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PATHOLOGY What's Wrong With My Mouse?As Use of Gene-altered Mice Increases, So Does Demand For Rodent Pathologists What's wrong with my mouse? That is the question rodent pathologist Roderick Bronson has been answering for the last 20 years. The question echoes in labs across the country. Demand for expert mouse pathology has risen in proportion to the exponential growth of genetically engineered mice used to study human biology and diseases. Mouse pathologists diagnose the often subtle or unexpected problems with mice when genes have been knocked out, knocked in, mutated, or manipulated in other ways.
For expert phenotyping of genetically altered mice, dozens of postdocs and professors turn to the rodent histopathology core: (top row) Li Xhang, Andrew Thompson, (bottom row) Jennifer Griffin, Montserrat Michelman, and Roderick Bronson. (Photo by Graham Ramsay) "You can't predict what is going to be wrong in an animal," said Bronson, an HMS lecturer on pathology. "You have to look at everything." In a murine necropsy several years ago, for example, he dashed the hopes of dieters everywhere when he found holes in the brains of older mice with a promising gene mutation that kept them thin no matter what they ate. Detecting DifferencesThe number of mouse mutants needing diagnoses will only grow after the public mouse genome sequence is released later this fall. The databases of mouse and human genome sequences give scientists dazzling new tools to focus on the biology of more common and complex diseases, such as diabetes, Alzheimer's, cardiovascular disease, and cancer. The ability to analyze the functions of genes and their proteins in mice and turn those discoveries into new medical therapies depends in part on accurate diagnoses of their effects in mice. Expertise such as Bronson's is in short supply."A genotype is just a sequence of DNA," Bronson said. "Phenotype is what a gene does. That's the pathology. Pathology is the mother of all medical disciplines." Two years ago, HMS hired Bronson to anchor the rodent histopathology core for the Dana-Farber/Harvard Cancer Center. For dozens of postdocs and professors, four technicians dissect mice, stain the tissues, and slice them paper-thin for microscope viewing. Bronson examines the slides and then reviews the key findings with researchers on a microscope with three sets of eyepieces for teaching. One day recently, Bronson was pointing out problems in a cross-section of eye tissue to an enthusiastic Mark Anderson, a clinical endocrinologist and HMS research fellow in medicine at Joslin Diabetes Center. After more than two years of trial and error, Anderson has demonstrated a mechanism of autoimmune disease with his knockout mice, with the bonus that his mice also display a phenotype of spontaneous autoimmune retinopathy also seen in patients. The resulting research article has been accepted by the journal Science. Each new mouse model he examines makes Bronson more valuable to the next researcher. "Bronson plays an absolutely fundamental role in my research," said Peter Sicinski, an HMS assistant professor of pathology at the Dana-Farber Cancer Institute. "By looking at what's wrong with the mouse, we can get a good idea of what our protein does. Bronson takes this several steps further. He's looked at so many mutants, he can make connections. Not only does he point to what's wrong, he can tell us if it's similar in appearance to other mice, which may suggest interaction with another gene or protein it encodes. His involvement contributes in an essential way to deciphering the molecular interpretation of the phenotype." Sicinski first consulted Bronson as a postdoc at MIT eight years ago and credits him with key observations that launched his career. Sandy Zinkel, an HMS postdoctoral fellow in the DFCI lab of Stanley Korsmeyer, has been looking at slides of a new mouse model with Bronson to test the effect of a gene involved in apoptosis. "He basically found the phenotype, although he would say we found it together," said Zinkel, a hematologist-oncologist. "His vast experience is invaluable. He's able to distinguish between a phenotype and what happens normally in aging mice. He's able to keep you from heading in the wrong direction." These days, Bronson adds about 20 minor and several major new phenotypes every month to his repertoire. Since 1985, he has spent about four days a month at the Jackson Laboratory in Bar Harbor, Maine, the world's largest mammalian genetics research facility, where he examines mice with spontaneous mutations in search of new animal models of disease, collaborates with several researchers, and helps teach specialized mouse pathology short courses. Bronson also maintains a full professor appointment with Tufts Schools of Medicine and Veterinary Medicine. Altered Mice Now Roaring"Our country is experiencing a growing shortage of mouse pathologists, particularly as the number of genetically altered mice being used in research increases," said Franziska Grieder, a grants administrator at the National Center for Research Resources (NCRR) at the National Institutes of Health. "This isn't something that can be fixed in a year," she said. "You don't educate these people overnight. These are complex skills that somebody acquires over years and years." To address the shortage, NCRR has awarded six grants under its midcareer investigator award in mouse pathobiology research for mentorship of young investigators."There is a fundamental need for people who can validate mouse models as being related to human disease," said Bob Cardiff, a human surgical pathologist who directs the mutant mouse pathology lab for the Center for Comparative Medicine at UC Davis. As principal investigators funded by large NIH research grants have become ever more specialized, he said, the subsequent demand for mouse pathologists has grown into a broader service need. "Most RO1 investigators know a great deal about their specific organ system," Cardiff said, "but all of a sudden their mouse comes down with diabetes, and they thought they were studying lymphomas. They need someone specifically trained to look at genetically engineered mice." Observers say the shortage of expert mouse pathologists may be affecting the validity of published papers. "A lot of new people are coming into the field as the mouse has become increasingly important," said Jackson Lab researcher Muriel Davisson, who directs the lab's famous mutant mouse repositories. "They often can make mistakes defining the pathology of mutations because they are not familiar with the phenotypes of the strain's genetic background." Co-authors such as Bronson and Cardiff confer significant credibility on papers. The dearth of mouse pathologists is part of a larger problem that extends beyond academia, said biochemist Michael Falk, executive director of Life Sciences Research Office, a nonprofit organization in Bethesda, Md. "We've heard that if you want to hire molecular biologists, you can run an ad in Science and have hundreds of résumés on your desk next week," he said, "but if you try to hire an in vivo pharmacologist or physiologist or mouse pathologist, it's an 18-month job search." In his preliminary analysis for a report to be presented at an Oct. 21 consensus conference on the supply and demand of integrative and systems scientists, Falk sees a dwindling number of dissertations and a similar downward trend in published articles despite a reasonably constant job supply. "We've had a marvelous expansion of information," he said, "but all along the problem has been how to interpret the information. It all funnels through whole animals." --Carol Cruzan Morton |
