Sir

For a researcher in the area of bioenergetics, like myself, it was a delight to read Leslie Orgel's Millennium Essay1. Peter Mitchell's formulation in 1961 of the chemiosmotic theory as an alternative to the covalent intermediate opened a completely new vista in the field.

But Mitchell never suggested that the electron-transfer complexes in respiration and photosynthesis function as proton pumps; in fact, he was an ardent opponent of the idea of redox-linked proton pumps. For example, after Wikström reported2 that cytochrome oxidase is a proton pump, Mitchell wrote an article called “Cytochrome c oxidase is not a proton pump”3. Mitchell's idea of how the proton gradient across the membrane is created was the ‘redox loop’. According to this concept, a hydrogen atom is first transferred from one side of the membrane to the other, where it is split into a proton and an electron; the electron is then transported back across the membrane, leaving the proton behind. The difficulty with this clever mechanism is that it can only have a H+/e− stoichiometry of −1, which would mean that about half of the energy available from the electron-transfer reactions would be wasted.

The Royal Swedish Academy of Sciences awarded Peter Mitchell the Nobel Prize for Chemistry in 1978, on the recommendation of its Nobel Committee for Chemistry, of which I happened to be chairman at the time. The committee was well aware of the fact that Mitchell was wrong about how the proton gradient is created (proton pumps rather than redox loops) and how it is utilized to make ATP (conformational coupling rather than mass action). This is why the academy's citation read rather vaguely “for the contribution to the understanding of energy transfer through the formulation of the chemiosmotic theory”.

As Mitchell was right only on the phenomenological and not on the mechanistic level, one could argue that he should have been given the Nobel Prize for Physiology or Medicine instead. As one of my teachers used to say: “Physiology is that part of biochemistry which we do not yet understand”.