Well, prepare for a shock. Most vertebrate species, including many mammals, have a small chemosensory structure in the nose called the vomeronasal organ (VNO) dedicated to detecting chemical signals that mediate sexual and territorial behaviors. Modern human anatomy texts state flatly that the human VNO almost always disappears during embryonic development. But they're wrong! Researchers who have looked carefully find that the noses of most adults have a structure that appears to be a VNO. It has the right shape, and it is in the right place - two small sacks about 2 mm deep that open into shallow pits on either side of the nasal septum. Reports challenging the dogma that humans lack a VNO were published in the mid-1980s, but have only slowly begun to be accepted.

The existence of a human vomeronasal structure is hard to refute. Anyone with sharp eyes, a box of Kleenex. a flashlight, and a speculum can find it easily enough. Rochelle Small, a program administrator in the Division of Communication Sciences and Disorders Is of the National Institute on Deafness and other Communication Disorders (NIDCD) in Bethesda, Md., says that just realizing most adults have a VNO is intriguing.

Since the 1930s, people have always said that the VNO is not present in adults, so we have taken a big step just to show the structure is there," says Small. However, it is not yet clear whether the human VNO actually connects to the brain, or if chemicals binding to the epithelial cells that line the organ actually exert any behavioral or physiological effects, says Small. "The question now is what, if anything, its function might be."

On this question, the jury is definitely still out. There are very few published reports about the human vomeronasal system. The Pherin Corporation in Menlo Park, Calif., a new company formed to exploit the human VNO as a route for drug delivery, is hard at work probing the structure's capabilities, using compounds that it says specifically affect the VNO. But Pherin is keeping the results of its research close to its corporate vest, as is a perfume company that is marketing fragrances it says contain compounds that the human VNO can detect. But if other mammals are a guide, the human VNO may have a funky function indeed: It may be a sensor for non-odoriferous chemical signals that pass between men and women to subtly influence sexual behavior.

The existence of what would amount to human pheromones chemical compounds released by one individual that cause specific behavioral or physiological effects in other members of the same species would not mean that humans will henceforth have to worry about devastating chemical weapons in the war between the sexes. On the contrary, the effects of chemical cues in mammals depend strongly on other visual, auditory, or tactile stimuli received at the same time. Furthermore, mammals are behaviorally more complex than other animals. Human sexual behavior depends on everything from hormonal state to childhood memories and moral philosophy. A chemical cue is unlikely to override a lifetime of socialization.

Sarah Newman, a neuroanatomist at the University of Michigan at Ann Arbor, has devoted 20 years of research to the vomeronasal system. Although the precise anatomy of the VNO varies considerably from one vertebrate species to the next, Newman says it generally is a pair of small sacs lined with sensory neurons, tucked inside the vomer bone, where the hard palate and nasal septum meet behind the nostrils. The VNO is separate from the primary olfactory epithelium, and in animals such as mice and rats, it is connected to the brain through an independent neural pathway.

The olfactory epithelium sends axons to the main olfactory bulb, which in turn connects to the olfactory cortex and the amygdala, which are parts of the limbic system‹an evolutionarily old part of the brain that regulates survival behaviors such as feeding, fleeing, fighting, and reproducing. In non human mammals, VNO neurons connect first to a histologically distinct structure called the accessory olfactory bulb, and from there project to a separate part of the amygdala, and extend on to the preoptic area of the hypothalamus and other limbic structures.

As for VNO function, in animals as diverse as garter snakes and golden hamster, the structure clearly receives chemical signals that pass between individuals to affect reproductive behavior. "In many species, disrupting the vomeronasal system causes clear behavioral deficits," says Newman. For example, Michael Meredith of the Florida State University in Tallahassee reported in 1986 that removing the VNO from sexually naive male hamsters seriously impairs their sexual behavior. Newman has also conducted studies in hamsters in which she has demonstrated that lesions in the limbic structures that receive input from the VNO change or eliminate sexual behavior.

But if the VNO is this interesting, how did anatomists manage to omit the structure from the human inventory? The VNO wasn't completely overlooked; it was forgotten. Called Jacobson's Organ, it was described in humans as long ago as the 18th century. Charles Wysocki of the Monell Chemical Senses Center in Philadelphia says that a few prominent neuroanatomists in the 1930s, including the late Elizabeth Crosby and Tryphena Humphrey, concluded that the organ was absent from adults, largely because humans lack a distinct accessory olfactory bulb. "It's a lot like the fable of the emperor's new clothes," says Wysocki. "Once Crosby concluded that humans didn't have a vomeronasal organ, no one challenged her view."

But the anatomical neglect may have deeper roots. Newman suggests that a reluctance to face up to the human VNO stems in part from a bias against olfactory function. "As humans, we tend to downplay the importance of our sense of smell even though walking through a drugstore and counting the products that are perfumed or deodorized should be enough to convince anybody that olfaction is important to us," says Newman.

Other psychological forces could also be at work, suggests David Moran, a cell biologist at the Smell and Taste Center of the University of Pennsylvania in Philadelphia who is studying the human VNO. "People are scared to death of unconscious forces, especially unconscious forces that have anything to do with the opposite sex," says Moran "We like to think we are in control.'' Moran also notes that because losing the sense of smell is not nearly as debilitating as blindness or deafness, olfaction research in general has attracted less funding.

In the mid-1980s, two groups of researchers independently took a fresh look at the accepted dogma denying the existence of the VNO in humans. Robert Josephson and his colleagues at the University of Toronto in Canada reported in the Journal of Otolaryngology that vomeronasal pits were present in about 40 percent of the adults they examined. Moran and Bruce Jafek, an otolaryngologist at the University of Colorado at Denver, found the pits in virtually all of the people they examined. Electron micrographs of tissue behind the pits showed that the epithelium lining the VNO sacks differs from the adjacent respiratory epithelium, and is unlike any other in the body. says Moran. "It is generally similar to the epithelium that lines the rat VNO," he says, although the match is not perfect. "We see a cell type, which we call 'light cells,' in human tissue that we don't see in the rat, but we don't find neurons [in the human VNO] that look like the putative sensory cells in the rat VNO," he says.

Moran says that his findings attracted little attention until David Berliner, a researcher turned biotechnology entrepreneur in Menlo Park, Calif., organized two companies to capitalize on possible human VNO functions. Berliner says he first became interested in human chemical communication in the 1970s, while he was a professor of anatomy at the University of Utah in Salt Lake City. In the course of research on the chemical components of skin, he says, he noticed that, when left open to the air, some extracts of skin cells seemed to put people in the lab in a good mood.

Berliner says he put these observations on the back burner until the late 1980s. Since then, he has formed two companies to exploit possible applications of compounds that bind to the VNO and exert effects in the brain. Berliner helped to found the Erox Corp., a perfume company now headquartered in Fremont, Calif. for which he is currently a scientific consultant. He is also president of Pherin Corp. in Menlo Park, Calif., which is searching for compounds that might act through the VNO to exert pharmacologically important neurological effects. Citing pending patent applications and competitive pressures, Berliner declined in an interview to discuss what these compounds and pharmaceutical applications are.

When Berliner began searching for the mechanism by which his compounds made his lab workers cheerful he quickly zeroed in on the VNO. "I didn't understand why the products that had these effects didn't have any smell and, therefore, didn't go through the olfactory epithelium,'' says Berliner. "But when I looked in old anatomy books, especially the French books, I found out that the human [vomeronasal] organ had been described as early as 17()~." Berliner enlisted the aid of other scientists, including Moran, Larry Stensaas, a neuroanatomist at the University of Utah, Thomas Getchell of the University of Kentucky at Lexington, and Luis Monti-Bloch, a physiologist at the University of Utah.

Stensaas and Moran separately presented data on human VNO ultrastructure at an Erox-sponsored conference on mammalian chemical communication held in Paris in 1991. The Journal of Steroid Chemistry and Molecular Biology published the proceedings of the conference in its October 1991 issue. "Humans don't have anything to apologize for in terms of size of the VNO." says Stensaas. "How the structure is innervated, however, is a critical issue." Stensaas says he is currently searching for neuronal connections between the human VNO and the brain.

In human fetuses, several large nerves extend from the VNO to the accessory olfactory bulb and on to the hypothalamus, similar to the connections in other mammalian embryos says Stensaas. He is currently trying to determine whether similar nerve tracts exist in adults by using cadavers and a lipid-soluble fluorescent dye called DiI, which diffuses from neuronal cell bodies down axons to mark their paths. Stensaas suggests that the human accessory olfactory bulb does not degenerate during development but simply becomes too thin to be visible as a distinct structure. It takes months for the dye to travel, and Stensaas says he has no definitive results yet. However, he says he has found that a substantial nerve is still present in human neonates months after the VNO and its connections were previously thought to disappear.

The most recently published work on the human VNO is from Getchell, Shigeru Takami, and their colleagues in Kentucky. In the April 1993 issue of Neuroreports, the researchers show that the epithelium lining the human VNO contains cells that structurally resemble the olfactory receptor neurons that respond to the binding of odoriferous molecules in the human olfactory epithelium. These bipolar cells bind antibodies against two proteins found in most neurons, neuron-specific enolase and protein gene product 9.5.

The researchers also find a protein on the surface of the human VNO epithelium called vomeromodulin, which occurs in the VNO in other animals. The researchers have so far failed to find evidence that the cells contain olfactory marker protein, which occurs in receptor neurons in the human olfactory epithelium and in receptor neurons in both the olfactory epithelium and VNO of other mammals. These results suggest that the human VNO has at least some of the cellular and molecular components of the vomeronasal organs found in other species.

To probe the function of the human VNO, Monti-Bloch devised a e combination electrode and microspritzer that he used to blow small amounts of the compounds Berliner had isolated from human skin directly into either the VNO or olfactory epithelium of volunteers, while simultaneously recording the surface electrical potential of the tissue. He and Utah colleague Bernard Grasser reported at the 1991 Paris conference that two of the compounds, which Erox supplied to him, induced a large decrease in surface potential in the VNO, similar to that caused by odorant molecules when they bind to the olfactory epithelium. Furthermore, the response varied by gender: One compound elicited a stronger VNO response in men than in women, and another induced a stronger response in women than men.

The results suggest that the VNO can at least respond to specific compounds, a necessary first step in including a physiologic or behavioral effect. Also, the fact that the compounds did not elicit a response from the olfactory epithelium at the concentrations tested indicates they may exert an effect without eliciting a conscious awareness of any odor. In their report, however, the researchers did not divulge the chemical identities of the compounds they tested.

Florida State's Meredith says such functional studies are interesting but are impossible to evaluate or replicate until the researchers reveal more information about their experiment, including the names of the compounds they used. "The science that [Monti-Bloch, Berliner, and their colleagues] have presented so far looks OK, if they did what they said they did, but I think it should be independently verified," says Meredith.

Advertising firms do not need such independent confirmation, however. Erox is currently marketing two perfumes, called Realm Men and Realm Women, that it says contain compounds that elicit an electrophysiological response in the human VNO. A spokesman for Erox declined to identify these compounds. But in March of last year, the company filed a patent application with the European Patent Office for rights to use specific androstenes and estrenes ?steroids related to testosterone and estrogen in perfume products. The patent application states that 1,3,5(10), 16-estratetraene-3-ol uniquely elicits a change in surface potential in the male VNO, and that the female VNO responds to D4,16-androstadien-3-one.

The purpose of adding the "human pheromones" to the Erox perfumes, which also contain conventional perfume fragrances, is not what most people assume, says Berliner. "Everybody is looking for an aphrodisiac," says Berliner. "But I have said it a million times such a thing doesn't exist." In fact, the intended target of the compounds in the Erox products is the person who wears them, not someone he or she may encounter. Berliner says the men's perfume contains a compound produced by women that affects men, and the women's perfume contains a compound produced by men that affects women. The idea, described in a press release from Erox, is that the compounds make the wearer feel more relaxed and self confident, and therefore more attractive. (A male writer for THE JOURNAL OF NIH RESEARCH thought both products smelled very nice, although several applications of Realm Men failed to relieve anxiety brought on by an impending deadline.)