Interview with Tim Hunt at the 57th Meeting of Nobel Laureates in Lindau, Germany, July 2007.

Tim Hunt, welcome to this interview with Nobelprize.org. You won the 2001 Nobel Prize for Physiology or Medicine together with Lee Hartwell and Paul Nurse.

Tim Hunt: Correct.

And you seem to have been blessed with the lucky chance of knowing that you wanted to be a biologist or a chemist from quite early.

Tim Hunt: Yes, very early on. I think I was sort of scientifically minded but I can’t really remember it, it’s a sort of construct now, but I did very well in a biology exam when I was, I think, 11 years old or something like that and I came out something like 13th in the whole school. In those days everybody took the same science exam whether you were 7 or 12, 13, so you knew exactly where you were in the whole school. I was in the middle of that point, and I did very well and I realised that it came very naturally to me. I also knew another thing, I had a great friend who was a good physicist, he’s an FRS and all that stuff, Peter Pusey, and he was so much better at physics than I was. I liked physics, I would have loved to have been good of physics but the fact of the matter was I just wasn’t. Peter always zoomed ahead.

A man’s got to know his limitations.

Tim Hunt: I think it’s terribly important to know what you’re good at and what you’re not good at. There’s no harm in trying to make yourself better at certain things. Some people love doing nature walks or collect insects and things. I didn’t really. We had a lead factory in the garden; we discovered a lead mine in the garden. It was great. My friend Bill Nimmo Smith and I followed this lead pipe and it disconnected so we cut off bits and then melted it down in the garden in a kind of improvised blast furnace. We would pour them in the back of dinky toys and then stick a piece of green baize. To begin with they were really shiny, and they looked really great and they were very good paperweights so we sold them. We had a little cottage industry. I forgot, did we sell them or did we give them? I can’t remember anyway. That was the kind of thing I liked doing, the usual stuff. Everybody likes tinkering with radios and making crystal sets and in those days radios had lovely bits inside them, valves and one knew about the high tension supply to the valve and you understood how the valves worked and the low tension thing which just made the cathodes glow. It was all very mysterious and listening to test matches, it must have been, was it 1953, Len Hutton’s tour of Australia, listening to it under the blankets at 5 a.m. or whenever it was. That habit of listening to the radio under the blankets has never left me.

That’s a deep seductive pleasure, yes.

Tim Hunt: But you could always tell when the … was it the low tension battery or the high tension battery that was giving out, because I can’t remember, I’ve now forgotten what the symptoms were but they were different and you could always tell which battery needed and they were rather expensive so I forget whether you had to persuade mum and dad to buy a new battery or whether you saved up your pocket money.

But an early love of making things and piecing things together?

Tim Hunt: Yes, my room was always a complete mess with mostly soldering irons and stuff and making funny things. I remember I constructed a clock radio that would turn on the radio in the morning. It could have been the timer for a bomb mechanism but it actually turned on the radio and I can’t now remember anything about how it worked or where I got the idea. I expect I read it in some magazine. Another thing, we used to get book tokens as Christmas presents and Blackwell’s, in those days, had a lovely children’s bookshop, a tiny little one where, if you went up the stairs and you were an adult, you would have hit your head. The trick was to find the book you really wanted. So you’d go in there, they didn’t mind you reading, so you could read quite a lot before you actually plonked down your book token to get the book. Among the books that I very much liked were books which were mostly American, and they were therefore expensive, but they were do it yourself, like the ‘Amateur Scientist’ in the Scientific American, you wrap the coil around the lavatory roll and then made something that did something and that kind of stuff. My friend Peter and I we used to do a lot of electrolysis, I seem to remember. We used to make chlorine gas. I don’t know why we did it, just liked doing it, electrolysing sodium chloride and stuff. It wasn’t very quantitative but it was messy and it was fun and it was sort of slightly naughty. Now it’s strictly frowned upon. I suppose we could have done ourselves an injury.

It’s a step above electroplating your pencil sharpener, which I think is what I was doing.

Tim Hunt: I don’t think it was very directed or anything but you did get a sort of feel for how things worked and it was between that and cricket. I remember a lot of cricket, I was absolutely fanatical about cricket. I think at school I really did like biology and we had a very inspiring biology teacher, a man called Terence Doherty, who really wanted to be an artist. He’d been a researcher at Roth instead and got really fed up, hated that, so he came to the school to teach and there were only three of us in this A level Biology class and among the other things we did, this would have been 1957 I think, or -58, the anniversary of the publication of The Origin of Species. Do you remember which year that was?

-57, I think.

Tim Hunt: I think it was ’57. Anyway, the Oxford University had the series of extramural lectures and there were three in the series, it still resonates with me. One was on evolution, I don’t know who gave the lectures, it was probably somebody quite distinguished, but I don’t know, I was only little, 13 or 14 I suppose. Born in 1943, 14 yes. Then there was a series on radio activity which was very resonant because the bomb had just gone off and I read Brighter than a Thousand Suns and the biological effect of ionising radiation, the idea of your teeth dropping out and your hair dropping out and that had a medical thing as well. Then there was one on biochemistry, which was quite boring probably, but except that I do remember this amazing movie of a biochemical pathway which still people can’t do. You had compounds flowing down the glycolysis and then into the crib cycle and there were ATPs spinning off and NADs and all that kind of stuff and I remember thinking at the time, and I don’t know what year that might have been, so that must have been later, 1958 or -59, maybe even 1960, I can’t quite remember, wondering it was all very well this sort of pathway but there didn’t seem to be any control. How can you have all these reactions going on simultaneously, there must be something controlling it. It was really thrilling to go to Cambridge and then sort of /- – -/ and /- – -/ and all these people discovered /- – -/ and the principles of metabolic control and that was just gorgeous. It was so great, you finally understood that the thing that had been worrying you by its nonexistence did exist and that’s how it worked.

Worlds were unfolding?

Tim Hunt: Worlds were unfolding, yes, and much more so. What I recollect about the A level syllabus. First of all, the books were unbelievably tedious. The most exciting thing was to go out into the field and ask the questions, why were the lilies growing here and the daisies there? There’s a certain amount of ecology, but it was mostly about plant sex. Do you remember alternation of generation and the mosses compared to the ferns compared to the /- – -/. I never did understand how pinecones work and then when I finally read, much much later, Barbara McClintock and her studies of jumping genes, understanding what the pollen nuclei and the endosperm which is triploid. Nobody should teach a teenager about plants’ sex. It’s far too complicated. It’s really, really difficult to understand and there is no point in understanding it.

It’s true but the practicals are cheap.

Tim Hunt: Yes, I suppose that’s right. I remember still the thrill of dropping my fist earthworm into boiling alcohol and dissecting it; that felt very grownup and then there was the famous time when my brother’s rabbit died and I rushed it into the lab and dissected. It was much bigger than a frog, so you could really see what was inside.

Those were the days; you wouldn’t be allowed to do that.

Tim Hunt: Probably not, but we did, and that carried on too, into Cambridge I think, when the physiology practicals were fantastic because there were ones where you did experiments on yourself and there was the one where you re-breathed your own oxygen through/- – -/. I didn’t dare to do that but I watched people doing it, and they just passed out and the demonstrators then had to sort of come and resuscitate them. As far as I know no undergraduates were lost and it was great because the pure biologists, scientists like me, were doing these classes together with people who were going to be medics and there was absolutely no distinction made between the medics and the scientists, which is really, really good. It was a black, black, gloomy day when the medical course was hived off. Medical biochemistry is not the same as the biochemistry. It’s stupid, really, really stupid, it’s all the same.

Now medicine’s tried to reinvent it all.

Tim Hunt: I don’t know what’s going on because I haven’t taught in a course for a long time and the fashions change. It probably comes in and out. I think I was terribly lucky with teachers and lecturers and also colleagues at Cambridge. Again, that’s something which is sort of rather out of fashion now, the idea that you select some really bright people and put them together. I probably learnt more from my friends than I did from the courses but it was done in a very nice sort of framework. Particularly the zoology practicals were also very, very good. That was a first year practical because the guy who taught Jonathan Miller philosophy, a man called Frank Hollick and Ken Joysey and Anna Bidder had a sort of very clear idea of how they wanted to teach these undergraduates and to make them realise that everything was based on your senses, and you could so easily get it wrong by misinterpreting or by having expectations and you really had to look at the material carefully. It was really a comparative physiology course, it just ran through the invertebrate filer. It was tremendous, dissecting snails and stuff like that and that, together with the human physiology, it was a wonderful counterpoint. The medics didn’t take this zoology course but I did and I found it very … you just saw everything. You realised that invertebrates were facing the same problems as the vertebrates and it was wonderful.

Marvellously integrative and also teaching you to look at things from a sort of sideways as well as taking …

Tim Hunt: Yes, and often you found there were some amazing biochemistry practicals that were run in the physiology course. They were run by, now I’ve forgotten his name, this was the first man to measure the molecular weight of a protein. He measured the molecular weight of haemoglobin and got it absolutely spot on in about 1920 something and had been given a fellowship at Trinity on the basis and never done anything very much since. It was sort of in the department of /- – -/ science. Those practicals were very primitive but they had a certain … They were really important in a way because what happened was that you would add carbon monoxide to blood and watch it turn pink or you would acidify the milk and it would throw out a precipitator as though you were making yoghurt and then you would find that if you boiled that you would never re-dissolve the precipitate but if you didn’t it would go straight back in. It was actually a very good introduction to practical physical chemistry and it was the thing the biochemists were way too sophisticated, with those Warburg manometers which were much too complicated to understand really. One thing I should say, I was always much, much better at the practical. I did much better at the practical than I ever did at the theory. I wasn’t particularly good at writing essays. I was much better at dissecting the given frog.

I suppose that’s understandable of course because the theory really goes on in your head.

Tim Hunt: I don’t know, but there were lots of people who were much clever than I who could write brilliant essays about stuff and I just didn’t like that. It was much more the actual, the contact with the material and looking at results. Later on that led very naturally into actually getting data, which you had to make sense of and then you had to imagine what it would be like. I think that’s one of the things, that it’s very hard to convey to the general public. For many years we measured the rates of protein synthesis and that entailed putting samples into a scintillation counter and the standard assay always gave 8,000 counts, sometimes 9,000 and you knew that if it was 1,000 something had gone horribly wrong and if it was 50,000 something had gone wrong, you just threw away the experiment. You could tell what was going on, the whole hypothesise with the rate of which these little nixie tubes would flicker, you could say whether the experiment worked or not and whether your ideas were right or not and that was really great. But the active imagination, these little flickering numbers on the scintillation counter and to imagine what it was like to be a ribosome or what was going on inside the cell, it was such a huge disconnect. I remember thinking that too, in going to hear a lecture, it must have been by Sydney Brenner and Tony Stretton on establishing the collinearity of the code or working out the sequence of the basis in the stop codons, the idea was wonderful. You could deduce the sequence of bases in the amber codon, but the actual data was whether the phage grew or didn’t grow or something like that. It was making that connection between a very carefully constructed experiment and what was going on inside the cell always requires a considerable act of imagination.

And you find it difficult to get that across to the public, the sort of unpalatable nature of the rather dull data?

Tim Hunt: Yes, you collect all this data and you’re pipetting away and sometimes things turn yellow, but mostly they don’t even do that. They just get more or less radioactive or there’s a change in the absorbance at 340 nanometres or whatever that is, because NAD is being reduced or oxidised. It amused me that idea, because we were very biochemical and I grew up in a very biochemical tradition. The cell biology, looking down a microscope, came ever so much later and I wasn’t very good at it and I never have been, so I really like this biochemistry.

I think you have to enjoy the repetitive nature of it.

Tim Hunt: Yes, that’s right. I say to people it’s like gardening. If you don’t enjoy pulling out the weeds and encouraging the young plants you probably shouldn’t be a gardener. You’ve got to like going into the lab and just doing nice experiments, making sure that everything is neat and tidy and that things work and all the controls are in place. I remember some students. I was rather proud of these practicals they’d evolved and they were first year cell biology practicals and mostly they just involved plating out bacteria and assaying phage, which it turned out that most first year Cambridge students were totally incapable of doing. I’ve never seen such scrutty plates in all my born days and it wasn’t that difficult, just doing dilution series and stuff, and the students at the end of that, it’s already the era where you’ve got feedback from the students and the students said, ‘Well, these were really boring practicals. All we did was pipette.’ and I felt like slapping them about the chops and say, ‘If that’s how you feel why don’t you quit science now because that’s all you’re ever going to be doing, pipetting, it’s so important.’

Isn’t there a machine to do that, they ask! But maybe it’s a way to connect with the public because, as you say, people garden, people cook. People do things that are highly repetitive and involve lots of tactile stuff, maybe actually showing people that that’s what science basically is and that the higher deals are what lives on top of it but most of the day is spent…

Tim Hunt: Up in your head, yes. I mean you’re trying to prepare a dinner party to impress somebody or to please yourself or whatever it may be, but what you’re actually doing is chopping onions. It’s exactly like that. Everything is the same. The artist goes out and buys his new paintbrushes or paints or whatever I suppose. It’s like my 9-year-old daughter, Agnes, likes to go to stationery shops and buy lots of crayons and pads and things. I know where she gets that from.

I still like to do that. You published, I think as a graduate student, a Nature paper.

Tim Hunt: Yes, that’s right and I sometimes wonder about that, because we didn’t have any idea in those days how important it was to publish. It was just an absolutely natural. We thought we’d found something interesting, we just sent it in to the editor of Nature and whoever it was, I don’t know who it would have been in those days, found it interesting and so it was published in Nature. We didn’t think anything of it at all. I don’t think champagne was broken out or anything.

As you say, nowadays that would have probably led to you trying to set up an independent group as quickly as possible. It’s a huge feather in your cap. It obviously was a feather then.

Tim Hunt: I think people did notice, yes. I think probably our friends up the road noticed that there was something quite interesting going on down here and we were accepted and it was nice, but there was no big song and dance made about it. Later on, I did encounter a certain amount of … I don’t know what you’d call it, we were accused of being trendy because we published in Nature. It was as if this was not something a gentleman would want to do because what was wrong with the Biochemical Journal or something like that? Just recently Satoru and I had a paper accepted by Nature. We were really, really pleased because that was the first one for a very long time and it is important, but it’s funny that in the olden days, because nobody counted publications. I wouldn’t say we were unpleased, of course we were pleased and the journal that was more important to get into in those days was the Journal of Molecular Biology. That was what today would be Cell, that was the JMB and then it got so hoity toity or boring. The early issues of the Journal of Molecular Biology are very interesting because they’re full of interesting articles, some of them completely batty and wrong as you can now see, but they were always interesting. I think that’s a thing that people still don’t understand that the whole idea of making a good journal is that it should be interesting. You should want to know about the origin of the universe or why the Hox genes are in a particular order and what that means. There are lots of really interesting things out there and you don’t very often find very interesting papers. They tend to be more ‘P38 map kinase is important for the left lung of the lactating valves’ sort of thing.

Safer for editors to deal with?

Tim Hunt: Yes, and you get referees to say this is technically ok and all the controls are in place, but the idea that you should take a risk because something is interesting, I think that’s slightly been lost sight of and the whole editing business is more professionalised now than it perhaps was back then. It probably comes from the fact that everything is now so compartmentalised, and competitive. I wouldn’t know if something out there was interesting, I wouldn’t even know what was known in that field because although once it was all under one roof, now they’re under many, many roofs. That’s regrettable but inevitable I suppose.

I just wanted to return to your career path. You took the decision to stay on soft money for quite a long time, which obviously turned out to be absolutely correct …

Tim Hunt: It wasn’t entirely my decision. I did apply for a job and didn’t get, much to my fear at the time, but in retrospect it was terrific. I think now, looking back on it, it was wonderful to be in charge of your own destiny without having to answer for anybody. I don’t remember how many years of grants I had. I had a Bright Fellowship, I had a Royal Society Fellowship and I think I was on sort of some MRC grant, hired by my friend Richard Jackson at one point too. In all of that you could just get on and do what you wanted to do, you could teach as much or as little. I used to supervise undergraduates and in those days a boy, we had some really, really talented undergraduates pass through my hands. In fact at one point, it was the late 1970s, I was thinking of giving up because they were just so much better than I was. There were three of them in a row, it probably went; Hugh Pelham first, Richard Treisman second, and Andrew Murray third; he’s just awesomely good. Really, really talented people.

I was going to ask you, I don’t suppose you really did, but did you ever think of doing anything else?

Tim Hunt: Not really. I still wouldn’t know what to do. After the Nobel Prize I remember asking Paul, ‘What the hell should I do now?’ I wasn’t feeling very confident about my ability to run a lab at the time, and I was rather taken aback by the prize. Then suddenly you think that maybe you should become a politician or reform the school curriculum and you quickly find out that walking on water is not one of the things that a Nobel Prize allows you to do. I remember Paul saying, ‘Well you know, Tim, I think you’re a pretty good scientist’, and I think that’s right but the trouble is the pleasure of finding things out is a really deep and important pleasure. But you have to find stuff out and there’s an element of luck in that and if you’re travelling as much as you do in the wake of the prize it’s very hard to be in the lab as much. It always surprised me, I used to go off to Woods Hole for the summers and I always would leave the students behind with a clear idea of how much they might have got done by the time I got back. I was always rather disappointed that they didn’t seem to have got very much done, whether they weren’t in the lab at all and playing hooky. When my bosses went away, we got on and did things. Maybe that means that your supervision is important. You can tell people not to do this and do that but just suggest to them that maybe this is… As I said earlier, the people with whom you have a really good relationship, they can reject your bad advice and take the good ideas.

I wanted to land on that point you made of being in the lab enough to find things out because it seems that several points in your career, most notable at Woods Hole, you’ve found something that you weren’t looking for and obviously it’s been a case of chance favour in the prepared mind and all that.

Tim Hunt: I think that’s my talent. The first thing that happened was we were trying to work on polio virus. We were going to map the order of genes in polio virus because I thought I could that. David Baltimore ended up doing it first, he had much better polio virus and stuff. The result of that was I ended up discovering that double stranded RNA was an incredibly potent inhibitor of protein synthesis with Ellie Ehrenfeld and that was when I was a postdoc, that must have been 1970 or -71. That was another Nature paper and it was pure serendipity but doing the right experiments and then just getting an unexpected result which we correctly interpreted and found out what this mysterious inhibitor was, it was very mysterious. The Vietnam war was going so it felt almost immoral to be working in the lab because it was so iniquitous. We used to go down sometimes at weekends to Washington to protest and one day I got tear gassed and wrote a postcard to my mum which caused her to ring up anxiously in the transatlantic phone. In the days when that wasn’t so easy and Grace was very cross with me for writing this rather frivolous postcard; ‘Went to White house, got tear gassed, love Tim’. This was a Jewish school and one was very aware of doing experiments while Rome burned around you. Anyway, we discovered this. It was a wonderful thing because the inhibitor was resistant to DNAs, RNAs and protease and it had a high molecular weight, it was 20S, rather a sharp band, and it took ages, about six weeks for the penny to drop that double stranded RNA doesn’t get digested by ribonuclease. Then we went to Jerry Hurwitz and said, ‘Jerry, what enzyme can we use to digest double stranded RNA?’ and he said ‘Micrococcal nuclease and don’t forget to add the calcium’ and that’s the origin of the messenger RNA dependent reticulocyte lysate because I knew this enzyme need calcium and I knew that calcium didn’t inhibit the reticulocyte if you then added plenty of EGTA to follow it up, that didn’t collate magnesium. There were a little funny cross connections and they all came out of finding weird things. We didn’t expect to find an inhibiter in polio virus infected healer cells which was heat stable and RNA insensitive and stuff and so it was all these sort of little things doing stuff on the side.

But is it fair to say that the majority of people have a lot of this stuff occurring but are missing it because they’re just not …

Tim Hunt: I don’t know, I really don’t know actually. I think I’ve always been a bit naughty and more interested in the highways and byways than the main line. The most recent thing that I said that really pleased me very much recently, that was also a funny little result that Satoru came and showed me, this thing and a band just subside and that’s very interesting, that must mean calcium induced phosphatase is turned on. He’d noticed it but hadn’t put two and two together. I think I’m quite good at noticing those odd little things and putting two and two together and realising immediately what they must mean and rather kicking myself for never having thought of that before. It very often happens that way, you know, ‘Idiot, why did it take us so long to get to this point?’

One can see how this might become a distraction though because you’re good at seeing the side paths, you might get led them too far.

Tim Hunt: I do get very easily misled. There was a time when I should really have been learning how to clone cyclins and get on with that when I got very interested in the fact that rabbit reticulocyte lysate had a cell lysing activity in it which we never got to the bottom of, because it was lipid biochemistry. I spent a lot of time trying to work on that, to no good avail. There are lots of projects which never worked and one of the ones that I really, really wanted to get to work, and it still needs to be got to work, is to find out about the global control of protein synthesis. We wasted quite a few graduate student years on that trying to make really active cell free systems from healer cells and it never seemed to work. We wanted to be able to get growth factors to turn protein synthesis on and off and it just never worked. The cell free system was never accurately replicated what went on in the cells and we never did find out and you never know when it doesn’t work whether it’s because of utterly trivial reasons. When one more push and you get over the top and when it’s a problem which is not going to be solved for the next 25 years because the techniques that you need to solve it haven’t yet been invented and once or twice I’ve come across that too. We’ve found all these protein kinases that inhibited protein synthesis and perhaps we should have purified them, but we didn’t and it was just as well because that’s another story. I think sometimes and I see people getting locked on to problems and it’s very admirable that, they just struggle with them and struggle with them and soon, finally they break but there are often more interesting things which you should be pursuing and it’s not that important to do the main thing.

When you made the cyclin discovery at Woods Hole you then seemed to be remarkably relaxed about it because you dropped the project when you came back to England and then returned to the project when you came back to Woods Hole the following year.

Tim Hunt: It was immediately obvious to me that I’d made a very, very, very important discovery and I was very well aware, right from day one really, of its significance although not many people believed me.

So you’d identified proteins that were regulating cell division?

Tim Hunt: Yes, we didn’t know that though, that had to be proven later and what we had to do was clone and sequence the message, which took a long time to do and could have been done more efficiently. I think, at some point, we certainly had a little look in frogs to see if we could see it there, but we didn’t really dare hope because this was something that had been found in clams and sea urchin eggs, marine invertebrate eggs in water, seawater, it just seemed so remote. The problem was it wasn’t easy to get frog eggs and we didn’t have any frogs and I went to our administrator and said, I would like to keep some frogs’ and she said, ‘Over my dead body, Tim’ and proceeded to then have a head on collision on the A604, the Huntingdon Road, and was never the same since, so it was obviously awful. She was a brilliant administrator, really, really good, but she didn’t want me to have frogs. We did eventually have frogs and they were great frogs too and learn how to keep frogs. I’m really quite an expert on frog husbandry.

Does Agnes have a pet frog?

Tim Hunt: No, the girls have horses, they don’t have frogs. It was just difficult to get the material, and if you don’t have command on your material … The Gurdon lab had it but they were pretty short of frogs and John Gurdon injected /- – -/ one at a time, the idea that you could have a beaker full of them. I’d seen these beakers full of them in the Kirschner lab, by that time but you just didn’t have the resources.

So it was a methodological reason that you had to drop the project?

Tim Hunt: Yes, there were no sea urchins. You just literally couldn’t do anything and then another funny thing happened. Number one, Tom Evans who came with me that summer to work with me had already signed up to do a PhD with David Secher at the LMB and the arrangements had all been made. I thought it was rather a shame because he should really have come to work with me on the cyclin project and we would have got a much better start. The following year Jon Pines did a project with me and I thought that he would be a very good person to do the cyclin project and so he did. He took the course in Woods Hole one summer, I can’t remember if it was that summer or the summer after, no that’s right, Richard Cornell did it that summer and Jon Pines was going to join me at the end of the summer, came through. He wanted to bike across America so he started on the West coast and joined us in Woods Hole right at the end of the summer, which was too late to get any material or do anything but at least he sort of saw what Woods Hole was like and went himself the following summer. That summer it was a terrible summer for sea urchin eggs so we couldn’t collect any material. The result was that Jon Pines and Paul Robiolio, who was a very nice American student who joined us, and I went down to the south of France in Jon Pines’ mother’s car. Jon drove hell for leather down the auto route to …

Not cycling this time?

Tim Hunt: No, no cycling this time, but he’s a very keen motorist as well, to Villefranche-sur-mer where we knew there were sea urchins which should be ripe at that time of year. There was the question of who was going to collect them and Jacky, the diver, was supposed to show up at 8 o’clock the following morning and, ‘Jacky the diver, he’s had a bad night, he’s not here’, so we had to dive for these sea urchins. They were just on the dock and then I remember sending Jon and Paul off to have dinner while I cut the things open and so we harvested the thing. Jon didn’t really want to use those because they were the wrong species, but it wouldn’t really have mattered. It was all completely chaotic. It was hopelessly badly managed, but it was fine. It came out right in the end.

And you weren’t worried about being scooped on cyclins?

Tim Hunt: No, not at all. Mainly because unlike most of the previous discoveries, which had been made by graduate students this was an experiment I did with my own hands, it was a gel that I developed with my own hands and it was an interpretation that I’d made with my own eyes and my own brain, so it was absolutely 100% mine. It was very interesting. That’s quite important psychology because otherwise you feel that it belongs to somebody else a bit and it didn’t in this case. Nobody else had spotted this and they really should have. It was pretty disgraceful that some people, naming no names, hadn’t seen this because it was such a simple experiment and it was so the interpretation was so…

Do you think the experiment had actually been done before? People had had it on their gels and not seen it?

Tim Hunt: The story really is the following that it was all a question of looking for patterns of protein synthesis in newly fertilised sea urchin eggs. The time before Bridget Hogan and Paul Gross had had a look at this but the SDS polyacrylamide gel hadn’t been invented.

That was pre 1970 or something?

Tim Hunt: They did it in 1968, -69, something like that, yes, just the wrong side of that. Then the next time, a guy called Bruce Brandhorst had a look at it, but by that time the 2D gel had been invented and these proteins simply don’t focus on 2D gels plus when you’re running 2D gels – I don’t know if you’ve ever run any – but you would not take 2D gels every 10 minutes. This was perfectly suited to the original studio programme. There are certain people who deserve a lot of credit here and people think that Ulrich Laemmli invented the SDS gel; that’s not actually true. Jake Maizel was the real hero here and he was an Einstein person, so I knew him from Einstein. Then he went and did this sabbatical at the LMB and he and Ulrich collaborated and got this method working and then Bill Studio wanted to look at the patterns of protein synthesis after T7 infection of e coli. That time we were all running tubes and you couldn’t line up the tubes. Mostly the gels broke when you got them out of the tubes and they stretched so you couldn’t really compare. Bill invented this very simple method which lasted a day of building the slab gels with the funny ears, and so you can load the samples side by side. Putting those two things together, I mean it’s bizarre, nobody between 1970 and 1982 had ever run a 1D SDS slab gel of timed samples of proteins after fertilisation in either sea urchin or clam eggs where it’s really easy to see these things. They just hit you between the eyes. I always consider it was an unbelievable luck that nobody had bothered to do that before and it’s such a simple experiment to label the eggs.

It’s coming together a question and the right technology but a relatively simple technology.

Tim Hunt: Very, very simple and that was all you could do in Woods Hole because there was all this sea blowing in through the windows. Cloning was quite difficult because the sodium chloride concentration in all solutions was inexorably rising, there’s a damp fog and fungus growing everywhere. Some people tried to do tissue culture. It was jolly difficult but this was something that was robust and over the years, also, I must admit, together with three important people, Dennis Ballinger, Eric Rosenthal and Andrew Murray who came along and acted as my … Dennis was a PhD student at MIT and Andrew and Eric were graduate students at Harvard and they helped out. We worked out how to run gels of fertilised sea urchins. It’s not completely trivial actually, because fertilised sea urchin eggs, the sperm have a huge concentration of proteases in the acrosome, I don’t know quite why but they do. If you don’t watch out you get a phenomenon known as upper gel wipe out, which was all the high molecular bands are completely missing from. I lost my sense of smell, I think, in the process because our first method was to have boiling SDS gel sample buffer which has mercaptoethanol so the lab stank to heaven. Mercaptoethanol, and I could never smell primroses or roses after that but maybe I’d lost it already before then.

Then we discovered that just acid precipitation with trichloroacetic acid was fine. There was some methodology that had to be worked out and then Andrew found – which was a great advance – that you didn’t have to have SDS in the gel running solution. You could store those solutions in the fridge. If you stored them in the fridge with the SDS the SDS came out a solution and that was rather off putting, but Andrew correctly reasoned that actually the SDS that’s in the gel comes from the upper gel compartment because they run down so there was no point in putting SDS in. These little technical advanced made it … I think one of the problems with doing experiments is the energy barrier often gets very high. You often see people it’s not worth doing that experiment but you should always do the experiment but only if it’s relatively easy. Anything that makes it easier to do the experiments and the reticulocyte lysate experiments are particularly good because the material was frozen in liquid nitrogen and you could do an experiment any day of the week, any time of the day and the material was always exactly available and there. I’m the kind of person that if I had to prepare the cells so that they would be ready at 5 o’clock on a Friday afternoon and there was something more interesting going on I just wouldn’t be able to get it together to …

I can see you really live for the moment of the experiment and you love solving the problem there and then, as it’s confronting you.

Tim Hunt: Yes, and once you’re on the track of something you can then do experiments one after the other very quickly; the result of the next one depending on the result of the previous one, that’s tremendously important to me. I think it’s partly because I don’t have a very good memory and I forget what I’ve done or what I was thinking. You’ve got to keep going otherwise I can’t be dealing with it.

All this brings me on to a question of what’s happening to cell biology as a discipline now. This approach it was, I suppose, very well suited to cataloguing the players and now people are talking a great deal about systems and putting it all together. Is the time right for that?

Tim Hunt: I think systems biology is going back to what we were talking about earlier, it’s just plain old physiology. What you want to know is how things work and I’m not very keen on people making these great big lists of things.We do it ourselves. For example I would really like to know how many proteins get phosphorylated, how much when a cell enters mitosis? Right, simple question. We don’t know the answer. We’ve been trying to get it for the last 20 years and it turns out to be extremely difficult to do that but we’ve had some partial successes, perhaps more than most and we’ve got a list of proteins that get phosphorylated when cells enter mitosis but it’s just a list of proteins. It doesn’t tell you what that does and I recently called up my friend, Eric Karsenti in Heidelberg, and said, ‘Eric, do you understand how CDK assemble the mitotic spindle?’ and he laughed and said, ‘No, you know, we’re none the wiser now’. We’ve know that that’s what does it but how it actually does it. I think the reason is because it’s a very, very difficult problem. You’re talking about one enzyme activity in a super molecular with hundreds and hundreds of components and the guys who work on the form of the mitotic spindle don’t really understand which motors are really important. They know an awful lot; much more than I do, but you still can’t actually say what it is about changing the phosphorylation status. Something that assembles this beautiful structure that serves to separate the chromosomes and that’s what you want to know. We have some idea of how you disassemble a nuclear envelope but the tendency is just to produce these lists of things without actually saying what they do.

It’s like the human genome project. I honestly believe there were some people who thought that when the sequence of a human was established you could be able to predict the shape of your nose and the width of your ears and stuff from that and it’s just ridiculous, you can’t. We do these kind of things because they’re possible but I don’t think that’s the right way to go about it. What you actually want to do is to have, in my case, a biochemical cell free system that does whatever you want to study and then you start pulling it apart and seeing whether you can reconstruct it. It’s like organic chemistry in the old days, that you didn’t know that you’d really got the structure of your thing until you could synthesise it and it’s the same.

But in the current climate is it more difficult to have this approach?

Tim Hunt: I think it is difficult because most people don’t have the training or the courage. It requires a certain nerve to do that. I have a high admiration for people, like my friend Andrew Murray for example. He took a system which was working quite well and he made it really good, this frog cell free system, which will actually do mitosis in a test tube without any membranes around it. It took him two years of development to get that working. It was no guarantee that it would have actually worked and it took a long time to make it reliable and robust and it now is reliable and robust and that’s great. I think there are a number of other things like that. Fred Sanger working away towards being able to sequence DNA and that took a very long time and there’s a funny story. My wife was sitting next to Fred Sanger on the way going out to Stockholm for the celebrations and she introduced herself, I guess she must have recognised him. He said, ‘Oh I was so happy when I could retire’, he said, which he did. On the day he became 65 he just didn’t show up in the lab, just cleaned out. Because it was so hard, you know, I find science so difficult, very interesting, very interesting.

But he’d always found science so hard?

Tim Hunt: I don’t know. As everybody knows, I mean absolutely probably, in many ways, the most brilliant scientist. I mean in terms of actual achievements in the second half of the 20th century. Fred is peerless; proteins RNA and then DNA. I once asked him, I said, ‘Fred’, it was in a public lecture, I said, ‘Fred, this is a silly question but which gave you the most pleasure, was it proteins or DNA?’ He said, ‘Yes Tim, that is a silly question but the answer is DNA’. Because when I was growing up in Cambridge it was said to be impossible to sequence DNA. People said it simply couldn’t be done but Fred figured out how.

And got two prizes along the way.

Tim Hunt: A prize for proteins and a prize for DNA and I was just in Vienna with Roger Kornberg and Rich Roberts and we were reminiscing about Fred. Roger was there at the time when all this stuff was being worked out and he said it was amazing because the post docs used to compete with Fred. They thought they knew better at how to work these things out and they didn’t actually. I remember having dinner with them, after the lab burned down we had dinner up at the hospital, that’s where the new lab was, and I got to know all these people really well. It’s clear that the people working with Fred didn’t really understand the methods that Fred was developing, it was very interesting but you could see them. They were sort of groping towards the solution but it was interesting to hear that he found it hard. I think people around him gave him a … You got the impression that Sydney Brenner didn’t rate him all that highly and stuff, I don’t know why. If you met him, compared to people like Francis and Sydney, who were absolutely brilliant, clearly brilliant and superior beings, Fred just looked like the gardener or something. He was a very nice man and his lectures weren’t particularly good but boy, could he do the science! Which shows I think that it really takes all sorts. Everybody’s different and approaches are different. If everybody was the same it would be A) a dull place and B) I don’t think so much would get done. I think you need the cross cutting.

Yes, that makes perfect sense but you need it all, that’s the thing.

Tim Hunt: But you need it all. I think I was unbelievably privileged growing up at the particular time I did and in the particular place I did, because Cambridge really was the centre. All these famous biologists wanted to come there to be graduate students or post docs from America, and quite a few of them have won Nobel Prizes now as a result. Andy Fire is a recent example. All those nematode people, and everyone said, Oh, you know, the nematode project is useless, it will never work and blah, blah, blah, because they really studied and looked hard and took the worm on its own terms, they got all these wonderful things, the apoptosis and the cell lineage. Then later on, the double stranded RNA business came much later, it wasn’t done in Cambridge but the seeds were sown in Cambridge and one knew these people and they just wanted to know. I think it was a very nice atmosphere and you had these role models too, that’s the other interesting thing. You had the Sanger’s and Perutz’s and the Crick’s, the Brenner’s, César Milstein and so forth, to say nothing of all those physicists and sort of the Waite tradition in the first half of the 20th century.

And they were accessible?

Tim Hunt: They were utterly accessible. Some of them gave lectures to us, some of them went to seminars and you could hear them ask questions, you met them at parties and what was interesting I think, very important I think is they set a standard, you knew you couldn’t be better, these were the best scientists in the world. But you could also see that they weren’t superhuman, they had frailties, they had lacuni in their knowledge but also they gave you a wonderful example of how you operated and the trick was to want to know how things worked, and figure out any means possible to get at it. Just constantly coming at the problems from all possible sides and just trying to work it out so it felt like you probably could get to the bottom of it. The time was ripe and so I think that was a precious, precious example and most people haven’t seen so many people in action simultaneously. I think the idea of getting everyone together in one place… it was really a very small community I guess and lots of interesting problems. That’s the other thing. There was Gurdon’s group and wanting to understand developmental biology and the worm people and the /- – -/ people and we were working on the control of protein synthesis. It’s nice because you’re not actually competing with one another, there’s no direct competition so you can take pride and pleasure in other people figuring out their particular problem and that’s great to see them solved.

That must be an important part, enjoying other people’s success.

Tim Hunt: I think enjoying other people’s success is terribly, terribly important. It’s certainly terribly important for directors of labs, which thank god I’ve never been, and a sort of celebration of science and success and feeling that you can just do it. You’re going to have to work hard, you’re going to have to learn new stuff, it’s going to be very edgy at times and risky and there are always competitors somewhere else in the world but I think the local environment was very nutritious.

The last thing I wanted to address was the local environment in Europe, because particularly after you got the Nobel Prize you became very actively involved in European Research Council and the direction of European …

Tim Hunt: Yes, that’s something I feel very strongly about because I think the sort of balkanisation of European science is very undesirable and I’ve seen it on all kinds of levels. The MRC hates the EMBL because they think it should be money spent with them and on grants panels you saw … There’s a tendency to say we must have somebody working on whatever it must be and he’s the only Brit who’s working on this particular topic. You don’t ask the question where does he stand in the international pecking order, you just say, ‘We got to have that’ and that’s not a good recipe. What you actually want to do is just find out who is doing really good and interesting work anywhere in the world and know where they stand in the world. You don’t have to be a sort of genius, you just have to be good, and lots of people are really good. Science is so international it should really be judged on a Europe wide basis.

For the last four years, this is the last year of doing it, I’ve been involved in helping to select something called European Young Investigators. We have little panels and this is a very wonderful European scheme actually, because the research councils put in money to a pot with no guarantee that they will get anything back, they may and they may not. The Brits, needless to say, stay well clear of this, they’ve never participated and I think it was the first year the Spaniards did terribly well. I was so pleased about that, just that the young scientists we interviewed were just better than anybody else so they got the money and then the /- – -/ did very well one year. I think this year the French are going to do rather well and the first year I remember the French was just hopeless. It’s really nice and that’s the way it should be and it’s like giving out NIH grants. I had an awful argument last night with the person I was sitting next to, who’s the wife of somebody who’s deeply involved with the Framework Programme, and the Eurocrats are very proud of the Framework Programme because by their lights it is a success but by my lights it has all the wrong priorities because I think the only thing you need to do is to say is the science really good? There are lots of different ways in which science can be really good, I mean exciting, cutting edge, interdisciplinary and all that kind of stuff but just seriously good, exciting, something that really turns you on.

But without all the positive discrimination that surrounds…

Tim Hunt: You know, these Framework Programmes … I discovered this talking to the administrator, I was in one of these things, I mean don’t get me wrong, I’m perfectly happy to take the queen’s shilling, the Brussels shilling, but I discovered, talking to our local administrator, who was sort of auditing our programme, that actually the scientific excellence was very low down on their priority. Much more important was the human capital mobility stuff, you must have some Portuguese or whatever it was and then, milestones and then the most important thing of all, which I think is a real disaster about it, was that they issued contracts for research. Now my contention is you cannot have a contract for this kind of research because you have no idea what you’re going to discover. I mean you can have a contract to pipette but you cannot contract and that’s why most people have grants, right.

So they’re milestone dependent contracts so you have to deliver?

Tim Hunt: Yes, you will do in the first year, you will have done this reagent and then that will enable you to do that experiment; it’s just not how it works and how should they know? Because it’s being run by people who … It’s designed by politicians and administrators and I think they just need educating, that’s my experience. We went to see Commissioner Buscan, we went to see Commissioner Patoshnik and the ERC is established. Hope to god it works because otherwise there’ll be terrible egg on our face because it may not work, it may just be the wrong instrument and I think there are quite a lot of people who would quite like to see it not work and people who, early on, were very much not in favour, particularly in the United Kingdom but I think it’s the right way to go. It’s starting out in a relatively modest way, so I think that’s good because it needs to evolve. It’s very unlikely to get it absolutely right first time so I think it needs to evolve and hopefully become a real sort of pan-European funding mechanism. But the other thing I discovered in the course of doing all this and talking to all these sort of politicians and people was that the realisation that unfortunately education is not something that Brussels has any say in.

Again, I was very lucky in a way because at the time when I went to university, you passed the 11+ and you got into Cambridge and it was very elitist, selective system and a very successful one. Three of the top 20 universities in the world, judged by research output, are British. Only one is continental and that’s a Swiss one. Paris, Berlin, Rome, Amsterdam, Stockholm do not feature. I don’t know where they come in the list. They’re sort of way down in the lower 50s or 70s or something like that. You have to ask yourself, why is that? Because these people are just as smart and if any of them ever said, ‘Oh well, the Americans have got so much money’, it isn’t that, it really isn’t that. It’s to do with the spirit and how things are organised. I think the best thing that ever happened to me was the fact that I had no job, no tenure, because I think people unfortunately, like it or not, they need sticks as well as carrots. The knowledge that if you don’t produce something in those three years you won’t get the next grant is actually in the back of people’s minds. In America people really rely on their salaries. If they don’t get their grant, their salary goes down. There’s nowhere in Europe where that’s true.

No, you’re really putting your ability on the line there.

Tim Hunt: Absolutely, absolutely and if you’re good, you’ll be well rewarded. We’re a little bit too comfortable and so I think we’re wasting talent. Not because of the brain drain but it is true that a lot of talented people go to America and the reverse is no longer true. I lived in an era when the Gerry Rubin’s and the Doug Melton’s and the Andy Fire’s and Bob Horvitz’s all came to Cambridge to study at the feet of these masters and understandably so. I don’t think that happens very much anymore. George Bush is on our side. That’s another funny thing, the Americans are very generous and hire all our post docs. Why don’t we have funds to bring Americans in this direction? I think if you suggested that to a European administrator they would hold up their hand in horror but it seems to make sense to me and the same goes for Indians and Chinese. I was very surprised, for example, I had an Indian post doc, she’s just left to go to America needless to say, because her husband’s there, that’s another story. You might imagine that after all the empire there would be earmarked funds for Indians to come to work as post docs in the UK. No, nothing. One or two exchange programmes to take people across for three months and it’s very odd that because we ought to be trawling for this talent.

The US seem to just emphasise getting good people from wherever.

Tim Hunt: Wherever, yes, exactly and they have a much better system in one way because they have these junior colleges so they can actually sift people and they’re much more generous. There are quotas for a certain number of Chinese and a certain number of Koreans and all that kind of stuff whereas we look with horror at these people crossing our borders and there are all kinds of other problems as well.

Thank you very much indeed for offering such a lovely insight.

Tim Hunt: That’s just the way I see things and maybe other people do it differently and much more professional than I am. I always feel a bit like that scientific American, the amateur scientist I think would be …

Successful amateur. Well, it takes all sorts as you yourself said.

Tim Hunt: Yes, it does and I’m good at discovering things, I think.

Thank you very much indeed.

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