Peter Dennis Mitchell
Mitchell, Peter Dennis
MITCHELL, PETER DENNIS
(b. Mitcham, Surrey, United Kingdom, 29 September 1920; d. Glynn near Bodmin, Cornwall, United Kingdom, 10 April 1992),
biochemistry, chemiosmotic theory, bioenergetics.
Mitchell pursued the development of theoretical approaches in biochemistry, culminating in the proposal and acceptance of his chemiosmotic theory. This theory helped forge the field of bioenergetics (the study of how energy is obtained, transformed, and used in living cells) by unifying several apparently disparate fields, and, in the estimation of some, produced a paradigm shift by introducing spatial directionality into biochemistry. He was awarded the Nobel Prize in Chemistry in 1978. Although his research program was formulated at the universities of Cambridge and Edinburgh, the testing and refinement of his theory was effected at his private, independent research laboratory, the Glynn Research Institute. Here he engaged in a double experiment to explore the potential of his chemiosmotic ideas as well as to see if world-class science could be done in such a small, private research establishment.
Origins and Early Education . Peter Mitchell was the second son of Christopher Mitchell, a distinguished civil engineer and administrator in the Ministry of Transport, and Kate (née Taplin) Mitchell. The Mitchell family was from Dorset, England, but descended from seventeenth-century French Huguenot immigrants. Peter Mitchell’s uncle, Sir Godfrey Mitchell, built Wimpy Construction into one of the largest contracting firms in Europe; gifts of shares of Wimpy stock provided Mitchell with considerable financial freedom and funds for establishing and maintaining the Glynn Research Institute.
Mitchell’s academic record at local grammar schools and his secondary education at Queen’s College, Taunton, were not particularly distinguished. He excelled in mathematics and physics, but was otherwise an indifferent student, doing poorly in subjects such as history and geography that seemed to lack fundamental principles. At Queen’s he found that he could reason from first principles to deduce on his own what he could otherwise find in textbooks, which made physics attractive, although not chemistry as it was then taught. This established a pattern that persisted throughout his life, in which he confidently developed his own understanding of a subject through reasoning rather than consulting standard texts or experts. He failed the scholarship entrance examination for Cambridge and it was only through the intervention of his headmaster, Christopher Wiseman, who recognized Mitchell’s talent and potential, that Mitchell was admitted to Jesus College, Cambridge for the fall of 1939.
Education and Work at Cambridge, 1939–1955 . Mitchell chose to study physics, chemistry, physiology, and biochemistry for his Tripos I (first two years) and then biochemistry for his Tripos II (third year). Again, Mitchell’s performance was not stellar (second-class marks on his examinations) but he flourished in the Biochemistry Department, then probably the best in the world, under the encouragement of Frederick Gowland Hopkins, who perceived Mitchell’s potential for research. Mitchell stayed on, as a graduate student, doing war-related research in the department under the supervision of James Danielli.
Mitchell was intellectually shaped by Hopkins’s approach of dynamic biochemistry that emphasized understanding enzyme-catalyzed metabolism. Although biochemists viewed the cell as a “bag of enzymes,” Mitchell noted that the way enzymologist Malcolm Dixon drew reactions could imply a directionality in the action of enzymes rather than a directionless, or scalar, catalytic process. Working with Danielli on the nature of cellular membranes and the movement of chemicals across them reinforced Mitchell’s emerging idea that the directionality, or vectorial character, of transport across membranes was somehow connected with the directionality and spatial-temporal organization of biochemical processes more generally.
After the war and Danielli’s departure for King’s College London, Mitchell worked essentially unsupervised on his thesis research, working out the implications of his intuitions about biochemical organization. He submitted an unconventional thesis in 1948. It opened with a philosophical discussion about directional processes and the roles of static and dynamic elements in such processes. A theoretical section followed on the diffusion of substances in biological systems, in which Mitchell set out a mathematical formulation of his vectorial ideas. After a section on the nature of the bacterial surface there was a final section in which Mitchell’s preliminary, but solid, experimental results on amino acid uptake by bacteria were presented. His examiners, Ernst Gale of the department and external examiner A. G. “Sandy” Ogston, rejected the thesis as being inchoate and incoherent.
Mitchell’s friendship with David Keilin of the nearby Molteno Institute, who provided Mitchell with temporary space in his laboratory, was crucial in helping him through this setback. Keilin was angered by the committee’s action and encouraged Mitchell to rewrite the thesis. Indeed, Keilin was something of a scientific and personal father figure to Mitchell; Mitchell’s Nobel Prize lecture, “David Keilin’s Respiratory Chain Concept and Its Chemiosmotic Consequences,” reflected the intellectual debt Mitchell felt to Keilin’s influence (Mitchell, 1979). In the event, the then head of department, Albert Chibnall, assigned Gale to supervise Mitchell’s second effort, which involved research on the mechanism of action of penicillin. Mitchell’s second thesis was more conventional and was accepted on 6 December 1950.
Although it turned out that Mitchell’s proposed mechanism for penicillin action was incorrect, the thesis served to focus his thinking on phosphate transport into bacteria and how that was connected to the role of phosphate in intermediary metabolism. Mitchell began developing a research program on such phenomena, and although he continued thinking in the terms of his first thesis he did not state such notions explicitly except in a paper presented in Moscow in 1956, after he had left Cambridge. There he spelled out his ideas, described in the first thesis, on directionality and intracellular gradients (Mitchell, 1957a). In effect, these ideas provided an intuitive metaphor for nonequilibrium thermodynamic processes, which helped Mitchell organize his thinking in relation to cellular structure and the “flame” of metabolism.
After Mitchell completed his doctoral degree, the new head of the department, Frank Young, appointed him to a five-year position as a demonstrator. Mitchell worked in the Sub-Department of Microbiology, now headed by Gale, but founded by Marjorie Stephenson. She also helped found the Society for General Microbiology in 1944 and was one of the first two women to be elected to the Royal Society in 1945. When, in 1948 as president of the society, she was organizing the meeting for 1949 on the bacterial surface, she asked Mitchell, though still a graduate student, to give a major talk, in which he identified the osmotic barrier of bacteria with their cytoplasmic membrane. Further, he speculated that membrane proteins were not inert and unstructured, but acted as globular, precisely folded enzymes in facilitating transport (Mitchell, 1949).
Stephenson did not live to preside at this meeting, but before she died she intervened again in Mitchell’s career in a way that had a lasting effect. She suggested that Jennifer Moyle, who was a research assistant in her laboratory, work with Mitchell. This began a formidable and productive collaboration that lasted, with one brief interruption, until Moyle’s retirement in 1983. Both Mitchell and Moyle felt that Stephenson had real insight into their unique and complementary strengths, Mitchell as an imaginative and brilliant theorist and Moyle as a meticulous and superb experimentalist. Together they pursued a line of research on bacterial transport informed by Mitchell’s increasingly more precise and articulated theoretical speculations and tested by Moyle’s careful experimentation.
In a series of well-crafted publications on phosphate transport in bacteria, Mitchell and Moyle agued that metabolism (involving chemical work) and transport (involving osmotic work) were but two aspects of an underlying unitary process. Summarizing this work Mitchell wrote 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” (Mitchell, 1954, p. 254). This was Mitchell’s first mention of a possible link of oxidative phosphorylation and an osmotic (transport) type of process. Oxidative phosphorylation is the process in bacteria and mitochondria in which electrons, derived from nutrients, are passed through a complex set of membrane-bound proteins, known as the respiratory chain, to an oxygen molecule, with the concomitant synthesis of ATP (adenosine triphosphate). ATP then can provide energy to drive other processes in the cell. The process of cellular respiration just described should not be confused with the respiration, or breathing, of organisms. Cellular respiration is why oxygen is needed by all aerobic organisms.
Mitchell did not get along well with Young, and his contract at Cambridge was not renewed in 1955. However, Michael Swann, who knew Mitchell from Swann’s time at Cambridge, offered Mitchell a position as director of a new Chemical Biology Unit in the Department of Zoology at the University of Edinburgh; Mitchell accepted on the condition that Moyle be hired to be his research associate.
Research at Edinburgh, 1955–1963 . Mitchell’s time at Edinburgh was perhaps his most creative. During it he brought his research program based upon a holistic theoretical approach to living systems to fruition and developed a detailed theory of vectorial metabolism, linking transport and metabolism, and applied it specifically to the problem of the mechanism of oxidative phosphorylation. In this new environment, where he independently directed his own subdepartment, Mitchell theorized with greater assurance, aided by the skilled experimental work of Moyle.
Mitchell and Moyle showed that the respiratory chain in bacteria was located in the cytoplasmic membrane and concluded that it might have a direct role in ion transport. Mitchell, in his 1957 paper “A General Theory of Membrane Transport from Studies of Bacteria,” developed a notion of “ligand conduction” as the mechanism of transport. He argued 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 enzyme-catalysed group-transfer reactions” (p. 136). Arguing from the necessarily vectorial nature of enzymes involved in transport, Mitchell and Moyle, in their 1958 paper “Group-Translocation: A Consequence of Enzyme-Catalysed Group-Transfer,” presented a generalization that enzymes act to “transport” substrates vectorially through their active sites but that the consequence of this is only observable when the enzymes are plugged through a membrane. In their 1959 paper “Coupling of Metabolism and Transport by Enzymic Translocation of Substrates through Membranes” they proposed that such a mechanism would couple metabolism and transport. This concept was further articulated in Mitchell’s 1959 Biochemical Society symposium paper “Structure and Function in Micro-organisms” where he introduced the term chemiosmotic in which the osmotic link of compounds or ions being transported from one side of a biological membrane to the other involves a chemically linked group, or ligand, being conducted through a membrane enzyme (p. 91). He extended this notion of chemiosmotic linkages to cells more generally, including the mitochondrial membranes of more complex eukaryotic cells.
In August 1960 Mitchell summarized the work of the previous five years when he presented the opening lecture, “Biological Transport Phenomena and the Spatially Anisotropic Characteristics of Enzyme Systems Causing a Vector Component of Metabolism,” at the Prague Symposium on Membrane Transport and Metabolism. In this lecture he articulated, at a general level, his theory based upon chemiosmotic principles.
Six weeks later, in Stockholm in a symposium session on “Specific Membrane Transport and its Adaptation,” at the end of a paper reporting work of his graduate student B. P. Stephen, Mitchell speculated that the enzyme glucose-6-phosphate phosphatase, which they had shown to be located in the bacterial cytoplasmic membrane, could be considered as an example of chemiosmotic coupling. He proposed that the reaction could be reversed to synthesize, rather than hydrolyze, the glucose phosphate if there were a proton gradient across the membrane. Mitchell further speculated that similar considerations could apply to the synthesis of ATP in photosynthetic and oxidative phosphorylation.
Mitchell’s application of his theoretical approach to the problem of the mechanism of oxidative phosphorylation had several key features as set forth in an abstract submitted mid-February 1961: (1) The respiratory-chain reactions in the membrane released protons vectorially to one side of the membrane and hydroxyl ions to the other side, thus generating a difference in proton concentration across the membrane (a pH gradient); (2) such a trans-membrane pH gradient can arise only if the membrane is impermeable to protons; (3) ATP can be made by reversal of the ATPase (ATP synthase) reaction if there is a mechanism to utilize the energy in the pH gradient to drive the synthesis of ATP. Such reversal of the ATPase means that, instead of reacting ATP with water and releasing energy at the ATPase enzyme, water is removed from ADP and phosphate to make ATP using energy in the proton gradient, thus making the enzyme an “ATP synthase.” In 1966 Mitchell provided a specific mechanism by which protons were transported across membranes. In a process he termed ligand conduction the transported proton was linked to an electron in a hydrogen atom bonded to
another atom. This bound proton was called the ligand. When the molecule containing the liganded proton moved from one side of the membrane to the opposite side, the effect was to transport the proton across the membrane and to release it to bulk solvent on the other side (Mitchell, 1966). Mitchell also proposed a direct role of the proton in the ATP synthase active site.
The possibility of such proton translocation by the respiratory chain had already been suggested by several authors, including Robert Davies, Heinrich Lundegårdh, and Sir Rutherford Robertson; however, it still needed to be shown that such proton translocation occurred in bacteria, mitochondria, and chloroplasts. Proton impermeability of membranes was a novel suggestion and most biochemists at that time thought it unlikely. The mechanism by which Mitchell thought protons could make ATP by reversing the ATPase was novel. Davies had earlier speculated that a pH gradient could somehow catalyze ATP synthesis. However, no one had demonstrated that protons could indeed drive ATP synthesis.
During the fall of 1960 Mitchell conducted preliminary experiments demonstrating that bacterial membranes were indeed proton impermeable and in 1961 he extended the work to mitochondria. In January 1961 a paper (submitted August 1960) by Robert J. P. Williams of Oxford University, “Possible Functions of Chains of Catalysts,” appeared in the premier issue of the new Journal of Theoretical Biology, in which Williams proposed intramembrane anhydrous proton gradients as the common intermediate between the respiratory chain and ATP synthesis. Before submitting his “Coupling of Phosphorylation to Electron and Hydrogen Transfer by a Chemi-osmotic Type of Mechanism” paper to Nature (published in July 1961), Mitchell opened a correspondence with Williams on 24 February 1961, in part to see how similar their mechanisms were. This led to misunderstandings and controversies that continued past Mitchell’s death (see Williams, 1993; also see Prebble and Weber, 2003, as well as Weber and Prebble, 2006). To Mitchell’s satisfaction, though not to Williams's, Mitchell concluded the mechanisms were distinct and went forward with the publication of his proposal, without mention of Williams’s paper or the correspondence.
Shortly thereafter Mitchell’s ill health due to ulcers led him to take a leave and ultimately to resign from Edinburgh. He purchased a property with a beautiful but derelict Regency house, Glynn, near Bodmin in Cornwall and in 1962 began renovations of it, acting as master of works, to restore the building and remodel it to serve both as a research laboratory and family residence. Moyle came to join in the work and help set up the formal organization of Glynn Research Ltd. By fall 1964 research began at Glynn.
Research at Glynn, 1964–1997 . Mitchell made the decision to continue the line of experimental work on membrane impermeability that he had begun at Edinburgh. With Moyle he devised experiments to test not only if the respiratory chain in mitochondria ejected protons but also to quantify how many protons were translocated per electron moving to an oxygen molecule at the end of the chain. As Mitchell’s proposal had not attracted much serious attention in the field, it made sense for Mitchell’s small research team to focus upon experimental testing of his approach. Fortunately Mitchell’s proposal was amenable to empirical scrutiny in the 1960s with relatively simple equipment.
The small size of the group, the simplicity and elegance of the experiments, and the close connection of theory and experiment all became hallmarks of the Glynn style of science. Given that the prevailing paradigm of the field of oxidative phosphorylation was the chemical theory proposed in 1953 by E. C. “Bill” Slater (based upon the expectation that there should be chemical intermediates analogous to those seen in metabolism), Mitchell realized that he had to convince his colleagues to view the phenomenon in a radically different manner. So shifting the field, while working from a small and independent research facility, became the other aspect of the Glynn program.
Mitchell realized that the theorizing and experimenting at Glynn would need to leverage allies from the more traditional research laboratories, something Mitchell sought to do through active correspondence, frequent presentations at international meetings, and bringing scientists for consultations and extended visits to his beautifully situated institute. Indeed, the Glynn guest book reads as a who’s who of the emerging field of bioenergetics.
One of the first visitors to Glynn was André Jagendorf, then at the McCollum-Pratt Institute in Baltimore, Maryland. Jagendorf had obtained data that chloroplasts upon illumination translocate protons, which fitted Mitchell’s prediction, and he wanted to further understand the theoretical arguments. A year later Jagendorf showed that chloroplasts in the dark synthesized ATP when subjected to an artificial pH gradient of just the size Mitchell had predicted would be required. Additional evidence supporting aspects of the chemiosmotic approach was obtained by Brian Chappell and Anthony Crofts at Bristol University in their studies of ion transport in mitochondria. By 1968 Mitchell had supporting evidence for all three “pillars” of his proposal. These results meant that the chemiosmotic hypothesis could no longer be ignored and a storm of controversy broke out that persisted for a number of years. Meanwhile, Mitchell made revisions to his theoretical model of oxidative phosphorylation, presented in two volumes published by the Glynn Research Institute (Mitchell, 1966, 1968).
Mitchell’s program at Glynn could be considered a success, and by 1973 most bioenergeticists acknowledged that a proton gradient was the energy-conserving link between the oxidation-reduction reactions of the respiratory chain and ATP synthesis. However, aspects of Mitchell’s specific mechanisms were not so widely accepted. Paul Boyer at the University of California at Los Angeles had proposed a quite different alternative mechanism for the synthesis of ATP by ATPase, one involving protein conformational changes via indirect interaction with protons. In contrast, Mitchell’s ATPase mechanism, as it was developed in the 1970s, based upon his ideas of ligand conduction, involved a direct use of protons in the active site. Similarly Mitchell in his 1966 reformulation of his model used ligand conduction to explain the proton to electron ratios he observed. However, many in the field doubted both the ratios Mitchell reported and his mechanistic explanation.
Starting in 1974 Al Lehninger from Johns Hopkins University and Mårten Wickström from the University of Helsinki presented results with ratios higher than those
observed by Mitchell and Moyle. This led to another controversy that lasted for over a decade. At stake were not just the experimental results but also Mitchell’s ligand conduction mechanisms. In the middle of this controversy Mitchell was awarded the Nobel Prize in Chemistry in 1978 for his chemiosmotic theory of biological energy transfer even though mechanistic details were still in dispute.
Ultimately, by 1985 Mitchell had to concede that the higher ratios were correct, but he still sought to explain them by further development of his fundamental theory of ligand conduction. He also continued to argue for his direct, vectorial explanations of the higher numbers of protons (3 to 4) needed to synthesize ATP than his theory originally had predicted (2 protons per ATP). Indeed almost to his dying day Mitchell was refining his ATPase mechanism. Besides the confidence he always had in his intellectual abilities, he felt that his basic approach had been vindicated by his solution of the basic mechanism of oxidative phosphorylation.
In 1975 he successfully modified his theory to account for the proton/electron ratio for one part of the respiratory chain, that between the initial protein complex that oxidized NADH and the final protein complex, the cytochrome oxidase, that transferred electrons to oxygen to make water. He did this by assuming that the ligand conduction could be done by a mobile membrane-soluble molecule, known as coenzyme Q, which would ferry the extra protons across the membrane. This was an extraordinary feat of imagination going well beyond the experimental data available at the time. The Q cycle, as Mitchell called it, is essentially accepted today. Mitchell’s attempts to repeat the Q-cycle feat with the ATPase and the cytochrome oxidase were not successful. Accumulated experimental results overwhelmingly support Boyer’s conformational-coupling mechanism for the ATPase and Boyer was awarded a share of the Nobel Prize in Chemistry in 1997. What is presented in textbooks today as the mechanism of oxidative phosphorylation is best characterized as the Mitchell-Boyer mechanism.
From the mid-1970s on, the endowment of Glynn from the Wimpy shares was insufficient to fully sustain the operation of the Glynn Research Institute. Moyle retired in 1983 and in 1985 Mitchell retired as director of research, although he still headed the institute; Peter Rich, a bioenergeticist from Cambridge, became the research director. Rich obtained extramural funding to support the more instrument-intensive research that was mandated as the field matured. Aside from continuing his theoretical work, Mitchell sought to obtain funding to maintain Glynn as an institution. In this endeavor he met with limited success, and after his death in 1992, it became even harder to obtain support for Glynn per se, despite its illustrious record of success. Ultimately, in 1996 Rich transferred the research operations to University College London as the Glynn Laboratory of Bioenergetics. Thus what had been started as an attempt to do major research outside of university or government laboratories ended up absorbed back into the university system.
A comprehensive bibliography of Peter Mitchell’s publications can be found in Slater, 1994. There is an extensive archive of Mitchell’s unpublished papers held at the University of Cambridge Library.
WORKS BY MITCHELL
“The Osmotic Barrier in Bacteria.” In The Nature of the Bacterial Surface, edited by A. A. Miles and N. W. Pirie. Oxford: Blackwell Scientific, 1949. “Transport of Phosphate though an Osmotic Barrier.” Symposia of the Society for Experimental Biology 8 (1954): 254–261.
“A General Theory of Membrane Transport from Studies of Bacteria.” Nature 180 (1957a): 134–136.
“The Origin of Life and the Formation and Organizing Functions of Natural Membranes.” In International Symposium on the Origin of Life on the Earth, edited by A. Oparin et al. Moscow: House Academy of Science USSR, 1957b.
With Jennifer Moyle. “Group-Translocation: A Consequence of Enzyme-Catalysed Group-Transfer.” Nature 182 (1958): 372–373.
With Jennifer Moyle. “Coupling of Metabolism and Transport by Enzymic Translocation of Substrates through Membranes. ” Proceedings of the Royal Physical Society of Edinburgh 28 (1959): 19–27.
“Structure and Function in Micro-organisms.” In The Structure and Function of Subcellular Components, edited by Eric Mitchell Crook. Biochemical Society Symposia 16. Cambridge, U.K.: Cambridge University Press, 1959.
“Approaches to the Analysis of Specific Membrane Transport.” In Biological Structure and Function, vol. 2, edited by T. W. Goodwin and O. Lindberg. London: Academic Press, 1961. The Stockholm symposium paper presented in September 1960.
“Chemiosmotic Coupling in Oxidative and Photosynthetic Phosphorylation.” Biochemical Journal 79 (1961): 23P–24P. The abstract submitted mid-February prior to presentation at the Biochemistry Society meeting and published in July 1961.
“Coupling of Phosphorylation to Electron and Hydrogen Transfer by a Chemi-osmotic Type of Mechanism.” Nature 191 (1961): 144–148.
“Biological Transport Phenomena and the Spatially Anisotropic Characteristics of Enzyme Systems Causing a Vector Component of Metabolism.” In Membrane Transport and Metabolism, edited by Arnost Kleinzeller and A. Kotyk. Prague: Czechoslovak Academy of Sciences, 1962. The paper read by Mitchell in August 1960 at the Prague Symposium.
“Chemiosmotic Coupling in Oxidative and Photosynthetic Phosphorylation.” Biological Reviews 41 (1966): 445–502. A shorter version of Chemiosmotic Coupling in Oxidative and Photosynthetic Phosphorylation. Bodmin, U.K.: Glynn Research Ltd., 1966.
Chemiosmotic Coupling and Energy Transduction. Bodmin, U.K.: Glynn Research Ltd., 1968.
“A Chemiosmotic Molecular Mechanism for Proton-Translocating Adenosine Triphosphatases.” FEBS Letters 43 (1974): 189–194. A presentation of Mitchell’s ATPase mechanism in which protons have a direct involvement.
“The Protonmotive Q Cycle: A General Formulation.” FEBS Letters 59 (1975): 137–139. An early version of the Q cycle.
“David Keilin’s Respiratory Chain Concept and Its Chemiosmotic Consequences.” In Les Prix Nobel en 1978. Stockholm: Nobel Foundation, 1979. Also available from http://nobelprize.org/. Mitchell’s Nobel Prize lecture, which provides an account of the development of the chemiosmotic theory and reviews its status as of that time.
With Roy Mitchell, John A. Moody, Ian C. West, et al. “Chemiosmotic Coupling in Cytochrome Oxidase: Possible Protonmotive O-Loop and O-Cycle Mechanisms.” FEBS Letters 188 (1985): 1–7. In this paper Mitchell concedes that the ratio of protons ejected to electrons is nonzero but proposes how his fundamental ligand conduction mechanism could account for the results.
“Foundations of Vectorial Metabolism and Osmochemistry.” Bioscience Reports 11 (1991): 297–346.
Orgel, Leslie E. “Are You Serious Dr. Mitchell?” Nature 402 (1999): 17. This article attempts to assess the historical significance of Mitchell’s contribution to science. Orgel compares Mitchell’s originality and impact with those of Copernicus and Darwin.
Prebble, John N. “The Philosophical Origins of Mitchell's
Chemiosmotic Concepts.” Journal of the History of Biology 34 (2001): 433–460.
_____, and Bruce H. Weber. Wandering in the Gardens of the Mind: Peter Mitchell and the Making of Glynn. New York: Oxford University Press, 2003. This is, at present, the only full-length biography of Mitchell as well as an account of his Glynn Research Institute.
Saier, Milton. “Peter Mitchell and His Chemiosmotic Theories.” ASN News 63 (1997): 13–21. This article also assesses Mitchell’s contribution to science.
Weber, Bruce H. “Glynn and the Conceptual Development of the Chemiosmotic Theory: A Retrospective and Prospective View.” Bioscience Reports 11 (1991): 577–647.
_____, and John N. Prebble. “An Issue of Originality and Priority: The Correspondence and Theories of Oxidative Phosphorylation of Peter Mitchell and Robert J. P. Williams, 1961–1980.” Journal of the History of Biology 39 (2006): 125–163.
Williams, Robert J. P. “Possible Functions of Chains of Catalysts.” Journal of Theoretical Biology 1 (January 1961): 1–17. Submitted August 1960.
_____. “The History of Proton-Driven ATP Formation.” Bioscience Reports 13 (1993): 191–212.
_____. “Bioenergetics and Peter Mitchell.” Trends in Biochemical Sciences 27 (2002): 393–394.