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| Vol. 20, No. 20 |
| November 1, 1998 |
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Dr. Murad's Grand Adventure Nobel Winner Tracks Effects of Molecule for 20 Years
"Even as a kid, I planned to be a doctor. But in college, the research was just too exciting, and I knew that it would always have to be a part of my life," says Dr. Ferid Murad, co-recipient of the 1998 Nobel Prize for Physiology or Medicine and chairman of the integrative biology, pharmacology and physiology department at The University of Texas-Houston Medical School. Research has indeed been a part of his life, and it appears that his research may have some very real benefits on everyone else's life.
For Ferid Murad, life 'as a kid' was pretty good in Whiting, Indiana. "We had a great childhood," says Dr. Murad's lifelong friend Ronald Delismon, a retired Boeing engineer who spoke with the News from his home in Seattle. The two began their friendship in elementary school. "I guess we competed in about everything - test scores, grades," says Delismon. "Just about everything became a game. We were bright enough so that we didn't have to work very hard at our grades. At lunch we would race each other at crossword puzzles. But the classes at Whiting High School were wonderful. Very small student-teacher ratio, so that in trigonometry we'd have maybe 15 kids." Murad loved math games. He waited tables at the restaurant his parents owned and would calculate in his head the total bill for each table before the check arrived. "We loved the restaurant. John and Josephine - Fred's parents - were always giving me a lot to eat. I was six feet tall and weighed 120!" says Delismon.
"In fact, I was so interested in chemistry in college that I nearly decided not to pursue an M.D. degree," reflects Dr. Murad. It was at this time - 1958 - that Western Reserve University School of Medicine in Cleveland offered - for the first time anywhere - a combined M.D./Ph.D. program which took seven years to complete. They were extraordinary years for Murad. He married his wife Carol; by the time he graduated, they had four children. He studied under Drs. Earl Sutherland (a 1971 Nobel Prize winner "for his discoveries concerning the mechanisms of the action of hormones") and Theodore Rall. And some trail-blazing molecular discoveries were being made. "Yes, I was one of his mentors," says Dr. Rall, from his home in Charlottesville, Va. "He was a graduate student of mine, and I directed his thesis work. It was an exciting time to be in Cleveland. We had just isolated and crystallized the first second messenger, so we were attracting some very bright and highly motivated students and researchers. Fred Murad and Al Gilman (a 1994 Nobel Prize winner) were in the combined M.D./Ph.D. program, and we sensed that these two would make some significant contributions." After he completed his degree at Western Reserve, Dr. Murad did his residency at Massachusetts General Hospital in Boston, one of the very finest teaching hospitals in the country. "I loved the clinical rotations during my residency," says Dr. Murad. "Mass General was absolutely a wonderful place." Dr. Murad next went to the National Institutes of Health, where he was a clinical associate professor in cardiology - but continued his research work on second messengers. A few years later, when both Drs. Murad and Gilman were at the University of Virginia Medical School, they recruited their mentor and old friend, Dr. Rall. "They each had one of my arms and pulled me there," Dr. Rall says. "I can tell you it was a real blast being around those two. It was an exciting time in their careers."
In the early- and mid-1970s the first experiments were being conducted with small compounds which activated enzymes within tissues. Dr. Murad and his colleagues focused on the molecular mechanisms of drug actions, hoping to get some clues about how cells "communicate" with each other. Dr. Murad studied nitroglycerin and other vasodilators trying to determine the precise mechanism of their actions on the cardiovascular smooth muscles. On Nov. 5, 1976, he discovered that the nitroglycerin in fact released a fairly common environmental gas, nitric oxide (NO), as part of its action. The nitric oxide produced in the endothelium - the innermost part of the arteries - rapidly spreads through the cell linings to the surrounding muscle cells. The NO "turns off" the contractions which are limiting blood flow through the arteries; the arteries quickly relax, or dilate. That nitric oxide was the second messenger was all the more startling because the gas is a "free radical," a molecule with an unshared electron in its outer shell and, hence, very reactive. In the scientific community, it was unimaginable that a free radical molecule could activate an enzyme. The discovery meant that, essentially, the gas was produced by one cell, penetrated the membrane of a neighboring cell and regulated the function of that cell. It was a breathtaking development in biologic signaling. "I'm not sure that we immediately saw that we'd figured out the mechanism, but we certainly knew that we had just demonstrated that the nitric oxide had relaxed a smooth muscle," says Dr. Murad. "It was stunning." By now it was accepted that second messengers - the small molecules - regulated a number of biologic processes. "All cells make it [nitric oxide] for communicating with each other, so the significance of it can be pretty far-reaching in terms of the body's systems - the airway, cardiovascular, gastrointestinal," says Dr. Murad. "And it plays a role in many other functions: memory and smell, for instance." "By 1987 or so, there were probably only 50 scientific papers about the biologic effects of nitric oxide," says Dr. Murad. "There was a whole literature about it as a pollutant and about its toxicity. It is, after all, a gas emitted from automobiles and other sources of pollution. But, since 1987, there have been probably 20,000 papers about NO's biologic functions. Nothing I can remember in the field of biology has attracted this kind of attention." Though the Nobel Prize was given to Dr. Murad for "discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system," the Nobel citation goes on to discuss the significance of nitric oxide "in medicine today and tomorrow." In septic and circulatory shock, NO plays a harmful role: white blood cells, reacting to the invasion of bacteria, release huge amounts of NO, causing the blood vessels to dilate and blood pressure to drop dramatically. Inhibitors of NO synthesis would be very useful in these cases. Patients under intensive care can receive inhalations of NO along with oxygen; it reduces the dangerously high pulmonary and systemic blood pressure. It is used frequently in neonatal intensive care units. "Its use for preemies is not yet approved by the FDA because all the clinical protocols aren't completed," says Dr. Murad, "but it is very effective for these babies." In cancer, NO may be very useful in the same way that it works against bacteria and parasites. Because NO can induce apoptosis - cell death - researchers believe it may be useful in stopping the growth of tumors. Inflammatory diseases such as asthma and colitis can be revealed by analyzing the production of NO at the disease's source (the lungs or bowels, in these two examples). In the nervous system, production of NO in the nerve cells can stimulate many of the brain's functions, including behavior. In 1996, Dr. Murad was awarded the Albert Lasker Basic Medical Research Award for his pioneering work in cell regulation and signal transduction. The Lasker Award is not so near well known as the Nobel, perhaps because its $25,000 prize is dwarfed by the near-$1 million of the Nobel. The 26 members of the Lasker Award committee conduct a rigorous review. "It was very gratifying to win that," says Dr. Murad. "I have so much respect for Mary Lasker and her interest in health care and research." "As the research goes on, you know what you're doing is important," says Dr. Murad, reflecting on the years following his identification of nitric oxide as a signal molecule. "As a pioneer in the field, I have, of course, wanted to do everything. In the beginning of my work with NO, I didn't appreciate the significance of what we were doing. Today, it's one of the most active areas of basic and clinical research. The opportunity of developing new pharmaceuticals for a plethora of illnesses is very exciting." Dr. Murad had visited Houston many times before he joined The University of Texas-Houston Medical School. "Every time I came, there were more buildings, more resources," he says. "What really snowed me was the size of the Texas Medical Center. There are many quality scientists and projects here; the volume of activity is very impressive. I love being in an exciting environment." "I'm no brighter than I was last year, but all of a sudden, people are listening more closely to me. And the honors! Whiting, Indiana, has asked me to be the grand marshal for their 4th of July parade. My old high school has asked me to be the commencement speaker for their 100th graduating class. "But I do sense that I have a position of responsibility - to this UT campus and to the research we are involved in which will certainly lead to improved clinical outcomes. The research still excites me. We are looking at a brand new enzyme. We are developing a speedier assay. "It is a lot of fun doing this," says Dr. Murad. "There are not many professions where one can jump out of bed in the middle of the night to jot down your ideas, and then come to work the next day to test your thoughts and plans with such excitement day after day." - ROGER WIDMEYER
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