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Joseph S. Takahashi, Ph.D. As a child, Joseph S. Takahashi lived in "some unusual places where there were a lot of exotic animals." His father, an economist, had a number of overseas assignments, taking the family first to Burma and then to Pakistan. In Burma, Takahashi remembers riding elephants and taking boat trips up the Irrawaddy River. In Pakistan, it was riding camels and deep-sea fishing in the Arabian Sea. "I always had many pets, and our house was a menagerie of dogs, cats, rabbits, pigeons, and tropical fish," he says. His interest in animals eventually led him to major in biology at Swarthmore College, thinking he would likely pursue a career in medicine. But Kenneth Rawson, a Swarthmore professor who was Takahashi's first mentor, taught a course with a "remarkable field and laboratory section on the physiological basis of animal behavior," Takahashi recalls. It was Rawson who set Takahashi on the research path he now vigorously pursues—circadian rhythms. As a Howard Hughes Medical Institute (HHMI) investigator and professor of neurobiology and physiology at Northwestern University in Evanston, Illinois, Takahashi, 48, leads an effort to sort out the genes and proteins that make up the mammalian circadian clock—and then to figure out how they work together ultimately to control the behavior of the animal. In 1997 Takahashi's lab discovered the first circadian rhythm gene in mammals, the mouse gene Clock, an acronym for "circadian locomotor output cycles kaput." Since then, researchers have identified eight other mammalian circadian genes, enabling scientists to study the interplay of proteins that make up the clock's negative-feedback mechanism at the most basic molecular level. Most recently, in a major paper in the April 21, 2000, issue of Science, Takahashi and his colleagues reported cloning the gene responsible for the tau mutation in hamsters, a spontaneous mutation first recognized in 1988 by Takahashi's Ph.D. mentor, Michael Menaker. When present in two mutant copies, the gene shortens the animal's daily cycle to 20 hours rather than 24. It codes for an enzyme that is involved in regulating several other circadian-clock proteins. It is closely related to a Drosophila gene known as doubletime and to a human gene known as casein kinase I epsilon—another demonstration of what Takahashi calls "a striking level of evolutionary conservation" of the clock mechanism in animals. Takahashi's genetic circadian discoveries have given him the reputation in some quarters of being a hard-core molecular geneticist. In fact, his Ph.D. training at the University of Oregon in Eugene in 1981 was in neuroscience. It was in the laboratory of Michael Menaker—"a remarkable person who provided vast resources and an unusually stimulating environment for research"—that Takahashi's appreciation for neuroscience, evolutionary biology, and large-scale experiments began in earnest. Later, Takahashi did postdoctoral work as a pharmacology research associate trainee at the National Institute of Mental Health. At Northwestern, whose faculty he joined in 1983, most of his early research was conducted at the cellular level, and he didn't begin to work on mouse genetics until the early 1990s. But all through his career, Takahashi has pursued the mechanism of circadian rhythms as a model for understanding how the brain controls behavior. "Since graduate school, I have always been focused on the mechanism of circadian clocks," he says. "And I will do anything it takes to understand that problem—whatever task we have to do, whether it's molecular biology, genetics, or electrophysiology." This attitude will probably lead him to another discipline, biophysics, before he is done. Takahashi says that a biological mechanism, such as the circadian clock, can't be called "solved" until it can be expressed in the analytical, quantitative language of biophysics. "The beauty of biophysics is that you can write equations which describe the behavior of particular molecules in quantitative terms," he says. "We're not there for rhythms. We are just beginning to understand the kinetics of circadian mechanisms." Although today his lab is largely a molecular genetics lab, "we've never lost our behavioral and physiological roots," he says. "We started with the behavior. And the behavior is what's taken us to genes. Understanding those genes was really the key that we needed to understand the behavior." Takahashi emphasizes that this approach is hardly unique in neuroscience. His lab is, if not unique, at least highly unusual in another respect. Harking back to his days at Richard Montgomery High School in Rockville, Maryland—when he and a friend rebuilt the V8 engine in a 1959 Ford Thunderbird as a senior project—he insists that the people in his lab not only know how to operate complex laboratory instruments but also understand how those instruments work. "I strongly believe that one must begin with first principles," he says. If someone uses a microscope, Takahashi says, he or she ought to be familiar with optics and should know how the instrument functions. "Otherwise, they're not going to use the microscope properly." If they use a scintillation counter—a device that measures the presence and concentration of radioactively labeled substances such as proteins—"they really should understand how the instrument works." Otherwise, they will just have to take the machine's numbers at face value. "If they don't know how it works, they cannot make a judgment about whether those numbers are valid or not, or what kind of artifacts compromise those numbers," he says. Takahashi may be a hard taskmaster, but he apparently is a generous collaborator. Although many scientists are reluctant to share credit, Takahashi believes collegiality is "very important" in science, and he seeks out collaborations in which each partner can bring special strengths to a project. For example, he recruited Menaker and Martin R. Ralph as collaborators in the effort to find the gene responsible for the hamster tau mutation. Menaker, now at the National Science Foundation Center for Biological Timing at the University of Virginia in Charlottesville, and Ralph, who is at the University of Toronto, made the original discovery of the tau mutation, Takahashi explains. "I felt it was important for them to participate in the ultimate discovery of the gene," he says. "I think that's the way it should be." His work keeps Takahashi incredibly busy. "The schedule for professionals is just brutal," he says. He tries to get home by 6 p.m. each evening—he lives just 10 minutes away from his lab—but he often puts in some work at night, linking with his lab's computers remotely. His wife, Barbara Takahashi, a medical doctor who also holds a master's degree in public health, stopped practicing medicine to look after their children, Erika, 9, and Matthew, 6. "She felt it was more important to raise the children," Takahashi says. "This is a very complicated decision—career versus family. I feel incredibly fortunate to have such a wonderful and supportive family." He likes to give Matthew a ride to school in the morning in his bright blue Miata sports car and to handle other small chores. "I can pitch in a little bit," he says. "What I would call very minor, though." Perhaps surprisingly, because science is typically thought of as a stay-in-the-lab endeavor, Takahashi finds that the biggest drain on his family time is travel. He makes about 25 trips a year to scientific conferences, advisory committee meetings, and symposia of one sort or another. Recently, his travel pace has been accelerating. "That's because the field is sort of hot right now," Takahashi says. "Clocks are hot." |
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