Putting a smell theory to the sniff test - The Rockefeller University Scientist

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Putting a smell theory to the sniff test

BY RENEE TWOMBLY

Of the five senses, only one remains a mystery to scientists: scent. Despite decades of study, the theories of how we detect odors remain, at least on a molecular level, theories.

Now, in an attempt to cast new light on how the nose works, Rockefeller’s Leslie Vosshall has, for the first time, put a controversial scientific theory of smell to the test. Her results should lay to rest a debate over the “vibration theory” of scent that has until now largely been based on speculation and hearsay.

There are two theories of smell. Most researchers believe that the shape of a chemical determines how it smells. That is, the sense of smell works like a lock and key: the shape of a chemical (the key) fits into odorant receptor proteins on the outside of cells (the lock) that are dedicated to the sense of smell.

Then there’s the vibration theory. It states that mol-ecules in every substance generate a specific vibration frequency that the nose interprets as a distinct smell.

Though both theories are unproven, vibration theory has recently received some press attention, first by a

BBC-TV documentary, then by a book titled The Emperor of Scent. The book’s author, Chandler Burr, argues that the biophysicist who came up with vibration theory, Luca Turin, is a pioneering researcher who is being ignored by the smell research community because of his unconventional ideas. Many reviews of his book parroted that theme.

Turin, a physiologist by training and a recognized expert on perfumes, expanded upon a theory first offered in the 1930s that suggested smell was dependent on intramolecular vibrations, or the stretching of chemical bonds, within an odor molecule. He hypothesizes that the receptors lining the nose function as a biological “spectroscope” to measure the vibrational energy of odorant molecules.

Yet Turin never undertook a series of experiments

that he said, in a theoretical paper, would prove his theory. “Since Turin’s theory was based solely on his unverified reports about the smell of certain odorants, the scientific community rejected it as a universal theory of smell based on one man’s olfactory impressions,” says postdoc Andreas Keller, first author of a report on the research published in the April issue of Nature Neuroscience.

But problems exist with the shape theory as well: humans can detect many more smells than there are odorant receptors, and even if the locks are a little “loose,” the shape theory can’t explain how two chemicals, each with a unique shape, can smell essentially the same.

“There are cases that are not intuitive for the shape theory, and that is why scientists have been looking for alternative theories for a very long time,” says Vosshall, head of the Laboratory of Neurogenetics and Behavior.

A few months ago, Keller and Vosshall — who normally study olfaction in fruit flies — decided to conduct the human studies that Turin never did.

“This is a theory that has been universally rejected by every scientist, so you might ask why we bothered,” Vosshall says. “We felt that his theory has been given, by virtue of press coverage, some degree of credibility although it was never been put up to scientific scrutiny.”

Keller designed a series of three controlled, double-blind human tests with several dozen human volunteers. In the Rockefeller University Hospital Heilbrunn Outpatient Clinic, he asked volunteers to smell different odors presented in coded vials and answer a series of questions.

In the first experiment, Keller tested Turin’s prediction that if two different chemicals, one that smells like smoke and one that smells like bitter almond, were mixed together, they would smell like vanilla, because their combined molecular vibrations would match those of vanilla. None of the volunteers agreed.

A second experiment tested whether aldehydes (the major components of Chanel No. 5 perfume), composed of an even number of carbon atoms, smell different from those with an odd number. Turin hypothesized that they would because vibrational frequencies between the two groups would be different. But the participants did not detect such a trend.

The final experiment was based on Turin’s proposal that two chemicals which have almost identical shapes but markedly different molecular vibrations would have distinct smells. In several different tests, none of the subjects could tell the difference between the similarly shaped chemicals.

“In order for science to have integrity, you have to do studies properly. You can’t just sniff the substances yourself, decide in advance what the answer is supposed to be, confirm by testing it yourself and then publish a paper,” says Vosshall.

“I did the boring work of actually doing Turin’s experiments and showing what the real answer is,” says Keller, with a laugh.

Because the study was not designed to prove either theory, the results say only how smell doesn’t work. They don’t bring us any closer to knowing how it does work.

“This is a paper of solely negative results,” Vosshall says. “We didn’t disprove the vibration theory, we just didn’t find anything to support it. The results show that molecular vibrations alone cannot explain the perceived smell of a chemical. And while all of our data are consistent with the shape theory, they don’t prove the shape theory.”

March 26, 2004

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