Tim Hunt Interview - part two

Second part 28th July 2015

0:05:06 I went to Cambridge to get away from home, though it was not a decision that I made but my parents made for me, and also because, as was well known, Cambridge was the place to be a scientist; two of my uncles had been at Clare so there was a family connection; I did not get a scholarship; in those days one did serious exams over a number of days and I did botany, zoology and chemistry; frankly, I didn't know any botany at all and cared less; I wrote an essay on peat bogs based on an article I had read in New Scientist, but I suspect it looked a bit thin luckily they let me in to read natural sciences; I had always wanted to be a biochemist because that was the thing in those days that we all wanted to be; because my maths was so feeble I did have a bit of a problem so I could really only do organic chemistry because physical chemistry would have taxed my maths and physics too much; I did a mixture of invertebrate zoology which in those days was a wonderful course because it was actually comparative invertebrate physiology, and the Professor, Carl Pantin, that's what he did; it was terrific; every week we had a new phylum to examine some part of it; I also did proper physiology which in those days was very good, and stupidly swept away, the medics and the scientists all took the same course; that was terrific because there was a lot of information flow in both directions; so the combination of invertebrate comparative physiology and proper human physiology; the latter was a great course and they used to bring in people who were suffering from Huntington's chorea to show us what it look like; I am sure that couldn't happen nowadays, and I shan't go into the ghastly things that were done to animals in the name of teaching; we did a lot of experiments on ourselves; people were rebreathing their own air over sodium hydroxide so the CO2 was absorbed out of their exhalation; they gradually ran out of oxygen and then they passed out; they were asked to do little mental arithmetic tasks so that the supervisor, the demonstrator, could terminate the experiment before they actually died; things like that you never forget; you would take a beating heart out of a rabbit and perfuse it with Ringer's solution and the heart would go on beating; then you would take the calcium out of the solution and the heart stopped beating, and you added calcium back and the heart started beating again; it was fantastic; the zoology course similarly; there was a man called Frank Hollick who taught Jonathan Miller philosophy, and it was all about believing the evidence of your senses and how easy it was to fool yourself; there were lots of wonderful demonstrations, and we went out and about and looked at things, thought about things; it wasn't just science, there was a strong strand of philosophical underpinning for all of this stuff; but we wanted to be molecular biologists, or, as you said in those days, biochemists, so we did organic chemistry and biochemistry; I also took experimental psychology and that was interesting because it told me I didn't want to be an experimental psychologist; Professor Zangwill was the Professor and there was a woman [Alice Heim] who taught us about intelligence; in retrospect it was a marvellous education; the other thing we didn't realize at the time was that we were a hand-picked bunch of the nations future leading scientists; it didn't feel like that at all; I remember vividly at the end of my first year being absolutely convinced I was going to fail because I knew how little I knew or understood; when it turned out that I had actually got a first I thought it was some sort of cruel trick; when I looked at the breakdown of the marks what I found was that I had scored very highly on all the practical things and not so much in the theory; I think I have always been good with my hands and not so brilliant at writing essays; Colin Reese was my organic chemistry teacher; he had a very bare room and I always thought that he tuned his voice to the resonant frequency of that room; Asher Korner, who sadly died very young, taught me biochemistry; he was wonderful and everybody loved him; I loved him because once I had gone into a supervision with a ghastly cold and he handed me a full glass of whisky; he was open and enthusiastic, a thoroughly nice man; my physiology supervisor was Nevill Willmer; we quickly learned that only one person need ever write an essay because he was very old-fashioned; he had grown up in Oxford and the rule there was that somebody had to read their essay out loud and he would make comments; he would never ask for essays to be handed in or look at them; that saved a bit of work; Willmer had a very beautiful wife and two beautiful daughters, but they weren't particularly bright; when I was a Junior Research Fellow later on, we were discussing the admission of women to Clare College and all the youngsters wanted women and all the oldsters thought it was better to leave things as they were; Willmer got up in one of these governing body meetings and said that as a physiologist he could assure us that female sex hormones totally unsuited women to any form of higher education, whereupon everybody fell about laughing; he couldn't have made a more potent argument for the admission of women

10:47:24 In those days, 1961-62, there were no girls to speak of; we used to sit around on Saturday evenings drinking bottles of Beaujolais, which then cost 7/6d and came from Dolamore’s, a nice wine merchant in Petty Cury, and worrying about the lack of women; there were one or two, my friend Brigid Hogan, for example, but they were the exception rather than the rule, these Newnhamites, and quite unattainable and inaccessible; but I sang in CUMS which I scraped into; Friday evening was rehearsal night and I was very faithful in my attendance; we sang in King's Chapel and at Snape Maltings, conducted by Imogen Holst; my friends and I were very interested in science and society though I am not quite sure what we thought we meant; I never belonged to the Labour Club though others did; I was just a nerdy scientist, and it was very hard work keeping up with the courses and a very exciting time to be learning this science; I eventually ended up doing biochemisty because it combined biology and chemistry, both of which I was good at; it was a wonderful time as the structure of DNA had been worked out some time before but the principles of messenger RNA were discovered in my first or second undergraduate year; so suddenly everything was becoming clear, how it worked, and we were being taught by the people who were making this revolution; that was the extraordinary thing; we had many lectures from Nobel Laureates, and you went to seminars and Francis Crick would ask questions and so on; this was an enormous privilege; I often say nowadays that I was really born with a scientific silver spoon in my mouth because you couldn't have had a more exciting and wonderful environment in which to grow up; we all knew that we wanted to do research, that was the thing in those days as it was clear that the highest calling was to be a researcher; we worried about whether we were good enough and whether we had the necessary commitment to hard work, but we also had the confidence that money would come for it; I don't know where that confidence came from because growing up had been quite hard; food was rationed and we did not live luxurious lives, but maybe that was a good training too because you realized that you didn't need tons of money to live; I signed up as a graduate student and got a studentship which paid the bills, and my parents very kindly gave me a living allowance that made life supportable; I got firsts in my first two years but like to say I got glandular fever at the end, anyway I scraped by; that is rather my feeling, I am very conscious of my own limitations

16:29:01 I did know Dan Brown but that was later on; he was an extraordinarily nice man; actually he was the one who really worked out the structure of DNA because you had to know the chemical structure before you knew what...as Lord Todd said, Crick and Watson merely discovered the configuration of the two strands; it was Dan Brown who actually worked out how the atoms were hooked up together; Sidney Brenner used to give these amazing lectures; the biochemists were forbidden from hearing Sidney; the lectures took place in the Biochemistry Department but we were told by the Professor not to go to them on the grounds that our brains were already so full of facts one more would probably burst them; the geneticists all went and we snuck in, making sure that the Professor wasn't there to see us; they were amazing; he would ask what he should talk about and then do so on whatever took his fancy; he would just talk for an hour beautifully on whatever it was, all the facts at his fingertips, an extraordinary tour de force; he was the cleverest person, but also a cruel person; he used to hold court in weekly seminars in his room in the Gibbs Building, and various graduates or post-docs would come along and talk about what they were doing, and we sat at their feet; one time there was a man called Bob Round who was working on recombination; my friend Brigid Hogan at the end asked whether he had tried the effects of ethidium bromide on his system because she had a friend who was working on ethidium bromide (this is a compound which intercalates between the bases of DNA and sort of stretches the molecule and does funny things to it), and Sidney rounded on her and said, "No, and we haven't tried Coca Cola either", whereupon Brigid burst into tears; he was very scary and gratuitously cruel

19:25:23 The subject of my Ph.D research is interesting; how do you find a problem in science? I went to Asher who was now my Ph.D supervisor; he had a lab with lots of people and he took about three students a year; they were doing all kinds of things and in retrospect is was absolutely crazy; I asked him what I should work on and he told me to go to the library and find myself a problem; I went to the library and found a very good problem which as far as I know hasn't been solved to this day; the trouble was you had to make rats nephrotic that means that you mashed up some rats kidneys and injected them in rats; they made auto-immune antibodies which destroyed their glomerular membrane so they peed out serum albumin, the holes in the filter got so big that the albumin went out, and that stimulated albumin synthesis in the liver; I thought that would be an interesting thing to try and find out how albumin synthesis was controlled by albumin, god knows whether it really is or not; I didn't read the materials and methods carefully enough and so my rats did not become nephrotic, and try as I might they never showed any signs of protein in their urine; which was good because I discovered that I hated killing rats; then I got interested in ethionine, and then a wonderful thing happened; we went to my first scientific conference about the synthesis of haemoglobin; the keynote lecture was given by Henry Borsook who was a professor at CALTECH; he had discovered a couple of things, one is that when sea urchin eggs are fertilized they activate protein synthesis and I was interested in the control of protein synthesis; the other thing he had discovered was that haemoglobin synthesis requires iron; that is hardly surprising because haemoglobin contains iron, that is why it is bright red, the colour of the haem it contains; but what he discovered was that the haem is chemically completely different from protein and is made in a quite different way, and actually the synthesis of the protein and the synthesis of the prosthetic group are coordinated, and that's what he had really discovered; that was interesting, and nobody knew how that worked at all; then there was another talk by Vernon Ingram who was the man who had solved the conundrum of sickle cell anaemia, he discovered that sickle cell haemoglobin was actually chemically different from wild type haemoglobin and that was why it tended to precipitate when it was deoxygenated; he had made some measurements which suggested that the reason why there was a coordination between haem synthesis and globin synthesis was the question when does haem actually get put into the protein that is going to hold it; his hypothesis was as proteins are made starting at one end and finishing at another end, always in the same direction, at some point you had made the pocket where the haem was going to fit; if there was haem there it would go in and you would finish off making the protein; if the haem wasn't there the ribosomes would stop on the messenger RNA and wait for the haem to arrive, so a queue would form; we thought how interesting, why do the ribosomes know how to form this queue? we went back to the lab and we realized that he had completely misinterpreted his own data; this is where I can't reconstruct what happened but basically what we did was to say this was so interesting that we should take a look ourselves; who can the "we" have been? I was lucky to have a lab mate who was American called Lou Reichardt, a famous mountaineer; I climbed Snowdon with him but he later climbed Mount Everest without oxygen; Lou knew how to make rabbit reticulocytes; he had learnt this at Harvard and he had come just for the year; so it must have been Lou and me and maybe somebody else in the lab, but I can't remember how it happened; we decided we would just do the experiment and worked out that we actually had a better way of doing it than Ingram; what we showed was that Ingram had not only misinterpreted his data, but his data were not right anyway; I started studying haemoglobin synthesis and eventually ended up working on this problem of how the haem and the globin synthesis were coordinated; one day we went to the pub, the Eagle, and stayed too long - at the time I and my friend, Rupert Sheldrake, lived on the minstrels' gallery there, it was very convenient, close to the centre of town, and cheap; I could never understand why we couldn't do much work in the afternoon after lunch, but we always had half a pint of beer and sometimes a pint; we used to stay up terribly late and get in about coffee time; after coffee and chat it was lunchtime, then you couldn't do anything until after dinner - but on this particular occasion I had some centrifuge running and we were rather late getting back to the labs; I should have canned the whole experiment, but, being lazy, I analysed the experiment anyway; as a result of things running too far I discovered that alpha chains are made on much smaller polysomes than beta chains, and nobody knew that; that was my first Nature paper; in those days it was very easy to publish there as nobody knew anything, and this was really rather interesting; we confirmed it and eventually came up with the wrong explanation as to why it was, and that also taught me a great lesson; we had failed to do a very obvious control experiment and one of the things I learnt then was to always do all the controls; then we analysed and found we could artificially make queues, we knew our methods could detect queues, and when you removed the haem there was no queue; another accident happened in the middle of all this; my second conference was in Thessaloniki and it was something like the World Conference on Molecular Haematology; I went with a friend via Italy; we stayed at the British School in Rome by blagging our way in somehow; we tried to stay at the British School in Athens but failed, then made my way to Thessaloniki; there I ran into an American called Irving London; when it came to the official lunch I was cruelly rebuffed because I hadn't actually registered or paid the conference fee; I went to a local taverna and when I came out, ran into Irving with whom I had already had an interesting conversation because he was interested in exactly the same problem, how haem and globin synthesis were coordinated; he was probably the only other person in the world who was really interested in this; he asked me what I was going to do after finishing my Ph.D; I asked whether I could come and work in his lab in the summer, and by the time I had got back to England by slow train there was an airline ticket waiting to go to his lab in New York; I went and spent the summer there and discovered I really liked America; in those days there was lots of money around and the Vietnam War wasn't yet up to speed, research was booming and I very much enjoyed the collaborative aspects of that; we did actually find out anything important there but liked it; I went back there when I had finished my Ph.D, by which time, 1968, the whole world was in revolt; it got very interesting and hadn't really happened before or since; I became a published photographer not so long ago because we were at the Grosvenor Square demonstration, and I happened to spot Mick Jagger and took a photograph; I then went to America and Nixon was invading Cambodia and it was very peculiar; I had very long hair and I lived on the Upper West Side and had to commute on the Seventh Avenue IRT to the lab in the Bronx, through some of the most high-crime neighbourhoods; you had to look pretty shabby otherwise you risked being mugged; the people in the lab gave me a fairly hard time because of my hair; I did finally get mugged but that was towards the end of my stay there; it was a peculiar time because we would fly down to Washington for demonstrations and one time I got tear-gassed in the Mall; we had to take refuge in the Hilton Hotel which had some air conditioning which cleared the tear gas; people spat at you in the street if you looked a bit hippyish; we used to have fantastic conversations round the lunch table about politics; in those days I was regarded as a subversive lefty which I am certainly not now; at Clare it didn't really matter; when I came back I had a girlfriend; we got married and tried to live in Clare which was against the statutes; they sent the Chaplain to try and get us out, but they found us a very nice place to live, though I hardly deserved it

33:18:10 I completed my Ph.D and had a pretty decent publication record, two very solid articles and the Nature letter; I collaborated with another long-term friend of mine, Tony Hunter, a very distinguished molecular biologist who eventually ended up in California; we collaborated on my Ph.D and I couldn't have done it by myself; it was a real education, we worked out how to do it for ourselves, built a lot of the apparatus; sometimes I thought it would have been good to have some training; my supervisor, Asher, actually left to be Professor at Sussex University after a year or two; his place was taken by a very old friend of mine called Alan Munro who later became the Master of Christ's and set up a biotech company in Cambridge; I got a Junior Research Fellowship just before I graduated; it was a bit tricky because my friend Rupert was much cleverer than me and a more obvious candidate; Asher had left so they needed a biochemist to teach biochemistry; there were two of us, and Rupert got a fellowship at Clare; I had had to compete in the regular manner by submitting a thesis; I was a research fellow for ages; I started my post-doc in America July 1968 and it ended in December 1970, so it wasn't all that long; I didn't really achieve very much except that I'd found out some things that turned out to be very important later on; so I came back with only a college research fellowship to support me; no one was going to offer me a job on the basis of what I had done; in retrospect that was the best thing that could have happened; I had a friend who had also been a member of Asher's lab and he had just got a demonstratorship, so I had a foot in the lab, and could just join that lab; so we had a kind of loose, federated lab; Tony Hunter was there, Richard [Jackson] and Tony had done a nice piece of work which had attracted attention and I was a bit jealous of that as they had done such a nice job; then Tony went off to America and I stayed on - there were two graduate students, a technician and two senior people; I had no responsibilities and could just do whatever I liked; the lab was on Tennis Court Road; then by an amazing stroke of good fortune, in 1974 the lab burnt down; it was probably me that did it as I had been doing some ether extractions and had gone home early on a Friday afternoon, possibly leaving some ether residues; sometime on Friday night something ignited the lab and it was utterly destroyed; it was extraordinarily lucky because the graduate students we had at the time had just graduated, so we had lost no Ph.Ds or anything; we lost all the data that we had, but at that point we were terribly confused and had no idea what was going on; they found us a new lab which was a teaching lab at the hospital site at New Addenbrookes, opposite the famous molecular biology lab; Max Perutz very kindly said that we could use his stores and also have lunch in his canteen; so I got to know people in the LMB very well; I mostly hung out with people in the John Gurdon group, but there were other visitors there; occasionally Max Perutz would come and sit at the table, or Francis Crick, and explain things; again, an absolutely amazing privilege; Aaron Klug had a graduate student I was very pally with, and Aaron was friendly and helpful; we did some experiments on tobacco mosaic virus just because they were there, really; people were working on its structure so they grew immense amounts of this virus, and you could see it as a cloudy solution; it turned out that you could take the RNA out of the virus and that was a wonderful messenger RNA and became our test; we knew from genetic evidence that this RNA encoded the coat protein but we couldn't detect the protein being made from it; we now know that it makes the preliminaries but not the coat protein even though the coat protein genes are there; the ribosomes can't get down that far on the messenger RNA; we knew that when this virus was infecting the tobacco plant it made tons and tons of coat protein so there must be messenger RNA for the coat protein; what we did was to get some infected tobacco leaves, freeze them in liquid nitrogen, mash them up and extract the RNA; sure enough then there was the messenger RNA and the messenger RNA for the coat protein was a little bit chopped off the end of the main piece of RNA; so that was a Nature paper, quite important I suppose; just because it was there it was easy to do the experiments and we had the wherewithal to do it; at lot of people at that time compared ourselves to Francis Crick and Fred Sanger who were godlike scientific figures for us; I would never had considered myself in the same breath as them, and I suspect that most of my contemporaries wouldn't either; but the fact of the matter is that an awful lot of that generation won Nobel Prizes; I think that we had these role models, we talked to them at lunch and we saw how they operated; we saw that it was just a matter of putting one foot in front of another, making sure that the back foot was firmly planted until you put the next one down; we chatted among ourselves trying to find out how the nematode developed, or I was trying to find out how protein synthesis was controlled and stuff like that; you just thought hard about it and did an experiment, and one experiment led to another; it was hard but it was basically straightforward and simple, and the trick was to see very clearly what you were trying to do; Fred Sanger was very ordinary; if you met him you would have thought he was the gardener, janitor, something like that; frankly, he was a poor lecturer; I once had the amazing privilege of hearing his technician explain how they had come to sequence DNA, and it was extraordinary because they knew about this enzyme because they had used it here, and the properties there, and they knew about that; Fred always had his eye on sequencing DNA and at the time people said it would be impossible because they knew how Fred had sequenced proteins, and that method was totally inappropriate for DNA; but Fred figured out how to do it, he was passionate, he knew what he wanted to get at and he could see how these methods would work; he had tremendous intelligence both in his fingertips and brain, he was an analytical chemist; he was the most impressive of all that lot; Sidney was very clever and flashy, Francis had an amazing grasp of everything and was really our hero and we wanted to be like him, but Fred was the real hero because he just got on and did it; my wife sat next to him in the plane going out to Stockholm and she introduced herself; he told her that it was so hard and he was so glad when he could finally retire; I don't know quite what he meant by that and what was so hard about it, but it probably was; we were all astounded when he reached his 65th birthday, the day before he was working in the lab and the day after he was nowhere to be seen; he just stopped coming in and tidied everything up; when he won his second Nobel Prize they had a champagne party and Fred was asked to say a few words; he said that “people think I am a very modest man, but actually I think I'm bloody good”; he was; he was kind to me and made sure I got a fellowship, but just quietly doing the right thing in the background

46:57:09 Partly as a result of being taken away from down-town biochemistry we solved an important problem; we discovered there was a protein kinase which inhibited protein synthesis; kinases was turned on by the absence of haem and another couple of conditions that I discovered while I was a post-doc; I think my talent, such as it is, is spotting funny things that don't quite make sense, things that were rather trivial but actually important; I think as a scientist I have always felt that you are often really baffled, you don't know what's going on, and you just have to keep chipping away, you never know where the real breakthrough is going to come; sometimes it is an experiment, sometimes you might read a random sentence in a paper or even a book; once you see it its very easy to confirm or refute it; in my experience things always look very complicated before they get simple; you know when you have got the right answer because only that answer could explain the previous tangled mess of conflicting data; that is immensely satisfying, when everything falls into place just because of one tiny little observation that explains everything; in 1976 we had another lucky break; we were rather pleased with ourselves at having solved the problem and how haem and globin synthesis were coordinated and we had to move back down-town; once you have solved a problem you don't have a problem any more and I think the big problem with being a scientist is getting a good problem to work on; it is much more difficult than people would think because it is easy to think of problems like how does the brain work, but that is a very bad problem because it is too big and you don't know how to break it down into its component parts; you need to find something that is solvable in a reasonable time, doable, and the results will be interesting and important for yourself and others; having solved our problem we decided to make an EMBO conference about it and among the people I invited was somebody who worked on how protein synthesis was activated in the fertilized sea urchin egg; now there are no sea urchins in Cambridge so I invited somebody who worked in Hawaii to come and give us a talk; it turned out that he was a very keen cyclist and he wanted to go for a ride when he hit Cambridge; in those days you couldn't rent bikes here so I lent him mine, and we became friends; unbeknownst to me he was the organizer of a course in Woods Hole and he asked if I would like to come and teach in the embryology course there in the following year; I leapt at the chance because it meant I could work on sea urchins with him and maybe investigate this problem of how protein synthesis turned on when the sea urchin eggs were fertilized; I had been to Woods Hole because Irving London my post-doc mentor had a house there and had actually spent a weekend and had got stuck in Woods Hole with Alex Rich; we had been trying to go against the tide although there was a stiff breeze blowing, and we had to be towed off by a Boston whaler in the end; so I went to Woods Hole and tried to work on this problem; it turned out that the equipment there was useless for purpose, but I did learn quite a lot because one of the other teachers was a guy called Stan Cohen who had discovered epidermal growth factor and was later to win a Nobel Prize for this, and I think I may have helped to get him out of a rut; he and I got on very well; we played tennis together; he had been a polio victim and was about ten years older, but we were very evenly matched; he was in a low point in his life; his wife had left him, his boy was on drugs, and he had got stuck; he was looking for the EGF receptor and the one phylum he hadn't been able to get was a crocodile; it turned out that the local pet shop had a small one and Stan got hold of it; but then the pet shop owner got cold feet because it was an endangered species and Federal Marshalls showed up to repossess it from the lab before he had had a chance to whip its liver out to look for the receptor; Stan's lectures were just wonderful, the way that he got at EGF; he assayed for this little growth factor by injecting preparations that might or might not contain the factor into baby mice; if the fractions contained EGF then their teeth erupted or eyes opened a day earlier; so he was assaying column fractions which normally did some biochemical reactions by looking at baby mice's teeth coming out or eyes opening prematurely; I was absolutely captivated by the idea that it didn't matter what the assay was as long as it was reliable and reproducible; baby mice's eyes were just as good as a spectrophotometer; we spent a lot of time following a man who sang slow Elvis songs, would go dancing and ate a lot of pizza late at night; it was very enjoyable but not much science got done; I swore I would never go back there ever again, and we didn't make any progress with the sea urchin synthesis because they didn't have enough freezers, gel tanks or anything; the following summer I really missed it because it was a lovely place to be and intellectually very exciting; everybody came and gave talks about what they were doing and unlike most American labs, which are really rather competitive and apt to be closed, in the relaxed circumstances of Woods Hole people were really rather open about what they were doing and thinking, and we would cross-question them after they had given their lectures; so in 1979 I went back there again, and thereafter every summer until 1985, teaching or researching, usually a bit of both; in 1979 I heard a wonderful lecture by John Gerhart about this magic stuff MPF - maturation promoting factor - which made frog eggs mature; John laid it out absolutely beautifully and I thought what an interesting problem; here again is an enzyme which has these dramatic effects on the cell cycle; what was this stuff and how did it work? I began to think about that, and that same summer I collaborated with a graduate student [Eric Rosenthal] who I liked very much who was working with a woman called Joan Ruderman; they were following up an observation that somebody had made a couple of summers before about patterns of protein synthesis in clam eggs; we discovered that there was translational control going on which means that the messenger RNA is present already in the clam eggs but is not being translated, and when the clam eggs are fertilized these messenger RNA are recruited onto ribosomes and start being translated and make these proteins; that was a good example and this was published in Cell; that was very satisfying because at the time it was very confused, was there such a thing as translational control and this made it absolutely clear that there was; we didn't know how it worked; I couldn't work on it because if was Eric's problem, so I was stuck with these wretched sea urchins which didn't yield up their secrets nearly so easily; then we began to wonder why these clams start making these proteins after they are fertilized; that set wheels whirring at the back of my mind but in a very incoherent kind of way; it wasn't until the summer of 1982, by which time I had read a book by Jacques Loeb 'Artificial Parthenogenesis in Fertilization', a late nineteenth early twentieth century Rockefeller researcher; for some reason I read a much more modern paper that said that parthenogenetically activated eggs were somehow different from actually fertilized eggs; I had had a very religious upbringing so the idea of doing some molecular experiments on virgin birth was sort of appealing to me; I decided to investigate the patterns of protein synthesis in parthenogenetically activated eggs versus properly fertilized eggs; it was a very simple experiment and by that time I really knew how to handle the eggs and do the experiment; when I looked at the result I noticed that one of the most abundant proteins that was newly synthesised early on disappeared about the same time that the eggs divided for the first time; that was remarkable because proteins couldn't disappear like that, just one protein goes away and all the rest accumulate as you would expect; that evening, Friday night, was lecture night after which there was a wine and cheese party, and who should I run into but John Gerhart, the man who had given the beautiful lecture on MPF three years before; I told him about this amazing disappearing protein and he told me an electrifying fact that he and his colleagues had found out which was that for MPF to come back the second time it needed new protein synthesis; that was two and two equals four as far as I was concerned because I had seen this disappearing protein; of course, to make it afresh you just have to make it afresh, so it immediately said that there was a connection between the disappearance of this protein and the thing that catalysed cell division; now I think most people would have said this is ridiculous, how can you be so sure, but to me it was another of those cases where suddenly...nobody had even remotely suggested that proteins might disappear and then come back because it would have been impossible, but I had seen it with my own eyes actually happen, there was no doubt about it; I wrote a letter home to my friend Richard who had been the long-term collaborator saying that I thought I had made an important discovery, I just felt it in my bones; but it wasn't entirely clear what to do about it, lots of questions come to mind, and trying to figure out the relationship between this protein and the magic MPF which catalysed cell division; it seemed too good to hope for that there was a really direct connection; I gave it a name, cyclin, for two reasons; one that it described these cyclical appearances and disappearances, and two I was a rather keen cyclist; it turns out that if you discover a protein you can call it anything you like; that caused a bit of a problem as somebody else called another protein cyclin which was completely different; fortunately for me the other cyclin went away because somebody had called it something else before; later on that summer a very strange thing happened; we wanted to know whether this thing happened in just sea urchin eggs after they were fertilized so we had a look at clam eggs which my friend Eric Rosenthal had been working on; to our amazement we discovered that two of the proteins which we had previously described as translationally regulated proteins, and the proteins that Eric had been working on all this time for his Ph.D from 1979 to 1982 were in fact cyclins; this is quite important because they hadn't noticed that they went away because they hadn't done this very simple experiment of just taking samples; Eric had noticed that sometimes the amount of these proteins was a bit variable but he hadn't thought to investigate the reason; the reason for the variability was that sometimes they were at the peak of their synthesis and sometimes they had gone away and were just coming back again; that was an important result, so clams had two of these things - sea urchins do too, but in clams it is much stronger; it turns out that clams are an awful long way evolutionarily from sea urchins - sea urchins are more closely related to humans that they are to clams; that meant that this behaviour was pretty universal, but we didn't know that it happened in humans or frogs; we did some simple experiments of when it came and went and what factors determined that but we couldn't figure out the consequence of it not going away, for example, because we didn't know how it went away; clearly what had to be done was to clone and sequence the wretched thing and the techniques for doing that were just coming in; I had never done it and in retrospect we could have done it much more efficiently if I had gone on a course; I hired a graduate student, Jon Pines, who was going to do this and we taught ourselves cloning sequencing and stuff; we also invented methods for studying the thing; there was just me and two graduate students; I decided to stop doing what I had been doing because it was clear to me that this was much more important and interesting; it was scary because here I was in a completely different field about which I knew nothing, having been the world's expert on the control of protein synthesis; I knew that the only reason why I was the world's expert was that I had made every single dumb mistake and learnt from it over the years, so I knew there were more idiotic mistakes to make in the new field but fortunately not many people worked in the new field; although you might have said that the control of cell division was one of the most important things to study in the whole of biology, nobody could see how to study it; the only people who knew something about it were yeast geneticists; I think people probably felt that the way yeast cells divided was not going to be the same way that human cells divided, because yeast cells were regard as rather primitive at the time, and different; Paul Nurse, for example, worked in this field and so he and I became pals, and there was a period whenever I was passing through London I would go and see Paul to have a chat; it was just me and the two graduates working in Cambridge on the problem, Marc Kirschner in UCSF, John Gerhard in the background who knew about MPF but wasn't really working on it any more; you could easily fit all the world's experts into this room; luckily for me I published the paper though one reviewer said it was wild speculation based on faulty logic; the Editor said that they would however publish it but not in the current form; even the finished paper is not one that I am terribly proud of, but it announced the behaviour of this protein and that it looked as though it had something to do with the control of cell division but needed more work; from 1983 to 1988 the three of us worked in the lab, working out the methods; I also started working with Joan and her lab in the summers, just wanting to find out what was going on in clams; we had no idea how it worked or what it was, and even the sequences of it were not very informative when we finally started getting them because there was nothing like it in the data base; the DNA sequences were not informative; we were very slow to figure out what was going on; the whole thing started to unravel and come out because Paul Nurse's protein which was called cdc2 turned out to be a partner of cyclin; Paul's protein is completely dead and inactive until my protein comes and opens it up and activates it; but we didn't know that and didn't even suspect it; I remember walking round a field in Bath with Paul; he said that he knew the sequence of cdc2 made it look like a protein kinase but they had tested it was it wasn't; I knew about protein kinases because I had discovered them in controlling protein synthesis; it had never crossed my mind that a protein kinase might need to be turned on by something, because the only example we had was a protein kinase being turned off by something; it is amazing how your preconceived notions blind you to the blindingly obvious; I wouldn't have said that any of us were particularly stupid people; some that I worked with like Marc Kirschner, Andrew Murray, were really smart people, and none of us saw it; the whole thing could have been solved much more quickly if we had really been unprejudiced and thinking straight, and examined all the possibilities instead of the ones we were prejudiced to; in the miraculous summer of 1988 the whole thing suddenly tumbled out and the truth emerged, and I can't reconstruct who had the idea first; there were a lot of people; Nurse had an ex-collaborator called David Beach who was very active in the field; my erstwhile collaborator Joan Ruderman had antibodies against the thing, and she might have; I asked my two students afterwards and I don't think they understood quite what they were doing; eventually we really nailed the whole thing; I had a student in Clare called Andrew Murray, one of the brightest and most original students I ever saw as an undergraduate; he is now a Harvard professor but then he was working with Marc Kirschner in UCSF; he asked if he could have the cyclin clone and he did a really beautiful experiment; somebody else had worked out a cell-free system that catalysed cell division; there is actually nothing to divide but you can tell where you are in the cycle by various surrogate markers; it turned out that for this system to enter mitosis and go out the other side and then reenter mitosis needed ongoing protein synthesis; what Andrew did was to destroy all the messenger RNA in the system and then add cyclin messenger RNA, so the only protein being made in this frog egg extract was cyclin, actually from a sea urchin; what happened was that the cyclin went up, the extract entered mitosis; if you didn't add the cyclin messenger RNA it never went anywhere; Andrew also found out that if you lopped off the front end of the molecule then what happened was that the cyclin became indestructible and just went on accumulating, then the extract entered mitosis and couldn't get out; his experiment showed very clearly and beautifully that actually what was happening was that cyclin synthesis drove you into mitosis, and cyclin destruction allowed you out the other side, then it came back again and you went into the next cell division and out again; this was a wonderful experiment that absolutely convinced everybody; then it turned out that cyclin combined with cdc2 making a very tight bond so that once they get together they cannot come apart; that is how it all worked; so from knowing absolutely nothing about MPF was, or how the cell cycle was catalysed we suddenly knew, and everything became incredibly simple as so very often happens in biology; that is why it was a Nobel Prize; I made absolutely no contribution to how the thing was degraded, but somebody in Marc Kirschner's lab worked that out; it is such a good invention that it is used again and again in biology but nobody had noticed it; between 1982 when I first saw this thing - July 22nd, it's labelled on the gel - and sometime in the summer of 1988, we had almost no competition whatsoever; so we had all the time and space in the world to do things properly; then once the doors had been opened everybody piled in, and there was an enormous stampede and it became very difficult to work in this field; it has taken a long time for that to go away; I have discovered that there are two really good places to be in science; one is to be an unbelievable pioneer, to be miles ahead of the field, where everyone thinks you are crazy and stupid to be working on it; that is great because it allows one to do things properly, or wait until the stampeding armies have passed by; then you go over the field which has been thoroughly churned up, and mistakes have been made left, right and centre, and you can make a very good living then, and often find nourishing scraps for the seeds of whole new projects; right at the end of my career I came across something, again completely by chance; protein kinases stick phosphates on and that alters the properties of the proteins, but protein phosphatases have to take the phosphates off again; it is a cyclical thing; in mitosis lots of proteins get phosphorylated, when mitosis is over they all have to get dephosphorylated to restore the status quo; trying to have the kinases and the phosphatases working at the same time which is like trying to fill a bath but forgetting to put the plug in; I always thought that there had to be some control over the plug hole, as it were; it turns out that that is true and you can't have two things fighting like that; if this one is dominant the other has to be turned off vice versa, and that is actually how it works; I didn't discover that until right at the very end after a long period from about 1990 to 2005 when things did not go at all well; in fact I jolly nearly got fired from the lab because I was so useless

1:22:03:10 I didn't mention this but one of the things I should have said was that when I started out in research was the people who were the most inspiring were Jacob and Monod, and there were some others like André Lwoff; they worked on transcriptional control and that was clearly the thing to work on at that time; I never wanted to work on that because it was way too competitive and difficult, and I knew I would not thrive in that environment; so I tried to find a place that I thought was interesting and liked, and was out of the way; you could make a good living and find out interesting stuff without having to compete with the big boys; so when suddenly the cell cycle became infested with all these big boys it was a very uncomfortable place, because you are looking over your shoulder all the time, and you can't work like that; the most exciting thing that happened during that period when we had got the first cyclin sea urchin clone, to go looking for it in frogs; it was terribly exciting when we found these same molecules in frogs, because once we knew they were in frogs then they had to be in humans; I sent Jon Pines who was the graduate student who first cloned sea urchin cyclin to go off to Tony Hunter, my old friend and colleague to get the human clones; it took him hardly any time at all because by that time he knew how to do things; if it is in frogs it has got to be in humans, but it was surprising how many wanted to see it; the significance of my work was to explain how cells divide, we like to call it the cell-cycle engine; cells must divide otherwise we wouldn't be here; you need lots of cells to make a multicellular organism; and they divide in two because DNA has two strands, and therefore when DNA is replicated it makes an exact copy; the question is what coordinates all that DNA synthesis with the actual act of cell division; how do you make sure that DNA replication is complete before you actually think about dividing because if you do it prematurely you will actually rip the DNA molecules apart; I think what people probably thought was that the control mechanism would be impossibly complicated and very difficult to figure out; in gents' lavatories there is an automatic flushing system, and the way that the system works is that there is a tap dripping steadily; every so often when the cistern fills up it suddenly all empties out; well it is exactly the same with cell division; this stuff just gradually accumulates and then the cell divides; nothing more complicated than that really; it is important to know that; people say you have cured cancer because you understand cell division, cancer is cell division gone out of control, but unfortunately I don't think that is really true; the analogy is with a car; if the car's engine doesn't start the car goes nowhere; but it is not enough for the engine to start, the driver has to know where they are going, and to know that you have to know what is going on in the driver's life; the engine is necessary but not sufficient to explain that; we know what happens if you inhibit the engine; that was very beautifully discovered and demonstrated in Hiroshima and Nagasaki; when you stand at the right distance from an atom bomb when it goes off, if you are lucky you will be close enough to be instantly vaporised; but at a certain distance you get a lethal dose of ionising radiation, all DNA synthesis stops in your body, all cell division stops, and you die an agonizing death after about a week, with your hair dropping out and skin peeling off; so it is no good just inhibiting cell division, you have to inhibit cell division in the cancer cells if you want to cure cancer; then the question is, what is the mind of the driver in terms of a cell, why to cells divide or not divide, decide to grow or not grow; that is a much more complicated question; cell division machinery is necessary for them to divide but what you really want to understand is... it is obvious, if you cut yourself the cells at the edge of the wound grow back and repair the cut; normally the cells in your arm don't divide, they just quietly replace the cells that are rubbing off all the time; how do they know they have been rubbed off, and how to they know at what rate to exactly make good? if you did an experiment, you would find you had a new nose something like every seven years; in my nose there is not a single molecule that is more than seven years old, yet it is the same nose, it hasn't grown longer or shrunk back, and it knows that it is a nose; one of the biggest problems in biology is how do you stay the same, how do you repair and maintain things; it is pretty miraculous, and still is a really important mystery; people are beginning to get at that; there are growth factors and inhibitors, and cells are talking to each other all the time, and react to a wound to make it good again; that is a whole different problem; what me and my mates helped to solve was just the engine problem, not where you drive the car to

1:31:06:06 What do you need to be a good scientist? I think the answer is that it takes all sorts actually, and there are lots of ways of succeeding; for me the important thing is to have fun; in those periods when things have been going well, and let me emphasise that is not the majority of the time, the number of really happy times in the lab have been quite small; most of the time you are scraping around thinking you will never either find out anything or solve a problem; people don't say this but I feel it very strongly; most of the time it is very foggy; you don't understand what is going on and this is a very uncomfortable feeling; I think it is important to have the confidence that actually there is a solution, and to have the self-confidence to think it might actually be you who will find it if you keep scraping around enough; I mentioned Stan Cohen who I liked very much; I went to see him after he became a Nobel Laureate before I was; he worked in Vanderbilt University and by this time he was in his seventies; I found him in a white lab coat in the cold room still doing something; I asked him what he was doing there as he didn't need to and he said, "Tim, it is pain and suffering, pain and suffering. I can't stand not knowing what the answer is. I putshky around and every ten years or so I find out something that makes it all worth while"; I thought that was spot on; it is the pain and suffering of not knowing that really drives you forward; it is a real obsession; you feel there is an answer, there must be and answer, and it is within grasp; that is the importance of having a good problem; I am sure that how the brain works is a tremendously important question, and in one sense we know that it is nerves connected to each other and fire off when they are stimulated, but we don't understand how we think thoughts or think logically; think of the nematode worm; all it does is wiggle away from noxious stimuli and towards food; nobody understands how the worm wiggles; its nervous system is completely worked out; Sidney Brenner and his colleagues worked out the wiring diagram of the worm, but nobody understands how it wiggles; if you can't understand that you are very unlikely to understand a human brain with its ten to the twelfth neurons works; there are so many different kinds of scientist; some people are very good at discovering things, others at cleaning up and working out things; physicists come at problems in a very different way to that of biologists; the physicist wants there to be an equation that describes accurately and precisely what's going on whereas biologists don't believe in that kind of stuff, it is too complicated, there are too many different ways of doing it; people today say that we ought to have much more communication between physicists and biologists and that is going to be very productive, but I am a little bit sceptical of that; there are some problems where that is probably true but there are an awful lot of interesting and important biological problems where it is way too complicated for physics to make much of a contribution

1:35:51:20 It does help to do experiments yourself, you notice things other people would miss, but I always really like working with other people and have never been much of a one for working alone; for example, studying the haem problem, a colleague Richard Jackson was terribly important; I have often said it is like a love affair, a very intense relationship and a lot of thoughts can go unspoken because you are so focussed on the material, when you get a result you instantly know what it means, and you both know that the other knows what it means; I think having a collaborator like that, with whom one can be open and honest; to be able to say that their idea is stupid and for them not of take offence; you just make little mistakes all the time, and you would be amazed at how little mistakes compound to take you away from the main tracks; this becomes more difficult with age and being more distinguished because if I say to a graduate student that an idea is stupid, this could be devastating, but the student also has to be able to say the same to me; latterly I think the three really good periods in my life were, one, working with Richard, working with Jon and Jeremy [Minshull] trying to clone these frog cyclins and sea urchin cyclins, and at the end working with Satoru [Mochida] on the phosphatases; in each case it had the same kind of feeling; we were all in it together and there were just two or three of us with a few supporting people of course; the whole lab environment is a very social kind of place; there are important bit players that fan out from the centre and sometimes they can be incredibly useful; it should be a happy place, a fun place; you have got to be able to enjoy yourself and take pleasure in other people's successes, and to have a shoulder to cry on when you fail

1:38:59:09 It is pretty difficult to combine family life with life in the lab; I guess in a way that was why my first marriage broke up; she really didn't understand what I was doing or trying to do, and I probably was exceedingly inconsiderate about the long hours that I spent; Missy left probably in 1972 or early 1973, so she wasn't around when we actually solved the problem; all those Woods Hole years I didn't have anybody really, and I couldn't have had; it would have been quite unreasonable to abandon your family for long periods at a time; I was often three months away from home; finally, getting married to another scientist is good because you both understand what the nature of the business is; by that time my life had changed quite a bit; the Prize came in 2001 and after that your life really does change and you stop being so much of a lab rat and become more of an ambassador; now I am retired it is great because I can do the shopping and cooking and support my wife, but I still spend an awful lot of time away from home which is not so good; it did occur to me to wonder whether we shouldn't have talked more about sex, but I think on the whole it is better not to go there; I did go to single-sex schools except for the first school which doesn't really count; then all the way through Cambridge there were no girls, or very few of them, so I do think we had a very funny time of it, actually; some of us had sisters; I had a great friend who did but she was much younger than us, and we treated her abominably it seems to me in retrospect; the only women in my life were my mother and a housekeeper-nanny kind of person; my mother was a powerful influence and it was difficult to get out from under her; I think that at that time we put women on a pedestal and thought they were special and different; I notice that my daughters see lots of boys and I think they just regard them as other people; I don't know, but they clearly are not shy around them; that can only be good it seems to me; my recent experiences have just been bewildering to me, bizarre; let me explain what I think happened; firstly I think I had been working too hard; this was my third trip to Korea that year; I had been twice to Singapore, once to India, once to China, so I was travelling these twelve hour journeys, giving multiple talks, more than once a month since Christmas, and before then also; this particular trip I was only doing as a favour to somebody from the ERC; I didn't think it was an especially good idea because it was a journalists' conference; we had two young women who were researchers who were scheduled to give talks and I was supposed to introduce them; then they asked me to give a talk; you get treated like a tame laureate; most of the laureates jet in and jet out having given their talk, but I was around; that morning I had to give a talk and something happened that had never happened before, namely, you advance your slides with a clicker but the clicker was on the same wavelength as the speaker in the next hall; so every time I clicked to advance, her slides advanced, and every time she clicked back, my slide went back; for the first five or ten minutes it was impossible; finally I dispensed with the clicker and just asked for the next slide; I was kind of cross about that; I had been asked to say a few words at this lunch for female scientists and engineers, but actually they were mostly journalists, and of both sexes; there were four speakers and the three before me were women; I was still feeling a bit irritated about having to do this; I began by noting that there was a difference between me and the three previous speakers; then a sort of devilment got in me and I said "Let me tell you about my trouble with girls"; I was thinking about you fall in love with them and they fall in love with you, and when you criticise their work they cry; it was incredibly stupid of me and I shouldn't have gone there; I could have easily said "the ERC takes gender equality extremely seriously..."; I didn't have anybody to discuss with what I should say because the person with whom I might have discussed it from the ERC wasn't there, and a new boy was there whom I didn't know and who didn't know me; I was thinking about how I had once fallen in love with a graduate student - unrequited love - and it was very painful for two or three years; then there was another time when a woman in the lab fell in love with me and it wasn't reciprocated; telling her that there was absolutely no hope, I remember she deflated like a punctured balloon, it was awful, just awful; I am glad to say in both cases both situation finally resolved; I said the only way to avoid this would be to have single-sex laboratories; I was thinking, there are single-sex schools, monasteries, nunnerys, but this is silly; then I said "Seriously..." and then I went off on a jag about how much I admired Korea and how women had made an important contribution to that, and how women should carry on and ignore sexist monsters like me; I thought nothing more of it; nobody afterwards came up and said anything to me; the following day I had several interviews; nobody mentioned it; the first I knew of it was in the departure lounge going back to England the following day when the 'Today' programme got in touch; I had no idea that this storm was brewing, so I very foolishly agreed to say some words; at that time it was 1:30am in England or something like that; that made it much worse because they transformed "let me tell you about my trouble with girls" to "the trouble with girls"; I couldn't understand why everybody had reacted so badly because I hadn't denigrated girls at all, I just had some trouble that I wanted to explain; Nurse actually said that he hoped everybody would get married; it is true that scientists tend to marry other scientists because they fall in love and everything is fine; so it was really bizarre; then I got home and I had a call from my seventeen year old daughter asking if I was OK as I was on the front page of every newspaper; Fiona Fox phoned from the Science Media Centre; she had been sent by Paul Nurse to take care of me; I got home and my wife rang and told me I had to resign from UCL; I looked at their e-mail and decided to resign; that was rather a stupid thing to do; I should have asked why, what have I said, what am I being accused of? It took me weeks to find out what actually I had been said to have said because in my mind I hadn't said anything terrible at all, but had just been talking about my trouble; so I resigned from everything very quickly; I didn't resign from the Royal Society because Paul was very nice about it; I was removed from one committee to get the critics out of the way; the thing that really upset me, and this hasn't really come out, was that the ERC, which is something that I have been working at and with for years, and which I care very strongly about because it is a wonderful research council; it covers not only science but all academic fields; they fired me because I think that they couldn't believe that if UCL fired me it must be that I had been having affairs with their undergraduates; nobody would fire you just for saying a few silly, ill-chosen words; they kept it very hush-hush; the trouble was that the original 'Today' programme had this woman called Connie St Louis, who I don't know at all; her account was quite inaccurate and very selective; she said that nobody laughed and later the tape came to light and everybody did laugh; it was a most inaccurate and unfair accusation actually; I thought it was odd because if I had really been so awful surely one of the women who had interviewed me the following day would have said why was I so awful, and nobody mentioned it; I was bewildered and shattered, it was very strange; then the Daily Mail came and started investigating marriages and affairs, and went to try to interview Celia (my daughter) in Balliol, interviewed my ex-wife in New York, it was awful, you didn't know what they were going to rake up and find; my wife was offered £20,000 by The Sun to spill the beans; you can laugh about it in retrospect; a photograph was taken on the Saturday after the news broke, when I went to Richard Perham's memorial service in St John's, which was a very grand affair; somebody took a photograph of me setting out; it is a bizarre picture of me wearing a black tie and a formal suit, carrying a shopping basket; there must have been somebody down the road checking my movements; I rather suspect they followed me to Cambridge because somebody knew that I had been in Clare College Cambridge, and raised the question of why I was doing that; so there was this awful business of being followed and investigated; then it unravelled; I still don't really understand why these people had it in for me; they tried to find evidence that I was indeed a sexist monster; there was this guy in UCL called David Colquhoun who found a picture of me throwing ice water over my wife, which was part of the ALS Ice Bucket Challenge; well, throwing ice water over his distinguished wife clearly proves he hates women; the tide had really turned; Louise Mensch has become obsessed by this story and gone into it; it turns out that Twitter leaves a really beautiful paper trail of what everybody said when; she has now done an analysis of what the 'Today' programme said I said, and it is quite clear that they put words in my mouth which I had never uttered and were far from what I had meant; the tide is turned but the damage is done; I am finished as far as all that kind of stuff is concerned; you can't avoid some mud sticking no matter how unfair; I was stupid, it was a daft thing to say, but it was only because I was so fed up really; I do say daft things, and that's what the Dragon trained us to do, and its not that important....