Going Where Science Leads, continued

But these problems are universal in the realm of scientific exploration. Researchers everywhere complain about the obstacles they deal with to obtain funding for their work, says Wistar professor Dr. Meenhard Herlyn. Since grants and scientific productivity are tightly tethered, Herlyn explains, Wistar’s administration has learned to cater to the research. The grants office, for example, formats and prepares grant proposals for investigators so that they need only spend their grant-writing time on the science and their budgetary needs. The development office identifies donors who might want to underwrite specific research projects.
    Buck calls Wistar “the best of all possible worlds for a researcher.” The Institute is relatively small and administratively streamlined. Investigators have virtually no bureaucratic obligations or teaching responsibilities to eat up their time. And they have access to all the assets Penn has to offer, including libraries, seminars, patient samples and graduate students, who come to work in their labs.

Dr. Ellen Puré

    Though Wistar is a separate and independent entity, it has a strong history of research collaboration with Penn. Some of the researchers at Wistar hold joint appointments at the University and many Penn degree candidates do much of their accreditation work at Wistar. As a result, there’s no shortage of comparisons between the two institutions. For example, Wistar, unlike Penn, can be likened to a farmer’s market, where everyone has his own stall. The institute, which boasts a 50 percent rate of Ph.D.s among its 300 or so employees, is populated by independent labs with little overlap in their specific fields of expertise. Yet Wistar fosters interdisciplinary interaction that allows the scientists to share, and use, each other’s knowledge. Ellen PurČ, who studies the inflammatory mechanisms behind atherosclerosis, says her research benefits, for instance, from the interaction she has with the molecular genetics group down the hall and the structural biologist next door. By contrast, she says, Penn is so big that one needs to really work at getting to know another’s research.
    But what Penn offers to Wistar is an enormous supply of M.D.s who are in the trenches and can deliver patient samples for research purposes. An additional benefit: the possibility for unique fusions of the clinical and the research perspectives, says PurČ. She explains that a doctor might remark to her, “‘I have a patient that lacks the enzyme that results in this phenotype. Can we think about this problem together?’” A place like “Wistar-Penn” is fertile ground for such collaborations, she says. “We need these two types of people talking so that they can connect the dots.”
    In her research on atherosclerosis and airway inflammation associated with asthma, PurČ works closely with several physicians within the University of Pennsylvania Health System, including pulmonary specialists and an internist who specializes in lipid disorders. While both of these disease processes share a common enemy—inflammation—PurČ foresees atherosclerosis to be the domain in which she may have the most immediate clinical impact. PurČ hopes to combat this battle in the vessels by identifying the genes and molecular mechanisms that facilitate the atherosclerotic process. She studies the receptors in the blood vessel that allow for the adhesion of the inflammatory cells that comprise plaques, and she has uncovered the role of a significant receptor—the CD44 molecule—in the development of plaques that may be more susceptible to rupture and clot formation leading ultimately to heart attack or stroke.
    The mechanisms that underlie chronic inflammatory disease, which are also key players in tumor metastasis, are potential targets for new drugs aimed at preventing atherosclerosis and other inflammatory conditions, she says. But this pathologic machinery cannot be manipulated until it is understood.
    “There’s been a lot of discussion about getting all of this basic research to be translated into human healthcare,” PurČ adds. The conventional wisdom, she continues, has been to “get M.D.s to do science. And then everyone said, ‘Let’s get people with combined degrees to do science.’ But neither solution has worked completely.” She believes that the therapies of tomorrow will come from basic scientists—working with research tools like lab mice and test tubes—in collaboration with their counterparts in the clinical world.
    Dr. Thanos Halazonetis, assistant professor at Wistar, is busy mapping the distinctions between tumor cells and normal cells, and defining certain “checkpoint” genes that, when mutant, fail to assume their normal function of inhibiting cells from entering into the spiraling growth patterns of cancer. He laments the fact that basic science is given little popular attention. “The people think that their doctor will figure out better ways to treat cancer. But that’s not going to happen,” he says. “If the public understands that laboratory research is important for the development of new therapies, then so will the politicians.” In his laboratory just inside Wistar’s elegantly marbled, first-floor atrium, to the left of the steep grand staircase, Halazonetis walks past a row of large beakers filled with yellowish liquid. He stops for a moment to make a prediction—that his exhaustive research on seemingly esoteric bits of DNA will materially improve the way in which doctors treat patients within the next 20 years.

Wistar’s melanoma research lab, headed by Meenhard Herlyn, is the institute’s largest laboratory. It also comprises the largest melanoma research group outside of the NIH. Like Halazonetis, Herlyn hopes to advance clinical medicine through his bench work. Herlyn describes a study conducted a few years ago in which seven world-class pathologists were given 38 samples of lesions that represented either melanoma or dysplastic—abnormally-growing—tissue. Shockingly, the doctors disagreed on their diagnoses in 40 percent of the cases.
    Herlyn is striving to understand the early changes that take place in the growth of melanomas, and to develop highly accurate molecular models that will help pathologists to better diagnose them. He notes that the cure rate for melanoma is about 100 percent when it is caught and treated early. And by better defining the transcription factors that promote the proliferation of melanoma cells, Herlyn hopes to pinpoint ways in which chemotherapy and radiation could be rendered more effective in treating melanoma.
    Unfortunately, this research did not come soon enough to save Noreen O’Neill, who died last summer of metastatic melanoma. O’Neill was president of the Foundation for Melanoma Research, an organization that Herlyn cofounded with a group of melanoma patients. Herlyn continues to be inspired by O’Neill’s plight, from which, he says, “it became clearly obvious to me that therapy for melanoma is very much in its infancy.”
    To better characterize the behavior of melanoma cells, Herlyn, who has been engaged in melanoma research since 1977, uses a mouse model to cultivate the disease. He grafts human skin, which he obtains from surgeons at the Hospital of the University of Pennsylvania, onto the backs of his mice. He then injects them with growth factor and places them under ultraviolet lights. After about three months, some 10 percent of the mice have melanoma lesions, which are then harvested, grown in tissue culture, and analyzed during their successive growth phases. Herlyn scrutinizes the abnormal melanocytes to determine how they escape the control of the keratinocytes, which are the normal cellular gatekeepers in this growth process. And he also tries to ascertain which genes are the culprits in transforming the melanocytes from normal to aberrant cells.
    Dr. Louise Showe, an associate professor and core facility director at Wistar, runs the microarrayer that Herlyn and some of the other cancer researchers hope to soon rely on to better define the differences between normal and cancerous cells. Showe, who last year received a five-year, $500,000-a-year NCI grant to develop microarray technology at Wistar, produces arrays that consist of spots, or “probes,” of DNA for 1,700 selected genes. RNA is extracted from the cells—melanoma cells, for example—that are under investigation. Copies of the RNA are then produced, each incorporating a radioactive tag. Once brought into contact with the DNA probes, these RNA targets bind to the probes that correspond to the genes that generated them. The resulting DNA-RNA complexes are read radiographically to assess which genes in the study sample are active, and how strongly they are expressed.


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