Evidence for the chemical olfactory code in man.

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The sense of smell involves the interaction of a biological detector, the nose, with a chemical stimulus, the odor. Hence the most logical methods to attack the problem would appear to be those of biochemistry. Although the human nose may not be the most sensitive or the most discriminating, it probably ranks first in economic importance. Yet, by the aame token it is also the most inaccessible to direct experimentation by the usual neurophysiological or biochemical techniques. Nevertheless, a classical biochemical principle is showing considerable promise in unraveling the odor problem. Most of the chemical steps in pathways of intermediary metabolism were worked out by taking advantage of mutations. A strain of microorganisms so afflicted has lost the genetic capacity to produce a certain enzyme, so the normal substrate of this enzyme accumulates, reaching a level at which it can be chemically identified. Admittedly, most such mutations are artificially induced by x ray or UV radiation, but some occur naturally, and man himself is not immune to this phenomenon. Occasionally such inborn errors of metabohm1 are actually diagnosed by the physician’s sense of smell, as in the recently described isovaleric acidemia, in which the enzyme isovaleryl coenzyme A dehydrogenase is defective, and the unfortunate young patient reeks of stale cheese? Paradoxically, about one physician in fifty would probably not at first believe that anything was wrong with the child, because the doctor himself happens to have a mutated nose that cannot perceive isovaleric acid or related short-chain fatty acids. Here is our chance to disentangle the olfactory problem. This biochemical defect of odor blindness or spCcific anosmia is relatively common and occurs in many varieties. As a working hypothesis, I assume that the olfactory epithelium of an affected person lacks the specific receptor protein for detecting one whole family of odorants that belong to one of the primary odors. Although not couched in biochemical terms, this concept was first clearly enunciated by the physicist Marcel Guillot a quarter of a century ago8 in his paper e n titled “Anosmies Partielles et Odeurs Fondamentales.” For the past eight years I have been elaborating the techniques to exploit this phenomenon, and I have been enabled to map out quite thoroughly the domains of two such “odeurs fondamen tales.”