As he studies the ras pathway that leads from a receptor on the cell's surface to DNA in its nucleus, Kim no longer needs to work out, step by step, each of the signals that make a cell growor not growin response to messages from outside the cell. "With the aid of DNA chips, you can look at all of the cell's genes at once," Kim says. "You can ask, 'When a cell begins to grow, what genes are newly activated inside that cell?' You can illuminate the entire process."
Microarrays will be far more important in the study of worms than of yeast, Kim believes. As a one-celled organism, yeast does not have a nervous system to regulate learning and behavior. Nor does it have any of the major signaling pathways that regulate development. "But animals have conserved signaling pathways that regulate the development of the spinal cord and the brain, how we grow our fingers, how big we make our arms. They regulateyou name it!" he says.
"So that's where I see C. elegans as having a profound effect," Kim continues. "We now have DNA chips that contain all of the genes in the worm, and we can get a molecular description of what happens."
In the past, it was difficult to follow all the genes that might be activated at once during cell signaling. "It's very, very complicated to study things that become branched," Kim says. "But the chips get us around that. We can easily identify genes that are turning on in parallel."
Kim is now using DNA chips to study several signaling pathways, including one that directs the development of the worm's germ line (eggs and sperm). "In C. elegans, the germ line is more than half of the animal," he says. "The worm is mostly a hollow tube filled with the intestine and the gonad [the organ that produces eggs or sperm], which is bigger than the intestine." The rest of the worm consists of a carcass and muscles to make it move, he explains.
Germ-line cells are "immortal and totipotent," Kim points out. "We can all make a baby. We can make everything that's needed for an entire humanthe eyes, the nose, the fingersfrom the egg and sperm cells in our germ line. And that baby can make another baby." All the other cells in the body, however--the so-called somatic cellsare differentiated into brain, liver, muscle, and so on, and they are mortal. "We will age and die, although our germ line, or the results of our germ line, continue on," Kim says.
What Kim wants to know is how the genes in these two types of cellsthe immortal cells in the germ line and the mortal cells in the rest of the bodydiffer in their activity. With the help of microarrays, he has already identified 1,432 worm genes that are expressed (turned on) in the germ line but not in the soma. "These genes might give us a handle on what makes the germ line so special," Kim says.
Kim's lab also uses microarrays to analyze the process of aging. Some mutant worms live much longer than others, and he would like to know how they do it. "Does all aging slow down at the same time in these worms, or just specific kinds of aging in specific tissues? We might be able to get at a subset of genes that are key to making an animal age at the rate it does." This, conceivably, might someday lead to an age-retarding drug.
Such studies could not be done without DNA chips, Kim emphasizes. "It's as if we had a new type of microscope," he says. "We can now use a DNA chip as a gene-expression microscope to look at a process and describe it in molecular terms."
He is so enthusiastic about microarrays that he has volunteered to run such tests for any lab that sends him samples of worm RNA. "We'll just hybridize their RNA and send them back the data," he says. Some scientists have already sent him worm RNA that seems related to a variety of human diseases, such as Alzheimer; others want to find out how nerve cells change as a result of learning. Kim provides such services nationally through grants from Rhône-Poulenc Rorer Gencell, the Merck Genome Research Institute, and the NIH's National Center for Research Resources.
"The grammar used to construct genetic pathways is simpler in worms than in mammals because there are fewer words, fewer synonyms, and simpler sentence structures," Kim wrote recently. "Thus, to learn how to read the book of an organism's genome, it makes sense to start with the worm."
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Stuart Kim (left) and John Wang discuss their C. elegans microarrays, one of which is shown on the monitor behind them. It compares the activity of genes in cells of a male worm and a hermaphrodite.
Photo: Kay Chernush