Welcome to the huberman live podcast where we discuss science and science based tools for everyday life. I'm Andrew huberman and I'm a professor of neurobiology and Ophthalmology at Stanford school of medicine. Today, my guest is dr. David Linden, dr. David Linden as a professor of neuroscience at Johns Hopkins school of medicine. His laboratory has studied neuroplasticity. That is how Connections in the Brain Change in response to experience much of that work focused on.
A structure called the cerebellum, which is also sometimes referred to as the mini brain, because it looks like a mini brain in the bottom and back of the human brain. And it's responsible for an enormous number of basic functions that we use in everyday
life, including
our motor behavior. That is our ability to walk and talk. But also dance play instruments and it's responsible for an enormous number of basic functions that we use in everyday life, including our sense of balance. Our ability to learn new motor behaviors as well as our sense of timing.
We will discuss the cerebellum in what it does. But dr. David Linton will also teach us about the important sense of touch as well as what makes us different as individuals. The reason today's discussion and Compass has so many important topics. Is that dr. David Linden's laboratory has focused on many of those topics and he is also the author of five. Excellent popular books about Neuroscience that focus on, for instance, our sense of pleasure, and where it originates from and what controls it in the brain, as well as our sense of touch.
Much. And today we start off our discussion by talking about the recent discovery of a set of neurons that have been known about for a long period of time. But that only recently have been characterized that are involved in sensual touch in particular and it's a fascinating conversation. I assure you in addition to that dr. David Linden informs us about what makes us individuals, how each, and every one of us, perceives the same things differently. And it's an absolutely fascinating conversation, which tells you for instance, why some of you think a
Is putrid, indeed smells like vomit. Whereas others perhaps are not bothered by that smell and why others still are attracted to that smell or something that you look at or something that you hear. We also talked about nature versus nurture and how we come to be who we are, not just through our genes and epigenetics. But also through our early childhood experience and adult experience, and then in the latter, third of our conversation, we shift to talking about the so-called Mind Body Connection and the
the science, underlying how our thoughts inform our bodily health or lack thereof as well as how the organs of our body control, the chemicals hormones and thoughts within our brain. Then we shifted discussing dr. David Linden himself and the fact that in 2020, he was diagnosed with a form of heart cancer that led his Physicians to tell him that he had six to 12 months to live now obviously, because he was in our studio to record this conversation, he has outlived that
Sis. But he lives day-to-day with the knowledge that his death may very well come soon. Although it isn't clear exactly. When that day will come of course he tells us how the initial prognosis of his cancer as well as outliving that prognosis has informed his day-to-day life, as well as his thinking and his relationships and that leads to a very direct and frankly, emotional conversation that includes advice on how all of us can get the most out of our daily living. And
Out of our overall life. It's an extremely powerful conversation that I believe everyone regardless of age or health status can benefit from and it's one that makes clear. That not only is dr. David Linden a spectacular scientist but also a spectacular educator, a spectacular, popular writer a spectacular Family Man. Including husband and father and friend to many people and his colleagues. But he is also a courageous and spectacularly, generous human being before we begin.
I'd like to emphasize that this podcast is separate from my teaching and research rules at Stanford. It is however, part of my desire and effort to bring zero cost to Consumer information about science and science related tools to the general public in keeping with that theme. I'd like to thank the sponsors of today's podcast. Our first sponsor is rokka rokka makes eyeglasses and sunglasses that are of the absolute highest quality. The company was founded by two All-American, swimmers from Stanford and everything about Roca eyeglasses and sunglasses were designed with performance in mind.
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Free month for carrying out this survey, you can find the link to the survey in the show, notes for this podcast episode and on our website huberman lab.com. So if you would be so kind as to take a few minutes to fill out the survey and help us continue with bringing you the best possible content here at The huberman Lab podcast. And as always, thank you for your interest in science and now for my discussion with dr. David Linden Professor Linden welcome. Thanks so much for having me. I'm looking forward to our conversation, and we have a lot to
Talk about we do lots of different aspects of science, lots of different aspects of personal journey and what you're confronting. Now as it relates to your health and your future. I want to start off with a question that I learned from the one. And only the great Karl deisseroth, who was the first guest on this podcast, my colleague at Stanford. And for those of you that don't recognize Carl's name, he is a absolute Phenom. He's a
Say active clinical psychiatrist. So he's an MD and he also is a bioengineer who's developed a lot of the modern tools for probing the brain. And any time I've met with Carl, the first thing he says, is what do you most excited about lately? That's a good question. It is. So I'm going to steal that approach and say, what do you most excited about lately? Well, very, very lately. The most interesting thing that
Run in Neuroscience, is the answer to a scientific problem that I think is really dear to a lot of people's hearts and that is what are the nerve endings in the genitals that are responsible for sexual sensation. And you know, if you think about it, right, people can feel sexy from being touched on lots of different parts of the body but there's something special about the jungle.
Miles, doesn't matter. Male or female or intersex, or gay, or straight, or bi, or whatever you are. You know, the genitals are a hotspot, and why? And you'd think, as biologists, we know this by now, this would be something we could just answer, but but it's been a mystery for a long time. And if you go back to to 1860, there was a German neuroanatomist name Krause, and he cut thin sections of tissue from the penis.
The clitoris and he looked at them under the microscope and he saw a particular kind of nerve ending there that has since been called the Krause corpuscle. And there were lots of them in these two places. And so he thought, well maybe this is the cellular basis of sexual sensation. Maybe these are the particular nerve endings that are responsible for this but
There were some things that that were in favor of that and some not. So these nerve endings are also in some other places that people can find more or less sexy like they're in the nipples and they're on the lips and they're in the anus, all places that get popular in in that domain but they're also in places like the cornea or the lining of the joints. So distribution doesn't quite make sense and so it
Never known. And so if you wanted to really test as a scientist, whether these nerve endings are responsible, you want to record their electrical signals, while the genitals are being touched, you'd want to inactivate these cells and see if you could interfere with SNAP with sexual sensation and this in a preprint from David guilty is group at. Harvard is just what they have been able to do in mice. They found a way to label and record from
and activate and inactivate artificially the Krause corpuscles. And so you see a nerve endings in the skin, it could be conveying all kinds of information. It could be tuned for hot or cold or for rich or for pain or Fuller in or for inflammation or for mechanical sensation, stretching vibration indentation and sure enough. When they recorded from these Krause corpuscles they really are.
Chemical sensors as you would expect if they were involved in sexual sensation. So that was good. And then the other thing that they did is they try to artificially, turn them on. And so the way they did that is they use genetic tricks to express one of Carl. Dicers Oaths, a molecule that activates neurons when they're when blue light is Shone on them and they found that if they express this, artificial protein.
Seen in the crowd cells in a, in a male Mouse and then shine, blue light, the mouse gets an erection. Alright. So far so good. What happens if you turn them off? Well, it should turn them off in a male Mouse. It's just as interested in females when they're in heat, but it won't mount and thrust, and ejaculate as much. And if you turn them off in a female Mouse, during the time of her cycle, where she would normally be sexually receptive,
If you find that she is much less interested. She's much less likely to let him Mount. She is much less likely to let him finish. So this is the remarkable results that finally, after all these years since 1860 now we know what the nerve endings are that convey sexual sensation and like all good science. Then you know there are a lot of questions.
That are really interesting to our everyday lives. Like, you know, people like different things in bed and have different propensity for orgasm or, or like like to be touched in different ways. Well, is part of that reason because of individual variation in their Krauss corpuscle structure. We know that sexual sensation diminishes with aging is that in part, because Krause corpuscle density is lost
From the skin of the genitals and that's a reasonable idea because we know for example, that fine touch sensors in the fingertips so called Merkel and meissner endings also named after German anatomist, like so many things are, are also lost with age. So that's a reasonable idea. So so this finding from grantees Lab is opened up a whole world of science and I've been my, let my own lab doesn't work on touch, but I've been a fan boy of touch for
For, for many many years mostly because where I work at Johns Hopkins, Medical School. There have been many terrific touch researchers. It's been a world center for it and I hear about it over lunch and I got all fired up. So years ago, I wrote a book about it, I still follow the field and this is the most interesting thing in that field recently. And as I recall ginty was your neighbor at Hopkins, before he moved to Harvard. That's right. That's right. He was one of the ones ginty Stephen Chow Michael.
To Reno Shin Jang, dong there have been a number of world leaders among in the cellular basis of touch sensation at Hopkins. Do you recall if in the preprint that you were describing there was an experiment where they activated these Krause corpuscles in females. It's funny, you should mention that I sent that exact email to David guilty and they said they are in the process of doing that right now and they don't quite know yet. And so I asked
Him. I said, so, for example, is erection of the clitoris, even a thing in mice. He said, well, we're really not sure. So, we're activating the crowd score, puzzles and female mice, and we're just kind of staring at it and looking and see if anything happens just there, you know, does the, you know, does the the body change shape? Is there a color change? They don't even quite know what it is they're looking for because it's that much on the Leading Edge of things but it's a good question or perhaps the female mice would be more willing to mate.
Outside of the usual time frame of receptivity, if these Krause corpuscles are stimulated, that's possible. My suggestion, my guess would be not because I think that the hormonal regulation of receptivity is like a sledgehammer and very hard to overcome but they might be more willing to continue mating or make for a longer during their fertile time. And I just want to remind people because we had a guest
recently dr. Veena Malik who's a urologist reproductive and sexual health expert. She's an MD and she made clear that the the clitoris and the penis come from the same embryonic origin. They are analogous tissues. In different individuals. I do have one more question about this sexual touch thing.
These are peripheral nerves, right? So, these are not of the brain and spinal cord. They are in what we call the periphery. And my understanding is that peripheral neurons regenerate and can remodel themselves extensively in ways that neurons within the brain and spinal cord, tend to remodel less, especially as one gets older out of the so-called critical period. Is it possible that these cross Corpus schools and their patterns of innovation?
The genitals change according to the stimulation that people experience. In other words is sexual sensation, experience dependent. That is a great question. And so we don't know because monitoring this in people is not technically possible, Right? It requires cadaver tissue so you can only do it once in animals. It
It will be possible and it could be for a couple of different reasons. And other words, it could be. I think what you're imagining is that there's actual structural plasticity. If you looked at these crowds corpuscles or that you would actually see them changing their shape, or their size, or their, or their density as a result of experience. But what can also happen is phenomenal, like desensitization that is to say when they're stimulation for
A long time, then the receptors transiently can become less sensitive to touch, and it's well known for particularly in males, that that chronic masturbation can produce desensitization of sexual sensation in the penis. And that could be as a result of a physical change, a morphological change in the crowds corpuscles, but it's more likely to
to be a change in their function that you wouldn't be able to Simply see by looking at an outline of their structure in the microscope. Such an interesting topic, Thanks for opening, things up with with that. And I'll have to check out this preprint. I'm also a huge fan of David guarantees work. And and colleagues, there are many people involved in that domain of work. Of course, I'd like to talk about your recent book and the sort of underlying basis of what.
LED you to write it? And what intrigued you about this idea of human individuality the book unique is one that will provide a link to in the show. No captions. And it's a very interesting idea that we are all different especially coming from a neuroscientist who were trained at least similarly, it to learn that sure. The bumps and ripples of the brain and the fine wiring of the brain is different and we are all unique and different, we have different shapes.
Take a morphologies. But focusing on human individuality is not something that modern Neuroscience or classic Neuroscience has really done much of its really focused on how people do X or people do. Why this way tell us about unique and tell us about human individuality. Yeah, well, I mean, you're absolutely right. So, when I look at the experiments, my own lab, how do we do them? Well, we work on mice. Do we work on mice with genetic variation?
We work on highly inbred mice that are designed to be as genetically similar to each other as possible. And then we raise them basically in prism in little little cells, which may not be a good idea and we try to give them as similar experience as possible. They are given toys and food and water but I agree. It resembles a prison of sorts. They aren't free to roam. They're not. They have nothing like the experience of a wild mouse. Let me put it that way there.
And and yes, there are as you said correctly. There are plenty of experiments where there is enrichments, from mice, and they loved it. So, for example, in our lab, when we put running wheels in, the cages are mice and let them run overnight, they're active at night. Your average Mouse will run two kilometers in a night for a little tiny Mouse. And some of the mice are so intense, they will run 20 kilometers. Imagine
A mouse doing 20K but it will happen. They really, really like it. They don't like being in prison. They want to exercise and the really bored. So yes to get back to your general point. So much of science is designed to try to find general principles of a function of the brain of physiology of genetics and to ignore individual variation.
Individual variation is so important to our human experience. And actually is so important to to the process of evolution and natural selection and how how species make their way in the world. That that it's, it's something that that requires a lot of attention. And to me, what's really fascinating is that when you look at the variation in the way
A sense organs function. It's almost a miracle that we can agree on a common reality at all even within the human species. And this is true of more of some senses. More than others. Obviously, in your world in the retina, we have various kinds of loss of color vision that are well-known and some other more complicated phenomena having to do with.
Months in the perception of motion or form, but the place where this really happens is in the olfactory system. So we have approximately 400 functional receptors for different odorant molecules smells in our nose and if you sequence the genomes of many people you find that the
That the, the DNA that encodes, for these odorant receptors is unusually variable from Individual to individual. As a matter of fact, if you take two different people on average, they will have functional differences in 30% of their odor receptors. And if you do as Leslie vas, all and her colleagues did at Rockefeller University.
Give odor tests where they give people different things to smell and then they dilute them and find the threshold which they can detect them. You find enormous changes from People to People both in term in general terms, some people are just better smeller's than others. But in terms of individual odors as well there's some odors that some people can't detect and other people smell one way. For example, there is a there's a secrete a hormone called Andres.
Steen own androstenone there some people who can't smell it at all, for some people, it smells like rather Pleasant, like cut grass. And for some people, it smells foul like your owners sweat and it just depends on genetic variation in one particular odorant receptor sorry to interrupt another phenomenal researcher who studies olfaction among other things? Catherine, duloc.
Um, I once heard say that some people have a gene that for them makes the smell of microwave popcorn, they experience that smell as vomit. And other people who lack this Gene like the smell of microwave popcorn or at least for them, it's not aversive so it can really be a binary response. Well, it can actually that's a very particular funny case. So the remedy
relevant chemical there is butyric acid and also I swivel Eric acid and so there are researchers, I think Rachel Hertz is one of them who have given a mixture of these two chemicals to people. And they say this is parmesan cheese, they go yeah that's parmesan cheese and if they give it to other people and say this is vomit. They'll go. Oh yeah, that's vomit. And if they tell people, they give them one vial and say this is parmesan cheese in them.
I'll get another one. It says vomiting. Oh, yeah. And then they say, well, actually we fooled, you was the same vial. This it. No you didn't. You must have made a mistake. There are convinced that they couldn't have been the same thing. So this points out, not only is their genetic variation. That is responsible for around individuals, perceive odor. But we are incredibly suggestible in terms of odors and we, we are
very dependent upon them in terms of cultural context. And this can be this can be learned and and this is Central to our Humanity in the sense that, that we humans are what I like to call the anti pandas pandas live in one spot in in southern China and they eat one thing bamboo and that's it, humans are the opposite. Humans can live in any
Whole niche in the world from the tropics to the polls and humans, eat a wide wide wide variety of foods. And as a result it means that we have to have a very plastic olfactory system that have to be very few things that we find in Nate Lee. Reverse of their only, a handful of odors rotting meat. Odors molecules with the evocative names like cadaverine and putrescine are things that even babies
When their newborn find aversive but other things happen that they need to be learned. For example, pretty much. Every adult finds poop odors unpleasant but babies happily happily play with their own poop. They have to learn that that's disgusting. It's not because babies have a different nose, it's because they have to learn cultural not innate. It is not innate. They're only a few innate odor. Aversion
And a few innate Taste of versions that were were born with, and the other things are elaborated, culturally and we can think about this in terms of how we talk about, odors. So for example, we might say, vanilla smells sweet.
Well that's weird. That's like those are two different senses. How can something smells sweet? That's like saying it sounds read right? It's a statement about synesthesia, right? And but but how did it come to pass and do people say that vanilla smells sweet everywhere in the world? Well, the answer is no. So in places in the world, where vanilla is used with sugar in in sweet foods like desserts. Then people say that a vanilla smell sweet or mint. Similarly,
Ah smells sweet if it is typically used together with sugar. But if you go to a place like like Vietnam, where mint is mostly used in Savory dishes, people won't say that mint, smells sweet. So there's a parrot Association there that at least at our level of conscious understanding feeds back on to what we call.
Olfactory or smell perception. But really, it's a must be a parent Association at some point in development. Yeah, it is, it absolutely is a dissociation and it's something that goes on continually through your life, right? I mean, lots of people, for example, have stories of foods that they wouldn't eat as a child but they came to like as an adult's. A good example of that is coffee. A lot of people have to overcome bitter or version.
To, to become coffee aficionados. So, you know, this, this feeds into the more, the more General theme that
There is no, pure perception, perception is inference. It's not like there is a purely objective world that can somehow make its way through the senses and we can perceive that as the truth, all of our perception. Through all of our senses, both the outward pointing senses of the world like smell and taste and sight and hearing and the inward pointing senses like,
And is my stomach full and things like that. All of them are based on experience and expectation and the situation of the moment, as many of, you know, I've been taking a G1 daily since 2012. So I'm delighted that they're sponsoring the podcast. A G1 is a vitamin mineral probiotic drink. That's designed to me all of your foundational nutrition needs now. Of course, I try to get enough servings of vitamins and minerals through whole food sources that include vegetables and fruits.
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Special offer they'll give you five free travel packs. Plus a year supply of vitamin D3 K to again that's drink. AG one.com. Hubermann are there any examples of uniqueness of visual perception that come to mind? I recently did a social media post that involve. It was essentially three rings. A blue ring a red ring and a blue ring in the center or perhaps it was the other way around. Excuse me. It was
Red blue red and I asked which ring is in front or they all at the in the same plane. Now, of course, it's a two-dimensional image and interestingly it splits out into about thirds, some people see the blue ring in front quite a bit other. See a red ring out in front other, see them all in the same plane and this we think has to do with differences. In two things between individuals, one is the distribution.
You know, the cone photoreceptors which we know is essentially random between individuals, maybe even between the two eyes and then, and that gives rise to this phenomenon of chromatic aberration, which is the displacement of the visual image, according to the wavelength of the light and we won't get into the physics of it. Now I'll soon do a post that hopefully distills it in a manner. That simple enough, that people understand. But clearly some people see certain colors in front of others and the person, right?
Next to them could see the opposite color in front and others. Say what are you talking about all the colors are exactly the same plane of vision. So that's the one that I know I'm guessing, you know, some others and perhaps some more robust ones. Well I think, you know, perhaps this is maybe not what you had in mind. But one way in which experience modifies the visual world has to do with, how much light you're exposed to
In the first five years or so of your life. And so kids that don't get outside are much more likely to be myopic and it actually is nutted nearsighted. Yes, when they grow up, then kids who got outside and we now know that at least part of the story is that light seems to stimulate the
section of a class of molecules called trophic factors that you're well-acquainted with that actually change the shape of the eyeball. So it's not really the structure of the retina, or the lens of the cornea. The actual degree of elongation of the eyeball changes changing the way the the retinas, it's relative to the limbs and that seems to be light dependent early in life and which gives rise to two.
Higher incidence of myopia. And and to me this is really well. First of all, it's news, you can use, you should get your kids outside for absolute. All kinds of reasons you should get outside to especially in the morning set that circadian rhythm guy. I know that's a famous huberman esca point. They're gonna be putting me in the grave David and I'm going to be telling people to or it'll maybe I'll be on my Tombstone, say get get sunlight in your eyes. You got his specially on, especially on cloudy days because there is still
No sunlight, even if you can't see the physical object of the sun on cloudy days. Well, you know, I think this whole idea of having traits that are dependent upon early, life experience is fascinating because there are a number of situations where you would guess that something is genetic. But it isn't. It's actually dependent on early life experience and there's a there's an amazing story about this.
In to do, with the early days of World War Two. So in the early days of World, War 2, the Japanese Army, just swept through Asia. They defeated the, the British and Malaysia and Singapore. They overrun Thailand and Burma and they were knocking on the gates of India and everything was going great except the Japanese Army had a problem. There were an enormous number of their soldiers who became incapacitated with heatstroke. They got their core.
Sure, got too hot and when the Army doctors examine them, they found this was much more likely to happen in soldiers, who came from the northern part of Japan Hokkaido. Where it's where it snows in the winter as opposed to the southern part of Japan. Like you shoot, which is a semi tropical environment and the classical explanation. The biologists like us would guess would say. Oh, all right, well, this is
And genetically over many years, you have a family that's been in Kyushu for many generations. And you've selected for Gene variants that allow you to tolerate the heat better and we know actually what this is. So if you're more heat tolerant, it's because you have more of a particular class of sweat gland called the eccrine. Sweat glands, the sort of saltwater, sweat glands, not the Le Petit stinky armpits sweat, glands called the African ones, the Akron ones, you have a higher
Fraction of them that are innervated, meaning that the signals from your brain. That's a your core is too hot. Can then make you sweat. So the total density of sweat glands between northern and southern soldiers in Japan wasn't different, but the southern soldiers tend to have a higher degree of innovation. All right, so so okay well this happened genetically over many generations but if you look at those rare cases where you have soldiers from a long-established northern family and their parents moved,
And they grew up in the southern location. They had high sweat gland innervation. They were wealthy tolerant conversely. If you had a well-established, Southern Kyushu family and they moved to Hokkaido and then have their child that child developed the northern sweat gland, innervation pattern. So meaning less nerve, innervation of those sweat glands. As you mentioned before, just as many sweat glands, just less nerve innervation there for those sweat glands could not be activated.
Ooh, they couldn't dump heat as well. Their heat tolerance was lower, you're exactly right. And and what's what's wonderful is that this gives an advantage that you can't get through Evolution and that it can happen right away and this in one generation right evolutionary change is slow, right? And you can adapt as a species and as a family over over many, many, many generations. But when you have a phenomenon,
That is set by early life experience. Well, then you can benefit from that early life experience within your own life. It's not that your great-great great-great-great. Grandchildren will ultimately benefit. You benefit another wonderful example of this comes from field, mice voles, and we were talking earlier about how we both worked with the scientist nerves, Booker out at Berkeley. Who is a specialist in
In in voles and what people found is that if you take wild-caught field mice, and you have pregnant mothers and you have them in the lab, but you manipulate the lights so that you have artificial spring. In other words, day length is getting longer day after day during the pregnancy then what happens is when their pups were born.
It will have a low density of fur anticipating summer temperatures.
If you however put them in artificial fall, where day length is getting shorter, they will be born. Now, with high density of for anticipating winter temperatures and of course you can do this no matter what the season actually is in the world by manipulating these lights in the lab. And so, like the sweating Japanese soldiers, this is a great example of early life plasticity. And
Sort of trait that if you ask someone, they would probably guess is heritable. But actually is not thanks for mentioning our visitor, who has you also mentioned was an adviser to us both who's done, incredible work in circadian, biology seasonal, rhythms hormones, and behavior. I have such reverence for Irv. And the experiment you mentioned made me smile wide because it's but one of gosh, maybe hundreds of incredible study so if people are interested in seasonal rhythms and circadian
Ian rhythms, and biology of the most interesting kind. Definitely, check out Irving's occurs work at Berkeley. I'll provide a link to his PubMed there. Since we've been taking a tour of individual variation in olfactory perception, visual perception and now heat tolerance. I have to ask, are you aware of any examples off the top of your head in the auditory domain that particularly intrigued you?
Yeah, well, I would say one really interesting example, has to do with perfect pitch. So, Perfect Pitch as a trait that is to say, you have the ability to, to hear, a note played and say, oh, that's a c-sharp, right? This is a pretty rare trait. So even if you look among highly trained, musicians, if you went to Peabody conservatory, at my University, Johns, Hopkins, and tested people. There, you would find a higher incidence
So Perfect Pitch, then you would in the general population but still maybe one in ten trained musicians have perfect pitch and parenthetically having Perfect Pitch. Doesn't necessarily make you a better musician, but it's an interesting phenomena. And so the question is well, is perfect pitch heritable? And the answer is when you look at twin studies where which is what we use to estimate heritability, the answer is its kind of low.
If there's a heritable component, but it accounts for my recollection is on the, on the order of 30, 40 percent of the variability in Perfect Pitch. However, if people receive ear training, starting at a young age, the chance that they will develop Perfect Pitch, can improve drastically in your book unique. Do you cover aspects of human individuality? That extend beyond the
Cept action domain into the cognitive domain. Well, yeah, absolutely. And you know, I think I think it's good to set the stage here. If we're going to be talking about heritability and human individuality and and so if I can go off on a little bit of a riff for the benefit of your of your listeners and viewers here, he's so if you look at human traits whether they are behavioral traits like shyness.
Or very straightforward. Morphological traits like height. What you tend to find is that there are very few traits that are entirely heritable where all their variability can be predicted based on the gene variants you get from your mother and father and there are a few traits that are absolutely unhearable but that most fall in between. So let me give an example. Everyone in the world has either wet
Dry earwax and it turns out that this is determined by variation. In the single Gene, the name of the gene is boring. It's a b c, C11. It's a ion transporter and there is a variation in this Gene gives rise to either wet or dry earwax. It doesn't matter how your parents raised you, it doesn't matter what foods. You ate, growing up, doesn't matter what? What diseases your mother had when you were in the womb,
Umm, it's 100% heritable. Well, does this mean that a b c? C11 we should call it the earwax type Gene? Well, no, because it's not there just for that like this. This Gene is expressed in cells and all parts of the body, doing all kinds of things earwax is just something that we notice genes don't code for traits, they code for proteins and so we have to be careful about how we refer to them in that way.
For example, the wet earwax G of variant of the abcc. 11 Jean also, confers a slightly higher risk for breast cancer. So clearly it's not just for earwax it's for a bunch of things. Most of which we don't yet know about, but in the case of earwax, this trade is 100% heritable. At the other end of the scale speech accent is 0%, terrible. It is entirely
Be dependent upon the speech that you experience in your childhood. And interestingly it's the speech of your peers more than the speech of your family, which is why the children of immigrants sound like the place where they wound up, not like their parents and there is no evidence for any degree of heritability. Now, just to be clear, I'm talking about speech accent, like whether you have a high or a low voice or it's nasal or more or less resident, these are physical things having to do with the vocal,
Back then they are in part heritable. Okay, so we've got one thing, that's 100% heritable. One thing is 0% heritable, but where do most Things Fall? Most Things fall in the middle? One of the most heritable traits that we know about in humans, is height and in the United States. Height is about 85% heritable, 85 percent of the variation, in the trait of height can be explained by what
You inherit from your mother and your father. Well, what's the rest? Well it's nutrition. It's the diseases you fought off. It's also random variation which we'll talk about a lot later. Now you might say OK. Well that's an estimate for people. In the u.s. is this true all over the world? Will know if you go to a place where people routinely don't get enough nutrition and are routinely
Fighting off infectious diseases. Like, this is been studied in rural Bolivia, for example, a rural India, now height is no longer 85% heritable. It's only 50% terrible. Why? Because people in these situations where they don't get enough nourishment, where they're fighting off these diseases, can't live up to their genetic potential for height if you want.
To make things better for the people of the world. Then everyone needs to have basic things like the ability to learn and enough nutrition and and decent Medical Care and schools in order to fulfil their genetic potential for positive traits and height. I've used as an example because it is very uncontroversial.
We could apply the very same analysis to intelligence general intelligence. Now, there are people who argue about do things like IQ tests really measure anything real and there's been a lot of fighting in the scientific literature about this but I think intelligence tests aren't perfect and they are sometimes culture-bound, but they are actually quite predictive of of later success and much.
More so than say, sat tests or GRE tests or em cats or other standardized tests, and presumably those correlate in some way they do by do, but but the IQ tests are better. Actually there's any about the, the classic IQ test. I am talking about the modern variants of the classic IQ tests that are administered by trained psychologists and aren't just a paper form. And so they're not perfect and no.
It will be perfect, but they're pretty good. And so, then if you ask the question, well, what is the heritability for IQ test score? Well, the answer tends to be different depending upon the population. If you look again in in countries, like the us, or in Western Europe, that are fairly affluent, where people tend to have good access to to nutrition
And medical care and schooling and kids get to play on, they're not, and they're not traumatized by War. Then then IQ test score is heritable in the ballpark of 60-70 percent. But if you look at people who don't have those benefits who are poor and this can be in the United States as well. If you look at communities that that face too.
Termination and have consistently poor poor health care in schools then IQ is less heritable. Why for the very same reason that it is on height because people can't live up to their genetic potential. When they don't have the basic things that everybody needs. So presumably if two identical twins.
And I realize they aren't identical but you're familiar with twins, you have twin children. If two identical twins are raised separately, the correlation in their IQ is can only is it that only 65 think you said about 66 percent of their IQ can be predicted on the basis of their genetic makeup alone. I mean, it makes perfect sense to me as to why if one of those twins went to schools that
We're demanding of, you know, a lot of different topic matter and the other one went to schools where the instruction level was really deficient that one would perform far less well on an IQ test unless of course the IQ test is in tapping into school based. Knowledge is tapping into some other thermometer of so-called intelligence or IQ. Well you know the thing is that good schools correlate
With many other things, right? So the students that go to good schools aren't just benefiting from good schools. They tend to also have good medical care and safe or less traumatizing neighborhoods and they're more likely to have books parents with books in the home. And and and a whole number of things that are all beneficial. So when you try to do epidemiology on this, you have to be aware that things are very deeply interconnected but but you bring up a good point. So it turns out that the way we get these s
Months of heritability. There's two ways. One way is to compare, so-called identical or monozygotic twins, with so-called fraternal or dizygotic twins. So the identical twins will share, nearly 100 percents of their Gene variants and on average, fraternal twins share 50% of their of their Gene variants and generally speaking with
People do these studies in order to avoid confounds of sex. They'll compare same-sex fraternal twins. So boys, two boys and girls two girls. And when you put these incidents into a formula called Fisher's equation, then you can come up with an estimate of the heritability of the trade, but there is an assumption
Presence in that and it's called the equal environment. Assumption, you're saying, well to kids raised in the same family have the same environments. Well, that's not always true, right? That can be violated by a number of different situations, so it turns out that a more powerful, but much more difficult way to estimate heritability is by looking at twins.
Has reared apart either, identical twins or fraternal twins. Reared apart. And there was a landmark study called the Minnesota study of twins reared apart, which is abbreviated mystery. That is really the gold standard for assessing the heritability of many different human traits, both behavioral traits but also disease incidents but of course it's a small end because you know the population
Identical twins, reared apart that you can get into the lab isn't isn't that large? They had something. I don't remember the exact numbers, but they had something like 80, some identicals, and fifty some fraternal, 's in their, in their sample. But by doing this, they were able to come up with a lot of interesting estimates and so, for example, most personality traits, what the psychologists
Use the acronym ocean to mean, openness conscientiousness, empathy, agreeableness and neuroticism. I think I got that right spelled right. That these traits on average tend to be about 50% heritable and so, okay, stay right. Well, 50% of those personality traits is heritable. The rest is got to be like how you were raised. It's got to be in your family, and so everyone was shocked.
They actually did the analysis and found that family has almost nothing to do with it.
Ariel. And everyone. What? Are you kidding? It's got to and I think the important thing to realize is these traits. I just listed, you know, we call these personality traits but they are not the sum total of the way. You are in the world, parents can inculcate many things in their children, they can demonstrate trades. So people are much more likely to go into an occupation. If their parents did they can inculcate moral
Ideas and religious ideas. But in terms of these ocean personality traits, they have astonishingly little to do with it. So then this brings up the question. Well if 50 percent of the variation in these personality traits is not from your genetics and it's not from your family, where does it come from? And the answer seems to be is that it comes from
The random nature of the development of the body and the nervous system and this is, this is a point that I think many people don't understand. This is something that biologists know, but we've done a very poor job of communicating, to the general public. The genome, all your DNA, all 3 billion bases of DNA all 19,000.
Or so genes in human, don't make a blueprint for making your body and brain there. It's not all schematic diagram, that connects everything to everything, particularly in the nervous system where we have these hundreds of trillions of connections, rather, it's a rather vague recipe. So the genome doesn't say, oh okay, you glutamate using neuron in the brain region called the thalamus, you know, grow for 200 microns towards the top and then
And then and then cross the midline and then grow towards the ear for, you know, another distance. No, it says something like, hey, you bunch of glutamate neurons in the thalamus over here in this area about half of you, cross the midline. And so what does this mean in terms of individual variation, which means, well, for, for some individuals, 40% of their axons will cross the midline of the brain and for another individual 60% will even in identical twins.
And as you correctly, said, a moment ago. Identical twins aren't really identical either in their bodies or their temperament. So, if you take newborn identical twins and you give them a CT scan, just to measure the shape of their organs, they're not the same. You might have one twin whose spleen is 30% larger than than the other Twins or whose liver is 30% smaller than the other twins, even though they have the exact same DNA, and there were lying right next to each other. In the
And presumably have the same or very similar. Fetal environment. And the reason is the random or as we say, stochastic nature of neural development, a great way to study this is with nine-banded armadillo those. I know we're getting weird here but I love the armadillo because I've been told tell me I don't want to interrupt you too long but as far as I know the only
Animal in North America that carries leprosy. That is, that is true. And and there's a lot of twinning going on in Armadillos, right? Well what there is is actually quadding. So armadillos or the nine-banded armadillo in particular and they're different armadillos. I'm not really an armadillo specialist. I don't know if this holds for all of them but the nine-banded armadillo is born as identical quadruplets.
Awesome, awesome. So you can take these identical quadruplets newly-born armadillo. I do. You think you call them pups? I don't know what a baby armadillo is called. I'm sure there's some particular word for it and someone will tell us. I'm sure someone in the comments on YouTube. What is the name of a baby armadillo? I know like a ferret baby ferrets are kits. The moms are Jill's. The dads are bobs. I used to be obsessed with this kind of naming at, you know, it's a, it's a business of ferrets or what is like a gang of
Raccoons or whatever. It's so if you can tell us what the name is for the baby armadillos, as well as. What do you call a group of armadillos? You win? The pride associated with being right? That's right right. One of my favorites, nose on ostentation of peacocks amazing or a murder of crows who comes up with this guy. I know it's a raft of otters, I think it, I think that's correct. But so if you have for newborn identical 9
Unbounded armadillos. Then this is a great model system that biologists can use to study stochastic, differences and development and sure enough their brains are wired slightly differently. Their bodies are slightly different, if you test them behaviourally, even very very early in life, they have different propensities summer. Bolder will Explore More somewhere. Will tend to hide in the corner more and you know we know this from the lab you get a box of mice.
They're inbred from the breeder and you pluck them out and they're not behaviourally identical. Some might try to bite your hand, some will run away, some will stand stockstill. Where does this behavioral variation come from in mice? That are nearly genetically identical? Well, it comes from bunch of things. They don't always have exactly equal experience, but mostly it comes from the pseudo-random stochastic nature of development. I'd like to take a quick break and
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Again that's inside tracker.com huberman to get 20% off and is the pseudo, random stochastic nature of development. One of the maging, major scuse me driving forces for evolution because, you know, we hear about mutations and we always think we're people tend to think rather that mutations are bad. But of course, mutations provide the variation that can also subserve. Adaptive traits. I mean, if you're a fan of the X-Men, as I am huge, fan of the X-Men, the entire series, every single one, including the
In movies, you quickly, come to learn. That genetic mutation is at the heart of variation, which is at the heart of individuality, which is what we're talking about, right? And so, genetic variation is at the heart of individuality. But there is also, there are also these other things, right? That we've talked about, there's the effects of early life experience. And there is the stochastic nature and development. Because if you through the randomness of development happen to have like a
Early great liver. You're not going to pass that on to your children, right? That isn't in your germ line, you won't pass that traits along just brief insert here on germline. We had ODed rush off, e, on the podcast who studies epigenetic transmission and and an inheritance of of it's not lamarckian we have to point that out but inheritance of sort of acquired traits, it does happen at the germ line is the
That are present in the sperm and in the eggs, all the other cells of your body have genes, of course. But the best way to put this is simply going to the gym and getting fit does not make your children more fit because the germ line as far as we know, is not modified in a direct way. In other words, the DNA within sperm and eggs are not modified according to your behaviors in most but not all cases. That's right. And as you as you correctly said,
Said about oh Dad's work and other people's work. There is what's called transgenerational epigenetic inheritance, which means that you can have traits that are passed not from one generation to the next. But even two generations to the grandchildren that don't require modification of DNA, but to date that has been shown very convincingly in in a worms. And implants, the evidence in mammals is is really not there yet.
In my opinion and most of the claims for that and it's a very popular thing to say I epigenetically inherited my grandmother's our great-grandmother's. Trauma, the evidence that presence is is poor. Actually, a lot of it comes from epidemiology, most of which came from famines in the other colics region of Northern Sweden and they had very good medical
Kurds and they said, oh well, if your grandfather, went through the famine, then you're more likely to have this trait if you're male, or if your grandmother went through this, then if you're, if you're male, this train, your female have that trait. And I mean, there are two problems, one is that there's not a biological mechanism, but the other problem is that, the way these things were discovered, is by something called harking, or hypothesizing. After the Revolt results are known, they did very many
Statistical comparisons to try to find something significant and you know from your work in the lab that when you do many comparisons you're going to get some things that look significance, just occasionally random way through through luck and you have to apply a statistical, correction called a bonferroni correction. When you make many, particularly post hoc comparisons after the experiment comparisons to set the bar, much higher for accepting that
At data. And most of those studies they didn't apply that correction. And I remain unconvinced of transgenerational epigenetic inheritance in mammals. Now let's be clear.
Just because it hasn't been shown convincingly now doesn't mean that it won't be. There are some good people working very hard on this and they may well describe a mechanism and show this convincingly in the years to come. But right now, you may well inherit your grandma's or great grandma's trauma, but you're probably doing it socially not through marks on your DNA. That changes. How your
Genes are expressed or not expressed. Yes so I subscribe to the idea that there is absolutely certainly transgenerational inheritance of parenting and upbringing, right? I mean your grandparents raised your parents who raised you? Not always people can be adopted. In fact, I have adopted members in my family but I understand what you're saying correctly.
The evidence that, for instance, some stress-related Gene was modified during a trauma in my grandparents or great-grandparents. And the idea that that was passed to me. Through my parents, that the evidence there is far weaker, right? And when you think about it, well, like, how did that happen that had to get into your, your grandparents sperm or egg cell and then produce that effect in the brain of your parents? And then
How to get into their sperm and eggs or egg cell and then contribute to producing it in you, but damn, but fragmentation of DNA and sperm is, or in eggs, is a common thing, especially, as people age, DNA, sperm, and eggs fragment, and it's possible that some of those mutations still allow for viable embryos. So, it's in theory, the germline could be changed by environmental events. Well, right? But now, I
I think you're starting to talk about things that are heritable, right? You're not talking about marks on DNA, you're talking about the structure of the DNA right itself and that is its own separate issue. Now, I think I want to be really careful about this because what is now, I think fairly well-established is that you can transfer things epigenetically over a single generation,
As a result of experiences that the mother has during pregnancy. So for example, we know that during the 1918 pandemic, flu, many women were pregnant and got the flu. And if you look at their children, you find interesting statistical anomalies and those children. For example, the male's wound up going
Into the army for World War 2. And of course, the Army does a complete physical and the records are very good so you can go into that database. And you find that the male children that were in utero during the winter of 1918. During the pandemic flu are on average a millimeter or two shorter myself, mm to that's nothing. But in a huge statistical sample of millions of people that's enormously significant.
More interesting. Is that the incidence of schizophrenia went up about four fold from about 1 percent to about 4%? And even though autism wasn't a term in 1918 yet, I don't think came along later. What we now retrospectively would call autism. Also went up by about four fold. So there's something about mom being stressed.
And carrying the fetus at a particular stage, that seems to impact brain development in a way that then makes that child more likely to be schizophrenic or autistic when they grow up, do we know that it's stress and my recollection of this? I believe this was the late Paul sternberg's work as well. Maybe have that name incorrect but in any event that it is if pregnant mom gets the flu.
In the first trimester, you see this higher incidence of schizophrenia and autistic Offspring and but do we know that it's stress per se because it's stressful to have the flu but the flu is a bunch of other. Things could be fever, could be some breakdown in the immune barrier, I just want to open up the the number of variables that this could be 2 or do we know that it's something in the hypothalamic pituitary so-called stress axis, that is adrenals. So I perform
Pituitary, adrenal axis like is it elevated cortisol or could it literally be an immune neural interaction of some other sort? It's probably the last thing you mentioned an immune neural interaction. And the reason I say that is that Gloria Troy at MIT together with her, collaborators has made a mouse model of this phenomenon. So she takes pregnant, female mice, and she injects him with something that that it's
she doesn't actually infect them with virus. She puts a chemical in that is on the code of viruses that mimics viral infection. And then what happens is that in a way that interestingly is an interaction with the, with the bacterial content of her of her, God's produces a surge of a immune signaling molecule called interleukin 17 interleukin 17 can
Through the placenta into the fetus. And if it's present just, as you said at a particular point in development doesn't work anywhere during pregnancy, but during something that is sort of a mouse equivalent of the first trimester if that occurs, it causes disorder development of the layers of the cortex instead of it looking like layers of a cake. You see balls and clumps of cells and parenthetically in some but not all
All post-mortem tissue from autistic people. You can also see those balls and clumps of cells are those balls and clumps of cells thought to reflect alterations in cell migration, they are yes. Um, I don't know if it's entirely known how much of it is cell division or migration but certainly migration is a part of it and it's very likely that that critical moments to disrupt this ordering of the brain and produce.
These increases in schizophrenia or or Autism, vulnerability are coming at a point where neurons are migrating during development. And so what choice group did is they did all the things you would want to do as a biologist. So they gave things to block the function of a of this interleukin signaling molecule and it blocked the phenomenon, they artificially injected the signaling molecule into fetal brain when the
mom hadn't been stressed and they could, they could reproduce it. So I'm not saying that there aren't effects of stress hormones from the hypothalamic pituitary axis that are important that you mentioned. But in this mouse model system work, it seems that you can produce it through this immune signaling pathway. And and so then the question is well, like RV is mice, autistic. Well, how do you
No of a mouse is autistic and the answer is, it's actually a little vague right there. Are behaviors that Neuroscience just say are analogous of human autism and one of them is, If You Give a Mouse on marble in its home cage, it will bury it over and over again compulsively or bury many marbles, and people say that that is somehow analogous to some of the compulsive behaviors is in autism. It's a bit of a stretch, right? I mean, it's a
Challenge to interpret mouth behavior in in human terms but it's a reasonable first step.
Incredible. And I hope more will continue to be done as it surrounds the first, trimester influenza hypothesis because it's been around a while and and obviously, there's a spectrum of what we call autism, Asperger's, and nowadays. People refer to it as sometimes it's the neuro, a typical, there's some high functioning people with Autism, there's some low functioning people with Autism and for that matter. There's some hi.
Functioning and low functioning people who don't have autism. So but it is something that I think demands our attention and it that hopefully will be resolved at some point because also influenza is, but one immune insult and presumably pregnant, women are being bombarded with all sorts of viruses and bacteria and fungal infections and fighting them off. We're not fighting them off. And who knows what the
The ocean in neuro-immune. Interactions exist in there that give rise to you know, good variation and let's call it, you know, debilitating variation. Well, that's, that's absolutely right. And so for one example, is that we don't know what the effects are on. The children who were in utero while their mothers were fighting off coded, right? We won't know.
For for a while or the common cold and their might I mean there might be nothing but or there might be something serious lurking there. Like there was for pandemic flu and will be very interesting and and important to find out agreed, I'd love to talk with you about mind body, but before we do that, I would be totally remiss if I didn't ask for your
Broad top Contour understanding of the mini brain, the cerebellum the so-called mini brain. And here's why I've been a practicing neuroscientist for close to three decades. I know where the cerebellum is. I've dissected a bunch of them, I could tell you where a few things are in there and I certainly have read about what the cerebellum does but whenever I do a PubMed search on cerebellum I see
See, an ever-expanding said of things that the cerebellum has implicated in, not just balance as most people here. But also timing, also cognition, I hear about timing in particular motor Behavior, but then I also hear that's involved in learning and not just motor learning and it certainly is involved in motor learning, perhaps that little mini brain is doing 50 or a thousand different things. But how should we think about the cerebellum? What,
Is putrid, indeed smells like vomit. Whereas others perhaps are not bothered by that smell and why others still are attracted to that smell or something that you look at or something that you hear. We also talked about nature versus nurture and how we come to be who we are, not just through our genes and epigenetics. But also through our early childhood experience and adult experience, and then in the latter, third of our conversation, we shift to talking about the so-called Mind Body Connection and the
the science, underlying how our thoughts inform our bodily health or lack thereof as well as how the organs of our body control, the chemicals hormones and thoughts within our brain. Then we shifted discussing dr. David Linden himself and the fact that in 2020, he was diagnosed with a form of heart cancer that led his Physicians to tell him that he had six to 12 months to live now obviously, because he was in our studio to record this conversation, he has outlived that
Sis. But he lives day-to-day with the knowledge that his death may very well come soon. Although it isn't clear exactly. When that day will come of course he tells us how the initial prognosis of his cancer as well as outliving that prognosis has informed his day-to-day life, as well as his thinking and his relationships and that leads to a very direct and frankly, emotional conversation that includes advice on how all of us can get the most out of our daily living. And
Out of our overall life. It's an extremely powerful conversation that I believe everyone regardless of age or health status can benefit from and it's one that makes clear. That not only is dr. David Linden a spectacular scientist but also a spectacular educator, a spectacular, popular writer a spectacular Family Man. Including husband and father and friend to many people and his colleagues. But he is also a courageous and spectacularly, generous human being before we begin.
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Free month for carrying out this survey, you can find the link to the survey in the show, notes for this podcast episode and on our website huberman lab.com. So if you would be so kind as to take a few minutes to fill out the survey and help us continue with bringing you the best possible content here at The huberman Lab podcast. And as always, thank you for your interest in science and now for my discussion with dr. David Linden Professor Linden welcome. Thanks so much for having me. I'm looking forward to our conversation, and we have a lot to
Talk about we do lots of different aspects of science, lots of different aspects of personal journey and what you're confronting. Now as it relates to your health and your future. I want to start off with a question that I learned from the one. And only the great Karl deisseroth, who was the first guest on this podcast, my colleague at Stanford. And for those of you that don't recognize Carl's name, he is a absolute Phenom. He's a
Say active clinical psychiatrist. So he's an MD and he also is a bioengineer who's developed a lot of the modern tools for probing the brain. And any time I've met with Carl, the first thing he says, is what do you most excited about lately? That's a good question. It is. So I'm going to steal that approach and say, what do you most excited about lately? Well, very, very lately. The most interesting thing that
Run in Neuroscience, is the answer to a scientific problem that I think is really dear to a lot of people's hearts and that is what are the nerve endings in the genitals that are responsible for sexual sensation. And you know, if you think about it, right, people can feel sexy from being touched on lots of different parts of the body but there's something special about the jungle.
Miles, doesn't matter. Male or female or intersex, or gay, or straight, or bi, or whatever you are. You know, the genitals are a hotspot, and why? And you'd think, as biologists, we know this by now, this would be something we could just answer, but but it's been a mystery for a long time. And if you go back to to 1860, there was a German neuroanatomist name Krause, and he cut thin sections of tissue from the penis.
The clitoris and he looked at them under the microscope and he saw a particular kind of nerve ending there that has since been called the Krause corpuscle. And there were lots of them in these two places. And so he thought, well maybe this is the cellular basis of sexual sensation. Maybe these are the particular nerve endings that are responsible for this but
There were some things that that were in favor of that and some not. So these nerve endings are also in some other places that people can find more or less sexy like they're in the nipples and they're on the lips and they're in the anus, all places that get popular in in that domain but they're also in places like the cornea or the lining of the joints. So distribution doesn't quite make sense and so it
Never known. And so if you wanted to really test as a scientist, whether these nerve endings are responsible, you want to record their electrical signals, while the genitals are being touched, you'd want to inactivate these cells and see if you could interfere with SNAP with sexual sensation and this in a preprint from David guilty is group at. Harvard is just what they have been able to do in mice. They found a way to label and record from
and activate and inactivate artificially the Krause corpuscles. And so you see a nerve endings in the skin, it could be conveying all kinds of information. It could be tuned for hot or cold or for rich or for pain or Fuller in or for inflammation or for mechanical sensation, stretching vibration indentation and sure enough. When they recorded from these Krause corpuscles they really are.
Chemical sensors as you would expect if they were involved in sexual sensation. So that was good. And then the other thing that they did is they try to artificially, turn them on. And so the way they did that is they use genetic tricks to express one of Carl. Dicers Oaths, a molecule that activates neurons when they're when blue light is Shone on them and they found that if they express this, artificial protein.
Seen in the crowd cells in a, in a male Mouse and then shine, blue light, the mouse gets an erection. Alright. So far so good. What happens if you turn them off? Well, it should turn them off in a male Mouse. It's just as interested in females when they're in heat, but it won't mount and thrust, and ejaculate as much. And if you turn them off in a female Mouse, during the time of her cycle, where she would normally be sexually receptive,
If you find that she is much less interested. She's much less likely to let him Mount. She is much less likely to let him finish. So this is the remarkable results that finally, after all these years since 1860 now we know what the nerve endings are that convey sexual sensation and like all good science. Then you know there are a lot of questions.
That are really interesting to our everyday lives. Like, you know, people like different things in bed and have different propensity for orgasm or, or like like to be touched in different ways. Well, is part of that reason because of individual variation in their Krauss corpuscle structure. We know that sexual sensation diminishes with aging is that in part, because Krause corpuscle density is lost
From the skin of the genitals and that's a reasonable idea because we know for example, that fine touch sensors in the fingertips so called Merkel and meissner endings also named after German anatomist, like so many things are, are also lost with age. So that's a reasonable idea. So so this finding from grantees Lab is opened up a whole world of science and I've been my, let my own lab doesn't work on touch, but I've been a fan boy of touch for
For, for many many years mostly because where I work at Johns Hopkins, Medical School. There have been many terrific touch researchers. It's been a world center for it and I hear about it over lunch and I got all fired up. So years ago, I wrote a book about it, I still follow the field and this is the most interesting thing in that field recently. And as I recall ginty was your neighbor at Hopkins, before he moved to Harvard. That's right. That's right. He was one of the ones ginty Stephen Chow Michael.
To Reno Shin Jang, dong there have been a number of world leaders among in the cellular basis of touch sensation at Hopkins. Do you recall if in the preprint that you were describing there was an experiment where they activated these Krause corpuscles in females. It's funny, you should mention that I sent that exact email to David guilty and they said they are in the process of doing that right now and they don't quite know yet. And so I asked
Him. I said, so, for example, is erection of the clitoris, even a thing in mice. He said, well, we're really not sure. So, we're activating the crowd score, puzzles and female mice, and we're just kind of staring at it and looking and see if anything happens just there, you know, does the, you know, does the the body change shape? Is there a color change? They don't even quite know what it is they're looking for because it's that much on the Leading Edge of things but it's a good question or perhaps the female mice would be more willing to mate.
Outside of the usual time frame of receptivity, if these Krause corpuscles are stimulated, that's possible. My suggestion, my guess would be not because I think that the hormonal regulation of receptivity is like a sledgehammer and very hard to overcome but they might be more willing to continue mating or make for a longer during their fertile time. And I just want to remind people because we had a guest
recently dr. Veena Malik who's a urologist reproductive and sexual health expert. She's an MD and she made clear that the the clitoris and the penis come from the same embryonic origin. They are analogous tissues. In different individuals. I do have one more question about this sexual touch thing.
These are peripheral nerves, right? So, these are not of the brain and spinal cord. They are in what we call the periphery. And my understanding is that peripheral neurons regenerate and can remodel themselves extensively in ways that neurons within the brain and spinal cord, tend to remodel less, especially as one gets older out of the so-called critical period. Is it possible that these cross Corpus schools and their patterns of innovation?
The genitals change according to the stimulation that people experience. In other words is sexual sensation, experience dependent. That is a great question. And so we don't know because monitoring this in people is not technically possible, Right? It requires cadaver tissue so you can only do it once in animals. It
It will be possible and it could be for a couple of different reasons. And other words, it could be. I think what you're imagining is that there's actual structural plasticity. If you looked at these crowds corpuscles or that you would actually see them changing their shape, or their size, or their, or their density as a result of experience. But what can also happen is phenomenal, like desensitization that is to say when they're stimulation for
A long time, then the receptors transiently can become less sensitive to touch, and it's well known for particularly in males, that that chronic masturbation can produce desensitization of sexual sensation in the penis. And that could be as a result of a physical change, a morphological change in the crowds corpuscles, but it's more likely to
to be a change in their function that you wouldn't be able to Simply see by looking at an outline of their structure in the microscope. Such an interesting topic, Thanks for opening, things up with with that. And I'll have to check out this preprint. I'm also a huge fan of David guarantees work. And and colleagues, there are many people involved in that domain of work. Of course, I'd like to talk about your recent book and the sort of underlying basis of what.
LED you to write it? And what intrigued you about this idea of human individuality the book unique is one that will provide a link to in the show. No captions. And it's a very interesting idea that we are all different especially coming from a neuroscientist who were trained at least similarly, it to learn that sure. The bumps and ripples of the brain and the fine wiring of the brain is different and we are all unique and different, we have different shapes.
Take a morphologies. But focusing on human individuality is not something that modern Neuroscience or classic Neuroscience has really done much of its really focused on how people do X or people do. Why this way tell us about unique and tell us about human individuality. Yeah, well, I mean, you're absolutely right. So, when I look at the experiments, my own lab, how do we do them? Well, we work on mice. Do we work on mice with genetic variation?
We work on highly inbred mice that are designed to be as genetically similar to each other as possible. And then we raise them basically in prism in little little cells, which may not be a good idea and we try to give them as similar experience as possible. They are given toys and food and water but I agree. It resembles a prison of sorts. They aren't free to roam. They're not. They have nothing like the experience of a wild mouse. Let me put it that way there.
And and yes, there are as you said correctly. There are plenty of experiments where there is enrichments, from mice, and they loved it. So, for example, in our lab, when we put running wheels in, the cages are mice and let them run overnight, they're active at night. Your average Mouse will run two kilometers in a night for a little tiny Mouse. And some of the mice are so intense, they will run 20 kilometers. Imagine
A mouse doing 20K but it will happen. They really, really like it. They don't like being in prison. They want to exercise and the really bored. So yes to get back to your general point. So much of science is designed to try to find general principles of a function of the brain of physiology of genetics and to ignore individual variation.
Individual variation is so important to our human experience. And actually is so important to to the process of evolution and natural selection and how how species make their way in the world. That that it's, it's something that that requires a lot of attention. And to me, what's really fascinating is that when you look at the variation in the way
A sense organs function. It's almost a miracle that we can agree on a common reality at all even within the human species. And this is true of more of some senses. More than others. Obviously, in your world in the retina, we have various kinds of loss of color vision that are well-known and some other more complicated phenomena having to do with.
Months in the perception of motion or form, but the place where this really happens is in the olfactory system. So we have approximately 400 functional receptors for different odorant molecules smells in our nose and if you sequence the genomes of many people you find that the
That the, the DNA that encodes, for these odorant receptors is unusually variable from Individual to individual. As a matter of fact, if you take two different people on average, they will have functional differences in 30% of their odor receptors. And if you do as Leslie vas, all and her colleagues did at Rockefeller University.
Give odor tests where they give people different things to smell and then they dilute them and find the threshold which they can detect them. You find enormous changes from People to People both in term in general terms, some people are just better smeller's than others. But in terms of individual odors as well there's some odors that some people can't detect and other people smell one way. For example, there is a there's a secrete a hormone called Andres.
Steen own androstenone there some people who can't smell it at all, for some people, it smells like rather Pleasant, like cut grass. And for some people, it smells foul like your owners sweat and it just depends on genetic variation in one particular odorant receptor sorry to interrupt another phenomenal researcher who studies olfaction among other things? Catherine, duloc.
Um, I once heard say that some people have a gene that for them makes the smell of microwave popcorn, they experience that smell as vomit. And other people who lack this Gene like the smell of microwave popcorn or at least for them, it's not aversive so it can really be a binary response. Well, it can actually that's a very particular funny case. So the remedy
relevant chemical there is butyric acid and also I swivel Eric acid and so there are researchers, I think Rachel Hertz is one of them who have given a mixture of these two chemicals to people. And they say this is parmesan cheese, they go yeah that's parmesan cheese and if they give it to other people and say this is vomit. They'll go. Oh yeah, that's vomit. And if they tell people, they give them one vial and say this is parmesan cheese in them.
I'll get another one. It says vomiting. Oh, yeah. And then they say, well, actually we fooled, you was the same vial. This it. No you didn't. You must have made a mistake. There are convinced that they couldn't have been the same thing. So this points out, not only is their genetic variation. That is responsible for around individuals, perceive odor. But we are incredibly suggestible in terms of odors and we, we are
very dependent upon them in terms of cultural context. And this can be this can be learned and and this is Central to our Humanity in the sense that, that we humans are what I like to call the anti pandas pandas live in one spot in in southern China and they eat one thing bamboo and that's it, humans are the opposite. Humans can live in any
Whole niche in the world from the tropics to the polls and humans, eat a wide wide wide variety of foods. And as a result it means that we have to have a very plastic olfactory system that have to be very few things that we find in Nate Lee. Reverse of their only, a handful of odors rotting meat. Odors molecules with the evocative names like cadaverine and putrescine are things that even babies
When their newborn find aversive but other things happen that they need to be learned. For example, pretty much. Every adult finds poop odors unpleasant but babies happily happily play with their own poop. They have to learn that that's disgusting. It's not because babies have a different nose, it's because they have to learn cultural not innate. It is not innate. They're only a few innate odor. Aversion
And a few innate Taste of versions that were were born with, and the other things are elaborated, culturally and we can think about this in terms of how we talk about, odors. So for example, we might say, vanilla smells sweet.
Well that's weird. That's like those are two different senses. How can something smells sweet? That's like saying it sounds read right? It's a statement about synesthesia, right? And but but how did it come to pass and do people say that vanilla smells sweet everywhere in the world? Well, the answer is no. So in places in the world, where vanilla is used with sugar in in sweet foods like desserts. Then people say that a vanilla smell sweet or mint. Similarly,
Ah smells sweet if it is typically used together with sugar. But if you go to a place like like Vietnam, where mint is mostly used in Savory dishes, people won't say that mint, smells sweet. So there's a parrot Association there that at least at our level of conscious understanding feeds back on to what we call.
Olfactory or smell perception. But really, it's a must be a parent Association at some point in development. Yeah, it is, it absolutely is a dissociation and it's something that goes on continually through your life, right? I mean, lots of people, for example, have stories of foods that they wouldn't eat as a child but they came to like as an adult's. A good example of that is coffee. A lot of people have to overcome bitter or version.
To, to become coffee aficionados. So, you know, this, this feeds into the more, the more General theme that
There is no, pure perception, perception is inference. It's not like there is a purely objective world that can somehow make its way through the senses and we can perceive that as the truth, all of our perception. Through all of our senses, both the outward pointing senses of the world like smell and taste and sight and hearing and the inward pointing senses like,
And is my stomach full and things like that. All of them are based on experience and expectation and the situation of the moment, as many of, you know, I've been taking a G1 daily since 2012. So I'm delighted that they're sponsoring the podcast. A G1 is a vitamin mineral probiotic drink. That's designed to me all of your foundational nutrition needs now. Of course, I try to get enough servings of vitamins and minerals through whole food sources that include vegetables and fruits.
D-Day. But often times, I simply can't get enough servings but with a G1, I'm sure to get enough vitamins and minerals and the probiotics that I need. And it also contains adaptogens to help buffer, stress. Simply put, I always feel better. When I take a G1, I have more focus and energy and I sleep better and it also happens to taste great for all these reasons, whenever I'm asked, if you could take Just One supplement, what would it be? I answer a G1. If you'd like to try a G1. Go to drink. AG one.com huberman to claim.
Through your life, right? I mean, lots of people, for example, have stories of foods that they wouldn't eat as a child but they came to like as an adult's. A good example of that is coffee, a lot of people have to overcome bitter or version 2 to become coffee aficionados. So, you know, this, this feeds into the more, the more General theme.
That.
There is no, pure perception, perception is inference. It's not like there is a purely objective world that can somehow make its way through the senses and we can perceive that as the truth, all of our perception. Through all of our senses, both the outward pointing senses of the world like smell and taste and sight and hearing and the inward pointing senses like,
And is my stomach full and things like that. All of them are based on experience and expectation and the situation of the moment, as many of, you know, I've been taking a G1 daily since 2012. So I'm delighted that they're sponsoring the podcast. A G1 is a vitamin mineral probiotic drink. That's designed to me all of your foundational nutrition needs now. Of course, I try to get enough servings of vitamins and minerals through whole food sources that include vegetables and fruits every
D-Day. But often times, I simply can't get enough servings but with a G1, I'm sure to get enough vitamins and minerals and the probiotics that I need. And it also contains adaptogens to help buffer, stress. Simply put, I always feel better. When I take a G1, I have more focus and energy and I sleep better and it also happens to taste great for all these reasons, whenever I'm asked, if you could take Just One supplement, what would it be? I answer a G1. If you'd like to try a G1. Go to drink. AG one.com huberman to claim.
Special offer they'll give you five free travel packs. Plus a year supply of vitamin D3 K to again that's drink. AG one.com. Hubermann are there any examples of uniqueness of visual perception that come to mind? I recently did a social media post that involved. It was essentially three rings, A blue ring a red ring and a blue ring in the center or perhaps it was the other way around. Excuse me. It was
Red blue red and I asked which ring is in front or they all at the in the same plane. Now, of course, it's a two-dimensional image and interestingly it splits out into about thirds, some people see the blue ring in front quite a bit other. See a red ring out in front other, see them all in the same plane and this we think has to do with differences. In two things between individuals, one is the distribution.
You know, the cone photoreceptors which we know is essentially random between individuals, maybe even between the two eyes and then, and that gives rise to this phenomenon of chromatic aberration, which is the displacement of the visual image, according to the wavelength of the light and we won't get into the physics of it. Now I'll soon do a post that hopefully distills it in a manner, that simple enough, that people understand. But clearly some people see certain colors in front of others and the person right now.
X2 them could see the opposite color in front and others. Say what are you talking about? All the colors are in exactly the same plane of vision. So that's the one that I know I'm guessing, you know, some others and perhaps some more robust ones. Well I think, you know, perhaps this is maybe not what you had in mind. But one way in which experience modifies the visual world has to do with, how much light you're exposed to
In the first five years or so of your life. And so kids that don't get outside are much more likely to be myopic and it actually is not good nearsighted. Yes. When they grow up, then kids who got outside. And we now know that, at least part of the story is that light seems to stimulate the
Section of a class of molecules called trophic factors that you're well-acquainted with that actually change the shape of the eyeball. So it's not really the structure of the retina, or the lens of the cornea. The actual degree of elongation of the eyeball changes changing the way the the retinas, its relative to the limbs. And that seems to be light dependent early in life and which gives rise to two.
Higher incidence of myopia. And and to me this is really well. First of all, it's news, you can use, you should get your kids outside for absolute. All kinds of reason you should get outside to especially in the morning. Yeah, thats circadian rhythm guy. I know that's a famous huberman. Esca point. They're going to be putting me in the grave David and I'm going to be telling people to or two, maybe you'll be on my Tombstone. Say get get sunlight in your eyes. You got his harshly on, especially on cloudy days because there is still
Oh sunlight, even if you can't see the physical object of the sun on cloudy days. Well, you know, I think this whole idea of having traits that are dependent upon early, life experience is fascinating because there are a number of situations where you would guess that something is genetic. But it isn't. It's actually dependent on early life experience and there's a there's an amazing story about this.
To do with the early days of World, War Two. So in the early days of World, War 2, the Japanese Army, just swept through Asia. They defeated the, the British and Malaysia and Singapore. They overrun Thailand and Burma and they were knocking on the gates of India and everything was going great except the Japanese Army had a problem. There were an enormous number of their soldiers who became incapacitated with heatstroke. They got their core.
Sure, got too hot and when the Army doctors examined they found, this was much more likely to happen in soldiers who came from the northern part of Japan Hokkaido where it's it, where it snows in the winter as opposed to the southern part of Japan. Like you shoot, which is a semi tropical environment and the classical explanation. The biologists like us would guess would say. Oh, all right, well, this is
Genetically over many years you have a family that's been in Kyushu for many generations and you've selected for Gene variants, allow you to tolerate the heat better and we know actually what this is. So if you're more heat tolerant, it's because you have more of a particular class of sweat gland called the eccrine. Sweat glands, the sort of saltwater, sweat glands, not the Le Petit stinky armpits sweat, glands called the African ones, the Akron ones, you have a higher
Fraction of them that are innervated, meaning that the signals from your brain that say your core is too hot. Can then make you sweat. So the total density of sweat glands between northern and southern soldiers in Japan wasn't different, but the southern soldiers tend to have a higher degree of innovation. All right, so so okay well this happened genetically over many generations but if you look at those rare cases where you have soldiers from a long-established northern family and their parents moved,
And they grew up in the southern location. They had high sweat gland innervation they were well tolerant conversely. If you had a well-established, Southern Kyushu family and they moved to Hokkaido and then have their child that child developed the northern sweat gland, innervation pattern. So meaning less nerve, innervation of those sweat glands. As you mentioned before, just as many sweat glands, just less nerve innervation there for those sweat glands could not be activated.
Do they couldn't dump heat as well? Their heat tolerance was lower, you're exactly right. And and what's what's wonderful is that this gives an advantage that you can't get through Evolution and that it can happen right away and this in one generation right evolutionary change is slow, right? And you can adapt as a species and as a family over over many, many, many generations. But when you have a phenomenon,
That is set by early life experience. Well, then you can benefit from that early life experience within your own life. It's not that your great-great great-great-great. Grandchildren will ultimately benefit. You benefit another wonderful example of this comes from field, mice voles, and we were talking earlier about how we both worked with the scientist nerves, Booker out at Berkeley. Who is a specialist in
Involves and what people found is that if you take wild-caught field mice and you have a pregnant mothers and you have them in the lab, but you manipulate the lights so that you have artificial spring. In other words, day length is getting longer day after day during the pregnancy then what happens is when their pups were born.
They will have a low density of fur. Anticipating summer temperatures.
If you however put them in artificial fall, where day length is getting shorter, they will be born. Now, with high density of for anticipating winter temperatures and of course, you can do this no matter what the season actually is in the world by manipulating these lights in the lab. And so, like the sweating Japanese soldiers, this is a great example of early life, plasticity.
Today. And just the sort of trait that if you ask someone, they would probably guess is heritable. But actually is not thanks for mentioning our visitor, who has you also mentioned was an advisor to us both who's done, incredible work in circadian, biology seasonal, rhythms hormones, and behavior. I have such reverence for Irv. And the experiment you mentioned made me smile wide because it's but one of gosh, maybe hundreds of incredible study. So if people are interested in seasonal rhythm,
Eames and circadian rhythms and biology of the most interesting kind. Definitely, check out Irving's hookers. Work at Berkeley. I'll provide a link to his PubMed there. Since we've been taking a tour of individual variation in olfactory perception, visual perception and now heat tolerance. I have to ask, are you aware of any examples off the top of your head in the auditory domain that particularly intrigued you?
Yeah, well, I would say one really interesting example, has to do with perfect pitch. So, Perfect Pitch as a trait that is to say, you have the ability to, to hear, a note played and say, oh, that's a c-sharp, right? This is a pretty rare trait. So even if you look among highly trained, musicians, if you went to Peabody conservatory, at my University, Johns, Hopkins, and tested people. There, you would find a higher incidence
So Perfect Pitch, then you would in the general population but still maybe one in ten trained musicians have perfect pitch and parenthetically having Perfect Pitch. Doesn't necessarily make you a better musician, but it's an interesting phenomena. And so the question is well, is perfect pitch heritable? And the answer is when you look at twin studies where which is what we use to estimate heritability, the answer is its kind of low.
If there's a heritable component, but it accounts for my recollection is on the, on the order of 30, 40 percent of the variability in Perfect Pitch. However, if people receive ear training, starting at a young age, the chance that they will develop Perfect Pitch, can improve drastically in your book unique. Do you cover aspects of human individuality? That extend beyond the
Cept action domain into the cognitive domain. Well, yeah, absolutely. And you know, I think I think it's good to set the stage here. If we're going to be talking about heritability and human individuality and and so if I can go off on a little bit of a riff for the benefit of your of your listeners and viewers here, he's so if you look at human traits whether they are behavioral traits like shyness.
Or very straightforward. Morphological traits like height. What you tend to find is that there are very few traits that are entirely heritable where all their variability can be predicted based on the gene variants you get from your mother and father and there are a few traits that are absolutely unhearable but that most fall in between. So let me give an example. Everyone in the world has either wet
Dry earwax and it turns out that this is determined by variation. In the single Gene, the name of the gene is boring. It's a b c, C11. It's a ion transporter and there is a variation in this Gene gives rise to either wet or dry earwax. It doesn't matter how your parents raised you, it doesn't matter what foods. You ate, growing up, doesn't matter what? What diseases your mother had when you were in the womb,
Umm, it's 100% heritable. Well, does this mean that a b c? C11 we should call it the earwax type Gene? Well, no, because it's not there just for that like this. This Gene is expressed in cells and all parts of the body, doing all kinds of things earwax is just something that we notice genes don't code for traits, they code for proteins and so we have to be careful about how we refer to them in that way.
For example, the wet earwax G of variant of the abcc. 11 Jean also, confers a slightly higher risk for breast cancer. So clearly it's not just for earwax it's for a bunch of things. Most of which we don't yet know about, but in the case of earwax, this trade is 100% heritable. At the other end of the scale speech accent is 0%, terrible. It is entirely
Be dependent upon the speech that you experience in your childhood. And interestingly it's the speech of your peers more than the speech of your family, which is why the children of immigrants sound like the place where they wound up, not like their parents and there is no evidence for any degree of heritability. Now, just to be clear, I'm talking about speech accent, like whether you have a high or a low voice or it's nasal or more or less resident, these are physical things having to do with the vocal,
Back then they are in part heritable. Okay, so we've got one thing, that's 100% heritable. One thing is 0% heritable, but where do most Things Fall? Most Things fall in the middle? One of the most heritable traits that we know about in humans, is height and in the United States. Height is about 85% heritable, 85 percent of the variation, in the trait of height can be explained by what
You inherit from your mother and your father. Well, what's the rest? Well it's nutrition. It's the diseases you fought off. It's also random variation which we'll talk about a lot later. Now you might say OK. Well that's an estimate for people. In the u.s. is this true all over the world? Will know if you go to a place where people routinely don't get enough nutrition and are routinely
Fighting off infectious diseases. Like, this is been studied in rural Bolivia, for example, a rural India, now height is no longer 85% heritable. It's only 50% terrible. Why? Because people in these situations where they don't get enough nourishment, where they're fighting off these diseases, can't live up to their genetic potential for height if you want.
To make things better for the people of the world. Then everyone needs to have basic things like the ability to learn and enough nutrition and and decent Medical Care and schools in order to fulfil their genetic potential for positive traits and height. I've used as an example because it is very uncontroversial.
We could apply the very same analysis to intelligence general intelligence. Now, there are people who argue about do things like IQ tests really measure anything real and there's been a lot of fighting in the scientific literature about this but I think intelligence tests aren't perfect and they are sometimes culture-bound, but they are actually quite predictive of of later success and much.
More so than say, sat tests or GRE tests or em cats or other standardized tests, and presumably those correlate in some way they do by do, but but the IQ tests are better. Actually there's any about the, the classic IQ test. I am talking about the modern variants of the classic IQ tests that are administered by trained psychologists and aren't just a paper form. And so they're not perfect and no.
It will be perfect, but they're pretty good. And so, then if you ask the question, well, what is the heritability for IQ test score? Well, the answer tends to be different depending upon the population. If you look again in in countries, like the us, or in Western Europe, that are fairly affluent, where people tend to have good access to to nutrition
And medical care and schooling and kids get to play on, they're not, and they're not traumatized by War. Then then IQ test score is heritable in the ballpark of 60-70 percent. But if you look at people who don't have those benefits who are poor and this can be in the United States as well. If you look at communities that that face too.
Termination and have consistently poor poor health care in schools then IQ is less heritable. Why for the very same reason that it is on height because people can't live up to their genetic potential. When they don't have the basic things that everybody needs. So presumably if two identical twins.
And I realize they aren't identical but you're familiar with twins, you have twin children. If two identical twins are raised separately, the correlation in their IQ is can only is it that only 65 think you said about 66 percent of their IQ can be predicted on the basis of their genetic makeup alone. I mean, it makes perfect sense to me as to why if one of those twins went to schools that
We're demanding of, you know, a lot of different topic matter and the other one went to schools where the instruction level was really deficient that one would perform far less well on an IQ test unless of course the IQ test is in tapping into school based. Knowledge is tapping into some other thermometer of so-called intelligence or IQ. Well you know the thing is that good schools correlate
With many other things, right? So the students that go to good schools aren't just benefiting from good schools. They tend to also have good medical care and safe or less traumatizing neighborhoods and they're more likely to have books parents with books in the home. And and and a whole number of things that are all beneficial. So when you try to do epidemiology on this, you have to be aware that things are very deeply interconnected but but you bring up a good point. So it turns out that the way we get these s
Months of heritability. There's two ways. One way is to compare, so-called identical or monozygotic twins, with so-called fraternal or dizygotic twins. So the identical twins will share, nearly 100 percents of their Gene variants and on average, fraternal twins share 50% of their of their Gene variants and generally speaking with
People do these studies in order to avoid confounds of sex. They'll compare same-sex fraternal twins. So boys, two boys and girls two girls. And when you put these incidents into a formula called Fisher's equation, then you can come up with an estimate of the heritability of the trade, but there is an assumption
Presence in that and it's called the equal environment. Assumption, you're saying, well to kids raised in the same family have the same environments. Well, that's not always true, right? That can be violated by a number of different situations, so it turns out that a more powerful, but much more difficult way to estimate heritability is by looking at twins.
Has reared apart either, identical twins or fraternal twins. Reared apart. And there was a landmark study called the Minnesota study of twins reared apart, which is abbreviated mystery. That is really the gold standard for assessing the heritability of many different human traits, both behavioral traits but also disease incidents but of course it's a small end because you know the population
Identical twins, reared apart that you can get into the lab isn't isn't that large? They had something. I don't remember the exact numbers, but they had something like 80, some identicals, and fifty some fraternal, 's in their, in their sample. But by doing this, they were able to come up with a lot of interesting estimates and so, for example, most personality traits, what the psychologists
Use the acronym ocean to mean, openness conscientiousness, empathy, agreeableness and neuroticism. I think I got that right spelled right. That these traits on average tend to be about 50% heritable and so, okay, stay right. Well, 50% of those personality traits is heritable. The rest is got to be like how you were raised. It's got to be in your family, and so everyone was shocked.
They actually did the analysis and found that family has almost nothing to do with it.
Ariel. And everyone. What? Are you kidding? It's got to and I think the important thing to realize is these traits. I just listed, you know, we call these personality traits but they are not the sum total of the way. You are in the world, parents can inculcate many things in their children, they can demonstrate trades. So people are much more likely to go into an occupation. If their parents did they can inculcate moral
Ideas and religious ideas. But in terms of these ocean personality traits, they have astonishingly little to do with it. So then this brings up the question. Well if 50 percent of the variation in these personality traits is not from your genetics and it's not from your family, where does it come from? And the answer seems to be is that it comes from
The random nature of the development of the body and the nervous system and this is, this is a point that I think many people don't understand. This is something that biologists know, but we've done a very poor job of communicating, to the general public. The genome, all your DNA, all 3 billion bases of DNA all 19,000.
Or so genes in human, don't make a blueprint for making your body and brain there. It's not all schematic diagram, that connects everything to everything, particularly in the nervous system where we have these hundreds of trillions of connections, rather, it's a rather vague recipe. So the genome doesn't say, oh okay, you glutamate using neuron in the brain region called the thalamus, you know, grow for 200 microns towards the top and then
And then and then cross the midline and then grow towards the ear for, you know, another distance. No, it says something like, hey, you bunch of glutamate neurons in the thalamus over here in this area about half of you, cross the midline. And so what does this mean in terms of individual variation, which means, well, for, for some individuals, 40% of their axons will cross the midline of the brain and for another individual 60% will even in identical twins.
And as you correctly, said, a moment ago. Identical twins aren't really identical either in their bodies or their temperament. So, if you take newborn identical twins and you give them a CT scan, just to measure the shape of their organs, they're not the same. You might have one twin whose spleen is 30% larger than than the other Twins or whose liver is 30% smaller than the other twins, even though they have the exact same DNA, and there were lying right next to each other. In the
And presumably have the same or very similar. Fetal environment. And the reason is the random or as we say, stochastic nature of neural development, a great way to study this is with nine-banded armadillo those. I know we're getting weird here but I love the armadillo because I've been told tell me I don't want to interrupt you too long but as far as I know the only
Animal in North America that carries leprosy. That is, that is true. And and there's a lot of twinning going on in Armadillos, right? Well what there is is actually quadding. So armadillos or the nine-banded armadillo in particular and they're different armadillos. I'm not really an armadillo specialist. I don't know if this holds for all of them but the nine-banded armadillo is born as identical quadruplets.
Awesome, awesome. So you can take these identical quadruplets newly-born armadillo. I do. You think you call them pups? I don't know what a baby armadillo is called. I'm sure there's some particular word for it and someone will tell us. I'm sure someone in the comments on YouTube. What is the name of a baby armadillo? I know like a ferret baby ferrets are kits. The moms are Jill's. The dads are bobs. I used to be obsessed with this kind of naming at, you know, it's a, it's a business of ferrets or what is like a gang of
Raccoons or whatever. It's so if you can tell us what the name is for the baby armadillos, as well as. What do you call a group of armadillos? You win? The pride associated with being right? That's right right. One of my favorites, nose on ostentation of peacocks amazing or a murder of crows who comes up with this guy. I know it's a raft of otters, I think it, I think that's correct. But so if you have for newborn identical 9
Unbounded armadillos. Then this is a great model system that biologists can use to study stochastic, differences and development and sure enough their brains are wired slightly differently. Their bodies are slightly different, if you test them behaviourally, even very very early in life, they have different propensities summer. Bolder will Explore More somewhere. Will tend to hide in the corner more and you know we know this from the lab you get a box of mice.
They're inbred from the breeder and you pluck them out and they're not behaviourally identical. Some might try to bite your hand, some will run away, some will stand stockstill. Where does this behavioral variation come from in mice? That are nearly genetically identical? Well, it comes from bunch of things. They don't always have exactly equal experience, but mostly it comes from the pseudo-random stochastic nature of development. I'd like to take a quick break and
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Again that's inside tracker.com huberman to get 20% off and is the pseudo, random stochastic nature of development. One of the maging, major scuse me driving forces for evolution because, you know, we hear about mutations and we always think we're people tend to think rather that mutations are bad. But of course, mutations provide the variation that can also subserve. Adaptive traits. I mean, if you're a fan of the X-Men, as I am huge, fan of the X-Men, the entire series, every single one, including the
In movies, you quickly, come to learn. That genetic mutation is at the heart of variation, which is at the heart of individuality, which is what we're talking about, right? And so, genetic variation is at the heart of individuality. But there is also, there are also these other things, right? That we've talked about, there's the effects of early life experience. And there is the stochastic nature and development. Because if you through the randomness of development happen to have like a
Early great liver. You're not going to pass that on to your children, right? That isn't in your germ line, you won't pass that traits along just brief insert here on germline. We had ODed rush off, e, on the podcast who studies epigenetic transmission and and an inheritance of of it's not lamarckian we have to point that out but inheritance of sort of acquired traits, it does happen at the germ line is the
That are present in the sperm and in the eggs, all the other cells of your body have genes, of course. But the best way to put this is simply going to the gym and getting fit does not make your children more fit because the germ line as far as we know, is not modified in a direct way. In other words, the DNA within sperm and eggs are not modified according to your behaviors in most but not all cases. That's right. And as you as you correctly said,
Said about oh Dad's work and other people's work. There is what's called transgenerational epigenetic inheritance, which means that you can have traits that are passed not from one generation to the next. But even two generations to the grandchildren that don't require modification of DNA, but to date that has been shown very convincingly in in a worms. And implants, the evidence in mammals is is really not there yet.
In my opinion and most of the claims for that and it's a very popular thing to say I epigenetically inherited my grandmother's our great-grandmother's. Trauma, the evidence that presence is is poor. Actually, a lot of it comes from epidemiology, most of which came from famines in the other colics region of Northern Sweden and they had very good medical
Kurds and they said, oh well, if your grandfather, went through the famine, then you're more likely to have this trait if you're male, or if your grandmother went through this, then if you're, if you're male, this train, your female have that trait. And I mean, there are two problems, one is that there's not a biological mechanism, but the other problem is that, the way these things were discovered, is by something called harking, or hypothesizing. After the Revolt results are known, they did very many
Statistical comparisons to try to find something significant and you know from your work in the lab that when you do many comparisons you're going to get some things that look significance, just occasionally random way through through luck and you have to apply a statistical, correction called a bonferroni correction. When you make many, particularly post hoc comparisons after the experiment comparisons to set the bar, much higher for accepting that
At data. And most of those studies they didn't apply that correction. And I remain unconvinced of transgenerational epigenetic inheritance in mammals. Now let's be clear.
Just because it hasn't been shown convincingly now doesn't mean that it won't be. There are some good people working very hard on this and they may well describe a mechanism and show this convincingly in the years to come. But right now, you may well inherit your grandma's or great grandma's trauma, but you're probably doing it socially not through marks on your DNA. That changes. How your
Genes are expressed or not expressed. Yes so I subscribe to the idea that there is absolutely certainly transgenerational inheritance of parenting and upbringing, right? I mean your grandparents raised your parents who raised you? Not always people can be adopted. In fact, I have adopted members in my family but I understand what you're saying correctly.
The evidence that, for instance, some stress-related Gene was modified during a trauma in my grandparents or great-grandparents. And the idea that that was passed to me. Through my parents, that the evidence there is far weaker, right? And when you think about it, well, like, how did that happen that had to get into your, your grandparents sperm or egg cell and then produce that effect in the brain of your parents? And then
How to get into their sperm and eggs or egg cell and then contribute to producing it in you, but damn, but fragmentation of DNA and sperm is, or in eggs, is a common thing, especially, as people age, DNA, sperm, and eggs fragment, and it's possible that some of those mutations still allow for viable embryos. So, it's in theory, the germline could be changed by environmental events. Well, right? But now, I
I think you're starting to talk about things that are heritable, right? You're not talking about marks on DNA, you're talking about the structure of the DNA right itself and that is its own separate issue. Now, I think I want to be really careful about this because what is now, I think fairly well-established is that you can transfer things epigenetically over a single generation,
As a result of experiences that the mother has during pregnancy. So for example, we know that during the 1918 pandemic, flu, many women were pregnant and got the flu. And if you look at their children, you find interesting statistical anomalies and those children. For example, the male's wound up going
Into the army for World War 2. And of course, the Army does a complete physical and the records are very good so you can go into that database. And you find that the male children that were in utero during the winter of 1918. During the pandemic flu are on average a millimeter or two shorter myself, mm to that's nothing. But in a huge statistical sample of millions of people that's enormously significant.
More interesting. Is that the incidence of schizophrenia went up about four fold from about 1 percent, to about 4%? And even though autism wasn't a term in 1918, yet, I'd I think came along later. What we now retrospectively would call autism also went up by about four fold. So there's something about mom being stressed.
And carrying the fetus at a particular stage, that seems to impact brain development in a way that then makes that child more likely to be schizophrenic or autistic when they grow up, do we know that it's stress and my recollection of this? I believe this was the late Paul sternberg's work as well. Maybe have that name incorrect but in any event that it is if pregnant mom gets the flu.
In the first trimester, you see this higher incidence of schizophrenia and autistic Offspring and but do we know that it's stress per se because it's stressful to have the flu but the flu is a bunch of other. Things could be fever, could be some breakdown in the immune barrier, I just want to open up the the number of variables that this could be 2 or do we know that it's something in the hypothalamic pituitary so-called stress axis, that is adrenals. So I perform
Pituitary, adrenal axis like is it elevated cortisol or could it literally be an immune neural interaction of some other sort? It's probably the last thing you mentioned an immune neural interaction. And the reason I say that is that Gloria Troy at MIT together with her, collaborators has made a mouse model of this phenomenon. So she takes pregnant, female mice, and she injects him with something that that it's
she doesn't actually infect them with virus. She puts a chemical in that is on the code of viruses that mimics viral infection. And then what happens is that in a way that interestingly is an interaction with the, with the bacterial content of her of her, God's produces a surge of a immune signaling molecule called interleukin 17 interleukin 17 can
Through the placenta into the fetus. And if it's present just, as you said at a particular point in development doesn't work anywhere during pregnancy, but during something that is sort of a mouse equivalent of the first trimester if that occurs, it causes disorder development of the layers of the cortex instead of it looking like layers of a cake. You see balls and clumps of cells and parenthetically in some but not all
All post-mortem tissue from autistic people. You can also see those balls and clumps of cells are those balls and clumps of cells thought to reflect alterations in cell migration, they are yes. Um, I don't know if it's entirely known how much of it is cell division or migration but certainly migration is a part of it and it's very likely that that critical moments to disrupt this ordering of the brain and produce.
These increases in schizophrenia or or Autism, vulnerability are coming at a point where neurons are migrating during development. And so what choice group did is they did all the things you would want to do as a biologist. So they gave things to block the function of a of this interleukin signaling molecule and it blocked the phenomenon, they artificially injected the signaling molecule into fetal brain when the
mom hadn't been stressed and they could, they could reproduce it. So I'm not saying that there aren't effects of stress hormones from the hypothalamic pituitary axis that are important that you mentioned. But in this mouse model system work, it seems that you can produce it through this immune signaling pathway. And and so then the question is well, like RV is mice, autistic. Well, how do you
No of a mouse is autistic and the answer is, it's actually a little vague right there. Are behaviors that Neuroscience just say are analogous of human autism and one of them is, If You Give a Mouse on marble in its home cage, it will bury it over and over again compulsively or bury many marbles, and people say that that is somehow analogous to some of the compulsive behaviors is in autism. It's a bit of a stretch, right? I mean, it's a
Challenge to interpret mouth behavior in in human terms but it's a reasonable first step.
Incredible. And I hope more will continue to be done as it surrounds the first, trimester influenza hypothesis because it's been around a while and and obviously, there's a spectrum of what we call autism, Asperger's, and nowadays. People refer to it as sometimes it's the neuro, a typical, there's some high functioning people with Autism, there's some low functioning people with Autism and for that matter. There's some hi.
Functioning and low functioning people who don't have autism. So but it is something that I think demands our attention and it that hopefully will be resolved at some point because also influenza is, but one immune insult and presumably pregnant, women are being bombarded with all sorts of viruses and bacteria and fungal infections and fighting them off. We're not fighting them off. And who knows what the
Ocean in neuro-immune. Interactions exist in there that give rise to you know, good variation and let's call it, you know, debilitating variation. Well, that's, that's absolutely right. And so for one example, is that we don't know what the effects are on. The children who were in utero while their mothers were fighting off coded, right? We won't know.
For for a while or the common cold and their might I mean there might be nothing but or there might be something serious lurking there. Like there was for pandemic flu and will be very interesting and and important to find out agreed, I'd love to talk with you about mind body, but before we do that, I would be totally remiss if I didn't ask for your
Broad top Contour understanding of the mini brain, the cerebellum the so-called mini brain. And here's why I've been a practicing neuroscientist for close to three decades. I know where the cerebellum is. I've dissected a bunch of them, I could tell you where a few things are in there and I certainly have read about what the cerebellum does but whenever I do a PubMed search on cerebellum I see
Intelligence general intelligence. Now, there are people who argue about do things like IQ tests really measure anything real. And there's been a lot of fighting in the scientific literature about this, but I think intelligence tests aren't perfect and they are sometimes culture-bound, but they are actually quite predictive of of later success and much more. So than say, sat tests or GRE tests or
Or em cats or other standardized tests, and presumably those correlate in some way they do by do but, but but IQ tests are better. Actually there's any about this, the classic IQ test, I am talking about the modern variants of the classic IQ tests that are administered by trained psychologists and aren't just a paper form. And so they're not perfect and no test will be perfect but they're pretty good. And so then if you
The question. Well, what is the heritability for IQ test score? Well, the answer tends to be different depending upon the population. If you look again in in countries, like the us, or in Western Europe, that are fairly affluent, where people tend to have good access to to nutrition and medical care and schooling and kids get to play on their not and
Are not traumatized by War. Then then IQ test score is heritable in the ballpark of 60-70 percent, but if you look at people who don't have those benefits who are poor and this can be in the United States as well. If you look at communities that that face discrimination and have consistently poor, poor health care in school.
Then IQ is less heritable. Why for the very same reason that it is on height because people can't live up to their genetic potential. When they don't have the basic things that everybody needs. So presumably if two identical twins and I realized they aren't identical, but you're familiar with twins. You have twin children. If two identical twins are raised separately.
Lee the correlation in their IQ is can only is it that only 60? I think you said about 66 percent of their IQ and be predicted on the basis of their genetic makeup alone. I mean it makes perfect sense to me as to why if one of those twins went to schools that were demanding of, you know, a lot of different topic matter. And the other one went to schools where the instruction level was really difficult.
Sent that one would perform far less well on an IQ test unless of course the IQ test is in tapping into school based. Knowledge is tapping into some other thermometer of so-called intelligence or IQ. Well, you know, the thing is that good schools correlate with many other things, right? So the students that go to good schools aren't just benefiting from good schools. They tend to also have good medical care and safe or less traumatizing.
Neighborhoods and they're more likely to have books parents with books in the home. And, and and a whole number of things that are all beneficial. So when you try to do epidemiology on this, you have to be aware that things are very deeply interconnected, but, but you bring up a good point. So, it turns out that the way we get these estimates of heritability, there's two ways. One way is to compare,
So called identical or monozygotic twins with so-called fraternal or dizygotic twins. So the identical twins will share nearly 100% of their Gene variants and on average, fraternal twins share 50% of their of their Gene variants. And generally speaking when people do these studies in order to avoid confounds of sex, they'll compare same sex for turn
Twin. So boys, two boys and girls two girls, and when you put these incidents into a formula called Fisher's equation, then you can come up with an estimate of the heritability of the trade, but there is an assumption presence in that and it's called the equal environment. Assumption, you're saying, well to kids raised in the same family, have the same environments.
Oh, well, that's not always true, right? That can be violated by a number of different situations. So it turns out that a more powerful, but much more difficult way to estimate heritability, is by looking at twins, reared apart, either identical twins or fraternal twins, reared apart, and there was a landmark study called the Minnesota study of twins.
Her to part which is abbreviated mystery. That is really the gold standard for assessing the heritability of many different human traits, both behavioral traits but also disease incidents. But of course it's a small end because you know, the population of identical twins reared apart that you can get into the lab isn't isn't that large? They had something. I don't remember the exact numbers, but they had something like 80 some
identicals and fifty some for eternals in their in their sample. But by doing this, they were able to come up with a lot of interesting estimates. And so, for example, most personality traits, what the psychologists use the acronym ocean to mean, openness conscientiousness, empathy, agreeableness and neuroticism. I think I got that right, spelled right.
That these traits on average tend to be about 50% heritable and so, okay, stay right. Well, 50% of those personality traits is heritable. The rest is got to be like how you were raised. It's got to be in your family and so everyone was shocked when they actually did the analysis and found that family has almost nothing to do with it.
Ariel. And what are you kidding? It's got to and I think the important thing to realize is these traits. I just listed, you know, we call these personality traits but they are not the sum total of the way. You are in the world, parents can inculcate many things in their children, they can demonstrate trades. So people are much more likely to go into an occupation. If their parents did they can inculcate moral
Ideas and religious ideas. But in terms of these ocean personality traits, they have astonishingly little to do with it. So then this brings up the question. Well if 50 percent of the variation in these personality traits is not from your genetics and it's not from your family, where does it come from? And the answer seems to be is that it comes from
The random nature of the development of the body and the nervous system and this is, this is a point that I think many people don't understand. This is something that biologists know, but we've done a very poor job of communicating, to the general public. The genome, all your DNA, all 3 billion bases of DNA all 19,000.
Or so genes in human, don't make a blueprint for making your body and brain there. It's not all schematic diagram, that connects everything to everything, particularly in the nervous system where we have these hundreds of trillions of connections, rather, it's a rather vague recipe. So the genome doesn't say, oh okay, you glutamate using neuron in the brain region called the thalamus, you know, grow for 200 microns towards the top and then
And then and then cross the midline and then grow towards the ear for, you know, another distance. No, it says something like, hey, you bunch of glutamate neurons in the thalamus over here in this area about half of you, cross the midline. And so what does this mean in terms of individual variation, which means, well, for, for some individuals, 40% of their axons will cross the midline of the brain and for another individual 60% will even in identical twins.
And as you correctly, said, a moment ago. Identical twins aren't really identical either in their bodies or their temperament. So, if you take newborn identical twins and you give them a CT scan, just to measure the shape of their organs, they're not the same. You might have one twin whose spleen is 30% larger than than the other Twins or whose liver is 30% smaller than the other twins, even though they have the exact same DNA, and there were lying right next to each other. In the
And presumably have the same or very similar. Fetal environment. And the reason is the random or as we say, stochastic nature of neural development, a great way to study this is with nine-banded armadillo those. I know we're getting weird here but I love the armadillo because I've been told tell me I don't want to interrupt you too long but as far as I know the only
Animal in North America that carries leprosy. That is, that is true. And and there's a lot of twinning going on in Armadillos, right? Well what there is is actually quadding. So armadillos or the nine-banded armadillo in particular and they're different armadillos. I'm not really an armadillo specialist. I don't know if this holds for all of them but the nine-banded armadillo is born as identical quadruplets.
Awesome, awesome. So you can take these identical quadruplets newly-born armadillo. I do. You think you call them pups? I don't know what a baby armadillo is called. I'm sure there's some particular word for it and someone will tell us. I'm sure someone in the comments on YouTube. What is the name of a baby armadillo? I know like a ferret baby ferrets are kits. The moms are Jill's. The dads are bobs. I used to be obsessed with this kind of naming at, you know, it's a, it's a business of ferrets or what is like a gang of
Raccoons or whatever. It's so if you can tell us what the name is for the baby armadillos, as well as. What do you call a group of armadillos? You win? The pride associated with being right? That's right right. One of my favorites, nose on ostentation of peacocks amazing or a murder of crows who comes up with this guy. I know it's a raft of otters, I think it, I think that's correct. But so if you have for newborn identical 9
Unbounded armadillos. Then this is a great model system that biologists can use to study stochastic, differences and development and sure enough their brains are wired slightly differently. Their bodies are slightly different, if you test them behaviourally, even very very early in life, they have different propensities summer. Bolder will Explore More somewhere. Will tend to hide in the corner more and you know we know this from the lab you get a box of mice.
They're inbred from the breeder and you pluck them out and they're not behaviourally identical. Some might try to bite your hand, some will run away, some will stand stockstill. Where does this behavioral variation come from in mice? That are nearly genetically identical? Well, it comes from bunch of things. They don't always have exactly equal experience, but mostly it comes from the pseudo-random stochastic nature of development. I'd like to take a quick break and
HR sponsor inside tracker inside tracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you meet your health goals. I'm a big believer in getting regular blood work done. For the simple reason that many of the factors that impact your immediate and long-term Health can only be analyzed from a quality blood test. However, with a lot of blood tests out there, you get information back about blood lipids, about hormones, and so on. But you don't know what to do with that information with inside tracker. They have a personalized platform that makes it very
Easy to understand your data, that is to understand what those lipids with those hormone levels, etc, mean and behavioral supplement nutrition and other protocols to adjust those numbers, to bring them into the ranges that are ideal for your immediate and long-term Health inside. Trackers ultimate plan. Now includes measures of both apob and of insulin which are key indicators of cardiovascular, health and energy regulation. If you'd like to try inside track or you can visit inside tracker, dot, coms huberman, to get 20% off any of inside, trackers plans,
Again that's inside tracker.com huberman to get 20% off and is the pseudo, random stochastic nature of development. One of the maging, major scuse me driving forces for evolution because, you know, we hear about mutations and we always think we're people tend to think rather that mutations are bad. But of course, mutations provide the variation that can also subserve. Adaptive traits. I mean, if you're a fan of the X-Men, as I am huge, fan of the X-Men, the entire series, every single one, including the
In movies, you quickly, come to learn. That genetic mutation is at the heart of variation, which is at the heart of individuality, which is what we're talking about, right? And so, genetic variation is at the heart of individuality. But there is also, there are also these other things, right? That we've talked about, there's the effects of early life experience. And there is the stochastic nature and development. Because if you through the randomness of development happen to have like a
Early great liver. You're not going to pass that on to your children, right? That isn't in your germ line, you won't pass that traits along just brief insert here on germline. We had ODed rush off, e, on the podcast who studies epigenetic transmission and and an inheritance of of it's not lamarckian we have to point that out but inheritance of sort of acquired traits, it does happen at the germ line is the
That are present in the sperm and in the eggs, all the other cells of your body have genes, of course. But the best way to put this is simply going to the gym and getting fit does not make your children more fit because the germ line as far as we know, is not modified in a direct way. In other words, the DNA within sperm and eggs are not modified according to your behaviors in most but not all cases. That's right. And as you as you correctly said,
Said about oh Dad's work and other people's work. There is what's called transgenerational epigenetic inheritance, which means that you can have traits that are passed not from one generation to the next. But even two generations to the grandchildren that don't require modification of DNA, but to date that has been shown very convincingly in in a worms. And implants, the evidence in mammals is is really not there yet.
In my opinion and most of the claims for that and it's a very popular thing to say I epigenetically inherited my grandmother's our great-grandmother's. Trauma, the evidence that presence is is poor. Actually, a lot of it comes from epidemiology, most of which came from famines in the other colics region of Northern Sweden and they had very good medical
Kurds and they said, oh well, if your grandfather, went through the famine, then you're more likely to have this trait if you're male, or if your grandmother went through this, then if you're, if you're male, this train, your female have that trait. And I mean, there are two problems, one is that there's not a biological mechanism, but the other problem is that, the way these things were discovered, is by something called harking, or hypothesizing. After the Revolt results are known, they did very many
Statistical comparisons to try to find something significant and you know from your work in the lab that when you do many comparisons you're going to get some things that look significance, just occasionally random way through through luck and you have to apply a statistical, correction called a bonferroni correction. When you make many, particularly post hoc comparisons after the experiment comparisons to set the bar, much higher for accepting that
At data. And most of those studies they didn't apply that correction. And I remain unconvinced of transgenerational epigenetic inheritance in mammals. Now let's be clear.
Just because it hasn't been shown convincingly now doesn't mean that it won't be. There are some good people working very hard on this and they may well describe a mechanism and show this convincingly in the years to come. But right now, you may well inherit your grandma's or great grandma's trauma, but you're probably doing it socially not through marks on your DNA. That changes. How your
Genes are expressed or not expressed. Yes so I subscribe to the idea that there is absolutely certainly transgenerational inheritance of parenting and upbringing, right? I mean your grandparents raised your parents who raised you? Not always people can be adopted. In fact, I have adopted members in my family but I understand what you're saying correctly.
The evidence that, for instance, some stress-related Gene was modified during a trauma in my grandparents or great-grandparents. And the idea that that was passed to me. Through my parents, that the evidence there is far weaker, right? And when you think about it, well, like, how did that happen that had to get into your, your grandparents sperm or egg cell and then produce that effect in the brain of your parents? And then
How to get into their sperm and eggs or egg cell and then contribute to producing it in you, but damn, but fragmentation of DNA and sperm is, or in eggs, is a common thing, especially, as people age, DNA, sperm, and eggs fragment, and it's possible that some of those mutations still allow for viable embryos. So, it's in theory, the germline could be changed by environmental events. Well, right? But now, I
I think you're starting to talk about things that are heritable, right? You're not talking about marks on DNA, you're talking about the structure of the DNA right itself and that is its own separate issue. Now, I think I want to be really careful about this because what is now, I think fairly well-established is that you can transfer things epigenetically over a single generation,
As a result of experiences that the mother has during pregnancy. So for example, we know that during the 1918 pandemic, flu, many women were pregnant and got the flu. And if you look at their children, you find interesting statistical anomalies and those children. For example, the male's wound up going
Into the army for World War 2. And of course, the Army does a complete physical and the records are very good so you can go into that database. And you find that the male children that were in utero during the winter of 1918. During the pandemic flu are on average a millimeter or two shorter myself, mm to that's nothing. But in a huge statistical sample of millions of people that's enormously significant.
More interesting. Is that the incidence of schizophrenia went up about four fold from about 1 percent to about 4%? And even though autism wasn't a term in 1918 yet, I don't think came along later. What we now retrospectively would call autism. Also went up by about four fold. So there's something about mom being stressed.
And carrying the fetus at a particular stage, that seems to impact brain development in a way that then makes that child more likely to be schizophrenic or autistic when they grow up, do we know that it's stress and my recollection of this? I believe this was the late Paul sternberg's work as well. Maybe have that name incorrect but in any event that it is if pregnant mom gets the flu.
In the first trimester, you see this higher incidence of schizophrenia and autistic Offspring and but do we know that it's stress per se because it's stressful to have the flu but the flu is a bunch of other. Things could be fever, could be some breakdown in the immune barrier, I just want to open up the the number of variables that this could be 2 or do we know that it's something in the hypothalamic pituitary so-called stress axis, that is adrenals. So I perform
Pituitary, adrenal axis like is it elevated cortisol or could it literally be an immune neural interaction of some other sort? It's probably the last thing you mentioned an immune neural interaction. And the reason I say that is that Gloria Troy at MIT together with her, collaborators has made a mouse model of this phenomenon. So she takes pregnant, female mice, and she injects him with something that that it's
she doesn't actually infect them with virus. She puts a chemical in that is on the code of viruses that mimics viral infection. And then what happens is that in a way that interestingly is an interaction with the, with the bacterial content of her of her, God's produces a surge of a immune signaling molecule called interleukin 17 interleukin 17 can
Through the placenta into the fetus. And if it's present just, as you said at a particular point in development doesn't work anywhere during pregnancy, but during something that is sort of a mouse equivalent of the first trimester if that occurs, it causes disorder development of the layers of the cortex instead of it looking like layers of a cake. You see balls and clumps of cells and parenthetically in some but not all
All post-mortem tissue from autistic people. You can also see those balls and clumps of cells are those balls and clumps of cells thought to reflect alterations in cell migration, they are yes. Um, I don't know if it's entirely known how much of it is cell division or migration but certainly migration is a part of it and it's very likely that that critical moments to disrupt this ordering of the brain and produce.
These increases in schizophrenia or or Autism, vulnerability are coming at a point where neurons are migrating during development. And so what choice group did is they did all the things you would want to do as a biologist. So they gave things to block the function of a of this interleukin signaling molecule and it blocked the phenomenon, they artificially injected the signaling molecule into fetal brain when the
mom hadn't been stressed and they could, they could reproduce it. So I'm not saying that there aren't effects of stress hormones from the hypothalamic pituitary axis that are important that you mentioned. But in this mouse model system work, it seems that you can produce it through this immune signaling pathway. And and so then the question is well, like RV is mice, autistic. Well, how do you
No of a mouse is autistic and the answer is, it's actually a little vague right there. Are behaviors that Neuroscience just say are analogous of human autism and one of them is, If You Give a Mouse on marble in its home cage, it will bury it over and over again compulsively or bury many marbles, and people say that that is somehow analogous to some of the compulsive behaviors is in autism. It's a bit of a stretch, right? I mean, it's a
Challenge to interpret mouth behavior in in human terms but it's a reasonable first step.
Incredible. And I hope more will continue to be done as it surrounds the first, trimester influenza hypothesis because it's been around a while and and obviously, there's a spectrum of what we call autism, Asperger's, and nowadays. People refer to it as sometimes it's the neuro, a typical, there's some high functioning people with Autism, there's some low functioning people with Autism and for that matter. There's some hi.
Functioning and low functioning people who don't have autism. So but it is something that I think demands our attention and it that hopefully will be resolved at some point because also influenza is, but one immune insult and presumably pregnant, women are being bombarded with all sorts of viruses and bacteria and fungal infections and fighting them off. We're not fighting them off. And who knows what the
Ocean in neuro-immune. Interactions exist in there that give rise to you know, good variation and let's call it, you know, debilitating variation. Well, that's, that's absolutely right. And so for one example, is that we don't know what the effects are on. The children who were in utero while their mothers were fighting off coded, right? We won't know.
For for a while or the common cold and their might I mean there might be nothing but or there might be something serious lurking there. Like there was for pandemic flu and will be very interesting and and important to find out agreed, I'd love to talk with you about mind body, but before we do that, I would be totally remiss if I didn't ask for your
Broad top Contour understanding of the mini brain, the cerebellum the so-called mini brain. And here's why I've been a practicing neuroscientist for close to three decades. I know where the cerebellum is. I've dissected a bunch of them, I could tell you where a few things are in there and I certainly have read about what the cerebellum does but whenever I do a PubMed search on cerebellum I see
See, an ever-expanding said of things that the cerebellum has implicated in, not just balance as most people here. But also timing, also cognition, I hear about timing in particular motor Behavior, but then I also hear that's involved in learning and not just motor learning and it certainly is involved in motor learning, perhaps that little mini brain is doing 50 or a thousand different things. But how should we think about the cerebellum? What,
Is it doing? And what are some of its core operations that inform both what it's doing and perhaps what other areas of the brain are doing as well? Because I can point to the retinas or to auditory cortex or the thalamus and yes, there's some mysterious nuclei in the brain but to me, the cerebellum is one of the most cryptic and complicated structures to understand. And I know you spent some time in there. So
What's the cerebellum do well cerebellar researchers like to joke that the cerebellum was a counterweight to keep your head from falling forward perfect. Well with all the texting nowadays people need bigger Sarabeth's, right? That's right. Probably. Over many generations them that will happen along with a expansion of the thumbs. So but of course, everybody's going to text with their minds and about another 10 years, right? You'll have elon's implant them, you won't need your thumbs at all. Yeah, or maybe just five or my friend Eddie Chang is a neurosurgeon and
Works on the auditory system has been on this podcast before he was saying that, if in theory and actually in practice, you could just record the neural output to the muscles of the speech system essentially and you could just amplify that and you could text without actually speaking. In fact, when we read he told me we are actually receiving the signals.
As if we were going to speak the words we're reading but they don't quite arrived at the place where you could get a full-blown postsynaptic potential. So you're not actually moving the vocal Machinery. So that means the motor signals are getting sent out there and so you're speaking what you are reading but you just don't know it. That's right. It's very analogous to what happens during the REM phase of sleep, right? When you have commands, your brain is issuing commands to your muscles to to do things like behave.
In your dreams to her to run away or go here. Go there. But those signals actually are blocked in the brainstem prevented from from reaching your muscles because the nerves that don't go through your brain stem, like the ones that control, your eye movements aren't subject to that block. Hey, that's why you can produce the rapid eye movements in in REM sleep. But yeah, this is a general theme in the brand a lot of times you have the output but then you
You shut it down and there are REM sleep behavior disorders, where people thrash and move in their sleep during during REM. And it's because this outflow that's normally blocked isn't isn't blocked. Have you ever had the reverse happen? I have where you wake up and you're still in so called REM atonia, you're still paralyzed? Yes. And there's that Split Second that feels like eternity where you are wide awake and you cannot move and I'll tell you, it's terrifying. Yeah.
Sleep paralysis and actually, you know, it's been known forever. You can actually find ancient Greek depictions of people lying with a demon on their chest paralyzing them. And that is actually from sleep paralysis later. Hogarth did a drawing of exactly that. So yeah, there's a well-known phenomenon but to get back to the cerebellum as we started. So,
The cerebellum is as you said, definitely involved in motor coordination so people who have damage to the cerebellum aren't paralyzed but they tend to be clumsy. They tend to not coordinate their movements, they have a disturbed Gates, if they're reaching for an object, they often overshoot it and have to make success of approximating motions to get back to their target. So that's
Well understood but if you look through Evolution the cerebellum is connected to this brain region called the thalamus. And it's connected from there to many reasons, including the frontal cortex where phenomena like like planning and decision-making and moral sense, and many aspects of Personality seemed to be encoded. So then the
Question becomes well that's very far away from being clumsy. What are these connections doing? And as time has gone on, I've been in this business from over 40 years. Now I'm going to old guy and so initially we said oh yeah, cerebellum movement, control motor coordination. That's what it's for as time goes on. As you correctly, said, the cerebellum has been implicated in more and more functions. Many of which are far removed from the motor system and
We're looking for a theme about what the cerebellum does is that it is there too.
Predict the immediate future it's trying to determine what's going to happen in the next second or two to best guide behavior. And as you can imagine, this kind of General computation could be applied very well. You can see why it's important for her, you know, motor systems and doing sports. And you know if you're trying to hit a baseball looking what the picture is doing and trying to anticipate what the pitch is but it also comes up in
Social realm if we're trying to read someone and predict. What they are going to do is this person Friend or Foe? Which is one of the first things that we try to assess when meeting someone, are they competent? Which is the second thing we try to assess when meeting something. A lot of this depends upon predictive circuitry and it depends in part on the cerebellum. And it seems to be at least partially impaired in people who sustained cerebellar damage. So, it seems as if
If interestingly the cerebellum started out for prediction related for motor control and through Evolution, its basic computation has been applied to other non motor behaviors. Now, I'm speaking in generalities and a lot of the details of this remain to be worked out and understood. But I would say that is in a nutshell, the modern conception of the cerebellum.
Thank you finally somebody explains to me that a top Contour but highly informed way, what the cerebellum does. I couldn't be more grateful. My pleasure in all aspects of biology and life. The term nature versus nurture is relevant but never so much as when thinking about the nervous system and I know this firsthand because I've studied neural development. Both the nature side, the so-called
Hard stuff that genes just set up neurons wire up to that neuron etcetera. The cerebellum is in the back, the eyes are in the front, the hardwired stuff. And then the softwired stuff, the nurture stuff is the stuff that can be modified by experience. What are your thoughts on nature versus nurture and should there even be a versus in there? Yeah, I don't think there should. And I have a lot of problems with
with nature versus nurture as a as an expression, it was popularized by Francis Galton in the 19th century, a colleague of of Darwin's and I think it's wrong in or misleading in a lot of ways. So of course, the nature in nature versus nurture is meant in this case. To me and heritability, write, what you inherit it.
Gene variations from your mother and father and nurture means like how your parents are your community raised you. The problem I have with nurture is that it is too narrow. A term that really it should be replaced with the word experience and experience in the broadest possible sense. Not just social experience, but
the food's your mother ate when she was carrying you in utero. The diseases you fought off or your mother fought off while she was carrying you in utero, the bacterial population of your guts so experience. Meaning anything that impinges on you starting from the earliest stages of fetal developments, continuing to the last day of your life.
I think it should be very expansive, much, much more of them social experience in the family or the or the community. And as you mentioned I have a problem with a versus because there's this idea that these things are, are essentially in opposition. Well, is he that way because of of his Gene variants or is that way because of what what happened to him and I think the thing to realize
Why's is that experience and heredity, interact and all kinds of interesting ways. Some of which are oppositional and some of which are reinforcing a classic one from genetics, has to do with a genetic disease called phenylketonuria or PKU, which is an inability to to metabolize the dietary. Mmm.
Acid phenylalanine. And so, in order to have this, you have to inherit broken copies of this Gene from both your mother and your father. So, it's a so-called recessive trait and here's where the experience comes in. It only matters if you eat foods rich in the phenylalanine, if you don't, it doesn't matter that you inherited these things, right? So that's the way in which genes and experience, interact and idea of ways in which the
then they interact positively, think about athletic ability, right? So a lot of athletic ability is has a heritable component. If you are born fast, for example, then you're more likely to do Sports and practice them and get better at sports as a result of your experience. So here, genes and experience are feeding back on each other in a
Feedback loop. So, there really isn't a versus versus at all. And then, of course, the last thing is that this isn't the entirety. So, we talked earlier about the pseudo, random nature of development, stochastic development, and so if I were to take the phrase nature versus nurture and reconfigure it, I would change it to read.
Heritability, interacting with experience, filtered through the round of nature of development. Now, that doesn't fall off the tongue as elegantly as nature versus nurture. You know nature versus nurture is like if the govs the gloves don't fit, you must acquit. You know. It's got that kind of Snappy snare drum beats but I think it's a more accurate. So heritability interacting with experience filtered through the randomness of
Element. Yeah. So we can shorten that up and we'll just call it the Linden hypothesis. You know? I don't think I can take credit for that. It doesn't gets it belongs to other people. Sure. But but there's a long history and science of things being shortened up and coined. And that's as important. I'm not, we're not trying to rob attribution here. And the good news is perhaps
You can't call it the Linden hypothesis but I can write and what I found is as with the Galpin equation, which is now out there as a hydration. It's a formula formula that gives broad but research informed parameters as to how much water one should drink in order to maintain proper hydration for physiologist, dr. Andy Galpin who's a PhD in physiology and an expert in all aspects of exercise science. There's the Galpin equation. There's the sobered principle, so I'm naming these things left.
and right, where appropriate and
So I'm naming these things sparingly and where appropriate. So from here on out heritability, interacting with experience filtered through the randomness of development is the Linden hypothesis and I'll be damned if anyone's going to rename it faster than I'm going to propagate it. Sorry. Well, I think all the the geneticists will be gnashing their teeth about this being named after someone, who isn't actually a geneticist quite. All right, and their dentists will thank me.
I earwax, and it turns out that this is determined by variation. In a single Gene, the name of the gene is boring. It's a b c, C11. It's a ion transporter and there is a variation in this Gene gives rise to either wet or dry earwax. It doesn't matter how your parents raised you, it doesn't matter what foods. You ate, growing up, doesn't matter what? What diseases your mother had when you were in the womb,
It's 100% heritable. Well, does this mean that a b c? C11 we should call it the earwax type Gene? Well, no, because it's not there just for that like this. This Gene is expressed in cells and all parts of the body of doing, all kinds of things earwax is just something that we notice genes don't coach for traits, they code for proteins and so we have to be careful about how we refer to them in that way.
For example, the wet earwax G of variant of the abcc. 11 Jean also, confers a slightly higher risk for breast cancer. So clearly it's not just for earwax, it's for a bunch of things. Most of which we don't yet know about, but in the case of earwax, this trade is 100% heritable. At the other end of the scale speech accent is 0%, terrible. It is entirely dependent.
Dependent upon the speech that you experience in your childhood. And interestingly it's the speech of your peers more than the speech of your family, which is why the children of immigrants sound like the place where they wound up, not like their parents. And there is no evidence for any degree of heritability. Now, just to be clear, I'm talking about speech accent, like whether you have a high or a low voice or it's nasal or more or less resident, these are physical things having to do with the vocal tract,
They are in part heritable. Okay, so we've got one thing, that's 100% heritable. One thing is 0% heritable, but where do most Things Fall? Most Things fall in the middle? One of the most heritable traits that we know about in humans, is height and in the United States. Height is about 85% heritable, 85 percent of the variation, in the trait of height can be explained by what you inherited.
Heard from your mother and your father. Well what's the rest? Well it's nutrition. It's the diseases you fought off. It's also random variation which we'll talk about a lot later. Now you might say OK. Well that's an estimate for people. In the u.s. is this true all over the world? Will know if you go to a place where people routinely don't get enough nutrition and are routinely
Fighting off infectious diseases. Like, this is been studied in rural Bolivia, for example, a rural India, now height is no longer 85% heritable. It's only 50% terrible. Why? Because people in these situations where they don't get enough nourishment, where they're fighting off these diseases, can't live up to their genetic potential,
For height. If you want to make things better for the people of the world, then everyone needs to have basic things like the ability to learn enough nutrition and decent Medical Care and schools in order to fulfil, their genetic potential for positive traits and height. I've used as an example because it is
Very uncontroversial, but we could apply the very same analysis to intelligence general intelligence. Now, there are people who argue about do things like IQ tests really measure anything real, and there's been a lot of fighting in the scientific literature about this, but I think intelligence tests aren't perfect and they are sometimes culture-bound, but they are actually quite predictive of
Later success and much more. So than say, sat tests or GRE tests or em cats, or other standardized tests, and presumably those correlate in some way they do by do but but but IQ tests are better. Actually there's any about this, the classic IQ test, I am talking about the modern variants of the classic IQ tests that are administered by trained psychologists and aren't just a paper.
And so they're not perfect and no test will be perfect, but they're pretty good. And so, then if you ask the question, well, what is the heritability for IQ test score? Well, the answer tends to be different depending upon the population. If you look again in in countries, like the us, or in Western Europe, that are fairly affluent, where people tend
To have good access to two nutrition and medical care and schooling and kids get to play on. They're not, and they're not traumatized by War. Then then IQ test score is heritable in the ballpark of 60-70 percent, but if you look at people who don't have those benefits who are poor and this can be in the United States as well. If you look at
It is that that face discrimination and have consistently poor, poor health care in schools then IQ is less heritable. Why for the very same reason that it is on height because people can't live up to their genetic potential when they don't have the basic things that everybody needs. So presumably if two identical twins and I realized they aren't identical but your
Familiar with twins. You have twin children. If two identical twins are raised separately, the correlation in their IQ is can only is it that only 60, I think you said about 66 percent of their IQ and be predicted on the basis of their genetic makeup alone. I mean it makes perfect sense to me as to why if one of those twins went to schools that were demanding of you know, a
Different topic matter. And the other one went to schools where the instruction level was really deficient that one would perform far less well on an IQ test unless of course the IQ test isn't tapping into school based knowledge is tapping into some other thermometer of so-called intelligence or IQ. Well, you know, the thing is that good schools correlate with many other things, right?
So the students that go to good schools aren't just benefiting from good schools. They tend to also have good medical care and safe or less traumatizing neighborhoods and they're more likely to have books parents with books in the home. And and and a whole number of things that are all beneficial. So when you try to do epidemiology on this, you have to be aware that things are very deeply interconnected but but you bring up a good point. So it turns out that the way we get these estimates of heritability, there's two ways.
One way is to compare so-called identical or monozygotic twins with so-called fraternal or dizygotic twins. So the identical twins will share nearly 100% of their Gene variants, and on average, fraternal twins share 50% of their of their Gene variants. And generally speaking, when people do these studies in order to avoid,
Boyd confounds of sex, they'll compare same-sex fraternal twins. So boys, two boys and girls two girls. And when you put these incidents into a formula called Fisher's equation, then you can come up with an estimate of the heritability of the trade, but there is an assumption presence in that and it's called the equal environment assumption. You're saying well, two kids,
Is raised in the same family. Have the same environment. Well, that's not always true, right? That can be violated by a number of different situations. So it turns out that a more powerful, but much more difficult way to estimate heritability, is by looking at twins, reared apart, either. Identical twins or fraternal twins, reared apart. And there was a
A landmark study called the Minnesota study of twins reared apart, which is abbreviated mistress. That is really the gold standard for assessing the heritability of many different human traits, both behavioral traits but also disease incidents. But of course, it's a small end because, you know, the population of identical twins reared apart that you can get into the lab isn't isn't that large? They had something I don't
The exact numbers, but they have something like, 80 some identicals, and fifty some fraternal, 's in their, in their sample. But by doing this, they were able to come up with a lot of interesting estimates. And so, for example, most personality traits, what the psychologists use the acronym ocean to mean, openness conscientiousness, empathy agreeableness,
Us and neuroticism. I think I got that right spelled right. That these traits on average tend to be about 50% heritable and so, okay, stay right. Well, 50% of those personality traits is heritable. The rest is got to be like how you were raised. It's got to be in your family and so everyone was shocked when they actually did the analysis and found that family has almost nothing to.
With that.
Ariel's and everyone. But what are you kidding? It's got to and I think the important thing to realize is these traits. I just listed, you know, we call these personality traits but they are not the sum total of the way. You are in the world, parents can inculcate many things in their children, they can demonstrate trades. So people are much more likely to go into an occupation. If their parents did they can inculcate moral
Ideas and religious ideas. But in terms of these ocean personality traits, they have astonishingly little to do with it. So then this brings up the question. Well if 50 percent of the variation in these personality traits is not from your genetics and it's not from your family, where does it come from? And the answer seems to be is that it comes from
The random nature of the development of the body and the nervous system and this is, this is a point that I think many people don't understand. This is something that biologists know, but we've done a very poor job of communicating, to the general public. The genome, all your DNA, all 3 billion bases of DNA all 19,000.
Or so genes in human, don't make a blueprint for making your body and brain there. It's not all schematic diagram, that connects everything to everything, particularly in the nervous system where we have these hundreds of trillions of connections, rather, it's a rather vague recipe. So the genome doesn't say, oh okay, you glutamate using neuron in the brain region called the thalamus, you know, grow for 200 microns towards the top and then
And then and then cross the midline and then grow towards the ear for, you know, another distance. No, it says something like, hey, you bunch of glutamate neurons in the thalamus over here in this area about half of you, cross the midline. And so what does this mean in terms of individual variation, which means, well, for, for some individuals, 40% of their axons will cross the midline of the brain and for another individual 60% will even in identical twins.
And as you correctly, said, a moment ago. Identical twins aren't really identical either in their bodies or their temperament. So, if you take newborn identical twins and you give them a CT scan, just to measure the shape of their organs, they're not the same. You might have one twin whose spleen is 30% larger than than the other Twins or whose liver is 30% smaller than the other twins, even though they have the exact same DNA, and there were lying right next to each other. In the
And presumably have the same or very similar. Fetal environment. And the reason is the random or as we say, stochastic nature of neural development, a great way to study this is with nine-banded armadillo those. I know we're getting weird here but I love the armadillo because I've been told tell me I don't want to interrupt you too long but as far as I know the only
Animal in North America that carries leprosy. That is, that is true. And and there's a lot of twinning going on in Armadillos, right? Well what there is is actually quadding. So armadillos or the nine-banded armadillo in particular and they're different armadillos. I'm not really an armadillo specialist. I don't know if this holds for all of them but the nine-banded armadillo is born as identical quadruplets.
Awesome, awesome. So you can take these identical quadruplets newly-born armadillo. I do. You think you call them pups? I don't know what a baby armadillo is called. I'm sure there's some particular word for it and someone will tell us. I'm sure someone in the comments on YouTube. What is the name of a baby armadillo? I know like a ferret baby ferrets are kits. The moms are Jill's. The dads are bobs. I used to be obsessed with this kind of naming at, you know, it's a, it's a business of ferrets or what is like a gang of
Raccoons or whatever. It's so if you can tell us what the name is for the baby armadillos, as well as. What do you call a group of armadillos? You win? The pride associated with being right? That's right right. One of my favorites, nose on ostentation of peacocks amazing or a murder of crows who comes up with this guy. I know it's a raft of otters, I think it, I think that's correct. But so if you have for newborn identical 9
Unbounded armadillos. Then this is a great model system that biologists can use to study stochastic, differences and development and sure enough their brains are wired slightly differently. Their bodies are slightly different, if you test them behaviourally, even very very early in life, they have different propensities summer. Bolder will Explore More somewhere. Will tend to hide in the corner more and you know we know this from the lab you get a box of mice.
They're inbred from the breeder and you pluck them out and they're not behaviourally identical. Some might try to bite your hand, some will run away, some will stand stockstill. Where does this behavioral variation come from in mice? That are nearly genetically identical? Well, it comes from bunch of things. They don't always have exactly equal experience, but mostly it comes from the pseudo-random stochastic nature of development. I'd like to take a quick break and
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Again that's inside tracker.com huberman to get 20% off and is the pseudo, random stochastic nature of development. One of the maging, major scuse me driving forces for evolution because, you know, we hear about mutations and we always think we're people tend to think rather that mutations are bad. But of course, mutations provide the variation that can also subserve. Adaptive traits. I mean, if you're a fan of the X-Men, as I am huge, fan of the X-Men, the entire series, every single one, including the
In movies, you quickly, come to learn. That genetic mutation is at the heart of variation, which is at the heart of individuality, which is what we're talking about, right? And so, genetic variation is at the heart of individuality. But there is also, there are also these other things, right? That we've talked about, there's the effects of early life experience. And there is the stochastic nature and development. Because if you through the randomness of development happen to have like a
Early great liver. You're not going to pass that on to your children, right? That isn't in your germ line, you won't pass that traits along just brief insert here on germline. We had ODed rush off, e, on the podcast who studies epigenetic transmission and and an inheritance of of it's not lamarckian we have to point that out but inheritance of sort of acquired traits, it does happen at the germ line is the
That are present in the sperm and in the eggs, all the other cells of your body have genes, of course. But the best way to put this is simply going to the gym and getting fit does not make your children more fit because the germ line as far as we know, is not modified in a direct way. In other words, the DNA within sperm and eggs are not modified according to your behaviors in most but not all cases. That's right. And as you as you correctly said,
Said about oh Dad's work and other people's work. There is what's called transgenerational epigenetic inheritance, which means that you can have traits that are passed not from one generation to the next. But even two generations to the grandchildren that don't require modification of DNA, but to date that has been shown very convincingly in in a worms. And implants, the evidence in mammals is is really not there yet.
In my opinion and most of the claims for that and it's a very popular thing to say I epigenetically inherited my grandmother's our great-grandmother's. Trauma, the evidence that presence is is poor. Actually, a lot of it comes from epidemiology, most of which came from famines in the other colics region of Northern Sweden and they had very good medical
Kurds and they said, oh well, if your grandfather, went through the famine, then you're more likely to have this trait if you're male, or if your grandmother went through this, then if you're, if you're male, this train, your female have that trait. And I mean, there are two problems, one is that there's not a biological mechanism, but the other problem is that, the way these things were discovered, is by something called harking, or hypothesizing. After the Revolt results are known, they did very many
Statistical comparisons to try to find something significant and you know from your work in the lab that when you do many comparisons you're going to get some things that look significance, just occasionally random way through through luck and you have to apply a statistical, correction called a bonferroni correction. When you make many, particularly post hoc comparisons after the experiment comparisons to set the bar, much higher for accepting that
At data. And most of those studies they didn't apply that correction. And I remain unconvinced of transgenerational epigenetic inheritance in mammals. Now let's be clear.
Just because it hasn't been shown convincingly now doesn't mean that it won't be. There are some good people working very hard on this and they may well describe a mechanism and show this convincingly in the years to come. But right now, you may well inherit your grandma's or great grandma's trauma, but you're probably doing it socially not through marks on your DNA. That changes. How your
Genes are expressed or not expressed. Yes so I subscribe to the idea that there is absolutely certainly transgenerational inheritance of parenting and upbringing, right? I mean your grandparents raised your parents who raised you? Not always people can be adopted. In fact, I have adopted members in my family but I understand what you're saying correctly.
The evidence that, for instance, some stress-related Gene was modified during a trauma in my grandparents or great-grandparents. And the idea that that was passed to me. Through my parents, that the evidence there is far weaker, right? And when you think about it, well, like, how did that happen that had to get into your, your grandparents sperm or egg cell and then produce that effect in the brain of your parents? And then
How to get into their sperm and eggs or egg cell and then contribute to producing it in you, but damn, but fragmentation of DNA and sperm is, or in eggs, is a common thing, especially, as people age, DNA, sperm, and eggs fragment, and it's possible that some of those mutations still allow for viable embryos. So, it's in theory, the germline could be changed by environmental events. Well, right? But now, I
I think you're starting to talk about things that are heritable, right? You're not talking about marks on DNA, you're talking about the structure of the DNA right itself and that is its own separate issue. Now, I think I want to be really careful about this because what is now, I think fairly well-established is that you can transfer things epigenetically over a single generation,
As a result of experiences that the mother has during pregnancy. So for example, we know that during the 1918 pandemic, flu, many women were pregnant and got the flu. And if you look at their children, you find interesting statistical anomalies and those children. For example, the male's wound up going
Into the army for World War 2. And of course, the Army does a complete physical and the records are very good so you can go into that database. And you find that the male children that were in utero during the winter of 1918. During the pandemic flu are on average a millimeter or two shorter myself, mm to that's nothing. But in a huge statistical sample of millions of people that's enormously significant.
More interesting. Is that the incidence of schizophrenia went up about four fold from about 1 percent to about 4%? And even though autism wasn't a term in 1918 yet, I don't think came along later. What we now retrospectively would call autism. Also went up by about four fold. So there's something about mom being stressed.
And carrying the fetus at a particular stage, that seems to impact brain development in a way that then makes that child more likely to be schizophrenic or autistic when they grow up, do we know that it's stress and my recollection of this? I believe this was the late Paul sternberg's work as well. Maybe have that name incorrect but in any event that it is if pregnant mom gets the flu.
In the first trimester, you see this higher incidence of schizophrenia and autistic Offspring and but do we know that it's stress per se because it's stressful to have the flu but the flu is a bunch of other. Things could be fever, could be some breakdown in the immune barrier, I just want to open up the the number of variables that this could be 2 or do we know that it's something in the hypothalamic pituitary so-called stress axis, that is adrenals. So I perform
Pituitary, adrenal axis like is it elevated cortisol or could it literally be an immune neural interaction of some other sort? It's probably the last thing you mentioned an immune neural interaction. And the reason I say that is that Gloria Troy at MIT together with her, collaborators has made a mouse model of this phenomenon. So she takes pregnant, female mice, and she injects him with something that that it's
she doesn't actually infect them with virus. She puts a chemical in that is on the code of viruses that mimics viral infection. And then what happens is that in a way that interestingly is an interaction with the, with the bacterial content of her of her, God's produces a surge of a immune signaling molecule called interleukin 17 interleukin 17 can
Through the placenta into the fetus. And if it's present just, as you said at a particular point in development doesn't work anywhere during pregnancy, but during something that is sort of a mouse equivalent of the first trimester if that occurs, it causes disorder development of the layers of the cortex instead of it looking like layers of a cake. You see balls and clumps of cells and parenthetically in some but not all
All post-mortem tissue from autistic people. You can also see those balls and clumps of cells are those balls and clumps of cells thought to reflect alterations in cell migration, they are yes. Um, I don't know if it's entirely known how much of it is cell division or migration but certainly migration is a part of it and it's very likely that that critical moments to disrupt this ordering of the brain and produce.
These increases in schizophrenia or or Autism, vulnerability are coming at a point where neurons are migrating during development. And so what choice group did is they did all the things you would want to do as a biologist. So they gave things to block the function of a of this interleukin signaling molecule and it blocked the phenomenon, they artificially injected the signaling molecule into fetal brain when the
mom hadn't been stressed and they could, they could reproduce it. So I'm not saying that there aren't effects of stress hormones from the hypothalamic pituitary axis that are important that you mentioned. But in this mouse model system work, it seems that you can produce it through this immune signaling pathway. And and so then the question is well, like RV is mice, autistic. Well, how do you
No of a mouse is autistic and the answer is, it's actually a little vague right there. Are behaviors that Neuroscience just say are analogous of human autism and one of them is, If You Give a Mouse on marble in its home cage, it will bury it over and over again compulsively or bury many marbles, and people say that that is somehow analogous to some of the compulsive behaviors is in autism. It's a bit of a stretch, right? I mean, it's a
Challenge to interpret mouth behavior in in human terms but it's a reasonable first step.
Incredible. And I hope more will continue to be done as it surrounds the first, trimester influenza hypothesis because it's been around a while and and obviously, there's a spectrum of what we call autism, Asperger's, and nowadays. People refer to it as sometimes it's the neuro, a typical, there's some high functioning people with Autism, there's some low functioning people with Autism and for that matter. There's some hi.
Functioning and low functioning people who don't have autism. So but it is something that I think demands our attention and it that hopefully will be resolved at some point because also influenza is, but one immune insult and presumably pregnant, women are being bombarded with all sorts of viruses and bacteria and fungal infections and fighting them off. We're not fighting them off. And who knows what the
Ocean in neuro-immune. Interactions exist in there that give rise to you know, good variation and let's call it, you know, debilitating variation. Well, that's, that's absolutely right. And so for one example, is that we don't know what the effects are on. The children who were in utero while their mothers were fighting off coded, right? We won't know.
For for a while or the common cold and their might I mean there might be nothing but or there might be something serious lurking there. Like there was for pandemic flu and will be very interesting and and important to find out agreed, I'd love to talk with you about mind body, but before we do that, I would be totally remiss if I didn't ask for your
Broad top Contour understanding of the mini brain, the cerebellum the so-called mini brain. And here's why I've been a practicing neuroscientist for close to three decades. I know where the cerebellum is. I've dissected a bunch of them, I could tell you where a few things are in there and I certainly have read about what the cerebellum does but whenever I do a PubMed search on cerebellum I see
See, an ever-expanding said of things that the cerebellum has implicated in, not just balance as most people here. But also timing, also cognition, I hear about timing in particular motor Behavior, but then I also hear that's involved in learning and not just motor learning and it certainly is involved in motor learning, perhaps that little mini brain is doing 50 or a thousand different things. But how should we think about the cerebellum? What,
Is it doing? And what are some of its core operations that inform both what it's doing and perhaps what other areas of the brain are doing as well? Because I can point to the retinas or to auditory cortex or the thalamus and yes, there's some mysterious nuclei in the brain but to me, the cerebellum is one of the most cryptic and complicated structures to understand. And I know you spent some time in there. So
What's the cerebellum do well cerebellar researchers like to joke that the cerebellum was a counterweight to keep your head from falling forward perfect. Well with all the texting nowadays people need bigger Sarabeth's, right? That's right. Probably. Over many generations them that will happen along with a expansion of the thumbs. So but of course, everybody's going to text with their minds and about another 10 years, right? You'll have elon's implant them, you won't need your thumbs at all. Yeah, or maybe just five or my friend Eddie Chang is a neurosurgeon and
Works on the auditory system has been on this podcast before he was saying that, if in theory and actually in practice, you could just record the neural output to the muscles of the speech system essentially and you could just amplify that and you could text without actually speaking. In fact, when we read he told me we are actually receiving the signals.
As if we were going to speak the words we're reading but they don't quite arrived at the place where you could get a full-blown postsynaptic potential. So you're not actually moving the vocal Machinery. So that means the motor signals are getting sent out there and so you're speaking what you are reading but you just don't know it. That's right. It's very analogous to what happens during the REM phase of sleep, right? When you have commands, your brain is issuing commands to your muscles to to do things like behave.
In your dreams to her to run away or go here. Go there. But those signals actually are blocked in the brainstem prevented from from reaching your muscles because the nerves that don't go through your brain stem, like the ones that control, your eye movements aren't subject to that block. Hey, that's why you can produce the rapid eye movements in in REM sleep. But yeah, this is a general theme in the brand a lot of times you have the output but then you
You shut it down and there are REM sleep behavior disorders, where people thrash and move in their sleep during during REM. And it's because this outflow that's normally blocked isn't isn't blocked. Have you ever had the reverse happen? I have where you wake up and you're still in so called REM atonia, you're still paralyzed? Yes. And there's that Split Second that feels like eternity where you are wide awake and you cannot move and I'll tell you, it's terrifying. Yeah.
Sleep paralysis and actually, you know, it's been known forever. You can actually find ancient Greek depictions of people lying with a demon on their chest paralyzing them. And that is actually from sleep paralysis later. Hogarth did a drawing of exactly that. So yeah, there's a well-known phenomenon but to get back to the cerebellum as we started. So,
The cerebellum is as you said, definitely involved in motor coordination so people who have damage to the cerebellum aren't paralyzed but they tend to be clumsy. They tend to not coordinate their movements, they have a disturbed Gates, if they're reaching for an object, they often overshoot it and have to make success of approximating motions to get back to their target. So that's
Well understood but if you look through Evolution the cerebellum is connected to this brain region called the thalamus. And it's connected from there to many reasons, including the frontal cortex where phenomena like like planning and decision-making and moral sense, and many aspects of Personality seemed to be encoded. So then the
Question becomes well that's very far away from being clumsy. What are these connections doing? And as time has gone on, I've been in this business from over 40 years. Now I'm going to old guy and so initially we said oh yeah, cerebellum movement, control motor coordination. That's what it's for as time goes on. As you correctly, said, the cerebellum has been implicated in more and more functions. Many of which are far removed from the motor system and
We're looking for a theme about what the cerebellum does is that it is there too.
Predict the immediate future it's trying to determine what's going to happen in the next second or two to best guide behavior. And as you can imagine, this kind of General computation could be applied very well. You can see why it's important for her, you know, motor systems and doing sports. And you know if you're trying to hit a baseball looking what the picture is doing and trying to anticipate what the pitch is but it also comes up in
Social realm if we're trying to read someone and predict. What they are going to do is this person Friend or Foe? Which is one of the first things that we try to assess when meeting someone, are they competent? Which is the second thing we try to assess when meeting something. A lot of this depends upon predictive circuitry and it depends in part on the cerebellum. And it seems to be at least partially impaired in people who sustained cerebellar damage. So, it seems as if
If interestingly the cerebellum started out for prediction related for motor control and through Evolution, its basic computation has been applied to other non motor behaviors. Now, I'm speaking in generalities and a lot of the details of this remain to be worked out and understood. But I would say that is in a nutshell, the modern conception of the cerebellum.
Thank you finally somebody explains to me that a top Contour but highly informed way, what the cerebellum does. I couldn't be more grateful. My pleasure in all aspects of biology and life. The term nature versus nurture is relevant but never so much as when thinking about the nervous system and I know this firsthand because I've studied neural development. Both the nature side, the so-called
Hard stuff that genes just set up neurons wire up to that neuron etcetera. The cerebellum is in the back, the eyes are in the front, the hardwired stuff. And then the softwired stuff, the nurture stuff is the stuff that can be modified by experience. What are your thoughts on nature versus nurture and should there even be a versus in there? Yeah, I don't think there should. And I have a lot of problems with
with nature versus nurture as a as an expression, it was popularized by Francis Galton in the 19th century, a colleague of of Darwin's and I think it's wrong in or misleading in a lot of ways. So of course, the nature in nature versus nurture is meant in this case. To me and heritability, write, what you inherit it.
Gene variations from your mother and father and nurture means like how your parents are your community raised you. The problem I have with nurture is that it is too narrow. A term that really it should be replaced with the word experience and experience in the broadest possible sense. Not just social experience, but
the food's your mother ate when she was carrying you in utero. The diseases you fought off or your mother fought off while she was carrying you in utero, the bacterial population of your guts so experience. Meaning anything that impinges on you starting from the earliest stages of fetal developments, continuing to the last day of your life.
I think it should be very expansive, much, much more of them social experience in the family or the or the community. And as you mentioned I have a problem with a versus because there's this idea that these things are, are essentially in opposition. Well, is he that way because of of his Gene variants or is that way because of what what happened to him and I think the thing to realize
Why's is that experience and heredity, interact and all kinds of interesting ways. Some of which are oppositional and some of which are reinforcing a classic one from genetics, has to do with a genetic disease called phenylketonuria or PKU, which is an inability to to metabolize the dietary. Mmm.
Acid phenylalanine. And so, in order to have this, you have to inherit broken copies of this Gene from both your mother and your father. So, it's a so-called recessive trait and here's where the experience comes in. It only matters if you eat foods rich in the phenylalanine, if you don't, it doesn't matter that you inherited these things, right? So that's the way in which genes and experience, interact and idea of ways in which the
then they interact positively, think about athletic ability, right? So a lot of athletic ability is has a heritable component. If you are born fast, for example, then you're more likely to do Sports and practice them and get better at sports as a result of your experience. So here, genes and experience are feeding back on each other in a
Feedback loop. So, there really isn't a versus versus at all. And then, of course, the last thing is that this isn't the entirety. So, we talked earlier about the pseudo, random nature of development, stochastic development, and so if I were to take the phrase nature versus nurture and reconfigure it, I would change it to read.
Heritability, interacting with experience, filtered through the round of nature of development. Now, that doesn't fall off the tongue as elegantly as nature versus nurture. You know nature versus nurture is like if the govs the gloves don't fit, you must acquit. You know. It's got that kind of Snappy snare drum beats but I think it's a more accurate. So heritability interacting with experience filtered through the randomness of
Element. Yeah. So we can shorten that up and we'll just call it the Linden hypothesis. You know? I don't think I can take credit for that. It doesn't gets it belongs to other people. Sure. But but there's a long history and science of things being shortened up and coined. And that's as important. I'm not, we're not trying to rob attribution here. And the good news is perhaps
You can't call it the Linden hypothesis but I can write and what I found is as with the Galpin equation, which is now out there as a hydration. It's a formula formula that gives broad but research informed parameters as to how much water one should drink in order to maintain proper hydration for physiologist, dr. Andy Galpin who's a PhD in physiology and an expert in all aspects of exercise science. There's the Galpin equation. There's the sobered principle, so I'm naming these things left.
and right, where appropriate and
So I'm naming these things sparingly and where appropriate. So from here on out heritability, interacting with experience filtered through the randomness of development is the Linden hypothesis and I'll be damned if anyone's going to rename it faster than I'm going to propagate it. Sorry. Well, I think all the the geneticists will be gnashing their teeth about this being named after someone, who isn't actually a geneticist quite. All right, and their dentists will thank me.
Let's talk about Mind Body. Okay, I'm fascinated by this for a couple of reasons and I promise to keep this brief, but when I was growing up, I was very interested in animals and biology in my father's a scientist. And I got very interested in Neuroscience early as people crap snow and so much of Neuroscience as I was coming up through the mid 90s 2000s, 2000 10 to 20 stretch, which focused on the brain piece.
Very little on the body, there was nothing about gut-brain axis in the early discussions and coursework in parallel to all of that I've been interested in mental health, physical health, and let's just call it performance and got interested in meditation respiration based practices things. Like Yoga Nidra, things, that by way of experience, I understood immediately had a profound influence on the nervous system states of Mind and Body nowadays. There's an entire Institute at the national
National Institutes of Health, for complementary health and Medicine, essentially, exploring things like, Yoga Nidra, respiration practices, even supplements, and things of that sort, and there's this understanding that, oh, my goodness.
The nervous system extends into the body and the body sends neural signals back into the brain. And so this whole notion of Mind Body has fortunately, migrated away from kind of California counterculture esalen Institute, only, you know, hippie new-age Magic Carpet stuff by the way, that's not what I believe that's but that's often how it was looked at in the past. And now, people at every level of
Science and medicine at every major university. And in, every scientific journal are starting to publish papers about the interactions between bodily, organs, like the breathing apparatus. I the diaphragm lungs, the heart heart rate, variability. We hear about the liver the gut brain axis in particular. And so mind-body, the idea that our thoughts could influence our body and that our bodily State could influence our thoughts is. Fortunately, not just
Just understood. But it seems to be both accepted and appreciated. So what are your thoughts on mind-body? What does that mean to you? And what do you think is the potential of the mind-body interaction? It seems to me. We've just barely scratched the surface. Yeah. Well I'm glad you asked because I think it's a really fascinating situation and where things are changing very very quickly. And I think
Me the most important thing for people to understand is that when you have a hypothesis, let's say you have a hypothesis that meditation can attenuate, chronic pain, alright? Well, there is a temptation to think that this operates outside the realm of Science and biology. That is
In some airy-fairy realm in the clouds that this happens. And and, and I mean for for good reason, there are a lot of people who will describe it in exactly that way with auras or they Co-op scientific terms like resonance and energy but they don't actually use them in scientific way. So, you know, there's a lot of very fuzzy language that surrounds this but it shouldn't obscure. The fact that when you have a hypothesis that say
Some mental state like meditation or, or guided breathing effects, some process in the body. That
You should be trying to understand this in terms of a biological hypothesis. Not in terms of some some some
Indistinct realm. That that is, that is different like manifestation. Yeah, and you know, I really learned this initially from my father. My father was a psychiatrist. And fact, kind of a talking pure old-fashioned psychoanalyst, who had his practice in Los Angeles, and we would have dinner together every Wednesday night, and
He would always tell me about his patients, he was very careful to keep confidentiality, right? He wouldn't break confidentiality but you know, I would say, oh yes, how is your narcissist? Oh we had this dream. So this was, you know this was this was normal conversation when I was 14 15 years old with my dad and one day, I said, Dad it's really clear to me that through this talking cure, a large fraction of your patients feel better and they conquer their depression or or their obsessive thoughts or
Things that are blocking them. How do you think it works? And he says, well, we don't really know the mechanics, but ultimately when it works it's not working in some area. Farrier realm, it is working by changing the biology of the brain.
And when he said that it was like a lightning bolt went off in my head and I thought well I don't have the kind of personality to be a talking cure psychiatrist. I'm not nearly nice enough but I could understand the underlying biology. Maybe I'll do that. And so as you correctly pointed out, when you say the phrase mind-body, you're talking about two directions.
You're talking about mental functions, affecting the body and then you are also talking about how phenomena in the body effects affect the mind. And we're understanding so much more about how that happens. And I think the general thing for your listeners to appreciate is that we have some culprits.
Here, right? And generally speaking, there are there are two classes of culprits. So if you want to get signals about body to the mind, there's two ways to do that. One of them is through neurons that reach out into the body and sense things. And this is referred to as interoception, right? So as opposed to extra reception your outward, pointing senses. These are the senses that monitor your own body and
And while we can consciously be aware of a lot of that information. A lot of it is happening subconsciously, like your breathing is happening automatically most of the time without you thinking about it and that depends upon sensors about your blood chemistry and the state of your lungs, on a number of other things that are regulating that process and it's all happening in the brain. Usually below the level of your conscious attention in addition to the nurse
Neural signals. There is also a whole realm of hormonal or diffusible immune signals. And what these are is that, these are chemicals that are released into the bloodstream and that move throughout the body and that can activate neurons in the brain, or in other parts of the nervous system to produce a changes in, in mental in mental function. And I think the
Little thing that is exciting, a lot of people right now has to do with immune signaling molecules, so there's a class of molecules called cytokines and cytokines are basically the signaling hormones of the immune system and they they can flow through the bloodstream and through, lymphatic fluid and reach many parts of the body. We've known for a number of years that the specialized receptors for these
Cytokines are found throughout the brain and yet we know very, very, very little about about what they do. And that's going to be an astonishingly, fruitful area of scientific research but but to give 11 Exemplar, there are a lot of things. These days, suggesting a link between inflammation in the body, whether it be in the gut
Or in other places to depression. Well, how might that work? Well, it could work. Either through inflammation sensing neurons sending electrical signals to the brain or and it's not either, or it could be both, it could be immune signaling cytokine molecules produced at the site of inflammation, that then travel through the bloodstream and lymphatic system. To then reach the brain bind receptors and have
Effects. And so, you know, one of the mysteries about depression is that it's not that tractable to pharmacological therapy. So, if you look at people who suffer with depression, about a third of people see significant benefit from Modern SSRI and related antidepressant, drugs, about a third state, see, very tiny benefit and about
Third, see, no benefit at all and part of the reason is because maybe our term depression is too big, a bucket depressions. Actually many different biological disorders. And only a subset of those are are helped by ssris and will need different therapies for the other ones, that's certainly part of it, but part of it might actually have to do with inflammation. So, if you think that inflammation is a risk factor in depression, well, you could do something.
Very simple, right? You could you could gobble and ibuprofen, right? There's a whole bunch of anti-inflammatory drugs that are very well understood and so well what if you just say, all right, you know let's have a study where we have a bunch of depressed people and we have them all. Eat anti-inflammatory drugs for a few weeks and we see if this really is their depression and the answer seems to be no
It doesn't. And that's that's a little bit hard to understand because there are definitely links between inflammation and depression. So for example, one of the early treatments for for Hepatitis C, that's since been superseded by more, modern drugs was a pro-inflammatory cytokine molecule and when you gave it to people to treat their hepatitis C, almost everyone became depressed.
On this truck. Well, this really seems like, like, like a link likewise, there are certain neurological diseases, like multiple sclerosis, it turns out the incidence of depression as a comorbidity in multiple sclerosis is enormous. And you might say, well, there's a trivial reason for that. If you're paralyzed from Ms, you're bummed out about life and that's the reason. But if you look at people who have spinal cord injuries from accidents, they
Actually have major depression at an order at a rate from people who are uninjured. So that doesn't seem to be, it's not just that you're bummed out from being paralyzed. Although, of course, it's reasonable to be bummed out about being paralyzed but that's not it. So, what happens in Ms? Well, there's a bunch of cytokines including one called interleukin 6, aisle 6. That's elevated massively. If you, if you take a spinal tap and you look at the cerebral spinal fluid and so that could be causative for depression. So all these real reason,
To think that inflammation is involved, but yet the idea is still a little messy. So, now, what if instead of looking at the general population of depressed, people, you look at the subset of people that don't respond to SSRI, antidepressants are they helped by anti-inflammatories and there? There's a bit of a hint that maybe they are, it's not definitive yet. There are a couple of studies. It's right on the edge but I think this is
A really good example of how we are going to see progress very soon in the body to mind part of mind-body medicine that is going to be of enormous benefit to people. So interesting. Could I get your thoughts on one candidate hypothesis that I've been thinking about? I've covered depression on a few episodes and I've had a robin Carter.
Harris from UCSF and dr. Matthew Johnson from your very own John Hopkins. University, both of whom work run, laboratory studying psychedelics for the treatment of depression. The clinical trials, on psilocybin and to be clear. So Simon still illegal. It's been decriminalized a few places but we're not talking about recreational use we're talking about several therapy sessions and then to without psilocybin then to 2.5 g, approximately dosage
Of psilocybin given separately again with therapist present and then follow-up therapy session seemed to lead to relief of depression in approximately somewhere between 65 and 80 percent of people, in some cases, total remission, and some cases some relief without remission. Okay? So we can kind of set that result on the Shelf. It's been repeated a number of different times, compare that to the results of ssris, which seemed to help a third of people, a third minimally and a third, not at all.
And, of course, there's a side effect profiles of the ssris and Associated drugs, not just the ssris, but group prior, on, in the other antidepressants that are taken in prescription drug form. And then there's this inflammation piece. So could we hypothesize that relief from depression has something to do with neuroplasticity rewiring of neural circuits and that psilocybin? We know can encourage neuroplasticity and that perhaps
Ssris can encourage neuroplasticity. In some people, not all. And that inflammation is a barrier to neuroplasticity, to me. This is the only thing that can reconcile the current status of the of the results. And then there's ketamine based therapies. And so we have to also kind of set that on the Shelf, let's set that aside on the shelf for now to keep it simple. It seems to me that based on the time course over, which ssris work, the fact that they increase serotonin very quickly but the real
From depression comes from months later. The fact that neuromodulators like serotonin are intimately involved in neuroplasticity. They can in some cases gate neuroplasticity that are all centers back to changing neural circuits and so what we're really trying to do whether or not it's transcranial magnetic stimulation. Are now we can throw ketamine in there or psilocybin or ssris. We're that treating depression is about rewiring the brain. It's not about chemical A or B per se although serotonin seems involved.
To me, what I'd love to see is our more studies about the interaction between neuroplasticity and inflammation. And are we seeing that kind of work out there and because these results sort of sit as disparate somewhat conflicting. But it seems like inflammation is, is anti neuroplasticity. And broadly speaking here, I realized there are many interleukins, there are many, you know, some of which are inflammatory somewhere which are anti-inflammatory. But is that is that a meaningful hypothesis and
Um, can do you think there's any hope whatsoever to actually cure depression if we if we sort of start to unify that results in these different camps? Yeah, I think it's a completely reasonable hypothesis. And I would be broader. And I would say, honestly, the relief of any Neuropsychiatric condition, ultimately is from neural plasticity in some form or another. And I think it's worthwhile to step back a bit and talk about what neural plasticity means.
And to date there has been a focus on synapses on the contacts between neurons as the site of neuroplasticity and bats warranted synapses are plastic. They change as a result of experience as a result of hormone changes, as a result of exercise, as a result of lots of things but synapses are not the be-all and end-all of neural function. So for example, neurons work
Sending electrical signals along their lengths and, and between neurons and interconverting, those with chemical signals and the processes of generating, those electrical signals, the ion channels that are involved. That are embedded in membranes that are involved in that are also plastic, they can also change as a result of experience. That's what we call intrinsic plasticity as opposed to synaptic plasticity. In addition there are
Literal morphological changes. So when we talk about the wiring of the brain, sometimes we're talking about literal wiring like sell a wasn't connected to Selby and now it is and that changes and then sometimes well actually sell a was connect to Selby but so be wasn't responsive enough. And now there's a change in cell be so now sell a can fire Selby and that could have been a result of a change in its synapse, making it more recent, but receptive to neurotransmitter release from sell a, or it could be something.
Intrinsic can sell it, that makes it fire. Its electrical signal its Spike, more easily. I think that one of the key cell types that's going to be important for your hypothesis. Linking inflammation to synaptic plasticity is going to be a cell called a microglial cell and microglial cells are non-neuronal cells in the brain, their
Tile, they can crawl around. They have long processes and they can gobble things up. They can literally sort of chew away and digest bits of the extracellular, scaffolding that surrounds neurons and synapses, and thereby renders them plastic. They can destroy synapses. And there is a lot of indication that certain disease States may involve over-exuberant microglia
Pruning synapses to a degree that they shouldn't and we know that microglia are chock-full of cytokine receptors and so are responsive to inflammatory signals when we're talking about inflammation, and we're talking about drugs, it's worthwhile to mention that there are a lot of Behavioral things that also can influence the signaling so we know and I know you've discussed on your program.
The incredibly salubrious effects of physical exercise, on mental function. So exercise is about as good. An antidepressant as ssris are and the side effects are only good side effects as opposed to the bad side effects of ssris. And again, this isn't working through some Airy fairy realm. The reason that Exercise Works to relieve depression. And the reason that Exercise Works to maintain your car,
Of function as you age is because of biological Pathways that we are now uncovering some of which will involve microglial cells and neurons and other types of cells and brains some of which will involve not the neurons in the brain at all but the brains vasculature. So we know that exercise is very salubrious for keeping blood flowing to the brain and when you're young, you have a super abundance of blood flow.
Into your brain so it doesn't matter if it's reduced transiently, you're fine. But as you get older your blood vessels become more occluded and less elastic. And you're closer to the to the to the trouble spot. And if you exercise regularly, you can dilate and make your blood vessels, including those in your brain more elastic and that is almost certainly a protective against both depression.
I am cognitive decline as we age.
I am a fan of exercise, but I'm fortunate that I enjoy running and some forms of resistance training. So I always assumed that the good side effects were just the positive mood effects, until the recent literature. That, as you mentioned improve vascular, vasculature blood flow and reduced inflammation. If not during the exercise when inflammation actually increases decreases inflammation. I'm delighted to hear you say the word microglia and
My postdoc advisor, the late been beerus would be, especially delighted people can look up. Then I'll provide a link to his biography in the show notes captions because he really championed to the point of no, of Champions, even a sufficient word. I mean, Ben was beating the drums saying, we have to pay attention and glia. We have to pay attention to glia for the longest time, glia were relegated to these other journals, even have their own journals and in the last what is it 10 years? There's been a kind of explosion of research.
Search exploring the role of microglia and other glial cell types. And it's really fantastic to see that this actually the most abundant cell type in the brain is the glial cell are getting the attention they deserve. It's absolutely true. And you know, we scientists like to think that we're very rational creatures and we're not subject to fads but we totally are right when I started out in this field in the early 80s.
Thing was about opioid peptides and then there was a period where gaseous neurotransmitters like nitric oxide were all the rage and, you know, right now glia are in the spotlight for good reason. I'm not trying to say sure that it isn't worthwhile, but there is this phenomenon of things being fattish and people jumping on the bandwagon. So it happens both in terms of the subject we study but also in terms of the techniques we use and
Right. Now, the technique that is most fattish involves single-cell expression, profiling, that is creating a list of what genes are turned on and how strong they are turned on in single cells and seeing how that changes in different cell types and with experience and it's a very, it's a very valuable technique, but one could argue that it is perhaps a bit overused on that.
15 years from now. People will go back and say, gosh, those folks in 2023 were really overdoing it with the Single Cell profiling and if anyone's thinking about getting into the field of Neuroscience or another area of biological or other research, I can just tell you that, if you're starting your PhD, or your postdoc, take a look at whatever fat is happening now, and just know that in five years, it will be something different. And it takes to you about five years to finish your PhD or postdoc. So pick something different than what's faddish now and you'll, you'll land right on the money.
Any, but there's always a lot to do, you don't have to do what everyone else is doing him. And indeed the deletion test becomes relevant here, the deletion test as it was described to be by my colleague EJ, chillness key at Stanford is if you look around and you see one or more groups doing what you want to do very well, just pick something else, your life's going to be a lot more pleasant. Absolutely, I agree with, with EJ on that entirely, let's get back to mind body.
They're a bunch of different domains of mind-body as you. So, aptly, pointed out. It's bi-directional mind and forms the body body and forms the mind, but we could probably break this down into respiration. So breathing conscious patterns of breathing emphasizing inhales are emphasizing exhales cyclic hyperventilating Etc. Could also be thought patterns little bit harder to break those down but many
All but many forms of meditation involves having a very still body. Not all there's walking meditation, Etc but still body focused mind kind of a, not a state that we are in a lot of times unless we direct that state, there are still other mind-body patterns of communication through very still body deep relaxation, things like Yoga, Nidra and on sleep deep rest. There's hypnosis there's touch-based
Body Mind. Communication. If we're going to talk about Mind, Body. Also, we should refer to as body-mind. How do we dive in? And think about this, because this is evolving clearly a thousand different neural Pathways not just the Vegas nervous, it's caught, you know, typically people just kind of hang their hat on Mind Body must be vagus nerve and of course, it involves the Vegas, but the Vegas is an extensive set of Pathways. So how do you like to frame up mind body and what's most intriguing to you about Mind Body?
Communication both in terms of the biology and it's practical applications. Well, I think just as we talked about how there are two potential Pathways in conveying signals from the body to the mind. There are also two potential Pathways at least two potential Pathways to conveying signals from the brain to the body. And they are the the neural signals that are conveyed by neurons that actually get there. And they are
Hormones and neurotransmitters and cytokines that are released from the brand. I should mention that. That hormones are actually produced by neurons. Including, for example, some of the hormones that you think about as being produced as sex hormones, like estrogen is produced by neurons in your brain, for example. So let me give an example that I think is a bit out there, but I think is really, really fascinating.
Have this comes from from the cancer world and so melanoma is a, is a, is a bad cancer, it kills. A lot of people that can spread its highly metastatic, and we know that melanomas often become Innovative that is to say, they become contacted by neurons and wrapped and receive signals from them. And we also know that if a melon
Noma becomes innervated, then the prognosis for that patient is worse. It's more likely to grow. It's more likely to spread. Well, how does that happen? Well, recently, there have been some reports that show that neurons, that innervate, the melanoma don't act directly on to the tumor cells, rather, what they do is they secrete a signaling.
Molecule. That has a receptor on immune cells that are patrolling the edges of the melanoma tumor and nibbling away atoms. And they, when that signaling molecules released from the neuron, it shuts down or reduces that immune patrolling function, and then as a consequence, the tumor can grow.
Grow and spread and but off more readily. So this signal that comes from neurons is sending the ambulances home so to speak. Yeah, exactly. I'm and the signal is something called calcitonin Gene, related peptide or CG RP. Hmm. I'm familiar with see, grp from the domain of touch and its involvement in Click pitch perception. It do. I in perception a niche perceptional, right there. Yeah, and
all right, so if
Neurons can can affect the progression of cancer through their activity and these neurons in the periphery are ultimately connected to the brain.
Through a couple of different hops them, is it reasonable to hypothesize that mental processes could affect cancer progression. So let's say we have a hypothesis and it's a while hypothesis. And I want to just emphasize that there is not evidence for this. But let's make the hypothesis that says that through meditative practice, you can
Slow the progression of certain tumors that tend to get Inner fated right. Well, right now this is just kind of a wild idea but I think the important thing as I've said before, if this is a wild idea with the biological substrate, it's not like you meditate and Magic happens and force fields open in the Angels Sing
And then your tumor shrinks this is, we are saying that activity, in certain areas of the brain, is increased by this meditative practice, and that this sends signals to this neuron and this neuron that actually go to the tumor and make something happen through this biochemical pathway that we have defined, right? And to me, this is speculative but it's also extraordinarily
Exciting, right? It opens a kind of Investigation of mind-body signaling that has received very little attention up to now incredible. And I say incredible because
while you're giving an example of see, grp and nerve, innervation and metastatic tumors, I absolutely love the idea that
Phenomenon involving some practice that could be put under the umbrella of Mind, Body or Body, Mind becomes something entirely different when we're trying to hang that on the hook of a biological process, it's like something fundamentally changes there, right? You know, it's amazing to me for instance that early on psychedelics and breathwork conscious breath work, we're lumped together, cost people their
Jobs at major universities, I won't name the universities because we're all you work at one. I work at another and there's a third one called Harvard. I guess I just name them. But nowadays, their Laboratories at every single one of those institutions studying deliberate respiration on health as well as psychedelics and meditation for that matter. With the goal of understanding, what cytokines what neurotransmitters and started, our change through defined Pathways including Vegas, but
But phrenic nerves and frontal cortex and all the stuff that is considered you know, classic rigorous Neuroscience. So I do think we've entered a new era so it's not costing people their jobs anymore. It's actually giving people their jobs and it's federally funded which itself is also fantastic. In my opinion. So we are in a new era. What do you think needs to be done to really nail down?
On the idea that how we think influences our biology, even though it's a total, duh because everyone knows this chronic stress for instances can be detrimental, short term stress can actually be beneficial but and stress is a mental process that essentially deploys chemicals in the body that then create other issues in the body that then create shifts and mental processes such as you know. It's so it's so obvious when it's spelled out but it's just remarkable to me how this is just
Been lumped in the category of like woo science and I can't quite figure out what needs to be done in order to convince people that their nervous system includes stuff outside the skull and spinal cord and of course of course of course it would work this way. Well, right? And I think,
It is the job of biomedical researchers, right now to reclaim a lot of this from from the realm of nonsense. And the problem is, there has been a lot of nonsense and, you know, there's sort of a visceral reaction in when someone says, oh yeah, well you can do reth work and it'll realign your chakras. And that is, you know what?
Will reduce your anxiety or gut inflammation. And I'm tempted to just go, oh, shut up. But what if the chakras are collections of nerve, innervation of bodily sphincters and, you know, it could make sense right? It could. But it's Gotta Be, there's gotta be some, some biology in some cases. These analogies are rooted in something real and in some cases they're just made up bullshit, right? And
I think the challenge is to have really rigorous scientific tests of these things to take it back and to be willing to say all right there have been a lot of claims for example made about how mental processes can influence the body and only a subset of those are going to be true and of that subset. It is our job to understand how they work, both to rationalize them but
Also to optimize them and and make them better. I mean there's no question that mental processes affect the body. I mean, we know for example, that if we just keep you awake and don't let you sleep long enough, you'll die, and what will you die from? You'll die from sepsis because the barrier between your gut contents, and, and your perineum will will, will will break down, right? Well,
So how does that happen? Right. We're just starting to understand like there's a really dramatic example but there are going to be many more subtle example. So you've mentioned breathwork a couple of times and I think this is really interesting. My colleagues who are interested in respiration, tell me that you can record in many different places in the brain. Many different places in the neocortex.
And other regions and find a signature of the breathing Rhythm sort of has a background to neural activity. You can find in the cerebellum, you can find it in the frontal cortex, you can find it in on the habenula which is implicated in many things, including depression, you can find a lots of places. So the idea that conscious
Modulation of your breathing could have manifold effects on neural function, I think is reasonable. Given that kind of observation here here.
Let's talk about.
You a bit more. You've been so gracious and covering this wide array of topics and with such eloquence and I must say, I've been delighting in all of it.
You are in a unique position these days because if I understand correctly, you've been diagnosed with a fatal illness. I suppose we've all been diagnosed with a fatal illness of sorts because we're all going to die sooner or later. Yes, if you're willing, could you tell us the story of how that diagnosis came to be, what your initial reaction was, and where things stand now? And then perhaps we can explore some of
The well, let's just say pleasant surprises. That have emerged since that initial diagnosis. Well sure, I'd be happy to. So in the the summer of 2020 in the dark days of covid, when things were looking really bad, I developed profound shortness of breath. I couldn't get up a flight of stairs without without huffing and puffing and I thought, oh well, I've got
Kovac. But I took covid fests, and there was they were all - I thought, oh, I must have covid. I've got the symptoms of covid. I have respiratory issues and feeling weak. It's got to be covid. And after a while, when this didn't go away, my wife said, look, you got to go into the doctor. This is crazy. It's you got to find out what's going on and I did and they hooked me up to an electrocardiogram and they said, oh, you've got atrial fibrillation, meaning that your heart is doing two Beats.
Time it should do. Once I have a very high heart rate and when the heart beats that fast, it can't work. Very effectively, there's enough time to recharge before the next bead comes now it turns out that there is a very straightforward therapy. For this atrial fibrillation comes from electrical signaling in the heart sort of swirling about in a circle and and reactivating part of a heart muscle faster than it should. And so if you
Thread through a catheter in your inner inner inner, groin up up through blood vessels. You can put in a little needle and use that cauterize and to ablate a tiny little strip of cells in the heart, that will produce a barrier that will prevent that aberrant return of electrical activity and will cure atrial fibrillation. So, I have that process that ablation surgery, and sure enough it cured my age.
All fibrillation. I was feeling terrific. And they said, oh, as a follow-up, come back, a few months later. And we'll do an echocardiogram to see how your heart looks. And they did. And I went, oh my God. There's this huge mass pressing against your heart. It's like the size of a Coke can
Here's what we think it is. We think it's a hiatal hernia. We think your stomach has poked up through the diaphragm muscle and it's nestling next to your hearts. The way we diagnose, this is kind of humorous. They say chug this can of diet dr. Pepper and then quickly get up on the table and we'll do the echocardiogram. And in the echocardiogram, we can see a signature of the popping CO2 bubbles in your soda. And if we see those in the mass, then we know it's your stomach.
So I did it. I chucked it. I got up there. I know it's not your stomach. I said, okay, well, we think this is is a Teratoma and a Teratoma. Is a developmental anomaly that you carry usually from, fetal life, where there's a group of different cells that gets in a place where it shouldn't during development. And then grows, you've probably heard about people who sometimes get like a tooth that grows hair in their abdomen. Sometimes we're going to have
Around their ovaries and they're not malignant. They don't spread. It's a fairly easy thing. But I have this enormous Coke can pressing on my heart? It may have, we don't know, have been the source of my atrial fibrillation to start with. But in order to deal with this, I have to have open heart surgery so I had the surgery and it was a big hairy deal. I was told it would last about five hours, it turns out a lasted, two days.
They have me on the heart-lung bypass machine longer than you're supposed to because you're very likely to throw a clot and get a stroke. Fortunately, that didn't happen. I had very skilled surgeons at Johns Hopkins. It was bleeding so much that they couldn't close the chest. So they had to do all the surgery and then just leave me anesthetized with my chest open until the bleeding stopped, and they got. So, the surgery was a bear and then I'm waiting to get the pathology report back on the tissue They removed and it came back and it was bad news. Sorry.
It's not a Teratoma. It's not benign. It is a kind of cancer called synovial, sarcoma and synovial. Sarcoma is a moderately rare cancer. And it usually affects the synovium, which is the lining of the joints or some other places. It's pretty rare to have it happen in the heart. There are a few examples. If you look in the biomedical literature for common cancers, like justice testicular, cancer, and breast cancer, they're huge table.
Of Statistics, from millions of patients, on what's been tried and what works, and what the prognosis is for synovial, sarcoma of the heart, they're only individual case report. So there's a guy in Kenya and he got it on this, what happened. There's there's there's, there's a woman in Minnesota and this is what happened with her right there. No statistics. Because, because it's that rare. And, and, and the oncologist said, well, I think you've got 6 to 18 months to live
Now, this was about now, 27 months ago, so I've fortunately exceeded that lifespan estimate and I think we got to be clear. Also that, you know, be an oncologist has got to be a terrible job for many reasons, but one of them is that you got to give a lifespan estimate even if you really don't have the data to do it in a very in for you can't just say I won't do it right, you gotta do it. People expect it. So,
You know, I'm not saying like oh the oncologist was incompetent because I've outlived my estimate. You know he was trying to do something based on very little information made his best guess so. So you know I got this information and I was Furious. I was so angry hard cancer. Who the hell gets her cancers? That even a thing I've ever heard of somebody with heart cancer until no heart cancer. What the f?
I've got hurt cancer. This is this is crazy time. I was 59 years old as I got a lots of do I can't have heart cancer and
What was?
I think transformative for me, is that
At the same time that I was feeling a white-hot angry with the Universe. I was also feeling a deep sense of gratitude for what I've had. I've had a terrific life. I'm not that young. I've had a lot of it and I had great parents, wonderful friends, growing up. I'd had a good career. It's been a fairly easy run of it and I think,
The ability to have a job where you follow your own curiosity every day. There's nothing like that. So few people in the world get to live that way. I feel incredibly grateful and I feel incredibly grateful to my family and I have a wonderful wife named Dina and she's just the best. How do I deserve this? I don't deserve her. You know, honestly, so you know, in Neuroscience, we often think oh well there's a, you know, you
Have a state, you have a set point, are you anxious or are you relaxed? Are you fleeing or are you approaching, you know, it's like a single axis well but it is MM. You know, when I think most people understand that but but dumb me I didn't until that moment really understand that I could feel profoundly grateful and profoundly angry in the very in the very same moments.
And you know, having cancer and getting the kind of treatments that chemo the radiation, you know, it's famously deeply unpleasant and I had all that and it was just as unpleasant as anyone's cancer story that that, that you've heard radiation burn. My esophagus I couldn't eat for weeks. It was months. It was painful to swallow in a bad stuff. Lots of people have had to have bad stuff like this and and what I
Realize this is, It's a deeply unempowered ring situation to be a medical patient. What? Particularly, when there's something serious, you have, you have a limited sense of agency. Things are being done to you, drugs, go in new that make you feel really bad. And there isn't, there isn't that much to do when I realized that for me the sense of agency can
Him from being curious from being a total nerd about things. And part of what it made me curious about was my own mental processes as they related to my cancer and my cancer diagnosis. So, for example, I'm getting the chemo and I should just say as background, I'm fortunate, I don't have a tendency for it.
Depression. I'm a pretty upbeat guy. I don't take any credit for that. I think I was just born lucky and raised lucky right? But day after day is feeling bad in your body from chemo, boy. It's hard to be positive. It really is, I could not overcome my mood God really, really low. And I could tell myself,
This is going to be over, it's not going to go on forever. You won't feel this way forever and you would think that as a rational person, I could talk myself out of that mood, but I couldn't, you know, probably because there was my brain was Awash in interleukin 6 and I couldn't overcome what I felt really low. But at the same time, I was sort of at a remove being a nerd about going like, huh? I bet these cytokines are messing me up right now. I bet that's what's going on and that gave me some sense of agency in a time where otherwise
I really wouldn't have that another thing. It really brought home to me is this issue that we were discussing earlier about how malleable perception is and perception of time in particular. If someone had said to me when I was healthy before I was diagnosed, you're going to die in five years. I would have won. Oh no, no no, no. I'm 59 years old. I should get way more than five years. I got a lot of things to do.
Professional things, personal things, family, things. I got other things to do, no, that wouldn't be right, would be very upset. But, you know, if you told me after my diagnosis of 6 to 18 months, oh you had five years, I've been five years. Yeah, that's pretty good. I can do a lot in five years, I can finish up a lab and I can, I can do some good work and I can spend time with my family and travel and save her life's pleasures. And to
All kinds of things. Five years, great. And, of course, it's the same five years, right? The only thing that's different is the is the context.
but I think the thing that really,
I realized the most is that I really couldn't and still can't engage with the idea of myself being gone. So yeah, I can do practical things, I can update my will I can write letters for my people in my lab. So you know, if I kick off, you know, they've got that to take to their next job, you know, I can do all these nuts and bolts things, but in terms of
The only engaging with my own demise, I really find that as much as I try. I really can't do that. And at first, I thought, well, that's just your own lack of imagination Linden. It's just because, you know, you're not very good at this. But the more I thought about it, I thought actually know this is a human thing, this is a fundamental human thing. And at one of the
Things. When I look back on the 40 plus years I've been doing Neuroscience, that's different. Is that when I was first trained, the brain was really described as a reactive structure. Something happens in the world, you know, it comes to your sense, organs, your eyes, your ears, it goes into your brain, to trigger some things. You've you think you make decisions and then you make an action that goes out to your muscles or or, and that's the loop, and that's what the brain does. And what we have known in more recent years.
Hers. Is that actually, when the brain is waiting for something to happen, it's not just idling and spacing out that the brain is at every moment. Subconsciously, trying to predict the near future
Predicting the near future is predicated on the idea that there will be a near future. That is to say that you won't be dead and gone, right? That they'll be a future for you. And so I think that my ability, which I think is actually a human
I mean, not my ability, my failure, which I think is actually a human failure to truly engage with my own demise is a feature, it is it is a side effect of the fact that the brain is always trying to predict the future. And so that was interesting to me, just, as a way that my illness was revealing something about the brain, but it also made me think a lot about the world's religions, right religion.
Everywhere in the world, if you ask anthropologists, is there any society that doesn't have religious ideas? They'll say no, they say they don't always have the word religion, and I just say, well, yeah. And this place everybody knows that, you know, the world's, on the back of a turtle and, you know, this and this happened there. These rules, they may not call it religion, but every place in the world has religion, not everyone is religious, but it is a cross cultural Universal and most religions but absolutely every single one. But almost
Most every single one has stories of afterlife or reincarnation in which your Consciousness indoors. Well, why would that be? And, and many religions, they've got a deal right? Follow these rules in life and then you'll be rewarded in the afterlife. And that's what that's a very very general idea or punished in the after or punished and afterlife friends and
You know, when some of religions you meld with the Divine in other religions, you're reincarnated as this or that they even heaven or hell. Right. There's there's a variance but but they share that your Consciousness indoors and so why is this so popular all over the world? Well, I would hypothesize that it is a side effect of the fact that the brain can't help but always trying to predict the future when we
I can't imagine the world without us in it. Then we are forced to concoct stories of the afterlife.
Fascinating and makes me want to ask about this feature of time perception. My undergraduate graduate and post doc advisors all sadly died earlier early really by a pretty much any standard. And I was fortunate enough to be in communication with the last two as they were going through that process, both of them.
So for example, one of the early treatments for for Hepatitis C, that's since been superseded by more, modern drugs was a pro-inflammatory cytokine molecule and when you gave it to people to treat their hepatitis C, almost everyone became depressed on this truck. Well, this really seems like like like a link likewise, there are certain neurological diseases, like multiple sclerosis.
Is it turns out the incidence of depression as a comorbidity in multiple sclerosis is enormous? And you might say, well there's a trivial reason for that. If you're paralyzed from Ms, you're bummed out about life and that's the reason. But if you look at people who have spinal cord injuries from accidents, they actually have major depression at an order at a rate from people who are uninjured, so that doesn't seem to be at. It's not just that you're bummed out from being paralyzed. Although of course it's reasonable to be bummed out about being paralyzed, but that's not
So, what happens in Ms? Well, there's a bunch of cytokines including one called interleukin 6, aisle 6. That's elevated massively. If you, if you take a spinal tap and you look at the cerebral spinal fluid and so that could be causative for depression. So all these real reasons to think that inflammation is involved, but yet the idea is still a little messy. So now, what if instead of looking at the general population of depressed people you look at the subset of people
That don't respond to SSRI, antidepressants are they helped by anti-inflammatories and there there's a bit of a hint that maybe they are, it's not definitive yet. There are a couple of studies. It's right on the edge but I think this is a really good example of how we are going to see progress very soon in the body to mind part of mind-body Medicine.
Son, that is going to be of enormous benefit to people so interesting. Could I get your thoughts on one candidate hypothesis that I've been thinking about? I've covered depression on a few episodes and I've had a robin card, art Harris from UCSF and dr. Matthew Johnson from your very own John Hopkins. University, both of whom work run, laboratory studying psychedelics for the treatment of depression. The
Clinical trials on psilocybin and to be clear. So Simon still illegal. It's been decriminalized a few places but we're not talking about recreational use we're talking about several therapy sessions and then to without psilocybin then to 2.5 g approximately dosages of psilocybin given separately again with therapist present and then follow-up therapy session seemed to lead to relief of depression in approximately somewhere between 65 and 80 percent of people.
In some cases, total remission and some cases some relief without remission. Okay. So we can kind of set that result on the Shelf. It's been repeated a number of different times, compare that to the results of ssris, which seemed to help a third of people, a third minimally, and a third, not at all. And of course, there's a side effect profiles of the ssris and Associated drugs, not just the ssris, but group prior, on, in the other antidepressants that are taken in prescription drug form. And then there's this inflammation piece.
So could we hypothesize that relief from depression has something to do with neuroplasticity rewiring of neural circuits? And that psilocybin? We know can encourage neuroplasticity and that perhaps ssris can encourage neuroplasticity in some people, not all. And that inflammation is a barrier to neuroplasticity
To me, this is the only thing that can reconcile the current status of the of the results. And then there's ketamine based therapies. And so we have to also kind of set that on the Shelf, but let's set that aside on the shelf for now to keep it simple. It seems to me that based on the time course over, which ssris work, the fact that they increase serotonin very quickly but the really from depression comes from much later. The fact that neuromodulators like serotonin are intimately involved in neuroplasticity, they can in some cases gate neuroplasticity that are
All centers back to changing neural circuits. And so what we're really trying to do whether or not it's transcranial magnetic stimulation. Or now we can throw ketamine in there or psilocybin or ssris if we're that treating depression is about rewiring the brain. It's not about chemical A or B per se. Although serotonin seems involved to me what I'd love to see is our more studies about the interaction between neuroplasticity and inflammation and are we seeing that kind of work out there and
And because these results sort of sit as disparate somewhat conflicting. But it seems like inflammation is, is anti neuroplasticity. And broadly speaking here, I realize there are many interleukins, there are many, you know, some of which are inflammatory somewhere which are anti-inflammatory. But is that is that a meaningful hypothesis and can do you think there's any hope whatsoever to actually cure depression if we if we sort of start to unify the results in these different camps?
I think it's a completely reasonable hypothesis and I would be broader. And I would say, honestly, the relief of any Neuropsychiatric condition, ultimately is from neural plasticity in some form or another. And I think it's worthwhile to step back a bit and talk about what neural plasticity means to date. There has been a focus on synapses on the contacts between neurons as the site of neuroplasticity and bats.
Rented synapses are plastic. They change as a result of experience, as a result of hormone changes, as a result of exercise, as a result of lots of things. But synapses are not the be-all and end-all of neural function. So, for example, neurons work by sending electrical signals along their lengths and and between neurons and interconverting those with chemical signals and the processes of
Those electrical signals the ion channels that are involved. That are embedded in membranes that are involved in that are also plastic, they can also change as a result of experience. That's what we call intrinsic plasticity as opposed to synaptic plasticity. In addition, there are literal morphological changes. So when we talk about the wiring of the brain sometimes we're talking about literal wiring like sell a wasn't connected to Selby and now it
It is and that changes and then sometimes well actually sell a was connect to Selby but so be wasn't responsive enough. And now there's a change in cell be so now sell a can fire Selby. And that could have been a result of a change in its synapse, making it more recent, but receptive to neurotransmitter release from sell a, or it could be something intrinsic and sell a that makes it fire. Its electrical signal its Spike, more easily. I think that one of the key cell type
That's going to be important for your hypothesis. Linking inflammation to synaptic. Plasticity is going to be a cell called a microglial cell and microglial cells are non-neuronal. Cells in the brain. There motile, they can crawl around. They have long processes and they can gobble things up. They can literally sort of chew away and Digest.
Of the extracellular scaffolding that surrounds neurons and synapses and thereby renders them plastic. They can destroy synapses. And there is a lot of indication that certain disease States may involve over-exuberant. Microglia pruning synapses to a degree that they shouldn't. And we know that microglia are chock-full of cytokine receptors and so on.
Are responsive to inflammatory signals when we're talking about inflammation. And we're talking about drugs, it's worthwhile to mention that there are a lot of Behavioral things that also can influence the signaling so we know and I know you've discussed on your program, the incredibly salubrious effects of physical, exercise, on mental function. So exercise is about as good. An antidepressant as ssris
Our and the side effects are only good side effects as opposed to the bad side effects of ssris. And again, this isn't working through some Airy fairy realm. The reason that Exercise Works to relieve depression. And the reason that Exercise Works to maintain your cognitive function as you age is because of biological Pathways, that we are now uncovering some of which will involve microbial cells and neurons.
Ons and other types of cells and brains, some of which will involve not the neurons in the brain of all but the brains vasculature. So we know that exercise is very salubrious for keeping blood flowing to the brain and when you're young you have a super abundance of blood flowing to your brain so it doesn't matter if it's reduced transiently, you're fine but as you get older your blood vessels become more occluded and less elastic and your
Or closer to the to the to the trouble spot and if you exercise regularly you can dilate and make your blood vessels including those in your brain more elastic and that is almost certainly protective against both depression and cognitive decline as we age.
I am a fan of exercise, but I'm fortunate that I enjoy running and some forms of resistance training. So I always assumed that the good side effects were just the positive mood effects, until the recent literature. That, as you mentioned improve vascular, vasculature blood flow and reduced inflammation. If not during the exercise when inflammation actually increases decreases inflammation. I'm delighted to hear you say the word microglia.
And my postdoc advisor. The late been beerus would be, especially delighted people can look up and I'll provide a link to his biography in the show notes captions because he really championed to the point of. I don't know if Champions even a sufficient word. I mean, Ben was beating the drum saying, we have to pay attention and glia. We have to pay attention to glia for the longest time, glia were relegated to these other journals, even have their own journals and in the last what is it 10 years? There's been a kind of explosion of
Research exploring the role of microglia and other glial cell types. And it's really fantastic to see that this actually the most abundant cell type in the brain is the glial cell are getting the attention they deserve. It's absolutely true. And you know we scientists like to think that we're very rational creatures and we're not subject to fads but we totally are right when I started out in this field in the early.
Is everything was about opioid peptides and then there was a period where gaseous neurotransmitters like nitric oxide were all the rage and, you know, right now glia are in the spotlight for good reason. I'm not trying to say sure that that it isn't worthwhile, but there is this phenomenon of things being fattish and people jumping on a bandwagon, some happens both in terms of the subject we study but also in terms of the techniques we use
And right now, the technique that is most fattish involves single-cell expression, profiling, that is creating a list of what genes are turned on and how strong they are turned on in single cells and seeing how that changes in different cell types and with experience and it's a very, it's a very valuable technique, but one could argue that it is perhaps a bit overused.
That 15 years from now. People will go back and say, gosh, those folks in 2023 were really overdoing it with the Single Cell profiling and if anyone's thinking about getting into the field of Neuroscience or another area of biological or other research, I can just tell you that, if you're starting your PhD, or your postdoc, take a look at whatever fat is happening now, and just know that in five years, it will be something different. And it takes you about five years to finish your PhD or postdoc. So pick something different than what's faddish now and you'll you'll land right on.
On the money. But there's always a lot to do. You don't have to do it, everyone else's doing him. And indeed, the deletion test becomes relevant here, the deletion test, as it was described to me by my colleague EJ, chillness key at Stanford is if you look around and you see one or more groups doing what you want to do very well, just pick something else, your life's going to be a lot more pleasant. Absolutely, I agree with with EJ on them entirely, let's get back to mind body.
There are a bunch of different domains of mind-body as you. So, aptly, pointed out. It's bi-directional mind and forms the body body and forms the mind, but we could probably break this down into respiration. So breathing conscious patterns of breathing emphasizing inhales are emphasizing exhales cyclic hyperventilating Etc. Could also be thought patterns a little bit harder to break those down but
Many not all but many forms of meditation. Involves having a very still body. Not all there's walking meditation, Etc but still body focused mind kind of a, not a state that we are in a lot of times unless we direct that state, there are still other mind-body patterns of communication through very still body deep relaxation, things like Yoga, Nidra and on sleep deep rest. There's hypnosis there's touch-based
Body Mind. Communication. If we're going to talk about Mind, Body. Also, we should refer to as body-mind. How do we dive in? And think about this, because this is evolving clearly a thousand different neural Pathways not just the vagus nerve as it's called. You know, typically people just kind of hang their hat on Mind Body must be vagus nerve and of course, it involves the Vegas, but the Vegas is an extensive set of Pathways. So how do you like to frame up mind body and what's most intriguing to you about Mind Body?
The communication both in terms of the biology and it's practical applications. Well, I think just as we talked about how there are two potential Pathways in conveying signals from the body to the mind. There are also two potential Pathways at least two potential Pathways to conveying signals from the brain to the body. And they are the the neural signals that are conveyed by neurons that actually get there. And they are
Hormones and neurotransmitters and cytokines that are released from the brand. I should mention that. That hormones are actually produced by neurons. Including, for example, some of the hormones that you think about as being produced as sex hormones, like estrogen is produced by neurons in your brain, for example. So let me give an example that I think is a bit out there, but I think is really, really fascinating.
And this comes from from the cancer world. And so melanoma is a, is a, is a bad cancer, it kills, a lot of people that can spread its highly metastatic, and we know that melanomas often become Innovative that is to say, they become contacted by neurons and wrapped and receive signals from them. And we also know that if
A melanoma becomes innervated, then the prognosis for that. Patient is worse. It's more likely to grow. It's more likely to spread. Well, how does that happen? Well, recently, there have been some reports that show that neurons, that innervate, the melanoma don't act directly onto the tumor cells, rather, what they do is they secrete
Knowing molecule that has a receptor on immune cells that are patrolling the edges of the melanoma tumor and nibbling away atoms. And they, when that signaling molecule is released from the neuron, it shuts down or reduces that immune patrolling function, and then as a consequence, the tumor
Can grow and spread and but off more readily. So this signal that comes from neurons is sending the ambulances home so to speak. Yeah exactly. Am I on the signal? Is something called calcitonin Gene, related peptide, or CG RP. Hmm. I'm familiar with see, grp from the domain of touch. And its involvement in Think Like pitch perception. It do I in perception on its perception, right? Yeah.
so, all right, so if
neurons can can affect the progression of cancer through their activity and these neurons in the periphery are ultimately connected to the brain.
Through a couple of different hops them, is it reasonable to hypothesize that mental processes could affect cancer progression. So let's say we have a hypothesis and it's a while hypothesis. And I want to just emphasize that there is not evidence for this. But let's make the hypothesis that says that through meditative practice, you can
Slow the progression of certain tumors that tend to get Inner fated right. Well, right now this is just kind of a wild idea but I think the important thing as I've said before, if this is a wild idea with the biological substrate, it's not like you meditate and Magic happens and force fields open in the Angels Sing
And then your tumor shrinks this is, we are saying that activity, in certain areas of the brain, is increased by this meditative practice, and that this sends signals to this neuron and this neuron that actually go to the tumor and make something happen through this biochemical pathway that we have defined, right? And to me, this is speculative but it's also extraordinarily
Exciting, right? It opens a kind of Investigation of mind-body signaling that has received very little attention up to now incredible. And I say incredible because
while you're giving an example of see, grp and nerve, innervation and metastatic tumors, I absolutely love the idea that
Phenomenon involving some practice that could be put under the umbrella of Mind, Body or Body, Mind becomes something entirely different when we're trying to hang that on the hook of a biological process, it's like something fundamentally changes there, right? You know, it's amazing to me for instance that early on psychedelics and breathwork conscious breath work, we're lumped together, cost people their
Jobs at major universities, I won't name the universities because we're all you work at one. I work at another and there's a third one called Harvard. I guess I just name them. But nowadays, their Laboratories at every single one of those institutions studying deliberate respiration on health as well as psychedelics and meditation for that matter. With the goal of understanding, what cytokines what neurotransmitters and started, our change through defined Pathways including Vegas, but
But phrenic nerves and frontal cortex and all the stuff that is considered you know, classic rigorous Neuroscience. So I do think we've entered a new era so it's not costing people their jobs anymore. It's actually giving people their jobs and it's federally funded which itself is also fantastic. In my opinion. So we are in a new era. What do you think needs to be done to really nail down?
On the idea that how we think influences our biology, even though it's a total, duh because everyone knows this chronic stress for instances can be detrimental, short term stress can actually be beneficial but and stress is a mental process that essentially deploys chemicals in the body that then create other issues in the body that then create shifts and mental processes such as you know. It's so it's so obvious when it's spelled out but it's just remarkable to me how this is just
Been lumped in the category of like woo science and I can't quite figure out what needs to be done in order to convince people that their nervous system includes stuff outside the skull and spinal cord and of course of course of course it would work this way. Well, right? And I think,
It is the job of biomedical researchers, right now to reclaim a lot of this from from the realm of nonsense. And the problem is, there has been a lot of nonsense and, you know, there's sort of a visceral reaction in when someone says, oh yeah, well you can do reth work and it'll realign your chakras. And that is, you know what?
Will reduce your anxiety or gut inflammation. And I'm tempted to just go, oh, shut up. But what if the chakras are collections of nerve, innervation of bodily sphincters and, you know, it could make sense right? It could. But it's Gotta Be, there's gotta be some, some biology in some cases. These analogies are rooted in something real and in some cases they're just made up bullshit, right? And
I think the challenge is to have really rigorous scientific tests of these things to take it back and to be willing to say all right there have been a lot of claims for example made about how mental processes can influence the body and only a subset of those are going to be true and of that subset. It is our job to understand how they work, both to rationalize them but
Also to optimize them and and make them better. I mean there's no question that mental processes affect the body. I mean, we know for example, that if we just keep you awake and don't let you sleep long enough, you'll die, and what will you die from? You'll die from sepsis because the barrier between your gut contents, and, and your perineum will will, will will break down, right? Well,
So how does that happen? Right. We're just starting to understand like there's a really dramatic example but there are going to be many more subtle example. So you've mentioned breathwork a couple of times and I think this is really interesting. My colleagues who are interested in respiration, tell me that you can record in many different places in the brain. Many different places in the neocortex.
And other regions and find a signature of the breathing Rhythm sort of has a background to neural activity. You can find in the cerebellum, you can find it in the frontal cortex, you can find it in on the habenula which is implicated in many things, including depression, you can find a lots of places. So the idea that conscious
Modulation of your breathing could have manifold effects on neural function, I think is reasonable. Given that kind of observation here here.
Let's talk about.
You a bit more. You've been so gracious and covering this wide array of topics and with such eloquence and I must say, I've been delighting in all of it.
You are in a unique position these days because if I understand correctly, you've been diagnosed with a fatal illness. I suppose we've all been diagnosed with a fatal illness of sorts because we're all going to die sooner or later. Yes, if you're willing, could you tell us the story of how that diagnosis came to be, what your initial reaction was, and where things stand now? And then perhaps we can explore some of
The well, let's just say pleasant surprises. That have emerged since that initial diagnosis. Well sure, I'd be happy to. So in the the summer of 2020 in the dark days of covid, when things were looking really bad, I developed profound shortness of breath. I couldn't get up a flight of stairs without without huffing and puffing and I thought, oh well, I've got
Kovac. But I took covid fests, and there was they were all - I thought, oh, I must have covid. I've got the symptoms of covid. I have respiratory issues and feeling weak. It's got to be covid. And after a while, when this didn't go away, my wife said, look, you got to go into the doctor. This is crazy. It's you got to find out what's going on and I did and they hooked me up to an electrocardiogram and they said, oh, you've got atrial fibrillation, meaning that your heart is doing two Beats.
Time it should do. Once I have a very high heart rate and when the heart beats that fast, it can't work. Very effectively, there's enough time to recharge before the next bead comes now it turns out that there is a very straightforward therapy. For this atrial fibrillation comes from electrical signaling in the heart sort of swirling about in a circle and and reactivating part of a heart muscle faster than it should. And so if you
Thread through a catheter in your inner inner inner, groin up up through blood vessels. You can put in a little needle and use that cauterize and to ablate a tiny little strip of cells in the heart, that will produce a barrier that will prevent that aberrant return of electrical activity and will cure atrial fibrillation. So, I have that process that ablation surgery, and sure enough it cured my age.
All fibrillation. I was feeling terrific. And they said, oh, as a follow-up, come back, a few months later. And we'll do an echocardiogram to see how your heart looks. And they did. And I went, oh my God. There's this huge mass pressing against your heart. It's like the size of a Coke can
Here's what we think it is. We think it's a hiatal hernia. We think your stomach has poked up through the diaphragm muscle and it's nestling next to your hearts. The way we diagnose, this is kind of humorous. They say chug this can of diet dr. Pepper and then quickly get up on the table and we'll do the echocardiogram. And in the echocardiogram, we can see a signature of the popping CO2 bubbles in your soda. And if we see those in the mass, then we know it's your stomach.
So I did it. I chucked it. I got up there. I know it's not your stomach. I said, okay, well, we think this is is a Teratoma and a Teratoma. Is a developmental anomaly that you carry usually from, fetal life, where there's a group of different cells that gets in a place where it shouldn't during development. And then grows, you've probably heard about people who sometimes get like a tooth that grows hair in their abdomen. Sometimes we're going to have
Around their ovaries and they're not malignant. They don't spread. It's a fairly easy thing. But I have this enormous Coke can pressing on my heart? It may have, we don't know, have been the source of my atrial fibrillation to start with. But in order to deal with this, I have to have open heart surgery so I had the surgery and it was a big hairy deal. I was told it would last about five hours, it turns out a lasted, two days.
They have me on the heart-lung bypass machine longer than you're supposed to because you're very likely to throw a clot and get a stroke. Fortunately, that didn't happen. I had very skilled surgeons at Johns Hopkins. It was bleeding so much that they couldn't close the chest. So they had to do all the surgery and then just leave me anesthetized with my chest open until the bleeding stopped, and they got. So, the surgery was a bear and then I'm waiting to get the pathology report back on the tissue They removed and it came back and it was bad news. Sorry.
It's not a Teratoma. It's not benign. It is a kind of cancer called synovial, sarcoma and synovial. Sarcoma is a moderately rare cancer. And it usually affects the synovium, which is the lining of the joints or some other places. It's pretty rare to have it happen in the heart. There are a few examples. If you look in the biomedical literature for common cancers, like justice testicular, cancer, and breast cancer, they're huge table.
Of Statistics, from millions of patients, on what's been tried and what works, and what the prognosis is for synovial, sarcoma of the heart, they're only individual case report. So there's a guy in Kenya and he got it on this, what happened. There's there's there's, there's a woman in Minnesota and this is what happened with her right there. No statistics. Because, because it's that rare. And, and, and the oncologist said, well, I think you've got 6 to 18 months to live
Now, this was about now, 27 months ago, so I've fortunately exceeded that lifespan estimate and I think we got to be clear. Also that, you know, be an oncologist has got to be a terrible job for many reasons, but one of them is that you got to give a lifespan estimate even if you really don't have the data to do it in a very in for you can't just say I won't do it right, you gotta do it. People expect it. So,
You know, I'm not saying like oh the oncologist was incompetent because I've outlived my estimate. You know he was trying to do something based on very little information made his best guess so. So you know I got this information and I was Furious. I was so angry hard cancer. Who the hell gets her cancers? That even a thing I've ever heard of somebody with heart cancer until no heart cancer. What the f?
I've got heart cancer. This is this is crazy time. I was 59 years old as I got a lots of do I can't have heart cancer and
What was?
I think transformative for me, is that
At the same time that I was feeling a white-hot angry with the Universe. I was also feeling a deep sense of gratitude for what I've had. I've had a terrific life. I'm not that young. I've had a lot of it and I had great parents, wonderful friends, growing up. I'd had a good career. It's been a fairly easy run of it and I think,
The ability to have a job where you follow your own curiosity every day. There's nothing like that. So few people in the world get to live that way. I feel incredibly grateful and I feel incredibly grateful to my family and I have a wonderful wife named Dina and she's just the best. How do I deserve this? I don't deserve her. You know, honestly, so you know, in Neuroscience, we often think oh well there's a, you know, you
Have a state, you have a set point, are you anxious or are you relaxed? Are you fleeing or are you approaching, you know, it's like a single axis well but it is MM. You know, when I think most people understand that but but dumb me I didn't until that moment really understand that I could feel profoundly grateful and profoundly angry in the very in the very same moments.
And you know, having cancer and getting the kind of treatments that chemo the radiation, you know, it's famously deeply unpleasant and I had all that and it was just as unpleasant as anyone's cancer story that that, that you've heard radiation burn. My esophagus I couldn't eat for weeks. It was months. It was painful to swallow in a bad stuff. Lots of people have had to have bad stuff like this and and what I
Realize this is, It's a deeply unempowered ring situation to be a medical patient. What? Particularly, when there's something serious, you have, you have a limited sense of agency. Things are being done to you, drugs, go in new that make you feel really bad. And there isn't, there isn't that much to do when I realized that for me the sense of agency can
Him from being curious from being a total nerd about things. And part of what it made me curious about was my own mental processes as they related to my cancer and my cancer diagnosis. So, for example, I'm getting the chemo and I should just say as background, I'm fortunate, I don't have a tendency for it.
Depression. I'm a pretty upbeat guy. I don't take any credit for that. I think I was just born lucky and raised lucky right? But day after day is feeling bad in your body from chemo, boy. It's hard to be positive. It really is, I could not overcome my mood God really, really low. And I could tell myself,
This is going to be over, it's not going to go on forever. You won't feel this way forever and you would think that as a rational person, I could talk myself out of that mood, but I couldn't, you know, probably because there was my brain was Awash in interleukin 6 and I couldn't overcome what I felt really low. But at the same time, I was sort of at a remove being a nerd about going like, huh? I bet these cytokines are messing me up right now. I bet that's what's going on and that gave me some sense of agency in a time where otherwise
I really wouldn't have that another thing. It really brought home to me is this issue that we were discussing earlier about how malleable perception is and perception of time in particular. If someone had said to me when I was healthy before I was diagnosed, you're going to die in five years. I would have won. Oh no, no no, no. I'm 59 years old. I should get way more than five years. I got a lot of things to do.
Professional things, personal things, family, things. I got other things to do, no, that wouldn't be right, would be very upset. But, you know, if you told me after my diagnosis of 6 to 18 months, oh you had five years, I've been five years. Yeah, that's pretty good. I can do a lot in five years, I can finish up a lab and I can, I can do some good work and I can spend time with my family and travel and save her life's pleasures. And to
All kinds of things. Five years, great. And, of course, it's the same five years, right? The only thing that's different is the is the context.
but I think the thing that really,
I realized the most is that I really couldn't and still can't engage with the idea of myself being gone. So yeah, I can do practical things, I can update my will I can write letters for my people in my lab. So you know, if I kick off, you know, they've got that to take to their next job, you know, I can do all these nuts and bolts things, but in terms of
The only engaging with my own demise, I really find that as much as I try. I really can't do that. And at first, I thought, well, that's just your own lack of imagination Linden. It's just because, you know, you're not very good at this. But the more I thought about it, I thought actually know this is a human thing, this is a fundamental human thing. And at one of the
Things. When I look back on the 40 plus years I've been doing Neuroscience, that's different. Is that when I was first trained, the brain was really described as a reactive structure. Something happens in the world, you know, it comes to your sense, organs, your eyes, your ears, it goes into your brain, to trigger some things. You've you think you make decisions and then you make an action that goes out to your muscles or or, and that's the loop, and that's what the brain does. And what we have known in more recent years.
Hers. Is that actually, when the brain is waiting for something to happen, it's not just idling and spacing out that the brain is at every moment. Subconsciously, trying to predict the near future
Predicting the near future is predicated on the idea that there will be a near future. That is to say that you won't be dead and gone, right? That they'll be a future for you. And so I think that my ability, which I think is actually a human
I mean, not my ability, my failure, which I think is actually a human failure to truly engage with my own demise is a feature, it is it is a side effect of the fact that the brain is always trying to predict the future. And so that was interesting to me, just, as a way that my illness was revealing something about the brain, but it also made me think a lot about the world's religions, right religion.
Everywhere in the world, if you ask anthropologists, is there any society that doesn't have religious ideas? They'll say no, they say they don't always have the word religion, and I just say, well, yeah. And this place everybody knows that, you know, the world's, on the back of a turtle and, you know, this and this happened there. These rules, they may not call it religion, but every place in the world has religion, not everyone is religious, but it is a cross cultural Universal and most religions but absolutely every single one. But almost
Most every single one has stories of afterlife or reincarnation in which your Consciousness indoors. Well, why would that be? And, and many religions, they've got a deal right? Follow these rules in life and then you'll be rewarded in the afterlife. And that's what that's a very very general idea or punished in the after or punished and afterlife friends and
You know, when some of religions you meld with the Divine in other religions, you're reincarnated as this or that they even heaven or hell. Right. There's there's a variance but but they share that your Consciousness indoors and so why is this so popular all over the world? Well, I would hypothesize that it is a side effect of the fact that the brain can't help but always trying to predict the future when we
I can't imagine the world without us in it. Then we are forced to concoct stories of the afterlife.
Fascinating and makes me want to ask about this feature of time perception. My undergraduate graduate and post doc advisors all sadly died earlier early really by a pretty much any standard. And I was fortunate enough to be in communication with the last two as they were going through that process, both of them.
Bribed a heightened sense of gratitude, especially for things that previously. They had not paid attention to, so we call this noticing, the little things. Yes. But that makes me conclude that something about the knowledge of one's impending, death, however, far off, that might be shifts our attention at least temporarily leads to this.
Sense of slowing down a bit because in order to shift our attention to quote unquote, the little things or things that we previously overlooked, there's this sense of slowing down and we know from basic videography photography that slowing down means an increase in frame rate, right? You know, you're shooting it strobe frame rates of gives you the strip perception of strobe shooting at very high frame rates allows you to see things in very slow.
You're noticing subtle variations. That normally you overlooked I did not trying to be overly reductionist about this this process of enhanced gratitude. That's that you described and how it was alongside intense anger. But have you noticed a shift in your perception of time? Because you were given initially this, okay, X number of months. And then now with the
You're still here. Fortunately in with this open-ended. Well, it wasn't the prediction that was given to you by your oncologist, but it's unclear how long you're going to be here, right? Which is how most of us exist. You have the sense that it's sooner rather than later, but you don't really know. So I'm curious as to how the idea that okay, you have 12 months more to live versus more than 12 months but not infinite but of
I know that I have hopefully have more than 12 months, but it's not infinite. So, you know, this, this idea of the Finish Line, the cliff leaving aside, whatever might happen afterwards, I don't know. Haven't been there. It changes, what we notice by way of changing our perception of time, I mean, this is a, this is a profound tuning of our perception. What are your thoughts on that? And do you notice the
each sip of coffee, you probably don't notice each step across the kitchen floor in the morning. You're probably paying attention to your lovely wife and kids and things that day. But presumably, it's Dynamic. But what is your perception of time? Like now with the understanding that, yes, you made it through the past, the gate that was predicted. But what's lies ahead is, is uncertain. Yeah, so that's really interesting. And I would say, definitely my
Enough time of slower and it seems like an age since I was diagnosed. But I think part of that is because it's been action packed. In other words, since I was diagnosed so many emotionally, Salient things non trivial things have happened. So many intense discussions with my wife and my friends, and the people in my lab, my wife. And I've
And a lot more vacations than we normally do. So you know we're running all over the world and there's a certain sense of of packing it in that I think influences time perception. But I would say actually for me personally the Gratitude isn't about the little things. The Gratitude is about the very biggest things. The Gratitude is gratitude for being a sentient being.
and having that blessing,
The Gratitude is for being able to have a life where I can follow my own ideas and creativity and my gratitude is for choked up.
The profound love that I felt from my wife and my children.
You know, it's not the little stuff, it's the big stuff that I think about when I think about gratitude it's not noticing this of T. It's it's the big issues and
You know, for me, I, you know, I don't want to delay my death as much as possible, of course.
but,
When I think about it, the part that makes me upset.
Is leaving people behind.
It's not for myself. I've, I've had a great life.
I've had a lot of it, I'm 61, I like to go longer but that's, that's a pretty good run. I've gotten to do lots of things in those 61 years and have wonderful loving interconnected experiences. And so, the negative part is about what I leave.
Pint.
Certainly what you've left behind is enormous and has been the consequence of actions long before your diagnosis which I think is that is a clear lesson to everyone. I can't speak for you, but don't wait for the diagnosis. You've mentioned the sense of agency that you felt by being able to
Pay attention to and explore your experience of let's call it. What it is, impending death and at the same time you, as you mentioned, you've Amplified and accelerated, the number of things that you've put into the world recently, writing incredible articles about your experience of life and death and we will, of course, link to those. So people can read them. I've read them all and they are profound. And
They don't just feel important, they clearly are important. So very few people have your insight into the nervous system at the mechanistic level. But also at this more holistic level that you've clearly displayed to us here in an, in your research, and in your book writing and public speaking. You know, I think it's a, it's a risky thing to ask somebody for advice, but I can't help myself.
Well, because I think it's a it's a real opportunity. If you had advice to give to any and all of us based on the whole experience. Yeah. All of it from go as they say, right? If you're willing and feel free to pass, but if you're willing, what is your advice? Well,
I would say the advice that is really Universal is what? Everybody already knows and is a bit trite, but I'll say it anyway. And that is appreciate what you got, while you got it. And you know, this isn't any big secret and everyone knows it. I would say for a subset of people, the way of the nerd is very empowering, I don't think that's the case for
Everyone, I think for a subset of people who are deeply, curious, as their nature, turning that Curiosity to your own mortality, in your own medical situation can be empowering and and useful but I don't think that should be broad advice. I think that's all.
Way for fraction people is probably the worst thing they could do and there's nothing wrong with that. Everybody's everybody's difference, right? Not everyone should adopt the way of the nerd, but for a fraction of people it's a really really good thing to do.
This is normally the portion of a conversation with a guest, where I list off the many, many things they've done and how grateful I am. And all of that is absolutely true. In the case of you being here today in the work you've done, but I think it's self-evident how much you don't just accomplish but how much knowledge you put into the world and not just scientific knowledge but knowledge about The Human Experience of others and of yourself. And
So, I just want to extend a giant. Thank you on behalf of the listeners and viewers and myself. Thank you for coming here today. Thank you for doing what you do, and, so, great to still have you here and to have this conversation, and I hope it goes longer, and no matter when it ends you've done an enormous service to humanity. Well, thank you. That's very kind. It's been, it's been a pleasure to have this discussion.
Russian with you. Thanks. David. Thank you for joining me today for this discussion with dr. David Linden, if you're learning from and, or enjoying this podcast, please subscribe to our YouTube channel. That's a terrific, zero cost way to support us. In addition, please subscribe to the podcast on Spotify and apple and on both Spotify and apple. You can leave us up to a five star review if you have questions for me or comments about the podcast or guessed that you'd like me to consider hosting on the huberman Lab podcast. Please put those in the comment section on YouTube. I do read all the
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