by Bob Holmes
When attendees are not by the pool or talking science in the bar, they can often be found in the exhibit hall, where they can peruse posters that describe current research, or browse new scientific gadgets that vendors are selling. That’s where I first met Richard Doty, who was looking relaxed and informal in a green and black-striped rugby shirt. Doty—a fit-looking seventy-year-old with short, gray-tinged hair and a cheerful manner—is one of the world’s leading experts on the senses of smell and taste. In fact, he literally wrote the book on the subject: His Handbook of Olfaction and Gustation is the classic in the field. But even if you didn’t know that, you could guess his stature by the steady stream of eminent scientists who stop by to chat. Right now, though, Doty is playing the role of pitchman. The company he founded is hawking a new machine for testing people’s sense of smell, and they’re inviting all comers to try it out. Clearly, that’s an opportunity I can’t pass up.
Specifically, Doty’s machine is designed to measure olfactory threshold, an indication of how sensitive your sense of smell is. By “olfactory threshold,” he means the most diluted trace of an odorant you’re able to detect; the lower your threshold, the more acute your nose. One of Doty’s assistants took me through the process. You sit in front of the machine and put your nose into this little mask, he explained. Then the machine will give you two puffs of air, one after the other, and the computer will ask you which of the two carried the scent of phenylethyl alcohol, a pleasant roselike odor. And then you repeat the test again and again, until the computer instructs you to stop.
What the assistant didn’t tell me—but Doty did later—was that the olfactometer could vary the concentration of the rose scent in the loaded puff. If I failed to answer correctly which puff had the scent, the computer assumed there was too little scent for me to detect, and it stepped up the dose for the next round; if I answered correctly, it assumed the concentration was above my detection threshold and reduced the dose. Over and over we went, wandering up and down like a hyperactive kid on a staircase, until we settled on the odor concentration that sat at the boundary between right and wrong answers—my olfactory threshold.
At this point, Doty strolled over and glanced idly at the printout of my result. His eyebrows went up. He stopped and peered more intently at the printout, and then turned to me with an expression of concern. “Do you have an impaired sense of smell?”
Uh-oh. When the world expert on olfactory dysfunction takes an interest in my test results, that can’t be a good sign. Especially for me, especially now: How can a guy with an impaired sense of smell credibly write a book about flavor? (You’ll recall from the jelly bean test that flavor is mostly about the sense of smell.) As Doty showed me the printout, the news looked pretty grim: according to his machine, the rose scent had to be present in more than one part per thousand before I could reliably detect it, making my threshold about a thousand times worse than average.
Doty must have seen the pained expression on my face, because he pulled an envelope from a nearby box and said, “Here, why don’t you take this test, too?” The envelope contained another of Doty’s many claims to fame, the University of Pennsylvania Smell Identification Test. This test, universally referred to as the UPSIT, is a forty-item multiple-choice test that uses scratch-and-sniff scents. (“This odor smells most like a. gasoline b. pizza c. peanuts d. lilac.” Pizza, I thought.) Picking one of four multiple-choice answers avoids the well-known difficulty people have in putting a name to a smell. Most of the time, the right answer seemed obvious, but maybe five or ten of the forty were tough. “Is this turpentine or Cheddar cheese? I’m not sure,” I found myself saying. Even distinctive smells can be hard to recognize sometimes.
A few hours later, I bumped into Doty on the exhibit floor again and gave him my UPSIT for scoring. To my relief, I got thirty-seven of the forty right—enough to put me in the seventy-third percentile for fifty-five-year-old men. “You did very well,” said Doty. “Three-quarters of your friends did worse.” Whew! My nose doesn’t disqualify me after all.
Most likely, Doty speculated, the problem with the threshold test was the environment we were in: A bustling exhibit hall isn’t the ideal place to concentrate on subtle, barely detectable odors. Plus, I’d raced through the test as quickly as I could so that the next person could try it; in a doctor’s office, the test is given much more slowly, with pauses that allow the scent from one trial to dissipate fully before the next trial starts. These minor differences in procedure can make a huge difference to the outcome—a complication that colors almost all research on the sense of smell.
That was my introduction to the messy world of olfaction research, where everything is harder—and more complicated—than it looks. While taste research is enjoying something of a golden age, smell researchers are, for the most part, still mired in the Dark Ages. Given an unknown molecule, even the best scientists have only recently been able to predict whether it has an odor at all, and can barely guess at what that odor might be. In fact, researchers can’t even agree on the details of how olfactory cells recognize odor molecules. All of which means that we’re a long way from understanding the most important mystery of the sense of smell, at least from the perspective of flavor: Do your perceptions differ from mine, and if so, what does that mean for our appreciation of flavor?
The reason olfaction has proven such a tough nut to crack is that it’s much, much more complex than taste. As we saw in the last chapter, these two flavor senses really serve two different purposes. Taste draws us toward nutritive foods and pushes us away from poisonous ones—a fairly simple yes/no decision. That makes taste the easy part of the flavor equation: Our tongues use at most thirty or forty receptors to keep track of a half-dozen or so basic tastes. It’s pretty straightforward to understand what we’re talking about, and how our sense of taste works. Smell, on the other hand, answers the question “What is it?” which is a much more open-ended question. There are, after all, a vast number of smelly things out there in the world, and our noses need to be able to cope with all of them.
Imagine taking a whiff of your morning coffee. The steam rising from your cup carries with it hundreds of different aromatic molecules, which enter your nose as you sniff. Way up at the top of your nasal cavity is a little patch of cells, less than one square inch in area, called the olfactory epithelium. The nerve cells within this patch—about six million of them—each carry one of about four hundred different odor receptors on their surface. (Actually, a few cells major in one receptor and minor in another, but we can ignore that detail here.) These olfactory sensory nerve cells send their signals straight in to the brain, giving them the distinction of being the only nerve cells in your body that connect the brain directly to the outside world.
Each receptor, in turn, recognizes particular features of specific odor molecules from the coffee. Surprisingly, scientists still don’t know for sure how this recognition happens. Most think that particular shapes on the odorant molecules fit into complementary shapes on the receptors, like the camera-in-foam-case analogy we used for bitter receptors. A vocal minority, however, thinks that instead, each odor molecule has a unique pattern of molecular vibrations, which receptors recognize using an arcane process called quantum tunneling. A lively debate is still raging between the “shapists” and the “vibrationists,” though of late it looks like the shapists are winning.
For most purposes, though, it doesn’t matter exactly how this recognition happens. What’s important is that each odor receptor recognizes several to many different odorants, and each odorant binds to several different receptors. That means that each odor molecule activates a different mix of receptors—a different chord, if you will, on the olfactory keyboard. And your coffee contains not just one odor molecule but hundreds, each sounding its own distinctive chord in your brain. Some of those chords probably sound so faintly that you can’t actually “hear” them as part of your flavor experience. (In technical terms, their concentration is below your detection
threshold.) But that still leaves a whole orchestra’s worth of important chords, as each above-threshold odorant tickles its own particular mix of receptors. Out of that cacophony, your brain somehow extracts a harmony: the flavor you know as coffee.
No wonder olfaction is so hard to understand. It has three separate sorts of complexity: diverse odor molecules, diverse receptors, and diverse “harmonies.” Let’s look at each one in turn, starting with the molecules. No one knows exactly how many different odor molecules there are in the world. For many decades, the standard answer to that question has been “about 10,000.” You’ll see that number bandied about everywhere from chefs’ blogs to scientific papers to neuroscience textbooks. Even Richard Axel and Linda Buck, who won the Nobel Prize for finding the receptors responsible for detecting odors, used it in their key paper. Bathed in Nobel glory, the notion of 10,000 different odors has come to take on the aura of received wisdom. And it adds to our general sense of incompetence when it comes to the human sense of smell. After all, psychologists estimate that we can recognize as many as 7.5 million different colors and 340,000 audible tones. Compared with that, recognizing 10,000 smells is pretty pathetic.
But a closer look shows that this 10,000-smells number, far from being hard science, is completely bogus. It comes from a seat-of-the-pants calculation dating way back to 1927. Two chemists, E. C. Crocker and L. F. Henderson, thought that smells, just like tastes, could be sorted according to four independent qualities. For taste, we have sweet, sour, salty, and bitter. (We can cut them some slack for missing umami, which few except the Japanese knew about back then.) For smell, they suggested fragrant, acid, burnt, and one more, which they first called putrid and later changed to caprylic, or goaty. And they further guesstimated that each of the four odor qualities could be assigned an intensity score between 0 (absent) and 8 (overwhelming). If so, there are 9 × 9 × 9 × 9 different ways to score a smell, a total of 6,561, which they generously rounded up to 10,000. Of such stuff is scientific orthodoxy made. If Crocker and Henderson had chosen to include a fifth quality—musky, say—and rate on a scale of 0–9, we would all have been talking about a universe of 100,000 smells instead.
So far, so bad. Joel Mainland, an olfaction researcher at Monell, thinks he can do better. Mainland is a compact, enthusiastic guy with a thin face, wire-framed glasses, and rapid speech. He started out in science thinking he would study vision, but realized early on that it would be hard to build a career there. “As I looked around the field, I realized that the big problems were solved,” he says. “And then you look at olfaction and the big problems are still not solved. To me, it was an easy switch to go to olfaction.” His hunch has paid off in spades: Mainland has become one of the brightest rising stars of olfaction research.
Recently, Mainland has tried to come up with a more educated guess at how many different odor compounds there are in the world. His reasoning goes like this: In order for us to smell a molecule, it has to be volatile—in other words, willing to launch itself into the air in gaseous form. Big molecules generally can’t do that, and in fact, chemists know of few smelly molecules that have more than twenty-one “heavy” atoms in them—that is, atoms other than hydrogen, the atomic featherweight. So let’s assume, he says, that only molecules with twenty-one or fewer heavy atoms could have odors. That gives us, by his estimate, about 2.7 trillion candidate molecules.
But not every one of those small molecules actually has a scent. Some have boiling points so high that they never become airborne at normal temperatures; others are so oily that they’re repelled by the watery mucus layer that lines the nose, so they can’t activate odor receptors. After some tinkering, Mainland and his colleagues came up with a way to use a molecule’s oiliness and boiling point to predict whether it would be smelly.
One morning in Mainland’s lab at Monell, I helped test some of his predictions. It turns out you can’t just give someone a sample and say, “Do you smell anything?”—the power of suggestion is so strong that they’ll often “notice” an odor that’s not really there, or pick up some stray odor in the room. Instead, the researchers use something called a “triangle test.” Mainland’s assistant sat me down at a table and blindfolded me, then waved three vials under my nose, one at a time, as a synthesized computer voice asked which one—A, B, or C—had the odor. After each set of three, they gave me a thirty-second “distraction break” to avoid nose fatigue: the computer played a short song clip and asked me whether the singer was male or female. (Mainland had intentionally picked ambiguous voices, so this was hard. Showing my age, I got Tiny Tim and a young Michael Jackson right, but was clueless on much of the contemporary stuff.)
Tests like these, performed on many different individuals, give Mainland the confidence to say that most people have a hard time telling male singers from female ones. More to the point, he also knows he’s about 72 percent correct in predicting whether an unknown molecule will have an odor. Applying his prediction method to the whole universe of 2.7 trillion candidates, he calculates that there must be a staggering 27 billion different smelly molecules in the world.
That’s not the same thing as saying there are twenty-seven billion different smells, though. After all, we know that several different molecules have an apparently identical sweet taste, and there might be hundreds of different molecules that give rise to a single bitter taste. If the odor universe is similarly full of “smell alikes,” then the number of unique odors could be much, much less than twenty-seven billion. But when I asked Mainland if he knew of any two molecules that smell exactly alike, he couldn’t think of any. “I was always told that no two molecules smell the same,” he said.
Now let’s switch over to the other side of the equation and look at the receptors that are responsible for detecting all those smelly molecules. Buck and Axel showed that the odor receptors are protein molecules embedded in the membranes of nerve cells in the olfactory epithelium. When geneticists first sequenced the human genome a few years after Buck and Axel’s discovery, they therefore knew an odor receptor gene when they saw it. To their astonishment, they found not just a few dozen olfactory receptor genes in the genome, but nearly a thousand! Stop and think about that for a moment: The human genome contains about twenty thousand genes in all, so out of all the genetic instructions needed to turn a fertilized egg into a functioning human being—hundreds of cell types organized into tissues and organ systems and a brain, all the molecular signals needed to keep everything running—one out of every twenty genes is for an odor receptor. That’s like walking into a library containing the world’s accumulated knowledge and finding that one in twenty books is about car repair. Who would have guessed that olfaction makes up such a large chunk of who we are?
On closer inspection, more than half of these odor receptor genes turned out to be what geneticists call “pseudogenes”—that is, the rusted-out hulks of genes that had broken sometime in our evolutionary past. Exactly how many odor receptor genes are still functional is a bit tricky to answer. The official human genome—largely that of the flamboyant genetic entrepreneur Craig Venter—has about 350 working odor receptors. But if the Human Genome Project’s gene sequencers had looked instead at your genome, they would have found that some of those 350 are broken in your genome, while others that were broken in the official version are working in yours. One team of researchers looked at a sample of one thousand human genomes and found 413 odor receptors that were functional in at least 5 percent of the population. If the researchers had looked at more people, they would no doubt have found a few more.
It’s one thing to count odor receptor genes, though, and quite another to understand which receptors recognize which odor molecules. The latter is much harder, largely because odor receptors normally live on the surface of nerve cells, which are challenging to grow in petri dishes in the lab. That makes experimentation difficult. As a result, the vast majority of receptors are what scientists, in a rare burst of colorful metaphor, call “orphan” receptors, meani
ng that we don’t yet know which odorant molecules they recognize.
Fortunately, molecular biologists have found a work-around by putting odor receptors onto the surface of kidney cells, which are much easier to grow in the lab. A few years ago, with a bit of hard work, Mainland and other researchers created a panel of kidney cell cultures expressing the whole range of human odor receptors, one per culture. With the panel in place, they looked forward to testing odorants, one after another, to see which receptors they triggered. Soon, they thought, they’d be able to “de-orphan” the lot. The olfactory code looked within reach at last.
No such luck. So far, Mainland and the other workers have only managed to find targets for about 50 human odor receptors. Try as they might, the other 350-odd receptors have remained stubbornly orphaned. “That means that about 85 percent of these receptors do not work in our assay system,” says Mainland. “That’s a lot.” It’s possible that the apparent failures detect uncommon odorants that Mainland simply hasn’t got around to testing yet—though the longer he looks, the less likely that possibility becomes. It’s also possible that some overlooked complication is preventing those receptors from working properly in the kidney cells.
There’s another, more interesting possibility: Maybe some of our odor receptors aren’t there to detect odors at all. If you take a step back and look at the big picture, what odor receptors really do is to alert the body when they recognize particular small molecules in the environment. Some of those molecules are odors, but this sort of recognition plays lots of other roles, too. Our bodies need to recognize hormones and other signaling molecules that help the body keep organized during growth and development; they need to turn functions like digestion, reproduction, and immune defense on and off at the right times, and so on. Since evolution is the ultimate MacGyver, cobbling together solutions from whatever materials happen to be lying around, it would be surprising if at least a few odor receptors hadn’t been pressed into service for other functions now and then. Sure enough, when biologists have looked, they’ve found ORs all over the place: testis, prostate, breast, placenta, muscles, kidneys, brain, gut, and more. Some of these, no doubt, occur in the nose as well—but it’s at least possible that some do not.