Rescuing Cells from the Brink of Death (or Pushing Them Over It)
Multicellular life is a balance between cell survival and cell death. The genetically programmed death of cells is a normal part of embryonic development and occurs throughout the lifetime of organisms to rid abnormal (e.g. pre-cancerous) and surplus cells from the body. Research at Cold Spring Harbor Laboratory now reveals that under special circumstances, cells programmed to die during nervous system development can be brought back from the brink of death. This finding has important implications for the treatment of neurodegenerative disease, stroke, and cancer.
The study, to be published July 12 in Nature, focused on the developing nervous system of a favored experimental organism: the soil nematode worm Caenorhabditis elegans. Cell survival and cell death during development in this animal is highly stereotyped. Among different embryos, cells in corresponding positions virtually always share the same fate. Because the worms are transparent, the fate of all cells-living, dead, or dying-can be followed relatively easily and filmed by using a video camera attached to a microscope.
Under normal circumstances, dead cells are engulfed by neighboring cells to eliminate them from the embryo. Until now, the engulfment process was viewed as an after-the-fact, disposal operation. Cold Spring Harbor Laboratory researchers Daniel Hoeppner and Michael Hengartner, together with Ralf Schnabel of the Institute for Genetics (Braunschweig, Germany), studied how the death and "burial" (engulfment) processes are coördinated during development of the C. elegans nervous system. They made two interesting discoveries.
First, the scientists found that when they weakened the genetically programmed signal for cells to die, most cells still died (65%) and an expected cohort of cells survived (15%). Surprisingly, however, a few cells (5%) proceeded all the way to death's door but at the very last stage before death (stage 3 of 4), they reverted to a normal appearance and survived.
Second, the researchers found that blocking engulfment in animals with a genetically weakened cell death signal increased the number of cells that escaped death to nearly 20%. Moreover, some 40% of cells slated for death in these animals survived outright, never displaying signs of death. In essence, when the engulfment machinery was disabled, cells lived that otherwise would have died. This finding indicates that the engulfment machinery actively contributes to cell killing, rather than merely eliminating dead cells.
Because many features of programmed cell death and engulfment are conserved between C. elegans and humans, the scientists suggest that modulating the activity of the engulfment machinery in humans might be an effective therapy for neurodegenerative disease, stroke, and cancer.
Daniel Hoeppner is currently at the National Institutes of Health (Bethesda, Maryland).
Michael Hengartner is currently at the University of Zurich (Zurich, Switzerland).