Because of research by HHMI investigators Charles Zuker, University of California, San Diego, Linda Buck, Fred Hutchinson Cancer Center, and colleagues, we know a lot more about taste-sensing cells than we did a decade ago.

How an organism recognizes a "vast universe" of odors is indeed "a fascinating problem in molecular recognition and perceptual discrimination," agrees Richard Axel, an HHMI investigator at New York's Columbia University.

Put simply, how do we know what we're smelling? Scientists are exploring this question in everything from worms to fruit flies to mice to humans, bringing a variety of new molecular tools and computational methods to bear.

Only in the last decade and a half, scientists, including Axel and HHMI investigator Linda Buck at Seattle's Fred Hutchinson Cancer Research Center, have begun breaking the code the olfactory system uses to define different incoming odor molecules—the first step in recognizing them.

They have revealed how the coded information for a smell is represented or "mapped" in certain parts of the brain. Now the scientists are in hot pursuit of the next steps. "How does the brain transform that map into meaningful neural information so that odors will elicit appropriate cognitive responses and behaviors?" Axel says. "This is the central problem facing my laboratory."

The nasal cavity and the tongue are laced with cells that detect chemical compounds—millions of neurons in the nose and specialized taste bud cells on the tongue. These cells are wired to relay stations and processing centers in the brain, which are thought to create sensory "images" of the perceived odors or flavors.

In parallel with the main olfactory system used for odor sensing, evolution has also spawned a separate, "accessory olfactory system" in some animals for detecting "pheromones"—chemical signals used by individuals of the same species to mark territory, warn of danger, identify close relations, and induce mating.

The lack of accessory olfactory structures in humans has suggested a corresponding lack of human pheromones. But interesting new discoveries are rewriting the textbook, demonstrating that in some mammals, at least, pheromones can be detected by the odor-sensing olfactory system as well.

A smell begins when volatile odor molecules (odorants) dissolve in nasal mucus and bind with receptors in the olfactory epithelium—specialized tissue located in the upper-rear nasal cavity. (The convoluted olfactory epithelium in humans, if flattened out, would be the size of a cookie, while the equivalent area in a bloodhound, for example, would be the size of a small pizza.) The odorant receptors are located on olfactory sensory neurons, which transmit signals through their axons to the olfactory bulb, a relay station in the front of the brain. Olfactory bulb neurons, in turn, transmit signals to the olfactory part of the cortex, which distributes olfactory information to yet other brain areas.

Mammals can detect at least 10,000 different odors. How the mammalian olfactory system can distinguish so many odorant chemicals was a longstanding mystery until 1991, when Axel and Buck, then his postdoctoral associate, made a discovery that opened a new chapter in olfactory research. They identified a gene family that encodes about 1,000 different types of olfactory receptors in the mouse, and a smaller number, about 350, in humans, and then independently went on to explore how olfactory information is organized and encoded in the nervous system. In 2004, Axel and Buck were awarded the Nobel Prize in Physiology or Medicine for "their discoveries of odorant receptors and the organization of the olfactory system."

Photos: Zuker, Jeffrey Lamont Brown; Buck, Dan Lamont

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