by Bree Iskandar
All of us are familiar with the distinctly unpleasant smells of rotten eggs, garlic breath, skunk spray, or overcooked cabbage. But what exactly causes these smells, and how do our brains detect it? The chemical culprits behind these odorous offenders are called thiols. Thiols are made of two chemical elements, a sulfur atom (S) bonded to a hydrogen atom (H), and are represented in chemistry as an “-SH” group (Figure 1A). While sulfur itself has no apparent smell, when paired with just two hydrogen atoms to form hydrogen sulfide, or H2S, it becomes responsible for the distinct rotten egg smell we know and, well, hate.
Human smell receptors have an insanely high sensitivity to thiols. To illustrate this, let’s consider two chemicals, ethanethiol and ethanol (Figure 1B and 1C). Ethanol is a common alcohol found in hand sanitizer and ethanethiol is a compound found in petroleum. Chemically, the only difference between these two compounds is that ethanol has an oxygen atom bonded to hydrogen (“-OH”) instead of sulfur. According to the National Institutes of Health, our ability to smell ethanethiol is over one million times times greater than our threshold for detecting ethanol. In fact, our threshold for smelling ethanethiol has been reported to be as low as one part per 50 billion–in other words, if there was one molecule of ethanethiol floating around in a room full of 50 billion other molecules, we would still be able to smell it!
So how are such tiny molecules responsible for such a foul odor? Our smell receptors, also known as odorant receptors, are proteins in our nose that bind various compounds and give rise to our sense of smell. They exist on the surface of larger cells called olfactory receptor cells (Figure 2). When small thiols bind to our odorant receptors, they cause an electrical signal to travel from the receptor cell to a part of our brain called the olfactory bulb. Within the bulb, additional clusters of neurons are then activated in different patterns. Different odorants are responsible for different activation patterns, which are then processed by a part of the brain–the olfactory cortex—as distinct smells. The small thiols found in rotten eggs and skunk spray trigger a similar activation pattern, resulting in the perception of a rank, rancid odor.
We may have evolved our super sensitive sulfur sniffers out of necessity, as those scents often signal the presence of rotten food, dangerous vapors, or unsanitary conditions (which increase the likelihood of infection and illness). Up until a few years ago however, the molecular basis of our thiol sensitivity still remained a mystery. In 2016, a team of researchers from the US and China published a paper in the Journal of the American Chemical Society reporting the discovery of a specific human odorant receptor that responded to small molecular weight thiols, like ethanethiol. These scientists determined that this thiol receptor needed copper ions to function properly—in fact, without copper, the receptor lost almost all activity. It was the first scientific proof that some human odorant receptors need metal ions to aid in our sense of smell. The alcohol counterparts of these thiols did not have any effect on the receptor, implying that thiols and alcohols are likely detected via different smell receptors.
Scientists are still investigating how the structure of any given odorant correlates with its smell. Recent advances in artificial intelligence and machine learning have made it possible to look at large databases of known odorants and find patterns between smell and structure, allowing us to build computational models to start to predict smell from chemical structure alone. This gives insight into the relatively poorly understood relationships between molecular structure and odor, and could streamline product development for the fragrance industry. Certain structures however, such as thiols, are not shy about making themselves known—regardless of their presence, one must admire them for being out, loud, and proud of what they are.
