Researchers known for their work on C. elegans frequently get phone calls from scientists who want information about some of the worm's newly sequenced genes. "I am studying disease X and have just cloned a human gene that is involved in this disease," a caller says, "but I have no idea what this gene does. It is very similar to the C. elegans gene Y. Can you tell me anything about the function of Y?"
Most of the time, the experts are stumped. Even though the DNA sequences of all the worm's 19,099 genes have been deciphered, only 7 percent of the proteins that these genes encode have been studied at the genetic or biochemical level. At this rate, it might take several decades to learn much about the remaining 93 percent of the proteins in this small creature.
This thought hit Stuart Kim, a professor of developmental biology at Stanford University, with sudden force as the worm genome neared completion in 1997. Kim had been studying the ras pathway in C. elegans. "It was painstaking," he recalls. "You would start with a completely black box. You would find one gene and study it in quite excruciating detail, and then after years of work you might actually get to a second gene and then a third gene. That's how we used to build up genetic pathwaysstep by step. But when you start this way, you never know how big the network is," he says, "and you can't get a really satisfactory answer about how something works until you have the entire pathway."
So in 1997 Kim found himself becoming restless. The worm's DNA sequences had been posted on the Web as soon as they had become available, and most of the genome was known to researchers well before the official announcement of its completion. "I was thinking, the genome is supposed to be so powerful, yet it didn't seem to be affecting what I did," Kim recalls. "It made certain things a bit more efficient, no doubt, but I didn't feel that I was doing anything different from the old stuff."
Meanwhile, a graduate student working with Kim, John Wang, brought exciting reports about the whole-genome studies of yeast in Pat Brown's lab. Wang was friendly with some of Brown's graduate students, who showed him how to do microarrays. "And then, all of a sudden, we were using Pat's equipment to study the worm," Kim recalls. "We used Pat's equipment for two years. And it just worked better and better, and we liked it more and more, and so we got
our own equipment. Now we're self-sufficient. In fact, we're helping other labs to do microarrays with worm RNA."
This experience totally changed Kim's approach to research, he says. Since then, everything he has done has involved the whole worm genome.
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Each of the yellowish clumps of this 3-D view of gene activity in a worm cell represents a group of genes that are expressed together and probably have similar functions.
Image: Stuart Kim