035. 10. Franklin M. Harold, “Gleanings of a Chemiosmotic Eye,” Bioessays 23 (2001): 848–855; see p. 848. 11. See, for example, Marcel Weber, “Theory Testing in Experimental Biology: The Chemiosmotic Mechanism of ATP Synthesis,” Stud. Hist. Phil. Biol. Biomed. Sci. 33 (2002): 29–52; Douglas Allchin, “To Err and Win a Nobel Prize: Paul Boyer, ATP Synthase, and the Emergence of Bioenergetics,” J. Hist. Biol. 35 (2002): 149–172. 12. Michael Mulkay, The Word and the World: Explorations in the Form of Sociological Analysis (London: Allen and Unwin, 1985). 13. Guy D. Greville, “A Scrutiny of Mitchell’s Chemiosmotic Hypothesis of Respiratory Chain and Photosynthetic Phosphorylation,” Curr. Topics Bioenergetics 3 (1969): 1–78. 14. Reference for a Glynn appeal provided by Lord Michael Swann, 10 June 1982.

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Index




Aberdeen University, 232 Acid bath experiments, 134, 147 Active transport, 152, 156 and the mechanism of oxidative phosphorylation, 87, 152, 156, 270 Mitchell’s view of, 69–70, 74, 76–77, 170 Adenosine triphosphate. See ATP Adrian, Lord Edgar Douglas, 25 Albany, New York, 232 Allchin, Douglas, 119, 174 American Academy of Arts and Sciences, 177 American Society of Cell Biology, 92, 96, 112, 118 Amino acid transport, 45, 53, 72 Amsterdam University, 111, 117, 224, 236 Anderson, John Gayer, 25, 40, 60, 69, 100 Andover, New Hampshire, 112, 118 Annual Review of Biochemistry, 195–96, 199, 201–8 Antimycin, 225 Antiport, 90–91, 138, 157 Aristotle, 27 Arnon, Daniel, 79 Art, 272 Athletics, 272 ATP, 4, 120, 230, 270 ATP, hydrolysis, 122 ATP, number of molecules synthesized per

oxygen atom reduced, 122, 178, 233 ATP synthase. See ATPase ATP synthesis and Boyer’s conformational theory, 143, 259 experimentally induced, 125, 134, 165–66 Mitchell’s view of, 86–88, 95, 120, 130–32, 160, 270 and Slater’s chemical theory, 86 and Williams’s theory, 81, 84 ATPase bacterial, 155 and Boyer’s conformational theory, 143, 167, 203, 207 cation translocating, 156–57 in the chemiosmotic theory, 85–86, 130–33, 147 discovery of proton coupled enzyme, 260 high energy intermediate in, 133, 160–61 and ion movement, 78, 90 location of, 132 Mitchell’s models of, 260 mechanism of, 160–65, 209, 258–60, 274 number of protons transported by, 178, 183, 259 proton transport by, 131

307

ATPase (continued) role of protons in, 161–165, 259 structure of, 162 Augustus, 192 Australian National University, 89 Avron, Mordhay, 141, 173 Azzi, Angelo, 231 Azzone, Giovanni, 178, 230–231

Babraham, Institute of Animal Physiology, 92, 141 “Backlash,” 136–37 Bacteria, photosynthetic, 114, 152 Bacterial cell surface, 52–53, 55 Bacterial cytochrome oxidase, 231, 242 Bacterial membranes cytochromes in, 70–71 as osmotic barrier, 55–56, 62, 69–70 and oxidative phosphorylation, 86, 91–94, 109–11, 121, 124 and substrate transport, 55–56, 61, 71–73, 154–55 Bacterial motility, 56–57, 153 Bacteriorhodopsin, 165–66 Bailey, Kenneth, 47 Baldwin, Ernest, 32, 35–36, 45–46 Bank of England, 192 Bari conference, 1965, 111–12, 117, 126–28 Bari conference, 1969, 148–49 Bari conference, 1971, 152 Bari conference, 1972, 155 Bari conference, 1975, 178–79, 189, 205–6 Bari international meeting, 265 Barker-Starkey, Juliette, 39 Barrow Hedges School, 15 Baum, Harold, 135, 169 and cytochrome oxidase, 246 as director of the Glynn Research Foundation, 215, 252, 276 and the interpretation of proton concentrations, 139–40 and the Q cycle, 190 b-cycle, 190 Behavioral biology, 109, 214–16, 236, 249, 256 Behavioral research, director of, 256

308

index

Beinert, Helmut, 218 Bern University, 231 Bernal, J. D., 60 Bernard, Claude, 31, 56 Bernhard, Professor, 219 Betjeman, John, 116 Biochemical Society, 209 CIBA medal and lecture, 170, 172 Hopkins memorial lecture, 175 Keilin lecture, 167 meeting, 1982, 232 meetings, 1961, 80, 91 symposium, 1951, 88 symposium, 1962, 82–83, 90, 93, 154, 163 Biochemical Society of the Soviet Union, 261 Biochemist, The, 265 Biochemistry, nature of, 30 Biochemistry Department, Cambridge, 28–38, 41–42, 46–47, 51, 57–59, 63, 65, 67 discussion of the chemiosmotic theory in, 90 Bioenergetics, 109, 113 assessment of field, 196–201 discipline of, 270 funding of, 195, 198, 207 future research in, 214 workshop on, 202 Biological Reviews, 127–128 Bioscience Reports, 263 Black, Sir James, 258, 266 Blisland Manor (Mansion), 115–116 Boats, 157 Bodmer, Sir Walter, 263 Bodmin, 96, 105, 112 isolation of, 199 Bodmin moor, 23, 115–116 Boston, 201–202 Boyer, Paul, 173 awarded the Nobel prize, 174, 221 conformational theory of oxidative phosphorylation, 119, 143, 167, 226, 271 correspondence with Mitchell, 161–163, 203

and the joint review on oxidative phosphorylation, 196, 199–207 limerick, 208 Bremner, Helen, 38 Bristol, 68–69 Bristol University, 161–62, 263 links with Glynn, 112–13, 129, 156, 169 British anti-lewisite (BAL), 37 British Association for the Advancement of Science, 30 British Petroleum Venture Research, 255–56 Bromthymol blue, 139 Buddhist ceremony, 242 Building refurbishment of Blisland Manor, 115 of Carrington, 67–69 of Cuilan, 116 of the French Cottage at St Pons-deMauchiens, 210 of Glynn House, 97–101, 103–107 Mitchell’s interest in, 7, 157, 193, 272 of Silbury, 39

Calcium, 139, 149, 157 and proton numbers, 183–85 Cambridge University consequence of Mitchell’s time at, 159, 161, 276 consultation with scientists at, 85 Enzyme club, 90 Hardy Club, 59 Mitchell’s chairmanship of a reasearch unit at, 264 Mitchell’s time at, 22–66, 102, 234, 250 Natural Sciences Club, 26–27, 286 n.4 Quastel and Cambridge, 112 Rich and Cambridge, 255–56 Canberra, 89 Carrington, 68–69, 96, 99, 102, 105, 115 Carshalton, Surrey, 15 Casey, Bob, 243–44 Caullery, Maurice, 41 Cearns, A. S., 187 Chance, Britton, 259 as candidate for the Nobel prize, 218 and Chappell, 112, 113

experimental objections to chemiosmotic theory, 123, 135, 138–40 and the joint review of oxidative phosphorylation, 196–97, 199–201, 203–7 meeting with Mitchell at Stockholm, 79 opposition to the chemiosmotic theory, 141, 145, 173 poem, 203–4 and role of ubiquinone, 187 and the silver Glynn, 194 Slater letter to, 134 as visitor to Glynn, 118 Chancellor of the Exchequer, 192 Chappell, Brian acceptance of chemiosmotic theory, 141, 173 at Cambridge, 33, 112 and Greville, 141–42 and Grey Books, 129 observation of Mitchell and Slater, 136 on transport and the chemiosmotic theory, 112–13, 156–57 visitor to Glynn, 118 Charitable Trust, 100, 105, 108, 277 Charles I, King, 98 Chelsea College, London, 169, 215, 232 Chemical biology lectures, 67 Chemical Biology Unit, 65, 70, 89 Chemical theory, 4 abandoned, 167, 174, 184, 207 amendments to, 180 and membrane transport, 156 opposition to, 150 standing of, 117, 119–29, 132, 135–36, 138, 140–44 support for, 92, 146, 147 weakness of, 79–80, 86–87, 149 Chemiosmotic theory acceptance of, 166–67, 172–75, 207 advice of Hill sought on, 33 advocacy for, 117, 121, 144, 146, 170 assessment of, 149, 163, 203, 220 and Chappell, 112–13 and cytochrome oxidase, 222–32, 236–47 defense of, 184, 195, 210, 246, 270

index

309

Chemiosmotic theory (continued) disproof by experiment, 175, 179–80, 205 evaluation of, 270–71, 273 experimental support for, 121–26, 165–66 explanatory value of, 230 falsification of, 135, 145–46, 151, 188, 194, 200, 246 as hypothesis, 122, 127 importance of mechanisms for, 179–80, 274 initial formulation of, 64, 73–95 in membrane transport, 154–55 Mitchell’s assessment of, 249, 251, 253 postulates of, 131–32 as a project for Glynn, 110–12, 253 revision of, 126–31, 209–10, 246 significance of, 4–6, 9 support for, 201, 207 testing 115–45 Chibnall, Albert Charles, 34, 41, 43–44, 46–47, 53, 58 Chicago, 113, 144 China, 41–42 Chloroplasts, 33, 78, 124–25, 134, 183 Churchill, Winston, 116 Cigars, 227–29, 245 Collins, Cecil, 41 Communication between scientists discussion with Mulkay, 247 as a field of research at Glynn, 168, 215–16 issues of, 236–39 Mitchell’s views on, 148, 159, 190–91, 249, 274 Company, setting up of, 105, 107, 110 Complex III, mechanism of, 262 See also Q cycle Conformational changes and the mechanism of cytochrome oxidase, 226–27 and the mechanism of oxidative phosphorylation, 156, 161–63, 199–200, 203, 226–27, Mitchell’s view of, 161–63, 210, 226–27, 259–60

310

index

Conformational theory debate over the, 149–50, 161–63, 167, 201, 203–5 as a haven for antichemiosmoticists, 119, 174, 184 and the mechanism of oxidative phosphorylation, 143–44, 203–5 and membrane transport, 156 Confucianism, 18 Conover, T. E., 127 Controversies, 5–6, 9, 212 Conway, E. J., 87, 166 Copley Medal of the Royal Society, 233 Copper, 223 Copper loop theory, 246, 259 Cornell University, 151, 175, 201 Cornish language, 254 Cornwall, 96–100, 114, 254 Coutts, Will, 193 Cows, Jersey, 102–3 Crane, Robert, 77–79, 90–91, 113, 118, 155 Cranshaw, Ted, 39 Crick, Francis, 40 Crofts, Anthony, 141, 173, 243 Cuilan, 116, 157, 209, 255 Culture of imagination, the, 152 Curie, Pierre and Jacques, 172 Curie principle, 172 Current Topics in Bioenergetics, 141 Cytochrome a, 223 Cytochrome b, 132, 187, 189 See also complex III, Q cycle Cytochrome c, 113 and cytochrome oxidase, 223, 225, 229–31, 240, 243–45 Cytochrome c1, 132, 187 See also complex III, Q cycle Cytochrome oxidase consultation on proton transport by, 237–40, 273 controversy with Azzone, Wikström and others, 51, 185, 222–47, 250–51, 258 electron donors to, 225 Hinkle’s interest in, 225–26, 228–31, 242–43 mechanisms of, 188, 246, 257–59

proton transport by, 150, 185, 209, 222–33, 236–47 as a research project for Glynn, 262 and Sone, 241–43 symposium, New York, 1988, 259 Cytochromes location of, 70–71 in the respiratory chain, 131 Cytoskeleton, 51

Dainty, Jack, 66, 85 Dakin, John Howard, 45 Dakin, Olive, M. See Moyle, Olive M. Danielli, James as editor of International Reviews of Cytology, 82 influence on Mitchell, 45, 55–56, 71, 220 relationship with Mitchell, 38 as research supervisor, 28, 44, 48, 53 teaching, 35–36 war work, 37 Danielli, Mary, 38 Dartmouth Medical School, 114 Darwin, Charles, 6 Daskal, Vladimir, 38 Datta, Prakash and Naomi, 219 Davies, Robert debate over priority, 82, 88, 127, 281 and the formulation of the chemiosmotic theory, 72, 79, 87, 90, 166 Davies-Williams-Mitchell theory, 271 Davson, Hugh, 37 Dawkins, Richard, 263 de la Mare, Walter, 52 Deamer, David, 143 Dehydrogenase, 82 Denver, 232 Diffusion, 77 Dinitrophenol, 122 Director of Research at Glynn, 108, 256 Directors of Glynn Research (Foundation) Ltd., 108, 252, 257, 264 Disputes. See controversies. Divorce

of Pat and Helen Robertson, 68 of Peter and Eileen Mitchell, 39, 61 Dixon, Malcolm, 31, 34–35, 37, 47, 58, 71 Doctoral studies, 37–38 Domesday book, 97 Dortmund, 241 Drew, S., 98 Dry rot, 97–101, 105 Dudley Coles, 100, 103–4, Dunn, Sir William, Professor of Biochemistry, 29 Dunn, Sir William, Reader in Biochemistry, 32 Dunn Board of Trustees, 29 Dunn Institute for Biochemistry, 34, 42 Dutton, Leslie, 265, 268

Eagle, the, 25 Ear operation, 157–59, 208, 230 Economic Research Council, 191 Economics, 27–28, 40, 168, 191–93 Edinburgh, life at, 64–95, 97, 99–101, 109 Edinburgh Festival, 66, 102 Edinburgh University appointment at, 63, 64–65 collaboration with Reid, 91, 134 research at, 69–76, 85–95, 109, 111, 117, 121, 126, 276 resignation from, 8, 95, 157, 208 Education and Science, U.K. government department of, 234 Egelhardt, Vladimir, 173 Eindhoven, Holland, 117, 126 Einstein, Albert, 6 Electrical supply, 100 Electricity generation, 171, 193, 276 Electromechanicochemical theory of oxidative phosphorylation, 204 Elizabeth I, Queen, 115 Elizabeth II, Queen, 194 Energy pressure, 149 Engelhardt, Vladimir, 176 Enzyme club, Cambridge, 90 Enzyme kinetics, 74 Enzymes as translocators, 72–77

index

311

Ernster, Lars and the future of Glynn, 214 and history of mitochondrial research, 129, 221 and the Indian prince story, 273–74 and the joint review of oxidative phosphorylation, 196, 199–202, 205, 207 and Lee, 118, 126–28 and the Nobel celebration, 219 and the Q cycle, 187, 190 response to the chemiosmotic theory, 121, 141, 144, 145, 173, 179–80, 207 European Bioenergetics conference, 265 European Community, 256 European Union, 267 Examinations and Mitchell, 22–23, 34–35, 52–54 Exeter University, 267

Faraday, Michael, 176 Faraday Society, 71 Farm manager, 103 Farmer’s House, Glynn, 255 Farming, 7, 102–3, 115, 154–55, 171 FEBS Letters, 219, 241, 259 Ferrocyanide, 225 ffrench, Raymont, 59 Helen. See Mitchell, Helen Fibroblasts, research on, 89 Financial Times, 192, 251–52 Fisons Ltd., 215 Flagella, bacterial, 56–57, 153 Flame as a model, 8, 50, 93–94 Flavin mononucleotide. See FMN Fleming, Sir Alexander, 56–57 Fluctid, 49–50, 52, 70 Fluctoid, 32, 49–53, 64, 70–71, 76, 93, 159 FMN, 131, 186 Forster, E. M., 40 Fortnum and Mason, 155 Foster, Michael, 29 Fowey, River, 98

312

index

Fox, H. Munro, 128 France, 60, 210, 244 Franklin, Harold, 232 Friedmann, Ernst, 27, 50 Fromm, Erich, 215 Fund manager, 266 Funding appeal for, 145, 194, 216, 266 exhaustion of, leading to closure of Glynn, 253 external, 110–11, 276 of Glynn, 11, 108, 266–67 raising of by Mitchell, 256, 264 for research, 233, 266–67

Gale, Ernest amino acid transport studies with, 54, 55, 72 as Cambridge academic, 32, 47 consideration of Mitchell for appointment as demonstrator, 57 as Mitchell’s Ph.D. examiner, 52 as Mitchell’s unofficial supervisor, 44, 48, 53–54 and Moyle, 46, 58 Gardens of the mind, 260–61 Garland, Peter, 263 Garlid, Keith, 256, 265, 269 Gastric ulcers, 100–101, 103, 144, 157, 208 Geering, Quin death of, 264 as director of Glynn, 215, 252, 276 friend of Mitchell, 24–25, 28, 39, 215 Genetics, 32 George Wimpey and Company Ltd., acquisition by Sir Godfrey Mitchell, 11 shares in, 11, 108, 191, 254 Gilbert, Nigel, 174–75, 197, 250 Girton College, Cambridge, 27, 45 Glucose transport, 77–78, 91, 155 Glucose-6-phosphatase, 78, 86 Glutamate transport, 55, 74 Glynn advantages and disadvantages of, 211–12 closure of, 268

consideration of future of, 168, 211–15, 253 expansion of, 253–54 as an experiment, 115, 177, 211, 266, 275–76 history of, 263 hospitality, 125 impressions of life at, 151, 154–55, 235–36 as an international center for bioenergetics, 169, 266 isolation of, 112, 276 laboratory equipment at, 257 possible relocation of laboratories, 168 research projects at, 109–11, 115–16, 168, 212–16, 233–35, 261–62 silver jubilee meeting, 1991, 259, 262–63 value of, 3–9 value of visitors to, 118 visitors to, 113, 118, 125, 134, 139, 150, 154, 169, 214, 224, 226, 240–41, 255 Glynn family, 98 Glynn Farm, 102–3 Glynn House acquisition of, 96–98 establishment as a research institute, 105–9 fire at, 98 history of, 98–99 plans of, 107 prayer room, 106, 238 proceeds of sale of, 268 restoration of, 99–104 Glynn Laboratory of Bioenergetics, 268, 277 Glynn Mill, 96, 99 Glynn Mill Cottage, 96, 101 Glynn piece, silver, 7, 193–94, 220, 276 Glynn Research Foundation Ltd. (1985–1996) annual general meeting, 254 chairman, 256, 264–65 closure of, 268 directors, 25, 257–58, 264, 268 endowment, 253, 262 finances, 252–54, 268

options for future, 268 purchase of freehold, 253–54 Glynn Research Ltd. (1964–1985) annual general meetings and reports of, 107, 110–12, 113–14, 118–19, 145, 211–12, 214–16, 258 auditors and accounts, 108–9 change of name to Glynn Research Foundation Ltd., 253 council of management, 107–8, 210, 214–15 directors, 108, 210, 215 endowment of, 108, 168–69, 191, 193, 216 establishment and objectives of, 107–9, 249 financial position of, 110, 145, 168, 208, 216 investments of, 108, 145, 169 lease of premises, 107, 168, 216 publication of Grey Books by, 128, 137 strategy for, 233–35 Glynn valley, trunk road, 169 Gombrich, Ernst, 250 Good, Norman, 137, 173 Gordon, Michael, 239 Gordon conference, 1965, 112, 118 Gordon conference, 1974, 201 Gordon conference, 1981, 231 Gordon conference, 1985, 243 Gowans, Sir James, 266 Gray, Sir James, 127 Greece, 61, 145, 159–60, 208 Greek language, 160 Green, David and enzyme location, 94 and joint review on oxidative phosphorylation, 196, 200–1, 204–5 and the New York symposium, 1973, 165 and Perspectives in Biochemistry, 27 recollections of Hopkins, 34 response to the chemiosmotic theory, 173 and theories of oxidative phosphorylation, 119, 144, 204 Gregory, Richard, 263

index

313

Greville, Guy advice on the chemiosmotic theory, 80 collaboration with Chappell, 112 dedication of third Grey Book to, 153 laboratory in Cambridge, 47 review of chemiosmotic theory, 141–44, 147, 172, 274 testing the chemiosmotic theory, 90, 92, 121 Grey Book, first, 128–30, 133, 136–37, 140, 153, 164 Grey Book, second, 137–38, 140, 152–53 Grey Book, third, 153 Grey Books, 222, 245 See also Silver-Grey Book Group transfer reactions, 72, 75, 77, 152 Group translocation, 90, 172 Guggenheim, E. A., 36

Haberdashers’ Aske’s School, 11, 13 Haldane, J. B. S., 32, 35, 70, 287 n.17 Hamilton, William, 156 Hanson, J. B., 217–18 Hardy Club, the, 59 Harold, Franklin, 156, 263, 266, 271 Harper, Robert, 114, 154, 169, 170, 213, 262 Harris, E. J., 138 Harris, Leslie, 36 Hartree, Edwin Francis, 42 Hayek, Friedrich, 152, 191, 215 Heffer’s bookshop, 26 Helsinki, 224, 240 Henderson, Peter, 263–64 Heraclitus, 8, 27, 50, 52, 159 High energy intermediate in the chemical theory, 119, 127, 127, 135, 156 in oxidative phosphorylation, 138, 143, 149, 199 as proposed by Mitchell in the ATPase, 132, 160–62 Higher Education Funding Council, 267 Hill, Robin and advice on the chemiosmotic theory, 80

314

index

as Cambridge plant biochemist, 33, 35–36, 47, 137 relationship with Young, 58 war research, 37 Hind, Geoffrey, 124, 137 Hinkle, Peter and the cytochrome oxidase controversy, 225–26, 228–31, 242–43 early career, 150 as interpreter in the United States, 151 letters from Mitchell, 209, 214 and Mitchell’s birthday celebration, 230 and the New York symposium, 1973, 165 obituary for Mitchell, 269–70 visit to Glynn, 150–52, 154 Hitchin, F., 98 Holton, F. A., 78 Holton, George, 236 Hopkins, Sir Frederick Gowland and Cambridge biochemistry, 29–34, 58 influence on Mitchell, 4, 30–31, 45, 51, 65 philosophy of biochemistry, 30–31, 33 retirement, 42 Human relations and communication, 168 Humanity, interests of, 105 Hydroxybutyrate and calcium transport, 185

Ibbotson, Eva, 59, 69, 210 Imperial College, 34 Indian prince story, 274 Inflation, 191–93 Information Exchange Group Bulletin, 139 Institut Pasteur, 72, 154 International Congress of Biochemistry, Cambridge, 1949, 29, 34 International Congress of Biochemistry, Stockholm, 1973, 166–67 International Congress of Biochemistry, Tokyo, 1967, 144, 149 International Congress of Pure and Applied Chemistry, 1970, 157 International Reviews of Cytology, 82

International Union of Biochemistry and Molecular Biology Conference, second, 265 Investments See Glynn Research Foundation Ltd., Glynn Research Ltd. Ion transport and the antiport, monoport, symport, 91, 138 and the chemical theory, 127, 135 and the chemiosmotic theory, 89, 137 and cytochromes, 71 Iron sulphur proteins, 131 Isocitrate dehydrogenase, 58 Italy, 61

Jagendorf, André and his chloroplast ATPase experiments, 123–25, 129, 132, 134, 139, 147 response to the chemiosmotic theory, 141, 173 Slater’s comment on, 137 and the Stockholm symposium 1960, 79 transfer to Cornell, 151 visit to Glynn, 113–14, 118, 125 Japan, 229 Mitchell’s visit to, 242 Japanese Chemical Society, 249 Jeal, Alan, 169, 170, 213, 262 Jesus College, Cambridge, 23, 24–26 Jichi Medical School, 242 John Curtin School of Medical Research, 89 Johns Hopkins University, 89, 118 Jones, Bryn, 66, 101 Jones, Trevor, 266 Journal of Chemical Education, 143 Journals at Glynn, 105, 107, 169 Jubillee celebrations, cost of, 263 Jubillee symposium, 262–63 cost of, 263 Junge, Wolfgang, 268

Kagawa, Yasuo, 242 Kapitsa, Piotr Leonidovich, 219

Katchalsky, Aharon, 77 Keilin, David accomodation for Mitchell provided by, 48–49 advice on the chemiosmotic theory, 78, 80–81 appreciation of Mitchell by, 44, 53 awarded the Copley medal of the Royal Society, 233 as director of the Molteno Institute, 41–43 influence on Hill, 33 influence on Mitchell, 12, 49, 71, 102, 152, 219–20, 274 rediscovery of cytochromes, 175–76 and Slater, 117 Keilin, Joan, 42, 46–47, 53 Keilin lecture, 167 Kendrew, Sir John, 42, 257–58, 264, 266 Kepes, Adam, 156 Key, Stephanie, née Phillips, 168–69, 170, 215–16, 253 King, Hugh, 25 King, Rosetta. See Taplin, Rosetta King, Tsoo, 186–87, 196, 199, 241 King’s Building, Edinburgh, 66–67 King’s College, London, 38, 232, 241 Klingenberg, Martin, 141, 187 Kornberg, Sir Hans, 266 Krebs, Sir Hans advice to Robert Williams, 82 and Cambridge, 34 criticism of Mitchell, 55, 94 nomination of Sir Karl Popper for a Nobel prize, 152 proposal of a chemiosmotic mechanism for oxidative phosphorylation, 88, 166 Kuhn, Thomas, 236

Laboratory, creation of at Glynn, 104–5, 108, 110–14 Lactose , membrane transport of, 154– 55 Lardy, Henry, 173, 196 Lee, Chuan-Pu, 118, 126–28

index

315

Lehninger, Albert and the controversy on proton numbers, 178–85, 224, 230–32, 258 discussion on oxidative phosphorylation with Mitchell at Stockholm, 79–81 discussions at Edinburgh, 117–118 in history of oxidative phosphorylation, 176 invitation to Mitchell to lecture, 118 and the joint review on oxidative phosphorylation, 196, 201, 206 Mitchell’s criticism of, 138–39 and reception of the chemiosmotic theory, 92 response to chemiosmotic theory, 141, 173 reviews of oxidative phosphorylation, 89–90, 120–23 Leicester University, 238–39 Lewisite, 37 Library at Glynn, 105, 169, 262 Liebig, Justus, 94 Lipmann, Fritz influence on Mitchell, 77 and Mitchell’s ATPase mechanism, 120, 132–33, 161 theory of oxidative phosphorylation, 85, 89 treatment of Mitchell at Chicago, 144 Lloyds Bank, 217 Lomax, S.C., 108 Lonsdale, Kathleen, 32 Louis and Bert Freedman Foundation award, 177 Lumry, Rufus, 217 Luncheon vouchers, 155 Lundegårdh, H., 79, 87, 90 Lyons, Helen, 262

Madgwick, Sally, 262 Malmström, Bo, 220, 241 Manchester, 154 Mann, Thaddeus, 35 Manning, Audrey, 66 Marxism, 27–28, 40

316

index

McCabe, M., 139–40 McCollum Pratt Institute, 113, 123 McNeil, Eileen. See Mitchell, Eileen McNeil, John, 59, 61 Meaning of Meaning, 26, 151 Medical Research Council, 235 Mela, L., 139 Melbourne University, 117 Membrane polarity, 126, 129 Membrane potential and the chemiosmotic theory, 86, 131, 133, 140, 207 and conformational change, 163 and the cytochrome oxidase controversy, 244 and ion movement, 71 and Jagendorf’s experiments, 125–26 measurement of by Hinkle, 150–51 Membrane transport biochemical basis of, 89, 109, 152, 155–56 and chemiosmotic principle, 148, 153, 249 and membrane enzymes, 69–78 Membranes as the basis of Mitchell’s studies, 8, 69 and chemiosmotic principles, 69–95 and Dainty, 66 and enzymes, 55 as the osmotic barrier, 62–63 and vectorial principles, 36, 45 Metabolism and transport, 71–78, 156, 269–70, 273 Meyer, Alfred, 147 Michigan State University, 137 Microbial biochemistry, 31–32, 45, 53 Microbial physiology, 55 Microbiology subdepartment, Cambridge, 47, 57 Miles, A. A., 55 Military Intelligence, 45–46 Mineral water. See Water Ministry of Supply, 37 Minnesota University, 217 Mitcham, Surrey, 10 Mitchell, Christopher, 10–11, 14,16 Mitchell, Christopher Gibbs, 10–14, 17, 272

Mitchell, Christopher John (Bill), 10, 14–16, 20, 22 donations to Glynn by, 105, 108, 254 Mitchell, Eileen, née Rollo (later Eileen McNeil), 38–40, 61, 209 Mitchell, Gideon, 68 Mitchell, Sir Godfrey Way, 6, 10–12, 191, 254 Mitchell, Helen, née ffrench (formerly Helen Robertson) as an artist, 250 early life, 59–60 French retreat, 210–11 holidays in Greece, 145 home in Glynn, 96, 100–2 life in Edinburgh, 66, 68–69 marriage, 68, 96, 209 and Mitchell’s final illness, 265 Nobel ceremony, 219–20 Mitchell, Jason, 60, 68 Mitchell, Jeremy, 39 Mitchell, Julia , 39 Mitchell, Kate Beatrice Dorothy, née Taplin, 10, 12–18, 28, 272 Mitchell, Margaret, née Way, 10, 14 Mitchell, Peter ancestry, 12–14 Annual Review article, 201–8 appearance, 25, 28, 60, 67 approach to theory and experiment, 7–8, 54–55, 140, 274 assessment of bioenergetics field, 148, 196–202 assessment of Moyle, 234 and athletics, 20 beliefs, 194 birth of, 10 cars owned by, 23, 40, 59, 61, 67–68, 255 childhood, 12–16 children, 39, 60, 68, 89, 145, 157 collaboration with Moyle, 46, 58, 140, 145, 151, 234, 275 as Cornish gnome, 234 cost of Glynn to, 108, 255, 276 deafness, 157–60, 208 deafness and music, 158–59 death of, 260–61, 265, 269

depressions, 160, 208 diaries, 103, 241, 260, 293 n.7 doctoral studies, 48–49, 52–54 dress, 7, 25 ear operation, 157–59, 208, 230 early education, 15–17, 20–23 economic interests, 191–93 election to fellowship of the Royal Society, 166–67, 170 embarassment over cytochrome oxidase, 243–45, 247 as entrepreneur, 193–94 “forgettery,” 209 health of, 93, 95, 100–2, 110, 125, 144–45, 157–60, 208–9, 230, 244, 256, 264–65 holiday retreat, 210 Honorary Director of the Foundation, 256 intelligence assessment, 18 interpretation of experiments, 179–83, 210, 224, 227, 230–31, 233, 240, 249, 260 invitation to Australia, 89 language used in papers, 229 letters to the Press, 191–92, 251–52 marriage, 39, 65, 68, 209 membership of Biochemical Society of Soviet Union, 261 memorials, 261, 265, 269–70 models for research, 66, 189 and music, 7, 13, 18–19, 24–26, 28, 38, 40, 158, 186, 272 nervous breakdown, 209 personality, 5–6, 20–23, 40, 43, 47–49, 67, 85, 116, 148, 151, 211, 221, 269, 271–73 and philosophy, 8, 27, 49–53, 64, 70, 74, 93–95, 236–37 and piano, 28, 40, 67, 69 practical skills, 16, 19, 70, 210–11, 272 proposed book by, 214 relationships with women, 208–9, 211, 272 residences, 10, 15, 39, 68–69, 96, 99, 101, 105, 145, 159, 210 retirement of, 256, 265

index

317

Mitchell, Peter (continued) rhetorical strategies, 294 n.1 schemes for biochemical systems, 189 sixtieth birthday celebration, 230 sleeplessness, 67, 186, 188–89 teaching by, 57–58, 67, 97 thesis of, 36, 44, 52–54 undergraduate studies, 25–26, 34–37 Mitchell, Roy doctorate, 255 redundancy of, 213 as scientist, 235, 243, 262, 267–68 as technician, 114, 169, 170 Mitchell biennial lecture, 265 Mitchell-Boyer theory, 271 Mitchison, Murdoch, 65, 67–68 Mitochondria ATP synthesis by, 124–25, 134 and the chemiosmotic theory, 86–87, 90–92, 109–12, 120–22, 147 conformational change in, 143 and the cytochrome oxidase experiments, 222–25, 228, 243–44 location of the ATPase in, 132 osmotic properties, 122, 126 preparation of, 151, 240, 244–45 proton concentration in, 139–41 proton transport by, 126, 155 in the Stockholm symposium, 78 transport into, 152, 156 Mitochondrial fragments, 122–23 Molecular biology, 214–15 Molecular research, director of, 256 Molteno Institute, 33, 41–42, 48, 52, 71, 117 Monod, Jacques, 72 Monoport, 90–91 Moody, John, 235, 262, 267–68 Morphogenesis, 94 Morse, Sir Jeremy, 192 Morton, R. K., 46 Moss, David, 256 Moyle, Jennifer and calcium transport, 185 and the closure of Glynn, 268 as collaborator, 140, 145, 151, 211, 275–76

318

index

and the creation of Glynn, 103–5, 108, 110–11, 114, 234, 266, 268 and cytochrome oxidase, 150, 224, 226, 228, 230–32, 239, 243 as director of Glynn Research Ltd., 108, 146, 168–69, 252–53, 255, 258, 268 early life, 27, 45–46 at Edinburgh, 65, 69–71 experimental support for the chemiosmotic theory, 122–23, 134, 136 139, 147, 152 as experimentalist, 154 and the future of Glynn, 213–16 interest in music, 45 and the jubilee symposium, 263 with Mitchell in Cambridge, 46–48, 58, 61–62 and Mitchell’s death, 265 and the Nobel ceremony, 219 and proton numbers, 181, 183 retirement of, 233, 255 as senior research fellow, 170 Moyle, Olive M., née Dakin, 45 Moyle, S. H. Leonard, 45 Moyle, Vivien, 46 Mulkay, Michael, 174–75, 197, 247, 250, 274 Murdoch, Iris, 40 Myson, 147 Myxothiazol, 225

NAD, 131 NADH, 122 NADH dehydrogenase, 186, 188, 224 National Institutes of Health, 150, 196 Natural Sciences Club, 26–27 Nature article on chemiosmotic theory, 1961,80, 83, 85, 88, 90, 92, 120, 124, 126, 129, 274 article on proton pumping by cytochrome oxidase, 224 article supporting Mitchell’s theory, 112 articles criticizing the chemiosmotic theory, 139–40 rejection of Mitchell’s paper by, 75

report of jubilee event, 263 as a suggested location for a statement by bioenergeticists, 199 Naval Research, U.S. office of, 253 Needham, Dorothy, 30, 36, 47 Needham, Joseph as Cambridge biochemist, 32, 34, 36–37, 40–42 influence on Mitchell, 50–51 and Perspectives in Biochemistry, 27 recollections of Hopkins, 30 Neuberger, Albert, 35 New Scientist, 263 New York, State University of, 232 New York Academy of Sciences, 177 New York Academy of Sciences symposium, 259 New York symposium, 165 Newcastle University, 235, 255 Nicotinamide adenine dinucleotide. See NAD, NADH Nitrogen fixation, 213 Nobel Prize award in Stockholm, 194, 219–21, 273 effects of award, 220–21, 229–30, 246, 267, 277 for Mitchell, 5, 49, 183, 216–19, 229–30, 235, 252 nomination of Karl Popper for, 152 reasons for Mitchell’s award, 217, 269–70 North Cornwall Bank, 98 North Cornwall District Council, 172 North Cornwall Planning Authority, 105 Northcote, Don, 46, 48, 53, 58 Norwich, 45 Nuffield Foundation, 70 Nuttall, George Henry, 41

O cycle, 244, 246, 258–59 Ochoa, Severo, 176 Octavian meeting, 237–40, 273 Ogden, C. K., 26, 151, 236, 250 Ogston, Sandy, 52–53, 72, 87–90 Orient Express, 159

Origin of life symposium, Moscow, 50, 70–71, 93 Osferd, 97 Osmotic barrier, 55–56, 61–62, 69 Osmotic energy, 88 Osmotic work, 72–73 Osselton, David, 169 Ox phos wars, 147, 183, 226 Oxford, 113, 154, 218 Oxidative phosphorylation cost of solving mechanism, 119 field resistance to chemiosmotic theory, 172, 174 as a field for study at Glynn, 109–11, 146, 177, 253 history, 175–76 importance of osmotic issues in, 62 quest to solve the mechanism of, 116–45 reviews of, 120, 199–208 theories for, 64, 74–95 See also chemical theory, chemiosmotic theory, conformational theory Oysters, the, 59

Packer, Lester, 141 Painting, 250 Papa, Sergio correspondence with, 182 and the cytochrome oxidase controversy, 228, 231, 244 and the Q cycle, 190 response to the chemiosmotic theory, 173 Paradigm change, 3, 6, 64, 271 Paris, 41 Paris symposium, 1985, 243 Pasternak, Charles, 263 Patrons of Glynn, 257–58, 262–63 Pax unit of currency, 191–92 Peacock, the, 25, 38 Penicillin, 53–54, 56–57, 61 Pennsylvania University, 135 Permeases, 72, 91, 154–55 Perry, Sam, 47 Perutz, Max, 42, 233

index

319

Peter’s Blue, 37 Peters, Sir Rudolph, 37, 51, 80 Philadelphia, 112, 118, 256, 265 Phillips, Sir David, 265–66 Phillips Ltd., Eindhoven, 112 Philosophy Cambridge lectures in, 27, 45 Mitchell’s, 26–28, 32, 49–51, 151–52, 249–51, 274 Philosophy Department, Cambridge, 50 Phosphate and calcium transport, 185 and measurement of proton transport, 181, 183 transport of, 61–62, 71–74, 112, 154 Phosphotransferase system, 75 Photosynthesis and the chemiosmotic theory, 137 and Hill at Cambridge, 33, 36 and Jagendorf’s experiments, 123–26, 132 response to the chemiosmotic theory, 146–47, 172–73 Rich’s work on, 262 Photosynthetic phosphorylation and the ATPase, 160 and Jagendorf, 112–13, 118, 124–25 research project for Glynn, 110 theories of, 79, 86–87, 138, 146 Pirie, Norman W., 27, 55 Pittman, Dorothy, 59 Planning permission, 105, 171–72 Plato, 27, 50 Plumber, 103–4 Plymouth, Mass., 231 Plymouth, U.K., 104 Plymouth University, U.K., 267–68 Popper, Sir Karl as a friend of Mitchell, 250 introduction of Mitchell to the philosophy of, 151–52 and Mitchell’s theory formulation, 246 philosophy of, 207, 215, 236, 250–51, 272 as possible essay contributor at the jubilee celebration, 262 Porter, Lord George, 257–58, 264, 266

320

index

Porter, Rodney, 47 Potassium, 157 Powell, Anthony, 40 Power generation. See electricity generation Prague symposium, 1960, 76–78, 90, 113, 155 Prague symposium, 1968, 143 Press, for silver Glynns, 193 Pressman, Bert C., 138, 141 Primary Communications Research Centre Leicester, 239 Proteins, role of, 33, 161, 221, 274, 257 Proton and chemiosmotic principles, 79–95, 126–28 meaning of concentration of in mitochondria, 140 measurement of number translocated across mitochondrial membranes, 122, 178–85, 233, 258 role in biology, 270 role in Williams’s theory of oxidative phosphorylation, 81–82 theoretical number translocated, 126, 130, 133, 222–24, 145–46 theories based on, 150 transport of sugars linked to, 154–56 Proton conducting loops and the chemiosmotic theory, 130, 136, 299 n.19 and cytochrome oxidase, 222–23, 230, 246 experimental evidence for, 152 formulation of, 186 Proton gradient as cause of conformational change in the ATPase, 163 and Curie principle, 172 experimental evidence for, 124–25, 138–40 and formulation of chemiosmotic theory, 79, 84, 86, 121, 131–33, 138 as intermediate between respiratory chain and ATPase, 201, 207, 230, 270

in membrane transport, 152, 155–56 in photosynthesis, 147 Proton motive force, 129–30, 138–40, 147, 153–54, 273 Proton transport by bacteriorhodopsin, 165–66 and chemiosmotic theory, 85–87, 126–28, 147 and cytochrome oxidase, 222–25, 229, 244–45 experiments on, 125–26 by pyrophosphatase and transhydrogenase, 152 in Racker’s statement, 199 as secondary event in oxidative phosphorylation, 135–38, 149 theory of, 130–31, 152–53 Protonic motor, 153 Public Health Research Laboratory New York, 118, 150 Pyrophosphatase, 152

Q cycle acceptance of, 258–59, 270 evidence required for, 255 formulation of, 185–90, 273 as modification of proton conducting loops, 5, 210 and proton numbers transported, 224 reception of, 212, 217 Quastel, Juda, 102 Queen Elizabeth. See Elizabeth I, Elizabeth II Queen’s College, Taunton, 16–23 Quinone, 79, 223 See also ubiquinone Quinones, chemistry of, 256

Racker, Efraim and ATPase, 134, 162 and chemical theory, 180 comment on field of oxidative phosphorylation, 127 comment on Mitchell’s ideas, 147

correspondence with, 157–58, 181, 213 and cytochrome oxidase, 228 and Hinkle, 150–51 Hopkins Memorial lecture, 175–77 invitation to Mitchell to contribute to a book, 165 letter on the state of bioenergetics, 196–201 and the Nobel prize, 218 response to chemiosmotic theory, 141, 173 and the review of oxidative phosphorylation, 201–8 Radio talks, 70 Rail services, 169 Randle, Sir Philip, 266 Rat liver, 139, 151 Readership at Cambridge, 101 Redox loop mechanism, 259 Redundancy of staff, 213 Reed, Betty, 60 Reid, Bob, 91, 134, 151, 235 Religion and the Mitchells, 13, 17–18, 24–25 Research areas, 109–110 Respiratory chain arrangement of in the membrane, 153, 172, 223 See also proton conducting loops in the chemiosmotic theory, 85–87, 90, 95, 130–32 in the conformational theory, 143, 161 location of in bacteria, 70–71 number of protons transported by, 209 place of ubiquinone in, 187 proton transport by, 121, 135–36, 185, 188, 219–20, 233, 246 in Williams’s theory, 81–83 Reuters, 216 Review of oxidative phosphorylation, 195–96, 201–8 Rheumatism, 70, 89, 101 Rich, Peter career, 255–56 as chairman of Glynn Research Foundation, 265–68

index

321

Rich, Peter(continued) as director of molecular research, 215, 246, 256–57, 277 and the jubilee event, 263 research projects of, 262 Richards, Alison, 261 Richards, I. A., 26, 151, 236, 250 Rieske, John, 190 Roberts, Brenda, 28–29, 38 Robertson, Bryan, 39–41, 48, 59 Robertson, Daniel, 59, 96 Robertson, Helen. See Mitchell, Helen Robertson, Jason. See Mitchell, Jason. Robertson, Pat, 59–60, 68, 96 Robertson, Sir Rutherford, 79, 82, 87, 166 Robertson, Vanessa, 59, 96 Robinson, Joseph, 250 Rockefeller University, 177 Rollo, Eileen. See Mitchell, Eileen Roughton, Francis J. W., 26 Rowe, Matthew Ascot, 10–11 Royal Physical Society of Edinburgh, 75 Royal Society, 32, 114, 145, 233, 257 Royal Society professorship, 233 Royal Swedish Academy, 216, 219 Rumberg, B., 141, 173 Rushton, William, 25 Russell, Bertrand, 13, 27

Saari, Herkko, 226 Sailing, 157, 234 St. Mawes, 116 Sakharov, Andre, 263 Salisbury, Ann, 60–61 Sanadi, Rao, 196 Sanger, Frederick, 47, 58, 233, 257–58 Saris, Nils-Erik, 224 Scatchard, George, 175–77 Schatz, Gottfried, 129, 144, 221 Scholes, Peter, 114, 150, 154 Schrödinger, Erwin, 70 Science and humanity 236, 249–51 Science and humanity essays planned for Glynn’s jubilee, 262–63 Science for humanity, meaning of Glynn’s motto, 248–51

322

index

Science policy of U.K. government, 252 Science Research Council, 114, 169 Science, 199 Science, as human activity, 261 Science, meaning of according to Mitchell, 249 Scottish Hospital Endowments Research Trust, 65 Selleck, Claude, 97–98 Shakespeare, William, 22, 25–26 Siekevitz, Philip, 177 Silbury, 38–39, 41, 60–61 Silver-Grey Book, 263, 265 Simon, Herbert, 257–258 Skiathos, 145, 159–60 Skou, Jens, 174 Skulachev, Vladimir, 161, 173, 230, 263 Slater, Edward C. (Bill) as adviser to Glynn, 266 and the chemical theory, 85, 118–19, 135, 176 correspondence on Glynn, 104 correspondence on oxidative phosphorylation, 79, 81, 111, 122, 126 and the cytochrome oxidase dispute, 224–27, 232, 236 disputes with Mitchell, 136–37, 159 and the future of Glynn, 233–35 influence on Mitchell, 220 and Jagendorf’s photosynthetic experiments, 125–26, 134–35 and the joint review of oxidative phosphorylation, 196–97, 198–201, 203, 205–6 and Mitchell’s problems with editors, 259 Mitchell’s visit to the laboratory of, 118 on mitochondrial particles, 123 at the Molteno institute, 42 response to the chemiosmotic theory, 89, 91, 120–21, 129–30, 138–39, 141, 145, 173, and the theories of oxidative phosphorylation, 143–44, 148–49, 165, 167 theory for phosphorylation in the cytochrome b-c1 complex, 187–88

Smith, Cyril, 24 Smith, Lucille, 114, 139 Society for Experimental Biology, 62, 154 Society for General Microbiology, 32, 55–57, 62 Socrates, 27 Sodium ion transport, 77–78, 91, 153–55, 157 Sone, Nobuhito, 231, 241–44 Soup Kitchen, the, 61 Spectrophotometer, 145, 151, 262 Staff, dismissal of, 268 Staircase, spiral, 103–7 Statid, 49–50, 52, 70, 93 Stein, Wilfred, 154 Stephen, B. P., 78 Stephenson, Marjory, 31–32, 36–37, 44–46, 55, 102 Sterne, Peter, 39 Stockholm, 118, 214, 216 and award of Nobel prize, 219–20, 273 symposium, 1960, 78–80, 85–86, 110, 291 n.30 Stoeckenius, Walther, 165–66 Streatham Grammar School, 15 Succinate transport, 74 Sugar transport, 71–72, 75, 77, 91, 154–56 Sugden, Maurice, 24, 26 Swann, Lord Michael and assessing costs of Glynn, 109 as head of zoology department, Edinburgh, 67, 70, 89 invitation of Mitchell to Edinburgh, 63, 64–65 and invitation to write a review, 127–28 as patron of Glynn, 257–58 on the significance of Glynn, 277 support for an award for Moyle, 234 Sweden, king of, 194, 220 Sydney University, 219 Symport, 90–91, 138

Taoism, 18 Taplin, Kate. See Mitchell, Kate Beatrice Dorothy

Taplin, Rosetta 12, 14 Taplin, William George, 12, 14 Taxation, 155, 191 Tea club, Cambridge, 58 Teichoic acid, 54 Temple, Scotland, 68 Terry lectures, 32 Thatcher, Margaret, 192 Theoretical biology club, Cambridge, 51 Theory choice, 236–37, 250–51 Thompson, D’Arcy, 50 Three worlds of Popper, 250–51 Times (newspaper), 192 Tiselius, Arne, 81 Transhydrogenase, 152, 235 Treasurer, Hon. of Glynn, 257 Tudor Trust, 254

Ubiquinone, 131–32, 187–90, 245 Uncouplers, 87, 91, 121–22 Uniport, 90–91, 138 University College, London, 28, 31–32, 34, 83, 268, 277 University funding, 251–52, University life, 102 University research, 251–52, 267 Uribe, E., 139 Ussing, H. H., 72

Valencia, Spain, 265 van Dam, Karel, 147, 178–79, 182 van’t Hoff, 207, 236, 249 Vectorial metabolism and the chemiosmotic theory, 86–87, 93–95, 152, 172, 249, 263 formulation of the concept, 64, 66, 69–81, 93–95 importance of, 221, 231, 271, 274 influence of Cambridge on the ideas of, 35–36 Vellacott, Elizabeth, 7, 41, 59 Vernon, L. P., 138 Vesicles, lipid, in experiments with cytochrome oxidase, 232, 237–40 Visual arts 26, 35, 38, 41, 66, 250, 272

index

323

Vivian, Hussey, 98 von Jagow, Gebhard, 256

Waddington, Conrad, 67 Wadebridge, Cornwall, 103–4 Wadkins, C. L., 90 Walker, Sir John, 174, 221, 268 War research at Cambridge, 28, 37–38, 44 Warren triennial prize, 176 Warsaw, 136 Water, sale of bottled, 193, 276 Water skiing, 159 Water supply, 102, 160 Waterloo, battle of, 98 Way, Margaret. See Mitchell, Margaret Webb, Edwin, 31, 35, 37, 58 Weber, Bruce, 263 Weber, Gregorio, 47, 58 Weekes, Donald, 96–97 Wellcome PLC, 266 Wellcome Trust, 267 Wellington, Duke of, 98 Wenner Gren Institute, 79 West, Ian at Glynn, 1970–1973, 154–55, 157, 169 at Glynn, 1983–1988, 235, 239, 241, 243, 255 Whiteley, Joan Keilin. See Keilin, Joan Wikström, Mårten and cytochrome oxidase, 224–32, 239–41, 243–46, 258 and the opening of the Glynn Laboratory of Bioenergetics, 268 and the Q cycle, 188 received a silver Glynn, 194 and the standing of the chemiosmotic theory, 184 Wilhelm Feldberg Foundation prize, 177 William Dunn Professor of Biochemistry. See Dunn, Sir William, Professor of Biochemistry

324

index

Williams, Maurice, 257 Williams, Robert J. P. advice on the chemiosmotic theory, 126, 139 controversy with Mitchell, 127, 133–34, 137 correspondence, 1961, 82–85, 133, 164–65 correspondence, 1973, 164–65 and the Nobel prize, 218 response to the chemiosmotic theory, 173 role of proton in ATP synthesis, 81–82, 149–50, 162 theory of oxidative phosphorylation, 80–85, 119, 149–50, 162, 167, 203, 207, 271 view of the chemiosmotic theory, 133 Wimpey, George and Company Limited. See George Wimpey and Company Ltd. Windmill, 7, 171–72, 276 Wisdom, John, 50 Wiseman, Christopher Luke, 12, 17–19, 22, 36, 42 Witt, H. T., 141, 173 Wittgenstein, Ludwig, 27 Wolpert, Lewis, 261 Woodger, Joseph, 50, 52 Workshop at Glynn, 262 Worlds, Popper’s three, 152 Wrigglesworth, John, 232, 241, 246

York University, 134, 235, 247 Young, Frank G., 34, 47, 57–58, 65 Youngman, Nan, 60

Zoology Department, Edinburgh, 64–67