The rest of the death pathway is now being explored, both upstream and downstream of these killer genes. Hermann Steller, an HHMI investigator who recently moved from MIT to The Rockefeller University, is conducting his search in the fruit fly. After looking for mutant flies in which apoptosis fails to occur, Steller and his associates identified two genesreaper and hidthat act together to switch on the suicide program in Drosophila. Then John Abrams, a former postdoctoral fellow in Steller's lab, identified a third gene, grim, after setting up his own lab at the University of Texas Southwestern Medical Center.
"We can take these three Drosophila genes and express them in mammalian cells, and they induce apoptosis in those cells," says Steller. "So these genes are interacting with other components in the death program in mammals. That makes us absolutely certain there will be mammalian homologs with equivalent function." He adds that the targets of reaper, hid, and grim are the "inhibitors of apoptosis proteins," or IAPs, which are found all the way up to humans.
Meanwhile, since the development of the fly's eye has been studied in great detail, Steller has been able to look for genes that modify the effects of the three death genes. He can identify them simply by examining the eye's condition. Severe defects in the fly's eye, resulting from too many cell deaths, can lead the researchers to genes that promote apoptosis. Healthy fly's eyes can help the researchers identify genes that inhibit cell death. Steller expects that systematic analysis of this sort will lead to a fuller understanding of apoptotic pathways not only in Drosophila but also in humans.
He has already developed a fly model of the human genetic disease retinitis pigmentosa, in which retinal cells die, leading to blindness. "The same mutation that causes retinitis pigmentosa in humans causes a very similar disease in flies," Steller says. "So we investigated whether we could block cell death in our fly modeland whether this would lead to retention of vision in these flies. In other words, could we prevent them from going blind?"
He could. "If you block apoptosis in the retina of such mutant flies, the cells will no longer die and, more importantly, the cells will continue to function," he says. "They will not be perfect, but good enough for robust vision." Maybe the diseased retinal cells realize they are not functioning perfectly and therefore kill themselves, Steller speculates. "If you could prevent such cells from killing themselves in a human with retinitis pigmentosa, or perhaps similar degenerative disorders, maybe cells could continue to function and the patient would benefit significantly."
As Horvitz points out, "The number of cells in our bodies is really an
equilibrium number. Cells are always being added to our bodies, by the process of cell division, but cells are also always being taken away, by the process of programmed cell death. We can generate too many cellsas in cancernot only by too much cell division but also by too little cell loss.
"On the other hand, the normal pathway that causes cells to die by programmed cell death is sometimes unleashed in nerve cells that were not meant to die," Horvitz says. "Some researchers believe that diseases such as Alzheimer disease, Huntington disease, ALS [Lou Gehrig's disease], and Parkinson disease, which are characterized by the deaths of nerve cells, are diseases in which the normal process of apoptosis has gone amok. How might we stop such deaths? By blocking the killer genes that are responsible."
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A revealing look at proteins in the cell-death pathway of a worm embryo...
Image: Brad Hersh