Speaker 1Welcome to Huberman Lab Essentials, 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. 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 or 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? Obviously, where I like to think it involves the nose at some level. It does. If you could just give us the top contour or even deep contour, if you like. of the parts list and the various roles they play. -
Speaker 2Primary olfaction is referred to as ortho-nasal 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, so molecules, airborne molecules travel up our nose, a distance in the human of about six or seven centimeters 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 seven million such receptors aligning a structure known as the olfactory epithelium. This is the sensory surface of the olfactory system, the olfactory epithelium. Again, probably about six or seven 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, 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 an implore glomeruli. 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 ototopes, the molecular aspects of the odorant. And each ototope will activate a different subset of receptors. Then because of this convergence, you end up having on the bulb in a way a map reflecting receptor identity. So let's say this coffee activates receptors of type one, three, and seven. So the glomeruli of receptors one, three, and seven will light up, quote unquote, when I smell the coffee. And if you can 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 enthorinal 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. It goes all over the brain. So information projects widely from there. And as far as people understand, the map that may exist on the bulb doesn't exist in the rest of the brain. And the understanding of how coding occurs in the rest of the brain is murky. Again, in our lab, we already said, yeah, we know this, this is old news, but to people who come from different worlds, we have to reiterate this. Sometimes when I give public lectures 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 in the way we look at what people are doing. We try to think, if I was a dog, what would I think of this? If you look at dogs, 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. I mean, it's. We're sort of. Obliged to sniff our babies, that's considered almost something you're supposed to do. And it's not culturally taboo to sniff our loved ones. It sort of doesn't seem like an odd thing to do, but we don't sniff strangers, right? Well, or do we? So we're finding more and more mechanisms where we do this. 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. 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 we noticed, or it seemed to us that we're noticing, that, you know, people will shake hands and then go like this and like this. -
Speaker 1For those of you listening, not watching, Noam is taking his hand and wiping it on his face. - Yeah, or touching myself. - Grabbing his nose. -
Speaker 2Yeah, these things that we do all the time. - After a handshake. - Well, 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 these behaviors that, you know, you could easily not notice, right? And so we asked whether that's a real thing. And this was a study led by Dan Fruming 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, experiment room, 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 three minutes. And during those three minutes, we could later quantify how much indeed they, just by baseline, how much they touched their nose or their forehead or their chin, or how many times their hand reaches their face. And by the way, that baseline is not low. And then three minutes later, an experimenter would walk into the room and would share a consistent text that would be, you know, we're still setting up our equipment in the other room, 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'd be a low, 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. - So the hand goes to the nose. Now we did a few controls here to verify that this is an olfactory behavior. One is, unbeknownst to participants, we measured nasal airflow. 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 quite confident. And there's an interesting thing going on here too, because people didn't only smell the hand, 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 reflect that. -
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Speaker 2There's a study we published by Inbal Ravrebi in our lab where Inbal came with this 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 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 deeper here? 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 actually recruited click friends from all over Israel. She posted all over social media to identify people. Pares of friends. So these are same-sex non-romantic dyads. So these are friends, men and women, whose friendship started as a click. And then she sampled their body odor. And we have a protocol for this. So they're given, you know, odorless shampoo and soap to use for three weeks or something. And then they sleep two nights in this t-shirt 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. So we have a way to extract, a method to extract body odor. And then 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 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 moxers, as 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 than you would expect by chance by random dyads. And this was a significant difference. And after she found that a device could do this, she had other participants do this. So she had people smelling the click friends versus non-click friends, and they judged them as being more similar to each other than not. Now, again, you might wonder, is this causal or not, right? Because maybe click friends go to the same restaurant together all the time or whatever, or live in the same neighborhood, and that's why 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. One prediction there panned out, but another didn't. The one that didn't, so she predicted that people would smell more 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 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, et cetera, et cetera. So we could actually predict friendship using the electronic nose. So this is not a result of friendship. It plays into the causal elements of building friendship. People are constantly smelling themselves,
Speaker 1constantly smelling others. - I want to touch on some other 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? - Yeah, sort of like nerdy inside ball. -
Speaker 2It's all semantics. So I don't, 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, we call it 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 was always said, but it wasn't really shown effectively. It was shown about a year and a half ago in a 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 then in our lab and in other labs, 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 the state of fear or not, and this influences their behavior. And they just highlight, again, that we're incredibly olfactory animals. -
Speaker 1We had a guest on this podcast who I'm sure you're familiar with, Charles Zucker. - Yeah. - 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, the nape of their, the back of their neck, and how he misses that smell, because when he thinks about missing his grandchild or children, it's that smell that's associated with that feeling. - Hexadecanal. - Hexadecanal? - Yes.
Speaker 2This is a study ran by Eva Mir. She 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. And we had all sorts of ideas going, and 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 a molecule, hexadecanal, that was a chemo signal, and it was using mammalian 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 discovered the receptor for this. And then they went and discovered that the receptor is very highly conserved throughout mammalian evolution. And therefore they hypothesized that maybe, you know, they could have a different signal. Now, which is unusual because in chemo signaling, typically 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 lots of people study mice and zebrafish and whatnot, and we're the human group. And eventually he just FedExed us hexadecanal. And Eva was not going anywhere with her with sweat from human participants. And yet she built the entire paradigm to study human aggression. So they're standard paradigms. This is a paradigm known as the TAP, the Tyler Aggression Paradigm. And what's nice about this is that then allows you to quantify aggression. And so you have a measure of aggression. Again, the Tyler Aggression Paradigm, obviously invented by Tyler, very well validated, studied all over, you know, a very standard protocol. So we brought in participants and had them play the Tyler, the TAP, 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. The effect size was quite meaningful compared to the effects seen in the aggression world in research, really, really strong effects. So unusually strong. Hexadecanal lowered aggression in men. And we were like, cool, this is, you know, sort of what we were hoping to see consistent with the hypothesis 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. -
Speaker 1Is this thought to be something related to maternal protectiveness? -
Speaker 2We'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 can also track brain activity while this was happening. And first of all, it replicated again. So once again, hexadecanal men made men less aggressive and women more aggressive. And yet I was telling Eva, you know, but you know, this makes no sense to me. And then her insight, which of course afterwards is like, duh, 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 you. and sadly there's mail-agreement 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 hexadecanol is the most abundant semi-volatile in baby hits. It's tons of it coming out of baby hits. 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. -
Speaker 1I'd like to take a quick break and acknowledge our sponsor, AG-1. I'm excited to share that AG-1 has just launched their newest formulation, AG-1 Pro. AG-1 Pro takes the clinically backed AG-1 formula, which is a blend of vitamins, minerals, probiotics, and adaptogens, and adds three important new ingredients, creatine monohydrate, calcium, HMB, and zinc carnosine. Each serving has five grams of creatine monohydrate to support muscle strength and performance, as well as brain health. Calcium HMB to support muscle recovery and reduce muscle breakdown, and zinc carnosine to support and improve the lining of your gut. All three of these ingredients have compelling science to support them, and therefore I love seeing them added to the existing AG-1 formula. As most of you know, I've been taking AG-1 every day for nearly 14 years now. I started taking it long before I even knew what a podcast is. It's a great product, and it's now made even better with the new AG-1 Pro formula. If you would like to try AG-1 Pro, you can go to drinkag1.com/huberman to get a special offer. AG-1 is giving away a free bottle of omega-3 coenzyme Q10 with your first subscription. Again, go to drinkag1.com/huberman to get a free bottle of omega-3 coenzyme Q10 with your first AG-1 subscription. What is the relationship between odors and hormones? And in particular, crying? -
Speaker 2Tears are a bodily liquid, emotional tears that we emit in emotional situations where these are situations where nonverbal communication is critical and key. The most influential text, I think, till this day in emotion research is Darwin's book, "The Showing of the Emotions in Man and Animals," I think is the full name of the book. And an entire chapter, chapter 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 antecedent. So he ended up saying, this is an epic phenomenon. So we thought, well, maybe the function is a chemical signal. So with that in mind, we harvested emotional tears. So we collected the tears and we exposed, we exposed participants to these tears. First of all, the tears are completely odorless. You cannot detect them at all, completely odorless. And yet when you sniff them, you have a pronounced reduction in testosterone within about 20 minutes, half an hour. -
Speaker 1This is men and women smelling women's tears? - Men, yeah. - Men smelling women's tears, but not perceiving any odor. -
Speaker 2Nothing. - Just sniffing them. And you have about a 14% drop in free testosterone. And people who studied testosterone, which is not me, but they tell me this is a really strong effect. Like it's hard to even pharmacologically get an effect like that that fast. I mean, no in pharmacology. -
Speaker 1Yeah, years ago I spent time studying endocrine effects of this sort and that's a tremendous resized effect. -
Speaker 2And so here I'll point out in passing that one of the concerns we had because of the effort to run this study is that nobody would ever try to replicate it. And to our joy, about two years later, an independent group from South Korea, Oh It Al, who I don't know at all, replicated the testosterone effect to a T. I mean, like same numbers. So it lowers testosterone. And we then also looked using MR, at the effect on brain activity and saw pronounced effect on activity, a dampening, a lowering of activity under an arousing state, a lowering of activity, both in the hypothalamus and in the fusiform gyrus, for whatever reason, I don't know. - Face recognition area. - Amongst other things, yes. And we don't know why, but pronounced. 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 two years later found that mouse tears, mouse pup tears, lower aggression in male adult mice towards them. - In a smell dependent way. - Yeah, yeah. And they also actually found the actual component in tears that, so the tear pheromone, that lowers aggression, right? So, you know, this has us thinking of tears as you can think of tears as like a chemical blanket in a way that you're covering yourself up again with, you know, to protect against aggression, right? -
Speaker 1Smell being such a rich source of behavioral and hormonal and other sorts of deep, deep information. What is your experience with generating smells in silico in computers? And here, folks, for those of you that aren't catching on to this, I expect that everyone would, because what we're really alluding to here is the idea that you'll look at, you'll put into a search engine 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
Speaker 2an April Fool's spoof. - Oh, right. - And they put out this video of Google smell, okay? 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 all these things, right? So Google is now trying to do that, you know, to digitize a smell. And there are other companies that are trying to do this as well. And recently in our lab, we've had, and I hope this doesn't come across as overly arrogant, but, we've had a sort of mini breakthrough on this front. - To call something a mini breakthrough is far from arrogant. - And this is a paper led by Arun Raviah from our lab and Kobi Snit's also a major contributor there, a paper published in Nature. And in this paper, we develop an algorithmic framework 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 will smell them to be, okay? Not only could we predict that, but we could design it. So we can generate mixtures with known similarities. The result was highlighted, and you'll appreciate this coming from vision, is that using our algorithmic solution, we generated olfactory metamers. So we measured mixtures, completely, 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 anybody can recreate them. This is simple actually. And in the paper, we do a few things, like we generate a metamer for Chanel number five, and we have a toned from Chanel number five in it. -
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Speaker 2In a way, we've generated the infrastructure for digitizing smell, because again, what our algorithm predicts, our framework predicts, is similarity. But in a way, enough for you. Why is that enough? We have a map of 4,000 molecules. 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 on tomato, then what you generated smells like tomato. So we now solve that problem. We can predict the odor of any molecular mixture. We can see 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 a lab of Jonathan Williams at Max Planck in Munich. Jonathan Williams is an atmospheric chemist. But he's really good at using GCMS, these tools that measure molecules. So Jonathan Williams measured odorants in Germany, transmitted the information to us over IP. We fed that into our algorithmic framework and recreated it from a device that mixes primaries. And we tried to do four different odorants in our proof of concept test. One of them was rose. And we failed at recreating rose. We, in fact, recreated something that had a precept, but most people perceived it as bubble gum. The second one we tried to do was anise. And we failed at recreating anise. 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, 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 the path. We're talking now of trying to achieve the olfactory equivalent of circa 1956 black and white TV, okay? Basically, right? I mean, you know, I'm not dreaming, let's say, of being able to transmit to you the different. 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 4K odor transmission, then medical diagnostics is what you wanna be talking about. Because this is over 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 high resolution, which again, in our hands, it's not gonna 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 olfaction digitization is brought to the equivalent of 4K vision and audition that you have now, then it will be in medical diagnosis. Excuse me for the imagery, but you will have an electronic nose in your bathroom. Each one of us will have in the toilet and it will be doing diagnostics all the time. And that's where it's gonna go. But again, not anywhere in the very close future.
Speaker 1Noam, I wanna say thank you for your time today. First of all, this was a tremendously interesting conversation. I mean, we touched on so many things, hormones, the architecture of the olfactory system. I know that people listening to this are realizing, but I'm gonna say it anyway, what an incredible gift you've given us as a expert in this field, giving us this tour of the work that you and others who you credit so generously have done and the spirit that you bring to it. Whatever drives that spirit, as the great late Ben Barris used to say, keep going because we are all benefiting tremendously. And I also just wanna say that for people listening to this, 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 so I delight in it. I'm grateful for it. I'm grateful for your time today. And so on behalf of me and the many, many people listening to this, I just wanna extend a huge debt of gratitude. Thank you so much. Thank you so much for very warm words. Thank you.
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