Large as the number of receptors may be, it is probably smaller than the number of odors we can recognize.

"Most likely, the number of odorants far exceeds the number of receptor proteins—by a ratio of at least 10 to 1," Axel says. "In that case, how does the brain know what the nose is smelling?"

The visual system needs only three kinds of receptors to distinguish among all the colors that we can perceive, he points out. These receptors all respond to the same thing—light. Light of different wavelengths makes the three kinds of receptors react with different intensity, and then the brain compares these receptors' signals to determine color. But the olfactory system must use a different strategy in dealing with the wide variety of molecules that produce odors.

To figure out this strategy, Axel began by asking how many kinds of receptor proteins are made in a single olfactory neuron. "If a single neuron expresses only a small number of receptors, or a single receptor, then the problem of determining which receptors have been activated reduces to determining which neurons have been activated," he says.

He thought he would make more rapid progress by working with simpler organisms than rats. So he turned to fish, which respond to fewer odorants and were likely to have fewer receptors.

From studies with catfish, whose odorant receptors proved very similar to those of rats, Axel and his associates soon concluded that a given olfactory neuron can make only one or a few odorant receptors. (Buck and her colleagues have come to the same conclusion from their work with mice.)

The next step was to find out how these odorant receptors—and the neurons that make them—are distributed in the nose. Also, what parts of the brain do these neurons connect with?

"We wanted to learn the nature of the olfactory code," Axel says. "Do neurons that respond to jasmine relay to a different station in the brain than those responding to basil?" If so, he suggested, the brain might rely on the position of activated neurons to define the quality of odors.

Each olfactory neuron in the nose has a long fiber, or axon, that pokes through a tiny opening in the bone above it, the cribriform plate, to make a connection, or synapse, with other neurons. This synapse actually forms in the olfactory bulb , which is a part of the brain. A round, knob-like structure, the olfactory bulb is quite large in animals with an acute sense of smell but decreases in relative size as this ability wanes.

Thus, bloodhounds, which can follow the scent of a person's tracks for long distances over varied terrain, have larger olfactory bulbs than humans do, even though humans are more than twice the total size of these dogs.

In the olfactory epithelium of the nose, Axel and Buck's groups found, neurons that make a given odorant receptor do not cluster together; instead, these neurons are distributed randomly within certain broad regions of the epithelium, called expression zones, which are symmetrical on the two sides of the animals' nasal cavities.

Once the axons get to the olfactory bulb, however, they reassort themselves so that all those expressing the same receptor converge on the same place in the olfactory bulb. The result is a highly organized spatial map of information derived from different receptors.

"The brain is essentially saying something like, 'I'm seeing activity in positions 1, 15, and 54 of the olfactory bulb, which correspond to odorant receptors 1, 15, and 54, so that must be jasmine," Axel suggests. Most odors consist of mixtures of odorant molecules. Therefore, other odors would be identified by different combinations.

Surprisingly, the spatial map is identical in the olfactory bulbs of all the mice that have been tested, Buck says. As she points out, this information provided the key to an ancient riddle.

— Maya Pines

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Separate zones of the olfactory epithelium of mice are shown in red, blue, and yellow.

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