Plausibility of the vibrational theory of smell

Plausibility of the vibrational theory of smell
Harrison's Musk cologne and soap, Philadelphia. Credit: Carfleurebon perfume blog

The vibrational theory of olfaction explains several aspects of odorant detection that theories based purely on receptor binding do not. It provides for additional selectivity through receptors that are tuned to specific vibrational bands of the odorants they bind, and also through the subsequent conduction of electrons across the odorant, presumably by a tunneling mechanism. A lot of people seem like the theory, or at least its main theorist, Luca Turin. Over the years, efforts to prove, or disprove the vibrational theory have progressed through a long series of olfactory touchstones: molecular enigmas like carvone, acetophenone, or benzaldehyde, whose experimentally perceived scent is a seemingly fickle amalgam of various molecular vibrations, mirror images, and isotopes.

The latest assault designed to topple the theory comes from Eric Block of State University of New York, and several of his colleagues. Their new results, published today in PNAS, focus on a peculiar class of odorants collectively know to us as musks. The power of some of these musks, like those related to civetone, are well known to hunters and photographers who have been said to use Calvin Klein's Obsession perfume to lure big cats. Taking a cue from Turin's own suggestions and experiments that humans could distinguish large musk molecules whose vibration frequencies were altered in a sufficient number of places by substituting deuteriums for hydrogens, Block set out to see whether the actual receptors might pass similar judgment.

To do this his group synthesized a panel of various 'isotopomers' of different musks, in particular, Exaltone® (cyclopentadecanone) and muscone. Isotopomers are simply isotopic isomers—ie. with isotopic atoms, having the same number of each isotope of each element but differing in their positions. The researchers identified a putative human musk olfactory receptor, OR5AN1, and found that all of their isotopomers gave similar receptor responses. They also looked at the responses of a homologous mouse musk receptor, MOR244-3, to their isotopomer panel as well as to deuterated and nondeuterated acetophenone and benzaldehyde, and to selected 13C isotopomers.

The way researchers typically evaluate olfactory receptor responses is to express them in either oocytes or kidney cells, and then measure any electrical or chemical response to application of the odorant. Here the researchers use a luciferase reporter assay to measure response elements like c-Fos, which are activated by cAMP. As G-protein coupled receptors (GPCRs), generate cAMP upon activation. Compared to direct electrical effects, the cAMP route (and especially any subsequent gene induction), would in turn be expected to be a much slower response.

After making various NMR and IR spectrographic measurements of some sample odorants, the researchers suggest that Turin's results may be due either to impurities, or to extra-receptor events. They also claim that their finding with musks, and a few other odorants casts doubt on the entire vibrational foundation. Turin, in the meanwhile, has moved on to solving other unanswered biophysical conundrums, like for example, the more general question of electron transport in proteins. In particular, as it pertains to other esoteric phenomena like electron spin effects in anesthesia. Naturally enough, Turin has a few objections to these claims, both with respect to the physical mechanisms and the biological mechanisms under interrogation here.

Plausibility of the vibrational theory of smell

Regarding the physics aspects Turin notes,

"I have asked Klaus Schulten, Ilya Solov'yov, Andrew Horsfield and Eric Bittner whose work is discussed in the article to comment. Their unanimous reaction was that they were well aware of the problems raised by Block et al. and had in fact discussed them at length in their publications. All feel that a definite conclusion must await a proper structure for an olfactory receptor."

As to the biology, Turin pointed out several contraindications which I will just list below;

1- An obvious question that they do not touch upon is: do the deuterated musks smell different? If not, why did they not mention it since it would have been strong evidence against our previous paper. If yes, surely they should mention it. Either way, we would be grateful for some samples for evaluation, or of course we could make our own.

2- A negative in vitro result is hard to compare with a positive in vivo one:

- We have no idea whether these olfactory receptors expressed in kidney cells work identically to the native ones or whether they have been altered/damaged by heterologous expression. There are many ways of getting a negative result, not all of which are interesting.

- Receptor activation in the vibrational theory requires two steps: A- binding, and B- a match of the band perceived by the receptor to vibrations of the odorant. Block and colleagues do not know whether the receptors they are looking at sense the correct band.

3 -They make much of differences between deuterium and hydrogen: "Thus, the acidity of D2O and H2O are different, hydrogen bonding of O–H and O–D bonds are different, boiling points and freezing points are different, etc. In particular, the gas chromatographic retention times of isotopomeric pairs in the present study are significantly different in all cases examined."

- True, but none of these things are related in any way to odorant-receptor interactions, since the deuteriums they introduce are non-exchangeable, i.e. not acid, do not form hydrogen bonds, and the boiling and freezing points are irrelevant as of course is retention time in a chromatography column.

- Furthermore, all their results contradict the above, since they show in all cases that the deuterated odorant have identical affinity to the receptor.

Explore further

Odorant shape and vibration likely lead to olfaction satisfaction

More information: Implausibility of the vibrational theory of olfaction , PNAS,

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Apr 20, 2015
also, some interesting and timely observations on electron transfer complications of FRET active fluorescent tryptophan residues in proteins, like myoglobin:

Apr 20, 2015
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Apr 20, 2015
Probably an oversimplification, but doesn't the theory predict that odorants with identical weights would have similar aromas?

For instance the following three molecules all have weights of 188.226 g/mol:




...i've no idea if these even have any significant aroma, however they're roughly in the middle of the olfactory weight bandwidth (17 to ~300 g/mol) so should have identical resonant freqs and thus similar or related aspects of scent, no?

Apr 20, 2015
not so sure of any hard-and-fast relationships that provide for a relation between molecules < 300 Daltons and their IR spectra/band although maybe someone can attest to that

Apr 20, 2015
...i just mean they'd resonate at the same frequencies, so perhaps smell similar in some respect, if i understand the proposed principal correctly.

I looked up the weight range of odorants here, which states that the smallest is ammonia at 17 Daltons, and that the largest are under 300, with optimum odorant efficacy falling midway between. I'm interested in sensory bandwidths so noted that this corresponds to around 4 octaves of frequency range - also that 17 divides into 300 around 17 times, though this is probably entirely incidental. I was looking for potential similarities at octave points - doublings or halvings of a given odorant's weight - when it struck me that by the same token, 'unisons' should be even more perceptually alike...

Apr 20, 2015
So I guess JVK-Skippy's stinky love potions are really going to take a hit once this article gets around.

@ John-the-Hew-Skippy. I thought you and the JVK-Skippy were podnas thick as thieves. You and him have a falling out over something to make you contradict his smells theories? Maybe he called you a science idiot like he does everybody else. Don't take that personal if he did Cher. Non. He calls all the really smart peoples that. The smarter they are, the more often he will call them the science idiot.

Apr 20, 2015
@MrVibrating I had no idea that molecules of similar g/mol resonated at the same frequencies. My understanding was more to do with what atoms are bonded to what atoms, and by how many bonds etc. The strength of the bonds etc, the chirality the spin states, blocks to rotation etc etc. Far more complex than just g per mol I'm afraid!!!!

Apr 21, 2015
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Apr 21, 2015
Luca Turin's objections to the PNAS criticism of his vibrational theory of smell are well founded. He asks the key question: did the deuterated odorants smell differently, noting the PNAS piece compares receptor assays to actual smell, which is a conscious sensation. Such sensations are known as 'qualia', and how they occur is unknown, part of the grand mystery of consciousness.

Turin's theory is based on quantum vibrations in odorant molecules with complex aromatic rings and pi resonance clouds, the same sort of non-polar structures mediating quantum coherent electron excitations (excitons) and resonance transfers within photosynthesis proteins, shielded from the polar environment, and enabling efficient food production. A similar mechanism has been proposed among aromatic amino acid rings in tubulin, the subunit proteins of microtubules, the major component of the cytoskeleton in animal cells. (to be continued)

Apr 21, 2015
Quantum coherent excitons and resonance transfers in a non-polar quantum underground in microtubules have been proposed as the mechanism of consciousness (Penrose and Hameroff), and inhibited by anesthetics gas molecules which bind specifically in non-polar regions. Deuteration at polar surfaces wouldn't necessarily alter odorants' quantum vibrations. (to be continued)

As excitons and resonance transfers propagate as quantum vibrations through photosynthesis proteins, and perhaps through microtubules, Turin's theory could be interpreted in a similar way, i.e. that odorant quantum vibrations resonate with aromatic pi resonance groups in their receptors, as well as intra-cellular proteins including microtubules. The PNAS piece studied intra-cellular effects of the G-protein coupled receptors, but perhaps not the right effects. G-coupled proteins interact with microtubules. (to be continued)

Apr 21, 2015
I would bet odorant binding and smell involves propagation of particular vibrations through the 'quantum underground', i.e. non-polar channels buried within microtubules in olfactory cells and cortex. And that anesthetics dampen such vibrations to prevent conscious smell.

I think Luca Turin is on the right track, and we may have a whiff of understanding consciousness.

Apr 21, 2015
@BHJ & Docite - Ah i knew i was oversimplifying.. thanks for clarifying. And yes, upon reading further there has been evidence from drosophila studies of ambiguity between different molecules with the same vibrational modes (as if Turin wouldn't have thought of that already)..

Apr 21, 2015
no doubt we need to know more about the origins of the GPCR family, which apparently predate the origins of nervous systems themselves, and perhaps the original peptide transmitter signal molecules alleged to activate them, at least in the unpolarized crude nerve nets of our radially-symmetric jellied sea-brethren. whether they predate their own canonical 2nd messenger systems too, and used even more primal signal transduction mechanisms, I wouldn't know.

Apr 26, 2015
@Stuart Hameroff:
What happened to all the links on your "quantum consciousness" page?

Tracing links from Google Scholar yields, "Page Not Found."
e.g.: /penrose-hameroff/orchor.html
and /Cosmology160.html

Apr 27, 2015
Attempts to "explain" consciousness as a sort of physical mechanism is an age old pursuit akin to attempting to square the circle. Descartes notoriously located the soul in the pineal gland. The problem is that no system of formal logic can account for its own biological existence because life per se is of a difference ordering principle. This issue is akin to Cantor's transfinite, Godel's proof and the NP hard problem in "artificial intelligence." The metaphysical stance of reductionism, whether admitted or not, is to blame for this unnecessary confusion. http://thingumbob...eas.html

Apr 27, 2015
Though if your nervous system is merely a hydraulic circuit the pineal is actually an excellent choice for its soul

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