The worm people's most important contribution, however, may be their analysis of the curious process of programmed cell death, or apoptosis—the controlled suicide of certain cells for the good of the whole animal.

Apoptosis is essential to all animal life. It is a key part of development and a safety feature in adulthood. As an animal develops from a single fertilized egg, it faces a series of challenges that arise from complexity: It must produce many different types of cells from one cell; it must coordinate these varied cells' activities; and the cells must have ways to communicate with each other. Every cell must work for the common good.

Sometimes this means that a cell must kill itself. Such sacrifices occur in a most orderly fashion. While cells that suffer injuries have messy deaths—they swell up, burst, spill their contents over their neighbors, and produce inflammation—those that commit suicide die neatly and disappear. Theirs are useful deaths, helping to sculpt the body and to keep other cells functioning properly.

For example, human fetuses start out with a duck-like webbing between their fingers and toes; apoptosis makes this webbing dissolve before birth. Only about half of the nerve cells in a newborn's brain manage to establish useful connections to other brain cells; rather than clutter up the developing brain, the remaining nerve cells self-destruct. Millions of immune system cells that might improperly attack the body's own tissue commit suicide every day. All this is for the best—unless apoptosis gets derailed.

Much of what is known about programmed cell death comes from pioneering studies by HHMI investigator Robert Horvitz of the Massachusetts Institute of Technology (MIT) in Cambridge, who first worked with Brenner in England and later identified many of the genes controlling apoptosis in C. elegans.

The worm is particularly well suited to such research. Brenner had originally selected it as a model organism because he wanted a really stripped-down animal, one with a minimum number of cells to investigate. As an added attraction, the worm's cells are clearly visible in its transparent body, especially when researchers use Nomarski differential contrast optics to highlight cell nuclei under the microscope.

John Sulston, until recently director of the Sanger Centre, spent 10 years patiently staring at the worm's cells under a microscope when he collaborated with Brenner. He started with a fertilized egg and traced the history of each cell in the developing embryo as these cells grew, migrated, or divided. Together with Horvitz, he then produced a detailed lineage map of C. elegans cells, whose fate was identical in every worm. This revealed that although each worm generated 1,090 cells, the adult animal consisted of only 959 cells. Exactly 131 of the worm embryo's cells were programmed to die, often within minutes of their birth.

Focusing on this suicide program, Horvitz identified a "death pathway"—three steps that the doomed cells follow. "First, killing the cell," Horvitz says in a dramatic tone. "Next," and his voice deepens, "getting rid of the body. And third, destroying the evidence."

Basically, he explains, "you produce a corpse and you must do something with it. A neighboring cell swallows the corpse to remove it from the animal. But then the body, now swallowed, must be degraded. This sequence involves a genetic pathway that we have defined in the worm and that may prove universal among organisms, including ourselves."

Each of these steps is controlled by different genes, Horvitz has found. At least 15 worm genes play some role in apoptosis. For example, killing the cell requires the activity of two genes, ced-3 and ced-4. "Since these are killer genes," Horvitz explains, "it's very important to regulate them." So another gene, ced-9, prevents these two genes from being active at the wrong time and thus protects the worm against unwanted cell death. "ced-9 acts genetically upstream of these two killer genes," Horvitz says. A third killer gene, egl-1, kills cells by preventing ced-9 from performing its protective duties.

— Maya Pines

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Robert Horvitz pioneered studies of the "death pathway" through which unwanted cells commit suicide. Together with Sydney Brenner and John Sulston, he won the Nobel Prize in Physiology or Medicine in 2002.

Photo: Paul Fetters

	A Family Tree of Every Cell in the Worm

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