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

00:00:00.000 | - Welcome to the Huberman Lab Podcast,

00:00:02.280 | where we discuss science and science-based tools

00:00:04.880 | for everyday life.

00:00:05.900 | I'm Andrew Huberman,

00:00:10.080 | and I'm a professor of neurobiology and ophthalmology

00:00:13.000 | at Stanford School of Medicine.

00:00:15.060 | Today, my guest is Dr. Noam Sobel.

00:00:17.600 | Dr. Noam Sobel is a professor of neurobiology

00:00:19.920 | in the Department of Brain Sciences

00:00:21.600 | at the Weizmann Institute of Science.

00:00:23.840 | His laboratory studies olfaction and chemosensation.

00:00:27.160 | Olfaction is, of course, our sense of smell.

00:00:29.720 | Chemosensation is our ability

00:00:31.320 | to respond to chemicals in our environment.

00:00:33.760 | Today, you are going to learn

00:00:34.620 | some absolutely incredible facts

00:00:36.320 | about how you interact with the world

00:00:38.120 | and other people around you.

00:00:39.840 | For instance, you will learn

00:00:41.760 | that humans can smell things around them

00:00:44.520 | as well as dogs can.

00:00:46.480 | In fact, humans are incredibly good

00:00:48.920 | at sensing the chemical world around them.

00:00:51.360 | You also learn, for instance,

00:00:52.600 | that every time you meet somebody,

00:00:54.480 | you are taking chemicals from that person,

00:00:56.860 | either from the chemical cloud that surrounds them

00:01:00.200 | or directly from the surface of their body,

00:01:02.420 | and you are actually applying it to your own body,

00:01:04.980 | and you are processing information

00:01:06.940 | about that person's chemicals

00:01:08.420 | to determine many things about them,

00:01:10.200 | including how stressed they are, their hormone levels,

00:01:13.180 | things that operate at a subconscious level

00:01:15.220 | on your brain and nervous system,

00:01:16.780 | and that impact your emotions, your decision-making,

00:01:19.900 | and who you choose to relate to or not to relate to.

00:01:23.820 | You will also learn that tears,

00:01:25.500 | yes, the tears of others,

00:01:27.460 | are impacting your hormone levels in powerful ways.

00:01:31.220 | You will also learn that every so often,

00:01:34.100 | actually on a regular schedule,

00:01:36.340 | there is an alternation of ease

00:01:38.680 | through which you can breathe

00:01:39.740 | through one nostril or the other,

00:01:41.840 | and that alternation reflects an underlying dynamic

00:01:45.420 | of your nervous system and has a lot to do

00:01:48.060 | with how alert or sleepy you happen to be.

00:01:50.880 | The list of things that Dr. Noam Sobel's laboratory

00:01:54.100 | has discovered that relate to everyday life

00:01:56.420 | and that are going to make you say,

00:01:58.060 | "Wow, I can't believe that happens,"

00:02:00.180 | but then go out into the real world

00:02:01.380 | and actually observe that that happens

00:02:03.140 | in ways that are incredibly interesting,

00:02:05.300 | just goes on and on.

00:02:06.700 | In fact, his laboratory discovered

00:02:08.680 | that we are always sensing our own odors.

00:02:11.280 | That's right.

00:02:12.120 | Even though you might not notice your own smell,

00:02:14.740 | you are always sensing your own odor cloud,

00:02:18.020 | and throughout the day,

00:02:19.020 | you periodically smell yourself deliberately,

00:02:22.060 | even though you might not realize it,

00:02:23.960 | in order to change your cognition and behavior.

00:02:27.100 | I first learned of Dr. Sobel's laboratory

00:02:28.980 | through a rather odd observance.

00:02:30.700 | That observance took place when I was a graduate student

00:02:33.260 | many years ago at UC Berkeley.

00:02:35.360 | At the time, Noam Sobel was a professor at UC Berkeley.

00:02:38.140 | As I mentioned before, he has since moved to the Weizmann.

00:02:40.700 | Well, I was walking through the Berkeley campus

00:02:42.860 | and I saw people on their hands and knees,

00:02:45.600 | but with their head very close to the ground,

00:02:48.180 | and their eyes were covered, their hands were covered,

00:02:50.020 | their mouths were covered,

00:02:51.380 | and only their nose was exposed.

00:02:53.380 | And what I was observing was an experiment being conducted

00:02:56.640 | by the Sobel Laboratory,

00:02:58.220 | in which humans were following a scent trail.

00:03:01.100 | That scent trail was actually buried some depth

00:03:03.880 | underneath the earth,

00:03:05.300 | and yet they could follow that scent trail

00:03:07.420 | with a high degree of fidelity.

00:03:09.260 | It was from that experiment and other experiments

00:03:11.140 | done in Dr. Sobel's laboratory at Berkeley

00:03:13.080 | and at the Weizmann, involving neuroimaging

00:03:15.500 | and a number of other tools and techniques

00:03:17.640 | that revealed the incredible power of human olfaction,

00:03:21.260 | and human's ability to follow scent trails if they need to.

00:03:24.600 | And that of course led to many other important discoveries,

00:03:26.980 | some of which I alluded to a few moments ago,

00:03:29.340 | but you are going to learn about many,

00:03:31.100 | many other important discoveries

00:03:33.100 | in the realm of olfaction and chemosensation

00:03:35.540 | that have been carried out by Dr. Sobel's laboratory

00:03:37.700 | through the course of today's episode.

00:03:39.340 | And by the end of today's episode,

00:03:40.740 | I assure you that you will never look at

00:03:43.180 | or smell the world around you the same way again.

00:03:46.580 | Before we begin, I'd like to emphasize that this podcast

00:03:49.240 | is separate from my teaching and research roles at Stanford.

00:03:51.900 | It is, however, part of my desire and effort

00:03:54.080 | to bring zero cost to consumer information about science

00:03:56.660 | and science-related tools to the general public.

00:03:59.300 | In keeping with that theme,

00:04:00.440 | I'd like to thank the sponsors of today's podcast.

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00:06:43.960 | And now for my discussion with Dr. Noam Sobel.

00:06:46.920 | Dr. Sobel, Noam, welcome.

00:06:48.800 | - Thank you.

00:06:49.640 | - Must say, I am extremely excited for this conversation.

00:06:52.280 | I've been a huge fan of your work

00:06:54.120 | for more than a decade or two.

00:06:57.800 | Yes.

00:06:58.640 | - Kind of frightening.

00:06:59.880 | - We overlapped at UC Berkeley some time ago,

00:07:03.400 | although we did not meet.

00:07:05.320 | - Although we lived in the same apartment.

00:07:07.060 | - And we just learned that the amazing apartment

00:07:11.480 | that you moved out of was the apartment

00:07:13.260 | that my girlfriend and I, at the time,

00:07:14.560 | moved into in 2006, I believe.

00:07:18.260 | So we've shared quite a few things.

00:07:22.900 | And today I'd love for you to share with us

00:07:26.400 | all about the amazing landscape of chemosensation,

00:07:29.360 | in particular olfaction, our sense of smell,

00:07:32.000 | and some related perceptual abilities

00:07:34.620 | or subconscious abilities,

00:07:36.080 | including pheromones, et cetera.

00:07:37.720 | To get everybody on the same page,

00:07:40.260 | I'd like to just start off by asking,

00:07:42.800 | what are the major components of our ability to smell?

00:07:47.300 | Obviously, where I like to think it involves the nose

00:07:49.840 | at some level.

00:07:50.680 | - It does.

00:07:51.500 | - To what extent is that mixed in with other senses,

00:07:53.540 | like taste?

00:07:54.540 | And perhaps more importantly,

00:07:57.800 | what about the chemicals that we are sensing

00:08:01.020 | through this thing?

00:08:02.540 | And for those of you listening and not watching,

00:08:04.640 | I'm tapping my nose, that we are not aware of.

00:08:09.000 | You know, the chemicals that we're inhaling

00:08:11.560 | and making sense of without our awareness.

00:08:14.760 | If you could just give us the top contour,

00:08:17.540 | or even deep contour, if you like,

00:08:19.240 | of the parts list and the various roles they play.

00:08:24.240 | - So you've asked a lot of questions at once.

00:08:28.000 | You know, I'll start with a little comment

00:08:30.720 | on the way you said smelling through our nose,

00:08:32.960 | which we indeed do.

00:08:33.800 | We also smell through our mouth, actually.

00:08:36.080 | There's a process referred to as retronasal olfaction,

00:08:39.660 | where odorants come up through the back of our throat

00:08:43.840 | and out of our nose the reverse way.

00:08:47.140 | And we smell things that way as well.

00:08:48.520 | And in fact, a big part of the contribution of olfaction

00:08:52.620 | to food and taste comes from that,

00:08:55.380 | from retronasal olfaction.

00:08:57.380 | But primary olfaction is referred to as orthonasal olfaction,

00:09:02.120 | that is through our nose we sniff,

00:09:03.920 | and sniffing is a big thing.

00:09:05.320 | Well, I have a sense we might talk about that a lot today

00:09:08.320 | in all sorts of contexts.

00:09:10.040 | So we sniff in through our nose.

00:09:12.000 | And to answer your general question

00:09:13.560 | of the organization of the system,

00:09:15.440 | so molecules, airborne molecules, travel up our nose

00:09:20.120 | a distance in the human of about six or seven centimeters

00:09:23.660 | to about here, where they interact with,

00:09:26.880 | I will use the word sheet of receptors,

00:09:30.560 | but sheet is a bit misleading here.

00:09:33.120 | It's not a sheet, it's very convoluted.

00:09:35.180 | We have about seven million such receptors

00:09:39.640 | aligning a structure known as the olfactory epithelium.

00:09:42.540 | This is the sensory surface of the olfactory system,

00:09:45.240 | the olfactory epithelium.

00:09:46.520 | Again, probably about six or seven million receptors

00:09:49.240 | in the human.

00:09:50.440 | In the human, probably of about 350 different kinds.

00:09:55.440 | So that's amazing.

00:09:57.880 | That means a meaningful percentage of your genome

00:10:01.320 | is devoted just to this,

00:10:03.000 | just to the kinds of olfactory receptor subtypes

00:10:05.760 | you have in your nose.

00:10:07.280 | By the way, I can share an amusing story.

00:10:08.800 | I would imagine amusing stories are good for podcasts.

00:10:12.080 | So that number of six or seven million receptors

00:10:15.800 | is probably not very well grounded.

00:10:19.280 | It's hard to count, but it's reasonably grounded.

00:10:22.840 | And there was this thing roaming around in the literature

00:10:26.400 | about bloodhounds having a billion receptors in their nose,

00:10:30.320 | which is why they're so amazing.

00:10:32.240 | And this number, it sort of propagated

00:10:35.600 | through the literature.

00:10:36.960 | And our lab has written over the years

00:10:40.360 | a few review chapters,

00:10:41.840 | and we were repeatedly writing the olfaction chapter

00:10:45.600 | for a very large, one of these large textbooks,

00:10:48.160 | the "Gazaniga Handbook of Cognitive Neuroscience"

00:10:51.400 | I think it's called.

00:10:54.200 | And we had that in there as well somewhere.

00:10:56.760 | And one time when we were renewing the chapter

00:10:59.400 | for a new version of the book,

00:11:00.680 | I told the graduate student who was leading that at the time,

00:11:03.160 | Araya Sharoon, she's now a professor at Tel Aviv University.

00:11:06.720 | I told her, check that, check that reference out.

00:11:09.240 | Where in the world did that come from?

00:11:10.800 | And we started going back and back and back.

00:11:13.200 | And it turns out it comes from a textbook,

00:11:16.520 | an Australian textbook.

00:11:19.560 | And we found the author of the textbook and we wrote her.

00:11:22.200 | And I said, look, there's this thing in the literature

00:11:24.600 | of a billion receptors in the bloodhound.

00:11:28.240 | Where did that come from?

00:11:30.040 | And surprisingly, she answered me.

00:11:32.200 | And I was hoping to get a reference, right?

00:11:34.480 | But it wasn't a reference.

00:11:35.960 | And this is where it really becomes funny for us

00:11:38.200 | because she said, I was once at a lecture

00:11:41.800 | of an olfaction geneticists,

00:11:44.480 | geneticist by the name of Daron Lancet.

00:11:48.560 | And he said that in the lecture.

00:11:50.360 | Now, this is really funny because she's in Australia.

00:11:52.280 | This is all over the world, this number.

00:11:54.240 | And I'm writing her from Israel.

00:11:56.160 | And Daron Lancet is in the building next to me, okay?

00:11:58.800 | He's in Weizmann Institute of Genetics.

00:12:01.360 | I mean, he used to be, he's retired now.

00:12:04.160 | And he had meaningful contributions

00:12:06.320 | in the history of olfaction.

00:12:07.720 | So I picked up the internal phone and I said,

00:12:10.760 | hey, Daron, did you say that there's a billion receptors

00:12:14.840 | in the bloodhound nose?

00:12:16.080 | And he said, what's a bloodhound?

00:12:18.680 | So this is totally made up, right?

00:12:20.200 | It totally made up and it propagated.

00:12:21.920 | I mean, you can probably go into Google

00:12:24.880 | and type like a billion receptors in the bloodhound

00:12:28.040 | and you'll get a lot of hits.

00:12:30.840 | But there was absolutely no evidence for that.

00:12:32.880 | - Amazing.

00:12:33.720 | And not just amazing in light of what it tells us

00:12:35.720 | about olfaction and bloodhounds or otherwise,

00:12:37.760 | but amazing because it sheds light

00:12:39.600 | on just how much of what is in textbooks,

00:12:42.760 | scientific and medical is absolutely wrong.

00:12:46.920 | Things propagate and you cite yourself.

00:12:49.720 | So we fixed that in that version of the...

00:12:52.800 | And so to finish the line,

00:12:53.960 | so odorants interact with these receptors

00:12:57.160 | here in our epithelium where they undergo

00:13:00.160 | what is referred to as transduction.

00:13:01.960 | That is the odorants are docked at a receptor

00:13:05.280 | and turn into a neural signal or enforce the receptor

00:13:10.080 | to respond in a neural signal.

00:13:12.000 | And this neural signal, in fact, action potentials,

00:13:14.680 | not gradient potentials of any kind,

00:13:17.280 | propagates via the olfactory nerve.

00:13:20.200 | Now this is a nerve that goes from our epithelium

00:13:22.920 | right here.

00:13:23.760 | - Behind the forehead.

00:13:24.800 | - No, well, yeah, here.

00:13:28.120 | Through the thinnest part of our skull,

00:13:31.800 | an area referred to as the cribriform plate,

00:13:33.920 | which is perforated, it has a lot of holes.

00:13:36.560 | The nerve goes through those holes

00:13:38.640 | and synapses at the first target in the brain,

00:13:41.440 | which is the olfactory bulb.

00:13:44.120 | In humans, that forms an interesting point of sensitivity

00:13:49.120 | because a lot of people lose their sense of smell

00:13:54.920 | due to trauma because of that structure.

00:13:58.280 | - A head-hit type trauma.

00:13:59.520 | - Well, yes, although you denoted hitting

00:14:02.480 | on the front of the head,

00:14:03.360 | which is where all this real estate is,

00:14:05.300 | but actually the more common cause

00:14:07.960 | for losing your sense of smell for trauma

00:14:09.360 | is the back of the head

00:14:10.640 | because of what's referred to as a contrecu injury.

00:14:13.280 | So as your listeners probably know,

00:14:16.520 | our brain is floating in liquid in CSF,

00:14:19.000 | in cerebrospinal fluid inside our skull.

00:14:21.840 | And when we get hit in the back of the head,

00:14:24.000 | the brain has this forward and backward movement

00:14:27.360 | in the liquid in the skull.

00:14:29.960 | It sort of crashes.

00:14:31.160 | It can crash against the front of the skull,

00:14:33.200 | which is why you also have, in a contrecu injury,

00:14:35.840 | you also often have frontal damage.

00:14:38.700 | But what happens is that this generates a shearing motion

00:14:41.760 | on the cribriform plate

00:14:43.420 | and the olfactory nerve is severed.

00:14:45.480 | And if it's completely severed, it's lost.

00:14:49.440 | - Forever, because my understanding is

00:14:50.920 | that the olfactory sensory neurons

00:14:52.540 | are among the few central nervous system neurons

00:14:55.200 | in adult humans that can regenerate

00:14:58.380 | or replenish themselves.

00:15:01.080 | - Right, so again, there are a few questions in one.

00:15:03.640 | - Yeah, that's okay.

00:15:04.480 | - So first of all--

00:15:05.320 | - We will spin many plates simultaneously.

00:15:06.840 | - If it's completely severed, completely,

00:15:09.880 | then yes, you're lost.

00:15:11.160 | - Forever.

00:15:12.000 | - Yeah, if it's completely severed.

00:15:13.560 | Because even if you'll have regeneration

00:15:16.100 | at the basal cell level at the epithelium,

00:15:19.040 | they won't manage to find their way back to the bulb.

00:15:23.280 | If you have partial or something left

00:15:27.200 | or something shows up in a short while after the injury,

00:15:31.000 | then you have a good chance of recovery.

00:15:33.080 | - Because they grow along the trajectory

00:15:34.800 | of the other axons, sort of pioneering the way for them.

00:15:37.680 | - Assumingly, yeah.

00:15:38.840 | - Interesting.

00:15:39.680 | So basically, and basically the timeframe,

00:15:42.320 | and you know, it's funny, I get a lot of emails on this,

00:15:45.080 | although I'm not a medical doctor,

00:15:46.460 | but I get a lot of emails from people

00:15:49.240 | who have lost their sense of smell

00:15:50.360 | because it's very distressing.

00:15:51.760 | And now more people know this because of COVID,

00:15:54.520 | that it's very distressing.

00:15:56.520 | And basically the rule of thumb is that

00:15:58.480 | if you don't get it back within a year to a year and a half,

00:16:01.740 | you'll never get it back.

00:16:03.920 | - My understanding of the statistics on olfactory loss

00:16:06.940 | and COVID and other viral type infections is that,

00:16:11.660 | first of all, I experienced that when I got COVID.

00:16:13.940 | - Including total anosmia?

00:16:15.500 | - For one day and not total.

00:16:17.540 | It was just, there was a remnant of an ability to smell

00:16:21.020 | or perceive the smell of a lemon.

00:16:23.100 | And I was huffing as hard as I possibly could.

00:16:26.020 | I actually, there's an over-the-counter remedy,

00:16:29.500 | and this is not a pseudoscience

00:16:31.300 | because there's a number of papers published

00:16:33.140 | about this on PubMed,

00:16:33.980 | that alpha lipoic acid can accelerate the recovery of smell.

00:16:38.980 | And so that's something that, it worked successfully for me.

00:16:42.180 | I'm not saying that that's the only route.

00:16:44.260 | - You don't know if it worked successfully for you

00:16:45.740 | or if you would have recovered anyway.

00:16:46.980 | I mean, you didn't do a controlled study.

00:16:48.420 | - But I was not willing to do the controlled experiment.

00:16:50.780 | Exactly.

00:16:51.860 | - Let me say two things on this front.

00:16:53.500 | First, the dean on the alpha lipoic acid is, ugh.

00:16:56.940 | - Yeah, it's not overwhelming.

00:16:58.780 | But losing your sense of smell is overwhelming.

00:17:01.260 | And so I think people feel desperate.

00:17:04.140 | - One word about the smelling the lemon,

00:17:06.180 | and this is, I'll take that opportunity

00:17:08.220 | to share more information.

00:17:11.140 | When we smell things, it's the result

00:17:14.180 | of more sensory subsystems than the olfactory system alone.

00:17:18.740 | So you have several chemosensory-sensitive nerves

00:17:21.780 | in your nose.

00:17:23.460 | A primary one beyond the olfactory nerve

00:17:25.540 | is the trigeminal nerve, the fifth cranial nerve.

00:17:28.460 | So the trigeminal nerve has sensory endings

00:17:31.220 | in your nose, in your throat, and in your eye.

00:17:33.260 | It has three branches.

00:17:34.660 | That's why an onion has smell and burns your eyes

00:17:37.780 | and burns in your throat.

00:17:39.100 | - Is that why?

00:17:39.940 | - It's trigeminal, yeah.

00:17:40.780 | - The tearing of cutting an onion is--

00:17:42.380 | - Trigeminal, it's a trigeminal reflex.

00:17:44.380 | - Amazing.

00:17:45.220 | We talked about trigeminal in the context of headache

00:17:47.460 | during a headache episode.

00:17:48.460 | - It's a trigeminal reflex.

00:17:49.580 | So the lemon you were smelling

00:17:52.820 | may have been a trigeminal sensation.

00:17:55.660 | - So smelling the lemon with my eyes is what you're saying?

00:17:58.100 | - Well, no, with your nose.

00:17:58.940 | - No, with my nose.

00:17:59.780 | - Trigeminal receptors are not your olfactory receptors.

00:18:03.140 | So within olfaction research or jargon,

00:18:07.700 | there's what we refer to as pure olfactants.

00:18:10.420 | These are odors that will stimulate

00:18:12.340 | your olfactory nerve alone.

00:18:13.860 | They won't influence your trigeminal nerve at all.

00:18:16.820 | And an example, just to get a sense of what that might be,

00:18:19.100 | would be the coffee right here is a pure olfactant.

00:18:23.300 | Vanilla is a known pure olfactant.

00:18:25.420 | These things have no trigeminal activation.

00:18:29.260 | As long as we're on this topic

00:18:30.460 | and we'll weave back and forth,

00:18:31.700 | but I'm glad we are on this topic

00:18:33.820 | because a tremendous number of people

00:18:35.180 | wrote to me during the pandemic

00:18:36.700 | and continue to about olfactory loss.

00:18:39.740 | I've heard of this olfactory training

00:18:44.620 | whereby if you have a partial or even a complete loss

00:18:48.460 | of primary olfaction that one is encouraged

00:18:52.340 | to smell a number of different smells.

00:18:54.260 | I grew up studying activity dependent wiring

00:18:58.060 | of the nervous system.

00:18:58.900 | It makes total sense to me why keeping neurons active

00:19:01.020 | keeps them alive.

00:19:02.220 | So this is not fire together, wire together type thing.

00:19:05.060 | By the way, that's a quote from Carla Schatz,

00:19:06.540 | not Donald Head folks or me.

00:19:09.180 | But this is about keeping neurons electrically active,

00:19:13.140 | in this case olfactory neurons,

00:19:14.660 | in order to maintain their connections

00:19:16.660 | because otherwise they will die.

00:19:18.260 | - Olfaction is a definite use it or lose it system.

00:19:24.100 | And so that makes total sense.

00:19:26.420 | And indeed there's very strong evidence for success

00:19:29.780 | of the training programs, more than the alpha lipoic acid.

00:19:33.660 | - Great to know.

00:19:34.500 | - And so that's a real thing.

00:19:35.780 | And what's cool about that is that you don't need to go out

00:19:38.580 | and buy expensive things, although you can.

00:19:40.980 | Of course, there are people who are capitalizing

00:19:42.500 | on this commercially already,

00:19:43.780 | but you can just take things from your refrigerator

00:19:47.380 | or your makeup cabinet or whatever and smell them

00:19:51.260 | intentionally and constantly and sniff them.

00:19:55.140 | And that exposure will help you recover.

00:19:57.780 | There is good data on that by now.

00:19:59.380 | You made that point in passing about regeneration

00:20:02.420 | in the olfactory system.

00:20:03.780 | And one of the cool things, so in olfaction,

00:20:07.220 | you can study many things through olfaction.

00:20:09.860 | Indeed, one of them is neuro regeneration

00:20:14.300 | because the olfactory neurons are really the only neurons

00:20:18.100 | that do that systematically in the adult mammalian brain.

00:20:21.780 | And whether the human olfactory system shows the same level

00:20:26.780 | of regeneration as it does in other mammals

00:20:32.020 | is and was somewhat questionable.

00:20:34.020 | And I'm just bringing that up to share a really cool study

00:20:36.740 | that was published in Neuron, I think somewhere around 2014,

00:20:40.700 | where to address this question,

00:20:43.460 | I just really liked the idea of doing that.

00:20:45.180 | What the authors did was look at,

00:20:50.940 | in post-mortem, they looked at levels of C-14

00:20:55.340 | in adults who were exposed to atomic bomb experiments.

00:21:00.340 | So you can actually look at these neurons

00:21:05.260 | and time them based on exposure to radiation.

00:21:09.700 | And that paper suggested that there's not as much turnover

00:21:17.860 | in the human olfactory bulb as there is in other mammals.

00:21:21.100 | Other lines of data suggest otherwise.

00:21:24.860 | So this is kind of a debated question

00:21:26.500 | as to what extent of neurodegeneration you have

00:21:29.380 | in the human olfactory system as opposed to other mammals.

00:21:34.020 | But that was just a really cool paper, I think,

00:21:35.820 | of doing that.

00:21:37.140 | - Fascinating.

00:21:38.060 | - Should I finish the path just so we have the,

00:21:43.100 | so information then synapses at the olfactory bulb

00:21:47.740 | from the olfactory epithelium.

00:21:51.140 | And the pattern of that synapsing follows

00:21:54.500 | what's referred to as the most extreme case of convergence

00:21:57.860 | in the mammalian nervous system.

00:22:01.180 | More specifically, what happens is that all the receptors

00:22:05.220 | of a given subtype, and remember in humans,

00:22:07.180 | we said we have about 350.

00:22:09.100 | In the mouse, we have about 1,200 probably.

00:22:12.860 | So all the receptors of one subtype converge

00:22:16.780 | to one location in the bulb.

00:22:19.220 | And this location is referred to as a glomerulus

00:22:21.740 | or an imploro glomeruli.

00:22:23.580 | And that may be a slight oversimplification.

00:22:25.660 | It's in fact two glomeruli.

00:22:27.140 | There's a mirror, sort of a mirror cut line.

00:22:29.660 | And so all the receptors of one subtype will converge

00:22:33.580 | to two mirror glomeruli on the olfactory bulb.

00:22:37.020 | So you end up having two glomeruli that reflect

00:22:40.420 | that one receptor subtype.

00:22:42.700 | And so if, and this is as far as, I'm giving you now

00:22:47.300 | the textbook view of how the system works.

00:22:49.740 | But then I can, I'll happily share with you things

00:22:51.900 | that pose a problem for the textbook view

00:22:54.700 | of how things work.

00:22:56.060 | But the textbook view of how things work

00:22:57.580 | is that every such receptor subtype is responsive

00:23:01.340 | to a small subset of different molecular shapes,

00:23:05.300 | what's sometimes referred to as ototopes,

00:23:07.260 | the molecular aspects of the odorant.

00:23:10.100 | So each receptor is responsive to a different subset

00:23:12.940 | of ototopes, let's say 10.

00:23:14.980 | And each ototope will activate

00:23:16.900 | a different subset of receptors.

00:23:19.260 | So potentially you have this insane combinatorics

00:23:21.940 | of this potentially 350 dimensional space

00:23:24.740 | in the human, potentially.

00:23:26.060 | But then because of this convergence,

00:23:28.940 | you end up having on the bulb in a way a map

00:23:33.180 | reflecting receptor identity.

00:23:35.860 | So let's say this coffee activates receptors

00:23:39.100 | of type 1, 3, and 7.

00:23:41.100 | So the glomeruli of receptors 1, 3, and 7

00:23:43.700 | will light up, quote unquote, when I smell the coffee.

00:23:46.580 | And if you can take a snapshot of that,

00:23:48.620 | theoretically you would have the map of coffee

00:23:52.300 | and so on and so forth.

00:23:53.820 | This is sort of the textbook view of how the system works.

00:23:56.580 | And then information goes from the bulb

00:23:58.620 | to several targets in the brain.

00:24:01.740 | I mean, what is referred to as primary olfactory cortex

00:24:04.220 | is piriform cortex and enthorhinal cortex.

00:24:07.060 | This is on the ventral surface of the brain,

00:24:09.020 | the lower portion of our temporal lobe.

00:24:10.980 | And information goes there directly,

00:24:13.580 | but it also goes directly to the amygdala.

00:24:16.020 | It probably goes directly to the hypothalamus.

00:24:18.660 | It may go directly to the cerebellum.

00:24:21.540 | It goes all over the brain.

00:24:23.180 | So information projects widely from there.

00:24:27.340 | And as far as people understand,

00:24:30.020 | the map that may exist on the bulb

00:24:33.500 | doesn't exist in the rest of the brain.

00:24:35.140 | And the understanding of how coding occurs

00:24:37.940 | in the rest of the brain is murky.

00:24:40.420 | - Commonly one hears that the memories

00:24:44.180 | that we have of odors are somehow more robust

00:24:46.820 | than the memories of other perceptual events in our life.

00:24:50.820 | I don't know if this is true or not,

00:24:52.900 | but people will say, for instance,

00:24:55.340 | I can still remember the smell of my grandmother's hands

00:24:58.420 | or the smell of cookies in her kitchen.

00:25:00.380 | At a minimum, it points to the fact that smell and memory

00:25:04.980 | are closely linked.

00:25:06.020 | And you just mentioned a direct, you know, multi-station,

00:25:10.020 | but nonetheless, somewhat direct path

00:25:13.300 | from the nostrils to the hippocampus,

00:25:15.980 | one of the primary encoding centers of memories.

00:25:17.820 | - Two synapses away.

00:25:18.860 | - Yeah, which is a remarkably short pathway,

00:25:20.980 | considering that, for instance, just by example,

00:25:23.660 | 'cause some of our listeners won't be familiar with this,

00:25:25.660 | but some will, that sound waves

00:25:27.940 | that are transduced into neural signals

00:25:30.300 | at the level of the inner ear go through many stations

00:25:33.980 | before they arrive at the location in the brain

00:25:35.860 | where we make sense of those sound waves

00:25:37.940 | as voices or music, et cetera,

00:25:39.780 | whereas olfaction is more of a direct route

00:25:42.580 | to the memory centers.

00:25:44.580 | Is there any just so story or real objective truth

00:25:50.540 | to the idea that olfactory memories are formed more easily

00:25:54.300 | or maintained longer or more robustly

00:25:56.980 | than other sorts of memories?

00:25:58.780 | - So, yes.

00:26:00.700 | But first, I should say that I'm not an authority

00:26:05.140 | on olfactory memory.

00:26:06.260 | It's sort of, olfactory memory is a huge field of research,

00:26:09.380 | and somehow, our lab has never really gone much into that,

00:26:14.380 | although, again, the same student

00:26:17.820 | I happened to talk about before, Yarai Sharun,

00:26:19.740 | who's, again, now a faculty at Tel Aviv,

00:26:22.140 | ran a study, a paper, I think we published

00:26:26.300 | in Current Biology called The Privileged Representation

00:26:29.460 | of Early Olfactory Associations.

00:26:32.380 | Basically, there's something about the first time

00:26:34.860 | you experience a smell that generates

00:26:37.700 | a particularly robust representation

00:26:40.460 | more than other sensory stimuli,

00:26:42.260 | and that's what she, in fact, compared.

00:26:44.260 | So, there's something about the first exposure to a smell

00:26:47.180 | in terms of the brain encoding

00:26:50.180 | that etches it into our being.

00:26:54.780 | And this is an effect that has, you know,

00:26:57.220 | it has echoes, of course, in literature.

00:26:59.220 | I mean, you know, the biggest cliche in this

00:27:01.060 | is to bring up the Proust effect, right?

00:27:02.540 | So, the Proust effect is when he ate the madeleine,

00:27:04.500 | and then immediately, the taste and smell immediately

00:27:06.540 | reminded him of an event in his childhood

00:27:09.940 | where the same madeleine appeared.

00:27:14.340 | But, so that's something very real.

00:27:19.620 | There's a lot of research on it not coming from our work,

00:27:23.380 | so I'm not an authority.

00:27:24.900 | - But it does sound like there's something special

00:27:26.700 | about olfaction, and that doesn't mean

00:27:29.860 | that there isn't something special about vision or audition.

00:27:33.660 | Each one has its own unique tone.

00:27:36.140 | - I'm the last to argue that there's something special

00:27:37.940 | about olfaction.

00:27:39.620 | My students make fun of me because they say,

00:27:43.580 | and there's some truth to that,

00:27:44.860 | that I try to explain everything

00:27:46.580 | through the olfactory system.

00:27:47.740 | I mean, for me, everything is olfactory, so yes.

00:27:51.100 | - Through the lens of the nose.

00:27:52.700 | I'd like to take a quick break

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00:29:07.420 | When I was at Berkeley,

00:29:10.480 | I was walking across campus one day,

00:29:12.860 | and I saw, I think, students,

00:29:15.980 | but I saw people on their hands and knees

00:29:18.760 | with goggles on, gloves on,

00:29:21.180 | and I think their mouths were covered too?

00:29:24.940 | - Everything was covered.

00:29:25.780 | - Was covered, and they were walking,

00:29:28.180 | well, they were crawling along the ground,

00:29:31.020 | and I thought this was peculiar,

00:29:32.640 | but then again, it's UC Berkeley,

00:29:34.520 | and the joke is if it,

00:29:36.180 | to get noticed on the UC Berkeley campus,

00:29:37.840 | you have to be naked and on fire, right?

00:29:39.780 | One or the other would not be sufficient.

00:29:41.340 | Please don't run this experiment, anybody.

00:29:43.540 | It's that kind of place.

00:29:45.400 | - Yeah.

00:29:46.240 | - But nonetheless, a paper came out a few years later,

00:29:50.960 | describing the results of what turned out

00:29:53.340 | to be your experiment that your laboratory was running,

00:29:55.520 | which was having people follow an odor trail

00:29:57.860 | with their nose,

00:29:59.260 | and my understanding is that people can improve

00:30:04.020 | their ability to track sense quite robustly,

00:30:08.560 | especially if we deprive them of vision

00:30:12.580 | and somatic sensation that is touch

00:30:14.740 | and some other sensations.

00:30:16.320 | Maybe you could just tell us a little bit about that study,

00:30:18.180 | and for, I think in our audience,

00:30:20.860 | I'm suspecting that many people have a keen,

00:30:23.440 | keen sense of smell.

00:30:25.000 | I have a family member who just like can detect

00:30:27.700 | any negative, you know, putrid odor in the environment,

00:30:31.300 | but also good odors, exquisitely well,

00:30:34.960 | and I have other family members whose sense of smell

00:30:37.080 | is quite poor.

00:30:38.240 | I'd love for all of those people to learn a bit

00:30:44.060 | about what is possible in terms of training up

00:30:46.500 | or improving our ability to smell,

00:30:48.440 | perhaps in the context of that study, if you will.

00:30:50.960 | - Yeah, so first, before even talking about improving,

00:30:54.500 | just off the bat, humans have a remarkable sense of smell,

00:30:59.500 | and this is something, again, in our lab,

00:31:01.840 | we already said, you know, yeah, we know this.

00:31:03.700 | This is old news, but to people who come

00:31:06.540 | from different worlds, we have to reiterate this.

00:31:08.360 | Sometimes when I give, you know, public lectures

00:31:11.040 | to non-olfaction audiences, I reiterate this.

00:31:14.540 | Humans have an utterly remarkable sense of smell.

00:31:18.200 | To put that a bit into sort of, you know,

00:31:21.240 | things that are tangible.

00:31:23.540 | So for example, mercaptans, which are added

00:31:27.140 | to cooking gas so that we smell it,

00:31:28.680 | because otherwise it wouldn't have a smell,

00:31:30.320 | so that the smell of gas, it's not the smell of gas,

00:31:33.220 | of propane, it's an additive.

00:31:35.520 | - Mercaptan?

00:31:36.360 | - Yeah, it's mercaptan.

00:31:37.920 | - The sulfur-like smell?

00:31:38.920 | - Yeah, so our detection threshold,

00:31:42.480 | that is the level at which we can detect it,

00:31:45.060 | is 0.2 parts per billion.

00:31:49.040 | Okay, there's no machine that can really do that

00:31:51.980 | that effectively, no gas chromatograph, nothing.

00:31:54.980 | Now, to give you another sense of making this,

00:31:58.440 | again, really tangible, we're working with an odorant

00:32:00.780 | in our lab called estra tetra enol

00:32:02.900 | that our participants can detect when we have it mixed

00:32:08.480 | at 10 to the negative 12 molar in the liquid phase.

00:32:12.540 | To give you a real sense of that, we did the math,

00:32:15.960 | if you would take two Olympic-size swimming pools

00:32:19.820 | and you would pipe it one ml, one drop,

00:32:23.360 | into one pool versus the other,

00:32:25.800 | you could smell the difference between the pools.

00:32:27.760 | - Incredible.

00:32:28.600 | - That's the detection threshold

00:32:30.080 | that you have with your nose.

00:32:30.900 | People have an utterly amazing nose, okay?

00:32:34.560 | So that's just in terms of its detection abilities,

00:32:37.200 | which are just remarkable, really up there

00:32:39.600 | in the mammalian world.

00:32:40.620 | We're not a bad mammal in all factions.

00:32:44.000 | And beyond that, we can improve, okay?

00:32:51.720 | And the example you're talking about

00:32:53.240 | actually started off as a lab bet, okay?

00:32:57.040 | We were having a lab picnic.

00:32:59.200 | So I guess I should hear Phil in because I'm your guest

00:33:02.280 | from the Weizmann Institute of Science in Israel,

00:33:04.160 | but before going back to my home in Israel,

00:33:07.600 | I was a faculty at UC Berkeley

00:33:10.960 | in the Helen Wills Neuroscience Institute.

00:33:13.360 | And this study was done during that time.

00:33:16.280 | And we were on a lab picnic and we were having indeed

00:33:18.840 | one of these sort of lab discussions arguments

00:33:21.060 | on what humans can and can't do with their sense of smell.

00:33:23.880 | And I said that humans could truly even track odor

00:33:26.720 | like a dog and people there said, "No way."

00:33:29.400 | And we ran this quick experiment, which I have video of,

00:33:32.940 | but I don't think we'll show it here.

00:33:35.520 | But I actually have a real, the picnic video, we have it.

00:33:39.360 | And a graduate student by the name of Christina Zolano,

00:33:42.760 | a brilliant graduate student at that time,

00:33:44.560 | who's now, she's now a professor at Northwestern.

00:33:47.700 | And she's really leading the field

00:33:49.800 | of all faction imaging today.

00:33:51.800 | But she was the volunteer and we dragged a chocolate bar

00:33:56.240 | across the grass and blindfolded her

00:33:59.480 | and checked if she could track the track we made

00:34:03.600 | with the chocolate, which she did very effectively.

00:34:06.120 | - Did you place her at the starting point of the line?

00:34:08.640 | - I think we did.

00:34:09.640 | I don't exactly remember what we did

00:34:11.160 | on that sort of picnic tryout.

00:34:13.800 | But I assume she'd never practiced that

00:34:15.840 | in her life before, right?

00:34:17.080 | And yet, she did it really, really well.

00:34:20.340 | And then this went on as a lab bed in a way

00:34:24.480 | that I said to my students, okay,

00:34:27.120 | we have to make this into an experiment,

00:34:29.280 | put it in an experimental setting

00:34:31.360 | and quantify what's going on.

00:34:33.360 | And they all said that it would be uninteresting.

00:34:37.360 | That was the bet.

00:34:38.320 | And I told them it would be in nature,

00:34:40.440 | which is a bet I won in this case.

00:34:42.680 | - Nature, of course, being one of the three apex journals.

00:34:46.120 | - It was nature neuroscience, to be fair.

00:34:48.600 | But so then we turned it into an experiment.

00:34:52.080 | And what the experiment was is that we brought

00:34:55.120 | in participants, naive participants,

00:34:57.040 | not graduate students from our lab,

00:34:59.600 | completely deprived them of any other sensory input.

00:35:02.560 | So we blocked their eyes, we blocked their ears,

00:35:04.880 | we blocked everything.

00:35:06.400 | They were wearing heavy gloves.

00:35:08.240 | They couldn't sense anything.

00:35:11.080 | And we generated a consistent odor path in the grass,

00:35:16.880 | which is what you saw.

00:35:18.480 | We did that by burying twine under the grass,

00:35:21.240 | an odor impregnated twine.

00:35:23.700 | So that way we could generate

00:35:25.120 | a consistent odor trail every time.

00:35:27.840 | - Was it at the base of the grass or in the dirt?

00:35:30.200 | - It was buried.

00:35:31.280 | It was buried under the grass.

00:35:32.560 | - Really?

00:35:33.400 | - Yeah, yeah.

00:35:34.600 | - Wow, I did not know that.

00:35:36.320 | - It was buried under the grass.

00:35:38.400 | And we conducted aerial photography.

00:35:41.960 | And participants also had this sensor pack

00:35:44.920 | that they were wearing where we measured

00:35:47.400 | nasal airflow in each nostril in real time.

00:35:50.720 | And we also used something called RTK GPS,

00:35:55.400 | which is a way to lay a radio frequency grid

00:35:58.860 | over the GPS grid,

00:36:00.240 | so that you have millimeter resolution in space basically.

00:36:04.080 | It's used by surveyors mostly.

00:36:06.120 | So that we could track behavior.

00:36:10.160 | And we found a few things doing this.

00:36:11.840 | One is that people could just do this right off the bat.

00:36:14.640 | The second thing we found that is when we train them up,

00:36:19.840 | then within average of four days,

00:36:25.280 | the rate limiting factor became the speed

00:36:27.560 | at which they could crawl.

00:36:29.560 | So as fast as you could crawl, you could send track.

00:36:32.200 | Of course, you can't crawl as fast as a dog can run.

00:36:34.840 | But as fast as you can crawl, you can send track.

00:36:38.040 | And then to sort of add what made it really interesting

00:36:42.060 | from a systems neuroscience perspective

00:36:45.440 | is that we asked whether having two nostrils

00:36:49.660 | contributes to this.

00:36:53.000 | So we built, we constructed a nasal prosthesis, if you will,

00:36:58.000 | that had two versions.

00:37:00.940 | One is that it combined both nostrils

00:37:04.320 | into one big nostril centered.

00:37:07.600 | And the other is that it maintained

00:37:09.360 | two separated nostrils.

00:37:11.720 | And we compared performance under these two conditions.

00:37:14.460 | And people performed better with two nostrils

00:37:17.520 | over one centralized nostril,

00:37:18.920 | although the flow remained the same.

00:37:21.260 | So you're taking advantage of the information

00:37:24.240 | that comes from your two separate,

00:37:26.760 | totally separate nostrils.

00:37:28.500 | By the way, the system I described before

00:37:30.220 | of your epithelium and bulb and connection to cortex,

00:37:34.080 | you have two of those, right?

00:37:36.280 | It's completely unilateral,

00:37:37.900 | well, almost completely unilateral system.

00:37:40.780 | There are some very small exceptions to that.

00:37:44.500 | - So a representation on both sides of the brain.

00:37:46.940 | Much in the same way we have two eyes, we're not a cyclops.

00:37:49.700 | We can gain depth perception information.

00:37:52.460 | We can perceive motion better as a consequence

00:37:55.140 | and a number of depth, especially stereopsis.

00:37:57.800 | - And we can locate sound

00:37:59.140 | because of the difference between our ears

00:38:00.820 | and how the head blocks them between.

00:38:03.620 | - Amazing, another question about the mechanics

00:38:06.980 | and strategies that you observed,

00:38:08.640 | because I think there's information about the system,

00:38:12.000 | the brain as a consequence.

00:38:13.700 | Were you in a position to measure sniffing frequency?

00:38:17.540 | And the specific question I have is,

00:38:19.360 | were people doing something along the lines

00:38:21.700 | of a quick sniffing or a long draw in inhale?

00:38:26.700 | - So yes, we were measuring sniffing and recording it

00:38:33.780 | and we have all the data.

00:38:35.680 | There was nothing very remarkable in that data,

00:38:43.020 | in that study, although it may reflect

00:38:45.340 | that we didn't analyze it carefully enough as well.

00:38:47.540 | I mean, it wasn't a major component of our analysis.

00:38:51.560 | So although we did look at it to some extent,

00:38:54.540 | again, you're asking me about a paper

00:38:55.960 | from quite a few years ago,

00:38:57.080 | so I may be forgetting parts of it as well.

00:38:59.800 | - But I'm sure if it was a major component of it,

00:39:03.560 | it would have risen to the top.

00:39:05.020 | - It definitely wasn't a major finding

00:39:06.540 | of the sniffing behavior in the paper.

00:39:09.660 | Although again, sniffing behavior is a huge portion

00:39:14.100 | of our life in lab.

00:39:17.080 | And it's taking us to places

00:39:20.340 | and it's re-emerging now in our work.

00:39:22.480 | We're doing tons of sniffing work.

00:39:24.660 | I can share with you something

00:39:28.500 | that I think will interest your listeners

00:39:31.460 | and viewers as well.

00:39:32.720 | And we think is really one of the most overlooked things

00:39:37.720 | in neuroscience.

00:39:40.160 | I'll invite you to do the following experiments.

00:39:43.380 | So occlude one nostril by pressing on it from the side

00:39:46.100 | and sniff in, and then occlude the other and sniff in.

00:39:49.740 | Do you sense a difference in flow?

00:39:51.180 | - Yes.

00:39:52.020 | - Okay, do you know why that is?

00:39:53.200 | - No, and it was the next question on my list.

00:39:55.520 | - Don't feel badly about not knowing why that is.

00:39:58.420 | Most people don't.

00:39:59.540 | But that is a reflection of something referred to

00:40:03.400 | as the nasal cycle.

00:40:05.300 | So in fact, if you were to do that repeatedly,

00:40:07.300 | you would find that your high flow nostril

00:40:10.540 | and low flow nostril alternate

00:40:13.160 | every two and a half hours on average.

00:40:15.100 | In an absolute way, or is it kind of like a sine wave,

00:40:17.300 | like gradual shift to one and then gradual shift back?

00:40:20.180 | - It can vary.

00:40:22.060 | It can vary, and we don't yet know the rules, all the rules.

00:40:26.100 | But you have this constant shift from side to side.

00:40:29.960 | The shift becomes incredibly pronounced in sleep.

00:40:33.100 | So we can measure the power of the difference.

00:40:35.860 | And in sleep, you have this phase shift of power.

00:40:38.540 | You have a huge, like one closes and one opens totally.

00:40:43.100 | And it turns out that this is linked to balance

00:40:48.100 | in the autonomic nervous system.

00:40:49.980 | So as you and your listeners know,

00:40:51.460 | we have an autonomic nervous system

00:40:53.140 | that has a sympathetic and parasympathetic component to it.

00:40:56.260 | And they're in balance or imbalance in many diseases,

00:40:59.180 | for example.

00:41:00.020 | And this interplay between the sympathetic

00:41:05.020 | and parasympathetic nervous system drives the switch

00:41:08.380 | from left to right nostril.

00:41:10.460 | - Just to remind people, sympathetic nervous system

00:41:13.020 | has nothing to do with sympathy.

00:41:15.100 | Has everything to do with generating patterns of alertness.

00:41:18.020 | It's sometimes called the fight or flight system,

00:41:19.780 | but any pattern of arousal, positive or negative.

00:41:22.540 | And then it's balanced in a coordinated way,

00:41:25.740 | or at least in parallel with the parasympathetic

00:41:27.540 | nervous system, which is sometimes called

00:41:29.020 | the rest and digest system,

00:41:30.140 | but is associated with all sorts of things.

00:41:32.420 | The sexual arousal response and a number of other aspects

00:41:35.580 | of our physiology.

00:41:36.420 | So think of it like a seesaw of alertness and calm.

00:41:39.420 | - Perfect.

00:41:40.260 | So imagine, right, imagine you would walk around

00:41:43.500 | living your life, right?

00:41:44.620 | Half of the time with one eye closed like this,

00:41:47.420 | and the other half with one eye closed like this,

00:41:50.020 | and you had this eye cycle, right?

00:41:52.020 | And that was linked to autonomic arousal.

00:41:53.820 | I assure you, you would go to PubMed,

00:41:55.340 | there would be five million papers on the eye cycle, right?

00:41:57.900 | And the eye cycle and every disease you can name

00:42:00.860 | and what it denotes and what it tells us

00:42:02.940 | and what we can do with it.

00:42:04.340 | You have exactly this marker.

00:42:07.100 | You're walking around with the marker on balance

00:42:10.260 | in your autonomic nervous system,

00:42:12.020 | and we do nothing with it.

00:42:13.700 | So we're in fact now doing a lot with it, okay?

00:42:15.940 | So we built a wearable device that is pasted to your body

00:42:20.940 | and measures airflow in each nostril separately

00:42:24.500 | and logs it for 24 hours.

00:42:26.940 | And we're collecting these 24 hour recordings.

00:42:30.260 | We're calling it the nasal halter.

00:42:32.300 | So we measure with the nasal halter,

00:42:35.060 | and we're finding it as a disease marker.

00:42:38.700 | I can give you a nasal halter measurement as an adult,

00:42:44.580 | and I can say, this is work by Tim Nasaroka,

00:42:47.020 | a graduate student in our lab now.

00:42:48.820 | I can, so we can tell the difference between ADHD

00:42:52.900 | and non-ADHD adults.

00:42:55.300 | And we can tell just from the recording,

00:42:57.740 | we can tell if the adults are on Ritalin or not.

00:43:00.780 | So I can measure your nasal airflow and say,

00:43:04.140 | if you are or are not with ADHD,

00:43:05.900 | and if you are or are not on Ritalin.

00:43:08.020 | - Incredible.

00:43:09.060 | I have a couple of questions about this.

00:43:11.900 | Is it the case that airflow through one nostril

00:43:14.820 | is reflective of a sympathetic nervous system dominance

00:43:18.940 | versus parasympathetic, or is it simply the case

00:43:22.820 | that this alternating left-right nostril periodicity,

00:43:26.740 | which you said I think is on the order

00:43:28.140 | of about every two hours.

00:43:29.180 | - Two and a half. - Two and a half.

00:43:30.180 | It switches to maximal on one side versus the other.

00:43:34.300 | Is that simply reflective of an overall balancing,

00:43:38.140 | maybe is it the hinge in the seesaw,

00:43:40.100 | or is it the tilt of the seesaw?

00:43:42.060 | - So I don't have a good answer.

00:43:43.900 | I don't have a good answer.

00:43:44.780 | I mean, I could give you sort of a,

00:43:46.780 | I could say that to some extent,

00:43:48.740 | right nostril more open is more sympathetic,

00:43:53.900 | and left nostril more open is more parasympathetic,

00:43:56.820 | but that wouldn't be very correct.

00:43:58.980 | I'm sure that the yogis are gonna be all over this, right?

00:44:02.780 | 'Cause I get this, my lab does do some stuff on breathing,

00:44:05.820 | and the yogis are always saying,

00:44:07.260 | okay, you know, 'cause there's this thing,

00:44:08.820 | I don't do yoga anymore, not for any particular reason,

00:44:11.940 | but where they'll have you breathe

00:44:13.620 | through one nostril or the other.

00:44:15.100 | And I've probably been asked this question

00:44:18.040 | on social media 10,000 times.

00:44:21.460 | - Okay, wait, I'm gonna become public enemy

00:44:23.620 | number one of the yogis right now.

00:44:25.140 | So listen, so we-

00:44:27.020 | - They'll come at you with yoga mats,

00:44:28.720 | which are not very dangerous.

00:44:30.020 | - We really, so since we're so interested in this mechanism,

00:44:33.900 | one of the things we'd really like to know how to do

00:44:35.920 | is to gain control of it somehow.

00:44:38.820 | And there's this world out there of yoga

00:44:40.820 | who claims to have control over this.

00:44:43.400 | So we said, okay, let's bring like really serious

00:44:45.780 | yoga practitioners and see if they can shift

00:44:48.920 | their nasal cycle from left to right by will alone, right?

00:44:51.780 | Not by manipulating themselves somehow.

00:44:54.460 | And if yes, we'll learn from them how they do this,

00:44:56.740 | and then we might use this to cure ADHD or whatnot, right?

00:45:01.160 | So we posted like on all the lists of like the yoga teachers

00:45:06.160 | and had this parade of yoga teachers walking into our lab.

00:45:11.240 | This was one of the strangest-

00:45:12.620 | - Lot of sandalwood odors and bare feet.

00:45:14.880 | - White clothing and so on.

00:45:19.760 | And so we studied, I actually know,

00:45:21.760 | we studied 14 yoga teachers,

00:45:24.440 | all 14 by the conditions of enlistment for this

00:45:29.440 | came in saying that they can control

00:45:32.480 | shifting from left to right nostril.

00:45:34.980 | - Without plugging a nostril with your finger.

00:45:36.800 | - By the power of thought alone.

00:45:38.400 | And you know how many of 14 succeeded?

00:45:42.280 | Zero, including one, you know, there was an extreme one

00:45:46.200 | where we had this guy who, and we're recording,

00:45:50.880 | and we know how to record this really well, right?

00:45:52.760 | And he's sitting there saying, yeah, I'm switching now

00:45:55.320 | and it's switching.

00:45:57.040 | And you know, you're looking at the monitor

00:45:58.400 | and no, it's not switching.

00:46:00.440 | And so no yoga teacher that we found

00:46:04.120 | could willfully switch between left and right nostril flow.

00:46:08.740 | - And yet they are convinced that they are,

00:46:10.640 | and I have to imagine they're not trying to,

00:46:12.400 | you know, there's no incentive for them to lie, right?

00:46:15.120 | - Yeah, no, even the opposite.

00:46:17.360 | I mean, you know, this puts them in an awkward position.

00:46:20.760 | Yeah, I don't know what the deal is,

00:46:22.200 | but none of them can do it.

00:46:24.000 | - Given that the alternating flow

00:46:27.600 | through one or the other nostrils

00:46:28.880 | reflective of the autonomic nervous system

00:46:31.280 | has this two and a half hour periodicity,

00:46:34.080 | if I suddenly enter a bout of stress, for instance,

00:46:36.940 | does it switch?

00:46:37.780 | Because that's reflective of the autonomic nervous system.

00:46:39.760 | And the reason I'm asking this question

00:46:41.480 | is not because I think that's necessarily important

00:46:44.080 | as it relates to stress,

00:46:45.420 | but I'm trying to understand the direction of causality.

00:46:47.800 | In other words, is the unilateral smelling,

00:46:51.080 | or unilateral nostril smelling periodicity,

00:46:53.520 | there when we named it something,

00:46:55.040 | I could name it the wrong thing, I'm sure.

00:46:56.800 | Is that driving the shift in the autonomic nervous system,

00:47:00.560 | or is it merely reflective of the shift?

00:47:02.480 | - So you've very concisely now worded aim two of a grant

00:47:07.140 | that was probably just rejected,

00:47:09.140 | but basically we're trying to answer exactly that question,

00:47:13.660 | and we're currently running experiments on that line.

00:47:16.440 | So we have one experiment

00:47:19.140 | where we're looking,

00:47:22.360 | so we're exposing participants to pain.

00:47:27.280 | We're using cold water hand exposure.

00:47:30.080 | It's a really cool paradigm

00:47:31.160 | because there's huge individual differences.

00:47:33.820 | We just started this, we built the setup just now,

00:47:36.500 | and you have a lot of meat to work with there

00:47:38.680 | because there's a lot of individual differences.

00:47:41.360 | It's capped at three minutes for safety reasons

00:47:44.820 | because you have participants putting their hand

00:47:47.100 | in two degrees Celsius water,

00:47:50.600 | but there'll be participants who will pull it out

00:47:52.520 | at like 10 seconds, nine seconds,

00:47:54.660 | and then you'll have three minutes as well.

00:47:56.740 | So there's lots of, and already,

00:48:00.620 | so now I'm sharing pilot data with you,

00:48:02.480 | so when this ends up being published,

00:48:06.520 | it might be the opposite,

00:48:07.360 | but so far it seems that the exposure to cold

00:48:10.620 | generates a shift in the nasal flow and nasal balance.

00:48:13.680 | So autonomic arousal can drive the shift, potentially.

00:48:16.940 | Earlier you were describing the architecture

00:48:21.280 | of these smelling systems,

00:48:24.180 | and you mentioned these glomeruli

00:48:26.320 | where the olfactory receptors converge in the bulb,

00:48:29.040 | and then later you mentioned that the system is unilateral,

00:48:32.740 | but with a mirror representation on both sides of the brain.

00:48:34.960 | So for those who don't think in terms of neuroanatomy,

00:48:37.240 | what Noam was describing is the fact that,

00:48:39.720 | of course, there are two nostrils

00:48:41.600 | and then a bunch of receptors,

00:48:42.720 | they converge in these glomeruli,

00:48:43.880 | but you have a mirror representation of that

00:48:45.600 | on both sides of the brain

00:48:46.500 | and that most of that information

00:48:48.360 | is kept on one side of the brain or the other.

00:48:50.420 | There isn't a lot of extensive intermixing

00:48:52.080 | at the first order of processing.

00:48:54.320 | So the question I have is whether or not you believe,

00:48:57.760 | I'm not asking for data.

00:48:58.840 | First, I just want to know what you believe,

00:49:00.280 | that this alternating nostril airflow phenomenon

00:49:04.560 | has anything to do with preferential processing

00:49:07.640 | of olfactory information in terms of right brain,

00:49:09.960 | left brain, with the caveat that

00:49:13.240 | anytime we hear right brain, left brain,

00:49:16.080 | we've covered this in a previous episode,

00:49:17.780 | most of what people hear out there

00:49:19.360 | about right brain, left brain,

00:49:20.980 | emotionality, logical stuff is completely wrong,

00:49:24.000 | completely wrong, doesn't exist, is a total fabrication,

00:49:27.280 | and we'd like to abolish that myth.

00:49:29.040 | But with that aside, or set aside rather,

00:49:33.360 | what are your thoughts on why the information

00:49:35.840 | would switch from one side of the brain

00:49:37.160 | to the other at all?

00:49:39.040 | Yeah, I don't think that the nasal cycle

00:49:44.040 | is an olfaction story.

00:49:47.380 | So I don't think that this was shaped

00:49:54.080 | by the olfactory system,

00:49:57.840 | nor do I think this has major impact on olfaction.

00:50:01.720 | I think the nasal cycle story

00:50:03.140 | is a different story about brain function.

00:50:06.640 | So we have this sort of pet theory

00:50:11.480 | where calling now the snipping brain approach,

00:50:15.040 | where basically we think that nasal inhalation

00:50:20.040 | is timing and driving a lot of aspects and patterns

00:50:28.960 | of neural activity and cognitive processing.

00:50:31.920 | And this theory is olfaction inspired in its beginning.

00:50:35.400 | That is, I mean, if you think of the mammalian brain,

00:50:38.120 | right, which evolved from olfaction,

00:50:43.120 | it's sitting there and in olfaction,

00:50:46.200 | because olfaction depends on sniffing,

00:50:47.800 | you have this situation where you have a sniff,

00:50:51.000 | you have information, and then flat, nothing, right?

00:50:55.360 | And then you have information and then nothing.

00:50:57.660 | So information processing is one to one

00:51:02.160 | linked to nasal inhalation.

00:51:05.280 | And we think that this property evolved

00:51:10.280 | to be meaningful in brain processing in general,

00:51:15.160 | not only of olfactory information,

00:51:17.140 | but of any type of information,

00:51:18.360 | because the brain evolved in this way,

00:51:20.160 | in this way that it processes information

00:51:22.140 | on inhalation onset.

00:51:24.240 | So a study led by Ofer Perel from our lab

00:51:28.160 | two, three years ago,

00:51:31.360 | we looked at something completely non-olfactory.

00:51:33.960 | We looked at visuospatial processing,

00:51:36.720 | and we compared visuospatial processing

00:51:39.640 | on inhalation versus exhalation.

00:51:42.280 | And the brain does this completely different

00:51:44.440 | on inhalation versus exhalation.

00:51:46.760 | In that particular task,

00:51:48.640 | people performed significantly better

00:51:51.160 | on inhalation versus exhalation.

00:51:52.860 | - What was the task?

00:51:53.700 | Was it an olfactory task?

00:51:54.600 | - No, no, it's a visuospatial task.

00:51:56.480 | So this is a task where the specifics of the task

00:52:00.980 | were that you see a shape,

00:52:05.060 | and you have to determine if it's a shape

00:52:07.380 | that can or cannot exist in the real world.

00:52:09.740 | So some of them were these like,

00:52:11.260 | usher shapes like, you know,

00:52:12.840 | where one facet doesn't reach the other facet.

00:52:15.980 | - The impossible figure type of stuff.

00:52:17.460 | - Yeah, but structural shapes, not,

00:52:21.080 | and so a pure visuospatial task,

00:52:24.660 | we intentionally went for a task

00:52:26.500 | that is not considered a ventral temporal task,

00:52:30.460 | olfactory cortex task in any way.

00:52:32.780 | And people performed much better

00:52:37.160 | on inhalation versus exhalation at doing this task.

00:52:39.840 | - Was there a both nostrils occluded version

00:52:42.740 | where people were forced to mouth breathe?

00:52:44.280 | - Yes, and in this particular task,

00:52:47.580 | they also did better on mouth inhalation

00:52:51.120 | versus mouth exhalation.

00:52:52.760 | But the difference wasn't as pronounced

00:52:55.740 | as it was with nasal inhalation versus exhalation.

00:52:58.780 | So I'm a big proponent of nasal not mouth breathing

00:53:03.060 | whenever possible for many health-related reasons.

00:53:06.900 | I'm a big fan of the book, "Jaws, a Hidden Epidemic,"

00:53:09.920 | written by colleagues of mine at Stanford.

00:53:11.340 | - Familiar with it. - Yeah.

00:53:12.300 | And this idea that people who mouth breathe

00:53:15.620 | experience more colds, more infections of various kinds.

00:53:19.180 | It's not good aesthetically or for the dentature.

00:53:22.100 | I never know, the teeth, the gums, it's stuff.

00:53:25.500 | Sorry, my dentist is gonna come after me.

00:53:28.620 | The other dentist anyway.

00:53:29.860 | That nose breathing is great for your health

00:53:33.640 | relative to mouth breathing.

00:53:34.480 | - So I think it's also good for your cognition,

00:53:36.900 | not only for your dental health.

00:53:39.900 | I think that nose breathing shapes cognition.

00:53:43.740 | And there are other labs who are finding the same.

00:53:48.740 | Again, Cristina Zellano is doing work on this line.

00:53:53.040 | She had major contributions here.

00:53:55.380 | And Johan Lundström is doing work on this line.

00:53:58.900 | There's lots of studies suggesting

00:54:01.220 | that nasal inhalation is timing cognitive processing

00:54:06.220 | and modulating it.

00:54:08.660 | - Incredible, perhaps not surprising

00:54:12.380 | given what you've taught us about the olfactory system.

00:54:14.720 | I mean, these two holes in the front of our face,

00:54:17.960 | these nostrils, I mean, are a pathway to the brain, right?

00:54:22.700 | I love to tell people,

00:54:23.820 | 'cause I work on the visual system in my lab,

00:54:25.660 | that your eyes are two pieces of brain

00:54:27.580 | extruded from the cranial vault, which they are,

00:54:30.100 | the retinas anyhow.

00:54:31.820 | And then you never look at anyone the same way again.

00:54:35.600 | But the olfactory sensory neurons

00:54:39.340 | are right there at the top.

00:54:41.020 | So those caverns that we call nostrils and they are brain.

00:54:44.720 | - Yeah, definitely.

00:54:46.780 | It's the only place where your brain meets the outside world

00:54:49.800 | because in your retina, they're protected by a lens.

00:54:53.100 | And here you have neurons in contact with the world.

00:54:57.180 | This actually has been the source for some theories

00:55:01.220 | on a potential route for neurodegenerative mechanisms.

00:55:06.220 | So as you may know, loss of the sense of smell

00:55:11.920 | is one of the, if not the earliest sign

00:55:14.800 | of neurodegenerative disease.

00:55:16.860 | So for example, in Parkinson's disease,

00:55:19.060 | there's a loss in the sense of smell,

00:55:22.260 | probably 10 years before any other symptom.

00:55:25.020 | But people have failed to make this a diagnostic tool

00:55:29.620 | because it's nonspecific.

00:55:31.620 | So it's not as if you could come to your doctor

00:55:33.580 | and say, I'm losing my sense of smell.

00:55:35.820 | And they'll say, oh, early sign of Parkinson's

00:55:38.180 | because you can have many reasons

00:55:40.460 | to lose your sense of smell and so on.

00:55:43.100 | But olfactory loss again is an early sign

00:55:50.980 | of neurodegeneration.

00:55:52.260 | And there's at least one theory,

00:55:54.620 | particularly about Alzheimer's disease,

00:55:56.940 | suggesting that Alzheimer's may be the result

00:56:00.180 | of a pathogen that enters the brain

00:56:02.820 | through the olfactory system.

00:56:04.320 | It's not, of course, a mainstream

00:56:09.660 | or widely accepted theory of any type,

00:56:11.700 | but it just highlights this notion

00:56:14.580 | that the nose is a path to our brain.

00:56:18.480 | I think these non-invasive readouts

00:56:21.460 | of potential neurodegeneration,

00:56:24.840 | such as visual tests because of the fact

00:56:28.440 | that the retinas are part of the brain

00:56:29.980 | and loss of neurons in the retina

00:56:31.500 | is often associated with other forms

00:56:33.820 | of central degeneration, Alzheimer's, Parkinson's, et cetera,

00:56:37.580 | as it's a little more invasive than what you're describing.

00:56:39.380 | I'm beginning to wonder why we don't have

00:56:42.140 | a olfactory task every time we go to the doctor

00:56:45.220 | that would allow tracking over time

00:56:47.860 | because, of course, as you mentioned,

00:56:49.560 | someone can lose their sense of smell.

00:56:51.280 | Does that mean they're getting Alzheimer's?

00:56:52.400 | Not necessarily, but if their sense of smell

00:56:54.540 | was terrific the year before

00:56:56.080 | and it's 50% worse the next year--

00:56:58.320 | - That's a really bad sign.

00:56:59.320 | - Yeah, that's a bad sign.

00:57:00.340 | And so what we're talking about,

00:57:01.180 | something completely non-invasive

00:57:03.000 | and could be relatively pleasant to innocuous

00:57:06.920 | depending on the odors used.

00:57:07.900 | - So yeah, so first I can answer that, right?

00:57:11.140 | And the reason that that's not happened,

00:57:14.280 | and that may be changing right now,

00:57:17.260 | but the reason that has not happened

00:57:19.840 | is because olfaction has not been effectively digitized.

00:57:23.960 | Right, so if you need to generate

00:57:26.200 | really precise visual information,

00:57:28.080 | you can buy a monitor for 100 bucks

00:57:30.760 | that is at the resolution of the visual system basically.

00:57:34.000 | And if you wanna generate auditory stimuli really precisely,

00:57:37.680 | then you can buy an amplifier

00:57:39.040 | for maybe a bit more than 100 bucks, but not that much more,

00:57:42.060 | and you'll be at the resolution of the auditory system.

00:57:46.200 | In our lab, we build devices that generate odors,

00:57:49.140 | we call them olfactometers, which is a misnomer

00:57:51.300 | because they don't measure anything,

00:57:52.700 | but that's what they've always been called,

00:57:54.060 | so we call them olfactometers as well.

00:57:56.420 | And we've already built at least one olfactometer

00:57:58.640 | that cost a quarter of a million euro, and it's pathetic.

00:58:02.380 | Right, so it's pathetic, it's slow, it's contaminated,

00:58:07.380 | it's nowhere near the resolution of your system.

00:58:10.280 | So one of the reasons that's not happened

00:58:13.620 | is just the utterly poor control of the stimulus.

00:58:17.440 | Mind you, to some extent, it has happened

00:58:20.280 | in that there are standard clinical tests of olfaction,

00:58:24.960 | basically two that sort of control the world in this respect.

00:58:29.220 | The older one is a test called the UPSIT,

00:58:32.580 | which stands for the University of Pennsylvania

00:58:34.820 | Smell Identification Test.

00:58:37.140 | It was developed by Richard Doty in Penn,

00:58:39.820 | and it's a test where you scratch and sniff,

00:58:42.540 | and it's a four-alternative forced-choice test

00:58:44.740 | with 40 odorants.

00:58:45.700 | So you have these 40 pages that you page through,

00:58:48.940 | and you sniff and smell, and it's been normed

00:58:53.060 | on gazillions of tests.

00:58:54.920 | I'm always amused by it because,

00:58:58.660 | so Richard Doty made a ton of money on the UPSIT,

00:59:03.660 | but he needed it because he has a habit.

00:59:06.020 | He has a NASCAR.

00:59:07.940 | So this, every time we buy UPSITs in the lab,

00:59:10.580 | I say there's another gallon of gas into Richard Doty.

00:59:12.940 | - He races NASCAR?

00:59:14.460 | - Not like NASCAR, but like one lower than that.

00:59:17.220 | Like, I don't know, like some sort of Formula A

00:59:19.980 | or Formula Ford or some, he races a car.

00:59:22.880 | And so that's where all the UPSITs went.

00:59:24.620 | So I always feel good about buying UPSITs

00:59:26.820 | because I know they're going to that good cause.

00:59:29.340 | - Keeping him in the fast lane.

00:59:32.300 | - But so that's one test that's out there,

00:59:34.700 | and indeed, you know, has been shown as a,

00:59:37.300 | you know, so there's reduced UPSIT in Alzheimer's

00:59:40.260 | and Parkinson's and in a host of other diseases.

00:59:43.420 | And there's a European version called sniffing sticks

00:59:47.300 | that Thomas Hummel has developed.

00:59:49.420 | And it's basically the same sort of concept of this.

00:59:54.420 | That one isn't scratch and sniff.

00:59:55.980 | It's like these pens that you open up and sniff.

00:59:58.660 | But those exist, but they're not as convenient

01:00:03.140 | as delivering stimuli and vision and audition.

01:00:07.500 | And that's why you don't have what you've just suggested.

01:00:10.780 | - Interesting.

01:00:11.620 | - You know, another place where you don't have it,

01:00:13.020 | which I think is even more,

01:00:14.940 | would have been even more meaningful,

01:00:16.840 | is you don't, olfaction is not tested in newborns, right?

01:00:21.500 | Where vision and audition is.

01:00:23.420 | You know, there's this thing called congenital anosmia,

01:00:25.500 | right, which is being without the sense of smell

01:00:28.280 | from birth, supposedly, congenital,

01:00:30.520 | which is a half a percent of the population.

01:00:34.460 | - It's not a trivial number.

01:00:35.740 | - Not totally, yeah.

01:00:38.300 | But nobody knows if that really is true.

01:00:41.740 | Because here's an amazing factoid.

01:00:45.060 | Guess the average age at which congenital anosmia

01:00:49.740 | is diagnosed.

01:00:50.580 | And this is a horrible statistic for me

01:00:53.380 | for the way I see the world.

01:00:54.940 | But what do you think the average age of diagnosis is

01:00:57.660 | for congenital anosmia?

01:00:59.020 | - Five years of age.

01:01:00.180 | - 14, incredible, 14.

01:01:02.620 | So most people who are one half of a 1%

01:01:06.020 | of the human population, presumably,

01:01:08.860 | is without the sense of smell

01:01:11.780 | and doesn't realize that until they're 14 years old.

01:01:13.700 | - Well, I don't know when they realized it first,

01:01:15.620 | but it's formally diagnosed at 14 on average,

01:01:19.180 | which means some of them even later, right?

01:01:21.020 | - And, right, it's a distribution.

01:01:24.260 | What, do they suffer?

01:01:27.380 | - Yes, so first of all, they suffer socially.

01:01:33.140 | And there's a host of deleterious life events

01:01:38.140 | associated with congenital anosmia.

01:01:40.820 | They die younger.

01:01:43.900 | So this is work out of Ilona Croix in Germany.

01:01:51.220 | And amongst the various things that are predicted

01:01:56.580 | by anosmia is shorter lifespan.

01:01:59.740 | But things like reduced social contacts,

01:02:04.260 | reduced romantic social contacts, it's not a good thing.

01:02:09.260 | - And do they lack olfactory bulbs?

01:02:14.740 | I'm presuming they have noses and nostrils.

01:02:16.860 | There is a condition I'm aware of

01:02:18.420 | where children are born without noses or nostrils.

01:02:20.580 | Very rare, very rare.

01:02:22.140 | We won't focus on that because it's exceedingly rare.

01:02:24.780 | - So they're born with noses and nostrils.

01:02:28.780 | And here's the thing, right?

01:02:29.620 | They don't know if they're born with olfactory bulbs.

01:02:33.060 | Most of them, although not all of them,

01:02:35.540 | but most of them don't have olfactory bulbs in adulthood.

01:02:39.420 | Or I should rephrase that, have remnant olfactory bulbs,

01:02:42.820 | really shriveled olfactory bulbs.

01:02:45.100 | But nobody can see the cause and effect here.

01:02:48.500 | - Before we talk about the role of,

01:02:50.500 | the requirement for olfactory bulbs for olfaction,

01:02:53.540 | a very interesting topic in its own right,

01:02:55.620 | I'm curious as to whether or not

01:02:57.660 | their endocrine system is altered.

01:03:00.420 | Because as we'll soon talk about,

01:03:02.140 | there's a lot of signaling through the nose

01:03:04.260 | from between individuals that triggers things,

01:03:08.780 | everything from the onset of puberty

01:03:10.380 | to feelings of romantic attraction,

01:03:12.620 | attachment, these sorts of things.

01:03:15.060 | Is it known whether or not,

01:03:16.540 | and I should say, excuse me for interrupting myself,

01:03:18.940 | but as long as I'm interrupting you every five minutes,

01:03:20.780 | I might as well interrupt myself too,

01:03:22.380 | that we are well aware of the proximity

01:03:25.660 | of the olfactory system to some of the hypothalamic systems

01:03:29.580 | that regulate the release of gonadotropins,

01:03:31.380 | which control testosterone and estrogen production, et cetera.

01:03:34.860 | So are they hormonally normal?

01:03:38.460 | - So some are and some aren't, and I'll be specific.

01:03:41.460 | So there is a condition known as Kalman's syndrome,

01:03:44.900 | which is hypogonadic development in men.

01:03:52.100 | And in Kalman's syndrome, they're practically all anosmic.

01:03:57.100 | So to answer your question, yes, there's a direct link,

01:04:01.420 | and it materializes in Kalman's syndrome.

01:04:04.780 | That said, not all congenitally anosmic individuals

01:04:08.620 | have Kalman's syndrome, and not all,

01:04:11.700 | but almost all people who have Kalman's syndrome

01:04:13.700 | are anosmic.

01:04:14.740 | So Kalman's syndrome goes with anosmia.

01:04:19.740 | I think, so there's a female equivalent of Kalman's,

01:04:23.620 | or I don't remember its name.

01:04:25.740 | - It's not in the Turner syndrome family.

01:04:30.300 | - I'm not sure.

01:04:31.140 | And I think it's also associated with anosmia,

01:04:34.820 | but I'm not confident of that.

01:04:36.500 | But Kalman's is associated with anosmia.

01:04:39.500 | So the answer is yes.

01:04:41.740 | And we can maybe, olfaction and reproduction

01:04:47.100 | are tightly linked, and they're tightly linked

01:04:50.740 | in all mammals, and we are big terrestrial mammals,

01:04:54.620 | and olfaction and reproduction are linked in humans as well.

01:04:58.420 | - Yeah, we will definitely get into that.

01:05:01.380 | I'd like to just take a brief moment

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01:06:19.260 | I have a story/question that I'd like to tell you,

01:06:24.260 | ask you, as a segue to that.

01:06:26.900 | Noting, of course, that we'll get back

01:06:29.600 | to the requirement for olfactory bulbs,

01:06:31.940 | yes or no for olfaction.

01:06:33.440 | And this relates to when I was growing up,

01:06:37.180 | I grew up at the end of a street

01:06:39.380 | with a lot of boys of my age

01:06:42.180 | who, just by coincidence, had a lot of older sisters.

01:06:45.540 | They were my sister, my older sister's age.

01:06:47.220 | It was fortunate, so I had a lot of kids to play with.

01:06:49.800 | We would hang out at each other's houses,

01:06:51.620 | bike, build jumps, and do all those things,

01:06:54.020 | like kid stuff, fort stuff,

01:06:55.460 | get into trouble or whatnot.

01:06:59.200 | And oftentimes, we would end up leaving

01:07:02.100 | our articles of clothing at each other's houses

01:07:05.100 | all the time, like t-shirts and jackets.

01:07:07.220 | And so, my mom was constantly coming in and saying,

01:07:10.100 | there's this clothes, like someone left us here,

01:07:13.140 | I don't know who it was.

01:07:13.980 | We were all more or less the same size.

01:07:15.880 | And from as far back as I could remember,

01:07:19.480 | six, seven years old and onward,

01:07:22.460 | I could pick up a shirt or a jacket, smell it,

01:07:25.540 | and say, oh, well, that's Eric Eisenhart's shirt,

01:07:29.420 | a friend of mine there, I just gave his name.

01:07:30.940 | Or, oh, that's Scott Madsen's shirt.

01:07:32.780 | I could just smell the shirt and in a conscious way,

01:07:35.820 | know who it belonged to, having never, I promise,

01:07:39.140 | not that I would pretend if I had,

01:07:42.020 | pretend that I hadn't if I had,

01:07:43.460 | but having never actually done the exercise

01:07:46.140 | of going and taking and smelling my friend intentionally.

01:07:49.100 | - Right. - Okay?

01:07:50.060 | In fact, if anything, I had all the reasons in the world

01:07:52.060 | to avoid smelling the other young boys in my neighborhood.

01:07:54.980 | Okay, so that raises a question of whether or not

01:07:59.140 | we are consciously and/or subconsciously

01:08:02.340 | coding identification of people that we interact with

01:08:06.900 | frequently or infrequently in terms of their smell

01:08:09.700 | or some other aspect of their chemistry.

01:08:15.140 | - Yeah.

01:08:16.580 | So, yes.

01:08:17.840 | We're doing that all the time, in my view,

01:08:24.120 | and a lot of this processing, almost all of it,

01:08:29.120 | is subconscious, and I don't know why.

01:08:31.820 | I already put that out there, right?

01:08:33.920 | I have no idea why human nature or culture or whatnot

01:08:38.920 | has pushed this into the realm of subconscious

01:08:46.120 | and something we're unaware of.

01:08:47.980 | But we do it all the time,

01:08:50.680 | and our lab has lots of studies on this front.

01:08:55.600 | One of them you may be familiar with

01:08:58.680 | that had gained some notoriety because it's amusing.

01:09:03.860 | So we look at human behavior a lot.

01:09:08.520 | We try to look at it through our nose

01:09:10.980 | in the way we look at what people are doing.

01:09:13.380 | We try to think, if I was a dog, what would I think of this?

01:09:18.380 | And if you look at dogs, when they interact,

01:09:23.780 | they visibly sniff each other.

01:09:25.620 | It's very obvious.

01:09:26.540 | They walk up to each other and they sniff each other.

01:09:30.860 | And yet humans don't typically walk up to a stranger

01:09:34.320 | and carefully sniff them, right?

01:09:35.680 | I mean, we're sort of obliged to sniff our babies.

01:09:40.200 | That's considered almost something you're supposed to do.

01:09:43.680 | And it's not culturally taboo to sniff our loved ones.

01:09:47.360 | It sort of doesn't seem like an odd thing to do.

01:09:50.300 | But we don't sniff strangers, right?

01:09:53.160 | Well, or do we?

01:09:54.260 | So we're finding more and more mechanisms where we do this.

01:09:58.380 | And the one I'm referring to now, for one example,

01:10:01.540 | is we started looking at handshaking.

01:10:03.420 | Handshaking is this really odd behavior.

01:10:06.340 | And it's not only in the West, by the way,

01:10:07.900 | as some people think it's only a Western thing.

01:10:09.560 | It's not, it's almost everywhere.

01:10:12.340 | And there's really poor understanding

01:10:16.460 | of how this behavior evolved.

01:10:17.860 | Like where did this thing come from?

01:10:20.340 | So if you look for the Wikipedia version, right,

01:10:24.500 | then they'll tell you that it's to show

01:10:26.180 | that you're not holding a weapon in your hand.

01:10:29.300 | But there's really no good evidence for that.

01:10:31.600 | It's a bit like the trillion bloodhound receptor story,

01:10:34.780 | right, I mean, we tried to find it.

01:10:36.620 | Why do people say that?

01:10:38.420 | They just do.

01:10:39.760 | And we started looking at people handshaking.

01:10:42.060 | And we noticed, or it seemed to us that we're noticing

01:10:44.500 | that people will shake hands and then go like this

01:10:48.220 | and like this.

01:10:49.040 | - For those of you listening and not watching,

01:10:50.660 | Noam is taking his hand and wiping it on his face.

01:10:54.940 | Or grabbing his nose or touching the side of his cheek.

01:10:57.380 | - Yeah, these things that we do all the time.

01:11:00.220 | - After a handshake.

01:11:01.220 | - Well, so first of all, we do them all the time,

01:11:02.860 | just period, right?

01:11:03.680 | The baseline here is really high,

01:11:04.860 | and we'll get to that in a second.

01:11:05.820 | But these behaviors that you could easily not notice, right?

01:11:10.820 | And so we asked whether that's a real thing.

01:11:14.300 | And this was a study led by Yidan Froomin

01:11:18.700 | in our lab at the time.

01:11:19.940 | And what we did first, and if you want,

01:11:24.880 | we can link, so this was published in eLife.

01:11:27.580 | And one of the nice things about eLife

01:11:28.940 | is that it has a very effective way to embed videos

01:11:32.320 | in the publication.

01:11:33.320 | So if you want, we can link this to your system later on.

01:11:36.220 | - We'll put it in the show note captions

01:11:37.980 | as a link on YouTube and the other four platforms,

01:11:41.380 | Spotify, Apple.

01:11:42.360 | - So what we did is we brought in participants to our lab,

01:11:47.280 | and we sat them in the room, experiment room,

01:11:52.180 | and told them the experiment would start soon

01:11:54.260 | and they should wait for us there.

01:11:55.260 | They didn't know what they were coming from.

01:11:57.220 | Unbeknownst to them, they were already being videoed.

01:11:59.840 | Of course, later on, they had the opportunity

01:12:02.620 | to not agree to us saving the video,

01:12:05.260 | in which case we would delete it immediately

01:12:06.860 | or letting us use it for science

01:12:08.860 | or some letting us use it for more than science

01:12:10.740 | for the video that's now on eLife.

01:12:13.060 | And we walk into the room and say,

01:12:15.840 | "Okay, just wait here.

01:12:17.340 | "We'll be right back with you to set up our experiment."

01:12:21.060 | And they would sit there for three minutes.

01:12:24.180 | And during those three minutes,

01:12:25.620 | we could later quantify how much indeed they,

01:12:28.020 | just by baseline, how much they touch their nose

01:12:30.180 | or their forehead or their chin

01:12:32.300 | or how many times their hand reaches their face.

01:12:35.940 | And by the way, that baseline is not low, okay?

01:12:39.220 | And then three minutes later,

01:12:40.500 | an experimenter would walk into the room

01:12:42.340 | and would share a consistent text.

01:12:44.900 | It would be, "We're still setting up our equipment

01:12:47.160 | "in the other room, and so just wait here

01:12:50.100 | "and we'll be right back with you.

01:12:51.200 | "But in the meantime, just wait here."

01:12:53.380 | And the experimenter went through this

01:12:55.500 | like 20-second fixed text.

01:12:58.060 | And in half of the cases, it included a handshake.

01:13:01.260 | This was a new experimenter,

01:13:02.300 | not the one who put them in the room.

01:13:03.460 | So it's the first time they met.

01:13:05.020 | So it'd be, "Hello, I'm so-and-so."

01:13:06.700 | They would put out their hand

01:13:07.660 | and shake their hand or not, okay?

01:13:09.900 | And we did all possible interactions in terms of gender.

01:13:12.540 | So we matched male participants

01:13:14.940 | with male and female experimenters

01:13:16.220 | and female participants with female and male experimenters.

01:13:19.140 | And so you had handshake and no handshake conditions.

01:13:21.860 | And then you can quantify that behavior

01:13:24.020 | of the hand going to the nose after handshake.

01:13:27.740 | And there was a remarkable increase

01:13:29.940 | in the hand going to the nose after handshake.

01:13:32.920 | And this is one of the nice cases.

01:13:35.560 | The paper includes statistics,

01:13:37.000 | but you don't need statistics here.

01:13:38.440 | Just look at the video.

01:13:39.500 | It's unreal.

01:13:41.020 | The video is unreal.

01:13:42.140 | - So interesting.

01:13:42.980 | - So the hand goes to the nose.

01:13:44.180 | Now, we did a few controls here

01:13:45.740 | to verify that this is an olfactory behavior.

01:13:48.740 | One is, unbeknownst to participants,

01:13:50.660 | we measured nasal airflow.

01:13:52.420 | And people not only bring their hand to their nose,

01:13:54.780 | they sniff it.

01:13:55.660 | So, and this is perfectly timed.

01:13:57.040 | They go like this, okay?

01:13:58.660 | So they're sniffing their hand.

01:14:00.300 | And in an additional control study, we manipulated it.

01:14:02.940 | So we built this little James Bond thing

01:14:05.060 | of a watch on the experimenter's hand

01:14:07.620 | that could emit an odor.

01:14:08.980 | And the experimenter didn't know

01:14:10.060 | what odor they were emitting.

01:14:11.900 | And they could emit either a pleasant or an unpleasant odor.

01:14:14.760 | And we could drive the self-sampling afterwards up or down.

01:14:18.140 | So this was an olfactory behavior.

01:14:20.020 | No doubt about it.

01:14:20.860 | I mean, we're quite confident.

01:14:23.060 | - So people, in that case,

01:14:24.380 | people must have been sensing the odor on their own hand

01:14:26.740 | because they shook the hand of the experimenter,

01:14:30.540 | pleasant odor,

01:14:31.460 | and they're more frequently bringing that hand to their nose

01:14:33.700 | versus unpleasant odor that had been introduced

01:14:36.500 | to their own hand by the experimenter, correct?

01:14:38.380 | - Yeah, but no, I think they were sensing

01:14:41.020 | the ambient odor that came in with the hand that shook.

01:14:44.540 | And then that either drove them

01:14:45.920 | to sniff their hand more or less.

01:14:47.700 | - The odor cloud of the experimenter.

01:14:49.540 | - Yeah, and there's an interesting thing going on here, too,

01:14:52.060 | because people didn't only smell the hand that shook.

01:14:55.700 | They also smelled the other hand.

01:14:58.060 | And we think that there's something going on here

01:15:01.500 | comparing self to other.

01:15:03.860 | And we think a lot of self-sampling might reflect that.

01:15:07.380 | There's, on the same line,

01:15:09.180 | and again, to link to your childhood story

01:15:12.060 | of identifying your friends by smell,

01:15:17.280 | a study we published just last year by Inbal Ravrebi

01:15:21.120 | in our lab where Inbal came with this basic interest

01:15:26.120 | in this phenomenon that's loosely referred to

01:15:31.680 | as click friendships.

01:15:33.340 | So people you meet and you click right away, right?

01:15:35.900 | You immediately become close friends.

01:15:38.540 | And this is a phenomenon that is poorly described

01:15:41.660 | or is poorly described in literature as an entity,

01:15:45.260 | and yet anybody will tell you

01:15:47.300 | they know what you're talking about, right?

01:15:48.480 | I mean, if somebody you click with right away,

01:15:50.920 | you become intimate within five minutes, right?

01:15:53.960 | Everybody experienced this in their life to some extent.

01:15:58.340 | And the question is, what was there, right?

01:16:00.820 | What was it?

01:16:01.660 | Was it because you looked the same, could be?

01:16:03.640 | Was it because you had the same sports team that you liked?

01:16:07.820 | Or is there something deeper here?

01:16:11.960 | And Inbal's theory was that a similarity in body order

01:16:16.960 | may contribute to this, that people who smell the same

01:16:23.180 | will click in some way.

01:16:25.900 | And so to address that, she actually recruited

01:16:28.460 | click friends from all over Israel.

01:16:31.900 | She posted all over social media

01:16:33.660 | to identify pairs of friends.

01:16:37.660 | So these are same-sex, non-romantic dyads.

01:16:40.420 | So these are friends, men and women,

01:16:42.560 | whose friendship started as a clique,

01:16:46.120 | where here this becomes sensitive

01:16:48.120 | because it has to be a mutual clique, right?

01:16:50.140 | Later on, we discovered there could be one-sided cliques.

01:16:52.720 | So somebody who's sure they clicked with somebody else,

01:16:54.820 | but the other person.

01:16:55.900 | - There's a name for that in neurology

01:16:57.400 | that our common friend, the late Ben Barres taught me,

01:17:00.020 | which is there's a phrase that neurologists use

01:17:02.460 | called sticky.

01:17:03.740 | These are people that come up to you

01:17:05.900 | and start asking you questions

01:17:07.180 | and then won't leave you alone.

01:17:08.640 | They're so-called sticky people.

01:17:10.880 | And if you ask these sticky people,

01:17:13.940 | sticky in air quotes, 'cause they're not physically sticky.

01:17:17.000 | - They may be.

01:17:18.180 | - They could be.

01:17:19.020 | What do you think of this person?

01:17:23.380 | They'll say, "Oh, they're great.

01:17:24.220 | "We're really good friends."

01:17:25.800 | And so they've made a unilateral clique friendship.

01:17:29.520 | And yes, neurologists are talking about you.

01:17:32.040 | If you're one of these people,

01:17:33.300 | neurologists are talking about you,

01:17:34.420 | there's an informal diagnostic code, sticky.

01:17:39.160 | So she recruited clique friends

01:17:44.160 | and then she sampled their body odor.

01:17:50.080 | And we have a protocol for this.

01:17:52.060 | So they're given odorless shampoo and soap

01:17:55.860 | to use for three weeks or something.

01:17:57.840 | And then they sleep two nights in this t-shirt

01:18:00.700 | where they have to sleep alone.

01:18:02.020 | And then we extract the body odor from the t-shirt.

01:18:04.900 | And so we have a way to extract,

01:18:06.700 | a method to extract body odor.

01:18:08.980 | And then she first asked whether indeed

01:18:13.980 | clique friends are more similar in their body odor

01:18:16.480 | than you would expect by chance.

01:18:18.520 | And she first tested this with a device,

01:18:21.260 | a machine we call an electronic nose.

01:18:23.540 | So an electronic nose is sort of a very poor effort

01:18:27.120 | to mimic what the mammalian nose does.

01:18:28.800 | Basically, it's a bunch of sensors

01:18:30.260 | that respond to airborne molecules.

01:18:31.740 | In this case, sensors referred to as moxers,

01:18:34.180 | as metal oxide covered sensors.

01:18:36.620 | And so she used an electronic nose

01:18:40.340 | to sample these body odors.

01:18:42.140 | And she found that clique friends are indeed

01:18:44.260 | more similar to each other than you would expect by chance,

01:18:48.300 | by random dyads.

01:18:49.300 | And this was a significant difference.

01:18:51.740 | And after she found that a device could do this,

01:18:55.540 | she had other participants do this.

01:18:58.100 | So she had people smelling the clique friends

01:19:00.740 | versus non-clique friends.

01:19:02.140 | And they judged them as being more similar

01:19:04.500 | to each other than not.

01:19:07.140 | Now again, you might wonder, is this causal or not right?

01:19:10.420 | Because maybe clique friends go to the same restaurant

01:19:12.720 | together all the time or whatever,

01:19:14.220 | live in the same neighborhood,

01:19:15.220 | and that's why they smell the same.

01:19:18.780 | So to address causality, she recruited total strangers

01:19:23.540 | and first smelled them with the electronic nose,

01:19:27.100 | and then engaged them in a social interaction,

01:19:29.620 | something called the mirror game.

01:19:31.380 | So in the mirror game, one person moves their hands

01:19:34.040 | and the other person is really close to them,

01:19:35.860 | like right here, so they can smell each other

01:19:38.620 | and has to move their hands with the other person.

01:19:42.100 | And one prediction there panned out, but another didn't.

01:19:46.360 | The one that didn't, so she predicted that people

01:19:48.440 | who would smell more similar to each other

01:19:51.240 | would be better at the mirror game.

01:19:52.900 | That is, they would follow each other better.

01:19:54.980 | That did not pan out.

01:19:56.720 | However, she then also had,

01:19:59.420 | the interaction was completely nonverbal.

01:20:01.220 | They were not allowed to speak with each other,

01:20:02.620 | and she did an entire round robin,

01:20:04.240 | so everybody played with everybody else.

01:20:05.700 | This was an insane experiment to run.

01:20:08.380 | And she then, at the end of the experiment,

01:20:11.820 | each person rated each other person

01:20:14.080 | as to how much they think they would wanna be their friends,

01:20:16.780 | and also on a bunch of ratings,

01:20:18.100 | how nice they think they are,

01:20:19.340 | how affectionate they think, a bunch of ratings, okay?

01:20:22.620 | All of this was predicted by the electronic nose.

01:20:25.060 | So people who smell more similar to each other

01:20:28.300 | think that the other person is more likely

01:20:30.520 | to be their friend, is more likely to be a nice person,

01:20:33.500 | et cetera, et cetera.

01:20:34.340 | So we could actually predict friendship

01:20:37.340 | using the electronic nose.

01:20:38.840 | So this is not a result of friendship.

01:20:40.980 | It plays into the causal elements of building friendship.

01:20:45.700 | So this is to relate to your childhood story.

01:20:48.720 | There's something going on here.

01:20:50.180 | We're constantly smelling ourselves, constantly.

01:20:53.620 | This constantly, I mean, if you wanna look,

01:20:57.900 | the reason I'm smiling, I mean,

01:20:59.140 | and your viewers or listeners will understand

01:21:01.480 | why I'm smiling, I'll send you a video to link

01:21:04.000 | into your podcast here.

01:21:09.100 | We thought of calling,

01:21:10.120 | the fact that people constantly sniff themselves,

01:21:12.220 | we thought of calling this the Lowe effect.

01:21:15.120 | And Lowe, so in America, this won't pass that effectively,

01:21:18.260 | but in the rest of the normal world,

01:21:21.400 | Joachim Lowe is the national soccer coach

01:21:25.520 | of the German soccer team.

01:21:27.420 | So, I mean, I don't know who would be a very famous coach

01:21:30.960 | here, but Steve Kerr.

01:21:32.260 | I mean, this is a super, super famous name

01:21:37.260 | all around the world where soccer is the primary sport

01:21:39.960 | that people watch.

01:21:40.900 | And once people will see this video,

01:21:44.860 | they'll understand why we thought of calling this

01:21:47.180 | the Lowe effect.

01:21:48.880 | It's very graphic.

01:21:50.720 | But people are constantly smelling themselves.

01:21:53.660 | They're smelling themselves with their hands.

01:21:55.900 | They're smelling themselves explicitly.

01:21:58.160 | People are constantly smelling themselves,

01:22:00.760 | constantly smelling others.

01:22:02.200 | - I find this topic so interesting.

01:22:05.340 | And first of all, confession,

01:22:07.020 | I definitely smell myself multiple times per day.

01:22:09.800 | - Everybody does.

01:22:10.800 | - Okay, good.

01:22:11.640 | And I would do it anyway.

01:22:13.560 | I think I, like most people,

01:22:16.500 | I either find my own smell to be neutral to pleasant.

01:22:20.680 | Occasionally I'll be like, whoa, I need to take a shower.

01:22:24.860 | As long as we're talking about smelling oneself

01:22:27.380 | and friendship, kinship, and its relationship to smell,

01:22:31.620 | we have to talk about the relationship between smell

01:22:33.780 | and romantic attraction and bond.

01:22:35.780 | So my understanding is that if, for instance,

01:22:38.740 | a mouse is given the option to mate

01:22:40.900 | with any number of other different mice,

01:22:43.240 | they will bias their choice toward the mouse

01:22:47.820 | that has the immune composition, the so-called MHC,

01:22:51.220 | major histocompatibility complex,

01:22:52.860 | which reflects immune diversity,

01:22:55.100 | the immune system that is most distant from theirs.

01:22:58.460 | And the evolutionary argument being

01:23:00.960 | that were they to produce offspring,

01:23:03.780 | that the array of immune genes would be much broader

01:23:06.540 | than if they were to select an animal very close to them.

01:23:09.420 | And in addition to that,

01:23:11.140 | that one of the most strongly selected against behaviors,

01:23:15.540 | not just culturally,

01:23:16.860 | but at the level of eliciting a sense of disgust,

01:23:21.740 | maybe even from the activity of the hypothalamus,

01:23:24.780 | is mating with very close kin, AKA incest,

01:23:27.980 | because that can potentially,

01:23:29.860 | we know produces a higher rate of mutations.

01:23:31.780 | In other words,

01:23:32.780 | whereas you've described the relationship

01:23:34.780 | between smell and choice of friends

01:23:36.260 | as you choose people who smell more like you,

01:23:39.660 | my understanding is that in the context

01:23:41.380 | of choosing romantic partners or sexual partners or both,

01:23:46.380 | that you choose the person who's odor

01:23:50.700 | and therefore immune composition is most different.

01:23:53.660 | - Right.

01:23:54.500 | So the way you describe the animal literature is correct.

01:23:58.420 | And there's evidence to similar mechanisms in humans.

01:24:02.300 | Our lab has not worked directly on this issue

01:24:05.100 | of romantic selection based on odor.

01:24:10.100 | There's a bunch of papers,

01:24:12.860 | Wedkind et al. and the Wedkind lab,

01:24:17.780 | and also Porter.

01:24:19.160 | I'll email these to you later on,

01:24:21.180 | that have done a lot of this work

01:24:24.220 | and find exactly as you say

01:24:26.240 | that romantic odor preferences in humans

01:24:30.380 | are influenced by body odor,

01:24:32.740 | and that this is linked to MHC,

01:24:36.020 | histocompatibility, complex makeup of the portion

01:24:40.420 | of our genome that shapes our immune system to some extent.

01:24:44.500 | So this effect has been studied

01:24:48.460 | and reported on again extensively in mice

01:24:50.460 | and also in humans, not work that we've done.

01:24:55.460 | The one sort of tangent work we've done

01:25:03.000 | and I'd like to maybe tell you about,

01:25:08.000 | it relates to an effect that is one

01:25:13.400 | of the most remarkable effects

01:25:15.080 | in mammalian social chemo signaling.

01:25:17.620 | So, and also related to,

01:25:20.860 | so it's not related to romanticism in any way,

01:25:24.240 | but it's related to reproduction.

01:25:26.880 | And indeed in our lab, we've not looked at romanticism,

01:25:29.660 | we have looked at or are looking at reproduction.

01:25:32.740 | They're not always the same.

01:25:34.780 | - Certainly.

01:25:35.620 | - They can.

01:25:38.060 | Animal mammalian or terrestrial mammalian

01:25:41.760 | reproductive behavior is dominated

01:25:44.020 | by the sense of smell in mammals.

01:25:47.860 | And here, remember initially when you started off,

01:25:50.820 | I noted that there are several subsystems in our nose

01:25:54.200 | that transduce odorants,

01:25:55.460 | and so primarily the main olfactory system,

01:25:58.780 | which is cranial nerve number one,

01:26:00.660 | and the trigeminal nerve, which is cranial number five.

01:26:04.260 | Most terrestrial mammals have another subsystem

01:26:07.100 | referred to as the secondary olfactory system

01:26:10.180 | that has a separate sense organ in the nose.

01:26:13.740 | This organ is known as the vomeronasal organ.

01:26:16.340 | It's a small pit in the nasal passage

01:26:18.740 | of most terrestrial mammals.

01:26:21.500 | Sometimes it's described as a communicating pit

01:26:24.780 | because sometimes it connects the nasal passage

01:26:26.980 | to the roof of the mouth.

01:26:28.060 | Sometimes it connects both.

01:26:30.700 | And so there's the sense organ

01:26:33.540 | with its specific receptor subtypes,

01:26:36.460 | VNRs, vomeronasal receptors.

01:26:39.260 | And this is linked to a sort of separate portion

01:26:44.260 | of the olfactory bulb,

01:26:49.100 | not really the main olfactory bulb,

01:26:50.220 | but what's referred to as the accessory olfactory bulb.

01:26:52.920 | And from there directly to the limbic system,

01:26:55.940 | to the portions of the brain

01:26:58.060 | that control reproductive behavior and aggressive behavior.

01:27:03.060 | And in most terrestrial mammals,

01:27:08.380 | this subsystem processes odorants

01:27:10.900 | that are sometimes referred to as pheromones,

01:27:13.900 | although that's in many ways a problematic term,

01:27:16.540 | but odorants that are referred to as pheromones,

01:27:18.740 | namely odorants that are emitted

01:27:20.140 | by another member of the species

01:27:22.060 | to influence that member of the species

01:27:24.500 | and alter behavior or hormonal state.

01:27:27.540 | And some of these pheromonal effects

01:27:31.300 | are utterly remarkable.

01:27:33.560 | And in my view, the most remarkable of all

01:27:35.580 | is an effect known as the Bruce effect.

01:27:38.300 | This was an effect discovered by Margaret Bruce in 1959.

01:27:42.140 | She was a British scientist.

01:27:46.060 | And in the Bruce effect,

01:27:48.320 | when you expose a pregnant mouse

01:27:52.180 | at an early critical stage of the pregnancy,

01:27:55.440 | I think up to about day three,

01:27:57.740 | if you expose the pregnant mouse

01:27:59.780 | to the odor of what is referred to in technical terms

01:28:03.640 | as the non stud male,

01:28:05.020 | that is a male who did not father the pregnancy,

01:28:08.780 | she will miscarry the pregnancy.

01:28:10.420 | She will abort it.

01:28:11.960 | Now that's an insane decision made by the female here,

01:28:15.420 | because she's invested quite a lot in this,

01:28:18.020 | in biological terms and in forming this pregnancy

01:28:21.900 | and maintaining it.

01:28:23.220 | And yet she drops it on the basis of an odor.

01:28:26.100 | And this effect is remarkably robust.

01:28:31.300 | And what do I mean by remarkably robust?

01:28:33.180 | So this will occur on about 80% of exposures.

01:28:37.620 | Now as you know, 80% is 100% in biology, right?

01:28:40.180 | I mean, there's nothing that happens at more than 80%.

01:28:43.060 | So it's a remarkably robust effect,

01:28:47.900 | this dropping of the pregnancy.

01:28:50.780 | - And we know it's mediated by chemo sensation

01:28:52.960 | through the nose. - We know for sure.

01:28:54.340 | And we know in the following way.

01:28:55.580 | So first, it's enough to just bring the odor

01:28:58.580 | of the non stud male.

01:29:00.260 | You don't have to bring the male himself, right?

01:29:02.640 | So you just can bring bedding from a non stud male

01:29:05.260 | and that will induce the Bruce effect.

01:29:08.300 | But of course, the most telling set of experiments

01:29:10.660 | is that if in the female mouse,

01:29:12.900 | you ablate the vomeronasal organ,

01:29:14.700 | you just burn this tiny structure in the nose,

01:29:18.140 | then the effect disappears.

01:29:19.720 | So the effect is completely dependent

01:29:21.540 | on the vomeronasal organ.

01:29:22.980 | And I find this utterly a remarkable effect, right?

01:29:27.580 | I mean, again, because of the extent

01:29:31.900 | of cost that the female takes on here,

01:29:36.180 | based on this information and smell.

01:29:39.120 | Now, humans, the sort of the going notion

01:29:44.120 | in olfaction is that humans don't have

01:29:46.840 | a functional vomeronasal organ.

01:29:48.880 | So we don't have that functional organ in our nose.

01:29:52.580 | Now, I'll point out, we actually do have the pit.

01:29:57.840 | So the structure or the outlining structure is there.

01:30:02.260 | But the pit that we have is considered vestigial

01:30:06.480 | and non-functional.

01:30:07.760 | - And what about this thing I learned about at Berkeley

01:30:11.600 | in integrative biology class

01:30:13.880 | that we have something called Jacobson's organ?

01:30:16.920 | - This is the same organ.

01:30:18.140 | So Jacobson's organ is the vomeronasal organ.

01:30:21.200 | It's also called Jacobson because I think Jacobson

01:30:26.940 | was a military physician in like the 1800s in Holland

01:30:31.660 | or something, and he found it in a soldier

01:30:35.720 | he was operating on or something like that.

01:30:38.640 | The story comes from something like that.

01:30:40.440 | But Jacobson's organ is another name

01:30:42.800 | for the vomeronasal organ.

01:30:43.980 | These are one and the same.

01:30:45.420 | The sensory organ of the accessory olfactory system.

01:30:48.900 | And again, the going notion is that the human Jacobson organ

01:30:52.940 | or vomeronasal organ is vestigial, it's non-functional.

01:30:56.780 | - Does that necessarily mean

01:30:58.000 | that we don't have these pheromone effects?

01:30:59.840 | - No, it does not.

01:31:00.760 | So first of all, we know that lots of what are considered

01:31:03.740 | pheromonal effects, namely social chemosignal and rodents

01:31:06.600 | are mediated by the main olfactory system.

01:31:08.260 | We know that for sure.

01:31:09.360 | There are several examples for this in mice and rats

01:31:12.920 | and rabbits and so on and so forth.

01:31:15.080 | So A, these can be mediated by the main olfactory system.

01:31:19.720 | And I'll come back to that in a second.

01:31:22.600 | But first to finish the Bruce effect.

01:31:24.460 | And second, and I'm going out on a limb here,

01:31:29.460 | but I'm willing to take that risk.

01:31:34.820 | For me, the jury is still out on human vomeronasal organ.

01:31:39.920 | The decision or the notion that it's non-functional

01:31:46.900 | relies on about one and a half papers, post-mortem,

01:31:52.420 | looking for the nerve that connects this thing to the brain

01:31:55.560 | and failing to find it using staining

01:31:58.180 | and so on and so forth.

01:31:59.020 | But staining post-mortem studies in humans

01:32:01.300 | are notoriously complicated.

01:32:05.080 | Basically, for many reasons,

01:32:08.140 | one of them is that the material is just always,

01:32:10.540 | has gone through, it's not ideally set as it is

01:32:15.460 | when you sacrifice an animal and study its tissue.

01:32:21.620 | So based on really, really a paucity of studies

01:32:26.420 | that failed to find this nerve,

01:32:30.520 | the notion is that the structure is vestigial in humans.

01:32:34.720 | I don't have any evidence that it's functional, mind you,

01:32:37.420 | but I'm just not sure that it's not.

01:32:40.940 | But what we do have a suspicion is that humans

01:32:48.020 | may experience something similar to Bruce effect.

01:32:52.140 | So first of all, humans have an enormous number

01:32:57.460 | or ratio of spontaneous miscarriage.

01:33:02.180 | - Are they occurring more often in the first trimester?

01:33:05.620 | Because you mentioned that in the Bruce effect

01:33:07.660 | in the mice is in the first three days or so

01:33:09.420 | following pregnancy, which in the mouse gestation,

01:33:12.160 | as I recall, is about 21 days in the mouse.

01:33:14.080 | So you're talking about 1/7 of total gestation.

01:33:16.000 | So I'm not quick enough to,

01:33:18.320 | nor is it important to translate,

01:33:19.720 | but this will be first trimester.

01:33:20.960 | - Yes, which is indeed when most miscarriage occurs.

01:33:24.920 | Now humans have, again, a huge number of miscarriages

01:33:28.600 | and the numbers, I'll soon share them with you,

01:33:31.180 | they sound odd.

01:33:33.160 | And the reason they sound odd is because if you have

01:33:36.640 | what's sometimes simply referred to as failed implantation,

01:33:40.000 | this can occur in days one, two, nobody ever knows.

01:33:44.520 | So some papers talk about 90% of all human pregnancies

01:33:49.520 | end in miscarriage.

01:33:51.160 | This is counting a failed implantation

01:33:53.720 | in day one, two, et cetera.

01:33:55.280 | More conservative studies talk about 50%.

01:33:58.640 | Nobody will argue 30%, okay?

01:34:00.920 | So a huge number, a huge number of human pregnancies

01:34:05.920 | end in miscarriage.

01:34:07.780 | Now out of these, there's a portion that are unexplained.

01:34:14.440 | So nobody knows why.

01:34:15.280 | I mean, there are a portion that are explained

01:34:16.720 | by all sorts of genetic factors, developmental factors,

01:34:19.400 | and so on and so forth.

01:34:20.800 | But there's also a proportion that are unexplained.

01:34:24.100 | And so all I'm saying is that there's a statistical backdrop

01:34:29.100 | or setting, if you will,

01:34:30.440 | for something like a remnant bruce effect in humans.

01:34:34.920 | Now with that in mind, we approached a group of,

01:34:40.800 | we enlisted a group of, they're not really patients

01:34:44.880 | and participants in a study of people who,

01:34:48.160 | couples who are experiencing what is referred to

01:34:50.560 | as unexplained repeated pregnancy loss.

01:34:53.760 | So formally, if you have two consecutive

01:34:58.360 | unexplained miscarriages,

01:35:00.440 | then that is sufficient for the diagnosis

01:35:03.360 | of unexplained repeated pregnancy loss.

01:35:06.000 | However, in our cohort of 30,

01:35:09.040 | we had couples who experienced 12 consecutive

01:35:13.200 | unexplained repeated pregnancy losses.

01:35:15.280 | So the two is just the formal.

01:35:17.840 | All of our cohort was like 12, five.

01:35:21.240 | So this is an emotional, difficult place to be.

01:35:24.280 | And these are couples who are losing their pregnancy

01:35:29.680 | for no apparent reason.

01:35:30.760 | So they've gone through all the tests that you can imagine

01:35:33.400 | of genetic incompatibilities and all sorts of issues,

01:35:37.260 | clotting, all the known suspects for pregnancy loss.

01:35:41.820 | And the medical establishment remains totally at a loss

01:35:45.660 | as to why these pregnancies aren't holding.

01:35:48.200 | And so we hypothesized that perhaps here

01:35:52.200 | there's something akin to a bruce type effect.

01:35:55.380 | Obviously it's not gonna be the same as in mice,

01:35:57.340 | but something like a bruce effect.

01:35:59.720 | Now, of course, at that stage,

01:36:01.480 | we could not do anything causal to test this, right?

01:36:04.960 | But what we could do is to seek circumstantial evidence

01:36:09.920 | to see if where there's fire, maybe there's smoke.

01:36:13.380 | And what we did was we tested olfaction

01:36:17.740 | and more specifically the response to male body odor

01:36:22.140 | in the couples experiencing repeated pregnancy loss.

01:36:28.280 | And we found a few things.

01:36:34.660 | First of all, if you think of the mechanisms

01:36:37.740 | behind the bruce effect, the bruce effect implies

01:36:41.980 | that the female has to have a very clear memory

01:36:45.420 | of the fathering male, because if she's gonna miscarry

01:36:49.780 | in response to the non-father,

01:36:51.140 | she has to know father, non-father.

01:36:53.140 | I mean, that means that there's a pronounced olfactory memory

01:36:58.140 | at the moment of mating, okay?

01:37:01.500 | And in mice, this has been very well characterized

01:37:04.460 | and attributed to the anterior olfactory nucleus,

01:37:08.300 | a structure in the brain.

01:37:09.680 | But you'd have to have this memory

01:37:14.680 | in order to make that decision.

01:37:16.220 | Now, so to address that, and here you're gonna see

01:37:19.500 | that you and your childhood story from before

01:37:21.580 | stand out a bit as skillful,

01:37:24.220 | is that the first thing we did was just behaviorally test

01:37:29.700 | whether these women and control women

01:37:34.700 | could identify the smell of their spouse.

01:37:39.360 | And you might be disappointed,

01:37:44.460 | or we would all are probably a bit disappointed

01:37:47.860 | to learn that control women are very poor at this.

01:37:52.620 | So you would think that women would be good

01:37:55.620 | at identifying the body odor of their spouse.

01:37:58.260 | They're not, they're not far from chance.

01:38:02.100 | However, the women who experience repeated pregnancy loss

01:38:08.300 | are more, they're double at their performance level.

01:38:14.620 | So this is not a nuanced effect.

01:38:16.300 | Women who experience repeated pregnancy loss

01:38:21.620 | can identify their husbands or their spouses

01:38:25.980 | by their body odor.

01:38:27.700 | - With much greater acuity than the typical person?

01:38:30.060 | - Double, a bit more than double, and way above chance.

01:38:34.180 | - Yeah, no, sorry, I posed it as a question,

01:38:36.260 | but I meant, yes, with much greater acuity,

01:38:39.580 | and double is a significant improvement.

01:38:43.160 | Are they much better at detecting any odor?

01:38:46.380 | - No, they're not.

01:38:47.220 | We did the controls, and they're not.

01:38:50.060 | And then we also measured, using fMRI,

01:38:54.120 | we measured their brain response to stranger male body odor.

01:38:59.120 | And this was quite remarkable because we approached,

01:39:04.700 | so this was a full brain analysis,

01:39:07.260 | without a region of interest analysis.

01:39:08.900 | So it's not as if you're tweaking your statistics

01:39:12.220 | to look at one part of the brain.

01:39:13.720 | You're just looking at the entire brain

01:39:15.800 | in the response to male body odor and asking de novo,

01:39:18.520 | is there a difference between

01:39:19.460 | these two groups of participants?

01:39:21.380 | And there was one huge difference,

01:39:22.620 | and it was in the hypothalamus.

01:39:24.500 | And so there was a difference in response

01:39:26.920 | to stranger male body odor between the two groups.

01:39:30.300 | So olfaction is altered in spontaneous,

01:39:37.180 | repeated spontaneous pregnancy loss.

01:39:40.320 | We don't know this is causal, right?

01:39:42.920 | But that was enough for us to approach the ethics committee

01:39:47.220 | to run a causal experiment.

01:39:51.880 | And we're at the beginning of that now.

01:39:54.260 | - Incredible, I can't wait to hear the results of that.

01:39:56.620 | - It's gonna take, it'll probably take years, a few.

01:40:00.340 | Because these are slow experiments to run.

01:40:05.340 | Recruitment is complicated.

01:40:08.740 | But basically we're blocking smell in couples

01:40:12.700 | who are trying to maintain a pregnancy.

01:40:20.520 | - I want to touch on some other so-called pheromone effects.

01:40:23.680 | And one thing I heard you say during a talk,

01:40:25.160 | which I think really captures this whole issue of,

01:40:28.260 | are there pheromone effects in humans?

01:40:30.800 | Very nicely, as you said,

01:40:32.040 | whether or not it's a classic pheromone effect

01:40:34.140 | or whether or not it's olfaction or something else,

01:40:36.400 | this is chemosensory signaling between individuals.

01:40:40.440 | The reason this is important to me is a few years ago,

01:40:42.680 | I did a social media post about pheromone effects in animals

01:40:45.120 | and some potential pheromone effects in humans.

01:40:47.240 | And then a couple of the human olfactionistas,

01:40:52.240 | more from the, actually who work on animal models,

01:40:56.040 | really came after me with intense sniffing,

01:40:59.860 | saying there is no evidence for human pheromone effects,

01:41:03.680 | human pheromone organs.

01:41:04.560 | And I think today you've beautifully illustrated

01:41:06.120 | how regardless of the answer to that,

01:41:09.480 | humans contain and are emitting chemical signals

01:41:14.040 | that influence each other's physiology and behavior.

01:41:16.480 | - For sure, for sure.

01:41:17.720 | And the term pheromone is a problematic term in any case.

01:41:20.560 | I mean, the term was put forth

01:41:24.220 | to describe insect behavior, right?

01:41:26.520 | So if you were given a hard time by the mouse people,

01:41:29.480 | you could have given them an equally hard time

01:41:32.240 | if you were an insect person, right?

01:41:33.600 | Because really the place the term is accurate is,

01:41:38.600 | so the first pheromone that was discovered was bambical,

01:41:41.920 | which is the pheromone that has the male moth

01:41:44.000 | follow the scent trail of the female moth.

01:41:47.480 | Bambical is a pheromone.

01:41:48.720 | Insect pheromone people will argue that this stuff

01:41:54.520 | that people talk about in mice and rats is not pheromones.

01:41:57.720 | And it all becomes semantics.

01:41:59.880 | - Yeah, sort of like nerdy inside ball.

01:42:01.880 | - It's all semantics.

01:42:03.040 | So in our publications, we don't use the term pheromone

01:42:06.960 | because it would not help me

01:42:08.100 | and it would probably only hurt us.

01:42:10.200 | And so we talk about chemosignals

01:42:12.600 | and humans definitely emit chemosignals from their body.

01:42:16.320 | And these chemosignals influence other humans

01:42:19.640 | and influence their behavior.

01:42:21.440 | There are several examples of this.

01:42:27.000 | One of them I'll point out first,

01:42:29.160 | which is sort of the most widely studied

01:42:33.640 | and not mostly from our lab actually.

01:42:35.760 | I mean, the flavor of the month for the past 10 years

01:42:39.040 | in this field is what's referred to as the smell of fear.

01:42:42.920 | Right, so this is probably true of many mammals and humans.

01:42:47.920 | It's true of we emit a specific body odor

01:42:53.620 | when we're in a state of fear.

01:42:55.800 | This was first discovered in humans by Denise Chen

01:42:59.160 | out of I think Brown, I'm not sure.

01:43:02.720 | - I think that's right, yep.

01:43:04.000 | - Humans emit a particular body odor

01:43:06.160 | when they're in a state of fear

01:43:07.820 | and this body odor influences other humans,

01:43:10.640 | in effect increasing their autonomic arousal,

01:43:15.440 | their sympathetic state.

01:43:16.880 | So in effect, you could say that fear is contagious a bit.

01:43:21.600 | So the smell of fear is contagious.

01:43:24.100 | By the way, culturally, we know for ages

01:43:27.280 | that dogs can smell fear in humans,

01:43:29.640 | but actually that was only really shown

01:43:31.520 | about a year and a half ago in a study.

01:43:33.800 | So it was always said,

01:43:35.560 | but it wasn't really shown effectively.

01:43:37.120 | It was shown about a year and a half ago in a study

01:43:39.040 | that dogs indeed can smell human fear

01:43:41.600 | and humans can smell human fear.

01:43:44.460 | So several labs starting from Denise Chen

01:43:47.260 | and Haviland Jones and then in our lab and in other labs,

01:43:51.360 | if you collect body odor from people in a state of fear

01:43:55.480 | and collect body odor from the same people

01:43:57.520 | when they're not in a state of fear,

01:43:59.300 | other people can determine which is the state of fear or not

01:44:02.600 | and this influences their behavior.

01:44:04.940 | - What about the smell of safety

01:44:06.300 | or is that simply the absence of the odor

01:44:08.460 | corresponding to fear?

01:44:09.520 | And the reason I asked this is somewhat woven

01:44:11.580 | into our prior discussion about mate choice.

01:44:16.360 | Again, I'll ask the question in a form of brief anecdotes.

01:44:19.880 | I'll use the I had a friend who approach here,

01:44:22.900 | but well, one phenomenon that has nothing to do

01:44:26.140 | with me in particular, I think this is a common phenomenon,

01:44:28.620 | is romantic partners leaving articles of clothing

01:44:33.620 | at each other's homes.

01:44:34.780 | Now this could have other purposes to mark territory,

01:44:37.660 | but visually marking territory,

01:44:40.340 | but also scent marking territory is very common

01:44:43.460 | in the animal kingdom.

01:44:45.180 | It's not uncommon for romantic partners

01:44:49.180 | when one is traveling or away for the other partner

01:44:52.260 | to smell their article of clothing

01:44:53.760 | in order to bring about positive connotations

01:44:56.700 | of the other partner, very common behavior.

01:44:58.580 | If you're doing this, folks,

01:45:00.140 | other people are doing this too.

01:45:02.340 | It raises questions, for instance,

01:45:03.700 | about whether or not the mourning period post breakup,

01:45:06.780 | whether by decision by death

01:45:08.540 | or by some other phenomenon that's forced the breakup,

01:45:12.540 | whether or not that mourning period has something to do

01:45:14.540 | with an olfactory unlearning of,

01:45:18.020 | and mate selection and on and on and on.

01:45:20.260 | - With all these insights,

01:45:21.220 | I would offer you to be a postdoc.

01:45:22.660 | - Well, I was gonna say, listen,

01:45:24.000 | I have a sabbatical coming up,

01:45:25.420 | so I would love to do a sabbatical.

01:45:26.260 | - But it's gonna kill me.

01:45:27.500 | - No, exactly, you don't want me to work for you.

01:45:29.640 | We talked about this earlier for other reasons, exactly.

01:45:32.780 | There's a story there, what Noam is referring to.

01:45:34.780 | I'll just tell people 'cause inside jokes on the podcast

01:45:37.620 | that don't really work.

01:45:38.900 | Earlier, I was referring to the fact

01:45:40.420 | that I've had three incredible scientific mentors,

01:45:43.580 | undergraduate, graduate, and postdoc,

01:45:45.340 | but for reasons that are unclear to me,

01:45:49.260 | the first one died of suicide,

01:45:52.140 | the second one cancer at 50,

01:45:53.420 | and the third one pancreatic cancer in his early 60s,

01:45:56.680 | and the last one before he died,

01:45:58.260 | who was an MD and a common friend of Noam's,

01:45:59.980 | and I turned to me and said, Andrew,

01:46:03.180 | you're the common denominator,

01:46:04.500 | so the joke in my business is you don't want me

01:46:08.220 | to work for you, so nonetheless,

01:46:09.980 | I would love to do a sabbatical in your lab.

01:46:12.020 | - So what I was trying to say in that roundabout way

01:46:14.540 | is that those are all really keen observations

01:46:17.380 | and good ideas, for sure,

01:46:19.880 | and they just highlight, again,

01:46:22.340 | that we're incredibly olfactory animals,

01:46:25.580 | and you're even talking about the nuance.

01:46:28.900 | We're very olfactory even not in the nuance.

01:46:30.820 | I mean, I have this, when people tell me

01:46:32.860 | that we don't use our sense of smell

01:46:34.660 | and we don't need it and all that,

01:46:35.980 | and I have to deal with this a lot, right?

01:46:37.740 | I have to deal a lot.

01:46:38.860 | You study vision, nobody will tell you

01:46:40.260 | that vision is unimportant, right?

01:46:41.620 | - We're very visually dependent.

01:46:42.740 | I don't need a dog to take over my olfactory system

01:46:45.380 | if I lose olfaction, but I'll tell you,

01:46:47.100 | from having lost my sense of smell for one day,

01:46:50.360 | I was in intense fear.

01:46:52.620 | I bit into blueberries, I love blueberries.

01:46:54.420 | I'm like a drive-by blueberry eater.

01:46:55.780 | If they're there, I just kind of pick them up

01:46:57.100 | like a grizzly bear and cram them in my mouth.

01:46:58.900 | So keep them away from me if you don't want them eating.

01:47:01.300 | But I almost can't help myself.

01:47:04.260 | I bit into a blueberry, or a handful of blueberries,

01:47:07.280 | and it was the sensation of little bags of water,

01:47:10.480 | and I immediately felt a tremendous grief.

01:47:14.000 | - I'll tell you a sort of a throwaway line

01:47:16.940 | that I use in this when I talk with people.

01:47:18.980 | Take the two most basic behaviors that sustain us, right?

01:47:26.140 | Let's say I give you a choice

01:47:29.060 | between a beautiful-looking layer cake

01:47:34.060 | with strawberries and blueberries and whipped cream,

01:47:39.540 | but that smells of sewage,

01:47:42.360 | versus some gray-brown mix that smells of cinnamon.

01:47:48.140 | Which do you eat?

01:47:49.460 | - Simple, the latter.

01:47:50.280 | - Right, you eat the latter, right?

01:47:51.620 | Now, imagine I offer you a mate.

01:47:54.660 | Choose the gender of your liking, right?

01:47:57.380 | It looks like a Greek god or goddess, right?

01:48:02.340 | But smells of sewage.

01:48:04.220 | Or an ordinary-looking individual

01:48:06.380 | that smells of sin itself, who do you choose?

01:48:09.460 | - The latter.

01:48:11.700 | - Right, so in the two most basic behaviors we have,

01:48:16.220 | we follow our nose, not our eyes, right?

01:48:19.360 | - Definitely not always in predictable ways,

01:48:21.140 | because you offered an extreme example,

01:48:22.660 | which is the best example.

01:48:24.160 | But I, for instance, for reasons I don't know,

01:48:26.580 | I've never liked the smell of perfume, ever.

01:48:30.060 | In fact, I find it aversive.

01:48:31.880 | But I do, I confess, I do like the smell

01:48:35.160 | of certain body odors very much.

01:48:38.340 | And I'm very particular about that.

01:48:42.400 | And I know within an instant.

01:48:44.060 | And so, this is a problem for any romantic partner

01:48:49.500 | who likes perfume for me.

01:48:51.340 | But I know many people like perfumes

01:48:53.160 | and colognes and things of that sort.

01:48:54.780 | And in fairness, I've also been told that,

01:48:58.540 | by someone, that they couldn't spend time with me

01:49:00.580 | because they do not like my smell.

01:49:02.140 | In fact, they dislike it.

01:49:03.660 | And fortunately for me, there's at least one person

01:49:05.940 | on the planet who said the opposite.

01:49:08.340 | So, I completely agree with what you're saying.

01:49:12.500 | I can also say that I imprinted on the smell of my,

01:49:16.500 | I had a bulldog mastiff when I raised

01:49:19.300 | from the time he was a puppy.

01:49:20.900 | And I imprinted on, I imprinted on his smell immediately.

01:49:25.600 | And even though to other people,

01:49:26.920 | he was a bulldog mastiff after all,

01:49:28.240 | his smell was rather aversive.

01:49:30.360 | To me, he smelled delicious, right?

01:49:33.520 | And it made me, it smelled like home.

01:49:35.960 | And he was my best animal friend for a long time.

01:49:38.560 | So, and on and on and on, right?

01:49:40.440 | The smell of children, as you said, the backs,

01:49:42.620 | we had a guest on this podcast who I'm sure you're familiar,

01:49:44.480 | Charles Zucker, a professor at Columbia,

01:49:46.380 | has done incredible work in vision and olfaction,

01:49:49.240 | they're sensing it, and he,

01:49:51.240 | and I talked a little bit about this,

01:49:52.540 | that there's something in the breath of romantic partners

01:49:57.240 | that's hopefully appetitive, not aversive,

01:50:01.340 | as well as in children, he was talking about the smell

01:50:04.240 | of his grandchild's, the nape of their,

01:50:06.700 | or the back of their neck, and how he misses that smell,

01:50:09.760 | because when he thinks about missing his grandchild

01:50:12.940 | or children, it's that smell

01:50:15.020 | that's associated with that feeling.

01:50:17.480 | - Hexadecimal.

01:50:18.800 | - Hexadecimal.

01:50:19.860 | - Yes.

01:50:20.700 | - Is that, Charles, your grandchildren smell

01:50:22.760 | like hexadecimal.

01:50:23.800 | - Yes, they do.

01:50:24.640 | - He's gonna come after me now.

01:50:25.460 | - They do.

01:50:26.300 | And so, this is a study ran by Eva Michor,

01:50:31.140 | who was a graduate student in our lab.

01:50:33.180 | And Eva was interested in aggression.

01:50:39.500 | She was really into aggression.

01:50:42.400 | And actually, when she started, and so when she started off,

01:50:46.960 | she said, "Okay, let's do chemo signaling of aggression."

01:50:49.840 | She actually was going to MMA clubs

01:50:52.320 | and collecting body odors.

01:50:54.260 | And we had all sorts of ideas going,

01:50:57.720 | and she worked on that for quite a bit.

01:50:59.960 | It never went anywhere, really.

01:51:02.400 | And then, at the same time,

01:51:05.200 | we had a colleague of ours from Germany.

01:51:09.600 | I mean, when I say colleague,

01:51:11.240 | primarily a friend or acquaintance I met at conferences,

01:51:15.920 | Heinz Breer, and he was studying in his lab,

01:51:20.920 | a molecule, hexadecimal, that was a chemo signal in mice.

01:51:29.280 | Where in mice, it was described as a chemo signal

01:51:33.520 | that promotes social buffering.

01:51:36.480 | Where social buffering, as far as I understand,

01:51:39.220 | it's not my field, but as far as I understand,

01:51:41.280 | it's basically a feel good together thing.

01:51:44.160 | So when lots of mice are together,

01:51:45.600 | they feel good about being in a group,

01:51:47.720 | and that's social buffering.

01:51:49.600 | And it's promoted by hexadecimal,

01:51:51.720 | which they emit in their feces, mice.

01:51:54.520 | And in his work on hexadecimal,

01:51:59.620 | and so Breer and his colleague, Stortzman,

01:52:03.520 | they discovered the receptor for this,

01:52:06.120 | and then they went and discovered that the receptor

01:52:08.440 | is very highly conserved throughout mammalian evolution,

01:52:13.080 | and therefore they hypothesized that maybe

01:52:16.500 | this is a universal mammalian signal.

01:52:20.160 | Now, which is unusual because in chemo signaling,

01:52:23.140 | typically you tend to think of things

01:52:25.200 | as being very species specific.

01:52:27.340 | But here they hypothesized that maybe hexadecimal,

01:52:30.220 | which promotes social buffering in mice,

01:52:33.000 | may do something in all mammals.

01:52:34.720 | Again, because this receptor is very highly conserved,

01:52:37.440 | OR37B, I think.

01:52:40.640 | So he approached us and said,

01:52:43.820 | "Look, you gotta study this stuff in humans," right?

01:52:45.760 | Because he knows us as the human people, right?

01:52:47.840 | I mean, we go to these olfaction conferences

01:52:50.200 | where lots of people study mice and zebra fish and whatnot,

01:52:54.840 | and we're the human group.

01:52:56.580 | And eventually he just FedExed us hexadecimal.

01:53:02.000 | And so we had this thing sitting around,

01:53:05.080 | and Eva was not going anywhere with her aggression studies

01:53:09.600 | with sweat from human participants,

01:53:12.960 | and yet she built the entire paradigm

01:53:16.360 | to study human aggression.

01:53:17.520 | So they're standard paradigms.

01:53:19.600 | This is a paradigm known as the TAP,

01:53:21.440 | the Tyler Aggression Paradigm.

01:53:23.640 | I'll soon describe it.

01:53:25.360 | And so we said, "Okay, we have this hexadecimal stuff here,

01:53:28.400 | "and it promotes social buffering.

01:53:29.780 | "Social buffering sounds like

01:53:30.860 | "it would make you less aggressive.

01:53:32.520 | "Why don't you run your TAP experiment using hexadecimal?"

01:53:37.200 | What's the TAP experiment?

01:53:38.720 | So basically what you do is you bring in a participant to lab

01:53:43.320 | and you have them thinking that they're gonna be playing

01:53:48.020 | against another person in this game.

01:53:51.240 | And you can do something like have another person

01:53:53.480 | walk into the other room playing online, so connected.

01:53:57.200 | So you can fool them into being quite convinced

01:53:59.720 | that this is what's happening.

01:54:01.280 | And they go into their own room,

01:54:03.480 | and in the initial game they play,

01:54:07.660 | on each round they're provided with a sum of money,

01:54:12.120 | and this is real money that they'll receive

01:54:13.580 | at the end of the experiment.

01:54:15.280 | And by turn, each one of them decides

01:54:17.960 | how to divide the money up between the two, right?

01:54:20.800 | So they're playing against another person, they think,

01:54:23.220 | but that's actually a computer algorithm

01:54:25.040 | that they're playing against.

01:54:26.600 | And the computer algorithm is programmed

01:54:31.140 | to be in scientific terminology a jerk, right?

01:54:34.640 | So let's say they have to divvy up 100 shekel,

01:54:38.100 | which is the Israeli currency.

01:54:39.620 | So the other player would say,

01:54:42.140 | "Okay, I'll keep 96 and you get four," right?

01:54:46.620 | And then you can either accept it or not accept it,

01:54:50.660 | and then neither of you get anything, right?

01:54:52.640 | So basically you're being shafted

01:54:54.060 | by the other side all the time.

01:54:55.940 | And this is called the provocation phase.

01:54:58.100 | You're really getting angry at this person

01:54:59.680 | because they're really not nice, right?

01:55:02.640 | They're shafting you on every trial, almost.

01:55:05.420 | And you play this game and it goes to its end,

01:55:08.980 | and then you play a second game

01:55:11.060 | as far as you know against the same participant.

01:55:14.260 | And the second game is a reaction time game.

01:55:16.660 | So a target shows up and the first to press it wins.

01:55:20.260 | And on every trial where you win, if you want,

01:55:23.220 | you can blast the other participant with a loud noise.

01:55:27.040 | And it's a really loud noise.

01:55:28.740 | So you're also wearing earphones, it's 90 dB,

01:55:31.860 | and it's a screeching, horrible sound.

01:55:34.260 | It's the most punishment that an IRB committee

01:55:36.980 | will let you endure on a participant in an experiment,

01:55:40.620 | unless you're in Stanford 70 years ago

01:55:43.140 | or whatever that was.

01:55:43.980 | - No, I was referring to the classic prisoner experiment,

01:55:46.120 | which took place in the building next door

01:55:47.660 | to where I work, by the way.

01:55:49.940 | - So you can blast the other participant

01:55:51.740 | with varying levels of sound.

01:55:53.620 | And you have a selection box from something very low

01:55:56.140 | to something very high.

01:55:57.800 | And what's nice about this is that it then allows you

01:55:59.900 | to quantify aggression because the more volume

01:56:03.380 | you're blasting the opponent with,

01:56:04.860 | the more aggressive you are towards your opponent.

01:56:07.500 | And so you have a measure of aggression.

01:56:09.980 | Again, the Tyler aggression paradigm,

01:56:11.760 | obviously invented by Tyler, very well validated,

01:56:15.500 | studied all over, a very standard protocol.

01:56:18.900 | So we brought in participants and had them play

01:56:23.060 | the Tyler, the tap, either under exposure

01:56:26.820 | to hexadecimal or control.

01:56:29.820 | Now, hexadecimal doesn't, it's incredibly difficult

01:56:32.780 | to even detect hexadecimal.

01:56:34.860 | But just in case, because it's not very,

01:56:39.220 | it's considered a semi-volatile,

01:56:40.940 | it doesn't have a strong smell.

01:56:43.260 | But we buried both the control and the hexadecimal

01:56:46.140 | in a control order that hid them in a mask.

01:56:49.340 | And she ran lots and lots and lots and lots of participants,

01:56:52.580 | men and women.

01:56:53.480 | And I'll first tell you the result with men,

01:56:57.740 | which is that hexadecimal consistently reduced aggression.

01:57:02.300 | People were less aggressive under hexadecimal.

01:57:05.580 | The effect size was quite meaningful.

01:57:10.580 | And later on we learned, because I'm no specialist

01:57:14.260 | in the world of aggression,

01:57:15.100 | but compared to effects seen in the aggression world

01:57:17.820 | in research, really, really strong effects.

01:57:20.400 | So unusually strong.

01:57:22.300 | So hexadecimal lowered aggression in men.

01:57:24.800 | And we were like, cool, this is, you know,

01:57:26.540 | sort of what we were hoping to see,

01:57:28.700 | consistent with the hypothesis

01:57:31.060 | and consistent with what it seems to do in mice.

01:57:33.460 | But then we looked at data from women

01:57:36.700 | and hexadecimal increased aggression, equally significantly.

01:57:41.420 | - Is this thought to be something related

01:57:42.780 | to maternal protective?

01:57:43.860 | And we're getting there.

01:57:44.800 | So you got there really fast.

01:57:46.580 | It took me a year, but, and Eva got to it, really.

01:57:49.940 | I'll tell you.

01:57:51.540 | Because remember, we're reaching the back of the head

01:57:53.380 | of your, of whose was it?

01:57:56.780 | Grandchildren?

01:57:57.600 | - Charles Zucker.

01:57:58.440 | - Charles Zucker.

01:57:59.280 | - The Charles Zucker, one of the kingpins

01:58:01.740 | of the New York neuroscience mafia.

01:58:03.620 | - Yes, so this was really odd to me at that time.

01:58:08.620 | So I didn't have the intuition you just had.

01:58:11.660 | And I was like, Eva, this, there was some bug here.

01:58:13.900 | I mean, this, it makes no sense to me.

01:58:16.740 | You know, why would something increase aggression in women

01:58:19.360 | and decrease aggression in men?

01:58:20.800 | This is really, really strange.

01:58:23.800 | And I said, okay, I wanna see this happen again

01:58:27.360 | before, you know, we go ahead with this.

01:58:29.480 | So she went and did the entire experiment again.

01:58:31.560 | And this time she did it within the fMRI magnet

01:58:34.280 | so that we can also track brain activity

01:58:38.860 | while this was happening.

01:58:41.020 | And first of all, it replicated again.

01:58:43.080 | So once again, hexadecimal made men less aggressive

01:58:47.480 | and women more aggressive.

01:58:49.180 | And the extent of more than the effect alone,

01:58:52.500 | the dissociation was remarkable.

01:58:54.280 | This has, it's almost like a chromosomal test.

01:58:57.240 | I mean, you look at the data on the unit slope line

01:59:00.340 | and all the men are below and all the women are above.

01:59:03.520 | There's this figure in the paper.

01:59:05.740 | Then she also looked at the brain data.

01:59:08.720 | And this is, you know, although our lab does a ton of fMRI,

01:59:12.520 | it's one of the major tools we use

01:59:14.520 | to measure brain activity.

01:59:17.440 | I'm quite cognizant of the limitations of fMRI.

01:59:22.360 | And this is, I think sadly,

01:59:24.600 | I think the only study in my career at least

01:59:26.820 | where I actually managed to also get a mechanism

01:59:30.480 | out of fMRI, not only an area that's involved in activity.

01:59:35.160 | And so here's what we saw,

01:59:37.020 | that hexadecimal alone increased activity

01:59:42.020 | quite pronouncedly in an area of the brain

01:59:43.960 | known as the left angular gyrus.

01:59:46.560 | Now this is an area involved

01:59:47.860 | in what's referred to as social appraisal.

01:59:50.340 | So that was kind of cool in that a social order

01:59:53.140 | activated the social brain,

01:59:54.700 | not the olfactory system per se, and very pronounced.

01:59:59.160 | So on one hand that was cool,

02:00:00.660 | but then what was uncool was that it did the same

02:00:05.340 | in men and women.

02:00:06.800 | And this was in contrast to behavior,

02:00:08.680 | which you don't like seeing, right?

02:00:09.920 | I mean, because you would expect brain activity

02:00:12.360 | to reflect behavior.

02:00:14.200 | And it increased activity in the left angular gyrus

02:00:16.640 | in both men and women.

02:00:19.160 | But then she did a follow-up analysis,

02:00:21.560 | which was look at what's referred to

02:00:23.140 | as functional connectivity.

02:00:25.040 | That is, how does this region of the brain

02:00:27.480 | talk with the entire brain as it were

02:00:30.320 | under hexadecimal versus control?

02:00:34.240 | And here the dissociation reemerged powerfully

02:00:38.560 | whereby the connectivity from the angular gyrus

02:00:41.900 | was mostly to the classic neural substrates of aggression,

02:00:45.720 | so the amygdala and the temporal pole,

02:00:48.800 | and the connectivity went in opposite directions

02:00:51.280 | in men and women.

02:00:52.480 | So hexadecimal increased functional connectivity in men

02:00:56.880 | and decreased it in women.

02:00:59.180 | So in a way, this is almost saying

02:01:00.680 | that the default brain reaction is aggression, right?

02:01:03.600 | The default is to aggress.

02:01:05.600 | And in men, hexadecimal increases the control

02:01:09.900 | that the left angular gyrus is holding over your aggression

02:01:12.680 | and keeping you back.

02:01:14.400 | And in women, it let it roam free

02:01:16.560 | and they became more aggressive.

02:01:18.660 | But I was still puzzled.

02:01:20.460 | So I was convinced this happened twice.

02:01:22.880 | The MRO data provided not only a pattern,

02:01:26.840 | but a mechanism, which is unusual.

02:01:29.880 | And yet I was telling Eva, you know,

02:01:32.600 | but you know, this makes no sense to me.

02:01:34.600 | And then her insight, which of course afterwards is like,

02:01:37.320 | duh, is no, there's a place where this makes perfect sense.

02:01:41.920 | And that is if you're a mammalian offspring,

02:01:44.520 | because paternal aggression is often directed at you.

02:01:48.900 | There's infanticide all over

02:01:51.300 | and sadly there's male aggression

02:01:53.580 | towards human children as well.

02:01:56.280 | And maternal aggression is often protective.

02:01:59.400 | So if you're an offspring, if you have a molecule

02:02:02.380 | that will make your mother more aggressive

02:02:03.940 | and your daddy less aggressive,

02:02:05.640 | both of those are good for you.

02:02:07.100 | So you're winning.

02:02:08.020 | So we remembered a recently published paper

02:02:12.080 | from a group in Japan.

02:02:14.240 | That looked at the odors emanating from baby heads.

02:02:18.160 | We now come full circle to Suker's grandchildren.

02:02:20.980 | They used a method known as GCMS,

02:02:24.540 | gas chromatography mass spectrometry,

02:02:26.520 | to measure the volatiles from baby heads.

02:02:30.280 | Because baby head odor is a cultural thing

02:02:32.680 | across cultures, even in Japan.

02:02:34.840 | And so we quickly went to that paper

02:02:38.920 | and to see if one of the molecules that report

02:02:41.600 | is hexadecanol, and we were very disappointed

02:02:43.840 | that it wasn't one of the molecules

02:02:45.460 | that reported in the paper.

02:02:47.440 | And so we wrote to the authors,

02:02:49.860 | who are since then our co-authors,

02:02:52.680 | and we said, look, we're studying this molecule,

02:02:56.280 | hexadecanol, and we don't see in your results.

02:02:58.240 | And we were wondering, maybe you had some results

02:03:00.920 | that you didn't publish or some supplementary materials

02:03:03.240 | or whatever, and this lab, which is a hardcore GC lab,

02:03:06.840 | said, no, no, hexadecanol is a semi-volatile,

02:03:08.960 | which we knew.

02:03:10.720 | And our previous paper was not directed

02:03:13.440 | to the semi-volatile range, but we can now do,

02:03:16.160 | use what's called GCXGC, double GC,

02:03:18.500 | that is directed at semi-volatiles,

02:03:20.960 | and we can do this again.

02:03:21.800 | We just studied 11 babies,

02:03:24.400 | and we can see if this is an issue.

02:03:26.560 | So we said, yeah, please do.

02:03:28.340 | The bottom line of all this is that hexadecanol

02:03:30.520 | is the most abundant semi-volatile in baby heads.

02:03:34.320 | It's tons of it coming out of baby heads.

02:03:36.800 | So babies, again, speaking about if humans

02:03:39.080 | who don't chemosign, well, babies are conducting

02:03:41.800 | chemical warfare, right?

02:03:43.160 | They're reducing aggression in their fathers

02:03:48.160 | or males around them, and increasing aggression

02:03:52.980 | in their mothers or females around them,

02:03:54.920 | and both of those things are good for them.

02:03:57.460 | - Incredible.

02:03:58.340 | This is somewhat different than what we're talking about,

02:04:03.080 | and yet similar in other ways,

02:04:05.200 | because it's built off of anecdotal evidence,

02:04:09.480 | but it's anecdotal evidence that you hear all the time,

02:04:12.920 | and yet when you look in the scientific literature,

02:04:14.640 | at least by my read, the data are not clear,

02:04:18.800 | maybe even contradictory,

02:04:19.880 | and that relates to the coordination of menstrual cycles

02:04:23.240 | among co-housed women or women who are friends.

02:04:27.800 | Many women listening to this,

02:04:29.840 | and maybe some men who are aware of this effect,

02:04:32.100 | will say, oh yeah, absolutely.

02:04:33.520 | When I spend time with my friends or go away camping

02:04:36.280 | or even spend a day with them,

02:04:37.500 | our menstrual cycles become coordinated.

02:04:39.880 | However, my understanding is that the early literature,

02:04:43.500 | Barbara McClintock, discovered this phenomenon,

02:04:47.360 | published a paper in Science as an undergraduate.

02:04:49.520 | - 1971, Nature.

02:04:51.120 | - Amazing, Nature paper.

02:04:53.040 | Again, one of the three apex journals,

02:04:54.680 | and as an undergrad, fantastic.

02:04:55.920 | So discovered this, described this,

02:04:58.060 | and probably women all over the world

02:04:59.840 | who became aware of this one way or another

02:05:01.880 | probably said, yes, absolutely.

02:05:03.500 | This gives validation to what we've observed over and over.

02:05:06.980 | And yet, as subsequent papers have been published,

02:05:09.840 | this result has been called into question.

02:05:11.920 | Is there any final word on whether or not menstrual cycles

02:05:16.920 | become coordinated among women who spend time together,

02:05:19.520 | and if so, is there any role of olfaction in this,

02:05:23.880 | or chemosensing through the nostrils and/or mouth

02:05:27.800 | to support this idea?

02:05:30.560 | - So yeah, so I'll start off indeed to echo the background

02:05:35.560 | is that this study was conducted by Martha McClintock

02:05:39.920 | when she was an undergraduate at Wesleyan College.

02:05:42.940 | And she noticed that she thought her menstrual cycle

02:05:47.120 | and her co-inhabitants in her dorm room

02:05:49.300 | were coordinated in time.

02:05:53.580 | And I should say that this comes on the basis of similar

02:05:58.240 | or related type effects in rodents.

02:06:00.060 | Now, rodents don't have a menstrual cycle like humans do,

02:06:03.660 | but there's an effect in rodents referred to

02:06:08.420 | as the Witten effect, which resembles this type of effect.

02:06:13.420 | And she published indeed that paper as an undergraduate

02:06:17.920 | in Nature in 1971.

02:06:19.640 | And to answer your question, she published a followup

02:06:22.520 | in 1998, also in Nature, with then her graduate student

02:06:27.620 | at Chicago Stern, so this is Stern and McClintock, 1998.

02:06:32.620 | And here's what they did.

02:06:33.940 | They collected sweat from donor women and deposited it

02:06:38.940 | on the upper lip of recipient women.

02:06:43.120 | So this would be a fun experiment for you, at least,

02:06:45.720 | because you said you like body odors,

02:06:47.120 | but for many others, perhaps it would be daunting.

02:06:50.120 | - Well, I like certain body odors from certain individuals.

02:06:53.080 | - Okay. (laughs)

02:06:55.520 | - I don't think I uniformly like all body odors,

02:06:58.180 | although I do seem to uniformly not like the smell

02:07:01.540 | of perfume, although I, just to clarify,

02:07:03.460 | 'cause I put this out there and I learned the hard way

02:07:04.940 | in the comment section on YouTube,

02:07:06.660 | some of those perfumes I find downright aversive.

02:07:10.040 | Like it's, I think the great Marcus Meister,

02:07:12.520 | who a great neurobiologist once said,

02:07:14.160 | there's basically three responses.

02:07:15.420 | It's either yum, yuck, or meh.

02:07:17.440 | So some are truly yuck.

02:07:19.060 | - I've never heard that one.

02:07:19.900 | - Kinda like that one, right?

02:07:20.900 | In terms of the animal behavior, human behavior,

02:07:23.140 | we're either a move forward, move back, or pause.

02:07:26.540 | So some are truly a yuck.

02:07:29.320 | Some, many are meh.

02:07:32.860 | Zero to date are yum for me.

02:07:37.700 | Now, body odors, the distribution has shifted.

02:07:39.980 | It could be any one of those three, yum, yuck, or meh.

02:07:42.580 | So just to be clear,

02:07:43.740 | but the yum category is definitely included.

02:07:47.720 | Thank you for allowing me to do that.

02:07:51.100 | (laughing)

02:07:53.340 | So she did this study.

02:07:56.580 | So because right in the original McClintock study,

02:07:59.060 | you might suspect other drivers of the effect.

02:08:02.820 | Let's say you accept the effect,

02:08:04.900 | but still there might be other social drivers

02:08:06.740 | of the effect that are not body odor, right?

02:08:08.540 | There might be some dominant woman

02:08:11.060 | who's dominant in some other way,

02:08:12.660 | and this might be driving the coordination, right?

02:08:15.300 | So here there was no direct link

02:08:17.140 | between these women other than body odor.

02:08:18.940 | So if the effect re-emerged,

02:08:21.220 | it would definitely be an olfactory effect.

02:08:23.500 | And what she found is that if she took sweat

02:08:27.040 | from the follicular or the ovulatory phase of the donors,

02:08:30.560 | one extended the cycle in recipients

02:08:33.160 | and one shortened the cycle in recipient.

02:08:35.300 | I don't remember which was which,

02:08:36.660 | but basically definitely denoting a chemosignaling effect

02:08:41.660 | with opposing effects on duration

02:08:46.820 | based on the time it was collected from,

02:08:49.700 | again, published in Nature in 1998.

02:08:53.340 | That's it.

02:08:54.540 | There's a quotation, I think this is from,

02:08:57.160 | I'm not sure, but if something's published

02:09:05.260 | in Nature or Science,

02:09:06.540 | that doesn't necessarily mean it's not true.

02:09:09.380 | So with that in mind,

02:09:14.180 | the findings were since called into question widely.

02:09:19.020 | One reason is just statistics of cyclic events

02:09:26.340 | are surprisingly complicated.

02:09:28.620 | So it's tricky.

02:09:31.380 | Once you have a cyclic event, statistics become tricky.

02:09:35.020 | And so Martha took a lot of heat on the statistics

02:09:42.940 | of claiming an effect.

02:09:45.880 | And I think there was at least one effort of replication

02:09:52.340 | that didn't really work out.

02:09:54.100 | If you ask me, I'm on the fence.

02:09:57.780 | But I may be in a minority in my field.

02:10:01.620 | I think a majority in the field is currently negative.

02:10:06.620 | I'm not.

02:10:09.660 | And we've said in lab that we should do

02:10:13.660 | a planned replication.

02:10:14.920 | We will.

02:10:16.900 | Again, it's a horrible study to run.

02:10:20.300 | It's tons of work, and you have to run it

02:10:22.900 | for a really long time.

02:10:24.160 | And so it's just completely non-trivial.

02:10:30.140 | But we have a graduate student now in lab

02:10:32.380 | interested in these exact things,

02:10:34.140 | Ruud Weissgroßen, and she's doing similar stuff,

02:10:37.420 | and I hope we'll do that.

02:10:39.620 | I hope we'll try to replicate this.

02:10:42.580 | - Very interesting result.

02:10:44.660 | And I think interesting because of its real world,

02:10:49.180 | meaning outside the laboratory, of course,

02:10:51.940 | or experiment, analog, but also because

02:10:55.180 | pheromone effects and olfactory effects in humans

02:11:00.460 | seem unique among neurobiological/endocrine phenomena

02:11:06.040 | because there seems to be so many stories

02:11:10.300 | that we all have of the smell of our grandmother's hands

02:11:13.060 | or the recognizing the scent of somebody,

02:11:15.780 | or I knew from the moment that I smelled their breath,

02:11:19.260 | or I just liked their smell kind of thing.

02:11:23.100 | These kind of things that inform the deep potential

02:11:27.460 | for a real biological phenomenon,

02:11:29.980 | as opposed to the kind of thing like,

02:11:31.820 | oh, you just throw something out there.

02:11:34.140 | Oxytocin is bonding, and all of a sudden,

02:11:36.760 | the general public, to no fault of their own,

02:11:40.240 | comes to think that every aspect of bonding is oxytocin,

02:11:43.500 | and every defect in bonding is lack of oxytocin.

02:11:46.100 | But the general public provides a sort of a rich,

02:11:51.100 | it's fodder for exploring all these things,

02:11:54.920 | and a lot of times they turn out to be true,

02:11:57.560 | in the context of olfactory.

02:11:58.720 | - Yeah, no, it's a very primal system.

02:12:00.940 | So it's linked to the most limbic, primal mechanisms

02:12:05.940 | in our brain, and it drives primal behavior.

02:12:09.340 | - It's an incredible system.

02:12:10.660 | I have a question about a particular study,

02:12:15.220 | but I'm just gonna cue it up,

02:12:16.420 | and you'll know immediately what I'm cuing up.

02:12:18.700 | And that is, what is the relationship

02:12:21.860 | between odors and hormones, and in particular, crying?

02:12:26.860 | - As I pointed out previously,

02:12:28.980 | the sort of flavor of the month

02:12:31.180 | in human social chemosignaling research

02:12:33.340 | is the smell of fear,

02:12:34.820 | and the media of the month is sweat, right?

02:12:38.660 | So the few, maybe tens of labs in the world

02:12:43.660 | that study human social chemosignaling all collect sweat,

02:12:48.060 | and that's the media they look at.

02:12:51.060 | - Is it always from the armpit,

02:12:52.620 | or are there meaningful differences

02:12:54.800 | in terms of the sweat emitted

02:12:55.940 | from different locations on the body?

02:12:57.740 | - I already know the answer to that as I ask it,

02:12:59.460 | but let's just stay above the waistline and--

02:13:02.140 | - Oh, no, no, yeah, yeah.

02:13:02.980 | - Or below the waistline.

02:13:04.540 | We're biologists after all.

02:13:06.180 | - We just, yeah, so it's funny.

02:13:09.180 | We're working on a paper on that right now

02:13:11.140 | on the smell of fear.

02:13:12.460 | So we have a nice paradigm for generating fear.

02:13:15.920 | We throw people out of airplanes.

02:13:17.660 | It's a very effective way to generate fear.

02:13:19.180 | - I have to come to your lab.

02:13:20.820 | It sounds like the greatest lab in the world.

02:13:22.460 | - We didn't invent that, by the way.

02:13:24.340 | The first to do that was,

02:13:26.320 | and I hope I'm pronouncing her name correctly.

02:13:28.280 | I think it's Mujika Peroudi.

02:13:30.020 | But that's our paradigm for generating fear,

02:13:35.120 | and we started that on our own,

02:13:36.660 | but we've since entered into collaboration

02:13:39.580 | with the Israeli Paratroopers Brigade,

02:13:41.940 | and we now collect body odor from every first-time jumper.

02:13:46.020 | So we went that path because we,

02:13:50.500 | like everybody else in this field,

02:13:52.620 | you know, the holy grail there is finding the molecules.

02:13:55.780 | Right, I mean, if you'll have the fear molecules,

02:13:59.240 | that's a bonanza, right?

02:14:00.960 | Because I mean, you know, you can think of many reasons

02:14:03.960 | why it would be a bonanza, but for me, you know,

02:14:05.860 | if you find the molecules,

02:14:07.120 | you can then try and find the receptors.

02:14:08.980 | And when you find the cognate receptors,

02:14:10.420 | you can then develop blockers, and you can imagine,

02:14:14.160 | you know, what's the term I'm looking for?

02:14:19.160 | I'm switching into Hebrew.

02:14:22.380 | It's about midnight now, right?

02:14:24.100 | I'm sorry, it's two in the morning.

02:14:25.520 | You're doing incredibly well considering

02:14:27.020 | the inversion of the circadian clock.

02:14:28.720 | We would never know.

02:14:29.680 | No one traveled in today from Israel,

02:14:32.500 | so he's a circadian inverted, as we say.

02:14:35.020 | Anxiety, so you can imagine developing

02:14:40.380 | like a nasal spray against anxiety, right?

02:14:42.500 | Where you would quell those receptors

02:14:45.080 | and kill the fear response, right?

02:14:47.180 | Which rather than going the current path,

02:14:49.020 | which is through neurotransmitters

02:14:50.460 | that then have effects all over the place,

02:14:53.040 | you would be getting fear at its source, right?

02:14:56.140 | So that would be why I would want that.

02:14:58.500 | And we figured out that doing that,

02:15:00.720 | you know, collecting fear from like three,

02:15:03.500 | four or five people in an experiment,

02:15:06.360 | you'll never be able to do analytical chemistry on that.

02:15:08.860 | So we now have a setting we call fear bank,

02:15:13.820 | which now has more than a thousand samples in it.

02:15:16.340 | So we're trying to do analytics on that.

02:15:19.540 | But in doing that, we've joined the crowd.

02:15:23.800 | Everybody's doing fear and everybody's doing sweat.

02:15:27.040 | And in one of our discussions in lab,

02:15:28.840 | we were saying, well, there's gotta be,

02:15:31.380 | or there potentially definitely could be

02:15:33.600 | additional bodily media that are playing

02:15:37.760 | into social chemo signaling.

02:15:39.160 | Now, many of these, you know, you can't really study, right?

02:15:43.340 | I mean, so, you know, just to throw it,

02:15:45.280 | most terrestrial mammals communicate

02:15:47.120 | social information through urine.

02:15:49.380 | But, you know, starting doing experiments

02:15:51.540 | with humans with smelling urine,

02:15:53.660 | it would be difficult, you know,

02:15:55.420 | both in IRB and in agreement and, you know.

02:15:58.940 | And then we, you know, this is a rare case

02:16:02.580 | where we actually hypothesized what we set out to do.

02:16:04.640 | And, you know, did only claim in retrospect

02:16:07.020 | that it was hypothesis, is tears.

02:16:11.140 | We started thinking about tears and looking into tears

02:16:16.700 | because tears are a bodily liquid, emotional tears,

02:16:21.700 | that we emit in emotional situations

02:16:24.740 | where these are situations where nonverbal communication

02:16:27.640 | is critical and key.

02:16:29.340 | And tears are a liquid that is puzzling

02:16:35.300 | beyond ocular maintenance, right?

02:16:41.560 | And so, you know, the most influential text,

02:16:46.160 | I think till this day, in emotion research,

02:16:49.220 | is Darwin's book, The Showing of the Emotions

02:16:53.320 | in Men and Animals, I think is the full name of the book.

02:16:56.320 | And an entire chapter, chapter six, is devoted to tears.

02:17:00.800 | An entire chapter of this book, why?

02:17:04.040 | With no conclusion, why?

02:17:05.820 | Because the book revolves around

02:17:08.600 | describing the functional antecedents

02:17:13.220 | of emotional expressions.

02:17:15.020 | So for example, showing of the teeth

02:17:17.540 | is a sign of aggression, right?

02:17:19.320 | So animals first bit with their teeth

02:17:21.600 | and Darwin argued that through evolution,

02:17:24.580 | just showing the teeth alone became an aggressive sign

02:17:28.080 | because it started from biting.

02:17:30.400 | Or what I find is a beautiful example,

02:17:32.600 | and this is work partly done by Adam Anderson

02:17:34.960 | now at Cornell, is the emotional expression of disgust.

02:17:41.740 | So disgust, which comes from one, disguise, distaste, right?

02:17:46.560 | Is spitting something out of your mouth.

02:17:49.480 | Now what Adam showed is that the musculature patterns

02:17:54.480 | of activation and the temporal sequence of activation,

02:17:59.160 | when you experience moral disgust,

02:18:01.520 | are the same as when you spit a bitter taste

02:18:04.000 | out of your mouth, right?

02:18:05.300 | So again, so there's a functional antecedent

02:18:07.800 | spitting something out.

02:18:09.640 | And through evolution, the argument was that it became

02:18:12.640 | an expression of emotion and you express disgust

02:18:15.280 | just as if you're spitting something out of your mouth,

02:18:17.080 | even though in the case of moral disgust,

02:18:18.960 | there's nothing you're spitting out of your mouth.

02:18:21.120 | So Darwin systematically went through the expressions

02:18:24.240 | of emotions and for each one,

02:18:25.900 | went to their functional antecedent

02:18:27.680 | and explained everything very nicely.

02:18:29.680 | And then he got stuck with tears, right?

02:18:31.260 | Because tears are an obvious emotional expression

02:18:34.040 | and he could not find a functional antecedent.

02:18:39.040 | So he ended up saying this is an epic phenomenon basically,

02:18:41.920 | right, I don't know.

02:18:43.040 | - What all scientists do when they don't have

02:18:44.880 | a good explanation, blame it on nature.

02:18:47.520 | - Right, right.

02:18:48.360 | But he bothered to write this entire chapter

02:18:52.140 | on the ocular sort of maintenance function of tears

02:18:56.400 | and so on and so forth, but nothing emotional.

02:18:58.800 | So we thought, well, maybe the function

02:19:00.760 | is a chemical signal.

02:19:06.620 | So with that in mind, we harvested emotional tears,

02:19:10.920 | which was also an amusing event on its own, right?

02:19:14.020 | Because we posted messages on all sorts of boards

02:19:19.020 | that were seeking experiment participants

02:19:27.800 | who cry with ease.

02:19:29.060 | Now this generated an unfortunate gender bias in our study,

02:19:33.980 | right, because we received about 100 women volunteers

02:19:36.920 | and about one man.

02:19:38.480 | And I think this is not a problem only in macho Israel,

02:19:41.960 | probably anywhere in the West.

02:19:43.440 | I mean, definitely in America it would be the same,

02:19:45.040 | I think.

02:19:45.880 | - My guess is that there are probably men out there

02:19:47.320 | who cry easily, emotional tears.

02:19:49.920 | - Oh, I'm sure.

02:19:50.760 | - But they're not gonna show up.

02:19:51.580 | - Yeah, yeah, that's what I'm saying.

02:19:52.420 | It's a cultural thing, you're not gonna come to a lab

02:19:54.800 | and say, I cry all the time, it's just not gonna happen.

02:19:59.560 | And then what we did is for each one of these participants,

02:20:04.560 | we would ask them, is there a particular film event

02:20:08.620 | that you know of, a scene that makes you cry?

02:20:11.560 | And interestingly in these effective criers,

02:20:14.940 | there's always, oh yes, the scene in so and so,

02:20:18.400 | I always cry profusely from that.

02:20:20.520 | You know, they have their--

02:20:21.360 | - Can you give me an example

02:20:22.180 | of one of the more commonly known scenes?

02:20:24.140 | - Yeah, with ease.

02:20:25.940 | The movie The Champ.

02:20:29.380 | The Champ dies, he's a boxer.

02:20:32.760 | And he dies literally in the hands

02:20:36.340 | of his about eight-year-old son.

02:20:38.680 | And his son is standing next to his bed

02:20:44.140 | and you know, saying, champ, champ.

02:20:46.780 | And he dies, right?

02:20:48.780 | It's a winner, okay?

02:20:51.660 | - Waterfalls.

02:20:53.500 | - Yeah, yeah.

02:20:54.400 | - Got it.

02:20:55.240 | - So you know, we're probably the neurobiology lab

02:20:57.340 | with most sad movie films on those shelves in the world,

02:21:01.120 | right, we have a whole huge collection.

02:21:02.620 | - There is such a thing as tears of joy, by the way.

02:21:05.300 | - So no.

02:21:06.340 | - No?

02:21:07.180 | - Well, we're going ahead of ourselves,

02:21:08.780 | but I have to say, we tried to collect them and failed.

02:21:11.900 | Even people who think they shed tears of joy and laughter,

02:21:15.180 | their eyes water a bit, but it's not the same thing.

02:21:17.740 | In the effective criers we end up screening,

02:21:23.140 | so we collect a full ML of tears,

02:21:27.600 | a full ML of tears in about 15 minutes.

02:21:30.500 | So that's pouring, right?

02:21:32.540 | And that doesn't happen from laughter.

02:21:34.500 | Or we've never seen that.

02:21:36.500 | We've never seen that happen from laughter, we tried.

02:21:38.940 | So we have all these sad films,

02:21:44.580 | and by the way, one of the amusing things is

02:21:47.460 | when we ultimately published this paper in Science,

02:21:51.580 | we were forced, in retrospect,

02:21:53.900 | to go out and actually buy the films, right?

02:21:57.100 | I mean, originally we downloaded them from here and there,

02:21:59.920 | but you can't because you'd be violating copyright laws.

02:22:02.920 | Right, so we had to buy, purchase all these films

02:22:09.100 | that the participants-- - And watch them.

02:22:10.740 | - So we actually have these in lab,

02:22:13.000 | like DVDs that we actually purchased.

02:22:15.400 | - Nice coverage of potential legal fallout there, gnome.

02:22:21.140 | - No, no, no, no, we did.

02:22:22.440 | - No, I believe you, I believe you.

02:22:23.860 | - Yeah, it was that.

02:22:24.780 | - I believe you.

02:22:25.860 | - So, and yeah, and well, we can touch on that later.

02:22:30.540 | So most of these volunteers who come saying

02:22:38.780 | they can cry with ease actually don't meet the bill.

02:22:42.540 | And so out of the about 100 at least more women

02:22:45.740 | that we screened, we ended up with about six

02:22:49.300 | who could really come to lab week after week in poor tears.

02:22:54.300 | - There's a name for this in psychiatry,

02:22:57.060 | they call it narrative distancing.

02:23:00.100 | Some people, when they watch a film

02:23:02.180 | where someone's getting hit, they flinch quite a lot.

02:23:06.540 | It's almost as if they're experiencing it,

02:23:08.320 | but it works in the opposite direction too.

02:23:09.960 | I know someone like this, where if they watch a film

02:23:12.860 | that someone's experiencing something even mildly positive,

02:23:16.340 | their mood elevates, so they can quickly bridge.

02:23:19.620 | And it's not always adaptive, as you can imagine,

02:23:22.720 | so there's lack of narrative distancing.

02:23:24.700 | - Right, yeah, one issue you can bring up

02:23:27.260 | with this entire line of studies in our lab

02:23:28.660 | is I don't know if there's something very unique

02:23:31.220 | about the donors, right?

02:23:33.260 | I mean, we're assuming these are tears.

02:23:34.980 | - No, this is pretty common.

02:23:35.980 | I think that the numbers I saw out there

02:23:37.900 | are about five to 8% of people.

02:23:40.460 | - That's exactly what we got about, right, about 600?

02:23:43.260 | - So we collected tears, and we exposed participants

02:23:48.260 | to these tears, and we found a few things.

02:23:58.100 | First of all, the tears are completely odorless.

02:24:00.740 | You cannot detect them at all, completely odorless.

02:24:04.240 | And yet, when you sniff them,

02:24:09.340 | you have a pronounced reduction in testosterone

02:24:14.340 | within about 20 minutes, half an hour.

02:24:18.380 | - This is men and women smelling women's tears,

02:24:21.220 | men smelling women's tears, but not perceiving any odor.

02:24:24.620 | - Nothing, just sniffing them.

02:24:26.940 | And you have about a 14% drop in free testosterone, free.

02:24:31.940 | - Okay, so this is testosterone

02:24:35.220 | that's already been liberated from the testes.

02:24:37.420 | - Free testosterone.

02:24:38.260 | - We've done a few hormones that's either bound or unbound,

02:24:41.900 | is unbound, excuse me, from sex hormone binding globulin,

02:24:45.220 | et cetera, and it's the active form.

02:24:46.940 | So it's subject to very short timescale changes.

02:24:51.940 | - Yeah, and this is, you know,

02:24:55.100 | people who study testosterone, which is not me,

02:24:58.060 | but they tell me this is a really strong effect.

02:25:00.340 | Like, it's hard to even pharmacologically

02:25:02.320 | get an effect like that that fast.

02:25:04.260 | I mean, no one pharmacology.

02:25:05.940 | - Yeah, years ago, I spent time studying endocrine effects

02:25:08.160 | of this sort, and that's a tremendous resized effect.

02:25:12.060 | - So, and so here I'll point out in passing

02:25:14.800 | that one of the concerns we had

02:25:18.100 | because of the effort to run this study

02:25:22.620 | is that nobody would ever try to replicate it.

02:25:26.220 | And to our joy, about two years later,

02:25:28.780 | an independent group from South Korea,

02:25:33.020 | Oh It Al, who I don't know at all,

02:25:35.860 | replicated the testosterone effect to a T.

02:25:38.560 | I mean, like, same numbers.

02:25:40.840 | So it lowers testosterone.

02:25:44.580 | And we then also looked, using MR,

02:25:49.580 | at the effect on brain activity

02:25:55.000 | and saw a pronounced effect on activity,

02:26:00.280 | a dampening, a lowering of activity

02:26:02.800 | under an arousing state, a lowering of activity,

02:26:07.040 | both in the hypothalamus and in the fusiform gyrus,

02:26:11.900 | for whatever reason, I don't know.

02:26:13.340 | - Face recognition area.

02:26:14.420 | - Amongst other things, yes.

02:26:16.300 | And we don't know why, but pronounced.

02:26:20.280 | And currently, Shania Groen in our lab

02:26:25.780 | is replicating this again,

02:26:27.900 | and this time with a stronger behavioral component,

02:26:32.300 | and I can share with you unpublished data now under review,

02:26:36.700 | that's, as you would expect,

02:26:40.000 | given the effect on testosterone, perhaps,

02:26:42.500 | sniffing tears lowers aggression in men,

02:26:44.540 | using again the TAP, the same experiment

02:26:47.720 | used by Eva in the hexadecimal experiment.

02:26:51.320 | - The TAP, I'm gonna think of that as the SEDIS,

02:26:54.000 | the control, the titration, the SEDIS titration.

02:26:57.440 | - Yeah, yeah, Tyler aggression paradigm.

02:26:59.480 | - So not unlike the Milgram experiments

02:27:01.300 | of the 1950s, which post,

02:27:04.780 | this is looking at sort of post-Holocaust behavior,

02:27:08.700 | people basically in American laboratories

02:27:12.780 | thinking they were torturing other people

02:27:14.980 | simply because they were told to,

02:27:16.260 | and a lot of people did that,

02:27:17.900 | even though most people would report

02:27:19.120 | that they would never torture someone else.

02:27:20.060 | - Yeah, yeah, no, humans are not a wonderful species.

02:27:23.120 | - Or, as we could say, I think it was the great Carl Jung

02:27:26.140 | that said, "We have all things inside of us,"

02:27:29.500 | but the goal is not to experience them all, certainly.

02:27:34.280 | It's an incredible study, and it points, again,

02:27:37.260 | to the power of these chemosensory systems and pathways,

02:27:42.260 | and obviously there's so much here.

02:27:46.860 | - I don't know if you want me to tell about this or not,

02:27:49.540 | and I guess you can edit it out if you don't,

02:27:51.260 | but this is just sharing stories

02:27:53.860 | about the politics of science.

02:27:58.220 | - So whereas the effect on testosterone

02:28:00.180 | was replicated by an independent group,

02:28:03.800 | in the original study in science,

02:28:07.380 | where it had three components.

02:28:09.820 | One was the effect on testosterone, which was robust,

02:28:13.900 | the second, which was brain activity, which was robust,

02:28:16.540 | and there was a significant but weaker effect on behavior,

02:28:22.640 | and I don't think we studied the right behavior

02:28:24.520 | in retrospect.

02:28:25.360 | What we looked at then was ratings of arousal

02:28:29.600 | associated with pictures, and there was an effect.

02:28:34.600 | It was significant, but it was not what carried the story.

02:28:38.240 | Now, there's a lab in Holland of a guy by the name of,

02:28:45.100 | I'm probably mispronouncing this,

02:28:49.920 | but I think it's Vingerhoutz.

02:28:52.180 | - For the non-Dutch.

02:28:55.040 | - Yeah.

02:28:55.880 | - Dutch names are always a little bit of a challenge, but.

02:28:58.040 | - And I shouldn't say that, being an Israeli,

02:29:00.720 | I shouldn't go too much on that line,

02:29:02.500 | but that lab really didn't like our original tear story,

02:29:07.500 | and the reason they didn't like it

02:29:12.080 | is because they've built a career on this notion,

02:29:17.080 | including a book with this title

02:29:20.260 | that emotional tears are uniquely human.

02:29:24.740 | Now, here I should, well, I should share,

02:29:28.740 | so one of the things we really liked about the tear result

02:29:33.740 | is that partially before we did our work,

02:29:37.800 | but more afterwards, and we liked that

02:29:39.840 | because usually things,

02:29:40.800 | so usually in our chemo signaling work,

02:29:42.320 | like what I told you before about the Bruce effect,

02:29:44.240 | we look at what happens in ruins,

02:29:45.620 | and we see if the same thing is happening in humans.

02:29:48.080 | This was a rare case where after we did this work,

02:29:53.020 | more or less identical effects were discovered in rodents.

02:29:55.820 | So a paper published in "Nature" two years later

02:29:59.120 | found that mouse tears, mouse pup tears,

02:30:03.280 | lower aggression in male adult mice towards them.

02:30:07.720 | - In a smell-dependent way.

02:30:09.800 | - Yeah, yeah, and they also actually found

02:30:13.280 | the actual component in tears, so the tear pheromone,

02:30:16.760 | that lowers aggression, right?

02:30:18.520 | So this has us thinking of tears as,

02:30:21.960 | you can think of tears as like a chemical blanket

02:30:24.180 | in a way that you're covering yourself up again

02:30:26.920 | with, to protect against aggression, right?

02:30:30.000 | And so our finding, which to me, I mean,

02:30:35.000 | this is consistent with how I think about behavior

02:30:37.300 | in general, I don't think, beyond language,

02:30:41.160 | there are very few things, definitely sensory things

02:30:43.440 | that are uniquely human, I'd be hard pressed.

02:30:47.680 | But so our finding went against their story, right?

02:30:52.680 | Because here we're saying, no,

02:30:54.920 | tears are this chemo signaling mechanism like all animals.

02:30:58.400 | And by the way, just after this entire debate,

02:31:01.160 | about six months ago, there was a paper in "Current Biology"

02:31:05.240 | that dogs emit emotional tears.

02:31:07.920 | And the dogs emit emotional tears

02:31:10.960 | when they reunite with their owners.

02:31:13.320 | And you were talking before about oxytocin.

02:31:18.120 | So I think what they showed there is that not only that,

02:31:20.840 | but that the view, seeing the tears in the dog

02:31:25.840 | influences oxytocin in the humans.

02:31:29.520 | I hope I'm getting this right.

02:31:31.680 | - No, I absolutely believe this.

02:31:33.480 | I mean, from the time I brought Costello home

02:31:36.840 | at eight weeks old.

02:31:37.800 | - Costello's your dog.

02:31:38.640 | - He's my dog, unfortunately he passed away,

02:31:40.000 | but had him a long time.

02:31:40.960 | Actually, the only time I can recall crying,

02:31:45.200 | listen, I've certainly cried before,

02:31:47.280 | many times in my life, many, many times.

02:31:50.040 | The only time I ever recall crying to the point

02:31:53.920 | where I wasn't sure that I could keep producing tears,

02:31:56.480 | but somehow it is when I had to put him down, right?

02:31:59.080 | Is this like, you know, and if I talk about too long now,

02:32:01.360 | I'll start crying, you know, it's one of those things.

02:32:04.000 | I think it's a healthy emotional state.

02:32:06.520 | But I recall when he was a puppy thinking

02:32:09.600 | this oxytocin thing must be real

02:32:11.560 | because I can recall being in faculty meetings,

02:32:14.320 | which, you know, are fairly stated

02:32:16.880 | are not always that interesting,

02:32:18.120 | but they could be pretty interesting.

02:32:19.320 | And someone presenting data in my mind thinking,

02:32:22.800 | I hope Costello's okay, what's he doing down in my office?

02:32:25.480 | This is when he was very little.

02:32:26.840 | And also not needing to eat,

02:32:29.960 | not being able to focus on anything else

02:32:32.320 | except my attachment to him for about the first

02:32:34.400 | two or three weeks that I had him, then it was easy.

02:32:36.440 | Then I could focus off on other things.

02:32:38.120 | I think that dogs, perhaps through oxytocin,

02:32:41.920 | hijack the circuitry that's intended for child rear.

02:32:44.960 | I really do.

02:32:45.800 | Otherwise, why would people be so ridiculously

02:32:48.240 | attached to their dogs?

02:32:49.680 | Hence all the posts of everyone thinks their dog

02:32:52.120 | is the cutest dog, the same way everyone thinks

02:32:53.640 | their children are the cutest children.

02:32:55.760 | Costello, by the way, was a very handsome bulldog.

02:32:58.080 | (laughing)

02:33:00.320 | - So again, so even, you know, to put another nail

02:33:04.640 | in that story of tears are uniquely human,

02:33:07.960 | so they're not.

02:33:08.800 | Dogs shed emotional tears.

02:33:11.000 | And so that group really didn't like this,

02:33:16.080 | and they went ahead and tried to replicate.

02:33:20.920 | And to your listeners, I'm showing double quotations

02:33:23.640 | on the replicate, only the behavioral part,

02:33:26.480 | the ratings of arousal in women, of women,

02:33:31.480 | and failed to replicate that.

02:33:35.640 | - I see.

02:33:36.680 | Now, this was, you know, just sharing on how science works

02:33:40.120 | and doesn't work in my notion in this case.

02:33:43.520 | So at the time, after they got this accepted

02:33:48.520 | in some journal, not a field journal,

02:33:54.280 | in the journal of memory of something,

02:33:56.760 | they contacted me for a response.

02:34:03.460 | And I wrote to the authors, and I said,

02:34:06.200 | "Look, you know, this is very odd to me.

02:34:08.640 | Why don't you come, why don't we replicate this again

02:34:12.160 | together and see if it doesn't work.

02:34:13.440 | If it doesn't work, I'll publish it with you

02:34:15.120 | that it doesn't work, but you know."

02:34:16.920 | And so I said, "Why don't you send over a graduate student

02:34:20.360 | or the lead author, and we'll do it here,

02:34:22.160 | and we'll show them how it's done?"

02:34:23.600 | Because they did it very wrongly in the paper.

02:34:26.400 | And so they replied that, "No, they don't have money

02:34:29.840 | to send over a graduate student to do it."

02:34:31.880 | So I replied saying, "Okay, I'll fund the graduate student

02:34:35.800 | coming over and I'll fund the entire study

02:34:38.560 | and their stay and so on and so forth,

02:34:40.120 | and let's do this together."

02:34:41.640 | And they replied, "No, they're not willing to do that,"

02:34:45.280 | which I don't think is the way things should work.

02:34:47.920 | And they published this sort of failed behavioral effect

02:34:52.920 | in that paper.

02:34:55.560 | So I'm just sharing this, you know, that it's not only,

02:34:57.960 | there was that successful replication

02:34:59.920 | with the effect on testosterone,

02:35:01.540 | but there was supposedly this failed replication

02:35:03.520 | on the effect in behavior.

02:35:06.320 | And then I published a rebuttal on that,

02:35:09.960 | which I don't know if I should have done, but I did.

02:35:11.960 | - Well, I think it's interesting.

02:35:13.440 | I mean, I think provided studies are done correctly,

02:35:17.440 | I mean, the positive result almost always trumps

02:35:20.440 | the negative result, and yet I think replication is key.

02:35:23.840 | The problem, as you pointed out,

02:35:24.800 | is that replication is rarely pure replication

02:35:27.160 | of the exact study. - Yeah, yeah, this one

02:35:28.520 | is not even remotely, but I published a detailed,

02:35:31.760 | so actually they hid something in their data

02:35:34.320 | that did partially work.

02:35:35.440 | So I asked for their data and I reanalyzed it,

02:35:37.600 | and that's what I published in the rebuttal.

02:35:39.480 | But you know, this is just sharing on how science works.

02:35:42.160 | I took advice, so it's not that I'm friends with him,

02:35:46.440 | but at that time I was communicating a bit

02:35:48.600 | because we were on some board with Daniel Kahneman,

02:35:52.840 | who's a Nobel lawyer. - Thinking fast and slow.

02:35:54.960 | - Right, and so I asked him, "How should I deal with this?"

02:35:59.140 | You know, give me some advice here.

02:36:01.800 | Yeah, I was really, you know, it was emotionally not fun

02:36:05.800 | to be in that position.

02:36:07.440 | And he said, "Don't, never publish a rebuttal.

02:36:12.440 | "Don't do anything."

02:36:14.320 | And I was, you know, "How can I?

02:36:15.960 | "I have to do something."

02:36:16.800 | He said, "No, don't, because once you do that,

02:36:19.020 | "then people don't go into the details.

02:36:21.560 | "They won't read the details of your rebuttal.

02:36:23.140 | "They'll be like, well, there's a group that says this

02:36:25.220 | "and there's a group that says that."

02:36:26.520 | So it's unclear, and-- - Yeah, I mean,

02:36:29.200 | I appreciate that you're bringing it up today,

02:36:30.800 | and I do appreciate that you publish the rebuttal

02:36:33.400 | and that you offered, in a very magnanimous way,

02:36:36.040 | to do a collaboration. - That's what he then said.

02:36:38.960 | So Kahneman's advice after that was that,

02:36:41.360 | well, if you insist, then just publish, write a response

02:36:46.360 | that you offered them to come do it together.

02:36:48.600 | They refused, and there's nothing you can do about that.

02:36:51.320 | - It's a lot like fight sports, right?

02:36:54.320 | People talk a lot of trash.

02:36:55.880 | Although in science, you know, I will say this,

02:36:57.720 | you know, as long as we're on the sociology of science,

02:37:00.120 | the stakes are lower.

02:37:01.400 | - Science is very different than podcasting

02:37:03.240 | or social media or other fields,

02:37:05.600 | because in science, people generally are very kind

02:37:08.800 | to your face, and then you get it in the neck

02:37:12.320 | on grant reviews or anonymous reviews.

02:37:16.120 | I was on a grants review panel this morning.

02:37:17.560 | I'm a nice reviewer, meaning I judge things objectively,

02:37:20.360 | but I try to always think from the perspective

02:37:23.920 | of the graduate student or author of the proposal.

02:37:26.960 | - Listen, I think that science is a game of people

02:37:31.360 | who most of them are seeking facts.

02:37:33.760 | However, the ego is strongly woven into it,

02:37:37.520 | like anything else.

02:37:38.720 | So I think it was very magnanimous of you

02:37:41.280 | to offer the collaboration.

02:37:42.280 | So I'm going to tell this lab whose name I can't pronounce,

02:37:45.040 | please accept the collaboration,

02:37:46.320 | and then we can invite everyone on here for a round table.

02:37:49.840 | I appreciate that you shared that story,

02:37:51.280 | and I know a number of other people will

02:37:54.000 | for a number of reasons.

02:37:55.400 | I have a couple of more questions, and I realize,

02:37:58.280 | and thank you, by the way,

02:37:59.640 | for your willingness and stamina,

02:38:02.400 | because it is probably 1 a.m. Israel time now,

02:38:04.920 | and you just arrived, but you're doing terrifically well.

02:38:08.480 | So if you'll indulge us just a touch further,

02:38:12.120 | there are two topics that I want to touch on,

02:38:15.120 | and if you want to cover these in Shorter Thrift,

02:38:17.440 | that's fine, although I don't feel any obligation to.

02:38:20.160 | The first one is I think most people are familiar

02:38:23.800 | with the scent of food or foods

02:38:26.240 | as a signal of the nutrient contents of those foods.

02:38:29.600 | An orange that smells great,

02:38:32.360 | or the smell of something baking,

02:38:34.360 | it suggests something about the contents

02:38:37.520 | and quality of that food.

02:38:38.640 | After all, you and I both separately lived

02:38:41.180 | in the same apartment in Berkeley above the cheese board,

02:38:43.560 | which the smell of cheese wafting up

02:38:45.880 | through the cheese board is something I will never forget,

02:38:47.960 | and the breads, never forget it.

02:38:49.960 | Amazing bread.

02:38:52.480 | - I don't know if you've conveyed that clearly enough

02:38:55.520 | to listeners or watchers.

02:38:56.960 | - No, the probability is-

02:38:57.800 | - That we really just discovered that we lived

02:38:59.860 | in the same, we never met, I mean, like this before,

02:39:04.140 | and we lived in the same apartment.

02:39:05.280 | - Exactly, are we click friends?

02:39:07.220 | (laughing)

02:39:09.880 | - In a lingering way, I guess.

02:39:11.680 | - Absolutely, through the-

02:39:14.560 | - Floorboards, it had a great floor, that place.

02:39:16.520 | It had a great wooden floor.

02:39:17.360 | - It was an amazing place.

02:39:18.280 | I lived there with my girlfriend for a year and a half,

02:39:20.280 | and then it was an amazing place.

02:39:23.040 | We won't give out the address out of respect

02:39:26.480 | for the people that live there now,

02:39:28.600 | but do check out the cheese board if you're ever in Berkeley.

02:39:30.300 | Their hours are weird, so you have to look online,

02:39:32.620 | but it's a unique place with great bread and cheese

02:39:35.620 | and some good flavors of pizza.

02:39:38.920 | In any case, I'm wondering whether or not smell

02:39:43.280 | can signal things about the nutrient contents of foods

02:39:49.520 | in a way that's divorced from the smell

02:39:51.880 | that we are perceiving.

02:39:53.400 | So for instance, I could imagine,

02:39:56.120 | based on what you've told us about smell today,

02:39:59.400 | that I don't know, I smell a piece of meat cooking

02:40:04.400 | and it smells great to me.

02:40:08.700 | And I think of it as, oh, that's so savory

02:40:11.080 | and my mouth is watering and I love the smell of this.

02:40:13.860 | And I'm thinking, okay, this is protein and fat

02:40:16.280 | and I love the taste of steak and a little bit of char,

02:40:18.960 | but that nature has co-opted that

02:40:22.000 | to ensure or I should say increase the likelihood

02:40:27.000 | that I will ingest some other thing that's in steak

02:40:30.080 | that has no odor but whose nutrient content

02:40:33.120 | is very important to me.

02:40:33.960 | For instance, amino acids, right?

02:40:36.680 | I mean, amino acids are essential to life

02:40:39.560 | and yet we don't go around sniffing for amino acids.

02:40:42.640 | We go around sniffing for savoriness,

02:40:45.640 | umami type tastes and things of that sort.

02:40:49.760 | So I could imagine a million different examples of this

02:40:52.960 | in the same way I could imagine that the scent of somebody

02:40:55.720 | that we fall in love with or become romantically attached to

02:40:58.880 | or sexually attracted to is signaling all sorts of things

02:41:02.640 | about sure, the potential for offspring

02:41:05.340 | of a particular immune status, that's a long-term game,

02:41:08.020 | but also something about pleasure and safety

02:41:13.020 | of a potential interaction.

02:41:14.840 | - So what I'm asking here is about whether or not

02:41:17.200 | there are subconscious signals that the olfactory system

02:41:21.320 | has learned to seek but learned to seek

02:41:24.960 | through more overt signals,

02:41:27.320 | sort of the tip of the iceberg phenomenon.

02:41:29.780 | - So you know, I don't have a good answer for you,

02:41:31.920 | although I think it's a really good question

02:41:34.120 | or a good idea, in fact.

02:41:37.480 | So whether there's, you know,

02:41:43.640 | odor cues on nutrient value is a really good idea.

02:41:48.640 | Moreover, it's probably good to the extent

02:41:51.440 | that somebody probably did it and I should know and don't.

02:41:54.420 | We haven't done anything on that line.

02:41:58.200 | So I don't know.

02:41:59.340 | I don't know if the nutrient value of food

02:42:04.140 | is systematically encoded in odor.

02:42:06.880 | If that's not been done,

02:42:10.240 | and I will check after our meeting today,

02:42:13.920 | then it should be, it's a really good idea.

02:42:17.680 | - I mean, one of the reasons I asked this is because,

02:42:20.000 | you know, the obesity crisis in the US is a huge issue

02:42:22.740 | and elsewhere and highly processed foods, you know,

02:42:27.200 | have a lot of things that are problematic,

02:42:28.880 | but one of the things that they don't have often

02:42:32.840 | is a direct relationship between the scent,

02:42:36.120 | the taste and the nutrient content.

02:42:39.000 | I don't mean macronutrient, sugar, fat, excuse me,

02:42:42.120 | carbohydrates, fats, and proteins,

02:42:43.800 | but the vitamins and micronutrients,

02:42:46.160 | things that support the microbiome.

02:42:47.600 | Whereas foods that are not highly processed,

02:42:51.000 | for instance, meat or a piece of fruit,

02:42:53.200 | contain many micronutrients that are vital

02:42:56.760 | to aspects of our biology.

02:42:58.000 | We don't go around sniffing for probiotics.

02:43:00.120 | - I'll tell you one sort of factoid

02:43:02.560 | that may support your hypothesis here.

02:43:05.520 | And that is that there appears to be potential olfactory

02:43:10.520 | perceptual similarity in metabolic products.

02:43:16.320 | So something that's metabolized from something else

02:43:21.880 | has perceptual similarity across those two things.

02:43:26.880 | So metabolic cascades play into the coding

02:43:33.940 | of olfactory space, and that is consistent

02:43:37.280 | with the direction you're implying.

02:43:40.920 | But again, I don't know of a direct test

02:43:43.160 | of nutritional value in smell.

02:43:47.840 | And again, the fact that I don't know doesn't mean,

02:43:51.520 | of course, that it doesn't exist.

02:43:52.860 | And in this case, I would suspect that it should exist

02:43:55.520 | in scientific press, and if not there,

02:43:59.260 | then with the companies that have vested interest in this,

02:44:03.220 | which are many.

02:44:04.060 | - Briefly share, just please.

02:44:08.540 | - An amusing anecdote to share with you

02:44:10.200 | is that we've received two independent

02:44:13.360 | companies who have turned to our lab recently

02:44:21.360 | asking for help to bring odor to engineered meat, right?

02:44:26.360 | That's a growing thing.

02:44:28.160 | And all these meats that are not--

02:44:30.440 | - Yeah, to bring it up.

02:44:31.920 | - This audience is going to be very polarized

02:44:34.760 | along the lines of engineered meat.

02:44:37.300 | You're not promoting.

02:44:40.600 | - Oh, no, no, no, no, I'm agnostic.

02:44:42.960 | But we've had two companies turn to us and say,

02:44:47.020 | look, you know, we have this great product,

02:44:48.720 | but it just doesn't smell like meat,

02:44:50.460 | so help us make it smell like meat.

02:44:52.640 | - Interesting.

02:44:53.680 | The reason it's so polarizing is that anything

02:44:55.500 | related to nutrition on social media

02:44:57.680 | is a total barbed wire topic.

02:44:59.440 | We've had experts on nutrition come on here,

02:45:01.040 | we'll have more, but--

02:45:02.060 | - I know nothing about nutrition.

02:45:04.060 | - You're safe, no, don't worry.

02:45:05.760 | No, he's not promoting, he hasn't even said

02:45:09.040 | whether or not he's going to help them out.

02:45:10.540 | - No, we're not, actually.

02:45:12.680 | Not because, yeah, it didn't happen.

02:45:15.520 | - No, whether or not those engineered meats

02:45:19.000 | are yum, yuck, or meh is a personal issue

02:45:22.920 | to people in terms of taste.

02:45:24.040 | Whether or not they are better for,

02:45:26.640 | neutral or worse for you and the planet

02:45:29.400 | than given the ingredients that are required,

02:45:31.760 | that's a whole world we'll avoid now.

02:45:34.440 | - I will, but I'll take the opportunity

02:45:37.000 | to highlight something related, maybe,

02:45:39.720 | because on what you were saying on the scale,

02:45:43.800 | you know, I'll take the opportunity

02:45:47.600 | to dispel another misconception about olfaction, right?

02:45:52.080 | There's this common notion that our sense of smell

02:45:57.440 | is incredibly subjective, right?

02:46:00.040 | And that what you might like in a smell,

02:46:02.040 | I will not like in a smell, and that we all have our own,

02:46:04.840 | you know, totally subjective world of olfaction.

02:46:08.320 | - I think I know the study you're gonna tell me.

02:46:09.880 | - There are many.

02:46:10.720 | - The cross-cultural similarity.

02:46:11.880 | - There are many, that is utterly untrue.

02:46:15.120 | Many not only from my lab, there are many from many labs.

02:46:17.640 | - Please clarify for those that follow this literature.

02:46:19.960 | - So, yeah, so humans are incredibly subjective.

02:46:24.960 | Humans are incredibly similar to one another

02:46:28.800 | in their olfactory perception,

02:46:30.640 | and this is in contrast to what most people think.

02:46:33.880 | So why is there this misconception?

02:46:36.440 | The misconception is there for two reasons.

02:46:39.720 | First of all, or for several reasons, but two stand out.

02:46:43.240 | First of all, we're attracted by outliers,

02:46:47.280 | because, you know, I'll tell somebody,

02:46:50.040 | look, you know, for example, olfactory pleasantness

02:46:52.880 | is highly correlated amongst humans.

02:46:55.160 | And let's first put this in numbers.

02:46:56.720 | You'll take a bunch of humans and a bunch of odorants

02:46:59.400 | and have them rate pleasantness.

02:47:01.040 | The correlation across the humans will be about 0.8.

02:47:05.200 | That's incredibly high, incredibly high.

02:47:07.920 | - What do you think is pleasant, I think is pleasant.

02:47:09.560 | - Yeah, yeah.

02:47:10.640 | Now, why is that go against what culturally people think?

02:47:15.640 | For two reasons.

02:47:16.880 | First of all, we're attracted or biased by outliers,

02:47:22.640 | but that's particularly, that shows, in fact, the result.

02:47:25.320 | What do I mean?

02:47:26.160 | So you'll tell somebody, look,

02:47:27.240 | people are very similar in their pleasantness estimates.

02:47:29.440 | And so you know that can't be.

02:47:30.560 | I love cilantro and, you know,

02:47:32.680 | my girlfriend hates the smell of cilantro, right?

02:47:35.080 | Or, and there are a few classic examples there.

02:47:37.560 | Guiava, right, you know, is another polarizing odor.

02:47:41.520 | So there are a few polarizing odors, right?

02:47:44.040 | And that's true, right?

02:47:45.480 | So that's true that, you know,

02:47:47.280 | half of the population loves the smell of cilantro

02:47:49.320 | and half hates it, half loves guiava, half hates it.

02:47:52.440 | That's true.

02:47:53.280 | - Microwave popcorn.

02:47:54.880 | - However, I assure you that, you know,

02:47:58.000 | you can come to our lab,

02:47:58.840 | we have about 1,000 odorants in our lab, okay?

02:48:01.760 | We won't smell the 1,000, right?

02:48:03.280 | But I assure you, you know, take 100 odorants, okay,

02:48:06.360 | from our mixtures and labs, right?

02:48:09.800 | And we'll smell them, right?

02:48:12.120 | And out of the 100 odors, 90 we'll totally agree on, right?

02:48:17.120 | And including, I mean, you know,

02:48:20.360 | nobody will say they like the smell of feces

02:48:22.760 | or fecal smells and everybody will say

02:48:25.560 | they like the smell of rose and flowery smells.

02:48:28.440 | There will be rare, rare exceptions.

02:48:31.200 | Again, the correlation is about 0.8 across individuals.

02:48:34.280 | So a 90 of 100 will usually be in high agreement.

02:48:37.800 | Then five odorants will be in sort of intermediate agreement

02:48:41.440 | and yes, there'll be the five odorants

02:48:43.240 | that we're in total disagreement on.

02:48:45.400 | But I asked you, you know, if we agree on 95

02:48:47.560 | and disagree on five, are we the same or are we different?

02:48:50.320 | We're the same, they're just outliers to this rule.

02:48:53.800 | And so one reason is this issue of outliers attract

02:48:58.040 | how we think about things,

02:48:59.160 | but no, we're actually much more similar than what we think.

02:49:03.720 | And the second thing that drives this cultural effect

02:49:07.360 | is our poor application of language to olfaction, right?

02:49:12.080 | So in other sensory systems, we grow up with,

02:49:15.880 | we develop with anchors, right?

02:49:18.720 | So since you're a little kid, your mother shows you a cow

02:49:21.960 | and says, what does a cow do, moo, right?

02:49:24.000 | And we all know moo, moo.

02:49:25.240 | And what color is this?

02:49:26.720 | It's, well, this is kind of an odd black,

02:49:28.800 | but it's black, right?

02:49:29.720 | Or what color is that?

02:49:30.880 | It's red, right?

02:49:31.840 | So you have these anchors, but as you all know,

02:49:34.280 | the red that I'm seeing is not necessarily

02:49:36.080 | the red that you're seeing.

02:49:36.920 | We just both know to call that red.

02:49:38.600 | And since you say red and I say red,

02:49:40.360 | I think why we're seeing the same thing.

02:49:42.240 | But no, we're not seeing the same thing, right?

02:49:44.800 | And in odor, we don't have those anchors, right?

02:49:47.280 | We don't from childhood, you know,

02:49:48.880 | our mom doesn't tell us, so what's this smell

02:49:50.520 | and what's that smell, right?

02:49:51.640 | And so we don't have these language anchors

02:49:54.360 | that make us think that we're perceiving the same thing.

02:49:57.760 | Now, how can you quantify that?

02:50:00.600 | The most important term in measuring sensory systems

02:50:04.080 | is similarity, right?

02:50:05.760 | That's the measure, right?

02:50:07.440 | So what can you, let's say we take 10 odorants

02:50:10.720 | and I have you rate all the pairwise similarities, right?

02:50:13.640 | So you'd end up with 45 numbers, right?

02:50:15.640 | So, you know, how similar is one to two, one to three,

02:50:18.400 | one to four, and then two,

02:50:19.400 | and all the possible pairwise similarities.

02:50:22.400 | Let's say you rate similarity from one,

02:50:24.400 | which is totally dissimilar to 100, exactly the same, right?

02:50:27.800 | So now I have a similarity matrix

02:50:31.200 | that describes Andrew's perception of smell, right?

02:50:34.240 | I have, you know, based on these 10 odorants

02:50:36.560 | that I selected.

02:50:37.720 | Now I can run my similarity matrix

02:50:40.400 | and then I can see if the similarity matrix

02:50:42.360 | are correlated, right?

02:50:43.560 | And then we've gotten rid of the issue of names

02:50:45.600 | and orders, right?

02:50:46.440 | It doesn't matter if I'll call this lemon and this orange

02:50:48.840 | and you call this sweet potato and this marshmallow, right?

02:50:52.640 | It doesn't matter.

02:50:53.760 | If I think that these two are highly similar and you agree,

02:50:58.080 | and I think that these two are very different

02:51:00.240 | and you agree, right?

02:51:01.480 | We perceive the world in the same way.

02:51:03.120 | If our similarity matrices are aligned, right?

02:51:06.240 | And what's nice about that is that then you can do that

02:51:08.200 | for vision, audition, and all faction in a common group.

02:51:11.800 | And you can see where we're more alike each other or not.

02:51:16.160 | And we've done that for color vision, all faction,

02:51:19.080 | and tonal audition, okay?

02:51:21.600 | And we are most dissimilar in color vision, okay?

02:51:26.600 | We're, in color vision, the variance is about 100%.

02:51:31.240 | - Amazing, that's quite different.

02:51:32.920 | - And there's tons of literature on this.

02:51:34.320 | Tons of it, tons of it, right?

02:51:36.520 | And in all faction and audition, they're about the same.

02:51:40.040 | So we're not different, we're very similar.

02:51:43.000 | We're just very poor at appreciating this.

02:51:46.720 | And mind you, not that there's not variability,

02:51:48.680 | there is variability.

02:51:50.040 | And of course, the system is malleable

02:51:52.080 | as all sensory systems are.

02:51:53.400 | So you can learn to like an order

02:51:55.120 | and that will change you and learn to dislike an order, right?

02:51:57.800 | But just the way you can learn to like a sound

02:51:59.800 | or dislike a sound.

02:52:01.040 | So this doesn't take away from the hardwired link

02:52:04.000 | of a structure to its perception that they're malleable.

02:52:07.520 | And we're not very variable, we're actually kind of similar.

02:52:12.520 | - That's a perfect segue to the question I have next,

02:52:16.480 | which is, if in general,

02:52:19.560 | people perceive certain odors similarly,

02:52:22.400 | you could imagine that odors could be manufactured,

02:52:28.960 | co-opted, et cetera, in order to elicit

02:52:33.160 | richer sensory experiences and drive choice making.

02:52:37.240 | That's obvious at the level of the smell of a hot dog stand

02:52:41.520 | or freshly baked bread, et cetera.

02:52:43.440 | But what I'm talking about here,

02:52:45.200 | and I'd like to ask you about is doing this at scale

02:52:47.520 | and scientists, geeks like to say in silico,

02:52:51.640 | through computers.

02:52:52.600 | So for a long time now, there's been this idea

02:52:54.880 | that there will soon be Google smell,

02:52:58.280 | not to call out Google as the only search engine,

02:53:00.280 | but Duck Go smell,

02:53:02.480 | for those of you that don't want to hear smell--

02:53:03.960 | - Chat GPT.

02:53:05.280 | - Chat GPT and on and on.

02:53:07.480 | In other words, visual information is sent

02:53:11.840 | through computer interfaces as is auditory information,

02:53:15.360 | not so much haptic somatosensory, although it can,

02:53:19.520 | our lab uses VR, it can be done,

02:53:22.400 | but it hasn't really taken hold.

02:53:24.840 | However, smell being such a rich source of behavioral

02:53:29.520 | and hormonal and other sorts of deep, deep information

02:53:34.520 | that can drive people into yum, yuck or meh

02:53:37.920 | type decision making, seems like an amazing candidate.

02:53:42.200 | So what is your experience with generating smells

02:53:46.640 | in silico and computers?

02:53:48.600 | And here folks, for those of you that aren't catching

02:53:50.320 | on to this, and I don't expect that everyone would

02:53:52.520 | because what we're really alluding to here

02:53:55.440 | is the idea that you'll look at,

02:53:57.840 | you'll put into a search engine,

02:54:01.120 | a blueberry pancakes recipe and that not only will you

02:54:04.720 | get photos of those blueberry pancakes and a recipe,

02:54:08.200 | but you will get the hopefully validated odor

02:54:11.640 | of those pancakes and that recipe coming at you

02:54:14.960 | in real time through the computer.

02:54:18.520 | - So I'll start off answering from the name

02:54:23.280 | you threw out there, Google.

02:54:25.360 | So about, probably about five years ago,

02:54:30.760 | Google had an April Fool's spoof.

02:54:33.520 | - Oh, right.

02:54:34.360 | - And they put out this video of Google smell.

02:54:38.080 | Okay, and it had all these like classic like sales images

02:54:43.080 | of holding up your phone to a rose and it generating rose

02:54:47.400 | and all these things, right?

02:54:50.680 | So Google is now trying to do that.

02:54:52.480 | And they just published, I mean,

02:54:58.640 | I know they've been trying to do it for a while.

02:55:00.560 | They visited our lab, but they just sort of went public

02:55:05.560 | with this that really just like about a month ago

02:55:09.000 | or something that they have this offshoot startup.

02:55:13.680 | I think it's called Osmo or something like that

02:55:16.400 | that started off with a ridiculous sum of money

02:55:19.600 | for a startup like, I don't know, tons of money.

02:55:23.280 | - There's a lot of money in that world.

02:55:24.560 | - Yeah, in Google, yeah.

02:55:29.440 | - To digitize smell.

02:55:31.520 | And there are other companies

02:55:35.800 | that are trying to do this as well.

02:55:38.320 | And we've been talking now for quite a while

02:55:40.480 | about our labs chemo signaling work,

02:55:42.720 | but actually half of our lab is devoted to this question

02:55:46.800 | of ultimately digitizing smell.

02:55:50.280 | And so this is a very, very active field of research.

02:55:56.400 | And I'll say one thing that dovetails

02:56:01.400 | with what you were talking about before,

02:56:04.520 | in many ways, COVID is going to be one of the best things

02:56:08.720 | that ever happened to olfaction research.

02:56:11.200 | Because suddenly all the world is, or all the world,

02:56:14.880 | lots of people are very cognizant

02:56:19.440 | of the importance of smell and smells like way up there

02:56:22.960 | in people's awareness because of COVID.

02:56:25.240 | And this is driving a renaissance of olfaction research.

02:56:29.240 | And awareness to olfaction is something

02:56:33.200 | that's worth paying attention to.

02:56:35.240 | And our lab has been involved in this way,

02:56:40.600 | in this effort for a long time

02:56:42.000 | where the initial part of this effort

02:56:44.960 | is in fact to develop a set of rules

02:56:47.560 | that link odor structure to odor perception.

02:56:51.120 | That is, the going thing was that until recently,

02:56:55.040 | at least there was no scientist or perfumer for that matter

02:56:57.480 | who could look at the structure of a novel molecular mixture

02:57:01.440 | and predict for you how it will smell or smell something

02:57:04.720 | and tell you what molecular structure could or should be.

02:57:07.640 | So in contrast, let's say to trivial like color vision,

02:57:13.320 | let's say, so if you know what the wavelength of the light

02:57:16.240 | is, you more or less know what perceived color

02:57:18.600 | it's gonna be.

02:57:19.420 | Of course, there are exceptions to that

02:57:20.240 | and all sorts of issues, but as a rule, you would know.

02:57:23.280 | Or the other way around, you can generate a wavelength

02:57:26.480 | and you would know what color light

02:57:28.680 | it's going to be perceived.

02:57:30.840 | So that's an example of where the rules linking structure,

02:57:34.880 | in this case, measured by wavelength and perception,

02:57:37.160 | in this case, experienced this color,

02:57:39.480 | the rules are well-known.

02:57:41.040 | In olfaction, we didn't have that until recently.

02:57:44.300 | But over the past few years,

02:57:47.120 | a bunch of labs have really pushed this forward.

02:57:51.400 | There's a bunch of work out of Leslie Voshall's lab

02:57:54.600 | at Rockefeller and Andreas Keller working with Leslie,

02:57:57.780 | who've done a lot of work on this front.

02:58:02.680 | Also worked from Joel Mainland's lab at Monell

02:58:06.960 | and Fair Discovery.

02:58:08.520 | Joel was a graduate student in our lab.

02:58:10.900 | And recently in our lab, we've had,

02:58:15.200 | and I hope this doesn't come across as overly arrogant,

02:58:17.820 | but we've had a sort of mini breakthrough on this front.

02:58:21.880 | - To call something a mini breakthrough is far from arrogant.

02:58:24.880 | - And this is a paper led by Aaron Ravia from our lab

02:58:30.880 | and Coby Snitz, also a major contributor there,

02:58:34.280 | a paper published in Nature about a year and a half ago

02:58:38.240 | in the height of a COVID pandemic.

02:58:40.420 | So nobody really, I won't say nobody,

02:58:42.400 | but it wasn't noticed in the way

02:58:44.040 | otherwise would have been.

02:58:44.980 | It was published in Nature really on like a week

02:58:48.200 | where the whole world was like going berserk over COVID.

02:58:51.980 | And in this paper, we develop an algorithmic framework

02:58:57.560 | where we can predict the perceptual similarity

02:59:03.560 | of any two molecular mixtures

02:59:07.300 | with very, very high accuracy.

02:59:09.940 | So if you give me two molecular mixtures,

02:59:12.200 | I can predict how similar you will smell them to be, okay?

02:59:16.520 | Now, not only could we predict that, but we could design it.

02:59:19.900 | So we can generate mixtures with known similarities.

02:59:24.900 | And the result was highlighted,

02:59:29.480 | and you'll appreciate this coming from vision,

02:59:32.380 | is that using our algorithmic solution,

02:59:35.820 | we generated olfactory metamers.

02:59:38.160 | So we measured mixtures completely non-overlapping

02:59:42.400 | in their molecular structure,

02:59:44.360 | but they smell exactly the same, okay?

02:59:47.660 | Now, if you would come to a classic perfumer

02:59:50.000 | or most classic perfumers and tell them

02:59:52.540 | that you can generate two mixtures

02:59:54.620 | with zero molecules in common,

02:59:56.960 | but smell exactly the same, they would tell you no.

03:00:00.620 | And yet we did, and anybody can recreate them.

03:00:04.400 | This is simple, actually.

03:00:07.780 | And in the paper, we do a few things,

03:00:09.520 | like we generate a metamer for a Chanel No. 5.

03:00:13.280 | So you don't like perfumes, so this one.

03:00:15.360 | But we take, so we generate a Chanel No. 5

03:00:18.400 | with no component from Chanel No. 5 in it, okay?

03:00:21.980 | And we actually have a publicly available website.

03:00:24.800 | I'll give it to you for your links.

03:00:26.040 | If you want that anybody can do this,

03:00:27.560 | we built an engine that you can generate these metamers.

03:00:31.680 | Now, once we did that,

03:00:35.280 | in a way, we've generated the infrastructure

03:00:39.320 | for digitizing smell.

03:00:40.620 | Because, again, what our algorithm predicts,

03:00:46.580 | our framework predicts is similarity.

03:00:49.460 | But in a way, that's enough for you.

03:00:50.740 | Why is that enough?

03:00:51.780 | We have a map of 4,000 molecules.

03:00:56.660 | For each one, we know there are perceived smell.

03:01:00.580 | Now you can make up any mixture you want for me.

03:01:03.060 | I can project it into that map

03:01:05.700 | and measure its pairwise distance

03:01:07.740 | from all the points in the map.

03:01:09.300 | If it falls on lemon,

03:01:10.980 | then what you generated smells like lemon.

03:01:13.120 | And if it falls on tomato,

03:01:15.120 | then what you generated smells like tomato.

03:01:17.480 | So we now solve that problem.

03:01:20.440 | We can predict the odor of any molecular mixture.

03:01:23.920 | We can see how it's going to smell.

03:01:26.520 | What we can do is then find a set of components,

03:01:29.400 | which we call odor primaries,

03:01:31.680 | that can be used to mix any odor that you can perceive.

03:01:35.560 | And that's what we're working on now.

03:01:39.560 | And about a month ago,

03:01:42.240 | so this is in collaboration with a lab

03:01:44.080 | of Jonathan Williams at Max Planck in Munich.

03:01:47.280 | Jonathan Williams is an atmospheric chemist,

03:01:52.720 | but he's really good at using GCMS,

03:01:55.240 | these tools that measure molecules.

03:01:57.540 | So Jonathan Williams measured odorants in Germany,

03:02:02.420 | transmitted the information to us over IP.

03:02:05.160 | We fed that into our algorithmic framework

03:02:08.780 | and recreated it from a device that mixes primaries.

03:02:12.480 | And we tried to do four different odorants

03:02:16.360 | in our proof of concept test.

03:02:18.680 | One of them was rose,

03:02:22.460 | and we failed at recreating rose.

03:02:25.760 | We in fact recreated something that had a precip,

03:02:27.880 | but most people perceived it as bubblegum.

03:02:30.040 | The second one we tried to do was anise,

03:02:33.800 | and we failed at recreating anise.

03:02:36.480 | And most people said it was cherry,

03:02:38.820 | which is not very far, but it failed.

03:02:42.120 | The third was gasoline.

03:02:44.640 | And we were slightly but significantly better than chance

03:02:48.640 | at recreating gasoline.

03:02:50.220 | And the fourth was violets.

03:02:54.140 | And 15 of 16 people said violets.

03:02:57.560 | So the first odor ever transmitted over IP is violets,

03:03:01.020 | and we did that last month.

03:03:02.600 | Of course, this is not anything near a practical solution.

03:03:08.680 | The device that Jonathan was using to measure

03:03:14.160 | is a $1.5 million device bigger than this table.

03:03:18.840 | - That's right, I remember when VCRs,

03:03:20.400 | half the audience won't even know what that is.

03:03:22.240 | - The VCRs were like this big, so we're all good.

03:03:25.460 | I'm all good with the prediction

03:03:27.860 | that things will come down in size and cost.

03:03:30.080 | - Yeah, I was just saying,

03:03:31.660 | don't hold your breath for this to be

03:03:33.680 | on your table tomorrow.

03:03:35.740 | And again, all we have in hand

03:03:39.960 | is this very initial proof of concept.

03:03:42.060 | It's not even yet close to being a paper we are submitting

03:03:46.260 | because there's still lots of work to be done.

03:03:48.500 | But we're on the path.

03:03:51.740 | We're on the path, and Google will probably beat us to it.

03:03:56.300 | They got a lot more--

03:03:57.140 | - I don't know, you seem pretty dogged in there.

03:03:58.940 | - Yeah, but they have so much more resources

03:04:01.820 | that at this stage, and they've already published

03:04:06.820 | two papers from that effort that are good.

03:04:10.060 | Yeah, you know--

03:04:12.740 | - They definitely have a lot of dollars

03:04:14.000 | and a lot of people, a lot of good neuroscience

03:04:16.980 | and other biology, engineering,

03:04:19.320 | graduate students, and postdocs go there.

03:04:20.840 | But the real question is, are they getting the best people?

03:04:24.200 | Because as you and I both know in science,

03:04:26.700 | oftentimes it's small groups of the very best

03:04:30.020 | and most creative people that can outrun

03:04:33.380 | and outgun large groups.

03:04:34.940 | And here I don't have anything against Google, by the way.

03:04:37.920 | I use it all the time.

03:04:39.540 | - I'm not a betting man,

03:04:41.100 | but I would put my money on Google on this race.

03:04:44.860 | But I'll try and give them a run for their money.

03:04:48.220 | - There you go.

03:04:49.060 | - So since like most of us want to see the problem solved,

03:04:51.300 | regardless of who gets there first,

03:04:53.320 | what I'll say is you better get going, Google,

03:04:54.800 | 'cause Noam's being, he's humble and he's dogged,

03:04:57.560 | so better get cracking.

03:05:00.400 | There, we just cost the weekends

03:05:01.980 | and broke up the relationships of a bunch of scientists.

03:05:05.040 | I remember when I was a graduate student at Berkeley,

03:05:06.680 | I remember hearing there was a guy in our common friend,

03:05:09.880 | Irving Zucker's lab that worked 100 hours a week.

03:05:12.560 | So I was like, oh, I'll work 102 hours a week,

03:05:14.680 | which was not a good choice.

03:05:16.400 | In any case, it's abundantly clear

03:05:19.820 | that you're making progress here.

03:05:21.380 | And I go to some of the earlier discussions we had,

03:05:24.380 | and I think we're not just talking about

03:05:26.060 | transferring recipes and smells of food,

03:05:29.980 | gasoline from the people watching the F1 race or something,

03:05:33.580 | but I'm thinking dating apps, I'm thinking you,

03:05:38.060 | nowadays everyone knows that when you travel

03:05:39.740 | and you want to see your family, your grandkids or kids,

03:05:43.060 | it's better to get on FaceTime and see them or Zoom

03:05:46.480 | than to just hear their voice.

03:05:47.960 | We're all talking about being able to smell them.

03:05:49.760 | - I'll tell you more than that.

03:05:50.720 | I'll tell you more than that.

03:05:51.640 | I mean, we're talking now of trying to achieve

03:05:56.640 | the olfactory equivalent of circa 1956 black and white TV,

03:06:01.960 | okay, basically, right?

03:06:03.760 | I mean, I'm not dreaming, let's say,

03:06:05.960 | of being able to transmit to you the difference

03:06:07.880 | between a Cabernet or a Merlot, right?

03:06:09.920 | But if I can generate something that's vaguely wine,

03:06:12.920 | that will be an amazing success from my perspective, right?

03:06:16.180 | But jump ahead in your imagination to 4K odor transmission,

03:06:21.180 | then medical diagnostics is what you want to be talking about

03:06:26.220 | because this is over extension,

03:06:31.220 | but you can almost say that every disease will have an odor.

03:06:36.740 | I mean, every disease is a specific metabolic process.

03:06:40.000 | Metabolic process have metabolites,

03:06:41.780 | metabolites have a smell.

03:06:43.100 | Olfaction, once it's digitized and high resolution,

03:06:49.780 | which again, in our hands, it's not gonna be,

03:06:52.600 | I mean, we're talking, you know, in my retirement,

03:06:54.920 | maybe I'll read about this one day if I'll still have vision.

03:06:57.480 | I mean, this is not close,

03:07:00.200 | but when olfaction digitization is brought

03:07:04.860 | to the equivalent of 4K of vision and audition

03:07:08.680 | you have now, then it will be in medical diagnosis.

03:07:12.020 | You'll have, excuse me for the imagery,

03:07:16.060 | but you will have an electronic nose in your bathroom,

03:07:19.600 | each one of us will have in the toilet,

03:07:21.760 | and it will be doing diagnostics all the time.

03:07:24.980 | And that's where it's gonna go.

03:07:27.880 | But again, not anywhere in the very close future.

03:07:32.880 | - Well, it's certainly an exciting proposition,

03:07:37.180 | and I'm delighted that you and other groups

03:07:39.860 | who are so strong are working on it.

03:07:41.520 | I really am.

03:07:42.540 | Noam, I wanna say thank you for your time today.

03:07:47.600 | First of all, this was a tremendously

03:07:51.200 | interesting conversation.

03:07:52.560 | I mean, we touched on so many things, hormones, smells,

03:07:55.120 | the architecture of the olfactory system.

03:07:57.360 | I know that people listening to this are realizing,

03:07:59.860 | but I'm gonna say it anyway,

03:08:01.280 | what an incredible gift you've given us

03:08:04.560 | as a expert in this field,

03:08:07.580 | giving us this tour of the work that you and others

03:08:11.980 | who you credit so generously have done

03:08:15.260 | to elucidate this incredible system

03:08:17.320 | that we call olfaction and chemosensation.

03:08:20.260 | Also, just for the incredibly pioneering work

03:08:22.700 | that you've done.

03:08:23.540 | You know, I don't have many heroes in science.

03:08:26.780 | I have heroes outside of science and a few in science,

03:08:28.880 | but I'm gonna purposely embarrass myself a little bit

03:08:32.620 | by saying that from the time I was at Berkeley

03:08:35.680 | and I then saw that experiment being done

03:08:38.540 | of people foraging falling scent trails.

03:08:41.620 | And then until I was a junior professor,

03:08:44.760 | I used that in my teaching slides in a class that I taught

03:08:48.800 | that was sort of the early origins of this podcast

03:08:50.800 | in many ways.

03:08:51.640 | And over and over again,

03:08:54.000 | when your laboratory publishes papers,

03:08:56.320 | I find like this is super interesting, super cool.

03:08:58.640 | And I find myself telling everybody about it.

03:09:00.400 | And that's really what I do for a living is I learn

03:09:03.280 | and then I blab about it to the world.

03:09:05.320 | So thank you so much for the work that you've done

03:09:07.800 | and the spirit that you bring to it.

03:09:09.000 | Whatever drives that spirit,

03:09:10.400 | as the great late Ben Barres used to say, keep going,

03:09:13.760 | because we are all benefiting tremendously.

03:09:16.240 | And I also just wanna say that, you know,

03:09:20.080 | for people listening to this,

03:09:21.640 | that the spirit of science is one of, as you mentioned,

03:09:25.520 | there's complex politics and all these things,

03:09:27.500 | but it's absolutely clear that you delight in the work

03:09:30.660 | you do.

03:09:31.500 | And so I delight in it.

03:09:33.100 | I'm grateful for it.

03:09:34.100 | I'm grateful for your time today.

03:09:35.500 | And so on behalf of me and many,

03:09:37.820 | many people listening to this,

03:09:38.880 | I just wanna extend a huge debt of gratitude.

03:09:41.340 | Thank you so much.

03:09:43.100 | - So I'm blushing.

03:09:46.580 | I don't know if this doesn't come across

03:09:48.020 | on the radio podcast,

03:09:49.740 | but thank you so much for very warm words.

03:09:52.820 | I mean, you know, as you know,

03:09:55.900 | when you work in your lab,

03:09:58.940 | you don't, there's these moments

03:10:01.860 | where you suddenly discover that somebody is like,

03:10:05.180 | cares a bit about it.

03:10:06.340 | And those are always very rewarding moments

03:10:08.700 | because usually you function without that.

03:10:11.420 | I mean, I guess that's one of the things you need

03:10:13.860 | to be a scientist is to have the, you know,

03:10:17.020 | the drive to work without that because it comes only rarely.

03:10:21.860 | - There's immense gratitude and appreciation for you

03:10:24.020 | and what you do from me.

03:10:25.380 | And now I know from a large segment of the world as well.

03:10:29.340 | So my only request is that you come back

03:10:31.660 | and tell us about the next results.

03:10:33.540 | Sometime not too long from now.

03:10:35.620 | - Yeah, well, I'm gonna catch you live now,

03:10:37.940 | although you have the power to edit this.

03:10:39.900 | I guess that's not fair.

03:10:41.260 | But first you come visit us in Israel

03:10:44.100 | and tell us both about the science

03:10:46.780 | and the public science work you're doing.

03:10:48.300 | And then I'll come again.

03:10:49.580 | - Good bargain and I accept, delighted.

03:10:53.460 | Thank you so much.

03:10:54.380 | - Yeah, pleasure.

03:10:55.460 | - Thank you for joining me for today's discussion

03:10:57.260 | about olfaction and chemosensation with Dr. Noam Sobel.

03:11:01.140 | If you'd like to learn more about the work

03:11:02.400 | in the Sobel Laboratory or read some of the papers described

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03:13:01.020 | Once again, I'd like to thank you for joining me

03:13:02.560 | for today's discussion about olfaction and chemosensation

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Dr. Noam Sobel: How Smells Influence Our Hormones, Health & Behavior | Huberman Lab Podcast

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