Vibration theory of olfaction
The Vibration theory of smell proposes that a molecule's smell character is due to its vibrational frequency in the infrared range. The theory is an extension to the more widely accepted shape theory of olfaction, which proposes that a molecule's smell character is solely due to its shape and electrostatic charge.
- 1 Introduction
- 2 Major proponents and history
- 3 Support
- 4 Challenges to vibration theory
- 5 See also
- 6 References
The current vibration theory has recently been called the "swipe card" model, in contrast with "lock and key" models based on shape theory. As proposed by Luca Turin, the odorant molecule must first fit in the receptor's binding site. Then it must have a vibrational energy mode compatible with the difference in energies between two energy levels on the receptor, so electrons can travel through the molecule via inelastic electron tunneling, triggering the signal transduction pathway.
The odor character is encoded in the ratio of activities of receptors tuned to different vibration frequencies, in the same way that color is encoded in the ratio of activities of cone cell receptors tuned to different frequencies of light. Although vibration theory explains odor character, it does not explain intensity: why some odors are stronger than others at the same concentrations.
Some studies support vibration theory while others challenge its findings.
Major proponents and history
The theory was first proposed by Malcolm Dyson in 1928 and expanded by Robert H. Wright in 1954, after which it was largely abandoned in favor of the competing shape theory. A 1996 paper by Luca Turin revived the theory by proposing a mechanism, speculating that the G-protein-coupled receptors discovered by Linda Buck and Richard Axel were actually measuring molecular vibrations using inelastic electron tunneling, rather than responding to molecular keys that work by shape alone. In 2006 a Physical Review Letters paper by Marshall Stoneham and colleagues at University College London and Imperial College London showed that Turin's proposed mechanism was consistent with known physics and coined the expression "swipe card model" to describe it. A PNAS paper in 2011 by Turin, Efthimios Skoulakis, and colleagues at MIT and the Alexander Fleming Biomedical Sciences Research Center reported fly behavioral experiments consistent with a vibrational theory of smell. The theory remains controversial.
A major prediction of Turin's theory is the isotope effect: that the normal and deuterated versions of a compound should smell different, although they have the same shape. A 2001 study by Haffenden et al. showed humans able to distinguish benzaldehyde from its deuterated version. In addition, tests with animals have shown fish and insects able to distinguish isotopes by smell. 
It should be noted, however, that deuteration changes the heats of adsorption and the boiling and freezing points of molecules (boiling points: 100.0°C for H2O vs. 101.42°C for D2O; melting points: 0.0°C for H2O, 3.82°C for D2O), pKa (i.e., dissociation constant: 9.71×10−15 for H2O vs. 1.95×10−15 for D2O, cf. Heavy water) and the strength of hydrogen bonding. Such isotope effects are exceedingly common, and so it is well known that deuterium substitution will indeed change the binding constants of molecules to protein receptors. Any binding interaction of an odorant molecule with an olfactory receptor will therefore be likely to show some isotope effect upon deuteration, and the observation of an isotope effect in no way argues exclusively for a vibrational theory of olfaction.
A study published in 2011 by Franco, Turin, Mershin and Skoulakis shows both that flies can smell deuterium, and that to flies, a carbon-deuterium bond smells like a nitrile, which has a similar vibration. The study reports that drosophila melanogaster (fruit fly), which is ordinarily attracted to acetophenone, spontaneously dislikes deuterated acetophenone. This dislike increases with the number of deuteriums. (Flies genetically altered to lack smell receptors could not tell the difference.) Flies could also be trained by electric shocks either to avoid the deuterated molecule or to prefer it to the normal one. When these trained flies were then presented with a completely new and unrelated choice of normal vs. deuterated odorants, they avoided or preferred deuterium as with the previous pair. This suggested that flies were able to smell deuterium regardless of the rest of the molecule. To determine whether this deuterium smell was actually due to vibrations of the carbon-deuterium (C-D) bond or to some unforeseen effect of isotopes, the researchers looked to nitriles, which have a similar vibration to the C-D bond. Flies trained to avoid deuterium and asked to choose between a nitrile and its non-nitrile counterpart did avoid the nitrile, lending support to the idea that the flies are smelling vibrations. Further isotope smell studies are under way in fruit flies and dogs.
Explaining differences in stereoisomer scents
Carvone presented a perplexing situation to vibration theory. Carvone has two isomers, which have identical vibrations, yet one smells like mint and the other like caraway (for which the compound is named).
An experiment by Turin filmed by the 1995 BBC Horizon documentary "A Code in the Nose" consisted of mixing the mint isomer with butanone, on the theory that the shape of the G-protein-coupled receptor prevented the carbonyl group in the mint isomer from being detected by the "biological spectroscope". The experiment succeeded with the trained perfumers used as subjects, who perceived that a mixture of 60% butanone and 40% mint carvone smelled like caraway.
The sulfurous smell of boranes
According to Turin's original paper in the journal Chemical Senses, the well documented smell of borane compounds is intensely sulfurous, though these molecules contain no sulfur. He proposes to explain this by the similarity in frequency between the vibration of the B-H bond and the S-H bond.
Consistency with physics
Correlating odor to vibration
A 2004 paper published in the journal Organic Biomolecular Chemistry by Takane and Mitchell shows that odor descriptions in the olfaction literature correlate with EVA descriptors, which loosely correspond to the vibrational spectrum, better than with descriptors based on the two dimensional connectivity of the molecule. The study did not consider molecular shape.
Lack of antagonists
Turin points out that traditional lock-and-key receptor interactions deal with agonists, which increase the receptor's time spent in the active state, and antagonists, which increase the time spent in the inactive state. In other words, some ligands tend to turn the receptor on and some tend to turn it off. As an argument against the traditional lock-and-key theory of smell, no olfactory antagonists have yet been found until recently.
Additional challenges to shape theory
- Similarly shaped molecules with different molecular vibrations have different smells (metallocene experiment and deuterium replacement of molecular hydrogen)
- Differently shaped molecules with similar molecular vibrations have similar smells (replacement of carbon double bonds by sulfur atoms and the disparate shaped amber odorants)
- Hiding functional groups does not hide the group's characteristic odor
Challenges to vibration theory
Three predictions by Luca Turin on the nature of smell, using concepts of vibration theory, were addressed by experimental tests published in Nature Neuroscience in 2004 by Vosshall and Keller. The study failed to support the prediction that isotopes should smell different, with untrained human subjects unable to distinguish acetophenone from its deuterated counterpart. (However another study did find that subjects could distinguish deuterated benzaldehydes from regular benzaldehydes. See Isotope effects above.) In addition, Turin's description of the odor of long-chain aldehydes as alternately (1) dominantly waxy and faintly citrus and (2) dominantly citrus and faintly waxy was not supported by tests on untrained subjects, despite anecdotal support from fragrance industry professionals who work regularly with these materials. Vosshall and Keller also presented a mixture of guaiacol and benzaldehyde to subjects, to test Turin's theory that the mixture should smell of vanillin. Vosshall and Keller's data did not support Turin's prediction. However, Vosshall says these tests do not disprove the vibration theory.
In response to the 2011 PNAS study on flies, Vosshall acknowledged that flies could smell isotopes but called the conclusion that smell was based on vibrations an "overinterpretation" and expressed skepticism about using flies to test a mechanism originally ascribed to human receptors. For the theory to be confirmed, Vosshall stated there must be further studies on mammalian receptors. Bill Hansson, an insect olfaction specialist, raised the question of whether deuterium could affect hydrogen bonds between the odorant and receptor.
In 2013, Turin and coworkers confirmed Vosshall and Keller's experiments showing that even trained human subjects were unable to distinguish acetophenone from its deuterated counterpart. At the same time Turin and coworkers reported that human volunteers were able to distinguish cyclopentadecanone from its fully deuterated analog. To account for the different results seen with acetophenone and cyclopentadecanone, Turin and coworkers assert that "there must be many C-H bonds before they are detectable by smell. In contrast to acetophenone which contains only 8 hydrogens, cyclopentadecanone has 28. This results in more than 3 times the number of vibrational modes involving hydrogens than in acetophenone, and this is likely essential for detecting the difference between isotopomers." Turin and coworkers provide no quantum mechanical justification for this latter assertion.
Vosshall, in commenting on Turin's work, notes that "the olfactory membranes are loaded with enzymes that can metabolise odorants, changing their chemical identity and perceived odour. Deuterated molecules would be poor substrates for such enzymes, leading to a chemical difference in what the subjects are testing. Ultimately, any attempt to prove the vibrational theory of olfaction should concentrate on actual mechanisms at the level of the receptor, not on indirect psychophysical testing." Richard Axel co-recipient of the 2004 Nobel prize for physiology for his work on olfaction, expresses a similar sentiment, indicating that Turin's work "would not resolve the debate - only a microscopic look at the receptors in the nose would finally show what is at work. Until somebody really sits down and seriously addresses the mechanism and not inferences from the mechanism... it doesn't seem a useful endeavour to use behavioural responses as an argument."
- "Access : Rogue theory of smell gets a boost : Nature News". Retrieved 2008-04-11.
- Turin L (1996). "A spectroscopic mechanism for primary olfactory reception". Chem. Senses 21 (6): 773–91. doi:10.1093/chemse/21.6.773. PMID 8985605.
- Dyson GM (1928). "Some aspects of the vibration theory of odor". Perfumery and Essential Oil Record 19: 456–459.
- Brookes JC, Hartoutsiou F, Horsfield AP, Stoneham AM (2007). "Could humans recognize odor by phonon assisted tunneling?". Phys. Rev. Lett. 98 (3): 038101. arXiv:physics/0611205. Bibcode:2007PhRvL..98c8101B. doi:10.1103/PhysRevLett.98.038101. PMID 17358733.
- Ball, Philip (14 February 2011). "Flies Sniff Out Heavy Hydrogen". Nature. doi:10.1038/news.2011.39. Retrieved 16 February 2011.
- Haffenden LJ, Yaylayan VA, Fortin J (2001). "Investigation of vibrational theory of olfaction with variously labelled benzaldehydes". Food Chem. 73 (1): 67–72. doi:10.1016/S0308-8146(00)00287-9.
- "David MacKay: Smells: Summary". Retrieved 2008-04-11.
- Havens BR, Melone CD (1995). "The application of deuterated sex pheromone mimics of the American cockroach (Periplaneta americana, L.), to the study of wright's vibrational theory of olfaction". Dev. Food. Sci. 37 (1): 497–524. doi:10.1016/S0167-4501(06)80176-7.
- Hara J (1977). "Olfactory discrimination between glycine and deuterated glycine by fish". Experientia 33 (5): 618–9. doi:10.1007/BF01946534. PMID 862794.
- Flies sniff out heavy hydrogen Nature 14 February 2011 . Reporting Franco, M. I., Turin, L., Mershin, A. & Skoulakis, E. M. C. Proc. Natl Acad. Sci. USA doi:10.1073/pnas.1012293108 (2011).
- Schramm, V. L. Binding isotope effects: boon and bane, Curr. Opin. Chem. Biol. 2007, 11, 529-536.
- Franco, M. I., Turin, L., Mershin, A. & Skoulakis, E. M. C. (2011). "Molecular vibration-sensing component in Drosophila melanogaster olfaction". Proceedings of the National Academy of Sciences of the USA 108 (9): 3797–3802. Bibcode:2011PNAS..108.3797F. doi:10.1073/pnas.1012293108. PMC 3048096. PMID 21321219.
- Courtland, Rachel (14 February 2011). "Fly sniffs molecule's quantum vibrations". New Scientist. Retrieved 16 February 2011.
- "Rogue Odour Theory Could Be Right". Retrieved 2008-04-11.
- Takane SY, Mitchell JBO (2004). "A structure-odour relationship study using EVA descriptors and hierarchical clustering". Org. Biomol. Chem. 2 (22): 3250–5. doi:10.1039/B409802A. PMID 15534702.
- Oka Y, Nakamura A, Watanabe H, Touhara K (2004). "An odorant derivative as an antagonist for an olfactory receptor". Chem. Senses 29 (9): 815–22. doi:10.1093/chemse/bjh247. PMID 15574817.
- "Testing a radical theory". Nat. Neurosci. 7 (4): 315. 2004. doi:10.1038/nn0404-315. PMID 15048113.
- "Putting a smell theory to the sniff test", Renee Twombly; Rockefeller Scientist, March 26, 2004
- Rinaldi, Andrea (2011). "Do Vibrating Molecules Give Us Our Sense of Smell?". Science Now. Retrieved 2011-02-17
- Ball, Philip (2011). "Flies Sniff out heavy hydrogen". Nature. doi:10.1038/news.2011.39. Retrieved 2011-02-17
- Gane S, Georganakis D, Maniati K, Vamvakias M, Ragoussis N, Skoulakis EMC, Turin L (2013). "Molecular vibration-sensing component in human olfaction." PLoS ONE 8, e55780. doi:10.1371/journal.pone.0055780
- New study strengthens olfactory vibration-sensing theory Bob Yirka,, Physorg , January 29, 2013
- Burr, Chandler (2003). The Emperor of Scent: A Story of Perfume, Obsession, and the Last Mystery of the Senses. New York: Random House. ISBN 0-375-50797-3.
- Flexitral website 
- Zyga, Lisa. Quantum mechanics may explain how humans smell. PhysOrg.com (2007). 
- TED Talks: Luca Turin: The science of scent
- BBC, Horizon, "A Code in the Nose".