Peter Mitchell (1920 - 1992) Chemiosmotic Hypothesis Essays

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 oxidati on, 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 i n 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 Andr? 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 hypothe sis. 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