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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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February 18, 2011

Smell The Vibrations? Fruit Flies Might Be Able To. . .

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Posted by Derek

A few years ago, I wrote here about Luca Turin and his theory that our sense of smell is at least partly responsive to vibrational spectra. (Turin himself was the subject of this book, author of this one (which is quite interesting and entertaining for organic chemists), and co-author of Perfumes: The A-Z Guide, perhaps the first attempt to comprehensively review and categorize perfumes).

Turin's theory is not meant to overturn the usual theories of smell (which depend on shape and polarity as the molecules bind into olfactory receptors), but to extend them. He believes that there are anomalies in scent that can't be explained by the current model, and has been proposing experiments to test them. Now he and his collaborators have a new paper in PNAS with some very interesting data.

They're checking to see if Drosophila (fruit flies) can tell the difference between deuterated and non-deuterated compounds. The idea here is that the size and shape of the two forms are identical; there should be no way to smell the difference. But it appears that the flies can: they discriminate, in varying ways, between deuterated forms of acetophenone, octanol, and benzaldehyde. Deuterated acetophenone, for example, turns out to be aversive to fruit flies (whereas the normal form is attractive), and the aversive quality goes up as you move from d-3 to d-5 and d-8 forms of the isotopically labeled compound.

The flies could also be trained, by a conditioned avoidance protocol, to discriminate between all of the isotopic pairs. Most interestingly, if trained to avoid a particular normal or deutero form of one compound, they responded similarly when presented with a novel pair, which seems to indicate that they pick up a "deuterated" scent effect that overlays several chemical classes.

There's more to the paper; definitely read it if you're interested in this sort of thing. Reactions to it have been all over the place, from people who sound convinced to people who aren't buying any of it. If Turin is right, though, it may indeed be true that we're smelling the differences between C-H stretching vibrations, possibly through an electron tunneling mechanism, which is a rather weird thought. But then, it's a weird world.

Comments (35) + TrackBacks (0) | Category: Biological News | Chemical News


COMMENTS

1. sgcox on February 18, 2011 1:00 PM writes...

I wonder if it affects the claims that deuterated drugs are similar to normal apart from improved stability.
If one class of GPCR can discriminate isotopes, why not others ? Or kinases ? Or nuclear receptors ?

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2. Allan on February 18, 2011 1:14 PM writes...

This finding is not completely surprising since some enzymes are known to have kinetic isotope effects. It make some sense that other proteins might also be sensitive to isotopic differences. That one can monitor this through behavior is just way cool!

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3. Hap on February 18, 2011 1:20 PM writes...

I thought that bonds to hydrogen and deuterium do differ in length, just not by much - so the size of a deuterated molecule should differ from its nondeuterated counterpart, and potentially be distinguishable on that basis rather than upon its vibrational spectra.

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4. Imaging guy on February 18, 2011 1:29 PM writes...

When small molecules are labeled for binding assay or imaging, isotopic labeling (3H) is claimed to be much better than fluorescence labeling as the former involves atomic substitution and is therefore not likely to change the properties of small molecule being labeled. I also think that peptides labeled with stable isotopes are also used in mass spectrometry as references. Their claims are quite extraordinary.

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5. Jim Trenkle on February 18, 2011 1:40 PM writes...

Fascinating work. The sceptical part of me wonders if it isn't downstream metabolic differences. Possibly the fruitfly feels some toxic effects from a new metabolite not otherwise seen (a common effect among deuterated compounds that you see metabolic switching). I would think an interesting check would be to take fruitfly microsomes (if available) and see what metabolites form (and at what rate) on each deuterated/non-deuterated pair. If you could show similar rates and distributions, that would be a nice confirmation.

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6. Bunsen Honeydew on February 18, 2011 1:42 PM writes...

I wonder if this wouldn't be better demonstrated by 13C labelling.

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7. rogi on February 18, 2011 2:15 PM writes...

Fellow Labrats

Take some methanol, drop it on a Kimwipe. Sniff, then take some deuteromethanol and do the same. You will be able to tell the difference. Try it blinded with your lab mates. I did with 8 of them years ago and to a man/woman, they were able to tell the difference. The CD3OD has a fruitier smell. Try it and put up the results here.

Rogi

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8. Cato on February 18, 2011 3:09 PM writes...

DELENDA EST NATIVIS!

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9. NoDrugsNoJobs on February 18, 2011 3:41 PM writes...

I don't have the paper but I can see where if there is deuterium on an -N or -O it would make more of a difference due to its ability to affect hydrogen bonding which is a more substantial effect than any minimal changes in other bonding effects (Van der waals, etc)

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10. MTK on February 18, 2011 3:54 PM writes...

Darn it.

Now I can't get Brian Wilson out of my head.

"Close my eyes
She's somehow closer now
Softly smile I know she must be kind"

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11. luca turin on February 18, 2011 5:04 PM writes...

Thanks for all the comments ! Many people are writing in proposing subtle isotope effects to account for our results but please first read the paper and the Nature dscussion http://www.nature.com/news/2011/110214/full/news.2011.39.html or if you have no access to PNAS email me lucaturin@me.com and I'll send you a pdf. What needs to be explained is that the flies generalise isotope preferences from one isotope pair to another and from deuterium to nitrile with apparently no chemistry in common, only a stretch mode around 2150 cm-1. All feedback gratefully accepted.

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12. Curious Wavefunction on February 18, 2011 6:04 PM writes...

Very interesting. I gave a literature seminar to my department on this a few years back and have followed some of the work in addition to corresponding with the authors. In preparation for the seminar, I asked 20 people from my department whether they could detect a difference between dimethyl sulfide and deuterated dimethyl sulfide. 18 out of 20 could. There is certainly some deuterium-specific effect here, and vibration is as good a candidate as any other. Other specific features of deuterium should of course also be investigated.

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13. lgf on February 18, 2011 7:53 PM writes...

Well, I was all fired up about this researcher and his vibrational sniffing theory a couple years ago. However, the major problem is that since olfaction is so sensitive it exceeds our ability to characterize impurities in samples. It is more than likely that there are some super trace components that differ deuterated vs. non-deuterated compounds. It is very difficult, if not impossible to exclude different trace impurities as the source of differing olfactory response. I am not convinced you can smell deuterium, but I am sure the solvents and other compounds the deuterated material has come into contact with in its lifetime is different than the non-deduterated.

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14. yonemoto on February 18, 2011 10:43 PM writes...

@lgf: Easy enough to test. Put it through a GC first, and sniff at the correct retention time.

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15. Luca Turin on February 18, 2011 10:55 PM writes...

@lgf: please read the paper, the experiments were designed precisely to get arount this perennial problem.

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16. Wagonwheel on February 19, 2011 6:48 AM writes...

Is there no chance for any covalent interactions with these acetophenones? They look like the sort of things which would be susceptible to neucleophiles. Any bond breaking or forming ought to show primary or secondary KIEs and could be the origin in a difference of binding or behaviour of the compounds.
As mentioned above, identify KIEs in enzyme catalysis is used to uncover the likely enzymatic reaction mechanism.

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17. Mikesh on February 19, 2011 7:43 AM writes...

It is not very surprising. The interaction of hydrogen bonds with other hydrogen bonds (that is, the energy of the so-called hydrogen bond dimer) is sensitive to isotopic substitution. Precisely, the energy of the heterodimer (H-D) is anomalously low. That's why intermediate (but not 100%) concentrations of D2O disrupt DNA. See the works of Henryk T. Flakus.

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18. Mikesh on February 19, 2011 8:19 AM writes...

H-bonds stick to H-bonds and D-bonds stick to D's, because of having same stretching frequencies. For the same reason, nitriles are 'mistaken' for deuterated stuff.

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19. Luca Turin on February 19, 2011 8:48 AM writes...

@ Mikesh
The stretch modes of C-D and C-H are at energies approx 10kT and will not be vibrating at all at 300 K

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20. Luca Turin on February 19, 2011 8:53 AM writes...

@Wagonwheel
Again, the point of the paper is that while a single individual difference in response to isotopes could be due to a large number of mechanisms the fact that tthe flies can be trained with one molecule and tested with another, and that tthe learning transfers from deuterium to nitriles is what needs to be accounted for. if you cannot access the paper let me know and I will send you a pdf. Please read it carefully before sounding off :-)

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21. milkshake on February 19, 2011 3:38 PM writes...

on practical note, if it appears that deuterated version of fragrances can have a substantially altered olfactive profile, it would be worthwhile to examine partially deuterated version of some easy-to-make commercially important fragrance compounds, i.e. spirambrene. (Several common NMR solvents are cheap enough to be acceptable as a staring material for fine fragrance applications)

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22. Mikesh on February 19, 2011 5:01 PM writes...

@Luca Turin
I meant the stretching vibrations of hydrogen bonds (vibrations of the bridge X-H..Y), not the bonds to hydrogen. I don't know if this is correct for weak H-bonds to C-H, but for strong hydrogen bonds there is an interesting theory developed by H.T. Flakus (see for example this: doi:10.1016/S0022-2860(02)00487-8 ). In short: in some hydrogen-bonded molecular crystals that contain cyclic hydrogen-bond dimers and are partially deuterated, the distribution of H-bonds and D-bonds is not random. There are domains containing only H-bonds and domains containing only D-bonds, and no H-D dimers can be detected. The reason is that the interaction energy between two H-bonds or two D-bonds is much larger than between a H-bond and a D-bond (note that the stretching frequency of a H-bond is different than that of a D-bond), because of some kind of "resonance" caused by vibronic effects (I hope I didn't mess it up, I'm not an IR spectroscopist). This effect operates only if the hydrogen bonds are close to a multiple bond or aromatic ring.

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23. Luca Turin on February 19, 2011 7:43 PM writes...

@Mikesh
Thanks for the clarification. The work you rescribe is very interesting. it reminds me of some remarkable anomalous results of Ole Faurskov Nielsen obtained in isotope mixtures of formamides. In our case the (CH) hydrogen bond donors are very weak, as you point out.

Permalink to Comment

24. cookingwithsolvents on February 19, 2011 9:45 PM writes...

The first thing I want to see is the purity of the D vs H compounds down to extreme trace levels. I don't doubt the results but I wonder if a different impurity profile could produce the observed results (due to different synthetic routes; very common for D vs H compounds). Reason: I've seen trace impurities change kinetics when doing k H/D measurements for kinetics/mechanism.

Still, very very cool results!

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25. JRnonchemist on February 20, 2011 12:13 AM writes...

First thought was, neat, a possible new way for people with dysfunctional sensory processing to be hypersensitive to things. Maybe some ramifications for industrial hygiene.

Next I thought of using isotopes of C, O, etc in gases like O2 and CO2, and then see if the result is noticeable in regular air.

Then I decided that if an isotope was not found in regular air, it might have enough stability issues that decay might be a confounding factor.

Accounting for decay might be possible with something extremely stable chemically, and testing several times over the course of many isotope half lives. If the later tests show a stronger distinction between the originally near identical samples...

Anyway, I guess I will be tracking down a copy of the article after all. I'd have thought my background would have been too weak to think of anything worth saying.

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26. Jan Jensen on February 20, 2011 12:58 PM writes...

@ Luca Turin
"The stretch modes of C-D and C-H are at energies approx 10kT and will not be vibrating at all at 300 K"

All vibrational modes vibrate, even at 0 K. I am probably misreading you, but could you clarify?

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27. Luca Turin on February 20, 2011 3:56 PM writes...

@ Jan Jensen

I should have said "aside from zero-point motion", thanks for the reminder.

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28. Curious Wavefunction on February 20, 2011 6:12 PM writes...

Is enthalpy-entropy compensation (EEC) the same for normal hydrogen bonds and deuterated hydrogen bonds? Jack Dunitz showed that EEC is almost perfect for normal hydrogen bonds (Chemistry & Biology, November 1995, 2:709-712). If it's not so for deuterated bonds, then there might be possible thermodynamic differences in bonding for H vs D. Of course these should not just show up in olfactory molecules then.

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29. drug_hunter on February 21, 2011 6:37 AM writes...

#8 Cato

I appreciate and heartily agree with the sentiment, but -- if I can be so bold -- I believe it should be "Nativis delenda est" or "Nativis delendum est", depending on whether Nativis is feminine or neutral. Of course I'm just a chemist and could well be mistaken.

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30. TX Raven on February 21, 2011 9:49 AM writes...

@ 12.Curious Wavefunction

You asked 20 people to smell dimethylsulfide?
Are they still your friends? :-)

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31. sgcox on February 21, 2011 11:46 AM writes...

@30. I am pretty sure he meant dimethyl sulfoxide...

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32. Curious Wavefunction on February 21, 2011 1:27 PM writes...

It was dimethyl sulfide. They were all organic chemists so they were used to vile-smelling substances.

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33. @@ on February 22, 2011 9:52 AM writes...

So many comments trying to challenge the paper, many of which clearly did not read the article. try ti understand before firing your guns

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34. higvas on February 22, 2011 9:55 AM writes...

Brilliant paper! fascinating work Turin

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35. luca turin on February 23, 2011 8:15 AM writes...

@ Milkshake
I find your suggestion of making deuterated spirambrene very interesting. Woody-amber compounds are on a pretty narrow cusp between woody and musky, and this may be a great place to look for a striking change in odor character with isotopic substitution. All the more so since spirambrene is an approved fragrance compound, i.e. no safety issues. Would you be interested in collaborating on this ? You can contact me at lucaturin@me.com .

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