Second Part

0:09:07 At the LMB became acquainted with an extraordinary group of people - Francis Crick, Sidney Brenner, Hugh Huxley, Fred Sanger, Max Perutz and Aaron Klug; the ones who shone publicly were Crick and Brenner; they dominated the seminar discussions; Crick left soon after to join the Salk Institute; Perutz was succeeded as Head of the LMB by Brenner in 1979, and Brenner by Aaron Klug in 1986. Klug is a brilliant thinker; in the 1990's he got interested in Alzheimer's disease and put together a group of people at the LMB to look at bodies that are found associated with people who died from the disease called tangles; these were tangles of proteins but not known what they were made of; team included César Milstein, myself, and a medical person, Claud Wischik, who had access to the material; I was doing the chemical analysis, Milstein, immunochemical analysis; Michel Goedert was also part of it; Klug managed this group effectively although we were doing this work in our spare time; results were quite important and published in three papers; I learnt about managing people from that experience

4:34:03 César Milstein was in the next laboratory to me and I knew him well; he had worked under Malcolm Dixon but was encouraged by Sanger to come back from Argentina and to work on immunological topics in the Department of Biochemistry; later worked in Sanger's Division; he was a delightful person with a seemingly illogical mind which infuriated Brenner who was very logical; Milstein would make seemingly illogical jumps that often turned out to be correct but he wasn't very good at explaining; I came into slight conflict with him when he took over from Sanger as Head of Division because he wanted to focus the whole division on immunology, and that is not what I did; managed to persuade him not to change the name of the Division which he agreed to; thus it remains a broad church which can incorporate all kinds of people; to be fair to him he was tolerant of me and didn't try to close me down; once it became clear that I was going to be successful he became extremely interested in me and was very happy; Hal Dixon and Dan Brown; Aaron Klug and zinc fingers; the Walker motif

12:38:16 Peter Mitchell and his concepts of chemiosmosis dominated the biogenetics field; had been difficult to get established even after his 1978 Nobel Prize; Mitchell's view, which is correct, was that it was an intermediate in energy conversion was disputed by some; my field was dominated by debates on chemiosmosis and how proton pumps work but without any discussion or experimentation to understand the fundamentals of the pumps themselves; Mitchell hung on to ideas too long and this forced other people to keep on doing experiments that they might not have done and which probably were not very profitable; his general concepts were correct but some of the details he gave over the years turned out not to be precise and that was true of the ATPase that I worked on from the early 1980's; there had been some good chemistry done but none of the proteins had been characterised properly so I set about sequencing them using recompetent DNA; Brenner helped me there and provided me with material; Sanger did not want me to use DNA but to develop methods with proteins but I disagreed and he let me continue; I worked on establishing the chemical composition of the enzyme and the number of proteins in it and discovered many components that were unknown, and reconstituted parts of it; from the very beginning I was trying to grow crystals of a very large protein complex which many thought was impossible; I was variously advised that I was wrecking my career and why didn't I do something easier; it appealed to people like Perutz that I would be prepared to take on something like that; I seemed to be making progress so they backed me; I never despaired because we were incrementally making progress and I was in a community of people who didn't think it was unusual to struggle with a problem as long as it was an important problem; I started trying to grow crystals in 1982-3 and by the time they were any good was ten years later; I kept at it the whole time with a particular post-doc., RenÈ Lutter, and a particular research assistant, Michael Runswick; we had crystals from the very beginning but they didn't diffract very well and I didn't know much about growing crystals, but we learnt; I have always said that it is important to have an important biological problem and then use whatever techniques you need to solve it and not be frightened to learn new methodologies; it all worked out in 1994 when we solved this high-resolution structure; it was clearly important because one could interpret the catalytic cycle in a way that we could not really have hoped to have been able to do; these were single snap shots taken by X-ray-crystallography from which we could work out a great deal of information that linked to work that had been done by Paul Boyer which related to the way in which ATP was being made; from this it was inescapable that the enzyme was driven by a rotary mechanical mechanism which was something really quite new

19:01:07 The issue with Mitchell was how was the proton motive force linked to the generation of ATP, a chemical synthesis; Mitchell's view was that the protons went across the inner membrane of the mitochondrion and they participated directly in the catalytic site of the enzyme in phosphorus chemistry to produce ATP; this he called direct or chemical coupling; another chemist at Oxford, R.J.P. Williams, had similar views; the catalytic site is a long way from the membranes so you have to transport protons through a proton wire which seemed pretty unlikely to me; the alternative view was called indirect coupling but Mitchell was against this idea right up to his death; it turned out that it was indirectly mechanically coupled and that was a new concept in enzymology, of rotary action produced by consumption of electrical energy, the proton motive force being used to generate directation, rather like water flowing through a dynamo generates electricity; it now turns out that this rotary principle is quite widely dispersed which hadn't been realized; it has been pretty fulfilling to see that happen; the motif comes back to when we were determining a lot of protein sequences and we knew that some of the proteins bound ATP and we wondered whether we could work out in this 500 amino acids which bits were involved; we started comparing sequences that we determined with enzymes that were known to bind ATP; we found some similarities; at that stage the mathematical methods for doing this sort of calculation were not very well developed; the best method was devised by Andrew McLaughlin and we used it to do this; today people would not find what we found at all surprising but then there was extreme scepticism that what we had found was of any significance; eventually we published a paper and it turned out that we were correct; found it had highly predictive properties and if one finds these motifs one can be pretty sure they have something to do with binding a purine nucleotide which is very important in biochemistry; there were two motifs A and B and people now call them Walker A and Walker B motif

24:02:12 John Meurig Thomas; have never really been tempted to leave as the environment at the Laboratory of Molecular Biology is so stimulating; one of the great attractions was having the long term support that one justified by a five-yearly review; one didn't need to spend a lot of time writing grant applications; although I have enjoyed the little teaching that I have done it did mean one was free from any teaching responsibilities; as full-time researchers we are different from a University department; I have lectured; impressed that Brenner and Perutz both lectured undergraduates so decided I would do so on bioenergetics for Part II biochemistry; it was part of the curriculum and has evolved into an option given by several of my colleagues at the Dunn of which I give two of twelve lectures; enjoy contact with students; have had a lot of Ph.D. students and at the Dunn we have fifty Ph.D. students; I take a lot of care over them as much research is actually done by them and we depend upon them

28:09:13 Had taught at Sidney Sussex for a friend, Peter Henderson, when he was away; having worked for fifteen years in a research institute felt I would like to relearn the subject which I found extremely valuable; Gabriel Horn invited me to become a Fellow after the announcement of my Nobel Prize; I knew that it was something missing from my life having experienced college life at Oxford and realizing that I was spending most of my life just with other scientists and having very little contact with people from other disciplines; I enjoy this contact and the collegiate nature of Sidney Sussex is extremely pleasant; music still means a lot to me; still enjoy singing in church, listening to classical music and opera; encouraged to follow George Radda's example and ask to be taken to the opera rather than taking a fee when I lecture in Italy; as an undergraduate was interested in folk music and did Morris Dancing; wife also keen on traditional jazz which I also like; on politics, belonged to the Labour club as an undergraduate but had always felt too busy for formal commitments but tend more to left than right; in favour of broadening access to Oxford and Cambridge; had an early association with the church but like most people who become interested in science there is a conflict between the Christianity you were brought up with and the logic of science; I tried to protect my position as a believing Christian as an undergraduate and ultimately decided they were incompatible, so lost my religion; however, I still enjoy going to Chapel and taking part in the service, though not participating properly, but participating in a ritual that is part of me but which I cannot resolve; now decided that I don't want to resolve it; I do get some spiritual satisfaction in a way that I can't fully explain, so don't apologise for going to Chapel in Sidney where we now have very fine music; I read novels and also biographies of scientists; interested in the history of science and history in general; still very much imbued with something that comes from my mother, that you should be improving yourself all the time; want to learn about things I didn't know so learning Italian at the moment to improve my ability to listen to Italian opera; my intention is not to retire as long as I am physically able, in something that is close to laboratory science; in the past ten years I have had to assume an administrative role and I have enjoyed building up the Dunn and getting people there and bringing along younger people; I am interested in continuing my own research which I have managed to keep going during this period; feel I am still reasonably productive and there is more in me yet

40:28:14 Difficult time to start out in science as so many other careers appear attractive so many of the best minds don't come in to science for financial reasons; for somebody who is committed if you are going to be successful in research it is very important to find a topic to work on; exactly how you do that is much more difficult than it was twenty years ago because fields of science, at least the ones I work in, are much more heavily occupied, so finding a niche is difficult; thinking carefully in the area in which you work and then committing yourself to that area is important; I would want to work on some aspect of neurobiology today; there are so many unknowns there that I think you really could find a niche and make important contributions