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Christine E. Seidman, M.D. "I've been a science person since I was a little kid," says Christine Seidman, known by friends and colleagues as Kricket. "I've always been interested in how things happen and why they happen." As a child, Seidman collected butterflies in jars and experimented with anesthesia. "I almost killed myself trying to find the right dose of ammonia and cleanser to anesthetize those animals," she laughs. As an intern at Johns Hopkins University School of Medicine, Seidman focused her scientific interest on medicine and disease. She attended Harvard University as a pre-med student and there met Jonathan Seidman, the man who would become her husband and close collaborator. After completing a B.S. in biochemistry in 1974, Seidman enrolled in medical school at George Washington University. She found the traditional "name that body part" style of learning unsatisfying. "We had to memorize what this nerve is and what that bone was," says Seidman. "It was not particularly thought-provoking." Seidman also felt her medical school training was not bringing her any closer to her goal of helping people. "We kept seeing the same diseases walk through the door," says Seidman. "But we weren't making any fundamental progress in understanding why a disease occurred or what we could do to make an important difference in a person's life." Her perception changed when she became an intern and then a resident at Johns Hopkins University and met Victor McKusick, an accomplished geneticist and the chief of medicine. "He showed me that you could bring science to medicine," she says. McKusick, who was studying a variety of genetic disorders found in Amish people, would spend time with residents, talking about patients and about the latest scientific discoveries. Seidman says that McKusick impressed her with his love of science, especially genetics. "It was terrific to have a world-class geneticist not only willing to help you understand scientific manuscripts but also dedicated to having you apply new concepts to the practice of medicine," she adds. Rainy Day Revelations For Seidman, it all came together one rainy Sunday afternoon in the early 1980s. She was sitting on the sofa, thumbing through Science, when she came across a paper that described the isolation of atrial natriuretic factor (ANF)—a peptide hormone secreted by the heart that appeared to regulate blood pressure. Seidman was inspired. "I realized that the heart is more than just a pump that squeezes—it's a smart pump," she says. So she and her husband set out to clone the gene for ANF, by no means a simple task. "In the old days," says Seidman, "many of the techniques now used routinely to isolate and purify genetic material were still considered 'witchcraft'—as much art as science." And though the ANF peptide is small—only 21 amino acids long—the researchers ended up synthesizing more than 400 different bits of DNA to fish the ANF gene out of genetic material isolated from rat hearts. By 1984, Seidman and her husband had cloned the ANF gene. "Nothing could have made me happier," says Seidman, who then became convinced that she could apply molecular biology to the study of the heart and the diseases affecting its structure and function. Probing the Pump Seidman was interested in understanding how the heart responds to stresses such as valvular heart disease and high blood pressure. In these disease states, the heart swells, or hypertrophies; the swelling taxes the heart and reduces its pumping efficiency. In the case of some inherited diseases, such as familial hypertrophic cardiomyopathies, heart muscle may thicken spontaneously in the absence of occlusion, hypertension, or other outside factors, implicating an inherited problem. Seidman set out to identify the genes that signal the heart to hypertrophy. Family Reunion To identify genes that cause hereditary hypertrophic cardiomyopathy, Seidman first hit the phones, calling physicians all over the country to help her track down large families affected by the disease. In the extended Canadian family she first chose to work with, so many members had died of sudden cardiac arrest that family members referred to the disease as the Coaticook curse, for the place they lived. Seidman organized a family reunion, complete with a picnic, to gather the relatives for blood samples and to determine—using physical examination, electrocardiograms, and echocardiograms—which members showed the thickening of the heart muscle that was indicative of the disease. To identify the chromosomal location of the mutant gene, DNA was extracted from a small blood sample obtained from each family member. The DNA was analyzed for genetic markers called polymorphisms, variations from individual to individual. Scientists have found the locations of hundreds of genetic markers, which are used to identify specific places along all of the human chromosomes, just as ZIP codes can be used to identify where in the country a person lives. By identifying a marker sequence that is present in affected but not unaffected members of a family, the chromosomal location of the disease gene can be pinned down. Using this approach, Seidman determined that a gene form causing cardiomyopathy in the subject family was located on chromosome 14. From there, finding the gene was not difficult, says Seidman, because chromosome 14 happens to house the gene that encodes cardiac myosin—the major protein that makes muscles contract. Sure enough, when Seidman sequenced the cardiac myosin gene from affected family members, she found a mutation that causes familial hypertrophic cardiomyopathy. Sarcomere Disease But myosin isn't the whole story. In some families with cardiomyopathies, the myosin gene is normal. That finding sent Seidman looking for mutations in other genes. So far, she has found dozens of mutations in seven different genes that can cause hypertrophic cardiomyopathy. The genes all encode proteins that form the sarcomere—the highly structured assembly of fibrous proteins that are the muscle cells' contractile machinery. Seidman is now exploring how mutations in different genes—and different mutations in the same gene—affect disease severity. For example, families that have a mutation in the myosin gene show a high incidence of sudden death at an early age. But in an Icelandic family that has a mutation in the gene that encodes cardiac myosin binding protein C, affected individuals don't develop enlarged hearts until they are 40 or 50 years old. Turning to Mice Why do the mutations cause heart cells to hypertrophy or die? And why are some mutations more severe than others? To answer these questions, Seidman has used genetic engineering to make strains of mice with these disease-causing mutations. Researchers can manipulate and examine genetically engineered mice in ways they can't with human subjects. The mice are genetically much more similar to one another than any two humans are to each other (except identical twins, of course); using genetically engineered mice, researchers can tease apart the role of environment or habits and the direct consequences of a mutation. By examining mutant mice, Seidman hopes to determine whether exercise worsens or alleviates hypertrophy—and whether the results differ for males and females. Studying mice should also allow Seidman to identify drugs that might eventually reduce hypertrophy and perhaps prevent the arrhythmias that cause sudden cardiac arrest in humans. Additional links |
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