Sci. Aging Knowl. Environ., 23 October 2002
Gary Ruvkun's career has meandered from planting trees to studying aging in worms. Next on his horizon: hunting for life on Mars
His students and postdocs call them the Lost Years: those 2 years in the '70s, long before he ever pondered the charms of a wriggling worm named Caenorhabditis elegans, when Harvard geneticist Gary Ruvkun lived the life of a long-haired hippie nomad. They began in 1973, after Ruvkun graduated from the University of California (UC), Berkeley, with a degree in biophysics. He bought a blue-and-white '69 Dodge van and started driving up the Pacific Coast. "I had no idea where I was going," recalls Ruvkun, who grew up near Berkeley. "I just drifted up Highway 1." Along the way, he interviewed for a job at a nuclear power plant and tried out as a disc jockey at a radio station. He wound up working at a tree-planting cooperative outside Eugene, Oregon, a job he landed while schmoozing in a bar, and spent a year planting about 50,000 trees all over Oregon and Washington. He lived out of his van and chugged beer with loggers after hours. "It was a lot of fun," he says with a grin.
Then a friend invited him to travel through South America. "We took third-class buses from the Mexican border to Tierra del Fuego [in Argentina] and back, just all over," he says. After a year of roaming, Ruvkun found himself in Cochabamba, Bolivia, at a Bolivian-American friendship club, where he came upon a stack of magazines. "I sat down all day reading Scientific American," he says. "It had been the best day I had in a month. I thought, 'You know, it's time to go back.' "
Two weeks later, he returned to California--and to his love for science. As an undergraduate, he "got really switched on" by microbial genetics while taking a molecular biology course, he says. But he wasn't sure how to channel his interest. Mulling over his next move, Ruvkun worked for a year as a nuclear medicine technician at UC San Francisco and even toyed with the idea of becoming a physician, but he decided medicine wasn't for him. So he applied to graduate school--his "default solution"--and got into Harvard.
True to his drifter roots, Ruvkun has, since then, gamely followed the road of science as it has twisted and turned toward his current pursuit: studying the neuroendocrine control of metabolism, development, and longevity in C. elegans. In the course of this journey, he has made influential contributions to the understanding of the genetics of aging. Ruvkun, a tall, looming, yet soft-spoken man, looks as though he's already found the secret to long life: At 50, with a dark mustache and a shaggy mop of hair, he could easily pass for 40.
When Ruvkun arrived at Harvard in 1976, the excitement of the recombinant DNA revolution pulled him in. Under the tutelage of geneticist Fred Ausubel, Ruvkun earned a Ph.D. in microbial genetics in 1982 by figuring out how to knock out nitrogen-fixation genes in Rhizobium meliloti, a bacterium that has a symbiotic relationship with alfalfa. At the time, creating specific mutations in a "weird microbe" like Rhizobium posed a big challenge, Ruvkun says, because scientists knew less about its genetics than that of classic organisms such as Escherichia coli. His technique worked for altering genes in a wide range of bacteria--and won him a prestigious junior fellowship from the Society of Fellows at Harvard.
The next swerve in Ruvkun's path took him into developmental biology. Attracted by the "big questions" of how an organism grows from a fertilized egg into a creature with specialized body parts, he did a 3-year postdoc with Harvard biophysicist Walter Gilbert, already a Nobel laureate, and neurobiologist H. Robert Horvitz at the Massachusetts Institute of Technology, who just won his Nobel Prize this month. It was in Horvitz's lab that Ruvkun first got to know the tiny, millimeter-long C. elegans. In 1985, as a new assistant professor at Harvard, he started his own lab at Massachusetts General Hospital in Boston, focusing on developmental genetics in the nematode.
Among other things, Ruvkun's group scrutinized a hibernation phase in the C. elegans life cycle--the dauer larval stage--in which the nematode stops growing under unfavorable conditions. Various genes, including one called daf-2, were known to influence dauer formation. In 1993, UC San Francisco biochemist Cynthia Kenyon and her colleagues reported that a mutant version of daf-2 doubled the worm's life-span. Suddenly and unexpectedly, Ruvkun's dauers were leading him into the study of aging.
In 1997, Ruvkun and his associates isolated and sequenced the daf-2 gene from C. elegans and showed that it resembles human genes that encode cell surface receptors that bind insulin and insulin-like growth factor-1. The finding hinted that genes affecting longevity in the nematode might hold relevance for humans, too. Ruvkun's lab later demonstrated that the daf-2 pathway functions specifically within the worm's neurons--and not elsewhere, such as in muscle cells--to control life-span. The group isolated all of the major genes in the pathway. Activation of daf-2 ultimately suppresses production of a protein called daf-16, which switches on genes encoding enzymes that scavenge free radicals, prime suspects behind aging (see "The Two Faces of Oxygen"). Ruvkun's group is now using bioinformatics to figure out which other genes are controlled by daf-16.
Ruvkun has broken ground in other areas, too. Two years ago, his group was among the first to discover 21-nucleotide RNA duplexes--"microRNAs"--that trigger developmental transitions in the worm by switching off target genes. Ruvkun's work showed that a microRNA called let-7 regulates maturation from the larval stage to adulthood--and that it operates in many creatures, from fruit flies to zebrafish to mollusks.
Despite the scientific glory that roundworms have brought him, Ruvkun confesses that he doesn't particularly care for them. "I like furry animals, not slimy ones," he says. "But what made them grow on me is the community that evolved around them. While there is a lot of competition in science, there's a lot of cooperation in the C. elegans community."
In keeping with his preference for mammals, Ruvkun is, at heart, a people person. "He deeply cares about the people in his lab," says geneticist Heidi Tissenbaum, a former graduate student who is now an assistant professor at the University of Massachusetts Medical School in Worcester. "It didn't matter what time or when; if you needed to talk to him, the door was open." When Tissenbaum took 3 months off during grad school to have a baby--something almost unheard of at Harvard--Ruvkun was "extremely supportive," telling her not to worry about her dissertation work.
Ruvkun not only possesses a great enthusiasm for science that energizes his troops, Tissenbaum says, but he also keeps life at the bench lively. In lab group meetings, he was always making bets with students and postdocs over theories and experiments. "People put ideas out there, and he would say, 'OK, $3 bet,'" she recalls.
Former postdoc Oliver Hobert, now a neuroscientist at Columbia University in New York City, says that the Ruvkun lab was fertile ground for brainstorming. Unlike in research groups where the principal investigator is the voice of caution, Ruvkun is always proposing off-the-wall experiments. "He has completely wacko ideas," says Hobert. "But the great thing is if he's proven wrong, he's perfectly fine with it. And it just prompts you to think about things. He was clearly the one who was the least conservative of all--and it was us who had to sort of bring him down. But that's what you want as a postdoc: somebody who has ideas and who's creative." Says Ruvkun, "In my lab, most of the other people are the grownups."
One of Ruvkun's latest "wacko" schemes is to use the polymerase chain reaction (PCR) to look for life on Mars. He hopes to test samples of martian soil for ancient ribosomal RNA gene sequences that are conserved in all of Earth's known life forms. "At first, people think it's just nuts," he says. "But over time, they come around."
Ruvkun has been fascinated with astronomy since he was 5 years old, the year Russia launched Sputnik. "I bit hook, line, and sinker," the geneticist says. In 1975, he built his own telescope. These days, outside the lab, Ruvkun reads up on astronomy, geology, and planetary science when he's not spending time with his wife, Natasha Staller, an art historian, or teaching their 5-year-old daughter how to ride a bicycle. For the Harvard Mars project, Ruvkun and colleagues (including former postdoc Michael Finney, co-founder of MJ Research, a major manufacturer of PCR machines) are designing a small, robotic PCR detector that would perform onsite amplification and sequencing of any DNA present in extraterrestrial dirt. They've applied to NASA for funding to build the field instrument.
Ruvkun clearly thrives on exploring the boundaries of scientific disciplines. "The reason geneticists stay young scientifically," he muses, "is that [we] get thrown into new fields." He never knows exactly where the next experiment will take him, he says, but that's just fine. Doing science, it turns out, isn't so different from life as a drifter: "It's like hopping on a bus and just seeing where it goes."
October 23, 2002
Ingfei Chen writes from Santa Cruz, California. She is still on her first career.
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--> Citation: I. Chen, The Drifter. Science's SAGE KE (23 October 2002), http://sageke.sciencemag.org/cgi/content/full/sageke;2002/42/nf11
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