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Written by Eric McHenry   
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Buck was always an enthusiastic student. “I loved going to school at the UW,” she says. “I loved my courses.” But by the time she completed the requirements for her degree in psychology, she had decided it wasn’t the field for her. So she delayed graduation and took some time off. When she returned to the University, she discovered immunology—the subject from which she “never looked back.” After graduating in 1975 with degrees in both psychology and microbiology, she made her way to the doctoral program at UT, which was emerging as a hub of immunology research. It was there, Buck says, under the exacting gaze of Vitetta, that she really came into her own as a scientist.

The next step was postdoctoral work at Columbia, where her interest in studying biological systems at the molecular level eventually led her to the lab of Richard Axel. For a while she assisted in his research on the nervous system of a sea snail. But in 1985 she read a paper that got her thinking, for the first time, about what a sophisticated piece of equipment the nose is. This, she realized, was the “monumental puzzle” she’d been looking for. “How could humans and other mammals detect 10,000 or more odorous chemicals, and how could nearly identical chemicals generate different odor perceptions?” Buck wrote in an autobiographical essay for the Nobel Web site. “In my mind, this was … an unparalleled diversity problem.”

Linda Buck
Linda Buck. Photo courtesy of the Fred Hutchinson Cancer Research Center.
For years, scientists had posited the existence of odorant receptors—proteins that pick up smell molecules and excite the olfactory neurons in the back of the nose. But everyone who had tried to find them had hit a brick wall. Within the field, the cause had come to seem so hopeless that when Buck was ready to leave Columbia, she found she had nowhere to go. “I actually applied for a job, saying that I was going to try to find these odorant receptors,” she says. “I didn’t even get an interview.”

So she stayed in Axel’s lab, knowing she would have support and a certain amount of freedom. Axel, she writes, “was an unusual mentor in that he gave people … extensive independence in charting their own course once they had established themselves.”

Because the odorant receptors had eluded everyone who’d gone looking for them, Buck and Axel decided to try a different tack—looking, instead, for the genes that encode them. At first they found nothing. But then Buck came up with what Axel has called “an extremely clever twist.” She radically narrowed the field of possible genes by making three educated assumptions about them: that they’re a multigene family; that they’re expressed only in the olfactory epithelium; and that the proteins they encode resemble rhodopsin (the receptor protein in the eye). “Had we employed only one of these criteria, we would have had to sort through thousands more genes,” Axel told a reporter. “This saved us years of drudgery.”

Still, the breakthrough didn’t come overnight. Buck estimates she worked 15 hours a day for two and a half years on the project. Makous remembers visiting her in New York at the time. “I came in at around dinnertime,” he says, “but she had to work in the lab until around 10 o’clock or so before we could go out to eat.”

When the results finally began rolling in, Buck’s first feeling was neither pride nor relief, but awe. “Looking at the first sequences of odorant receptors …” she writes, “I was moved by Nature’s marvelous invention.” Buck always capitalizes ‘Nature’ in her writing—a reverence that’s audible when she speaks, too. “Nature is quite elegant in its design,” she says. “It’s a wonderful puzzle.”

After the first findings were published, Buck no longer had trouble getting job interviews. She moved on to a professorship at Harvard, pursuing research that built on the odorant receptor work. By answering an old question, she and Axel had put all sorts of new ones in play. They had shown, for example, that the family of odorant receptor proteins was indeed large—about 1,000 in all. But that’s nothing compared to the number of odors out there. Why is it that we mammals can sense so many smells using so few smell sensors? For the same reason we can form close to a million English words using only 26 letters, Buck has proven—we use them in combination. The Nobel committee recognized Buck and Axel not only for their breakthrough, but for a decade’s worth of subsequent discoveries.

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