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.
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 nematode Caenorhabditis 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).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 fro a part of the developing nervous system. He sowed 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.
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.
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.
