Eyes on the Prize

In 1976, when Ferid Murad discovered nitric oxide’s critical biological role, he sensed he was onto something that might win him a Nobel. He was right.

December 1999By Comments

ONE OF 1998 NOBEL PRIZE WINNER Ferid Murad’s many gifts is a certain prescience. When he was twelve years old, Murad predicted that he would one day be a doctor, a teacher, and a pharmacist—and today he is all three (well, he’s a professor of pharmacology rather than your friendly neighborhood pharmacist). And in 1976, when he and his lab mates at the University of Virginia discovered that the odorless, colorless gas nitric oxide plays a critical role in the body’s cellular signaling system—helping regulate body functions ranging from the relaxation of arteries to the fighting of infections and tumors—he had a feeling he might be onto something that would one day win the prize. “The odds are so against it that most scientists don’t advertise that they think that way,” says Murad, who is the chairman of the Department of Integrative Biology, Pharmacology, and Physiology at the University of Texas—Houston Medical School. “But I knew we were onto something important.”

Many of Murad’s peers at the time weren’t quite as impressed. Indeed, for at least the next ten years, Murad’s discovery was considered, at best, mildly interesting, quirky, unimportant science. After all, before Murad’s finding, nitric oxide had been known primarily as a noxious air pollutant and a dangerous free radical (a renegade molecule associated with cancer and other diseases). “People just didn’t want to believe that this free radical could act like this,” says Murad, whose smooth, round face and slightly impish grin make him look considerably younger than his 63 years. “Nitric oxide was known for destroying things.”

Murad’s recognition came two decades after the fact, which is typical of Nobels for medicine and science, and he shares the prize with two other scientists who had performed similar research over the same period of time: Robert Furchgott of the State University of New York in Brooklyn and Louis Ignarro of the University of California—Los Angeles. Meanwhile, the subject of their research, nitric oxide (not to be confused with nitrous oxide, the laughing gas your dentist administers as an anesthetic), has become like a pop-culture phenomenon with a growing cult of acolytes who extol it as the greatest medical discovery since penicillin. The journal Science dubbed it the “Molecule of the Decade.” And it may be the only chemical gas in history to have its own fan club (the Nitric Oxide Society), official publication (The Nitric Oxide Journal), and Web site (2005/08: website is no long active.) Finally, nitric oxide—which consists of one atom of nitrogen and one of oxygen and is called NO for short—would seem to be giving the Y2K problem a run for its money as the most scrutinized scientific topic of the decade: In the past five years NO has been the subject of an astounding 18,000 scientific studies, all exploring its role in regulating cellular activity in the body. As it turns out, NO is involved in just about everything, from blood pressure to blood clotting, respiration to digestion, retrieving memories to fighting infections. Concludes Murad: “There are very few things in the body that nitric oxide doesn’t regulate. And we are still discovering more.”

Since receiving the Nobel, Murad has given more than one hundred speeches and lectures and countless interviews. Unlike some scientists, who bristle at or shy away from all the attention, Murad seems to bask in it. He is refreshingly frank, admitting that he has always wanted to win the award, and now that he has, he thinks he deserves it. “Some other people thought that too,” he adds, flashing that impish smile.

Ferid Murad has earned the right to beat his chest a little. The eldest son of an Albanian immigrant, he grew up in a small apartment behind the family restaurant in the tiny town of Whiting, Indiana. It was not always a sure bet that he would be able to realize his dream of a career in science and medicine. His family’s finances were limited, and he had to finance a dozen years of higher education with scholarships, grants, loans, and part-time work. He married his wife, Carol Ann, just before entering medical school, so for much of that time, he was also supporting a family that eventually numbered five children.

“I knew I wanted considerable education so that I wouldn’t have to work as hard as my parents,” Murad wrote in his official biography for the Nobel Book. After graduating from Indiana’s DePauw University in 1958, he decided to pursue not only an M.D. at the prestigious Case Western Reserve University School of Medicine, in Cleveland, Ohio, but also a Ph.D. in pharmacology.

Like many aspiring young scientists at the time, Murad became fascinated with the exotic new disciplines of molecular and cell biology, where the mysteries of human life were being solved at the most elemental level. He became especially interested in the processes of intercellular communication. Science already knew that such communication was initiated by hormones and neurotransmitters; now it had turned its attention to the so-called secondary messengers, those chemicals that took the instructions from the hormones and instigated several series of chemical reactions that resulted in a biological activity—the beating of the heart, a memory surfacing from the brain, the immune system releasing white blood cells to fight off an invading virus.

After graduating from Case Western, Murad kept up with the research on secondary messengers while completing his internship and residency at Massachusetts General Hospital in Boston; while subsequently serving for three years as a clinical associate at the National Institutes of Health in Bethesda, Maryland, he even did a little lab work on the subject.

When he left the NIH to join the faculty of the University of Virginia in 1970, he was eager to establish a reputation in cellular-signaling research. Unfortunately, a number of projects were already under way at the school focusing on the best known of these signalers or secondary messengers, cyclic adenosine monophosphate, or cyclic AMP. (Among the most prominent were experiments being conducted by Alfred Gilman, now at the University of Texas Southwestern Medical Center at Dallas, who won the Nobel in 1994 for his own breakthroughs in the field of cellular signaling.) So that he wouldn’t get lost in the cyclic AMP shuffle, Murad turned his attention to another, similar secondary messenger, cyclic guanosine monophosphate (cyclic GMP), which hadn’t received nearly as much attention. “All any of us knew was that cyclic GMP was present in the body,” he says.

Murad set out to discover two things about the chemical: How do hormones regulate its formation, and once it is formed, what does it do? To test this, he exposed smooth-muscle tissue from the bovine trachea and tissue from rodents’ hearts, livers, and brains to various hormones to see which triggered production of cyclic GMP in the tissues’ cells. He first found that all of the hormones incited cyclic GMP production only when the tissue was intact. If the tissue was damaged in some way, the chemical interaction didn’t happen—which suggested that there was something in the intact tissue that chemically interacted with the hormones to prompt the formation of cyclic GMP.

But what was that something? At this point, serendipity intervened to give Murad’s team a little nudge in the right direction. To prevent possible contamination, Murad had the tissues treated with some toxic, nitrogen-bearing substances, including sodium azide and sodium nitrite. To his surprise, some of the substances instigated cyclic GMP formation, and they did so in both intact and damaged tissue. What’s more, when Murad applied the substances to the smooth-muscle tissue, he found that they relaxed it.

“That part was luck,” Murad admits. Perhaps. But “it takes a prepared mind to see that he’s at the right place at the right time, and to seize the opportunity as Fred did,” says L. Maximilian Buja, the dean of the UT-Houston Medical School (Murad’s friends and colleagues call him Fred). “That’s what separates a Nobel laureate from everyone else.”

Murad’s intuition was to cross-check these findings by bombarding the tissues with a well-known smooth-muscle relaxant, nitroglycerin, to see if it incited GMP formation. Though the drug had been used for a century to relieve the debilitating effects of angina (the chest pain associated with heart disease) by relaxing and dilating constricted blood vessels, no one in science had ever figured out the biochemistry of how it worked or why.

When Murad’s testing confirmed his hypothesis—that nitroglycerin works by releasing nitric oxide, which makes cyclic GMP, which makes the smooth muscles of the blood vessels relax—he started thinking really radically. “Now we had a family of nitrogen-carrying compounds—some complicated, some simple—that promoted cyclic GMP production and smooth-muscle relaxation in both intact and broken-up tissue,” he says. “We reasoned that the compounds were being reduced to some common intermediate, and we guessed that it was nitric oxide.” Sure enough, when he bubbled the NO gas through yet more tissue, the GMP levels shot up and the smooth muscles relaxed.

Murad had thus proved the improbable on several counts. He had finally uncovered how nitroglycerin works for heart patients. He had proved for the first time that a gaseous substance could serve as a cellular signaler. And he had proved that that gas, nitric oxide, was not your garden-variety free radical but one of the most versatile cellular-signaling substances in the body, serving as a secondary messenger within an individual cell or a primary signaler between different cells, and affecting cellular function in a dizzying variety of tissues. Murad further hypothesized that nitric oxide occurred naturally in the tissues of the body as part of the cardiovascular, pulmonary, nervous, and immune systems.

He knew then and there that he had entered the realm of Big Science. “What does that suggest when a compound this simple plays such an important role?” he asks excitedly. “To me it suggests that nitric oxide is one of the most primitive elements of cellular signaling, that it goes way back into evolution.”

Over the next two decades, as he worked his way through numerous distinguished academic posts (including acting chairman of the Department of Internal Medicine at Stanford University) and stints in the private sector at Abbott Laboratories and, for a time, as CEO of his own biotech company, Murad continued to explore the mysteries of nitric oxide. So did a lot of other scientists. In the eighties his two Nobel-winning colleagues, Furchgott and Ignarro, helped promote NO’s acceptance as a cellular messenger by confirming in separate experiments Murad’s hypothesis that it is produced in the body and plays a role in relaxing blood vessels and heart tissue.

Murad and others then turned their attention to NO’s possible uses in the smooth muscles of the respiratory system. As a researcher and medical doctor—not to mention as a father of five—Murad is especially proud of the ongoing role that NO plays in alleviating symptoms among patients with pulmonary disease—in particular, premature infants born with underdeveloped lungs. “Nitric oxide has helped to increase the salvage rate in preemies under one pound from five to ten percent to sixty to seventy percent,” he says. “There’s a ton of nitric oxide in the nasal cavity, and we think it’s there to facilitate breathing. Isn’t that ironic? Here’s this pollutant that causes sometimes severe respiratory distress but can also be crucial to healthy breathing.”

By the time Murad joined the staff at UT-Houston, in 1997, he had an even stronger feeling that a Nobel might be in the offing. The previous year, he and Furchgott had shared the prestigious Lasker Award, and many winners of this American science award have gone on to win Nobels. His NO discoveries had become conventional wisdom, and the area of cellular signaling continued to have a certain cachet in research circles.

When Murad got the phone call from Stockholm at four in the morning, there was a sense of relief, he says, but also a realization of new responsibilities. “There’s the responsibility to continue to think creatively and the responsibility to young scientists, especially those who may be from backgrounds like mine,” he says. “And there’s the responsibility of how to use this award to build more buildings here [at UT-Houston] and to improve health care for patients.” Indeed, UT-Houston administrators expect the Nobel to jump-start the relatively obscure medical school’s fundraising and recruitment efforts.

Recently, Murad and other scientists still on the NO trail have turned their attention back to its dark side. While Murad is happy to have uncovered NO’s benign alter ego, he says, “It is still a poison, and too much of it in the tissues can cause problems.” For example, too much NO can cause blood vessels to overdilate, resulting in shock and death. An excess of the compound has also been associated with certain chronic diseases such as arthritis and colitis. “The fear is, when you go to make new medications for one tissue, how do you make them specific enough that they don’t negatively affect another tissue? In a decade or two, we’ll have some wonderful new treatments for hypertension and colitis and cancer based on this biology. But we’re still a long way off.”

When science does get there, you can bet that Ferid Murad will once again be at the head of the class. Proud as he is of winning the prize, he’s not about to rest on his laurels. “Once you have one of these,” he says, “you want to go back for a second.”

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