VOL. 23, NO. 12	JANUARY 23, 1998

Stuart Firestein. Record Photo by Eileen Barroso.

olecular biologists at Columbia for the first time have linked a particular odor with the proteins in the human nose that detect it.

  The research, by a team of biologists led by Stuart Firestein, associate professor of biological sciences, was reported in the Jan. 9 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, in an interview.

  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 meat.

  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 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," 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.

  Firestein's approach 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. 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.

  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.

  The discovery will help answer many questions about smell, the least understood of the human senses. 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?

  Firestein, who holds a Ph.D. in biology from U.C.-Berkeley, and who 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.