How the Nose Knows


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a generalist model for smell

Whether sniffing flowers, freshly baked bread, or the fumes of a passing automobile, the human olfactory system is an amazing scent-sleuth, capable of distinguishing between millions of different smells. Now Weizmann Institute scientists have revealed one of the secrets behind this impressive ability.
To produce a response in the olfactory system, the molecules of a particular substance must penetrate the nose. There they encounter olfactory receptors -- specialized proteins protruding from the surface of nerve cells in the inner lining of the nose. When an odor molecule lands on a receptor, the nerve cell dispatches an electrical signal to the brain, which processes this information and identifies the smell.
Theoretically, one could imagine that for every odor molecule there might be a different receptor, determined by specific genes. However, even if there were only, say, 10,000 discernible smells, this would mean that fully one-tenth of humankind's hereditary code (comprising some 100,000 genes) would have to be dedicated to smell receptors -- obviously impossible. If, on the other hand, unique receptors do not exist for each individual smell, how does the olfactory system make sense of such a vast variety of odors?
Several years ago Prof. Doron Lancet of the Weizmann Institute's Molecular Genetics Department proposed that olfactory receptors are "generalists"; they have the capacity to bind with several odor molecules. Conversely, each odor molecule can bind with a range of potential receptors. The intensity of the binding varies, depending on the quality of the fit. Thus a given odor molecule might bind to receptor A with great intensity, but to receptor B with only mild intensity, and so forth. The pattern of different bonds creates a unique "fingerprint" that the brain can understand as a particular smell. The signaling mechanism used by different receptors is the same; it is the brain that tells the signals apart by knowing which nerve cell it is coming from.
This model grew out of Lancet's hunch that the olfactory system might function in a way similar to the immune system, which also needs to recognize a vast array of molecules. To that end, the immune system produces a large set of antibodies capable of trapping a wide variety of invaders.
Now, Lancet and doctoral student Yitzhak Pilpel have provided new evidence on how the "generalist" model works at the structural level. They have also shown that the similarity between olfactory receptors and antibodies may go a lot further than Lancet originally proposed.
By analyzing the DNA sequences of 200 olfactory receptors -- out of the estimated total of 500-1,000 in the olfactory system -- the scientists were able to model the receptors' 3-D structure. The results indicate that all olfactory receptors -- made up of some 300 amino acids -- have a similar structure: they contain large, framework-like regions that are shared by all members of the enormous family of recognition devices. In these regions there is a small, well-defined section made up of about 20 amino acids, which vary greatly from one receptor to another. That is precisely the site where an odor molecule can fit like a key into a keyhole.
These results reveal the secret of smell in all its simplicity and elegance: the "keyhole" region can easily be altered to accommodate a vast array of new odors while the "framework" of the receptor remains largely unchanged. This structural picture is very similar to what has long been known about antibody molecules: they contain a small, highly variable region geared to recognize a multitude of foreign invaders. Pilpel and Lancet believe that in the receptors for odor molecules they have uncovered the long-sought equivalent of the antibodies' "hyper-variable" region.
Other than providing us with information about one of the five senses, the Institute model of olfactory receptors, if supported by further studies, may prove useful for the development of new fragrances and flavors, and perhaps also in the design of artificial smell sensors.