Laying a controversial smell theory to rest.

In the 50 y before the cloning of the odorant receptors (ORs) by Linda Buck and Richard Axel in 1991 (1), two competing mechanisms for odor detection were discussed, one chemical and one spectral. The chemical theory posited that “detectors” respond to physicochemical attributes of the odorant, including molecular size, molecular shape, and functional groups (2, 3). The alternative spectral theory hypothesized that the olfactory system detects molecular vibrations of the odor molecules (4, 5). This vibration theory was revived in 1996, along with a proposed mechanism of inelastic electron tunneling spectroscopy activated by ligand–receptor interactions (6). These early theories of how ORs detect odorants were developed using psychophysical experiments, in which human volunteers sniffed odor molecules and described what they perceived. In PNAS, Block et al. (7) shift the “shape vs. vibration” debate from olfactory psychophysics to the biophysics of the ORs themselves. The authors mount a sophisticated multidisciplinary attack on the central tenets of the vibration theory using synthetic organic chemistry, heterologous expression of ORs, and theoretical considerations to find no evidence to support the vibration theory of smell. What are the predictions of the vibration theory of smell and how would one test it? Proponents of the theory argue that the answer lies in chemical stimuli that are considered “identical” in structure but are fully deuterated analogs in which hydrogen atoms are exchanged with deuterium atoms. The thinking is that such molecules, known as isotopomers, would have identical molecular shapes and functionality but very different vibrational spectra. Sniff-testing of isotopomers has yielded mixed results. Although acetophenone and fully deuterated acetophenone were said in the original 1996 theoretical paper to be readily discriminable by humans (6), this observation was not reproduced in a later study (8). These same isotopomers were tested in insects and shown to be discriminable by flies (9) and honey bees (10). Gane et al. (11) returned to the acetophenone question in 2013 and now confirmed that humans could not discriminate the acetophenone isotopomers after all, but offered new musk isotopomers that could be discriminated. Aside from being poorly reproducible, these psychophysical experiments are fraught with confounding variables. One cannot rule out that minute quantities of impurities in the isotopomers account for their discriminability or that the molecules are enzymatically transformed to novel odorants by nasal mucus long before they interact