CHEMICAL COMMUNICATION
What will it take to find a human pheromone? Despite decades of research into chemical communication, scientists are no closer to determining whether a human pheromone exists ALLA KATSNELSON, SPECIAL TO C&EN
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CREDIT: C&EN/SHUTTERSTOCK
n 1991, at a conference sponsored by a fragrance company called Erox Corp., two University of Utah scientists presented research on a tantalizing pair of chemical compounds provided by the company. They reported that in a few dozen human volunteers, the molecules androstadienone and estratetraenol activated the vomeronasal organ (VNO)—an olfactory organ that senses pheromones in many animals—in a sex-specific manner. The company patented these molecules as putative human pheromones. About 10 years later, University of Chicago biopsychologist Martha K. McClintock and a colleague tested the molecules’ ability to affect the emotional states of men and women. The results, when published in 2000, did not support Erox’s claim: “It is premature to call these steroids human pheromones,” the authors concluded (Horm. Behav. 2000, DOI: 10.1006/ hbeh.1999.1559). Still, the paper brought the compounds to the attention of the scientific community. The human body naturally produces androstadienone and estratetraenol, but the compounds’ activity as pheromones— substances produced and emitted by one individual of a species as signals affecting the behavior or physiology of another individual of the same species—has never been rigorously demonstrated. Most researchers today also agree that the VNO in humans, located just behind the nasal septum, is vestigial, an organ that’s no longer of use to today’s Homo sapiens. Even so, these molecules pop up in studies to this day. And Erox, still operating, is using them in its products. Tristram Wyatt, a zoologist at the University of Oxford, has tracked every mention of them in the scientific literature, following their trail either to McClintock’s 2000 paper or the 1991 symposium paper in which they were first presented. “It’s as if the company just plucked these molecules from the air,” Wyatt says.
“And people simply took them on trust, so the idea of doing proper chemistry and experiments was short-circuited.” Wyatt and other researchers have long tried to address a thorny question: Do human pheromones actually exist? Despite more than half a century of vigorous debate on the topic, there’s still no answer in sight. Indirect evidence suggests they might. For Wyatt, one strong indicator is that humans develop a permanently strong body odor during puberty; it’s at least possible that such odors act as chemical signals, as they do in some other sexually mature mammals at breeding times. The fact that other mammals have pheromones suggests that we may, too. Knowing either way would shed light on this primal and poorly understood communication system. To date, though, no actual molecules that serve as human pheromones have ever been identified—in part because molecules falsely called pheromones diverted the search, but also because identifying the molecular basis of human behaviors is exceedingly complicated. A close look at the
history of research on pheromones in other mammals reveals some of the challenges in the search and why settling the question will be no easy matter.
On the pheromone trail By definition, pheromones are detected by the olfactory system and affect behavior either directly or by influencing the hormone system of a member of the same species. (Molecules that serve as signals to members of a different species are called kairomones.) For a molecule to count as a pheromone, the behavior it elicits must be innate, not learned, and the chemicals must be able to signal anonymously to any member of the species, rather than providing an NOVEMBER 21, 2016 | CEN.ACS.ORG | C&EN
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olfactory fingerprint of any one individual. The classic example is bombykol, which is released by female silkworm moths, Bombyx mori, to attract mates. Researchers first speculated that animals use pheromone-based communication in the late19th century, but it took until 1959 to identify bombykol and to coin the term “pheromone” itself. Since then, pheromones have
Whitten was an outdoorsman; when NoTests can probe things such as mating votny and Carmack came to visit, he took and aggression in mice, Yu explains, but bethem on walks along snowy trails, pointing cause these behaviors are always performed out markings of foxes. The hikers bagged in the presence of other animals, in most some yellow snow, shipped the samples to cases you can’t just wave a molecule in Novotny’s lab for analysis, and found that front of a mouse’s nose and track how it rethey could differentiate males from females sponds. “If we don’t know which behavior by volatile compounds in their urine. to screen, we don’t know which compound They then began to study mice, develis responsible for it, and without knowing oping techniques to the compound, it’s tough to identify the O profile the molecular function of receptors,” he says. N N constituents of mouse And if screening for these behaviors is difN O urine and various gland ficult in a lab mouse, it’s exponentially more S secretions. Ultimately, difficult in humans and other primates. In Dehydro2,5-Dimethylpyrazine 2-sec-Butyl-4,5they hit on a pair of molthe early 1970s, researchers claimed to have dihydrothiazole exo-brevicomin ecules—a heterocyclic identified sex pheromones in Old World priThese molecules, found in mouse urine, were described as compound, 2-sec-bumates that directly affected mating behavior; the first mammalian pheromones, but questions remain tyl-4,5-dihydrothiazole, aliphatic acids in the vaginal secretions of about whether they truly are pheromones. and a terpene derivative, rhesus monkeys primed with estrogen were dehydro-exo-brevicomreported to trigger male attraction, but these been identified across the evolutionary in—that provoked aggression in male mice so-called copulins were later discredited betree—including in spiders, lobsters, fish, and were attractive to females. cause the behavioral responses could not be frogs, snakes, sheep, deer, dogs, rabbits, eleIn adult female mouse urine, they also reproduced. “I just had a graduate student phants, and, of course, mice, in which much identified 2,5-dimethylpyrazine, a molecule write to me asking about human pheroof the research on mammalian pheromones produced by the adrenal gland that delayed mones, saying she was interested in pursuing has been conducted. puberty in juvenile females, perhaps acting copulins,” says George Preti, an analytical It wasn’t long after pheromones’ initial as a signal to individuals that the population organic chemist at Monell Chemical Senses discovery that researchers began to look was too large to favor reproduction. “It’s an Center. “I told her not to waste her time.” for them in humans. In a 1971 Nature comembarrassingly simple compound—someThe irresistible draw of pheromone rementary, University College, London, phything a chemist would yawn over,” Novotny search is the prospect of tracing the whole sician Alex Comfort exhorted researchers notes, “but it had a very distinctive odor, as chain of action, from pheromone and to apply analytical chemistry techniques many pyrazine derivatives do.” behavior to receptor and brain circuitry, such as gas chromatography to search Wyatt says. Yet few mammalian pherofor human pheromones to “open a new mones have been so definitively nailed. chapter in reproductive pharmacology at a One problem is that most researchers study time when it is badly needed” (1971, DOI: These and a handful of other volatile pheromones from the perspective of be10.1038/230432a0). Comfort’s piece ran in molecules identified during the 1980s are havior, neuroscience, or molecular biology, response to a Nature study published just credited as the first mammalian pherosays Kazushige Touhara at the University of a few months earlier by McClintock, who mones. Today, their status is less clear. Tokyo. But few chemists isolate and study as an undergraduate at Wellesley College Some later work failed to find them in difthe actual molecules. “If more people were found that the menstrual cycles of women ferent laboratory mouse working on the chemiswho lived together tended to synchronize strains and couldn’t try, the entire field would (1971, DOI: 10.1038/229244a0). Since then, replicate their behavioral speed up,” he says. multiple publications have cast doubt on and reproductive effects. Touhara’s chemothis so-called “dormitory effect,” attributSeveral other proposed sensory signaling lab ing the observation to errors in research pheromone candidates managed to lay out the design and data collection (Psychoneurohave spurred similar full picture for one mouse endocrinology 1992, DOI: 10.1016/0306debates, reflecting how pheromone: exocrine 4530(92)90016-z). At the time, however, the slippery research on gland-secreting peptide 1 study was heralded as the first demonstramammalian pheromones (ESP1). They found that tion of the existence of human pheromones. can be. secretions from male Also in 1971, about 1,600 km away, a Although insect phermice from a minor tear young Czech-born analytical chemist omones are generally gland called the extraornamed Milos Novotny joined the faculty single molecules that probital lacrimal gland, locatat Indiana University, Bloomington. Nomote well-defined behaved under the ear, triggered votny’s main gig was developing analytical iors—attracting mates, VNO activity in females. separation methods such as gas chromatog- swarming, or egg laying, —Kazushige Touhara, “It was really an acciraphy-mass spectrometry. But a senior colfor example—mammaprofessor, University of Tokyo dent,” Touhara says. The league, Marvin Carmack, soon introduced lian pheromones often gland was so understudhim to a consuming side interest: chemical work in combinations, says C. Ron Yu, a neu- ied that they could barely find mention of communication among mammals. roscientist at Stowers Institute for Medical it in the literature. And yet, it makes sense Novotny reached out to a leading bioloResearch, and their effects can change with as a source of pheromones, he explains. gist in this area, Wesley Whitten at the Jack- context. Pheromones also change behaviors, Watch a mouse or a cat grooming and you’ll son Laboratory, to propose a collaboration. which for mammals are complicated. see it rubbing around its ears with its paw;
A difficult road
“If more people were working on the chemistry, the entire field would speed up.”
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C&EN | CEN.ACS.ORG | NOVEMBER 21, 2016
CREDIT: J. BIOL. CHEM. 2013, DOI: 10.1074/JBC.M112.436782, © 2013 AMERICAN SOCIETY FOR BIOCHEMISTRY & MOLECULAR BIOLOGY
that motion could facilitate the spread The peptide ESP1 (two views of secretions onto the animal’s fur. The shown) is one of the only molecules researchers isolated the molecule in whose complete mechanism as a 2005, but it took five more years mammalian pheromone has to determine its role in enhancbeen traced. ing females’ sexual receptivity and to identify the receptor. biolreprod.102.008268). And Unlike Novotny’s and Israeli researchers reported some other proposed pherthat smelling women’s tears omones, ESP1 is a peptide, reduced both testosterone not a volatile small molecule. levels and feelings of arousTouhara believes that, origal in men (Science 2011, DOI: inally, all land-dwelling ani10.1126/science.1198331). But mals’ pheromones were volaa serious search for the specific tiles, but that mice and certain chemicals modulating these and other terrestrial animals evolved other effects has never been done. a more durable, protein-based markPreti and his long-term collaboraing system that signals through an animal’s tor Charles Wysocki, also at Monell, touching of its nose to the marked area. envision a wide-ranging study in These can act alone or with which compounds, once isolatvolatile pheromones. ed, would be tested in bioasA handful of other pepsays that looked for mood tides identified since then alteration or changes in are widely considered to be luteinizing hormone. Preti pheromones in mice. A male says the place to start looking pheromone, darcin, named is the armpit. after Mr. Darcy in Jane Austen’s “The mechanism of odor pro“Pride and Prejudice,” belongs to a duction there is similar to other protein family called major urinary mammalian communication sysproteins. Steroid derivatives—sultems, where volatile small molecules fated steroids and, more recently, carboxylare carried to the surface by a protein,” he ic acid steroids, both in females—have also says. So far, the duo has not managed to get been proposed, as have bile acids in feces of such a study funded, but Preti is convinced both sexes. Touhara’s team also proposed that analytical chemistry is advanced another ESP-family peptide, ESP22, as a enough to yield valuable results. pheromone in juvenile males. Advances in Wyatt, however, proposes a different chromatographic techniques for purifying starting point. If human pheromones do such peptides as well as in exist, the interaction between O methods for identifying recepmothers and babies would be tors have spurred recent proga prime place to look for them, H ress, but researchers say they’ve he says: The elicited behavior barely scratched the surface in 2-Methyl-2-butenal would be relatively easy to understanding this type of cheobserve, and because the submo-olfactory communication, jects include infants, it would This rabbit even in the laboratory mouse. definitely be innate. Indeed, a pheromone guides French team that identified a newborn rabbits to their mother’s milk. rabbit mammary pheromone, 2-methyl-2-butenal, has more Despite the challenges the work will recently observed that human newborns inbring, Wyatt and Preti both argue that it’s hale more and move their mouths seeking time to turn back to humans. After decades food in response to breast secretions from wasted on molecules such as androstadien- lactating women (PLOS One 2009, DOI: one and estratetraenol, researchers should 10.1371/journal.pone.0007579). launch a concerted effort to analyze human “If those molecules could be found,” secretions to try to finally settle the quesWyatt says, “it would be really exciting tion of whether they contain pheromones, because it would give you the confidence to Wyatt and Preti say. start looking for much more difficult things Some studies have provided hints that in humans.” pheromone communication exists. Preti and his colleagues, for example, showed Alla Katsnelson is a freelance writer. A that extracts of sweat from men’s underversion of this story first arms stimulated in women a rush of luteinappeared in ACS Central izing hormone, the molecule that triggers Science: cenm.ag/ ovulation (Biol. Reprod. 2003, DOI: 10.1095/ humanpheromone.
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