The fragrance of thoughts / Deborah Blum

Although we are often unaware of it, we communicate with each other using chemical signals just like birds and bees

The moment that launched Martha McClintock's scientific career was a youthful whim. Even a ridiculous moment, she recalls. In the summer of 1968, while studying at Wellesley College, she attended a workshop at Jackson Laboratories in Maine. Over lunch, some well-known researchers discussed how mice seem to synchronize their ovarian cycles. And 20-year-old McClintock, who was sitting nearby, tweeted something like: “Well, don't you know? Women do it too."

"I don't remember the exact words," she says today, sitting calmly and rather amused in her well-equipped lab at the University of Chicago. "But they all turned their faces to me and stared." It is easy to imagine her in that meeting - the same direct gaze, the same friendly expression and fluttering hair. But the lunch group was not impressed; They told her she didn't know what she was talking about.

McClintock did not hesitate and presented the question to several doctoral students who also participated in the workshop. They bet you that you wouldn't be able to find data to support her claim. She returned to college and discussed the issue with her undergraduate supervisor, Patricia Sampson. And Sampson answered her: "Accept the challenge, do the research, prove whether you are right or wrong."

Three years later, when she was already a doctoral student, McClintock published a two-page paper entitled "Synchronization and Suppression of the Menstrual Cycle" in the prestigious journal Nature. The article describes a fascinating phenomenon observed in 135 female residents of Wellesley College's student dormitories during one academic year. During this period, it seemed that the timing of menstrual cycles began to change, especially among women who spent a long time together. The menstrual cycle becomes more synchronized, with an increasing overlap in its start and end times.

Today, the concept of menstrual synchronization in women is generally known as the McClintock effect. But the idea that continued to shape both her research and her reputation, the same idea that still drives a thriving field of research, is that this mysterious synchronization, this social network of reproductive systems, is caused by chemical messages between women. According to this concept, humans, like many other creatures, communicate with each other through chemical signals.

It was more difficult than expected to isolate specific chemical signaling substances, and to track their effects on our body and brain as precisely as entomologists do with countless such signaling substances, called pheromones, in insects. But in the forty years since McClintock's discovery, researchers have mapped the effects of chemical signals on a variety of human behaviors. Not only do women synchronize their reproductive cycles, but we are also able to recognize our relatives, respond to feelings of stress and moods of others, such as fear or sadness or "not tonight, honey", and all this by distinguishing chemical substances that those around us secrete quietly. As researchers learn more about this web of human interactions, they help blur the arbitrary dividing line between humans and the natural world.

Chemistry of the animal kingdom

This intriguing idea, that animals share invisible chemical signals, has a long and distinguished history, at least with respect to other biological species. In ancient Greece, they talked enthusiastically about the possibility that fed dogs produce a mysterious secretion capable of leading dogs to pant madly. Charles Darwin saw biological species known for their smelly wombs as evidence that chemical signals are part of the sexual selection process. In the late 19th century, the great French naturalist Jean-Henri Fabre wondered about evidence that the siren song of chemistry could make winged insects fly with determination.

However, it was only in 1959 that this science began to really gain momentum. In this year Adolf Buttenandt, a Nobel laureate in chemistry, isolated and tested a compound that female silkworm moths release to attract males. Buttenandt dissected the insects and carefully extracted the chemical their microscopic glands secrete. He collected an amount of material that was sufficient for its formation and deciphering its molecular structure using X-ray crystallography. He called the compound "bombicol", after the Latin name of the silk weaver.

It was the first pheromone to be discovered, although the concept did not yet exist. Shortly after, two of Buttenandt's colleagues, the German biochemist Peter Carlson and the Swiss entomologist Martin Luscher, coined the name pheromone from two Greek words: pherein (to lead) and horman (to provoke). They defined a pheromone as a type of small molecule that carries chemical messages between individuals of the same biological species. The compounds must be active in minute amounts and have an effect below the conscious odor threshold. When they are released by one individual of a biological species and absorbed by another, the two researchers wrote, they cause an outcome that can be measured, "for example, a specific response, a distinct behavior, or a developmental process."

Since then, an amazing array of pheromones has been discovered in insects and today it is the most well-known and well-established type of molecule for chemical signaling between animals. Pheromones work not only in the silkworm, but also in bark beetles, cabbage moths, termites, leaf-cutter ants, aphids and bees. According to a 2003 report by the National Academy of Sciences, entomologists have "cracked the code for the pheromone-based communication of more than 1,600 insects." And pheromones serve many other purposes beyond attracting mates: they warn of danger, identify relatives, change moods and influence relationships.

In the late 80s of the 20th century, they also found that pheromones affect a wide range of biological species that do not belong to the insect family, including lobsters, fish, algae, yeasts, ciliates, bacteria, and more. When this new science of chemical communication developed and received the more formal name of semiochemistry, from the Greek word semyon (meaning "sign or signal"), scientists extended the search to mammals. They were almost immediately met with opposition from their peers. "In the 70s and 80s, people would pounce on you if you said 'mammalian pheromone,'" recalls Milos Novotny, director of the Pheromone Research Institute at Indiana University. "They would say, 'There is no such thing: mammals are not like insects. They are too developed and too complex to respond spontaneously to something like a pheromone.'"

But by the mid-80s, Novotani not only identified a pheromone in mice that regulates aggression between males, but he also synthesized it. Compounds such as these have also been found in rats, hamsters, rabbits and squirrels. And as the list got longer, it became clear that mammalian pheromones are very similar, if not identical, to pheromones found in insects. As an example, most researchers cite the impressive work of the late biochemist L. A. L. "Bets" Rasmussen of Oregon Health and Science University, who showed in 1996 that a sex pheromone secreted by Asian elephants is chemically identical to the pheromone used by more than 100 biological species of Moth for a similar purpose of attracting members of the opposite sex.

McClintock proposed a similar idea in 1971 in her groundbreaking paper on menstrual synchronization. "It is possible," she wrote at the time, "that at least one female pheromone affects the timing of other women's menstrual cycles."

Fragrant environment

McClintock, now 63, sits in a small, light-filled room with folders, computers, stands full of test tubes and corked vials and smell sticks, all of which contribute to a faint, slightly sweet chemical aroma, as well as a dark-haired doctoral student named David Kern. ("All the other PhD students would have to climb over my dead body to be in this room," he says.) McClintock's lab belongs to the Institute of Psychiatry and Biology, of which he is one of the founders. She wears a tweed jacket over a brightly colored shirt and ponders the question: How much has the science of semiochemistry progressed since that day, some 40 years ago? Chemical communication between humans has been proven, she says, and "our goal is to deal with the identification of the chemical compounds. Then we can improve our understanding of their basic roles."

This task is not easy. It is estimated that human body odor is derived from about 120 compounds. Most of these compounds are found in an aqueous solution produced by the sweat glands, or released from apocrine glands, i.e. scent glands, in the fatty ducts of hair follicles. The apocrine glands are mostly concentrated under the arms, around the nipples and in the genital areas.

It's a complex environment, further complicated by our use of what researchers call exogenous compounds, such as soap, deodorants and perfumes, says Johan Lundström of the Monell Center for Chemical Senses in Philadelphia. Even so, Lundström marvels at the skill with which our brain organizes this chemical tangle. Brain imaging work done in his lab showed a 20% faster response to human chemical signals, compared to chemically similar molecules found elsewhere in the environment. "The brain always detects body odor," says Lundstrom.

This ability already exists in infancy. Many human studies have shown that mothers and toddlers tune in to the smell of the other just as animals tune in. The sense of smell is so precise that babies prefer pieces of clothing worn by their mother (and only their mother) and that have been in contact with sweat compounds. It is interesting that the identification is clearer in breastfed babies than in babies raised on milk substitutes.

"We're still just mapping the compounds that have an effect versus the compounds that don't," says Lundstrom. "I don't think we are dealing with a single compound but with a variety of different compounds that may be important in different cases." Pheromones operate under the radar, he says, and they influence, but do not necessarily completely control, many behaviors. "If we compare pheromones to behavioral signals, they may be less important than the simple obvious ways in which we communicate," says Lundstrom. But, he says, the ability to communicate by pheromones probably aided survival during our evolution by helping us tune into each other in a better way.

Psychologist Denise Chen of Rice University also claims that this chemical vigilance confers an evolutionary advantage. In her research, she collects scent samples from people while they watch horror movies. Gauze pads are placed in the armpits of the scouts to collect sweat released in moments of fear. The pads are then placed under volunteers' nostrils. For comparison, Chen also collected sweat from people who watched comedies or neutral films such as documentaries.

One of her first experiments showed that participants could tell whether the sweat donor was scared or happy while the sweat was being produced. Participants' estimates were correct more often compared to random guessing, especially when the sweat was caused by fear. A follow-up study by Chen showed that exposure to "fear sweat" increased the anxiety response so that participants tended to interpret facial expressions as fearful. Exposure to the sweat even improved cognitive performance: in word association tests that included terms suggestive of danger, women who smelled fear sweat outperformed those exposed to neutral sweat. "If you smell fear, you are faster at detecting scary words," explains Chen.

In a study to be published soon, Chen, along with Wen Zu of the Chinese Academy of Sciences, compared the responses of couples in long-term relationships with those of people in less long-term relationships. Perhaps it is not surprising that the results showed that the longer the couple lives together, the better they interpret the information related to fear or joy that is apparently coded in sweat. "I hope people will learn from this that understanding the sense of smell is important to understanding ourselves," says Chen.

The evidence that continues to accumulate shows that the unconscious sense of smell affects a range of human behaviors, from cognitive to sexual. In January 2011, for example, a group of scientists from the Weizmann Institute of Science in Rehovot, led by psychologist Noam Sobel, reported that men who smelled drops of crying tears created after an emotional response from women suddenly felt a reduced sexual attraction compared to men who smelled a saline solution. Sobel found a direct physical response to this obvious chemical signal: a small but measurable drop in the men's testosterone levels. The signal may have evolved to indicate lower fertility, such as during menstruation. More generally, the discovery could help explain crying, which is a uniquely human behavior.

Solid science

One of the main goals now is to identify the key substances that covertly transmit the signals and to understand how the body notices and responds to these signals. George Peretti, a chemist at the Monell Center in Philadelphia, has designed a research project that involves tracking these signaling substances by analyzing sweat and apocrine secretions and hormone levels in people who smell them. "We have not yet identified the exact signals that transmit the information," agrees Lundstrom. "And if we are interested in this field gaining solid status, this is the next thing that needs to be done."

McClintock agrees with these priorities. In recent years, she has focused on a detailed understanding of one of the more effective chemical signals, a steroid compound called ondrostadienone. She believes that this small molecule provokes a strong enough response to meet the criteria of a human pheromone: it is a small molecule that acts as a chemical signal of a biological species and affects physiology and behavior. Over the years, research laboratories, including McClintock's and Lundstrom's, have found that this compound has measurable effects on cognition, and that it can change levels of sex hormones such as cortisol, and trigger changes in emotional response. In a new study, McClintock and her colleague Soma Jacob of the University of Illinois at Chicago investigated Androstadianone's tendency to affect mood. They dissolved a very small amount of the substance in propylene glycol, and masked its smell with clove oil. They then exposed one study group to a solvent containing the compound and another group to a solvent without the compound. The subjects were asked to smell gauze pads containing one of the versions. The only thing they were told was that they were participating in a smell study. All participants continued to fill out a long and tedious questionnaire.

In general, subjects exposed to androstadienone maintained a much more cheerful mood during the 15-20 minute test. A follow-up study repeated the same process, but also included brain imaging. The scans showed that brain areas associated with attention, emotion and visual processing were more active in subjects exposed to the chemical signaling compound. McClintock interprets this as a classic pheromone effect, the kind of effects she hypothesized existed decades ago.

However, she and other researchers use careful wording and talk about "putative" pheromones. Humans are complex creatures, and it is difficult to definitively demonstrate causal relationships between certain chemicals and changes in behavior. Indeed, it is still impossible to determine with certainty which substances are responsible for McClintock's original discovery, menstrual synchronization. Even the phenomenon itself is already in doubt: it has been verified in many follow-up studies but has been hidden by others, and it is still not universally accepted by the scientific community.

The main discussion focuses on what exactly is synchronized. Maybe the timing of ovulation, maybe the length of the cycle. A review of human data from the 90s, conducted by a father and son, Leonard and Aaron Weller of Bar Ilan University, revealed that synchronization occurs only occasionally. "Even if the phenomenon of synchronization exists," reported Leonard Weller, "it certainly does not always come to fruition."

Although McClintock still retains the assertiveness of her college days, she agrees that the phenomenon is more refined than she first thought. But she also believes that her critics tend to miss the most important thing: that since her first study there has been more and more evidence of chemical communication between humans, and that it is no surprise that our chemical communication is becoming as complex as any other form of human communication.

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on the notebook

Deborah Blum won the Pulitzer Prize in 1992 and is the author of "The Poisoner's Handy Book: Murder and the Birth of Forensic Medicine in Jazz Age New York" recently published. She first learned about pheromones from watching her entomologist father extract them from ants.

And more on the subject

Menstrual Synchrony and Suppression. Martha McClintock in Nature, Vol. 229, pages 244-245; January 22, 1971.

Pheromones and Animal Behavior: Communication by Smell and Taste. Tristram D. Wyatt. Cambridge University Press, 2003.

Insect Pheromones: Mastering Communication to Control Pests. Margie Patlak et al. National Academy of Sciences, 2009.

Fifty Years of Pheromones. Tristram D. Wyatt in Nature, Vol. 457, pages 262-263; January 15, 2009.