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How the nose knows

For decades, scientists have been trying to learn how the sense of smell works. Now, they're getting close.

Smelling seems so simple -- you get a whiff of a rose or a brownie and you smile. Sniff garbage and you turn your head away in disgust.

But for almost two decades, scientists have been trying to unravel the mystery of how the brain translates odor chemicals inhaled in the nose into these perceptions and actions. Why would the flower remind you of your last date? The brownie, your grandmother? Why do some smells make your heart race with fear?

Two years ago, Linda Buck and an early colleague, Richard Axel, shared the Nobel Prize for their work chipping away at these questions. This spring, Buck published a study in Science showing how the brain, once it receives a coded message for a particular smell, begins to ''decode" that message.

The work is basic science, but the implications are significant. Researchers, including one at Tufts University, are using this deeper understanding of smell to develop better artificial noses -- good for detecting explosives, or pollutants, or finding people alive in the wreckage of a building. Cancer patients on chemotherapy and people with appetite problems may someday be helped by medications that restore smell.

And, because the sense of smell often degrades with age -- roughly half of people over 65 suffer significant loss of smell -- the work could be particularly relevant to aging baby boomers.

''Smell is important in our enjoyment of food and drink," said Buck, now at the Fred Hutchinson Cancer Research Center in Seattle. ''People who lose their sense of smell really feel that they've lost something important."

When Buck first started researching smell in the late 1980s, researchers knew that the tiny cells in the nose sent electrical signals to neurons in the brain. But no one understood how the cells detected an odor or what happened in the brain after that odor was detected.

Working in Axel's lab at Columbia University, she set out to discover the first step in the smell pathway: the genes that create the odor receptors on those tiny cells in the nose.

''I was fairly obsessed with this problem," Buck said recently. ''There was really nothing else I wanted to do at that time than find these receptors."

After two years of searching, she found them. In 1991, she and Axel published a pivotal paper on a new family of genes that codes for olfactory receptors in mice -- the basis for the whole system of smell in mammals.

Human sight requires just three kinds of receptors to distinguish colors; taste buds interpret just five different flavors -- sweet, salty, savory, sour and bitter. Buck, by then working at Harvard Medical School, figured out that mice have about 1,000 different olfactory receptors, each designed to match and latch on to a different component on the surface of an odor molecule -- like a lock fitting a key. Humans, who rely much less on their sense of smell than rodents, have only about 350 receptors.

Each olfactory neuron in the nose has only one type of those receptors and sends a signal to the brain when the receptor binds to an odor molecule. But it takes a ''code" of two or more receptor types to spell out a particular odor, so the combination of receptors needed to code for rose is different from the combination that codes for brownie, or rotting garbage.

''It's like letters of the alphabet can be used in many different combinations to make a multitude of different words -- in the same way, these receptors are used in different combinations to indicate different odorants," Buck said.

These findings turned olfaction research on its ear.

''Linda Buck's work completely revolutionized the field," said Boston University neuroscientist and olfaction researcher Matt Wachowiak. ''So much of what we work on now builds on her and Richard Axel's research."

Wachowiak and his colleagues are now studying what happens at the other end of the olfactory neurons, in a region of the brain called the olfactory bulb. They inject a fluorescent dye into mice that lights up when a neuron is firing, allowing the scientists to see under a microscope which neurons are active when a mouse sniffs a particular odor. They have found that the strength, duration, and timing of a neuron's signal varies depending on the odor's strength, changes that Wachowiak believes may be as important as the code Buck and others have investigated. (Most olfaction research has been conducted in mice and rats, not people, but researchers believe human smell is probably quite similar.)

Another Boston researcher, John Kauer at Tufts University, along with his collaborators, has engineered an electronic nose that uses many of these recent olfactory discoveries. It is about half the size of a shoe box and can detect explosives, molds, and other odors in the environment.

''The patterns of unknown odors can be compared to known odors, which is probably similar to how our brains work," Kauer said.

Other research has shown that age-related smell loss may happen when the neurons in the nose -- the only neurons that come in direct contact with the environment -- are damaged or die, either from a lifetime of upper respiratory infections, rhinosinusitis, or even zinc-based nasal sprays like Zicam that treat the common cold. Aging may also alter the distribution and density of the receptors and other characteristics of the olfactory neurons.

Buck has now moved on to the next key step in the olfaction process: How to read the ''words" encoded in the alphabet soup of receptors.

In her recent Science study, Buck and former fellow Zhihua Zou, now a neuroscientist at the University of Texas Medical Branch in Galveston, reported that there are neurons in a part of the brain called the olfactory cortex that seem to read the receptors' code -- they fire only when stimulated by two or more neurons that connect all the way back to the original odor receptors in the nose. In essence, the odor's ''word" that was deconstructed into letters in the nose is now recombined back into a word.

These neurons are linked to various parts of the brain, and Zou and Buck are still trying to figure what that means: Does the fact that they link to the amygdala, the center of emotion, explain why certain smells evoke warm memories of grandma or suffuse us with fear? Does the link to the hypothalamus, where hormones and hunger are controlled, explain why sexual attraction and appetite are connected to smell? What does it mean that parts of the frontal cortex, normally associated with thought, are activated?

''We really don't know much about this yet," Buck said. ''There are higher cortical areas involved in perception, there are deep areas of the brain involved in emotion. How is it that certain odorants elicit emotional responses and instinctive behavior? It's still a mystery."

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