Just what do the VNOs of rodents—or, perhaps, humans—respond to? Probably pheromones, a kind of chemical signal originally studied in insects.

The first pheromone ever identified (in 1956) was a powerful sex attractant for silkworm moths. A team of German researchers worked 20 years to isolate it. After removing certain glands at the tip of the abdomen of 500,000 female moths, they extracted a curious compound. The minutest amount of it made male moths beat their wings madly in a "flutter dance." This clear sign that the males had sensed the attractant enabled the scientists to purify the pheromone. Step by step, they removed extraneous matter and sharply reduced the amount of attractant needed to provoke the flutter dance.

When at last they obtained a chemically pure pheromone, they named it "bombykol" for the silkworm moth, "Bombyx mori" from which it was extracted. It signaled, "come to me!" from great distances. "It has been soberly calculated that if a single female moth were to release all the bombykol in her sac in a single spray, all at once, she could theoretically attract a trillion males in the instant," wrote Lewis Thomas in The Lives of a Cell.

In dealing with mammals, however, scientists faced an entirely different problem. Compared to insects, whose behavior is stereotyped and highly predictable, mammals are independent, ornery, complex creatures. Their behavior varies greatly, and its meaning is not always clear.

What scientists need is "a behavioral assay that is really specific, that leaves no doubt," explains Alan Singer of the Monell Chemical Senses Center. A few years ago, Singer and Foteos Macrides of the Worcester Foundation for Experimental Biology in Massachusetts did find an assay that worked with hamsters—but the experiment would be hard to repeat with larger mammals.

It went as follows: First the researchers anesthetized a male golden hamster and placed it in a cage. Then they let a normal male hamster into the same cage. The normal hamster either ignored the anesthetized stranger or bit its ears and dragged it around the cage.

Next the researchers repeated the procedure with an anesthetized male hamster on which they had rubbed some vaginal secretions from a female hamster. This time the normal male hamster's reaction was quite different: instead of rejecting the anesthetized male, the hamster tried to mate with it.

Eventually Singer isolated the protein that triggered this clear-cut response. "Aphrodisin," as the researchers called it, appears to be a carrier protein for a smaller molecule that is tightly bound to it and may be the real pheromone. The substance seems to work through the VNO, since male hamsters do not respond to it when their VNOs have been removed.

Many other substances have powerful effects on lower mammals, but the pheromones involved have not been precisely identified and it is not clear whether they activate the VNO or the main olfactory system, or both.

Humans are "the hardest of all" mammals to work with, Singer says. Yet some studies suggest that humans may also respond to some chemical signals from other people. In 1971, Martha McClintock, a researcher who is now at the University of Chicago (she was then at Harvard University), noted that college women who lived in the same dormitory and spent a lot of time together gradually developed closer menstrual cycles. Though the women's cycles were randomly scattered when they arrived, after a while their timing became more synchronized.

McClintock is now doing a new study of women's menstrual cycles, based on her findings from an experiment with rats. When she exposed a group of female rats—let's call them the "A" rats—to airborne "chemosignals" taken from various phases of other rats' estrous cycles, she discovered that one set of signals significantly shortened the A rats' cycles, while another set lengthened them. Now she wants to know whether the same is true for humans—whether there are two opposing pheromones that can either delay or advance women's cycles. In this study, she is focusing on the exact time of ovulation rather than on synchrony.

The most direct scientific route to understanding pheromones and the VNO may, once again, be through genetics. Working with sensory neurons from the VNOs of rats, Catherine Dulac and Richard Axel found a new family of genes that "are likely to encode mammalian pheromone receptors," they reported in 1995. Axel and Buck's teams also found a similar family in the VNO's of mice.

Both groups estimate there must be 50 to 100 distinct genes of this kind in VNO neurons. Since then, Buck's team and that of Catherine Dulac, who is now an HHMI investigator at Harvard, have found a second family of likely pheromone receptors in mammalian VNOs; these, too, are expected to include about 100 genes. "Now we have to match up pheromones and receptors," Buck declares.

Once the genes for such receptors are definitively identified, it should be relatively easy to find out whether equivalent genes exist in humans. Scientists could then determine, once and for all, whether such genes are expressed in the human nose. If they are, the receptors may provide a new scientific clue to the compelling mystery of attraction between men and women—some evidence of real, measurable sexual chemistry.

— Maya Pines

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