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

[0] Welcome to the Huberman Lab podcast, where we discuss science and science -based tools for everyday life.

[1] I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine.

[2] Today, my guest is Dr. Nome Sobel.

[3] Dr. Nome Sobel is a professor of neurobiology in the Department of Brain Sciences at the Weisman Institute of Science.

[4] His laboratory studies olfaction and chemosensation.

[5] Elfaction is, of course, our sense of smell.

[6] Chemosensation is our ability to respond to chemicals in our environment.

[7] Today you are going to learn some absolutely incredible facts about how you interact with the world and other people around you.

[8] For instance, you will learn that humans can smell things around them as well as dogs can.

[9] In fact, humans are incredibly good at sensing the chemical world around them.

[10] You also learn, for instance, that every time you meet somebody, you are taking chemicals from that person, either from the chemical cloud that surrounds them or directly from the surface of their body and you are actually applying it to your own body and you are processing information about that person's chemicals to determine many things about them, including how stress they are, their hormone levels, things that operate at a subconscious level on your brain and nervous system and that impact your emotions, your decision -making, and who you choose to relate to or not to relate to.

[11] You will also learn that tears, yes, the tears of others are impacting your hormone levels in powerful ways.

[12] You will also learn that every so often, actually on a regular schedule, there is an alternation of ease through which you can breathe through one nostril or the other.

[13] And that alternation reflects an underlying dynamic of your nervous system and has a lot to do with how alert or sleepy you happen to be.

[14] The list of things that Dr. Nome Sobel's laboratory has discovered that relate to everyday life and that are going to make you say, wow, I can't believe that happens, but then go out into the real world and actually observe that that happens in ways that are incredibly interesting, just goes on and on.

[15] In fact, his laboratory discovered that we are always sensing our own odors.

[16] That's right, even though you might not notice your own smell, you are always sensing your own odor cloud, and throughout the day, you periodically smell yourself deliberately, even though you might not realize it, in order to change your cognition and behavior.

[17] I first learned of Dr. Sobel's laboratory through a rather odd observance.

[18] That observance took place when I was a graduate student many years ago at UC Berkeley.

[19] At the time, Nome Sobel was a professor at UC Berkeley, as I mentioned before you, since moved to the Weissman.

[20] Well, I was walking through the Berkeley campus and I saw people on their hands and knees, but with their head very close to the ground and their eyes were covered, their hands were covered, their mouths were covered, and only their nose was exposed.

[21] And what I was observing was an experiment being conducted by the Sobel Laboratory in which humans were following a scent trail.

[22] That scent trail was actually buried some depth underneath the earth and yet they could follow that scent trail with a high degree of fidelity.

[23] It was from that experiment and other experiments done in Dr. Sobel's laboratory at Berkeley and at the Wiseman involving neuroimaging and a number of other tools and techniques that revealed the incredible power of human olfaction and human's ability to follow scent trails if they need to.

[24] And that, of course, led to many other important discoveries, some of which I alluded to a few moments ago, but you are going to learn about many, many other important discoveries in the realm of olfaction and chemo -sensation that have been carried out by Dr. Solverill's laboratory through the course of today's episode.

[25] And by the end of today's episode, I assure you that you will never look at or smell the world around you the same way again.

[26] Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford.

[27] It is, however, part of my desire and effort to bring zero cost to consumer information about science and science -related tools to the general public.

[28] In keeping with that theme, I'd like to thank the sponsors of today's podcast.

[29] Our first sponsor is Element.

[30] Element is an electrolyte drink with everything you need and nothing you don't.

[31] That means plenty of salt, magnesium and potassium, the so -called electrolytes, and no sugar.

[32] Now, salt, magnesium, and potassium are critical to the function of all the cells in your body, in particular to the function of your nerve cells, also called neurons.

[33] In fact, in order for your neurons to function properly, all three electrolytes need to be present in the proper ratios.

[34] And we now know that even slight reductions in electrolyte concentrations or dehydration of the body can lead to deficits in cognitive and physical performance.

[35] Element contains a science -backed electrolyte ratio of 1 ,000 milligrams, that's 1 gram of sodium, 200 milligrams of potassium, and 60 milligrams of magnesium.

[36] I typically drink Element first thing in the morning when I wake up in order to hydrate my body and make sure I have enough electrolytes.

[37] And while I do any kind of physical training and after physical training as well, especially if I've been sweating a lot.

[38] If you'd like to try Element, you can go to Drink Element.

[39] That's LMNT .com slash Huberman to claim a free element sample pack with your purchase.

[40] Again, that's Drink ElementLMNT .com slash Huberman.

[41] Today's episode is also brought to us by Eight Sleep.

[42] Eight Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity.

[43] Now, I've spoken many times before on this podcast about the critical need for us to get adequate amounts of quality sleep each night.

[44] One of the best ways to ensure a great night's sleep is to control the temperature of your sleeping environment.

[45] And that's because in order to fall and stay deeply asleep, your body temperature actually has to drop by about one to three degrees.

[46] And in order to wake up, feeling refreshed and energized, your body temperature actually has to increase by about one to three degrees.

[47] Eight sleep makes it incredibly easy to control the temperature of your sleeping environment by allowing you to program the temperature of your mattress cover at the beginning, middle, and end of the night.

[48] I've been sleeping on an eight sleep mattress cover for well over three years now, and it has completely transformed my sleep for the better.

[49] Eight Sleep recently launched their newest generation pod cover, the Pod4 Ultra.

[50] The Pod 4 Ultra has improved cooling and heating capacity, higher fidelity sleep tracking technology, and it also has snoring detection that remarkably will automatically lift your head a few degrees to improve your airflow and stop your snoring.

[51] If you'd like to try an eight sleep mattress cover, you can go to 8Sleep .com slash Huberman to save $350 off their Pod4 Ultra.

[52] Eight Sleep currently ships to the USA, Canada, UK, select countries in the EU and Australia.

[53] Again, that's 8Sleep .com slash Huberman.

[54] And now for my discussion with Dr. Noam Sobel.

[55] Dr. Sobel, Noam, welcome.

[56] Thank you.

[57] Must say, I am extremely excited for this conversation.

[58] I've been a huge fan of your work for more than a decade or two.

[59] Yes.

[60] Kind of frightening.

[61] Yeah.

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

[63] Although we lived in the same apartment.

[64] And we just learned that the amazing apartment that you moved out of was the apartment that my girlfriend and I at the time moved into in 2006, I believe.

[65] So we've shared quite a few things.

[66] And today I'd love for you to share with us all about the amazing landscape of chemo sensation, in particular olfaction or sense of smell, and some related perceptual abilities or subconscious abilities, including pheromones, etc. To get everybody on the same page, I'd like to just start off by asking, What are the major components of our ability to smell?

[67] Obviously, where I like to think it involves the nose at some level.

[68] It does.

[69] To what extent is that mixed in with other senses like taste?

[70] And perhaps more importantly, what about the chemicals that we are sensing through this thing?

[71] And for those of you listening and not watching, I'm tapping my nose, that we are not aware of.

[72] you know, the chemicals that are, that we're inhaling and making sense of without our awareness.

[73] Now, if you could just give us the top contour or even deep contour of you like, of the parts list and the various roles they play.

[74] So you've asked a lot of questions at once.

[75] You know, I'll start with a little comment on the way you said smelling through our nose, which we indeed do, but we also smell through our mouth, actually.

[76] There's a process referred to as retronasal olfaction where odorants come up through the back of our throat and out of our nose, the reverse way.

[77] And we smell things that way as well.

[78] And in fact, a big part of the contribution of olfaction to food and taste comes from that, from retronasal olfaction.

[79] But primary olfaction is referred to as orthonasal olfaction that is through our nose.

[80] We sniff, and sniffing is a big thing.

[81] Well, I have a sense we might talk about that a lot today in all sorts of contexts.

[82] So we sniff in through our nose.

[83] And to answer your general question of the organization of the system, so molecules, airborne molecules travel up our nose, a distance in the human of about six or seven centimeters to about here where they interact with, I will use the word sheet of receptors, but sheet is a bit misleading here.

[84] It's not a sheet, it's very convoluted.

[85] We have about seven million such receptors lining a structure known as the olfactory epithelium.

[86] This is the sensory surface of the olfactory system, the olfactory epithelium.

[87] Again, probably about six or seven million receptors in the human.

[88] In the human, probably of about 350 different kinds.

[89] So that's amazing.

[90] That means a meaningful percentage of your genome is devoted just to this, just to the kinds of olfactory receptor subtypes you have in your nose.

[91] By the way, I can share an amusing story.

[92] I would imagine amusing stories are good for podcasts.

[93] So that number of six or seven million receptors is probably not very well grounded.

[94] It's hard to count, but it's reasonably grounded.

[95] And there was this thing roaming around in the literature about bloodhounds having a billion receptors in their nose, which is why they're so amazing.

[96] And this number was, you know, it's sort of propagated through the literature.

[97] And our lab has written over the years a few review chapters, and we were repeatedly writing the olfaction chapter for a very large, one of these large textbooks, the Gazanaga handbook of cognitive neuroscience, I think it's called.

[98] And we had that in there as well somewhere.

[99] And one time when we're renewing the chapter for a new version of the book, I told the graduate student who is leading that at the time.

[100] Araya Sharun, she's now a professor at Tel Aviv University.

[101] I told her, check that, check that reference out.

[102] Where in the world did that come from?

[103] And we started going back and back and back.

[104] And it turns out it comes from a textbook, an Australian textbook.

[105] And we found the author of the textbook and we wrote her and I said, look, there's this thing in the literature of a billion receptors in the bloodhound.

[106] Where did that come from?

[107] And surprisingly, answered me. And I was hoping to get a reference, right?

[108] But it wasn't a reference.

[109] And this is where it really becomes funny for us because she said, I was once at a lecture of an olfaction geneticist by the name of Daron Lancet.

[110] And he said that in the lecture.

[111] Now, this is really funny because she's in Australia.

[112] This is all over the world, this number.

[113] And I'm writing her from Israel.

[114] and Doran Lansett is in the building next to me. Okay, he's in Weitzman Institute, genetics.

[115] I mean, he used to be, he's retired now.

[116] And he had meaningful contributions in the history of olfaction.

[117] So I picked up the internal phone, and I said, hey, Daron, you know, did you say that there's a billion receptors in the bloodhound nose?

[118] And he said, what's a bloodhound?

[119] So this was totally made up, right?

[120] It totally made up and it propagated.

[121] I mean, you can probably go into Google and type, a billion receptors in the bloodhound and you'll get a lot of hits but there was absolutely no evidence for that amazing and not just amazing in light of what it it tells us about olfaction and bloodhounds or otherwise but amazing because it sheds light on just how much of what is in textbooks scientific and medical is absolutely wrong things things propagate and you know you cite yourself and right so we fix that in that version of great of the and so to finish the line.

[122] So odorants interact with these receptors here in our epithelium, where they undergo what is referred to as transduction.

[123] That is, the odorants dock at a receptor and turn into a neural signal or enforce the receptor to respond in a neural signal.

[124] And this neural signal, in fact, action potentials, not gradient potentials of any kind, propagates via the olfactory nerve.

[125] Now, this is a nerve that goes from our epithelium right here.

[126] Behind the forehead.

[127] No, well, yeah.

[128] Yeah.

[129] Through the thinnest part of our skull, an area referred to as the Criborform plate, which is perforated.

[130] It has a lot of holes.

[131] The nerve goes through those holes and synapses at the first target in the brain, which is the olfactory bulb.

[132] And humans, that forms an interesting point of sensitivity.

[133] Because a lot of people lose their sense of smell due to trauma because of that structure.

[134] A head hit type trauma.

[135] Well, yes, although you denoted hitting on the front of the head, which is where all this real estate is.

[136] But actually, the more common cause for losing your sense of smell for trauma is the back of the head because of what's referred to as a contrariqoo injury.

[137] So as your listeners probably know, our brain is floating in liquid and CSF and cerebrospinal fluid inside our skull.

[138] And when we get in the back of the head, the brain has this forward and backward movement in the liquid in the skull.

[139] It sort of crashes.

[140] It can crash against the front of the skull, which is why you also have in a contrawindory, you also often have frontal damage.

[141] But what happens is that this generates a shearing motion on the crib form plate and the olfactory nerve is severed.

[142] And if it's completely severed, it's lost.

[143] Forever because my understanding is that the olfactory sensory neurons are among the few central nervous system neurons in adult humans that can regenerate.

[144] So, or replenish themselves.

[145] Right.

[146] So, so I'll, again, there are a few questions.

[147] Yeah, that's okay.

[148] So first of all, we will spin many plates simultaneously.

[149] If it's completely severed, completely, then yes, you're lost.

[150] Forever.

[151] Yeah.

[152] If it's completely severed, because even if you'll have regeneration at the basal cell level at the epithelium, they won't manage to find their way back to the bulb.

[153] If you have partial or something left or something shows up in a short while after the injury, then you have a good chance of recovery.

[154] Because they grow along the trajectory of the other axons or pioneering the way for them.

[155] Assumingly, yeah.

[156] Interesting.

[157] And so basically the time frame, and you know, it's funny, I get a lot of emails on this, although I'm not a medical doctor, but I get a lot of emails from people who have lost their sense of smell because it's very distressing and now more people know this because of COVID, that it's very distressing.

[158] And basically the rule of thumb is that if you don't get it back within a year to a year and a half, you'll never get it back.

[159] My understanding of the statistics on olfactory loss in COVID and other viral type infections is that, first of all, I had, I experienced that when I got COVID.

[160] Including total an osmium?

[161] For one day and not total.

[162] It was just there was a remnant of an ability to smell or perceive the smell of a lemon and I was huffing as hard as I possibly could.

[163] I actually, there's an over -the -counter remedy and this is not pseudoscience because there's a number of papers published about this on PubMed, the alpha lopoic acid can accelerate the recovery of smell.

[164] Yeah.

[165] And so that's something that it worked successfully for me. I'm not saying that that's the only route.

[166] You don't know if it works successfully for you or if you would have recovered anyway.

[167] I mean, you didn't do a controlled study.

[168] But I was not willing You do the control experiment, exactly.

[169] So, yeah, let me say two things on this front.

[170] First, the deane on the alpha -opoic acid is, yeah, it's not overwhelming, but losing your sense of smell is overwhelming.

[171] Yeah, no, no, I know.

[172] And so I think people feel desperate.

[173] One word about smelling the lemon, and this is, I'll take that opportunity to share more information.

[174] When we smell things, it's the result of more sensory subsystems than the olfactory system alone.

[175] So you have several chemosensory sensitive nerves in your nose.

[176] A primary one beyond the olfactory nerve is the trigeminal nerve, the fifth cranial nerve.

[177] So the trigeminal nerve has sensory endings in your nose and your throat and in your eye.

[178] It has three branches.

[179] That's why an onion has a smell and burns your eyes and burns in your throat.

[180] Is that why?

[181] It's trigeminal, yeah.

[182] The tearing of cutting an onion is...

[183] Trigeminal.

[184] It's a trigeminal reflex.

[185] Amazing.

[186] We talked about trigeminal in the context of headache during a headache.

[187] episode.

[188] It's a trigeminal reflex.

[189] So the lemon you are smelling may have been a trigeminal sensation.

[190] So smelling the lemon with my eyes is what you're saying.

[191] Well, no, with your nose, but with your trigeminal receptors and not your olfactor receptors.

[192] So within, you know, olfaction researcher jargon, there's what we refer to as pure olfactants.

[193] These are orders that will stimulate your olfactory nerve alone.

[194] They won't influence your trigeminal nerve at all.

[195] And an example, just to get a sense of what that might be, would be the coffee right here is a pure olfactant.

[196] Vanilla is a known purelifactant.

[197] These things have no trigeminal activation.

[198] As long as we're on this topic and we'll weave back and forth, but I'm glad we are on this topic because a tremendous number of people wrote to me during the pandemic and continue to about olfactory loss.

[199] I've heard of this olfactory training whereby if you have a partial or even, complete loss of a primary olfaction that one is encouraged to smell a number of different smells.

[200] I grew up studying activity -dependent wiring of the nervous system.

[201] It makes total sense to me why keeping neurons active keeps them alive.

[202] So this is not fired together, wire together type thing.

[203] By the way, that's a quote from Carla Schatz, not Donald Head folks, or me. But this is about keeping neurons electrically active, in this case olfactory neurons, in order to maintain their connections because otherwise they will die.

[204] Olfaction is a definite use -it -or -lose -it system.

[205] And so that makes total sense.

[206] And indeed, there's very strong evidence for success of the training programs more than the alpha -opoic acid.

[207] Great to know.

[208] And so that's a real thing.

[209] And what's cool about that is that you don't need to go out and buy expensive things, although you can.

[210] Of course, there are people who are capitalizing on this commercially already.

[211] But you can just take things from your refrigerator or your, you know, makeup cabinet or whatever and smell them, you know, attentionally and constantly and sniff them.

[212] And that exposure will help you recover.

[213] There is good data on that by now.

[214] You made that point in passing about regeneration in the olfactory system.

[215] Indeed, one of the cool things, so in olfaction, you can study many things through olfaction.

[216] Indeed, one of them is neuroregeneration.

[217] because the olfactory neurons are really the only neurons that do that systematically in the adult mammalian brain.

[218] And whether the human olfactory system shows the same level of regeneration as it does in other mammals is and was somewhat questionable, and I'm just bringing that up to share a really cool study that was published in neuron, I think, somewhere around 2014, where to address this question, I just really like the idea of doing that.

[219] What the authors did was look at, in post -mortem, they looked at levels of C -14 in adults who were exposed to atomic bomb experiments, right?

[220] So you can actually look at these neurons and time them based on exposure to radiation.

[221] And that paper, suggested that there's not as much turnover in the human olfactory bulb as there is in other mammals.

[222] Other lines of data suggest otherwise.

[223] So this is kind of a debated question as to what extent of neurodegeneration you have in the human olfactory system as opposed to other mammals.

[224] But that was just a really cool paper, I think, of doing that.

[225] Fascinating.

[226] I should I finish the path?

[227] Just so we have that.

[228] So we said, so information then synapses at the olfactory bulb from the olfactory epithelium.

[229] And the pattern of that synapsing follows what's referred to as the most extreme case of convergence in the mammalian nervous system.

[230] More specifically, what happens is that all the receptors of a given subtype, and remember in humans we said we have about 350, in the mouse we have about 1 ,200, probably.

[231] So all the receptors of one subtype converge to one location in the bulb.

[232] And this location is referred to as a glomerolus or an implore glomeruli.

[233] And that may be a slight oversimplification.

[234] It's in fact two glomeruli.

[235] There's a mirror, sort of a mirror cut line.

[236] And so all the receptors of one subtype will converge to two mirror glomeruli on the olfactory bulb.

[237] So you end up having two glomeruli that reflect that one receptor subtype.

[238] And so you end up having two glomeruli that subtype.

[239] And so if, and this is as far as, I'm giving you now the textbook view of how the system works, but then I can, I'll happily share with you things that pose a problem for the textbook view of how things work.

[240] But the textbook view of how things work is that every such receptor subtype is responsive to a small subset of different molecular shapes, what sometimes referred to as ototopes, the molecular aspects of the odorant.

[241] So each receptor is, responsive to a different subset of ototopes, let's say 10, and each ototope will activate a different subset of receptors.

[242] So potentially you have this insane comet and torques of this potentially 350 dimensional space in the human, potentially, but then because of this convergence, you end up having on the bulb in a way a map reflecting receptor identity.

[243] So let's say this coffee activates receptors of type 1, 3, and 7.

[244] So the glomeruli of receptors 1, 3, and 7 will light up, quote, unquote, when I smell the coffee.

[245] And if you can take a snapshot of that, theoretically, you would have the map of coffee and so on and so forth.

[246] This is sort of the textbook view of how the system works.

[247] And then information goes from the bulb to several targets in the brain.

[248] I mean, what is referred to as primary olfactory cortex is peripheral cortex and endothorineal cortex.

[249] This is on the ventral surface of the brain, the lower portion of our temporal lo, and information goes there directly, but it also goes directly to the amygdala.

[250] It probably goes directly to the hypothalamus.

[251] It may go directly to the cerebellum.

[252] It goes all over the brain.

[253] So information projects widely from there.

[254] And as far as people understand, the map that may exist on the bulb doesn't exist in the rest of the brain.

[255] And the understanding of how coding occurs in the rest of the brain is murky.

[256] commonly one hears that the memories that we have of odors are somehow more robust than the memories of other perceptual events in our life.

[257] I don't know if this is true or not, but people will say, for instance, I can still remember the smell of my grandmother's hands or the smell of cookies in her kitchen.

[258] At a minimum, it points to the fact that smell and memory are closely linked.

[259] And you just mentioned a direct, you know, multi -station, but nonetheless somewhat direct path from the nostrils to the hippocampus, one of the primary encoding centers of memories.

[260] Two synapses way.

[261] Yeah, which is a remarkably short pathway, considering that, for instance, just by example, because some of our listeners that won't be familiar with this, but some will that sound waves that, you know, are transduced into neural signals at the level of the inner ear go through many stations before they arrive at the location in the brain where we make sense of those sound waves as voices or music, et cetera.

[262] Whereas, Elfaction is more of a direct route to the memory centers.

[263] Is there any just -so story or real objective truth to the idea that olfactory memories are formed more easily or maintained longer or more robustly than other sorts of memories?

[264] So, yes.

[265] But first, I should say that I'm not an authority in olfactory memory.

[266] It's sort of – alfactory memory is a huge field of research and somehow our life.

[267] lab has never really gone much into that.

[268] Although, again, the same student I happened to talk about before, A. R. A. A. Sharon, who's again, now a faculty at Tel Aviv, ran a study, a paper, I think we published in current biology called the privilege representation of early olfactorious associations.

[269] Basically, there's something about the first time you experience a smell that generates a particularly robust representation more than other sensory stimuli and that's what chain fact compare it so there's something about the first exposure to a smell um in terms of the brain encoding that that etches it into our being and and this is an effect that has you know it has echoes of course in literature i mean you know the the biggest cliche in this is to bring up the proust effect right so the proust effect is when he ate the madeline and it immediately the taste and smell immediately reminded him uh of of of an event in his childhood where the same Madeleine appeared.

[270] But so that's something very real.

[271] There's a lot of research on it not coming from our work.

[272] So I'm not an authority.

[273] But it does sound like there's something special about all faction.

[274] And that doesn't mean that there isn't something special about vision or audition.

[275] Each one has its own unique.

[276] I'm the last to argue that there's something special about all faction.

[277] 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.

[278] I mean, for me, everything is olfactory.

[279] So, yes, through the lens of the nose.

[280] I'd like to take a quick break and acknowledge one of our sponsors, Athletic Greens.

[281] Athletic Greens, now called AG1, is a vitamin mineral probiotic drink that covers all of your foundational and nutritional needs.

[282] I've been taking Athletic Green since 2012, so I'm delighted that they're sponsoring the podcast.

[283] The reason I started taking athletic greens and the reason I still take athletic greens once or usually twice a day is that it gets to be the probiotics that I need for gut health.

[284] Our gut is very important.

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

[286] And those probiotics and athletic greens are optimal and vital for microbiotic health.

[287] In addition, athletic greens contains a number of adaptogens, vitamins, and minerals that make sure that all of my foundational, nutritional needs are met, and it tastes great.

[288] If you'd like to try athletic greens, you can go to athletic greens .com slash Huberman, and they'll give you five free travel packs that make it really easy to mix up athletic greens while you're on the road in the car, on the plane, et cetera, and they'll give you a year's supply of vitamin D3K2.

[289] Again, that's athletic greens .com slash Huberman to get the five free travel packs and the year supply of vitamin D3 K2.

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

[291] Everything was covered.

[292] It was covered.

[293] And they were walking, well, they were crawling along the ground.

[294] and I thought this was peculiar but then again it's UC Berkeley and the joke is if it 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 but that kind of place yeah but nonetheless a paper came out a few years later describing the results of what turned out to be your experiment that your laboratory was running which was having people follow an odor trail with their nose And my understanding is that people can improve their ability to track sense quite robustly, especially if we deprive them of vision and somatic sensation that is touching some other sensations.

[295] Maybe you could just tell us a little bit about that study.

[296] And I think in our audience, I'm suspecting that many people have a keen, keen sense of smell.

[297] I have a family member who just like detect any negative, you know, you know, putrid odor in the environment, but also good odors, exquisitely well.

[298] And I have other family members whose sense of smell is quite poor.

[299] I'd love for all of those people to learn a bit about what is possible in terms of training up or improving our ability to smell and perhaps in the context of that study, if you will.

[300] Yeah.

[301] So first, before we've been talking about improving, just off the bat, humans have a remarkable sense of smell.

[302] And this is something, again, in our lab, we already said, you know, yeah, we know this.

[303] This is all news.

[304] But to people who come from different worlds, we have to reiterate this.

[305] Sometimes when I give, you know, public lectures to non -alfection audiences, I reiterate this.

[306] Humans have an utterly remarkable sense of smell.

[307] To put that a bit into sort of, you know, things that you could, that are tangible.

[308] So, for example, mercaptains, which are added to cooking gas so that we smell it because otherwise it wouldn't have a smell so that the smell of gas it's not the smell of gas of propane it's an additive yeah it's more captain yeah it's sulfur like smell so 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 of making this again, really tangible.

[309] We're working with a notarant in our lab called estra tetra enol that our participants can detect when we have it mixed at 10 to the negative 12 molar in the liquid phase.

[310] To give you a real sense of that, we did the math, if you would take two Olympic -sized swimming pools and you would pipe it one ML, one drop into one pool versus the other, you could smell the difference between the pools.

[311] incredible that's the detection threshold that you have with your nose people have an utterly amazing nose okay so so that's just in terms of its detection abilities which are are just you know remarkable really up there in the mammalian world we're not a bad mammal at all faction um and and beyond that we can we can improve okay and the example you're talking about actually started off uh is a lab bet okay we we were were having a lab picnic.

[312] So I guess I should hear fill in because I'm your guest from the Weisman 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.

[313] And this study was done during that time.

[314] 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.

[315] And I said that humans could truly even track odor like a dog And people there said, no way.

[316] And we ran this quick experiment, which I have video of, but I don't think we'll show it here.

[317] But I actually have original, the picnic video, we have it.

[318] And a graduate student by the name of Christina Zalano, a brilliant graduate student at that time, who's now, she's now a professor at Northwestern.

[319] And she's really leading the field of olfaction imaging today.

[320] But she was the volunteer, and we dragged a chocolate bar across the grass.

[321] and blindfolded her and checked if she could track the track we made with the chocolate, which she did very effectively, right?

[322] Did you place her at the starting point of the line?

[323] I think we did.

[324] I don't exactly remember what we did on that sort of picnic tryout.

[325] But, you know, I assume she never practiced that in her life before, right?

[326] And yet, you know, she did it really, really well.

[327] And then this went on as a lab -bed in a way that I said to my students, It's okay, we have to make this into an experiment, put it in an experimental setting and quantify what's going on.

[328] And they all said that it would be uninteresting.

[329] That was the bet.

[330] And I told them it would be in nature, which is a bet I won in this case.

[331] Nature, of course, being one of the three apex journals.

[332] It was nature neuroscience, to be fair.

[333] But so then we turned it into an experiment.

[334] And what the experiment was is that we brought in participants, naive participants.

[335] not graduates from our lab, completely deprived them of any other sensory input.

[336] 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.

[337] And we generated a consistent odor path in the grass, which is what you saw.

[338] We did that by burying twine under the grass and an odor impregnated twine, so that way we could generate a consistent odor tree trail every time.

[339] Was it at the base of the grass or in the dirt?

[340] It was buried.

[341] It was buried under the grass.

[342] Really?

[343] Yeah.

[344] I did not know that.

[345] It was buried under the grass.

[346] And we conducted aerial photography.

[347] And participants also had this sensor pack that they were wearing where we measured nasal airflow in each nostril in real time.

[348] And we also use something called RTK GPS, which is a way to lay.

[349] radio frequency grid over the GPS grid so that you have millimeter resolution in space basically.

[350] It's used by surveyors mostly so that we could track behavior.

[351] And we found a few things doing this.

[352] One is that people could just do this right off the bat.

[353] The second thing we found that is when we trained them up, then within average of four days, the rate limiting factor became the speed at which they could crawl.

[354] So as fast as you could crawl, you could send track.

[355] Of course, you can't crawl as a dog can run, but as fast as you can crawl, you can send track.

[356] And then to sort of add what made it really interesting from a system's neuroscience perspective is that we asked whether having two nostrils contributes to this.

[357] So we built, we constructed a nasal prosthesis, if you will, that had two versions.

[358] One is that it combined both nostrils into one big nostril, centered, and the other is that it maintained two separated nostrils.

[359] And we compared performance under these two conditions, and people performed better with two nostrils over one centralized nostrils, although the flow remain the same.

[360] So you're taking advantage of the information that comes from your two separate, totally separate nostrils.

[361] By the way, the system I described before of your epithelium and bulb and connection to cortex, you have two of those, right?

[362] It's a completely unilateral, well, almost completely unilateral system.

[363] There's some very small exceptions to that.

[364] So a representation on both sides of the brain.

[365] Much in the same way we have two eyes.

[366] We're not a cyclops.

[367] We can gain depth perception information.

[368] We can perceive motion better as a consequence.

[369] and a number of a depth, especially stereopsis.

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

[371] Another question about the mechanics and strategies that you observed because I think there's information about the system, the brain, as a consequence.

[372] Were you in a position to measure sniffing frequency?

[373] And the specific question I have is, were people doing something along the lines of a quick sniffing or a, like a, you know, a long drawl in inhale.

[374] You know, we didn't, so yes, we were measuring sniffing and recording it and we have all the data.

[375] There was nothing very remarkable in that data in that study, although it may reflect that we didn't analyze it carefully enough as well.

[376] I mean, it didn't, it wasn't a major component of our analysis.

[377] Although we did look at it to some extent.

[378] Again, you're asking me about a paper from quite a few years ago, so I may be forgetting parts of it as well.

[379] I'm sure if it was a major component of it, it would have risen to the top.

[380] It definitely wasn't a major finding of the sniffing behavior in the paper.

[381] Although, again, you know, sniffing behavior is a huge portion of our life in lab.

[382] And it's taking us to places.

[383] and it's re -emerging now in our work.

[384] We're doing tons of sniffing work.

[385] You know, 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.

[386] I'll invite you to do the following experiment.

[387] So occlude one nostril by pressing on it from the side and sniff in and then include the other and sniff in.

[388] Do you sense it?

[389] difference in flow.

[390] Yes.

[391] Okay.

[392] Do you know why that is?

[393] No, and it was the next question on my list.

[394] Don't feel badly about not knowing why that is.

[395] Most people don't, but that is a reflection of something referred to as the nasal cycle.

[396] So in fact, if you were to do that repeatedly, you would find that your high flow nostril and low flow nostril alternate every two and a half hours on average.

[397] In an absolute way, or is it kind of like a sine wave, like gradual shift to at one and then gradual shift back it can vary it can vary and we don't yet know the rules uh all the rules but 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 uh balance in autonomic nervous system.

[398] So as you and your listeners know, we have an autonomic nervous system that has a sympathetic and parasympathetic component to it, and they're in balance or imbalance in many diseases, for example.

[399] And this interplay between the sympathetic and parasympathetic nervous system drives the switch from left to right nostril.

[400] Just to remind people, sympathetic nervous system has nothing to do with sympathy, has everything to do with generating patterns of alertness.

[401] It's sometimes called the fight or flight system, but any pattern of arousal, positive or negative, and then it's balanced in a coordinated way, or at least in parallel with the parasympathetic nervous system, which is sometimes called the rest and digest system, but is associated with all sorts of things, the sexual arousal response and a number of other aspects of our physiology.

[402] So think of it like a seesaw of alertness and calm.

[403] Perfect.

[404] So now imagine, right, imagine you would walk around living your life, right?

[405] 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 pub med there would be five 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 you have exactly this marker you're walking around the 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 We built a wearable device that is pasted to your body and measures airflow in each nostrils separately and logs it for 24 hours.

[406] And we're collecting these 24 hour recordings.

[407] We're calling it the nasal halter.

[408] So we measure with the nasal halter and we're finding it as a disease marker.

[409] I can give you a nasal halter measurement as an adult and I can say this is worked by my team Nostaroka graduates in our lab now.

[410] I can tell the difference between ADHD and non -ADHD adults.

[411] And we can tell just from the recording, we can tell if the adults are in Ritalin or not.

[412] So I can measure your nasal airflow and say if you are or are not with ADHD and if you are or not on Ritalin.

[413] Incredible.

[414] I have a couple of questions about this.

[415] Is it the case that airflow through one nostril is reflective of, of a sympathetic nervous system dominance versus parasympathetic?

[416] Or is it simply the case that this alternating left -right nostril periodicity, which you said, I think, is on the order of about every two hours.

[417] Two and a half.

[418] Two and a half.

[419] It switches to maximal on one side versus the other.

[420] Is that simply reflective of an overall balancing?

[421] Maybe is it the hinge in the seesaw or is it the tilt of the seesaw?

[422] So I don't have a good answer.

[423] I don't have a good answer.

[424] I mean, you know, I could give you sort of a, you know, I could say that to some extent, uh, right nostril more open, um, is more sympathetic and the left nostril more open is more parasympathetic.

[425] But that that wouldn't be very correct.

[426] I mean, you know, it's, I'm sure that it's, you know, the yogis are going to be all over this, right?

[427] So wait, I have to describe my lab does do some stuff on, on breathing.

[428] And the, the yogis are always saying, okay, you know, because there's this thing, I don't do yoga anymore, but not for any paranayama, but, um, where they'll have you breathe through one nostril or the other.

[429] And I've probably been asked this question on social media 10 ,000 times.

[430] Okay, wait.

[431] I'm going to become public enemy number one of the yogis right now.

[432] So listen, so we, we, they'll come at you with yoga mats, which are not very dangerous.

[433] 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, is to gain control of it somehow.

[434] And there's this world out there of yoga who claims to have control over this.

[435] 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 not by manipulating themselves somehow and and if yes you know we'll learn from them how they do this and then we might you know use this to cure ADHD or or whatnot right so so we posted like on all lists of like the yoga teachers and had this parade of yoga teachers walking into our lab this was one of the strangers a lot of sandalwood odors and bear their feet white clothing and so on and and so we we study i actually know we studied 14 yoga teachers all 14 uh by you know by the conditions of enlistment for this uh came in saying that they they can control shifting from left to right uh nostril without plugging a nostril by by the power of thought alone um and you know how many of 14 succeeded zero including including including one, you know, there was extreme one, was we had this guy who, you know, and we're recording, and we know how to record this really well, right?

[436] And he's sitting there saying, yeah, I'm switching now, and it's switching.

[437] And you know, you're looking at the monitor and no, it's not switching.

[438] And so no yoga teacher that we found could willfully switch between left and right nostril flow.

[439] 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?

[440] Yeah, no. Even the opposite, I mean, you know, this puts them in an awkward position once, yeah, I don't know what the deal is, but none of them can do it.

[441] 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?

[442] Because that's reflective of the autonomic nervous system.

[443] 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.

[444] In other words, is the unilateral smelling through, or unilateral nostril smelling periodicity that we named it something, I could name it the wrong thing, I'm sure.

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

[446] So you've very concisely now worded aim two of a grant that was probably just rejected.

[447] But basically we're trying to answer exactly that question and we're currently running experiments on that line so so we have one experiment where we're looking um so we're exposing participants to pain we're using cold water hand exposure it's a really cool paradigm because it there's huge individual differences we just started this we built the setup just now and you have a lot of meat to work with there because there's a lot of individual differences.

[448] It's capped at three minutes for safety reasons because you have participants putting their hand in two degrees Celsius water.

[449] 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.

[450] 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 are the exposure to cold generates a shift in the nasal balance.

[451] So autonomic arousal can drive the shift, potentially.

[452] Earlier, you were describing the architecture of these smelling systems.

[453] And you mentioned these glomeriali where the olfactory receptors converge in the bulb.

[454] And then later you mentioned that the system is unilateral but with a mirror representation on both sides of the brain.

[455] So for those who don't think in terms of neuroanatomy, what Noam was describing is the fact, fact that of course there are two nostrils and then a bunch of receptors they converge in these glomeruli, but you have a mirror representation of that on both sides of the brain and that most of that information is kept on one side of the brain or the other.

[456] There isn't a lot of extensive intermixing at the first order of processing.

[457] So the question I have is whether or not you believe, I'm not asking for data.

[458] 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.

[459] Most of what people hear out there about right brain, left brain, emotionality, logical stuff is completely wrong, completely wrong, doesn't exist, is a total fabrication, and we'd like to abolish that myth.

[460] But with that aside, or set aside, rather, what are your thoughts on why the information would switch from one side of the brain?

[461] to the other at all.

[462] I don't think, I don't think that the nasal cycle is an olfaction story.

[463] So I don't think that this was shaped by the olfactory system, nor do I think this has major impact on olfaction.

[464] I think the nasal cycle story is a different story about brain function.

[465] So, you know, we have this sort of pet theory where 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.

[466] And this theory is olfaction inspired in its beginning.

[467] 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?

[468] And then you have information and then nothing.

[469] So information processing is one -to -one linked to nasal inhalation.

[470] 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.

[471] So a study led by Ofer Perel from our lab two, three years ago, we looked at something completely non -alphactory.

[472] We looked at visual spatial processing.

[473] And we compared visuospatial processing on inhalation versus exhalation.

[474] And the brain does this completely different on inhalation versus exhalation.

[475] In that particular task, people performed significantly better on inhalation versus exhalation.

[476] What was the task?

[477] Was it an olfactory task?

[478] No, no, it's a visuospatial task.

[479] So 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.

[480] So some of them are these like usher shapes like, you know, where one facet doesn't reach the other facet.

[481] The impossible figure type of stuff.

[482] Yeah, but structural shapes, not, not.

[483] 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.

[484] And people performed much better on inhalation versus exhalation at doing this task.

[485] Was there a both nostrils occluded version where people were forced to mouth breathe?

[486] Yes.

[487] And in this particular task, they also did better on mouth inhalation versus mouth exhalation.

[488] But the difference wasn't as pronounced as it was with nasal inhalation versus exhalation.

[489] So I'm a big proponent of nasal, not mouth.

[490] breathing whenever possible for many health -related reasons.

[491] I'm a big fan of the book.

[492] Jaws, a hidden epidemic written by colleagues of mine at Stanford.

[493] You're familiar with it.

[494] And this idea that people who mouth breathe experience more colds, more infections of various kinds.

[495] It's not good aesthetically or for the dentature.

[496] I never know the teeth, the gums, it's stuff.

[497] Sorry, my dentist is going to come after me. Need to go to the dentist anyway.

[498] Okay, that nose breathing is great for your health relative to mouth breathing.

[499] So I think it's also good for your cognition, not only for your dental health.

[500] I think that nose breathing shapes cognition.

[501] And there are other labs who are finding the same.

[502] Again, Christina Zellano is doing work on this line.

[503] She had major contributions here, and Yuan Lundstrom is doing work on this line.

[504] And there's lots of studies suggesting that nasal inhalation is timing, cognitive processing, and modulating it.

[505] Incredible.

[506] Perhaps not surprising, given what you've taught us about the olfactory system.

[507] I mean, these two holes in the front of our face, these nostrils, I mean, are a pathway to the brain.

[508] 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.

[509] which they are, the retinas anyhow.

[510] And then you never look at anyone the same way again.

[511] But the olfactory sensory neurons are right there at the tops of those caverns that we call nostrils, and they are brain.

[512] Yeah, definitely.

[513] It's the only place where your brain meets the outside world, because in your retina, they're protected by a lens.

[514] And here you have neurons in contact with the world.

[515] This actually has been the source.

[516] for some theories on a potential route for neurodegenerative mechanisms.

[517] So as you may know, loss of the sense of smell is one of the, if not the earliest sign of neurodegenerative disease.

[518] So for example, in Parkinson's disease, there's loss in the sense of smell probably 10 years before any other symptom.

[519] But people have failed to make this a diagnosis diagnostic tool because it's nonspecific.

[520] 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.

[521] But olfactory loss, again, is an early sign of neurodegeneration.

[522] 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.

[523] 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.

[524] 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.

[525] I'm beginning to wonder why we don't have a olfactory task every time we go to the doctor that would allow tracking over time because, of course, as you mentioned, someone can lose their sense of smell.

[526] Does that mean they're getting Alzheimer's and not necessarily?

[527] but if their sense of smell was terrific the year before and it's 50 % worse the next year.

[528] That's a really bad sign.

[529] Yeah, that's a bad sign.

[530] And so what we were talking about, something completely non -invasive and could be relatively pleasant to innocuous, depending on the odors used.

[531] So yeah, so first I can answer that, right?

[532] And the reason that that's not happened.

[533] And that may be changing right now.

[534] But the reason that has not happened is because olfaction has not been effectively digitized.

[535] right so if you need to generate you know really precise visual information you can buy a monitor for you know 100 bucks that is at the resolution of the visual system basically and if you want to generate auditory stimuli really precisely then you can buy an amplifier for you know maybe a bit more than hundred bucks but not that much more and you'll be at the resolution of the auditory system in our lab we build devices that generate odors we call them all factometers which is a misnomer because they don't measure anything, but that's what they've always been called.

[536] So we call them all spectrometers as well.

[537] And we've already built at least one olfactometer that cost a quarter of a million euro.

[538] And it's pathetic, right?

[539] So it just, it's pathetic.

[540] It's, it's slow.

[541] It's contaminated.

[542] It's nowhere near the resolution of your system.

[543] So one of the reasons that's not happened is just the utterly poor control of the stimulus.

[544] Mind you, to some extent, it has happened in And there are standard clinical tests of olfaction, basically two that sort of control the world in this respect.

[545] The older one is a test called the UPSIT, which stands for the University of Pennsylvania smell identification test.

[546] It was developed by Richard Doty in Penn. And it's a test where you scratch and sniff and it's a four alternative force choice test with four deodorants.

[547] So you have these 40 pages that you page through and you sniff and smell.

[548] and, you know, it's been normed on gazillions of tests.

[549] 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.

[550] He has a NASCAR.

[551] So this, every time we buy UPSITs in the lab, I say there's another gallon of gas into Richard Doty.

[552] He races NASCAR?

[553] It's not like NASCAR, but like one lower than that.

[554] Like, I don't know, like some sort of formula A or formula.

[555] the Ford or some he races a car and so that's where all the ubsites went so i always feel good about buying you the PSITs because i know they're going to that good cause but keeping him in in the fast lane yeah but but so so that's one test that's out there and and indeed you know has been shown as a you know so there's reduced uPSIT in alzheimer's in parkinson's and in a host of other diseases and there's a european version called sniffing sticks uh that thomas humel uh has developed and And it's basically the same sort of concept of that one isn't scratch and sniff.

[556] It's like these pens that you open up and sniff.

[557] But those exist, but they're not as convenient as delivering stimuli and vision and audition.

[558] And that's why you don't have what you've just suggested.

[559] You know, another place where you don't have it, which I think is even more, would have been even more meaningful, is you don't.

[560] 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 contenderal uh which is half a percent of the population it's not a trivial number not totally yeah but nobody knows if that really is true because here's an amazing factoid guess the average age at which congenital anosmia is diagnosed.

[561] And this is a horrible statistic for me for the way I see the world.

[562] But what do you think the average age of diagnosis is for congenital anosmia?

[563] Five years old age.

[564] 14.

[565] Incredible.

[566] 14.

[567] So most people who are one half of 1 % of the human population, presumably, yeah, is without the sense of smell and doesn't realize that until they're 14 years old.

[568] Well, I don't know when they realized it first, but it's formally diagnosed.

[569] at 14 on average, which means some of them even later, right?

[570] And, right, it's a distribution.

[571] What, do they suffer?

[572] Yes.

[573] So, first of all, they suffer socially.

[574] And there's a host of deleterious life events associated with congenital an osmium.

[575] They die younger.

[576] So it's, it's, it's, it's, it's, it's, this is work out of, uh, Ilona Kroy in Germany.

[577] Um, and, you know, amongst the various things that are predicted by an osmia is shorter lifespan.

[578] Uh, but things like, you know, reduced, uh, social contacts, uh, reduced, um, romantic social contacts.

[579] Um, it's not a good thing.

[580] Um, and, and, and do they lack olfactory bulbs.

[581] I'm presuming they have noses and nostrils.

[582] There is a condition I'm aware of where children are born without noses or not.

[583] Very rare.

[584] Very rare.

[585] We don't focus on that because it's exceedingly rare.

[586] But they're born with noses and nostrils.

[587] And here's the thing, right, we don't know if they're born with olfactory bulbs.

[588] Most of them, although not all of them, but most of them don't have olfactory bulbs in adulthood.

[589] Or I should rephrase that, have remnant olfactory bulbs, really shriveled olfactory bulbs.

[590] But, you know, nobody can say the cause and effect here.

[591] 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 feeling, of romantic attraction, attachment, these sorts of things.

[592] Is it known whether or not, and I should say, excuse me, for interrupting myself, but as long as I'm interrupting you every five minutes, I might as well interrupt myself too, that we are well aware of the proximity of the olfactory system to some of the hypothalamic systems that regulate the release of gonadotropins, which control testosterone and estrogen production, et cetera.

[593] So are they hormonally normal?

[594] So some aren't, some aren't, in I'll be specific, so there is a condition known as Kalman's syndrome, which is hypogonatic development in men.

[595] And in Kalman syndrome, they're practically all anasmic.

[596] So to answer your question, yes, there's a direct link and it materializes in Kalman syndrome.

[597] That said, not all congeneral the anosmic individuals have Kalman syndrome.

[598] And not all, but almost all, people who have common syndrome are an osmic.

[599] So Kalman syndrome goes with anosmia.

[600] I think, so there's a female equivalent of Kalmans or I don't remember its name.

[601] It's not in the Turner syndrome family.

[602] I'm not sure.

[603] And I think it's also associated with anosmia, but I'm not confident of that.

[604] but commons is associated with an osmia so the answer is is yes and and you know we can maybe you know olfaction and reproduction are are 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 you ask you as a segue to that.

[605] Noting, of course, that we'll get back to the requirement for olfactory bulbs, yes or no for olfaction.

[606] And this relates to when I was growing up, I grew up at the end of a street with a lot of boys of my age, who just by coincidence had a lot of older sisters that were my sister, my older sister's age.

[607] It was fortunate, so I had a lot of kids to play with.

[608] We would hang out of each other's houses, bike, build jumps and do all his things like kid stuff, fort stuff, get into trouble or whatnot.

[609] And oftentimes we would end up leaving our articles of clothing at each other's houses all the time, like t -shirts and jackets.

[610] And so my mom was constantly coming in and saying, there's all, there's this clothes like someone left us here.

[611] I don't know who it was.

[612] We were all more or less the same size.

[613] And from as far back as I could remember, six, seven years old and onward, I could pick up a shirt or a jacket.

[614] it, smell it, and say, oh, well, that's Eric Eisenhart's shirt, a friend of mine there.

[615] I just gave his name.

[616] Or, oh, that's Scott Madsen's shirt.

[617] I could just smell the shirt and in a conscious way know who it belonged to.

[618] Having never, I promise, not that I would pretend if I had, pretend that I hadn't if I had, but having never actually done the exercise of going and taking and smelling my friend intentionally.

[619] Right.

[620] Okay.

[621] In fact, if anything, I had all the reasons in the world to avoid smelling, the other young boys in my neighborhood.

[622] Okay, so that raises a 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.

[623] Yeah.

[624] So, yes.

[625] We're doing that all the time.

[626] in my view and a lot of this processing almost all of it is subconscious and I don't know why already I already put that out there right I have no idea why why human nature has has or nature or culture or whatnot has as pushed this into the realm of of subconscious and something we're unaware of but we do it all the time and and And in our lab has lots of studies on this front.

[627] One of them you may be familiar with it that had gained some notoriety because it's amusing.

[628] So we look at human behavior a lot.

[629] We try to look at it through our nose and in the way we look at what people are doing.

[630] You know, we try to think, you know, if I was a dog, what would I think of this?

[631] And, you know, if you look at dogs, right, they've, you know, when they interact, they visibly sniff each other.

[632] It's very obvious.

[633] They walk up to each other and they sniff each other.

[634] And yet humans don't typically walk up to a stranger and carefully sniff them, right?

[635] I mean, we're sort of obliged to sniff our babies.

[636] That's considered almost something you're supposed to do.

[637] And it's not culturally taboo to sniff our loved ones.

[638] 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 and there's really poor understanding of how this behavior evolved like where did where did this thing come from so if you you know if you look for the wikipedia version right then they'll tell you that it's to show that you're not holding a weapon in your hand but there's really no good evidence for that it's a bit like the trillion bloodhound receptor story right i mean we tried to find that you know why do people say that and they just do and we started looking at people handshaking And we noticed, or it seemed to us, that we're noticing that, you know, people will shake hands and then go like this and like this.

[639] For those of you listening not watching, Gnome is taking his hand and wiping it on his face.

[640] Grabbing his nose or touching myself.

[641] Yeah, these things that we do all the time.

[642] After a handshake.

[643] Well, so first of all, we do them all the time, just period.

[644] The baseline here is really high and we'll get to that in a second.

[645] But these behaviors that, you know, you could easily not notice, right?

[646] And so we asked whether that's a real thing.

[647] And this was a study led by Don Fruming in our lab at the time.

[648] And what we did first, and if you want, we can link.

[649] So this was published in E -Life.

[650] And one of the nice things about E -Life is that it has a very effective way to embed videos in the publication.

[651] So if you want, we can link this to your system later on.

[652] We'll put it in the show note captions as a link on YouTube and the other four.

[653] platform, Spotify, Apple.

[654] So what we did is we brought in participants to our lab, and we sat them in the room, experiment room, and told them the experiment would start soon and they should wait for us there.

[655] They didn't know what they were coming from.

[656] Unbeknownst to them, they were already being videoed.

[657] 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 for the video that's now on e -life and and we walk into the room and say okay just wait here we'll be right back with you to set up our experiment and they would sit there for three minutes and during those three minutes we could later quantify how much indeed they just by baseline how much they touch their nose or their forehead or their chin or how many times their hand reaches their face and by the way that baseline is not low okay um and And then three minutes later, an experimenter would walk into the room and would share a consistent text.

[658] It would be, you know, we're still setting up our equipment in the other room.

[659] And so just wait here and we'll be right back with you.

[660] But in the meantime, just wait here.

[661] And the experimenter went through this like 20 second fixed text.

[662] And in half of the cases, it included a handshake.

[663] This was a new experimenter, not the one who put them in the room.

[664] So it's the first time they met.

[665] So it would be a little, I'm, you know, so -and -so, they would put out their hand and shake their hand or not.

[666] Okay, and we did all possible interactions in terms of gender.

[667] So we matched male participants with male and female experimenters and female participants with female and male experimenters.

[668] And so you had handshake and no handshake conditions.

[669] And then you can quantify that behavior of the hand going to the nose after handshake.

[670] And there was a remarkable increase in the hand going to the nose after handshake.

[671] And this is one of the nice cases.

[672] The paper includes statistics, but you don't need statistics here.

[673] Just look at the video.

[674] 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 unbeknown stand to participants we measured nasal airflow and and people not only bring their hand to their nose they sniff it so and this is perfectly time they go like this okay so they're sniffing their hand and in an additional control study we manipulated it so we built this little james bond thing of a watch on the experimenter's hand they could emit an odor.

[675] And the experimenter didn't know what odor they were emitting and they could emit either a pleasant or an unpleasant odor and we could drive the self -sampling afterwards up or down.

[676] So this was an olfactory behavior, no doubt about it.

[677] I mean, we're quite confident.

[678] 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, correct?

[679] 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.

[680] The odor cloud of the experimenter.

[681] Yeah, and there's an interesting thing going on here, too, because people didn't only smell the hand that shook.

[682] They also smelled the other hand.

[683] And we think that there's something going on here comparing self to other.

[684] And we think a lot of self -sampling might reflect that.

[685] There's on the same line, and again, to link to your childhood story of identifying your friends by smell.

[686] Study we published just last year by Inbal Ravrebi in our lab, where Inbal came with this basic interest in this phenomenon that's loosely referred to as click friendships.

[687] So people you meet and you click right away, right?

[688] you immediately become close friends and this is a phenomenon that you know is poorly described or is poorly described in literature as as 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 what was there right what was it was it because you look the same could be was it because you know you had the same sports team that you liked or is there something deeper here and and in by the theory was that that um that a similarity in body odor may contribute to this that people who smell the same will click in some way and so to address that she she actually recruited click friends from all over israel she posted all over social media to identify pairs of friends.

[689] So these are same -sex non -romantic dyads.

[690] So these are friends, men and women, whose friendship started is a clique where here this becomes sensitive because it has to be a mutual click, right?

[691] Later on, we discovered there could be one -sided clicks.

[692] So somebody's sure they clicked with somebody else, but the other person.

[693] There's a name for that in neurology that our common friend, the late Ben Barris, taught me, which is there's a phrase that neurologists use okay called sticky these are people that come up to you and and start asking you questions and then won't leave you alone they're so -called sticky people that and if you ask these sticky people um sticky in air quotes because they're not physically sticky um they may be what they could be um you know what do you think of the this person they'll say oh they're great we're really good friends and so they've made a unilateral um click friendship yeah yeah and uh yes neurologists are talking about you if you're one of these people neurologists are talking about you there's a an informal diagnostic code sticky so so so uh she she recruited um click friends and then she um sampled their body order and we have a protocol for this so they're given you know uh odorless shampoo and soap to use for three weeks or something and then they sleep two nights in this t -shirt where they have sleep alone and then we extract the body order from the t -shirt and so we have a way to extract a method to extract body order and then she she first asked um whether indeed click friends are more similar in their body order than you would expect by chance and she first tested this with the device a machine we call on the 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.

[694] In this case, sensors referred to as moxers as metal oxide covered sensors.

[695] And so she used an electronic nose to sample these body orders.

[696] And she found that click friends are indeed more similar to each other than you would expect by chance by random diads.

[697] And this was a significant difference.

[698] And after she found that a device could do this, she had other participants do this.

[699] So she had people smelling the click friends for versus non -Click friends, and they judge them as being more similar to each other than not.

[700] Now again, you might wonder, is this causal or not right?

[701] Because maybe Click friends go to the same restaurant together or all the time or whatever, live in the same neighborhood, and that's why they smell the same.

[702] 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.

[703] 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.

[704] And one prediction there panned out, but another didn't.

[705] The one that didn't, so she predicted that people would smell more similar to each other would be better at the mirror game.

[706] That is, they would follow each other better.

[707] That did not pan out.

[708] However, she then also had, the interaction was completely not.

[709] 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 okay all of this was predicted by the electronic nose so people who smell more similar to each other think that the other person is more likely to be their friend, is more likely to be a nice person, et cetera, et cetera.

[710] So we could actually predict friendship using the electronic nose.

[711] So this is not a result of friendship.

[712] It plays into the causal elements of building friendship.

[713] So this is to relate to your childhood story.

[714] There's something going on here.

[715] We're constantly smelling ourselves.

[716] Constantly.

[717] This constantly, I mean, if you want to leak, I'm now, the reason I'm smiling, I mean, and your viewers or listeners will understand why I'm smiling.

[718] I'll send you a video to link into your podcast here.

[719] We thought of calling, the fact that people constantly sniff themselves, we thought of calling this the low effect.

[720] And low, so in America, this won't pass that effectively, but in the rest of the normal world, Joachim Lowe is the soccer, the national soccer coach of the German soccer team.

[721] So, I mean, I don't know who would be a very famous coach here, but Steve Kerr.

[722] 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.

[723] And once people will see this video, they'll understand why we thought of calling this the low effect.

[724] it's a very graphic, but people are constantly smelling themselves.

[725] They're smelling themselves with their hands.

[726] They're smelling themselves explicitly.

[727] People are constantly smelling themselves, constantly smelling others.

[728] I find this topic so interesting.

[729] And first of all, confession, I definitely smell myself multiple times per day.

[730] Everybody does.

[731] Okay, good.

[732] And I would do it anyway.

[733] I think I like most people, I either find my own smell to be neutral to pleasant.

[734] Occasionally, I'll be like, whoa, I need to take a shower.

[735] 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.

[736] So my understanding is that if, for instance, a mouse is given the option to mate with any number of other different mice, they will bias their choice toward the mouse that has the immune composition, the so -called MHC, major histocompatibility complex, which reflects immune diversity, the immune system that is most distant from theirs.

[737] 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.

[738] 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.

[739] In other words, whereas you 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.

[740] Right.

[741] So the way you describe the animal literature is correct.

[742] And there's evidence to similar mechanisms in humans.

[743] Our lab has not worked directly on this issue of romantic selection based on odor.

[744] there's a bunch of papers Wedkind et al in the Wedkin lab and also Porter I'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 order and that this is linked to MHC histocompatibility complex makeup of the portion of our genome that shapes our immune system to some extent.

[745] So this effect has been studied and reported on, again, extensively in mice and also in humans, not work that we've done.

[746] 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.

[747] So, and also related to, so it's not related to romanticism in any way, but it's related to reproduction.

[748] And indeed in our lab, we've not looked at romanticism, we have looked at, or are looking at reproduction.

[749] They're not always the same.

[750] Certainly.

[751] But they can't.

[752] They can.

[753] Animal, mammalian or terrestrial mammalian reproductive behavior is dominated by the sense of smell in mammals.

[754] 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.

[755] Most terrestrial mammals have another subsystem referred to as the secondary.

[756] olfactory system that has a separate sense organ in the nose.

[757] This organ is known as the vomeronasal organ.

[758] It's a small pit in the nasal passage of most terrestrial mammals.

[759] Sometimes it's described as a communicating pit because sometimes it connects the nasal passage to the roof of the mouth.

[760] Sometimes it connects both.

[761] And so there's this sense organ with its specific receptor subtypes v &Rs, vermoneazole receptors.

[762] And this is linked to a sort of separate portion of the olfactory bulb, not really the main olfactory bulb, but it's referred to as the accessory olfactory bulb.

[763] And from there directly to the limbic system, to the portions of the brain that control reproductive behavior and aggressive behavior.

[764] And, and 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.

[765] And some of these pheromonal effects are utterly remarkable.

[766] And in my view, the most remarkable of all is an effect known as the Bruce Effect.

[767] This was an effect discovered by Margaret Bruce in 1959.

[768] She was a British scientist.

[769] 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 order 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.

[770] She will abort it.

[771] Now, that's an insane decision made by the female here, right?

[772] Because she's invested quite a lot in this, right, in biological terms in forming this pregnancy and maintaining it.

[773] And yet she drops it.

[774] on the basis of an odor.

[775] And this effect is remarkably robust.

[776] And what do I mean by remarkably robust?

[777] So this will occur on about 80 % of exposures.

[778] Now, as you know, 80 % is 100 % in biology, right?

[779] I mean, there's nothing that happens at more than 80%.

[780] So it's a remarkably robust effect, this dropping of the pregnancy.

[781] And we know it's mediated by chemo -sensation through the nose.

[782] know for sure and we know in the following way.

[783] So first, it's enough to just bring the odor of the non -studd male.

[784] You don't have to bring the male himself, right?

[785] So you just can bring bedding from a non -sad male and that will induce the bruise effect.

[786] But of course, the most telling set of experiments is that if in the female mouse, you ablate the vomor nasal organ, you just burn this tiny structure in the nose, then the effect disappears.

[787] So the effect is completely dependent on the former nasal organ.

[788] And I find this utterly a remarkable effect, right?

[789] I mean, because, again, because of the extent of costs that the female takes on here based on this information and smell.

[790] Now, humans, the sort of the going notion in all faction is that humans don't have a functional vulnerable nasal organ.

[791] So we don't have that functional organ in our nose.

[792] Now, I'll point out we actually do have the pit.

[793] So the structure or the outlining structure is there.

[794] But the pit that we have is considered vestigial and non -functional.

[795] And what about this thing I learned about at Berkeley in Integrative Biology class that we have something called Jacobson's organ?

[796] This is the same organ.

[797] So Jacobson organs is the vomor nasal organ.

[798] It's also called Jacobson because I think Jacobson was a military physician in like the 1800s in Holland or something and he founded in a soldier who was operating on or something like that.

[799] The story comes from something like that.

[800] But Jacobson organ is another name for the formalisal organ.

[801] These are one in the same, the sensory organ of the accessory olfactory factory system.

[802] And again, the going notion is that.

[803] the human Jacobson organ or vomone's organ is vestigial.

[804] It's non -functional.

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

[806] No, it does not.

[807] So first of all, we know that lots of what are considered pheromonal effects, namely social, chemosignolian rodents are mediated by the main olfactory system.

[808] We know that for sure.

[809] There are several examples for this in mice and rats and rabbits and so on and so forth.

[810] So A, these can be mediated by the main olfactory system.

[811] And I'll, I'll come back to that in a second, but first to finish the Bruce effect.

[812] And second, and I'm going out on a limb here, but I'm willing to take that risk.

[813] For me, the jury is still out on human vomoranasal organ.

[814] The decision or the notion that it's non -functional relies on about one and a half papers postmortem looking for the nerve that connects this thing to the brain and failing to find it using staining and so on and so forth but staining postmortem studies and 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 it's not ideally set as it is when you sacrifice an animal and study its tissue.

[815] So based on really, really a paucity of studies that fail to find this nerve, the notion is that the structure is vestigial in humans.

[816] I don't have any evidence that it's functional, mind you, but I'm just not sure that it's not.

[817] But what we do have a suspicion is that humans may experience something similar to Bruce Effect.

[818] So, first of all, humans have an enormous number or ratio of spontaneous miscarriage.

[819] Are they occurring more often in the first trimester?

[820] Because you mentioned that in the Bruce Effect and the Mises, in the first three days or so fall in pregnancy, which in the mouse gestation, as I recall, is about 21 days in the mouse.

[821] So you're talking about one seventh of total gestation.

[822] So I'm not quick enough to, nor is it important to translate.

[823] But this would be first trimester.

[824] Yes, which is indeed when most miscarriage occurs.

[825] Now, humans have, again, a huge number of miscarriages.

[826] And the numbers, I'll soon share them with you.

[827] They sound odd.

[828] 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.

[829] So some papers talk about 90 % of all human pregnancies end in miscarriage.

[830] This is counting a failed implantation in day one, two, et cetera.

[831] More conservative studies talk about 50%.

[832] Nobody will argue 30%.

[833] Okay, so a huge number, a huge number of human pregnancies end in miscarriage.

[834] Now, out of these, there's a portion that are unexplained.

[835] Right?

[836] So nobody knows why.

[837] I mean, there are a portion that are explained by all sorts of genetic factors, developmental factors, and so on and so forth.

[838] But there's also a proportion that are unexplained.

[839] 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.

[840] 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 is unexplained repeated pregnancy loss.

[841] So formally, if you have two consecutive unexplained miscarriages, then that is sufficient for the diagnosis of unexplained repeated pregnancy loss.

[842] However, in our cohort of 30, we had couples who experienced 12 consecutive, unexplained repeated pregnancy losses.

[843] So the two is just the formal.

[844] All of our cohort was like 12, 5, you know, so this is an emotional, difficult place to be.

[845] And these are couples who are losing their pregnancy for no apparent reason.

[846] 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.

[847] And the medical establishment remains totally at a loss as to why these pregnancies aren't holding.

[848] And so we hypothesized that perhaps here there's something akin to a Bruce -type effect.

[849] Obviously, it's not going to be the same as in mice, but something like a Bruce effect.

[850] Now, of course, at that stage, we could not do anything causal to test this, right?

[851] but what we could do is 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 and we found a few things first First of all, if you think of the mechanism is behind the Bruce Effect, the Bruce Effect implies that the female has to have a very clear memory of the fathering male.

[852] Because if she's going to miscarry in response to the nonfather, she has to know father non -father.

[853] I mean, that means that there's a pronounced olfactory memory at the moment of mating.

[854] okay and in mice this has been very well characterized and and attributed to the anterior olfactory nucleus a structure in the brain um but 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 in your childhood story from before stand out a bit as 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.

[855] 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.

[856] So you would think that women would be good at identifying the body order of their spouse.

[857] they're not.

[858] They're not far from chance.

[859] However, the women who experience repeated pregnancy loss are more than, they're double at their performance level.

[860] So this is not a nuance effect.

[861] Women who who experience repeated pregnancy loss can identify their husbands or their spouses by their body order.

[862] with much greater acuity than the typical person double a bit more than double and way above chance yeah no i i sorry i posed it as a question but i meant yes with much greater acuity uh and double is it is a significant um improvement are they much better at detecting any odor no they're not we did the controls and they're not and then um we also measured using fmri we measured their their brain response to a stranger male body order and there and and 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 you're just looking at the entire brain in the response to male body order and asking de novo is there a difference between these two groups of participants and there was one huge difference and it was in the hypothalamus.

[863] And so there was a difference in response to strange or male body order between the two groups.

[864] So olfaction is altered in spontaneous, repeated spontaneous pregnancy loss.

[865] We don't know this is causal, right?

[866] But that was enough for us to approach the ethics committee to run a causal experiment.

[867] And we're at the beginning of that.

[868] now.

[869] Incredible.

[870] I can't wait to hear the results of the experiment.

[871] It's going to take, it'll probably take years, a few, because these are slow experiments to run.

[872] Recruitment is complicated, but basically we're blocking smell in couples who are trying to maintain a pregnancy.

[873] I want to touch on some other so -called pheromone effects.

[874] 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?

[875] As you said, whether or not it's a classic pheromone effect or whether or not it's olfaction or something else, this is kemosensory signaling between individuals.

[876] The reason this is important to me is a few years ago, I did a social media post about pheromone effects and animals and some potential pheromone effects in humans.

[877] And a couple of the human olfaction, is more from the, actually who work on animal models, really came after me with intense sniffing, saying, you know, there is no evidence for human pheromone effects, human pheromone organs.

[878] And I think today you've beautifully illustrated how regardless of the answer to that, humans are contain and are emitting chemical signals that influence each other's physiology and behavior.

[879] For sure, for sure.

[880] And the term, the term is a problematic term in any case.

[881] I mean, the term, The term was put forth to describe insect behavior, right?

[882] 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?

[883] 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.

[884] Bambicol is a pheromone.

[885] Insect pheromone people will argue that this stuff that people talk about in mice and rats is not pheromones.

[886] I see.

[887] And it all becomes semantics.

[888] Yeah, sort of like nerdy inside ball.

[889] It's all semantics.

[890] So I don't, in our publications, we don't use the term pheromone, you know, because it would not help me and it would probably only hurt us.

[891] And so, you know, we talk about chemo signals.

[892] And humans definitely emit chemo signals from their body.

[893] and these chemo signals influence other humans and influence their behavior.

[894] You know, and there are several examples of this.

[895] One of them, I'll point out first, which is sort of the most widely studied and not mostly from our lab, actually.

[896] I mean, the flavor of the month for the past 10 years in this field is what's referred to as the smell of fear.

[897] Right?

[898] to this is probably true of many mammals and humans it's true of we emit a specific body odor when we're in the state of fear this was first discovered in humans by Denise Chen out of I think brown not true I think that's right yeah humans emit a particular body order when they're in a state of fear and this body order influences other humans in effect increasing the their autonomic arousal, their sympathetic state.

[899] So in effect, you could say that fear is contagious a bit.

[900] So the smell of fear is contagious.

[901] 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.

[902] So it was always said, but it wasn't really shown effectively.

[903] It was shown about a year and a half ago in a study.

[904] The dogs indeed can smell human fear.

[905] and humans can smell human fear.

[906] So several labs starting from Denise Chen and Havelin 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.

[907] What about the smell of safety or is that simply the absence of the odor corresponding to fear?

[908] And the reason I ask this is somewhat woke into our prior discussion about mate choice.

[909] Again, I'll ask the question in a form of brief anecdotes.

[910] I'll use the I had a friend who approach here.

[911] But 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.

[912] 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.

[913] 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.

[914] Very common behavior.

[915] If you're doing this, folks, other people are doing this too.

[916] It raises questions, for instance, about whether or not the morning period post -breakup, whether by decision by death or by some other phenomenon that's forced to, the breakup, whether or not that morning period has something to do with an olfactory unlearning of, um, and made slush, and on and on, with all these insights, I would offer you to be a postdoc.

[917] Well, I was going to say, listen, I have a sabbatical coming up.

[918] So I would love to do a sabbatical.

[919] But it's going to kill me. No, exactly.

[920] You don't want me to work for you.

[921] We talked about this earlier.

[922] That's what I'm saying.

[923] For other reasons.

[924] There's a story there.

[925] What Noam is referring to, I'll just tell people because inside jokes on a podcast that don't really work.

[926] Earlier I was just, I was referring to fact that I've had three in.

[927] incredible scientific mentors, undergraduate, graduate, and postdoc.

[928] 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 its early 60s.

[929] And the last one before he died, who was an MD and a common friend of gnomes, and I turned to me and said, you know, Andrew, you're the common denominator.

[930] So, you know, the joke in my business is you don't want me to work for you.

[931] So nonetheless, I would love to do a sabbatical in your last.

[932] So what I was trying to say in that roundabout way is that those are all really keen observations and good ideas for sure.

[933] And they just highlight, again, you know, that we're incredibly olfactory animals.

[934] You know, and you're even talking about the nuance.

[935] We're very olfactory, even not in the nuance.

[936] 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.

[937] And I have to deal with this a lot, right?

[938] I have to deal a lot.

[939] You study vision.

[940] Nobody will tell you that vision is unimportant.

[941] I have to visually dependent.

[942] 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.

[943] I bit into a blue, I love blueberries.

[944] I'm like a drive -by blueberry eater.

[945] If they're there, I just kind of pick them up like a grizzly bear and cram them in my mouth.

[946] So keep them away from me if you don't want them eating.

[947] But I almost can't help myself.

[948] I bit into a blueberry or a handful of blueberries and they just, it was the sensation of little bags of water and I immediately felt like tremendous grief.

[949] I'll tell you, a sort of a throwaway line that I use in this when I talk with people.

[950] You know, I mean, you know, take the two most basic behaviors that sustain us, right?

[951] Let's say I give you a choice between a beautiful looking layer cake with strawberries and blueberries and whipped cream.

[952] but that smells of sewage versus some gray -brown mix that smells of cinnamon which do you eat simple the latter right now imagine i offer you a mate choose the gender of your liking right that looks like a greek god or goddess right but smells of sewage or an ordinary -looking individual that smells of sin itself who do you choose the latter.

[953] Right.

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

[955] Definitely not always in predictable ways because you offered an extreme example, which is the best example.

[956] But I, for instance, for reasons I don't know, I've never liked the smell of perfume, ever.

[957] In fact, I find it aversive.

[958] But I do, I confess, I do like the smell of certain body odors very much.

[959] And I'm very, um, particular about that.

[960] And I know within an instant.

[961] 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 that sort.

[962] 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.

[963] In fact, they dislike it.

[964] And I've, and fortunately for me, there's at least one person on the planet who said the opposite.

[965] So the, so I completely, I completely agree with what you're saying.

[966] I can also say that I imprinted on the smell of my, I had a bulldog mastiff when I raised from the time he was a puppy, and I imprinted on, I imprinted on his smell immediately.

[967] And even though to other people, it was a bulldog mastiff after all, his smell was rather aversive.

[968] To me, he smelled delicious, right?

[969] And it made me, it smelled like home, and he was my best animal friend for a long time.

[970] So, and on and on and on.

[971] Right?

[972] The smell of children, as you said, the backs, we had a guest on this podcast, who I'm sure you're familiar, Charles Zucker.

[973] Yeah.

[974] A professor of Columbia has done incredible work in vision and olfaction, thirst sensing.

[975] And he, and I talked a little bit about this, that there's something in the breath of romantic partners that's hopefully appetitive, not aversive, as well as in children, he was talking about the smell of his grandchild's, the nape of their neck, under the back of their neck and how he misses that smell because when he thinks about missing his grandchild or children, it's that smell that that's associated with that feeling.

[976] Hexadecanal.

[977] Hexadecanal.

[978] Yes.

[979] Charles, your grandchildren smell like hexadecanal.

[980] Yes.

[981] He's going to come after me now.

[982] They do.

[983] And so this is a study ran by Eva Michore, who was a graduate student in our lab.

[984] And Eva was interested in aggression.

[985] She was really into aggression.

[986] And actually when she started and so when she started off, we said, okay, let's do chemo signaling of aggression.

[987] She actually was going to like MMA clubs and collecting body odors.

[988] And we had all sorts of ideas going.

[989] And she worked on that for quite a bit.

[990] It never went anywhere really.

[991] And then at the same time, we had a colleague of ours from Germany.

[992] I mean, when I say colleague, primarily a friend or acquaintance I met at conferences, Heinz Breer.

[993] And he was studying in his lab, a molecule, hexadecanal, that was a chemo signal in mice, where in mice it was described as a chemical.

[994] 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.

[995] 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.

[996] and in his work on hexadecanal, and so Breer and his colleague's swordsman, they discovered the receptor for this, and then they went and discovered that the receptor is very highly conserved throughout mammalian evolution, and therefore they hypothesized that maybe this is a universal mammalian signal.

[997] Now, which is unusual because in chemo signaling, typically you tend to think of things as being very species specific.

[998] But here they hypothesized that maybe hexadecanal, which promotes social buffering in mice, may do something in all mammals.

[999] Again, because this receptor is very highly conserved OR -37B, I think.

[1000] So he approached us and said, look, you gotta study this stuff in humans, right?

[1001] Because he knows us as the human people, right?

[1002] I mean, we go to these olfaction conferences where lots of people study mice and zebrafish and whatnot and we're the human group so and eventually he just fedexed us hexadecanal and 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 progression paradigm.

[1003] I'll soon describe it.

[1004] And so we said, okay, we have this hexadecanal stuff here and it promotes social buffering.

[1005] Social buffering sounds like it would make you less aggressive.

[1006] Why don't you run your tap experiment using hexadecanal?

[1007] What's the tap experiment?

[1008] 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.

[1009] And you can, you can, you can, you can do something like have another person walk into the other room playing online so so connected so you can fool them into being quite convinced that this is what's happening and they go into their own room and in the initial game they play um on each round they're uh 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 term each one of them decides how to divide the money up between the two right so they're playing against a another person, they think, but that's actually a computer algorithm that they're playing against.

[1010] And the computer algorithm is programmed to be an inside typic terminology, a jerk, right?

[1011] So, you know, like, let's say they have to divvy up 100 check -all, which is the Israeli currency.

[1012] So, so the other player would say, okay, you know, I'll keep 96 and you get four, right?

[1013] And then if you can either accept it or not accept and then neither of you get anything.

[1014] right so basically you're being shafted by by the other side all the time and this is called the provocation phase you're really getting angry at this person because they're they're really not nice right there 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.

[1015] And it's a really loud noise.

[1016] So you're also wearing earphones.

[1017] It's 90 dB, and it's a screeching horrible sound.

[1018] It's the most punishment that an IRB committee will let you endure on a participant in an experiment.

[1019] Unless you're in Stanford 70 years ago or whatever that was.

[1020] No one's referring to the classic prisoner experiment, which took place in the building next door to where I work.

[1021] So you can blast the other participant with varying.

[1022] levels of sound and you have a selection box from something very low to something very high.

[1023] And what's nice about this is that then allows you to quantify aggression because the more volume you're blasting the opponent, the more aggressive you are towards your opponent.

[1024] And so you have a measure of aggression.

[1025] Again, the Tyler aggression paradigm, obviously invented by Tyler, very well validated, studied all over, you know, a very standard protocol.

[1026] So we brought in participants and had them play the Tyler or the tap, either under exposure to hexadecanal or control.

[1027] Now, hexadecanal doesn't, it's incredibly difficult to even detect hexadecanal, but just in case, because it's not very, 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.

[1028] And she ran lots and lots and lots and lots of participants, men and women.

[1029] And I'll first tell you the result with men, which is that hexadecanal consistently reduced aggression.

[1030] People were less aggressive under hexadecanal.

[1031] The effect size was quite meaningful.

[1032] And later on we learned because I'm no specialist in the world of aggression.

[1033] But compared to the effects seen in the aggression world in research, really, really strong effects, so unusually strong.

[1034] So hexadecinell 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 it seems to do in mice.

[1035] But then we looked at the data from women, and hexadecinell increased aggression, equally significantly.

[1036] Is this thought to be something related to maternal protectiveness?

[1037] We're getting there.

[1038] So you got there really fast.

[1039] It took me a year, And Eva got to it, really, I'll tell you.

[1040] Because remember, we're reaching the back of the head of your, of, whose was it, grandchildren?

[1041] Charles Zucker.

[1042] The Charles Zucker.

[1043] One of the kingpins of the New York neuroscience mafia.

[1044] Yes.

[1045] So this was really odd to me at that time.

[1046] So I didn't have the intuition you just had.

[1047] And I was like, Eva, there was some bug here.

[1048] I mean, this, it makes no sense to me. You know, why would something increase, in women and decrease aggression in men.

[1049] This is really, really strange.

[1050] And I said, okay, I want to see this happen again before we go ahead with this.

[1051] 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.

[1052] And first of all, it replicated again.

[1053] So once again, hexadecanal men made men less aggressive and women more aggressive.

[1054] and the extent of more than the effect alone, the dissociation was remarkable.

[1055] This has, it's almost like a chromosomal test.

[1056] I mean, you look at the data on the unit slope line and all the men are below and all the women are above.

[1057] There's this figure in the paper.

[1058] Then she also looked at the brain data.

[1059] 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.

[1060] And this is, I think, sadly, I think the only studying 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.

[1061] 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.

[1062] now this is an area involved in what's referred to as social appraisal so that was kind of cool in that a social order activated the social brain not the 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 to angrilygiris and both men and women.

[1063] But then she did a follow -up analysis, which was look at what's referred to as functional connectivity.

[1064] That is, how does this region of the brain talk with the entire brain, as it were, under hexadecanal versus control?

[1065] And 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.

[1066] And the connectivity went in opposite directions in men and women.

[1067] So hexadecanal increased functional connectivity in men and decreased it in women.

[1068] So in a way, this is almost saying that the default brain reaction is aggression, right?

[1069] The default is to aggress.

[1070] And in men, hexadecanal increases the control that the left angular tyrus is holding over your aggression and keeping you back.

[1071] And And in women, it let it roam free and they became more aggressive.

[1072] But I was still puzzled.

[1073] So I was convinced this happened twice.

[1074] The MR.

[1075] Data provided not only a pattern but a mechanism, which is unusual.

[1076] 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.

[1077] And that is if you're a mammalian offspring.

[1078] because paternal aggression is often directed at you.

[1079] There's infanticide all over, and sadly, there's male aggression towards human children as well.

[1080] And maternal aggression is often protective.

[1081] 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.

[1082] So you're winning.

[1083] So we remembered a recently published paper from a group in Japan.

[1084] that looked at the odors emanating from baby heads.

[1085] We now come full circle to Suker's grandchildren.

[1086] They used a method known as GCMS, gas chromatography, mass spectrometry, to measure the volatiles from baby heads because babyhead odor is a cultural thing across cultures, even in Japan.

[1087] 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.

[1088] And so we wrote to the authors who are since then our co -authors.

[1089] And we said, look, we're studying this molecule, hexadecanol, and we don't see it in your results.

[1090] And we were wondering, maybe you had some results that you didn't publish or some supplementary materials or whatever.

[1091] And this lab, which is a hardcore GC lab, said, no, no, hexadecanol is a semi -volatile, which we knew.

[1092] And our previous paper was not directed to the semi -volatile range, but we can now do use what's called GCX -G -C -W -G -C that is directed at semi -volatiles, and we can do this again.

[1093] We just studied 11 babies, and we can see if this is an issue.

[1094] So we said, yeah, please do.

[1095] The bottom line of all this is that hexadecanol is the most abundant semi -volatile in baby hits.

[1096] It's tons of it coming out of baby hits.

[1097] So babies, again, speaking about if humans do or don't chemo -signol, babies are conducting chemical warfare, right?

[1098] They're, they're, you know, reducing aggression in their fathers or males around them and increasing aggression in their mothers or females around them.

[1099] And both of those things are good for them.

[1100] Incredible.

[1101] 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.

[1102] And that relates to the coordination of menstrual cycles among co -housed women or women who are friends.

[1103] Many women listening to this, and maybe some men who are aware of this effect, will say, oh, yeah, absolutely.

[1104] When I spend time with my friends or go away camping or even spend a day with them, our menstrual cycles become coordinated.

[1105] However, my understanding is that the early literature, Barbara McClintock, Correct.

[1106] Discovered this phenomenon, published a paper in science as an undergraduate.

[1107] 1971, nature.

[1108] Amazing, nature paper.

[1109] Again, one of the three apex journals and as an undergrad, fantastic.

[1110] So discover this, describe this and probably women all over the world who became aware of this, one way or another, probably said, yes, absolutely.

[1111] This gives validation to what we've observed over and over.

[1112] And yet, as subsequent papers have been published, this result has been called into question.

[1113] Is there any final word on whether or not menstrual cycles become coordinated among women who spend time together?

[1114] And if so, is there any role of olfaction in this?

[1115] Or chemo -sensing through the nostrils and or mouth to support this idea.

[1116] So, yeah.

[1117] 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.

[1118] And she noticed that she thought her menstrual cycle and her co -inhabitants in her dorm room were coordinated in time.

[1119] And I should say that this comes on the basis of similar or related type effects in rodents.

[1120] Now, Roons don't have a menstrual cycle like humans do, but there's an effect in ruins, referred to as the Witten Effect, which resembles this type of effect.

[1121] And she published indeed that paper is an undergraduate in Nature in 1971.

[1122] And to answer your question, she published a follow -up in 1998, also in Nature, with then her graduate student in Chicago Stern.

[1123] Stern.

[1124] So this is Stern and McClintock, 1998.

[1125] And here's what they did.

[1126] They collected sweat from donor women and deposited it on the upper lip of recipient women.

[1127] 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.

[1128] Well, I like certain body odors from certain individuals.

[1129] I don't think I uniformly like all body odors, although I do seem to uniformly not like the smell of perfume.

[1130] Although I should just to clarify, because I put this out there and I learned the hard way in the comment section on YouTube, some of those perfumes I find downright aversive.

[1131] Like it's a, I think the great Marcus Meister, who the great neurobiologist, one said, there's basically three responses.

[1132] It's either yum, yuck or meh.

[1133] So some are truly yuck.

[1134] I've never heard that one.

[1135] I got like that one, right?

[1136] In terms of the animal behavior, human behavior, we're either move forward, move back or a, or stop or pause.

[1137] So some are truly a yuck.

[1138] Some many are meh.

[1139] Zero to date are yum for me. Now, body odors, the distribution is shifted.

[1140] It could be any one of those three, yum, yuck, or meh, so just to be clear, but the yum category is definitely included.

[1141] Thank you for allowing me to do that.

[1142] So, so she did this.

[1143] this study.

[1144] So because right in the original McClintock study, you might suspect other drivers of the effect.

[1145] Let's say you accept the effect, but still there might be other social drivers of the effect that are not body odor, right?

[1146] There might be some dominant woman who's dominant in some other way, and this might be driving the coordination, right?

[1147] So here there was no direct link between these women other than body odor.

[1148] So if the effect reemerged, it would definitely be an olfactory effect.

[1149] And what she found is that if she She took sweat from the follicular or the ovulatory phase of the donors.

[1150] One extended the cycle in recipients and one shortened the cycle in recipient.

[1151] I 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.

[1152] Again, published in Nature in 1998.

[1153] That said, there's a quotation, I think this is from, from, I'm not sure, but, you know, that if something is published in nature or science, that doesn't necessarily mean it's not true.

[1154] So with that in mind, the findings were since called into question widely.

[1155] One reason is just statistics of cyclical.

[1156] events are surprisingly complicated.

[1157] So it's tricky.

[1158] Once you have a cyclic event, statistics become tricky.

[1159] And so Martha took a lot of heat on the statistics of claiming an effect.

[1160] And I think there was at least one effort of replication that didn't really work out.

[1161] If you asked me i'm on the fence so i'm and but i may be in a minority in my field i think a majority in the field uh is currently negative i'm not um and i've we've said in the lab that we should do a planned replication um we will it's just again it's a horrible study to run it's tons of work and you and you have to run it for really long time.

[1162] And so it's just completely non -trivial.

[1163] But we have a graduate student now in lab, interested in these exact things, Raute Weiss Gross, and she's doing similar stuff, and I hope we'll do that.

[1164] I hope we'll try to replicate this.

[1165] Very interesting result.

[1166] 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 grandmother's hands or the recognizing the scent of somebody or I knew from the moment that I smelled their breath or, you know, or I just liked their smell kind of thing.

[1167] These kind of things that inform the deep potential for a real biological phenomenon, as opposed to the kind of thing like, oh, you know, you just throw something out there.

[1168] Oxytocin is bonding.

[1169] And all of a sudden, you know, the general public, not at no fault of their own, comes to think that every aspect of bonding is oxytocin and every defect in bonding is lack of oxytocin.

[1170] But the general public provides a sort of a rich, it's fodder for exploring all these things.

[1171] And a lot of times they turn out to be true, right, in the context of old action.

[1172] Yeah, no, it's a very primal system, you know.

[1173] So it's linked to the most, you know, limbic primal mechanisms in our brain.

[1174] And it drives primal behavior.

[1175] It's an incredible system.

[1176] I have a question about a particular study, but I'm just going to queue it up and you'll know immediately what I'm queuing up.

[1177] And that is, what is the relationship between odors and hormones and in particular crying?

[1178] As I pointed out previously, the sort of flavor of the month in human social chemo -sigling research is the smell of fear and the media of the month is sweat, right?

[1179] 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 is there are there meaningful differences in terms of the sweat emitted from different locations on the body i already know the answer to that as i ask it but let's just stay above the waistline and um oh no no yeah so or below the waistline i mean we're biologists after all we just yeah so it's it's funny we we we we We have, we're working on a paper on that right now, on the smell of fear.

[1180] So we have a nice paradigm for generating fear.

[1181] We throw people out of airplanes.

[1182] It's a very effective way to generate fear.

[1183] I have to come to your lab.

[1184] It sounds like the greatest lab in the world.

[1185] We didn't invent that, by the way.

[1186] The first to do that was, and I hope I'm pronouncing her name correctly, I think.

[1187] It's Mujica Perudi.

[1188] But that's our paradigm for generating fear.

[1189] And we started that on our own, but we've since entered.

[1190] into collaboration with the Israeli paratroopers brigade and we now collect body odor from every first -time jumper.

[1191] So we went that path because we like everybody else in this field, you know, the holy grail there is finding the molecules, right?

[1192] I mean, if you'll have the fear molecules, that's a bonanza, right?

[1193] 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.

[1194] And when you find the cognate receptors, you can then develop blockers.

[1195] And you can imagine, you know, what's the term I'm looking for?

[1196] I'm switching into Hebrew.

[1197] It's about midnight now, right?

[1198] I'm sorry, it's two in the morning.

[1199] You're doing incredibly well considering the inversion of the circadian.

[1200] We would never know.

[1201] No one traveled in today from Israel.

[1202] So he's a circadian inverted as we say anxiety so so you can imagine developing like a nasal spray against anxiety right where 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 so that would be why i would want that and we figure out that doing that you know collecting fear from like three four five people in an experiment, you'll never be able to do analytical chemistry on that.

[1203] So we now have a setting we call Fear Bank, which now has more than a thousand samples in it.

[1204] So we're trying to do analytics on that.

[1205] But in doing that, we've joined the crowd.

[1206] Everybody's doing fear and everybody's doing sweat.

[1207] And in one of our discussions in the lab, we were saying, well, there's got to be, you know, or there potentially definitely could be the additional bodily media that are playing into social chemo signaling.

[1208] Now, many of these, you know, you can't really study, right?

[1209] I mean, so, you know, just to throw it right, most terrestrial mammals communicate social information through urine.

[1210] 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 then we, we, you know, this is a rare case where we actually, hypothesized what we said out to do and the only claim in retrospect that it was hypothesis is is tears um we we started thinking about tears and looking into tears because tears are a bodily liquid emotional tears that that we emit in emotional situations where these are situations where nonverbal communication is is critical and key and and tears are a a liquid that is puzzling beyond ocular maintenance, right?

[1211] And so, you know, the most influential text, I think, till this day in emotion research is Darwin's book, The Showing of the Emotions in Man and Animals, I think is the full name of the book.

[1212] And an entire chapter, Chapter 6, is devoted to tears an entire chapter of this book why with no conclusion why because the book revolves around describing the functional antecedents of emotional expressions so for example uh showing of the teeth as a sign of aggression right so so animals first bit with their teeth and and darwin argued that through evolution uh just uh showing the teeth alone became an aggressive sign because it started from biting Or what I find is a beautiful example, and this is work partly done by Adam Anderson now at Cornell, is the emotional expression of disgust.

[1213] So disgust, which comes from the line, dysgoosia, distaste, right, is spitting something out of your mouth.

[1214] 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.

[1215] So again, so there's a functional antecedent spitting something out.

[1216] And through evolution, the argument was that it became an expression of emotion.

[1217] And you express disgust just as if you're spitting something out of your mouth, even though in the case of moral disgust, there's nothing you're spinning out of your mouth.

[1218] So Darn systematically went through the expressions of emotions and for each one went to their functional antecedent and explained everything very nicely.

[1219] And then he got stuck with tears, right?

[1220] Because tears aren't obviously emotional expression, and he could not find a functional antecedent.

[1221] So he ended up saying, you know, this is an epic phenomenon, basically, right?

[1222] I don't know.

[1223] What all scientists do when they don't have a good explanation, blame it on nature.

[1224] Right, right.

[1225] 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.

[1226] but nothing emotional.

[1227] So we thought, well, maybe the function is a chemical signal.

[1228] And, you know, so with that in mind, we harvested emotional tears, which was also an amusing event on its own, right?

[1229] Because we posted messages on all sorts of boards that were seeking experiments.

[1230] participants who cry with ease now this generated an unfortunate gender bias in our study right because we received about a hundred women volunteers and about one man and you know i think this is not a problem only in in macho israel right probably anywhere in the west this would i mean definitely in america would be the same i think my guess is that there are probably men out there who cry easily emotional tears easily 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 in a lab and say i you know i cry all the time.

[1231] It's just not going to happen.

[1232] And then what we did is for each one of these participants, you know, we would ask them, you know, is there a particular film event that you know of that, you know, a scene that makes you cry.

[1233] 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.

[1234] You know, they have - Can you give me an example of one of the more commonly named scenes?

[1235] yeah with ease um the movie the champ the champ dies he's a boxer and he dies and literally in the hands of his about eight -year -old son and his son is standing next to his bed and you know saying champ champ and he dies right it's a winner okay waterfalls yeah yeah yeah got it so you know we're probably the neurobiology lab with most sad movie films on those health in the world right we have a whole huge collection there is something is tears of joy so no no well we're going ahead of ourselves but i just 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 in in the effective criers we end up screening so uh you know it's We collect a full ML of tears, a full ML of tears in about 15 minutes.

[1236] Wow.

[1237] So that's pouring, right?

[1238] And that doesn't happen from laughter.

[1239] That we've never seen that.

[1240] We've never seen that happen from laughter.

[1241] We tried.

[1242] So, so, so we have, we have all these sad films.

[1243] And by the way, one of the amusing things is, when we ultimately published this paper in science, we were forced, in retrospect, to go out and actually buy the films, right?

[1244] I mean, you know, originally we, like, downloaded them here and there, but you can't because you'd be violating, you know, copyright laws.

[1245] Right.

[1246] So we had to buy, like, purchase all these films that the parts of the stuff.

[1247] And watch them.

[1248] So we actually have these in live, like DVDs, you know, that we actually purchased.

[1249] But so.

[1250] Nice coverage of potential legal fallout there.

[1251] No. No, we did.

[1252] No, I believe you.

[1253] I believe it.

[1254] Yeah, it was that.

[1255] So, yeah, and, well, we can touch on that later.

[1256] But, but, so we, so most of these volunteers who, who come saying they can cry with ease actually don't meet the bill.

[1257] And so out of the about hundred at least more women that we screened, we ended up with about six who, who, who could.

[1258] really come to lab week after week and poor tears.

[1259] There's a name for this in psychiatry.

[1260] They call it a narrative distancing.

[1261] Some people, when they watch a film where someone's getting hit, they flinched quite a lot.

[1262] It's almost as if they're experiencing it.

[1263] But it works in the opposite direction too.

[1264] I know someone like this, where if they watch a film that someone's experiencing something even mildly positive, their mood elevate.

[1265] So they can quickly bridge and it's not always adaptive, as you can imagine.

[1266] So there's lack of narrative distancing.

[1267] Right, yeah.

[1268] 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?

[1269] I mean, we're assuming these are tiers.

[1270] No, this is pretty common.

[1271] I think the numbers I saw out there about 5 to 8 % of people.

[1272] That's exactly what we got about, right?

[1273] So we collected tiers.

[1274] And we exposed participants to these tears.

[1275] And we found a few things.

[1276] First of all, the tears are completely odorless.

[1277] You cannot detect them at all, completely odorless.

[1278] And yet, when you sniff them, you have a pronounced reduction in testosterone within about 20 minutes, half an hour.

[1279] This is men and women smelling women's tears, men smelling women's tears, but not perceiving any odor.

[1280] Nothing.

[1281] Just sniffing them.

[1282] And you have about 14 % drop in free testosterone, free.

[1283] Okay, so this is testosterone that's already been liberated from the testes.

[1284] Free testosterone.

[1285] We've done a few hormones that's either bound or unbound, is unbound, excuse me, from sex hormone, binding, globulin, et cetera.

[1286] and it's the active form.

[1287] So it's subject to very short time scale changes.

[1288] Yeah.

[1289] And this is, you know, people who studied testosterone, which is not me, but they tell me this is a really strong effect.

[1290] Like, it's hard to even pharmacologically get an effect like that that fast.

[1291] I mean, no in pharmacology.

[1292] Yeah, years ago, I spent time studying endocrine effects of this sort, and that's a tremendous resized effect.

[1293] So, and so here I'll point out in passing, that one of the concerns we had because of the effort to run this study is that nobody would ever try to replicate it and to our joy about two years later, an independent group from South Korea, O. It Al, who I don't know it all, replicated the testosterone effect to a T. I mean, like same numbers.

[1294] So it lowers testosterone.

[1295] And we then also looked using MR at the effect on brain activity and saw a 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.

[1296] Base recognition area.

[1297] amongst other things, yes, and we don't know why, but pronounced.

[1298] And currently, Shanier -Gron 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 evine in the hexadecinal experiment i'm going to think of that as the the sadist the titration the satus titration yeah yeah tyler aggression paradigm so not unlike the milgram experiments of the of the 1950s which post um 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.

[1299] And a lot of people did that, even though most people would report that they would never torture something else.

[1300] Yeah, yeah.

[1301] No, humans are not a wonderful species.

[1302] Or as we could say, I think it was the great Carl Jung that said, we have all things inside of us.

[1303] But the goal is not to experience them all, certainly.

[1304] It's an incredible study.

[1305] And it points again to the power.

[1306] of these chemo -sensory systems and pathways.

[1307] And obviously, there's so much here.

[1308] I don't know if you want me to tell about this or not.

[1309] And I guess you can edit it out.

[1310] This is just sharing stories about the politics of science.

[1311] So whereas the effect on testosterone was replicated by an independent group, in the original study in science where we had the, It had three components.

[1312] One was the effect on testosterone, which was robust.

[1313] The second, which was brain activity, which was robust.

[1314] And there was a significant but weaker effect on behavior.

[1315] And I don't think we studied the right behavior in retrospect.

[1316] What we looked at then was ratings of arousal associated with pictures.

[1317] And there was an effect.

[1318] It was significant, but it was not what carried the story.

[1319] Now, there's a lab in Holland of a guy by the name of Ving.

[1320] I'm probably mispronouncing this, but I think it's Vingerholtz.

[1321] For the non -Dutch.

[1322] Yeah.

[1323] Dutch names are always a little bit of a challenge.

[1324] And I shouldn't say that.

[1325] Being in Israeli, I shouldn't go too much on that line.

[1326] But that lab really didn't like our rejection.

[1327] tier story.

[1328] 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 tiers are uniquely human.

[1329] Now, here I should, well, I should share.

[1330] So one of the things we really liked about the tier result is that partially before we did our work, but more, afterwards, 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.

[1331] This was a rare case where after we did this work, more or less identical effects were discovered in rodents.

[1332] So a paper published in nature two years later found that mouse tears, mouse pup tears, lower aggression in male adult mice towards them in a in a smell dependent way yeah yeah so and and and they also actually found the actual component in tears that so the tear pharmon that lowers aggression right so you know this has us thinking of aggrat as tears as as as you can think of tears as like a chemical blanket in a way that that you're covering yourself up again with you know to protect against aggression right and and so our finding you know which to me i mean this is consistent with how i think about behavior in general, I don't think, you know, beyond language, there are very few things, definitely sensory things that are uniquely human.

[1333] You know, I'd be hard -pressed.

[1334] But so, you know, our finding went against their story, right?

[1335] Because, you know, here we're saying, no, you know, tears are this chemist signaling mechanism like all animals.

[1336] 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 and it was uh the dogs emit emotional tears when they reunite with their owners and you were talking before about about um oxytocin so i think what they showed there is that not only that but that the the view as seeing the tears and the dog influences oxytocin and in the humans i absolutely hope i'm getting this right no i absolutely believe this i mean i From the time I brought Costello home at eight weeks old.

[1337] Costello's your dog.

[1338] He was my dog.

[1339] I'm forcing to pass away, but haven't a long time.

[1340] Actually, the only time I can recall crying, listen, I've certainly cried before many times in my life, many, many times.

[1341] The only time I ever recall crying to the point where I wasn't sure that I could keep producing two years, but somehow it is when I had to put him down, right?

[1342] It's just like, you know, and if I talk about too long now, I'll start crying to me. You know, it's one of those things.

[1343] I think it's a healthy emotional state.

[1344] But I recall when he was a puppy thinking this oxytocin thing must be real because I can recall being in faculty meetings, which are fairly stated are not always that interesting, but they could be pretty interesting.

[1345] And someone presenting data and my mind thinking, I hope Costello is okay.

[1346] What's he doing down in my office?

[1347] This is when he was very little.

[1348] 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.

[1349] Then I could focus off on other things.

[1350] And I think that dogs, perhaps through oxytocin, hijack the circuitry that's intended for child rear.

[1351] I really do.

[1352] Otherwise, why would people be so ridiculously attached to their dogs?

[1353] Hence all the posts of everyone thinks their dog is the cutest dog, the same way everyone thinks their children are the cutest children.

[1354] You know, Costello, by the way, was a very handsome bulldog.

[1355] So, yeah, so again, So even, you know, to put another nail in that story of tears are uniquely human, so they're not.

[1356] Dogs shed emotional tears.

[1357] And so that group really didn't like this.

[1358] And they went ahead and tried to replicate.

[1359] And to your listeners, I'm showing double quotations on the replicate, only the behavioral part, the ratings of arousal in women.

[1360] of women and and failed to replicate that i see now this was you know just sharing on how science works and doesn't work in my in my notion in this case so at the time um after they got this accepted in some journal um not a field journal in the journal of memory of something um they contacted me for a uh a recent response.

[1361] And I wrote to the authors and I said, look, you know, this is very odd to me. Why don't you come?

[1362] Why don't we replicate this again together and see if it doesn't work.

[1363] If it doesn't work, I'll publish it with you that it doesn't work.

[1364] But, you know, 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.

[1365] And so they replied that, no, they don't have money to send over a graduate student to do it.

[1366] 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.

[1367] Then let's do this together.

[1368] And they replied, no, they're not willing to do that, which, you know, I don't think is the way things should work.

[1369] And they published this sort of failed behavioral effect in that paper.

[1370] 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 supposed.

[1371] supposedly the failed replication on the effect in behavior.

[1372] And then I published a rebuttal on that, which I don't know if I should have done, but I did.

[1373] Well, I think it's interesting.

[1374] I mean, I think provided studies are done correctly.

[1375] I mean, the positive result almost always trumps the negative result.

[1376] And yet, I think replication is key.

[1377] The problem, as you point out, is that replication is rarely pure replication of the exact study.

[1378] This one is not even remotely.

[1379] But I published the detail.

[1380] So actually they hid something in their data that did partially work.

[1381] So I asked for their data and I reanalyzed it and that's what I published in the rebuttal.

[1382] But, you know, this is just sharing on how science works.

[1383] I took advice.

[1384] 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 Conman, who's Nobel laureate.

[1385] They came fast and slow.

[1386] And so I asked him, how should I deal with this?

[1387] You know, give me some advice here.

[1388] I was really, you know, it was emotionally not fun to be in that position.

[1389] And he said, don't, don't, don't, never publish a rebuttal.

[1390] Don't do anything.

[1391] And I was, you know, how can I?

[1392] You know, I have to do something.

[1393] He said, no, don't.

[1394] Because once you do that, then, you know, people don't go into the details.

[1395] They won't read the details of your rebuttal.

[1396] They'll be like, well, there's a group that says this and there's a group that says that.

[1397] So it's unclear.

[1398] Well, and, yeah.

[1399] I mean, I appreciate that you're bringing it up today.

[1400] and I do appreciate that you publish the rebuttal and that you offered in a very magnanimous way to do a collaboration.

[1401] That's what you then said.

[1402] So Conn's advice after that was that, well, if you insist, then just publish, write a response that you offered them to come and do it together.

[1403] They refused, and there's nothing you can do about that.

[1404] It's a lot like fight sports, right?

[1405] People talk a lot of track.

[1406] Although in science, you know, I will say this, 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 you get it in the neck on grant reviews or anonymous reviews.

[1407] I was on a grants review panel this morning.

[1408] I'm a nice reviewer, meaning I judge things objectively, but I try to always think from the perspective of the graduate student or author of the proposal.

[1409] Listen, I think that science is a, is a game of people who most of them are seeking facts.

[1410] However, the ego is strongly woven into it like anything else.

[1411] So I think it was very magnanimous of you to offer the collaboration.

[1412] So I'm gonna tell this lab whose name I can't pronounce.

[1413] Please accept the collaboration.

[1414] Then we can invite everyone on here for a round table.

[1415] I appreciate that you shared that story and I know a number of other people will for a number of reasons.

[1416] I have a couple more questions and I realize, and thank you by the way, for your willingness and stamina because it is probably 1 a .m. Israel time now, and you just arrived.

[1417] Later, I think.

[1418] But you're doing terrifically well.

[1419] So if you'll indulge us just a touch further, there are two topics that I want to touch on.

[1420] And if you want to cover these in shorter thrift, that's fine, although don't feel any obligation to.

[1421] 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.

[1422] 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.

[1423] After all, you and I both separately lived in the same apartment in Berkeley above the cheeseboard, which the smell of cheese wafting up through the cheeseboard is something I will never forget.

[1424] And the breads, never forget it.

[1425] Amazing bread.

[1426] I mean, I don't know if you've conveyed that clearly enough to listeners or watchers.

[1427] The probability is...

[1428] That we really just discovered that we lived in the same...

[1429] We never met, I mean, a fit like this before.

[1430] Yep.

[1431] And we lived in the same apartment.

[1432] Are we clicked friends?

[1433] What?

[1434] I had a, in a lingering way, I guess.

[1435] Absolutely.

[1436] Through the floor boards.

[1437] It had a great floor that place.

[1438] It had a great wooden floor.

[1439] It was an amazing place.

[1440] I lived there with my girlfriend for a year and a half.

[1441] And then it was an amazing place.

[1442] We won't give it out the address out of respect for the people, that live there now.

[1443] Do check out the cheeseboard if you ever in Berkeley.

[1444] 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.

[1445] 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.

[1446] So, for instance, I could imagine, based on what you've told, told us about smell today that, you know, I, I don't know, I, I, 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.

[1447] And 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 stake for that has no odor but whose nutrient content is very important to me. For instance, amino acids.

[1448] Right.

[1449] I mean, amino acids are essential to life.

[1450] And yet we don't go around sniffing for amino acids.

[1451] We go around sniffing for savouriness, umami type tastes and things of that sort.

[1452] So I could imagine a million different examples of this.

[1453] 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.

[1454] That's a long -term game, but also something about pleasure and safety of a potential interaction.

[1455] So what I'm asking here is about that whether or not there are subconscious signals that the olfactory system has learned to seek, but learn to seek through more overt signals, sort of the tip of the iceberg phenomenon.

[1456] 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.

[1457] So whether there's, you know, odor cues on nutrient value is a really good idea.

[1458] 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.

[1459] So I don't know.

[1460] I don't know if the nutrient value of food is systematically encoded in order.

[1461] If that's not been done and I will check after our meeting today, then it should be.

[1462] It's a really good idea.

[1463] I mean, one of the reasons I ask this is because, you know, the obesity crisis in the U .S. is a huge issue and elsewhere.

[1464] And highly processed foods, you know, have a lot of things that are problematic.

[1465] But one of the things that they don't have often is a direct relationship between the scent, the taste, and the nutrient content.

[1466] And I don't mean macronutrient, 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.

[1467] We don't go around sniffing for probiotics.

[1468] I'll tell you one sort of factoid that may support your hypothesis here.

[1469] And that is that there appears to be potential olfactory perceptual similarity in metabolic products.

[1470] So something that's metabolized from something else.

[1471] has perceptual similarity across those two things so so so metabolic cascades play into the coding of olfactory space and and that is consistent with the direction you're you're implying but again i don't i don't know of a direct test of of of nutritional value in smell and 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 um in scientific press and and if not there then with the companies that have vested interest in this which are many um briefly just just an amusing anecdote to share with you is that we've received two independent um um people you know companies who have turned to our lab recently asking for help to bring odor to engineered meat, right?

[1472] That's a growing thing and all these, you know, meats that are not.

[1473] You had to bring it up.

[1474] This audience is going to be very polarized along the lines of engineered meat.

[1475] You're not promoting.

[1476] Oh, no, no, no. I'm agnostic.

[1477] 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.

[1478] so help us make it smell like mead interesting uh the reason it's so polarizing is that anything related to nutrition on social media is a total barbed wire topic we've had experts on nutrition come on here we'll have more but i know nothing about nutrition you're you're safe no don't worry no it's not and is not uh promoting uh as he hasn't even said whether or not he's going to help them out no we're not actually not because yeah it just never it didn't happen Yeah.

[1479] 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 than given the ingredients that are required.

[1480] That's a whole world we'll avoid now.

[1481] I will, but you know, I'll take the opportunity to highlight something related maybe because on what were you saying on the scale.

[1482] you know, there's this, you know, I'll take the opportunity to dispel another misconception about olfaction, right?

[1483] There's this common notion that our sense of smell is incredibly subjective, right?

[1484] 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.

[1485] I think I know the study you're going to tell you.

[1486] There are many.

[1487] The cross -cultural similarity.

[1488] There are many.

[1489] That is utterly untrue.

[1490] Many, not only from my lab, there are many from many labs.

[1491] Please clarify for those that follow this literature.

[1492] So, yeah.

[1493] So humans are incredibly similar to one another and their olfactory perception.

[1494] And this is in contrast to which most people think.

[1495] So why is there this misconception?

[1496] The misconception is there two reasons.

[1497] First of all, or for several reasons, but two are stand out.

[1498] first of all we're attracted by outliers because you know what i'll tell somebody look you know for example a factory 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 point eight that's incredibly high incredibly what do you think is pleasant i think is pleasant yeah yeah now why why is that go again against what culturally people think for two reasons.

[1499] First of all, we're attracted or biased by outliers.

[1500] But that's particularly, that shows, in fact, the result.

[1501] What do I mean?

[1502] So you'll tell somebody, look, people are very similar in their pleasantness estimates.

[1503] And they'll sell you know, that can't be.

[1504] I love cilantro.

[1505] And, you know, my girlfriend hates the smell of cilantro, right?

[1506] Or, and there are a few classic examples there, Guillaava, right?

[1507] You know, is another polarizing order.

[1508] So there are a few polarizing orders, right?

[1509] And that's true, right?

[1510] So that's true that, you know, half of the population loves the smell of cilantro and half hates it.

[1511] Half loves Guiava, half hates it.

[1512] That's true.

[1513] Microwave popcorn.

[1514] However, I assure you that, you know, you can come to our lab.

[1515] We have about 1 ,000 odorants in our lab, okay?

[1516] We won't smell the 1 ,000, right?

[1517] But I assure you, you know, take 100 odorants, okay, from our mixtures in labs, right?

[1518] and we'll smell them, right?

[1519] And out of the 100 odors, 90 will totally agree on, right?

[1520] And including the 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.

[1521] There will be rare, rare exceptions.

[1522] Again, the correlation is about 0 .8 across individuals.

[1523] So on 90 of 100 will really be in high agreement.

[1524] then five orderants will be in sort of intermediate agreement.

[1525] And yes, there'll be the five orderants that we're in total disagreement on.

[1526] But I ask you, you know, if we agree on 95 and disagree on five, are we the same or are we different?

[1527] We're the same.

[1528] They're just outliers to this rule.

[1529] 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.

[1530] And the second thing that drives this cultural effect is our poor application of language to olfaction.

[1531] Right.

[1532] So in other sensory systems, we grow up with, we develop with anchors, right?

[1533] So since you're a little kid, you know, your mother shows you a cow and says, what does a cow do, moo, right?

[1534] And we all know moo, moo, and what color is this?

[1535] It's, well, this is kind of an odd black, but it's black, right?

[1536] Or what color is that?

[1537] It's red, right?

[1538] 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.

[1539] We just both know to call that red.

[1540] And since you say red and I say red, I think, why, we're seeing the same thing.

[1541] But no, we're not seeing the same thing, right?

[1542] And in odor, we don't have those anchors, right?

[1543] We don't from childhood, you know, our mom doesn't tell us, so what's this smell and what's that smell, right?

[1544] And so we don't have these language anchors that make us think that we're perceiving the same thing.

[1545] Now, how can you quantify that?

[1546] The most important term in measuring sensory systems is similarity, right?

[1547] That's the measure, right?

[1548] So what can you do?

[1549] Let's say we take 10 odorants and I have you rate all the pairwise similarities, right?

[1550] So you end up with 45 numbers, right?

[1551] So, you know, how similar is one to two, one to three, one to four, and then two, and all the possible pairwise similarities, let's say you rate similarity from one, which is totally dissimilar to 100 exactly the same, right?

[1552] So now I have a similarity matrix that describes Andrew's perception of smell, right?

[1553] I have, you know, based on these 10 odors that I selected.

[1554] Now I can run my similarity matrix.

[1555] And then I can see if the similarity matrix are correlated, right?

[1556] And then we've gotten rid of the issue of names and odors, right?

[1557] It doesn't matter if I'll call this lemon and this orange and you call this sweet potato and this marshmallow, right?

[1558] It doesn't matter.

[1559] If I think that these two are highly similar and you agree.

[1560] And I think that these two are very different, and you agree, right, we perceive the world in the same way if our similarity matrices are aligned, right?

[1561] And what's nice about that is that then you can do that for vision audition and all faction in a common group.

[1562] And you can see where we're more alike each other or not.

[1563] And we've done that for color vision, all faction, and tonal audition.

[1564] Okay.

[1565] And we are most dissimilar in color vision.

[1566] Okay.

[1567] We're, In color vision, the variance is about 100%.

[1568] Amazing.

[1569] That's quite different.

[1570] And there's tons of literature on this.

[1571] Tons of it, tons of it, right?

[1572] And in olfaction and audition, they're about the same.

[1573] So we're not different.

[1574] We're very similar.

[1575] We're just very poor at appreciating this.

[1576] And mind you, not that there's not variability.

[1577] There is variability.

[1578] And of course, the system is malleable, as all sensory systems are.

[1579] So you can learn to like an odor, and that will change you and learn to this like an order.

[1580] Right, but just the way you can learn to like a sound or dislike a sound.

[1581] So, you know, this doesn't take away from the hardwired link of a structure to its perception that they're malleable.

[1582] And we're not very variable.

[1583] We're actually kind of similar.

[1584] 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, et cetera, in order to elicit richer sensory experiences and drive choice -making.

[1585] That'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.

[1586] So for a long time now, there's been this idea that there will soon be Google smell, not to call out Google is the only search engine, but duck, duck go smell.

[1587] For those of you that don't want to hear smell.

[1588] Chat GPT, chat GPT, and on and on.

[1589] In other words, you know, visual information is sent through computer interfaces, as is auditory information, not so much haptic somatosense.

[1590] three, although it can, you know, our lab uses VR.

[1591] It's, it, it can be done.

[1592] Right.

[1593] But it hasn't really taken hold.

[1594] However, smell being such a rich source of behavioral and hormonal and other sorts of deep, deep information that can drive people into yum, yuck, or me type decision making.

[1595] Yeah.

[1596] Seems like an amazing candidate.

[1597] So what is your experience with generating smells in silico?

[1598] in computers.

[1599] 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 look at, you'll put into a search engine blueberry pancakes recipe and that not only will you get photos of those blueberry pancakes and a recipe, but you will get the hopefully validated odor of those pancakes and that recipe coming at you in real time through the computer.

[1600] So I'll start off answering from the name you threw out there, Google.

[1601] So about probably about five years ago, Google had an April Fool spoof.

[1602] Oh, right.

[1603] And they put out this video of Google Smell.

[1604] Okay.

[1605] And it had all these like classic like sales images of, you know, holding up your phone to a rose and it generating rows.

[1606] and all these things, right?

[1607] So Google is now trying to do that.

[1608] And they just published, I mean, I know they've been trying to do it for a while.

[1609] 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.

[1610] I think it's called Osmo or something like that, that started off with a ridiculous sum of money for a startup.

[1611] Like, I don't know, tons of money.

[1612] There's a lot of money in that world.

[1613] Yeah, yeah, in Google, yeah.

[1614] To digitize smell.

[1615] And there are other companies that are trying to do this as well.

[1616] 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.

[1617] of ultimately digitizing smell.

[1618] And so this is a very, very active field of research.

[1619] And I'll say one thing that dovetails with what you were talking about before.

[1620] In many ways, COVID is going to be one of the best things that ever happened to olfaction research.

[1621] Because suddenly all the world is all the world.

[1622] Lots of people are, are very cognizant of the importance of smell.

[1623] And the smell is like way up there in people's awareness because of COVID.

[1624] And this is driving a renaissance of olfaction research and awareness to olfaction is something that's worth paying attention to.

[1625] And 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 sense, set of rules that link odor structure to odor perception?

[1626] That is, the going thing was that until recently, at least there was no scientist or a 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.

[1627] So in contrast, let's say, the trivial like color vision, let's say.

[1628] So if you know what the wavelength of the light is, you more or less know what perceived color is going to be.

[1629] Of course, there are exceptions to that and all sorts of issues, but as a rule, you would know, or the other way around, you know, you can generate a wavelength and you would know what color of light it's going to be perceived.

[1630] 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.

[1631] The rules are well known.

[1632] In olfaction, we didn't have that until recently.

[1633] But over the past, two years, a bunch of labs have really pushed this forward.

[1634] There's a bunch of work out of Leslie Voschhal's lab at Rockefeller and Andreas Keller working with Leslie, who've done a lot of work on this front.

[1635] Also work from Joel Mainland's lab at Monel, and Fair Discovery, Joel was a graduate student in our lab.

[1636] And recently, in our lab, we've had, and I hope this doesn't come across is overly arrogant, but we've had a sort of mini breakthrough on this front.

[1637] To call something a mini breakthrough as far from arrogant.

[1638] And this is a paper led by Arn Ravilla from our lab.

[1639] And Kobe Snits also a major contributor there, a paper published in Nature about a year and a half ago in the height of a COVID pandemic.

[1640] So nobody really, I won't see nobody, but it wasn't noticed in the way otherwise would have been.

[1641] It was published in nature really on like a week where the whole world was like going berserk over COVID.

[1642] 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.

[1643] So if you give me two molecular mixtures, I can predict how similar you will smell them to be.

[1644] Okay.

[1645] Now, not only could we predict that, but we could design it.

[1646] So we can generate mixtures with known similarities.

[1647] And the result was highlighted, and you'll appreciate this coming from vision, is that using our algorithmic solution, we generated olfactory metameres.

[1648] So we measured mixtures completely non -overlapping in their molecular structure.

[1649] But the smell like exactly the same.

[1650] Okay.

[1651] 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.

[1652] This is simple, actually.

[1653] And in the paper, we do a few things.

[1654] Like, we generate a metamere for Chanel number five.

[1655] So you don't like perfume.

[1656] So this one.

[1657] But we take, so we generate a Chanel number five with no component from Chanel number five in it.

[1658] Okay.

[1659] And we actually have a publicly available website.

[1660] I'll give it to you for your links.

[1661] If you want, that anybody can do this.

[1662] We built an engine that you can generate these metameras.

[1663] Now, once we did that, in a way, we've generated the infrastructure for digitizing smell.

[1664] Because, again, what we, what our, what our algorithms, them predicts our framework predicts his 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 there are perceived smell now you can make up any mixture you want for me i can project it into that map and measure its pairwise distance from all the points in the map if it falls on lemon then what you generated smells like lemon and if it falls you know on tomato than what you generated smells like tomato.

[1665] So we now solve that problem.

[1666] We can predict the odor of any molecular mixture.

[1667] We can say how it's going to smell.

[1668] What we can do is then find a set of components, which we call odor primaries, that can be used to mix any odor that you can perceive.

[1669] And that's what we're working on now.

[1670] And about a month ago, so this is in collaboration with the lab of Jonathan Williams and Max Planck in Munich.

[1671] Jonathan Williams is an atmospheric chemist, but he's really good at using GCMS, these tools that measure molecules.

[1672] So Jonathan Williams measured odorants in Germany, transmitted the information to us over IP.

[1673] We fed that into our algorithmic framework and recreated it from a device that mixes primaries.

[1674] and we tried to do four different odorants in our proof of concept test.

[1675] One of them was Rose and we failed at recreating Rose.

[1676] We in fact recreated something that had a percept but most people perceived it as bubble gum.

[1677] 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.

[1678] The third was gasoline, and we were slightly but significantly better than chance at recreating gasoline.

[1679] And the fourth was violets, and 15 of 16 people said violets.

[1680] So the first odor ever transmitted over IP is violets, and we did that last month.

[1681] Of course, this is not anything near a practical solution.

[1682] The device that Jonathan was using to measure is a $1 .5 million device bigger than this table.

[1683] That's right.

[1684] I remember when VCRs, half the audience won't even know what that is.

[1685] VCRs were like this big.

[1686] So we're all good.

[1687] I'm all good with the prediction that things will come down in size and cost.

[1688] Yeah, I was saying, you know, don't hold your breath for this to be on your table tomorrow.

[1689] And, you know, again, even, even, you know, all.

[1690] what we have in hand is this very initial proof of concept you know it doesn't it's not even yet close to being a paper we are submitting because there's so lots of work to be done uh but we're on we're on the path uh we're on the path and you know google will probably beat us to it uh they got a lot no you seem pretty dogged in there yeah but they have so much more resources that uh that um at this stage it and they've already published uh two papers from that effort that are are good.

[1691] Yeah, you know.

[1692] 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.

[1693] But the real question is, are they getting the best people?

[1694] Because as you and I both know in science, the oftentimes it's small groups of the very best and most creative people that can outrun and outgun large groups.

[1695] And here I don't have anything against Google by the way.

[1696] I use it all the time.

[1697] I'm not a betting man, but I would put my money on Google on this race.

[1698] But I'll try and give them a run for their money.

[1699] There you go.

[1700] 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.

[1701] Better get crack.

[1702] And there, we just cost the weekends and broke up the relationships of a bunch of signs.

[1703] I remember when I was a graduate student at Berkeley, I remember hearing there was a guy in our common friend.

[1704] Irving Zooker's lab that worked 100 hours a week.

[1705] So I was like, oh, I'll work 102 hours a week, which is not a good choice, folks.

[1706] In any case, it's abundantly clear that you're making progress here.

[1707] 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, I'm thinking you, nowadays everyone knows that when you travel and you want to see your family, your grandkids or kids, you better to get on FaceTime and see them or Zoom than to just hear their voice.

[1708] We're all talking about being able to smell them.

[1709] I'll tell you more than that.

[1710] I'll tell you more than that.

[1711] I mean, we're talking now of trying to achieve the olfactory equivalent of circa on 1956 black and white TV, okay, basically, right?

[1712] I mean, you know, I'm not dreaming, let's say, of being able to transmit to you the difference between a Cabernet or Marlowe, right?

[1713] But if I can generate something that's vaguely wine, that will be an amazing success from my perspective, right?

[1714] But jump ahead in your imagination to 4K odor transmission, then medical diagnostics is what you want to be talking about.

[1715] Because this is over extension, but you can almost say that every disease will have an odor.

[1716] I mean, every disease is a specific metabolic process.

[1717] Metabolic process have metabolites.

[1718] Metabolites have a smell.

[1719] Olfaction, once it's digitized and high resolution, which, again, in our hands, it's not going to be.

[1720] I mean, we're talking, you know, in my retirement, maybe I'll read about this one day if I'll still have vision.

[1721] I mean, this is not close.

[1722] But when olfaction digitization is brought to the equivalent of four kids, you know, it's a little bit.

[1723] a vision and audition that you have now, then it will be in medical diagnosis.

[1724] You'll have, excuse me for the imagery, but you will have an electronic nose in your bathroom each one of us will have in the toilet, and it will be doing diagnostics all the time.

[1725] And that's where it's going to go.

[1726] But again, not anywhere in the very close future.

[1727] Well, it's certainly an exciting proposition and I'm delighted that you and other groups who are so strong are working on it.

[1728] I really am.

[1729] Noam, I want to say thank you for your time today.

[1730] First of all, this was a tremendously interesting conversation.

[1731] We touched on so many things, hormone smells, the architecture of the olfactory system.

[1732] 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 as a, as a, as a, you know, expert in this field, 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 and chemo sensation.

[1733] Also just for the incredibly pioneering work that you've done.

[1734] You know, I don't have many heroes in science.

[1735] 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, falling scent trails.

[1736] And then 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 way.

[1737] And over and over again, when your laboratory publishes papers, I find like, this is super interesting, super cool.

[1738] And I find myself telling everybody about it.

[1739] And that's really what I do for a living is I learn and then I blab about it to the world.

[1740] So thank you so much for the work that you've done and the spirit that you bring to it.

[1741] Whatever drives that spirit, as the great late Ben Beres used to say, keep going because we are all benefiting tremendously.

[1742] 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.

[1743] But it's absolutely clear that you delight in the work you do.

[1744] And so I delight in it.

[1745] I'm grateful for it.

[1746] I'm grateful for your time today.

[1747] And so on behalf of me and many, many people listening to this, I just want to extend a huge debt of gratitude.

[1748] Thank you so much.

[1749] So I'm blushing.

[1750] I don't know if this doesn't come across on the radio podcast, but thank you so much for very warm words.

[1751] 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.

[1752] And those are always very rewarding moments because usually you function without that.

[1753] 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.

[1754] There'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.

[1755] So my only request is that you come back and tell us about the next results, sometime not too long ago now.

[1756] Yeah, well, I'm going to catch you live now, although you have the power to edit this.

[1757] So I guess that's not fair.

[1758] 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.

[1759] A good bargain, and I accept.

[1760] Delighted.

[1761] Thank you so much.

[1762] Yeah, pleasure.

[1763] Thank you for joining me for today's discussion about olfaction and chemo -sensation with Dr. Noam Sobel.

[1764] 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.

[1765] If you're learning from and or enjoying this podcast, please subscribe to our YouTube channel.

[1766] That's a terrific zero cost way to support us.

[1767] In addition, please subscribe to the podcast on both Spotify and Apple.

[1768] And on both Spotify and Apple, you can leave us up to a five -star review.

[1769] 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.

[1770] I do read all the comments.

[1771] Please also check out the sponsors mentioned at the beginning and throughout today's episode.

[1772] That's the best way to support this podcast.

[1773] Not so much on today's episode, but on many previous episodes of the Huberman Lab podcast, we discuss supplements.

[1774] While supplements aren't necessary for everybody, many people derive tremendous benefit from them for things like improving their sleep, their focus, and hormone support.

[1775] The Huberman Lab podcast is, proud to have partnered with Momentus supplements.

[1776] If you'd like to see the supplements discussed on the Huberman Lab podcast, please go to Live Momentus, spelled OUS, so that's livemometus .com slash Huberman.

[1777] If you're not already following the Huberman Lab podcast on social media, we are Huberman Lab on LinkedIn, Facebook, Twitter, and Instagram.

[1778] And on all those accounts, I include information, some of which overlaps with content of the Huberman Lab podcast, but often which is distinct from information covered on the Huberman Lab podcast.

[1779] So again, it's Huberman Lab on all social media platforms.

[1780] If you haven't already subscribed to our newsletter, we have a zero -cost monthly newsletter.

[1781] It's called the Neural Network newsletter.

[1782] And it includes podcast summaries and toolkits or protocols for things like enhancing sleep, for exercise, for meditation, for dopamine, for focus, and many other topics.

[1783] To sign up, you simply go to Hubermanlap .com, go to the menu, and click on newsletter and provide your email.

[1784] And I want to be clear that not only is the neural network newsletter zero cost.

[1785] We also do not share your email with anybody.

[1786] Once again, I'd like to thank you for joining me for today's discussion about olfaction and chemo -sensation with Dr. Noam Sobel.

[1787] And last, but certainly not least, thank you for your interest in science.