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To pluck molecules of scent from the air and make sense of them - discriminating the perfume of a rose from the stench of a skunk, for example - requires an intricate system of detection and neural processing.
Until recently, how this is accomplished was unknown. But the work of HHMI investigator Linda Buck has in large part unraveled the mechanisms that underlie our sense of smell.
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The sense of smell is mediated by the olfactory system, a system that is characterized by exquisite sensitivity and discriminatory power. Even a slight change in the structure of an odorant can change its perceived odor.”
-- Linda Buck, Nobel Lecture 2004
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Buck's seminal contribution to the science of smell began with the discovery of a family of some 1,000 genes responsible for producing protein receptors on key cells on the wall of the nasal cavity - work that she did in the laboratory of HHMI investigator Richard Axel at Columbia University as an advanced postdoctoral fellow. These receptors - located on the surface membranes of neurons that populate the swathe of cells known as the olfactory epithelium — are responsible for detecting odorous chemicals, or odorants, that are inhaled. In her own laboratory at Harvard Medical School, Buck, herself an HHMI investigator, then went on to explore how the brain organizes signals from different odorant receptors to translate those signals into the perceptions of a multitude of diverse scents.
The work of Buck and Axel effectively defined the biological pathway for the olfactory system, showing how a large family of genes generates a system capable of detecting and discriminating among as many as 10,000 different odors. For their accomplishment, which demystified the molecular underpinnings of smell, Buck and Axel were awarded the 2004 Nobel Prize in Physiology or Medicine for their discoveries of "odorant receptors and the organization of the olfactory system".
Buck, now an HHMI investigator at the Fred Hutchinson Cancer Research Center in Seattle, spent years searching for the genes that make the odorant receptors that detect odor chemicals. Through a test of three critical assumptions - that the receptors would be distantly related in appearance to the receptors for sight, that the different odorant receptor proteins would share certain similarities to each other but also differ in order to recognize different odor chemicals, and that the genes would be expressed only in the olfactory epithelium of her model, the rat - Buck narrowed the search by thousands of genes.
One of the critical waystations in the olfactory system is the olfactory epithelium, a gathering of roughly 5 million neural cells occupying a small corner of the nasal cavity. Each of those neurons is equipped with odorant receptors that recognize and capture specific odorants wafting through the air. Once a receptor hooks up with an odorant, the neuron sends signals to the olfactory bulb of the brain, which then relays the signals to the olfactory cortex. From there, odor signals are sent to the higher cortex, which is involved in odor perception and discrimination, as well as to the limbic system, which generates emotions and physical responses to odors.
Once the receptor proteins and their genes had been identified, Buck, then at Harvard Medical School, focused on how the brain converts information from those receptors into the perception of scents. Her group and Axel's independently investigated the receptors on the neurons carpeting the olfactory epithelium. The two labs found that the receptors are not distributed by type in the olfactory epithelium; instead, receptors of the same type are scattered throughout the millions of cells. A sense of order is restored in the olfactory bulb of the brain, where related nerve fibers converge on specific spots that are the same in different individuals.
Buck went on to show that although each neuron in the olfactory epithelium expresses only one type of odorant receptor, each receptor can recognize several odorant molecules. Conversely, a single odorant molecule is typically recognized by multiple receptors - but each odorant molecule triggers a unique combination of receptors. Thus, different combinations of receptors identify a multitude of odorants similar to the way different combinations of letters form words. These findings showed how we are able to sort through and distinguish among a vast number of different odorants, using little more than 1,000 distinct odorant receptors. It also showed how a tiny shift in the chemical structure of an odorant molecule can dramatically alter our perception of it - changing, for example, from sweaty socks to orange.
Buck's work changed the way scientists study olfaction. By focusing on finding the genes that make the olfactory receptors, as opposed to hunting for the proteins, and then using those genes to study the brain, she helped bring the tools of molecular and cell biology to bear on the sense of smell.
Photo: Rex Rystedt
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