These findings led to some exciting coincidences. While studying patients with follicular B cell lymphoma, a cancer of the immune system, in 1985, HHMI investigator Stanley Korsmeyer of the Washington University School of Medicine, St. Louis (he is now at the Dana-Farber Cancer Institute in Boston) discovered that these patients carried a human oncogene called BCL2. Shortly afterwards, in Australia, David Vaux, Suzanne Cory and Jerry Adams at the Walter and Eliza Hall Institute of Medical Research announced that DNA from human BCL2 made mouse cells survive longer than normal; during this extra time, some of the cells acquired additional mutations and became malignant. Korsmeyer and his associates then bred transgenic mice that carried human BCL2 and showed that it leads to an excess of B cells—not by making cells grow faster, as other oncogenes do, but by preventing normal cell death.

Before long, all eyes turned to the worm. Collaborating with Irving Weissman and Stuart Kim at Stanford University, Vaux showed that human BCL2 greatly reduced cell deaths in the worm. Robert Horvitz's lab then proved that human BCL2 and the worm gene ced-9 did, in fact, encode similar proteins. Furthermore, when BCL2 was inserted into worms that lacked a ced-9 gene, BCL2 could substitute for the missing worm gene and protect the worm's cells against cell death. "This argues very strongly that the worm pathway and the human pathway share components," Horvitz said.

Other similarities followed. The protein made by the worm's ced-3 (a killer gene) was found to be closely related to the human enzyme ICE (interleukin-1 beta-converting enzyme). A dozen additional human enzymes in the ICE family—caspases, which cut up their target proteins at specific sites—were soon identified. Caspases of various kinds are present in all human cells in an inactive form, but during apoptosis they seem to activate one another in sequence, setting off a storm of protein destruction. Taking due note of these findings, several drug companies have started testing chemicals that might control the activity of caspases, in the hope of blocking apoptosis.

The worm's second killer gene, ced-4, also has a counterpart in humans—APAF1, a gene recently discovered by HHMI investigator Xiaodong Wang at the University of Texas Southwestern Medical Center at Dallas. Mice lacking this gene die at birth. Many of their brain cells fail to commit suicide during development, and their growing mass eventually takes up so much space that the animals' skulls cannot close around the enlarged brains.

— Maya Pines

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