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Ronald M. Evans, Ph.D. “Follow the energy—that's my story,” says Ron Evans, an HHMI investigator at the Salk Institute in San Diego. “It's all about the energy.” The focus on energy applies equally well to both Evans's science and his personal philosophy. In the lab, Evans explores the regulation of metabolism: how cells balance their energy input and expenditure. But his investigations are powered by his enthusiasm, curiosity, and irrepressible energy. “I was a real lab rat,” says Evans of his early days at the bench. “Fifteen- or 16-hour days were pretty normal. It was work, work, work—and I loved it.” That degree of dedication is not unusual, says Evans. “When you're engaged in a scientific adventure, it really gets your juices flowing.” And science has been working its charms on Evans since he was in high school. “I was good at it,” he says, “and I think I had a good feel for it.” But he enrolled at UCLA as a business major. “My father filled out the application,” says Evans. “It was different in those days!” Evans's father, a doctor, believed that the medical profession was in decline and the future lay in the world of business. “But I immediately regressed to science,” says Evans. He began to do research, studying whether immune cells could be taught to recognize more than one foreign entity. The lifestyle, says Evans, “suited my personality. It was a solitary, self-motivating activity—not driven by teachers or schedules or classes. If you were hungry for results, you put more time in.” And getting data was always a thrill. “Even the tiniest result was exciting.” Those results, says Evans, were “not profound.” But they did lead to a publication and set Evans on the road to becoming a research scientist. He signed on as a graduate student to work with UCLA researcher Marcel Baluda. The lab was studying tumor-causing viruses that use RNA as their genetic material. What Baluda—and his competitors—were trying to figure out was how these viruses convert their RNA to DNA, a feat that they perform after infecting a host cell but that runs counter to the way all other organisms operate. Baluda and his lab got scooped. Two other biologists—Howard Temin and David Baltimore—discovered the enzyme that transforms RNA into DNA, work that eventually earned them a Nobel Prize. Evans plowed ahead. “My goal—and it wasn't necessarily the most lofty goal—was to get a Ph.D. fast.” To do that, he seriously buckled down. “I worked longer and harder than anyone else. I basically lived in the lab,” he says. His self-imposed enslavement was made easier by the fact that the lab was in the basement and had no windows. “You'd go in and work and have no idea what time of day it was.” Evans's efforts paid off. He published half a dozen papers in under four years and was well positioned to secure a good postdoctoral fellowship. His first choice was the lab of “the arch nemesis, David Baltimore,” says Evans. But when Evans went for a visit, he discovered that Baltimore was preparing to go on sabbatical to Rockefeller University to work with molecular biologist James Darnell. Evans decided to go there as well. “That was an exciting time and an ideal choice,” he says of his stay in Darnell's lab. He began studying a problem that would hold his interest throughout the rest of his career: how cells control the activity of their genes, a process central to life. Although Evans started out studying viruses, which were easy to work with, he really wanted to work with mammalian genes. In particular, he wanted to determine how the growth hormone gene is regulated by steroid and thyroid hormones. Researchers believed that receptor proteins that bind to these hormones could function as a genetic switch to control gene activity. To find the switch, Evans first needed to isolate the growth hormone gene. The only problem was that scientists had imposed a moratorium on manipulating cellular genes until they could sort out the relevant ethical and safety issues. While they debated, Evans prepared the proper facilities for handling mammalian DNA and got all his reagents ready. Finally the moratorium was lifted. “At midnight on the day you could start cloning,” he says, “we made the first library”—a collection of fragments that represents all the genes in an organism. Within days, they'd found the growth hormone gene, which Evans packed up and took with him to the Salk Institute, where he started his own lab. With the gene in hand, Evans next focused his attention on identifying the genetic switch that turns it on. “It was extremely difficult,” he says, “because nobody really knew how to do it.” In addition to his effort, several labs around the country were taking different approaches to find the molecules that would help unlock the secrets of gene control. This time, Evans got there first. He and his colleagues were able to isolate the gene for the glucocorticoid receptor, the first of a series of related switches that allow hormones to control genes. In short order, Evans found two more receptors capable of regulating the gene for the growth hormone, and more soon followed. Each works in a similar way. It binds to some sort of activating molecule—a hormone or vitamin—and then heads for the nucleus, where it finds the proper chromosomes and tweaks gene activity. The first dozen receptors form what Evans calls a “nuclear receptor superfamily.” And these were just the beginning. Evans knew that when he searched the genome for genes that were similar to those that encode these nuclear receptors, he could see “faint signals” indicating their presence. “We knew there were more receptors out there.” He and his team decided to chase them. To date their search has turned up nearly 50 receptors that are part of the nuclear receptor family. For many, Evans is not sure what hormones or signal molecules might activate them, so they're dubbed “orphan receptors.” Tracking down the molecules that bind to these orphans helps open up whole new areas of physiology. For example, PPAR-gamma and PPAR-delta play key roles in controlling the storage and burning of fat. Evans and his crew are now focused on trying to understand how these receptors work—and how their misbehavior can lead to disease, including high blood pressure, obesity, diabetes, and cancer. In his spare time, Evans is looking to discover what regulates the regulators. “I think there's another level of coordination,” he says—a way to guarantee that the body's 10 trillion cells act in harmony to balance their energy expenditure. “And I'd like to know what that is.” With any luck, the combined energy of his 30 postdocs, students, and research associates will carry Evans and his lab to that next level. 10/04
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