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A
nontraditional approach
David M. Holtzman, M.D., makes his mark on neuroscience -- and has fun along the way By Gila Z. Reckess From hobbies to training to research, David M. Holtzman, M.D., evades the boundaries of tradition and is inspired by two main goals: to have fun and make an impact.
Enchanted by the opportunity for dramatic advancements in such a critical area of medicine, Holtzman dedicated both his clinical and academic pursuits to demystifying the process of nerve-cell death in diseases such as Alzheimer's. Just 20 years later, Holtzman, now the Charlotte and Paul Hagemann Professor of Neurology, professor of molecular biology and pharmacology, has drastically improved science's understanding of the disease. "Dave's studies place him in an elite research position and are cause for expectation that we will have far more successful interventions for this cruel disease in the not-so-distant future," says David B. Clifford, M.D., head of the Department of Neurology and the Melba and Forest Seay Professor of Clinical Neuropharmacology in Neurology. "His successful melding of physician and scientist is an inspiration for many of us at the University and is a source of pride for our department." Aiming high According to his former research mentor, William C. Mobley, M.D., Ph.D., professor and chair of the Department of Neurology and Neurological Sciences at Stanford University, Holtzman's ability to go beyond the norm and push the envelope is part of what makes him a superb physician-scientist. For example, instead of intertwining Ph.D. training with medical school, Holtzman first dedicated himself to becoming a good clinician and gaining a thorough appreciation for neurological conditions. Even then, he continued on a nontraditional training route. Rather than focusing on getting another degree, he spent the five years it normally takes to get a Ph.D. in Mobley's lab concentrating on how to think critically and learn research techniques. By the end of his training, Holtzman had branched off from his adviser's pediatric neurology focus and began applying his newly honed clinical and research expertise to his own experimental interests. "Dave's really been able to carve out a field and then become the world's leader in it," Mobley says. "He's been able to remain focused on fundamental mechanisms while continuing to ask questions about how his basic research relates to disease processes." That appreciation for the larger perspective is clear in Holtzman's work. Not only is he a leading investigator of the most common cause of dementia in older adults, but he also is an accomplished researcher on one of the most common causes of lifelong neurological problems, perinatal stroke.
"If we can understand a little more about some of the differences between the adult and developing nervous system, it may help research in both areas," Holtzman explains. "There might be some differences in the two systems, but if you understand what protects the brain in different settings, you might be able to apply that information to other situations." For example, decreased blood and oxygen flow to the brain occurring around the time of birth, called a perinatal stroke, is a common cause of injury to the developing brain. There is no current treatment to intervene or reverse the damage caused by such an incident. But in a study published in the July issue of Annals of Neurology, Holtzman's team reported the first evidence that the antibiotic minocycline protects baby rats from brain damage caused by perinatal stroke, even when given shortly after injury. Unlike damage caused by a momentary, traumatic event such as perinatal stroke, Alzheimer's disease leads to slow, progressive degeneration of brain cells. Nonetheless, the two disorders both share a key element: cell death. Holtzman hopes that clues from learning to protect developing brains from injury also may provide insight into degenerative diseases in the elderly. Holtzman's laboratory also is extremely active in studying the specific stages that lead to symptomatic Alzheimer's disease. His team has been instrumental in showing how dangerous amounts of a protein called amyloid-ß (Aß) begin to accumulate in the brain many years before symptoms arise. Now that his team has made significant progress, Holtzman's focus is shifting toward applying basic findings to clinical research. Translating laboratory research into clinical results always was Holtzman's ultimate goal. In fact, part of what attracted him to the School of Medicine is its focus on collaboration, both between different laboratories and between basic and clinical science. As a postdoctoral student at the University of California, San Francisco, Holtzman instituted the university's first clinic dedicated to treating patients with dementia. Now he takes advantage of Washington University's renowned Alzheimer's Disease Research Center (ADRC).
In collaboration with Eli Lilly and Co., Holtzman's team has identified a monoclonal antibody called m266, which, in mice, draws Aß out of the brain and into the blood. In the March issue of Science, the team published the successful use of m266 to identify Alzheimer's-type changes in living mice. The test is the first proposed blood test to diagnose the disease before clinical symptoms arise. Since m266 appears to lure Aß out of the brain, it also may be useful in breaking down amyloid plaques and thereby treating the disease. Several companies now are considering clinical trials to determine whether administration of anti-Aß antibodies improves cognitive symptoms in patients with Alzheimer's disease. "The past decade has been a revolution," Holtzman says. "We're now talking about treatments that are being tried in the clinic based on what we've learned just this decade. It's amazing to be involved in that." Staying grounded "Dave's secret advantage is his wife, Tracy," Morris offers. "She understands the demands of a scientific career and keeps Dave well-grounded." The couple's secret, Holtzman agrees, is remaining active. Between running a laboratory, training medical and doctoral students, treating Alzheimer's patients and running a research seminar series, Holtzman plays basketball weekly and tennis three times a week. Holtzman and Tracy, a physical therapist in the Department of Pediatrics in the Division of Immunology and Rheumatology, also enjoy adventurous vacations, including sports such as hiking, tennis and windsurfing. Balancing work and play is routine for Holtzman. As a student in the rigorous Honors Program in Medical Education at North- western University, which fast-tracks students through an undergraduate and medical degree in six years, Holtzman always managed to stay active in various sports. When he graduated at 23, he went on to continue his clinical and research training in the vibrant setting of San Francisco. While at UCSF, he continued to be involved in several sports, particulary basketball, and played with the school's team. He also organized a medical group of basketball players, including students, residents and faculty, to tour China, giving lectures and playing ball. On the court and in the lab, Holtzman continues to live up to his mission, leaving an influential mark on the field of neuroscience and having fun along the way. But his proudest achievement to date is neither his research nor his jump shot; it's his team. "My main hope is that everyone enjoys working together and gets the most out of their experience," Holtzman says. "I'm most proud of the people who have worked in my laboratory, because not only are they outstanding scientists, but they're also great people. If their experience in the lab helps them in their future endeavors both in science and in life, that's all I can ask for." |
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