Reply to Hettinger: Olfaction is a physical and a chemical sense in Drosophila

Abstract

We would like to thank Dr. Hettinger (1) for his positive comment on our results showing that flies can discriminate isotopes by smell and are capable of cross-learning between odorants sharing a molecular vibration. Our article (2) demonstrated the presence of a physical (vibrational) component to odor character necessitating a vibration-sensing mechanism, the nature of which was not addressed experimentally and remains to be elucidated. We suggest that it likely involves inelastic electron tunneling, because this is consistent with our experimental data and with Brookes et al. (3), who have shown that an inelastic tunneling mechanism in olfaction is physically plausible. As pointed out by Luca Turin, this odorant detection mechanism does not require generation of free electrons by NADPH (4) and offers a potential explanation to why most enantiomer pairs smell identical. Further, Takane and Mitchell (5) have found IR spectra to be good predictors of odor character.In our article, we described data obtained for Drosophila olfaction; we did not discuss or extend our findings to vertebrate olfactory systems or claim that humans can smell isotopes. Hence, a description of how the deuterated odorants we use smell to humans is unnecessary. Several of the issues repeated here with respect to human olfaction were originally raised by Dr. Hettinger in the journal Chemical Senses in 2008 and answered by one of us (6). We seize this opportunity to point out the following: the change in C-H stretch frequency upon substitution by deuterium is indeed large, but its effect on odor character would be proportional to the intensity of the deuterium peak as measured by fly olfactory receptors, which is unknown at this stage and may be small, but nevertheless our experiments show that flies can consistently detect it.The notion that smell, like hearing and color vision, may be a spectral sense is indeed attractive, but this does not make it true. We have shown that in Drosophila one component of odorant recognition is conferred by molecular vibration, and this clearly implies a vibration-sensing mechanism. Another component to odor character could be the shape of the odorant molecules. If so, then olfaction in Drosophila combines both chemical (shape) and spectral (vibrations) components and may be evolutionarily intermediate between the purely spectral senses (vision and hearing) and a purely chemical one (taste). We further speculate that it is possible that vibration and shape sensing are used differentially for detection of different odorants. This, Dr. Hettinger argues, requires a continuous odor space, which he dismisses. However, this is at odds with the fact that odor character requires multiple descriptors (rosy, musky, woody, etc.), and their relative prominence in related odorants often varies in a strikingly continuous fashion. Finally, as Dr Hettinger points out, using vibrations to detect isotopes is likely not very important to Drosophila. However, because all molecules vibrate, sensing molecular vibrations may be a...

Implausibility of the vibrational theory of olfaction

“…Ligand-receptor interactions can be both attractive and repulsive, involving hydrogen bonding, van der Waals, cation-π, π-π, ion-ion, dipoledipole, steric, and hydrophobic interactions with the receptor, with water channels and bridging water molecules mediating hydrogen bonds, as well as metal-ion coordination, as we have recently demonstrated in the latter case (15,16). Therefore, molecular shape can be considered a "straw-man" alternative to the vibration theory when describing the differing affinities of ligands bound to GPCRs (17,18), including isotopomers (19,20). Some of these attractive and repulsive interactions were identified in 1940 by Pauling and Delbrück (21), who note that interacting biomolecules "must have complementary surfaces, like die and coin, and also a complementary distribution of active groups."…”

“…In addition, shape-related features are misrepresented by vibration theory proponents. For example, Franco et al (17) stated: "Given that proteins are chiral, a shape-only theory cannot account for the identical odors of most enantiomeric pairs," echoing similar comments by Turin (22): "One would therefore generally expect enantiomers to have completely different smells. This is emphatically not the case."…”

“…Also, given that the ORs and their downstream signaling in Drosophila and humans are completely unrelated, the Drosophila study should not be considered predictive of the ability of humans to distinguish isotopomers (2,17). In view of the above discussion, it is interesting that in a blinded behavioral study, smell panelists distinguished between deuterated and nondeuterated isotopomers of cyclopentadecanone (1; Fig.…”

“…We investigated whether other ORs respond differently to isotopomer pairs by assaying 14 other known receptor/ ligand pairs using 10 human and mouse ORs and 10 odorous ligands with purchased or synthesized H/D isotopomers, including octanol and octanol-d 17 , discriminated by Drosophila in the aforementioned study (36). Our assay included MTMT (8) and MTMTd 5 (8-d 5 ) (Fig.…”

Molecular vibration-sensing component in human olfaction

“…However, the question of which vibrational band might be responsible for the ''deuterated'' character is difficult to answer at present. Our studies on Drosophila [28] have shown that fruit flies can generalize avoidance from a nitrile to a deuterated odorant of unrelated structure and vice versa. This is difficult to explain except by assuming that Drosophila perceives the <2150 cm-1 vibrational band, common to both, as having a distinctive odor.…”