Coming Full Cycle

Courtesy OF ROCKEFELLER UNIVERSITY For Paul Nurse, a biologist who has spent his career unraveling the molecular underpinnings of cell-cycle control, few things have come easy - not even learning that he'd won the 2001 Nobel Prize. The day of the announcement, Nurse was meeting with Jim Watson and a passel of architects to discuss plans for renovating Mendel's monastery, when his office called to tell him to switch on his cell phone. On his voicemail was a message from Stockholm. "It was very garbled and very Swedish," laughs Nurse, who couldn't make out whether he'd been given the nod or was being asked for his opinion regarding someone else's worthiness. The uncertainty drove him to utter one of the silliest things he claims he's ever said. "I went back to the room and announced: 'I've got to leave now, because I think I've won a Nobel Prize.'" The story is typical of Nurse. "What makes him so endearing is that he wasn't born with a silver spoon in his mouth," says Melanie Lee, a former postdoc who's now director of R&D for UCB Pharmaceuticals in Slough, UK. "He doesn't see himself as anything but ordinary." Indeed, Nurse relishes describing his academic setbacks. "In Britain in the late 1960s, to get into university, you had to be generally educated, and that included being able to speak some sort of foreign language. The British aren't very good at speaking foreign languages and I'm worse than most. I failed the most basic examination in French on six separate occasions. This actually led to my rejection from all universities." An astute professor, however, read Nurse's entire application and decided it might be worthwhile to give the lad a chance. As a graduate student at the University of East Anglia, Nurse analyzed amino acid pools in fungi and simple plants. It was an esoteric project that he says was technically demanding, but not very interesting. He soon realized he needed to tackle something bigger. "The way I thought about it was: I'm a biologist, what are the key questions in basic biology?" Because reproduction is a fundamental feature of all living things, Nurse decided that a study of cell division would provide a "key to understanding life." ONTO THE CELL CYCLE Around that time in the early 1970s, he starting reading Lee Hartwell's papers on the genes needed for progression through the cell cycle in Saccharomyces cerevisiae. "This was much better than the sort of work I was doing at the time," says Nurse, "and I thought I'd like to do something similar." So in 1973 he accepted a postdoctoral position at the University of Edinburgh and essentially repeated Hartwell's experiments using the fission yeast Schizosaccharomyces pombe. These cells are rod-shaped and reproduce by forming a partition down their middle, similar to the way that most eukaryotic cells divide. By isolating mutants that were unable to divide when grown at a higher-than-normal temperature, Nurse confirmed that a gene called cdc2 was critical for cell-cycle progression in fission yeast. Since he was more interested in determining how cells regulate their reproduction, he decided to look for cells whose timing was off - cells that divided more quickly or more slowly than usual. At first, Nurse set his sights on finding mutants that grew larger because they had trouble dividing. He centrifuged cell cultures, figuring that the bigger cells would collect at the bottom. What he found when he examined the pellet, however, was a plethora of smaller cells: yeast cells that were actually reproducing faster than they could grow. As it turns out, these little yeast were forming aggregates that sank to the bottom of the centrifuge tube. He called these mutants wee, the Scottish term for small. In mapping where their dysfunctions originated, Nurse found that almost every single mutant had some sort of defect in a gene he dubbed wee1. One mutant, however, mapped to a different locus, the gene for cdc2. "That was a crucial clue," explains Tim Hunt of Cancer Research, UK, who shared the Nobel Prize with Nurse and Hartwell. When cdc2 is inactivated, as both Hartwell and Nurse had initially shown, yeast can't divide at all, so the cells just grow larger. Nevertheless, if the gene is mutated in a different way (Nurse didn't yet know how), it would become hyperactive and the yeast then divide faster than they normally would, generating smaller cells. "That's what made Paul realize that cdc2 had to be a really important cell-cycle regulator," says Hunt. Wee1, it turns out, influences cell-cycle progression by phosphorylating and inhibiting cdc2. The genius, says Hunt, was in recognizing that these small cells were something worth exploring. "One thing Paul is good at," says Ed Southern of Oxford University, "he's very observant and makes connections that other people wouldn't make." Former postdoc Paul Russell, now at the Scripps Institute in La Jolla, Calif., agrees. "Many people would have looked at those cells and tossed them away, figuring it wasn't what they were looking for," he says. "I think Paul has a real affinity for the organism that comes from working with these cells and trying to let them tell him what's going on." CANCER IN YEAST? Even more impressive, however, was the experiment Nurse and his postdoc Melanie Lee conducted after he was recruited to join the staff at London's Imperial Cancer Research Fund (ICRF) in 1984. "I found myself surrounded by people working with human cells or mouse cells," says Nurse. "I felt I ought to try and do something to persuade them that what I was doing with yeast was interesting." So the researchers set out to clone the human homolog of cdc2. As Lee remembers it, Nurse described the project as "one that is very high risk but will validate my existence in a cancer institute." The strategy was straightforward. Nurse and Lee planned on introducing a human cDNA library into a mutant strain of S. pombe and isolating those cells that regained the ability to divide. But few people, not even Nurse, thought the approach would work. "I couldn't really believe we could clone such an immense distance in evolutionary terms," he says. What's more, Lee had already failed to identify the human gene by the more conventional means of hybridization using probes for the pombe gene or using antibodies that recognized the pombe protein. "I was a year at the bench with people walking past saying, 'stupid experiment, it'll never work,'" says Lee. But it did work, and the results were fairly stunning. "The eureka moment was when we saw the amino acid sequence [of the human cdc2 protein] translated on the computer screen outside Paul's office," says Lee. Although the nucleotide sequences of the yeast and human genes had diverged, they were 60% identical in the amino acids they encoded. "We knew in a flash, not only had we cloned a human gene that was like the fission yeast cdc2 gene, but that the proteins had exactly the same function," a job that had been conserved for 1.5 billion years, says Nurse. "That meant that the cell cycle in every other living organism that you can see was likely to be controlled the same way." The experiment was "very bold," says Southern. "Not many people thought that human and yeast would have any connection in something as important as cell-cycle control." And the results certainly validated Nurse's presence at ICRF. "People criticized Walter Bodmer quite heavily for hiring someone who worked on a rather obscure kind of yeast," says Hunt. "But his instincts were absolutely spot-on." In 1996, a decade after cloning human cdc2, Nurse took over as director, where he helped to engineer the merger that made ICRF part of Cancer Research UK. In a way, Nurse's rise to the directorship, and his 2003 hire as president of Rockefeller University, came as no surprise. "Paul always sees the big picture," says Southern. Or, as long-time collaborator Jacky Hayles of Cancer Research UK puts it, "If you know the expression 'can't see the wood for the trees,' Paul can always see the wood.""He also thinks very deeply and clearly about things," says Hunt. "His original papers are models of scientific argument. They're very clear and very profound and almost always right, which is a pretty good combination." SHAPING MODEL ORGANISMS In addition to continuing work on the cell cycle, Nurse is now focusing on the question of cell shape. "Understanding how cells achieve spatial order is a very difficult and basic problem, and one we simply don't understand," he says. Such studies could be relevant to understanding cancer, as metastatic cells often change shape as they escape their parent tissue and strike out to colonize other areas of the body. Paul Nurse, (second from left) with fellow Nobel Laureates Timothy Hunt (at left, medicine), George A. Akerlof (second from right, economics) and Michael Spence (right, economics) applauding V.S. Naipaul (center, literature) in 2001. © JONAS EKSTROMER/EPA/CORBIS Nurse continues to champion the use of S. pombe as a model organism. Not only has he pushed for the development of technologies to make pombe amenable to genetic manipulation, but he somehow also managed to cobble together the money to get the pombe genome sequenced, says Russell. He also spearheaded a project to get the pombe genes placed onto microarrays and is coordinating an effort to generate a library of pombe gene knockouts. "Paul has single-handedly kept this organism a viable experimental system for all these years," notes Russell. Despite the intense amounts of activity, Nurse somehow manages to make his labs, both in New York and London, fun places to work. "His levels of enthusiasm and energy are way beyond anything I've ever encountered, to ludicrous extremes sometimes," recalls former postdoc Chris Norbury of the University of Oxford. Current postdoc Atanas Kaykov agrees. "Every time you have a good result, he comes to you and he kisses you." Nurse also enjoys watching his laboratory charges choose their projects and develop into independent young scientists. "I'm not sure if he has an explicit philosophy that binds him to this level of permissiveness, but 99 out of 100 people would not have put up with as much crap as he put up with," says Norbury, recalling his days in the lab. "Of course, who knows what we might have achieved if he'd been a complete bastard." khopkin@the-scientist.com

Coming Full Cycle

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Karen Hopkin

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May 2006

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