SCIENTISTS HAVE SPENT MILLENNIA dismembering, dissecting, and diagramming
the human body. After all that poking around, to discover an anatomical
structure big enough to be seen with the naked eye would be a surprise,
particularly if it requires no surgery to expose. And given the human
preoccupation with all things carnal, it would be downright shocking
to find that the new structure is an overlooked piece of sexual equipment.
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
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 system땇n
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
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
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
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.)
But why should humans possess chemical signals to make members of the opposite
sex feel better? The short answer is that nobody knows. After all, conclusive
data have yet to be published in peer reviewed journals to show that the
compounds Berliner and his colleagues are studying affect human behavior in
any way. Nonetheless, it is interesting to speculate.