Albert Lasker
Basic Medical Research Award

An Interview with Paul Nurse
Interviewed by Dr. Gerard Evan

Dr. Gerard Evan interviews Lasker Award winner Paul Nurse, September 1998. Dr. Evans is currently the Service Chief for the Infectious Diseases Service of the Southeastern Ontario Health Sciences Centre and has an interest in medical education, both at the undergraduate and postgraduate level, antimicrobial use, clinical trials in new anti-infective agents, and home parenteral antibiotic therapy. Active interests in the sphere of clinical infectious diseases include infective endocarditis, sexually transmitted diseases, fungal infections, and CAPD peritonitis.

Part 1: Interest in the Cell Cycle Sprang from Desire to Do Something 'Important'
Paul Nurse describes his genetic approach to cell reproduction and tells interviewer Gerard Evan how a grueling night in the laboratory as a graduate student prompted him to search for something "interesting and important" to work on. Nurse then details why he chose to study the cell cycle in yeast.

Evan: Hi, my name is Dr. Gerard Evan, and I'm interviewing Dr. Paul Nurse, who is a joint recipient of the 1998 Lasker Award for his work on the cell cycle. Paul, can you describe to me what you work on?

Nurse: Yes, Gerard. I have been interested, in fact for many years, more years than I would like to remember, in the cell cycle—that's the process by which cells reproduce themselves—from one to two. And I've taken a genetic approach to this problem, working with a very simple organism, yeast—that's a single-celled fungus. And I've isolated mutants, which are altered in the cell cycle and its control, and then studied these mutants to find out what the basic process is that is underlying the cell cycle. And then used these mutants to clone the genes and then establish what the molecular basis of how they work might be. By using these various approaches, you can then work out exactly what molecules are controlling cell cycle progression and how they are regulated.

Evan: As you say, you've been working for a very long time on the cell cycle. So why is this? Is it because it is innately so interesting? Or does it tell us a lot about other aspects of biology, or is it relevant to particular diseases, or what?

Nurse: Well, I have to say, my interests in the cell cycle, they started when I was a graduate student. And I was working all night with a machine that was actually in the development stage, so it kept breaking down. I remember I had to keep putting rubber bungs in all the safety switches to keep the thing working. And this was extraordinarily tedious, and my mind drifted off into other things about what sort of better world might there be somewhere else outside of this room with this little machine. And I thought it's very important, if you are going to suffer like this doing science, to actually work on something that's interesting and important. And the cell cycle came to mind then for several reasons.

The first is that one of the basic properties of life is its ability to reproduce. And that is seen in its simplest and most basic form with the reproduction of a cell, during the cell cycle, the division from one to two.

In fact, the reproduction of all living things, including complicated organisms, such as human beings, can be understood in terms of the division of a cell from one to two. So, it was a process that was central to understanding life, of defining one of the major distinguishing characteristics of life. So that was one reason.

A second reason was that the cell cycle is an example of a simple developmental pathway. Now, lots of biology has got to do with development, but it's usually quite complex. Whereas, the growth and division of a cell, although actually quite complicated, is relatively simple compared with most development that we're trying to understand. I mean, working out how a frog is made is certainly much more difficult than working out how a cell is reproduced.

Evan: So this is the advantage of yeast as a single-celled organism, when doing this sort of thing?

Nurse: It is, indeed, because a yeast is so simple that it barely does very much more than actually reproduce itself...and make beer and bread, of course. Many of the genes that it has are really devoted towards this process of cell reproduction. And the point about this is this—that I felt this was an example of a simple developmental sequence which, in principle, we could perhaps one day completely understand. Whereas, I think it will be a very long time before we understand how, for example, a tadpole is made. So that was another reason—that we could understand a developmental sequence in detail.

And the final reason was that because cells are in all living organisms, because they all have to undergo cell division, there was the possibility that we were looking at a process that was likely to be universal across all of life. And that had its attractions because it meant that it was relevant to all different sorts of living things and situations. And also, that perhaps we could use a whole variety of different tools, exploiting the different advantages of different organisms, to actually work this problem out. So I think that was what originally attracted me to this. And I suppose it was mainly thinking well into the night whilst looking after this ghastly machine that prompted most of this.

Part 2: On the Need to Identify Crucial Elements Amid Biological Complexity
Nurse discusses the growing complexity of the cell cycle field and cautions that it is necessary to identify crucial elements. On the other hand, any biological problem is, indeed, complex, Nurse says, and figuring out how to analyze this complexity will be "one of the greatest challenges of the first half of the 21st century."

Evan: So, I mean, these processes that underlie all biological organisms, I mean, some would say that they are all very well, but the thing that distinguishes different organisms is the complexity of the processes. And certainly as an outsider to the cell cycle field, it looked very simple when it first started, and it has gotten immensely complicated. Every gene, every protein involved seems to have multiple copies, and the more complex the organism the more complicated the system. I do have this tendency when I read a review, that it seems to have gotten very bogged down in the detail. I mean how do you feel about this? Because the work that you did seemed to show that the underlying simplicity was the thing that was most important about it.

Nurse: Yes, I know what you mean. You know, when you read these reviews, it's a bit like looking at the underground map in London or the metro in New York. And you've got all these different things connected by these different lines. And it's difficult to sort out the wood from the trees. Well, I think this is a very interesting question you're asking here, because I think the answer is also complex. Some of this complexity is very real, and we have to face it, and some of it is, in a sense, generated by the work that's being done on it.

Now what do I mean by the latter? When one is faced with a biological problem, biology being very complex, I think the key question is to try and focus on those parts of the problem which are, in fact, illuminating and are most important. And the key is to try and approach that—there's different ways of doing that and that depends on the system to system that you use—but it's very important to hold that in your mind, because not everything is of equal importance in the system.

I think that at the beginning, the people who were working on the cell cycle thought a lot about this and tried to focus on those parts of it and those aspects which were, indeed, most important and which were particularly relevant for control. Now when the field became established, many more people became attracted to work on it. And they identified new aspects of it, because they were trying to perhaps make a new contribution that they naturally were excited about. And it may be that not all of this was actually of equal interest and importance. But when you now are trying to describe it all, what you have is a whole set of bits out there, and unless you really think about it very carefully, they may look as if they are all of equal importance, when, in fact, they are not.

And I think what is absolutely crucial here when we are thinking about problems like the cell cycle—in fact, any biological problem—is to try and get to grips as to what is, in fact, the crucial part of the problem. And that does get lost as more and more people get into a field and, perhaps, try and promote their little bit of it. And unless you are ruthless in your assessment of what's important or not, that can get lost. So that's what I meant by saying that maybe it may not be as complicated, in that sense, as perhaps as it was in the beginning.

In another real sense, of course, it is complex. There are many different steps that have to be carried out, and there are many different steps that we have to understand. There's no doubt that biology is about to move into a new dimension, where it has to cope with this complexity. And I would suggest that one of the greatest challenges of the first half of the 21st century will be managing this...how to analyze this complexity. We already see it with sequencing the genomes and identifying so many of the genes, and so on, that are there—that we are being overwhelmed with information, and we've got to make sense of that information.

And this is going to require new ways of thinking about it; analyzing complex patterns of data, the computer analysis that is required there; conceptual ways of thinking about how you cope with complex networks, mathematics there, the conceptual basis of dealing with that; actually putting together all these functions of molecules so that we know how they operate in real time and space. And I think that's another important issue there that often gets lost in most analysis—that we don't actually know what's happening in the single cell, in different parts of that single cell.

Part 3: The Importance of Interactions Over Space and Time
Biochemists "mash everything up" and loose sight of interactions over space and time beyond the local molecular interactions, Nurse says. He also notes that he is interested in turning his attention to larger-scale structures and to how cells organize themselves in space.

Evan: Most technologies give a static picture, I guess.

Nurse: We do! We lose the dynamics. We lose the information in space and time. What we do—we are biochemists—we mash everything up, and we lose this organization. And we have to put that organization back. Now, at first sight, that may seem as if it makes it more complex, but I have a feeling that when we put that extra information back (which is only the information that is present in life itself) that in fact there's a chance that it may make some of this complexity more straightforward. Because, once again, I suspect it will make us focus on that which is more important, rather than that which is simply necessary for something to work.

Evan: There also seems to be a problem—I don't know what you think of this—when you're teaching, which I sometimes call the hardware/software problem, which is when people come into science at the undergraduate level, they often think there's a basic machine and then the system that regulates it. And, of course, in biology it's all mixed up.

Nurse: Yes, that's quite right. In some ways, the analogy of the software program driving the computer is not such a useful one, but because we are now so computer-minded, we're starting to think like that. As you absolutely are right to say, the information flow—which is really what you mean by the software—the information flow is built into the hardware. There are some interesting issues here. The fact is that we tend to think about biology and molecular biologies as interactions of molecules at a very local level—that is, one molecule touches another, and it's limited over space and time in a very limited way. Whereas, in a living system, although that's extremely important, there is also communication between different regions of the cell, at different times in the life of that cell, as well as, of course, between cells. And this requires transduction mechanisms, means of detecting information, means of transferring information. And all that adds an extra dimension and expands the interactions over space and time beyond the local molecular interactions. And there's a lot of exciting stuff in there that I think we have really barely got to grips with yet.

Evan: So, I mean, obviously there is a lot of complexity, and I guess for younger scientists, they're all trying to carve out their particular gene or process. And that's why, in a sense, more and more information comes out, and it's quite difficult to consolidate it. From your point of view though—you've made some of the very important basic discoveries in the basic mechanisms of the cell cycle—do you now ever get the feeling that there may be other things that you would become interested in or have become interested in?

Nurse: Yes, I do, because I also have to recognize what my own limitations are and what hopefully some of my strengths might be. And I'm very much a biologist. In some ways, quite a lot of the cell cycle—this isn't yet quite true, but may be in a relatively few number of years—that we understand the basic outline of how the cell cycle works. And perhaps much work now has got to work at a rather more detailed level, which is perhaps not my particular forte. Increasingly, I'm thinking about other issues which I think are important and central to life where I can take a more biological approach, where I think my own skills perhaps are best found.

And another problem which very much interest me, it's certainly related to the cell cycle, is how cells organize themselves in space. You know, we're not going into Star Wars or anything here. What I mean is that...the point about biology is that it is extended in time and space. What we have is a cell, which although the basis of it is molecular interaction, is, in fact, extended over a much larger scale.

Evan: Large-scale structures.

Nurse: Exactly. And so how is that organized? How does a cell know what a front end is from a back end? How does a cell know where its middle is? How does it grow in particular directions? There's a whole series of problems there, which are to do with organizing itself in space, which are relevant, of course, also to larger organisms. I mean, I'm looking at a fish in an aquarium over here, which has got extraordinary shapes. How are these actually made? I think this is one of the wonders of life, yet another characteristic of life. Just like reproduction is seen in the dividing cell, the generation of form—which is a central characteristic of life—is also seen in the single cell and perhaps has not received as much attention as, for example, developmental biologists have given to the acquisition of form at a bigger scale in the formation of embryos and adult organisms.

Evan: So, is your thought then that perhaps large-scale structures are sort of just iterations of the processes that allow a cell to know where its back and front is, and where its middle is?

Nurse: No, I don't. I think that the problems are analogous, rather than homologous, by which I mean that I don't think the same molecular mechanisms will be involved, but I think the ways of thinking about the problem...

Evan: So maybe the same sorts of general rules...

Nurse: There may be general rules that can be derived. And I, as before, think that understanding this in single cells will be simpler. And because all living things are made of cells, there may be, as with the cell cycle, universal answers to the questions of how a cell organizes itself in space. Whereas, I suspect that the way in which this fish is organizing the structure of its fins will have differences compared with the way in which we organize our feet. I'm, of course, very much aware that there are conserved systems, so that it is interesting to think about the conservations. But I suspect that it will be much more conserved at the level of the cell than at the level of the organism. I could be wrong there, but that's my view.

Part 4: Nurse to Young Science Students: Be 'Totally Motivated,' Curious and Bold
Nurse tells Evan that curiosity, above all, keeps him motivated. Asked to offer advice for young people going into science, Nurse says they need to the "totally motivated" because this is a difficult profession. Curiosity and boldness are pluses, he adds. And finally, he notes, "completely ignore the advice of your elders."

Evan: Okay, so I mean, anyone looking in from outside would say, "Hey, this guy has spent the last 20, 25 years working on one particular thing. He's at last thinking about perhaps getting involved in some other things." To most people this sounds either crazy, bizarre or as though we are mentally ill (and, of course, a lot of people would think scientists are). What keeps you interested in your work and keeps you motivated?

Nurse: I think really I can answer that with one word, and that's curiosity. Scientists can be motivated by different things, actually. That's one of riches of science. We shouldn't all try and be put in the same mold. Different types of scientists are good at different stages of the problem. Some scientists are motivated straightforwardly by competition, being the best in that field. There's nothing wrong with that. It means that they generally like being in the hurly-burly of competition and being the best in that situation. I'm not really quite of that sort. I think that I'm...

Evan: But they're all legitimate ways of deriving motivation, is what you're saying?

Nurse: All legitimate ways of driving motivation. I mean even, I suppose, it's perfectly legitimate to want to earn your salary. The problem is that in the U.K. we don't get good enough salaries for that to be such a motivation. At least the U.S. is much better in that respect. But what I was going to say is that, for me personally, I think it has to be curiosity. That is, I'm very curious about living things, and they fascinate me. I like thinking about the detail of a problem. I like concentrating really hard on particular problems which are very simply stated. I mean, I've stated them already. Like, you know, with respect to space, how a cell knows where its middle is. It sounds so ridiculously simple, but is, in fact, very fundamental. So I'm very naturally curious about that. I think that type of scientist, you can make a case that they've suffered from retarded development, because curiosity is something that is seen very much in young children.

Evan: And puppies.

Nurse: And puppies. And it usually gets knocked out of them by about 14, 15. I think often scientists, who in my scientific management role seem like a lot of adolescents most of the time, I think a common trait is retarded development, which maintains curiosity to late in life.

Evan: So, obviously younger people coming into science, I mean, they're going to look at you and they're going to say, "What do you advise for me?" Did you have any advice for younger people coming in?

Nurse: Well, given what I have just said, clearly you have to be totally motivated, because it is a difficult profession. And often it can be depressing, because if you're working on something important, and you're at the cutting edge, then frequently you will fail, perhaps even 90 percent of the time, in what you're trying to do. So you have to be highly motivated. So I think that's absolutely certain. I am clearly going to also promote, from what I have just said, curiosity...is extremely important. To remain curious, not only is it wonderful—nature and what's around us—but curiosity is a very good motivator.

Secondly, I would argue strongly for boldness. Be bold, aim high, try and address something that's very important. Not only is that satisfying, but why waste your time on something that isn't bold. You know, at least aim high, and you never know, you might get to it. And I suppose the last thing I have to say is really to repeat what Max Perutz said when I think he was asked this question: That is, completely ignore the advice of your elders.

Evan: Paul Nurse, thanks very much, indeed. It's been a pleasure talking to you.

Nurse: Thank you, Gerard.