2002..Nobel Prize in Medicine and Physiooggy

Sydney Brenner

H. Robert Horvitz

John E. Sulston

The Nobel Prize in Physiology or Medicine 2002 was awarded jointly to Sydney Brenner, H. Robert Horvitz and John E. Sulston "for their discoveries concerning 'genetic regulation of organ development and programmed cell death'"

Genetic regulation of programmed cell death

Sir John Sulston of the Wellcome Trust Sanger Institute developed techniques to study cell divisions in the nematode, from the fertilized egg to the 959 cells in the adult organism

SYDNEY BRENNER, H. Robert Howvitz and John . E. Sulston have been jointly awarded the Nobel prize in physiology or medicine. The prize has been awarded by the Nobel assembly at karolinksa Institute for 2002 for their discoveries concerning genetic regulation of organ development and programmed cell death.

The human body consists of hundreds of cell types, all originating from the fertilized egg. During the embryonic and foetal periods, the number of cells increase dramatically. The cells mature and become specialised to form the various tissues and organs of the body. Large numbers of cells are formed also in the adult body. In parallel with this generation of new cells, cell death is a normal process, both in the foetus and adult, to maintain the appropriate number of cells in the tissues. This delicate, controlled elimination of cells is called programmed cell death.

Developmental biologists first described programmed cell death. They noted that cell death was necessary for embryonic development, for example when tadpoles undergo metamorphosis to become adult frogs. In the human foetus, the interdigital mesoderm initially formed between fingers and toes is removed by programmed cell death. The vast excess of neuronal cells present during the early stages of brain development is also eliminated by the same mechanism.

H. Robert Horvitz used C. elegans to investigate whether there was as a genetic program controlling cell death.

Sydney Brenner realized, in the early 1960's, that fundamental questions regarding cell differentiation and organ development were hard to tackle in higher animals. Therefore, a genetically amenable and multicellular model organism simpler than mammals, was required. The ideal solution proved to be the nematodeCaenorhabditis elegans. This worm, approximately 1 mm long, has a short generation time and is transparent, which made it possible to follow cell division directly under the microscope. Brenner provided the basis in a publication from 1974, in which he broke new ground by demonstrating that specific gene mutations could be induced in the genome of C. elegans by the chemical compound EMS (ethyl methane sulphonate).

Different mutations could be linked to specific genes and to specific effects on organ development. Detailed studies in this simple model organism demonstrated that 131 of totally 1090 cells die reproducibly during development, and that this natural cell death is controlled by a unique set of genes.

John Sulston extended Brenner's work with C. elegans and developed techniques to study all cell divisions in the nematode, from the fertilized egg to the 959 cells in the adult organism. In a publication from 1976, Sulston described the cell lineage for a part of the developing nervous system. He showed that the cell lineage is invariant, i.e. every nematode underwent exactly the same program of cell division and differentiation. As a result of these findings Sulston made the seminal discovery that specific cells in the cell lineage always die through programmed cell death and that this could be monitored in the living organism. He described the visible steps in the cellular death process and demonstrated the first mutations of genes participating in programmed cell death, including the nuc-1 gene.

Sulston also showed that the protein encoded by the nuc-1 gene is required for degradation of the DNA of the dead cell. Robert Horvitz continued Brenner's and Sulston's work on the genetics and cell lineage of C. elegans. In a series of elegant experiments that started during the 1970's, Horvitz used C. elegans to investigate whether there was a genetic program controlling cell death. In a pioneering publication from 1986, he identified the first two bona fide "death genes", ced-3 and ced-4. He showed that functional ced-3 and ced-4 genes were a prerequisite for cell death to be executed. Later, Horvitz showed that another gene, ced-9, protects against cell death by interacting with ced-4 and ced-3. He also identified a number of genes that direct how the dead cell is eliminated. Horvitz showed that the human genome contains a ced-3-like gene. We now know that most genes that are involved in controlling cell death in C. elegans, have counterparts in humans.

Salk Institute professor Sydney Brenner demonstrated that specific gene mutations could be induced in genome of C. elegans by the chemical compound EMS (ethyl methane sulphonate).

Knowledge of programmed cell death has helped us to understand the mechanisms by which some viruses and bacteria invade our cells. We also know that in AIDS, neurodegenerative diseases, stroke and myocardial infarction, cells are lost as a result of excessive cell death. Other diseases, like autoimmune conditions and cancer, are characterized by a reduction in cell death, leading to the survival of cells normally destined to die.

Research on programmed cell death is intense, including in the field of cancer. Many treatment strategies are based on stimulation of the cellular "suicide program". This is, for the future, a most interesting and challenging task to further explore in order to reach a more refined manner to induce cell death in cancer cells.

This year's Nobel Laureates in Physiology or Medicine have made seminal discoveries concerning the genetic regulation of organ development and programmed cell death. By establishing and using the nematode Caenorhabditis elegans as an experimental model system, possibilities were opened to follow cell division and differentiation from the fertilized egg to the adult.

The Laureates have identified key genes regulating organ development and programmed cell death and have shown that corresponding genes exist in higher species, including man. The discoveries are important for medical research and have shed new light on the pathogenesis of many diseases.