Programmed Cell Death

'NO GENE IS AN ISLAND': A paper coauthored by MIT's Robert Horvitz describes genetic similarities between mammals and worms. This paper is one of the many to have been published in the last few years that have added to the growing understanding of what factors control cell death. "We have for some years been attempting to understand the mechanisms that control programmed cell death by studying the genetics of cell death in the nematode C. elegans," says H. Robert Horvitz, an investigator with the Howard Hughes Medical Institute and a professor of biology at the Massachusetts Institute of Technology. "We have identified a pathway of genes that function in this process. At the beginning of this pathway is the gene ced-9, which we showed a few years ago to be a negative regulator of cell death [M.O. Hengartner et al., Nature, 356:494-9, 1992]. What the Cell paper showed is that the worm ced-9 gene encodes a protein that is similar to bcl-2, a mammalian proto-oncogene." This finding, he suggests, helps link the study of cell death in the worm and oncogenesis in people. "There were a number of papers that had suggested a relationship between cell death and oncogenesis, but it was this tie between ced-9 and bcl-2 that really put the nail in the coffin," comments Horvitz. Results described in the paper more generally suggest that the molecular mechanism of programmed cell death has been conserved evolutionarily from worms to mammals. "Concerning evolutionary universality, there are two additional striking observations beyond the similarity between ced-9 and bcl-2 reported in the paper: One is that when human bcl-2 is put into a worm it protects against cell death. That experiment was first published by David Vaux at Stanford University [D.L. Vaux et al., Science, 258:1955-7, 1992] and was repeated by us using a different assay. "We took this finding a step further. We showed that not only would bcl-2 work in a worm, but also that it would substitute for a defective worm ced-9 gene. This result established that bcl-2 is working at the same step in the pathway as ced-9." Horvitz remarks that this finding has another "profound implication" in terms of genetic conservation: "No gene is an island. Genes work in conjunction with other genes. Proteins interact with other proteins. So the fact that human bcl-2 could work in a worm and substitute for the worm ced-9 gene indicates that human bcl-2 is interacting with whatever proteins the worm ced-9 protein interacts with. That, in turn, suggests that not only the gene, but also the pathway of cell death, is likely to be universal-conserved at least between worms and humans. That, I think, is also big news." Horvitz mentions two other papers from his laboratory that helped confirm the idea of pathway universality: J.Y. Yuan et al., Cell, 75:641-52, 1993, which has been cited more than 200 times through November 1995; and D. Xue, H.R. Horvitz, Nature, 377:248-51, 1995. He asserts that the 1993 and 1994 Cell papers have been cited so often because "cell death has become a very major interest. If you plot the number of cell-death papers as a function of time, you'll see they've skyrocketed in the recent past. The cell-death gene that is best known and studied is bcl-2. This paper shows that a bcl-2-like gene is functioning in a cell-death pathway in vivo and, in particular, is acting like ced-9 to protect cells against programmed cell death."

Programmed Cell Death

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