Sci. Aging Knowl. Environ., 22 January 2003
Vicki Lundblad won first prize at the science fair in seventh grade. Today, she's unraveling the mechanisms that cells use to protect the ends of their chromosomes
A few years ago, Nobel laureate Tom Cech visited geneticist Vicki Lundblad at Baylor College of Medicine in Houston. Cech was collaborating with the younger professor on research involving telomeres, the DNA-and-protein caps that guard chromosome tips. After gathering her students and postdocs to meet with their guest and making introductions, Lundblad broke the ice by commenting, "Tom, as you can tell, we spend most of our free time ... shoe shopping together."
Everyone laughed. Lundblad's joke--a wisecrack about her own penchant for stylish shoes--acknowledged the lab's distinctive composition at the time: Most of the people gathered around the table were women. But at least one female grad student's chuckles were mingled with mortification because she feared that Cech might get the wrong impression about their priorities. No one familiar with Lundblad's track record in the field of telomere biology would dismiss the members of her team as featherweights, however.
Lundblad, a tall woman whose wavy brown hair is touched with gray, has been studying telomeres for almost 20 years. In that time, she has uncovered key elements in the biological machinery that prevents telomeres from shortening with each cell division. Without this crucial process, cells would eventually fall into a zombielike senescent state (see "More Than a Sum of Our Cells", "How a clk Ticks", and "Short and Solid").
Lundblad, who was born in Berkeley, California, gravitated toward biology as a preteen. "I was a science nerd from early on," she says. Her father, a biochemist at a small pharmaceutical firm called Cutter Laboratories--which made blood plasma products as well as bug repellent--nurtured her inquisitive nature. For Lundblad's first science fair project in seventh grade, she recalls, "I extracted the pigments from red and green poinsettia leaves and ran thin-layer chromatography plates in our family room to figure out the difference in the pigments. ... I had an incredible time. My dad put a lot of time into it." In eighth grade, she attempted to test whether people secrete odors from their skin that repel or attract mosquitoes. She took first prize both years.
Lundblad earned a biochemistry degree from the University of California (UC), Berkeley, in 1976, then pursued graduate studies at Harvard. In molecular biologist Nancy Kleckner's lab, she investigated the genetic mechanisms that regulate bacterial transposons: segments of DNA that can jump from one spot in a genome to another. One day, while sipping sherry with faculty and students after a seminar, Lundblad heard about an exciting discovery. Don Wiley, the late structural biologist at Harvard Medical School in Boston, mentioned that Elizabeth Blackburn, a postdoc in cell biologist Joseph Gall's lab at Yale University, had just published a curious finding. She had discovered that the ends of Tetrahymena thermophila minichromosomes consisted of many repeats of short DNA sequences, structures that were later confirmed to be telomeres. "Don was really jazzed about the paper," Lundblad says. Intrigued, after finishing her Ph.D. in 1983, she decided to study telomeres as a postdoc with Harvard Medical School chromosome biologist Jack Szostak.
By 1985, Blackburn, who had started her own lab at UC Berkeley, and Carol Greider, a grad student in Blackburn's group, had discovered telomerase, an enzyme that synthesizes and preserves telomeric DNA. Meanwhile, in Szostak's lab, Lundblad identified the first known subunit of telomerase--a protein she dubbed Est1--by laboriously screening for yeast mutants that fail to maintain their telomeres, a novel approach at the time. In 1988, Lundblad returned to California; her husband, Lou Zumstein, a molecular biologist, had secured a postdoc position at Stanford University, so she arranged to do a second postdoc with Blackburn. Working in Berkeley, Lundblad discovered that even without telomerase, yeast cells can sustain their chromosome tips--the first example of an alternative telomere-lengthening pathway. Other researchers subsequently found similar pathways in mammalian cells.
In 1991, Lundblad took her first faculty job, at Baylor. With a grant from the National Institute on Aging, she launched another search for yeast strains with defective telomere maintenance, but on a far larger scale than in her postdoctoral work. "This was a big, ugly screen," Lundblad says. She had only two undergrads and a technician in her lab. Over a year and a half, this small but dedicated group grew 350,000 yeast colonies, picked out and cultured 35,000 promising mutants, and, for a selected subset of those, analyzed their telomere lengths. To process the last 100,000 colonies, Lundblad brought in 12 undergrads from nearby Rice University to set up cultures one weekend. "I paid them $150 each and fed them all the pizza they could eat," she says.
The grueling 18 months unearthed a gold mine: Lundblad's team found three genes that are crucial for telomerase function, results that generated a flurry of groundbreaking papers from the members of her group in 1996 and 1997. Collaborating with Cech's team at the University of Colorado, Boulder, Lundblad and co-workers discovered that one of the genes, EST2, encodes the long-sought subunit of telomerase that adds DNA to replenish telomeres. In other research, Lundblad showed that certain defects in the DNA repair system--the same kind of glitches that foster cancer in humans--enhance yeast cells' ability to use the alternative pathway of telomere maintenance. The results explained for the first time how flaws in DNA repair and telomere maintenance could collaborate to promote cancer.
What makes Lundblad so effective as a scientist, says Titia de Lange, a friend and cell biologist at Rockefeller University in New York City, is "the powerful combination of clean logic and creativity that she brings to her experiments." According to Ronald DePinho, a cancer geneticist at Harvard Medical School, Lundblad's strategy of using yeast screens exemplifies what Aristotle, in defining genius, referred to as "uncommon common sense." Not only has she made one seminal contribution after another, but her findings hold up over time, he says.
Lundblad's success contributes to telomere biology's reputation for claiming a large number of women investigators. Insiders trace the tradition to the influence of Yale's Gall, who trained not only Blackburn but also cell biologists Virginia Zakian and Mary Lou Pardue; Blackburn, the leader of telomere science, in turn has trained many women, including Greider and Lundblad. Although some observers have described the field as being "dominated" by women, Lundblad is quick to set the record straight. "Telomere biology is one of the few fields that doesn't show a gender bias--and so, by frame of reference, it seems like it's dominated by women," she says. "But while there are many prominent women, there are prominent men as well." She has mentored roughly equal numbers of men and women, although for a while--such as when Cech visited--the amount of estrogen exceeded that of testosterone.
Former lab members say that Lundblad is tough and sets high standards. She challenges her students and postdocs to think independently, coaches them on how to give well-designed presentations, and prepares them for the day they'll run their own labs. "She definitely teaches you to be more than just a scientist," says former grad student Erin Pennock. For instance, Lundblad pushed Pennock to give her first talk at a national scientific meeting in her third year. And, with Lundblad's guidance, Pennock interviewed, hired, and supervised her own technician to help with her graduate research. "Vicki gave me a lot of autonomy," says Pennock, who's now in her first year of an M.D. program at Jefferson Medical College in Philadelphia. "It was an incredible learning experience."
Although Lundblad expects a lot from her group, she's evenhanded and willing to give people a chance to prove themselves, according to pediatric oncologist Alison Bertuch. When Bertuch applied for a research fellowship in Lundblad's lab, she had already completed her residency and a Ph.D. program but had no publications from her graduate work; that phase of her training had been thrown into turmoil by her adviser's suicide after a scandal involving the questionable work of a star postdoc. Nonetheless, Lundblad--who says she was impressed with Bertuch's intelligence and clinical expertise--welcomed the oncologist to the lab. "She was very compassionate," says Bertuch, adding that when it comes to scientific work, it's quality, not number of publications, that counts with Lundblad.
Lundblad also supports lab members who make choices different from her own. After grad student Sara Evans decided to become a science writer, Lundblad hired her for an additional year to help prepare manuscripts and write a manual on the lab's techniques and protocols. And Lundblad, who doesn't have children, has accommodated students and postdocs who've taken time off with new babies.
Lundblad works long hours--she describes herself as "driven"--but she also knows how to relish the high points. Parties to celebrate birthdays or publications are a tradition with the group. "She jokes that it's a requirement for graduating with your Ph.D. to know how to open a bottle of champagne," says Evans. When she's not in the lab, Lundblad enjoys sailing and kayaking with Zumstein. And, as Cech learned, she is also known for her passion for fine footwear: "The woman loves her shoes," says Pennock. "She must have a million different pairs." But whichever set of heels she slips on, Lundblad is clearly making big tracks in telomere biology.
January 22, 2003
SAGE KE Contributing Editor Ingfei Chen was a science nerd in high school. She still wishes that she had won a prize at a science fair.
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Citation: I. Chen, Endless Drive. Science's SAGE KE (22 January 2003), http://sageke.sciencemag.org/cgi/content/full/sageke;2003/3/nf2
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