By Ryan P. Dalton on August 13, 2019

Subject cDa29—well-known yet anonymous—resides somewhere in the north of England. You can almost see it: the peat stacks and old textile mills; the limestone and turf ruins where, on divine calling, Hadrian marked the northernmost reach of the Roman Empire. But even were you there, you wouldn’t see it the way cDa29 does. That’s because cDa29 is tetrachromatic: while most people see their world as a mix of three colors—red, green and blue—cDa29 sees hers in four. Difficult to imagine as that world may be for trichromats, your sense of smell provides access to an even richer world, one painted not in four colors but 400. You can almost smell it: the peat, the mills, the turf.

How do your senses build these worlds? They begin with sensory “receptors,” which sit on the surfaces of cells and are activated by specific stimuli. In the case of vision, there are three color photoreceptors in your retina—activated by red, green or blue light. By keeping these receptors separated—such that no two photoreceptors occur together in one cell—your retina can keep track of what colors came from where. As a counterexample, you have a few dozen “bitter receptors” on your tongue, but each bitter taste cell contains several of them. This arrangement allows you to detect many different bitter compounds, but it does not help you distinguish between them. As these examples illustrate, you must both be able to detect a wide range of stimuli and to discriminate between those stimuli—and generally, your senses strike a balance between these two objectives.

Ever the romantic, your sense of smell casts aside the suggestion of balance and optimizes for both detection and discrimination. Olfactory neurons in your nose have evolved some 400 odor receptors, and each neuron contains only one. Receptors are tuned to detect a few basic odors apiece: some detect geranium petals or pine needles, while others detect the by-products of putrefaction. To organize all this information, your olfactory neurons wire into an “olfactory map” on your brain’s olfactory bulb. Olfactory neurons are one of the few types of neurons that are born throughout your life, and each of the roughly 10,000 such neurons born each day in your nose subsequently wires into the olfactory map in your brain.

Incredibly, all the neurons containing a given odor receptor wire to the same spot on the map, such that each half of your olfactory bulb has 400 distinct regions. The combination of regions turned on by a given odor is what makes it seem unique. This fact may be why odors are so evocative: that glass of wine reminds you of a freshly opened can of tennis balls because whatever was in the can is also in the wine.

Despite the fundamental importance of this 400-region map in building our sense of smell, how exactly it forms has remained mysterious—and that is not for a lack of trying. We have long known that there are several genes involved in wiring up the map. Like the joystick on an arcade’s toy crane, as these genes are engaged and disengaged, they help direct olfactory neurons to wire toward their prized targets. But that doesn’t answer the question of how 400 types of olfactory neurons might operate those genes in 400 different ways—to reliably deliver 400 prizes. As is often the case, it turns out the answer was right under our nose: it is the odor receptors themselves that guide the construction of the olfactory map. But they don’t smell their way there.

Instead, according to a study published recently in Science, it is what the odor receptors don’t smell that guides them. Imagine you are blindfolded, with your hand on the toy crane’s joystick, and a friend is preparing to give you instructions. As you wait, you rock on your feet or tremble, shifting the crane. The instructions never come, and when your time runs out, the crane’s claw drops, retrieving a stuffed peach. You then pull the same trick on your friend, only his or her own pattern of minute trembles moves the claw elsewhere, and it retrieves a stuffed watermelon. It was not what the two of you heard that drove the crane; it was your own internal noise.

It seems that this is the process employed by odor receptors. Working in mice—which have more than 1,000 odor receptors—the study’s authors showed that each receptor, in the absence of an odor, produces a specific type of electrical noise. This might mean firing in short bursts between long pauses; it could also mean firing on specific intervals. These noise events then exquisitely control the set of genes directing an olfactory neuron’s growth as it wires to the olfactory map. Because two neurons with the same odor receptor will experience very similar noise, they will end up wiring to the same place. And because all 400 of your receptors are different—if only slightly—the noise they produce is different, too, causing them to wire to distinct locations. The end result is a 400-location map that functions like the perfumer’s organ equivalent of the “The Library of Babel.”

These discoveries open up a number of avenues for further work. For example, we do not understand how noisy electrical activity could so precisely control the activity of genes involved in neuronal wiring. Through understanding that process, scientists may learn to co-opt it. For example, we might be able to use certain types of noise—such as those linked to neurological diseases or injuries—to drive the production of biomarkers or even to activate repair pathways. This work also may help us understand the cause and progression of diseases of olfaction. Many people think of their sense of smell as an “accessory” or “leisure” sense, but defects in olfaction are widespread—affecting 1 to 2 percent of North Americans—and come with serious challenges to health and well-being. Lastly, while we have known since the middle of the 19th century what humans can and cannot see, we still do not know how to predict what we can or cannot smell. This discovery takes us one step closer to that knowledge.

Will total knowledge of what our noses are able to detect cost us the joy and magic that scent seems to bring? Don’t count on it. Taking the story back to the north of England, much of what makes smell so fascinating is that, while most of us see a world that looks the same, rarely can the same be said for the 400-color world of what we smell. And try as we might to communicate the richness of our olfactory world to one another, just like a Victorian-era perfumer cold-pressing flowers, the best we can hope for is a pleasant distillation.

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ABOUT THE AUTHOR(S)

Ryan P. Dalton
Ryan P. Dalton is a neuroscientist, writer and former Miller fellow at the University of California, Berkeley. His scientific work is centered on sensation and memory, and his writing focuses on minds, machines and the social impacts of biotechnology. He can be reached at [email protected]. More is available at http://ryandalton.weebly.com.