It was hormones that drew Judith Campisi to study science: her own hormones, that is. ?I went to an all-girl Catholic high school,? she laughs, ?and I decided I?d had enough of the girls. I wanted to be where the boys were, and the boys were in the sciences.? But it was the excitement of lab life that kept her there. ?Science is always challenging, it?s never dull,? says Campisi, now a researcher at the Lawrence Berkeley Labs and the Buck Institute for Age Research.
?She?s an outstanding scientist,? says Art Pardee, Campisi?s postdoctoral advisor, of the Dana-Farber Cancer Institute and Harvard Medical School. In Pardee?s lab, Campisi examined the cell-cycle profiles of cancer cells and their normal counterparts. One experiment involved labeling cells with thymidine to track their replication and then collecting samples for several days. ?Judy was a machine,? recalls Estela Medrano of the Baylor College of Medicine...
HEEDING THE HAYFLICK LIMIT
Following her stint in Pardee?s lab, Campisi took her studies of the molecular underpinnings of cancer to nearby Boston University, where she?d accepted a position as an assistant professor. There she was approached by fellow faculty members Rich Miller and Barbara Gilchrist. Miller was hoping to study T cell changes with age, while Gilchrist was studying aging skin. They proposed that Campisi study senescence. ?They said there?s this weird phenomenon where [cultured] human cells divide for a certain amount of time and then stop. And some people think that has to do with aging.?
?When I presented the idea to her, she looked at me as though I was crazy,? recalls Miller, now at the University of Michigan, Ann Arbor. Campisi felt that replicative senescence ? first observed in cultured human cells by Leonard Hayflick, then at the Wistar Institute ? had nothing to do with aging. ?Barbara and I agreed with her,? says Miller. ?But we told her to pretend it had something to do with aging for the duration of the site visit.? Even if senescence did not drive the aging of tissues or organisms, they reasoned, it might provide a powerful mechanism for the prevention of cancer: A cell that won?t proliferate cannot form a tumor or become malignant and colonize other tissues.
?That sounded fascinating,? says Campisi, who chose to play along. That decision would change the course of her career. ?We got the grant,? says Miller, and Campisi turned her attention to senescence. ?And the more she got into it, the more she became convinced that we had all been wrong,? says Miller, ?that [senescence] had something to do with aging after all.? Perhaps the strongest evidence, published when Campisi moved to the West Coast, was her demonstration that senescent cells not only exist in vivo but also accumulate in aging tissue. What?s more, she and her colleagues have found that in culture, these nonreplicating cells are far from inert. They produce a plethora of unpleasant proteins that can, among other things, destroy the structural integrity of the tissue that surrounds them.
The ultimate experiment, however, has yet to be conducted. ?The critical test would be to create an organism in which you prevent senescent cells from accumulating,? says Campisi. She and her colleagues are working on devising a system to do that test. They are developing a mouse in which an inducible promoter allows them to activate a gene that will selectively eliminate senescent cells.
Whether senescent cells contribute to aging, notes Miller, ?is the kind of scientific question that most people in the field decided not to pay attention to and hoped others would stop asking.? But Campisi thrives on attacking such puzzles. Take, for example, the observation that mouse cells and human cells behave differently in culture. Normal human fibroblasts divide maybe 50 or 60 times before they senesce; mouse cells, on the other hand, divide 5 or 10 times and then either die or become transformed.
?People had known about that phenomenon for 20 years and sort of ignored it,? says Miller. Campisi investigated and found that mouse cells are more sensitive to oxidative damage than human cells and that the oxygen concentration used in the typical incubator (about 20%) is more than mouse cells can handle. The observation raises a tantalizing possibility, says Campisi: ?One of the reasons why mice live so much shorter and develop cancer much more readily than humans is because they?re much more oxygen sensitive.?
THE CANCER CONNECTION
At the same time, Campisi has also done more extensive work to shore up the connection between senescence and cancer. In experiments in tissue culture and in mice, she finds that proteins produced by senescent fibroblasts, including proteases, growth factors, and even molecules that promote angiogenesis can fuel malignancy, encouraging premalignant cells to become fully cancerous and form tumors that can kill an animal. ?That was a very important observation,? notes DePinho. ?Advancing age is, far and away, the most important of all carcinogens, and understanding why that is has been one of the central questions in the aging field.?
In addition to confronting such questions, Campisi spends a good deal of her time mentoring young scientists and advising friends and colleagues. ?I always rely on Judy when I have something to publish,? says Medrano. ?I get her opinion about our ideas and ask if we were rigorous enough before I submit the paper.?
Campisi offered career advice to Gordon Lithgow, now her neighbor at the Buck Institute, when he met her in a cab as a postdoc attending an aging conference. ?Judy was one of my heroes, and she couldn?t have been nicer,? he says. ?It was amazing to have someone you held in such high regard trying to get to know your science and where you want to go with it.? And it wasn?t just Lithgow. ?She?s incredibly supportive of junior scientists,? he says, particularly those who?ve trained in her lab.
Campisi not only allows postdocs to take their projects with them when they set up their own labs, a situation that former postdoc Pierre-Yves Desprez found ?amazing,? but she also continues to offer all sorts of support. When Desprez was setting up his lab at the California Pacific Medical Center in San Francisco, he often called Campisi to talk through problems or ask for advice. ?Even if she was saturated with work,? he says, ?she never told me ?No, I don?t have time.? Never.?
When Junko Oshima, another former postdoc, was trying to clone the gene responsible for Werner syndrome, Campisi sent cell lines and a cDNA library. ?Today you can make a cDNA library with a kit. But in those days, 15 years ago, building a cDNA library was itself a project,? says Oshima, now at the University of Washington in Seattle. ?When I found that gene, the first person I phoned was Judy,? she says. ?To this day she?s like my mother. I think a lot of people feel that way. She takes care of people very well after they leave.?
In her spare time, Campisi jets off to meetings, where she harvests information to share with her colleagues and collaborators. ?She always comes back with tasty tidbits,? says Lithgow. ?She just loves the science so much and doesn?t like to see people wasting their time because of lack of knowledge.?
Being a ?major node in this information network,? says Lithgow, helps Campisi to navigate her way through the complicated matrix of molecular and cellular interactions that drive organismal aging, a task that is likely to keep her busy for years to come. ?It?s a mistake to imagine that the process is so simple that we?re going to find the aging gene or the aging pathway or the magic bullet to postpone all aging,? says Campisi. ?But I wouldn?t be working on aging if I thought it was so hopelessly complex that we?ll never understand firstname.lastname@example.org