Sci. Aging Knowl. Environ., 14 January 2004
Cell biologist Judith Campisi's lab has fermented new insights into cancer and the biology of aging
Ingfei Chenhttp://sageke.sciencemag.org/cgi/content/full/2004/2/nf6 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. The closest thing to a diploma on the walls of cell biologist Judith Campisi's office at Lawrence Berkeley National Laboratory (LBNL) in Berkeley, California, is a certificate from a course in wine tasting that she took about 15 years ago. Campisi, 55, is a serious wine connoisseur who makes regular pilgrimages to the vineyards of Napa, Sonoma, and Mendocino. On first appraisal, it might be easy to overlook her, a slender 4'11" (1.5-meter) brunette with unruly shoulder-length hair and a light, alto voice. Despite the high-heeled boots she often wears, other scientists tower over her at conferences; well into her 40s she was sometimes still mistaken as a postdoc because of her youthful looks. But like a well-balanced Syrah whose robustness and fruity, spicy complexity expand and linger upon the palate, Campisi has made a substantive impact in the field of gerontology. Over the past 20 years, she has been helping clarify the connections among aging, cancer, and a stage in a cell's life called senescence, in which cells stop splitting but do not die (see "More Than a Sum of Our Cells").
Campisi's lab is at the forefront in building evidence for the hypothesis that cell senescence is a double-edged sword: It might prevent the development of tumors early in life as well as promote the cancers of old age (see "Dangerous Liaisons" and Campisi Perspective). She has been an impressive force in the field of gerontology from the get-go, says George Martin, a pathologist at the University of Washington, Seattle, and editor-in-chief of SAGE KE. "When she came into this field, it was like a breath of fresh air," he says, recalling that he met her in the mid-'80s, not long after she began studying aging, when she was part of a scientific team sent by the National Institutes of Health to review his lab's research. "The kinds of questions she asked were very astute, very critical, right to the heart of the matter." Since then, Campisi's sharp mind and stellar background in cell biology have helped elevate the respectability of gerontological research, he says. (She also serves as a member of SAGE KE's scientific advisory board.)
Moreover, Campisi possesses a broad vision that allows her to identify relations between cellular behavior and whole-organism aging, says gerontologist Richard Miller of the University of Michigan, Ann Arbor (also a member of SAGE KE's scientific advisory board). In addition to investigating cancer, Campisi has delved into research problems from DNA repair mechanisms and the premature human aging disorder called Werner syndrome (see "Of Hyperaging and Methuselah Genes") to cellular resistance to oxidative stress. "She's imaginative enough to see the problems and brave enough to tackle them in ways that a lot of others in the field can only envy," Miller says. Campisi confesses that although her passion for science caught flame decades ago, it did so for purely unscientific reasons. Born and raised on Long Island, New York, the eldest child in an Italian-Polish family, she attended an all-girl Catholic high school. When she started college in 1966, "I had had it with Catholicism and I'd had it with girls. I wanted to major wherever the boys were--and that was science," she says with a mischievous smile. In her first year at the State University of New York (SUNY), Stony Brook, she found that the introductory chemistry class had approximately 65 men and only two women. Her reaction: "Sign me up, I can do chemistry," she recalls, rocking with laughter. As it turned out, she discovered that she liked chemistry--and was good at it--so she decided to major in the subject. She also minored in physics, where the males outnumbered the females by about 20 to 1.
From Hippie and Avon Lady to Biochemist
Campisi's undergraduate studies were interrupted, however, by a 4-year detour during the period of political unrest and idealism triggered by the Vietnam War. After her sophomore year at SUNY Stony Brook, she left school and drifted, holding various jobs for 6 to 9 months at a time. "I needed to rebel," she says. "It may have looked aimless, but I was young, I was free ... it was sort of time to break free and find out what you really want to do in life before you grow up." She pumped gas, waited tables, sold Avon products door-to-door, and worked on the production staff at a small-town newspaper. She also did stints as a quality-control technician, running chemical assays at several small Long Island pharmaceutical companies. Between jobs, she sang and played guitar and banjo with her younger sister, Karen, in a folk-music band originally called The Hyper Pipers; they traveled around the country performing at cafes and for radio programs. Joan Baez, Pete Seger, and Jerry Garcia--"who I still mourn," Campisi says--were the muses to her musical self-exploration.
By 1972, she was ready to hit the books again at SUNY, fully motivated. In her senior year, she got her first real taste of biology when she took an elective biochemistry class. "I thought it was a hell of a lot more interesting than all that chemistry. Something just clicked." She finished her bachelor's degree in 1974 and continued at Stony Brook in a Ph.D. biochemistry program.
At the time, cancer was a hot research topic, but little did Campisi know that she would devote her career to it. President Nixon had just proclaimed war on the disease, the second leading cause of death in the United States, in 1971. In her first year of grad school, Campisi learned that scientists studying a virus known to cause tumors in newborn hamsters had identified the region of the microbe's DNA that promoted malignancies. With that discovery, Campisi simplistically figured that the underlying cause of all cancers had been solved and that a cure was around the corner. "I thought, 'Well, they got the gene for cancer; I don't need to work on that one,' " she says with a touch of sheepishness. She decided to concentrate her graduate studies elsewhere, joining the lab of biophysicist Carl Scandella, who had been developing techniques to study cell membrane structure. Instructed to find herself a research project, Campisi applied those same techniques to sea urchin eggs to elucidate how fertilization triggers an egg's transformation into an embryo. Through a combination of luck, good instincts, and skilled hands at the bench, Campisi's work was groundbreaking and led to two first-author papers in Science and Nature--an achievement that happened so casually that it left her with the impression that publishing in the leading scientific journals was easy. "I was so na�ve," she says, rolling her eyes. "I thought it was just normal." The conversation with her adviser went something like this, she recollects:
"Do you think we should publish this stuff?" she asked.
"Yeah, why don't you write it up?"
"Where should we publish it?"
"Well, where do you think we should?"
"Well, how about Science?"
Meanwhile, as her grasp of cell biology deepened, Campisi soon realized--with much inner cringing at her earlier conclusion, she says--that cancer was a complex beast with multiple causes that was not going to be readily tamed. By the time she earned her Ph.D. in 1979, she wanted to tackle the challenge, and she arranged a postdoc with chemist Arthur Pardee at the Dana-Farber Cancer Institute in Boston, Massachusetts. After spending a year and a half pursuing one project, Campisi refocused her efforts to study differences in the cell cycles of normal and cancer cells. Pardee proved a good match as a mentor and, she says, hugely influenced her growth as a scientist. The two were on the same wavelength: When they sat down to look at her data, and he suggested follow-up experiments, half the time Campisi had already done them. From Pardee, she says she learned "just how much fun science can be. ... It was just like this big puzzle, and you're playing and trying to put the pieces together."
Pardee also taught her to follow the data. "If you had a result and it didn't quite fit what you were thinking, or it was puzzling, or you realized that you needed to do something that you'd never done before to get to the next level, his attitude was, 'Well, do it,' " she says. Scientists usually find that their experiments give answers that aren't quite what they expected, she says; they'd do well to avoid trying to shape their results to their hypothesis or doing only those studies that give the answers they want.
Fermenting Fresh Theories About Stale Cells
In 1984, Campisi landed a job in the biochemistry department at Boston University (BU). She had wanted to stay in the area because her husband, a plant physiologist named Sam Beale whom she'd wedded in grad school, was working at Brown University in Providence, Rhode Island. But they would divorce a few years after she started her lab. Although her personal life was headed toward chaos, her path into gerontology was laid when Miller, then based in the pathology department at BU, and another colleague, dermatologist Barbara Gilchrest, approached her with an idea. They were putting together an application for a National Institute on Aging (NIA) program project grant to study the role of cell proliferation in aging, with Miller focusing on immune-system cells and Gilchrest targeting skin cells. But the program project guidelines called for three principal investigators, so the pair asked Campisi if she could get interested in researching senescent cells--which, because they stop dividing, behave in exactly the opposite manner as do cancer cells. "I said, 'Sure, you know, that's pretty interesting. That sounds like a tumor-suppressor mechanism,' " Campisi recounts. "And they said, 'Good, because NIA thinks that [cell senescence] has something to do with aging.' " Ironically, though, she recalls, Miller and Gilchrest didn't think cell senescence had anything to do with whole-organism aging.
Neither did Campisi. Based on his discovery in the '60s that cells quit dividing after a set number of times, gerontologist Leonard Hayflick and other scientists equated the loss of proliferation ability with cellular "aging"; Hayflick hypothesized that people grow frail as they age because more and more of their cells senesce, leaving the body unable to replace worn-out or dead cells. But to Campisi, the first part of that rationale seemed ungrounded. "If you think about it, this makes no sense at all: Just because the cell stops dividing, why is it 'aging'? I mean, neurons never divide; are they born 'old'?" she explains. Still, Hayflick had also observed that cancer cells in culture proliferate forever, which suggested to Campisi, among others, that senescence was worth exploring as a potential anticancer mechanism. Although she was initially reluctant to market her cell-cycle studies as research into aging, Miller and Gilchrest talked her into it, arguing that given the high quality of her work, any findings she made would be a contribution to the scientific community in general. Campisi joined the program project, but in her mind, she was really just studying tumor suppression. "It probably took me 5 years to convince myself, 'My god, I really am studying aging!' " she says.
What changed Campisi's stance was her finding, reported in 1990, that senescent human cells show altered activity of several genes; for instance, they no longer turn on a gene called c-fos, which was known to be essential to proliferation and also to cause cancer when mutated. This result was one of the first clues that senescent cells were undergoing radical changes and malfunctioning, underproducing some proteins and overproducing others. Perhaps the loss of cell division was not in itself a cause of aging, Campisi recalls thinking, "but here your body is filling up with these cells, and they're spewing out stuff that is probably not good for tissue. And that's when I began to think, 'Ah, maybe this does have something to do with aging.' "
California, Here I Come
In 1991, Campisi moved to Berkeley to join LBNL. But her West Coast life got off to a distinctly unpropitious start: In October that year, a massive firestorm swept the hills of Berkeley and nearby Oakland. Although it raged dangerously close to LBNL, the institute escaped the blaze--but Campisi's house burned down along with more than 2800 other residences. Nonetheless, says former Campisi postdoc Pierre-Yves Desprez, "the week after the fire, Judy was back at work." She and her group kept forging ahead, with noteworthy results. In a landmark study published in 1995, postdoc Goberdhan Dimri, Campisi, and other collaborators discovered a marker for senescent cells that allowed them to develop the first test to detect such cells in living tissue; they subsequently reported that senescent cells accumulate with age in humans. Campisi went on to propose in 1997 that even a few of these cells might foster the tissue degeneration seen in aging, because they pump out abnormally large amounts of proteins such as cytokines and enzymes that can sully the microenvironment that cells live in--and potentially fuel cancer later in life. She and her group backed up that theory with evidence from several elegant experiments in cell cultures and in mice: In a 2001 paper, postdoc Ana Krtolica, Campisi, and colleagues found that senescent cells can stimulate the growth of nearby precancerous cells (see "Faustian Bargain").
Following the data, as Pardee had taught her, led Campisi down other trails as well. "If you set an experiment up right, you expect that if A happens, it means X, and if B happens, it means Y," she says. "And most of the time C happens instead--and you're like, 'What's going on here?' " Whereas some researchers might focus on rethinking their hypothesis, "I'm the kind of person who says, 'Oh, wow, C happens, who expected that? So let's go on and find out why C happens.' " Thus, in addition to her work illuminating how senescent cells might harm their neighbors, Campisi has been busy scrutinizing DNA repair enzymes--such as those that go awry in Werner syndrome and an inherited cancer disorder called Bloom syndrome--to learn how those proteins normally help keep cell genomes stable, suppressing senescence and cancer. Recently her lab has begun studying how mouse cells are more sensitive to oxygen, which causes oxidative damage that can trigger senescence, than human cells are, which might help explain why people live much longer than rodents do. In March 2002, she became a professor at the Buck Institute for Age Research, across San Francisco Bay in Novato, where she set up a second lab and is extending her investigations into roundworms; she spends one-quarter of her time at the Buck Institute and the rest at LBNL. "She's courageous," says Martin. "She's not afraid of going into new areas and embracing new methodologies."
Campisi also has a talent for connecting and brainstorming ideas in research areas outside her own, says Estela Medrano, a cell biologist at Baylor College of Medicine in Houston, Texas, who did her postdoc in the Pardee lab during Campisi's grad student years. "If I start talking to her about what I am doing [in my lab], she immediately can generate great and new ideas on areas she's not strictly familiar with," says Medrano, who started out investigating skin and breast cancer before branching into studies of chromatin and aging.
Campisi always challenges those around her to do their best, says Miller. "She doesn't take anything for granted and always asks people ... to question their assumptions, do some more reading, and become better grounded in the kinds of information needed to think critically" about the science, he says. She sets a formidable example with her own work habits: Desprez, who did research with Campisi from 1991 to 1996, recalls that she was often in her office till midnight or 2 a.m., never took a day of vacation, and one year even held a lab group meeting on Christmas Day. Desprez attended, but "I remember thinking, 'What am I doing here?' " he says. She applies a tough-love philosophy in her mentoring. At LBNL Desprez, now a cell and molecular biologist at the California Pacific Medical Center (CPMC) in San Francisco, focused on a family of factors that turn on and off genes important in mammary gland development and breast cancer, and on several occasions he remembers Campisi candidly telling him that his experiments were on the wrong track and that he was wasting time. "She can be very tough. ... But she is not mean at all--she does that to help people, actually." When Desprez left to start his own lab at CPMC, she told him to take his entire project--cells, plasmids, and all--and continue the work there. "That's unbelievable. I don't know too many mentors who can do that," Desprez says.
And Campisi emphasizes a feisty, can-do attitude in her nurturing of budding scientists. Junko Oshima, who came from Japan to earn a Ph.D. in Campisi's lab and is now an associate professor at the University of Washington, Seattle, remembers despairing over her English skills and fretting to her adviser that she wouldn't be able to do well in science because of the language barrier. Oshima recalls Campisi responding, "It really upsets me when people say, 'I'm a foreigner, therefore I can't do it,' or 'I'm a woman, therefore I can't do it.' " Although immigrants and women might face obstacles in establishing scientific careers that others do not, Campisi told Oshima that those hurdles are no excuse for failing to perform well.
Campisi explains further: "It just doesn't pay to wallow in self-pity because you don't have all of the talents that make the perfect scientist--because nobody does." Some of the people who come into science are natural public speakers--Campisi, who expresses herself smoothly and confidently, says she's always been good at putting together and delivering a scientific talk--but others struggle with that skill. "And some people can sit down and write a paper in a weekend," she says. "That is not my talent; I am not a facile writer. But it doesn't matter. You have to be good at all of these things, so you learn to appreciate those things you're good at. ... And if you're not good at something, you just learn how to [get] good at it."
Oshima says Campisi imparted many other pearls of wisdom about science and life. For instance: In the academic hierarchy, a senior political position isn't as important as an excellent reputation for one's scientific work. Quality, not quantity, of papers is what counts; Campisi only publishes when the pieces to a puzzle that she didn't understand have been put together, says Oshima, adding, "She will always be my hero."
Outside the lab, Campisi has dabbled in various extracurricular diversions over the years. While she was in Boston, she channeled her creative energy into making pottery. More recently, she has been exploring the aging process that takes place inside a wine barrel, meeting about once a month with a group of friends for wine tastings. Her preferences include the more eclectic wines; currently her favorite beverage is Amarone, a type of powerful, rich, and fruity Italian red wine fermented from grapes that have been semidried in the sun for months. She has even been learning winemaking from a friend, Roger Rosenblum, who with his brother founded Rosenblum Cellars in Alameda and who creates his own separate barrel every 2 years. Sometimes Campisi tells her colleagues that when she can no longer secure grants or stay competitive in science, she'll quit and become a vintner. But that day is unlikely to come, because just as an unopened bottle of fine wine improves in flavor and character in the cellar, Campisi's body of research in gerontology continues to grow in complexity and mature well with time.
January 14, 2004
Ingfei Chen is a SAGE KE contributing editor based in Santa Cruz, California. Until recently, she thought Amarone was a kind of squiggly pasta.
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