Olfactory research wins Nobel (doesn't smell good to me)

Richard Axel, of the Howard Hughes Medical Institute at Columbia University, NY, and Linda B. Buck from Fred Hutchinson Cancer Research Center in Seattle, Wash., have been awarded the 2004 Nobel Prize in Physiology or Medicine.

The Nobel Assembly at Karolinska Institutet said the two researchers were being recognized for their discovery of odorant receptors and the organization of the olfactory system. Their seminal paper, in which they described the large family of roughly 1000 genes for odorant receptors, was a watershed in the field.

"This has been of pretty immense significance," said Tim Jacob, professor of physiology at the School of Biosciences at Cardiff University, UK. "Their work has opened the door to all the current investigations trying to crack the molecular code of smells or tastes."

"Until their discovery, drawings of how olfaction takes place had a black box for reception," Matthew Cobb, from the faculty of life sciences at Manchester University, told The Scientist.

The two researchers showed that about 1000 genes—or roughly 3% of our genes—are used to code for the different odorant receptors on the membrane of olfactory receptor cells, although in humans, most are pseudogenes and only around 350 code for functional receptors. They also showed that this large family of odorant receptors are G protein–coupled receptors.

The two researchers were among many who were trying to understand the olfactory system. According to Axel, the breakthrough discovery came when Buck—a graduate student in his lab at the time—came up with "an extremely clever twist."

In a statement from Howard Hughes Medical Institute, Axel said Buck made three assumptions that drastically narrowed the field. First was that the receptors would be G protein–coupled receptors. Next, she assumed that the odorant receptors were members of a large family of related proteins. Third, the genes had to be expressed only in a rat's olfactory epithelium.

"Had we employed only one of these criteria, we would have had to sort through thousands more genes," said Axel. "This saved several years of drudgery."

"I had tried so many things and had been working so hard for years, with nothing to show for it," Buck said in the statement. "So when I finally found the genes in 1991, I couldn't believe it! None of them had ever been seen before. They were all different, but all related to each other. That was very satisfying."

Independently, Axel and Buck showed that every olfactory receptor cell expresses only one odorant receptor gene. They also independently showed that receptor cells carrying the same type of receptor converge into the same glomerulus, the Nobel Assembly said.

The research has been influential in fields beyond sensory reception, noted Barry Keverne, professor of behavioral neuroscience at the University of Cambridge. "It's not only olfaction," he told The Scientist. "It's helping us now to understand the evolution of the genome." In the wake of Buck and Axel's work, there has been an explosion of research into the phylogeny of olfactory receptors.

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"We think that we smell with our noses, [but] this is a little like saying that we hear with our ear lobes," writes Gordon Shepherd, professor of neuroscience at Yale University.

"In fact, the part of the nose we can see from the outside serves only to take in and channel the air containing odorous molecules." The neurons that sense these molecules lie deep within the nasal cavity, in a patch of cells called the olfactory epithelium.

Perched behind a sort of hairpin turn at the very top of the nasal cavity, the olfactory epithelium is only a few centimeters square. It contains some 5 million olfactory neurons, plus their supporting cells and stem cells. Actually, there are two such patches—one on each side of the nose—lying in a horizontal line just below the level of the eye.

Each olfactory neuron in the epithelium is topped by at least 10 hair-like cilia that protrude into a thin bath of mucus at the cell surface. Somewhere on these cilia, scientists were convinced, there must be receptor proteins that recognize and bind odorant molecules, thereby stimulating the cell to send signals to the brain.

The receptor proteins would be the key to answering two basic questions about olfaction, explains Richard Axel, an HHMI investigator at Columbia University. First, how does the system respond to the thousands of molecules of different shapes and sizes that we call odorants—"does it use a restricted number of promiscuous receptors, or a large number of relatively specific receptors?" And second, how does the brain make use of these responses to discriminate between odors?

The string of discoveries that totally changed the study of olfaction resulted from a new emphasis on genetics. Instead of hunting for the receptor proteins directly, Richard Axel and Linda Buck, who was then a postdoctoral fellow in Axel's group and is now an HHMI investigator at Harvard Medical School, looked for genes that contained instructions for proteins found only in the olfactory epithelium.

Their efforts produced nothing at first. "Now we know why our initial schemes failed," says Axel. "It's because there are a large number of odorant receptors, and each was expressed only at a very low level."

Finally, Buck came up with what Axel calls "an extremely clever twist." She made three assumptions that drastically narrowed the field, allowing her to zero in on a group of genes that appear to code for the odorant receptor proteins.

Her first assumption—based on bits of evidence from various labs—was that the odorant receptors look a lot like rhodopsin, the receptor protein in rod cells of the eye. Rhodopsin and at least 40 other receptor proteins criss-cross the cell surface seven times, which gives them a characteristic, snake-like shape. They also function in similar ways, by interacting with G proteins to transmit signals to the cell's interior. Since many receptors of this type share certain DNA sequences, Buck designed probes that would recognize these sequences in a pool of rat DNA.

Next, she assumed that the odorant receptors are members of a large family of related proteins. So she looked for groups of genes that had certain similarities. Third, the genes had to be expressed only in a rat's olfactory epithelium.

"Had we employed only one of these criteria, we would have had to sort through thousands more genes," says Axel. "This saved several years of drudgery."

Buck recalls that "I had tried so many things and had been working so hard for years, with nothing to show for it. So when I finally found the genes in 1991, I couldn't believe it! None of them had ever been seen before. They were all different but all related to each other. That was very satisfying."

The discovery made it possible to study the sense of smell with the techniques of modern molecular and cell biology and to explore how the brain discriminates among odors.

It also allowed researchers to "pull out" the genes for similar receptor proteins in other species by searching through libraries of DNA from these species. Odorant receptors of humans, mice, catfish, dogs, and salamanders have been identified in this way.

The team's most surprising finding was that there are so many olfactory receptors. The 100 different genes the researchers identified first were just the tip of the iceberg. It now appears that there are between 500 and 1,000 separate receptor proteins on rat and mouse—and probably human—olfactory neurons.

"That's really a lot of genes," Axel says. "It's 1 percent of the genome! This means that, at least in the rat, 1 out of every 100 genes is likely to be engaged in the detection of odors." This staggering number of genes reflects the crucial importance of smell to animals.

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Large as the number of receptors may be, it is probably smaller than the number of odors we can recognize.

"Most likely, the number of odorants far exceeds the number of receptor proteins—by a ratio of at least 10 to 1," Axel says. "In that case, how does the brain know what the nose is smelling?"

The visual system needs only three kinds of receptors to distinguish among all the colors that we can perceive, he points out. These receptors all respond to the same thing—light. Light of different wavelengths makes the three kinds of receptors react with different intensity, and then the brain compares these receptors' signals to determine color. But the olfactory system must use a different strategy in dealing with the wide variety of molecules that produce odors.

To figure out this strategy, Axel began by asking how many kinds of receptor proteins are made in a single olfactory neuron. "If a single neuron expresses only a small number of receptors, or a single receptor, then the problem of determining which receptors have been activated reduces to determining which neurons have been activated," he says.

He thought he would make more rapid progress by working with simpler organisms than rats. So he turned to fish, which respond to fewer odorants and were likely to have fewer receptors.

From studies with catfish, whose odorant receptors proved very similar to those of rats, Axel and his associates soon concluded that a given olfactory neuron can make only one or a few odorant receptors. (Buck and her colleagues have come to the same conclusion from their work with mice.)

The next step was to find out how these odorant receptors—and the neurons that make them—are distributed in the nose. Also, what parts of the brain do these neurons connect with?

"We wanted to learn the nature of the olfactory code," Axel says. "Do neurons that respond to jasmine relay to a different station in the brain than those responding to basil?" If so, he suggested, the brain might rely on the position of activated neurons to define the quality of odors.

Each olfactory neuron in the nose has a long fiber, or axon, that pokes through a tiny opening in the bone above it, the cribriform plate, to make a connection, or synapse, with other neurons. This synapse actually forms in the olfactory bulb , which is a part of the brain. A round, knob-like structure, the olfactory bulb is quite large in animals with an acute sense of smell but decreases in relative size as this ability wanes.

Thus, bloodhounds, which can follow the scent of a person's tracks for long distances over varied terrain, have larger olfactory bulbs than humans do, even though humans are more than twice the total size of these dogs.

In the olfactory epithelium of the nose, Axel and Buck's groups found, neurons that make a given odorant receptor do not cluster together; instead, these neurons are distributed randomly within certain broad regions of the epithelium, called expression zones, which are symmetrical on the two sides of the animals' nasal cavities.

Once the axons get to the olfactory bulb, however, they reassort themselves so that all those expressing the same receptor converge on the same place in the olfactory bulb. The result is a highly organized spatial map of information derived from different receptors.

"The brain is essentially saying something like, 'I'm seeing activity in positions 1, 15, and 54 of the olfactory bulb, which correspond to odorant receptors 1, 15, and 54, so that must be jasmine," Axel suggests. Most odors consist of mixtures of odorant molecules. Therefore, other odors would be identified by different combinations.

Surprisingly, the spatial map is identical in the olfactory bulbs of all the mice that have been tested, Buck says. As she points out, this information provided the key to an ancient riddle.

I was going to start a thread on this, but I see it's already been done. I'm still tempted to start a new one, because this one is begun so badly. Nevertheless, here's an article from Nature: Nobel committee honours work in understanding olfaction.

Our ability to smell, known as 'olfaction', is a potent yet often neglected player in our sensory world, and a surprising 3% of our genes are dedicated to fine-tuning its subtleties.

The Nobel Prize committee has now honoured two scientists who have done most to determine just how we recognize and differentiate the scents of roses, wines, or of good or bad meat. Their work also helps explain how an evocative smell can take us back to a poignant time in our lives.

Neuroscientists Richard Axel from Columbia University in New York and Linda Buck from the Fred Hutchinson Cancer Research Center in Seattle share this year's US$1.4-million Nobel Prize in Physiology or Medicine.

Exploiting state-of-the-art molecular techniques over the past two decades, they have developed a complete picture of how a scent is converted into a signal in the brain, where it is not only recognized, but remembered in association with accompanying emotions.

Making scents

Axel and Buck showed that each particular scent molecule activates a particular receptor on a particular cell in the lining of the nose. They identified the chain reaction that results from this activation, which involves a transducing 'G' protein and ion channels that open and close.

They also worked out the neural circuitry that passes the signal on to the higher parts of the brain, which deal with more complex matters, such as automatic recall of a childhood memory or, more pragmatically, deciding whether to discard a whiffy meal or move closer to a potential mate.

There are many different olfactory receptors, which belong to a more general family of proteins called G-protein receptors. But Axel and Buck showed that each cell in the lining of the nose contains just one sort of receptor.

This came as a surprise to the neuroscience community. But, as the pair went on to show, any receptor can be activated by a handful of related scent molecules at different intensities. And most odours are composed of many molecules, which activate different receptor-bearing cells. The researchers revealed a combinatorial code, often likened to the colours on a patchwork quilt, that allows us to recognize, and form memories of, around 10,000 different odours.

Wide application

The general principles of their work apply to other sensory systems such as that of pheromones. These are molecules that affect social behaviour in animals and that are regulated by a different family of G-protein receptors.

"The work has really been a tour de force in molecular biology," says Jonathan Ashmore, a sensory physiologist at University College London. "The pair saw the problem through from beginning to the end with extraordinary determination."

Buck is only the seventh woman ever to win the Nobel Prize in Physiology or Medicine.

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Prize in Physiology or Medicine awarded to Axel and Buck for research into the sense of smell | By Stephen Pincock