It Smells Quantastic, Doesn’t It?

Have you ever wondered how we know how something smells? I mean, the volatile molecules entering your nose have to tell your brain in one way or another: “Hey, it’s me!”.

But how do these messages get up there in the first place?

To find the answers to these questions, we need to turn to chemical messaging and electrical signaling between our nose and brain as well as within our brain. Most intriguingly of all, it seems that we invoke ideas from quantum physics to enable signals to get to our brain.

Let us break down all of this step by step.

An Anatomical-Physiological Exploration

Our sense of smell — called olfaction — is designed to serve multiple purposes: detect danger, identify food when hungry, increase our chances of reproduction, or avoid consuming toxic or spoiled substances. And our nose has physically evolved to optimize these functions.

About 7 cm (2.8 inches) above and behind our nostrils, we come across an air-filled space — the nasal cavity — that contains a tissue, i.e. the olfactory epithelium, in which plentiful odour receptors are planted. We have by estimation 50 million of these receptors.

Towards the base of the epithelium, the receptors have grown extensions (dendrites) which are embedded in a layer of mucus — the hair-like endings are referred to as olfactory cilia. This is the place where incoming particles (odorant molecules) will be picked up.

Odorants from, say, a fresh peppermint tea end up in our nasal cavity, integrate into the mucus, and stimulate certain odour receptors.

Fig. 1. Schematic overview of the anatomy of the olfactory system. (Source: Oregon State University).

In fact, there are two pathways for odorant molecules to reach the receptors: through the nostrils, and via the channel that links up the upper part of the throat to the nasal cavity. The aromas that are released while chewing our food follow the latter pathway.

Higher up inside the epithelium, each receptor cell is connected to just one olfactory sensory neuron. These nerve cells are in turn extended via the olfactory tract into the brain, namely the part that is known as the olfactory bulb.

Not only that, every olfactory neuron of the same type of receptor — functionally, the odour receptors can be organized into 400 different groups (some accounts go as high as 1,000) – terminates in the same region — called a glomerulus — in the olfactory bulb. That is, there are approximately 400 (or 1,000) glomeruli in the olfactory bulb.

It is then the timing, mix, and order of glomeruli activation that tell us with what unique smell we are dealing (only after that information has been translated by other parts of the brain). Still, the research, it has to be said, is not yet entirely clear on the precise underlying mechanism.

The broad variety in functional receptors is also why, by exciting various kinds of receptors, we are capable of sniffing out roughly 10,000 distinct odours, as maintained by the researchers Bettina Malnic et al.

However, an exact classification of the existing types of scent remains a subject of ongoing scientific discussion. Nonetheless, researchers commonly agree on at least seven basic categories (although some claim there are ten): musky, floral, pungent, peppermint, putrid, camphor, and ethereal.

It Is All About Chemistry

Upon stimulation of the receptor cells, they trigger via an intermediate process (G-protein cascade) the production of the biochemical substance cyclic adenosine monophosphate (cAMP).

In a next step, the molecular compound cAMP initiates the opening of miniscule pores (ion channels) in the olfactory cilium’s membrane. With positive ions — molecules that have lost electrons and are therefore positively charged, a.k.a. cations — now entering (Ca2(+) and Na(+)) and negative ions — molecules that have gained electrons, a.k.a. anions — leaving (Cl(-)) the cilium, its membrane is shifting from a negative to a positive charge (depolarization).

Fig. 2. A schematic view of the membrane depolarization process for olfactory receptor cells. (Source: Book “Neuroscience: Exploring the Brain, Enhanced Edition”).

This flip of charge polarity induces subsequently the creation of electrical signals (action potentials), which are transmitted through the olfactory tract to the olfactory bulb in the brain for further processing.

But let us return to the base of the olfactory epithelium and give some more thought as to how exactly inbound molecules connect to and stimulate the receptors.

To come up with the appropriate explanation, there are two main theories in the running: the shape theory and the vibrational theory.

Scientists usually fall back on the classical shape theory, the vibrational theory being slightly more controversial. As Philip Ball remarks: “[The vibrational] mechanism for how smell receptors work differs dramatically not just from conventional views but from anything else known in molecular biology.”

Who Holds the Key?

The older variant of shape theory is based on the lock-and-key principle: certain (parts of the) odorants only match with receptors that are shaped in a certain way.

The characteristic smell then stems from the brain deciphering the received aggregate response in binding strength between the volatile molecules and the receptors. Moreover, molecules with shared structural traits in terms of shape and size, so the theory goes, are responsible for a similar smell.

One issue with this particular description of shape theory, however, is that several similarly shaped odorant molecules lead to significantly dissimilar smells. A case in point is 1,1-dimethylcyclohexane (dominant smell: camphor) versus 1,1-dimethyl-1-silacyclohexane (dominant smell: chemical/green note).

Fig. 3. An anomaly of the shape theory: two similarly shaped compounds produce different odours. (Source: guidechem).

As a result, a newer version of the original theory, i.e. the docking theory, has hypothesized that, though odorants might acquire similar shapes and sizes, the distinctive smell originates from the brain decoding the different combinations in which the weak intermolecular forces, such as Van der Waals forces, hydrogen bonding, or electrostatic forces, act between the molecule and the receptor.

Even so, the docking theory is not fully ironclad: for one, it has so far not been successful in consistently predicting the relationship between molecular structure and odours.

For that reason, scientists have looked elsewhere, albeit in a somewhat controversial direction, to design a theory that — hopefully — satisfactorily explains how odorants excite olfactory receptors: the vibrational theory.

Smelling Vibrations

It is not shape nor intermolecular forces, but the frequency with which molecules vibrate (the molecular vibrational spectra) that determines whether an olfactory receptor responds to an odorant, according to the vibrational theory.

Let us take a step back for a moment. A molecule is held together by the bonds established between its atoms, and these bonds are basically electrons, i.e. negatively charged units, being shared between the atoms. These molecules can exhibit motion in various ways: rotational, translational, and vibrational. And the latter is of importance to our discussion; the vibrational movements of the bonds is what defines the frequency of the molecule.

Along an equivalent rationale as that of the lock-and-key model, molecules with similar vibrational spectra give rise to similar scents, and vice versa.

One corroborating example involves the musk odorant cyclopentadecanone (C₁₅H₂₈O) whereby hydrogen (¹H) is replaced with deuterium (²H). Both forms — undeuterated (¹H) and deuterated (²H) — bring about different odours, in spite of their identical shapes: as deuterium is twice the mass of hydrogen, the odorants’ molecular bonds vibrate at different frequencies.

This results in a dissimilar electronical signature received by the glomeruli in the olfactory bulb, interpreted in turn by other parts of the brain as distinct smells.

Fig. 4. The musk odorant molecule cyclopentadecanone. The grey balls refer to carbon atoms, the smaller white ones to hydrogen atoms, and the red one to an oxygen atom. For the experiment, the (undeuterated) hydrogen atoms would be replaced with a heavier hydrogen variant, i.e. deuterium (not presented in the image). (Source: pubchem).

Another supporting example, yet proven only for honeybees, is acetophenone (C₆H₅COCH₃). As for the reason why humans do not discriminate between the two forms, the researchers Wulfila Grunenberg et al. comment that “[i]nsects, in general, have smaller numbers of OR [olfactory receptor] proteins compared with vertebrates […] and it is possible that vibrationally assisted olfaction […] may provide an additional layer of odorant–OR interaction that could increase the insects’ ability to discriminate odorants.”

Your Nose is Full-Blown Quantum

Quantum physics — the realm of physics that describes the behaviour of subatomic particles, e.g. electrons — is in essence probabilistic. It also stipulates that matter particles possess a wave-like nature, much like light. Taken together, this means that the position of, say, an electron is rather spread out across space, and every possible position comes with a calculated probability. Once that electron is observed, its final position will be known.

This quantum idiosyncrasy furthermore entails that, when an electron faces an energy barrier (including the one in a chemical reaction), there is a very narrow window of opportunity for this electron to be finally positioned at the other side of the barrier, even though there was — in the classical sense — insufficient energy available to overcome the barrier to begin with. This effect is denoted as quantum tunneling.

And it is this quirky tunneling mechanism that helps explaining how geometrically similar molecules that vibrate at different frequencies, such as the above example of cyclopentadecanone, advance distinctive odours.

Generally, activation energy and enzymatic catalysis largely regulate the reaction rate of the change in the makeup of biochemical bonds. In contrast, quantum tunneling deviates from this standard picture: it can allow electrons in molecular bonds to shift position at energy levels below the required classical energetical threshold for chemical reactions.

Now, Luca Turin’s version of the vibrational theory claims that the odorants’ molecular vibrations facilitate the olfactory receptors to engage in quantum tunneling to identify the incoming volatile molecules.

Fig. 5. (a) The classical view on activation energy and enzymes in chemical reactions, (b) the concept of quantum tunneling enables reactions to occur below the enzymatic energy threshold. (Source: adapted from blissbiology and lumenlearning).

That is, in absence of the odorants’ frequencies, the electrons present in the receptor are stuck in one region, i.e. the donor site, rendering them unable to activate the G-protein cascade, whereby no signal can be transmitted to the brain.

For the electrons to spark the release of that G-protein, they must give off a bit of their energy to be able to end up in another region of the receptor, called the acceptor site. And here is where the odorant molecule comes in: due to the molecular bonds’ potential to vibrate, the odorant is flexible enough to absorb that excess energy of the electron, so that it can make the quantum jump, and kick off the production of an electrical signal.

Not So Fast

Notwithstanding its explanatory power for some anomalies of the shape theory, not all is rosy with the vibrational theory either.

For instance, it fails to clarify why the mirror-image molecules limonene (a right-handed molecule) and dipentene (a left-handed molecule) do not smell alike, despite having identical vibrational spectra and similar shapes.

Fig. 6. The molecular structure of the mirror-image molecules limonene and dipentene. In limonene, the lower chemical substructure comes out at the other end of your screen, whilst in depentene it comes out of your screen towards you. (Source: Paper Chukwuemba Asogwa).

In addition, scientists Eric Block et al. point out that their in vitro experiment with regard to the human musk-recognizing receptor OR5AN1 did not manage to distinguish between the undeuterated and deuterated forms of cyclopentadecanone, a chemical compound previously hailed as experimental evidence in favour of the vibration theory.

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Swipe Left and Right

To account for certain inconsistencies with Turin’s vibrational model, as is the case with limonene and dipentene, a hybrid theoretical framework has been suggested: the alleged swipe-card model.

To the same extent that your credit card has to be properly inserted into the reader and hold the right thickness and shape before any electric current can be fired off to initiate the payment, both right- (e.g. limonene) and left-handed (e.g. dipentene) molecules must first dock into their respective fitting receptor before a vibration-assisted quantum-tunneled induced electron flow can be discharged towards the brain.

Because both the right- and left-handed receptors belong to different types of receptors, they will trigger different glomeruli in the olfactory bulb, and, consequently, summon distinct odours.

Regardless of the swipe-card model’s ability to effectively fit the data, it should be noted, in the words of Jim Al-Khalili and Johnjoe McFadden, that “[n]o experiment has yet directly tested whether quantum tunneling is involved in smell. However, so far at least, inelastic quantum tunneling by electrons is the only known mechanism that provides a plausible explanation for how proteins can detect vibrations in odour molecules.”

All Is Well That Smells Well

We are closer now to understanding how something smells. Nonetheless, the theoretical debate on ‘shape and/versus vibration’ is not yet closed, since we have no exact knowledge to the present date of how the olfactory receptors are structured.

Once scientists accomplish that goal, a final theory on how smell reception and identification work can take a more definite form.

In the meantime, catch a good whiff of your morning coffee or your grapefruit-and-mandarin-flavoured tea to take your day off to a good start. And whether that whiff is quantum-driven is a question we will leave in the middle for now.

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