The cell cycle and beyond: an interview with Paul Nurse

As his fellow Nobel Laureate Tim Hunt has said, it is difficult to think of an abler, or more imaginative and accomplished, biologist alive today than Paul Nurse. One might add the word versatile to this description, for on the other occasion I have written about Paul it was to introduce his published lecture, delivered to Christ’s College Cambridge, on Two Views of Creation: Milton and Darwin: there aren’t many scientists who would attempt such a synthesis! That short piece, and Paul’s Nobel Prize autobiography (http://nobelprize.org/nobel_prizes/medicine/laureates/2001/nurse-autobio.html), provide many of the facts about Paul’s life and scientific career: about his early life and the prescience of Professor Jinks at Birmingham University, who allowed him to start his degree without the required qualification in a foreign language; about how he discovered that cdc2 regulates the onset of S-phase and mitosis in fission yeast; how he and Melanie Lee cloned the human CDC2 gene using a ‘rescue’ approach; and about his responsibilities as Director General of the Imperial Cancer Research Fund, which he went on to merge with the Cancer Research Campaign to create Cancer Research UK. An addendum to the Nobel Prize autobiography also describes how Paul felt when he discovered that the man and woman he thought were his parents were actually his grandparents, and that his biological mother was the young woman he believed was his sister. We did not discuss this part of his life to any extent, although Paul did comment that his working class background might have contributed to his ability to interact with people from all walks of life.

The interview that follows took place on the telephone on 21 October 2008; it has been edited only very slightly, and we have resisted the temptation to change the idiosyncratic order of my questions!

You managed to define fundamental parts of the human cell cycle machinery using a simple single-celled organism. How did you come to the conclusion that yeast was the model organism for you and your lab?

I originally became interested in the problem of cell division not so much because of its relevance to human disease, but because cell division was the basis of all growth and development. The process of reproduction is a crucial characteristic of all living organisms, which is seen at its simplest with cell division. Having got attracted to studying the basic process of cell division, I wanted a model system that would be efficient and effective with which I could make rapid progress. I chose a single-celled organism, good for genetics, and which did little else except divide. This meant using bacteria or yeast. Bacteria were clearly different from eukaryotes, so I went for yeast. There were just two papers in this area on budding yeast from Lee Hartwell and he showed that it was a good approach, so I wasn’t taking such a big risk in trying to develop such an approach with fission yeast.

The connection with human biology came later, when gradually I realised that we had identified important elements in yeast that were crucial for control and there was a possibility that these were conserved among the eukaryotic world. Some years before the key experiments, I had tried, unsuccessfully during the time I was in Sussex in the early 80s, doing some experiments with MPF, maturation promoting factor, in Xenopus with Chris Ford. These experiments gave hints, but they were never strong enough to be published. So the possibility of a human link was always in the back of my mind and later I thought we could just go for broke and look for human CDC2 protein kinase. If this worked, it was probably going to work the same way in every eukaryote from human through to yeast. I suppose the most astonishing thing was the way Melanie Lee in the lab did it by complementation. The ways that we had tried previously relied on structural similarity – we’d used Southern blotting, but it was just too crude. We were getting lots of protein kinases but we had no idea if they were the right ones. We were lucky to get the complementation approach to work. The principle was a good one but we had fortune on our side that it actually worked.

You have stuck with yeast throughout your career. Have you ever thought of working with any other organism?

I’m nervous about working with any other organism; I understand yeast biology really well and, particularly now that I do other administrative things like running institutions, if I’m going to be helpful to my colleagues in the lab I need to be really familiar with the system they are working on. I am familiar with fission yeast and thus I can still be helpful to colleagues in a way in which I wouldn’t be able to do if I was to work on flies, worms or frogs, because I have never worked with these organisms with my own hands. The other reason is in line with Barbara McClintock’s great quote that you need to have a feeling for the organism you work with, and I have a feeling for yeast. I can pretend to be a fission yeast and I can do it quite well. I can sort of imagine how a fission yeast feels, and it sounds crazy of course, but I can’t so easily imagine how a fly feels. If I was starting again today, I would think very carefully about whether I wanted to go more in the direction of problems to do with the cell, in which case I would stick with yeast, or problems to do with the organism in which case I would go for the fly or worm. I still wouldn’t go for work with human, mouse or Xenopus. I think Xenopus is very good for the in vitro systems but they are just a little too complicated and I’m driven by more genetic approaches.

Let me pick up on your remark about running institutions – you’re President of Rockefeller, before that you ran Cancer Research UK, and now you’re also heavily involved in the UK Centre for Medical Research and Innovation (UKCMRI). What made you turn to this administrative kind of work in addition to doing your science?

I personally enjoy, most of all, working and talking with people in my laboratory. It’s really what gives me the greatest pleasure. I like looking at data. I like looking at experiments. I like looking at cells. I like talking to my graduate students and post-docs about what they do. I do a lot of it. People often have no idea that I spend hours and hours each week doing that, and that I’m still very engaged. I feel I can never do enough of it because my office is separated from my lab, and that always dissatisfies me. But I still do a lot of working and talking in the laboratory because I enjoy it so much.

However, there are two reasons behind why I do ‘other things’ like administration. One is self-doubt. I’m pretty good at science, but worry that I’m getting over the hill and never want to be a second-rate research scientist. Standards are really something I respect, and I apply it to myself as well as to others. So I always wonder, am I good enough to still be supported on my research alone? The answer to that is probably yes, but I worry about it, and if I do something else that contributes to the community like running things I feel less guilty about it.

So you’re covering your arse, as it were?

I guess you’re right – I’m covering my arse. Another reason I work on these administrative tasks is that often the people who get attracted to running things are not always the people you want to run things. People who are totally engrossed in the science and who are still close to the coalface are the right people to be running research science. I’m quite good at it and it means that there is a real scientist doing it rather than a scientific administrator.

You are good at it – what qualities do you have that make you so good?

Overall, I think I’m a conservative radical. What I mean by that is I’m basically radical, but I will only try and bring about radical change from a very strong base. In other words, merging the Cancer Research Campaign and the Imperial Cancer Research Fund was quite a radical step but was done from a very secure base. I don’t tend to do radical things without a lot of preparation and a lot of thought about whether it will work. Only then am I prepared to take a risk. I do take risks but I take them only when they are really well considered.

Some of my friends say I am good at it because I’m a Machiavellian bastard. It’s literally true that I am a bastard and perhaps I can be Machiavellian as well. The Machiavellian bit is most to do with the fact that I try to avoid direct confrontation with people. When I talk to people I try to persuade them, or try to get them, to come to the same conclusions as me rather than direct or instruct them.

People skills are among the hardest, and scientists aren’t trained for them at all, but you’re pretty good at them it seems to me.

I like people and I have empathy for their concerns. So when someone is worried about their job, I have empathy for them. When you’re putting yourself into the shoes of the person you are talking to, it does help. Quite often, I have had to tell people that they haven’t got tenure or they have to leave and things like that, and this is deeply uncomfortable and unpleasant. The point is you have to be sitting in their shoes to do it well and that may be what helped me here – that I was not born with a silver spoon in my mouth, if I can put it that way. Having had a lot of difficulty getting jobs early on in my life, having worked on short-term contracts and so on, and having been rejected by a number of institutions that I applied for, I’m used to failure and that remains with you. When I’m talking to somebody who has failed at something, I know I’ve been there too. I’m aware of people’s feelings and share their distress.

Let me change the subject to the UKCMRI. This is a huge new Institute and a fantastic new opportunity. What problems do you want UKCMRI to address and solve?

I would like it to be a powerhouse for the highest quality biological and biomedical research. The main thing I would like to aim at is an institute of the highest quality, a place that thinks broadly about how to achieve that, and that will work over decades and not just a few years. That’s why I don’t focus so much on the programme side because all that will change within 5 to 7 years. What concerns me is the basic structures by which the institute operates that will generate the highest quality biological and biomedical research and will influence the world.

Influence the world in what way?

By understanding life and understanding how living things work for the benefit of humanity. The benefit of humanity falls into two categories. One is cultural, which is understanding the world better. This is a major motivation for most people who will work in it but it has to also be something that is of benefit to the world. By benefit to the world, I mean improving human health, the quality of life and the creation of wealth. The institute has to significantly impact on these things.

You can tell I’m a hopeless interviewer because it’s only now that I’m going to ask you when you first became interested in biology…

As a schoolboy I got interested in natural history. I was originally thinking of going into ecology but it was just too complicated and too wet for me. So my passion for biology developed from an interest in natural history from the age of about 11, and that developed into a real profound interest in how living things work. I chose problems that I felt I could address and be successful in, like cell division. A problem like ‘How do we think?’ isn’t a problem I would take on as I think it’s too difficult. That doesn’t mean we shouldn’t pursue it, but for me it wouldn’t have been satisfying because it is just so complicated.

You have an interest in astronomy too

Well, natural history for me includes astronomy as well – observing the natural world, plants, birds and insects, the stars and the planets for me. So my driving force is a strong curiosity. People get driven to do science in different ways, some people get driven to be successful and beat everybody else.

But you must have an element of that too…

I do but it isn’t my primary driving force. My primary driving force is curiosity coupled with coming up with good explanations for scientific problems. I don’t want to do research where if I can publish in October I’ve won and if somebody publishes in November they’ve lost. That is of no interest to me. Occasionally you get in those situations, but it’s not what drives me. I’m sufficiently competitive that I want to be doing interesting projects successfully, but I don’t get driven by wanting to get it published one month before someone else.

And what would you work on if you were just starting out now?

If I were starting out now, I’m not sure what I would do. I would give definite consideration to the fly or the worm or to plants, so that I could look into the whole problems of development. When I started on yeast, I worked on cell division because it was very tractable but I actually thought that it was going to be a stepping stone into development.

So you’re a frustrated developmental biologist?

Yes I am and I thought a lot in the early 70s about going into development, and I never made it because of the great attractions of yeast.

I’m just thinking of a headline for this piece – Paul Nurse: a frustrated developmental biologist – as a developmental biologist myself I quite like that!

It’s true! As an undergraduate I worked on fish and I thought about Arabidopsis and more complicated systems but yeast is so attractive that I never left it.

I took a risk at the beginning to work on something that wasn’t that interesting for most people. At the time when I was working on cell division the interests were elsewhere: it was all cot and rot curves and hybridization and the beginning of molecular biology. That’s one reason why I got nowhere with my job opportunities and offers early on, and so on, because I wasn’t in the mainstream, and this is why I’m so down on having too strong programmatic and strategic visions for a new institute: you have to get the best individuals rather than decide on a programme. But this gave me a lot of headroom because although I often worked alone, with one of two people at most, until about my mid-30s, I had very little competition up to that point because nobody was taking much notice of what I was doing.

So this is your advice to a young scientist. You’re not going to be able to make a big impression in one of the huge fields at the moment. You have to try to define something interesting that no one else is working on.

That’s exactly right. At the moment, search committees often say, ‘Why aren’t you working in stem cells or something else that is topical?’ But in reality, you’ve got to take a risk to work on something else other than the mainstream.

I was lucky and I managed to be successful, but I had quite a lot of difficulties prior to that. I would go for jobs and people would say he’s not really working on the cutting-edge science. By cutting edge they mean is it published in Cell, Nature or Science, otherwise it is not an interesting topic. As a young scientist, you should identify problems that are interesting to you, take a risk and stick with them. Let your passion lead you.

Dr Jim Smith, the interviewer for this piece, is the Editor-in-Chief of the journal Development and was recently appointed Director of the Medical Research Council National Institute for Medical Research. He and Paul Nurse were brought up and went to school in the same part of London. Although they did not know each other as children, they discovered during the course of editing this interview that Paul bought his sweets in the sweet shop owned by Jim’s Uncle Albert.

DMM greatly appreciates Sir Paul Nurse for sharing his story, and thanks Jim Smith for his time and for coordinating this interview. The interview text has been edited and condensed by Jim Smith and Nicole Garbarini, Associate Reviews Editor for DMM, with approval from the interviewee.