The sense of smell is a very distant fifth place in our senses: sight, hearing, taste, and touch all come before smell in our thoughts. Because of that, we underestimate both its sensitivity and its influence. Our sense of smell is what makes food tasty and repels us from rotting things. Our sense of smell evokes some of our strongest memories.

But frankly, the sense of smell is confusing.

At one level, sensing odors is easy: a molecule sticks to something in our nose. The thing it sticks to then sends a signal to the brain, which instructs our hand to grab the last cookie. But those two sentences sweep all the complexity under the carpet. Why does a molecule stick? And how do the nose (and brain) distinguish different molecules?

One odd-ball idea, based on the power of quantum mechanics, made a brief comeback a couple of years ago. But, now a paper based on theory shows that it is unlikely to work.

Smell my keys with your lock

The commonly accepted idea is that smell is basically shape based. The nose is lined with sensing molecules that have pockets with different shapes. Odorant molecules that have complementary shapes fit and stick. (Yes, your nose enjoys Tetris as much as you do.) But, waaaay back before anyone had thought about shape recognition, scientists wondered if smell might be due to electrons tunneling from odor molecules to receptor molecules. The idea is that, because each molecule is different, the tunneling rate and energy of electrons will change, allowing receptors to distinguish molecules.

Since this seemed an untestable proposal, it was pretty much ignored. Over time, the shape-based idea built up lots of good evidence, so the tunneling theory didn't seem necessary. But a few issues have kept tunneling floating around in the background.

The shape proposal is based on how other receptors work: the receptor and the thing it receives fit like a lock and key. But smell is known to be exquisitely selective, while proteins are known to be susceptible to something called "non-specific binding." Here, the lock and the key don't quite match, but the key jams itself in anyway. Yet the nose is seemingly not triggered by off-target molecules at all.

Another problem is that similarly shaped molecules do not always produce a similar response; they smell different. And, the opposite is also true: molecules that are structurally very different can smell the same. No one knows why this is, and variants of the lock-and-key type of ideas can explain only some of this behavior.

There are also some results that are, to put it simply, totally bonkers. Researchers have managed to teach bees to differentiate between two odorants. The catch being that the odorants were chemically identical, and the only difference was that the hydrogen was replaced with deuterium (deuterium is hydrogen with an extra neutron). And, just to make that result even more confusing, a follow-up experiment showed that the receptors that captured the odor molecule respond in exactly the same way no matter how much hydrogen is replaced with deuterium. Researchers ended up throwing up their hands and speculating that the reported sensitivity to isotopes (in multiple species) was due to contamination.

The Son of the Return of Quantum

Despite these annoying results, quantum effects in biology were thought to be stuff and nonsense, so a quantum sense of smell seemed rather implausible. Then it was discovered that photosynthesis relied on quantum transport. After that, it was found that some biological magnetic field sensors rely directly on quantum effects. Suddenly, a quantum nose didn't seem so outlandish.

Existing models for electron tunneling clearly didn't work. For instance, molecules that are chemically identical but have different "chirality" often smell different. (Chirality is like how your left and right hand are structurally the same, but are mirror images of each other.) But a simple model of electron tunneling would predict that changes in chirality should not change tunneling.

Of course, biology is rarely simple. So, researchers have been working on coming up with more realistic models and seeing how they might be tested. To understand the results and their limitations, we first need to take a look at how tunneling works.

Tunneling is a truly quantum process. Our electron is attached to a stinky molecule, which ends up in proximity to a smell receptor. To get from the smelly molecule to the receptor, the electron has to detach itself and fall into the receptor. If the electron doesn't have sufficient energy to do so, it would never make that jump if the world were classical.

In quantum mechanics, though, the electron is not really just a particle; it is actually a blob of probability. That blob of probability spreads out and contracts depending on the environment. In this case, it can spread out through the space between molecules. Now, because the probability blob extends across the barrier, the electron exists in both molecules. Under these circumstances, the electron might go from the odorant to the receptor, but afterward, it will just go back again. No net effect.

What we need is something that traps the electron in the receptor when it finds itself there. The solution is molecular vibrations. The idea is this: the electron is mostly in the odorant molecule, which is vibrating slightly. The electron gets kicked by the vibration, increasing its energy, which expands the probability blob deeper into the receptor molecule. The electron then jumps from the odorant to the receptor. In doing so, it also loses energy by exciting a vibration in the odorant molecule. That leaves the electron with very little energy, so its probability blob contracts, leaving it mostly in the receptor molecules. As a result, the chance of tunneling back to the odorant is very small.

The nice thing about this is that nearly every molecule, including molecules that have different isotopes, has different characteristic vibrational frequencies. That means the tunneling rate and the energy of the electrons that tunnel will be different for every molecule.

Tunneling with a twist

That's the good point. The downside is that a simple vibrational model means that chirality has no influence on electron tunneling.

Of course, tunneling may not be quite so simple. Researchers have shown that a series of vibrational forms, called "combination modes," lead to different tunneling behavior for different chirality. A combination mode means that a molecule is not just gently vibrating, but it might be vibrating and twisting at the same time. Combination modes are actually really common, so they might even be more likely than pure vibrational modes. In principle, then, electron-tunneling-based smell sensing seems possible.

Unfortunately, a closer look at the rates of symmetric versus asymmetric tunneling shows that electron-tunneling-based smell sensing is unlikely. The whole problem is that the relevant properties of molecules (vibrational frequencies, the strength of the coupling between the electron and the vibration, and the size of the barrier that the electron must pass through) vary so much. As a result, researchers can't really calculate how a real set of molecules would behave. Instead, they take typical values and vary them over a range to find out where electron tunneling might work and where it won't.

When doing that for odorant/receptor combinations, the news is not so positive. Electron tunneling only works over a narrow range.

The researchers show that electron tunneling is pressure- and temperature-dependent. As the pressure goes up, the vibrations of molecules get disrupted because other molecules keep colliding with them. The molecules don't stop vibrating; instead, they start and stop all the time, reducing the chance for an electron to interact. Indeed, certain types of vibration become, effectively, impossible. That stops asymmetric tunneling dead in its tracks.

The implication is clear: we shouldn't be able to smell stuff beyond a certain pressure. Of course, we don't know what that pressure is, and it probably varies from molecule to molecule. However, it is an experiment that can be done. Unfortunately, I doubt that it will be done, simply because, for each molecule that showed no electron tunneling, there would be an untested molecule that still might. The tests might go on endlessly.

My impression is that the authors hoped to find a nice wide range of properties for which electron tunneling worked and then a series of tests that could be used to find it in some lab rat's nose. To their disappointment, they have largely eliminated their own favorite theory, which is actually a very important achievement.

Scientific Reports, DOI: 10.1038/s41598-017-04846-8 (About DOIs).