When Kimble returned from Denmark, she decided to attend graduate school at the University of Colorado and study with David Hirsh, who had recently returned from the MRC. She became captivated by C. elegans. “I thought I could study development in this creature and ask in-depth molecular questions about animal development,” she recalls. “At the time, it was foreign to think that answers from a worm would be relevant to humans. But I thought it would be better to understand one simple organism in depth than to work on a mammal and not really understand it.”

One of the scientific attractions of C. elegans was the predictable sequence in which its cells emerge from the fertilized egg, which allowed researchers to begin tracing a genealogy of each of the worm's cells back to the egg. But when she and Hirsh tried to track the origin of cells in the gonad (a large, sausage-shaped structure producing a continuous stream of eggs and embryos), they discovered that germ cells broke the rule: germ-cell divisions varied from one worm to another. Still, intrigued by what the simple creature had to teach, Kimble moved to the MRC for a postdoctoral fellowship to delve more deeply into C. elegans development.

She had a habit of perusing old science journals and decided that her first MRC experiment would test a theory she'd read in an 1890s publication—that tiny undividing cells in early embryos might be vestigial (an “ancestral reminiscence,” in 1890s vernacular). If the distal tip cell had lost its function during evolution, Kimble figured that killing it should not affect the worm. But when she zapped the cell with a laser, the animal was sterile—all the germline stem cells differentiated, exhausting the worm's supply of eggs. “It was my first experiment at the MRC,” she says, “and it showed that I was wrong—the first of many times!”

In the course of refuting her hypothesis, however, Kimble discovered the first example of a stem-cell niche and opened a window into the complex mechanisms that govern the critical stasis-or-change decisions in stem cells.

It's hard to overstate the importance, or the ubiquity, of stem cells and the processes that control them. “Our bodies are full of stem cells, which must be regulated to maintain and replenish tissues,” Kimble says. In unraveling the ultimate point-A-to-point-B question—How do stem cells decide to become something else?—it became clear to Kimble that the same proteins that govern whether the worm's germline stem cells divide to produce more stem cells, or begin to differentiate and undergo meiosis, also help to determine whether the germ cells will be a sperm or an egg.

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