By By Joan P. Capuzzi Giresi
Photography by Jim Graham

It was pure accident that led Dr. Ellen Heber-Katz to make a 90-degree turn in her research focus. The year was 1994 and, in her investigations on T-cells and their role in autoimmunity, the Wistar Institute researcher was working with a special strain of mouse prone to developing the autoimmune disease lupus. As part of an experiment, Heber-Katz separated the small white critters into two batches, demarcating them by punching ballpoint-sized holes into the ears of one of the groups. A few weeks later, she was confounded to find that all of the holes had mysteriously closed, leaving behind no hint of their former existence, not even a scar.

Dr. Ellen Heber-Katz

   “When I saw there were no ear holes,” she recalls, “I didn’t know who was who.”
   Laboratory lemon or scientific serendipity? The future holds the answers. Heber-Katz, who is also an adjunct professor in the pathology and laboratory medicine department at Penn’s School of Medicine, now devotes about 80 percent of her time to mapping the gene loci that confer these unique regeneration properties and analyzing their patterns of expression. She hopes that her research on the “healer” mouse—as it was coined at Wistar—which exhibited full replacement of its epidermis, dermis and cartilage in three to four weeks following ear puncture, could be a boon to burn victims and might contribute to research on stem cells, wound healing, and cartilage and nerve regrowth. But that’s still a long way off. For now, Heber-Katz says, the leading question on her mind is, “Why are these mice able to do this and other mice are not?”
   Basic queries like this are what have kept the Wistar Institute at the forefront of scientific research through the years. Major accomplishments by Wistar investigators include the identification of a number of cancer-causing genes, the development of the TALL-104 cells—a promising immunotherapy currently in clinical testing against several forms of cancer, and the discovery of interleukin-12 (IL-12)—a messenger protein important in facilitating immune response to infection. Among the first research institutions to develop monoclonal antibodies, which can detect and destroy foreign invaders, including cancer cells, Wistar has been responsible for a host of other noted creations. These include the Wistar rat—the first standardized laboratory animal—from which over half of today’s laboratory rats are thought to be descended, and vaccines against rabies and rubella.

Dr. Frank J. Rauscher III

   The complexity of the work being done at Wistar is rivaled only by its pure simplicity. “Wistar is wholly devoted to basic research,” says Dr. Frank J. Rauscher III, professor and deputy director of the Institute’s cancer center. “Basic research” at Wistar runs the gamut, from the study of the fruit-fly genome and the remarkable immune systems of insects to investigations of the molecular mechanisms of cancer. The pursuit of the latter occupies the bulk of the lab space and brain power at Wistar today.
   The other hallmark of Wistar-style scientific exploration is that it is hypothesis driven. “Ninety-eight percent of our experiments don’t work,” Wistar professor Ellen PurČ confides. “At a drug company, if an experiment doesn’t work, it stops there. At Wistar, a failed hypothesis goes on to a new hypothesis and new experimentation.” Hence the unwritten guiding principle at Wistar: Go where the science leads. For Heber-Katz, this progressive approach allowed her to rapidly shift direction in her research from autoimmunity to cellular regeneration.
   In a different way, Rauscher has also followed where the seductive and meandering trail of science has led. In the mid-1990s, he was studying the intricacies of zinc- and RING-finger proteins, genetic proteins that modulate gene function. At the time, a group of scientists in Utah discovered the BRCA1 gene, which, when mutated, renders a woman’s chances of developing early-onset breast or ovarian cancer over 80 percent. When Rauscher realized that the protein coded for by this gene was a member of the protein family he’d been studying, he became elated and headed into the director’s office. “‘Look,’ I said to him, ‘I think I can make an impact here, but I need some basic support.’”
   Support was granted, and Rauscher and his team went on to discover the gene BAP1, which has the dual function of regulating BRCA1 levels and controlling its activities. Rauscher hopes eventually to identify drug receptors on oncogenes—the genes that activate the uncontrolled cell growth of cancer. He says that the discovery of BAP1 makes it possible to genetically test for its presence and then potentially use it as a target for cancer-fighting drugs.



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