Biologists have known for a long time that cells must die as part of the normal process of development. That fact of life is perhaps most transparent in animals like frogs, which undergo dramatic metamorphosis. When a tadpole sheds the structures needed for a completely aqueous existence and gains new ones to accommodate life on land and water, many cells die and are replaced.
The same process of naturally-occurring cell death, although less obvious, takes place in humans. For example, in the developing brain, many millions of cells die before taking on the characteristics of nerve cells, while in the blood of adults about 95% of the cells formed in the immune system die before having a chance to function.
Because such cell deaths occur as a part of the normal “program” of development, this process has been dubbed programmed cell death. But are there genes that govern programmed cell death? What mechanisms prompt otherwise healthy cells to commit suicide?
In the 1970s, HHMI investigator H. Robert Horvitz at the Massachusetts Institute of Technology began a search for the genes responsible for programmed cell death in the nematode worm Caenorhabditis elegans. This worm is a marvelous animal for developmental geneticists to work with because the developmental origin — and fate — of every one of its 1,090 cells is known. This has made it easier to identify many of the genes that control both how specific cells are generated and what they do once they are formed.
In 1986, Horvitz reported the discovery of the first cell-death genes, two genes with functions necessary for turning on the cell-death program. Subsequently, Horvitz and his group analyzed other genes, including those that decide which cells should live and which will die, those that protect cells from dying, those that direct neighboring cells to engulf dying cells, and those involved in cleaning up the debris generated by cell corpses. In essence, much of the molecular pathway for programmed cell death was elegantly mapped and found, from research done in many laboratories, that this pathway defined by Horvitz is similar to the cell-death pathways in other organisms, including humans. For his studies of programmed cell death and of other aspects of animal development, Horvitz was awarded the 2002 Nobel Prize in Physiology or Medicine. Horvitz shared the award with Sydney Brenner of The Salk Institute in La Jolla, California, and John Sulston of the Sanger Centre in Cambridge, England.
Detailed knowledge of the molecular interplay that governs programmed cell death is central to many aspects of human health. Cells commit suicide when they are infected with a virus, when they have damaged DNA, and when the body must cull immune cells that can be harmful. When this process goes awry, it can cause many different kinds of disease, including some forms of cancer, neurodegenerative disease, and autoimmune disorders. Horvitz and his colleagues are continuing to analyze how cells decide whether to live or die and what causes cells to die once this decision has been made.
Photo: Paul Fetters