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Sydney Brenner (right) with Gerry Rubin at Janelia Farm.
Other results flowed in. By 1977, after years of doggedly staring into microscopes, John Sulston—who had joined Brenner's group at the Medical Research Council in Cambridge, England—produced the complete lineage map of an adult worm, from a single fertilized egg cell to the 959 cells in the fully organized animal. H. Robert Horvitz, doing a postdoctoral fellowship in the same lab, teamed up with Sulston in the later stages of this work, tracing the fate of each cell during the worm's growth from embryo to adult. Their research revealed that cell division produced 131 more cells than actually make up the mature worm. They learned that those extra cells died through an orderly process known as apoptosis, or programmed cell death, during which certain cells commit suicide for the benefit of the whole animal.
In a series of experiments that began in the 1970s, Horvitz, who is now an HHMI investigator at the Massachusetts Institute of Technology, identified a number of genes that regulate apoptosis in the worm. He also found that one of those genes had a similar counterpart in humans. Researchers subsequently found versions of other worm apoptosis genes in humans, where they play an essential role in normal development. Both Sulston and Horvitz eventually shared the Nobel Prize in Physiology or Medicine with Brenner in 2002 for their achievements.
Brenner, a short man with bushy eyebrows who has been known to wave his cane in the air during arguments with other scientists, he has a low tolerance for delay. He became disappointed that the new findings did not make a dent in the much more complex problem he had started out with: how genes control the nervous system and behavior. Concluding that the right tools for this work were not yet available, he simply gave it up temporarily. "That's why I like to have a lot of things to do," he explains, "so that if one gets stuck, you can go on with the others."
Now, 30 years later, Brenner is once again eager to tackle one of biology's greatest challenges— "understanding how a complete brain works," as he puts it. That is also the stated goal of the Janelia Farm Research Campus, whose work so far has focused on the brains of flies and mice. But Brenner pins his hopes on the worm, which has the simplest and best-known nervous system. "We will fulfill the program of Janelia in C. elegans," he predicts.
Brenner helped organize the March conference on "Neural Circuits and Behavior in C. elegans." It was prompted by the fact that researchers have now obtained three types of information that Brenner considers crucial for relating brain to behavior, and all three are available in the worm.
First, "we have the wiring diagram—we know exactly how many neurons are in the worm's nervous system and how they are connected," Brenner points out. Second, "we know the complete cell lineage of the worm"—how a single egg cell develops into all the other cells, and which cell comes from which progenitor. And third, researchers have established the complete DNA sequence of the worm's genome, which was published in 1998.
With all this information, "you can make models of how some circuits work and test them," says Brenner. But the key, he adds, is to use "the real structure of the worm's neural circuits." What needs to be done, he says, is "to think hard about how the worm solves a problem."
The 40 scientists who came to the Janelia Farm conference talked about their first efforts in this direction. Cornelia I. Bargmann, an HHMI investigator at The Rockefeller University in New York City (and co-organizer of the meeting), described her studies of how worms regulate their patterns of locomotion after they have been removed from food. She analyzed the hungry worms' search patterns, located the neurons involved in each pattern, and confirmed their activity by means of imaging. Jamie White, a postdoc in the University of Utah lab of HHMI investigator Erik M. Jorgensen, took a different approach: he analyzed the neuronal circuits that make male worms differ from hermaphrodites in their responses to pheromones, the chemical signals with which animals communicate. The males were attracted to pheromones released by hermaphrodites, while other hermaphrodites avoided them.
Photo: Paul Fetters