How Smells Influence Our Hormones, Health & Behavior | Dr. Noam Sobel

Welcome to the Huberman Lab podcast where.

We discuss science and science based tools for everyday life.

I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today my guest is Dr. Noam Sobel. Dr. Noam Sobel is a professor of neurobiology in the Department of Brain Sciences at the Weizmann Institute of Science. His laboratory studies olfaction and chemosensation. Olfaction is, of course, our sense of smell. Chemosensation is our ability to respond to chemicals in our environment. Today, you are going to learn some absolutely incredible facts about how you interact with the world and other people around you. For instance, you will learn that humans can smell things around them as well as dogs can. In fact, humans are incredibly good at sensing the chemical world around them. You also learn, for instance, that every time you meet somebody, you. You are taking chemicals from that person, either from the chemical cloud that surrounds them or directly from the surface of their body. And you are actually applying it to your own body. And you are processing information about that person's chemicals to determine many things about them, including how stressed they are, their hormone levels, things that operate at a subconscious level on your brain and nervous system and that impact your emotions, your decision making, and who you choose to relate to or not to relate to. You will also learn that tears, yes, the tears of others are impacting your hormone levels in powerful ways. You will also learn that every so often, actually on a regular schedule, there is an alternation of ease through which you can breathe through one nostril or the other. And that alternation reflects an underlying dynamic of your nervous system and has a lot to do with how alert or sleepy you happen to be. The list of things that Dr. Noam Sobel's laboratory has discovered that relate to everyday life and that are going to make you say, wow, I can't believe that happens. But then go out into the real world and actually observe that that happens in ways that are incredibly interesting. Just goes on and on. In fact, his laboratory discovered that we are always sensing our own odors.

That's right.

Even though you might not notice your own smell, you are always sensing your own odor cloud. And throughout the day, you periodically smell yourself deliberately, even though you might not realize it, in order to change your cognition and behavior. I first learned of Dr. Sobel's laboratory through a rather odd observance. That observance took place when I was a graduate student many years ago at UC Berkeley. At the time, Noam Sobel was a professor at UC Berkeley. As I mentioned before, he has since moved to the Weissman well, I was walking through the Berkeley campus and I saw people on their hands and knees, but with their head very close to the ground and their eyes were covered, their hand were covered, their mouths were covered, and only their nose was exposed. And what I was observing was an experiment being conducted by the Sobel Laboratory in which humans were following a scent trail. That scent trail was actually buried some depth underneath the earth, and yet they could follow that scent trail with a high degree of fidelity. It was from that experiment and other experiments done in Dr. Sobel's laboratory at Berkeley and at the Wiseman involving neuroimaging and a number of other tools and techniques that revealed the incredible power of human olfaction and humans ability to follow scent trails if they need to. And that of course led to many other important discoveries, some of which I alluded to a few moments ago. But you are going to learn about many, many other important discoveries in the realm of olfaction and chemosensation that have been carried out by Dr. Sober's laboratory through the course of today's episode. And by the end of today's episode, I assure you that you will never look at or smell the world around you the same way again. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Roko. Roko makes eyeglasses and sunglasses that are of the absolute highest quality. I've spent a lifetime working on the biology of the visual system, and I can tell you that your visual system has to contend with an enormous number of challenges in order for you to be able to see clearly. Roka eyeglasses and sunglasses were designed with the biology of the visual system in mind. So no matter whether or not you're wearing them for sport, whether or not you're wearing them for work or for socializing, you can always see with crystal clarity. Their glasses are extremely lightweight, so most of the time you don't even realize.

That you're wearing them.

I wear Roka readers at night and sometimes when I drive at night, and I wear Roka sunglasses throughout the day. Except of course, I do not wear them for my morning sunlight viewing. If you'd like to try Roka eyeglasses or sunglasses, go to ROKA, that's R-O-K-A.com and enter the code HUBERMAN to save 20% off your first order. Order again, that's R O-K A.com and enter the code Huberman at checkout. Today's episode is also brought to us by Thesis. Thesis makes custom nootropics and nootropics is.

A word that I do not like.

Because it means smart drugs. As a neurobiologist, I can tell you that there is no neural circuit in your brain for being smart. There are neural circuits for focus, there are neural circuits for memory, there are neural circuits for creativity, and there are neural circuits for task switching. Thesis understands that there's a diversity of neural circuits that support different brain body states and therefore have designed neutral nootropics that are customized to achieve specific brain body states. If you go to the Thesis website and take a brief quiz, they will design a nootropic starter kit. Some of those nootropics that they'll send you are designed to enhance your focus, others for clarity, others for creativity, and so on. To get your own personalized nootropic starter kit, you can go to takethesis.com huberman and take a three minute quiz and Thesis will send you four different formulas to try in your first month. That's takethesis.com Huberman and use the code HUBERMAN at checkout to get 10% off your first order. Today's episode is also brought to us by Helix Sleep. Helix Sleep makes customized mattresses and pillows that allow you to get the best possible night's sleep. So if you go to the Helix website, you can take a very brief quiz. It only takes about two minutes and answer questions such as do you tend to sleep on your back or your side or your stomach? Do you tend to run hot or cold throughout the night? Maybe you don't know the answers to those questions, but they'll match you to a mattress that's ideal for your sleep needs. For me, that was the Dusk Dusk mattress, which is not too firm and not too soft and I've been sleeping.

On it for more than two.

The best sleep that I've ever had. If you'd like to try a Helix Mattress, go to helixsleep.com Huberman Take that two minute quiz and they'll match you to a customized mattress and you'll get up to $350 off any mattress order and two free pillows. Again, if you're interested, you can go to helixsleep.com huberman for up to $350 off and two free pillows. 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 for more than a decade or two.

Yes, kind of frightening.

We overlapped at UC Berkeley some time ago, although we did not meet, although.

We lived in the same apartment.

And we just learned that the amazing apartment that you moved out of was the apartment that my girlfriend and I at the time moved into in 2006, I believe. So we've shared quite a few things, 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, et cetera. 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, or I like to think it involves the nose at some level.

It does.

To what extent is that mixed in with other senses like taste? And perhaps more importantly, what about the chemicals that we are sensing through this thing? And for those of you listening and not watching, I'm tapping my nose. That we are not aware of the chemicals that we're inhaling and making sense of without our awareness. 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.

So you've asked a lot of questions at once. I'll start with a little comment on the way you said smelling through our nose, which we indeed do, but we also smell through our mouth. Actually, there's a process referred to as retronasal olfaction, where odorants come up through the back of our throat and out of our nose the reverse way, and we smell things that way as well. And in fact, a big part of the contribution of olfaction to food and taste comes from that, from retronasal olfaction. But primary olfaction is referred to as orthonasal olfaction. That is, through our nose, we sniff. And sniffing is a big thing. 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 6 or 7 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 7 million such receptors 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. By the way, I can share an amusing story. I would imagine amusing stories are good for podcasts. So that number of 6 or 7 million receptors is probably not very well grounded. It's hard to count, but it's reasonably grounded. And there was this thing roaming around in the literature about bloodhounds having a billion receptors in their nose, which is why they're so amazing. And this number was, you know, it sort of propagated through the literature. And our lab has written over the years, a few review chapters, and we were repeatedly writing the olfaction chapter for a very large one of these large textbooks, the Gazzaniga Handbook of Cognitive Neuroscience, I think it's called. And we had that in there as well, somewhere. And one time when we were renewing the chapter for a new version of the book, I told the graduate student who was leading that at the time, Araya Sharun. She's now a professor at Tel Aviv University. I told her, check that. Check that reference out. Where in the world did that come from? And we started going back and back and back, and it turns out it comes from a textbook, an Australian textbook. And we found the author of the textbook, and we wrote her. And I said, look, there's this thing in the literature of a billion receptors in the bloodhound. Where did that come from? And surprisingly, she answered me. And I was hoping to get a reference right, but it wasn't reference. And this is where it really becomes funny for us, because she said, I was once at a lecture of an olfaction geneticists, geneticist by the name of Daron Lancett. And he said that in the lecture. Now, this is really funny because she's in Australia. This is all over the world, this number. And I'm writing her from Israel, and Doron Lancet is in the building next to me. Okay, he's in Weitzman Institute, genetics. I mean, he used to be. He's retired now, and he had meaningful contributions in the history of wolf action. So I picked up the internal phone and I said, hey, daron, you know, did you say that there's a billion receptors in the bloodhound nose? And he said, what's a bloodhound? So this is totally made up, right? It totally made up and it propagated. I mean, you can probably go into Google and type like a billion receptors in the bloodhound and you'll get a lot of hits. But there was absolutely no evidence for that.

Amazing. And not just amazing in light of what it tells us about olfaction and bloodhounds or otherwise, but amazing because it sheds light on just how much of what is in textbooks, scientific and medical, is absolutely wrong.

Things propagate, and you cite yourself. So we fix that in that version of the. And so, to finish the line, so odorants interact with these receptors here in our epithelium, where they undergo what is referred to as transduction. That is, the odorants are dock at a receptor and turn into a neural signal or force the receptor to respond in a neural signal. And this neural signal, in fact, action potentials, not gradient potentials of any kind, propagates via the olfactory nerve. Now, this is a nerve that goes from our epithelium right here behind the forehead. No. Well, yeah, here through the thinnest part of our skull, an area referred to as the cribriform plate, 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. In humans, that forms an interesting point of sensitivity, because a lot of people lose their sense of smell due to trauma because of that structure.

A head hit type trauma?

Well, yes, although you denoted hitting on the front of the head, which is where all this real estate is. But actually, the more common cause for losing your sense of smell for trauma is the back of the head because of what's referred to as a contrecoup injury. So, as your listeners probably know, our brain is floating in liquid in csf, in cerebrospinal fluid inside our skull. And when we get hit in the back of the head, the brain has this forward and backward movement in the liquid in the skull. It sort of crashes. It can crash against the front of the skull, which is why you also have. In a contraindry, you also often have frontal damage. But what happens is that this generates a shearing motion on the cribriform plate, and the olfactory nerve is severed. And if it's Completely severed, it's lost forever.

Because my understanding is that the olfactory sensory neurons are among the few central nervous system neurons in adult humans that can regenerate or replenish themselves.

Right. So again, there are a few questions.

Yeah, that's okay. So first of all, we will spin many plates simultaneously.

If it's completely severed completely, then yes, you're lost forever. Yeah, if it's completely severed. Because even if you'll have regeneration at the basal cell level, at the epithelium, they won't manage to find their way back to the bulb. If, if you have partial or something left or something shows up in a short while after the injury, then you have a good chance of recovery because.

They grow along the trajectory of the other axons or pioneering the way for them, assumingly.

Yeah, interesting. And so basically, and basically the time frame, and you know, it's funny, I get a lot of emails on this, although I'm not a medical doctor, but I get a lot of emails from people who have lost their sense of smell because it's very distressing and now more people know this because of COVID that it's very distressing. And basically the rule of thumb is that if you don't get it back within a year to a year and a half, you'll never get it back.

My understanding of the statistics on olfactory loss in Covid and other viral type infections is that first of all, I experienced that when I got Covid, including.

Total anosmia for one day.

And not total, it was just there was a remnant of an ability to smell or perceive the smell of a lemon and I was huffing as hard as I possibly could. I actually there's an over the counter remedy and this is not pseudoscience because there's a number of papers published about this on pubmed that alpha lipoic acid can accelerate the recovery of smell. And so that's something that it worked successfully for me. I'm not saying that that's the only route.

You don't know if it worked successfully for you or if you would have recovered anyway. I mean, you didn't do a controlled study.

I was not willing to do the control experiment. Exactly.

So, yeah, let me say two things on this front. First, the date on the alpha lipoic acid is.

Yeah, it's not overwhelming, but losing your sense of smell is overwhelming. So I think people feel desperate.

One word about smelling the lemon and this is, I'll take that opportunity to share more information. When we smell things, it's the result of more Sensory subsystems than the olfactory system alone. So you have several chemosensory sensitive nerves in your nose. A primary one, beyond the olfactory nerve is the trigeminal nerve, the fifth cranial nerve. So the trigeminal nerve has sensory endings in your nose, in your throat and in your eye. It has three branches. That's why an onion has smell and burns your eyes and burns in your throat. Is that why it's trigeminal?

Yeah, the tearing of cutting an onion is trigeminal.

It's a trigeminal reflex.

Amazing. We talked about trigeminal in the context of headache.

During a headache episode, it's a trigeminal reflex. So the lemon you were smelling may have been a trigeminal sensation.

So smelling the lemon with my eyes is what you're saying?

Well, no, with your nose, but with your trigeminal receptors and not your olfactory receptors. So within, you know, olfaction researcher jargon, there's what we refer to as pure olfactants. These are odors that will stimulate your olfactory nerve alone. They won't influence your trigeminal nerve at all. And an example, just to get a sense of what that might be, would be the coffee right here is a purolfactant. Vanilla is a known pure olfactant. These things have no trigeminal activation.

As long as we're on this topic and we'll weave back and forth, but I'm glad we are on this topic because a tremendous number of people wrote to me during the pandemic and continue to about olfactory loss. I've heard of this olfactory training whereby if you have a partial or even complete loss of primary olfaction, that one is encouraged to smell of a number of different smells. I grew up studying activity dependent wiring of the nervous system. It makes total sense to me why keeping neurons active keeps them alive. So this is not fire together, wired together type thing. By the way, that's a quote from Carla Schatz, not Donald Head folks, or me. But this is about keeping neurons electrically active, in this case olfactory neurons in order to maintain their connections because otherwise they will die.

Olfaction is a definite use it or lose it system. And so that makes total sense. And indeed there's very strong evidence for success of the training programs more than the alpha lipoic acid. And so that's a real thing. And what's cool about that is that you don't need to go out and buy expensive things. Although you can, of course, there are people who are capitalizing on this commercially already. But you can just take things from your refrigerator or your makeup cabinet or whatever and smell them attentionally and constantly and sniff them, and that exposure will help you recover. There is good data on that by now. You made that point in passing about regeneration in the olfactory system. Indeed. One of the cool things in olfaction. You can study many things through olfaction. Indeed, one of them is neuroregeneration, because the olfactory neurons are really the only neurons that do that systematically in the adult mammalian brain. And whether the human olfactory system shows the same level of regeneration as it does in other mammals is and was somewhat questionable. And I'm just bringing that up to share a really cool study that was published in Neuron, I think, somewhere around 2014, where to address this question. I just really like the idea of doing that. What the authors did was look at, in postmortem, they looked at levels of C14 in adults who were exposed to atomic bomb experiments. So you can actually look at these neurons and time them based on exposure to radiation. And that paper suggested that there's not as much turnover in the human olfactory bulb as there is in other mammals. Other lines of data suggest otherwise. So this is kind of a debated question as to what extent of neurodegeneration you have in the human olfactory system as opposed to other mammals. But that was just a really cool paper, I think, of doing that.

Fascinating.

Should I finish the path? Just so we have the. So we said, so information, then synapses at the olfactory bulb from the olfactory epithelium, and 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 a given subtype. And remember, in humans, we said we have about 350. In the mouse, we have about 1,200, probably. So all the receptors of one subtype converge to one location in the bulb. And this location is referred to as a glomerulus or glomeruli. That may be a slight oversimplification. It's in fact, two glomeruli. There's a mirror, sort of a mirror cut line. And so all the receptors of one subtype will converge to two mirror glomeruli on the olfactory bulb. So you end up having two glomeruli that reflect that one receptor subtype. This is, as far as I'm giving you now, the textbook view of how the system works. But then I'll happily share with you things that pose a problem for the textbook view of how things work. But 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. Each receptor is responsive to a different subset of ototopes, let's say 10. And each ototope will activate a different subset of receptors. So potentially you have this insane comet in torics of this potentially 350 dimensional space in the human potentially. But 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 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 and so on and so forth. 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 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, 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.

Commonly one hears that the memories that we have of odors are somehow more robust than the memories of other perceptual events in our life. I don't know if this is true or not, but people will say, for instance, I can still remember the smell of my grandmother's hands or the smell of cookies in her kitchen. At a minimum, it points to the fact that smell and memory are closely linked. And you just mentioned a direct, you know, multi station, but nonetheless somewhat direct path from the nostrils to the hippocampus, one of the primary encoding centers of the homocystem.

Two synapses away.

Yeah, which is, which is a remarkably short pathway considering that, for instance, just by example, because some of our listeners won't be familiar with this, but some Will that sound waves that you know are transduced into neural signals at the level of the inner ear go through many stations before they arrive at the location in the brain where we make sense of those sound waves as voices or music, et cetera. Whereas olfaction is more of a direct route to the memory centers. Is there any just so story or real objective truth to the idea that olfactory memories are formed more easily or maintained longer or more robustly than other sorts of memories?

So, yes, but first I should. I should say that I'm not an authority on olfactory memory. Olfactory memory is a huge field of research and somehow our lab has never really gone much into that. Although again, the same student I happened to talk about before, Yara Sharon, who's again now faculty at Tel Aviv.

Ran.

A study, a paper I think we published in Current Biology, called the Privilege Representation of Early Olfactory Associations. Basically, there's something about the first time you experience a smell that generates a particularly robust representation more than other sensory stimuli. And that's what Chainfact compared. So there's something about the first exposure to a smell in terms of the brain encoding that etches it into our being. And this is an effect that has. It has echoes, of course, in literature. I mean, you know, the biggest cliche in this is to bring up the Proust effect, right? So the Proust effect is when he ate the madeleine, and it immediately. The taste and smell immediately reminded him of an event in his childhood where the same madeleine appeared. So that's something very real. There's a lot of research on it not coming from our work. So I'm not an authority, but it.

Does sound like there's something special about olfaction. And that doesn't mean that there isn't something special about vision or audition. Each one has its own unique.

I'm the last to argue that there's something special about olfaction. My students make fun of me because they say, and there's some truth to that, that I try to explain everything through the olfactory system. I mean, for me, everything is olfactory.

So, yes, through the lens of the nose.

I'd like to take a quick break and acknowledge one of our sponsors, Athletic Greens. Athletic greens, now called AG1, is a vitamin mineral probiotic drink that covers all of your foundational nutritional needs. I've been taking athletic greens since 2012, so I'm delighted that they're sponsoring the podcast. The reason I started taking athletic Greens and the reason I still take athletic greens once or usually twice a day is that it gets me the probiotics that I need for gut health.

Our gut is very important.

It's populated by gut microbiota that communicate with the brain, the immune system, and basically all the biological systems of our body to strongly impact our immediate and long term health.

And those probiotics and athletic greens are.

Optimal and vital for microbiotic health. In addition, athletic greens contains a number.

Of adaptogens, vitamins and minerals that make.

Sure that all of my foundational nutritional needs are met. And it tastes great. If you'd like to try athletic greens, you can go to athleticgreens.com huberman and they'll give you five free travel packs that make it really easy to mix up athletic greens while you're on the road, in the car, on the plane, et cetera. And they'll give you a year supply of vitamin D3K2. Again, that's athleticgreens.com Huberman to get the five free travel packs and the year's supply of vitamin D3K2.

When I was at Berkeley, I was walking across campus one day and I saw, I think, students, but I saw people on their hands and knees with goggles on, gloves on, and I think their mouths were covered too. Everything was covered, was covered. And they were walking well, they were.

Crawling along the ground.

And I thought this was peculiar. But then again, it's UC Berkeley. And the joke is if to get noticed on the UC Berkeley campus you.

Have to be naked and on fire.

Right. One or the other would not be sufficient. Please don't run this experiment. It's that kind of place. But nonetheless, a paper came out a few years later describing the results of what turned out to be your experiment that your laboratory was running, which was having people follow an odor trail with their nose. And my understanding is that people can improve their ability to track scents quite robustly, especially if we deprive them of vision and somatosensation, that is touch and some other sensations. Maybe you could just tell us a little bit about that study. And I think in our audience, I'm suspecting that many people have a keen, keen sense of smell. I have a family member who just detect any negative putrid odor in the environment, but also good odors exquisitely well. And I have other family members whose sense of smell is quite poor. I'd love for all of those people to learn a bit about what is possible in terms of training up or improving our ability to smell. And perhaps in the context of that study, if you will.

Yeah. So first, before even talking about Improving. Just off the bat, humans have a remarkable sense of smell. And this is something again, in our lab we already said, yeah, we know this, this is old news. But, but to people who come from different worlds, we have to reiterate this. Sometimes when I give, you know, public lectures to non olfaction audiences, I reiterate this. Humans have an utterly remarkable sense of smell, to put that a bit in sort of, you know, things that you could that are tangible. So, so for example, mercaptans, which are added to cooking gas so that we smell it because otherwise it wouldn't have a smell. So that the smell of gas is not the smell of gas of propane, it's an additive Mercaptan. Yeah, it's mercaptan, the sulfur like smell. So our detection threshold, that is the level at which we can detect it, is 0.2 parts per billion. Okay. There's no machine that can really do that, that effectively. No gas chromatograph, nothing. Now, to give you another sense of making this again, really tangible, we're working with an odorant in our lab called estratetraen that our participants can detect when we have it mixed at 10 to the negative 12 molar in the liquid phase. To give you a real sense of that, we did the math. If you would take two Olympic size swimming pools and you would pipette one milliliter, one drop into one pool versus the other, you could smell the difference between the pools.

Incredible.

That's the detection threshold that you have with your nose. People have an utterly amazing nose. Okay, so, so that's just in terms of its detection abilities, which are just, you know, remarkable. Really up there in the mammalian world, we're not a bad mammal at all. Faction and, and beyond that, we can, we can improve. Okay. And the example you're talking about actually started off as a lab bet. Okay. We were having a lab picnic. So I guess I should hear fill in because I'm your guest from the Weizmann Institute of Science in Israel. But before going back to my home in Israel, I was a faculty at UC Berkeley in the Helen Wells Neuroscience Institute. And this study was done during that time and we were on a lab picnic and we were having indeed one of these sort of lab discussions, arguments on what humans can and can't do with their sense of smell. And I said that humans could truly even track odor like a dog. And people there said, no way. And we ran this quick experiment which I have video of, but I don't think we'll show it here. But I actually have original the picnic video. We have it. And a graduate student by the name of Christina Zelano, a brilliant graduate student at that time, who's now. She's now a professor at Northwestern, and she's really leading the field of olfaction imaging today. But she was the volunteer, and we dragged a chocolate bar across the grass and blindfolded her and checked if she could track the track we made with the chocolate, which she did very effectively. Right in this.

Did you place her at the starting point of the line or.

I think we did. I don't exactly remember what we did on that sort of picnic tryout, but, you know, I assume she never practiced that in her life before. Right. And yet, you know, she did it really, really well. And then this went on as a lab bet in a way that I said to my students, okay, we have to make this into an experiment, put in an experimental setting and quantify what's going on. And they all said that it would be uninteresting. That was the bet. And I told them it would be in nature, which is a bet I want in this case.

Nature, of course, being one of the three Apex journals.

It was. Was Nature Neuroscience, to be fair. So then we turned it into an experiment. And what the experiment was is that we brought in participants, naive participants, not graduate students from our lab, completely deprived them of any other sensory input. So we blocked their eyes, we blocked their ears, we blocked everything. They were wearing heavy gloves. They couldn't sense anything. And we generated a consistent odor path in the grass, which is what you saw. We did that by burying twine under the grass and odor impregnated twine, so that way we could generate a consistent odor trail every time.

Was it at the base of the grass or in the dirt?

It was buried. It was buried under the grass.

Really?

Yeah. Yeah. Wow.

I did not know that it was.

Buried under the grass. And we conducted aerial photography. And participants also had this sensor pack that they were wearing where we measured nasal airflow in each nostril in real time. And we also used something called RTK gps, which is a way to lay radio frequency grid over the GPS grid so that you have millimeter resolution in space. Basically, it's used by surveyors mostly so that we could track behavior. And we found a few things doing this. One is that people could just do this right off the bat. The second thing we found that is when we trained them up, then within average of 4 days, the rate limiting factor became the speed at which they could crawl. So as fast as you could crawl, you could send track. Of course, you can't crawl as fast as a dog can run, but as fast as you can crawl, you can send track and then to sort of add. What made it really interesting from a systems neuroscience perspective is that we asked whether having two nostrils contributes to this. So we built, we constructed a nasal prosthesis, if you will, that had two versions. One is that it combined both nostrils into one big nostril centered. And the other is that it maintained two separated nostrils. And we compared performance under these two conditions, and people performed better with two nostrils over one centralized nostril, although the flow remained the same. So you're taking advantage of the information that comes from your two separate, totally separate nostrils. By the way, the system I described before of your epithelium and bulb and connection to cortex, you have two of those, right? It's completely unilateral. Well, almost completely unilateral system. There are some very small exceptions to that.

So a representation on both sides of the brain much in the same way. We have two eyes, we're not a cyclops, we can gain depth perception information. We can perceive motion better as a consequence, and a number of depth, especially stereopsis.

And we can locate sound because of the difference between our ears and how head blocks them between and amazing.

Another question about the mechanics and strategies that you observed, because I think there's information about the system, the brain, as a consequence, were you in a position to measure sniffing frequency? And the specific question I have is, were people doing something along the lines of a quick sniffing or a. Like a, you know, a long draw in inhale?

You know, we didn't. So yes, we were measuring sniffing and recording it, and we have all the data. There was nothing very remarkable in that data in that study, although it may reflect that we didn't analyze it carefully enough as well. I mean, it didn't. It was. It. It wasn't a major component of our analysis, although we did look at it to some extent. Again, you're asking me about a paper from quite a few years ago, so I may be forgetting parts of it as well, but I'm sure if it.

Was a major component of it, it would have risen to the top.

It definitely wasn't a major finding of the sniffing behavior in the paper, although again, sniffing behavior is a huge portion of our life in labor and it's taking us to places and it's re emerging now in our work. We're doing tons of sniffing work. I can share with you something that I think will Interest your listeners and viewers as well, and we think is really one of the most overlooked things in neuroscience. Please do. I invite you to do the following experiments. So occlude one nostril by pressing on it from the side and sniff in and then clued the other and sniff in. Do you sense a difference in flow?

Yes.

Okay. Do you know why that is?

No.

And it was the next question on my list.

Don't feel badly about not knowing why that is. Most people don't. But that is a reflection of something referred to as the nasal cycle. So, in fact, if you were to do that repeatedly, you would find that your high flow nostril and low flow nostril alternate every two and a half.

Hours on average in an absolute way. Or is it kind of like a sine wave, like gradual shift to the one and then gradual shift back?

It can vary. It can vary. And we don't yet know the rules, all the rules. But you have this constant shift from side to side. The shift becomes incredibly pronounced in sleep, so we can measure the power of the difference. And in sleep, you have this phase shift of power. You have a huge, like, one closes and one opens totally. And it turns out that this is linked to balance in the autonomic nervous system. So, as you and your listeners know, we have an autonomic nervous system that has a sympathetic and parasympathetic component to it, and they're in balance or imbalance in many diseases, for example. And this interplay between the sympathetic and parasympathetic nervous system drives the switch from left to right nostril.

Just to remind people, sympathetic nervous system has nothing to do with sympathy, has everything to do with generating patterns of alertness. It's sometimes called the fight or flight system. But any pattern of arousal, positive or negative, and then it's balanced in a coordinated way, or at least in parallel with the parasympathetic nervous system, which is sometimes called the rest and digest system, but is associated with all sorts of things. The sexual arousal response and a number of other aspects of our physiology. So think of it like a seesaw of alertness and calm.

Yeah, perfect. So now imagine, right, imagine. Imagine you would walk around living your life, right, Half of the time with one eye closed like this, and the other half with one eye closed like this. And you had this eye cycle, right? And that was linked to autonomic arousal. I assure you, you would go to PubMed, there would be 5 million papers on the icycle, right? And the eye cycle, in every disease, you can Name and what it denotes and what it tells us and what we can do with it. You have exactly this marker. You're walking around with a marker on balance in your autonomic nervous system. And we do nothing with it. So we're in fact now doing a lot with it. Okay, so we built, we built a wearable device that is pasted to your body and measures airflow in each nostril separately and logs it for 24 hours. And we're collecting these 24 hour recordings. We're calling it the nasal halter. So we measure with the nasal halter and we're finding it as a disease marker. I can give you a nasal halter measurement as an adult. And I can say this is work by Tim Nostroka, a graduate student in our lab. Now we can tell the difference between ADHD and non ADHD adults. And we can tell just from the recording, we can tell if the adults are on Ritalin or not. So I can measure your nasal airflow and say if you are or are not with ADHD and if you are or not on Ritalin.

Incredible. I have a couple of questions about this. Is it the case that airflow through one nostril is reflective of a sympathetic nervous system dominance versus parasympathetic? Or is it simply the case that this alternating left, right nostril periodicity, which you said, I think is on the order of about every two hours, two and a half, two and a half, it switches to maximal on one side versus the other. Is that simply reflective of an overall balancing? Let's maybe. Is it the hinge in the seesaw or is it the tilt of the seesaw?

So I don't have a good answer. I don't have a good answer. I mean, you know, I could give you sort of a, you know, I could say that to some extent, right nostril more open is more sympathetic and left nostril more open is more parasympathetic. But that wouldn't be very correct. I mean, you know, I'm sure that.

You know, the yogis are going to be all over this because I get this, my lab does do some stuff on, on breathing. And the, the yogis are always saying, okay, you know, because there's this thing, I don't do yoga anymore, but not for any particular, but where they'll have you breathe through one nostril or the other. And I've, I've probably been asked this question on social media 10,000 times.

Okay, wait, I'm going to become public enemy number one. Of the yogis right now. So listen, they'll come at you with.

Yoga mats, which are not very dangerous.

We really. So since we're so interested in this mechanism, one of the things we'd really like to know how to do is to gain control of it somehow. And there's this world out there of yoga who claims to have control over this. So we said, okay, let's bring really serious yoga practitioners and see if they can shift their nasal cycle from left to right by will alone, not by manipulating themselves somehow. And if yes, we'll learn from them how they do this, and then we might use this to cure ADHD or whatnot. Right. So we posted on all the lists of the yoga teachers and had this parade of yoga teachers walking into our lab. This was one of the strangest things.

A lot of sandalwood odors and bare.

Feet, white clothing and so on. And so we study. I actually know we studied 14 yoga teachers, all 14, by the conditions of enlistment for this, came in saying that they can control shifting from left to.

Right nostril without plugging a nostril.

Yeah, by the power of thought alone. And you know, how many of 14 succeeded? Zero. Including. Including one. You know, the most extreme one was we had this guy who, you know, and we're recording, and we know how to record this really well. Right? And he's sitting there saying, yeah, I'm switching now. And it's switching and you know, you're looking at the monitor and no, it's not switching. And so no yoga teacher that we found could willfully switch between left and right nostril flow.

And yet they are convinced that they are. And I have to imagine they're not trying to, you know, there's no incentive for them to lie, Right?

Yeah. No, even the opposite. I mean, you know, this puts them in an awkward position once. Yeah, I don't know what the deal is, but. But none of them can do it.

Given that the alternating flow through one or the other nostril is reflective of the autonomic nervous system has this two and a half hour periodicity. If I suddenly enter a bout of stress, for instance, does it switch? Because that's reflective of the autonomic nervous system. And the reason I'm asking this question is not because I think that's necessarily important as it relates to stress, but I'm trying to understand the direction of causality. In other words, is the unilateral smelling or unilateral nostril smelling periodicity there, when.

We named it something I contained it. The wrong thing, I'm sure.

Is that driving the shift in the autonomic nervous system, or is it merely reflective of the shift?

So you've very concisely now worded AIM2 of a grant that was probably just rejected, but basically we're trying to answer exactly that question, and we're currently running experiments on that line. So we have one experiment where we're looking. So we're exposing participants to pain. We're using cold water, hand exposure. It's a really cool paradigm because there's huge individual differences. We just started this. We built the setup just now. And you have a lot of meat to work with there because there's a lot of individual differences. It's capped at three minutes for safety reasons, because you have participants putting their hand in 2 degrees Celsius water. But there'll be participants who will pull it out at like 10 seconds, 9 seconds, and then you'll have three minutes as well. So there's lots of. Lots of. And already. So now I'm sharing pilot data with you. So, you know, this might, you know, when this ends up being published, it might be the opposite, but so far it seems that the exposure to cold generates a shift in the nasal flow in nasal balance.

So autonomic arousal can drive the shift, potentially. Earlier you were describing the architecture of these smelling systems, and you mentioned these glomeruli where the olfactory receptors converge in the bulb. And then later you mentioned that the system is unilateral, but with a mirror representation on both sides of the brain. So for those who don't think in terms of neuroanatomy, what Noam was describing is the fact that, of course, there are two nostrils and then a bunch of receptors, they converge in these glomeruli. But you have a mirror representation of that on both sides of the brain, and that most of that, that information is kept on one side of the brain or the other. There isn't a lot of extensive intermixing at the first order of processing. So the question I have is whether or not you believe. I'm not asking for data first. I just want to know what you believe that this alternating nostril airflow phenomenon has anything to do with preferential processing of olfactory information in terms of right brain, left brain. With the caveat that anytime we hear right brain, left brain. We've covered this in a previous episode. Most of what people hear out there about right brain, left brain, emotionality, logical stuff, is completely wrong. Completely wrong, doesn't exist. Is a total Fabrication. And we'd like to abolish that myth. But with that aside, or set aside rather, what are your thoughts on why the information would switch from one side of the brain to the other at all?

Yeah, I don't think. I don't think that. That the nasal cycle is an olfaction story. So. So I. I don't think that that this was shaped by the olfactory system, nor do I think this has major impact on olfaction. I think the nasal cycle story is a different story about brain function. So, you know, we have this sort of pet theory we're calling now the sniffing brain approach, where basically we think that nasal inhalation is timing and driving a lot of aspects and patterns of neural activity and cognitive processing. And this theory is olfaction inspired in its beginning. That is, I mean, if you think of the mammalian brain, right, which evolved from olfaction, it's sitting there and in olfaction, because olfaction depends on sniffing, you have this situation where you have a sniff, you have information and then flat nothing, and then you have information and then nothing. So information processing is one to one linked to nasal inhalation. And we think that this property evolved to be meaningful in brain processing in general, not only of olfactory information, but of any type of information, because the brain evolved in this way, in this way that it processes information on inhalation onset. So a study led by Ofer Perel from our lab two, three years ago, we looked at something completely non olfactory. We looked at visuospatial processing, and we compared visuospatial processing on inhalation versus exhalation. The brain does this completely different on inhalation versus exhalation. In that particular task, people performed significantly better on inhalation versus exhalation.

What was the task? Was it an olfactory task?

No, no, it's a visuospatial task. So this is a task where the specifics of the task were that you see a shape and you have to determine if it's a shape that can or cannot exist in the real world. So some of them are these, like, usher shapes, like, you know, where one facet doesn't reach the other facet.

The impossible figure.

Yeah. But structural shapes, not. So a pure visual spatial task. We intentionally went for a task that is not considered a ventral temporal task, an olfactory cortex task, in any way. And people performed much better on inhalation versus exhalation at doing this task.

Was there a both nostrils occluded version where people were forced to mouth breathe.

Yes. And in this particular task they also did better on mouth inhalation versus mouth exhalation. But the difference wasn't as pronounced as it was with nasal inhalation versus exhalation.

So I'm a big proponent of nasal not mouth breathing whenever possible for many health related reasons. I'm a big fan of the book Jaws A Hidden Epidemic written by colleagues of mine at Stanford familiar with it. And this idea that people who mouth breathe experience more colds, more infections of various kinds, it's not good aesthetically or for the dentist. Dentature, I never know the teeth, the gums and stuff. Folks, sorry, my, my dentist is going.

To come after me.

Need to go to the dentist. Anyway, the, that nose breathing is great for your health relative to mouth.

So I think it's also good for your cognition, not only for your, your dental health. I think that that nose breathing shapes cognition and there are other labs who are finding the same. Again, Christina Zelano is doing work on this line. She had major contributions here and Johan Lundstrom is doing work on this line. There's lots of studies suggesting that nasal inhalation is timing cognitive processing and modulating it.

Incredible. Perhaps not surprising given what you've taught us about the olfactory system. I mean, these two holes in the front of our face, these nostrils, I mean, are a pathway to the brain. Right. I love to tell people, because I work on the visual system in my lab, that your eyes are two pieces of brain extruded from the cranial vault, which they are the retinas anyhow. And then you never look at anyone the same way again. Okay, but the, the olfactory sensory neurons are right there at the tops of those caverns that we call nostrils. And they are brain.

Yeah, definitely. It's the only place where your brain meets the outside world because in your retina they're protected by a lens and here you have neurons in contact with the world. This actually has been the source for some theories on a potential route for neurodegenerative mechanisms. So as you may know, loss of the sense of smell is one of the, if not the earliest sign of neurodegenerative disease. So for example, in Parkinson's disease, there's loss in the sense of smell probably 10 years before any other symptom. But people have failed to make this a diagnostic tool because it's non specific. So it's not as if you could come to your doctor and say, I'm losing my sense of smell. And they'll say, oh, early sign of Parkinson's because you can have many reasons to lose your sense of smell and so on. But olfactory loss, again, is an early sign of neurodegeneration. And there's at least one theory, particularly about Alzheimer's disease, suggesting that Alzheimer's may be the result of a pathogen that enters the brain through the olfactory system.

How interesting.

It's not, of course, a mainstream or widely accepted theory of any type, but it just highlights this notion that the nose is a path to our brain.

I think these non invasive readouts of potential neurodegeneration, such as visual tests because of the fact that the retinas are part of the brain, and loss of neurons in the retina is often associated with other forms of central degeneration. Alzheimer's, Parkinson's, et cetera. It's a little more invasive than what you're describing. I'm beginning to wonder why we don't have a olfactory task every time we go to the doctor that would allow tracking over time. Because of course, as you mentioned, someone can lose their sense of smell. Does that mean they're getting Alzheimer's? Not necessarily. But if their sense of smell was terrific the year before and it's 50%.

Worse the next year, that's a really bad sign.

Yeah, that's a bad sign. And so what we're talking about is something completely non invasive and could be relatively pleasant to innocuous depending on the odors used.

So, yeah, so first I can answer that, right? And the reason that that's not happened, and that might, that that may be changing right now, but the reason that has not happened is because olfaction has not been effectively digitized. Right. So if you need to generate, you know, really precise visual information, you can buy a monitor for, you know, 100 bucks. That is at the resolution of the visual system, basically. And if you want to generate auditory stimuli really precisely, then you can buy an amplifier for, you know, maybe a bit more than a hundred bucks, but not that much more, and you'll be at the resolution of the auditory system. In our lab, we build devices that generate odors. We call them olfactometers, which is a misnomer because they don't measure anything, but that's what they've always been called. So we call them olfactometers as well. And we've already built at least one olfactometer that cost a quarter of a million euro. And it's pathetic, right? So it just, it's pathetic, it's slow, it's contaminated it's nowhere near the resolution of your system. So one of the reasons that's not happened is just the utterly poor control of the stimulus. Mind you, to some extent it has happened in that there are standard clinical tests of olfaction, basically two that sort of control the world in this respect. The older one is a test called the upsit, which stands for the University of Pennsylvania State Smell Identification Test. It was developed by Richard Doty in Penn. And it's a test where you scratch and sniff. And it's a four alternative forced choice test with 40 odorants. So you have these 40 pages that you page through and you sniff and smell and you know, it's been normed on gazillions of tests. I'm always amused by it because. So Richard Doty made a ton of money on the upsit, but he needed it because he has a habit. He has a nascar. So this. Every time we buy upsits in live, I say there's another gallon of gas into Richard Doty.

He races nascar.

Not like nascar, but like one lower than that. Like, I don't know, like some, some sort of Formula A or formula Ford or some. He races a car. And so that's where all the ubisits went. So I always feel good about buying ups its because I know they're going to that. That good cause.

But keeping him in the fast lane.

Yeah, but. So that's one test that's out there and indeed has been shown as a. You know, so there's reduced UPS it in Alzheimer's and Parkinson's and in a host of other diseases. And there's a European version called sniffing sticks that Thomas Hummel has developed. And it's basically the same sort of concept of sniff. That one isn't scratch and sniff. It's like these pens that you open up and sniff. But those exist, but they're not as convenient as delivering stimuli and vision and audition. And that's why you don't have what you've just suggested. You know, another thing, another place where you don't have it, which I think is even more. Would have been even more meaningful is you don't. Olfaction is not tested in newborns, right. Where vision and audition is. You know, there's this thing called congenital anosmia, right. Which is being without the sense of smell from birth, supposedly congenital, which is half a percent of the population.

It's not a trivial number.

Not totally. Yeah. But nobody knows if that really is true because here's an amazing factoid. Guess the average age at which congenital anosmia is diagnosed. And this is a horrible statistic for me for the way I see the world, but what do you think the average age of diagnosis is for congenital anosmia? 5 years old, age 14.

Incredible.

14.

So most people who are 1/2 of 1% of the human population, presumably is without the sense of smell and doesn't realize that until they're 14 years old.

Well, I don't know when they realized it first, but it's formally diagnosed at 14 on average, which means some of them even later. Right.

And right. It's a distribution. What do they suffer?

Yes. So first of all, they suffer socially. And there's a host of deleterious life events associated with congenital anosmia. They die younger. So this is work out of Ilona Croix in Germany. And amongst the various things that are predicted by anosmia is shorter lifespan, but things like reduced social contacts, reduced romantic social contacts. It's not a good thing.

And do they lack olfactory bulbs? I'm presuming they have noses and nostrils. There is a condition I'm aware of where children are born without noses. Very rare. Very rare. We won't focus on that because it's exceedingly rare.

But they're born with noses and nostrils. And here's the thing, we don't know if they're born with olfactory bulbs. Most of them, although not all of them, but most of them don't have olfactory bulbs in adulthood, or I should rephrase that, have remnant olfactory bulbs, really shriveled olfactory bulbs. But, you know, nobody can say the cause and effect here.

Before we talk about the role of the. The requirement for olfactory bulbs for olfaction. A very interesting topic in its own right. I'm curious as to whether or not their endocrine system is altered, because as we'll soon talk about, there is a lot of signaling through the nose from between individuals that triggers things, everything from the onset of puberty to feelings of romantic attraction, attachment, these sorts of things. Is it known whether or not, and I should say, excuse me for interrupting myself, but as long as I'm interrupting you every five minutes, I might as well interrupt myself too. That we are well aware of the proximity of the olfactory system to some of the hypothalamic systems that regulate the release of gonadotropins, which control testosterone and estrogen production, et cetera. So are they hormonally normal?

So some are and some aren't. And I'll be specific. So there is a condition known as Kalman syndrome, which is hypogonadic development in men. And in Kalman syndrome, they're practically all anosmic.

So.

So to answer your question, yes, there's a direct link and it materializes in Kalman syndrome. That said, not all congenitally anosmic individuals have Kalman syndrome and not all, but almost all people who have Kalman syndrome are anosmic. So Kalman syndrome goes with anosmia, I think. So there is a female equivalent of Kalman's or I don't remember it name.

It's not turn. It's not a. In the Turner syndrome family.

I'm not sure. Okay. And I think it's also associated with anosmia, but I'm not confident of that. But commons is. Is associated with anosmia. So. So the answer is, is yes. And, and you know, we can maybe, you know, olfaction and reproduction are, are tightly linked and, and they're tightly linked in all mammals and we are big terrestrial mammals and olfaction reproduction are linked in humans as well.

Yeah, we will definitely get into that.

I'd like to just take a brief moment and thank one of our podcast sponsors, which is Inside Tracker. Inside Tracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you reach your health goals.

I've long been a believer in getting regular blood work done for the simple.

Reason that blood work is the only way that you can monitor the markers.

Such as hormone markers, lipids, metabolic factors.

Et cetera, the impact your immediate and long term health. One major challenge with blood work, however, is that most of the time it does not come back with any information.

About what to do in order to.

Move the values for hormones, metabolic factors, lipids, et cetera into the ranges that you want. With InsideTracker, changing those values becomes very straightforward because it has a personalized dashboard that you can use to address the nutrition based, behavior based, supplement based approaches.

That you can use in order to.

Move those values into the ranges that are optimal for you, your vitality and your longevity. Inside Tracker now includes a measurement of apolipoprotein B, so called apob in their ultimate plan. APOB is a key marker of cardiovascular health and therefore there's extreme value to knowing your APOB levels. If you'd like to try InsideTracker, you can go to InsideTracker.comHuberman to get 20% off any of InsideTracker's plans. Again, that's InsideTracker.comHuberman to get 20% off.

I have a story slash question that I'd like to tell you, ask you as a segue to that noting, of course, we'll get back to the requirement for olfactory bulbs. Yes or no? For olfaction. And this relates to when I was growing up. I grew up at the end of a street with a lot of boys of my age who just by coincidence had a lot of older sisters that were my sister, my older sister's age. I was fortunate. So I had a lot of kids to play with. We would hang out at each other's houses, bike, build jumps, and do all these things like kids stuff, fort stuff, get into trouble or whatnot. And oftentimes we would end up leaving our articles of clothing at each other's houses all the time, like T shirts and jackets. And so my mom was constantly coming in and saying, there's this clothes. Like, someone left this here. I don't know who it was. We were all more or less the same size. And from as far back as I could remember, six, seven years old and onward, I could pick up a shirt or a jacket, smell it and say, oh, well, that's Eric Eisenhardt's shirt. A friend of mine there, I just gave his name, or, oh, that's Scott Madsen's shirt. I could just smell the shirt and in a conscious way, know who it belonged to. Having never, I promise, not that I would pretend if I had, pretend that I hadn't if I had, but having never actually done the exercise of going and taking and smelling my friend intentionally.

Right.

Okay. In fact, if anything, I had all the reasons in the world to avoid smelling the other young boys in my neighborhood. Okay. So that raises the question of whether or not we are consciously and or subconsciously coding identification of people that we interact with frequently or infrequently in terms of their smell or some other aspect of their chemistry.

Yeah. So, yes, we're doing that all the time, in my view. And a lot of this processing, almost all of it is subconscious. And I don't know why already put that out there. Right. I have no idea why human nature or nature or culture or whatnot has pushed this into the realm of subconscious and something we're unaware of. But we do it all the time. And. And our lab has lots of studies on this front. One of them, you may be familiar with that that had gained some notoriety because it's amusing. So we. 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, you know, if you look at dogs, right, They've, 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 sort of obliged to sniff our babies. That's considered almost something you're supposed to do. And. 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. Handshaking is this really odd behavior. And it's not only in the west, by the way. Some people think it's only a Western thing. It's not. Not. It's almost everywhere. And. And there's really poor understanding of how this behavior evolved. Like, where did. Where did this thing come from? So if you, 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. It's a bit like the Trillion Bloodhound receptor story, right? I mean, we tried to find it. You know, why do people say that? And they just do. 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.

For those of you listening, not watching, Noam is taking his hand and wiping it on his face, grabbing his nose.

Or touching my side. Yeah, these things. 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. But these behaviors that you could easily not notice, right? And so we asked whether that's a real thing. And this was a study led by Idan Fruming in our lab at the time. And what we did first, and if you want, we can link. So this was published in Elife. And one of the nice things about Elife is that it has a very effective way to embed videos in the publication. So if you want we can link this to your system later on, put.

It in the show. Note captions as a link on YouTube and the other four platforms, Spotify, Apple.

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. Of course, later on they had the opportunity to not agree to us saving the video, in which case we would delete it immediately or letting us use it for science or some letting us use it for more than science for the video that's now on Elife. And we would walk into the room and say, okay, just wait here, we'll be right back with you to set up our experiment. 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 touch 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. Then three minutes later, an experimenter would walk into the room and would share a consistent text that would be, 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 the experimenter went through this like 20 second fixed text. 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 it's the first time they met. So it'd be, hello, I'm, you know, so. And so they would put out their hand and shake their hand or not. Okay. And we did all possible interactions in terms of gender. So we matched male participants with male and female experimenters and female participants with female and male experimenters. 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. And this is one of the nice cases. The paper includes statistics, but you don't need statistics here. Just look at the video. It's unreal. The video is 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 the 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 hand. And in an additional control study, we manipulated it so we built this little James Bond thing of a watch on the experimenter's hand that could emit an odor. And the experimenter didn't know what odor they were emitting. And they could emit either a pleasant or an unpleasant odor. And we could drive the self sampling afterwards up or down. So this was an olfactory behavior. No doubt about it. I mean, we're quite confident.

So people, in that case, people must have been sensing the odor on their own hand because they shook the hand of the experimenter. Pleasant odor, and they're more frequently bringing that hand to their nose versus unpleasant odor that had been introduced to their own hand by the experimenter.

Yeah, but no, I think, I think they were sensing the ambient odor that came in with the hand that shook and then that either drove them to sniff their hands, more or less the.

Odor cloud of the experiment.

Yeah, 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 reflect that there's on the same line. And again, to link to your childhood story of identifying your friends by smell study we published just last year by Rav Rebbe 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. Right. You immediately become close friends. And this is a phenomena that is poorly described or is poorly described in literature as an entity. And yet anybody will tell you they know what you're talking about, right? I mean, if you tell, you know, if somebody you click with right away, you become intimate within five minutes. Right? 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 in Bala's theory, was that a similarity in body order 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 pairs of friends. So these are same sex, non romantic dyads. So these are friends, men and women whose friendship Started as a clique where here this becomes sensitive because it has to be a mutual click, right? Later on we discovered there could be one sided clicks. So somebody's sure they clicked with somebody else, but the other person, there's a.

Name for that in neurology that our common friend, the late Ben Barris taught me, which is there's a phrase that neurologists use called sticky. These are people that come up to you and start asking you questions and then won't leave you alone. They're so called sticky people. And if you ask these sticky people sticky in air quotes because they're not physically sticky, they may be what they could be, you know, what do you think of the per this person? They'll say, oh, they're great, we're really good friends. And so they've made a unilateral click friendship. And yes, neurologists are talking about you. If you're, if you're one of these people, neurologists are talking about you. There's an informal diagnostic code, sticky.

So she recruited click friends and then she sampled their body odor. And we have a protocol for this. They're given 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. And then she first asked whether indeed click friends are more similar in their body order 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 mock 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 judge 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. And 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 non verbal. 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. And 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. So this is to relate to your childhood story. There's something going on here. We're constantly smelling ourselves. Constantly. This, constantly. I mean, if you want to link the reason I'm smiling, I mean, and your viewers or listeners will understand why I'm smiling, I'll send you a video to link into your podcast. Here. We thought of calling the fact that people constantly sniff themselves. We thought of calling this the low effect. And low. So in America, this won't pass that effectively, but in the rest of the normal world, Joachim Lo is the national soccer coach of the German soccer team. So I mean, I don't know who would be a very famous coach here, but Steve Kerr. I mean, this is the, this is a super, super famous name all around the world, where soccer is the primary sport that people watch. And once people will see this video, they'll understand why. We thought of calling this the low effect. It's very graphic. But people are constantly smelling themselves. They're smelling themselves with their hands. They're smelling themselves. Explicitly. People are constantly smelling themselves, constantly smelling others.

I find this topic so interesting and first of all, confession. I definitely smell myself multiple times per day.

Everybody does.

Okay, good. I would do it anyway. I think I like most people. I either find My own smell to be neutral to pleasant. Occasionally I'll be like, whoa, I need to take a shower. As long as we're talking about smelling oneself and friendship, kinship and its relationship to smell, we have to talk about the relationship between smell and romantic attraction and bond. So my understanding is that if, for instance, a mouse is given the option to mate with any number of other different mice, they will bias their choice toward the mouse that has the immune composition, the so called MHC major histocompatibility complex, which reflects immune diversity, the immune system that is most distant from theirs. The evolutionary argument being that were they to produce offspring, that the array of immune genes would be much broader than if they were to select an animal very close to them. And in addition to that, that one of the most strongly selected against behaviors, not just culturally, but at the level of eliciting a sense of disgust, maybe even from the activity of the hypothalamus, is mating with very close kin, AKA incest, because that can potentially, we know, produces a higher rate of mutations. In other words, whereas you describe the relationship between smell and choice of friends as you choose people who smell more like you, my understanding is that in the context of choosing romantic partners or sexual partners or both, that you choose the person whose odor and therefore immune composition is most different.

Right. So the way you describe the animal literature is correct and there's evidence to similar mechanisms in humans. Our lab has not worked directly on this issue of romantic selection based on odor. There's a bunch of papers, Wedkind et al and the Wetkin Lab, and also Porter, I'll email these to you later on that have done a lot of this work and finding exactly as you say, that romantic odor preferences in humans are influenced by body odor and that this is linked to MHC histocompatibility complex makeup of the portion of our genome that shapes our immune system to some extent. So this effect has been studied and reported on again extensively in mice and also in humans. Not work that we've done. The one sort of tangent work we've done and I'd like to maybe tell you about it relates to an effect that is one of the most remarkable effects in mammalian social chemo signaling. So, and also related to. So it's not related to romanticism in any way, but it's related to reproduction. And indeed, in our lab we've not looked at romanticism. We have looked at or are looking at reproduction. They're not always the same.

Certainly they can.

They can. Animal, mammalian or terrestrial, mammalian reproductive behavior is dominated by the sense of smell in mammals. And here, remember initially when you started off, I noted that there are several subsystems in our nose that transduce odorants. And so primarily the main olfactory system, which is cranial nerve number one, and the trigeminal nerve, which is cranial number five. Most terrestrial mammals have another subsystem referred to as the secondary olfactory system system that has a separate sense organ in the nose. This organ is known as the vomeronasal organ. It's a small pit in the nasal passage of most terrestrial mammals. Sometimes it's described as a communicating pit because sometimes it connects the nasal passage to the roof of the mouth, sometimes it connects both. And so there's the sense organ with its specific receptor subtypes, VNRs, Vermorn, Azole receptors. And this is linked to a sort of separate portion of the olfactory bulb, not really the main olfactory bulb. It's referred to as the accessory olfactory bulb. And from there directly to the limbic system, to the portions of the brain that control reproductive behavior and aggressive behavior. And in most terrestrial mammals, this subsystem processes odorants that are sometimes referred to as pheromones, although that's in many ways a problematic term. But odorants that are referred to as pheromones, namely odorants that are emitted by another member of the species to influence that member of the species and alter behavior or hormonal state. And some of these pheromonal effects are utterly remarkable. And in my view, the most remarkable of all is an effect known as the Bruce effect. This was an effect discovered by Margaret Bruce in 1959. She was a British scientist. In the Bruce effect. When you expose a pregnant mouse at an early critical stage of the pregnancy, I think up to about day three, if you expose the pregnant mouse to the order of what is referred to in technical terms is the non stud male, that is a male who did not father the pregnancy, she will miscarry the pregnancy, she will abort it. Now, that's an insane decision made by the female here, right? Because she's invested quite a lot in this, right? In biological terms, and in forming this pregnancy and maintaining it, and yet she drops it on the basis of an odor. And this effect is remarkably robust. And what do I mean by remarkably robust? So this will occur on about 80% of exposures. Now, as you know, 80% is 100% in biology, right? I mean, there's nothing that happens at more than 80%. So it's a remarkable, remarkably robust effect. This Dropping of the pregnancy.

And we know it's mediated by chemosensation.

Through the nose for sure. And we know in the following way. So first it's enough to just bring the odor of the non stud male. You don't have to bring the male himself, right? So you just can bring bedding from a non stud male and that will induce the Bruce effect. But of course, the most telling set of experiments is that if in the female mouse you ablate the vomeronasal organ, you just burn this tiny structure in the nose and the effect disappears. So the effect is completely dependent on the vomeronasal organ. And I find this out earlier a remarkable effect, right? I mean, because again, because of the, the extent of cost that the female takes on here based on this information and smell. Now humans, the sort of the going notion in olfaction is that humans don't have a functional vomeronasal organ. So we don't have that functional organ in our nose. Now I'll point out, we actually do have the pit. So the structure or the outlining structure is there, but the pit that we have is considered vestigial and non functional.

And what about this thing I learned about at Berkeley in integrative biology class that we have something called Jacobson's organ.

This is the same organ. So Jacobson organ is the vomeronasal organ. It's also called Jacobson because I think Jacobson was a military physician in the 1800s in Holland or something, and he founded in, in the soldier he was operating on or something like that. The story comes from something like that. But Jacobson's organ is another name for the Vomernon nasal organ. These are one in the same, the sensory organ of the accessory olfactory system. And again, the going notion is that the human Jacobson organ or Vomornas organ is vestigial. It's non functional.

Does that necessarily mean that we don't have these pheromone effects?

No, it does not. So first of all, we know that lots of what are considered pheromonal effects, namely social chemo signaling in rodents, are mediated by the main olfactory system. We know that for sure. There are several examples for this in mice and rats and rabbits and so on and so forth. So a, these can be mediated by the main olfactory system. And I'll come back to that in a second. But first, to finish the Bruce effect and second, and I'm going out on a limb here, but I'm willing to take that risk. For me, the jury is still out on human vomeronasal organ, the decision or the notion that it's non functional relies on about one and a half papers postmortem, looking for the nerve that connects this thing to the brain and failing to find it using staining and so on and so forth. But staining postmortem studies in humans are notoriously complicated, basically, you know, for many reasons. One of them is that the material is just always has gone through, you know, it's not ideally set as it is when you sacrifice an animal and, and study its tissue. So based on really, really a paucity of studies that fail to find this nerve, the notion is that the structure is vestigial in humans. I don't have any evidence that it's functional, mind you, but I'm just not sure that it's not. But what we do have a suspicion is that humans may experience something similar to Bruce effect. So first of all, humans have an enormous number or ratio of spontaneous miscarriage.

Are they occurring more often in the first trimester? Because you mentioned that in the Bruce effect in the mice is in the first three days or so following pregnancy, which in the mouse gestation, as I recall, is about 21 days. In the mouse, you're talking about 1/7 of total gestation. So I'm not quick enough to, nor is it important to translate, but this will be first trimester, yes, which is.

Indeed early when most miscarriage occurs. Now, humans have again a huge number of miscarriages, and the numbers, I'll soon share them with you, they sound odd. And the reason they sound odd is because if you have what's sometimes simply referred to as failed implantation, this can occur in days. One, two, nobody ever knows. Some papers talk about 90% of all human pregnancies end in miscarriage. This is counting a failed implantation in day one, two, et cetera. More conservative studies talk about 50%, nobody will argue 30%. A huge number. A huge number of human pregnancies end in miscarriage. Now, out of these, there's a portion that are unexplained, so nobody knows why. I mean, there are a portion that are explained by all sorts of genetic factors, developmental factors, and so on and so forth. But there's also a proportion that are unexplained. And so all I'm saying is that there's a statistical background drop or. Right, so nobody knows why. I mean, there are a portion that are explained by all sorts of genetic factors, developmental factors, and so on and so forth, but there's also a proportion that are unexplained. And so all I'm saying is that there's a statistical backdrop or setting, if you will, for something like a remnant Bruce effect in humans. Now with that setting, if you will, for something like a remnant Bruce effect in humans. Now with that in mind, we approached a group of. We enlisted a group of they're not really patients and participants in a study of people who. Couples who are experiencing in mind, we approached a group of. We enlisted a group of they're not really patients and participants in a study of people who. Couples who are experiencing what is referred to as unexplained repeated pregnancy loss. So formally, if you have two consecutive unexplained miscarriages, then that is sufficient for the diagnosis of unexplained repeated pregnancy loss. However, in our cohort of 30, we had couples who experienced 12 consecutive unexplained repeated pregnancy losses. So the two is just the formal. All of our cohort was what is referred to as unexplained repeated pregnancy loss. So formally, if you have two consecutive unexplained miscarriages, then that is sufficient for the diagnosis of unexplained repeated pregnancy loss. However, in our cohort of 30, we had couples who experienced 12, like 12, five, you know, so, so this is an emotional difficult place to be. And, and these are couples who, who are losing their pregnancy for no apparent reason. So they've gone through all the tests that you can imagine of, you know, genetic incompatibilities and all sorts of issues, clotting, all the, all the, the known suspects for, for pregnancy loss. And the medical establishment remains totally at a loss as to why these pregnancies aren't holding. And so we hypothesized consecutive unexplained repeated pregnancy losses. So, so the two, the two is just the formal. All of our cohort was that, that perhaps here there's something akin to a Bruce type effect. Obviously it's not going to be this like 12, five, you know, so this is an emotional difficult place to be, same as in mice, but something like a Bruce effect. Now, of course, at that stage we could not do. And these are couples who are losing their pregnancy for no apparent reason. So they've gone through all the tests that you can imagine of anything causal to test this. Right. But what we could do is to see, to seek circumstantial evidence to see if where there's fire, maybe there's smoke. And what we did was we tested olfaction and more specifically the response to male body Order in the genetic incompatibilities and all sorts of issues. Clotting all the known suspects, couples experiencing repeated pregnancy loss. And we found a few things. First of all, if you think of the mechanisms for pregnancy loss and the medical establishment remains totally at a loss as to why these behind the Bruce effect. The Bruce effect implies that the female has to have a very. Pregnancies aren't holding. And so we hypothesized very clear memory of the fathering male. Because if she's going to miscarry that perhaps here there's something akin to a Bruce type effect. Obviously it's not going to be this in response to the non father. She has to know father, non father. I mean that means that there's a pronounced olfactory memory at the moment of mating. Okay. And in mice this has been very well characterized and attributed to the anterior olfactory nucleus structure in the brain. But you'd have to have this memory in order to tame as in mice. But something like a Bruce effect. Now of course at that stage we could not do anything causal to test this. Right? But what we could do is to see, you know, to make that decision now. So to address that. And here you're going to see that you in your childhood story from before stand out a bit as, as skillful to seek circumstantial evidence to see if, if where there's fire, maybe there's smoke. And what we. Is that the first thing we did was just behaviorally test whether did. Was we tested olfaction and more specifically the reason these women and control women could identify the smell of their spouse. And you might be disappointed or you know, we would all are probably a bit disappointed to learn that control women are very poor at this. So, so you, you would think that, that women would be good at identifying the body order of their spouse. They're not. They're not. Response to male body order in the couples experiencing repeated pregnancy loss. And we found a few things. First of all, if you think of the mechanisms behind the Bruce effect, the Bruce effect implies that the female has to have a very far from chance. However, the women who experience repeated pregnancy loss are more than. They're, they're double at their performance level. So this is not a nuance effect. Women who experience repeated pregnancy loss can identify their husbands or their spouses by.

Their body order with much greater acuity than the typical person.

Double. A bit more than double. And way above chance a clear memory of the following male. Because if she's going to miscarry.

Yeah, no, sorry. I posed it as a question, but I meant yes, with much greater acuity and double is a significant improvement. Are they much better at detecting any.

Odor in response to the non father. She has to know father. Non father. I mean that means that there's a pronounced olfactory memory at the moment of mating. Okay. And in mice this has been very well characterized and attributed to the anterior olfactory nucleus. No, they're not. We did the controls and they're not. And then we also measured using fmri, we measured their brain response to stranger male body order. And there. And this was quite remarkable because you know, we approached. So this was a full brain analysis. So without a region of interest analysis. So it's not as if you're tweaking a structure in the brain, but you'd have to have this memory in order to make that decision now. So to address that and here you can your statistics to look at one part of the brain, you're just looking at the entire brain in the response to male body order and asking de novo, is there a difference between these two groups of participants? And there was one huge difference and it was in the hypothalamus. And so there was a difference in response to stranger male body order. You're going to see that you in your childhood story from before stand out a bit as skillful is that the first thing we did was just behaviorally test whether between the two groups. So olfaction is altered in spontaneous, repeated spontaneous pregnancy loss. We don't know this is causal. Right. But that was enough for us to approach the ethics committee to run a causal experiment. And we're at the beginning of that now. These women and control women could identify the smell of their spouse.

And incredible. I can't wait to hear the results of that.

It's going to take. You might be disappointed or you know, we would all are probably a bit disappointed to learn probably take years, a few because. Because the. These are slow experiments to run. Recruitment is complicated. But basically we're, we're blocking, we're blocking that control. Women are very poor at this. So. So you, you would think that smell in, in couples who are trying to maintain a pregnancy.

I want to touch on some other so called pheromone effects. And one thing I heard you say during a talk which I think really captures this whole issue of are there pheromone effects in humans very nicely. As you said, whether or not it's a classic pheromone effect or whether or not it's olfaction or something else that.

Women would be good at identifying the body order of their spouse. They're not. They're not far from chance. However, the women who experience repeated pregnancy loss are more than they're.

This is chemo sensory signaling between individuals. The reason this is important to me is a few years ago I did a social media post about pheromone effects in animals and some potential pheromone effects in humans. And a couple of the human olfactionistas.

More from the double at their performance level. So this is not a nuance effect.

They actually who work on animal models really came after me with intense sniffing saying there is no evidence for human pheromone effects human pheromone organs. And I think today you've beautifully illustrated how regardless of the answer to that humans contain and are emitting chemical signals that influence each other's physiology and behavior.

Women who experience repeated parentals can identify their husbands or their spouses by their body order. For sure. For sure. And. And the. The term pheromone is a problematic term in any case. I mean the term.

The term was with much greater acuity than the typical person.

Double. A bit more than double. And. And way above chance put forth to describe insect behavior. Right. So you know, if, if you were given a hard time by the mouse people, you could have given an them an equally hard time if you were an insect person. Right. Because really the place that.

Yeah, no, I. Sorry I posed it as a question but I meant yes, with much greater acuity and double is a signal is accurate.

Is. You know. So the first pheromone that was discovered was Bambicol, which is the pheromone that has the male moth follow the scent trail of the female moth. Bambicol is a pheromone.

Insect pheromone significant improvement. Are they much better at detecting any odor?

People will argue that this stuff that people talk about in mice and rats is not pheromone. No, they're not. We did the controls and they're not. And then we also measured and it all becomes semantics.

Yeah. Sort of like nerdy inside ball.

It'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 problem Using FMRI remeasured their brain response to stranger male body odor. And there. And this was quite remarkable because we approached so this only hurt us. And so 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. And there are several examples of this. One of them I'll point out first, which is sort of the most was a full brain analysis. So without a region of interest analysis. So it's not as if you're tweaking your statistics to look at one part of the brain. You're just looking at the entire brain. Widely studied and not mostly from our lab, actually. I mean, the flavor of the month for the past 10 years in this field is what's referred to as the smell of fear. Right. So this is probably true of many mammals and humans. It's true of. We emit a specific body odor when we're in a state of fear in the response to male body odor. And asking de novo, is there a difference between these two groups of participants? And there was one huge difference, and it was in the hypothalamus. And so this was first discovered in humans by Denise Chen out of, I think Brown. I'm not sure.

I think that's right. Yep.

Humans emit a particular body order when they're in a state of fear. And this body order influences. There was a difference in response to stranger male body order to other humans, in effect increasing their autonomic arousal, their sympathetic state. So in effect, you could say that fear is contagious a bit between the two groups. So. So all fat. 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 urine action is altered in spontaneous, repeated spontaneous pregnancy loss. We don't know this is causal. Right. But that was enough for us to approach the ethics committee 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 the same state of fear to run a causal experiment, and we're at the beginning of that now, 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.

What about the smell of safety? Or is that simply the absence of the odor corresponding to fear? And the reason I asked this is somewhat woven into our priority discussion about mate choice. Again, I'll ask the question in a form of brief anecdotes. I'll use the I had a friend who approach here, but. Well, one phenomenon that has nothing to do with me in particular, I think this is a common phenomenon is romantic partners leaving articles of clothing at each other's homes. Now, this could have other purposes to mark territory, but visually marking territory, but also scent marking territory is very common in the animal kingdom. It's not uncommon for romantic partners when one is traveling or away for the other partner to smell their article of clothing in order to bring about positive connotations of the other partner. Very common behavior. If you're doing this, folks, other people are doing this too. It raises questions, for instance, about whether or not the mourning period part post breakup, whether by decision by death or by some other phenomenon that's forced the breakup, whether or not that mourning period has something to do with an olfactory unlearning of and made slash and on and on and on.

With all these insights, I would offer you to be a postdoc.

Well, I was gonna say, listen, I have a sabbatical finish, so I would love to do a sabbatical.

It's gonna kill me.

Yeah, exactly. You don't want me to work for you. We talked about this earlier.

That's what I'm saying.

There's a story there. What Noam is referring to. I'll just tell people, because inside jokes on the podcast don't really work. Earlier, I was referring the fact that I've had three incredible scientific mentors, undergraduate, graduate, and postdoc. But for reasons that are unclear to me, the first one died of suicide, the second one, cancer at 50, and the third one, pancreatic cancer in his early 60s. And the last one before he died, who was an MD and a common friend of gnomes, and I turned to me and said, you know, Andrew, you're the common denominator. So, you know, the joke in my business is you don't want me to work for you. So, nonetheless, I would love to do a sabbatical in your life.

So. So what I was trying to say in that roundabout way is that those are all really keen observations and good ideas, for sure. And. And they just highlight again, you know, that. That we're incredibly olfactory animals, you know, and you're. You're even talking about the nuance. We're very olfactory. Even not in the nuance. I mean, I have this. When people tell me that, you know, that we don't use our sense of smell and we don't need it and all that And I have to deal with this a lot, right? I have to deal a lot. You study vision. Nobody will tell you that vision is unimportant, right?

Visually dependent. I don't need a dog to take over my olfactory system if I lose olfaction. But I'll tell you from having lost my sense of smell for one day, right? I was in intense fear. I bit into blue. I love blueberries. I'm like a drive by blueberry eater. If they're there, I just kind of pick them up like a grizzly bear and cram them in my mouth. So keep them away from me if you don't want them eaten. But I can't, I almost can't help myself. I bit into a blueberry or a handful of blueberries and they just, it was the sensation of little bags of water. And I immediately felt like tremendous, tremendous grief.

I'll tell you a sort of throwaway line that I use in this when I talk with people. You know, I mean, you know, take the two most basic behaviors that sustain us, right? Let's say I give you a choice between a beautiful looking layer cake with strawberries and blueberries and whipped cream, but that smells of sewage versus some gray brown mix that smells of cinnamon. Which do you eat? Simple.

The latter, right?

You eat the latter, right? Now imagine I offer you a mate. Choose the gender of your liking, right? That looks like a Greek God or goddess, right? But smells of sewage. Or an ordinary looking individual that smells of sin itself. Who do you choose?

The latter, right?

So in the two most basic behaviors we have, we follow our nose, not our eyes, right?

Definitely not always in predictable ways. Because you offered an extreme example, which is the best example. But I, for instance, for reasons I don't know, I've never liked the smell of perfume, ever. In fact, I find it aversive. But I do, I confess, I do like the smell of certain body odors very much. And I'm very particular about that. And I know within an instant. And so this is a problem for any romantic partner who likes perfume for me. But I know many people like perfumes and colognes and things of that sort.

Perfume.

And in fairness, I've also been told that by someone that they couldn't spend time with me because they do not like my smell. In fact, they dislike it. And fortunately for me, there's at least one person on the planet who said the opposite.

So the.

So I completely agree with what you're saying. I can also say that I imprinted on the smell of my. I Had a bulldog mastiff when I raised from the time he was a puppy, and I imprinted on his smell immediately. And even though to other people he was a bulldog mastiff after all, his smell was rather aversive to me. He smelled delicious. Right. And it made me feel. It smelled like home. And he was my best animal friend for a long time, so. And on and on and on. Right. The smell of children, as you said, the backs. We had a guest on this podcast who I'm sure you're familiar with. 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 when he thinks about missing his grandchild or children, it's that smell that, that. That's associated with that feeling.

Hexadecanal.

Hexadecanal, yes. Is that Charles, your grandchildren smell like hexadecanal?

Yes.

He's going to come after me now.

And so this, this is a study ran by Eva Michore, who was a graduate student in our lab. And Eva was interested in aggression. She was really into aggression. And actually when she start. And so when she started off, we said, okay, let's do chemo signaling of aggression. She actually was going to 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. And then at the same time, we had a colleague of ours from Germany. I mean, when I say colleague, primarily a friend or acquaintance I met at conferences, Heinz Breer, and he was studying in his lab a molecule, hexadecinal, that was a chemo signal in mice. Where in mice it was described as a chemo signal that promotes social buffering. Where social buffering, as far as I understand, it's not my field, but as far as I understand, it's basically a feel good together thing. 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. Mice. In his work on hexadecanal, 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 this is a universal mammalian signal. Now, which is unusual because in chemo signaling, typically you tend to think of things as being very species specific. But here they hypothesize that maybe hexadecanal, which promotes social buffering in mice, may do something in all mammals, again, because this receptor is very highly conserved, or 37B, I think. So they. 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 so we had this thing sitting around, and Eva was not going anywhere with her aggression studies 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. I'll soon describe it. And so we said, okay. So he approached us and said, look, you got to study this stuff in humans because he knows us as the human people. 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. Hey, we have this hexadecanal stuff here, and it promotes social buffering. Social buffering sounds like it would make you less aggressive. Why don't you run your TAP experiment using hexadecanal? What's the TAP experiment? So basically what you do. And so we had this thing sitting around, and Eva was not going anywhere with her aggression studies 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. I'll soon describe it. And so we said, okay, is you bring in a participant to lab and you have them thinking that they're going to be playing against another person in this game. And you can do something like have another person walk into the other room playing online, connected, so you can fool them into being quite convinced that this is what's happening. And they go into their own room, hey, we have this hexadecanal stuff here, and it promotes social buffering. Social buffering sounds like it would make you less aggressive. Why don't you? And in the initial game they play on Each round, run your TAP experiment using hexadecanal. What's the TAP experiment? Basically what you do is you bring in a participant to lab and you have them thinking that they're, they're provided with a sum of money and this is real money that they'll receive at the end of the experiment. And by turn, each one of them decides how to divide the money up between the two, right? So they're playing against another person, they think, but that's actually a computer algorithm that they're playing against. And the computer algorithm is programmed to be in scientific. They're going to be playing against another person in this game. And you can do something like have another person walk into the other room playing online, connected, so you can fool them into being quite convinced that this is what's happening. And they go into their own room and in the initial game, they play on each round. Terminology, a jerk, right? So let's say they have to divvy up 100 checkl, which is the Israeli currency. So the other player would say, okay, you know, I'll keep 96 and you get 4, right? And then if you can either accept it or not accept, and then neither of you get anything, right? So basically you're being shafted by, by the other side all the time. And this is called the provocation phase. You're really getting angry at this person because they're, they're really not nice, right? They're, they're provided with a sum of money and this is real money that they'll receive at the end of the experiment. And by turn, each one of them decides how to divide the money up between the two. So they're playing against another person, they think, but that's actually a computer algorithm that they're playing again. They're shafting you on every trial almost. And you play this game and it goes to its end, and then you play a second game, as far as you know, against the same participant. And the second game is a reaction time game. So a target shows up and the first to press it wins. And on every trial where you win, if you want, you can blast the other participant with a loud noise. And the computer algorithm is programmed to be inside of it and it's a really loud noise. So you're also wearing earphones. It's 90 decibels and it's a screeching, horrible sound. It's terminology, a jerk, right? So let's say they have to. It's the most punishment that an IRB committee will let you divvy up 100 shekel, which is the Israeli currency. So the other player would say, okay, I'll keep 96 and you get four. Right? And then you can either endure on a participant in an experiment, unless you're in Stanford 70 years ago, or whatever that was.

No one's referring to the classic prisoner experiment, which took place in the building next door to us.

I work by L. So you can blast the other participant with varying levels of sound. And you have a selection box from something very low to something very high. Accept it or not accept it. And then neither of you get any thigh. And what's nice about this is that it then allows you to quantify aggression because the more volume you're blasting the opponent with, the more aggressive you are towards your opponent. And so you have a measure of aggression. Again, the Tyler aggression paradigm, obviously invented by Tyler, very well validated, studied all over, a very standard protocol. So basically, you're being shafted by the other side all the time. And this is called the provocation phase. You're really getting angry at this person because they're really not nice, right? So we brought in participants and had them play the Tyler the tap. They're shafting you on every trial or almost. And you play this game either under exposure to hexadecanal or control. Now, hexadecanal doesn't. It's incredibly difficult to even detect hexadecanal. But just in case, because it's not very, very. It's considered a semi volatile, it doesn't have a strong smell, goes to its end. And then you play a second game, as far as you know, against the same participant. But we buried it, both the control and the hexadecanalan in a control order that hid them in a mask. And she ran lots and lots and lots and lots of participants, men and women. And I'll first tell you the result with men, which is that hexadecanal consistently reduced aggression. And the second game is a reaction time game. So a target shows up and the first to press it wins. And on every trial where you win, if you want, you can block. People were less aggressive under hexadikanal. The effect size was last. The other participant with a loud noise. And it was quite meaningful. And later on we learned, because I'm no specialist in the world of aggression, but compared to effects seen in the aggression world in research, really, really strong effects. So unusually strong. So hexadecanal lowered aggression in men, and we were like, cool. And it's a really loud noise. So you're also wearing earphones. It's 90dB and it's a screeching, horrible sound. It's sort of what we were hoping to see. Consistent with the hypothesis, it's the most punishment that an IRB committee will let you endure on a participant in an experiment. Unless you're in Stanford 70 years ago, or whatever that was.

No one's referring to the classic prisoner experiment, which took place in the building next door to where I work, by the way.

And consistent with it seems to do in mice. But then we looked at data from women and hexadecanal increased aggression equally significantly.

Is this thought to be something related to maternal protectiveness?

We're getting there. So you. You got there really fast. It took me a year, but. And Eva got to it, really, I'll tell you. So you can blast the other parts participant with varying levels of sound. And you have a selection box from something very low to something very high. Because remember, we're reaching the back of.

The head of your.

Of. Of whose was it? Grandchildren. And what's nice about this is that then allows you to quantify aggression because the more volume you're blasting the opponent with, the more aggressive you are towards your opponent.

The Charles, one of the king pins of the New York neuroscience mafia.

Yes. So. So this was really odd to me at that time. And so I didn't have the intuition component. And. And so you have a measure of aggression again, the Tyler aggression paradigm, obviously invented by. You just had. And I was like, eva, this. There is some bug here. I mean, this, this. It makes no sense to me. You know, why would something increase aggression in women and decrease aggression in men? This is really, really strange. And Tyler very well validated, studied all over, you know, a very standard protocol. And I said, okay, I want to see this happen again before, you know, we go ahead with this. 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 made men less. So we brought in participants and had them play the Tyler or the tap, either under exposure to hexadecanal or control. Now, hexadecanal doesn't. It's incredibly difficult to even detect hexadecanal. But just in case aggressive and women more aggressive. And the extent of more than the effect alone, the dissociation was remarkable. It's almost like a chromosomal test. I mean, you look at the Data on the unit because it's not very, very, it's considered a semi volatile, it doesn't have a strong smell unit slope line. And all the men are below and all the women are above. There's this figure in the paper. Then she also looked at the brain data. And this is, you know, although our lab does a ton of fmri, it's one of the major tools we use to measure brain activity. I'm quite cognizant of the limitations of fmri, but we buried it, both the control and the hexadecanalyn in a control order that hid them in a mask. And she ran lots and lots and lots and lots of participants, men and women. And I'll first tell you the result with men, which is that hexadecanal consistently reduced aggression. And this is I think, sadly, I think the only study in my career, at least, where I actually managed to also get a mechanism out of fmri, not only an area that's involved in activity. And so here's what we saw. That hexadecanal alone increased activity quite pronouncedly in an area people were less aggressive under hexadicanal. The effect size was of the brain known as the left angular gyrus. Now this is an area involved in what's referred to as social appraisal. So that was kind of cool in that a social order activated the social brain, not the was quite meaningful. And later on we learned because I'm no special factory system per se and very pronounced. So on one hand that was cool. But then what was uncool was that it did the same in men and women. And this was in the world of aggression. But compared to effects seen in the aggression world in research, really, really strong effects. So unusually strong. So hexadecanal lowered aggression in men and we were like cool. This was in contrast to behavior which you don't like seeing, right? I mean, because you would expect brain activity to reflect behavior and it increases sort of what we were hoping to see. Consistent with the hypothesis, increased activity in the left angular gyrus in both men and women. But then she did a follow up analysis which was look at what's referred to as functional connectivity. That is how does this region of the brain talk with the entire brain as it were under hexadecinal versus and consistent with it seems to do in mice. But then we looked at data from women control and here the dissociation reemerged powerfully and hexadecanyl increased aggression equally significantly.

Is this thought to be something related to maternal protectiveness.

We're getting there. So you. You got there really fast. It took me a year, but. And whereby the connectivity from the angular gyrus was most. And Eva got to it really, I'll tell you to the classic neural substrates of aggression. So the amygdala and the temporal pole and the connectivity went in opposite directions in men and women. So hexadecanal increased functional connectivity in men and decreased it in women. So in a way, this is because, remember, we're reaching the back of the head of your. Whose was it? Grandchildren. Charles.

The Charles. One of the kingpins of the New York neuroscience mafia.

Yes. So. So this was really odd to me at that time. And so I didn't have the intuition was saying that the default brain reaction is aggression. Right. The default is to aggress. And in men, hexadecanal increases the control that the left angular gyrus is holding over your aggression and keeping you back. And in women, it let it roam free and they became more aggressive. But I was still just had. And I was like, eva, there is some bug here puzzle. So I was convinced this happened twice. The MRO data provided not only a pattern, but a mechanism, which is unusual. And yet I was telling Eva, but 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. I mean, this, this. It makes no sense to me. You know, why would something increase aggression in women and decrease aggression in men? This is really, really strange. And. And I said, okay, I want to see this happen again before, you know, we go ahead with this. So she went and did the entire experiment again. And this time she did it within the FMRI magnet so that we. 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 we can also track brain activity while this was happening. And first of all, it replicated again. So once again, hexadecanalam made men less remembered. A recently published paper from a group in Japan that looked at the odors emanating from aggressive and women more aggressive and the extent of more than the effect alone. Baby heads. We now come full circle to Zucker's grandchildren. They used a method known as gcms, gas chromatography, mass spectrometry. The dissociation was remarkable. It's almost like a chromosomal test. I mean you look at the data on the unit to measure the volatiles from baby heads because baby head odor is a cultural thing across cultures, even in Japan. And so we quickly went to that paper and to see if one of the molecules that report is hexadecinal. And we were very disappointed that it wasn't one of the molecules that reported in the paper. And so we wrote to the authors who are since unit slope line and all the men are below and all the women are above, there's this figure in the paper. Then she also looked at the brain data and this is, you know, although our lab does a ton of fmri, it's one of the major tools we use to measure. And our co authors and we said, look, we're studying this molecule hexadecanal, and we don't see new results. And we were wondering maybe you had some results that you didn't publish or some somehow brain activity. I'm quite cognizant of the limitations of fmri, elementary materials or whatever. And this lab, which is a hardcore GC lab said, no, no, hexadecanal is a semi volatile, which we knew. And our previous paper was not directed to the semi volatile range. But we can now do use what's called gcx, gcggc, that is directed at semi volatiles. And we can do this again. We just studied 11 babies and we can see if this is an issue. So he said, yeah, please do. The bottom line of all this is that hexadecanal is the most abundant semi volatile in baby hits. It's tons of it coming out of baby hits. So babies again, speaking about if humans do or don't chemosignal babies are. And this is, I think, sadly, I think the only study in my career, at least, where I actually managed to also get a mechanism out of fmri, not only an area that's involved in activity. And so here's what we saw, that hexadecanal alone increased activity quite pronouncedly in an area 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.

Incredible. This is somewhat different than what we're talking about and yet similar of the.

Brain known as the left angular gyrus. Now this is an area involved in what's referred to as social appraisal. So that was kind of cool in that a social order activated the social.

Brain, not the in other ways because it's built off of anecdotal evidence, but it's anecdotal evidence that you hear all the time. And yet when you look in the scientific literature, at least by my read, the data are not clear, maybe even contradictory. And that relates to the coordination of menstrual cycles among co housed women or women who are friends. The, you know, many women listening to this and maybe some men who are aware of this effect will say oh yeah, absolutely, when I spend time with my friends or go away camping or even spend a day with them, our menstrual cycles become coordinated. However, my understanding is that the early literature, Barbara McClintock, correct, discovered this phenomenon, published a paper in Science as an undergraduate 1971.

Nature Olfactory system per se and very pronounced. So on one hand that was cool, but then what was uncool was that it did the same in men and women. And this was in contrast to behavior which you don't like seeing, right? I mean because you would expect brain activity to reflect behavior. And it increased activity in the left angular gyrus in both, both men and women. But then she did a follow up.

Analysis, amazing Nature paper again one of the three apex journals and as an undergrad. Fantastic. So discover this, describe this and probably women all over the world who became aware of this one way or another probably said yes, absolutely.

This gives validation which was look at what's referred to as functional connectivity. That is how does this region of the brain talk with the entire brain as it were, under hexadecanal versus what.

We'Ve observed over and over again. And yet as subsequent papers have been published this result has been called into question. Is there any final word on whether or not menstrual cycles become coordinated among women who spend time together? And if so, is there any role of control?

And here the dissociation reemerged powerfully with.

Olfaction in this or chemosensing through the nostrils and or mouth whereby the connectivity.

From the angular gyrus was most to support this idea. Yeah. So I'll start off indeed to echo the background to the classic neural substrates of aggression. So the amygdala and the temporal pole and the connectivity went in opposite directions in men and women. So hexadecanal Inkland is that this study was conducted by Martha McClintock when she was an undergraduate at Wesleyan College and she noticed that she thought her menstrual cycle and her co inhabitants in her dorm room were coordinated in time, increased functional connectivity in men and decreased it in women. So in a way, this is almost saying that the default brain reaction is aggression. Right. And I should say that this comes on the basis of similar or related type effects in rodents. Now, rodents don't have a menstrual cycle like humans do, but there's an effect in rodents referred to as the Witten effect, which resembles this type of effect. The default is to aggressive. And in men, hexadecinal increases the control that the left angular gyrus is holding over your aggression and keeping you back. And she published indeed that paper as an undergraduate in Nature in 1971. And to answer your question, she published a follow up in 1998, also in nature with then her graduate student, Chicago Stern. So this is Stern and McClintock 1998. And here's what they did. They collected sweat from donor women and deposited it on women. It let it roam free and they became more aggressive. But I was still puzzled. So I was convinced this happened twice. The MRO data, the upper lip of recipient women. So this would be a fun experiment, provided not only a pattern, but a mechanism which is unusual for you at least, because you said you like body odors. But for many others, perhaps it would be daunting.

Well, I like certain body odors from certain individuals. I don't, I don't think.

And yet I, I was telling Eva, you know, but, you know, this makes no sense to me. And then, and then her insight.

Yeah, uniformly like all body odors, although I do seem to uniformly not like the smell of perfume. Although I should. Just to clarify, because I put this out there, and I learned the hard way in the comment section on YouTube, some of those perfumes I find downright aversive. Yeah, like it's a. I think the great Marcus Meister, who great neurobiologist once said there's basically three responses. It's either yum, yuck or meh. So some I are truly.

I never heard that one kind of like that one.

Right. In terms of the animal behavior, human behavior, we're either a move forward, back or, or, or pause.

Which of course afterwards is like, duh. It is. No, there's a place where this makes sense, 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.

So some are truly a yuck. Some many are meh0.

And maternal aggression is often protective. So if you're an offspring, if you.

Have to date, are yum for me. Now, body odors, the distribution has shifted. It could be any one of those three. Yum, yuck or meh. So just to be clear, but the, the yum category is definitely included. Thank you for, for allowing me to do that.

So so, so, so she did this study. So so, because right in the original 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 we remembered a recently published paper from a group in Japan that looked at the odors emanating from a Clintox study. You might suspect other drivers of the effect. Baby heads. We now come full circle to Zucker's grandchildren. Let's say you accept the effect, but still there might be other social drivers of the effect that are not body order. Right. There might be some dominant woman who's dominant in some other way, and this might be driving the coordination. They used a method known as GC Ms. Gas chromatography Mass spectrometry. Right. So here there was no direct link between these women other than body odor. So if the effect reemerged to measure the volatiles from baby heads, because baby head odor is a cultural thing, it would definitely be an olfactory effect. And what she found is that if she took cross cultures, even in Japan. And so we quickly went to that paper. Sweat from the follicular or the ovulatory phase of the donors. One extended the cycle in recipients and one shortened the cycle in recipients. I don't remember which was which, but basically to see if one of the molecules that report is hexadecinal. And we were very disappointed that it wasn't definitely denoting a chemo signaling effect with opposing effects on duration based on the time it was collected from. Again, published in nature in 1998. That said, there's a quotation, I think this is one of the molecules they reported in the paper. And so we wrote to the authors who are since then, our co authors, and we said, look, we're studying this molecule hexadecanyl, and we don't see in your results. And we were wondering maybe you had some results that you didn't publish or some supplement from, I'm not sure, but supplementary materials or whatever. And this lab, which is a hardcore GC lab, said, no, no. Hexadecanal is a stem that if something is published in Nature or Science that doesn't necessarily mean it's not true. So with that in mind the findings were since called into question. Why semi volatile which we knew and our previous paper was not directed to the semi volatile range but we can now do use what's called GCX GC double GC that is directed at semi volatile as it One reason is just statistics of cyclic events are surprisingly complicated and we can do this again. We just studied 11 babies and we can see if this is an issue. So he said yeah please do so it's tricky. Once you have a cyclic event statistics become tricky. And so she so Martha took a lot of the bottom line of all this is that hexadecanal is the most abundant semi volatile in baby hits heat on the statistics of claiming an effect and I think there was at least one effort of replication that didn't really work out. If you it's tons of it coming out of baby heads. So babies again speaking about if humans do or don't chemo signal babies are conducting chemical warfare. Right. They're ask me I'm on the fence but I may be in a minority in my field 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. I think a majority in the field is currently negative. I'm not and we've said in lab that we should do a planned replication. We will again it's a horrible study to run. It's tons of work and you have to run it for a really long time and so it's just completely non trivial but we have incredible this is.

Somewhat different than what we're talking about and yet similar in other ways because it's built off of now in lab.

Interested in these exact things Root Weisgross and she's doing similar stuff and I hope we'll do that I hope we'll try to to replicate this very interesting.

Result and I think interesting because of its real world anecdotal evidence but it's anecdotal evidence that you hear all the time and yet when you look in the scientific literature at least by my read the data are not clear maybe even meaning outside the laboratory of course or experiment analog but also because.

Pheromone.

Effects and olfactory effects in humans seem unique among neurobiological endocrine phenomena because there seems to be so many stories that we all have of the smell of our grandmothers and contradictory and that relates to the coordination of menstrual cycles among co housed Women or women who are friends, many women listening to this and maybe some men who are aware of this effect will say oh yeah, absolutely. When ice pans or the recognizing the scent of somebody or I knew from the moment that I smell bentime with my friends or go away camping or even spend a day with them, our menstrual cycles become their breath or I just liked their smell kind of thing. These kind of things that inform the deep potential for a real biological phenomenon as opposed to the kind of thing like oh, you know, you just throw something out there. Oxytocin is bonding and all of a sudden coordinated. However, my understanding is that the early literature, Barbara, you know, the general public, not at no to no fault of their own, comes to think that every, every aspect of Bond Clintock.

Correct.

Discovered this phenomenon. Published a paper in Science as an undergraduate, 1971 Nature, amazing Nature paper again, one of the three Apex journals and as an undergrad. Fantastic. So discover this, describe this and probably women all over the world who became aware of this one way or another probably said yes, absolutely. This gives validation is oxytocin. And every defect in bonding is lack of oxytocin. But the general public provides a sort of a rich. It's fodder for exploring all these things and a lot of times they turn.

Out to be true.

Right.

In the context of what we've observed over and over again. And yet as subsequent papers have been published, this result has been called into question. Is there any final word on whether or not menstrual cycles become coordinated among women who spend time together? And if so, is there any role of olfaction?

Yeah, no, it's a very primal system.

So it's olfaction in this or chemosensing through the nostrils and or mouth linked.

To the most limbic primal mechanisms in our brain and it drives primal behavior.

It's an incredible system. I have a question about a particular study, but I'm just going to queue it up and you'll know immediately what I'm queuing up. And that is what is the relationship to support this idea.

So yeah, so I'll start off indeed, to echo the background is that this study was conducted by Martha McClintock when she was an undergraduate at Wesleyan College.

Between odors and hormones and in particular crying.

As I pointed out previously, the sort of flavor of the month in human social chemo signaling research is the smell of fear. And she noticed that. She thought her menstrual cycle and her co and the media of the month is sweat, right? So the few, maybe tens of labs in the world that study human social chemo signaling, all inhabitants in her dorm room were coordinated in time, collect sweat. And that's the media they look at.

Is it always from the armpit or is there, are there meaningful differences in terms of the sweat emitted from different locations on the body? I already know the answer to that, as I ask it, but let's just stay above the waistline and. Oh no, no, yeah, or below the waistline. I mean we're biologists after all.

And I should say that this comes on the basis of similar or related type effects in rodents. Now rodents don't have a menstrual cycle like humans do. But. But we just. Yeah, so it's funny, we're working on a paper, there's an effect in rowdence referred to as the Witten effect, which resembles this type of effect around that right now on the smell of fear. So we have a nice paradigm for generating fear. We throw people out of airplanes. It's a very effective way to generate.

Fear to come to your lab. It sounds like greatest lab in the world.

We, we didn't invent that by the way. The first to do that was, and I hope I'm pronouncing her name correctly, I think it's Mujika Perudi. But, but that's our paradigm for generating fear. And we started that on our. And she published indeed that paper as an undergraduate in Nature in 1971. And to answer your question, she published a follow up in 1998, also in nature with then her graduates own. But we've since entered into collaboration with the Israeli Paratroopers Brigade and students at Chicago Stern. So this is Stern and McClintock 1998, and here's what they did. They now collect body odor from every first time jumper. So we went that path because we like everybody else in this field, you know, the holy grail there, they collected sweat from donor women and deposited it on. This is finding the molecules, right? I mean, if you'll have the fear molecules, that's a bonanza, right? Because I mean, you know, you can think of many reasons why it would be a bonanza. But for me, you know, if you find the molecules, you can then try and find the receptors. And when you find the cognate receptors, you can then develop blockers and you can imagine, you know, the upper lip of recipient women. So this would be a fun experiment for you at least because you said you like body odors. But for many others, perhaps it would be daunting. What's the term I'm looking for? I'm switching into Hebrew. It's about midnight now, right? I'm sorry, it's 2 in the morning.

You're doing incredibly well considering the inversion of the two in the morning. We would never know. No one traveled in today from Israel. So he's a circadian inverted, as we say, anxiety.

So you can imagine developing a nasal spray against anxiety, right. Where you would quell those receptors and kill the fear response, which rather than going the current path, which is through neurotransmitters that then have effects all over the place, you would be getting fear at its source. So that would be why I would want that. And we figured out that doing that, you know, collecting fear from like three, four, five people in an experiment, you'll never be able to do analytical chemistry on that. So we now have, we have a setting we call FearBank, which now has more than a thousand samples in it. So we're trying to do analytics on that. But, but in doing that we've, we've joined.

Well, I like certain body owners from certain individuals. I don't, I don't think I uniformly like all body odors, although I do seem to uniformly not like the smell of perfume. Although I should just declare by, because I put this out there and I learned the hard way in the comment section on YouTube, some of those perfumes I find downright aversive. Yeah, like it's. I think the great Marcus Meister, who a great neurobiologist once said there's basically three responses. It's either yum, yuck or meh. So some are truly.

I never heard that one. You know, the crowd, everybody's doing fear and everybody's doing sweat. And in one of our discussions in Latino.

I like that one.

Right.

In terms of animal behavior, human behavior, we're either a move forward, back or stop or pause. So some are truly a yuck. Some, many are meh. Zero.

We were saying, well there's got to be or there potentially definitely could be additional bodily media that are playing into social chemo signal. Now many of these, you know, you can't really study.

Right.

I mean, so you know, just to throw it right. Most terrestrial mammals communicate social information through urine. But you know, starting doing experiments with.

Humans to date are yum for me. Now body odors, the distribution has shifted. It could be any one of those three. Yum, yuck or meh. So just to be clear.

But the yuck smelling urine, it would be difficult, you know, both in IRB.

And In agreement and category is definitely included. Thank you for allowing me to do that.

So she did this study. So because right. In the original, you know, and then we, you know, this is a rare case where we actually hypothesized what we sought to do and did only claim in retrospect that it was hypothesis is tears. We started thinking about tears and looking into tears because tears are a bodily liquid. Emotional tears like Lintock study, you might suspect other drivers of the effect that we emit in emotional situations where these are situations where non verbal communication, let's say you expect you accept the effect. But still there might be other social drivers of the effect that are not body order. Right. There might be some dominant woman who's dominant in some other way and this might be driving the coordination is critical and key. And tears are a liquid that is puzzling beyond. Right. So here there was no direct link between these women other than body order. So if the effect reemerged fund ocular maintenance. Right. And so, you know, 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 6 is devoted to tears. An entire chapter of this book. Why? With no conclusion. Why? Because the book revolves around describing the functional antecedents of emotional expressions. It would definitely be an olfactory effect. And what she found is that if she took sweat from the follicular or the ovulatory phase of the donors, one extended the cycle in recipients and one shortened the cycle in recipients. I don't remember which was which, but basically. So for example, showing of the teeth is a sign of aggression. Right. So animals first bit with their teeth. And Darwin argued that through evolution just showing the teeth alone, but definitely denoting a chemo signaling effect with opposing effects on duration based on the time it was collected from again published in nature in 1998. That's it. There's a quotation. I think this became an aggressive sign because it started from biting or what I find is a beautiful example and this is work partly done by Adam Anderson now at Cornell, is the emotional expression of disgust. So disgust, which comes from the line disgusia distaste is spitting something out of your mouth. Now what from, from. From, from. I'm not sure, but. But you know, what Adam showed is, is that the musculature patterns of activation and the temporal sequence of activation when you experience moral disgust are the same as when you spit a bitter taste out of Your mouth. Right. So again, so there's a functional antecedent spitting something out. And through evolution the argument was that if something is published in Nature or science, that doesn't necessarily mean it's not true. So with that in mind it became an expression of emotion. And you express disgust just as if you're spitting something out of your mouth. Even though in the case of moral disgust there's nothing you're spinning out of your mouth. So darn systematically went through the. The findings were since called into question quite widely. One reason 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. It's just statistics of cyclic events are surprisingly complicated antecedent. So he ended up saying this is an epiphenomenon basically. Right.

I don't know what all scientists do when they don't have a good explanation. Blame it on nature.

So it's tricky once you have a cyclic event statistics period. Right, right. But he bothered to write this entire chapter on the ocular sort of meat become tricky. And so Martha took a lot of heat on the statistics of claiming an effect. And I think there was at least one effort of replication that didn't really work out. If you ask me, I'm on the fence, but I'm maybe in a minority in my field. I think a majority in the field is currently negative. I'm not. And we've said in lab that we should do a planned replication. We will. Again, it's a horrible study to run. It's tons of work and you have to run it for a really long time. So it's just completely non trivial. But we have a graduate student now in lab interested in these exact things. Root Weisgross. And she's doing similar stuff. And I hope we'll do that. I hope we'll try to replicate this very interesting result.

And I think interesting because of its real world meaning outside the laboratory. Of course our experiment analog. But also because pheromone effects and olfactory effects in humans seem unique among neurobiological endocrine phenomena. Because there seems to be so many stories that we all have of the smell of our grandmother's hands or the recognizing the scent of somebody or I knew from the moment that I smelled their breath or I just like their smell kind of thing. These kind of things that inform the deep potential for a real biological phenomenon as opposed to the kind of thing like oh, you Know, you just throw something out there. Oxytocin is bonding. And all of a sudden the general public, to no fault of their own, comes to think that every aspect of bonding is oxytocin and every defect in bonding is lack of oxytocin. But the general public provides a sort of a rich. It's fodder for exploring all these things, and a lot of times they turn out to be true. Right, in the context of olfaction.

Yeah. No, it's a very primal system. So it's linked to the most limbic primal mechanisms in our brain and it drives primal behavior.

It's an incredible system. I have a question about a particular study, but I'm just going to queue it up and you'll know immediately what I'm queuing up. And that is, what is the relationship between odors and hormones and in particular, crying.

As I pointed out previously, the sort of flavor of the month in human social chemo signaling research is the smell of fear. And the media of the month is sweat. Right. So the few, maybe tens of labs in the world that study human social chemo signaling, all function of tears and so on and so forth, but nothing emotional. So we thought, well, maybe the function is we harvested emotional tears, which was also an amusing event on its own, right. Because we, we posted messages on all sorts of boards that were seeking experiment participants who cry with ease. Now, this generated an unfortunate gender bias in our study, right. Because we received about 100 women volunteers and about one man. And, you know, I think this is not a problem. Only in macho Israel. Right. Probably anywhere in the west, this, I mean, definitely in America it would be the same.

I think my guess is that there are probably men out there who cry easily. Emotional tears, easily. Oh, I'm sure. But they're not going to show up.

Yeah, yeah, that's what I'm saying. It's a cultural thing. It's not, you know, you're not going to come to a lab and say, you know, I cry all the time. It's just not going to happen. And then what we did is for each one of these participants, you know, we would ask them, you know, is there a particular film event that you know of that you know, a scene that makes you cry? And interestingly, in these effective criers, there's always, oh, yes, you know, the scene in. In so and so. I always cry profusely from that. You know, they, they have.

Can you give me an example of one of the more commonly named scenes?

Yeah, with ease.