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