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Taking Personalized Medicine to New Heightsby Ruth SoRelle, M.P.H. 
The Wright brothers at Kitty Hawk in 1903. Courtesy of Special Collections and Archives, Wright State University. A photograph of the first airplane flight at Kitty Hawk, N.C., in 1903, haunts Jeffrey Steinbauer, M.D., Medical Director of the Baylor Clinic and one of the architects of personalized medicine at Baylor College of Medicine and its soon-to-be-built clinic and hospital. That grainy black and white picture shows Orville Wright prone at the controls of the rudimentary plane while his brother Wilbur stands confidently to the side as the plane just begins to lift into the air. It evokes both the loneliness of invention and the intellectual certainty of those who go first into any field. "They knew it would fly," said Steinbauer. "They couldn't have told you what flight would mean in 50 years time. They did not know what jet planes would look like, but they knew their plane would fly and that flight would revolutionize the world." Steinbauer and his colleagues at BCM feel the same about personalized medicine—particularly genomic medicine. They know that it will "fly" in its first iteration at Baylor Clinic and the Baylor Clinic and Hospital, which is scheduled to open in 2011. Where this initial flight will lead to is anyone's guess, and Steinbauer will not even hazard a prediction of what genomic medicine will look like at mid-century, except for one thing. With or without genomics, personalized medicine begins and ends with a classic dyad: physician and patient. Physician and patient—the alpha and omega"When I think about personalized medicine, I like to think about it in terms of a patient—you as an individual human being getting what you want and need, when you want it and when you need it. My vision is based on taking the good values of service and striving to build a practice to use them to best benefit you. Your genetic code is another tool for providing good medicine," said Steinbauer. Peter G. Traber, M.D., President and CEO of BCM, estimates that knowledge gleaned from DNA—the genetic code—affects no more than 1 percent of medicine currently practiced at the Baylor Clinic. By the time the Baylor Clinic and Hospital opens in three years, he estimates that genomic medicine will be involved in 10 percent of care and within a decade, 50 percent. Ultimately, knowing your genetic code will be crucial in understanding you as a biologic being. Practicing medicine, however, means more than that. A personal relationship with your doctor"What makes a relationship personal?" said Steinbauer. "It's someone who knows more about you than anyone else, who understands you and who remembers you. It is someone with whom you have a history." In terms of the Baylor Clinic, "it's a group of people with whom you have some continuity. You have the opportunity to see the same doctors and the same staff members when you come to the Clinic. "From the molecular or genomic point of view, it's what makes it possible for someone to know more about you than anyone else. We have the opportunity to do that," he said. Currently, that view is limited. Steinbauer compares it to looking at the moon through a telescope. "We can see the surface. We can see some shapes. We can see some contours," he said. "As physicians taking care of you, we can do some tests from which we can infer certain things about you, but we really don't understand you as a biologic being any more than we really understand the moon by looking at it through a telescope. "When I think about personalized medicine, I think about an individual getting what you want and need, when you want it and when you need it. Your genetic code is another tool for providing good medicine." "However if we obtain your DNA and when we have learned to analyze it to your best advantage, we will know you in a way that's far more in depth," he said. "You are the only person in the world who will have that combination of DNA." However, personalized medicine does not have to wait for that. "That's where our information technology platform comes in," Steinbauer said. "It affects patients now. The IT platform becomes a ‘memory' for the Clinic about you as a patient. It records everything that happens to you here, anything you tell the doctor, the results of any test that you have had. It all becomes instantly available to anyone taking care of you at the Baylor Clinic." As these electronic health records become more standard across the health care industry, eventually any doctor can access that information, with the patient's permission. Collecting genomesUltimately, having your own genome sequenced will be quick, easy and of immense value to you and those attempting to understand you as an individual. Even though Richard Gibbs, Ph.D., Director of the Baylor Human Genome Sequencing Center, and representatives of 454 Life Sciences gave Nobel Laureate James Watson, Ph.D., his personal genome last May, they are among the first to point out that it is not possible to provide something similar to the public as a whole. It is too expensive at this point, and little of the information could be used to enhance health. Just analyzing and storing the information is a challenge. Gibbs had originally planned to burn Watson's genomic information onto a DVD. However, it would not fit, and he substituted a portable hard drive. "I never saw so much information," said James Lupski, M.D., Ph.D., Professor and Vice Chair of the Department of Molecular and Human Genetics at BCM, who was charged with elucidating the data for the scientist. As Gibbs told his colleagues in BCM's Department of Medicine, "In truth, it's not easy. It's still an expensive and clumsy growing science to produce whole genomes. It still costs millions to generate the raw data and it still takes six months, and that's no diagnostic test, right? There's still a lot of work to do, just in the basic effort of genomics." Whole genome sequences not necessaryPersonal genomics, however, does not have to wait for whole genomes to become available on an individual basis. Already, genetic differences can help doctors decide which drugs to prescribe and how to prescribe them. "Some people metabolize drugs differently," said John Belmont, M.D., Ph.D., Professor of Molecular and Human Genetics, Pediatrics and Immunology at BCM. "Nothing will happen if they are not exposed to the drug. The risk depends on the exposure." "We have identified genetic changes that cause you to be more or less sensitive to the drug. Physicians are beginning to incorporate the use of this genetic knowledge in deciding the best way to use anticoagulants with the goal of decreasing the many complications seen with these drugs." Recently, the U.S. Food and Drug Administration stopped just short of recommending a genetic test for doctors who prescribe warfarin (Coumadin), a blood thinner. New labeling alerts doctors to genetic tests that can identify patients who have a greater risk of bleeding when the drug is prescribed. "The way we've treated patients in the past is that everyone is given a standard starting dose of anti-coagulant (blood thinner) because we couldn't predict how patients would respond," said Sharon Plon, M.D., Ph.D., Associate Professor of Pediatrics, Molecular and Human Genetics and Director of Baylor Cancer Genetics Clinics and Neurofibromatosis Clinic. "Over the past couple of years, we have identified genetic changes in populations that cause you to be more or less sensitive to the drug. Physicians are beginning to incorporate the use of this genetic knowledge in deciding the best way to use anticoagulants with the goal of decreasing the many complications seen with these drugs. It's a good example of how we used to only base our treatment on how you responded and now we are including genetic information." Cancer genomicsMany new anti-cancer drugs target genetic changes that occur in tumors. One of the best known is Herceptin, or trastuzumab, a monoclonal antibody that targets tumors that express a protein known as HER2/neu. This drug is specifically effective in women whose tumors express this genetic change. Testing the breast tumor to determine if it has receptors for estrogen or progesterone can also provide clues about how to treat it best. "We are using a 21-gene assay with 16 cancer genes and five reference genes that has been shown to reliably prognosticate who will or will not relapse in their cancers," said Jenny Chang, M.D., Associate Professor in the Baylor Breast Center and an expert in treating the disease. "It could also tell us who will or will not benefit from chemotherapy. It spares those who will not benefit from the treatments." On the immediate horizon are other assays that look at even more genes. "We are moving forward to figure out how to use these assays," said Chang. Right now, one study is attempting to determine how to treat women who fall between high and low risk in the 21-gene assay. It is another test designed to find out how to treat a woman based on the genetic code of her tumor. "We are one of the first groups to look at expression profiles to figure out who would benefit from taxen-based chemotherapy," she said. One patient study seeks to determine who would benefit from treatment with Taxotere® and on whom other forms of chemotherapy would work better. Now experts in the Baylor Breast Center are looking at tumors that express neither HER-2/neu nor estrogen receptor to figure out what proteins do play a role in driving these cancers to grow and spread. "We are using a 21-gene assay with 16 cancer genes and five reference genes that has been shown to reliably prognosticate who will or will not relapse in their cancers. It could also tell us who will or will not benefit from chemotherapy. It spares those who will not benefit from the treatments. These are just a few of the advances in which genetics play a part. In the future, the National Institutes of Health's Cancer Genome Sequencing Project promises to play a major role in understanding the range of genomic changes involved in various tumors. The Baylor Human Genome Sequencing Center is part of that major effort, working in three areas—a brain tumor called glioblastoma, ovarian cancer and two kinds of lung cancer. In conjunction with the BCM department of surgery, the Sequencing Center is also looking at cancers of the pancreas, looking for mutations in certain genes. "We are also generating the pipeline where we can reliably move samples from the surgical suite to the laboratory to get these initial diagnostic profiles," said Gibbs. "We are creating a model of how one day we might have a true diagnostic pipeline. Instead of large tumor sections, you can use DNA amplification techniques that are novel and have robust and meaningful results." Gene chips as diagnosticsAs variations among genomes become apparent, Lupski and others have pinpointed a previously unrecognized alteration called copy number variation. When most people think of a genetic disease, they think of those—such as cystic fibrosis or sickle cell disease—that arise when there is a single change in one of the letters that make up the genetic alphabet. This change alters the protein associated with the gene and results in a disease. An estimated 8 to 10 percent of the population suffers from one of these rare diseases, and the ability to diagnose them is incredibly important to that population. However, Lupski and his colleagues have found large parts of the genome that are either duplicated or deleted. This does not change the gene itself, but the way it is regulated. These deletions or duplications could mean that too much or not enough protein gets made. Some may not cause disease, but some are associated with disorders such as color blindness, Charcot-Marie-Tooth disease type 1A and other nervous system disorders. These variations can affect a person's risk of becoming infected with HIV (human immunodeficiency virus) or developing Parkinson's, Alzheimer's or Crohn's diseases. Identifying these variations need not wait for the ability to sequence a whole genome. Gene chips called chromosomal microarrays can identify many of these gene copy variations. An array developed by Arthur Beaudet, M.D., Chair of Molecular and Human Genetics at BCM, and his colleagues is already being used to identify children with previously undiagnosed complex mental-retardation syndromes. Understanding that the number of copies of a gene in a cell can change the amount of protein in circulation and cause disease is an important step forward in developing ways to treat the problem, Lupski said in a recent analysis. The approach would be to modify the abnormal amounts of the protein rather than correct an abnormal or mutant protein. The path to personalized medicineBaylor College of Medicine, its researchers and physicians have never shied away from blazing new paths. Michael E. DeBakey, M.D., embarked on his own pursuit of excellence at BCM, and along the way pioneered and enhanced the field of vascular and cardiovascular surgery in a way that he could not have envisioned when he began his career. As he is fond of saying, there was no vascular surgery when he trained. He came to BCM in 1948, and five years later he performed the first successful carotid endarterectomy—removing the material clogging that important artery that brings blood to the brain. He developed the Dacron® graft for repair of aneurysms and performed the first excision and graft replacement for aneurysms of the descending and ascending thoracic aortas and the aortic arch. He was a pioneer in heart transplant, and by the 1960s he was well on the way to developing a pump to assist the heart in pumping blood. Today, his DeBakey Ventricular Assist Device (VAD) is in trials in human patients. "Few would doubt that biomedical science and technology, including genomics and informatics, will transform how we approach health and disease but the path may not always be straight and will change with time." During nearly 60 years at Baylor College of Medicine, he pursued his dream, and the way he achieved his goals changed as new knowledge and technology transformed his practice. In the same way, Baylor College of Medicine and its physicians, researchers and officials will pursue the goal of personalized medicine. As Traber said in a recent letter to the College, "Few would doubt that biomedical science and technology, including genomics and informatics, will transform how we approach health and disease but the path may not always be straight and will change with time. The realization of personalized medicine will be a process that develops over the next several decades, growing with technology and applications developed by creative minds. Baylor College of Medicine can, and should, be at the forefront of this innovation. That is our goal—to apply our excellence in science to patient care in an ever expanding and accelerating pace focused on a vivid vision of the future of health care." |
Best Minds Best MedicineBCM Campaign Seeks to Raise $1 Billion Attracting Stars: McNairs Give $100 Million To Recruit Top Scientists Lester and Sue Smith Gift Tackles Breast Cancer in the Clinic and Lab Two Alumni Share Commitment to Scholarship Support FeaturesTaking Personalized Medicine to New Heights Creating Culture While Building Walls Changing Complexion of Medicine SpotlightClick for your Doctor: New eVisits Trade Exam Room for Inbox Kjersti Aagaard: 2007 Winner of NIH New Innovator Award Getting World-Class Breast Cancer Care...With or Without Insurance James Lupski's Tenacity Founds New Field of Genomic Medicine BriefsBCM Named National Diabetes Research Center The Trash is no Place for Expired Medication Removing Brain Tumors Through the Nose SPORE Spawns New Lymphoma Efforts The Coffee-Cholesterol Connection
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Volume 4, Issue 1, Summer 2008 |
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| Last modified: October 7, 2008 |