Bernd Pulverer, LondonThe 2001 Nobels mark the centenary of themost prestigious prizes in science. So it isfitting that this year’s award for physiologyor medicine goes to three biologists whorevealed the mysteries of a process central tothe growth, development and maintenanceof all living organisms: cell division.

Leland Hartwell, president and director ofthe Fred Hutchinson Cancer Research Centerin Seattle, Paul Nurse, director-general of theImperial Cancer Research Fund (ICRF) inLondon, and Tim Hunt, also of the ICRF,have been honoured for their contributionsto our understanding of the cell cycle.

The molecular machinery underlying thecycle of cell growth and division remainedobscure until the early 1970s, whenHartwell’s pioneering work gave the firstglimpses of the processes involved.

Working with baker’s yeast, Saccharo-myces cerevisiae, Hartwell set out to identifythe genes involved in regulating the cell cycle.In a series of papers, he isolated yeastmutants that stopped at certain points in thecell cycle if the temperature was changed.

Hartwell identified more than 100 cell-division-cycle (CDC) genes, including one,dubbed CDC28 or start, that seemed to initi-ate the copying of a cell’s DNA, the step thatprecedes cell division. He went on to showthat there was a striking interdependencebetween the events controlled by the variousCDC genes — one would have to be complet-ed before the subsequent stages could begin.

Many researchers who today work on thecell cycle say they were inspired to enter thefield by Hartwell’s pioneering studies.“Without his fundamental insight, therewould be no such thing as the cell-cyclefield,” says Jim Roberts, also at the Hutchin-son centre.

By studying the sensitivity of yeast cells to irradiation, Hartwell in the late 1980sintroduced the concept of ‘checkpoints’, andidentified the first yeast genes involved.Checkpoints are control points at which reg-ulatory proteins halt the cell cycle upondetecting damage to DNA, or other abnor-malities, allowing repair before the cycleresumes. In their absence, cells would be

prone to genetic damage. Indeed, manyforms of cancer have since been linked toproblems with checkpoint control.

Shortly after Hartwell began identifyingCDC genes, Nurse started working on another species of yeast, Schizosaccharomycespombe. He identified mutants involved inregulating the cell cycle, and later showed thatone, labelled cdc2, was functionally equiva-lent to start. CDC28 and cdc2 have since beenshown to encode enzymes belonging to thefamily of cyclin-dependent kinases (CDKs).

Phenomenal successIn 1987, Nurse isolated the correspondinggene in human cells, which encodes anenzyme later named CDK1. This, saysNurse, confirmed that biologists workingon the cell cycle in yeast were identifyingfundamental phenomena conserved by evo-lution across a wide range of organisms —and validated the study of model organismsto gain insights into human biology. “Thesame gene controlled cell division in yeastand humans and hence everything inbetween,” he says.

Hunt’s contribution was the discovery,from studies of fertilized eggs of frogs and seaurchins, of a new class of proteins that hecalled cyclins. The activity of CDKs was laterfound to depend on their association withthese proteins.

In 1983, Hunt showed that the cyclins disappeared just before cell division, and

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immediately realized that this was a key find-ing. “I knew I had made an important dis-covery,” he says. Protein degradation hassince emerged as an important general phe-nomenon in cell-cycle regulation.

Contacted by Nature on 8 October shortlyafter receiving the phone call from Stock-holm, Nurse and Hunt were in ecstatic mood,with champagne corks popping in the back-ground. At a press conference later in the day,Nurse admitted that the news had him “run-ning around like a headless chicken”. Huntadded that it only sunk in after he hadchecked the citation on the Nobel website.

But as is often the case, the rule thatrestricts Nobel awards to three winners (seepages 560–564) means that other pivotal fig-ures go unrewarded. “If anyone will be slight-ly disappointed, it will be Yoshio Masui,”Nurse told Nature. In the 1970s, Masui, now aprofessor emeritus at the University ofToronto, found that an extract from frog eggs,called maturation-promoting factor, readiedthe eggs for their first cell division. This waslater found to be composed of the CDKencoded by cdc2 and a cyclin.

But researchers in the field agree thatHartwell, Nurse and Hunt are worthy winners. “I call Hartwell the ‘father’, Nursethe ‘great preacher’ and Hunt the ‘artist’ ofcell division,” says Mitsuhiro Yanagida ofKyoto University in Japan. ■

Additional reporting by Erica Klarreich.

➧ www.nobel.se

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Cell celebrators: centenary laureates Leland Hartwell (left), Paul Nurse (centre) and Tim Hunt.

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