Image: ICRF

Paul Nurse is one of Britains most distinguished scientists today. His groundbreaking work on the cell cycle in the 1970s and '80s revealed how cells make the decisions to grow and divide, thus laying the foundation for a molecular understanding of cancer. This has earned him numerous honors, including the Lasker Basic Medical Research Award in 1998, and many regard him a prime candidate for the Nobel Prize. Since 1996, Sir Paul, who was knighted last year, has also been director-general of the largest cancer research organization in the U.K., the Imperial Cancer Research Fund (ICRF).

I met Paul Nurse at the Cold Spring Harbor Laboratories in New York on a sunny afternoon in June, just a few hours before he was to give a talk to several hundred scientists attending the 65th CSH Symposium. Since alcohol-free beer was not available at the bar, he brought a bottle of Perrier water outside with him, where we planned to chat. I had a cup of English breakfast tea, hoping it would help tune my brain to his accent.

With his white shirt partly unbuttoned and his sleeves rolled up, Nurse did not give the immediate impression of someone in charge of 1,000 scientists, clinicians and technicians. But his appearance didnt fool anyone at the conference. Many people greeted him with respect as we made our way outside, fully aware that he is a scientific heavyweight. A biologist at heart, Nurse directed us to a tree, where we sat down on the grass; the birds sang above us, and only the occasional airplane disrupted the peaceful atmosphere of the labs. Highlights from our conversation follow.


SA: When did you decide to become a scientist? Was that quite early, or only at university?

PN: Well, I think actually already as a schoolchild. I remember seeing Sputnik 2 when I was in London. As a young child, eight or nine years old, I read about it in the newspaper and went out in our garden and saw Sputnik 2 fly over, I think in 1957 or 1958, and this was truly amazing. And then when I was a little older I became interested in natural history, and I watched birds, and I collected beetles, and was interested in plants and so on. So my main entre into biology was through natural history. I think that is quite common.

SA: Was it always clear you wanted to become a biologist, not a physicist or an astronomer?

PN: Yes, but I became a bit "harder," if you like, as I got older, because originally I was more interested in natural history and ecology, and then I found it so difficult, because the laboratory of this field [pointing to the grass] is too uncontrolled. So as I grew older, as an undergraduate and then as a postgraduate, I really wanted to work more on molecular and cellular things, because you could do controlled experiments so much better.

SA: So that led you into biochemistry rather than "old-fashioned" classic biology?

PN: Yes, into biochemistry rather than the "fur and feather."

SA: Who do you consider your most important teacher?

PN: I had a very good teacher of biology at school, who I recently met again actually, a man called Keith Neal. Then I think a very important person was my postdoctoral advisor, when I was in the University of Edinburgh, Professor Murdoch Mitchison, who gave me great freedom as a young investigator and allowed me to work in my own way. I owe him great debt for that. He encouraged me, he spoke to me, but he really made no attempt to control me, a very good situation.


THE CELL CYCLE

SA: You are mostly famous for your work on the cell cycle, the cell machinery that controls cell division in eukaryotes. Could you explain what your most important discovery was?

PN: I think the most interesting discovery that I made was to identify components of what is now sometimes called the cell cycle engine. All humans are made up of billions of cells, and they grow and divide. The process that brings about the reproduction of cells is called the cell cycle. I have been interested for many years in what controls progression through that cell cycle, what regulates the cell division process.

I have mostly worked on a very simple organism, a single-celled organism called fission yeast. Its not a very useful organism; it isnt even very good at making beer or wine or bread, so its not like bakers yeast, but it is quite a good model for looking at cell reproduction. Following Lee Hartwell's work in budding yeast, I isolated mutants that were defective in the process of cell division, and these identified genes that were important for the cell division process. In particular, one of these genes called cdc2 turned out to be very important for controlling the cell cycle.

This was originally demonstrated by the fact that when it was made more active, it actually made the cells divide more rapidly than normal. This meant it had to be in some way rate-limiting for the whole cell division process. For most of the genes required for the cell cycle, that isnt the case. You can make them more active, and they dont make the cells divide more rapidly. My laboratory then went on, in yeast, to establish what cdc2 did: it encodes something called a protein kinase, an enzyme that puts phosphates onto other proteins. Thus it modifies these other proteins and changes their activities. Its a way of triggering lots of changes in the cell in a very simple way.

Cdc2 is a special sort of protein kinase called a cyclin-dependent kinase. It turned out that this particular one controls when the DNA is copied, which is necessary in every cell cycle, and also when the DNA is separated during the process of mitosis. So it controls the two major processes found in every cell cycle. That was in fission yeast, and other workers, particularly Lee Hartwell, working in budding yeast, identified a similar gene, Cdc28. The fission yeast work started quite early, in 1975. It still continues, but the basic story was in place by 1990, so it was a period of 15 years.

But by the middle '80s, I realized that people were not that desperately interested in yeast, really, so I wanted to see whether the mechanisms that we had unraveled in yeast applied to other organisms, and I looked for the gene equivalent to cdc2 in humans. But it was very difficult to find, because there are many protein kinases. This type of enzyme is rather common, so it is easy to be misled. Melanie Lee in my lab used a rather unusual approach: she took a library of human genes and then placed them on yeast cells that had been treated in such a way that they would take up the DNA of the library. She put them on yeast cells that were defective in cdc2 and so couldnt grow. The idea was, if there was an equivalent gene to cdc2 in humans, then any yeast cell that took it up would now be able to grow and divide. This approach worked, and she pulled out the human equivalent of cdc2. And what this showed is that in fact, you could substitute the yeast gene with the human gene, even though these two organisms had diverged hugely in evolutionary terms, maybe 1,000 million years ago, and that the human gene could work perfectly well in yeast. That obviously implied that the way in which the cell cycle was controlled is basically the same in all living things, from yeast to human cells.

SA: Were you aware of that? Nowadays with the genomes of several organisms sequenced, including budding yeast, everybody knows that it is a good model system for humans. Was that the case in the '70s? What made you so sure at the time that these studies would have wider implications?

PN: Well, I wasnt sure at all. I thought that understanding it in yeast would be useful, and I hoped that in fact it would be the same. But frankly, I was by no means certain. Looking back, maybe I should have been more certain. The basic processes of DNA replication and mitosis looked pretty much the same, so maybe it wasnt so surprising that these controls are also similar. Now yeasts are considered good model systems for looking at all sorts of problems, not only the cell cycle but others as well, but it really wasnt the case in the '70s or even the '80s.

SA: Now they are even studying yeast in order to find new cancer drugs. As you are the director of a cancer research institute, may I ask you, what does the cell cycle have to do with cancer?

PN: I think there are two connections that are of interest: one is that cancerous cells are undergoing cell division in an uncontrolled way; they have to activate this engine, the cyclin-dependent kinase engine. Understanding how that works is important for understanding how you activate the reproduction of a cell in cancer. My own view is, although that is interestingand it may identify new targets for cancer therapyits perhaps not that important, because all cells have to activate the same cell cycle engine, whether they are cancerous or not.

My own view is that the main reason is a little less direct, and that is as follows: Cancer is basically a somatic genetic diseasethat is, you get errors in the copying of the genome. It is those defects, or errors, that generate the cancer. The cyclin-dependent kinase, the core engine, has to activate S-phase and mitosis when the cell is ready to do that. If there are defects, such as DNA damage or incorrectly replicated DNA or incorrectly segregated chromosomes, then you have to stop this cell cycle engine. In cancerous cells, there are defects in these controls that link mistakes in copying the DNA or DNA damage, for example, that allow cells to survive even though they have got this damage.

SA: These controls are the so-called cell cycle checkpoints?

PN: Exactly.

SA: Do you think our present knowledge of checkpoints will directly lead to new cancer drugs, and do you actually know an example of a drug under study right now?

PN: I do think that this is the most promising avenue. At the moment there are a number of drugs being investigated in pharmaceutical companies, but there is nothing yet that is being used therapeutically. But I suspect that even very traditional treatments may end up having some effect on checkpoints. You know, the classic treatments like radiotherapy, damaging DNA. Originally it was thought that radiotherapy would kill dividing cells. But I think that actually it is more likely that cancerous cells will respond differently to DNA damage than normal cells because they are altered in the checkpoints that we have been talking about. I think some current therapeutic treatments are crude ways of killing cancerous cells because they are modified in checkpoints, but our knowledge of them is likely to lead to much more specific and better ways of treating cancer.

SA: Could you give an example of a particularly good target?

PN: p53, which is very frequently damaged in cancerous cellsmaybe half of all cancers are altered in the p53 geneis almost certainly involved directly in checkpoint controls. I think thats perhaps the best example.

SA: What would be the rationale for a drug acting on p53?

PN: I think there are different ways that you could imagine it working. What we have to recognize is that these cells that are defective in p53 will be able to divide when they have suffered DNA damage. If we can just push these cells to divide more readily, when they have accumulated a lot of DNA damage, we may be able to get better specificity. Its more to do with looking at the consequences of p53 activity, in my view, rather than p53 itself. To encapsulate that: these cells are already defective in checkpoints. And what we need to do is to exploit that to find ways of speeding them up and damaging them more, so they cant recover and die more quickly, compared with normal cells.

SA: When would you expect such a novel treatment based on basic cancer research to become available? Is that a question of 5, 10, 15 years?

PN: I think people always underestimate how long it takes to get novel treatments developed. They often think its just around the corner, and often scientists perhaps encourage that too much as well. Generally, it takes 20 to 30 years for a new treatment to emerge. And what people often dont realize is that the mainstay treatments that we have in the clinic today are based on basic research that might have been carried out in the 1950s, for example.

A really good example that is not to do with cancer is infectious disease. Pasteur established the basis of disease, the infectious agent, in the 1870s. But the first really effective treatment was penicillin in the 1940s. It took 70 years of really quite a bit of extensive research to translate that new knowledge into a really effective treatment. We can do it more rapidly now, but it does take a long time. So my guess is, there has been a fantastic new understanding of cancer in the last 10 yearsthats real, there is no question about thatand I think we will see the benefit of that for the clinic in the next 10 to 20 years.

[Another good example is] a drug called tamoxifen, which is used to treat breast cancer and based on really quite simple biochemistry; it interferes with estrogen receptors. It was developed and researched 40 or 50 years ago and has been shown now, in work from ICRF, to be leading to very significant improvements in the survival of women with breast cancer. It is not a cure, but more people10, 15, 20 percentare surviving, and now you see for the first time, in both the U.K. and the U.S., that there is a real drop in breast cancer mortality in the last five to eight years. There are several reasons why, but tamoxifen is thought to be making an important contribution.

SA: Do you think epidemiological studies havent had enough support in the past?

PN: I think epidemiology is extremely important, and in fact ICRF supports some of the best epidemiological research in the world; actually, it is one of our strongest areas. Trying to understand the major environmental causes of cancer is very important. The influence of tobacco, for example, is of major interest for our epidemiology unit in Oxford. We [also] want to support more of what is called "genetic epidemiology," looking at the influence of the genetic makeup of people and how that interacts with the environment. It means, for example, that although we know tobacco consumption will cause lung cancer, it may be that some people are much more susceptible than others, depending on their genetic makeup. To understand the interaction between genetic makeup and the environment is extremely important. But its rather difficult to do it well. Everybody talks about it, but doing it well is another matter.

SA: Despite all this, you received the Lasker award two years ago for very basic research.

PN: That is correct, I am a basic scientist. Obviously I am responsible for this wide range of activities, but I myself am a basic scientist.

SA: You received it together with Lee Hartwell and Yoshio Masui...

PN: That is correct.

SA: ... and the prize is also referred to as the "American Nobel Prize."

PN: Yes, it is.

SA: Do you ever think of getting the Nobel Prize?

PN: Oh well, its best not to think about that, because it drives you mad, of course. So I try not to think about this.

SA: We will just wait and see....

PN: Exactly.

SA: You have two daughters, is either one planning to be a scientist?

PN: I have two daughters, that is true. One of them is, at the moment, a sports journalist at our local television station in Oxford, and the other is in her final year at Manchester University doing theoretical physics. So I have one who is a scientist and one who isnt.

SA: Did you ever encourage them to become scientists?

PN: No, but I would be quite pleased if one of them did. But I think they should make up their own minds.

SA: I also know you are a pilot. Do you think flying an airplane and heading a research institute have anything in common, or is it very different?

PN: Its very different, and I think thats why I am attracted to it. I am a glider pilot, mainly, and I fly gliders when I can at the weekend. Its really to do something totally different, having to concentrate on totally different sorts of things, like keeping this airplane up, and going in the right direction, and finding the up currents. Its a major relaxation because it is so different from what I do normally.

SA: Do you think you will always work on the cell cycle?

PN: I am still working on the cell cycle, but I also have a new area, which is related to the cell cycle, which is cell morphogenesis, or how a cell obtains its form, its shape. I think this is another very fundamental biological problem, like the cell cycle, which I find very interesting. It has some relevance to cancer also, because when cancer cells metastasize and spread through the body, they have to undergo a variety of cell shape changes to be able to escape from their tissue and to get into other places. But the basic mechanisms that control cell shape are simply not understood.

So my laboratory is doing screens, in yeast cells again, simply looking for yeast cells with funny shapes. Nothing very sophisticated, but the yeast cells I study are simple rods, and people in my group are looking for mutants which become completely spherical, or bent, or banana-shaped, or T-shaped, or branched, and this is yielding all sorts of interesting information about how global cell shape is controlled. It is a very interesting and actually very complex problem.

SA: What is your favorite hypothesis about how a cell knows, for example, where its middle is?

PN: This is exactly a question that is of interest for ushow does a cell know where its middle is? It is very simply stated, not so easily solved. There is no doubt that the cytoskeleton plays a very key role. Our mutant screens looking at cell morphogenesis have identified genes that regulate and interact particularly with the microtubules of the cytoskeleton, the rods inside a cell that make up a skeleton of a cell. I dont yet have a hypothesis, to be honest; our work is not yet sufficiently well developed, but there is no doubt that it is going to involve the organization of the cytoskeleton in a very global way, and I am very excited by that, much the way I was with the cell cycle 20 years ago.

SA: To take a slightly broader view, what do you think are the greatest challenges for biologistssay, in the next 30 yearsnow that we have full knowledge of our genes?

PN: Talking as a cell biologistI think there are interesting problems in understanding the environment, which is somewhat outside my own expertisebut talking as a cell biologist, I think it is extremely exciting, because the cell is the simplest example of life; it has all the properties of life. If we are going to understand what life isthe wonderful phenomena of lifeI think understanding how a cell works is the real way into it. A yeast cell is one of the simplest examples of that. It only has 5,000 or 6,000 genes, and its somehow comprehensible.

What we have got to do is be able to understand how a cell operates in real space and real time. What we have not had so much in our studies to date is a knowledge of how chemical processes become extended, so that they operate over the large domains of a cell. Chemistry underlies the action of life of a cell, but molecular interactions are very local, whereas in actual fact, the cell is organized over microns. And whats fascinating is how a cell can organize itself in space. That obviously touches with my own research.

Now that we have a list of the genes, which make up yeast, its a bit like having the actors in the play but no script. What we now have to do is to write the script. That is going to require an interdisciplinary approach. We are going to need new ways of investigating the processes. We are going to have to involve physicists and chemists and mathematicians, to look at the intricate networks that are involved. I think you are going to see biology really widen out in the next 30 years, and its going to be extremely exciting.

SA: In that context, do you think the increasing privatization of research will affect biology, or has already affected it?

PN: Yes, I think it has, and I am worried about it. Many scientists including myself fear, of course, the conflicts over the public and private human genome sequencing projects, and I personally am totally committed to this information being in the public arena. I think there will always behowever its dressed upa threat when this information is owned by a company, because they would want to protect their interests. It is not in their interest to share it with everybody else. So I think the basic structure and information upon which later inventions have to be based should be in the public arena, and I think there is a risk if the community start getting into the private arena too fast.

Obviously, there is a need for involvement of private industry, but I think more so when there is something very clearly identified. If all this basic foundation is privately owned, then we are going to see real inhibition of progress. I think that must be resisted at all costs. We have heard strong statements, from the president of the U.S. and the prime minister of Britain, protecting open public ownership of this information, and they mustnt be allowed to dilute those statements.

SA: Have you had any personal experience with cancer in your family or among friends, and did that change your view of cancer research?

PN: Because I am director-general of ICRF, it actually means that I meet now many people that have been affected by cancer. So although in my own family I have not, one of my friends certainly has. He survived, but that was really a tough time, and it was quite an experience for me. I meet many survivors who have become our supporters. Because the Imperial Cancer Research Fund is a charity, we have to raise the money to support our work, and this requires me to meet people who are committed to the charity. They are often people who either have suffered from cancer or their relatives and friends have done so.

It makes me realize that cancer isnt simply an academic problem, that it is a problem that obviously influences in very important ways peoples lives, and I think that changes the way you view the research that goes on in an institute. You have to have, in my view, a very wide policy in a research institute like ICRF. You have to have very high quality basic research, because it is out of that that we will see the new knowledge 30 years from now that will lead to better treatment. But we also need to have work going on thats much closer to the patient, to try and get improvements over the next few years.

SA: Do you think we will see a cure for cancer like our grandparents saw a cure for infectious diseases?

PN: I dont, actually. Cancer, first of all, is many different diseases, many different sites and forms; some people say it is as many as 200 different diseases. There are many different genes that can become defective to give rise to cancer, and they all have different characteristics. So I think the likelihood of having a common treatment for all of these is just not likely. There will be some treatments that will be useful across the board, but I think it would be a mistake to look for "the cure" to cancer. But what I think we can expect to see is steady improvement by applying this new knowledge to treating and preventing the disease.