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Barbara J. Meyer, Ph.D. Barbara Meyer has always loved intellectual puzzles—things you can think through, problems you can solve. Numbers, in particular, captivated her. By the age of five, Meyer had mastered arithmetic, and she seized every opportunity to apply her newfound talent. At the meat market in her hometown of Stockton, California, the young Meyer would race the grocer, calculating the total in her head while he punched prices into his adding machine. "I always beat him," she recalls with a smile. It was not until Meyer was an undergraduate at Stanford University that she discovered an interest in the life sciences. She had avoided biology at first, she says, "because it was so descriptive." Where was the logic? Where was the problem solving? Then she read James Watson's book, Molecular Biology of the Gene, and everything changed. "Watson showed that you could rationally dissect biological processes," she says. "You could puzzle through things and come up with a story that puts everything in perspective." Meyer's enthusiasm for figuring out how things worked carried her to David Clayton's laboratory, where she embarked on her first real research. "When I walked into the lab, I realized you could come up with an idea and do an experiment to see if you were right or wrong," she says. "There's something very beautiful about scientific analysis. It's a process of discovery built on story and logic. Not many things in life give you all that." But Meyer quickly realized she needed a more solid grounding in molecular biology. So as a graduate student at the University of California, Berkeley, Meyer set her sights on lambda phage, a well-studied virus that infects bacteria. Researchers working on lambda phage had already learned much about its basic biology and genetics, but many fundamental problems remained to be solved. One of the biggest mysteries: How does lambda phage decide what to do once it enters a bacterial cell? The phage has two choices. It can insert itself into the host's chromosome and lie quietly, or it can reproduce wildly until it bursts the host cell. A protein called the "lambda repressor" plays a key role in this decision, as it shuts down the cellular machinery required for lambda replication. But what controls the lambda repressor? Meyer wondered whether the repressor could regulate itself—boosting its own production to keep the phage in its quiescent state. Eager to tackle this question, Meyer approached her adviser—who told her the project would be too hard. Not one to back away from a tough problem, Meyer busied herself with other lab work, all the while toying with the problem of lambda repressor in the back of her mind. Then one day she attended a seminar given by Mark Ptashne, a Harvard investigator whose lab was at the cutting edge of gene regulation in lambda. Afterward, an exuberant Meyer revealed her fascination with this wily virus by peppering Ptashne with questions. And it wasn't long before the researcher invited her to do a sabbatical in his lab. Within two weeks, Meyer had performed the critical experiment—and it had worked perfectly. "There it was, the project that my thesis adviser at Berkeley told me was too hard to do—and yet I had done it," she says. In addition to being a feather in her cap, Meyer's finding propelled her to the forefront of molecular biology. Eventually she transferred to Harvard to pursue her Ph.D with Ptashne, who instilled in his people "clear thinking, synthesis, and vision," she says. Meyer found her time at Harvard "thrilling," and she published 13 papers as a graduate student. On the basis of her thesis work, Meyer was offered a position at MIT in Cambridge, but she decided to first take a detour to the other Cambridge—Cambridge, England. There she joined the laboratory of Sydney Brenner, a pioneer in the study of the worm C. elegans at the Molecular Research Council. Meyer wanted to work with worms in part because they had some experimental advantages over other model organisms. For one, they're easy to handle. "You can grow them on plates and, unlike fruit flies, you can even freeze them for later study," she notes. But more importantly, worms had not yet been studied exhaustively. "I wanted to start from scratch," she says. "Get a system up and running myself. I wanted to ask a question and take a problem from its genetic roots to its molecular mechanisms." Still interested in how cells make decisions, Meyer confronted the issue of how worms determine their sex. Like mammals, worms specify sex with a particular set of sex chromosomes: Animals with one X chromosome (XO) are males, while animals with two Xs (XX) develop into hermaphrodites, a sex that can produce both eggs and sperm. But how does a worm count how many X chromosomes it has? And how does it use that information to direct sexual development? Meyer was determined to find out. "It was clearly a pathway that was waiting to be fleshed out," she explains. "I wanted to find the genes that made it work." Serendipity and acumen led her to discover the master gene involved in sex determination, which launched the rest of her career. "From that point on, all the genetics worked incredibly well and the story got more and more exciting," she says. Meyer has since rooted out genes involved in the whole regulatory system that controls worm sex. Along the way, Meyer met her husband, fly geneticist Tom Cline, through their shared interest in sexual development in the animal world. Both secured jobs at the University of California, Berkeley, where they've worked since 1990. In addition to their common professional interests, they enjoy hiking, traveling, and watching movies. And at home, conversation often veers away from science. "It's nice that we can understand each other's work and help edit each other's papers, but enough's enough!" she laughs. Creative at designing experiments, Meyer also designs furniture, jewelry, and even her own laboratory. Her Berkeley lab has big bay windows that let in lots of light—a setup that makes hours of pipetting solutions much more pleasant for the 20 students, postdoctoral fellows, and staff who work there. Despite her extraordinary success, Meyer always asks herself whether the question she's working on is worth the time and money. "The bottom line is that I think I've chosen problems that are enduring," she says. How do animals choose their sex? Or, at a more fundamental level, says Meyer, "How does biology count to two?" Although Meyer's focus has changed somewhat since her preschool days, she still loves to count.
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