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Columbia Biologists Match Odor Receptor to Odor
Research Uncovers Details of How Sense of Smell Works;
First Aroma Scientists Detect Is That of Meat
Molecular biologists at Columbia University for the first time have linked a
particular odor with the proteins in the human nose that detect it. They made
their first match with the smell of meat.
The research, by a team of biologists led by Stuart Firestein, associate
professor of biological sciences at Columbia, is reported in the Jan. 9 issue of the
journal Science. It builds on work conducted at Columbia that discovered the
receptors - proteins that stick out from nerve cells in the nasal cavity and
connect to molecules floating in the air, setting in motion a cascade of reactions
that create a perception of odor in the brain.
"I believe this experiment will prove to be a Rosetta stone for olfaction, in
that we can now begin to match odorants to receptors and decode this elusive
sense," said Darcy Kelley, professor of biological sciences at Columbia, in an
Researchers sprayed 74 individual scents, one at a time, over rat nerve cells
that contained a particular odor receptor they had inserted in the cells. The first
odor they matched to a receptor was that of octanal, which to humans smells like
Linda Buck, a neuroscientist at Harvard Medical School, and Richard
Axel, Higgins Professor of Biochemistry and Molecular Biophysics at Columbia's
College of Physicians & Surgeons, in 1991 discovered both the family of
transmembrane proteins that they believed to be odor receptors and some of the
genes that code for those proteins. They found nearly 1,000 receptors, which in
the human body number second only to the receptors in the immune system. Yet
researchers had been unable to pair any single receptor or group of receptors with
any particular odor - until Professor Firestein's team reported their results.
If humans can make 1,000 odor receptors, they must have 1,000 genes to do
so, which would account for between 1 and 2 percent of the 50,000 to 100,000 genes
thought to reside in the human genome. "That's an enormous number devoted to
a single sensory activity," Professor Firestein said. "We'd like to know why
olfaction is so important that a hundredth of the entire genome is devoted to it."
Nerve cells in the epithelium, sensitive tissue lining the nasal cavity, are
capable of recognizing and responding to an extraordinarily large repertoire of
stimuli - some 10,000 chemical odors. They accomplish this feat, at least in part,
with numerous mucus-coated fibers, which contain the receptor proteins. Those
receptors recognize different chemicals and transmit that information to the
brain, which perceives the chemicals as an odor.
Professor Firestein developed a powerful approach to understanding the
coding of smell. The idea is a simple one: if a large enough population of
olfactory neurons were forced to produce one particular receptor, then the odor
that activated that receptor would cause a much larger response than normal,
one that could be easily measured.
The Columbia team inserted two linked genes, one that codes for a rat
olfactory receptor, called rat I7, and a gene for green fluorescent protein (GFP), a
substance found normally in fluorescent jellyfish but now used by molecular
biologists to mark genetically altered cells, into a disabled adenovirus - the same
virus that causes colds. The modified adenovirus was in turn introduced into rat
olfactory neurons. The genes carried by the adenovirus were taken up by about 2
percent of the olfactory neurons exposed to them. Cells that carried the rat I7
gene also carried the GFP gene, and could be discerned because they glowed
bright green when exposed to blue light.
Professor Firestein's graduate student, Haiqing Zhao, now at Johns
Hopkins Medical School, treated rats with the modified adenovirus and then
exposed their olfactory neurons to various odorants. He monitored the electrical
activity in the neurons, producing a chart called an electro-olfactogram.
Electrical activity was highest when the nerve cells were exposed to octanal, an
aldehyde that smells meaty to humans. Related aldehydes that smell grassy or
fruity to humans produced no effect in the modified rat nerve cells. Single
olfactory neurons also showed specific responses to octanal, confirming that rat
I7 protein responds to the chemical.
The discovery will help answer many questions about smell, the least
understood of the human senses. Do receptors that are coded by similar genes
detect odors of the same chemical class, or is genetic sequence unrelated to odor
chemistry? Do individual receptors recognize multiple odorants, or do single
neurons have multiple receptors? And how does the brain use this vast genetic
resource to form and remember olfactory perceptions?
Professor Firestein, who holds a Ph.D. in biology from the University of
California, Berkeley, and joined the Columbia faculty in 1993, is widely
acknowledged as a leader in the field of olfaction. Despite a relatively brief
scientific career, he has already received a number of awards, the most recent
being the Nakanishi Award for Excellence in Olfaction Research. Most recently,
he has demonstrated that olfactory neurons are capable of detecting and
responding to single odor molecules, placing them alongside photoreceptors in
the eye as biological detectors evolved to the physical limits of perception.
The work was supported by the McKnight Foundation, the Whitehall
Foundation and the National Institutes of Health.
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