Olfaction Scientists: Sniffing Out Some New Applications

A wide range of scientific challenges spawns a surge in basic research for this once unacclaimed discipline Most researchers long believed that the sense of smell was genetically determined and, therefore, unchangeable. But at least one scientist--Charles Wysocki of the Monell Chemical Senses Center in Philadelphia--doubted this theory. Wysocki, a psychobiologist who investigates the genetics of olfaction in the 45 percent of the adult population who can't detect androstenone, a component in sweat, repeatedly gave one subject a bottle of the odorant to smell in an experiment two years ago. For weeks the patient insisted he couldn't smell anything. But one day, given the same compound in the same amount, he responded, "You must have switched the bottles. How did you get the smell of Newark in the bottle?" For Wysocki, the distinctive aroma of Newark prompted a breakthrough. Two articles in Nature and Science that address fine points of signal transduction in olfactory neurons--the cellular pathways that get turned on in response to an odor--have far-reaching implications in the field of olfaction. The Nature piece (347:184-7, Sept. 13, 1990) moves researchers closer to isolating the elusive odor receptor. The article in Science (249:1166-8, Sept. 7, 1990) helps quell a controversy about whether olfaction transduction involves one or two pathways; the results show that it follows two. "Different odors depend on different pathways," says Randall Reed, an associate professor of molecular biology and genetics at Johns Hopkins School of Medicine and one of the authors of the Nature paper. "Pleasant ones seem to prefer one way, unpleasant ones, the other." Reed and his group were the first to clone and sequence an ion channel in an olfactory neuron. His results indicate that even a third pathway may be activated in olfaction. "This is the first evidence that cGMP [cyclic guanosine monophosphate, a chemical mediator in the cell] may play a role in olfaction," says Reed. Reed hopes that the ion channel he's cloned will also help him catch the olfactory odor receptor. "We still haven't isolated the odor receptor, even in this age of molecular cloning of many other receptors," he says. Odor receptors have been particularly hard to purify because they generally have a low attraction for their odor molecule--the odor falls off the receptor very easily--and there are many competing binding proteins acting as contaminants during the isolation. "When you try to label a rose essence molecule with a radioactive tag and then use it to bind to its receptor you only recover rose essence label," says Reed. Another problem is that in a population of olfactory neurons there are very few that express the receptor. So to try to isolate the receptor, some researchers have begun to explore expression cloning. That is microinjecting specific olfactory mRNA or cDNA into frog oocytes and seeing if the receptor is expressed. But before a researcher can do that, there has to be some method to measure the receptor function. "A very sensitive detector would be the ion channel we cloned," says Reed. Reed thinks that deciphering how the body perceives odors may unravel a completely novel way in which the body creates and is able to distinguish diversity. "How is a receptor able to distinguish the 10,000- some-odd odors it is exposed to during a lifetime?" he asks. "We know how the immune system can shuffle genes to create antibodies in response to the myriad of antigens it is exposed to. The olfactory system may do something similar. We don't know." --R.E. Until 10 years ago, researchers say, the way in which the language of odor gets deciphered in the brain was treated like a scientific sideshow compared with the ways in which questions about how we hear or see were being addressed in the other sensory sciences. Today, twice as many olfactory scientists work in academic research and in the fragrance industry as did five years ago. And opportunities are still available in both milieus, say their respective representatives. While a recent flurry of articles (two have been published this fall in Nature and Science) would seem to indicate that olfaction is a mature field in which researchers are filling in the details of a well-sketched picture of the sensory process, the truth is that many fundamental, clinical, and basic research projects are still up for grabs. On the research front, scientists are still attempting to isolate an olfactory neuron odor receptor in order to get a handle on the first step in odor perception. Others are trying to identify the factors that are responsible for the regeneration of olfactory neurons. They are the only neurons in the body that get replaced every 30 or 40 days after they die off. Wysocki thinks that the turnover of new neurons may be responsible for why subjects can now smell odors they couldn't before. "An odor receptor on a new neuron that has been exposed repeatedly to an odor may become sensitized to it," he suggests. "Earlier experiments didn't follow patients over a long enough period to catch that window of sensitivity." On the clinical side, it has been only within the last 10 years that scientists have been able to demonstrate how disorders in the sense of smell are involved in aging and in diseases like Alzheimer's. And even given budgetary constraints, funding agencies have begun to respond with more money for research in this discipline. Grants from the National Institutes of Health and the National Science Foundation for this field of research, for example, have doubled since 1980. The scope of the research funded by NIH ranges from how infectious agents and toxins enter the brain through the olfactory nerve to studying the epidemiology of taste and smell disorders. "For the last 10 years there has been a substantial burst of scientific interest in olfaction," according to Wysocki. "In general, research and interest has expanded in the whole area," he says. "And it has done so in a nontraditional sort of way." Rather than training scores of young investigators for the field in a few labs, olfaction science grew by drawing researchers from different disciplines, including pharmacology, neurophysiology, electrophysiology, nutrition, and molecular genetics. "It has become extremely multidisciplinary, and no longer does one call oneself a chemosensory scientist, as they once did," Wysocki says. "They are either a geneticist or a neurophysiologist who happens to opt to be in the chemical senses." While there are no graduate programs in olfaction, per se, students can get their Ph.D.degree and do their research in laboratories that conduct anatomical, electrophysiological, biochemical, physiopsycho-logical, or genetic studies related to the sense of smell. Postdocs do likewise. Monell, for instance, has trained 250 scientists in the chemical senses since it was founded in 1968; these scientists now work in government, industry, and academia in areas as diverse as fisheries management and fragrance development for cosmetics companies. Wysocki monitors his field for a newsletter, Focus on Fragrance, that provides updates on research in chemosciences for the fragrance and cosmetics industry. He has found that over the last decade, there has been an increasing percentage of dissertations and articles published in olfaction and related subjects. Between 1970 and 1980, the percentage of dissertations on these subjects was steady, at 2.5 percent of all dissertations published in the Dissertations Abstracts database. After 1980, that percentage jumped to 10. Article publication percentage, however, has been steadily rising. In 1965, the proportion of articles devoted to "smell" was 4 percent of all research articles published in the Medline and Biosis databases. That percentage has since doubled. Working in this somewhat untapped field allows investigators to create quite a splash with their research results, says Wysocki, who has been a chemoreception scientist for 17 years. And while membership in the professional society for the discipline, the Association for Chemoreception Sciences, has doubled from 250 in 1985 to 500 in 1990, the conferences they hold are still small enough, say researchers, that the attendees can talk to each other without being confounded by in- formation overload. The field of olfaction science only recently began to enjoy the bouquet of respectability it now has. "Why that is the case can be understood by asking the following question," says Richard Doty, director of the University of Pennsylvania Hospital's Smell and Taste Center, a clinical and basic research facility. "Which sense, if given a choice, could you live without? Most people would chose the sense of smell over seeing and hearing." But in the early 1980s, policymakers finally began to realize the relevance of disorders of the sense of smell. According to Max Mosell, director of the Clinical Olfactory Center at the State University of New York (SUNY) at Syracuse, the NIH funded research in olfaction through the development of clinical centers to deal with some 2 million Americans annually who suffered from olfactory disorders. Before the taste and smell research centers were built, patients who suffered from olfaction disorders were pushed through the medical profession's revolving door and would often end up on the psychiatrist's couch, says Mosell. "Patients who come to us now are relieved that we can verify that there is something medically wrong with them and not that they are suffering from some psychological disorder," he adds. The five centers are at Thomas Jefferson University Hospital in Philadelphia, SUNY-Syr-acuse's center, the Hospital of the University of Pennsylvania, the University of Colorado in Denver, and the University of Connecticut Health Center in Farmington. Since 1980, NIH has doubled its funding for basic and clinical research in olfaction from $4.3 million in 1980 to $9.8 million in 1988, says Marin Allen of the National Institute on Deafness and Communication Disorders (NIDCD), which oversees research and funding for olfaction at NIH. In 1988, the National Institute of Neurological and Communicative Disorders and Stroke split into two separate institutes, the NIDCD and the National Institute of Neurological Disorders and Stroke (NINDS). Researchers say that this should continue to help focus attention on the field of olfaction. "Simply, more attention can be given to it when it is part of a separate institute, NIDCD," says a policymaker who wishes to remain anonymous. NSF funding for research in olfaction also has doubled since 1980. "In the early 1980s, between 10 percent and 15 percent of all NSF applications and awards were for olfaction," according to Christopher Platt, NSF program director for sensory systems. It rose to between 20 percent and 25 percent by 1990. One of the goals of the NICDC's continuing effort in olfaction science is to quantify how many people suffer from olfaction disorders. While the precise number of people who suffer from chemosensory disorders is not known, a survey conducted by Monell researcher Wysocki in 1987 revealed interesting variations in people's sensitivity to odors. A scratch-and-sniff survey of six odorants--androsterone (sweat), iso-amyl acetate (banana), galaxolide (musk), eugenol (cloves), mercaptan (gas), and rose--inserted in the September 1986 issue of National Geographic, drew 1.5 million responses. One important result of the survey was the finding that the elderly suffer from a diminished sense of smell but not of taste. This has important clinical implications for treatment of a senior citizen who, for whatever reason, complains of lack of appetite. Food products can be tailored to such patients and artificially intensified without compromising health. Other clinical research has revealed a relationship between loss of the sense of smell and obesity, diabetes, hypertension, and neurological disorders such as Alzheimer's disease. Fragrance Industry Opportunities Academic researchers aren't the only scientists intensely interested in the sense of smell. The cosmetics and perfume industries use olfaction-oriented scientists to do basic and applied research related to isolating and stabilizing fragrances in products. The industry-sponsored Fragrance Research Fund (FRF) in New York is the only tax-exempt organization in the world dedicated to studying human reaction to olfactory stimulation. Since it started in 1982 it has increased its funding from $25 million to $500 million this year. The fund has given grants to academic scientists for topics ranging from "functional membrane proteins in olfactory cilia" to "the role of olfactory perception in social interaction" to "fragrance administration and relaxation training for treatment of anxiety during magnetic resonance imaging (MRI) in cancer diagnosis." Sometimes, research results can be used in consumer product marketing. "Industry representatives or anyone who provides monies to the fund have great interest in the results of the research," says Annette Green, secretary and vice president of the FRF. "If we see results that fragrances may reduce stress, and we know that stress makes people look older, well, we might say that using a product with a particular fragrance could result in a younger-looking appearance," says Green. Companies like Roure Inc. of Teaneck, N.J., and International Flavors and Fragrances Inc. of Union Beach, N.J.--both of which manufacture many of the fragrances for cosmetics or toiletry companies and for brand-name perfumers like Procter & Gamble, Chanel Inc., and Revlon Inc.--do other kinds of research as well. "While perfumers in our industry are considered artists, the army of people who service the perfumists are scientists," says Jack Mausner, senior vice president of research and development at Chanel Inc. "Synthetic chemists make new compounds. Analytic chemists identify components of a mixture. The finished product, the perfume, the lotions, are all formulated by chemists. They must address issues of stability and even analyze the glass used in the final packaging. An impurity in the glass can have devastating effects upon the fragrance." About five years ago, at the center of the fragrance industry in Grasse, France, researchers began to exploit biotechnological techniques to extract chemical essences, according to Mausner. "Scientists select bacteria which under controlled conditions can speed up the natural processes involved in extracting chemical essences from plants and flowers," he says. Japanese and American companies are now also using these methods. While herbal or floral fragrances have become essential ingredients for the sales of many American personal-use consumer products, like shampoos and deodorants, the Japanese and English have begun to experiment with scents a bit more expansively. This summer an English sachet company introduced a blast of fresh odor to the riders of the East London subway. The smell of mandarins, lemons, roses, and apple blossoms covered up some of the more offensive odors with which subway riders are all too familiar. And a Japanese construction company, Shimazu of Tokyo, recently developed the first computerized system to circulate fragrance within an enclosed environment like an office building or a high-rise apartment complex. Someday, industry and academia may meet in their research objectives. According to a coauthor of the recently published Nature article, Randall Reed, basic neuroscience researchers are in fact beginning to ask a question that perfumers have been investigating for centuries. What is it about the structure of the olfactory system that responds, say, to a whiff of someone's hair and conjures up these "multifaceted phenomena called emotions?"

Olfaction Scientists: Sniffing Out Some New Applications

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