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An Update on Vibrational Theories of Smell

I’ve written a few times over the years about the vibrational theory of olfaction (VTO), the hypothesis that (at least some) olfactory receptors work by sensing vibrational levels of various functional groups, rather than using traditional stereoelectronic interactions. At a deeper level, this could involve electron tunneling at the receptors themselves – a direct quantum mechanical sensor. This idea, which has popped up more than once over the years, has most recently been identified with the work of Luca Turin, and it is fair to describe it as controversial.

Some in the field are prepared to dismiss it more or less out of hand (out of nose?), but the proposal has gotten a hearing. The problem is, experimental proof has been very difficult. An obvious test would be whether olfactory receptors respond differently to deuterated compounds as opposed to the standard light-hydrogen ones (same size, same polarity, different vibrational frequencies) but running that experiment at the desired level of accuracy has been unexpectedly difficult. Here’s an excellent recent review that goes into the details – from what I can see, it’s quite thorough and evenhanded. It takes the experimental attempts in historical order, and it’s a tangled tale. The first problem is purity: olfactory receptors are notoriously sensitive to particular compounds and functional groups. If a sample has even very small amounts of an impurity with a distinctive scent of its own, the experiment is demolished.

This has been an objection (over and over) to the various results in this area, which have been generated with work involving humans, bees, and flies in various formats. Some of these have shown discrimination is possible between deuterated and nondeuterated compounds, but all of the experimental results, as you’d figure, can also be explained by the presence of trace contaminants. Indeed, some of them have later been shown to have been confounded by just that problem, so it’s not just a hypothetical objection. Getting reliable sensory readouts from human subjects is rather tricky as well, even under the best conditions; the bees and flies are probably more convincing overall.

The review goes on to ask whether there are in fact results that can’t be explained by the existing theories of olfaction – in other words, is there a need for a new theory at all? The arguing is vigorous around this question as well, but a good case can be made that olfaction can still be explained by molecular surface shape, electrostatics, etc. Not everyone is convinced, of course. But the review goes on to mention something that many people in the field don’t bring up: even if vibrational sensing of this type isn’t going on in natural olfactory receptors, that doesn’t mean that it can’t work in artificial systems instead. We could perhaps engineer sensors for various applications that take advantage of the inelastic electron tunneling effect, and they could well be very sensitive and specific. In the end, this whole idea might still turn out to be quite useful, and the question of whether it occurs in nature or not may be come to be seen as an unfortunate and confusing detour. The VTO is dead, but long live the VTO?

38 comments on “An Update on Vibrational Theories of Smell”

  1. Mad Chemist says:

    The electron tunneling explanation just doesn’t smell right to me. . .

    1. passionlessDrone says:

      Need a +1 button. Nicely done.

    2. MTK says:

      May not pass the sniff test?

      1. gwern says:

        They turned up their noses at it because it seems fishy.

        1. luca turin says:

          You guys are amazing wits. Who knew that chemists could be fun?

  2. Uncle Al says:

    Insects are shown to be both selective and sensitive to pheromones. Assay with electro-antennaeography. Fluorination is an obvious adjunct. Either way, beware of creating new chiral centers.

    1. anonymous says:

      Someday someone should publish a book of Uncle Al’s poetic responses

      1. Uncle Al says:

        “8^>) Tell a physicist that M-theory is a Cauchy horizon. There obtains a color not in the rainbow. What is the worst thing you can do to a chemist?

        http://www.mazepath.com/uncleal/bitrypt2b.png
        … “You spelled it wrong. Make it anyway.”

        Fe3Cl3(anh)/MeNO2 suggests it’s doable. Add side chains for solubility. Be careful with scaling up benzyne reactions. Na emulsion, cha cha cha.

      2. Nick K says:

        Uncle Al – Pipeline’s own absurdist poet.

    2. Istvan Ujvary says:

      Chirality, indeed; Textbook example: (+)- and (–)-carvone. (However, could we consider ORD as ‘vibrational spectroscopy’?)
      In the world of chiral insect semiochemicals, where VTO has been extensively discussed, examples abound.

  3. Shawn Erickson says:

    I have an abiding interest in perfumery so Luca Turin’s “Perfumes: A-Z Guide” is always within reach. It’s a great, fun book! I was surprised to learn that he’s in the middle of the VTO story.

    1. Alistair Martin says:

      Suggest you read The Emperor of Scent by Chandler Burr or Lucas own book The Secret of Scent which is quite technical at times but still an entertaining read.

  4. Thomas Dobbins says:

    A captivating read on perfumery and a radical theory of smell:

    https://www.amazon.com/Emperor-Scent-Story-Perfume-Obsession/dp/0375759816

  5. loupgarous says:

    When I was at LSU Baton Rouge, a friend worked in their plant pathology lab, which had the interesting assignment of growing marijuana in carbon-14 dioxide tagged air. It makes me wonder about two closed environments growing aromatic plants, one watered with heavy water, one watered with light water, but otherwise identical in every way.

    That should, theoretically, reduce potential for contamination (apart from changes in metabolism in commensal organisms and/or the plants themselves which make new and different aromatic compounds) and give you bioequivalent natural and deuterated plant organics for scent comparisons.

    Or would it be easier and cheaper just to synthesize the aromatics with deuterated precursors?

    1. Design Monkey says:

      Nope, doesn’ t work. Plants die on 100 % heavy water. Bacteria can be completely deuterated and will somehow clunker along, but more complex lifeforms die.

      1. Derek Lowe says:

        Yet another example of how bacteria can be so ridiculously hard to kill.

      2. loupgarous says:

        Yeah, I know that on 100% D2O, anything more complex than bacteria dies. Just as marijuana grown entirely on carbon-14 dioxide wouldn’t do well, either (its DNA wouldn’t survive the beta rays). I ought to have mentioned that the “study” closed environment would irrigate with 30% heavy water, which would ideally give you aromatic plant compounds deuterated to that extent.

        Going by the review paper, this wouldn’t work with any isotopic substitution but deuteration, which is a pity because N-15-substituted ammonia was part of another experiment in the LSU soils lab I briefly worked in as work-study labor (we used mass spec to spot the tracer).

        1. Design Monkey says:

          Use of only partially deuterated compunds wouldn’t be conclusive. Also growing plants on partial heavy water content would be stress enviroment for them and that would likely alter their fragrance production nuances.

          Chemical synthesis and rigorous purification by the same procedures of both deutero/nondeutero compounds would be way to go, if one would care to test that stuff carefully.

          1. loupgarous says:

            Thanks for answering my question, I suspected “stress” would come into play at some point with a toxic isotopic substitution such as strong in vivo deuteration. Nice to have confirmation of that. Although it’s an experiment worth running (if it hasn’t been already) to see exactly what happens at that level of in vivo deuteration (apart from slowed cellular metabolism).

            In a 1996 paper, “In vivo deuteration of transfer RNAs: overexpression and large-scale purification of deuterated specific tRNAs” Jünemann, et al tweaked the expression of tRNA in E. coli via plasmids to get useful amounts of deuterated tRNA for their neutron scattering work at 100% deuteration. At least in bacteria, we can get some complex biodeuterated molecules.

            Might not be useful for vibrational studies of smell, but knowledge of any kind is never wasted.

  6. Curious Wavefunction says:

    I do think that smell poses a novel problem in that shape and electrostatics cannot account for the similarity of pairs like hydrogen cyanide and benzaldehyde (both smelling of bitter almonds). A simple exercise would be to use the tool ROCS to find Tanimoto shape and electrostatic similarity coefficients between pairs like the ones above: bet it won’t assign a high value.

    1. tlp says:

      given that smell can be extremely concentration-dependent (think of skatole), structure-smell relationship might not make that much of a sense at all

      1. luca turin says:

        The notion that skatole and indole smell “floral” at low concentrations and “fecal” otherwise is a myth. They smell of bad teeth all the way through, but a ittle bad teeth makes jasmine smells great.

    2. AVS-600 says:

      Benzaldehyde and cyanide don’t actually have similar smells at all. Benzaldehyde has a sweet, fruity smell akin to the taste of marzipan (or cherry, to some people). Cyanide has a bitter/burnt smell. The description of both as “bitter almond smell” probably comes from the fact that they’re both components of the almond glycoside amygdalin, so someone who is actually smelling genuine bitter almonds is detecting both at once.

  7. Crocodile Chuck says:

    Why do spearmint and caraway smell different?

    https://archives.nbclearn.com/portal/site/k-12/flatview?cuecard=51988

    1. Barry says:

      the caraway/spearmint discrimination is a classic challenge to the vibrational theory of olfaction.

      1. luca turin says:

        answered in the first paper on the subject https://academic.oup.com/chemse/article/21/6/773/488342

      2. luca turin says:

        answered in the first paper on the “modern” VTO (1996), https://academic.oup.com/chemse/article/21/6/773/488342

      1. Istvan Ujvary says:

        Published in the ‘Chemical nonSenses’ 😉
        (Sorry, but I, as an ex-pheromone chemist, could not resist…)

        1. Luca Turin says:

          Joke lost on me, I’m afraid.

  8. peptoid says:

    I certainly swear methanol and deuterated methanol smell completely different (the latter smells like Juicy Fruit).

    1. myma says:

      That would certainly make the experiment easier: buy compounds that are already deuterated.

      1. luca turin says:

        perdeuterated compounds that are commercially available are mostly NMR solvents, and therefore cover a fairly limited range. Fortunately mild deuteration methods are available to deuterate many useful odorants.

  9. Alistair Martin says:

    “In the end, this whole idea might still turn out to be quite useful, and the question of whether it occurs in nature or not may be come to be seen as an unfortunate and confusing detour. The VTO is dead, but long live the VTO?”

    What?! Are we no longer interested in what occurs in nature, only in what is useful?

    1. Hap says:

      Nature (life) may have done what it did because it was convenient or accessible from its historical path. Other things might be possible, though, and if you’re interested in understanding how chemistry works (the rules of the game), then finding them and seeing that they work is also useful.

      If it’s not possible to get an unambiguous answer to how smell works in living things, then asking the question isn’t helpful, and finding a working model system might be another reasonable attack on the problem. If the model is useful for other things, so much the better.

    2. Derek Lowe says:

      If I were interested only in what occurs in nature, I wouldn’t be trying to make drugs that do what nature can’t do for me. . .

  10. Scott says:

    I know you also run into some taste/scent issues with … stereoisomers? Is that the word? Some people can detect them, and those that can almost all hate the taste of broccoli (IIRC). But it’s not something that is a dominant gene, this ability doesn’t seem to run in families. Just seems to randomly pop up.

  11. Chris says:

    I’m pretty jazzed to see Luca Turin *and* Uncle Al (of USENET fame) show up in this post.

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