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Press Release
8 October 2001 The Nobel Assembly at Karolinska Institutet has today decided to award The Nobel Prize in Physiology or Medicine for 2001 jointly to& Leland H. Hartwell, R. Timothy (Tim) Hunt and Paul M. Nurse for their discoveries of "key regulators of the cell cycle"

Summary
All organisms consist of cells that multiply through cell division. An adult human being has approximately 100 000 billion cells, all originating from a single cell, the fertilized egg cell. In adults there is also an enormous number of continuously dividing cells replacing those dying. Before a cell can divide it has to grow in size, duplicate its chromosomes and separate the chromosomes for exact distribution between the two daughter cells. These different processes are coordinated in the cell cycle. This year's Nobel Laureates in Physiology or Medicine have made seminal discoveries concerning the control of the cell cycle. They have identified key molecules that regulate the cell cycle in all eukaryotic organisms, including yeasts, plants, animals and human. These fundamental discoveries have a great impact on all aspects of cell growth. Defects in cell cycle control may lead to the type of chromosome alterations seen in cancer cells. This may in the long term open new possibilities for cancer treatment. Leland Hartwell (born 1939), Fred Hutchinson Cancer Research Center, Seattle, USA, is awarded for his discoveries of a specific class of genes that control the cell cycle. One of these genes called "start" was found to have a central role in controlling the first step of each cell cycle. Hartwell also introduced the concept "checkpoint", a valuable aid to understanding the cell cycle. Paul Nurse (born 1949), Imperial Cancer Research Fund, London, identified, cloned and characterized with genetic and molecular methods, one of the key regulators of the cell cycle, CDK (cyclin dependent kinase). He showed that the function of CDK was highly conserved during evolution. CDK drives the cell through the cell cycle by chemical modification (phosphorylation) of other proteins.

Timothy Hunt (born 1943), Imperial Cancer Research Fund, London, is awarded for his discovery of cyclins, proteins that regulate the CDK function. He showed that cyclins are degraded periodically at each cell division, a mechanism proved to be of general importance for cell cycle control. One billion cells per gram tissue Cells having their chromosomes located in a nucleus and separated from the rest of the cell, so called eukaryotic cells, appeared on earth about two billion years ago. Organisms consisting of such cells can either be unicellular, such as yeasts and amoebas, or multicellular such as plants and animals. The human body consists of a huge number of cells, on the average about one billion cells per gram tissue. Each cell nucleus contains our entire hereditary material (DNA), located in 46 chromosomes (23 pairs of chromosomes). It has been known for over one hundred years that cells multiply through division. It is however only during the last two decades that it has become possible to identify the molecular mechanisms that regulate the cell cycle and thereby cell division. These fundamental mechanisms are highly conserved through evolution and operate in the same manner in all eukaryotic organisms. The phases of the cell cycle The cell cycle consists of several phases (see figure). In the first phase (G1) the cell grows and becomes larger. When it has reached a certain size it enters the next phase (S), in which DNA-synthesis takes place. The cell duplicates its hereditary material (DNAreplication) and a copy of each chromosome is formed. During the next phase (G2) the cell checks that DNA-replication is completed and prepares for cell division. The chromosomes are separated (mitosis, M) and the cell divides into two daughter cells. Through this mechanism the daughter cells receive identical chromosome set ups. After division, the cells are back in G1 and the cell cycle is completed. The duration of the cell cycle varies between different cell types. In most mammalian cells it lasts between 10 and 30 hours. Cells in the first cell cycle phase (G1) do not always continue through the cycle. Instead they can exit from the cell cycle and enter a resting stage (G0). Cell cycle control For all living eukaryotic organisms it is essential that the different phases of the cell cycle are precisely coordinated. The phases must follow in correct order, and one phase must be completed before the next phase can begin. Errors in this coordination may lead to chromosomal alterations. Chromosomes or parts of chromosomes may be lost, rearranged or distributed unequally between the two daughter cells. This type of chromosome alteration is often seen in cancer cells. It is of central importance in the fields of biology and medicine to understand how the

cell cycle is controlled. This year's Nobel Laureates have made seminal discoveries at the molecular level of how the cell is driven from one phase to the next in the cell cycle. Cell cycle genes in yeast cells Leland Hartwell realized already at the end of the 1960s the possibility of studying the cell cycle with genetic methods. He used baker's yeast, Saccharomyces cerevisiae, as a model system, which proved to be highly suitable for cell cycle studies. In an elegant series of experiments 1970-71, he isolated yeast cells in which genes controlling the cell cycle were altered (mutated). By this approach he succeeded to identify more than one hundred genes specifically involved in cell cycle control, so called CDC-genes (cell division cycle genes). One of these genes, designated CDC28 by Hartwell, controls the first step in the progression through the G1-phase of the cell cycle, and was therefore also called "start". In addition, Hartwell studied the sensitivity of yeast cells to irradiation. On the basis of his findings he introduced the concept checkpoint, which means that the cell cycle is arrested when DNA is damaged. The purpose of this is to allow time for DNA repair before the cell continues to the next phase of the cycle. Later Hartwell extended the checkpoint concept to include also controls ensuring a correct order between the cell cycle phases. A general principle Paul Nurse followed Hartwell's approach in using genetic methods for cell cycle studies. He used a different type of yeast, Schizosaccharomyces pombe, as a model organism. This yeast is only distantly related to baker's yeast, since they separated from each other during evolution more than one billion years ago. In the middle of the 1970s, Paul Nurse discovered the gene cdc2 in S. pombe. He showed that this gene had a key function in the control of cell division (transition from G2 to mitosis, M). Later he found that cdc2 had a more general function. It was identical to the gene ("start") that Hartwell earlier had identified in baker's yeast, controlling the transition from G1 to S. This gene (cdc2) was thus found to regulate different phases of the cell cycle. In 1987 Paul Nurse isolated the corresponding gene in humans, and it was later given the name CDK1 (cyclin dependent kinase 1). The gene encodes a protein that is a member of a family called cyclin dependent kinases, CDK. Nurse showed that activation of CDK is dependent on reversible phosphorylation, i.e. that phosphate groups are linked to or removed from proteins. On the basis of these findings, half a dozen different CDK molecules have been found in humans. The discovery of the first cyclin

Tim Hunt discovered the first cyclin molecule in the early 1980s. Cyclins are proteins formed and degraded during each cell cycle. They were named cyclins because the levels of these proteins vary periodically during the cell cycle. The cyclins bind to the CDK molecules, thereby regulating the CDK activity and selecting the proteins to be phosphorylated. The discovery of cyclin, which was made using sea urchins, Arbacia, as a model system, was the result of Hunt's finding that this protein was degraded periodically in the cell cycle. Periodic protein degradation is an important general control mechanism of the cell cycle. Tim Hunt later discovered cyclins in other species and found that also the cyclins were conserved during evolution. Today around ten different cyclins have been found in humans. The engine and the gear box of the cell cycle The three Nobel Laureates have discovered molecular mechanisms that regulate the cell cycle. The amount of CDK-molecules is constant during the cell cycle, but their activities vary because of the regulatory function of the cyclins. CDK and cyclin together drive the cell from one cell cycle phase to the next. The CDK-molecules can be compared with an engine and the cyclins with a gear box controlling whether the engine will run in the idling state or drive the cell forward in the cell cycle. A great impact of the discoveries Most biomedical research areas will benefit from these basic discoveries, which may result in broad applications within many different fields. The discoveries are important in understanding how chromosomal instability develops in cancer cells, i.e. how parts of chromosomes are rearranged, lost or distributed unequally between daughter cells. It is likely that such chromosome alterations are the result of defective cell cycle control. It has been shown that genes for CDK-molecules and cyclins can function as oncogenes. CDK-molecules and cyclins also collaborate with the products of tumour suppressor genes (e.g. p53 and Rb) during the cell cycle. The findings in the cell cycle field are about to be applied to tumour diagnostics. Increased levels of CDK-molecules and cyclins are sometimes found in human tumours, such as breast cancer and brain tumours. The discoveries may in the long term also open new principles for cancer therapy. Already now clinical trials are in progress using inhibitors of CDK-molecules.

The different phases of the cell cycle. In the first phase (G1) the cell grows. When it has reached a certain size it enters the phase of DNA-synthesis (S) where the chromosomes are duplicated. During the next phase (G2) the cell prepares itself for division. During mitosis (M) the chromosomes are separated and segregated to the daughter cells, which thereby get exactly the same chromosome set up. The cells are then back in G1 and the cell cycle is completed. This year's Nobel Laureates, using genetic and molecular biology methods, have discovered mechanisms controlling the cell cycle. CDK-molecules and cyclins drive the cell from one phase to the next. The CDK-molecules can be compared with an engine and the cyclins with a gear box controlling whether the engine will run in the idling state or drive the cell forward in the cell cycle.

Tm tt

Cc phase khc nhau ca chu trnh t bo. Trong phase u tin ( G1) t bo tng trng. Khi t c mt kch thc no , t bo bc vo phase tng hp DNA ( s) ni nhim sc th c nhn i. Trong sut phase tip theo (G2) t bo t chun b cho phn bo. Trong nguyn phn (M) nhim sc th c phn tch v chia cho hai t bo con, do mt cch chnh xc mi t bo s nhn cng mt s lng nhim sc th. Cc t bo sau tr li G1 v chu trnh t bo c hon tt. Nhng ngi c gii Nobel nm nay s dng cc phng php sinh hc phn t v di truyn hc,khm ph ra cc c ch kim sot chu trnh t bo. Cc phn t CDK v cyclin iu chnh t bo t mt phase sang phase k tip. Cc phn t CDK c th c so snh vi ng c v cyclin vi hp s hoc ng c s chy vo giai on ngh hoc s iu chnh t bo bc vo phn bo. Mi c th sng c to thnh t cc t bo c nhn ln thng qua s phn bo. Mt c th ngi trng thnh cha xp x 100 000 t t bo, tt c t bo u xut pht t mt t bo u tin - t bo trng c th tinh. ngi trng thnh, thng xuyn c mt s lng rt ln t bo tip tc phn chia thay th cc t bo cht i. Trc khi phn chia, t bo s tng trng v kch thc, nhn i nhim sc th ca n v phn tch nhim sc th phn phi chnh xc cho hai t bo con. Nhng qu trnh khc nhau ny c phi hp trong chu trnh t bo. Gii Nobel trong sinh l hc hay y hc nm nay l nhng khm ph mang tnh nn tng lin quan ti s iu ha chu trnh t bo. Nhng ngi c gii xc nh cc phn t then cht iu ha chu trnh t bo tt c cc c th eukaryotic, bao gm nm, thc vt, ng vt v ngi. Nhng khm ph c tnh nguyn tc ny li mt tc ng ln trn mi bnh din tng trng ca t bo. Nhng sai st trong iu ha chu trnh t bo

c th dn ti nhng loi bin i nhim sc th quan st thy cc t bo ung th. iu ny c l trong mt thi gian di m ra nhng kh nng mi trong iu tr ung th. Leland Hartwell (sinh nm 1939), Fred Hutchinson Cancer Research Center, Seattle, USA, c nhn gii v cng khm ph ra mt dng gene chuyn bit iu ha chu trnh t bo. Mt trong s gen ny gi l "m u" c nhn thy l ng vai tr trung tm trong kim sot bc u tin ca mi chu trnh t bo. Hartwell cng a ra khi nim "checkpoint" (im kim tra), mt tr gip c gi tr hiu thu chu trnh t bo. Paul Nurse (sinh nm 1949), Imperial Cancer Research Fund, London, xc nh, to dng v biu hin bng phng php di truyn phn t, mt trong nhng yu t iu ha then cht ca chu trnh t bo, CDK (cyclin ph thuc vo kinase). ng cho thy chc nng ca CDK c bo tn mt cch cao trong sut qu trnh tin ha. CDK iu chnh t bo xuyn sut chu trnh t bo bng cch bin i (phosphoryl ha) cc phn t protein khc. Timothy Hunt (sinh nm 1943), Imperial Cancer Research Fund, London, c trao gii v cng khm ph ra cc cyclin, nhng protein iu ha chc nng CDK. ng cho thy s cyclin suy gim c tnh chu k trong mi ln phn bo, c ch c hon thin gi mt tm quan trng c bn trong kim sot chu trnh t bo. Mt nghn t t bo trong mt gram m Nhng t bo ct gi cc nhim sc th trong nhn v phn tch nhim sc th tnh t giai on ngh ngi ca t bo, c gi l t bo eukaryotic, xut hin cch y khong hai t nm. Cc t chc sng cha ng nhng t bo nh th c th l n bo nh nm v amip, c th l a bo nh ng vt v thc vt. C th ngi cha ng mt s lng rt ln t bo, trung bnh vo c mt nghn t t bo trong mt gram m. Mi nhn t bo cha ng ton b nguyn liu di truyn (DNA) ca chng ta, nm trn 46 nhim sc th (23 cp nhim sc th). T bo ni ting hn mt trm nm qua nh s nhn ln ca t bo thng qua phn bo. Tuy nhin iu ch din ra sut hai thp k cui [th k XX ] khi m bt u c kh nng xc nh cc c ch phn t iu ha chu trnh t bo nh t bo phn chia. Nhng c ch mang tnh nguyn tc ny c bo tn cao xuyn sut tin ha v vn hnh cng mt kiu tt c c th nhn chun. Cc giai on ca chu trnh t bo Chu trnh t bo bao gm nhiu phase (giai on). pha u tin ( G1 ), t bo tng trng v bt u ln ln. Khi t n mt kch c no , t bo bc vo phase k tip ( S ), trong din ra s tng hp DNA. T bo nhn i nguyn liu di truyn ca n (sao chp DNA) v mt bn sao ca mi nhim sc th c hnh thnh. Trong sut phase tip theo ( G2 ), t bo kim tra s sao chp DNA hon tt cha v chun b cho s phn bo. Cc nhim sc th c phn tch ( Nguyn phn, M ) v t bo chia i

thnh hai t bo con. Thng qua c ch ny cc t bao con nhn mt lot nhim sc th xc nh. Sau khi phn bo,t bo quay tr li pha G1 v chu trnh t bo c hon tt. Din tin ca chu trnh t bo khc nhau gia nhng loi t bo khc nhau. hu ht t bo ng vt c v, chu trnh t bo dao ng gia 10 v 30 gi ng h. Nhng t bo no pha G1 lun lun khng tip tc chu trnh. Thay vo , chng thot khi chu trnh t bo v bc vo giai on ngh (G0). Kim sot chu trnh t bo i vi tt c c th sng eukaryotic iu ti quan trng bi s khc nhau gia cc phase trong chu trnh t bo cn phi c phi hp mt cch chnh xc. Cc phase phi din ra theo mt trt t nht nh, v mt phase phi c hon tt trc khi phase k tip c th bt u. Nhng sai st trong s phi hp ny c th dn ti cc bin i nhim sc th. Cc nhim sc th hay mt phn ca cc nhim sc th c th b mt i, sp xp li hoc phn phi khng ng u gia hai t bo con. Loi bin i nhim sc th ny hay thy t bo ung th. Hiu thu chu trnh t bo bng cch no c kim sot l iu quan trng mang tnh trung tm trong cc lnh vc ca sinh hc v y hc. Nhng ngi c gii Nobel nm nay thc hin cc khm ph mang tnh nn tng mc phn t bng cch no t bo c iu chnh t mt phase n mt pha k tip trong chu trnh t bo. Cc gene chu trnh t bo trong t bo nm Leland Hartwell nhn thy kh nng c th nghin cu chu trnh t bo bng phng php di truyn hc vo cui nhng nm 1960. ng s dng nm men bnh m, Saccharomyces cerevisiae, nh mt m hnh h thng, loi nm c ci tin rt ph hp cho nhng nghin cu chu trnh t bo. Trong lot th nghim c khi nht vo 19701971, ng phn tch cc t bo nm men trong cc gene kim sot chu trnh t bo c bin i (b t bin). Bng phng php ny, ng thnh cng khi xc nh hn mt trm gene bit ha c dnh dng ti kim sot chu trnh t bo, ng gi l cc gene CDC ( cc gene chu trnh phn bo). Mt trong nhng gene ny, c Hartwell thit k l CDC28, kim sot bc u tin trong tin trnh, phase G1 ca chu trnh t bo, v v th ng gi l "m u". Hn na, Hartwell nghin cu tnh mn cm ca t bo nm men khi chiu x. Nn tng pht hin ca ng l a ra khi nim checkpoint (im kim tra), ci khi nim c ngha chu trnh t bo b dng li khi DNA b h hng. Mc ch ca iu ny l tr cp thi gian sa sai DNA trc khi t bo tip tc phase k tip ca chu trnh. Later Hartwell cng m rng khi nim checkpoint nhm bao gm lun kim sot tnh chc chn mt trt t nht nh gia cc phase ca chu trnh t bo. Mt nguyn l chung

Paul Nurse tip bc Hartwell s dng phng php di truyn trong cc nghin cu chu trnh t bo. ng s dng mt loi nm khc, Schizosaccharomyces pombe, nh mt m hnh c th. Loi nm ny ch c h hng xa vi nm men bnh m, k t lc chng tch nhau ra trong tin ha cch y hn mt t nm. Vo gia thp nin 1970, Paul Nurse khm ph ra gene cdc2 S.pombe. ng chng minh gene ny gi chc nng then cht trong kim sot s phn bo (s chuyn t G2 sang M). Lu sau ng nhn ra cdc2 gi chc nng c bn hn nhiu. cdc2 xc nh gene "m u" m trc Hartwell xc nh nm men bnh m, kim sot s chuyn t G1 sang S. T gene cdc2 ny c pht hin ra l iu ha cc phase khc nhau ca chu trnh t bo.Vo nm 1987, Paul Nurse phn tch cc gene tng ng ngi, t lu sau a ra tn gi CDK1 (cyclin ph thuc kinase 1). Gene ny m ha mt protein m l thnh vin ca h cyclin ph thuc kinase, CDK. Nurse nhn ra s kch hot ca CDK ph thuc vo s phosphoryl ha thun nghch, v d cc nhm phosphate lin kt hoc tch khi protein. Da trn nhng pht hin c bn ny, mt na t CDK c tm thy ngi. S khm ph ra cyclin u tin Tim Hunt khm ph ra cyclin u tin vo nhng nm u 1980. Cyclin l protein c hnh thnh v suy bin sut mi chu trnh t bo. Chng c tn gi l cyclin v mc cc protein ny bin i c tnh chu k trong sut chu trnh t bo. Cyclin bm vo phn t CDK, do iu ha hot ng CDK v chn la protein phosphoryl ha. S khm ph cyclin, bng cch s dng nhm bin, Arbacia, nh mt m hnh h thng, l kt qu pht hin ca Hunt rng protein ny b thoi bin c tnh chu k trong chu trnh t bo. Sau Tim Hunt khm ph ra cc cyclin nhng loi khc v ng cng nhn ra cc cyclin c bo tn xuyn sut tin ha. Hin nay c khong 10 cylcin khc nhau c tm thy ngi. ng c v hp s ca chu trnh t bo Ba ngi nhn gii Nobel nm nay khm ph ra cc c ch iu ha chu trnh t bo. S lng phn t CDK khng thay i trong sut chu trnh t bo, nhng nhng hot ng ca chng li thay i do s iu ha chc nng ca cyclin. CDK v cyclin cng nhau iu chnh t bo t mt phase ca chu trnh t bo sang phase k tip. Cc phn t CDK c th so snh vi ng c v cyclin vi hp s hoc c my s chy vo giai on ngh hoc iu chnh t bo bc vo chu trnh t bo. nh hng cc ln ca nhng khm ph Hu ht cc nghin cu trong lnh vc y sinh hc s c li t nhng khm ph ny, bi dn ti kt qu c th m rng kh nng ng dng trong nhiu lnh vc khc nhau. Nhng khm ph ny kh quan trng thu hiu nhng pht trin nhim sc th mt n

nh cc t bo ung th, v d nhng phn no ca nhim sc th b sp xp li, mt i hoc phn phi khng u gia hai t bo con. iu tng t nhng bin i nhim sc th kiu nh th l kt qu ca s kim sot chu trnh t bo thiu st. iu cho thy cc gene m ha cho CDK v cyclin c th c chc nng nh oncogene (gene ung th). Cc phn t CDK v cyclin cng phi hp vi nhng sn phm ca gene c ch khi u (v d p53 v Rb) trong sut chu trnh t bo. Nhng pht hin trong chu trnh t bo c s dng chn on khi u. Mc gia tng phn t CDK v cyclin i khi c tm thy cc khi u, chng hn ung th v v u no. Nhng khm ph ny c l trong thi gian di cng m ra nhng nguyn l mi cho liu php ung th. By gi c nhng th nghim lm sng trong tin trnh s dng cht c ch phn t CDK.