Controlling the cell cycle

Three scientists win a Nobel Prize for Physiology and Medicine for seminal discoveries on the control of cell cycles, which are of significance to biomedical research.

ALL living organisms consist of cells, which divide and multiply. Except for bacteria, viruses and blue-green algae, all organisms are made up of eukaryotic cells, which have their genetic information, in the chromosomes, located in a nucleus separated from the rest of the cell, the cytoplasm. During cell division, while the nucleus goes through a cycle, cytoplasm divides by constriction in animals and by the formation of a membrane in plants. Yeasts and amoebae are unicellular, plants and animals are multi-cellular. An adult human being, for instance, is made up of about a billion cells per gram of tissue, all of which have originated from a single fertilised egg cell. There are also cells in an adult organism that continuously divide and replace dying ones. The molecular basis of cell cycle and cell division, which has come to be understood fully in recent years, is highly conserved in evolution and operates in the same way in all eukaryotic organisms.

The cell cycle consists of several phases. The duration of the cycle is dependent on the cell type. In most mammalian cells it ranges from 10 to 30 hours.

It is essential that the different phases are precisely coordinated and controlled so that one phase is completed before the next one can begin. Errors in coordination can lead to chromosomal aberrations D chromosomes or their parts can be lost, rearranged or distributed unequally between the daughter cells. This type of alteration is often seen in cancer cells. Therefore, an understanding of the regulation of cell division D how cells determine when and how to multiply or otherwise develop, and how that process can go awry D is fundamental to understanding how cancer cells mutate and to developing approaches that predict, prevent or reverse the alteration.

This year's Nobel Prize for Physiology and Medicine has been awarded for seminal discoveries concerning the control of the cell cycle. The award is shared by Leland Hartwell (62) of the Fred Hutchinson Cancer Research Centre, Seattle, United States, and Timothy Hunt (58) and Paul Nurse (52) of the Imperial Cancer Research Fund, London. The three scientists together have enabled an understanding at the molecular level how the cell is driven from one phase to the next during division.

Using yeast as a model organism D since it is simpler and easier to manipulate than human cells and also undergoes easily visualised morphological changes D Hartwell was the first to harness the tools of genetics to study which genes cause cells to divide. Hartwell recalls that at that time it was "a fairly risky assumption" as he was the only one looking at yeast cells. In an elegant series of experiments during 1970-71, Hartwell used baker's yeast, Saccharymyces cerevisiae. He isolated yeast cells in which genes controlling the cell cycle were mutated, the so-called CDC (cell-division-cycle) mutants. These mutations prevented progression through specific parts of the cell cycle. Hartwell's collection of CDC-mutants has proved to be an invaluable treasure for the cell-cycle field. From this collection he and others have been able to isolate many of the key genes of cell cycle control.

Hartwell demonstrated that DNA replication and nuclear events are coordinated with cytoplasmic events at a point, which he called START, and this crucial point was controlled by a gene, which he designated CDC28. That is, the START gene (CDC28) controlled the transition from the G1 phase to the S phase. Hartwell also documented the existence of cell-cycle checkpoints, control mechanisms, whereby the cell checks for completion of upstream events before proceeding further in the cell cycle. Later he extended the checkpoint concept also to include controls ensuring a correct order between the cell-cycle phases. The most remarkable fact is that the CDC genes and the pathways they control are highly conserved during evolution and the CDC genes in all eukaryotes are similar. Recently he suggested a role for checkpoint defects and proposed how cancer cells may bypass checkpoints. This new insight has provided a framework that links cancer, chromosomal instability, genetic loss and DNA damage. This has led Hartwell to propose practical ways in which yeast might be used to screen novel anti-cancer drugs.

Following Hartwell, Paul Nurse used a different yeast, Schizzosaccharomyces pombe, which is distantly related to baker's yeast, as a model organism and discovered the gene CDC2 which had a key role in the control of the transition from the G2 phase to mitosis. Later Nurse found that CDC2 had a more general function. In 1987 Nurse isolated the corresponding gene in humans, later called CDK1. The gene encodes a protein that belongs to a family cyclin dependent kinases, CDK. Nurse showed that activation of CDK is dependent on reversible "phosphorylation" D phosphate groups' addition to and removal from proteins. This finding has formed the basis for the identification of several other CDK molecules in humans. CDC28 was actually the first CDK gene identified, which has formed the basis for major advances in the understanding of cell cycle in the last 15 years.

Hunt's work in the 1980s complemented the above. In sea urchins, Arbacia, that he studied as a model system, he found the first cyclin. Cyclins are proteins formed and degraded during each cell cycle. The amount of CDK molecules is constant during the cell cycle. But the cyclins bind to the CDK molecules, thereby regulating CDK activity and selecting the proteins to be phosphorylated. Periodic protein degradation is thus the key control mechanism. CDK and cyclin together drive the cell from one phase to the next in the cell cycle. Hunt later discovered cyclins in other species as well and found that cyclins were conserved during evolution. Today we know of 10 different cyclins in humans.

While the findings are of significance to all biomedical research, they have a crucial bearing on the treatment of cancer. It is likely that chromosomal aberrations are owing to defective cell cycle control. It has been suggested that genes for CDK molecules and cyclins function as oncogenes, the cancer-causing genes. Increased levels of CDK and cyclins are sometimes found in human tumours. CDK molecules and cyclins have also been shown to collaborate with the products of tumour-suppressor genes during the cell cycle. These discoveries are about to be applied to tumour diagnostics. The above Nobel Prize winning research may give rise to new principles for cancer therapy. Inhibitors of CDK molecules are already undergoing trials as anti-cancer drugs.