News FocusNOBEL PRIZE IN PHYSIOLOGY OR MEDICINE

Cycling Toward Stockholm

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Science  19 Oct 2001:
Vol. 294, Issue 5542, pp. 502-503
DOI: 10.1126/science.294.5542.502

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Three new laureates per prize—the maximum number Nobel rules allow—gain recognition for fundamental advances in their fields

LONDON—Paul Nurse and Tim Hunt have been good friends for nearly 20 years. Indeed, they have much in common. Both have conducted pioneering research into the intricate molecular choreography that drives cell division. Both work for Britain's Imperial Cancer Research Fund (ICRF): Nurse as its director-general and Hunt as head of ICRF's Cell Cycle Control laboratory in South Mimms, north of London. “We are very complementary,” Nurse tells a visitor who has come to see the pair in Nurse's London office, overlooking the lush green gardens of Lincoln's Inn Fields. Now, Nurse and Hunt have something else to share. With yeast geneticist Leland Hartwell, director of the Fred Hutchinson Cancer Research Center in Seattle, Washington, they have been awarded this year's Nobel Prize in physiology or medicine for identifying the key molecular steps in the cell cycle.

The winners' work led to the revelation that the cell cycle is controlled through the cooperation of two sets of proteins: the cyclins and enzymes called kinases. Their discoveries not only illuminated cell biology's most fundamental process—the ability to grow and divide—but also have had important implications for medicine. “The principal problem in cancer cells is they divide when they shouldn't,” says cell biologist Ted Weinert of the University of Arizona in Tucson. “Without these discoveries, cancer research would still be in the dark ages.”

Things were dark indeed in the late 1960s, when Hartwell began his work in yeast genetics. “People knew there was a cell cycle, but as for how to get at the genes, it didn't cross anyone's mind that it was even possible at that point,” Weinert says. Hartwell's research sprang from a project he had assigned to Brian Reid, an undergraduate student in his new lab at the University of Washington, Seattle. “I gave him mutant [yeast strains] that formed very odd shapes at high temperatures,” Hartwell recalls.

The oddly shaped cells, it turned out, were having trouble dividing. After one or two generations, for example, each would have a very large bud, which had failed to separate and become a daughter cell. “We were immediately stunned by the amount of information they gave us on cell division,” Hartwell says. They could see the physical consequences of the mutation as well as at what point in the cell cycle the mutation exerted its effect. By the early 1970s, the Hartwell lab had identified dozens of gene mutations that disrupt the cell cycle, although the nature of the proteins encoded by these “cell division cycle” (cdc) genes wasn't known.

While Hartwell was making his seminal discoveries, Nurse was completing his graduate studies in amino acid metabolism at the University of East Anglia in Norwich, U.K. But the lab's amino acid analyzer kept breaking down, and Nurse had to spend many hours babysitting the machine. This gave him plenty of time to read journal articles, including Hartwell's early papers. “I saw that this genetic approach is really powerful,” Nurse says.

After receiving his Ph.D., Nurse began working at the University of Edinburgh, U.K., searching for cell cycle genes in the fission yeast Schizosaccharomyces pombe. Like Hartwell, he soon identified a number of cdc genes, as well as so-called “wee” mutations that caused the yeast to go into mitosis early, stunting the growth of the cells. When one of these mutated genes, wee2, turned out to be a mutant form of a gene Nurse had isolated earlier called cdc2, he reasoned that cdc2 must control when mitosis begins.

Cell mates.

Leland Hartwell (top); Paul Nurse and Tim Hunt (bottom, left to right).

CREDITS: (TOP TO BOTTOM) FRED HUTCHINSON CANCER RESEARCH CENTER; AP PHOTO/ALASTAIR GRANT

Subsequent work revealed that cdc2 operates as a master control switch that determines the timing of key steps in cell division. Moving on to the University of Sussex, and later to Oxford and London, Nurse and his co-workers found that the cdc2 gene codes for a protein called a kinase, part of a family of regulatory enzymes important to many cell functions. The group also showed that cdc2 is nearly identical to Hartwell's cdc28 gene in bakers' yeast.

In the meantime, Hunt, who had received his Ph.D. from Cambridge University, began spending summers at the Marine Biological Laboratory in Woods Hole, Massachusetts. He was trying to figure out how fertilization of the sea urchin egg triggers protein synthesis, one of the first steps in the development of the sea urchin embryo. But the work seemed to be going nowhere. Then, in 1982, Hunt tried what he now calls “a completely off-the-wall” experiment “of the desperate variety.”

He decided to compare the protein synthesis patterns in fertilized eggs with those that developed parthenogenetically—that is, without fertilization. The results, he says, were a “complete revelation.” In the fertilized eggs, the levels of a protein present in high concentrations dropped drastically just when the cells divided. Then the levels rose again, only to drop at the next round of cell division. Hunt named this protein cyclin, the first of many such proteins to be discovered.

It soon emerged that Hunt and Nurse were independently looking at two facets of the same problem. Further work showed that cyclins regulate the enzymatic activity of the Cdc2 protein and other so-called cyclin dependent kinases (CDKs). In fact, Cdc2 and its cyclin regulators actually join together to form a larger molecular complex called maturation promoting factor (MPF). MPF—which had first been identified as the key initiator of cell division in frog eggs in the early 1970s by the Japanese scientist Yoshio Masui—had long resisted biochemical analysis. Now, that mystery was solved.

In 1987, when Nurse isolated the human version of Cdc2—called CDK1—it also became clear that the cell cycle is controlled by a universal mechanism that has been conserved in yeast, amphibians, mammals, and other organisms over nearly 2 billion years of evolution.

Since then CDKs, cyclins, and their associates have been at the center of research on both normal and cancerous cell growth. “If you said, ‘Let's give a prize for CDK,’ these are the three people you would give it to,” says cell biologist Kim Nasmyth of the Research Institute of Molecular Pathology in Vienna, Austria. “I think [the Nobel committee] got it absolutely right.” In fact, says cell biologist Joan Ruderman of Harvard University, who worked with Hunt on some of his early studies, the whole field is enjoying the moment in the spotlight. “For many of us, it feels like cyclin/Cdc2 has won the Nobel Prize, and we are all very happy about that!”

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