CHAPTER 12
Our Olfactory Destiny
They were, I now saw, the most unearthly creatures it is possible to conceive. They were huge round bodies—or, rather, heads—about four feet in diameter, each body having in front of it a face. This face had no nostrils—indeed, the Martians do not seem to have had any sense of smell.
—H. G. WELLS, The War of the Worlds
IN THE IMAGINATION OF H. G. WELLS, MARTIANS WERE more advanced than humans: they didn’t need a primitive sensory system with nostril holes and wet mucous membranes. Martians were big-eyed, big-brained, and gutless, with squidlike tentacles instead of arms and legs. What these creatures lacked in biology they made up for with technology: they roamed the Earth in mechanical exoskeletons. Since The War of the Worlds appeared in 1898, science-fiction writers and alien abductees have insisted that space visitors are noseless. I remember an Outer Limits episode in which the hero, a radio station engineer, makes contact with a creature from the fourth dimension. The curious alien asks him about the function of those strange holes below his eyes.
Like the Freudians, futurists are quick to dismiss the sense of smell as an evolutionary dead end. They speculate that our noses will shrink and our smelling ability will devolve along with it. But is this really our fate? To peer into our olfactory future, we must look toward smelling machines and olfactory genes.
Unlike space aliens, electronic noses are already among us—the first commercial units were delivered around 1992, intended for use in quality control in the flavor and fragrance industries. An e-nose uses an array of chemical sensors to detect odor molecules, and pattern analysis software to distinguish between them. Early models were large boxes that sat in the laboratory; more-recent handheld versions resemble something the meter reader might carry. What sets the e-nose apart from other chemical detectors—like those that measure breath alcohol or warn of carbon monoxide—is that it responds to a broad range of molecules. (Smoke alarms that work on optical principles are even less specific, which is why they sometimes mistake steam or fine dust for smoke.) The chemical sensors of an e-nose can be made from all sorts of materials, with conducting polymers being a popular choice. A conducting polymer changes its electrical resistance in the presence of volatile molecules. Some versions respond to odor at concentrations near the limits of human perception. These polymers are sensitive but not sophisticated; they are basically chemical sponges with different absorbent qualities.
The usefulness of an e-nose depends on its software as much as its sensors. The software extracts a pattern from the sensor input using formidable statistical methods. Multiple sensors give the e-nose a big advantage over single-molecule detectors. In particular, they avoid the pitfall of cross-interference. Imagine a fart detector that works by responding to a single molecule, namely hydrogen sulfide. Embarrassingly, it would go off every time your mom makes some egg salad. In contrast, a broadband e-nose reads the hydrogen sulfide along with other molecules, and would be less likely to mistakenly insult the lady of the house.
How well does an e-nose actually perform? Does it have the potential to take jobs away from humans? Early models were intensely hyped by their manufacturers, and when the devices failed to live up to expectations, customers were left with a lingering negative impression of the technology. The hype hasn’t entirely disappeared. An informal test in 2006 concluded that one brand of consumer e-nose—a handheld, battery-operated model that detected spoiled meat using the amines released by contaminating bacteria—oversold both the accuracy and the benefits of the device.
In general, the practical skills of the e-nose are real but modest; they include telling whether two smells are the same or different. This simple talent is useful in quality control where a manufacturer needs to keep batch-to-batch variation within limits or reject tainted raw materials. An e-nose excels at same/different judgments, and unlike human sensory panelists, it doesn’t get tired or bored. (This doesn’t mean it’s maintenance-free; e-noses have to be recalibrated frequently owing to “sensor drift.”) E-noses are good for dirty and dangerous jobs that humans don’t want, such as monitoring emissions from animal feed lots and sewage treatment plants, or searching for land mines.
The e-nose also has a future in medicine. One device can detect diabetes from volatiles in the breath of a patient; another can find evidence of lung cancer. (Those cancer-sniffing dogs might be out of work before they know it.) An e-nose diagnostic scan would be quick and noninvasive. The main technical challenge is detecting a disease-related odor signal against a varying background of body odor.
Potential consumer applications could be in the offing, such as monitoring ambient fragrance levels—built-in scent systems for homes and offices will be more attractive if they include a feedback mechanism. A programmable olfactostat would maintain a pleasant level of scent in your environment; a wearable one could gauge the odor levels on your person.
Executives in the fragrance and flavor business dream of an e-nose that could stand in for a consumer test panelist. The device would be programmed with the exact preferences of urban preteens or suburban soccer moms in different zip codes. When presented with a test sample, it would respond “I like it” or “it’s too floral.” A roboconsumer has many advantages over human panelists: it’s always on time and you don’t have to pay it.
A surprising number of scientists are working on smell-capable robots; one of them published an entire book on the topic in 1999. Amy Loutfi, a researcher at Sweden’s University of Örebro, has attached an e-nose to an intelligent, mobile robotic system. Her prototype resembles a Roomba—it wanders around an apartment under its own control, locating and identifying smells in the air. Loutfi improved her nose-bot’s performance by adding psychological context to its decision-making process. The device identifies smells better when it knows it’s in the living room rather than the bathroom.
Will police departments deputize the e-nose for remote drug sniffing? The U.S. Supreme Court held that thermal imaging of a suspected marijuana grower’s home, because it relies on sense-enhancing technology that is not “in general public use,” is an unconstitutional invasion of privacy. Under this standard, waving an e-nose downwind of a suspected grow house would also violate the Fourth Amendment’s guarantee against unreasonable search and seizure. Until e-noses are available at Circuit City, police officers are going to have to rely on their own noses.
As with all technology, the law of unanticipated consequences will undoubtedly affect how the commercial e-nose market develops. For example, one near-term application is a pocket-size sniffer that tells from a woman’s breath whether she is ovulating. The Ovulatron 5000 certainly will be a boon to couples trying to conceive, but it might also become a must-have technology for single guys on the prowl.
YOU CAN’T EXPECT an e-nose to work as soon as you take it out of the box. Training is essential, even to achieve competence at a simple same/different task. If its job is to pick out rotten apples, you must fill its database with examples of good apples and bad apples, so that it can create a statistical profile for each, and a decision-rule for telling them apart. An untrained e-nose would probably group wine samples according to alcohol content. It must be trained to distinguish Pinot Noir from Zinfandel. An e-nose is only as impressive as the training it gets. You can’t follow your e-nose—you have to lead it.
An electronic sensing device appeals to hard-boiled process engineers because it is “objective.” It frees them from discussions with sensory experts, and from dealing with emotional consumer panelists, at least in theory. But wait until the e-nose in Manufacturing gives a different reading than the one in Quality Control. Who does the engineer believe then? Good luck finding an objective way to settle that argument.
One thing our brain does very well is separate signal from noise. We can, for example, follow a single conversation at a cocktail party full of chattering voices. Similarly a perfumer can work in an office reeking of background smells that change from day to day. But tracking a target against ever-changing background odors is hard for an e-nose. Even harder is following a moving target against such a background: a ripening peach in a farmer’s market, for example. Until it solves the cocktail-party problem, the e-nose will not be serious competition for the human nose.
AS TECHNOLOGY ADVANCES, the line between biology and hardware starts to blur. A group in Britain has developed what it calls “a truly biomimetic olfactory microsystem” by creating an artificial olfactory mucosa. In other words, they embedded electronic sensors in synthetic snot—a 10-micron-thick layer of an odor-retentive polymer called Parylene C. By delaying the detection of incoming odor molecules, the polymer slows the response time of the artificial nose, making it perform more like a biological one.
At the leading edge of technology, biological tissue is used as the odor sensor. For example, researchers can insert a mammalian odor receptor gene into yeast cells, which then manufacture the receptor and install it on their own cell surface. A tiny shred of the yeast cell membrane—including an intact, functioning receptor—is cut out and anchored to a chip that produces an electronic signal whenever the receptor is activated.
In a different approach, researchers use bacteria cells to produce odor receptors and then paint receptor-laden cell membrane fragments onto a tiny quartz crystal. The vibrational frequency of the crystal changes along with the weight of the layer coating it; this setup—known as a quartz crystal microbalance—is so sensitive it can tell when the receptors in the layer of bioslime have latched on to odor molecules, increasing its weight. An English company is using this technology to detect explosives. Another group has gone further and integrated entire rat olfactory cells into a semiconductor chip. They call this setup an olfactory neurochip, but it’s really a rat-machine hybrid.
University-based scientists in France have pushed hybridism a step further: they have inserted a human odor receptor gene into yeast cells, which then express functioning human receptors for the odor molecule helional. The modified yeast cells become biosensors for helional. This is a technologically elegant but somewhat disturbing achievement: a combination of human DNA controlled by a foreign organism, which in turn is enslaved to a machine. Is this really a direction we want to pursue?
At some point in the development of these fusions of silicon and biology, the question becomes not whether the e-nose can replace the human nose, but whether we want it to. Would I let an e-nose sniff-scan me for lung cancer? Sure. Would I use a robotic odor sentinel? Maybe, especially if I had a BO problem. But do I really want my refrigerator to tell me, “I’m sorry, Avery, I can’t let you eat those cold cuts”?
Genes of Scent
Supermarket tomatoes have no flavor. It’s a common complaint, and a valid one. Commercial tomato varieties have less sugar, acid, and aroma than the wild type. On the other hand, they have better color, yield, disease resistance, and physical toughness, or what growers like to call “shippability.” (Tomatoes are picked while still hard and green, to help them survive the trip to the store.) The guiding principle for tomato breeders is that it is better to look good than to taste good.
Help may be on the way: as scientists decipher the genetics of flavor chemical production in plants, they open the door to bioengineered flavor enhancement. One research group has discovered genes for the enzymes that are the first step in the biochemical production of phenylethyl alcohol, a key ingredient in tomato aroma. When overexpressed in transgenic tomato plants, these genes give the fruit ten times more rose alcohol, making it more fragrant than the ordinary variety. Another scientific team recently created a tastier tomato by altering the gene controlling a key enzyme involved in aroma production. They took the enzyme gene from lemon basil and inserted it into a tomato plant, where it modified biochemical activity to produce higher levels of key aroma molecules. This is cool science, but the proof of the pudding is in the eating, and here the new transgenic tomato is a winner: It was preferred by panelists in taste tests.
Rather than import genes from other plant species, genetic engineers may decide to pluck useful ones from so-called heirloom tomatoes, the distinctive-looking and interesting-tasting varieties prized in farmers markets across the country. Heirloom tomatoes—with names like Marvel Striped and Purple Cherokee—existed before the breeding programs that created the standardized, disease-resistant, high-yield, shippable kind that dominate today’s supermarket shelves. Ann Noble, the UC Davis wine expert and creator of the Wine Aroma Wheel, has been lured out of retirement by Central Valley tomato growers looking to promote their heirloom business. They hope she will do for tomatoes what she did for wine—encourage sensory analysis to help consumers understand and appreciate all their varied aromatic qualities.
If there is anything more dispiriting than a flavorless tomato, it is a scentless rose. Along with chrysanthemums, tulips, lilies, and carnations, roses are the top sellers in the cut-flower market, with worldwide sales estimated at $40 billion a year. Where has all the fragrance gone? There are more than a hundred species of roses, yet most of those in commercial production result from crosses between only eight species. Like tomatoes, these varieties were not selected for fragrance, but for traits that the cut-flower industry prizes: flower color and shape, yield, vase life, and resistance to insects and disease.
Perfume chemists analyze floral scents down to the last molecule, but it’s not their job to find out how plants make the scent in the first place. Nor were academic researchers interested: in 1994, not a single floral scent enzyme had been identified. Then the biologist Eran Pichersky began to study a native California wildflower known as Brewer’s Clarkia. This unusual species—a night-blooming, moth-pollinated evening primrose—grows in only the San Francisco Bay Area. Pichersky’s team chemically characterized its scent and found that one ingredient—linalool—is produced by an enzyme called linalool synthase. When they successfully identified the gene that produced the enzyme, they opened up a whole new scientific field: floral scent biochemistry.
Since then, Pichersky and others have looked for the scent-producing enzymes in the Fragrant Cloud rose, and the genes that code for them. They hope to transfer those genes into a scentless rose like the Golden Gate cultivar.
Biotechnologists may ride to the rescue of rose scent. They have a toolbox full of techniques to transfer genes into plants. They can literally shoot new genes into plant cells using microscopic DNA-coated particles of gold or tungsten. Or they can use the microorganism Agrobacterium to install the genes for them. Not only can genetic engineers restore a plant’s original scent, they can give it the scent of another species. It’s a dizzying thought: roses that smell like violets, asters that smell like lilacs. The creation of transgenically fragrant flowers will be a victory for biotechnology and may ease public acceptance of biotech crops.
This would all seem like a perfect opportunity for the cut-flower industry. Yet Eran Pichersky tells me that producers are reluctant to make the effort. According to their market research, consumers claim that scent matters, but sales figures don’t reflect it. Consumer choice is driven by color and visual appeal. In any case, most flowers are bought as gifts, which means the purchaser doesn’t live with the scent, or lack thereof. Perhaps it is true, as Shakespeare said, that “to throw a perfume on the violet…Is wasteful and ridiculous excess.”
The Genes of Perception
Imagine a DNA test in which a marketer predicts your fragrance preferences in ten minutes using a drop of your saliva. Rapid, saliva-based clinical diagnostics like home pregnancy tests are already in use. Why shouldn’t there be point-of-sale diagnostics? Wouldn’t you trade a little spit to find your perfect fragrance?
The person-to-person variability in odor perception is enormous. To get an idea of the scale, compare it to color vision. Imagine that instead of three kinds of color blindness there were dozens, and that each type affected up to 75 percent of the population instead of only 6 percent. Smell scientists struggle to explain this variability; it remains one of the biggest mysteries about the sense of smell. Why are some people able to smell a particular molecule and others not? Why do some people find it pleasant and others do not?
Cultural factors—the favorite explanation of academic researchers—certainly play a role in odor preferences. But cultural explanations don’t go too far in explaining the extensive differences between people within the same culture. Biological factors, which receive surprisingly little attention, may account for much of this variation. For example, certain specific anosmias—the inability of a person with otherwise normal smell to detect a specific type of molecule—have a biological basis, namely the lack of a receptor for the molecule in question. There are a couple of dozen specific anosmias, but they account for merely a fraction of the total variation in odor perception.
The key to the mystery may reside more broadly in the human genome. A tantalizing possibility is that your olfactory receptor genes determine how you smell the world, and why you smell it differently than other people. Everyone has roughly 350 olfactory receptors, but not necessarily the same 350 as the next person. In addition, the gene for a given receptor can show subtle variation in DNA sequence from person to person.
The science of genetics links genotype (a person’s DNA profile) to phenotype (a person’s physical and mental traits). Several laboratories around the world are exploring the genetics of odor perception. Their first challenge is to characterize a person’s odor perception phenotype—in other words, to measure the sensitivity to, and preference for, a wide range of smells. The next step is to use DNA analysis to establish a person’s odor receptor genotype. Researchers expect that people with similar phenotypes have certain genetic traits in common. For example, people who like musk, hate grape, and are indifferent to patchouli may have certain odor receptor variants in common, and these biomarkers could become the basis of the in-store perfume preference diagnostic.
The first step toward a functional genomics of olfaction has already been taken. Researchers at Rockefeller and Duke Universities have discovered that variations in one odor receptor gene are responsible for differences in how people perceive the molecules called androstenone and androstadienone. These genetic variations, known as single nucleotide polymorphisms, have the effect of muting the intensity and unpleasantness of these two smelly molecules. It’s astounding that such tiny mutations can have such major consequences for odor perception. Yet this is just the tip of the iceberg—we can expect many more examples in the years ahead.
Knowing the link between genes and odor perception will profoundly change how we think about smell. Pavlovian learning and Proustian remembering will have to share the stage with biology. The discovery of biological markers for scent preference would revolutionize the design and marketing of fragrance. Instead of making products that appeal to the market as a whole (and satisfy no one in particular), perfumers could target scents to biologically defined market segments. A perfumer designing something for the musk-loving, grape-hating, patchouli-indifferent audience will have a tremendous advantage over a competitor working with the old hit-or-miss method.
THE GENOMIC AGE of odor perception will be exciting. We will be able to alter odor perception at a fundamental biological level—enhancing the response of a receptor, for example, or blocking it from working at all. These molecular-level interventions could lead to new types of consumer products. Imagine a long-lasting nasal spray for the medical staff in hospitals and nursing homes. One squirt at the start of a shift would knock out the ability to smell the ammonialike notes in urine, but leave the perception of other odors unchanged. The product would work by stopping a specific class of molecules from triggering a sensation. A narrow-range odor blocker like this would make the hospital a more pleasant place to work; and happier staff make for happier patients. Think of all the other occupations—stockyard worker, plumber, refinery employee—that could benefit from selective molecular nose-filters.
Next, imagine a new kind of diet product—one with an immediate and profound effect on appetite: food would lose its appeal and odor-induced cravings would disappear. In biological terms this would be a wide-range odor blocker that interferes with many types of receptors. By reducing odor perception across the board, including food aroma, the blocker would help dieters stay on their program. A recent patent application makes such a claim for a calcium channel blocker—a type of drug usually used to control high blood pressure. Applied directly into the nose, it would temporarily stop the sensory cells from functioning, and reduce or abolish the user’s ability to smell.
By changing receptor function in other ways, we may be able to enhance odor perception. Imagine a product that selectively boosts the perception of certain body odors, like your husband’s pheromones. It might heighten sexual interest or arousal and be a useful treatment for sexual dysfunction. (It would probably become popular with ravers, clubbers, and swingers too—a nasal Ecstasy.) Another possibility is a broad-range odor booster. The results could be mind-blowing. The neurologist and essayist Oliver Sacks once described a patient who experienced heightened smell awareness while pumped up on amphetamines, cocaine, and PCP. The immediacy and clarity of smells was so great that he could find his way around New York by nose alone. Not everybody would want to have such a peak experience, although it’s a product that Emily Dickinson would have paid top dollar for. At a lower dose, a broad-range odor booster might relieve smell impairment in the elderly. Their food will taste better, they will eat more, and their nutrition will improve. Who knows, it might even alleviate the psychological depression that creeps along in tandem with the sensory deprivation of old age.
The temporary tweaking of existing odor receptors is, from a biotechnologist’s point of view, pretty straightforward. The sensory cells of the nose are in direct contact with the outside world, separated by only a thin layer of mucus. They can be reached easily with a topical nasal spray, which means a minimal amount of active ingredient and less chance of side effects. The really weird possibilities go deeper: imagine acquiring a new odor receptor gene. All you would have to do is take a big snort from spray bottle of genetically modified adenovirus, and within days you’d be having a new smell experience. Perhaps your specific anosmia to androstenone will be cured, enabling you for the first time to enjoy the expensive pleasure of truffles. Perhaps you will have a new, deeper appreciation of musky perfumes. Suppose the inhaled virus particles contained all the odor receptors a dog has and you haven’t. By the weekend you’d be smelling things our species hasn’t picked up in millions of years. The experience might be disconcerting at first, like getting powerful new contact lenses. Your brain would need time to adjust to the new odor input and bring it into focus.
This is a fantasy, but not a completely implausible one. Gene-transfer technology is routinely used in research labs. DNA is carried from one organism to another in a modified adenovirus—the virus that causes the common cold. The virus is unable to replicate on its own, but it can worm its way into the DNA of the host cells and trick them into reproducing the transferred gene.
Gene-transfer technology for humans is usually thought of in terms of treatment for life-threatening illness. But in the spirit of William Gibson’s Neuromancer, where characters favor trans-species body modification, I predict it will be used first for nonmedical and entirely unnecessary aesthetic enhancements to the human body. In similar fashion, the first animal-to-human odor receptor implant will take place for kicks, not for cure.
Transspecies genetic engineering of sensory systems is already happening in the lab. Mice have been given new photoreceptor genes, and the sex pheromone receptor of the silkworm moth has been transferred into a fruit fly. One day we will be able to control our own olfactory destiny. What do you want to smell like?
The horizon’s edge, the flying sea-crow, the fragrance of salt
marsh and shore mud,
These became part of that child who went forth every day,
and who now goes, and will always go forth every day.
—WALT WHITMAN, Leaves of Grass