What’s that smell — and how’d you know?

Peter Mombaerts is a man of strong preferences. He likes Belgian beer — partly, but not entirely, for patriotic reasons. He likes classical music and observing the Earth from above while flying small planes with his amateur pilot’s license. He loves the feel of alpaca clothing during winter.

But Mombaerts, who leads the Max Planck Research Unit for Neurogenetics in Frankfurt, Germany, says he has no favorite odor — even though he has been studying smells for more than 30 years.

Mombaerts’s research has focused on how the brain processes odors, and on the impressive group of genes encoding odorant receptors in mammals. Humans have about 400 of these genes, which means that 2 percent of our roughly 20,000 genes help us to smell — the largest gene family known to date, as Mombaerts noted back in 2001 in the Annual Review of Genomics and Human Genetics. More than two decades later, it remains the record holder, and Mombaerts continues to delve into the genetics and neuroscience of how we smell the world around us.

He spoke with Knowable Magazine about what’s been learned about the genes, receptors and neurons involved in sensing odors — and the mysteries that remain. This interview has been edited for length and clarity.

Why did you start working on smell?

When studying medicine in my native Belgium in the 1980s, I learned that I don’t really like to work so much with patients. But research interested me. I wanted to do neurobiology. I did my PhD in immunology with mice and genetics, and then moved to neuroscience. It was what I always wanted to do, but I had to find the right topic, the right lab and the right mentor — and all that came together when Linda Buck and Richard Axel published their paper about their discovery of the genes for odorant receptors.

This paper came out in the journal Cell on April 5, 1991, and when I read the first few sentences I thought, “That’s what I want to work on.” Axel became my postdoc mentor. When Buck and Axel won the Nobel Prize in Physiology or Medicine in 2004, I wrote a Perspective piece for the New England Journal of Medicine  that I titled “Love at First Smell.”

How does the sense of smell work?

Terrestrial mammals such as humans perceive smells that are volatile, that arrive through the air. The many chemicals that make up an odor diffuse in the mucus layer inside our noses and interact with odorant receptors on olfactory sensory neurons. Each odorant interacts with multiple receptors and, conversely, each odorant receptor interacts with multiple odorants. These neurons generate electrical signals that are transmitted to the olfactory bulb of the brain, where they are processed and sent to the olfactory cortex, the portion of the brain’s cerebral cortex concerned with the sense of smell.

That’s it in a nutshell. But how exactly we recognize banana as banana, we still don’t know. It’s one of the big unsolved questions.

Why don’t we understand it yet?

I have been in this field for 30 years and it’s a very simple question with a difficult answer. There are many chemicals that together make the smell of a banana. The exact mixture of chemicals and the relative proportions vary from one banana to the next — yet we still recognize them all as bananas. One can mimic the smell of a banana with molecules that are not even present in a banana. We know the components of the olfactory system — the odorant receptors, the olfactory sensory neurons, the regions in the nervous system — that allow us to do that. But how exactly it works, we don’t understand yet.

How do researchers study the olfactory system?

The initial discovery of odorant receptor genes by Buck and Axel was made in rats. Soon the field moved to mice because of the possibility of genetic manipulation. Nearly all we know about the sense of smell, in terms of molecular biology, histology, physiology and anatomy, is based on studies with mice — actually, with genetically manipulated mice.

But I feel that the olfactory systems of mice and humans might be different enough to raise questions about how much we can learn about human olfaction by extrapolating from mice.

Species differ dramatically in how many odorant receptor genes they have. African elephants, for example, have the largest number of odorant receptor genes, roughly 2,000 — nearly twice as many as mice and dogs, and five times more than humans. Does that make them better smellers?

The enormous size of the odorant receptor gene repertoire is one of the perplexing findings of the 1991 breakthrough paper by Buck and Axel. But there is no simple relationship between the number of genes that encode receptors for odors and the performance of the olfactory system of the species. Because odorant receptor genes are so small, species seem to be able to expand or contract their repertoire relatively quickly during evolution, in response to changing needs.

With so many genes involved in the sense of smell, is it possible to say that a good sense of smell is a trait you can inherit?

I don’t know of good evidence that there is a genetic basis for a “good” sense of smell, but there probably is. With 400 odorant receptor genes, that question is actually difficult to study.

There are individuals who are very good at olfaction. In the perfume industry, they’re called in French a nez, a nose. They are not really “super smellers”; they train every day. But there’s no evidence that there is a genetic basis to it.

A small percentage of human beings are born with congenital anosmia, without a functional sense of smell. In a fraction of these cases, the genetic cause is known — such as in Kallmann syndrome — but more often, it’s not.

Surprisingly, scientists have found that odorant receptor genes are active — expressed — not only in the nose, but elsewhere in the body. Does that mean these genes may do something more than just detect odors?

Apparently so. I have been working on one receptor called Olfr78, which is expressed in several tissues of the body other than the nose, such as in the prostate, in melanocytes and in the carotid body, which helps regulate breathing. Recently, collaborators in Seville, Spain, and I reported that Olfr78 is required for maturation of the cells in the carotid body that detect low oxygen levels in the blood. How exactly Olfr78 does that is not yet understood.

Do these findings have implications for medicine or therapeutics?

At this moment, there is no medical therapeutic application I know of, possibly because of the intrinsic complexity of the sense of smell. At some point, there will be some smart scientists or an innovative company that comes up with a therapeutic application. Right now, it is basic research, satisfying curiosity, studying genes, receptors, evolution without knowing directly if we’re going to cure this or that disease.

You’ve also studied the loss of the sense of smell caused by SARS-CoV-2 and the possibility that the olfactory system offers a route for the virus to enter the brain. What have you learned?

There was particular concern to know if the virus could invade the brain via the olfactory route. The olfactory bulbs are located only a few millimeters away from the olfactory mucosa in the nose, separated by a thin bit of perforated skull bone with the projections, or axons, of the olfactory sensory neurons running through it. So the virus could, in principle, use the olfactory route to get into the cranial cavity and may contribute to causing what we call long Covid, specifically neuro-Covid.

There were a few initial papers, of the quick and dirty type, that claimed that SARS-CoV-2 could infect olfactory sensory neurons in humans. From 2020 to 2022, we conducted a big study in Leuven, my hometown in Belgium, where we examined tissue samples of 115 patients who died from or with Covid-19 soon after the diagnosis of infection.

We looked hard for evidence of infection of olfactory sensory neurons, of the olfactory bulb and of the brain. And we could not find it. I believe that the field now believes that, indeed, SARS-CoV-2 does not infect olfactory sensory neurons in humans. But — in English, this sounds very nice — the absence of evidence does not equate to evidence of absence, right? One cannot prove a negative in science.

If SARS-CoV-2 doesn’t infect olfactory sensory neurons, then why do people with Covid often lose their sense of smell?

Cells called sustentacular cells or supporting cells surround the olfactory sensory neurons in the olfactory epithelium, and support them in ways that are still poorly understood. We showed that these unsung heroes are infected by SARS-CoV-2. So you can easily imagine that when the supporting cells are infected, the olfactory sensory neurons, which they support, are affected: They no longer function normally, at least for a while. But exactly how we go from infection of sustentacular cells to the loss of the sense of smell is still not understood. The dots need to be filled in.

What fascinates me, if I may use that word, is that the loss of the sense of smell in Covid-19 patients can be very abrupt. Usually, they experience it in the morning, sometimes in a matter of hours. And then it recovers, most of the time, over a period of a few weeks. This abrupt onset of the symptoms makes me think that we have been looking at the mechanism in the wrong way. It may not matter so much what happens in the olfactory mucosa, but maybe something happens in the olfactory bulb or elsewhere in the brain — perhaps a vascular problem — that causes an abrupt defect in the sense of smell.

Does this still matter?

The pandemic is not over. The emergency phase has been declared over by the World Health Organization, but lots of people are still being infected, and many are still losing their sense of smell. People have become so used to it that it’s no longer news for the mainstream media. Approximately 1 in 20 to 1 in 10 people who lose their sense of smell in association with a SARS-CoV-2 infection do not recover it, at least for as long as the pandemic has lasted. It looks like if after eight weeks the sense of smell has not come back, the olfactory dysfunction may persist for a long time and possibly even for the rest of the lifetime of the individual — who knows?

There are by now millions, perhaps tens of millions, of people around the world with a chronic olfactory dysfunction associated with a bout of Covid-19. We in the scientific and medical community should continue to work on understanding the mechanism so that a rational cure can be developed. Even though it doesn’t kill you or affect your brain directly, an impaired or distorted sense of smell can drastically affect the quality of your life.

Given that there are so many basic aspects that science still doesn’t know about olfaction, would you say that the study of the olfactory system lags behind research on the other senses?

Yes, I think it does. It was the last one, together with taste — both called chemical senses — to be elevated to mainstream neuroscience. To me, the field of olfaction consists of two eras: before and after Buck and Axel, 1991. It’s become a very, very big field, with many labs working on it. We just completed a global conference in Reykjavik, Iceland with 725 participants from 30 countries working on the chemical senses.

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After 30 years in the field, what are the questions that interest you now?

They’re actually the same as when I entered the field in 1993 as a postdoc with Richard Axel. They are easy to phrase but not easy to answer. One of them is the banana question — why does a banana smell like a banana? There are hundreds of compounds typically emitted by a banana, but our brain says, “OK, that smells like a banana.”

Another question is how odorant receptor genes are activated. A mature olfactory sensory neuron only uses one of these genes. How then does an olfactory neuron choose one of these 1,141 genes in a mouse to activate? It’s a very interesting question and there is no definitive answer.

And the third question is what we call axonal wiring. As a postdoc, I showed that in mice, all the olfactory sensory neurons that express a particular odorant receptor gene send their axons to one or a few specific regions in the olfactory bulb, called glomeruli. There are a few thousand glomeruli in a mouse olfactory bulb. How these axons manage to find a common target in the olfactory bulb remains a mystery and continues to excite me.