Sci. Aging Knowl. Environ., 26 May 2004
A Life of Fusion
Olivia Pereira-Smith moved from Bombay to Berkeley to pursue science. Focusing initially on experiments that merged cells, she built a career in gerontology and a successful working relationship with her husband and research partner
Ingfei Chenhttp://sageke.sciencemag.org/cgi/content/full/2004/21/nf53 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. In the late 1970s, Olivia Pereira-Smith was working as a technician with cell biologist James Smith, her husband, at the W. Alton Jones Cell Science Center in Lake Placid, New York. One week, the pair went to a conference to present a poster on the aging of human cells in culture. Pereira-Smith had done all the experiments. But when another scientist dropped by, he snubbed her: As she began explaining the work, he turned away and questioned Smith. "That got me kind of ticked off," recalls Pereira-Smith. She decided she would have to get a Ph.D.
She marched off into her doctoral studies, earning her degree in 1981 from the Worcester Polytechnic Institute in Massachusetts based on research she conducted in Smith's lab. Afterward, she continued to work closely with him, but her own ideas soon established her as an independent scientist. She used cell fusion methods to study senescence, the zombielike state in which cells, after a limited number of divisions, cease splitting yet do not die (see "More Than a Sum of Our Cells"). "She was a real pioneer in defining the genetics of cellular immortality," says cell biologist Judith Campisi of Lawrence Berkeley National Laboratory in Berkeley, California.
Starting in 1983, Pereira-Smith and Smith published a series of studies establishing that senescence is a dominant genetic trait involving several as-yet-unknown genes (or groups of genes): In the simplest scenario, a cell enters cellular limbo only if it carries at least a single normal copy of each of the genes. But when two copies of any of the genes are defective, the cell can multiply indefinitely. "Those are really classic papers," Campisi says.
Now a gerontologist at the University of Texas Health Science Center, San Antonio (UTHSCSA), Pereira-Smith, 54, pursues the same research theme. She is no wallflower. The first time Smith spoke with her, by phone, he pictured a "big sort of Englishwoman-type person" because of her British accent. But Pereira-Smith is a 5-foot-tall (1.5 meters), curly-haired, dark-complexioned woman with high spirits and the gift of gab. Like an eager first-grader playing show-and-tell, she's been known to pass around a flask of cultured cells so that visiting scientific reviewers can see the raw data and share her excitement. "What strikes absolutely everybody is her energy," says friend and cell biologist Gretchen Darlington of Baylor College of Medicine in Houston, Texas. "She is so enthusiastic about her work. ... She just has a very outgoing personality and a positive attitude."
Pereira-Smith began her journey into science from half a world away. She was born to a Portuguese physician and an English-Irish nurse in Bombay, India, a port city that was a fusion of East and West, old and new, poor and rich: People pushing handcarts intermingled on the streets with cows, bicycles, cars, and double-decker buses. Milk, rice, and flour were rationed. Many people spoke English, and the University of Bombay featured the spires and courtyards of British architecture. Teenagers listened to the Beatles. Pereira-Smith attended a private, British-style school from kindergarten through high school. Students pledged allegiance every morning to the Indian flag. Like people in the larger society, classmates adhered to a medley of faiths--Hinduism, Islam, and Catholicism. "It was actually quite nice to get an exposure to various people of the world," Pereira-Smith recalls. "You learned to have no strong biases one way or another."
From kindergarten on, she usually ranked first in her class in science and math, as well as English. She was a voracious reader--Kenneth Grahame's The Wind in the Willows and Charles Dickens's The Pickwick Papers ranked among her favorites--but novels were hard to come by because they were expensive. "They were like a major treasure," she says. At the end of the year, her school gave prizes to the top students in each subject. "The award was always a book. And that was my most exciting day, because I'd get a big pile of books every time."
Pereira-Smith's father wanted her to follow in his footsteps as a physician and medical professor, but it was a hard act to top: He had been a brilliant student who won gold medals every year of medical school in addition to being a star sprinter and soccer player. The expectations were too much, Pereira-Smith says. She chose a different path: As a high school senior, she won a college scholarship in a nationwide science talent search. With that funding, she went to the University of Bombay and earned a bachelor's degree in microbiology in 1969. While there, she studied a fungal enzyme, which led to her first publication, in the Journal of Postgraduate Medicine. She liked doing research and grew set on becoming a scientist. Paradoxically, in a country where women had to bring dowries to get married and where stories of wife abuse in villages were not uncommon, Pereira-Smith says, women nonetheless could pursue their own careers. Being female "doesn't stop you if you are an achiever in India," she says, citing Indira Gandhi, the second woman prime minister in the world, as the ultimate example.
Pereira-Smith stayed in the microbiology department for a master's degree, but those studies were interrupted in 1971 by sudden pain when a disk in her back degenerated. She spent a year almost entirely confined to bed, wasting away. "It was pretty scary," she says. But under her parents' care, she slowly recovered. "It was quite a day when I was able to walk again." Returning to school, she graduated in 1973. During her training, Pereira met Peter Ashby, an administrator for the U.S. National Science Foundation in Delhi. They became friends, and Ashby later introduced her to Lester Packer, a cell biologist at the University of California (UC), Berkeley, who came to India to teach once a year. Packer invited her to get another master's degree in his lab.
From Bombay to Berkeley
At the time, the prospects of a scientific career in India looked dim: "Everyone was pretty realistic about science in India. There was not very much money for it," Pereira-Smith says. For lack of resources, researchers could conduct only relatively simple experiments; if investigators wanted P32 or other radioactive material, they had to order it 6 months in advance to have some made. And getting ahead in science often required political connections. For example, her father had wanted to become a surgeon, she says, but "he couldn't get into surgery because he didn't know the right people." Today, the scenario is much improved, she says; India has a reasonable science budget and a number of government research institutes. But back in the early '70s, Pereira-Smith's parents encouraged her to seek her fortunes abroad. Her older sister, Patricia, had already left for New York City to study political science. In 1973, Pereira-Smith headed for California.
Coming from cosmopolitan Bombay, Pereira-Smith says the biggest shock she faced in Berkeley wasn't cultural, it was meteorological. "I half froze to death," she says, laughing. She had packed her bags for the warm, sunny California of Beach Boys songs instead of the San Francisco Bay Area's cool, fickle summers. When she arrived, she met Smith, who was a research associate running Packer's lab at the Veterans Affairs Medical Center in nearby Martinez. The research group studied the role of oxidative stress (see "The Two Faces of Oxygen") in cell senescence, and at Packer's request, Smith began teaching Pereira-Smith cell culture techniques. Because her training in India had led her to take a descriptive scientific approach rather than attempting to unravel how things work, Smith recalls, "I didn't know if she was actually going to make a scientist or not." She spent about a year getting used to thinking about science in a more critical way, he says. Then "she took off." For her master's project, Pereira-Smith showed that senescent cells resist the oxidative damage caused by light exposure better than young cells do.
American education also required some adjusting to. Pereira-Smith enrolled in several science classes in which all exams were in multiple-choice format. She scored poorly and was pulling a C in a physiology course. "I didn't know how to take those stupid tests," she says. Frustrated, she sought help from Satyabrata Nandi, an Indian-born cancer biologist at UC Berkeley. He said, "Yes, yes, it happens to all of us, because you're not used to this style of taking exams," she recalls. British-style exams typically pose essay questions that require students to synthesize their learning. Nandi suggested that Pereira-Smith study with a classmate named Nathan Piers, an undergrad--who told her they would start reviewing the course material the night before their next exam. When they sat down together, Pereira-Smith recalls, "I was reading around, researching around. ... And Nathan's like, 'No, no, no, no, they don't want you to do that. They just want you to know the facts and just regurgitate them.' " Pereira-Smith eked out a B in the class.
A Career of Her Own
She and Smith fell in love and married in 1975. They moved to Lake Placid when Smith landed his first faculty job at the nonprofit Jones Cell Science Center. When Pereira-Smith tackled her Ph.D., she did it the British way, without coursework. Her formal adviser was Audrey Muggleton-Harris, a cell biologist at the Worcester Polytechnic Institute, a research affiliate of the Jones center. But Pereira-Smith did all her experiments in Smith's lab. "Jim pretty much always left me to do my stuff. If I ran into any snags, he was there."
From Muggleton-Harris, Pereira-Smith learned delicate techniques to fuse two cells into one, with a single nucleus containing all of the chromosomes from both cells. She melded, in various combinations, senescent cells and "immortal," endlessly dividing, tumor cells and tested whether the resulting hybrids underwent limited replications. Those experiments led to her results explaining the basic genetics governing senescence.
Pereira-Smith earned her doctorate--and gave birth to two children, Ayesha and Ajit--in 3 years. During each pregnancy, she worked in the lab until the day she went into labor. Afterward, she managed to mother both cell cultures and infants by sharing child-rearing responsibilities with Smith and hiring a full-time babysitter for about $25 a week. "You become very honed, superconcentrated in that you hit the lab and you do your stuff, you come back home, and then you become Mum," she says. "And then once the kid's in bed, you become Mum-scientist again." Later, whenever the kids got sick, the couple split the day caring for them. "If I had lots of experiments, Jim would just stay at home with the kids. He took a share of everything." When young women scientists ask Pereira-Smith how to succeed in research and also have a family, she advises them, half-seriously, to choose their mate carefully: "It's very hard otherwise."
In 1983, the couple moved to Baylor College of Medicine, which offered Smith an associate professorship and Pereira-Smith an assistant professorship. They set up adjacent labs and essentially ran as one operation, holding weekly joint lab meetings, for instance. Smith's group was one of the first to report the existence of a protein called SDI, better known as p21--which helps inhibit a cell's DNA synthesis and thus initiates its entry into senescence--and Pereira-Smith worked with him on the project.
But from the start, she also developed her own line of inquiry, winning a grant from the National Institute on Aging (NIA) to continue studying genes that govern senescence. "Her research has dovetailed with Jim's over the years, but she's always had her own separate projects," says Huber Warner, an associate director at NIA in Bethesda, Maryland. "She had the right stuff on her own." After demonstrating the existence of several genes that control indefinite cell division, she, a grad student named Yi Ning, and their colleagues found a candidate for one of those genes on chromosome 4. The lab isolated the gene, called MORF4, in 1999. Since then, Pereira-Smith's team has moved into using genetic techniques in mice to study whether and how senescence is regulated by MORF4 and related genes. Members of this so-called MRG family encode factors whose interplay with chromatin--DNA in its coiled-up state--appears to influence the translation of other genes into proteins.
A Pied Piper of Mentoring
In addition to doing science, Pereira-Smith enjoys mentoring and bringing new faces into gerontology. She runs the NIA training grant program in the biology of aging at the Sam and Ann Barshop Center for Longevity and Aging Studies at UTHSCSA, and last year she organized a gerontology course for grad students and postdocs. Her high-energy style motivates those around her, colleagues say. At Baylor, Darlington recalls, "she was kind of like a Pied Piper with students, because she would talk to them a little bit and just get them all wound up. ... She works very hard with her students. She developed close relationships with the people who were in her lab."
Former grad student Ning, now at the University of Maryland, Baltimore, says she appreciated how--unlike some advisers who insist that students do exactly as told--Pereira-Smith gave her freedom to explore various ideas and techniques. Yet Pereira-Smith, who still pops into the lab periodically to do her own cell culture work, was always available to discuss results and offer encouragement. "She has a very good eye for cells," says Vera Gorbunova, who was a postdoc in the lab in 2001. "She taught us exactly when they were good [and] when they didn't look good. We could bring her our plates and she would look at them."
Pereira-Smith also pushes her postdocs to become proficient at communicating their work through giving talks and writing papers and grant proposals, Gorbunova adds. One time, Gorbunova served as corresponding author on one of their papers, handling reviewers' critiques and writing rebuttals. "She thought that this was an important lesson for me to learn," says Gorbunova, who has since joined the faculty in Baylor's biochemistry and molecular biology department.
For Gorbunova, Pereira-Smith also serves as a role model in another way: Gorbunova, too, works with her husband, cell biologist Andrei Seluanov. She had first been inspired to study aging when she read Pereira-Smith's papers in the late '80s as an undergrad in St. Petersburg, Russia; after earning her Ph.D., she wrote to the senior scientist inquiring about positions in her lab. Gorbunova and Seluanov were looking to do postdocs together. "I was concerned that not every PI would like to hire a husband and wife at the same time," says Gorbunova, who hadn't known of Pereira-Smith's partnership with Smith. But Pereira-Smith welcomed them both to the lab. They were raising a 4-year-old son, Michael. Once, when Michael fell ill, Pereira-Smith helped them find a pediatrician. Another time, because school was closed, Gorbunova was going to have to stay at home with him. But gerontologist George Martin of the University of Washington, Seattle (editor-in-chief of SAGE KE), was visiting the lab that day, and Pereira-Smith volunteered to baby-sit Michael in her office for a couple of hours so that Gorbunova could meet Martin.
With This Beaker, I Thee Wed
By and large, Gorbunova and other colleagues observe, Pereira-Smith and Smith's working arrangement is an equal partnership that has served each of them well. At the Barshop Center, where they moved in 2001, they still maintain a joint lab and eat lunch together every day. Pereira-Smith cites two keys to a successful husband-wife team. "One is that you actually really like each other, not just love each other." The other: "You have to be very willing to take criticisms from each other. We are each other's strongest and meanest critics." One time, she says, after Smith gave a seminar, he asked her how he'd done. "I said it was awful. ... He went off into a big tantrum, calmed down, and said, 'Yeah, you're right.' And he does the same thing to me."
Smith concurs that over the years, they have both benefited from having someone who gives candid feedback on ideas, talks, and papers. "You get mad at each other once in a while for being totally honest, but then you get over it in a few minutes." He adds, "She's the kind of colleague that everybody ought to have." What's it like to write a paper with your spouse? "Terrible," says Smith, deadpan. "She red-inks it all over." Pereira-Smith usually gets the final editing word on a manuscript, she says gleefully, "because my English is British."
Smith cites only one other complaint: His wife likes to discuss work at home more than he does. "The biggest downside for me is that when I'm ready to go to bed and read a book or go to sleep, she still wants to talk science," says Smith. Sometimes he asks her to stop, but he notes, "It doesn't do much good." Laughing, Pereira-Smith retorts that he has adjusted, however: "He just goes to sleep anyway, so it doesn't matter. ... He's gotten well-trained in that regard." The only time Pereira-Smith wasn't chatty, she admits, was when she used to go fishing in the Adirondacks in upstate New York. Catching trout or bass, she says, requires intense concentration. "If anyone talks, I'll say, 'Go away, go away.' " At day's end, Pereira-Smith finally quiets down by reading a science-fiction novel or spy thriller before falling asleep.
Another way she blows off stress is by working out at the gym three times a week. And she gardens: "Jim and I both like to play in mud. We just go out and buy plants that look interesting and throw them in the ground." As with their science, the endeavor is a partnership, she says: He digs the hole, and she places the plant.
May 26, 2004
Ingfei Chen is a SAGE KE contributing editor based in Santa Cruz, California. She grows plants that don't need watering.
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