Chemiosmotic Hypothesis


Peter Mitchell (1920 - 1992) : Chemiosmotic Hypothesis Peter Mitchell's 1961
paper introducing the chemiosmotic hypothesis started a revolution which has
echoed beyond bioenergetics to all biology, and shaped our understanding of the
fundamental mechanisms of biological energy conservation, ion and metabolite
transport, bacterial motility, organelle structure and biosynthesis, membrane
structure and function, homeostasis, the evolution of the eukaryote cell, and
indeed every aspect of life in which these processes play a role. The Nobel

Prize for Chemistry in 1978, awarded to Peter Mitchell as the sole recipient,
recognized his predominant contribution towards establishing the validity of the
chemiosmotic hypothesis, and ipso facto, the long struggle to convince an
initially hostile establishment. The seeds of the chemiosmotic hypothesis, which
lay in Peter's attempts to understand bacterial transport and homeostasis, were
pollinated by the earlier ideas of H. Lundergard, Robert Robertson, and Robert

Davies and A.G. Ogston, on the coupling of electron transport and ATP synthesis
to proton gradients. Mitchell's 1961 paper outlined the hypothesis in the form
of several postulates which could be subjected to test. In retrospect, it was a
great strength of this first paper that Peter did not go into too much detail;
the ideas were new and strange, and were introduced to a field dominated by a
few major laboratories with their own different ideas about how the coupling
between electron transport and phosphorylation occurred. It is interesting to
look back and remember how sparse the clues were on which the hypothesis was
based. At the time, the chemical hypothesis, based on analogy with Ephraim

Racker's mechanism of substrate level phosphorylation linked to triose phosphate
oxidation, seemed secure. A few niggling difficulties were apparent. Why did so
many different reagents act as uncouplers? Why were the enzymes of oxidative
phosphorylation associated with the mitochondrial membrane? Why did coupling
seem so dependent on the maintenance of structure? How did mitochondria maintain
their osmotic balance? How did substrates get in and out? But these must have
seemed second-order problems to the main protagonists. It was these niggles that

Mitchell's hypothesis addressed. I first met Peter in 1962 when he visited Brian

Chappell in Cambridge to talk mitochondriology. I was in my second year of Ph.D.
research, and becoming familiar with the field. Brian had, at the start of my
apprenticeship, set me to work in the library, with Peter's 1961 paper as a
starting point. I must confess that I had little idea at the time of the
importance of the paper; I didn't know enough, either of the background
bioenergetics or the physical chemistry, to understand what the issues were. But
by the time of Peter's visit, I had become involved in the work on mitochondrial
ion transport initiated by Brian in collaboration with Guy Greville, and Brian
had become interested in mechanisms. Peter arrived in an elegant if ancient

Bentley convertible, and wrapped us in a corduroy enthusiasm. He was in trouble
with his hypothesis, because three labs claimed to have disproved it by
isolating the intermediates expected from the chemical hypothesis. Peter was
undaunted, and engaged in a mischievous discussion of the data and its validity.

The challenge of the upstart chemiosmotic hypothesis to the prevailing chemical
view of mechanism was to become a running battle, in which Peter engaged the
establishment single-handed for several years before the first of a growing band
of brothers (and sisters) joined him in the fray. The early work from André

Jagendorf's lab on H+-uptake and pH-jump driven ATP synthesis by chloroplasts,
the parallel work on ion and metabolite transport in mitochondria from

Chappell's lab, the work on ionophores and uncouplers by Bert Pressman, and by

Brian Chappell and myself, the development of "artificial" membrane
systems by Alec Bangham and by Paul Mueller, and Mitchell's own work with

Jennifer Moyle on proton measurements following O2 pulses, had demonstrated
before 1965 the activities expected from the hypothesis, but it was to be ten
years before the established leaders in the field were coaxed into a grudging
acceptance of the hypothesis. The bones of the chemiosmotic hypothesis were
fleshed out by Mitchell in subsequent publications, most notably the two slim
volumes published by Glynn Research Ltd. in 1966 and 1968, known affectionately
in the laboratory as the Little Grey Books of Chairman M. Mitchell's views were
discussed in detail in an important review, "A Scrutiny of the Chemiosmotic

Hypothesis" by Guy Greville, published in 1969, which established the
seriousness of the challenge. The field was evolving rapidly, and to those of us
on the chemiosmotic side, the body of evidence favoring that point of view
looked overwhelming. The hypothesis found early favor among the photosynthetic
community, perhaps because of the elegance of the early demonstrations from

Jagendorf's lab, the explanation of amine uncoupling, the utility of the
electrochromic "membrane voltmeters", perhaps also because of the more
physico-chemical bent of the field. The eventual acceptance by the biochemical
community came with the demonstration of reconstituted proton pumping activities
for the isolated and purified enzymes of respiratory and photosynthetic chains
in liposomes, mainly from Racker's group, and the demonstration of coupled
phosphorylation in the chimeric bacteriorhodopsin-ATP-ase liposome system by

Walter Stoeckenius and Racker. Another important element was the growing physico-chemical
sophistication of the bioenergetics community, especially among the younger
research workers. Readers of Photosynthesis Research will need no guide to the
present status of chemiosmosis. The ideas Peter Mitchell introduced, which
seemed so rare at the time, are now the common currency of all our discussions.

The field has gone on to explore the deeper ramifications, from molecular
mechanism at one end, through the compartmentalization of the eukaryote cell and
metabolic integration, to evolution at the other. Although the chemiosmotic
hypothesis was Peter's most important contribution, he continued to introduce
new ideas, including the Q-cycle hypothesis, which has dominated discussion of
the mechanism of electron transfer and proton pumping in the quinol oxidizing
complexes since 1975, and now seems well established as the basic mechanism. I
found myself initially on the opposite side of the Q-cycle controversy. Of
course, there seemed to me perfectly good reasons for thinking that the Q-cycle
as then formulated was wrong, and Peter was always attentive in listening to
them. In trying to account for our objections (based on observation of electron
transfer kinetics in photosynthetic bacteria), he quite early pointed out that
the role of the Rieske iron-sulfur center might be crucial ("Don't you
think the electron might be getting hung up on the Rieske?"). Our own
results subsequently showed this to be the case, and led us to a modified

Q-cycle mechanism which was among the models discussed by Peter in his 1976
review. Although Peter won most of his battles, he suffered a few defeats. The
long controversy about the proton-pumping activity of cytochrome oxidase
involved some fairly heated debates before it finally went to Mårten Wikström;
and it looks as if the mechanism of ATP synthesis through the F1.F0 ATP-ase is
more along the lines envisaged by Paul Boyer than through Peter's earlier
proposals. In both these cases, with the benefit of hindsight it looks as if

Peter underrated the role of the protein and the subtlety of evolution in
designing molecular mechanism. It was part of Peter's charm that, no matter how
strongly he held his views, his stance was based on sound principles and
experimental results, was always well argued, fair, and devoid of malice. When
convinced, he conceded graciously; if his own views prevailed, he was happy to
recognize the contributions of his opponents, and his unfailing habit of giving
credit where credit was due allowed for an easy reconciliation. Peter's
contributions have been formally recognized through the many honors, prizes and
degrees conferred on him over the years. He was a Fellow of the Royal Society, a

Foreign Associate of the National Academy of Sciences, Honorary Fellow of the

Royal Society of Edinburgh, Fellow of Jesus College, Cambridge (his alma mater),
a Foreign Associate of the Académie des Sciences Francaise, and an Honorary
member of the Society of General Microbiology, and the Japanese Biochemical

Society. He received honorary doctorates from the Technical University, Berlin,
the Universities of Exeter, Chicago, Liverpool, Bristol, Edinburgh, Hull, East

Anglia, Cambridge and York. Among other honors and prizes awarded were the CIBA

Medal and Prize of the Biochemical Society in 1973, the Warren Triennial Prize
(jointly) from the Trustees of the Massachusetts General Hospital in 1974, the

Freedman Foundation award of the New York Academy of Sciences in 1974, the

Feldberg Foundation Prize in 1976, the Rosenberg Award of Brandeis University in

1977, the Lipmann Lecturer, Gessellschaft für Biologische Chemie, 1977, the

Medal of the Federation of European Biochemical Societies in 1978, Nobel

Laureate in Chemistry in 1978, the Copley Medal of the Royal Society in 1981,
and the Medal of Honor of the Athens Municipal Council in 1982. The dry facts of

Peter Mitchell's life do him scant justice, and although he was at ease with his
fame, I am sure he would not wish to be remembered simply in terms of the many
prizes and honorary degrees heaped on him. Peter listed among his leisure
interests (and here I quote from the International Who's Who), family life, home
building, the creation of wealth and amenity, the restoration of buildings of
architectural and historical interest, music, thinking, understanding,
inventing, making, sailing. I can picture him filling out the questionnaire
which elicited this list. There would have been a wry amusement in the task of
defining himself, and a certain self-deprecation, but Peter would have tackled
the job with characteristic honesty, diligence and intelligence. Glynn House and

Glynn Research Ltd. (later the Glynn Research Foundation), were the happy
outcome of a spell in hospital in the early 1960's. On the recommendation of his
doctor, Peter was looking for a vacation home in the South where he could
recuperate. The estate agent showed him the burnt-out shell of a country
mansion, and Peter, more in jest than earnest, said he would give £x,000 for
the lot. He was surprised when, a few weeks later, the man called him in

Edinburgh and said "It's yours". Using his private resources, Peter
had the building remodelled, with the west wing as a residence, and the east
wing and adjoining areas as research laboratories, library, seminar room,
workshop, etc., to accommodate a small research group. Over the years, Peter and

Helen welcomed many friends and colleagues to the now beautifully restored Glynn

House, and were unfailingly gracious and hospitable. Friendships were important
to Peter. He enjoyed conversation, and treated topics both high and low with a
mixture of deep seriousness and impish humor. Discussions were a test bed for
his latest ideas, and he relished the pursuit of odd angles and new
perspectives. He held the view that science progresses though open discussion,
and abhorred the notion that ideas or information should be closeted away,
hidden from "the competition". Peter's approach to science was based
on philosophical principles; he was interested not only in the science, but in
the mechanism of scientific discovery. He was fascinated by the nature of
creativity, the practice of science as a social system, the validation of
scientific "truth",- indeed, the whole process of science in action.

He was much affected by Popper and his ideas about the scientific method, and

Popper's influence can be seen in Peter's insistence that hypotheses should be
framed in the context of experimental tests. He regarded experimental results as
of prime importance, and was as much interested in the intriguing observation as
in the author's interpretation. He believed strongly that science advances
through the contributions of individuals, and that each individual is
responsible for selection or discrimination with regard to any piece of
information. He thought that much of the effectiveness of a successful scientist
lay in the adequacy of this filtration process. This view was captured in a nice
remark he once made to me, that "The trouble with most scientists is not
that they don't have good memories, but that they don't have good forgeteries."

Although in private he was not reluctant to criticize, he was generous and
helpful in his more public interactions, and treated with respect the opinions
of others, especially younger research workers coming into the field. In the
wider context of his social and political views, Hayek was an early influence,
and Peter would emphasize the role of the individual, and freedom of economic
and political expression. Much of his thinking in the last 15 years was directed
towards human and social problems, especially towards identifying mechanisms for
conflict resolution. In this context, he saw the bioenergetics community as a
microcosm and a vehicle for experiment, and the Round Table Discussion meeting
he organized at Glynn, was at least partly motivated by this interest. Although
he had little time for socialism, he was a very human person, aware of his own
foibles and vanities, and found through this a sympathy with the common human
lot. His belief in the individual was tempered by a recognition that in a
rational order, rights are earned and exercised in the context of the
responsibilities each owes to society. He held to a set of standards, those of
the gentleman, which many would see as archaic, and these and his talents raised
him above the fray. His inspiration, humor, friendship, and the high standards
of scholarship and behavior he brought to our field will be sorely missed.

Bibliography

Obituary, Photosynthesis Research, Antony Crofts, June 29th. 1992Mitchell, P. (1961) Nature (London) 191, 144-148.  Mitchell, P. (1966)

Chemiosmotic Coupling in Oxidative and Photosynthetic Phosphorylation, Glynn

Research, Bodmin.  Mitchell, P. (1968) Chemiosmotic Coupling and Energy

Transduction, Glynn Research, Bodmin.  Greville, G. (1969) Curr. Top.

Bioenerg. 3, 1-78.  Mitchell, P. (1976) J. Theor. Biol., 62, 327-367