Disease Models & Mechanisms 2, 113-115 (2009) doi:10.1242/dmm.002592 A MODEL FOR LIFE

The cell cycle and beyond: an interview with Paul Nurse

Sir Paul Nurse is a recipient of the 2001 Nobel Prize in Medicine for his work on one of the key regulators of the cell cycle, CDK (cyclin-dependent kinase). In this interview with Jim Smith, he discusses his choice of model organism, scientific leadership and the early influences on his career.

s his fellow Nobel Laureate Tim ability to interact with people from all Hunt has said, it is difficult to walks of life. think of an abler, or more imag- The interview that follows took place on inative and accomplished, biol- the telephone on 21 October 2008; it has ogist alive today than Paul been edited only very slightly, and we have ANurse. One might add the word versatile to resisted the temptation to change the idio- this description, for on the other occasion syncratic order of my questions! I have written about Paul it was to introduce his published lecture, delivered to Christ’s You managed to define fundamental College Cambridge, on Two Views of parts of the human cell cycle machinery

DMM Creation: Milton and Darwin: there aren’t using a simple single-celled organism. many scientists who would attempt such a How did you come to the conclusion that synthesis! That short piece, and Paul’s yeast was the model organism for you Nobel Prize autobiography (http:// and your lab? nobelprize.org / nobel_prizes / medicine/ I originally became interested in the laureates/2001/nurse-autobio.html), provide problem of cell division not so much many of the facts about Paul’s life and sci- because of its relevance to human disease, entific career: about his early life and but because cell division was the basis of all the prescience of Professor Jinks at growth and development. The process of Xenopus with Chris Ford. These experi- Birmingham University, who allowed him reproduction is a crucial characteristic of all ments gave hints, but they were never to start his degree without the required living organisms, which is seen at its sim- strong enough to be published. So the pos- qualification in a foreign language; about plest with cell division. Having got attracted sibility of a human link was always in the how he discovered that cdc2 regulates the to studying the basic process of cell division, back of my mind and later I thought we onset of S-phase and mitosis in fission I wanted a model system that would be ef- could just go for broke and look for human yeast; how he and Melanie Lee cloned the ficient and effective with which I could CDC2 protein kinase. If this worked, it was human CDC2 gene using a ‘rescue’ ap- make rapid progress. I chose a single-celled probably going to work the same way in Disease Models & Mechanisms proach; and about his responsibilities as organism, good for genetics, and which did every eukaryote from human through to Director General of the Imperial Cancer little else except divide. This meant using yeast. I suppose the most astonishing thing Research Fund, which he went on to bacteria or yeast. Bacteria were clearly dif- was the way Melanie Lee in the lab did it by merge with the Cancer Research ferent from eukaryotes, so I went for yeast. complementation. The ways that we had Campaign to create Cancer Research UK. There were just two papers in this area on tried previously relied on structural simi- An addendum to the Nobel Prize autobi- budding yeast from Lee Hartwell and he larity – we’d used Southern blotting, but it ography also describes how Paul felt when showed that it was a good approach, so I was just too crude. We were getting lots of he discovered that the man and woman he wasn’t taking such a big risk in trying to protein kinases but we had no idea if they thought were his parents were actually his develop such an approach with fission were the right ones. We were lucky to get grandparents, and that his biological yeast. the complementation approach to work. mother was the young woman he believed The connection with human biology The principle was a good one but we had was his sister. We did not discuss this part came later, when gradually I realised that we fortune on our side that it actually worked. of his life to any extent, although Paul did had identified important elements in yeast comment that his working class back- that were crucial for control and there was You have stuck with yeast throughout ground might have contributed to his a possibility that these were conserved your career. Have you ever thought of among the eukaryotic world. Some years working with any other organism? before the key experiments, I had tried, un- I’m nervous about working with any other Sir Paul Nurse is the President of The Rockefeller successfully during the time I was in Sussex organism; I understand yeast biology really University, where he is also a Professor and head of the Laboratory of Yeast Genetics and Cell Biology in the early 80s, doing some experiments well and, particularly now that I do other (e-mail: [email protected]) with MPF, maturation promoting factor, in administrative things like running institu-

Disease Models & Mechanisms 113 A MODEL FOR LIFE Sir Paul Nurse

tions, if I’m going to be helpful to my col- thing I respect, and I apply it to myself as about their job, I have empathy for them. leagues in the lab I need to be really famil- well as to others. So I always wonder, am I When you’re putting yourself into the iar with the system they are working on. I good enough to still be supported on my re- shoes of the person you are talking to, it am familiar with fission yeast and thus I can search alone? The answer to that is proba- does help. Quite often, I have had to tell still be helpful to colleagues in a way in bly yes, but I worry about it, and if I do people that they haven’t got tenure or they which I wouldn’t be able to do if I was to something else that contributes to the com- have to leave and things like that, and this work on flies, worms or frogs, because I munity like running things I feel less guilty is deeply uncomfortable and unpleasant. have never worked with these organisms about it. The point is you have to be sitting in their with my own hands. The other reason is in shoes to do it well and that may be what line with Barbara McClintock’s great quote So you’re covering your arse, as it were? helped me here – that I was not born with that you need to have a feeling for the or- I guess you’re right – I’m covering my arse. a silver spoon in my mouth, if I can put it ganism you work with, and I have a feeling Another reason I work on these adminis- that way. Having had a lot of difficulty for yeast. I can pretend to be a fission yeast trative tasks is that often the people who get getting jobs early on in my life, having and I can do it quite well. I can sort of attracted to running things are not always worked on short-term contracts and so on, imagine how a fission yeast feels, and it the people you want to run things. People and having been rejected by a number of sounds crazy of course, but I can’t so easily who are totally engrossed in the science and institutions that I applied for, I’m used to imagine how a fly feels. If I was starting who are still close to the coalface are the failure and that remains with you. When again today, I would think very carefully right people to be running research science. I’m talking to somebody who has failed at about whether I wanted to go more in the I’m quite good at it and it means that there something, I know I’ve been there too. I’m direction of problems to do with the cell, in is a real scientist doing it rather than a sci- aware of people’s feelings and share their which case I would stick with yeast, or entific administrator. distress. problems to do with the organism in which

DMM case I would go for the fly or worm. I still You are good at it – what qualities do you Let me change the subject to the wouldn’t go for work with human, mouse or have that make you so good? UKCMRI. This is a huge new Institute Xenopus. I think Xenopus is very good for Overall, I think I’m a conservative radical. and a fantastic new opportunity. What the in vitro systems but they are just a little What I mean by that is I’m basically problems do you want UKCMRI to too complicated and I’m driven by more radical, but I will only try and bring about address and solve? genetic approaches. radical change from a very strong base. In I would like it to be a powerhouse for the other words, merging the Cancer highest quality biological and biomedical Let me pick up on your remark about Research Campaign and the Imperial research. The main thing I would like to aim running institutions – you’re President of Cancer Research Fund at is an institute of the Rockefeller, before that you ran Cancer was quite a radical step I can pretend to be a highest quality, a place Research UK, and now you’re also heavily but was done from a fission yeast and I can do it that thinks broadly involved in the UK Centre for Medical very secure base. I don’t about how to achieve Research and Innovation (UKCMRI). tend to do radical quite well that, and that will work What made you turn to this administra- things without a lot of over decades and not tive kind of work in addition to doing preparation and a lot of thought about just a few years. That’s why I don’t focus so your science? whether it will work. Only then am I pre- much on the programme side because all Disease Models & Mechanisms I personally enjoy, most of all, working and pared to take a risk. I do take risks but I that will change within 5 to 7 years. What talking with people in my laboratory. It’s take them only when they are really well concerns me is the basic structures by really what gives me the greatest pleasure. considered. which the institute operates that will gen- I like looking at data. I like looking at ex- Some of my friends say I am good at it erate the highest quality biological and bio- periments. I like looking at cells. I like because I’m a Machiavellian bastard. It’s lit- medical research and will influence the talking to my graduate students and post- erally true that I am a bastard and perhaps I world. docs about what they do. I do a lot of it. can be Machiavellian as well. The People often have no idea that I spend hours Machiavellian bit is most to do with the fact Influence the world in what way? and hours each week doing that, and that that I try to avoid direct confrontation with By understanding life and understanding I’m still very engaged. I feel I can never do people. When I talk to people I try to per- how living things work for the benefit of hu- enough of it because my office is separated suade them, or try to get them, to come to manity. The benefit of humanity falls into from my lab, and that always dissatisfies me. the same conclusions as me rather than two categories. One is cultural, which is un- But I still do a lot of working and talking in direct or instruct them. derstanding the world better. This is a major the laboratory because I enjoy it so much. motivation for most people who will work However, there are two reasons behind People skills are among the hardest, and in it but it has to also be something that is of why I do ‘other things’ like administration. scientists aren’t trained for them at all, benefit to the world. By benefit to the world, One is self-doubt. I’m pretty good at but you’re pretty good at them it seems to I mean improving human health, the quality science, but worry that I’m getting over the me. of life and the creation of wealth. The insti- hill and never want to be a second-rate re- I like people and I have empathy for their tute has to significantly impact on these search scientist. Standards are really some- concerns. So when someone is worried things.

114 dmm.biologists.org Sir Paul Nurse A MODEL FOR LIFE

You can tell I’m a hopeless interviewer And what would you work on if you were nobody was taking much notice of what I because it’s only now that I’m going to just starting out now? was doing. ask you when you first became interested If I were starting out now, I’m not sure what in biology… I would do. I would give definite consider- So this is your advice to a young scientist. As a schoolboy I got interested in natural ation to the fly or the worm or to plants, so You’re not going to be able to make a big history. I was originally thinking of going that I could look into the whole problems of impression in one of the huge fields at the into ecology but it was just too complicated development. When I started on yeast, I moment. You have to try to define some- and too wet for me. So my passion for worked on cell division because it was very thing interesting that no one else is biology developed from an interest in tractable but I actually thought that it was working on. natural history from the age of about 11, going to be a stepping stone into That’s exactly right. At the moment, search and that developed into a real profound in- development. committees often say, ‘Why aren’t you terest in how living things work. I chose working in stem cells or something else that problems that I felt I could address and be So you’re a frustrated developmental is topical?’ But in reality, you’ve got to take successful in, like cell division. A problem biologist? a risk to work on something else other than like ‘How do we think?’ isn’t a problem I Yes I am and I thought a lot in the early 70s the mainstream. would take on as I think it’s too difficult. about going into development, and I never I was lucky and I managed to be success- That doesn’t mean we shouldn’t pursue it, made it because of the great attractions of ful, but I had quite a lot of difficulties prior but for me it wouldn’t have been satisfying yeast. to that. I would go for jobs and people because it is just so complicated. would say he’s not really working on the I’m just thinking of a headline for this cutting-edge science. By cutting edge they You have an interest in astronomy too piece – Paul Nurse: a frustrated develop- mean is it published in Cell, Nature or Well, natural history for me includes as- mental biologist – as a developmental Science, otherwise it is not an interesting

DMM tronomy as well – observing the natural biologist myself I quite like that! topic. As a young scientist, you should iden- world, plants, birds and insects, the stars It’s true! As an undergraduate I worked on tify problems that are interesting to you, and the planets for me. So my driving force fish and I thought about Arabidopsis and take a risk and stick with them. Let your is a strong curiosity. People get driven to do more complicated systems but yeast is so passion lead you. science in different ways, some people get attractive that I never left it. Dr Jim Smith, the interviewer for this driven to be successful and beat everybody I took a risk at the beginning to work on piece, is the Editor-in-Chief of the journal else. something that wasn’t that interesting for Development and was recently appointed most people. At the time when I was Director of the Medical Research Council But you must have an element of that working on cell division the interests were National Institute for Medical Research. He too… elsewhere: it was all cot and rot curves and and Paul Nurse were brought up and went I do but it isn’t my primary driving force. hybridization and the beginning of molec- to school in the same part of London. My primary driving force is curiosity ular biology. That’s one reason why I got Although they did not know each other as coupled with coming up with good expla- nowhere with my job opportunities and children, they discovered during the course nations for scientific problems. I don’t want offers early on, and so on, because I wasn’t of editing this interview that Paul bought his to do research where if I can publish in in the mainstream, and this is why I’m so sweets in the sweet shop owned by Jim’s October I’ve won and if somebody pub- down on having too strong programmatic Uncle Albert. Disease Models & Mechanisms lishes in November they’ve lost. That is of and strategic visions for a new institute: you DMM greatly appreciates Sir Paul Nurse no interest to me. Occasionally you get in have to get the best individuals rather than for sharing his story, and thanks Jim Smith those situations, but it’s not what drives me. decide on a programme. But this gave me a for his time and for coordinating this inter- I’m sufficiently competitive that I want to be lot of headroom because although I often view. The interview text has been edited and doing interesting projects successfully, but worked alone, with one of two people at condensed by Jim Smith and Nicole I don’t get driven by wanting to get it pub- most, until about my mid-30s, I had very Garbarini, Associate Reviews Editor for lished one month before someone else. little competition up to that point because DMM, with approval from the interviewee.

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