[[link removed]]

SUNDAY SCIENCE: WHAT’S THAT SMELL — AND HOW’D YOU KNOW?  
[[link removed]]


 

Peter Mombaerts, Daniela Hirschfeld
September 4, 2024
Knowable Magazine
[[link removed]]


*
[[link removed]]
*
[[link removed]]
*
*
[[link removed]]

_ It’s clear that genes, receptors and neurons all play a role in
detecting odors. But much of how we make sense of what we sniff
remains mysterious. A neuroscientist explains. Q and A with
Neurobiologist Peter Mombaerts. _

Our noses can easily smell the difference between a stinky sock and a
fragrant flower, thanks to a complex process that continues to
intrigue olfaction researchers., ESTHER AARTS

 

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 [[link removed]] 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
[[link removed]]
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
[[link removed](91)90418-X], 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 [[link removed]].”

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
[[link removed]],
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
[[link removed]] —
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
[[link removed]], 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
[[link removed](21)01282-4.pdf]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.

 

STAY IN THE KNOW
SIGN UP [[link removed]] for the
_Knowable Magazine_ newsletter today

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
[[link removed]].
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.

Read the original article with additional graphics HERE
[[link removed]]

Why Do Apes Make Gestures?
[[link removed]]
By Carl Zimmer
New York Times
Chimps and other apes have been observed making more than 80
meaningful gestures. Three theories have tried to explain why.
September 6, 2024

* Science
[[link removed]]
* biology
[[link removed]]
* neuroscience
[[link removed]]
* sense of smell
[[link removed]]
* genes
[[link removed]]
* receptors
[[link removed]]
* neurons
[[link removed]]

*
[[link removed]]
*
[[link removed]]
*
*
[[link removed]]

 

 

 

INTERPRET THE WORLD AND CHANGE IT

 

 

Submit via web
[[link removed]]

Submit via email
Frequently asked questions
[[link removed]]
Manage subscription
[[link removed]]
Visit xxxxxx.org
[[link removed]]

Twitter [[link removed]]

Facebook [[link removed]]

 




[link removed]

To unsubscribe, click the following link:
[link removed]