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How the Nose Knows


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Whether sniffing flowers, fresh-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.
In order to produce a response in the olfactory system, 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 to identify the smell.
Theoretically, one could imagine that for every odor molecule there may be a different receptor, determined by specific genes. However, even if there were, say, only 10,000 discernable smells, this would mean that fully one-tenth of humankind's hereditary code, comprising some 100,000 genes, must be dedicated to smell receptors -- obviously an impossible situation. If, on the other hand, unique receptors do not exist for each individual smell, how does the olfactory system make sense of 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" which 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, an odor molecule might bind to receptor A with great intensity, while binding to receptor B with only a 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, and the brain tells the signals apart by knowing which nerve cells they are 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 huge array of foreign molecules. To that end, the immune system produces a large set of antibodies capable of trapping different invaders.
Now, in a new study reported in the May issue of Protein Science, graduate student Yitzhak Pilpel and Lancet have provided new evidence showing how the "generalist" model works at the structural level. They have also shown that the similarity between olfactory receptors and antibodies may go even 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 this enormous family of recognition devices.
It is only a small and well-defined region containing about 20 amino acids that varies greatly from one receptor to another. That's 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-sized 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 an endless army of foreign invaders. Pilpel and Lancet believe they have uncovered the long-sought equivalent of the antibodies' "hypervariable" region in the receptors for odor molecules. If the Institute model of olfactory receptors is supported by further studies, it may prove useful for the development of new fragrances and flavors, and perhaps also in the design of artificial smell sensors.
Prof. Lancet, incumbent of the Ralph and Lois Silver Chair of Neurogenomics, coordinates the research on olfactory genes within the international Human Genome Project and heads the Weizmann Institute's Crown Human Genome Center. Lancet also heads the National Laboratory for Genome Infrastructure sponsored by the Israel Ministry of Science.

The Weizmann Institute of Science is a major center of scientific research and graduate study located in Rehovot, Israel.

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