"We think that we smell with our noses, [but] this is a little like saying that we hear with our ear lobes," writes Gordon Shepherd, professor of neuroscience at Yale University.

"In fact, the part of the nose we can see from the outside serves only to take in and channel the air containing odorous molecules." The neurons that sense these molecules lie deep within the nasal cavity, in a patch of cells called the olfactory epithelium.

Perched behind a sort of hairpin turn at the very top of the nasal cavity, the olfactory epithelium is only a few centimeters square. It contains some 5 million olfactory neurons, plus their supporting cells and stem cells. Actually, there are two such patches—one on each side of the nose—lying in a horizontal line just below the level of the eye.

Each olfactory neuron in the epithelium is topped by at least 10 hair-like cilia that protrude into a thin bath of mucus at the cell surface. Somewhere on these cilia, scientists were convinced, there must be receptor proteins that recognize and bind odorant molecules, thereby stimulating the cell to send signals to the brain.

The receptor proteins would be the key to answering two basic questions about olfaction, explains Richard Axel, an HHMI investigator at Columbia University. First, how does the system respond to the thousands of molecules of different shapes and sizes that we call odorants—"does it use a restricted number of promiscuous receptors, or a large number of relatively specific receptors?" And second, how does the brain make use of these responses to discriminate between odors?

The string of discoveries that totally changed the study of olfaction resulted from a new emphasis on genetics. Instead of hunting for the receptor proteins directly, Richard Axel and Linda Buck, who was then a postdoctoral fellow in Axel's group and is now an HHMI investigator at Harvard Medical School, looked for genes that contained instructions for proteins found only in the olfactory epithelium.

Their efforts produced nothing at first. "Now we know why our initial schemes failed," says Axel. "It's because there are a large number of odorant receptors, and each was expressed only at a very low level."

Finally, Buck came up with what Axel calls "an extremely clever twist." She made three assumptions that drastically narrowed the field, allowing her to zero in on a group of genes that appear to code for the odorant receptor proteins.

Her first assumption—based on bits of evidence from various labs—was that the odorant receptors look a lot like rhodopsin, the receptor protein in rod cells of the eye. Rhodopsin and at least 40 other receptor proteins criss-cross the cell surface seven times, which gives them a characteristic, snake-like shape. They also function in similar ways, by interacting with G proteins to transmit signals to the cell's interior. Since many receptors of this type share certain DNA sequences, Buck designed probes that would recognize these sequences in a pool of rat DNA.

Next, she assumed that the odorant receptors are members of a large family of related proteins. So she looked for groups of genes that had certain similarities. Third, the genes had to be expressed only in a rat's olfactory epithelium.

"Had we employed only one of these criteria, we would have had to sort through thousands more genes," says Axel. "This saved several years of drudgery."

Buck recalls that "I had tried so many things and had been working so hard for years, with nothing to show for it. So when I finally found the genes in 1991, I couldn't believe it! None of them had ever been seen before. They were all different but all related to each other. That was very satisfying."

The discovery made it possible to study the sense of smell with the techniques of modern molecular and cell biology and to explore how the brain discriminates among odors.

It also allowed researchers to "pull out" the genes for similar receptor proteins in other species by searching through libraries of DNA from these species. Odorant receptors of humans, mice, catfish, dogs, and salamanders have been identified in this way.

The team's most surprising finding was that there are so many olfactory receptors. The 100 different genes the researchers identified first were just the tip of the iceberg. It now appears that there are between 500 and 1,000 separate receptor proteins on rat and mouse—and probably human—olfactory neurons.

"That's really a lot of genes," Axel says. "It's 1 percent of the genome! This means that, at least in the rat, 1 out of every 100 genes is likely to be engaged in the detection of odors." This staggering number of genes reflects the crucial importance of smell to animals.

— Maya Pines

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Linda Buck (right) sniffs an odorant used to study the sense of smell. She and Richard Axel (left) discovered what appears to be the long-sought odorant receptor proteins.

Photo: Kay Chernush

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