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Richard P. Lifton, M.D., Ph. D. For Richard Lifton, the space race and moon landing incited an early interest in science. By the age of 10, Lifton was regularly dredging water from the local pond so he could watch euglena and paramecia swim across the visual field of his hand-me-down microscope. But Lifton was also interested in giving something back to the community. "I was a product of the idealism of the 1960s," he says. So his thoughts turned to becoming a physician. Although Lifton found medicine compelling, he wasn't sure that a career in the clinic would suit him. "It seemed that we were unable to do anything for so many people," he says. "There were just so many cases where all you could do was watch." Lifton changed his tune during his junior year as an undergraduate at Dartmouth College, when he accepted a summer internship working in a research laboratory with Larry Kedes, then an HHMI investigator at Stanford University. "It was a great experience for me," he says. "Larry was doing exactly what I wanted to do. He was a wonderful physician and was making outstanding contributions to science—basic things that in the long run were going to relate to the biology of human disease." His summer internship turned into a six-month fellowship that inspired Lifton to enroll in the combined M.D.-Ph.D. program at Stanford, where he could learn the latest techniques in molecular genetics and biochemistry. "At that time," Lifton says, "our tools were so primitive that I didn't seriously consider working on anything as complex as a human disease." Instead, Lifton started studying how genes are organized in the fruit fly Drosophila melanogaster. Working with molecular geneticist David Hogness and fellow graduate student Michael Goldberg, Lifton made a major discovery: the TATA box—a short DNA sequence that regulates the transcription of genes in all higher organisms. After finishing medical school, Lifton returned to the clinic and completed four years of training at the Brigham and Women's Hospital in Boston. When he finished his clinical rotation, he realized that things had changed. "While I was doing my residency, new tools were being developed that would permit us to study the causes of human disease like we dissect the genetics of Drosophila," he says. For example, researchers had published the first maps that indicated where different genes were located on human chromosomes. At the time, many researchers were studying diseases such as cancer and diabetes. But Lifton was interested in hypertension. "Nobody was looking into the genetics of hypertension," he says, although hypertension contributes to hundreds of thousands of deaths annually, and the care of patients with hypertension is one of the largest expenses in the U.S. health care budget. "Tackling such a difficult problem was viewed as impractical," he recalls. So he set up a collaboration with Jean Marc Lalouel, a Hughes investigator at the University of Utah who was studying cardiovascular genetics. Lifton then spent three years in Utah, where he discovered the first known gene affecting the regulation of human blood pressure. High Pressure, Low Pressure Like Christine Seidman with her studies of cardiomyopathy, Lifton identified a large family with severe high blood pressure. One woman had been hospitalized five times in unsuccessful efforts to control her blood pressure, and many of her relatives had died at young ages from cerebral hemorrhages due to hypertension. By looking at genetic markers present in the DNA of the woman and her siblings and their children, Lifton identified the gene and mutation responsible for the hypertension in the family. By painstakingly searching through DNA from hundreds of individuals in dozens of large families, Lifton has mapped more than a dozen genes that, when mutated, change blood pressure in humans. But not all of these gene mutations cause high blood pressure. Some mutations actually cause life-threatening forms of low blood pressure in newborns. Over the past seven years, Lifton has identified mutations in three genes that raise blood pressure, eight genes that lower blood pressure, and another two genes that can increase or decrease blood pressure, depending on whether the mutation activates the gene or shuts it down. The most intriguing aspect of these findings, says Lifton, is that all the mutations affect how the kidney handles salt. Importance of Salt An important function of the kidney is to control the volume of circulating blood and the concentration of salts in the blood. Control of blood volume is required for maintaining proper blood flow and delivery of nutrients to tissues, and tight control of the concentrations of sodium and other ions is necessary for the normal activity of many types of cells. The kidney controls blood volume by regulating the amount of salt it returns to the bloodstream and separately regulates ionic composition by reabsorbing more or less water from the blood. In a sense, the pressure in the cardiovascular system—the arteries and veins that carry blood from the heart around the body—is like a hose clamped at both ends, says Lifton. Increasing the volume of fluid in the hose increases the pressure. Similarly, when the kidneys increase the return of salt and water to the bloodstream, blood pressure rises. The genes that Lifton has identified encode channels, or transporters—proteins embedded in the cell membrane that control the flux of salt into the bloodstream. In the kidney, these proteins help regulate blood pressure. Mutations that cause hypertension increase the activity of the channels, causing the kidney to reabsorb more salt. And mutations that cause low blood pressure tend to block or reduce the activity of these channels. The Search Continues Lifton will continue to search for additional genes that play a role in controlling blood pressure and determining the clinical outcomes of patients with hypertension. He suspects that just as there are genes that predispose people to hypertension, there are other genes that help determine whether a patient with hypertension will go on to develop a heart attack, stroke, or kidney failure or will remain free of complications of hypertension. Understanding how these genes contribute to disease may also lead to the development of new treatments for heart failure and high blood pressure. For Lifton, being able to find the answers to such questions is the greatest joy of science. "In science, you have a tremendous freedom to pursue what you're really interested in, the ability to discover something new about how nature works, and the opportunity to improve human health," he says. "How much more fun can you have?" Additional links |
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