Research Uncovers Details Of How Sense Of Smell Works -- Columbia Biologists Match Odor Receptor To Odor

The research, by a team of biologists led by Stuart Firestein,associate professor of biological sciences at Columbia, is reported in theJan. 9 issue of the journal Science. It builds on work conducted atColumbia that discovered the receptors - proteins that stick out from nervecells in the nasal cavity and connect to molecules floating in the air,setting in motion a cascade of reactions that create a perception of odorin the brain.

"I believe this experiment will prove to be a Rosetta stone forolfaction, in that we can now begin to match odorants to receptors anddecode this elusive sense," said Darcy Kelley, professor of biologicalsciences at Columbia, in an interview.

Researchers sprayed 74 individual scents, one at a time, over ratnerve cells that contained a particular odor receptor they had inserted inthe 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 RichardAxel, Higgins Professor of Biochemistry and Molecular Biophysics atColumbia's College of Physicians & Surgeons, in 1991 discovered both thefamily of transmembrane proteins that they believed to be odor receptorsand some of the genes that code for those proteins. They found nearly1,000 receptors, which in the human body number second only to thereceptors in the immune system. Yet researchers had been unable to pairany single receptor or group of receptors with any particular odor - untilProfessor Firestein's team reported their results.

If humans can make 1,000 odor receptors, they must have 1,000 genesto do so, which would account for between 1 and 2 percent of the 50,000 to100,000 genes thought to reside in the human genome. "That's an enormousnumber devoted to a single sensory activity," Professor Firestein said."We'd like to know why olfaction is so important that a hundredth of theentire genome is devoted to it."

Nerve cells in the epithelium, sensitive tissue lining the nasalcavity, are capable of recognizing and responding to an extraordinarilylarge repertoire of stimuli - some 10,000 chemical odors. They accomplishthis feat, at least in part, with numerous mucus-coated fibers, whichcontain the receptor proteins. Those receptors recognize differentchemicals and transmit that information to the brain, which perceives thechemicals as an odor.

Professor Firestein developed a powerful approach to understandingthe coding of smell. The idea is a simple one: if a large enoughpopulation of olfactory neurons were forced to produce one particularreceptor, then the odor that activated that receptor would cause a muchlarger response than normal, one that could be easily measured.

The Columbia team inserted two linked genes, one that codes for arat olfactory receptor, called rat I7, and a gene for green fluorescentprotein (GFP), a substance found normally in fluorescent jellyfish but nowused by molecular biologists to mark genetically altered cells, into adisabled adenovirus - the same virus that causes colds. The modifiedadenovirus was in turn introduced into rat olfactory neurons. The genescarried by the adenovirus were taken up by about 2 percent of the olfactoryneurons exposed to them. Cells that carried the rat I7 gene also carriedthe GFP gene, and could be discerned because they glowed bright green whenexposed to blue light.

Professor Firestein's graduate student, Haiqing Zhao, now at JohnsHopkins Medical School, treated rats with the modified adenovirus and thenexposed their olfactory neurons to various odorants. He monitored theelectrical activity in the neurons, producing a chart called anelectro-olfactogram. Electrical activity was highest when the nerve cellswere exposed to octanal, an aldehyde that smells meaty to humans. Relatedaldehydes that smell grassy or fruity to humans produced no effect in themodified rat nerve cells. Single olfactory neurons also showed specificresponses to octanal, confirming that rat I7 protein responds to thechemical.

The discovery will help answer many questions about smell, theleast understood of the human senses. Do receptors that are coded bysimilar genes detect odors of the same chemical class, or is geneticsequence unrelated to odor chemistry? Do individual receptors recognizemultiple odorants, or do single neurons have multiple receptors? And howdoes the brain use this vast genetic resource to form and rememberolfactory perceptions?

Professor Firestein, who holds a Ph.D. in biology from theUniversity of California, Berkeley, and joined the Columbia faculty in1993, is widely acknowledged as a leader in the field of olfaction.Despite a relatively brief scientific career, he has already received anumber of awards, the most recent being the Nakanishi Award for Excellencein Olfaction Research. Most recently, he has demonstrated that olfactoryneurons are capable of detecting and responding to single odor molecules,placing them alongside photoreceptors in the eye as biological detectorsevolved to the physical limits of perception.

The work was supported by the McKnight Foundation, the WhitehallFoundation and the National Institutes of Health.