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

26:47So 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, you know, 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.

27:20But 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 tone. I'm the last to argue that there's something special about olfactory. 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.

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29:10When 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 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, everybody. 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.

30:02And my understanding is that people can improve their ability to track scents quite robustly, especially if we deprive them of vision and somatic sensation, that is touch and some other sensations. Maybe you could just tell us a little bit about that study. And, um, and for, I think in our audience, I'm suspecting that many people have a keen, keen sense of smell. Very, I have a family member who just like detect any negative, you know, putrid odor in the environment, but also good odors, um, exquisitely well. And I, I have other family members whose sense of smell is quite poor. Um, 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.

30:51And 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 all news. But to people who come from different worlds, we have to reiterate this. Sometimes when I give public lectures to non-olfaction audiences, I reiterate this. humans have an utterly remarkable sense of smell. To put that a bit into sort of, you know, things that are tangible. So for example, mercaptans, which are added to cooking gas so that we smell it because otherwise it wouldn't have a smell.

31:33So 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 a notarant in our lab called estratetraenol 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.

32:18If you would take two Olympic-sized swimming pools and you would pipette one ml, 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 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 factions.

32:51And beyond that, we can improve. And the example you're talking about actually started off as a lab bet. We were having a lab picnic. So I guess I should hear Phil 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 Wills 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 can truly even track odor like a dog and people there said no way.

33:31and 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 Zolano, 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? Did you place her at the starting point of the line?

34:11I think we did. I don't exactly remember what we did on that sort of picnic tryout. But, you know, I assume she'd 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 bed in a way that I said to my students, we have to make this into an experiment, put it 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 won in this case. Nature, of course, being one of the three apex journals. It was nature neuroscience, to be fair.

34:51But so then we turned it into an experiment. And what the experiment was is that we brought in participants, naive participants, not graduates from our lab, completely deprived them of any other sensory input. So we blocked their eyes, we blocked their ears, we blocked everything. We blocked where they were wearing heavy gloves. You know, 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 itself?

35:33It 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.

36:18The second thing we found is when we trained them up, then within average of four 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.

37:14and 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. But - So a representation on both sides of the brain, much in the same way we have two eyes, we're not a cyclops.

37:52We 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 the head blocks them between. That's 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 long draw in inhale? So yes, we were measuring sniffing and recording it, and we have all the data.

38:40there 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 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 lab. And it's taking us to places and it's reemerging now in our work.

39:25We'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'll invite you to do the following experiment. So occlude one nostril by pressing on it from the side and sniff in, and then occlude 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.

40:07So 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 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.

40:52So 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. It 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.

41:35The sexual arousal response and a number of other aspects of our physiology. So think of it like a seesaw of alertness and calm. 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 eye cycle, 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.

42:07You 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 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 Team Nassaroka, a graduate student in our lab now.

42:52So 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 are 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 um periodicity um 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.

43:37Is 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 the 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, right? Cause I get this, my lab does do some stuff on, on breathing and the yogis are always saying, okay, you know, cause there's this thing, I don't do yoga anymore, but not for any particular reason, but, um, where they'll have you breathe through one nostril or the other.

44:18And I've, I've probably been asked this question on social media, 10 ,000 times. Okay. I'm going to become public enemy. Number one of the yogis right now. So listen, we, so we, 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 like really serious yoga practitioners and see if they can shift their nasal cycle from left to right by will alone, right?

44:54Not 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 experiments. A lot of sandalwood odors and bare feet. White clothing and so on. And so we studied, I actually know, we studied 14 yoga teachers. All 14 by, you know, by the conditions of enlistment for this came in saying that they can control shifting from left to right nostril. Without plugging a nostril with your finger.

45:39Yeah, yeah, by the power of thought alone. And you know how many of 14 succeeded? Zero. 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're 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?

46:18Yeah, 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 none of them can do it. Given that the alternating flow through one or the other nostrils 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.

46:50In other words, is the unilateral smelling or unilateral nostril smelling periodicity, there when we named it something, I named 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 aim two 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.

47:36We 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 two degrees Celsius water. But there'll be participants who will pull it out at like 10 seconds, nine 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, to 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.

48:16So 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 chlamaroli, but you have a mirror representation of that on both sides of the brain, and that most of that information is kept on one side of the brain or the other.

48:53There 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.

49:28It's 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? I don't think that the nasal cycle is an olfaction story. So I don't think 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.

50:34And 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, right? 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 that it processes information on inhalation onset.

51:26So a study led by Ofer Perl 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. And 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 visual spatial 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.

52:12So some of them were these like usher shapes, like where one facet doesn't reach the other facet. The impossible figure type. Yeah, but structural shapes. And 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.

53:01So 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. Yeah, and this idea that people who mouth breathe experience more colds, more infections of various kinds, it's not good aesthetically or for the dentures, dentature, I never know, the teeth, gums, it's stuff, folks. Sorry, 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 breathing. So I think it's also good for your cognition, not only for your dental health.

53:41I think that nose breathing shapes cognition. And there are other labs who are finding the same. Again, Cristina Zelano is doing work on this line. She had major contributions here. And Johan Lundström 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, that 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, you know, your eyes are two pieces of brain extruded from the cranial vault, which they are, the retinas anyhow.

54:34And then you never look at anyone the same way again. And it's, but the olfactory sensory neurons are right there at the top. So 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 a loss in the sense of smell probably 10 years before any other symptom.

55:29But people have failed to make this a diagnostic tool because it's nonspecific. 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.

55:51But 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, as it's a little more invasive than what you're describing.

56:42I'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 were talking about, something completely non-invasive and could be relatively pleasant to innocuous, depending on the odors used. So, yeah. So, so first I can answer that, right?

57:14And 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, a hundred 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.

57:48In 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.

58:32The older one is a test called the UPSIT, which stands for the University of Pennsylvania 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 four deodorants. So you have these 40 pages that you page through and you sniff and smell and 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 every time we buy UPSITs in the lab, I say there's another gallon of gas into Richard Doty.

59:15He races NASCAR? It's not like NASCAR, but like one lower than that. Like, I don't know, like some sort of Formula A or Formula Ford or something. He races a car. And so that's where all the UPSITs went. So I always feel good about buying UPSITs because I know they're going to that good cause. Keeping him in the fast lane. So that's one test that's out there. And indeed, you know, it has been shown as a, you know, so there's reduced UPSIT 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 that one isn't scratch and sniff it's like these pens that you open up and sniff but those exist They're not as convenient as delivering stimuli in vision and audition, and that's why you don't have what you've just suggested.

1:00:14You know, another thing, another place where you don't have it, which, which I think is even more, would have been even more meaningful is, 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 a 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.

1:00:57But what do you think the average age of diagnosis is for congenital anosmia? Five years of age. 14. Incredible. 14. So most people who are one half 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.

1:01:48So this is work out of Ilona Kroi in Germany. And amongst the various things that are predicted by anosmia is shorter lifespan. but things like, you know, 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 or nostrils. Very rare, very rare. We don't focus on that because it's exceedingly rare. But they're born with noses and nostrils. And here's the thing, right? 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.

1:02:42Or 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 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's 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, So 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.

1:03:37So 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 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's a female equivalent of Kalman's or I don't remember its name. It's not in the Turner syndrome family.

1:04:33I'm not sure. And I think it's also associated with anosmia, but I'm not confident of that. But Kalman's is associated with anosmia. So the answer is yes. And, you know, we can maybe, you know, olfaction and reproduction are tightly linked. 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 have a story slash question that I'd like to tell you, ask you as a segue to that. Noting, of course, that we'll get back to the requirement for olfactory bulbs, yes or no for olfaction.

1:05:19and 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 it 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 those things like kid 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 all, there's this clothes, like someone left us here.

1:05:58I don't know who it was. We were all more or less the same size. And from the, 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 that's Scott Madsen shirt. I, 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, if I had pretend 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.

1:06:39Okay. 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 already put that out there right I have no idea why why human nature has has or nature or culture or whatnot has has pushed this into the realm of 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.

1:07:41One of them you may be familiar with that had gained some notoriety because it's amusing. So we look at human behavior a lot. We try to look at it through our nose in the way we look at what people are doing. We try to think, if I was a dog, what would I think of this? And, you know, if you look at dogs, right, 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, we're sort of obliged to sniff our babies. That's considered almost something you're supposed to do.

1:08:28And 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. It's almost everywhere. and there's really poor understanding of how this behavior evolved. Like where did this thing come from? So if you look for the Wikipedia version, right?

1:09:09Then 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 Trillian bloodhound receptor story, right? I mean, we tried to find it. Why do people say that? 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, Gnome is taking his hand and wiping it on his face. Grabbing his nose or touching the side of his cheek. Yeah, these things that we do all the time.

1:09:45After a handshake. Well, so first of all, we do them all the time, just period, right? The baseline here is really high and we'll get to that in a second. But these behaviors that, you know, you could easily not notice, right? And so we asked whether that's a real thing. And this was a study led by Dan Fruming in our lab at the time. 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. We'll put it in the show note captions as a link on YouTube and the other four platforms, Spotify, Apple.

1:10:27So 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.

1:11:06And 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. Okay. And then three minutes later, an experimenter would walk into the room and would share a consistent text. It would be, you know, we're still setting up our equipment in the other room. 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.

1:11:43And in half of the cases, it included a handshake. This was a new experimenter, not the one who put them in the room. So that's the first time they met. So it'd be a low, I'm, you know, so-and-so, they would put out their hand and shake their hand or not. 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.

1:12:17And 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 participants, we measured nasal airflow. And people not only bring their hand to their nose, they sniff it. So, and this is perfectly timed. They go like this. Okay. So they're sniffing their hands. 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.

1:12:53And 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, were 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 they were sensing the ambient odor that came in with the hand that shook and then that either drove them to sniff their hand more or less.

1:13:32The odor cloud of the experimenter. 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. a study we published just last year by Inbal 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?

1:14:21You immediately become close friends. And this is a phenomenon that, you know, 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?

1:14:56And Inba's theory was that a similarity in body odor may contribute to this, that people who smell the same will click in some way. And so to address that, she actually recruited click friends from all over Israel. She posted all over social media to identify 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 clique, right? Later on, we discovered there could be one-sided cliques. So somebody is sure they clicked with somebody else, but the other person...

1:15:40There'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. They could be. You know, what do you think of 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.

1:16:17If 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. So they're given, you know, odorless shampoo and soap to use for three weeks or something. And then they sleep two nights in this T-shirt where they have to sleep alone. And then we extract the body odor from the T-shirt. And so we have a way to extract, a method to extract body odor. And then she first asked whether indeed click friends are more similar in their body order than you would expect by chance.

1:17:03And she first tested this with a device, a machine we call an electronic nose. So an electronic nose is sort of a very poor effort to mimic what the mammalian nose does. Basically, it's a bunch of sensors that respond to airborne molecules. In this case, sensors referred to as moxers, as metal oxide covered sensors. and so she used an electronic nose to sample these body odors and she found that click friends are indeed more similar to each other than you would expect by chance by random dyads and this was a significant difference and after she found that a device could do this she had other participants do this so so she had people smelling the click friends versus non-click friends and and they judged them as being more similar to each other than not.

1:17:51Now, 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, 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.

1:18:31The one that didn't, so she predicted that people who 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, And the interaction was completely nonverbal. They were not allowed to speak with each other. And she did an entire round robin. So everybody played with everybody else. This was an insane experiment to run. 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.

1:19:06Okay. All of this was predicted by the electronic news. 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.

1:19:47I'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 Lowe. So in America, this won't pass that effectively, but in the rest of the normal world, Joachim Lowe 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, you know, 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.

1:20:33It'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. Well, then 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.

1:21:20So 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 histocombatibility complex, which reflects immune diversity, the immune system that is most distant from theirs. And 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.

1:22:16In other words, whereas you've described 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. in the Wedkind lab, and also Porter.

1:23:03I'll email these to you later on. that have done a lot of this work and find 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.

1:24:02So 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.

1:24:49Most terrestrial mammals have another subsystem referred to as the secondary olfactory 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, vomeronasal receptors. and this is linked to a sort of separate portion of the olfactory bulb, not really the main olfactory bulb, but what's referred to as the accessory olfactory bulb.

1:25:38And 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.

1:26:22This was an effect discovered by Margaret Bruce in 1959. She was a British scientist. And 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 odor of what is referred to in technical terms as 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.

1:27:08And 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 remarkably robust effect, this dropping of the pregnancy. And we know it's mediated by chemo sensation through the nose. We know 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.

1:27:53But 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, then the effect disappears. So the effect is completely dependent on the vomeronasal organ. and I find this utterly a remarkable effect, right? I mean, because, again, because of 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 ovomarinasal organ. So we don't have that functional organ in our nose. Now I'll point out, we actually do have the pit.

1:28:42So 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 organs is the vomeronasal organ. It's also called Jacobson because I think Jacobson was a military physician in like the 1800s in Holland or something. And he found it in a soldier he was operating on or something like that. The story comes from something like that. But Jacobson organ is another name for the vomeronasal organ.

1:29:28These are one and the same. The sensory organ of the accessory olfactory system. And again, the going notion is that the human Jacobson organ or vomerine's 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 chemosyngolion 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.

1:30:04And I'll come back to that in a second. But first to finish the Bruce effect.

1:30:13And 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 post-mortem 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 post-mortem 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 study its tissue.

1:31:06So 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.

1:31:59So you're talking about one seventh of total gestation. So I'm not quick enough to, nor is it important to translate, but this would be first trimester in humans. Yes, which is indeed 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, right? This can occur, you know, in days one, two, nobody ever knows, okay? So some papers talk about 90 % of all human pregnancies end in miscarriage. This is counting a failed implantation in day one, two, et cetera.

1:32:40More conservative studies talk about 50%. Nobody will argue 30%. Okay, so a huge number, a huge number of human pregnancies end in miscarriage. Now, out of these, there's a portion that are unexplained, right? So nobody knows why. I mean, there are portions 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 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.

1:33:38So 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 like 12, 5, you know, so this is an emotional, difficult place to be. 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, you know, genetic incompatibilities and all sorts of issues, clotting, all the known suspects for pregnancy loss.

1:34:26And the medical establishment remains totally at a loss as to why these pregnancies aren't holding. And so we hypothesized that perhaps here there's something akin to a Bruce type effect. Obviously, it's not going to be the same 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 seek 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 odor in the couples experiencing repeated pregnancy loss.

1:35:16And 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 clear memory of the fathering male. Because if she's going to miscarry 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. And in mice, this has been very well characterized and attributed to the anterior olfactory nucleus structure in the brain.

1:35:58But you'd have to have this memory in order to make that decision. Now, so to address that, and here you're going to see that you and your childhood story from before stand out a bit as skillful, is that the first thing we did was just behaviorally test whether 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 you would think that women would be good at identifying the body odor 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 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 odor.

1:37:12With much greater acuity than the typical person? Double. A bit more than double. And way above chance. 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? 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 odor. 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 your statistics to look at one part of the brain.

1:37:58You're just looking at the entire brain in the response to male body odor and asking de novo, there are differences 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 odor between the two groups.

1:38:19So olfaction is altered in 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. Incredible. I can't wait to hear the results of that. It's going to take, it'll probably take years, a few. Because these are slow experiments to run. Recruitment is complicated. but basically we're blocking smell 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, you know, whether or not it's a classic pheromone effect or whether or not it's olfaction or something else.

1:39:21This is chemosensory 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, actually who work on animal models, really came after me with, you know, intense sniffing saying, you know, 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 are contained and are emitting chemical signals that influence each other's physiology and behavior.

1:40:01For sure. For sure. And the term pheromone is a problematic term in any case. I mean, the term was put forth to describe insect behavior, right? So, you know, if you were given a hard time by the mouse people, you could have given them an equally hard time if you were an insect person, right? Because really the place the term 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.

1:40:36Insect pheromone people will argue that this stuff that people talk about in mice and rats is not pheromones. And it all becomes semantics. Yeah, sort of like nerdy inside ball. It's all semantics. So in our publications, we don't use the term pheromone because it would not help me and it would probably 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. You know, and there are several examples of this. One of them I'll point out first, which is sort of the most widely studied and not mostly from our lab, actually.

1:41:20I 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. 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 odor when they're in a state of fear. And this body odor influences other humans, in effect, increasing their autonomic arousal, their sympathetic state. so in effect you could say that fear is contagious a bit so the smell of fear is contagious by the way culturally we know for ages that dogs can smell fear in humans but actually that was only really shown about a year and a half ago in a study so it was always said but it wasn't really shown effectively it was shown about a year and a half ago in the study the dogs indeed can smell human fear.

1:42:27And humans can smell human fear. So several labs starting from Denise Chen and Haviland Jones, and then in our lab and in other labs, if you collect body odor from people in a state of fear and collect body odor from the same people when they're not in a state of fear, other people can determine which is the state of fear or not. And this influences their behavior. What about the smell of safety? Or is that simply the absence of the odor corresponding to fear? And the reason I ask this is somewhat woven into our prior discussion about mate choice. Again, I'll ask the question in a form of brief anecdotes.

1:43:04I'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.

1:43:43If you're doing this, folks, other people are doing this, too. Yeah. 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 on and on and on. With all these insights, I would offer you to be a postdoc. Well, I was going to say, listen, I have a sabbatical coming up, so I would love to do a sabbatical. But it's going to kill me. No, exactly. You don't want me to work for you. We talked about this earlier.

1:44:15That's what I'm saying. For other reasons, exactly. There's a story there. What Noam is referring to, I'll just tell people because inside jokes on a podcast don't really work. Earlier, I was referring to 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 Noam's and I, turned to me and said, you know, Andrew, you're the common denominator.

1:44:49So, um, you know, the joke, 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 lab. So, so what I was trying to say in that roundabout way is that those are all really keen observations and good ideas, um, for sure. And, and, and they just highlight again, you know, that, that we're incredibly olfactory animals, you know, and, and, 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.

1:45:20And 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? I have to - We're very 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, I was in intense fear. I bit into a 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.

1:45:49I 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 grief. I'll tell you a sort of a throwaway line that I use in this one. 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. You eat the latter. Right. Now, imagine I offer you a mate.

1:46:39choose the gender of your liking, right? It 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.

1:47:27And 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. 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 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 that I raised from the time he was a puppy. and I imprinted on, I imprinted on his smell immediately.

1:48:10And even though to other people, it was a bulldog mastiff after all, his smell was rather aversive. To me, he smelled delicious, right? And it made me, 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. Yeah. A professor at Columbia has done incredible work in vision and olfaction and thirst sensing it. And I talked a little bit about this, that there's something in the breath of romantic partners that's hopefully appetitive, not aversive.

1:48:46As well as in children, he was talking about the smell of his grandchild, the back of their neck, and how he misses that smell because when he thinks about missing his grandchild or children, it's that smell that's associated with that feeling. Hexadecanal. Hexadecanal? Yes. Charles, your grandchildren smell like hexadecanal. Yes, they do. He's going to come after me now. They do. And so this is a study ran by Eva Michore, who was a graduate student in our lab.

1:49:21And Eva was interested in aggression. She was really into aggression. And actually when she started off, we said, okay, let's do chemo signaling of aggression. she actually was going to like MMA clubs and collecting body odors uh and we we had all sorts of ideas going and and she 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 uh from Germany I mean when I say colleague primarily a friend or acquaintance I met at conferences, Heinz Breer.

1:50:05And he was studying in his lab, a molecule, hexadecanal, 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. And in his work on hexadecanal, and so Breer and his colleague Stortzman, they discovered the receptor for this, and then they went and discovered that the receptor is very highly conserved throughout mammalian evolution.

1:50:58And 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 hypothesized that maybe hexadecanal, which promotes social buffering in mice, may do something in all mammals. Again, because this receptor is very highly conserved, OR37B, I think.

1:51:27So he approached us and said, look, you've 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.

1:52:08I'll soon describe it. And so we said, okay, 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 hexadec now? What's the tap experiment? So basically what you do 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, so connected. So you can fool them into being quite convinced that this is what's happening.

1:52:46And they go into their own room. And in the initial game they play, on each round, 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 against. and the computer algorithm is programmed to be in scientific terminology a jerk, right? So, you know, like let's say they have to divvy up 100 check-out, which is the Israeli currency. So, you know, the other player would say, okay, you know, I'll keep 96 and you get four, right?

1:53:31And then you can either accept it or not accept it and then neither of you get anything, right? 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? They're shafting you on every trial or 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.

1:54:12And it's a really loud noise. So you're also wearing earphones. It's 90 dB. And it's a screeching, horrible sound. 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, I was referring to the classic prisoner experiment, which took place in the building next door to where I work, by the way. 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. And what's nice about this is that it then allows you to quantify aggression.

1:54:46Because the more volume you're blasting the opponent, 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, you know, a very standard protocol. So we brought in participants and had them play the tiler of the tap either under exposure to hexadecanal or control. Now, hexadecanal, it's incredibly difficult to even detect hexadecanal. But just in case, because it's considered a semi-volatile, it doesn't have a strong smell. but we buried it both the control and the hexadecanal in a control order that hid them in a mask.

1:55:34And 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. People were less aggressive under hexadecanal. The effect size was quite meaningful. and later on we learned because I'm no specialist in the world of aggression, but compared to the 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 is sort of what we were hoping to see, consistent with the hypothesis and consistent with what it seems to do in mice.

1:56:19But then we looked at data from women, and hexadechnyl increased aggression equally significantly. Is this thought to be something related to maternal protectiveness? We're getting there. So you got there really fast. It took me a year, and Eva got to it really. I'll tell you. Because remember, we're reaching the back of the head of your, whose was it? Grandchildren? Charles Zucker. The Charles Zucker. One of the kingpins of the New York neuroscience mafia. Yes. So this was really odd to me at that time. So I didn't have the intuition you just had. And I was like, Eva, there is some bug here. I mean, it makes no sense to me.

1:57:01Why would something increase aggression in women and decrease aggression in men? This is really, really strange. And I said, okay, I want to see this happen again before 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, hexadecanalum made men less 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 slope line and all the men are below and all the women are above.

1:57:48There'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. 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 of the brain known as the left angular gyrus. Now, this is an area involved in what's referred to as social appraisal.

1:58:35So that was kind of cool in that a social order activated the social brain, not the 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 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 hexadecanal versus control?

1:59:18And here, the dissociation reemerged powerfully, whereby the connectivity from the angular gyrus was mostly 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 almost 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 tyrus is holding over your aggression and keeping you back. And in women, it let it roam free and they became more aggressive.

2:00:03But I was still puzzled. So I was convinced this happened twice. The MRL data provided not only a pattern, but a mechanism, which is unusual. And yet I was telling Eva, you know, 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. 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.

2:00:51So you're winning. So we remembered a recently published paper from a group in Japan. that looked at the odors emanating from baby heads. We now come full circle to Zucker's grandchildren. They used a method known as GCMS, gas chromatography mass spectrometry, 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 hexadecanal, and we were very disappointed that it wasn't 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, you know, we're studying this molecule hexadecanal and we don't see any results.

2:01:43And we were wondering maybe you had some results that you didn't publish or some supplementary 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 GCXGC, double GC 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.

2:02:22So babies, again, speaking about if humans do or don't chemo signal, babies are conducting chemical warfare, right? They're, you know, 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 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.

2:03:04And 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, 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.

2:03:41So 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 to 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 in this or or chemo sensing through the nostrils and or mouth 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.

2:04:27And she noticed that she thought her menstrual cycle and her co-inhabitants in her dorm room were coordinated in time. 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. 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 at Chicago, Stern. So this is Stern and McClintock, 1998.

2:05:17And here's what they did. They collected sweat from donor women and deposited it on 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. Well, I like certain body odors from certain individuals. 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 a vibe 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.

2:05:54Yeah. 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 yuck i've never heard that one like that one right in terms of the animal behavior human behavior we're either a move forward or a stop or pause um so some are truly a yuck some many are meh zero to date are yum for me now body odors the distribution is shifted it could be any one of those three, yum, yuck, or meh. So just to be clear, but the yum category is definitely included. Thank you for allowing me to do that. So she did this study.

2:06:41So because right in the original McClintock study, you might suspect other drivers of the effect. Let's say you accept the effect, but still there might be other social drivers of the effect that are not body odor, There might be some dominant woman who's dominant in some other way, and this might be driving the coordination. So here there was no direct link between these women other than body odor. So if the effect reemerged, it would definitely be an olfactory effect. And what she found is that if she took a sweat from the follicular or the ovulatory phase of the donors, one extended the cycle in recipients and one shortened the cycle in recipients.

2:07:20I don't remember which was which, but basically 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 from, I'm not sure, but 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 widely. One reason is just statistics of cyclic events are surprisingly complicated. So it's tricky. Once you have a cyclic event, statistics become tricky. And so Martha took a lot of heat on the statistics of claiming an effect.

2:08:31and 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. So I'm, but I may be 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. It's just, 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 a graduate student now in lab interested in these exact things, Raoult Weiss-Gross, and she's doing similar stuff. And I hope we'll do that.

2:09:24I 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 slash endocrine phenomena because there seems to be so many stories that we all have of the smell of our granulose. mother's hands or the recognizing the scent of, of somebody, or I knew from the moment that, um, I smelled their breath or, uh, you know, or I just liked their smell kind of thing. These kinds of things that, that inform the, the deep potential for a real biological phenomenon, as opposed to the kind of thing like, oh, uh, you know, you just throw something out there.

2:10:19Oxytocin is bonding. And all of a sudden, you know, the, the general public not at no, to no fault of their own comes to think that every, every aspect of bonding is, is oxytocin and every defect in bonding is lack of oxytocin. But the, the general public provides a sort of a rich, um, it's fodder for, for exploring all these things. And a lot of times they turn out to be true, right. When, in the context of old fact. Yeah, no, it's, it's a very primal system, you know, so, so, uh, it's, it's linked to the most, you know, limbic primal mechanisms in our brain and it drives primal behavior. It's an incredible system.

2:10:55I have a question about a particular study, but I'm just going to cue it up and you'll know immediately what I'm cuing 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 collect sweat and that's the media they look at. Is it always from the armpit or are there meaningful differences in terms of the sweat emitted from different locations on the body?

2:11:42I 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. We just, yeah. So it's funny. We have, we're working on a paper on 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. I have to come to your lab. It sounds like the greatest lab in the world. 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 Mujica Perudi.

2:12:16but that's our paradigm for generating fear and we started that on our own but we've since entered into collaboration with the Israeli paratroopers brigade and we now collect body odor from every first time jumper so we went that path because we like everybody else in this field the holy grail there is finding the molecules 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.

2:12:56And you can imagine, you know,

2:13:03what's the term I'm looking for? I'm switching into Hebrew. It's about midnight now, right? I'm sorry, it's two in the morning. You're doing incredibly well considering the inversion of the screen. 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 like a nasal spray against anxiety, right? Where you would quell those receptors and kill the fear response, right? 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, right?

2:13:41So that would be why I would want that. And we figured out that doing that, 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 a setting we call Fear Bank, which now has more than a thousand samples in it. So we're trying to do analytics on that. But in doing that, we've joined the crowd. Everybody's doing fear and everybody's doing sweat. And in one of our discussions in the lab, we were saying, well, there's got to be, or there potentially definitely could be additional bodily media that are playing into social chemosignaling.

2:14:25Now, many of these, you can't really study, right? I mean, so just to throw it, most terrestrial mammals communicate social information through urine. but you know starting doing experiments with humans with smelling urine it would be difficult you know both in irb and in agreement and you know and and then we we we you know this is a rare case where we actually hypothesized what we set out to do and you know and then only claim in retrospect that it was hypothesis is is tears we we started thinking about tears and looking into tears because tears are a bodily liquid, emotional tears that we emit in emotional situations where these are situations where nonverbal communication is critical and key.

2:15:14And tears are a liquid that is puzzling beyond ocular maintenance. And so the most influential text, I think, till this day in emotion research is Darwin's book, The Showing of the Emotions in Man and Animals, I think is the full name of the book. And an entire chapter, chapter six, is devoted to tears. An entire chapter of this book. Why? With no conclusion. Why? Because the book revolves around describing the functional antecedents of emotional expressions. 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 became an aggressive sign because it started from biting.

2:16:14Or what I 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 dysgusia, distaste, right, is spitting something out of your mouth. Now, what Adam showed 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 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 spitting out of your mouth.

2:17:06So Darn systematically went through the expressions of emotions and for each one went to their functional antecedent and explained everything very nicely. And then he got stuck with tears, right? Because tears are an obvious emotional expression and he could not find a functional antecedent. So he ended up saying, this is an epic phenomenon, basically, right? I don't know. What all scientists do when they don't have a good explanation, blame it on nature. Right, right. So, but he bothered to write this entire chapter on the ocular sort of maintenance, you know, function of tears and so on and so forth.

2:17:42but nothing emotional. So we thought, well, maybe the function is a chemical signal. And, you know, so with that in mind, we harvested emotional tears, which was also an amusing event on its own, right? Because we posted messages on all sorts of boards that we're 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 I think this is not a problem only in macho Israel, right? Probably anywhere in the West, this would, I mean, definitely in America, it would be the same, I think.

2:18:30My 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 we, 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 so and so, I always cry profusely from that.

2:19:05Can you give me an example of one of the more commonly named scenes? Yeah, with ease. The movie The Champ. The Champ dies. He's a boxer. And he dies literally in the hands of his about eight-year-old son. And his son is standing next to his bed and saying, Champ, Champ. And he dies. Right? it's a winner okay waterfalls yeah yeah got it so you know we're probably the neurobiology lab with most sad movie films on the shelf in the world right we have a whole huge collection there is such a thing as tears of joy by the way so no no well we're going ahead of ourselves but i say we tried to collect them and failed um even people who think they shed tears of joy and laughter, their eyes water a bit, but it's not the same thing.

2:20:03In the effective criers we end up screening, we collect a full ml of tears, a full ml of tears in about 15 minutes. So that's pouring, right? And that doesn't happen from laughter. Or we've never seen that. We've never that happen from laughter we tried um so so um so we have we have all these sad films and by the way one of the amusing things is uh when we ultimately published this paper in in science um we were forced in retrospect to go out and actually buy the films right i mean you know originally we like downloaded them we're there but you can't because you're you'd be violating uh uh you know copyright laws.

2:20:50Right. So we had to buy, like, purchase all these films that the participants saw. And watch them. So we actually have these in lab, like DVDs, you know, that we actually purchased. But so - Nice coverage of potential legal fallout there. No. No, we did. No, I believe you. I believe you. Yeah, it was that. So, yeah. And, well, we can touch on that later. But But so most of these volunteers who come saying they can cry with ease actually don't meet the bill. And so out of the about 100 at least more women that we screened, we ended up with about six who could really come to lab week after week and pour tears.

2:21:40There's a name for this in psychiatry. They call it narrative distancing. Some people, when they watch a film where someone's getting hit, they flinch quite a lot. It's almost as if they're experiencing it. But it works in the opposite direction, too. I know someone like this, where if they watch a film that someone's experiencing something even mildly positive, their mood elevates. So they can quickly bridge. And it's not always adaptive, as you can imagine. So there's lack of narrative distancing. Right, yeah. One issue you can bring up with this entire line of studies in our lab is I don't know if there's something very unique about the donors, right?

2:22:18I mean, we're assuming these are tiers. No, this is pretty common. I think the numbers I saw out there, about 5 % to 8 % of people. That's exactly what we got about 600. So we collected tiers and we exposed participants to these tiers. And we found a few things. First of all, the tears are completely odorless. You cannot detect them at all. Completely odorless. And yet, when you sniff them, you have a pronounced reduction in testosterone within about 20 minutes, half an hour. This is men and women smelling women's tears? Men. Men smelling women's tears, but not perceiving any odor. Nothing. Just sniffing them.

2:23:11and you have about a 14 % drop in free testosterone, free. Okay, so this is testosterone that's already been liberated from the testes. Free testosterone. We've done a few hormones that's either bound or unbound, is unbound, excuse me, from sex hormone binding, globulin, et cetera. And it's the active form. So it's subject to very short timescale changes. Yeah. Yeah, and this is, you know, people who study testosterone, which is not me, but they tell me this is a really strong effect. Like it's hard to even pharmacologically get an effect like that that fast. I mean, no in pharmacology. Yeah, years ago I spent time studying endocrine effects of this sort, and that's a tremendously sized effect.

2:23:57So here I'll point out in passing that one of the concerns we had because of the effort to run this study is that nobody would ever try to replicate it. And to our joy, about two years later, an independent group from South Korea, O et al., who I don't know at all, replicated the testosterone effect to a T. I mean, like same numbers. So it lowers testosterone. And we then also looked using MR at the effect on brain activity and saw pronounced effect on activity, a dampening, a lowering of activity under an arousing state, a lowering of activity both in the hypothalamus and in the fusiform gyrus for whatever reason.

2:24:58Face recognition area. amongst other things, yes. And we don't know why, but pronounced. And currently, Shania Grone in our lab is replicating this again, and this time with a stronger behavioral component. And I can share with you unpublished data now under review that's, as you would expect, given the effect on testosterone perhaps, sniffing tears lowers aggression in men. Using again the tap, the same experiment used by Eva in the hexadecadal experiment. The tap, I'm gonna think of that as the sadist, the control, the titration, the sadist titration. Yeah, yeah, yeah, Tyler aggression paradigm.

2:25:44Not unlike the Milgram experiments of the 1950s, which post, this was looking at sort of post Holocaust behavior, you know, people basically in American laboratories thinking they were torturing other people simply because they were told to. And a lot of people did that, even though most people would report that they would never torture someone else. Yeah, yeah. No, humans are not a wonderful species. Or as we could say, I think it was the great Carl Jung that said, we have all things inside of us, but the goal is not to experience them all, certainly. It's an incredible study, And it points again to the power of these chemosensory systems and pathways.

2:26:28And obviously, there's so much here. I don't know if you want me to tell about this or not, and I guess you can edit it out. Please don't. But this is just sharing stories about the politics of science. So whereas the effect on testosterone was replicated by an independent group, In the original study in science where we had, it had three components. One was the effect on testosterone, which was robust. The second, which was brain activity, which was robust. And there was a significant but weaker effect on behavior. And I don't think we studied the right behavior in retrospect. What we looked at then was ratings of arousal associated with pictures.

2:27:17and there was an effect. It was significant, but it was not what carried the story. Now, there's a lab in Holland of a guy by the name of, I'm probably mispronouncing this, but I think it's Winger Hoots. For the non-Dutch. Yeah. Dutch names are always a little bit of a challenge. And I shouldn't say that. at being an Israeli. I shouldn't go too much on that line. But that lab really didn't like our original tear story. And the reason they didn't like it is because they've built a career on this notion, including a book with this title, that emotional tears are uniquely human.

2:28:10now here I should well I should share so one of the things we really liked about that the the tier result is that partially before we did our work but more afterwards and and we like that because usually things so usually in our chemo signaling work like what I told you before about the Bruce effect we look at what happens in ruins and we see if the same thing is happening in humans. This was a rare case where after we did this work, more or less identical effects were discovered in rodents. So a paper published in Nature two years later found that mouse tears, mouse pup tears, lower aggression in male adult mice towards them.

2:28:52In a smell dependent way. Yeah, yeah. And they also actually found the actual component in tears that, so the tear pheromone that lowers aggression, right? So, you know, this has us thinking of tears as you can think of tears as like a chemical blanket in a way that you're covering yourself up again with, you know, to protect against aggression, right? And so our finding, you know, which to me, I mean, this is consistent with how I think about behavior in general, you know, I don't think, you know, beyond language, there are very few things, definitely sensory things that are uniquely human. You know, I'd be hard pressed.

2:29:32But so, you know, our finding went against their story, right? Because, you know, here we're saying, no, you know, tears are this chemo signaling mechanism like all animals. And by the way, you know, just after this entire debate, about six months ago, there was a paper in Current Biology that dogs emit emotional tears. and it was the dogs emit emotional tears when they reunite with their owners. And you were talking before about oxytocin. So I think what they showed there is that not only that, but that the view of seeing the tears in the dog influences oxytocin in the humans. I hope I'm getting this right.

2:30:16No, I absolutely believe this. I mean, from the time I brought Costello home at eight weeks old. Because tell us your dog. He's my dog. Unfortunately he passed away but I haven't been a long time. Actually the only time I can recall crying, listen I've certainly cried before many times in my life. Many, many times. The only time I ever recall crying to the point where I wasn't sure that I could keep producing two years but somehow did is when I had to put him down. Right? It's just like you know and if I talk about too long now I'll start crying. You know it's one of those things and I think it's a healthy emotional state.

2:30:51For sure. But I recall when he was a puppy thinking this oxytocin thing must be real because I can recall being in faculty meetings, which, you know, fairly stated are not always that interesting, but they could be pretty interesting. And someone presenting data in my mind thinking, I hope Costello is okay. What's he doing down in my office? This is when he was very little. And also not needing to eat, not being able to focus on anything else except my attachment to him for about the first two or three weeks that I had him. then it was easy. Then I could focus off on other things. And I think, I think that dogs perhaps through oxytocin hijack the circuitry that's intended for child rear.

2:31:29I really do. Otherwise, why would people be so ridiculously attached to their dogs? I mean, hence all the, the posts of everyone thinks their dog is the cutest dog the same way everyone thinks their children are the cutest children. You know, Costello by the way was a very handsome bulldog. So, yeah. So, again, so even, you know, to put another nail in that story of tears are uniquely human, so they're not. Dogs shed emotional tears. And so that group really didn't like this. And they went ahead and tried to replicate. And to your listeners, I'm showing double quotations on the replicate. Only the behavioral part, the ratings of arousal in women, of women, and failed to replicate that.

2:32:20I see. Now, this was just sharing on how science works and doesn't work in my notion in this case. So at the time, after they got this accepted in some journal, not a field journal, in the journal of memory of something,

2:32:44they contacted me for a response. And I wrote to the authors and I said, look, this is very odd to me. Why don't you come? why don't we replicate this again together and see if it doesn't work. If it doesn't work, I'll publish it with you that it doesn't work. And so I said, why don't you send over a graduate student or the lead author and we'll do it here and we'll show them how it's done because they did it very wrongly in the paper. And so they replied that, no, they don't have money to send over a graduate student to do it. So I replied saying, okay, I'll fund the graduate student coming over and I'll fund the entire study and their stay and so on and so forth and let's do this together.

2:33:26And they replied, no, they're not willing to do that, which I don't think is the way things should work. And they published this sort of failed behavioral effect in that paper. So I'm just sharing this, you know, that it's not only, there was that successful replication with the effect on testosterone, but there was supposedly this failed replication on the effect in behavior. And then I published a rebuttal on that, which I don't know if I should have done, but I did. Well, I think it's interesting. I mean, I think provided studies are done correctly, I mean, the positive result almost always trumps the negative result.

2:34:07And yet I think replication is key. The problem, as you pointed out, is that replication is rarely pure replication of the exact study. This one is not even remotely. But I published the detail. So actually they hid something in their data that did partially rip. So I asked for their data and I reanalyzed it and that's what I published in the rebuttal. But this is just sharing on how science works. I took advice. So it's not that I'm friends with him, but at that time I was communicating a bit because we were on some board with Daniel Kahneman, who's Nobel laureate. Thinking fast and slow. Right.

2:34:40And so I asked him, how should I deal with this? Give me some advice here. I was really, you know, it was emotionally not fun to be in that position. And he said, don't, don't, don't, never publish a rebuttal. Don't do anything. And I was, you know, how can I, you know, I have to do something. He said, no, don't. Because once you do that, then, you know, people don't go into the details. They won't read the details of your rebuttal. They'll be like, well, there's a group that says this and there's a group that says that. So it's unclear. Well, yeah. I mean, I appreciate that you're bringing it up today.

2:35:15and I do appreciate that you published the rebuttal and that you offered in a very magnanimous way to do a collaboration. That's what he then said. So Conlon's advice after that was that, well, if you insist, then just publish, write a response that you offered them to come do it together. They refused and there's nothing you can do about that. It's a lot like fight sports, right? People talk a lot of trash. Although in science, you know, I will say this, you know, as long as we're on the sociology of science. science is very different than podcasting or social media or other fields because in science people generally are very kind to your face and then they you get it in the you get it in the neck on grant reviews or anonymous reviews yep um i was on a grants review panel this morning i'm a nice reviewer meaning i judge things objectively but i i try to always um think from the perspective of the graduate student or author of the proposal.

2:36:11Listen, I think that science is a game of people who most of them are seeking facts. However, the ego is strongly woven into it like anything else. So I think it was very magnanimous of you to offer the collaboration. So I'm going to tell this lab whose name I can't pronounce, please accept the collaboration. Then we can invite everyone on here for a round table. I appreciate that you shared that story. And I know a number of other people will. for a number of reasons. I have a couple of more questions. Um, and I realized, and thank you by the way, for your, uh, for your willingness and stamina, because it is probably 1am Israel time now.

2:36:49Um, and you just arrived, but you're doing terrifically well. So I, I, um, if you'll indulge us just a touch further, there are two topics that, um, I want to touch on. And if you want to cover these in shorter thrift, that's fine. Although don't feel any obligation to, um, the The first one is I think most people are familiar with the scent of food or foods as a signal of the nutrient contents of those foods. You know, an orange that smells great or the smell of something baking, you know, it suggests something about the contents and quality of that food. After all, you and I both separately lived in the same apartment in Berkeley above the cheese board, which the smell of cheese wafting up through the cheese board is something I will never forget.

2:37:32And the breads, never forget it. amazing bread. I mean, I don't know if you've conveyed that clearly enough to listeners or watchers. We really just discovered that we lived in the same we never met, I mean, like this before. And we lived in the same apartment. Are we click friends? In a lingering way, I guess. Absolutely. Through the floorboards. It had a great floor, that place. It had a great wooden floor. It was an amazing place. I lived there with my girlfriend for a year and a half, and then it was an amazing place. We won't give out the address out of respect for the people that live there now.

2:38:13But do check out the cheese board if you're ever in Berkeley. Their hours are weird, so you have to look online, but it's a unique place with great bread and cheese and some good flavors of pizza. In any case, I'm wondering whether or not smell can signal things about the nutrient contents of foods in a way that's divorced from the smell that we are perceiving. So for instance, I could imagine, based on what you've told us about smell today, that, you know, I don't know. I smell a piece of meat cooking and it smells great to me. And I think of it as, oh, that's so savory and my mouth is watering and I love the smell of this.

2:38:58And I'm thinking, okay, this is protein and fat and I love the taste of steak and a little bit of char. But that nature has co-opted that to ensure, or I should say, increase the likelihood that I will ingest some other thing that's in steak that has no odor, but whose nutrient content is very important to me. For instance, amino acids, right? I mean, amino acids are essential to life. and yet we don't go around sniffing for amino acids. We go around sniffing for savoriness, umami type tastes and things of that sort. So I could imagine a million different examples of this in the same way I could imagine that the scent of somebody that we fall in love with or become romantically attached to or sexually attracted to is signaling all sorts of things about sure, the potential for offspring of a particular immune status, that's a long term game, but also something about pleasure and safety of a potential interaction.

2:40:00So what I'm asking here is about whether or not there are subconscious signals that the olfactory system has learned to seek, but learned to seek through more overt signals, sort of the tip of the iceberg phenomenon. So, you know, I don't have a good answer for you, although I think it's a really good question or a good idea, in fact. So whether there's odor cues on nutrient value is a really good idea. Moreover, it's probably good to the extent that somebody probably did it and I should know and don't. We haven't done anything on that line. So I don't know. I don't know if the nutrient value of food is systematically encoded in odor.

2:40:52Um, if that's not been done and I will check after our, uh, uh, meeting today, then it should be. Um, it's a really good idea. I mean, one of the reasons I ask this is because, um, you know, the obesity crisis in the U S is a huge issue and elsewhere and highly processed foods. Um, you know, have a lot of things that are problematic, but one of the things that they don't have often is a direct relationship between the scent, the taste, and the nutrient content. And I don't mean macronutrients, sugar, fat, excuse me, carbohydrates, fats, and proteins, but the vitamins and micronutrients, things that support the microbiome, whereas foods that are not highly processed, for instance, meat or a piece of fruit, contain many micronutrients that are vital to aspects of our biology, but we don't go around sniffing for probiotics.

2:41:45I'll tell you one sort of factoid that may support your hypothesis here. And that is that there appears to be potential olfactory perceptual similarity in metabolic products. So something that's metabolized from something else has perceptual similarity across those two things. So metabolic cascades play into the coding of olfactory space. And that is consistent with the direction you're implying. But again, I don't know of a direct test of nutritional value in smell. And again, the fact that I don't know doesn't mean, of course, that it doesn't exist. And in this case, I would suspect that it should exist in scientific press.

2:42:42And if not there, then with the companies that have vested interest in this, which are many. Briefly, please. An amusing anecdote to share with you is that we've received two independent

2:43:03companies who have turned to our lab recently asking for help to bring odor to engineered meat. That's a growing thing. And all these meats that are not - You had to bring it up. This audience is going to be very polarized along the lines of engineered meat. You're not promoting it. Oh, no, no, no, no. I'm agnostic. But we've had two companies turn to us and say, look, you know, we have this great product, but it just doesn't smell like meat. So help us make it smell like meat. Interesting. The reason it's so polarizing is that anything related to nutrition on social media is a total barbed wire topic.

2:43:44We've had experts on nutrition come on here. We'll have more. I know nothing about nutrition. You're safe. No, don't worry. No, it's not promoting. He hasn't even said whether or not he's going to help them out. No, we're not actually. No, because yeah, it just didn't happen. No, whether or not those engineered meats are yum, yuck, or meh is a personal issue to people in terms of taste. Whether or not they are better for, neutral, or worse for you and the planet then given the ingredients that are required, that's a whole world we'll avoid now. I will, but I'll take the opportunity to highlight something related maybe because on what were you saying on the scale, there's this, I'll take the opportunity to dispel another misconception about olfaction, right?

2:44:37There's this common notion that our sense of smell is incredibly subjective. right? And that what you might like in the smell, I will not like in the smell and that we all have our own, you know, totally subjective world of olfaction. I think I know the study you're going to tell me. There are many. The cross-cultural similarity. There are many. That is utterly untrue. Many, not only from my lab, there are many from many labs. Please clarify for those that follow this literature. So, yeah. So, humans are incredibly similar to one another in their olfactory perception. And this is in contrast to what most people think.

2:45:18So why is there this misconception? The misconception is there for two reasons. First of all, or for several reasons, but two stand out. First of all, we're attracted by outliers because, you know, I'll tell somebody, look, you know, for example, olfactory pleasantness is highly correlated amongst humans. And let's first put this in numbers. You'll take a bunch of humans and a bunch of odorants and have them rate pleasantness, the correlation across the humans will be about 0.8. That's incredibly high. Incredibly high. What do you think is pleasant? I think it's pleasant. Yeah. Now, why is that go against what culturally people think?

2:46:00For two reasons. First of all, we're attracted or biased by outliers. But that's particularly, that shows in fact the result. What do I mean? And so you'll tell somebody, look, people are very similar in their pleasantness estimates. And they'll say, oh, you know, that can't be. I love cilantro. And, you know, my girlfriend hates the smell of cilantro, right? Or, and there are a few classic examples there. Guyava, right? You know, is another polarizing order. So there are a few polarizing orders, right? And that's true, right? So that's true that, you know, half of the population loves the smell of cilantro and half hates it.

2:46:35Half loves guyava, half hates it. That's true. Microwave popcorn. corn. However, I assure you that, you know, you can come to our lab. We have about a thousand odorants in our lab. Okay. We won't smell the thousand, right. But I assure you, you know, take a hundred odorants, okay, from our mixtures and labs, right. And we'll, we'll smell them, right. And out of the hundred odors, 90 will totally agree on, right. And including universe, I mean, you know, nobody will say they like the smell of feces or fecal smells. And everybody will say they like the smell of rose and flowery smells. There will be rare, rare exceptions.

2:47:16Again, the correlation is about 0.8 across individuals. So a 90 of 100 will really be in high agreement. Then five orderants will be in sort of intermediate agreement. And yes, there'll be the five orderants that we're in total disagreement on. But I asked you, you know, if we agree on 95 and disagree on five, Are we the same or are we different? We're the same. They're just outliers to this rule. And so one reason is this issue of outliers attract how we think about things. But no, we're actually much more similar than what we think. And the second thing that drives this cultural effect is our poor application of language to olfaction, right?

2:47:57So in other sensory systems, we develop with anchors. So since you're a little kid, your mother shows you a cow and says, what does a cow do? Moo, right? And we all know moo, moo. And what color is this? Well, this is kind of an odd black, but it's black, right? Or what color is that? It's red, right? So you have these anchors. But as you all know, the red that I'm seeing is not necessarily the red that you're seeing. We just both know to call that red. And since you say red and I say red, I think, why? We're seeing the same thing. But no, we're not seeing the same thing, right? And in odor, we don't have those anchors, right?

2:48:32We don't from childhood, you know, our mom doesn't tell us, so what's this smell and what's that smell, right? And so we don't have these language anchors that make us think that we're perceiving the same thing. Now, how can you quantify that? The most important term in measuring sensory systems is similarity, right? That's the measure, right? So what can you do? let's say we take 10 odorants and I have you rate all the pairwise similarities, right? So you'd end up with 45 numbers, right? So, you know, how similar is one to two, one to three, one to four, and then two, and all the possible pairwise similarities.

2:49:07Let's say you rate similarity from one, which is totally dissimilar to a hundred, exactly the same, right? So now I have a similarity matrix that describes Andrew's perception of smell, right? I have, you know, based on these 10 odorants that I selected. Now I can run my similarity matrix. And then I can see if the similarity matrix are correlated, right? And then we've gotten rid of the issue of names and odors, right? It doesn't matter if I'll call this lemon and this orange, and you call this sweet potato and this marshmallow, right? It doesn't matter. If I think that these two are highly similar, and you agree, and I think that these two are very different, and you agree, right?

2:49:46We perceive the world in the same way if our similarity matrices are aligned, right? And what's nice about that is that then you can do that for vision audition and olfaction in a common group. And you can see where we're more alike each other or not. And we've done that for color vision, olfaction, and tonal audition, okay? And we are most dissimilar in color vision, okay? In color vision, the variance is about 100%. Amazing. That's quite different. And there's tons of literature on this. Tons of it. Tons of it. Right? And in olfaction and audition, they're about the same. So we're not different.

2:50:26We're very similar. We're just very poor at appreciating this. And mind you, not that there's not variability. There is variability. And of course, the system is malleable, as all sensory systems are, so you can learn to like an odor and that will change you and learn to dislike second order, right? But just the way you can learn to like a sound or dislike a sound. So, you know, this doesn't take away from the hardwired link of a structure to its perception that you can, that they're malleable. And we're not very variable. We're actually kind of similar. That's a perfect segue to the question I have next, which is if in general, people perceive certain odors similarly, you could imagine that odors could be manufactured, co-opted, etc., in order to elicit richer sensory experiences and drive choice making.

2:51:21That's obvious at the level of the smell of a hot dog stand or freshly baked bread, etc. But what I'm talking about here, and I'd like to ask you about, is doing this at scale, and scientists, geeks like to say, in silico, through computers. So for a long time now, there's been this idea that there will soon be Google smell. Not to call out Google as the only search engine, but DuckDuckGo smell, for those of you that don't want to hear smell. Chat GPT. Chat GPT, and on and on. In other words, you know, vision, visual information is sent through computer interfaces, as is auditory information. Not so much haptic somatosensory, although it can.

2:52:03You know, our lab uses VR. It can be done. Right. But it hasn't really taken hold. Um, however, smell being such a rich source of behavioral and hormonal and other sorts of deep, deep information that can drive people in to yum, yuck or meh type decision making. Yeah. Uh, seems like an amazing candidate. So what is your experience with, um, generating smells in silico in computers? And here, folks, for those of you that aren't catching on to this, and I don't expect that everyone would, because what we're really alluding to here is the idea that you'll put into a search engine blueberry pancakes recipe, and that not only will you get photos of those blueberry pancakes and a recipe, but you will get the hopefully validated odor of those pancakes and that recipe coming at you in real time through the computer.

2:53:02So I'll start off answering from the name you threw out there, Google. So about probably about five years ago, Google had an April Fool's spoof. Oh, right. And they put out this video of Google Smelt. Okay. And it had all these like classic like sales images of, you know, holding up your phone to a rose and it generating rose. and all these things, right? So Google is now trying to do that. And they just published. I mean, I know they've been trying to do it for a while. They visited our lab. But they just sort of went public with this that really just like about a month ago or something that they have this offshoot startup.

2:53:58I think it's called Osmo or something like that that started off with a ridiculous sum of money for a startup. Like, I don't know, tons of money. There's a lot of money in that world. Yeah, in Google, yeah. To, you know, to digitize smell. And there are other companies that are trying to do this as well. And we've been talking now for quite a while about our lab's chemo signaling work. But actually half of our lab is devoted to this question. of ultimately digitizing smell. And so this is a very, very active field of research. And I'll say one thing that dovetails with what you were talking about before, in many ways COVID is going to be one of the best things that ever happened to all faction research because suddenly all the world is, or all the world, lots of people are very cognizant of the importance of smell.

2:55:06And the smell is like way up there in people's awareness because of COVID. And this is driving a renaissance of olfaction research. And awareness to olfaction is something that's worth paying attention to.

2:55:23And our lab has been involved in this way, in this effort for a long time, where the initial part of this effort is in fact to develop a set of rules that link odor structure to odor perception. That is, the going saying was that until recently, at least there was no scientist or perfumer for that matter, who could look at the structure of a novel molecular mixture and predict for you how it will smell or smell something and tell you what molecular structure could or should be. you know so in contrast let's say to trivial like color vision let's say so you know if you know what the wavelength of the light is you more or less know what perceived color is going to be of course there are exceptions to that and and all sorts of issues but as a rule you you would know or you know or the other way around you know you can generate a wavelength and you would know what color light it's going to be perceived so so that's an example of where the rules linking structure, in this case, measured by wavelength, and perception, in this case, experienced as color, the rules are well known.

2:56:25In all fashion, we didn't have that until recently. But over the past few years, a bunch of labs have really pushed this forward. There's a bunch of work out of Leslie Vashal's lab at Rockefeller and Andreas Keller working with Leslie, who've done a lot of work on this front. Also worked from Joel Mainland's lab at Monel. And fair discovery, Joel was a graduate student in our lab. And recently in our lab, we've had, and I hope this doesn't come across as overly arrogant, but we've had a sort of mini breakthrough on this front. To call something a mini breakthrough is far from arrogant. And this is a paper led by Arne Ravia from our lab and Kobe Snitz, also a major contributor there, a paper published in Nature about a year and a half ago in the height of a COVID pandemic.

2:57:25So nobody really, I won't say nobody, but it wasn't noticed in the way it otherwise would have been. It was published in Nature really on like a week where the whole world was like going berserk over COVID. and in this paper we develop an algorithmic framework where we can predict the perceptual similarity of any two molecular mixtures with very very high accuracy so if you give me two molecular mixtures i can predict how similar you you will smell them to be okay now not only could we predict that, but we could design it so we can generate mixtures with known similarities. And the result was highlighted, and you'll appreciate this coming from vision, is that using our algorithmic solution, we generated olfactory metameres.

2:58:22So we measured mixtures completely non-overlapping in their molecular structure, but they smell exactly the same. Okay. Now, if you would come to a classic perfumer, or most classic perfumers and tell them that you can generate two mixtures with zero molecules in common, but smell exactly the same, they would tell you no. And yet, we did and anybody can recreate them. This is simple, actually. And in the paper, we do a few things like we generate a metamere for Chanel No. 5. so you don't like perfume so this one but but we we take so we generate a Chanel number five with no component from Chanel number five in it okay and we actually have a publicly available website I'll give it to you for your links if you want that anybody can do this we built an engine that you can generate these these metameras now once we did that in a way, we've generated the infrastructure for digitizing smell.

2:59:28because, again, what our algorithm predicts, our framework predicts is similarity. But in a way, that's enough for you. Why is that enough? We have a map of 4 ,000 molecules. For each one, we know they're a perceived smell. Now you can make up any mixture you want for me. I can project it into that map and measure its pairwise distance from all the points in the map. If it falls on lemon, then what you generated smells like lemon. And if it falls on tomato, then what you generated smells like tomato. So we now solve that problem. We can predict the odor of any molecular mixture. We can see how it's going to smell.

3:00:11What we can do is then find a set of components, which we call odor primaries, that can be used to mix any odor that you can perceive. And that's what we're working on now. And about a month ago, so this is in collaboration with a lab of Jonathan Williams and Max Planck in Munich. Jonathan Williams is an atmospheric chemist, but he's really good at using GCMS, these tools that measure molecules. So Jonathan Williams measured odorants in Germany, transmitted the information to us over IP. we fed that into our algorithmic framework and recreated it from a device that mixes primaries. And we tried to do four different odorants in our proof of concept test.

3:01:04One of them was ROSE, and we failed at recreating ROSE. We, in fact, recreated something that had a percept, but most people perceived it as bubble gum. The second one we tried to do was anise, and we failed at recreating anise. And most people said it was cherry, which is not very far, but it failed. The third was gasoline. And we were slightly but significantly better than chance at recreating gasoline. And the fourth was violets. And 15 of 16 people said violets. So the first odor ever transmitted over IP is violets, and we did that last month. Of course, this is not anything near a practical solution.

3:01:54The device that Jonathan was using to measure is a$1.5 million device bigger than this table. That's right. I remember when VCRs, half the audience won't even know what that is. VCRs were like this big, so we're all good. I'm all good with the prediction that things will come down in size and cost. I was just saying, you know, don't hold your breath for this to be on your table tomorrow. And, you know, again, even, you know, all we have in hand is this very initial proof of concept. You know, it's not even yet close to being a paper we are submitting because there's still lots of work to be done.

3:02:34But we're on the path. We're on the path. and, you know, Google will probably beat us to it. They got a lot more. You seem pretty dogged in there. Yeah, but they have so much more resources that at this stage, and they've already published two papers from that effort that are good. Yeah, you know. They definitely have a lot of dollars and a lot of people, a lot of good neuroscience and other biology, engineering, graduate students, and postdocs go there. But the real question is, are they getting the best people? Because as you and I both know in science, oftentimes it's small groups of the very best and most creative people that can outrun and outgun large groups.

3:03:19And here I don't have anything against Google, by the way. I use it all the time. I'm not a betting man, but I would put my money on Google on this race. But I'll try and give them a run for their money. There you go. Well, since I mostly just want to see the problem solved regardless of who gets there first, what I'll say is you better get going, Google, because Noam's being, he's humble and he's dogged. So better get cracking. There, we just cost the weekends and broke up the relationships of a bunch of scientists. I remember when I was a graduate student at Berkeley, I remember hearing there was a guy in our common friend, Irving Zucker's lab, that worked 100 hours a week.

3:03:57So I was like, oh, I'll work 102 hours a week, which was not a good choice. In any case, it's abundantly clear that you're making progress here. And I go to some of the earlier discussions we had, and I think we're not just talking about transferring recipes and smells of food, gasoline from people watching the F1 race or something, but I'm thinking dating apps. Nowadays, everyone knows that when you travel and you want to see your family, your grandkids or kids, it's better to get on FaceTime and see them or Zoom than to just hear their voice. We're all talking about being able to smell them.

3:04:35I'll tell you more than that. I'll tell you more than that. I mean, we're talking now of trying to achieve the olfactory equivalent of circa 1956 black and white TV. Okay, basically, right? I mean, you know, I'm not dreaming, let's say, of being able to transmit to you the difference between a Cabernet or a Merlot, right? But if I can generate something that's vaguely wine, that will be an amazing success from my perspective, right? but jump ahead in your imagination to 4K odor transmission, then medical diagnostics is what you want to be talking about. Because this is over extension, but you can almost say that every disease will have an odor.

3:05:21I mean, every disease is a specific metabolic process. Metabolic process have metabolites. Metabolites have a smell. olfaction once it's digitized and and high resolution which again in our hands it's not going to be i mean we're talking you know in my retirement maybe i'll read about this one day if i'll still have vision i mean this is not close but when when olfaction digitization is brought to the equivalent of 4k uh vision and audition that you have now then it will be in medical diagnosis. You'll have, excuse me for the, uh, the imagery, but you will have an electronic nose in your bathroom.

3:06:04Uh, each one of us will have in the toilet and it will be doing diagnostics all the time. And, and, uh, that's, that's where it's going to go. But again, not anywhere in the very close future. Well, it's, it's certainly an exciting proposition and I'm delighted that you and other groups who are so strong are working on it. I really am. Noam, I want to say thank you for your time today. First of all, this was a tremendously interesting conversation. I mean, we touched on so many things, hormones, smells, the architecture of the olfactory system. I know that people listening to this are realizing, but I'm going to say it anyway, what an incredible gift you've given us.

3:06:49And as a expert in this field, be giving us this tour of the work that you and others who you credit so generously have done to elucidate this incredible system that we call olfaction chemo sensation. Also just for the incredibly pioneering work that you've done. You know, I don't have many heroes in science. I have heroes outside of science and a few in science, but I'm going to purposely embarrass myself a little bit by saying that from the time I was at Berkeley and I then saw that experiment being done of people foraging, following scent trails. And then when I was a, until I was a junior professor, I used that in my teaching slides in a class that I taught that was sort of the early origins of this podcast in many ways.

3:07:36And over and over again, when your laboratory publishes papers, I find like, this is super interesting, super cool. And I find myself telling everybody about and that's really what I do for a living is I learn and then I blab about it to the world. So thank you so much for the work that you've done and the spirit that you bring to it. Whatever drives that spirit, as the great late Ben Beres used to say, keep going because we are all benefiting tremendously. And I also just want to say that, you know, for people listening to this, the spirit of science is one of, as you mentioned, there's complex politics and all these things, but it's absolutely clear that you delight in the work you do.

3:08:16And so I delight in it. I'm grateful for it. I'm grateful for your time today. And so on behalf of me and the many, many people listening to this, I just want to extend a huge debt of gratitude. Thank you so much. So I'm blushing. I don't know if this doesn't come across on the radio podcast, but thank you so much for very warm words. I mean, you know, as you know, when you work in your lab, you don't, there's these moments where you suddenly discover that somebody is like, cares a bit about it. And those are always very rewarding moments because usually you function without that. I mean, I guess that's one of the things you need to be a scientist is to have the, you know, the drive to work without that because it comes only rarely.

3:09:06There's immense gratitude and appreciation for you and what you do from me. And now I know from a large segment of the world as well. So my only request is that you come back and tell us about the next results sometime not too long from now. Yeah. Well, I'm going to catch you live now, although you have the power to edit this. I guess that's not fair. But first, you come visit us in Israel and tell us both about the science and the public science work you're doing. And then I'll come again. A good bargain and I accept. Delighted. Thank you so much. Yeah, pleasure. Thank you for joining me for today's discussion about olfaction and chemo sensation with Dr.

3:09:45Noam Sobel. If you'd like to learn more about the work in the Sobel Laboratory or read some of the papers described during today's episode, as well as learn about the current and future projects in the Sobel Laboratory, please go to the link provided in the show note caption. If you're learning from and or enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero cost way to support us. In addition, please subscribe to the podcast on both Spotify and Apple. And on both Spotify and Apple, you can leave us up to a five-star review. If you have questions for me or comments about the podcast or guests or topics that you'd like me to include in future Huberman Lab podcasts, please put those in the comment section on YouTube.

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