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By Robert Ross Most people who follow their noses find only what's in front of them. Not Michael Marletta. For the past 38 years his nose has been luring him to the unknown, to risks and unexpected rewards. Once the associate professor of medicinal chemistry, pharmacognosy, and biological chemistry has taken measure with his sharp eyes, a precocious smile is likely to follow. A scarred chin and athletic build remain from countless evenings playing hockey and basketball. Thick forearms move in deft strokes when he speaks, as if he's still guiding a puck across the ice. A taut finger punches home a point. As a boy, he knew by smell when his father was home from another day of work in the spice mills of the RT French Company in Rochester, New York. "I'd jump onto his lap and he smelled of turmeric, chili peppers, or mustard. Then I'd rummage through the kitchen cupboard to taste what it was he smelled like. Chili pepper was always quite a surprise." In high school, he got a summer job in the same factory where his father worked as a production manager. One morning as he made Worcestershire sauce amidst the deafening mills, he realized from a distance there was a serious problem in mustard production when he saw workers congregating around the shut down mill and white-coated chemists hurrying off with bottled samples. No one could solve the problem. "Then I saw my father walk up," he recalls. "He rubbed a little of the mustard between his fingers, smelled it, tasted it, said something to the foreman, and left. A half hour later they were making mustard again. I'm still impressed by that, especially now that I know what the lab guys were doing." The mysteries of aroma and flavor led Dr. Marletta eventually to science, but not before he had a serious flirtation along the way with languages. Although his mother, born in Italy, and his father, the son of Italian immigrants, conversed with each other in Italian, they withheld their native tongue from their children, whom they were raising to be "Americans." But after three years of high school Spanish he cracked the code. "I had to tell my mother that no longer could she speak in Italian about the unmentionable things in our family thinking I wouldn't understand." He might have made a profession of being polyglot - he studied German and Spanish at State University of New York - were it not for a general biology course he took at the University of Rochester the summer between his sophomore and junior years. A professor of optics filling in for the summer brought the course to life and stirred in him a desire to make science his career. After returning to SUNY, he spent his last two years in chemistry and biology lectures and laboratories. He went to University of California in San Francisco for graduate study because the school's blending of chemistry and biology matched his growing interest in biochemistry and its use in designing drugs. At UCSF, he started a friendship with Ron Woodard, then a fellow graduate student, today a fellow faculty member at the U-M and a strong influence on his decision to work at Michigan. His thesis project - and current research - deals with mechanistic enzymology, the process of understanding the chemical behavior of an enzyme, then designing a drug to harness that chemistry and inhibit the action of an organism or tumor cell. Of sharks and cosmopolitans From San Francisco Dr. Marletta went to Boston for a postdoctoral fellowship in enzymology at the Massachusetts Institute of Technology. "College was important because I was on my own for the first time and graduate school was an intellectual influence," he says. "But MIT taught me about survival. When you're a small fish in a large aquarium that has a fair number of sharks, you find the sharks are not at all interested in eating small fish. They'll attack each other, though, and watching them you learn from that appetite. It teaches you something about an aspect of science not everyone appreciates. He found himself in the midst of "empire builders, who build very large labs that insulate them from other groups, and those I call the cosmopolitan professors, who are always traveling. They very often were not around or they were dealing with a group of 20 or 25 people and had little time for anything else. There's definitely a downside to what you might call big science. "But I also learned there are mistakes to be made and how not to make them. You can be very successful just by being an excellent scientist, but people are people and that's always a factor. Of two equally bright individuals, why does one succeed better than the other? It's usually because one knows how to deal with people in a nice way - or how to outfox them. And how do these big science luminaries, who made their name working in a very important area filled with competitors, stay on top? They have very good people working with them, of course, but they also have a certain way of approaching a problem. They take it apart science-wise and ask, what's the best way to stay on top, what experiments can we do better than anyone else? They focus on what they do best." Perhaps the greatest value of his two years in Boston was that he was encouraged to pursue his penchant for risk-taking. "I was challenged intellectually by some very tough people to tackle a whole new problem, even though it was risky. It could be a long time before I'd find anything. I could wander for quite a while and the tenure clock is short." The chase After a bit of wandering, during which he joined the faculty at Michigan, he stumbled onto a discovery which has excited a great number of scientists in different areas and started a competition every bit as fierce as a football game played by four teams at the same time. It all started in his laboratories with a study of the biochemistry of a certain macrophage cell with an enormous appetite for parasites, viruses, tumor cells, and more. Determined to find out what makes it go from a resting state to an active one, ready to devour its favorite prey, he and his students had characterized the pathway and knew what it started from and what the end products were. "Right about that time," he says, "a paper appeared by Salvador Moncada, director of research at the Wellcome Labs in Britain, saying that one of the substances that cause blood vessels to relax is nitric oxide. "It was unimportant to me," he continues, "except that it was a very strange metabolite in mammalian systems, as were the metabolites we were looking at, especially the end products. I recognized they had to be derived from nitric oxide. So we looked. It was clear as day. Sure enough, nitric oxide was the intermediate in the pathway whose beginning and end we'd already characterized. Meanwhile, Dr. Moncada was aware of our work. He looked at the literature and realized it must be coming from arginine. It must be an intermediate in the pathway we characterized. He looked to see if it came from arginine and it did." When Dr. Marletta discovered in early 1988 that each scientist had the missing piece from the other's jigsaw puzzle, he raced to publish his findings before year's end, hoping with the help of the alphabet to go down in history as the first credited with the breakthrough. His paper, which appeared in the November 1988 Biochemistry, is included in the Hot Papers section of the March 5, 1990 issue of The Scientist newspaper as a paper being cited much more than others of its type. Now he says there's a lot to be shared. "Moncada's paper was the key for me and mine the key for him. We're both indebted to each other and the rest of the field is bound to recognize that." Since their first meeting at an international nitric oxide symposium the British researcher organized in London last year, the two have kept in regular contact with each other. They've even discussed co-chairing a second symposium next year in Ann Arbor. An accidental celebrity Meanwhile, interest in the pathway continues to build. "It's emerging as a general cell communication pathway in controlling some very important physiological processes," he says. "It's now been found in a variety of other cells - in the kidney, the central nervous system, and the brain. If we can control this signal at the level of the enzymes producing, it we could create a whole new spectrum of pharmaceutical agents. Everyone's excited. I didn't realize there were so many cardiovascular pharmacologists in the world. People from all over the country and beyond, including in our own backyard, are calling us for results, compounds, and collaborations. We've just begun a collaboration with Peter Ward, head of the pathology department at the Medical School, for instance." His only regret about his sudden celebrity is that he finds himself having to travel more often to update researchers in the fast-moving field. "The science literature has exploded and we're all behind in our reading," he explains. "So I feel compelled when asked to give a talk to go and give it. If I tell people part of the story in a seminar they're apt to read more and know what we're up to. In a highly competitive environment that's important. Even so, there are plenty of reasons not to go. When I say no it's simply because I'm hopping around too much and not staying close enough to my lab." His dread of airports and air travel is yet an easier excuse. "I assume I'm going to be abused, get hassled, and arrive late when I travel, so I insulate myself. I bring plenty of work to do on the plane and I rarely engage in conversation. If I'm asked what I do, I say I'm a chemist. If they persist and ask what I work on, I say the immune system. After that my facial expression and tone of voice drive them off." He says that after seeing the movie The Accidental Tourist, about a travel writer who hates to travel, he bought the book and read it - on an airplane. His loaded schedule has also forced him to restrict to weekends the amount of time he spends in his other lab, the kitchen. He credits his love of cooking to lessons from his mother. "She was afraid no one would ever live with me," he says, laughing. "When you're fighting through new experiments in the lab, there's a certain amount of not knowing what you're doing, of risking failure. It's no different in the kitchen, but at least you can taste your results right away." This article first appeared in the Spring 1990 issue of INTERACTIONS, published by the University of Michigan College of Pharmacy. |
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