In the Realm of the Chemical

Smell and taste have helped us navigate a world of foul poisons and sweet, voluptuous pleasures.

By David H. Freedman|Tuesday, June 01, 1993
RELATED TAGS: SENSES
Here, smell this, says George Preti, smiling satanically as he offers a small vial of fluid. Despite the ominous presentation, the fluid is deemed only mildly noxious--a reaction Preti clearly finds disappointing. Well, most people find it very unpleasant, he grumbles. And well they might: the liquid is a dilute solution of (E)-3-methyl-2- hexenoic acid, a key component of human body odor. It took Preti months to track down and isolate the offending substance in sweat in his lab at the Monell Chemical Senses Center in Philadelphia. Yet the average human nose can pick out billionths of an ounce of it floating in the air--and human noses are among the least effective noses in the animal kingdom.

Smell, and its companion, taste, are chemical senses--gritty, primitive senses designed primarily to tell us whether stuff nearby (or, if it gets to that point, stuff in our mouths) is to be avoided or savored. In fact, of all our senses, smell provides our most direct link to the environment. Every time we inhale, we bring microscopic pieces of the outside world into physical contact with the nerves in our nose for chemical analysis. These nerves, it turns out, are unique in the body in that they have one end dangling in the outside world and the other feeding into the brain, providing a direct pipeline between the two. This physical intimacy between olfaction and the brain harks back to the dim evolutionary past when smell was absolutely crucial to survival--to finding food and mates, and escaping poisons and predators. Although we humans don’t pay much attention to odors anymore, we do still sometimes catch a whiff of their close, ancient relationship to the brain: we’ve all experienced the unbidden power of odors to evoke moods and memories. As Nabokov once wrote, Nothing revives the past so completely as a smell that was once associated with it.

The primitive precursor of smell and taste most likely appeared 3.5 billion years ago, beating out vision and possibly the other senses by hundreds of millions of years. Everything senses chemicals, from single- celled organisms to man, notes molecular biologist Richard Axel of Columbia University. It probably all started in bacteria with a behavior called chemotaxis, which helps them gravitate to food and steer away from toxins. Stuck in the bacterium’s outside membranes are four or five different types of receptors--proteins with pocketlike structures designed to catch chemicals with the right fit. When a receptor is activated by a chemical, it sends signals to the bacterium’s flagellum, a sort of spinning propeller mounted on the outside of the cell. If a receptor that fits sugarlike molecules scores a match, the flagellum pushes the bacterium toward the nutritional goodies. If a receptor for toxins is activated, the bacterium avoids heading in their direction. Moving up the evolutionary ladder, the jellyfish, a simple, still-brainless invertebrate, has hundreds of sensors to detect chemicals given off by the small animals it feeds on. And microscopic wormlets known as nematodes have specialized cells laden with receptors attuned to chemicals excreted by the bacteria they eat.

When brains first evolved some 550 million years ago, they were essentially olfactory computers. Insects, which were among the first owners of brains, may use up to half their brain neurons to figure out what their olfactory cells are sensing. That’s hardly surprising, considering how important smell is to many insects. Honeybees follow odor gradients to find nectar in a flower; a mosquito finds its next blood meal by sensing the plume of carbon dioxide expired by its victim. Ants rely on pheromones-- volatile substances akin to hormones--to signal danger, mark territory, recognize kin, and orchestrate their fabulous social lives. What’s more, maintains Edmund Arbas, a neurobiologist at the University of Arizona, insects have had separate smell and taste capabilities ever since their arthropod ancestors made the transition from sea to land. They use their antennae to catch odor molecules and do their tasting through chemoreceptors around their mouthparts and elsewhere--flies, for example, have receptors on their feet and wings.

The land snail, which appeared some 350 million years ago, also devotes about half its tiny brain to taste and smell affairs. It divides the job neatly between its two pairs of antennae: one pair is waved in the air to pick up smells, while the second pair is dipped tongue-style into promising substances as a final check before ingestion. By some accounts, the land snail is a pretty sophisticated sniffer. Unlike many lesser creatures, which tend to be programmed to respond with certain behaviors to certain smells, this snail can be taught to seek out smells to which it’s indifferent. The credit for this discovery goes to Ronald Chase, a neurobiologist at McGill University in Montreal, who (among other things) spent years patiently training snails to follow unappealing smells to food rewards. I’ve gotten snails to remember these smell associations for as long as 120 days, which I believe is a world record for snail memory, he says, beaming.

In higher animals like mammals, smell is restricted to the inside of the nose, and taste to the inside of the mouth.

The mammalian sense of taste, unfortunately, is nothing unusual, but mammalian olfaction can be top drawer, reaching its zenith in mice, pigs, dogs, and a few other supersmellers. Many researchers believe dogs can smell as little as a few molecules of some odorants, though they can’t verify this because their mass spectrometers can measure molecules only by the thousands. In primates, however, smell virtuosity tends to decrease. Humans possess one of the dullest mammalian senses of smell, hundreds of times less sensitive than that of dogs.

Instead, we get by with better visual systems, notes Albert Farbman, a biologist at Northwestern University, pointing out that humans have a much more highly developed visual cortex than other animals. Smell and taste can still be critical for warning us away from fires, gases, and spoiled food, but for the most part our chemical senses have become recreational--more a source of individual, sensuous pleasure than a generic tool for survival. A dog has a more sensitive sense of smell, but it also has a more stereotyped response to smells. When we’re exposed to an odorant, we don’t necessarily feel we have to chase after the source.

Still, we’re not entirely above being behaviorally influenced by smells, either, which is good news for perfume makers, new-car dealers, and stores that pipe in fragrances designed to stimulate an urge to purchase. Even Scrooge was vulnerable to the sentimental stimulation of smell: He was conscious of a thousand odors floating in the air, each one connected with a thousand thoughts, and hopes, and joys, and cares long, long forgotten, wrote Dickens in A Christmas Carol. Odors are, in fact, intimately wired into our emotions and memories. No sooner do we smell something than signals race from our nose to the olfactory bulbs nestling like pods at the base of our brain. From there the signals move to the limbic system--an ancient brain area concerned with moods, sexual urges, and powerful emotions such as fear--and then travel to the hippocampus, which controls memories. The signals then spread to the neocortex, which is thought to give rise to conscious thought. No wonder Scrooge was moved.

This complex and marvelous process of arousal all begins, of course, when something goes up your nose. The something is molecules-- individual molecules of a volatile substance that escape into the air. The molecules travel up the nose to a sheet of moist, mucus-bathed tissue at the back of the nose that consists of 5 million smell-sensing cells. These cells are neurons--the same type of cells that compose the brain--and each is tipped with a tassel of eight or more stringy cilia. Unlike brain neurons, though, which last a lifetime, olfactory neurons turn over every one or two months. Evolution presumably provided this mechanism to cope with the wear and tear cells suffer from constant airflow and exposure to the alien substances we inhale.

Embedded in the surface membranes of the cilia are receptors somewhat reminiscent of the ones that bacteria use to steer themselves toward nutritional goodies. These odor receptors have upper parts that form a pocket in the membrane for catching odor molecules, and lower parts that stick out inside the cell. When an odor molecule comes along, it dissolves in the mucus around the cilia and floats into the appropriately shaped receptor pocket. Its arrival, in turn, trips a series of events inside the nerve cell that culminates with the cell firing off its odor signal to the brain.

But how does a neuron accomplish this feat--how does it translate the presence of a molecule outside the cell into an electrical signal inside the cell? The key, explains Yale neurobiologist Stuart Firestein, turns out to be a type of protein called a G-protein. Up to 50 of these proteins cling to the base of the receptor, the part that juts into the cell’s interior, and together they act somewhat like amplifiers, turning the small stimulus of an odor molecule into a major cellular reaction. When a receptor snags an odor molecule, it twists just enough to set these proteins loose into the cell. They, in turn, interact with other cellular proteins that open up channels in the cell’s membrane, letting a rush of electrically charged sodium atoms, or sodium ions, into the cell’s interior. The charge builds rapidly until the cell fires. Finally the electric pulse zips up the entire length of the neuron’s long, tendrillike axon to the olfactory bulbs at the base of the brain, which relay the signal to other brain regions for interpretation. And all this happens in just thousandths of a second.

Until recently the question of how receptors help identify odors was wide open. Were there a small number of receptors, each capable of detecting a vast number of odors, just as in color vision three types of cells, sensitive to red, green, or blue light, can detect hundreds of hues? Or were there a relatively large number of receptors, each interacting with a small number of odors? Linda Buck, a neurobiologist at Harvard, apparently answered that question two years ago when she was a postdoc in Axel’s lab. She identified the genes for a family of as many as 1,000 receptors in mammalian olfactory neurons--which suggests that as much as one percent of all of our 100,000 genes may be occupied just with producing these receptors, as opposed to a mere three genes for color vision.

If each olfactory cell carried a receptor for just one specific smell, then the riddle of how the brain identifies an odor would be solved: by knowing which neuron fired, the brain would know which odor triggered the firing. Unfortunately, it’s not that simple. Humans have roughly 1,000 known receptors, but they seem to be capable of recognizing some 10,000 distinct odors. What’s more (as you might guess from this disparity), although each neuron may carry only one receptor type, the receptor may recognize more than one smell. That suggests the brain needs signals from more than one neuron to distinguish a particular odorant, and thus that it relies on some sort of code.

To get an idea of how a simplified coding scheme might work, imagine three neurons. The receptor on neuron A can bind with an odor molecule that is perceived as lemon, as well as with a molecule that is perceived as rose--presumably because they have a structural similarity. The receptor on neuron B can bind with lime or rose, and the one on neuron C can bind with lemon or lime. If neurons A and B fire, the brain knows the odor must be rose, since only those two neurons have receptors sensitive to that smell. Likewise, the firing of neurons A and C would indicate lemon, and B and C would indicate lime. Of course, says Buck, it’s possible that each neuron carries more than one type of receptor and that the coding scheme is more complicated.

Right now Buck is trying to figure out how the brain goes about organizing the information received from its odor receptors. Does some of the initial processing go on in the nose? Do the locations of the receptors provide the key to the codes? Might the receptors in one region be specialized to smell fruity odors, and those in another to smell flowery ones?

That’s a tantalizing question but a hard one to answer at the moment. Researchers barely have a clue which receptors snag which molecules. One way you can try to make a match, explains Buck, is by inserting a cloned odor receptor into nonneuronal cells in a lab dish, exposing the receptor to a bunch of known odorants, and watching for the chemical evidence of G-protein activation. In other words, to find out what receptor X is for, you take odor molecules like citralva (a fruity odorant), menthone (a minty odorant), 3-methoxy-2-isobutylpyrazine (the intensely vegetal, green-bell-pepper odorant), and so on, and you throw them at the receptor, hoping for a hit. You just keep testing many different odorants in the hope that one will give you a positive response, shrugs Buck. In January, for the first time, a German group actually succeeded in matching a receptor to particular odorants in this way.

While smell can help us identify thousands of different substances, taste provides us with only four distinct sensations--sweet, salty, sour, and bitter. (Okay, maybe five, if you count monosodium glutamate and its kin, which according to some researchers have a distinct taste.) Most of what we perceive as the flavor of a food is actually its aroma, the result of volatile food molecules making their way up our nasal passageways. Some of these molecules waft directly up our nostrils before ingestion, as we bring food to our mouth. Others travel to the nose after we’ve put food in our mouth, by what’s called the retronasal route--up the passage, called the pharynx, that connects the back of the mouth to the nose, familiar to most of us as the site of postnasal drip.

If you’re skeptical that flavor consists largely of smell, take different flavors of gourmet jelly beans and eat them while holding your nose. They’ll all taste like sweet paste. That’s because nose holding not only blocks the nostrils but also prevents smell molecules from being wicked up the pharynx, much as a fire won’t draw if the chimney is blocked. Now let go of your nose, and the distinct jelly bean flavors will emerge.

The four or five tastes may seem to compose a pathetically limited vocabulary, but evolution probably had good reason to narrow taste’s spectrum. These tastes, researchers speculate, help cut through the subtleties and complexities of smell to answer crucial questions about the substance that’s about to be dropped into your innards. For example: Is it a high-energy food (sweet)? Can it restore sodium and potassium chlorides lost during exercise (salty)? Is it poisonous or spoiled (bitter)? Is it unripe (sour)? While smell points an organism toward a promising treat, taste helps discern if swallowing the food is a good idea or a giant mistake.

Each of the 3,000 or so taste buds in the human tongue is a bundle of about 100 spindly cells clustered together to form an onion- shaped organ. The tops of these cells project up into a tiny pore in the tongue’s surface, so that molecules of food dissolved in saliva rain down on their chemical-sensing tips. Unlike olfactory cells, taste cells aren’t neurons, but they can send electric pulses, causing their associated neurons to fire and relay the taste messages to the brain.

Sweet and bitter tastants--molecules that can be tasted--excite the taste cells by binding to receptors at their tips. G-proteins at the base of these receptors, it’s believed, then create the cascade of chemical events that results in the taste cells firing an impulse. Salty and sour tastants, on the other hand, probably don’t act through receptors. Salt (sodium) and the protons (hydrogen atoms stripped of electrons) that are responsible for sourness excite taste cells by flowing directly through open ion channels at the tips of the cells. The mechanisms at work in taste may be more diverse than those for smell, says Sue Kinnamon, a neurobiologist at Colorado State University. But on the other hand, the brain’s coding scheme for taste will probably turn out to be simpler, since the brain need only distinguish a handful of tastes as opposed to thousands of smells.

Of course, the brain employs the chemical senses for more than we humans are aware of. Evolution seems to have rigged them up to perform an impressive array of functions. Exploring these functions is one of the raisons d’être of the Monell Chemical Senses Center. But if you ever think of dropping in at the center, be forewarned: in addition to facing Preti’s malodorous vial, you could be sprayed with a component of boar saliva or find yourself blindfolded, smelling mice through a hole in a box. (The occasional mouse tail has been known to find its way out the hole and into the unsuspecting sniffer’s nose.)

Monell’s 50 or so chemists, biologists, and psychologists have investigated almost every question anyone has ever thought to pose about smell and taste, including some that may not at first glance seem worth asking. For example: Do people always prefer better-tasting foods? Monell physiological psychologist Mark Friedman has found that the answer, oddly enough, isn’t always yes. The taste of food doesn’t control intake over the long term, he explains. People learn to prefer foods that are high in calories and thus higher in energy content. The taste of a sweet, high- energy food can even override satiety, he notes. When you refuse a slice of pecan pie after a huge meal and someone says, ‘Here, just try a bite,’ they know what they’re doing.

Smell and taste can even trigger immune system reactions, notes Monell’s director, Gary Beauchamp. For example, if a rat is repeatedly exposed to an odor when it receives a drug that suppresses the immune system, then the immune drop can occur even without the drug when the odor is present. This kind of conditioning came as a surprise when it was first noticed more than a decade ago, for it suggested that the brain, olfactory system, and immune system could somehow talk to one another.

An even more tantalizing interaction between smell and the immune system lies behind the ability of some animals, such as mice, to recognize their kin by their odor. The keys to this feat are the histocompatibility molecules used by the immune system to determine if a cell is friend or foe. These molecules are manufactured by the body’s cells to advertise the cells’ genetic makeup. Cells from a close relative will have a slightly different set of genes and will therefore produce slightly different histocompatibility molecules; cells from a distant relative or nonrelation will produce significantly different molecules. These proteins leave a signature odor in a mouse’s urine. Thus a female mouse confronted with multiple potential mates can pick out the least-related one (generally the preference in the animal kingdom) from a whiff of urine several feet away. Once impregnated, however, the same mouse will sniff her way to the most closely related mice to build her nest in a hospitable environment.

Are human relationships partly determined by how we smell to each other? When two people fall in love, we speak of the chemistry between them being right, says Monell chemist Alan Singer. That may be the case exactly. Humans do in fact seem capable of distinguishing one another by smell, at least as babies. A breast-fed newborn will turn to a cotton pad swabbed against its mother’s neck and away from a pad swabbed against a stranger’s. Surprisingly, blindfolded humans can often distinguish two mice by their smell--or at least those humans who don’t get a tail up their nose.

As for Preti, he doesn’t keep essence of body odor around just to get a rise out of visitors. (E)-3-methyl-2-hexenoic acid, the stinky chemical in sweat, is created when bacteria on the skin feed on otherwise inoffensive-smelling substances exuded from the underarm sweat glands. So Preti has developed substitutes that are equally appealing to bacteria but that lack the chemicals necessary to produce the gamy odor. Put these substitutes into deodorants, he says, and you could keep the bacteria busy and satiated with their decoys--leaving underarm sweat almost odor-free. Hopefully, this will be the deodorant method of the twenty-first century, he says. Not that body odor need be regarded as entirely useless, Preti notes; there is evidence, for example, that male body odor can help regulate the female reproductive cycle, keeping the menstrual cycle regular. Body odor may be a subtle form of chemical communication, he says. Indeed, some researchers suspect that humans, like many animals, secrete and subconsciously smell a range of pheromones employed to attract or warn off other members of the species. Our noses may know more than we realize.

Sometimes, though, our noses fail us. More than 2 million Americans suffer from a significant loss of their ability to smell, a condition known as anosmia. (Anosmia is often perceived as a loss of the sense of taste, but most cases are due strictly to olfactory problems.) Anosmia can be caused by a gene defect, by aging, by viral infections and allergies, or, inadvertently, by certain prescription drugs. Most commonly it occurs after a head trauma, when the jarring of the brain shears off the delicate axons running from the olfactory neurons to the brain through a bony plate in the skull. In many such cases the axons grow back, restoring smell, but the condition can be permanent, forever robbing its victims of, among other things, the pleasure of savoring their food.

Specific anosmia--the inability to smell particular odors--is less devastating, which is fortunate, since most of us probably suffer from it. Different species, and even different individuals within a species, appear to have genetic variations in their smell repertoire. Although the androstenone in boar saliva drives sows wild, only half of all humans can smell it at first sniff, according to Monell psychobiologist Charles Wysocki, who keeps a spray bottle of the substance handy. Most of the nonsmellers probably lack the genes that produce the necessary receptors, while some apparently have the right genes but for unknown reasons still don’t produce enough working receptors--at least not at first. About one- quarter of the nonsmellers can be trained to smell it, Wysocki says. We think exposing the receptor cells to the molecules induces them to function. (No word on whether there is hope for those of us who don’t find essence of body odor particularly offensive.)

At any rate, our personal limitations in smell shouldn’t necessarily be regarded as a problem, contends Wysocki. They are simply part of our genetic individuality. He, for one, actually likes the smell of skunk. I may have an anosmia for some of its offensive compounds, and what remains of the odor is pleasant, says Wysocki. I roll down the windows of my car to capture it.
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