Vibration theory of olfaction
Encyclopedia
The Vibration theory of smell
proposes that a molecule's smell character is due to its vibrational frequency in the infrared range. The theory is opposed to the more widely accepted shape theory of olfaction
, which proposes that a molecule's smell character is due to its shape.
, the odorant molecule must first fit in the receptor's binding site. Then it must have a vibrational energy mode compatible with the difference in energies between two energy levels on the receptor, so electrons can travel through the molecule via inelastic electron tunneling, triggering the signal transduction
pathway.
The odor character is encoded in the ratio of activities of receptors tuned to different vibration frequencies, in the same way that color
is encoded in the ratio of activities of cone cell
receptors tuned to different frequencies of light. Although vibration theory explains odor character, it does not explain intensity: why some odors are stronger than others at the same concentrations.
Some studies support vibration theory while others challenge its findings.
revived the theory by proposing a mechanism, speculating that the G-protein-coupled receptors discovered by Linda Buck and Richard Axel
were actually measuring molecular vibrations using inelastic electron tunneling, rather than responding to molecular keys that work by shape alone. In 2006 a Physical Review Letters
paper by Marshall Stoneham
and colleagues at University College London
and Imperial College London
showed that Turin's proposed mechanism was consistent with known physics and coined the expression "swipe card model" to describe it. A PNAS paper in 2011 by Turin, Efthimios Skoulakis, and colleagues at MIT and the Alexander Fleming Biomedical Sciences Research Center
reported fly behavioral experiments consistent with a vibrational theory of smell. The theory remains controversial.
effect: that the normal and deuterated
versions of a compound should smell different, although they have the same shape. A 2001 study by Haffenden et al. showed humans able to distinguish benzaldehyde
from its deuterated version. In addition, tests with animals have shown fish and insects able to distinguish isotopes by smell.
It should be noted, however, that deuteration changes the heats of adsorption and the boiling and freezing points of molecules (boiling points: 100.0C for H20 vs. 101.42 for D20; melting points: 0.0C for H20, 3.82C for D2O), pKa (i.e., dissociation constant: 9.71x10^-15 for H20 vs. 1.95x10^-15 for D2O, cf. Heavy water
) and the strength of hydrogen bonding. Such isotope effects
are exceedingly common, and so it is well known that deuterium substitution will indeed change the binding constants of molecules to protein receptors. Any binding interaction of an odorant molecule with an olfactory receptor will therefore be likely to show some isotope effect upon deuteration, and the observation of an isotope effect in no way argues exclusively for a vibrational theory of olfaction.
A study published in 2011 by Franco, Turin, Mershin and Skoulakis shows both that flies can smell deuterium, and that to flies, a carbon-deuterium bond smells like a nitrile
, which has a similar vibration. The study reports that drosophila melanogaster
(fruit fly), which is ordinarily attracted to acetophenone
, spontaneously dislikes deuterated acetophenone. This dislike increases with the number of deuteriums. (Flies genetically altered to lack smell receptors could not tell the difference.) Flies could also be trained by electric shocks either to avoid the deuterated molecule or to prefer it to the normal one. When these trained flies were then presented with a completely new and unrelated choice of normal vs. deuterated odorants, they avoided or preferred deuterium as with the previous pair. This suggested that flies were able to smell deuterium regardless of the rest of the molecule. To determine whether this deuterium smell was actually due to vibrations of the carbon-deuterium (C-D) bond or to some unforeseen effect of isotopes, the researchers looked to nitriles, which have a similar vibration to the C-D bond. Flies trained to avoid deuterium and asked to choose between a nitrile and its non-nitrile counterpart did avoid the nitrile, lending support to the idea that the flies are smelling vibrations. Further isotope smell studies are under way in fruit flies and dogs.
presented a perplexing situation to vibration theory. Carvone has two isomer
s, which have identical vibrations, yet one smells like mint
and the other like caraway
(for which the compound is named).
An experiment by Turin filmed by the 1995 BBC Horizon documentary "A Code in the Nose" consisted of mixing the mint isomer with butanone
, on the theory that the shape of the G-protein-coupled receptor prevented the carbonyl group in the mint isomer from being detected by the "biological spectroscope". The experiment succeeded with the trained perfumers used as subjects, who perceived that a mixture of 60% butanone and 40% mint carvone smelled like caraway.
compounds is intensely sulfurous, though these molecules contain no sulfur
. He proposes to explain this by the similarity in frequency between the vibration of the B-H bond and the S-H bond.
in 2006 suggest that Turin's proposal is viable from a physics standpoint.
s, which increase the receptor's time spent in the active state, and antagonists
, which increase the time spent in the inactive state. In other words, some ligand
s tend to turn the receptor on and some tend to turn it off. As an argument against the traditional lock-and-key theory of smell, no olfactory antagonists have yet been found until recently.
In 2004, a Japanese research group published that an oxidation product of isoeugenol
is able to antagonize, or prevent, mice olfactory receptor response to isoeugenol.
in 2004 by Vosshall
and Keller. The study failed to support the prediction that isotopes should smell different, with untrained human subjects unable to distinguish acetophenone
from its deuterated counterpart. (However another study did find that subjects could distinguish deuterated benzaldehydes from regular benzaldehydes. See Isotope effects above.) In addition, Turin's description of the odor of long-chain aldehydes as alternately (1) dominantly waxy and faintly citrus and (2) dominantly citrus and faintly waxy was not supported by tests on untrained subjects, despite anecdotal support from fragrance industry professionals who work regularly with these materials. Vosshall and Keller also presented a mixture of guaiacol
and benzaldehyde
to subjects, to test Turin's theory that the mixture should smell of vanillin
. Vosshall and Keller's data did not support Turin's prediction. However, Vosshall says these tests do not disprove the vibration theory.
In response to the 2011 PNAS study on flies, Vosshall acknowledged that flies could smell isotopes but called the conclusion that smell was based on vibrations an "overinterpretation" and expressed skepticism about using flies to test a mechanism originally ascribed to human receptors. For the theory to be confirmed, Vosshall stated there must be further studies on mammalian receptors. Bill Hansson, an insect olfaction specialist, raised the question of whether deuterium could affect hydrogen bonds between the odorant and receptor.
Olfaction
Olfaction is the sense of smell. This sense is mediated by specialized sensory cells of the nasal cavity of vertebrates, and, by analogy, sensory cells of the antennae of invertebrates...
proposes that a molecule's smell character is due to its vibrational frequency in the infrared range. The theory is opposed to the more widely accepted shape theory of olfaction
Shape theory of olfaction
The Shape theory of smell states that a molecule's particular smell is due to a 'lock and key' mechanism by which a scent molecule fits into olfactory receptors in the nasal epithelium.-History:In 1949, R.W...
, which proposes that a molecule's smell character is due to its shape.
Introduction
The current vibration theory has recently been called the "swipe card" model, in contrast with "lock and key" models based on shape theory. As proposed by Luca TurinLuca Turin
Luca Turin is a biophysicist with a long-standing interest in the sense of smell, the art of perfume, and the fragrance industry.-Vibration theory of olfaction:...
, the odorant molecule must first fit in the receptor's binding site. Then it must have a vibrational energy mode compatible with the difference in energies between two energy levels on the receptor, so electrons can travel through the molecule via inelastic electron tunneling, triggering the signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
pathway.
The odor character is encoded in the ratio of activities of receptors tuned to different vibration frequencies, in the same way that color
Color
Color or colour is the visual perceptual property corresponding in humans to the categories called red, green, blue and others. Color derives from the spectrum of light interacting in the eye with the spectral sensitivities of the light receptors...
is encoded in the ratio of activities of cone cell
Cone cell
Cone cells, or cones, are photoreceptor cells in the retina of the eye that are responsible for color vision; they function best in relatively bright light, as opposed to rod cells that work better in dim light. If the retina is exposed to an intense visual stimulus, a negative afterimage will be...
receptors tuned to different frequencies of light. Although vibration theory explains odor character, it does not explain intensity: why some odors are stronger than others at the same concentrations.
Some studies support vibration theory while others challenge its findings.
Major proponents and history
The theory was first proposed by Malcolm Dyson in 1937 and expanded by Robert H. Wright in 1954, after which it was largely abandoned in favor of the competing shape theory. A 1996 paper by Luca TurinLuca Turin
Luca Turin is a biophysicist with a long-standing interest in the sense of smell, the art of perfume, and the fragrance industry.-Vibration theory of olfaction:...
revived the theory by proposing a mechanism, speculating that the G-protein-coupled receptors discovered by Linda Buck and Richard Axel
Richard Axel
Richard Axel is an American neuroscientist whose work on the olfactory system won him and Linda B. Buck, a former post-doctoral scientist in his research group, the Nobel Prize in Physiology or Medicine in 2004....
were actually measuring molecular vibrations using inelastic electron tunneling, rather than responding to molecular keys that work by shape alone. In 2006 a Physical Review Letters
Physical Review Letters
Physical Review Letters , established in 1958, is a peer reviewed, scientific journal that is published 52 times per year by the American Physical Society...
paper by Marshall Stoneham
Marshall Stoneham
Arthur Marshall Stoneham, FRS , known as Marshall Stoneham, was a British physicist who worked for the United Kingdom Atomic Energy Authority, and from 1995 was Massey professor of physics at University College London...
and colleagues at University College London
University College London
University College London is a public research university located in London, United Kingdom and the oldest and largest constituent college of the federal University of London...
and Imperial College London
Imperial College London
Imperial College London is a public research university located in London, United Kingdom, specialising in science, engineering, business and medicine...
showed that Turin's proposed mechanism was consistent with known physics and coined the expression "swipe card model" to describe it. A PNAS paper in 2011 by Turin, Efthimios Skoulakis, and colleagues at MIT and the Alexander Fleming Biomedical Sciences Research Center
Alexander Fleming Biomedical Sciences Research Center
The Biomedical Sciences Research Center "Alexander Fleming" is a non-profit research organisation based in Vari, Athens, Greece. The Center is named after the scientist Alexander Fleming....
reported fly behavioral experiments consistent with a vibrational theory of smell. The theory remains controversial.
Isotope effects
A major prediction of Turin's theory is the isotopeIsotope
Isotopes are variants of atoms of a particular chemical element, which have differing numbers of neutrons. Atoms of a particular element by definition must contain the same number of protons but may have a distinct number of neutrons which differs from atom to atom, without changing the designation...
effect: that the normal and deuterated
Deuterium
Deuterium, also called heavy hydrogen, is one of two stable isotopes of hydrogen. It has a natural abundance in Earth's oceans of about one atom in of hydrogen . Deuterium accounts for approximately 0.0156% of all naturally occurring hydrogen in Earth's oceans, while the most common isotope ...
versions of a compound should smell different, although they have the same shape. A 2001 study by Haffenden et al. showed humans able to distinguish benzaldehyde
Benzaldehyde
Benzaldehyde is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. This colorless liquid has a characteristic pleasant almond-like odor...
from its deuterated version. In addition, tests with animals have shown fish and insects able to distinguish isotopes by smell.
It should be noted, however, that deuteration changes the heats of adsorption and the boiling and freezing points of molecules (boiling points: 100.0C for H20 vs. 101.42 for D20; melting points: 0.0C for H20, 3.82C for D2O), pKa (i.e., dissociation constant: 9.71x10^-15 for H20 vs. 1.95x10^-15 for D2O, cf. Heavy water
Heavy water
Heavy water is water highly enriched in the hydrogen isotope deuterium; e.g., heavy water used in CANDU reactors is 99.75% enriched by hydrogen atom-fraction...
) and the strength of hydrogen bonding. Such isotope effects
Kinetic isotope effect
The kinetic isotope effect is the ratio of reaction rates of two different isotopically labeled molecules in a chemical reaction. It is also called "isotope fractionation," although this term is somewhat broader in meaning...
are exceedingly common, and so it is well known that deuterium substitution will indeed change the binding constants of molecules to protein receptors. Any binding interaction of an odorant molecule with an olfactory receptor will therefore be likely to show some isotope effect upon deuteration, and the observation of an isotope effect in no way argues exclusively for a vibrational theory of olfaction.
A study published in 2011 by Franco, Turin, Mershin and Skoulakis shows both that flies can smell deuterium, and that to flies, a carbon-deuterium bond smells like a nitrile
Nitrile
A nitrile is any organic compound that has a -C≡N functional group. The prefix cyano- is used interchangeably with the term nitrile in industrial literature. Nitriles are found in many useful compounds, one example being super glue .Inorganic compounds containing the -C≡N group are not called...
, which has a similar vibration. The study reports that drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
(fruit fly), which is ordinarily attracted to acetophenone
Acetophenone
Acetophenone is the organic compound with the formula C6H5CCH3. It is the simplest aromatic ketone. This colourless, viscous liquid is a precursor to useful resins and fragrances.-Production:Acetophenone can be obtained by a variety of methods...
, spontaneously dislikes deuterated acetophenone. This dislike increases with the number of deuteriums. (Flies genetically altered to lack smell receptors could not tell the difference.) Flies could also be trained by electric shocks either to avoid the deuterated molecule or to prefer it to the normal one. When these trained flies were then presented with a completely new and unrelated choice of normal vs. deuterated odorants, they avoided or preferred deuterium as with the previous pair. This suggested that flies were able to smell deuterium regardless of the rest of the molecule. To determine whether this deuterium smell was actually due to vibrations of the carbon-deuterium (C-D) bond or to some unforeseen effect of isotopes, the researchers looked to nitriles, which have a similar vibration to the C-D bond. Flies trained to avoid deuterium and asked to choose between a nitrile and its non-nitrile counterpart did avoid the nitrile, lending support to the idea that the flies are smelling vibrations. Further isotope smell studies are under way in fruit flies and dogs.
Explaining differences in stereoisomer scents
CarvoneCarvone
Carvone is a member of a family of chemicals called terpenoids. Carvone is found naturally in many essential oils, but is most abundant in the oils from seeds of caraway and dill.-Stereoisomerism and odor:...
presented a perplexing situation to vibration theory. Carvone has two isomer
Isomer
In chemistry, isomers are compounds with the same molecular formula but different structural formulas. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical...
s, which have identical vibrations, yet one smells like mint
Mentha
Mentha is a genus of flowering plants in the family Lamiaceae . The species are not clearly distinct and estimates of the number of species varies from 13 to 18. Hybridization between some of the species occurs naturally...
and the other like caraway
Caraway
Caraway also known as meridian fennel, or Persian cumin is a biennial plant in the family Apiaceae, native to western Asia, Europe and Northern Africa....
(for which the compound is named).
An experiment by Turin filmed by the 1995 BBC Horizon documentary "A Code in the Nose" consisted of mixing the mint isomer with butanone
Butanone
Butanone, also known as methyl ethyl ketone or MEK, is an organic compound with the formula CH3CCH2CH3. This colorless liquid ketone has a sharp, sweet odor reminiscent of butterscotch and acetone. It is produced industrially on a large scale, and also occurs in trace amounts in nature...
, on the theory that the shape of the G-protein-coupled receptor prevented the carbonyl group in the mint isomer from being detected by the "biological spectroscope". The experiment succeeded with the trained perfumers used as subjects, who perceived that a mixture of 60% butanone and 40% mint carvone smelled like caraway.
The sulfurous smell of boranes
According to Turin's original paper in the journal Chemical Senses, the well documented smell of boraneBorane
In chemistry, a borane is a chemical compound of boron and hydrogen. The boranes comprise a large group of compounds with the generic formulae of BxHy. These compounds do not occur in nature. Many of the boranes readily oxidise on contact with air, some violently. The parent member BH3 is called...
compounds is intensely sulfurous, though these molecules contain no sulfur
Sulfur
Sulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...
. He proposes to explain this by the similarity in frequency between the vibration of the B-H bond and the S-H bond.
Consistency with physics
Biophysical simulations published in Physical Review LettersPhysical Review Letters
Physical Review Letters , established in 1958, is a peer reviewed, scientific journal that is published 52 times per year by the American Physical Society...
in 2006 suggest that Turin's proposal is viable from a physics standpoint.
Correlating odor to vibration
A 2004 paper published in the journal Organic Biomolecular Chemistry by Takane and Mitchell shows that odor descriptions in the olfaction literature correlate with EVA descriptors, which loosely correspond to the vibrational spectrum, better than with descriptors based on the two dimensional connectivity of the molecule. The study did not consider molecular shape.Lack of antagonists
Turin points out that traditional lock-and-key receptor interactions deal with agonistAgonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
s, which increase the receptor's time spent in the active state, and antagonists
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
, which increase the time spent in the inactive state. In other words, some ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
s tend to turn the receptor on and some tend to turn it off. As an argument against the traditional lock-and-key theory of smell, no olfactory antagonists have yet been found until recently.
In 2004, a Japanese research group published that an oxidation product of isoeugenol
Isoeugenol
Isoeugenol is a phenylpropene, a propenyl-substituted guaiacol. A phenylpropanoid, it occurs in the essential oils of plants such as ylang-ylang . It can be synthesized from eugenol and had been used in the manufacture of vanillin. It may occur as either the cis or trans isomer...
is able to antagonize, or prevent, mice olfactory receptor response to isoeugenol.
Additional challenges to shape theory
- Similarly shaped molecules with different molecular vibrations have different smells (metalloceneMetalloceneA metallocene is a compound typically consisting of two cyclopentadienyl anions bound to a metal center in the oxidation state II, with the resulting general formula 2M. Closely related to the metallocenes are the metallocene derivatives, e.g. titanocene dichloride, vanadocene dichloride...
experiment and deuteriumDeuteriumDeuterium, also called heavy hydrogen, is one of two stable isotopes of hydrogen. It has a natural abundance in Earth's oceans of about one atom in of hydrogen . Deuterium accounts for approximately 0.0156% of all naturally occurring hydrogen in Earth's oceans, while the most common isotope ...
replacement of molecular hydrogenHydrogenHydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
) - Differently shaped molecules with similar molecular vibrations have similar smells (replacement of carbonCarbonCarbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...
double bonds by sulfurSulfurSulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...
atoms and the disparate shaped amberAmberAmber is fossilized tree resin , which has been appreciated for its color and natural beauty since Neolithic times. Amber is used as an ingredient in perfumes, as a healing agent in folk medicine, and as jewelry. There are five classes of amber, defined on the basis of their chemical constituents...
odorants) - Hiding functional groupFunctional groupIn organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
s does not hide the group's characteristic odor
Challenges to vibration theory
Three predictions by Luca Turin on the nature of smell, using concepts of vibration theory, were addressed by experimental tests published in Nature NeuroscienceNature Neuroscience
Nature Neuroscience is a monthly scientific journal published by Nature Publishing Group. Its focus is original research papers relating specifically to neuroscience and was established in May 1998. According to the Journal Citation Reports, Nature Neuroscience has a 2009 impact factor of 14.345,...
in 2004 by Vosshall
Leslie B. Vosshall
-Biography:Leslie Birgit Vosshall, Ph.D., is an American neurobiologist who is well known for her contributions in the field of olfaction, particularly for the discovery and subsequent characterization of the insect olfactory receptor family. She received her Ph.D...
and Keller. The study failed to support the prediction that isotopes should smell different, with untrained human subjects unable to distinguish acetophenone
Acetophenone
Acetophenone is the organic compound with the formula C6H5CCH3. It is the simplest aromatic ketone. This colourless, viscous liquid is a precursor to useful resins and fragrances.-Production:Acetophenone can be obtained by a variety of methods...
from its deuterated counterpart. (However another study did find that subjects could distinguish deuterated benzaldehydes from regular benzaldehydes. See Isotope effects above.) In addition, Turin's description of the odor of long-chain aldehydes as alternately (1) dominantly waxy and faintly citrus and (2) dominantly citrus and faintly waxy was not supported by tests on untrained subjects, despite anecdotal support from fragrance industry professionals who work regularly with these materials. Vosshall and Keller also presented a mixture of guaiacol
Guaiacol
Guaiacol is a naturally occurring organic compound with the formula C6H4. Although it is biosynthesized by a variety of organisms, this colorless aromatic oil is usually derived from guaiacum or wood creosote. Samples darken upon exposure to air and light. Guaiacol is present in wood smoke,...
and benzaldehyde
Benzaldehyde
Benzaldehyde is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. This colorless liquid has a characteristic pleasant almond-like odor...
to subjects, to test Turin's theory that the mixture should smell of vanillin
Vanillin
Vanillin is a phenolic aldehyde, an organic compound with the molecular formula C8H8O3. Its functional groups include aldehyde, ether, and phenol. It is the primary component of the extract of the vanilla bean. It is also found in Leptotes bicolor, roasted coffee and the Chinese red pine...
. Vosshall and Keller's data did not support Turin's prediction. However, Vosshall says these tests do not disprove the vibration theory.
In response to the 2011 PNAS study on flies, Vosshall acknowledged that flies could smell isotopes but called the conclusion that smell was based on vibrations an "overinterpretation" and expressed skepticism about using flies to test a mechanism originally ascribed to human receptors. For the theory to be confirmed, Vosshall stated there must be further studies on mammalian receptors. Bill Hansson, an insect olfaction specialist, raised the question of whether deuterium could affect hydrogen bonds between the odorant and receptor.