Olfaction, taste and chemoreception: scientific evidence replaces “Essays in biopoetry”

Taste and olfaction were long considered to be outside the realm of science because of their seemingly subjective nature and lack of end points that could be measured and quantified. According to Galileo, nature is written “in lingua matematica, e i caratteri son triangoli, cerchi, ed altre figure geometriche”, and without this numerical connection, research is only “un aggirarsi vanamente per un oscuro laberinto”.¹ Galileo concluded, on the topic of this special issue, that “sapori, odori, non sieno altro che puri nomi”, whose physical basis is the interaction of “materie sottili e tenui” with “mammillule” located on the tongue and in the nose, where “son ricevuti I lor toccamenti con nostro gusto o noia”.² In other words, the volatility of a compound can be measured by its boiling point, which is science, while its odor is a subjective and unmeasurable trait, alien to science. Four centuries later, we still agree with Galileo that senses, although mediated by the activation of specific sensors, are actually the result of brain activity that assigns, for instance, the pleasant rose note to the vapors emitted by the flower of the same name. On the other hand, we now speak of molecules and not of materie sottili e tenui, receptors rather than mammillule and interactions rather than toccamenti, and the molecular mechanisms underlying sensation can be investigated by the means of modern science. Research on olfaction and taste, once mostly spurred by curiosity for their hedonic connections (perfumery and gastronomy), is now fully integrated into biomedical research as part of chemoreception, the way living organisms respond to environmental chemical stimuli. Quite remarkably, some of these chemical stimuli have also turned out to mimic physical sensations like heat and pressure, blurring the distinction between chemical and physical senses.³

Two seminal discoveries triggered the current intense research in chemoreception. The first was the identification of specific receptors for olfaction, taste and trigeminality, a term broadly covering the sensation of heat and pressure, incidentally already unified in Aristotle’s view of the senses.⁴ These mammillule, mostly metabotropic for taste and olfaction and ionotropic for trigeminality, make it possible to apply the methods of modern pharmacology to the study of chemoreception, a topic discussed in the highlight article by Krohn and colleagues (‘Human cell-based taste perception – a bittersweet job for industry’ (DOI: 10.1039/c6np00123h)). The second discovery was that chemoreceptors are also expressed ectopically in non-sensory tissues like the heart, brain, lungs, testes, sperm and ovaries, where their presence suggests the existence of endogenous ligands, possibly derived from the intestinal microbiome, our inner “environment”.⁵ If the capsaicin receptor (TRPV1) is a heat sensor, why is it expressed in the central nervous system or in the prostate, where temperature is constant?³ What do bitter receptors taste and olfactory receptors smell in muscles?⁶

The relevance of chemoreception is highlighted by the role it plays in the earliest event of our life, namely the fecundation of an ovule by a spermatozoon. Spermatozoa have been reported to follow a scent trail to locate the ovule, in a veritable cellular version of what Don Giovanni describes to Leporello as “odor di femmina” in a night dialogue of Mozart’s opera. A specific olfactory receptor (hOR17-4) is highly expressed in sperm, and was supposed to be used to locate the ovule.⁷ Since hOR17-4 is sensitive to the odor of lily-of-the-valley (Convallaria majalis L.) and its synthetic mimic bourgeonal, this compound was believed to somewhat mimic the bouquet of “odorants” released by the ovule.⁷ Later studies showed that the sperm trail to the ovule is actually hormonal, and based on two non-nuclear progesterone receptors, the ion channel CatSper (sperm-specific cation channel)⁸ and the serine protease ABHD2 (α/β hydrolase domain-containing protein 2), an enzyme of the endocannabinoid system.⁹ CatSper is sensitive to bourgeonal as well as to a few other odorants, although at much higher concentrations than that of progesterone,⁸ while some ABHD-type hydrolases are inhibited by triterpenoids.¹⁰ The sensitivity of these receptors to small molecules and the promiscuous ligand inventory of CatSper suggest that chemotaxis disruptors should be of no less concern for aquatic wildlife than hormonal disruptors, since some fragrance ingredients are stable and long lasting, with bourgeonal being found, for instance, to contaminate the water of Venice’s canals (too many tourists and too little water exchange).¹¹ The delicate network of chemical interactions going on in marine life is discussed in the reviews by Mollo and colleagues on ‘Taste and smell in aquatic and terrestrial environments’ (DOI: 10.1039/c7np00008a) and by Kamio and Derby on ‘Finding food: how marine invertebrates use chemical cues to track and select food’ (DOI: 10.1039/c6np00121a). There is little doubt that perfumes and cosmetics are confusing marine life, adding insult to the human devastation of the seas.

Despite recent advances that have made available receptors and ligands (both agonists and antagonists) for many Galilean mammillule, their study is fraught with difficulties. A major problem is the lack of appropriate animal models. For instance, most vertebrates including mice use two olfactory systems, the nasal and the vomeronasal systems, but only the first one seems to exist in humans.¹² Also, the function of taste receptors has been tuned by diet, and the human diet is significantly different from those of other vertebrates and even from the diet of our ancestors, at least in the Western world. Bitterness in particular has been evolutionarily acquired, and continues to evolve. The β-glucopyranoside salicin tastes bitter to humans, but leaves rodents indifferent.¹³ Finally, the ectopic expression of chemoreceptors and the reflexes associated with their activation make it dangerous to draw conclusions from animal studies. The clinical failure of TRPV1 antagonists, the most significant drug-discovery project based on chemoreceptors to date, was essentially due to the failure of knock-out animal models to predict the acute hyperthermic effects associated with blocking this ion channel in humans.³ This underlines the crucial importance of assays with human cell lines as a research tool, as outlined in the article by Krohn and colleagues. On the other hand, studying the animal world continues to be indispensable for deciphering molecular mechanisms triggered by distant vs. contact chemosensation, as outlined in the viewpoint on ‘Contact chemosensation of phytochemicals by insect herbivores’ by Boland (DOI: 10.1039/c7np00002b) and colleagues and the viewpoint on ‘Decoding chemical communication in nematodes’ by Butcher (DOI: 10.1039/c7np00007c). Studying non-model systems also allows scientists to understand how organisms actually interact in the natural world.

The issue of subjectivity is especially relevant for olfaction, the only sense that “travels” via the emotional center of the brain, the limbic system. Odor can, in fact, trigger dramatic responses, as realized by ancient historians who recorded the terror of Roman horses at the odor (and not the sight!) of the elephants of the Sasanian army of Shapur I during the long confrontation between the two empires in the 3^rd century AD.¹⁴ (Incidentally, elephants not only have the longest nose of any mammal, but also the largest number of olfactory receptors (1948),¹⁵ out-sniffing dogs, while their olfactory communication via the monoterpene frontalin has an interesting chirality aspect.¹⁶)

Other difficulties are related to the mechanisms involved in chemoreception, which are poorly known. Odorants must be volatile, and therefore essentially apolar and of small molecular weight. Nevertheless, many of them have single digit picomolar or even lower detection ranges, suggesting the existence of an additional molecular “glue” beyond the simple complementarity of shape and polarity that underlies the lock-and-key model for the interaction of small molecules with macromolecules. Block and colleagues provide strong evidence that this could be metal binding in their contribution ‘The role of metals in mammalian olfaction of low molecular weight organosulfur compounds’ (DOI: 10.1039/c7np00016b), arguing against the quantum chemistry-based vibrational theory of olfaction.

Finally, the neurophysiological logic of chemoreception is still largely elusive, especially for olfaction. Olfactory receptors are expressed in a unique olfactory neuronal cell type in a one-cell-one-receptor fashion. On the other hand, most odorants bind a large number of receptors, making the response combinatorial. For an odorant that can activate four receptors (1% of the human portfolio of receptors), the number of possible combinations is astronomical (400!/(4!) × (396!), that is > 10¹⁰), with an infinite palette of nuances. Conversely, the gustatory system has little discriminating power, and different tastants diverge only in terms of the intensity and not the quality of the sensation they evoke.

When the geologist Hess resurrected Wegener’s theory of the continental drift, he called his seminal 1962 article on the history of ocean basins ‘An essay in geopoetry’, acknowledging the still speculative side of his theory of seafloor spreading (later fully confirmed).¹⁷ In a similar vein, some articles in this issue have a variable but unavoidable trait of “Essays in biopoetry” that we hope will stimulate readers’ interest, and trigger further work in an area where secondary metabolites, as environmental messengers, play such a critical role.

References

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