April 08, 1999
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Researchers Sniff Out Secrets of Smell

By William J. Cromie

Gazette Staff

Linda Buck discovered that sensors in the nose are like letters of the alphabet. They can be used over and over in various combinations to encode different odors. (Staff photo Kris Snibbe/Harvard News Office)

It is said that people can identify as many as 10,000 different smells, ranging from blooming azaleas to frying zucchini. Some in the perfume business boast they can distinguish among 5,000 different scents. But when scientists look closely at the nose, that doesn't make sense.

Some years ago, Linda Buck, now an associate professor of neurobiology at Harvard Medical School, discovered that mice have approximately 1,000 different sensors in their noses. No one has counted them, but humans are thought to have about the same number. That leaves science with the mystery of how a human or a mouse can identify 10,000 different smells with 1,000 or fewer sensors.

Working with Bettina Malnic, a postdoctoral fellow at Harvard, and two colleagues in Japan, Buck has finally solved the mystery. Her team also has found new evidence about how the brain organizes information that the nose sends to it.

No matter how big or small your nose, inside the top of it, at about the level of your eyes, lies a small patch of tissue into which are crowded millions of nerve cells. On the surface of each nerve cell lies one type of the 1,000 different sensors, or odorant receptors. Buck and her colleagues discovered that each receptor recognizes multiple odorants, and a single odorant can be recognized by multiple receptors. These odorants are the molecules that humans and other animals perceive as smells, and different smells come from different combinations of receptors, so that 1,000 sensors can identify 10,000 odors.

"Each receptor is used over and over to define different odors, just like letters are used over and over again to spell different words," Buck explains. Such a system greatly reduces the number of sensors (letters) needed to code for smells (words). The way that different and overlapping combinations of letters can spell "red," "read," or "reed," similar combinations of sensors can identify jasmine, gardenia, or lilac.

Odor on the Brain

Buck, also a Howard Hughes Medical Institute investigator, and her team reported their findings in a recent issue of the journal Cell. These findings "explain several things that puzzled people for a long time," Buck notes. "If you alter the structure of an odorant -- even slightly, its smell can undergo profound change." And a shift in concentration can turn a scent from pleasant to disgusting.

Take octanol, for example. An ingredient of petroleum and natural gas, it exudes an orange- and rose-like bouquet. Change one atom in the molecule's structure, and it becomes octanoic acid, which is characterized by a rancid, sweaty smell.

When concentrated, indole, a substance found in both coal tar and perfumes, just plain stinks. When sufficiently diluted, indole gives off a fragrance like jasmine.

Odors waft up the nasal cavity to a patch of nerve cells above the eyes. From there, scent signals go to the olfactory bulb, higher brain areas involved in discrimination (frontal lobe), and primitive areas linked to emotions (limbic system).

"When you alter the concentration or structure of an odorant, you also change its receptor code and, thereby, its smell," Buck says.

Odorants are vaporized from gasoline, baking bread, or perfume, and waft up the nasal cavity, where they contact nerve cells. Each cell extends thin hairs, or cilia, and the odorant receptors sit on those hairs.

When an odorant binds with receptors, the cell sends a signal to the brain, specifically to the olfactory bulb above the eyes. In the nose, cells that use the same receptor lie scattered over the wall of the nasal cavity. Their signals, however, go to only two spots in the olfactory bulb. Signals from different sensors are targeted to different spots and so form a sensory map that is the same in every mouse and, probably, every human.

From this cerebral switching center, nerve fibers carry scent messages to both higher brain areas involved in conscious discrimination and perception of odors, and to more primitive areas that mediate emotions, such as fear, loathing, sex, and pleasure.

Memory of Smell

Sensor cells in the nose don't last a lifetime. After 30 to 60 days, in mice or humans, they die and are replaced by new nerve cells, which develop in the inner lining of the nose. That leaves the question of how a human or animal remembers a smell such as an apple pie baking in the oven, or an apple core rotting in the garbage.

The answer is that new nerve cells send out long extensions that find their way to the same spots in the olfactory bulb where their predecessors connected. Thus, roads on the odor map are constantly renewed so that destinations in the brain remain unchanged.

Although that goes a long way toward explaining how odor information gets encoded in the brain, "we don't yet know how it is decoded," Buck points out. "How, for example, is the quality 'rose' perceived consciously?"

Decoding of fragrant memories can trigger changes of behavior. The smell of rotten food sparks an unconscious avoidance response and, thus, increases an animal's chance of survival. On a higher level, the aroma of a roast cooking in the oven might bring back childhood recollections of a holiday dinner with the family.

Marcel Proust, the French novelist, described a vivid memory brought to his mind by the smell and taste of a small piece of cake (a madeleine) dipped in tea. On Sundays as a child, his aunt used to give him a piece of madeleine dipped in her tea. Many years later, when he did the same thing, "immediately, the old gray house on the street . . . rose up like a stage set," Proust recalled. "The entire town, with its people, and houses, gardens, church, and surroundings taking shape and solidity, sprang into being from my cup of tea."

The Smell of Taste

Proust referred to taste and smell as one entity and, indeed, one would not be much without the odor. Only four different tastes are recognized -- sweet, sour, salt, and bitter. (Asians sometimes add a fifth-- the taste of monosodium glutamate, called "umami" or "delicious" by the Japanese.) It is smell that adds almost endless variety to those meager choices.

"When chewing food or swallowing a drink, vaporized molecules waft from the back of the mouth to the sensory center of the nose," Buck explains. That's why food loses much of its taste when you have a cold.

In addition to the smells we are so aware of every day, humans may have an ability to sense chemical signals from each other without being aware of it. Other animals have this second system which enables them to detect sexual and social information via substances known as pheromones. A whiff of a pheromone from a male rat in its territory may spur another male to a quick attack. Such signals exchanged between males and females incite mating.

Animals detect pheromones via a special organ located in the septum that divides the nose. However, pigs recognize at least one pheromone by using the same sensors in the top of the nose that humans use to smell food. This leads researchers to speculate that humans have the ability to detect pheromones and these chemicals, in turn, influence their behavior.

The best evidence that this happens comes from experiments showing that the menstrual cycles of young women who live together change gradually and involuntarily until they are in synchrony.

"While it's likely that receptors for them exist in humans, no one has ever isolated and identified a human pheromone," Buck points out.


Copyright 1999 President and Fellows of Harvard College