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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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September 26, 2006

Smell the Vibrations

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Posted by Derek

Mentioning the C. S. Sell article on odors and molecules the other day leads me to talk about Luca Turin. I don't think you can seriously take up the topic of chemicals and their smells without mentioning him, although those mentions tend to be anything but neutral.

Turin is (in)famous for suggesting that there's more to smell than molecular shapes and functional groups. He has an impressive list of structures that provide almost the same scent, but have very different shapes, along with a complementary set of nearly identical molecules with very different ones. These, along with several other arguments (vide infra) have led him to propose that the human body responds not only to shapes, but to vibrational spectra. Your nose, by this theory, is smelling the infrared spectra of the molecules that reach it.

This isn't a new idea - it was first proposed in 1938, and again in the early 1980s. Both times it was shot down, though, primarily by counterexamples such as enantiomeric molecules (mirror-image, for the non-chemists) which smell different while having identical vibrational spectra. Another problem was that no one could figure out how an olfactory receptor could be sensing vibrational spectra, since, to the best of human knowledge, the majority of noses contain neither a source nor detector of infrared light.

Luca proposed that electron tunnelling might provide the answer, and took a cue from solid state electronics. If the receptor was senstive to electron flow, it could function as a switch. An unoccupied receptor would have no current, but if a molecule whose vibrational mode energy was the same as the energy gap between its filled and unfilled levels, then electrons could drop to the lower state by tunnelling across. The receptors wouldn't scan the range themselves - rather, each one would be tuned to a different energy gap. Whether or not a given molecule worked for a given receptor would depend on its size and shape (to fit into the active site) but also on its charge distribution (and thus its functional groups) and its vibrational spectrum. The most complete published version of his theory can be found here.

In 2003, a book came out extolling Luca's work: The Emperor of Scent. It goes into detail about how the vibrational theory was received, which was mostly with great scepticism. Reviews of the book itself were all over the place, from enthusiastic to vitriolic. In that last category was the one from Nature Neuroscience (subscriber link here). The author, Chandler Burr, must have known that he was going to be in for a rough time when the reviewer started things off by quoting "Good Vibrations" by the Beach Boys.

I'll say this for the idea: this theory is well-made, because it's wide-ranging enough to accommodate a lot of the puzzling data about chemical odors, while at the same time making some specific predictions. Counterexamples can be found to just about any simple theory of odor, but this one is harder to get rid of. Not that people haven't tried, though. In 2004, a group at Rockefeller University reported some tests of Luca's predictions in Nature Neuroscience, a journal that must have been happy to see their manuscript. Three of his proposals took a good pounding: that mixtures of guiacol and benzaldehyde take on a vanilla odor not found in either compound alone, that straight-chain aldehydes with an odd number of carbons smell different from even-numbered ones, and that deuterated acetophenone smells different from the parent compound. The group reported failure on all three counts. The accompanying editorial was especially nasty, and to my mind, rather uncalled-for.

Turin has addressed some of these results, and it can be inferred that he didn't care for the Rockefeller group's experimental design. (He's partnered with a British statistician to analyze past data in the field and propose new designs for such tests). It does seem though, from the available data, that many animals from insects to dogs can in fact distinguish deuterated compounds from their lighter analogs. Turin's also proposed deuterated/nondeutreated dimethyl sulfide as a more distinguishable pair of compounds (see this long but interesting review article). That one's from 2003, before the latest results, but even at that point he's pointing out that vibrational theory, taken by itself, can't explain many important things about odors (such as their perceived intensity). At the same time, though, he maintains that the standard "odotope" theory is even more lacking.

Turin has now come out with a book of his own, which is getting better treatment from the scientific press so far (here's the Science review for subscribers). He's also put his money where his, er, nose is by forming his own company, Flexitral, with the intention of finding new odorants more efficiently. So far, the company has several commercial products, which are claimed to be improvements over the existing analogs in stability and allergenicity.

As for me, I'm willing to believe that vibrational spectra might be a component of odor, although shape is clearly a factor, too. But I'm betting that downstream neural processing will be just as large an influence, if not greater. For now, I'm going to see if I can get some deuterated dimethyl sulfide, and if I do, I'll report back.

Comments (22) + TrackBacks (0) | Category: Chemical News


COMMENTS

1. katre on September 26, 2006 7:38 PM writes...

You're going to subject your nose willingly to DMS, in the name of science? You're a better scientist than I.

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2. hch on September 26, 2006 7:51 PM writes...

olfactory isotope effects!

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3. kiwi on September 26, 2006 8:06 PM writes...

this "X smells different to Y" stuff has the N-ray fiasco written all over it. you can get the whole turin paper can be found here fyi; http://www.flexitral.com/research/chemical_senses_complete.pdf

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4. milkshake on September 26, 2006 9:24 PM writes...

Deuterated dimethyl sulfide is quite inexpensive - try Cambridge isotopes. You should try and report back.

As far as I can tell, deuterated benzene, pyridine, acetone and chloroform smell remarkably like their non-deuterated cousins.

I believe there is huge role of brain processing - Smels combine in a very non-linear way.

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5. Jim on September 26, 2006 9:39 PM writes...

Personnaly, I am a big fan of olfactory head-space analysis in a lab environment.


Especially when you see a undergrad learn not to stick his nose into a RB to check if his TFA has all evaporated!

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6. New Hypothesis on September 26, 2006 10:22 PM writes...

Just wanted to share my review of The Emperor of Scent, which I posted to my now-moribund blog about a year ago. Funny that we used the same stupid pun to describe Turin's current business activities!

Great site, Derek. Keep up the good work!

http://newhypothesis.com/index.php?itemid=12&catid=2

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7. Dr Snowboard on September 27, 2006 2:38 AM writes...

Curiously, I find undeuterated dimethylsulfide quite sweet and pleasant. Recrystallising CuBr.DMS from neat DMS used to be quite a joy..

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8. milkshake on September 27, 2006 3:49 AM writes...

I bet your labmates find you to be a sweet and pleasant peson, as you do the re-crystallizations. I had a colleague across the lab and he would Swern all the time. He also had a dreadfull taste in music. (And he would insist on playing it full blast, to hear it over the sound of his hood.)

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9. kiwi on September 27, 2006 7:14 AM writes...

You smell that? Do you smell that? Swern, son. Nothing else in the world smells like that. I love the smell of Swern in the morning...

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10. Dr Snowboard on September 27, 2006 11:50 AM writes...

Perhaps it's a smell that gets better with higher concentration? I find the smell of DMSO or Swern ated glassware nauseating...

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11. Jose on September 27, 2006 4:44 PM writes...

Looking at CIL's offerings, I think d-pyridine would be a good choice- nice, obvious distinctive smell everyone can experience.

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12. Ashutosh on September 27, 2006 4:45 PM writes...

I gave a graduate seminar on Turin's theory last summer, and corresponded with both him and Burr. Burr is primarly a journalist and I don't think he is concerned about scientific nuances. That's why the book is extremely readable in terms of prose, but lacks accuracy in describing some scientific concepts.

Turin's ideas are provocative, although his computational calculations have been challenged by high-level quantum chemical calculations (for vibrational frequencies). There is also some ambiguity in his calculations; for eg. in one instance, the C=O stretching peak for a ketone was at 2100 cm-1, way off. Strictly speaking, he says the nose is doing electron tunneling spectroscopy.

I used DMS and DMS-d6 in the seminar, and asked ten people (small sample size) whether they smell the same or different. I have to say that without exception, all of them said they smelt different (and vile), and I too think they do.

Turin is largely innocent until proven guilty. There are other differences besides C-H and C-D vibrations between DMS and DMS-d6 (or other similar cases), including tunneling. However, we have to face the fact that nobody else has experimentally demonstrated a causal relation between these variables and different smells. The problem is, neither has Turin! He has demonstrated that changing a single parameter from H to D changes the smell. But like it is for other universal problems in physical organic chemistry, who knows whether we are also not tampering with other parameters. We are as noted above. So it's hardly a controlled experiment, necessary for establishing cause and effect.

What is really interesting in the book is Burr's description of the scientific review process, which rejected Turin's manuscript. He probably tries to vilify it a little too much and also criticizes some well-known scientists like Nobelist Linda Buck who he claims did not return his phone calls, but maybe peer review is too rigid, and maybe we need to have a separate 'Speculations' section in journals. Current peer review is like democracy; it has deep flaws, but it's probably the best system we have currently.

Also, I still don't think smell is 'objective' as both Turin and Burr claim. I think there is some objectivity to smell, but as I commented in a post before, there is no way of objectively judging whether a certain fragrance has '57% floral notes' in it.

And finally, yes, the inexpensive DMS and its isotope I used were from Cambridge Isotopes.

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13. Derek Lowe on September 27, 2006 5:11 PM writes...

Oy, won't that be an enjoyable way to spend the afternoon, carefully smelling pyridine and dimethyl sulfide? I'm looking forward to trying the experiment, but I have to say that I wish I could buy deuterated raspberry ketone instead.

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14. JB on September 27, 2006 5:50 PM writes...

This is very interesting. I've never heard of Turin and although I started out chuckling as I was reading your description of his theory, I do think he's onto something here. Case in point: I worked on some thio-beta-diketones a few years back. As bad smelling as they were, the smells were nothing compared to the resulting ones when the ligands were coordinated to copper or silver. The same ligand gave a vastly different (although all were gross and disgusting) smell when coordinated to silver instead of copper. These complexes have different structures, hence different vibrational spectra. Hmmm...
Add to this the size difference between copper and silver, his theory is starting to sound real good. Of course, until someone can figure out how our odor receptors can identify diffences in vibrational frequencies, there will always be reviewers ready to villify his theory.
BTW, I've been using DMSO and DMSO-D6 quite a bit lately and I do detect a difference, albeit faint, in smell between the two.

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15. TFox on September 27, 2006 6:34 PM writes...

I don't like the "X smells different from Y" assay either -- it's not obvious to me how to statistics on it. Better would be to train your observers in the putative scent difference, and then test them on blinded pairs of samples. It doesn't matter what you call the difference -- "floral", "deuterated", whatever; what matters is whether trained (and perhaps selected) observers can consistently detect it blinded, at least consistently enough to be sure their success isn't random. N=10 is not too small, if your observers can get it right 100% of the time, but larger sample sizes will allow you to identify a weaker effect.

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16. Chrispy on September 27, 2006 8:35 PM writes...

It seems like the test of deuterated vs. regular would be better done with (say) a series of identical vials containing one or the other compound. The idea would be to group like with like.

For example: 5 vials of each, numbered on the bottom and mixed up randomly. (I think) the odds of splitting up the two groups again by chance is 5/10 x 4/9 x 3/8 x 2/7 x 1/6 = .004% -- less if you don't know the split is 50/50. You are free to take your time, sniff one against the other, etc.

The object is not a statistical sample of people (people sense smells differently, after all) but, rather, whether even a single person can do it reliably.

You could be the one, Derek!

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17. The neurophilosopher on September 28, 2006 1:42 AM writes...

As a neuroscience undergraduate at UCL, I was fortunate to have Luca as a tutor. I say I was fortunate because I found him quite an inspiration.

I vividly remember his long, narrow office/lab, whose shelves were lined with hundreds of bottles of perfumes.

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18. BCP on September 28, 2006 8:19 PM writes...

Maybe I'm missing the point, but is any medicinal chemist out there surprised by the idea that two different shaped molecules can bind to a target with the same downstream effect? I will happily confess to knowing next to nothing about olfaction, but can anyone enlighten me as to why bioisosterism is not a plausible explanation for a similar odor among structurally distinct compounds?

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19. luca turin on September 29, 2006 1:39 AM writes...

Very interesting discussion !
Re: JB's mention of beta-dithioketones, could you please get in touch with me at l.turin@flexitral.com ?
Those molecules would be extremely useful both to me (I'm curious to smell them) and to people who are trying to solve the structure of the receptor, because the silver would be ideal as a heavy atom in X-ray crystallography.
Thanks in advance.

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20. Analyst on October 2, 2006 12:28 PM writes...

Another explanation as to why DMSO and DMSO-6 may smell different might be purity. Chemists realize that very small quanities of sulfur compounds can be quite odiferous. To really confirm or deny the proposition that the two are in fact distinguishable by smell, I would prepare and purify them in identical fashion and get at least pharmaceutical level analyses on both materials (impurity levels at least to ~ 0.02%)prior to running any comparison experiment.

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21. GC on October 4, 2006 7:25 PM writes...

Agreed with analyst. Sulfur compounds are rife with impurities that are smelly (recall that you smell mercaptans down into the ones of parts per billion). I have heard (this may be apocryphal) that scrupulously pure DMSO smells "ethereal" and has essentially no sulfur odor. It wouldn't surprise me if deuterated compounds had lower standards for chemical purity than other reagents (puriss. is only 98.5%+, anyway). In the Burr book they used some kind of analytical chromatography to purify the acetophenone-D8 and acetophenone before smelling, fwiw.

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