BREATHTAKING A sample of mouth air from a volunteer is directed to a gas chromatograph for analysis of volatile sulfur compounds in breath odor.
	PHOTO BY TOMMY LEONARDI

The center is the world's first research institute devoted to the multidisciplinary study of the chemical senses. Work there includes probing human pheromones, inquiring about food cravings, sniffing out body odors, understanding chemically induced sensations beyond taste and smell, and controlling environmental malodors. The center attracts the interest of companies in the food, fragrance, beverage, tobacco, chemical, pharmaceutical, and personal care industries.

Monell also interests ordinary folks. People with taste, smell, or body-odor disorders may find help at Monell. Couples in cross-cultural relationships may be comforted by information about the origin of food preferences and how individuals vary in their propensity to sample unfamiliar food.

Workers exposed to volatile chemicals want to know: Is this chemical really bad for my health, or do I find it irritating just because I don't like its smell? Employers are curious: Is there a magic odor that can be put in ventilation systems that will keep employees alert, motivated, and working hard?

From basic studies of the mechanism and function of the chemical senses to explorations of how the chemical senses frame our perceptions of reality, work at Monell illuminates many facets of the human condition and advances our quality of life. Take, for example, the visit of Monell associate member Pamela Dalton to New York City last October, in response to Fatsis' query.

During her visit to New York City, Dalton--a cognitive psychologist whose work focuses on how odor affects people--smelled the unpleasant odor that had been troubling Fatsis. She believes that New Yorkers, on smelling this odor later, "could reexperience the same emotions that they were having" in the aftermath of Sept. 11.

Odors usually are remembered in association with events, Dalton says. So, an odor linked to an adverse event often can trigger a physiological response that the person attributes to the components of the odor rather than to the bad experience the odor evokes.

With two postdoctoral researchers, Dalton collected air samples in and around Ground Zero. At Monell, analysis of the air samples so far indicate the presence of acids (acetic acid and nonanoic acid), aldehydes (formaldehyde and benzaldehyde), aromatic hydrocarbons (benzene and styrene), mercaptans, guaiacol, and diethyl phthalate. Dalton is now correlating the chemicals to the odor. When the components of the pervasive odor are identified, Dalton hopes to recreate it. "The recreation of this smell," she says, "may assist some therapists in helping some New Yorkers deal with post Sept. 11 stress," just as Dalton once helped herself deal with a bad experience.

	Dalton
	PHOTO BY MAUREEN ROUHI

MANY YEARS AGO, Dalton tells C&EN, she was mugged. Months after the incident, she began having panic attacks whenever she smelled modeling glue. Then she figured out that the smell reminded her of the attacker, who must have been a glue sniffer. "I went to a craft store, bought modeling glue, and taught myself to break the spell of that smell" by experiencing it in a safe environment. "Now the smell has no emotional hold over me anymore."

When people recognize that an odor that's causing physiological stress is really triggering unpleasant memories, they can be taught to break that association, Dalton says. The hypothesis is that when people smell the odor and nothing bad happens, then they can learn that the odor no longer predicts an adverse outcome. Dalton is testing the hypothesis and believes that it can be applied to war veterans experiencing post-traumatic stress disorder.

"Wars have distinctive odors associated with them," she says. Veterans of the Vietnam War remember the smell of jet fuel, napalm, and burning organic matter, among others. Those who served in the Gulf War remember the smell of certain insect repellents. "We think that when these veterans smell these odors later, when they're back in the safety of their communities, the odors may act like a flashback trigger." In a project being funded by the U.S. military, Dalton will study how to weaken the impact of the odors of war.

For analysis of odors, Dalton is collaborating with Monell staff member George Preti, an organic chemist. Such cross-disciplinary collaborations are standard at Monell. According to Mary M. Chatterton, Monell's director of resource development, the center was designed to foster such interactions.

"We have no departments, no divisions," Chatterton tells C&EN. She says that Monell's founder, Morley R. Kare, a pioneer in the study of smell and taste, "thought that by mixing up offices and putting a psychologist next door to a chemist, people would just naturally talk about their work in hallways and be much more likely to collaborate."

Monell's funding comes primarily from grants from the government (50%), corporations (30%), and various foundations. Only unrestricted grants are accepted from corporate sponsors. Every project is intended to be published.

When companies ask for help with their products, "we send them to commercial labs," Chatterton says. However, with sponsorship, companies gain access to Monell's know-how. Corporate sponsors "can call any of our scientists and ask, 'What do you know about this? Can you send me a paper on that? Can you speak at a meeting for us?'"

The access lets industry in on cutting-edge research even before it is made public, says Monell staff member Charles J. Wysocki. "Sometimes, we get stung by this practice," he adds, referring to the race to find a sweet receptor. Industry knew that Monell was getting close, Wysocki tells C&EN. He thinks the information reached other groups on the trail of a sweet receptor, who then shifted their efforts to even higher gear and got to the finish line first.

At any given time, about 50 Ph.D. scientists from a wide range of specialties work in the center. The almost totally unfettered freedom to ask questions and seek answers motivates researchers, several of whom joined Monell as postdocs and then chose to stay.

Monell's staff is "one of the things that makes this a fine and exciting place," says Gary K. Beauchamp, a biopsychologist and the center's director. "Here, you have to learn a bit of chemistry if you're a biologist and vice versa. That has made the place one of constant intellectual renewal. People who came here as postdocs, myself included, are continually doing new things. That's what keeps us here."

AS DIRECTOR, Beauchamp must ensure that Monell continues to be a vibrant and leading research institution for the chemical senses. "The only way to do it is to provide the resources and the freedom the investigators need," he tells C&EN.

Monell's location in Philadelphia's academic center--its neighbors include the University of Pennsylvania and Drexel University--allows its researchers to draw upon a culturally diverse pool of volunteers for its human studies and a deep well of expertise in various disciplines from which its researchers draw collaborators. Currently, the center occupies 60,000 sq ft of space in one building. That may be increased by up to 25%, Beauchamp says, to allow expansion of research in regeneration, development, and aging in the chemical senses.

The center also plans to bring in more people with expertise in biophysics, biochemistry, neuroscience, molecular biology, and molecular genetics. Of particular interest to the center are researchers with expertise in human sensory perception. Very few people in the U.S. are being trained in the chemical senses, Beauchamp notes. In the past, Monell has tended to bring in people at a junior level and then train them. Although it has been successful, that route is difficult, Beauchamp says. "We're casting our net worldwide to find people."

The multidisciplinary collaborative spirit allows Monell researchers to venture way out of their expertise, and Monell staff typically have projects all over the landscape. Take Wysocki, a psychobiologist by training. His projects range from the very basic--understanding the basis of human differences in olfaction--to the very applied--how to make pig farms or mushroom compost less stinky.

Nobody would choose to live where the air smells of pig slurry or spent mushroom compost--a mixture of hay, gypsum, and chicken and horse manures. As housing developments move into rural areas, however, people are increasingly bothered by odors from pig and mushroom farms, which are important to Pennsylvania's economy. With Preti, Wysocki has been working with the Pennsylvania Department of Agriculture to seek ways to ameliorate the odors coming from those farms.

In terms of improving the human condition or the quality of life, the agricultural work has a very direct impact on the neighbors of those farms, Wysocki says. But those neighbors are a small segment of the population. His work toward elucidating the variability of human olfaction, he believes, could have far greater consequences.

	Wysocki
	Preti
	PHOTOS BY MAUREEN ROUHI

"EACH OF US has our own reality, and it is based on what we perceive through our sensory systems," Wysocki tells C&EN. There is good evidence that great variations exist in the human sense of smell. So wherever smell plays a role--in foods, flavors, fragrances, or even in people's enjoyment of gardens--then different perceptions exist, he explains.

"It's hard to get into somebody else's brain to understand what they're perceiving," Wysocki continues. "But if we understand that differences in perception exist that may have a biological basis or may be environmentally induced, we are a step toward accepting individual differences and diversity."

Wysocki has been studying the variations in human olfaction at myriad levels: age, sex, disease, genetics, environment, and experience. "Individuals who work in a constant-odor environment--a pulp mill, a paint factory, or a fragrance company--will have a different sense of smell from a person who works in an odor-free environment," he says. "I've been studying how different factors make their contributions and where they show their effects."

There's smelly research, and there's sexy research. In the area of chemical communication by humans, Preti and Wysocki manage to combine both. One project involves male underarm secretions and whether they harbor human pheromones.

Many Internet sites peddle products containing what are claimed to be human pheromones. These products--touted as "invisible social magnets" or "nature's aphrodisiac"--promise that the wearer will be instantly irresistible to the opposite sex.

The products take advantage of the public's ignorance of what pheromones do, Wysocki explains. Androstenone, for example--the pheromone of male pigs and the "active ingredient" in many pheromone perfumes--is called a releaser pheromone because it releases a sequence of gross behavioral changes when it is detected by a sow in heat: The sow arches its back, assumes the mating stance, and is ready to mate. "There is no good evidence that the kind of pheromones people are selling releases a specific behavioral sequence in humans," he says.

However, a more subtle type of pheromone, called primer pheromones, affects female reproductive development, cyclicity in females, and female hormonal surges. For example, in 1998, researchers at the University of Chicago showed that secretions from female armpits cause women who live together to have synchronous menstrual periods. The work is regarded as the first real proof of chemical communication among women.

According to Preti, evidence had been developing in the early 1980s that male underarm secretions may have substances that can alter the menstrual cycle of females. That humans may produce substances at low levels that can affect something as important as the reproductive endocrinology of the opposite sex spurred Preti's interest in male armpit chemistry.

With Wysocki, Preti is studying whether male underarm secretions may alter the menstrual cycle. They have been looking at levels of luteinizing hormone (LH)--the hormone that induces ovulation--and how those are affected in women exposed to male armpit secretions by application of an extract to women's upper lips.

Over the course of a day--especially before ovulation--levels of LH pulse about every 90 minutes. Just before ovulation, a huge spike in LH occurs, which stimulates the release of an egg. Preti and Wysocki are examining the pulse intervals before the huge spike to see if they are affected by male underarm secretions.

An effect would support the notion that the male armpit is a source of a primer pheromone that mediates chemical communication between men and women. If something in the extracts could alter the timing of ovulation, whatever it is, women may be able to use it to schedule when to release an egg. And if an effect exists, it could be used as a bioassay to guide the identification of the active ingredients in male underarm secretions.

The winter holidays present many opportunities to indulge in a very sensual activity: eating. Research at Monell is helping people understand the factors that influence their choice of food and drink at different stages of life.

At one end of the spectrum, Monell staff member Julie Mennella, a biopsychologist, works with pregnant women and studies how their flavor preferences shape the food preferences of their babies as they develop into toddlers. Her work has shown that even while in utero, babies are exposed not only to what the mother eats and drinks but also to the perfume she wears. If breast-fed, the baby is further exposed through the mother's milk. These early exposures, Mennella's work has shown, shape a child's preferences. She has found, for example, that infants of women who regularly drank carrot juice while pregnant prefer cereal laced with carrot juice over cereal made with water.

At the other end of the spectrum, Monell associate staff member Marcia Levin Pelchat, an experimental psychologist, works with older people and examines how their chemical senses--especially olfaction--are changing as they age and how the changes are affecting their nutrition and quality of life. Most people think that the chemical senses uniformly decline with age. Pelchat's work indicates that some things decline in some people, but not everything, and not in everyone.

"Many elderly people living in institutionalized settings fail to thrive or risk becoming nutritionally deficient because they can't enjoy the food," Pelchat tells C&EN. When people have to eat homogenized food, for example, they can't get any visual cues about what they're eating. That exacerbates the decrease in sensory stimulation that failing olfaction causes.

 

	Pelchat
	Bryant
	PHOTOS BY MAUREEN ROUHI

SIMPLE but effective measures can help this segment of the population, Pelchat says. For example, instead of serving ready-made bread, communities for the elderly could prepare bread at the premises to infuse the dining area with the aroma of baking bread. Another is to re-form processed food to familiar shapes: Chicken meat shaped into a chicken leg provides a better visual cue about the food than does a random blob. Since older people are more sensitive to irritants, food preparers should hold off on spices and use herbs instead to enhance flavors. The elderly themselves should chew more slowly to allow more flavor components to permeate the oral and nasal cavities.

Monell's mission is "to advance knowledge of the mechanisms and functions of the chemical senses: taste, smell, and chemosensory irritation." Most people are familiar with taste and smell as chemically induced senses. Chemosensory irritations sometimes are perceived as either taste or smell because of their association with foods and beverages--for example, the heat of chili pepper and the tingling caused by carbonated drinks. The sting in the nostril caused by a whiff of ammonia or acetic acid is also a chemosensory irritation.

Using the term "chemosensory irritation" to refer to these sensations is unfortunate, says Bruce P. Bryant, a sensory biologist and senior research associate at Monell. "A small amount of menthol up your nose or in your mouth or on your skin" has a cooling effect, he explains. "It is not irritation. Irritation is noxious."

Bryant says a better word is "chemesthesis," which is defined as a chemically induced sensation that does not involve taste or odor receptors. Chemesthesis refers to those sensations that result from compounds activating receptor mechanisms for other senses, usually those involved in pain, touch, and thermal perception. For example, menthol activates receptors that are sensitive to cooling and not really specialized to receive menthol. The brain interprets signals from those receptors as cooling.

Like taste and smell, chemesthesis is important for survival, Bryant says. "It tells you that something is chemically impinging on your body, that tissue is in imminent danger. Burrow-dwelling animals can sense toxic levels of carbon dioxide and possibly even feel a sting when exposed to these levels."

Chemesthesis also vastly expands the sensory experience from food. "Plain starch really tastes blah," Bryant says. "But when you put in chemesthetic stimuli, you can alter the perception of the food's thermal or tactile qualities."

In trying to understand chemesthesis, Bryant focuses on neurons and their responses to chemical stimulation. By collaborating with researchers who study human responses to those chemical stimuli, he is able to relate the cell responses to the human sensation.

IN A HUMAN STUDY, volunteers are asked, for example, to rate the intensity of a burning sensation produced by various compounds. Bryant takes these compounds and, in an in vitro study using neurons known to respond to touch, pain, warming, or cooling, asks: Do these cells respond to the compounds in the same order that the humans rank them? Such studies tell which neurons are important in producing the sensation and whether the compounds can reach the nerve endings in the skin or tongue.

One of Bryant's current projects involves Szechuan pepper, a spice used widely in China, India, Japan, and Nepal. Szechuan pepper contains compounds that produce a vivid sensation that is little known to the Western palate, Bryant says. "On your tongue, these compounds feel like a six-volt battery. It's partly electric and partly numbing, and it's totally chemically induced."

The compounds that produce this unusual sensation are polyunsaturated alkylamides. Bryant is trying to pinpoint which types of cells are responding to the compounds. He suspects that the compounds are affecting ion channels. Furthermore, Bryant has learned that the sensation caused by polyunsaturated alkylamides may be related to a nervous dysfunction that is manifested as a tingling in the limbs. Understanding what molecular mechanisms respond to these compounds may lead to better understanding of, and perhaps even treatments for, the malady.

No one can tell where the basic work on polyunsaturated alkylamides will lead Bryant, but at Monell, he can take it anywhere within the bounds of good science, the center's mission, and the center's resources.

Although Monell addresses many biomedical problems, it does not command as much attention as institutions focused on high-profile diseases. Taste and smell dysfunctions and body-odor-production problems are not in the same league as cancer, for example. But inherently, the chemical senses--which are the center's raison d'être--are almost universally interesting. From the chemical stimuli to the biological sensors that detect these stimuli, to the processing of the signals and their interpretation in the brain, to how these processes converge to affect our well-being and happiness, research at Monell has something for everyone.

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ODOR WARFARE

Stinky Bombs

The task of forcing the terrorist Osama bin Laden and members of his inner circle from the caves of eastern Afghanistan might have been easier had U.S. forces used bombs with odor power in addition to firepower. If a conventional bomb misses its target, that's it. Odors, on the other hand, permeate to areas distant from the source.

The idea is not far-fetched. The U.S. military already has asked the Monell Chemical Senses Center to formulate bad smells for potential application in dispersing crowds and in preventing entry to designated spaces. The odors are nonlethal. They are due to compounds that can be detected by humans at levels way below the concentration at which the compounds become irritants or health hazards.

The U.S. military is studying how to make weapons out of stinky odors that have been formulated at Monell. Tests carried out by Monell associate member Pamela Dalton show that these odors are potent in making people want to flee in disgust.

"People really hated these odors," Dalton tells C&EN. "As they smelled the odor, their heads would jerk back, and you could see the revulsion on their faces." Physiological monitoring shows that the odors induce shallow breathing, increased heart rate, and increased stomach motility, which is an early indicator of nausea.

In designing the bad-odor mixtures, Dalton says, "we homed in on biological odors because we thought those had the best chance of being recognized universally." Among them are the smell of rotting garbage, human waste, and burnt hair. Common ingredients of the mixtures are skatole and mercaptoacetic acid.

NOSE JOB Researcher measures changes in congestion, swelling, or blood circulation in the nose of a volunteer after exposure to a volatile chemical.

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DIAGNOSIS

The Body-Odor Doctor Is In

For some people, George Preti, an organic chemist and a staff member at the Monell Chemical Senses Center, is the only doctor they can turn to.

Preti holds a doctorate in organic chemistry, not a medical degree. However, his expertise on human body odors based on three decades of research on the nature, origin, and function of human odors has drawn patients to his lab. Among them are people with the little-known genetic disease called trimethylaminuria, or fish odor syndrome.

People with extreme forms of this disease sporadically smell like fish--no matter how often they bathe and change their clothes. Their social lives are wrecked. Compounding the misery is that the smell isn't always there. Often when patients seek medical help, physicians can't even smell the problem. If they're willing to wait, patients can be examined in the lab of Preti, who is one of the very few researchers who can diagnose trimethylaminuria. The lab is not a clinic, he says. "So we see one patient a week when we can see them."

Preti has developed a diagnostic scheme for patients presenting odor-related problems. Using his own nose, he first assesses the level of breath and body odor produced by a patient--who is instructed to not use deodorants or antiperspirants for three days before the consultation, to not practice any oral hygiene the night before, and to wear clothing with easy access to the armpits.

"I don't stick my nose in the underarms," Preti says. But he does apply a swab to the underarms to sample the bacteria there. "When I'm taking the sample, I get very close. So if there's a lot of odor being produced, I can smell it."

The swab goes to the cutaneous microbiology lab at the dermatology department of the University of Pennsylvania, where Preti's collaborators look at the types and levels of bacteria from the patient's armpits. "That gives me an idea of the patient's odor-producing capability."

Next, Preti looks at the air in the patient's mouth for bad-breath-causing compounds. He puts a tube in the patient's mouth and pulls a sample of breath directly into a gas chromatograph. He also collects saliva for analysis of less volatile compounds.

Then comes the choline challenge test, developed by a collaborator of Preti's, Paul V. Fennessey, a professor of pediatrics and pharmacology at the University of Colorado Health Sciences Center, Denver. The patient ingests 5 g of choline dissolved in orange juice and collects a urine sample every eight hours for 24 hours. If a patient has trimethylaminuria, the culprit--trimethylamine--will show up here.

Trimethylaminuria is caused by defects in a flavin-containing monooxygenase called FMO3. This enzyme catalyzes oxidation of fish-smelling trimethylamine--produced by bacterial degradation of dietary choline in the large intestine--to odorless trimethylamine oxide. A person with defective FMO3 accumulates trimethylamine and excretes it in urine and sweat.

Finally, the patient gives a blood sample, which is analyzed by Preti's collaborators in the medical school for genetic abnormalities related to trimethylaminuria.

The workup in Preti's lab takes between two and two-and-a-half hours. Preti says he devotes a significant amount of time talking to patients about why and how body odors are produced. He gives them copies of popular magazine articles based on interviews with him about bad breath and body odors.

With the organoleptic, analytical, biochemical, and genetic analyses, a fairly complete picture emerges, and Preti can tell with great confidence if a patient has trimethylaminuria. For patients who have the disease, he tells them how to alleviate symptoms. For example, avoid foods high in choline, such as eggs, legumes, soy products, organ meats, and saltwater fish. Or take antibiotics such as metronidazole or neomycin. These will reduce the bacterial population in the intestine and temporarily halt the production of trimethylamine. This measure is particularly effective for patients who are anticipating a special occasion--a wedding, for example--and want to be sure they don't emit embarrassing odors, he notes.

However, Preti can't prescribe antibiotics. "I write every patient an extensive report, which I ask them to show to their doctors so they can get a prescription," he says. "If you have a body-odor-production problem, chances are your doctor may not know what you're talking about. So I ask my patients to educate their doctors."

Don't patients mind that he's not a "real" doctor? "Who else are they gonna call?" Preti replies.

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CRAVINGS

Dying For A Food Fix

Sometimes what people decide to eat seems almost beyond their control. Ever wonder why every so often some people just have to have chocolate, a cookie, or a potato chip? The desire is so intense that people go out of their way to satisfy the food craving. Research by Marcia Levin Pelchat, an associate member at the Monell Chemical Senses Center, is helping to understand what cravings are all about.

A food craving is not a response to hunger: Any food will satisfy hunger, but only the craved food can satisfy a craving, Pelchat says. It is also not simply a response to nutritional or caloric deficiencies, as is widely believed. The phenomenon is complex--influenced by age, sex, brain chemistry, hormonal status, nutritional status, psychological state, and environmental cues.

The good news is that food cravings diminish with age, although why that is so is not clear. Food cravings can be triggered by sensory stimulation, Pelchat says, so diminution of the senses of taste and smell as people age could be one reason.

Women are more prone to food cravings than men, Pelchat finds. In her studies, 100% of young women report food cravings, compared with only 70% of young men. And among those who are at least 65 years old, 70% of women report cravings, compared with only 50% of men. Pelchat also finds sex differences in the foods craved. Women report a 60%/40% preference for sweet foods over savory foods. Men report the same split for savory foods over sweet foods.

Pelchat's findings are based on studies in the U.S. With the help of collaborators with expertise in social psychology and anthropology, she plans to examine cultural effects on food cravings. For example, why is black licorice such a highly craved food in Europe?

For people who want or need to curb their food cravings, Pelchat has the following tips: Stick to a healthy and sensory-stimulating diet. Keep only small amounts of the foods craved at home. Learn to satisfy the craving with a limited amount of the food.

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SYNERGY

Carbon Dioxide Plays A Cool Trick

Take a can of well-chilled carbonated beverage, a glass, and a timer. Pour the beverage in the glass. Now stick your tongue into the liquid and simultaneously start the timer. How long can you keep your tongue immersed?

The sharp tingling we feel in the mouth when drinking a carbonated beverage is not caused by the bubbling of carbon dioxide, as many might think. It is caused by the protons produced when carbonic anhydrase acts upon CO₂. Acidification of nearby nerve endings gives rise to the sensation.

Carbon dioxide also stimulates certain cool-sensitive neurons, and researchers have found a mutually enhancing interaction between cooling and CO₂. Thus, at a constant CO₂ pressure, a cold soda will feel more pungent than a room-temperature soda. Conversely, at a constant temperature, a highly carbonated drink will feel cooler than one with less carbonation. As Bruce P. Bryant, a senior research associate at the Monell Chemical Senses Center, says, "You can make a beverage more refreshing just by adding carbon dioxide."

Chilling a carbonated beverage enhances the pungency caused by carbonic anhydrase-mediated acidification. On the other hand, the high concentration of CO₂ in a freshly opened soda makes a cold soda feel even colder. The mutual enhancement can make it really painful to keep your tongue in a cold, freshly opened soda for too long.

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