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