22 Jul What Makes a Molecule Smell?

By Ahmed Barakat, Communications Specialist

When I first learned about smell, my middle school science teacher said that molecules are the small particles responsible for all physical and chemical properties of a substance, including what that substance smells like. She would then spray a little bit of perfume to make the case that the particles floating around the classroom were the reason we could smell the perfume.

My then little brain never really understood how molecules did that. Thankfully, it turns out that it wasn’t just me. Such a basic and fundamental question like “what makes a molecule smell?” has remained unanswered for quite a long time.

To better understand that question, Dr. Joel Mainland, a neuroscientist at Monell Chemical Senses Center, suggests we compare our current understanding of smell to our understanding of vision. “We can see all around us because the light emitted by or bouncing off different objects is visible light,” he said. “Similarly, we can smell all around us when the molecules floating into our noses happen to be odorous molecules.”

Taking this thought process a step further, we can notice a fundamental gap in our knowledge of the sense of smell. On the one hand, the visibility of light can be predicted by properties like its wavelength falling within a certain range, a visible spectrum. On the other hand, the properties that allow molecules to act as odorants have, for the longest time, remained completely unknown.

Scientists have previously tried to fill in these gaps, but their efforts have failed to provide concrete empirical evidence for where the boundaries of an olfactory space are drawn. And just like how the visible spectrum represents a range of values that includes all visible light, an analogous olfactory space would represent a range of values that encompasses all the odorous molecules out there.

For years now, researchers from the Mainland Lab have been working on advancing our understanding of the olfactory space. “I inherited this project,” said Emily Mayhew, PhD, a former Monell postdoctoral fellow, now at Michigan State University. “Other members of the Mainland Lab had gathered most of the data before I came on board, but my job was to build a model that made sense of the data and to communicate the results.”

Molecules go through several phases on their way towards the olfactory receptors, the structures responsible for capturing odorants and initiating a perception of odors. First, they travel from their source towards the olfactory epithelium, a region at the very top of the nasal cavity where the olfactory receptors are located. In order for the molecules to complete this air phase, they need to have a level of volatility that allows them to easily evaporate or leave the surfaces of their sources.

However, the molecules need not be too volatile so that they are able to complete the next part of their journey: the mucus phase. At this stage, molecules will pass through the mucus layer coating the olfactory epithelium and protecting the olfactory receptors.

Finally, they reach the binding phase, where they are face-to-face with the olfactory receptors. However, in order to escape the mucus layer and enter the binding pockets of their receptors, the molecules need to be hydrophobic enough. Namely, they should have the ability to avoid dissolving in a water-based medium like the mucus layer.

With this understanding of an odorant’s journey in mind , the research team trained computer models to predict whether molecules were odorous based on the characteristics that allow them to successfully complete the journey: volatility and hydrophobicity. And even though olfaction is a complicated and incompletely understood sense, the computer models have now shown that “the rules for which molecules are odorants appear to be quite simple,” said Mayhew. “Molecules that are volatile enough, not too volatile, and also hydrophobic enough are generally odorous.”

In other words, according to their research paper, published earlier this year, if you were presented with a molecule that no human nose has ever encountered, but it could physically reach your olfactory receptors, you could still smell that molecule!

Richard Gerkin, PhD, a professor at Arizona State University and an affiliated scientist of Monell, helped build and evaluate some of the computer models. He said that prior to this project, he would have guessed that many molecules (perhaps hundreds or thousands every day) were reaching olfactory receptors and silently passing like ships in the night, failing to produce any signal and thus no odor.

“But this work shows that in fact nearly every molecule that can make it to the receptors is very likely to have an odor,” added Gerkin, who also produced a visualization of the odor space showing the universe of possible molecules and the regions of that universe where odorous molecules live.

This newly defined odor space is a major advancement in our understanding of the sense of smell. Based on the knowledge that molecules with sufficient volatility and hydrophobicity are generally odorous, there are likely billions of odorants in the olfactory space that have never been smelled before. It is almost as if our entire olfactory receptors repertoire has evolved to provide complete coverage of molecules that have the physical capacity to reach the olfactory epithelium.

The researchers hope that such a massive unexplored space of odorous molecules will inspire other scientists to explore novel types of odorants. “We now have a stronger-than-ever idea of where the boundaries of the odorous space are drawn,” said Mainland. And just like we could explain what makes light visible, now we can recognize an odorous molecule from its characteristics.