The Sniff of Legend

Human pheromones? Chemical sex attractants? And a sixth sense organ in the nose? What are we, animals?

By Karen Wright|Friday, April 01, 1994
It's Monday morning, and once again Brad Murray finds himself in the position of research subject: lying flat on his back on a lab bench, flaring his nostrils for science.

Luis Monti-Bloch bends over the supine graduate student and, murmuring apologetically, sticks a stork-bill-shaped instrument called a nasal speculum into the left chamber of Murray's nose. The subject flinches but hangs tough as Monti-Bloch spreads the bifurcated beak of the speculum, thereby enlarging the aperture of Murray's own beak. The researcher trains the light from his headlamp into the orifice. He peers through his binocular loupes.

"I can see it right . . . there," says Monti-Bloch, pointing with a cotton swab. He adjusts the loupes, his gaze never straying from Murray's mucosa. He sighs. "It's really beautiful."

Monti-Bloch is one of half a dozen distinguished scientists who believe they've discovered a new sense organ half an inch or so inside the human nose. It's called the vomeronasal organ, or VNO, and if the hunches of these researchers are correct, it detects chemical signals passed unconsciously among human beings--signals that might be about identity, arousal, or sexual receptivity and that go by the name of pheromones. Such chemical communication, common among other animals, was heretofore thought to be nonexistent in humans.

Using stalwart volunteers like Murray and equipment he designed himself, Monti-Bloch has been testing the effects of putative human pheromones on cells in the VNO. To do so, he has to locate the organ's opening, a pale, tiny pit near the bottom of the septal wall dividing the nose. Assuming that Murray is bilaterally symmetrical like the rest of us, a matching inlet lies on the other side of the septum, too. It's not the kind of thing you'd notice on casual inspection.

In fact, it's the kind of thing that anatomists have overlooked for centuries. Though the human vomeronasal organ was first described almost 300 years ago, the few investigators who bothered to look for it thereafter had trouble finding it. Consequently, even as pheromones and their corresponding sensory systems gained renown for their role in the social and mating behavior of other animals, researchers concluded that people got by (and down) without them. Modern medicine had declared the VNO to be mostly absent in humans, and where present, vestigial.

Still, several late-twentieth-century scientists were captivated by the notion that human beings might have a sixth sense. One was an electron microscopist in Boulder, Colorado, who scavenged the septal tissue of nose-job patients for VNO specimens. Another was a neuroanatomist in Salt Lake City who insisted on including a VNO primer in his lectures to medical students. And then there was the physician-cum-venture capitalist in Menlo Park, California, who suspected he'd accidentally isolated human pheromones from extracts of sloughed-off skin.

Five years ago, united by the enthusiasm and lucre of David Berliner, the venture capitalist, these researchers and a few colleagues began to compare notes. With the help of Monti-Bloch, a physiologist at the University of Utah, they've now presented the first strong evidence that human beings do indeed possess a functioning vomeronasal organ. Even skeptical observers admit that the team's findings seem solid; Berliner, who is not so skeptical, has already spun off a pharmaceutical company to synthesize drugs that could be delivered via the VNO, and he's bottled his alleged human pheromones in a perfume called Realm, 50 milliliters of which retails for $79.99.

But all parties concerned stress that the evidence is as preliminary as it is provocative. Although recent surveys show that almost everybody has a VNO after all, researchers still aren't absolutely sure the organ works. Until he received patents for his pheromones last December, Berliner had refused to divulge their makeup, so investigators outside his sphere of influence--that is, those not vested in his company--are only now attempting to replicate his group's findings. For now, no one inside or outside the Berliner camp has come close to answering the most provocative question of all: How might pheromones influence human beings?

Until recently, medical science claimed that they don't, period. Historical reports of the human VNO were as erratic and improbable as UFO sightings and were accorded as much credibility. A Dutch military surgeon first described the structure in 1703 in a soldier with a facial wound. In 1891 a French doctor reported seeing it in a quarter of the 200 people he examined. In 1934 one researcher wrote that the VNO "is almost constantly found in the human embryo and with diligence may occasionally be found in the adult." During the course of human development, this researcher noted, the VNO--like many a UFO--just seemed to disappear.

Finally, in the late 1930s, a widely respected neuroanatomist named Elizabeth Crosby dealt a seemingly decisive blow to the recurring rumors of the human VNO. The so-called sixth sense couldn't exist, she explained, because the place in the brain where other animals process neural impulses from the VNO--a structure known as the accessory olfactory bulb--doesn't persist past the first trimester of fetal development in humans. Even if the "end organ" was there, Crosby argued, it couldn't be functional.

Unlike her predecessors, Crosby never stooped to the level of actually searching for the VNO in embryos or adults. Instead she based her conclusion on her formidable knowledge of the olfactory processing center in the brain. Few medical researchers were qualified to challenge her; most took her word as gospel. And if the human VNO was kaput, they figured, there was no use looking for human pheromones either.

In the decades that followed, though, research amply demonstrated the importance of chemical signals to the sex lives of other animals. The vomeronasal organ was found in amphibians, reptiles, and most mammals, and it was implicated in the most intimate details of vertebrate physiology. For example, researchers discovered that pheromones in the urine of male prairie voles make a female vole's hormones go haywire. Her ovaries swell, her uterus triples in size, and she ovulates within two days.

Pheromones were also found to exert profound effects on reproductive behavior. When a female pig gets a whiff of the pheromones in a male pig's breath, she humps her back, steels her haunches, and submits her posterior to the inevitable. Behaviorists call this a fixed-action response because free will doesn't enter into it: one blast of boar breath and she's gotta have it. Similarly, male mice whose VNOs are surgically removed lose all interest in the procreative act. They won't mount a female nor even sniff at her nether regions.

"If you want to lead a life that is dictated by chemistry, then have a vomeronasal organ," says Charles Wysocki, a neuroscientist at the Monell Chemical Senses Center in Philadelphia who's studied the rodent VNO for 15 years. To be a rodent, Wysocki says, is to live from one pheromonal fix to the next. In addition to their orchestration of sex, pheromones help animals identify relatives, mark territories, and communicate bad intentions.

The discovery of pheromones' potent effects on other animals seemed to confirm the prevailing assumption that the chemicals aren't acting on human beings: if they were, scientists reasoned, we'd know it-- wouldn't we? Maybe not, says Wysocki. It's true that in humans socialization is shaped more by experience than it is in other animals, so our responses to chemical signals probably aren't as inflexible. But if they occurred, pheromonal exchanges among human beings couldn't be seen, felt, tasted, or heard--and probably not smelled, either. Unlike those conscious sensations, the messages conveyed via the VNO would bypass mental awareness and make a beeline for the primitive brain. Instead of distinct, discrete perceptions, like the taste of a cherry or the sight of a sunset, pheromones could be said to mediate impressions: bad vibes, warm fuzzies, instant dislikes, irresistible attractions.

It was a sudden change in vibes at his laboratory that led David Berliner to wonder whether such experiences could be ascribed, literally, to chemistry. Working at the University of Utah in the early 1960s, Berliner was trying to characterize the chemical components of human skin when, one day, he and his co-workers were overcome with an inexplicable bonhomie.

Someone suggested that they learn bridge over lunch. It was an unprecedented notion.

"We all looked at her and said, 'Uh-oh. Either she's having an affair or she's going to get married,' " says Berliner. "And then we all said, 'Sure!' So now over lunch we're playing bridge. The ambience of the group became much friendlier, and I was feeling very good.

"Until we closed those flasks," he says--the flasks containing his skin extracts. "I put them away, and bridge stopped automatically. No more bridge." When Berliner brought out the extracts again several months later, camaraderie revived, as did the card game.

Berliner noticed the connection, but he was a busy man with a surfeit of good ideas. A chance investment in an oral-contraceptive manufacturer would soon land him a pile of money with which he would launch biotech companies marketing technology he himself often helped pioneer. Cetus, Alza, Advance Polymer Systems, and Biosource Genetics are among the corporations Berliner has had a hand in; his more notable (and lucrative) involvements include the development of the skin-patch technique for drug delivery. The skin patch has been used to administer estrogen to menopausal women, nitroglycerin to people at risk of a heart attack, and nicotine to smokers trying to kick the habit.

Berliner never lacked inspiration but was always short of time. Not until the mid-1980s--several de-cades, several millions, and several companies later--would he again thaw "those flasks" to find the secret ingredients that could compel earnest scientists to squander their lunch hour on frivolous pursuits.

At about the same time Berliner began thinking about thawing his flasks, David Moran and Bruce Jafek were conferring in a University of Colorado clinic in Denver. Moran, an electron microscopist in the university's medical school, had recently tired of studying balance sensors in the giant African cockroach and had become intrigued with the processing of sensory information in higher animals. He was particularly interested in describing the microscopic structure of human olfactory tissue, a feat that had never been achieved, owing in part to the tissue's inconvenient location in a cleft just a few hundredths of an inch wide and roughly three inches up the human nostril. One of Moran's graduate students had designed an evil-looking wire device that could collect material from the olfactory cleft, and Moran had begun taking specimens for electron microscope preparations.

Jafek, who'd recently been appointed chairman of the otolaryngology department, heard about Moran's research and asked to collaborate with him on the biopsy work. During a rambling discussion of things olfactory, Jafek happened to mention that one of his graduate students was doing some research on the VNO of the human fetus. The question arose: Whatever happened to the adult VNO?

"Bruce said, 'I'm going to start looking for this thing, and see what I can see,' " says Moran. As a practicing surgeon specializing in nose jobs, Jafek had access to plenty of proboscises. His grad student's work on the fetal VNO gave him an idea of where the organ's inlets might be located in the adult. "And once he learned the right place to look, he saw the VNO in everybody," says Moran. "He used a long-working-distance dissecting microscope, and he'd lay people on their backs, shine a light in there looking for this thing, and--there it was.

"So we took everyone in the lab and did an I'll-show-you-mine-if- you-show-me-yours thing. And sure enough, I had one on each side; a friend of mine had one on each side; everyone we looked at in the lab had a pair of vomeronasal pits. That," says Moran, "bent the nail over for me," confirming his belief in the existence of an adult VNO.

Moran and Jafek examined more than 200 people and found the pits in every last one of them. Eventually, surveys done by other investigators would confirm that the structures are present in more than 90 percent of noses. That these other surveys did not find the VNO in all subjects can be explained, says Moran, by the fact that the noses in question were about to undergo surgical procedures and probably had higher-than-average proportions of nasal anomalies that could obscure the organ's opening. Also, he points out, many surveyors didn't realize that the size range of vomeronasal pits straddles the line between the visible and the invisible.

"Sometimes you can see them with the naked eye and sometimes you can't," he says. "The big ones you see right away--the largest I've seen is almost a tenth of an inch across, which is a big hole. But some are as small as a hundredth of an inch. That's the human eye's limit of resolution, so you can't see the small ones without magnification." Moran says that other surveyors, having seen the largest cavities, assumed they didn't need a microscope to find the pits and wound up missing the smallest ones.

For Moran, the electron microscopist, seeing the VNO at 40X wasn't entirely gratifying either. Moran asked Jafek to call him into the operating room when patients were having the part of the septum near the pits surgically removed; he then took biopsies from those patients for viewing at magnifications hundreds of times higher.

His preparations showed that each pit led into a tiny duct a few tenths of an inch long and that some of the cells lining the duct looked like neurons, or nerve cells--to be exact, like receptor cells, which pick up sensory information and pass it on to the brain. But they did not look like olfactory receptors. And they did not look like nociceptors, cells that react to painful stimuli. "They didn't look like any other nerve cells I'd ever seen before in the human body," says Moran.

In 1985 he presented his micrographs in a poster session at the annual meeting of the Association for Chemoreception Sciences. "People just sort of walked by and went, 'Huh,' and walked away," says Moran. "The work was met with apathy of exciting proportions." Moran's peers wanted to know what, if anything, the neurons were doing. He didn't claim to know the answer--but several years later David Berliner would.

It was 1989 when Berliner decided to let his genies out of their bottles. "Let me ask you a question," he'd said to his friend Larry Stensaas, a neuroanatomist at the University of Utah. "If you thought you had some human pheromones, how would you go about finding out whether they worked?"

Stensaas had just finished debriefing Berliner on a research project he'd conducted for one of Berliner's biotech companies. He had been working with Berliner for years, but the subject of pheromones had never come up before.

"I told him, 'In all other mammals, pheromones have to have a vomeronasal organ to work on,' " says Stensaas. "And nobody's seen the human vomeronasal organ for a long time. Berliner then said, 'Well, has anybody looked?' "

Stensaas didn't know the answer to that question, even though he himself was something of a fan of the organ. Year after year, over the protests of colleagues, he'd delivered to his medical students a detailed VNO lecture in which he candidly admitted that most experts believe the adult human version doesn't exist. He'd never had the time or the funding to pursue his interest, but it had persisted nonetheless.

"I found it fascinating that this stupid little organ could control sexual behavior in animals," Stensaas says. "And I liked the idea of the human vomeronasal organ, even if no one had seen one."

Actually, someone had seen the human VNO not long before. When Stensaas turned to the sensory literature, he found that in 1985 a group of Canadian investigators, working without magnification, had located at least one pit in 39 of the 100 people they examined. Discouraged by the numbers, the Canadians had abandoned their search; Stensaas took up the quest. His training as a neuroanatomist had taught him to look beyond surface phenomena, so he began to collect the brains and septal tissue from cadavers and aborted fetuses and dissect them. Unlike Elizabeth Crosby, Stensaas looked for the VNO as well as the nerve fibers associated with it, and he found the organ in most of his specimens. He also found that Crosby was right about the accessory olfactory bulb: it wasn't evident past the first trimester of fetal development. But Stensaas thought he knew why.

"Because the frontal lobes of the brain grow so big in human beings, the olfactory bulb is pulled away from its location near the brain stem," says Stensaas. As the cortex develops, the bulb becomes flattened, its nerve fibers stretched in order to maintain its connection with the frontal lobes and the brain stem; the result is that it becomes difficult to see. "Elizabeth Crosby couldn't find the accessory olfactory bulb, because it had been smeared out by this process. It isn't recognizable." But, Stensaas maintains, it's there.

The next step was to test whether or not the human VNO was operational. Is the organ sending signals to the brain? Or is it simply a burnt-out vestige of a scratch-and-sniff past? To help answer that question, Stensaas recommended Monti-Bloch, a longtime friend who'd spent decades studying the function of chemoreceptors. When the physiologist met Berliner early in 1990 he voiced some skepticism.

"I was not sure what could come out of this," says Monti-Bloch. "What I read was that in humans the organ was atrophic. And there wasn't any work we could refer to on studying the physiology of the VNO in mammals, let alone humans." He told Berliner he'd give the project six months. " 'If it doesn't work by then,' I said, 'it doesn't work, period,' " says Monti-Bloch.

In the next few months Monti-Bloch designed a system for delivering chemical substances to the VNO and measuring any electrical impulses that might be generated at the organ's entrance. The trick was to contain the dispersal of the test substances so they would trigger only the cells in the VNO pits and not the smell sensors in the olfactory cleft or other nerve receptors in the nose. Monti-Bloch found that he could get the desired effect using a thin wire electrode surrounded by two concentric plastic shafts--the inner one to administer chemicals in a puff of air, and the outer one to suck away the puff like a vacuum cleaner. Placed in the VNO pit of a cooperative human subject, the rounded tip of the electrode, protruding slightly from the plastic sheaths, could detect any electrical activity that followed the chemical pulse.

Monti-Bloch connected the instrument with wires and tubes to a device that would both control the puffs of air and receive electric signals. He could inject one-second blasts of test chemicals into the airstream by depressing a pedal. A computer monitored the entire procedure, recording the chemical and electrical impulses on a chart called--what else?--an electrovomeronasogram (aka EVG).

Building the electrovomeronasometer itself required the machining of several novel parts and the extensive modification of off-the-shelf equipment. When Monti-Bloch had the system together, he tested it by positioning the electrode in some poor unfortunate's olfactory cleft and recording the responses of olfactory receptors to smelly substances such as mint and clove oil. The apparatus worked for olfactants, but the six months were nearly up.

"I am going to send you a little package with some things for you to try on the VNO," Berliner told Monti-Bloch when the physiologist phoned in from Utah.

"I asked him, 'What are these things?' " says Monti-Bloch. "And he said, 'I can't tell you that.' But the first thing I noticed when I got them was that they didn't smell. So I grabbed one of my collaborators and tried the substances in his olfactory cleft, and indeed, they didn't have any effect.

"Then I placed the electrode in the vomeronasal organ, put a puff of the substance into the airstream, and all of a sudden--" Monti-Bloch raises his eyebrows and becomes speechless. In short, the substances Berliner had shipped put spikes all over the EVG of Monti-Bloch's volunteer, suggesting that neurons in the VNO were discharging in response to those substances.

Monti-Bloch has now tested several dozen of the putative pheromones, all of which are derived from the 20 natural isolates Berliner discovered in his skin extracts. The tests have shown that the substances can evoke other physiological reactions, including changes in heart rate, respiration, pupil size, and skin temperature. Responses vary from person to person, and some of the compounds affect only men or only women--as would be expected, given the role of pheromones in the rest of the animal kingdom.

The possible behavioral effects of Berliner's compounds are still unproved. Though Monti-Bloch has yet to conduct a systematic appraisal of subjective reactions (that is, vibes), some volunteers have mentioned feeling less nervous and more confident during their exposure to Berliner's elixirs. Brad Murray, for example, claims to have experienced "a little bit of a relaxing effect from one or two of the substances." But he admits to being distracted by procedural details. "Mostly it just feels like somebody stuck a wire up my nose," he says.

In 1991 Stensaas heard about David Moran's work through a colleague and passed his phone number on to Berliner. Moran's micrographs of the human VNO provided visual support for the physiological evidence Monti-Bloch had been collecting. In Moran's pictures the cells lining the vomeronasal pits look like receptor cells; Monti-Bloch's work suggests they act like receptor cells too. In 1992 Berliner asked olfaction experts at the University of Kentucky to identify the cell types; the Kentucky team treated VNO tissue with chemical markers that bind to nerve cells. The markers indicate that the apparent receptors in the VNO are indeed neurons and "probably some kind of receptor cells," says Kentucky neuroscientist Marilyn Getchell. "But the question we still haven't answered is, are there nerve fibers coming out of this organ to the brain?"

That's what everyone in VNO research would like to know. From Moran's and Getchell's work, it's clear that the surface of the VNO is chockablock with receptor cells. From Stensaas's exploration of fetal and cadaver tissue, it's clear that the region surrounding the VNO is laden with neurons that make all kinds of interesting connections to the brain. Monti-Bloch's experiments demonstrate that stimulating the VNO receptors can effect significant changes in physiology. For most people, this assembly of evidence would be proof enough that the VNO is sending signals to the brain.

But neuroscientists are not most people. And so far no one has demonstrated exactly how VNO receptor cells hook up with their neighboring nerve complex.

"The wiring diagram hasn't been worked out yet," says Moran. "And that's because not many people are willing to have dyes that trace nerve cells injected into their brains, then have their heads cut off so you can take sections and look to see where the dyes went."

Stensaas and his colleagues, believers in a functioning human accessory olfactory bulb, already suspect the general direction. They think nerve fibers emanating from the vicinity of the vomeronasal organ head straight through the bulb to the hypothalamus, the command center for basic body functions such as sleeping, eating, and mating. Nerves from the VNO may also rendezvous with the limbic system, where emotions are thought to originate.

To the researchers, these neural pathways suggest that the human vomeronasal organ is linked inextricably, albeit subconsciously, with psyche and soma alike. If true, the organ would be an ideal target for pharmaceutical intervention--a point that has not been lost on Berliner. Drugs delivered via the VNO could in theory remedy both psychological and somatic disturbances without the side effects, such as nausea, that can be common with oral and intravenous medications. Berliner's team claims it has already identified certain substances that may decrease anxiety, diminish hunger, and relieve PMS.

But what about, you know, the boar-breath effect.

If Berliner has discovered an aphrodisiac, he isn't saying. The substances in his perfume, for example, are meant to enhance only the wearer's "positive feelings of romance, confidence, attractiveness, and self-assurance," according to Realm's infomercial. True, the perfume comes in male and female versions, reflecting the fact that each has a sex- specific formula. But Berliner says his women's scent contains a pheromone only women can detect, while the men's will only boost the "positive feelings" of men. He claims to have an ethical aversion to substances that would act on other people rather than the user. Of course, there's nothing to stop a scheming man from liberally dousing himself with the female scent, or a designing woman with the male. Berliner's stance may have less to do with ethics than with the Food and Drug Administration's requirement that any product calling itself an aphrodisiac be sold as a prescription drug.

Whether or not Realm is l'eau de lust, the idea that chemicals can stimulate arousal in human beings is not farfetched. The presence of a vomeronasal organ could account for menstrual synchrony in women who are in frequent and close contact with one another, says Monell's Wysocki. It may also explain how mothers and infants can identify each other by what was thought to be smell alone. As for chemical communication between genders, Wysocki's colleague George Preti has shown that the timing of a woman's menstruation can be altered by smearing her upper lip with an extract of male underarm sweat.

Fortunately, there is a more palatable way to swap pheromones with your loved ones. "The kiss might play a very important role in the transference of chemical signals," says Wysocki. "In other species, physical contact is often necessary for the exchange of the substances that activate the vomeronasal organ.

"On the other hand, one could argue that in the course of evolution human beings are shedding control by pheromones and leading more of an independent life. If one takes that view, then the kiss is nothing more than a vestigial behavior for transmitting pheromones."

Of course, a kiss is nothing less, either. And for now, a sigh is still a sigh. But no doubt its role too will be clarified--as time goes by.
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