Authors: Bonnie Blodgett
And why we don't know.
T
O UNDERSTAND SMELL,
you first have to understand its primacy in human evolution. Smell is millions of years older than
Homo sapiens
, older even than man's most ancient ancestor, that nameless creature that first blundered onto land from the sea and in so doing made use of one of those evolutionary add-ons, a nose that could detect odor molecules in air as well as water.
To understand evolution, you have to erase from your brain the notion that it is a logical process resulting in exquisitely designed species.
Take the confusing jumble of cranial nerves in the human head. Paleontologist Neil Shubin likens them to the wiring and plumbing exposed when a building he once worked in was gutted. Constructed in 1896, it had undergone countless renovations. The pipes and wires, many of them damaged or useless or simply redundant, were good for something: they stored the record of how the building's mechanical infrastructure had evolved.
This I can relate to. My 1880 house still has bits of the original tube-and-post wiring, as well as quite a few ungrounded outlets and other issues that make pulling a permit a dicey proposition. The plumbing is a combination of galvanized steel, copper, and lead. We don't update the infrastructure because we'd have to tear down the house to do it. The cobbled-together system keeps us warm in winter; the appliances and lights function reasonably well; and the drinking water is as safe as the city can make it (we drink straight from the tap). My house makes a lovely metaphor for my brain. A bit of a mess, but it works.
Of the twelve paired cranial nerves in the human brain, the fifth one, the trigeminal nerve, is the most immediate example of evolution's nonlinear ways, and the most exasperating to medical students trying to keep track of its disparate functions and elaborate pathways. The trigeminal nerve controls some facial muscles and facial sensations. It registers the astringency of ammonia and the heat of jalapenos. We think of those as smells and tastes, but they're really sensations, closer to the sense of touch than to taste or smell. The trigeminal nerve also supplies the withering pain we associate with dental procedures, and the hammer blows of a migraine headache.
By contrast, the olfactory nerve is a thing of breathtaking clarity. It has one assignment only: to send odor messages from the nose to the brain.
Olfaction—the process of smelling—is another matter. It is like that building whose pipes and wires have undergone countless renovations. The human sense of smell is a work in progress whose original design has to support the weight of all the cumbersome improvements required for it to retain its value to our species.
Smelling is not only part of the limbic system—it created the limbic system. The several different species for which it was designed in the beginning depended on smell every minute of every day. Other limbic structures emerged to support this all-important alert system. The fight-or-flight response is regulated in the amygdala, while the hippocampus stores the meanings (perilous or pleasurable?) that odors convey. Deprived of smell, our dog, Mel, would be hunted down and eaten for supper by the nearest coyote; in the safety of our home, his demise would be more protracted but still inevitable without a working nose to remind him to eat. Dogs depend on smell to survive.
Humans don't. Perhaps there was a time when we did. That time is long gone. University of Chicago evolutionary biologist Yoav Gilad sparked renewed speculation about smell's long-term prospects in humans when he discovered that a certain type of rhesus monkey has color vision (most primates see in black and white). Mother Nature didn't come up with this so the monkey could enjoy the colorized version of
Citizen Kane.
Color vision enhances the monkey's ability to detect food and predators. However, it seems that the improvement required, in effect, handing over some of the rhesus monkey's smell genes in exchange for better sight. Have our human smell genes been going in the same direction?
Even if they have, smell's intimate link to the limbic system means it carries still-buried clues to how our brains evolved and to how they work now. The debate among psychologists—the few who bother to think about smell—is whether humans depend on the primary sense for emotional homeostasis. Do the myriad pleasures of scent—from the obvious ones connected with food and everyday delights like walking in the woods to the more subtle and mysterious fragrances we associate with sex—help to offset the burden that humans alone carry, the knowledge that we are mortal? Is smell's ability to trick us into losing ourselves in the moment (in pure delight) a cornerstone of human happiness? Without smell to make life worth living, indeed endurable, would our species have lasted this long?
Perfume designers call the chemicals they blend to make their alluring olfactory compositions notes. Anyone with an introductory chemistry class on her college transcript (that wouldn't be me) knows that recognizable scents are made up of molecules. The scents' formulas are like the ingredients in a recipe, a kind of shorthand that tells how much of which molecules an odor contains. The complex scent of a rose has 1,215 odor molecules; a carrot has 95.
An odor molecule must be light and lively to make it up the human nose. Most never do. Dogs smell more than we do because they have immense receptor sheets, lower stature, big snouts, and floppy ears. A bloodhound's ears are like the string mops sailors use to swab the deck: they don't let much get by them. A dog's world is saturated in smell. So is a reptile's world, but unlike snakes and lizards, dogs have excellent odor discrimination. A dog can deconstruct smell mixtures in the same way a human can inventory the contents of a room at a glance. There's the sofa, the coffee table, bookshelves, and so on. A person can't identify the ingredients in a bouillabaisse by smelling it unless he or she is a trained professional nose, as perfume designers are called. Dogs can.
So how do odorants and receptors pair up? It's critical that they do, because this hooking-up is what ensures that an odorant's electrical signal is sent to the brain. The prevailing theory is based on shape. An odor molecule and its receptor fit together like a lock and key. The odorant is the key that "unlocks" the receptor, which then sends an electrical signal along one of the nerve axons that run through the tiny holes in a wafer-thin section of the skull called the cribiform plate. Once inside the skull, the axons join together in clusters called glomeruli (pronounced "gluh-mehr-ya-lie" and less than expertly drawn by me) that transmit smell signals to the two olfactory bulbs located inside the brain just behind the nose and eyes and above the olfactory receptor sheet.
In the same split second that an odor molecule binds with its receptor, a signal is sent to the correct glomerulus in the olfactory bulb. A team led by Howard Hughes Medical Institute investigator Lawrence Katz of Duke University found that each glomerulus detects individual odorants only, and the olfactory bulb passes these pieces of information on to more advanced brain regions to make readable maps of the whole. The brain has to listen to each musician's melody to hear a symphony, explained Da Yu Lin, who took over the project in 2005 after Katz's death. "The whole is the sum of its parts."
Or is it? Peter Mombaerts of Rockefeller University collaborated with researchers at Yale to engineer mice that lacked a certain protein cell in the glomeruli of the olfactory bulb. The researchers don't know how the protein works, but without it, mice can't tell odors apart; smells sent on to the higher brain don't make sense. This suggests the olfactory bulb has a sorting role.
Next question: how does the brain combine sensory patterns with relevant memories, feelings, and thoughts into a single experience? In the olfactory (or piriform) cortex, where smells are consciously perceived, the odor is assigned certain characteristics specific to the smeller, such as whether or not he likes it; whether a lemon smells sour or a caramel roll sweet; and whether a particular coffee roast is pleasantly bitter or acrid.
How does the product of olfaction—this odor map created in the olfactory cortex—collaborate with inputs from other brain regions and result in (for example) someone lifting a mug of hot Kenyan to her lips, sniffing it once or twice, blowing on the surface, and sipping? What is the underlying logic of smell's passage from the receptor sheet to the neocortex, the thinking brain?
T
HE GENES THAT CODE
for olfactory receptors are the air-traffic controllers of smell. The modern conception of genes began in 1953, when James Watson and Francis Crick discovered the chemical structure of DNA, a double helix; the formation explained how genetic instructions could be stored and passed on from one generation to the next. Crick and Watson used the first image of DNA to propose what has come to be called the central dogma of molecular biology: in a nutshell, genes can make proteins (which are the building blocks of living organisms), but proteins can't make genes. Life is a one-way street. Though olfactory genes are present in every cell in the body, the genes' sole purpose is to allow us to smell. In olfactory cells, the genes are turned on. In other cells, they are not. Without smell genes to guide odorant and receptor binding, the smell brain wouldn't be able to tell a rose from a rotten egg.
How we recognize odors and how odorants bind to receptors has been a focus of the work of Columbia University geneticist and smell researcher Richard Axel. He's also concerned with what he refers to as the binding problem; as he put it in a lecture at Columbia in 2004, "How are bits of electrical activity integrated to allow for meaningful recognition of a sensory image?" How does the brain take a variety of sensory inputs and bind them together to form a full and complete perception of any one thing?
Richard Axel has long been intrigued by the binding problem in the context of the olfactory system. Unlike smell, the other senses take a direct route to the high brain. They don't pick up input from memory and emotion first, as smells do. Even taste and touch have proven relatively easy to understand, mainly because they're hard-wired. The taste of sugar remains sweet regardless of whether or not you were having a bad day when you first tasted it. But ask two people to sniff a cup of coffee and there's no telling what each will perceive. One might love the smell but call it tea; the other might know it's coffee all right but recoil in fear owing to a bad experience with burning hot coffee as a child.
Before Axel could begin to address this issue, though, he had to find the smell genes encoding odorant receptors. He assumed (correctly, as it turned out) that each gene coded for a specific smell receptor, and that each smell receptor opened the door of the olfactory system for just one particular odorant.
In 1988, Linda Buck, a sixth-year postdoctoral fellow in Axel's lab, came up with a way to identify the large family of genes encoding G protein-coupled smell receptors in the rat olfactory epithelium. These proteins tell enzymes inside the cell how to respond to an odorant. Based on what the receptor proteins
should
look like according to their genetic job description, Buck created a sort of smell-receptor-gene template consisting of three characteristics: (1) the genes that expressed the odorant-receptor proteins had to be active
only
in the olfactory epithelium; (2) the genes had to be abundant, because there were hundreds of thousands of individual odorants out there, each expecting to be greeted by a party of one; and (3) the genes had to code for proteins with a specific molecular structure that enabled them to deliver information across a cell.
Buck volunteered to put her smell-receptor-gene search engine to work on actually finding the genes. This meant she had to go through reams of lab data on mouse DNA. (The mapping of the human genome has allowed scientists to compare the human genetic blueprint with other creatures'. What separates man from mouse is minuscule, and the sense of smell isn't one of the separators.) Buck had to do her gene searching after hours; she knew that isolating the genes for the odorant receptors using all three parameters simultaneously would be tedious and time-consuming, but it was also an irresistible shortcut—and Axel didn't like shortcuts. A die-hard reductionist and devotee of the pure scientific method—he lived by the Austrian philosopher Karl Popper's doctrine that knowledge should be acquired through a process of verifying or falsifying hypotheses—Axel told Buck to take her project home.
Buck found the genes on a Saturday night. They coded for proteins with the necessary loops, all where they should be. She immediately told her boss the good news. The group of genes she'd teased out of the mouse DNA proved to be huge enough to make receptors for that warm one-on-one welcome for each odor molecule.
She and Axel coauthored the paper describing the process and outcome. Within six days of the paper's submission,
Cell
agreed to publish it; functional proof that these genes were the ones that encoded odorant receptors was delivered seven years after publication. The
Cell
article has been cited more than two thousand times in science papers. In 2004, Axel and Buck won the Nobel Prize in Physiology or Medicine for their discovery.
Olfaction may be old, but it's hardly rudimentary. There's little doubt among scientists that a thorough understanding of the molecular biology of the primary sense will lead to breathtaking new insights about not only how we smell but how we think. But scientists aren't there yet.
The discovery of such a large gene class dedicated to smell proved what evolutionary biologists had long suspected. As paleontologist Neil Shubin wrote, "Our sense of smell contains a deep record of our history as fish, amphibians, and mammals." Buck and Axel's finding was "a major breakthrough in understanding this."
In his Nobel acceptance speech, Axel called smell "the primal sense." The award alerted the world to olfaction's rock-star status in genetics, cell biology, and neuroscience. Axel made it clear, however, that the physiology of smell had not been entirely figured out. The shape theory of binding—the idea that a specific odorant fits into a specific receptor like a key in a lock, first proposed by biologist John Amoore in the 1950s—is still being debated. Cracking how the sensory inputs bind—binding problem number two—will require a breakthrough theory of consciousness. Francis Crick, of double-helix fame, was hard at work on it right up to his death in 2007. Crick and Watson's discovery of the structure of DNA came not so much from bottom-up reductionist research like Axel's but from connecting a speculative hunch with the concrete evidence in a blurry photograph of an actual double helix supplied by chemist Rosalind Franklin (see Matt Ridley's excellent biography
Francis Crick: Discoverer of the Genetic Code
for a detailed account of the matter). Their method is more akin to the work being done today in neuroscience labs that use functional MRIs and other imaging techniques to arrive at conclusions through a top-down approach. The members of Crick's team of brain scientists and geneticists at Caltech continue to pursue their late mentor's dream. Axel jokingly calls them "the ghost busters," a reference to consciousness as "the ghost in the machine."