Sci. Aging Knowl. Environ., 31 March 2004
Wind at His Back
Grad student Trey Powers has hunted with hawks and raced yachts. Now he's navigating his way toward an understanding of how yeast cells age
Ingfei Chenhttp://sageke.sciencemag.org/cgi/content/full/2004/13/nf34 This article comes to you through a collaboration between SAGE KE and Science's career development Web site, Next Wave. The joint venture is supported by the AARP Andrus Foundation. Trey Powers's journey into the biology of aging began in his first year of high school, with the death of a chocolate Labrador retriever named Buffy. When the pet succumbed to cancer, 14-year-old Powers was struck by the fact that some creatures poop out faster than others. "It didn't make sense," he recalls. "She was an old dog. But it was weird that the dog would be 10 years old and die of old age."
Most children accept the passing of a family pet as a fact of life and move on. But in Powers's mind, the puzzle of why and how organisms age has grown, not diminished. By 17, he was running his first experiments in a gerontology research lab; 3 years later, he mastered the delicate brain surgery techniques needed for an investigation into the senescence process in mice. Now on the cusp of 26--or just over 3 in dog years--Powers is a third-year grad student probing the mechanisms of yeast aging at the University of Washington (UW), Seattle.
His intense curiosity about gerontology quickly captured the notice of faculty members. "Trey stood out from among the masses at the very first visit," says pathologist Peter Rabinovitch, director of UW's Nathan Shock Center of Excellence in Basic Biology of Aging. Even then, during his last semester as an undergraduate, Powers was well read in and conversant about the gerontology research literature, Rabinovitch says. Yeast geneticist Stanley Fields, Powers's Ph.D. adviser, ranks him among the most independent grad students he's mentored. "He's very smart; he's very motivated," Fields says. Powers generates his own experimental ideas and goes out and tests them. "He doesn't need to run them by me or anyone. ... I think that's the best way for students to learn."
Powers, tall and dark blond with black-frame glasses and greenish hazel eyes, is a blend of nerd and outdoorsman. He gets carried away, talking fast as he scribbles diagrams of biochemical pathways that regulate metabolism and possibly aging. A piece of paper tacked up over his desk is covered with hatch marks, tallying the number of boxes of pipette tips he's used in experiments between Octobers of 2002 and 2003 (more than 150 boxes, containing a total of approximately 15,000 tips). Meanwhile, his black Ford Explorer is strewn with signs of life beyond the petri dish, including running shoes, dirty socks, a lacrosse stick, a life vest, and the smell of Spirit, his yellow Labrador. A competitive sailor, Powers usually looks like he just stepped off a boat: Flip-flops, shorts or khakis, a polo shirt, and a duck-yellow windbreaker are typical attire. Unassuming and laid-back, he bears with good nature the ribbing he gets from Fields about a favorite pair of garish plaid pants that seem better suited to a middle-aged golfer than a 20-something grad student.
The great outdoors, science, and nature engaged Powers early on, although his family background is steeped in the legal tradition. He grew up in rural Maryland, about 30 kilometers south of Annapolis. His father is a country lawyer who accepts home-baked pies in lieu of cash payments; his mother, a paralegal, runs the family law office. A grandfather and a great-uncle were judges. But Powers's first career goal was to become a veterinarian, an idea fueled by his fascination with the small menagerie--several goats, chickens, cats, and dogs (including Buffy)--that his family kept. When he was in the third grade, his father gave him a thick high school biology textbook about experimental design. The boy pored over it for hours. In fifth grade, he experimented on his pet fish, a Jack Dempsey cichlid. "I'd ring a bell and feed him to build a Pavlovian response," Powers recalls.
His parents encouraged Powers and his younger sister to read rather than watch television through an unusual bribery scheme. "I made this deal with my dad that if I didn't watch TV for a year, I would get a hawk," Powers says. His best friend's father trained and hunted with falcons, and Powers was captivated by the human relationship with the powerful, wild birds of prey. Under the agreement with his parents, Powers could watch only videos, special events such as the Super Bowl, and the McNeil-Lehrer News Hour. "My parents wanted to raise a 40-year-old," he says. He buried his nose in Civil War history and The Lord of the Rings and earned his reward, a red-tailed hawk. (His younger sister got a pony.) At 14, he earned his federal and state licenses for falconry. The sport is "a kind of symbiosis" between human and beast, he says. Maryland law permits falconers to capture immature hawks during their first passage south for the winter, which is when many of them die because food is scarce. The falconers feed the birds and teach them to hunt but release them to the wild after they reach sexual maturity. Powers cared for half a dozen birds over 4 years, keeping them tethered to an outdoor perch. Every day, he took them hunting, flying them along tree lines to flush out and catch squirrels and rabbits.
Bench Experience in Bar Harbor
In 1995, a chemistry teacher at Powers's high school told him of a summer student program at the Jackson Laboratory, a nonprofit mammalian genetics institute in Bar Harbor, Maine. Powers applied for the 10-week internship, which is open to outstanding high school and college students, and got in. On his application, the 17-year-old noted his interest in aging and falconry, both of which caught the eye of cell biologist Kevin Flurkey, a research associate in the laboratory of geneticist David Harrison. The scientists selected Powers to join their group, and in the first week, Flurkey sat down with him to talk about an unusual potential project. "It was a bit of a far-out idea," Flurkey says. "And as I was trying to sell him on the idea of doing this project, he kept quizzing me on the experimental evidence for the hypotheses I was talking about. And that was a bit of a shock, because here he'd just finished his junior year in high school." Powers showed a desire to grasp the experimental basis of scientific theories, a mode of thinking that many would-be researchers don't develop until grad school, Flurkey says, adding, "So it seemed to me he was built to be a scientist right from the beginning."
The "far-out" project was to test an old idea, proposed by endocrinologist W. Donner Denckla, that the pituitary gland produces a "death hormone." Denckla's hypothesis arose from two observations. First, studies in the 1960s and '70s had shown that removing the pituitary delays certain aspects of aging and increases longevity in rats. Second, Denckla's experiments demonstrated that as rats grow older, their baseline oxygen consumption drops, but the pituitary surgery prevents that decline. So, according to his theory, a mystery pituitary compound triggers senescence by decreasing the cell's ability to use oxygen as it ages. As a first step in Harrison and Flurkey's investigation, they wanted to find out whether the same slowdown in metabolic rate occurs in mice. Powers tackled the question with a complicated set of experiments and analysis: He measured the animals' oxygen intake and adjusted it for age-related differences in body composition, organ weight, and blood concentrations of thyroid hormone, which controls oxygen-dependent metabolism. Part of the research called for taking blood samples at 3 a.m., which Flurkey planned to do himself. But Powers insisted on being there, even though students weren't allowed to draw blood. "He had to sneak out of the dormitory at 2:30 in the morning and come down here in the dark," Flurkey says. "It was his project, and he wanted to see it from the beginning to end."
Every student had to conduct a research project, present a talk, and write a paper on the work by the end of the internship. In the 9th week, Powers scrambled to finish his experiments. After staying up into the wee hours to enter results into a statistical program, he analyzed the data with Flurkey. Bingo: Their observations showed that mice use less oxygen as they age, confirming one leg of the death-hormone theory. Powers says it was a sort of "eureka" moment--a thrill to know that the two of them were the first in the world to discover this result. "Dozens of other questions about aging and the way metabolism changed with age immediately formulated in my head," Powers says. "And so it just made me want to do all these other experiments."
Taking the Plunge
No time remained to do those studies, however. Powers returned to school and went on to college at the University of Virginia (UVa) in Charlottesville. Although the research experience had excited him, he says, other potential career ideas also beckoned. His parents had always encouraged him to keep his options open, emphasizing the value of being a well-rounded person with diverse interests. Powers had dropped the idea of becoming an animal doctor after working with a vet who treated his staff poorly. But he still entertained ideas of going into medicine--or studying law, like his father, or English literature, like his mother. He started out taking premed classes and double-majoring in biology and English. Toward the end of his sophomore year, he was no closer to resolving whether to give up his other interests for a life in science. "I wasn't sure that I could really take that plunge."
To test himself, he called Harrison and asked if he could apply for another research internship at the Jackson Laboratory. In summer 1998, Powers returned there to resume working with Flurkey on the hunt for Denckla's putative death hormone. Denckla had argued that this substance would decrease an animal's sensitivity to thyroid hormone, thereby lowering oxygen consumption. In a series of experiments designed to probe that theory, Powers first surgically removed the minuscule pituitary gland from young and middle-aged mice. They subsequently couldn't make pituitary hormones or thyroid hormone, the production of which is also regulated by the gland. Powers then assessed whether replacing the rodents' supply of either hormone alters their oxygen consumption. He did considerable groundwork to smooth out the investigation's methodological kinks, Flurkey says. By the time the stage was finally set to perform the key experiments, it was September--and, says Powers, "I wasn't ready to let my project go." So he took the academic year off to finish the research. By the end of summer 1999, Powers's studies had demonstrated that even after mice lose their pituitaries, they experience an age-related decline in oxygen consumption. And he found no evidence of any pituitary hormone that dampens the animals' responsiveness to thyroid hormone with age. The death hormone doesn't exist in mice, at least not in the form that Denckla envisioned. "The fact that we were able to get a definitive answer was entirely because of Trey's energy, creativity, and intellect," says Flurkey. (He and Harrison are still studying the role of pituitary hormones, however, in long-lived dwarf mice. See Bartke Viewpoint.)
The 15-month research stint clinched Powers's decision to go for a Ph.D. in science. "I decided, 'Forget about English. I can still read books, but I don't need the formal training in Shakespearean literature.' " Returning to UVa, he focused on completing his biology degree and began hunting for a grad school program during his senior year. Harrison suggested that he check out UW, which had a cluster of scientists studying aging and age-related diseases, including pathologist George Martin (who is also editor-in-chief of SAGE KE). In January 2001, Powers visited the campus to meet with Martin and Rabinovitch. He decided to apply to the school and later returned for a formal admissions interview. He was accepted.
From Mice to Baker's Yeast
Many researchers who study mammalian systems tend to look down their noses at single-celled yeast, he says. Yet, after rotating through several labs--including that of Fields and another yeast geneticist--Powers decided he wanted to work on the fungus. "If you had told me 5 years ago I would be studying aging in yeast, I would have laughed," he says. But the more he read about gerontology studies in Saccharomyces cerevisiae--baker's yeast--the more the organism impressed him as an excellent model for basic cell biology processes that are relevant to aging (see Kaeberlein Perspective). Some mutations and interventions that extend life span in yeast also boost survival in organisms such as worms, flies, and mice (see "Growing Old Together" and "One for All").
Powers opted to work with Fields, who studies how proteins interact with one another and contribute to diseases such as malaria and Alzheimer's, because his group is known for developing innovative technologies to do its work. In particular, the lab uses robot technology to conduct large-scale screening of the yeast genome, a "global" approach that Powers wanted to apply to detecting genes that control aging. Fields's hands-off mentoring style and the collegial atmosphere of the lab were also big draws, Powers says.
Researchers study aging in S. cerevisiae by using two measures. One yardstick of yeast longevity--called replicative life span--counts how many times a cell can produce a budding daughter cell. Another method tracks how long nondividing yeast cells can survive in liquid nutrient broth. Most previous research has suggested that the mutations that extend each kind of life span do not overlap (see Fabrizio et al. Science Article), but Powers's findings are adding to a small number of studies that indicate otherwise.
By working with a collection of 4300 yeast strains, each of which has a different gene knocked out but is otherwise genetically identical to the rest, Powers has identified a mutation that seems to extend both measures of longevity. The mutation lies in a mitochondrial gene that acts in the pathway that converts glucose into cellular fuel. He is investigating whether the gene influences the two types of aging through that biochemical process. Meanwhile, he has also developed a high-throughput strategy to find proteins that increase yeast survival when they're overproduced.
To test his hypotheses, Powers goes beyond doing all the obvious experiments, says UW molecular biologist Brian Kennedy, who also studies yeast aging; the student is always thinking ahead and mulling over how his results meld with models of aging. "He does a lot of reading and tries to fit his findings into a bigger picture, which is somewhat rare for a graduate student," says Kennedy. Also unusual, faculty members say, is an unfazed self-confidence that makes Powers a lively yet never overbearing contributor to scientific discussions, even at meetings where world-class investigators are present. "You can count on Trey to get up there and ask a great question as fast as anybody else," Rabinovitch says. And when senior investigators give him feedback on an idea, Powers displays independent critical judgment, adds Kennedy. Powers will incorporate comments into his research if he agrees, but he "doesn't necessarily just take everything you say as something he should pay attention to." That's a strength when it comes to running one's own lab, says Kennedy: "A little bit of stubbornness is a good thing to have in this field." Powers is still at least 2 years from finishing his degree, and Fields's instinct is that the grad student's current work will pan out, the adviser says. Whichever direction Powers takes in the future, Fields adds, "he sets a pretty high standard of success for himself, and I definitely think he's capable of meeting it."
Despite his enthusiasm for gerontology, Powers maintains a healthy balance between his time in the lab and his other favorite playground--the realm of wind and waves. He learned to sail on Chesapeake Bay as a preteen and now races in a crew of 12 in regattas on Puget Sound every Saturday throughout the year. Last May, he participated in the Swiftsure International Yacht Race, a grueling 24-hour, 140-nautical-mile competition from Victoria, Canada, through the Strait of Juan de Fuca to its mouth, and back; he will be entering the same event this year. Powers also likes hiking and fly-fishing, and he plays in a Monday night soccer league. As if the diversity of his recreational and academic interests weren't enough, he still contemplates the possibility of acquiring a law degree so that he can specialize in intellectual property issues (see "Careers in Patent Law"). But a departure from scientific inquiry seems unlikely. Like radar guiding a sailor home, Powers's instincts keep bringing him back to research.
March 31, 2004
SAGE KE contributing editor Ingfei Chen is a landlubber based in Santa Cruz, California.
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