Welcome to Huberman Lab Essentials,
[music] where we revisit past episodes
for the most potent and actionable
science-based tools for mental health,
physical health, and performance.
I'm Andrew Huberman, and I'm a professor
of neurobiology and ophthalmology at
Stanford School of Medicine. And now for
my discussion with Dr. Noam Sobel. Dr.
Sobel, Noam, welcome.
>> Thank you.
>> I must say I am extremely excited for
this conversation. I've been a huge fan
of your work, and today I'd love for you
to share with us all about the amazing
landscape of chemosensation, in
particular olfaction, our sense of
smell, and some related perceptual
abilities, or subconscious abilities,
including pheromones, etc. To get
everybody on the same page, I'd like to
just start off by asking
what are the major components of our
ability to smell?
>> [snorts]
>> Obviously, or I like to think it
involves the nose at some level.
>> It does.
>> Now, if you could just give us the top
contour, or even deep contour if you
like, of the the parts list, and the
various roles they play.
>> Primary olfaction is referred to as
orthonasal olfaction, that is through
our nose. We sniff, and sniffing is a
big thing. Well, I have a sense we might
talk about that a lot today, in all
sorts of contexts. So, we sniff in
through our nose, and to answer your
general question of the organization of
the system, um so, molecules, airborne
molecules, travel up our nose a distance
in the human of about 6 or 7 cm to about
here, where they interact with I will
use the word sheet of receptors, but
sheet is a bit misleading here. It's not
a sheet, it's very convoluted.
We have about 7 million such receptors
uh lining a structure known as the
olfactory epithelium. This is the
sensory surface of the olfactory system,
the olfactory epithelium. Again, about
probably about 6 or 7 million receptors
in the human.
In the human, probably of about 350
different kinds. So, that's amazing.
That means a
meaningful percentage of your genome is
devoted just to this, just to the kinds
of olfactory receptor subtypes you have
in your nose. So, odorants interact with
these receptors here in our epithelium
where they undergo what is referred to
as transduction. That is, the odorants
are docked at a receptor and turn into a
neural signal and this neural signal, in
fact, action potentials, not gradient
potentials of any kind, uh propagates
via the olfactory nerve through the
thinnest part of our skull, which is
perforated. It has a lot of holes.
The nerve goes through those holes and
synapses at the first target in the
brain,
which is the olfactory bulb. The pattern
of that synapsing follows what's
referred to as the most extreme case of
convergence in the mammalian nervous
system.
More specifically, what happens is that
all the receptors of one subtype
converge to one location in the bulb.
And this location is referred to as a
glomerulus or in plural, glomeruli. And
and that may be a slight
oversimplification. It's in fact two
glomeruli. The textbook view of how
things work is that every such receptor
subtype is responsive to a small subset
of different molecular shapes, what's
sometimes referred to as odoritopes, the
molecular aspects of the odorant. And
each odoritope will activate a different
subset of receptors. Then, because of
this convergence, you end up having on
the bulb in the way of a map reflecting
receptor identity. So, so let's say this
coffee activates receptors of type 1, 3,
and 7. So, the glomeruli of receptors 1,
3, and 7 will light up, quote unquote,
when I smell the coffee. And if you
could take a snapshot of that,
theoretically, you would have the map of
coffee. This is sort of the textbook
view of how the system works. And then
information goes from the bulb to
several targets in the brain. I mean,
what is referred to as primary olfactory
cortex is piriform cortex and and
entorhinal cortex. This is on the
ventral surface of the brain, the lower
portion of our temporal lobe, and
information goes there directly, but it
also goes directly to the amygdala. It
probably goes directly to the
hypothalamus. It may go directly to the
cerebellum. Uh it goes all over the
brain. So so
information projects widely from there,
and as far as people understand, the map
that may exist on the bulb uh doesn't
exist in the rest of the brain, and the
understanding of of how coding occurs in
the rest of the brain is is murky.
Again, in our lab, we already said, "You
know, yeah, we know this. This is old
news." But but to people who who come
from different worlds, we have to
reiterate this. Sometimes when I give
uh you know, public lectures to to
non-olfaction audiences, I reiterate
this.
Humans have an utterly remarkable sense
of smell. We look at human behavior a
lot. We try to look at it through our
nose and in the way we look at what
people are doing. You know, we try to
think, you know, if I was a dog,
what what would I think of this? And and
you know, if you look at dogs, right?
They they
you know, when they interact, they
visibly sniff each other. It's very
obvious. They walk up to each other, and
they sniff each other. And yet, humans
don't typically walk up to a stranger
and carefully sniff them, right? I mean,
it's We're we're sort of obliged to
sniff our our babies. That's considered
almost something you're supposed to do.
Um and it's not culturally taboo to
sniff our loved ones. It's sort of
doesn't seem like an odd thing to do.
But we don't sniff strangers, all right?
Well, or do we? So
we're finding more and more mechanisms
where we do this. And And the one I'm
referring to now, for one example, is we
started looking at handshaking. There's
really poor understanding of how this
behavior evolved. Like, where did where
did this thing come from? You know, if
you look for the Wikipedia version,
right? Then they'll tell you that it's
to show that you're not holding a weapon
in your hand. But there's really no good
evidence for that. And we started
looking at people handshaking, and and
we noticed, or it seemed to us that
we're noticing that you know people will
shake hands and then we'll go like this
and like
>> For those of you listening not watching,
Noam um he was taking his hand and and
wiping it on his face.
>> Yeah, they were
touching myself. Yeah, these things
these things that we do all the time.
>> After a handshake.
>> Well, so so first of all we do them all
the time just period, right? The
baseline here is really high and we'll
get to that in a second, but but but
these behaviors that you know you you
you could easily not notice, right? And
and so we we asked whether that's a real
thing.
And this was a study led by Idan Frumin
in our lab at the time. So what we did
is we brought in participants to our lab
and we sat them in the room
uh experiment room
and and told them the experiment would
start soon and they should wait for us
there. They didn't know what they were
coming from.
Unbeknownst to them they were already
being videoed and they would sit there
for 3 minutes.
And during those 3 minutes we could
later quantify how much indeed they just
by baseline how much they touch their
nose or their forehead or their chin or
how many times their hand
uh uh reaches their face. And by the way
that baseline is not low. And then 3
minutes later an experimenter would walk
into the room and would share a
consistent text it would be you know
we're still setting up our equipment in
the other room
uh and and so just wait here and we'll
be right back with you, but in the
meantime just wait here. And
in half of the cases it included a
handshake. This was a new experimenter,
not the one who put them in the room. So
that's the first time they met. So it
would be hello, I'm you know so-and-so
they would put out their hand and shake
their hand or not. And so you had
handshake and no handshake conditions
and then you can quantify that behavior
of the hand going to the nose after
handshake.
And there was a remarkable increase in
the hand going to the nose after
handshake. It's unreal.
>> So interesting.
>> hand goes to the nose. Now we did a few
controls here
to verify that this is an olfactory
behavior. One is unbeknownst to
anti-participants we measured nasal
airflow.
And and and people not only bring their
hand to their nose, they sniff it. So
and this is perfectly timed. They go
like this, okay? So, they're sniffing
their hands. So, this was an olfactory
behavior. No doubt about it. I mean,
we're we're quite confident. And there's
an interesting thing going on here, too,
because people didn't only smell the
hand that shook. They also smelled the
other hand. And we think that there's
something going on here comparing self
to other.
And we think a lot of self-sampling
might might reflect that.
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>> There's a study we published by Inbal
Raviv in in our lab. Um
where
Inbal came with this uh uh
basic interest
in this phenomenon that's loosely
referred to as click friendships. So,
people you meet and you click right
away. Everybody experienced this in
their life, you know, to some extent.
And the question is
what what was there, right? What was it?
Was it because you looked the same?
Could be. Was it because, you know, you
had the same
sports team that you liked? Or
is there something uh deeper here?
And and Inbal's theory was that a
similarity in body odor may contribute
to this.
That people who
smell the same will click in some way.
And so, to address that, she she
actually recruited click friends from
all over Israel. She posted all over
social media
uh to identify pairs of friends. So,
these are our same-sex non-romantic
dyads. So, these are friends, men and
women, whose friendship started as a
click. And then
she um sampled their body odor. And And
we have a a protocol for this. Uh
they're given, you know, uh odorless
shampoo and soap to use for 3 weeks or
something. And then they sleep two
nights in this T-shirt uh where they
have to sleep alone. And then we extract
the body odor from the T-shirt. And so,
we have a way to extract a method to
extract body odor. And then she she
first asked whether indeed click friends
are more similar in their body odor than
you would expect by chance. And she
first tested this with a with a device,
a machine we call an electronic nose.
So, an electronic nose is sort of a very
poor effort to mimic what the mammalian
nose does. Basically, it's a bunch of
sensors that respond to airborne
molecules. In this case, sensors
referred to as MOX sensors as a metal
oxide-covered sensors. And so, she used
an electronic nose to sample these body
odors. And she found that click friends
are indeed more similar to each other uh
than you would expect uh by chance, by
random dyads. And And this was a
significant difference.
And after she found that a device could
do this,
she had other participants do this. So
So she had people smelling the click
friends versus non-click friends and and
they judged them as being more similar
to each other than not. Now again, you
you might wonder is this causal or not,
right? Because maybe click friends go to
the same restaurant together or all the
time or whatever or live in the same
neighborhood and and that's why they
they they smell the same. So to address
causality, she recruited total strangers
and first smell them with the electronic
nose and then engage them in a social
interaction, something called the mirror
game. So in the mirror game, one person
moves their hands and the other person
is really close to them, like right
here, so they can smell each other
and has to move their hands with the
other person.
And one one prediction there panned out,
uh but another didn't. The one that
didn't So she predicted that people
would smell more
uh similar to each other would be better
at the mirror game. That is, they would
follow each other better. That did not
pan out. However,
she then also had
the interaction was completely
nonverbal. They were not allowed to
speak with each other and she did an
entire round robin, so everybody played
with everybody else. This was an insane
experiment to run.
She [snorts] then at the end of the
experiment, each person rated each other
person as to how much they think they
would want to be their friends and also
on a bunch of ratings, how nice they
think they are, how affectionate they
think a bunch of ratings, okay?
All of this was predicted by the
electronic nose. So people who smell
more similar to each other
think that the other person is more
likely to be their friend, is more
likely to be a nice person, etc. etc. So
we could actually predict friendship
using the electronic nose. So this is
not a result of friendship. It's It It
plays into the causal elements of of
building friendship. People are
constantly smelling themselves,
constantly smelling others.
>> I want to touch on some other uh
so-called pheromone effects. Whether or
not it's a classic pheromone effect or
whether or not it's olfaction or
something else. This is chemosensory
signaling between individuals.
>> It all becomes semantics, right?
>> of like nerdy inside ball.
>> Yeah, it's all semantics. So, I don't I
in our publications, we don't use the
term pheromone, you know, because it
would not help me and it would probably
only hurt us. And so, you know, we talk
about chemo signals and humans
definitely emit chemo signals from their
body
and these chemo signals influence other
humans and influence their behavior. The
flavor of the month for the past 10
years in this field
is what's referred to as the smell of
fear. Humans emit a particular body odor
when they're in a state of fear and this
body odor influences other humans in
effect increasing
their autonomic arousal, their
sympathetic state. So, in effect, you
could say that fear is contagious a bit.
So, the smell of fear is contagious. By
the way, culturally, we know for ages
that dogs can smell fear in humans, but
actually that was only really shown
about a year and a half ago in a study.
So, it it was always said, but it wasn't
really shown effectively. It was shown
about a year and a half ago in study
that dogs indeed can smell human fear.
And humans can smell human fear. So,
several labs starting from Denise Chen
and Haviland Jones and and then in our
lab and in other labs, if if you collect
body odor from people in a state of fear
and collect body odor from the same
people when they're not in a state of
fear,
other people can determine which is is
the state of fear or not and and this
influences their behavior. And they just
highlight again, you know, that that
we're incredibly olfactory animals.
>> We had a guest on this podcast who I'm
sure you're familiar Charles Zucker, a
professor at Columbia has done
incredible work in vision and olfaction
and
thirst sensing and I talked a little bit
about this that
there's something in the breath
of romantic partners
that's hopefully appetitive, not
aversive.
As well as in children, he was talking
about the smell of his grandchild's the
back the nape of their the back of their
neck and how he misses that smell
because it when he thinks about missing
his grandchild or children, it's that
smell that that that's associated with
that feeling.
>> hexadecanal.
>> Hexadecanal?
>> Yes. This is a study
uh ran by uh Eva Mishor uh who was a
graduate student in our lab. Eva was
interested in aggression. And so, when
she started off, we said, "Okay, let's
do chemo signaling of aggression."
She actually was going to like MMA clubs
and collecting body odors.
Uh and we we we had all sorts of ideas
going and and she's she worked on that
for quite a bit. It never went anywhere
really. At the same time, Heinz Breer,
he was studying in his lab uh a molecule
hexadecanal um that was a chemo signal
in mice that promotes social buffering.
So, when lots of mice are together, they
feel good about being in a group, and
that's social buffering.
And it's promoted by hexadecanal, which
they emit in their feces. So, Breer and
his colleague Stortzman, they they
discovered the receptor for this. And
then they went and discovered that the
receptor is very highly conserved uh
throughout mammalian evolution, and
therefore they hypothesized that maybe
this is a universal mammalian signal.
Now, which is unusual because in in
chemo signaling, typically you you tend
to think of things as being very
species-specific. So, he approached us
and said, "Look, you got to study this
stuff in humans, right?" Because he
knows us as the human people, right? I
mean, we go to these olfaction
conferences where where lots of people
study mice and and and and zebrafish and
whatnot, and we're the the human group.
And eventually, he just FedExed us
hexadecanal. And Eva was not going
anywhere with her aggression studies
with sweat from human participants.
And yet she built the entire um
paradigm to study human aggression. So,
they're standard paradigms. This is a
paradigm known as the TAP, the Taylor
Aggression Paradigm. And what's nice
about this is that then allows you to
quantify aggression. And so, you have a
a measure of aggression. Again, the
Taylor Aggression Paradigm, obviously
invented by Taylor, very well validated,
studied all over, you know, a very
standard protocol.
So, uh we brought in participants and
had them play uh the Tyler the tap uh
either under exposure to hexadecanal
or control. And I'll first tell you the
result with
men, which is that hexadecanal
consistently reduced aggression.
People were less aggressive under
hexadecanal.
Um the effect size was uh quite
meaningful compared to the effects seen
in the aggression world in in research.
Really, really strong effects. So,
unusually strong.
So, hexadecanal lowered aggression in
men, and we were like, "Cool, this is,
you know, sort of what we were hoping to
to see, consistent with the hypothesis
uh
and consistent with what it seems to do
in mice." But, then we looked at the
data from women.
And hexadecanal increased aggression,
equally significantly. Is this thought
to be something related to maternal
protectiveness?
>> We're getting there.
>> So, she went and did the entire
experiment again, and this time she did
it within the fMRI magnet so that we we
can also track uh brain activity uh
while this was happening.
And first of all, it replicated again.
So, once again, uh hexadecanal in men
made men less aggressive and women more
aggressive. And yet, I was telling you,
"You know, you know, but you know, this
makes no sense to me."
And then and then her insight, which of
course afterwards is like, "Duh." It is,
"No, there's a place where this makes
perfect sense. And that is if you're a
mammalian offspring."
Because
paternal aggression is often directed at
you. There's infanticide all over, and
sadly, there's male aggression towards
human children as well.
And maternal aggression is often
protective.
So, if you're an offspring, if you have
a molecule that will make your mother
more aggressive and your daddy less
aggressive, both of those are good for
you. So, you're winning. So, the bottom
line of all this is that hexadecanal is
the most abundant semi-volatile in baby
heads. It's tons of it coming out of
baby heads. Well, babies are conducting
chemical warfare, right? They're
reducing
aggression in their fathers or males
around them and increasing aggression in
their mothers or females around them,
and both of those things are good for
them.
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What is the relationship between odors
and hormones, and in particular
crying? Tears are a bodily liquid,
emotional tears,
that that we emit in emotional
situations where where these are
situations where nonverbal communication
is is critical and key. The most
influential text I think till this day
in in in emotion research is is Darwin's
book The Expression of the Emotions in
Man and Animals, I think is the full
name of the book.
>> six
is devoted to tears. So, Darwin
systematically went through the
expressions of emotions and for each one
went to their functional antecedent and
explained everything very nicely.
And then he got stuck with tears, right?
Because tears are an obviously emotional
expression.
And he could not find
a functional
uh antecedent.
So, he ended up saying, "You know, this
is an epiphenomenon."
So, we thought, "Well, maybe the
function is is a chemical signal." So,
with that in mind, we we harvested
emotional tears. So, we collected uh
tears and we exposed uh participants to
these tears. First of all, the tears are
completely odorless. You cannot detect
them at all. Completely odorless.
Um
and yet
when you sniff them
you have
a pronounced uh reduction in
testosterone
uh within about 20 minutes, half an
hour.
>> This is men and women smelling women's
tears. Just men smelling women's tears,
but not perceiving any odor.
>> Nothing. Just sniffing them.
And you have uh about a 14% drop in free
testosterone. And people who study
testosterone, which is not me, but they
tell me this is a really strong effect.
Like it's it's hard to even
pharmacologically get an effect like
that that fast. I mean, no in
pharmacology.
>> Yeah, years ago I spent time studying
endocrine effects of this sort um and
it's a a tremendous re-size effect.
>> Uh and so, here I'll point out in
passing
uh that uh what one of the concerns we
had because of the uh
effort to run this study is that nobody
would ever try to replicate it. And to
our joy, about 2 years later, an
independent group from uh
South Korea
uh Oh et al., who I don't know at all,
uh
replicated the testosterone effect to a
T. I mean, like same numbers.
So, [snorts] so um it
it lowers testosterone. And and we then
also looked uh using MR at the at the uh
effect
on brain activity and saw pronounced
effect on activity, a dampening, a
lowering of activity
under under an arousing state, a
lowering of activity
both in the hypothalamus
um, and in the fusiform gyrus for
whatever reason, I don't know.
>> area.
>> Amongst other things, yes.
Um, and we don't know why.
Um, but pronounced. So, usually in our
chemo signaling work, we look at what
happens in rodents and we see if the
same thing is happening in humans. This
was a rare case where after we did this
work, more or less identical effects
were discovered in rodents.
So, a paper published in Nature 2 years
later found that mouse tears
uh, mouse pup tears lower aggression in
in um, male adult mice towards them.
>> In a smell dependent way.
>> Yeah, yeah, yeah. And they also actually
found the actual component in tears that
so, the tear pheromone that lowers
aggression. Right? So, so, you know,
this has us thinking of a gret is tears
is is is you can think of tears is like
a chemical blanket in a way that that
you're covering yourself up again with,
you know, to protect against aggression,
right?
>> Smell being such a rich source of
behavioral and hormonal and other sorts
of deep deep information, [snorts]
what is your experience with generating
smells in silico in computers? And here
folks, if for those of you that aren't
catching on to this and and I don't
expect that everyone would because what
we're really alluding to here
um, is the idea that you'll look at
you'll put into a search engine um,
blueberry pancakes recipe
and that not only will you get photos of
those blueberry pancakes and a recipe,
but you will get the
hopefully validated odor of those
pancakes and that recipe coming at you
in real time through the computer.
>> So, Google had an April Fools spoof.
>> All right.
>> And they put out this video
of Google smell.
Okay? And and it had all these like
classic like sales images of you know,
holding up your phone to a rose and it
generating rose and and and all these
things, right?
So, Google is now trying to do that, you
know, to digitize uh smell. And there
are other companies that are trying to
do this as well. And recently in our lab
we've had and and I hope this doesn't
come across as overly arrogant, but we
we've had a sort of mini breakthrough on
this front.
>> To call something a mini breakthrough is
far from arrogant.
>> [laughter]
>> And and and and this is a paper uh led
by Aaron Raviv uh
uh from our lab and Kobe Snitz also a
major contributor there. A paper
published in nature. And in this paper
we develop an algorithmic framework
uh where we can
predict the perceptual similarity
of any two molecular mixtures
with very very high accuracy. So, if you
give me two molecular mixtures, I can
predict how similar you you will smell
them to be. Okay? Not only could we
predict that, but we could design it.
So, we can generate um
uh
mixtures with known similarities. The
result was highlighted and and and
you'll appreciate this coming from
vision
uh is that
using our algorithmic solution, we
generated olfactory metamers. So, we
measured mixtures
completely non-overlapping in their
molecular structure
but they smell exactly the same. Okay?
Now, if you would come to a classic
perfumer or most classic perfumers and
tell them that you can generate two
mixtures with zero molecules in common,
but smell exactly the same,
they would tell you no.
And yet, we did and and anybody can
recreate them. This is simple, actually.
And in the paper we do a few things like
we generate a metamer for uh Chanel No.
5 with no component from Chanel No. 5 in
it.
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>> In a way, we've generated the the the
infrastructure for digitizing smell
because, again, what our algorithm
predicts our our framework predicts is
similarity.
But in a way, that's enough for you. Why
is that enough? We have a map
of 4,000 molecules.
Uh for each one, we know their perceived
smell.
Now, you can make up any mixture you
want for me. I can project it into that
map
and measure its pairwise distance from
all the points in the map. If it falls
on lemon, then what you generated smells
like lemon. And if it falls, you know,
on tomato, then what you generated
smells like tomato.
So,
we we now solved that problem. We can
predict the odor of any molecular
mixture. We we say how it's going to
smell. What we can do is then find a set
of components, which we call odor
primaries,
that can be used to mix any odor that
you can perceive. And that's what we're
working on now. So, this is in
collaboration with the lab of a Jonathan
Williams and Max Planck in Munich.
Um Jonathan Williams is an
atmospheric chemist,
uh
>> [snorts]
>> but he's really good at at using GCMS,
these tools that measure molecules. So,
uh Jonathan Williams measured odorants
in Germany,
uh transmitted the information to us
over IP.
Uh we fed that into our algorithmic
framework and recreated it from a device
that mixes primaries. And we tried to do
four different odorants
uh in our our proof-of-concept test.
Uh one of them uh was rose, and we
failed at recreating rose.
It we in fact recreated something that
had a percept, but most people perceived
it as bubblegum.
Uh the second one we tried to do was
anise, and we failed at recreating
anise.
Um and most people said it was cherry,
which is not very far, but it failed.
The third was gasoline, and we were
slightly but significantly better than
chance at recreating gasoline. And the
fourth was violets.
And 15 of 16 people said violets.
So, the first odor ever transmitted over
IP is violets. You know, we're don't
hold your breath for this to be on your
table tomorrow. You know, all we have in
hand is this very initial
proof-of-concept, but we're on we're on
the path. We're talking now of trying to
achieve
uh the olfactory equivalent of circa
1956 black-and-white TV, okay?
Basically, right? And you know, I'm not
dreaming, let's say, of being able to
transmit to you the difference between a
cabernet or a merlot, right? But if I
can generate something that's vaguely
wine, that will be an amazing success
from my perspective, right?
But jump ahead in your imagination
to to 4K odor transmission then medical
diagnostics is where you want to be
talking about because this is uh uh
over uh extension but
you can almost say that every disease
will have an odor. I mean every disease
is a specific metabolic process.
Metabolic process have metabolites,
metabolites have a smell. Olfaction once
it's digitized
and and high resolution which again it
in our hands it's not going to be I mean
we're talking you know in my retirement
maybe I'll read about this one day if
I'll still have vision. I mean this is
not close.
But
when when olfaction digitization is
brought to the equivalent of 4K uh uh
vision and audition that you have now
then it will be in medical diagnosis.
Excuse me for the uh imagery but you
will have an electronic nose in your
bathroom.
Uh each one of us will have in the
toilet. And it will be doing diagnostics
all the time. And and uh that's that's
where it's going to go. But again not
anywhere in the very close future.
>> Now my I want to say thank you for your
time today. First of all uh this was a
tremendously interesting conversation. I
mean we touched on so many things
hormones, smells, the architecture of
the olfactory system. I know that people
listening to this are realizing but I'm
going to say it anyway uh what an
incredible gift you've given us in um as
a as a
expert in this field giving us this tour
of of the work that you and others uh
who you credit so generously um have
done and the spirit that you bring to
it. Whatever drives that spirit as the
great late Ben Barres used to say keep
going because we are all benefiting
tremendously. And I also just want to
say that you know for people listening
to this the the spirit of
science is one of as you mentioned
there's complex politics and all these
things but it's absolutely clear that
you delight in the work you do. And um
so I delight in it. I'm grateful for it.
I'm grateful for your time today. And so
on behalf of me and and the many, many
people listening to this, I just want to
extend a huge debt of gratitude. Thank
you so much.
>> Thank you so much for
very [music] warm words.
>> [music]