Life, Death & the Neuroscience of Your Unique Experience | Dr. David Linden

welcome to the huberman Lab podcast where we discuss science and science-based tools for everyday [Music] life I'm Andrew huberman and I'm a professor of neurobiology and Opthalmology at Stanford school of medicine today my guest is Dr David Linden Dr David Linden is a professor of neuroscience at John's 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 today we will discuss the cerebellum and what it does but Dr David Lindon will also teach us about the important sense of touch as well as what makes us different as individuals the reason today's discussion encompasses so many important topics is that Dr David lindon'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 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 lynon 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 smell 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 talk 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 mindbody connection and 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 shift to discussing Dr David lynon 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 6 to 12 months to live now obviously because he was in our studio to record this conversation he has outlived that prognos nois but he lives dayto 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 Lindon 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 roles at Stanford it is however part of my desire and effort to bring zero cost to Consumer information about science and science related tools to the general public in keeping with that theme I'd like to thank the sponsors of today's podcast our first sponsor is Roka Roa 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 Roa eyeglasses and sunglasses were designed with performance in mind now I've spent a lifetime working on the biology of the visual system and I can tell you that your visual system has to contend with an enormous number of challenges in order for you to be able to see clearly Roa understands those challenges and the biology the visual system such that they've designed sunglasses and Eyeglasses that always allow you to see with Crystal clarity now initially Roa ey glasses and sunglasses were designed for sports performance and as a consequence all of their glasses are designed to be very lightweight and to not slip off your face if you get sweaty however the design of the glasses incl includ some that are specifically for sport and others whose aesthetic really allows you to use them for sport as well as out to dinner or to work etc and that's how I use them if you'd like to try Roa eyeglasses and sunglasses you can go to roka.com that's r.com and enter the code huberman to save 20% off your first order again that's Roa r.com and enter the code huberman at checkout today's episode is also brought To Us by levels levels is a program that lets you see how different foods and behaviors affect your health by giving you real time feedback on your diet using a continuous glucose monitor one of the most important factors impacting your immediate and long-term health is the way that your body manages its blood glucose or sometimes 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free months 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 hubman Lab podcast and as always thank you for your interest in science and now for my discussion with Dr David Lynden Professor Lyndon welcome thanks so much for having me been 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 Carl daero 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 is a uh active clinical psych psychiatrist so he's an MD and he also is um a bioengineer who's developed a lot of the modern tools for probing the brain and um anytime 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 uh so I'm going to steal that approach and say what are you most excited about lately well very very lately the most interesting thing that that I read in Neuroscience is the answer to a uh 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 genitals doesn't matter male or female or interex or gay or straight or by or whatever you are you know the genitals are are a hot spot and why and you 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 if you go back to to 1860 there was a German neuroanatomist named Krauss and he cut thin sections of tissue from the penis and 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 Krauss cor pusle 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 uh for this um 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 in the lips and they're in the anus all places that get popular in uh in that domain but they're also in places like the cornea or the lining of the joints so the distribution doesn't quite make sense and so it was never known and so in 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 with uh sexual sensation and this in a preprint from David ginty's 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 uh The Krauss cor pusles and so you see a nerve ending in the skin it could be conveying all kinds of information it could be tuned for hot or for cold or for itch or for pain or for or for inflammation or for mechanical sensation stretching uh vibration indentation and sure enough when they recorded from these Krauss cor pusles they really are uh mechanical sensors as you would expect uh if if they were involved in sexual sensation so that was good and then uh the other thing then that they did is they they tried to artificially turn them on and so the way they did that is they Ed genetic tricks to express one of Carl Dao's uh uh molecule that activates neurons when they're when blue light is shown on them and they found that if they express uh uh this artificial protein in the crow cells in a in a male Mouse and then shine blue light the mouse gets an erection all right so far so good what happens if you turn them off well if you 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 uh you find that she is less interested she's much less likely to let him Mount she's much less likely to let him finish so this is the remarkable result that uh 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 cruss cor pusle structure um we know that sexual sensation diminishes with aging is that in part because kuss cor pussle density is lost from the skin of the genitals and that's a reasonable because we know for example that fine touch sensors in the fingertips uh so-called Merkel and Meisner endings also named after German anatomist like so many things are uh are also lost with age so that's a reasonable idea so so this finding from ginty's Lab has opened up a whole world of science and I've been my my own lab doesn't work on touch but I've been a fanboy of touch 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 and 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 uh uh Steven sha uh Michael Katarina Shin Jong dong there have been a number number of world leaders in the 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 Krauss Cor pusles in females it's funny you should mention that I sent that exact email to David giny 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 says well we're really not sure so we're activating the CR core pusles in female mice and we're just kind of staring at it and looking and see if anything happens does 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 yeah or perhaps the female mice would be more willing to mate outside of the usual time frame of receptivity if uh these kuss cor pusles are are stimulated that's possible my suggestion my 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 mate for longer during their uh fertile time and I just want to remind people because we had a a guest recently uh Dr Reena Malik um who's a urologist reproductive and sexual health expert she's an MD and um uh she made clear that the the clitoris and the penis come from the same embryonic origin they are analogous tissues um in um different individuals I do have one more question about this uh sexual touch thing um these are periperal 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 um neurons within the brain and spinal cord um tend to remodel less especially as one gets older out of the so-called critical period um is it possible that these CR corpuscules and their patterns of innervation within the genitals change according to the stimulation that uh people experience um 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 cadaa tissue so you can only do it once in animals it it it it will be possible and it it could be for a couple of different reasons in other words it could be I think what you're imagining is that there's actual structural plasticity if you looked at these kuss cor pusles or uh that you would actually see them changing their shape or their size or their or their density as a result of experience but uh what can also happen is a phenomena like desensitization uh that is to say when there's stimulation for a long time then uh The receptors transiently can become less sensitive to touch and it's well known uh particularly in males that uh 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 CR cor pusles uh but it's more likely to be a change in their function that you wouldn't be able to Simply see by looking uh at an outline of 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 ginty's work and and colleagues there are many people involved in uh 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 uh is one that we'll provide a link to in the show note captions and um it's a very interesting idea that we are all different um especially coming from a neuroscientist who we were trained at least similarly to learn that sure the bumps and ripples of the brain and the fine wiring of the brain um is different and we are all unique and different we have different shapes AKA morphologies but focusing on human individuality is not something that modern Neuroscience or classic neur science has really done much of it's really focused on how people do X or people do y this way um 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 in my own lab how do we do them well we work on mice do we work on mice with genetic variation no 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 prison 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 it resembles um a prison of sorts they aren't free to roam they they're they have nothing like the experience of a wild mouse let me put it that way they're uh uh and and yes there are as you said correctly there are plenty of experiments where there is enrichment uh for mice and and they love it so for example in our lab when we put running wheels in the cages or mice and let them run overnight they're active at night um your average Mouse will run 2 kilometers in a night for a little tiny Mouse and some of the mice are so intense they will run 20 kilomet imagine a mouse doing 20K but but it will happen they really really like it they don't like being in prison they they want to exercise uh and they're really Bor so yes to get back to your general Point uh so much of science is designed to try to find general principles of of function of the brain a physiology of genetics uh and to ignore individual variation but individual variation is so important to our human experience and actually is so important to to the process of evolution in natural elction and how how species uh 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 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 of more of of of some senses more than others obviously in your world in the retina we have various kinds of of loss of color vision uh that are well known and some other more complicated phenomena having to do with uh impairments in the perception of motion uh or form but uh the place where this really happens is in the uh ola system so we have approximately 400 functional receptors for different odorant molecule smells uh in our nose and if you uh sequence the genomes of many people you find that the uh 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 Lesley vosol and her colleagues did at Rockefeller University and give odor tests where they give people different things to smell and then they dilute them and find the Threshold at which they can detect them you find enormous changes from People to People both in term in general terms some people are just better smellers 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 uh there's a secreted hormone called androne androne there are some people who can't smell it at all for some people uh it smells like rather Pleasant like grass and for some people it smells foul like urine or sweat and it just depends on genetic variation in one particular odorant receptor sorry to interrupt uh another uh phenomenal researcher who studies ol faction among other things Katherine dck um I once heard uh say that some people have a gene that for them makes the smell of microwave popcorn um um 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 and actually that's a very particular funny case so the the relevant chemical there is buic acid and also isovic acid and so uh there are uh researchers I think Rachel Herz uh is one of them who have given a mixture of these two chemicals to people and if they say this is parmesan cheese they go oh 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 peran shees and they go yeah and they give them another one they say it's vom they go yeah and then they say well actually we fooled you it was the same vial they say no you didn't you must have made a mistake they're convinced that they couldn't have been the same thing so this points out not only is there genetic variation that uh is responsible 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 uh and 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 uh pandas live in one spot uh in in southern China and they eat one thing bamboo and that's it humans are the opposite humans can live in any ecological niche in the world from the tropics to the poles and humans eat a wide wide wide variety of foods and as a result it means that we have have to have a very plastic old factory system there have to be very few things that we find innately aversive there are only a handful of odors rotting meat odors uh molecules with the evocative names like cadaverine and putene are things that even babies when they're newborn find aversive but other things happen that they need to be learned for example um pretty much every adult finds poop odors uh unpleasant but babies Happ 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 culturally it's not innate it is not innate um they're only a few innate odor aversions and a few innate taste aversions that were were born with and the other things are elaborated culturally and we can think about this in terms of how we we we 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 smell sweet that's like saying it sounds red right it's 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 vanilla smells sweet or mint similarly uh smells sweet if it is typically used together with sugar but if you go to a place like uh uh like Vietnam where mint is mostly used in Savory dishes people won't say that mint smells sweet so there's a pair dissociation there that at least at our level of conscious understanding feeds back onto what we call old factory or smell perception but really it's a it must be a pair dissociation at some point in development yeah it is it absolutely is a pair Association and it's something that goes on continually through your life right I mean lots of people for example uh have stories of foods that they wouldn't eat as a child but they came to like as an adults um a good example of that is coffee uh a lot of people have to overcome bitter aversion to uh to become coffee aicad uh so uh you know this 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 uh and the inward pointing senses like balance and uh is my stomach full uh 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 ag1 daily since 2012 so I'm delighted that they're sponsoring the podcast ag1 is a vitamin mineral probiotic drink that's designed to meet 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 day but often times I simply can't get enough servings but with ag1 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 ag1 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 ag1 if you'd like to try ag1 go to drink a1.com huberman to claim a special offer they'll give you five free travel packs plus a year supply of vitamin D3 K2 again that's drink a1.com huberman are there any examples of uniqueness of visual perception that come to mind I recently did a social media post um that involved it was essentially three rings A blue ring um a red ring and a blue ring in the center perhaps it was the other way around excuse me it was red blue red and um I asked which ring is in front or are they all at the in the same plane now of course it's a two-dimensional image right um and interestingly it splits out into about thirds some people see the blue ring in front quite a bit others see a red ring out in front others see them all in the same plane and this uh we think has to do with um differences in two things between individuals one is the distribution of the cone photo receptors um which we know is essentially random between individuals maybe even between the two eyes and then um and that gives rise to this phenomenon of chromatic aberration yes um 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 MH um 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 in exactly the same plane of of vision um so that's the one that I know um 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 ised near yes uh uh when they grow up uh than kids who got outside and we now know that at least part of the story is that light seems to stimulate the um expression 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 retina sits relative to the lens and that seems to be light dependent early in life and uh which gives rise to uh uh to uh a higher incidence of myopia and and to me this is really well first of all it's it's it's news you can use you should get your kids outside absolutely all kinds of reasons and you should get outside too especially in the morning set that circadian rhythm I I know that's a famous huberman esque uh uh uh point they're gonna be putting me in the grave David and I'm going to be telling people to uh or it'll maybe it'll be on my Tombstone he'll say get get sunlight in your eyes especially especially on cloudy days because there is still 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 having to do with the early days of World War II so in the early days of World War II the Japanese Army just swept through Asia they defeated the the British and Malaysia and Singapore they over in Thailand and Burma and they 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 heat stroke they got their core temperature got too hot and uh when the Army doctors uh examine them they found this was much more likely to happen in solders uh who came from the northern part of Japan Hokkaido where it's uh where it snows in the winter as opposed to the southern part of Japan like kushu which is a semi-tropical environment and the classical explanation the biologists like us would guess would say oh all right well this has happened genetically over many years uh you have a family that's been in kushu for many generations and you've selected four Gene variants to 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 echine sweat glands the sort of saltwater sweat glands not the lipid stinky armpit sweat glands called the arrine ones the acine ones you have a higher fraction of them that are inovated 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 intervation all right so they said 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 South and then they grew up in the southern location they had high sweat gland inovation they were well heat tolerant conversely if you had a wellestablished southern kushu family and they moved to Hokkaido and then had their child that child developed the northern sweat gland inovation pattern so meaning less nerve inovation of those sweat glands as you mentioned before just as many sweat glands just less nerve inovation therefore those sweat glands could not be activated they couldn't dump heat as well their heat tolerance was lower correct exactly right and and what's 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 in this in 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 uh 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 uh comes from field mice vs and we were talking earlier about how we both worked with uh the scientist IR zuker at uh at Berkeley who was a specialist in uh in in inv Vols and uh what people found is that if you take uh wild caught uh field mice and uh you have uh a pregnant mothers and you have them in the lab but you manipulate the lights so that uh 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 are born they will have a low density of fur anticipating summer temperatures uh if you however uh put them in artificial fall where day length is getting shorter uh 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 just the sort of trait that if you ask someone they would probably guess is heritable but actually is not thanks for mentioning Irv zuker who uh 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 Irvin the experiment you mentioned made me smile wide because it's uh but one of gosh maybe hundreds of incredible studies so if people are interested in seasonal rhythms and circadian rhythms and biology of the most interesting kind definitely check out Irving zuker's work at at Berkeley we I'll provide a link to to his uh PubMed there since we've been taking a tour of individual variation in ol Factory perception visual perception and uh now heat tolerance um I have to ask are you aware of any examples off the top of your head um in the auditory domain that particularly Intrigue 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 uh you have the ability uh to to hear a note played and say oh that's a c 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 of Perfect Pitch than you would in the general population but still maybe one in 10 trained musicians have perfect pitch and parenthetically having Perfect Pitch doesn't NE necessarily make you a better musician uh 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 it's kind of low there's a heritable component but it accounts for uh my recollection is on the on the order of 30 40% 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 uh do you cover aspects of human individuality that extend beyond the perception domain um into the cognitive domain well yeah absolutely and uh 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 uh uh for the benefit of your of your listeners and viewers here pleas so if you look at human traits whether they are behavioral traits like shyness or very straightforward morphological traits like height uh 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 variance you get from your mother and father and there are a few traits that are absolutely UNH heritable but that most fall in between so let me give an example everyone in the world has either wet or dry ear wax and it turns out that this is determined by variation in a single Gene the name of the gene is boring it's abcc1 uh it's a ion transporter and uh there's a variation in this Gene gives rise to either wet or dry ear wax it doesn't matter how your parents raised you it doesn't matter what foods you ate growing up doesn't matter what what uh uh diseases your mother had when you were in the womb it's 100% heritable well does this mean that abcc1 we should call it the ear wax type Gene well no because it's not there just for that like this this Gene is expressed in cells in all parts of the body doing all kinds of things ear wax 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 um for example the wet ear wax G uh variant of the abcc 11 Gene also confers a slightly higher risk for breast cancer H uh so clearly it's not just for ear wax it's it's for a bunch of things most of which we don't yet know about but in the case of earwax this trait is 100% heritable at the other end of the scale speech accent is zero% heritable it is entirely dependent upon the speech that you experience uh in your childhood and interestingly it's the speech of your peers more than the speech of your family which which is why the children of immigrants sound like the place where they wound up not like their parents uh 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 resonant these are physical things having to do with the vocal tract and they are in part heritable Okay so we've got one thing that's 100% heritable one thing that's 0% heritable but where do most Things Fall most Things fall in the middle uh uh 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% of the variation in the trade of height can be explained uh 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 um now you might say okay well that's an estimate for people in the US is this true all over the world well no if you go to a place where people routinely don't get enough nutrition and are routinely fighting off infectious diseases like this has been studied in rural Bolivia for example or rural India now height is no longer 85% heritable it's only 50% heritable 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 fulfill their genetic potential for positive traits and uh 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 I Q 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 of of later success and uh much more so than say sat tests or GRE tests or mcats or other standardized tests but presumably those correlate in some way they do I do but but but the IQ tests are better actually they talking about this the the classic IQ test uh I am talking about the modern variants of the classic IQ test that are administered by trained psychologists uh 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 ask the question what is the heritability for IQ test score uh well the answer tends to be different depending upon the population if you look uh again in in countries like the us or in Western Europe that are fairly affluent where where people uh tend to have good access to to nutrition and medical care and schooling and kids get to play and they're not and they're not traumatized by War then uh then IQ test score is heritable in the ballpark of 60 70% 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 uh communities that that uh 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 in Heights 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 um if two identical twins are raised separately uh the correlation in their IQ is can only is it that only 60 I think you said about 66% of their IQ can be predicted on the basis of their genetic makeup Alone um 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 um and the other one went to schools where the 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 it's tapping into some other um thermometer of 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 safer less traumatizing neighborhoods and they're more likely to have books parents with books in the home and uh uh 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 twin TS will share nearly 100% of their Gene variant and on average fraternal twins share 50% of their uh of their Gene variants and generally speaking when people do these studies in order to avoid confounds of sex they'll compare same seex fraternal twins so boys to boys and girls to girls uh uh and uh when you put these incidents into a formula called Fisher equation then you can come up with an estimate of the heritability of the trait but there is an assumption present in that and it's called the equal environment assumption you're saying well two 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 uh 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 reared apart which is abbreviated mistra that is really the gold standard for assessing the heritability of many different human traits both behavioral traits uh but also disease incidents but of course it's a small n because you know the population of identical twins rear toart 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 uh uh identicals and 50 some fraternal uh 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 uh personality traits uh what the psychologists uh use the acronym ocean to mean openness conscientiousness empathy agreeableness and neuroticism I think I got that right spelled right uh that these traits on average tend to be about 50% heritable and so okay you say all right well 50 50% of those personality traits is heritable the rest has 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 um and found that family has almost nothing to do with it and what what are are you kidding it's it's it's it's 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% 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 three billion bases of DNA all 19,000 or so genes in a human don't make a blueprint for making your body and brain there it's not a 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 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 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 what means well for 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 the than the other Twins or whose liver is 30% smaller than the other twins even though they have the exact same DNA and they were lying right next to each other in the womb and presumably had the same or very similar fetal environment and the reason is the random or as we say stochastic nature nature of neural development a great way to study this is with nine banded armadillos I know we're getting weird here but I love the armadillo because I've been told tell me I don't want to uh uh interrupt you too long but um as far as I know the only animal in North America that carries leprosy uh that is that is true and um and there's a lot of twinning going on in Armadillos right well what there is is actually quading so armadillos or the nine-banded armadillo in particular and they're different armadillos I'm not really an armadillo specialist so I don't know if this holds for all of them but the nine bounded armadillo is born as identical quadruplets awesome awesome so you can take these identical quadruplet newly born armadillo I don't know you think you call them pups I don't know what a baby armadillo was called I'm sure there's some particular word for it and someone will tell us in the comments on YouTube what is the name of a baby armadillo I know like a feret baby ferrets are kits uh uh the moms are jills the dads are bobs I used to be obsessed with this kind of naming you know it's a it's a business of ferrets or a what is like a gang of raccoons or whatever 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 um you win the pride associated with being right that's right right one of my favorites is an a an ostentation of peacocks amazing or a murder of crows who comes up with this yeah I know it's it's a good or a raft of otter I think it I I think that's correct but uh so if you have four newborn uh identical nine-banded armadillos then this is a great model system that biologists can use to study uh uh uh stochastic differences in development and and sure enough their brains are wired slightly differently their bodies are slightly different if you test them behaviorally even very very early in life they have different propensities some are bolder and will Explore More some are will tend to hide in the corner more and you know we know this from the lab you you get a box of mice that are inbred from the breeder and you pluck them out and they're not behaviorally identical some might try to bite your hand some will run away some will stand stock still where does this Behavioral variation come from in mice that are nearly genetically identical well it comes from a 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 acknowledge our 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 what those hormone levels etc mean and behavioral supplement nutrition and other protocols to adjust those numbers to bring them in are the ranges that are ideal for your immediate and long-term Health inside tracker's 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 insid tracker you can visit insid tracker.com huberman to get 20% off any of insid tracker's plans again that's insid tracker.com huberman to get 20% off and is the pseudo random stochastic nature of development one of the major major excuse me driving forces for evolution ution because you know we hear about mutations and we always think or 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 Xmen the entire series every single one including the Wolverine 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 IND Duality 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 of development because if you through the randomness of development happen to have like a particularly 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 trait along just brief insert here on germline we had odad RFI on the podcast who studies um epigenetic transmission and um and inheritance of uh of of it's not lamaran we have to point that out but um inheritance of of sort of acquired traits it does happen and the germine is the genes that are present in the the sperm and in the eggs all the other uh cells of your body have genes of course but um the best way to put this is uh simply going to the gym and getting fit um does not make your children more fit because the germ line as far as we know is not modified in a direct way uh 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 and as you uh as you correctly said about od's work and 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 worms and in Plants uh the evidence in mammals is is really not there yet in 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 or great-grandmother's trauma uh the evidence at present is is poor actually a lot of it comes from epidemiology most of which came from famines in the overx region of Northern Sweden and they had very good medical records 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 you have this trait and your female you 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 re results are known uh 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 significant just occasionally randomly through through through luck and you have to apply a statistical correction called a bon foron correction when you make many particularly post Hawk comparisons after the experiment uh comparisons to set the bar much higher for accepting that data and most of those studies they didn't apply that correction and I remain unconvinced of transgenerational epigenetic in heritance 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 uh describe a mechanism and show this convincingly in the years to come but right now uh 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 raise your parents who raise you not always people can be adopted in fact I have adopted members of my family um but if 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 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 it had to get into their sperm and or egg cell and then contribute to producing it in you but but fragmentation of DNA in sperm is um or in eggs is is a is a common um thing especially as people age DNA sperm and eggs fragment um and it's possible that some of those mutations still allow for viable embryos so it's in theory The Germ line could be changed by um environmental events well right uh but now I think you're starting to talk about things that are heritable MH 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 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 uh if as a result of experiences that the mother has during pregnancy so uh for example we know that during the 1918 pandemic flu uh 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 males wound up going into the army for World War II 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 uh the male children uh that were uh in utero during the winter of 1918 during the pandemic flu are on average a millimeter or two shorter you might say a millimeter or two 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 fourfold from about 1% to about 4% and even though autism wasn't a term in 1918 yet uh 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 um the late Paul sternberg's work as well uh I maybe have that name um incorrect but in any event that it is um if pregnant mom gets the flu in the first trimester you see this higher incidence of schizophrenia and autistic Offspring um 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 um uh some breakdown in the immune barrier I just want to open up the the number of variables that this could be or do we know that it's something in the hypothalamic pituitary so-called stress axis that is adrenals um so hypothalamic pituitary adrenal AIS um like is it elevated cortisol um 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 uh Gloria Choy at MIT uh uh uh together with her collaborators has made a mouse model of this phenomena so she takes pregnant female mice and she injects them with something that that it's she doesn't actually in infect them with virus she puts a chemical in that is on the coat of viruses that mimics viral infection and uh then what happens is that in a way that interestingly is an interaction with the with the bacterial content of her of her gut produces a surge of a immune signaling molecule called interlan 17 interlan 17 can pass through the placenta into the fetus and if it's present just as you said at a particular point in development do doesn't work anywhere during pregnancy but during something that is sort of the mouse equivalent of the first trimester if that occurs it causes disordered 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 post morm tissue from autistic people you can also see those balls and clumps of cells are those balls and clumps of cells thought to reflect um alterations in cell migration they are yeah some some I don't know if it's entirely known how much of it a cell division or migration but certainly migration is a part of it and it's very likely that that critical moment uh to disrupt this ordering of the brain and produce these inre es in schizophrenia or or uh autism vulnerability uh are coming at a point where neurons are migrating uh during development and uh 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 of this interlan 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 uh it seems that uh you can produce it through this immune signaling pathway and and so then the question is well like are these mice autistic well how do you know if a mouse is autistic and and the answer is it's actually a little vague right there are behaviors that neuroscientists say are analogous of human autism and one of them is If You Give a Mouse a 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 you see in autism it's a bit of a stretch right I mean it's a challenge to interpret mouse behavior in in human terms but um it's a reasonable First Step incredible and uh I hope more will continue to be done um as it surrounds the uh first trimester influenza hypothesis because it it's been around a while and um and obviously uh there's a spectrum uh of what we call autism Asbergers and U nowadays people refer to it as sometimes is neuroatypical there's some high functioning people with Autism there's some low functioning people with Autism and for that matter there's some high functioning and low functioning people who don't have autism so um but it is something that I think uh demands our attention and and it that hopefully will be resolved at some point because also influenza is uh but one immune uh insult um and presumably pregnant women are being bombarded with all sorts of uh viruses and bacteria and fungal infections and fighting them off or not fighting them off and who knows what the variation in uh neuro immune interactions exist in there uh that give rise to you know good variation and let's call it um you know uh debilitating variation well that's that's absolutely right and so for one example is that uh we don't know what the effects are on the children who were in utero while their mothers were fighting off covid right we won't know for uh for a while or the calm and cold and there might I mean there might be nothing but or there might be something serious uh lurking there like there was for pandemic flu uh and it'll be very interesting and uh and important to find out agreed I'd love to talk with you about mindbody but before we do that I would be totally remiss if I didn't ask for your um broad top Contour understanding of the mini brain the cerebellum right the so-called mini brain and here's why I've been a practicing neuroscientist for you know close to three decades I know where the cerebellum is I've dissected a bunch of them I um 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 an ever expanding set of things that the cerebellum is implicated in not just balance as most people hear but also timing also cognition I hear about timing in particular of motor Behavior but then I also hear that it's involved in learning and not just motor learning and it certainly is involved in motor learning perhaps that little mini brain is uh 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 to the thalamus and yes there's some mysterious nuclei in the brain but to me the cerebellum is one of the most cryptic and um complicated structures to Jan and I know you spent some time in there so what's the cerebellum do well uh cerebella researchers like to joke that the cerebellum is a counterweight to keep your head from falling forward oh perfect well with all the texting nowadays people need bigger cerebellum that's right that's right probably over many generations then that will happen along with a expansion of the thumbs uh so uh but of course everybody's going to text with their mind in about another 10 years right you'll have elon's implant and you won't need your thumbs at all yeah or maybe just or my friend Eddie Chang who's a neurosurgeon and uh works on the auditory system he's been on this podcast before he was saying that if you 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 um in fact when we read he told me uh we are actually receiving the signals as if we were going to speak the words we're reading but they don't quite arrive at the place where you could get a full-blown postseptic potential so you're not actually moving the vocal Machinery um 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 and it's very analogous to what happens during the rim phase of sleep right when you have commands your brain is issuing commands to your muscles to to do things uh like behave in your dreams to to run away or go here or go there uh but those signals actually are blocked in the brain stem prevented from from reaching your muscles because the uh nerves that don't go through your brain stem like the ones that control your eye movements aren't subject to that blockade that's why you can produce the rapid eye movements in in RM sleep but yeah this is a general theme in the brain a lot of times you have the output but then you shut it down and there are Rim sleep behavior disorders where people thrash and move in their sleep uh during during REM and uh it's because this outflow that's normally blocked isn't isn't blocked have you ever had the reverse happen uh I have where you wake up and you're still in so-called remonia 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 uh 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 uh did a drawing uh of exactly that uh so yeah this is a well-known phenomenon but to get back to the cerebellum uh as we started um 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 uh they tend to not coordinate their movements they have a disturbed gate if they're reaching for an object they often overshoot it and have to make successive approximating motions to get back uh to their target so 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 regions including the frontal cortex where phenomena like uh like planning and uh decision making and uh moral sense and many aspects of Personality seem 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 an 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 and if we're looking for a theme about what the cerebellum does is that it is there to 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 you know motor systems and doing sports and you know if you're trying to hit a baseball and looking at what the pitcher is doing and trying to anticipate what the pitch is but it also comes up in a 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 uh when meeting something a lot of this depends upon predicative circuitry and uh it dep depends in part on the cerebellum and it seems to be at least partially impaired in people who sustain cerebellar damage so it seems as 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 of 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 at 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 hardwired stuff that genes just set up neurons wire up to that neuron Etc the cerebellums in the back the eyes are in the front the hardwired stuff uh 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 and I have a lot of problems with nature versus nurture as a as an expression it was popularized by Francis gton uh in the 19th century a a colleague of uh of uh of darwins 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 mean heritability right what you inherit in the gene variations from your mother and father and nurture means like how your parents or your community raised you uh 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 uh the foods your mother ate when she was carrying you in utero um the diseases you fought off or your mother fought off while she was carrying you uh in utero the bacterial population of your gut uh so experience meaning anything that impinges on you starting from the earliest stages of fetal developments uh continuing to the last day of your life I think it should be very expansive much much more than social experience in the family or the or the community and as you mentioned I have a problem with versus because there's this idea that these things are are essentially in opposition well is he that way because of of of his Gene variance or is that way because of what what happened to him and I think the thing to realize is that uh experience and heredity interact in 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 phenol ketonuria or PKU uh which is uh an inability to uh to metabolize uh the dietary amino acid phenyalanine and uh so uh 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 and fenal alanine if you don't it doesn't matter that you inherited these things right so that's a way which genes and experience interact an idea of in ways in which then they interact positively um think about athletic ability right so a lot of athletic ability is has a heritable component if you are born fast for example uh then you're more likely to do Sports and practice them and get better Sports as a result of your experience so here genes and experience are feeding back on each other in a positive feedback loop so there really isn't uh a vers a 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 random 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 glves the gloves don't fit you must quit you know it's got that kind of Snappy snare drum beat but I think it's it's a accurate so heritability interacting with experience filtered through the randomness of development yeah so we can shorten that up and um and we'll just call it um uh the Linden hypothesis you know I don't think I can take credit for that that's it belongs to other people sure but um but there's a long history in science of of things being U shortened up and uh coined and that's uh as important and I'm not we're not trying to rob attribution here um uh and the good news is perhaps you can't call it the lyen hypothesis but I can all right and what I found is as with the Galpin equation which is now out there as a hydration it's a formula a formula that uh gives broad but um research and formed 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 uh physiology and and an expert in all aspects of exercise science there's the Galpin equation there's the soberg principle so I'm naming these things left and right right um where appropriate and um so I'm naming these things uh sparingly and where appropriate um so from here on out heritability interacting with experience filtered through the randomness of development is the lynen hypothesis and I'll be damned if anyone's going to rename it uh um faster that I'm going to propagate it so all right well I think all the the the geneticists will be nashing their teeth uh 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 mindbody okay I'm am fascinated by this um 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 and my father's a scientist and I got very interested in Neuroscience early um as people perhaps know and so much of Neuroscience as I was coming up through the mid90s 2000s 2010 to 20 stretch was focused on the brain piece MH very little on the body there was nothing about gut brain AIS in the early discussions and cours work um in parallel to all of that I've been interested in mental health physical health and let's just call it performance and um 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 Institutes of Health for complimentary health and Medicine essentially exploring things like yoganidra 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 um California counterculture esselin Institute only uh you know um 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 and every major university and in every scientific journal are starting to publish papers about the interactions between bodily organs like the breathing apparati the diaphragm lungs the heart heart rate variability we hear about um 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 understood but it seems to be both accepted and appreciated so what are your thoughts on mindbody what ises that mean to you and what do you think is the potential of the mindbody interaction it seems to me we've just barely scratch the surface yeah well I'm glad you asked because I think it's a it's a really fascinating uh situation and uh where things are changing very very quickly and I think to me the most important thing for people to understand is that when you have a hypothesis let's say you have a hypothesis that uh meditation can uh attenuate chronic pain all right well there is a temptation to think that this operates outside the realm of Science and biology that is in some arery 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 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 or guided breathing uh uh affects 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 in initially from my father my father was a psychiatrist in fact kind of a talking cure old-fashioned psychoanalyst had his practice in uh Los Angeles and uh we would have dinner together every Wednesday night and uh he would always tell me about his patience he was very careful to keep confidentiality right he wouldn't great confidentiality but you know I would say oh yes how's your narcissist oh we had this dream so 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 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 araer realm it is was 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 uh and so as you've 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 were also talking about how phenomena in the body affect affect the mind and we're understanding so much more about how that happens and I think the general thing for your 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 the 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 Inception right so as opposed to extra reception your your outward pointing senses these are the senses that monitor or 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 and 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 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 uh uh activate neurons in the brain or in other parts of the nervous system to produce changes in uh in mental in mental function and I think the real 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 cyto kindes and cyto kindes are basically the signaling hormones of the immune system and they they can flow through the bloodstream and through lymphatic fluid uh and reach many parts of the body uh we've known for a number of years that the specialized receptors for these cyto kindes 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 one one Exemplar um there are a lot of things these days suggesting a a 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 cyto molecules produced at the site of inflammation that then travel through the bloodstream and the lymphatic system to then reach the brain bind ctors and have effects and so you know one of the mysteries about depression is that uh 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 anti-depressant drugs uh about a third C very tiny benefit and about a third SE no benefit at all and part of the reason is because maybe our term depression is too big a bucket depression is actually many different biological disorders and only a subset of those are are helped by ssris and we'll need different therapies for the other ones that's certainly part of it um but part of it might actually have to do with inflammation so if you think that inflammation is a a risk factor in depression well you could do something very simple right you could you could gobble an 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 uh 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 relieves their depression and the answer seems to be no it doesn't well 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 uh for Hepatitis C that's since been superseded by more modern drugs was a pro-inflammatory cyto molecule and when you gave it to people to treat their hepatitis C almost everyone became depressed on this drug so oh well this really seems like like like a link likewise there are certain uh neurological diseases like multiple sclerosis it turns out the incidence of depression as a comorbidity in multiple sclerosis is enormous and you might think 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 a at a at a rate from people who are uninjured so that doesn't seem to be it 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 cyto kindes including one called Incan 6 I6 that's elevated massively if you if you take a spinal tap and you look at cerebral spinal fluid and so that could be causitive for depression so all these real reasons to think that inflamation is involved but yet the idea is still a bit messy so now what if instead of looking of the general population of depressed people you look at the subset of people that don't respond to SSRI anti-depressants 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 it's 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 soon in the body to mind part of Mind Body medicine that is going to be of enormous uh 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 um I've had Robin cardart Harris um from UCSF and Dr Matthew Johnson from your very own John Hopkins University both of whom work run Laboratories studying psychedelics for the treatment of depression um the clinical trials on Sil cybin um and to be clear cybin 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 two without psilocybin then two um 2.5 gram approximately dosages of psilocybin given separately again with therapist present and then follow-up therapy sessions seem to lead to relief of depression in approximately somewhere between 65 and 80% of people um in some cases total remission in some cases um 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 seem to help a third of people a third minimally and a third not at all and of course there's the side effect profiles of the ssris and Associated drugs not just the ssris but gryon and the other anti-press uh that are taken in prescription drug form and then there's this uh 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 um to me this is the only thing that can reconcile the 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 um it seems to me that based on the time course over which ssris work the fact that they increase serotonin uh very quickly but the relief from depression comes much later the fact that neuromodulators like serotonin are intimately involved in neuroplasticity they can some cases gate neuroplasticity that it all centers back to changing neural circuits and so what we're really trying to do whether or not it's transrenal magnetic stimulation or 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 are more studies about the interaction between neuroplasticity and inflammation and are we seeing that kind of work out there and um because these results sort of sit as disperate somewhat conflicting but it seems like inflammation is is anti- neuroplasticity and broadly speaking here I realize there are many inter lucans there are many you know some of which are inflammatory some of which are anti-inflammatory but is that is that a meaningful hypothesis and it um can do you think there's any hope whatsoever to actually cure depression if we if we sort of start to uh unify the the the 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 neuros psychiatric condition ultimately is from neuroplasticity in some form or another and I think it's worthwhile to step back a bit and talk about what neuroplasticity means uh to date there has been a focus on synapses on the contacts between neurons as the site of neuroplastic and that's 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 Beall and end all of neural function so for example neurons work by sending electrical signals uh uh 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 C A wasn't connected to cell b and now it is and that changes and then sometimes well actually cell a was connected to cell b but cell b wasn't responsive enough and now there's a change in cell b so now cell a can fire cell b and that could have been a result of a change in its synapse making it more receptive to neurotransmitter released from cell a or it could be something intrinsic in cell a that makes it fire its electrical signal it Spike more easily I think that one of the key cell types that's going to be important for your hypothesis um linking inflammation to synaptic plasticity is going to be a cell called a micral cell and micral cells are non neuronal cells in the brain they're motile they can crawl around they have long processes and they can gobble things up they can literally sort of chew away way and digest bits of the extracellular scaffolding that surrounds neurons and synapses and thereby renders them plastic they can uh destroy synapses and there is a lot of indication that certain disease States may involve over exuberant microa pruning synapses to a degree that they shouldn't and we know that microa are chock full of cyto kind 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 anti-depressant 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 Ayer 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 micral cells and neurons and other types of cells in the brains some of which will involve not the neurons in the brain at all but the brain's 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 uh your blood vessels become more uded and less elastic and you're closer to the to the to the trouble spot uh 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 uh as we age I am a fan of exercise but I'm fortunate that I enjoy running and some forms of resistance training um so I always assumed that the good side effects were just the positive mood effects um until the recent literature that as you mentioned uh improved vascular vasculature blood flow and reduced inflammation if not during the exercise when inflammation actually increases um decreases inflammation um I'm delighted to hear you say the word microa and um my postto adviser the late Ben Baris would be especially delighted people can look up Ben I'll provide a link to his um uh biography in the show note captions because he really championed um to the point of of um I don't know if Champions even a sufficient word I mean Ben was beating the drum saying we have to pay attention to Gia we have to pay attention to Gia for the longest time gleo were relegated to these other journals they even had 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 microa and other gal cell types and it's it's really f fantastic to see that uh this actually the most abundant cell type in the brain is the the gal cell um are getting the attention they deserve it's absolutely true uh and uh 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 um in the early 80s 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 glea are in the spotlight for good reason I'm not trying to say that that it isn't worthwhile but there is this phenomenon of things being fattish and people jumping on bandwagons and 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 most fattish involves um single cell expression profiling that is creating a list of what genes are turned on and how strong they're 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 and that 15 years from now people will go back and say gosh those folks in 2023 we're really overdoing it with the Single Cell profiling yeah 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 postto 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 postto so pick something different than what's fattish now and you'll you'll land right on the money that there's always a lot to do you don't have to do what everyone else is doing and indeed uh the deletion test becomes relevant here um the deletion test as it was described to me by my colleague EJ Chichi at Stanford is um if you look around and you see um one or more groups um doing what you want to do very well just pick something else your life's going to be a lot more pleasant um absolutely I agree with uh with EJ on that uh entirely let's get back to mindbody um there are a bunch of different domains of mindbody as you um so apply pointed out it's bidirectional mind informs the body body informs the mind um but we could probably break this down into uh respiration so breathing um conscious patterns of breathing um emphasizing inhales or emphasizing exhales cyclic hyperventilating Etc could also be thought patterns um a little bit harder to break those down but um many not all but many forms of meditation involve having a very still body not all there's walking meditation Etc but still body um focused mind kind of a not a state that we are in a lot of times unless we direct that state um there are still other mindbody patterns of communication through very still body deep relaxation things like Yoga Nidra non-sleep deep rest um there's hypnosis there's um uh touchbased Body Mind communication if we're going to talk about Mind Body also we should refer to as body mind um how do we dive in and think about this because this is involving clearly a thousand different neural Pathways not just the Vegas nerve as it's you know typically people just kind of hang their hat on Mind Body must be Vegas nerve and of course it involves the Vegas but the Vegas is an extensive set of Pathways so um how do you like to frame up mind body and what's most intriguing to you about mindbody communication both in terms of the biology and its practical app 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 uh and they are the the the neural signals that are conveyed by neurons that actually get there and they are uh hormones and neurotransmitters and cyto kindes that are released from the brain I should mention that that hormones are actually produced by neurons including for example some of the hormones that you think about uh as being produced as as sex hormones like estrogen is produced by neurons in your brain for example um 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 uh from the cancer world and so uh melanoma is a is a is a bad cancer it kills a lot of people it can spread it's uh highly metastatic and we know that melanomas often become inovated 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 inated then the prognos is for that patient is worse it's more likely to grow it's more likely to spread well how does that happen well recently uh there have been some reports that uh show that neurons that innervate the melanoma don't act directly onto 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 at it and they when that signaling molecule is released from the neuron it uh shuts down or reduces that immune patrolling function and then as a consequence the tumor can grow and spread and butt off more readily so this signal that comes from neurons is sending the ambulances home so to speak yeah exactly and and the signal is something called calcitonin Gene related peptide or cgrp uh I'm familiar with cgrp from the domain of touch and its involvement in um I think like itch perception do I pain perception and itch perception right interesting yeah and so all right so if neurons can um 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 um then is it reasonable to hypothesize that mental processes could affect cancer progression so let's say we hypothesis and it's a wild 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 interated right well right now this is just kind of a wild idea but I think the important thing as I've said before that this is a wild idea with a biological substrate it's not like you meditate and Magic happens and force fields open and 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 send 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 to body signaling that has received very little attention up to now incredible and I say incredible because while you're giving an example of cgrp and nerve inovation and metastatic uh tumors I absolutely love the idea that a phenomenon involving some practice that could be put under the umbrella of Mind Body or body mind um becomes something en entirely different when we're trying to hang that on the hook of a biological process it's like something fundamentally changes there right um you know it's amazing to me for instance that early on psychedelics and breath work conscious breath work uh were 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 um called Harvard I guess I just Nam them um but nowadays there are Laboratories at every single one of those institutions studying deliberate respiration on health as well as psychedelics um and meditation for that matter um with the goal of understanding what cyto kindes what neurotransmitters Etc change through defined Pathways including Vegas but frenic nerves and uh frontal cortex and all the stuff that is considered you know classic rigorous Neuroscience so I do think we we've entered a new era um so it's not cting 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 um needs to be done to really nail down the idea that how we think influences our biology even though it's a total duh because everyone knows that chronic stress for instance is can be detrimental short-term stress can actually be beneficial but um 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 in mental processes you know it's so it's so obvious when it's spelled out but it's just remarkable to me how this has just been lumped in the category of like woo science um 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 I think it is the job of biomedic 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 there's sort of a visal reaction you when when someone says oh yeah well you can do me breath work and it'll realign your chakras and that is you know what will uh uh reduce your anxiety or your gut inflammation and I'm tempted to just go oh shut up but what if the chakras are collections of nerve ination of bodily sphincters and you know it could make sense right it could but it's got to there's got to be some some biology in some cases these analogies are rooted in something real and in some cases they're just made up 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 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 the barrier between your gut contents uh 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 examples so you you've mentioned breath work a couple of times and I think this is really interesting um 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 as a background uh to neural activity you can find it in the cerebellum you can find it in the frontal cortex you can find it in uh the habenula which is implicated in many things including depression you can find it 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 uh more uh you've been so gracious in covering this wide array of topics and with uh such eloquence and uh I must say I've been delighting in all of it you are in a unique position these days because uh if I understand correctly uh you've been diagnosed with a fatal illness um I suppose we've all been diagnosed with a fatal illness of sorts because um we're all going to die sooner or later yes um 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 and perhaps we can explore some of the well let's just say pleasant surprises that have emerged um since that initial diagnosis well sure I'd be happy to uh so in the uh the uh summer of 2020 uh 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 uh uh without huffing and puffing and I thought oh well I've got Co but I took covid tests and there was they they they were all negative but I thought oh I must have covid I've got the symptoms of covid I have respiratory issues I'm 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 uh they hooked me up to an electrocardiogram and they said oh uh you've got atrial fibrillation meaning that your heart is doing two beats every time it should do one so I have a very high heart rate and when the heart beats that fast it can't work very effectively there is enough time to recharge before the next beat comes now it turns out that there is a very straightforward therapy for this uh atrial fibrillation comes from uh electrical signaling in the heart sort of swirling about in a circle and and reactivating part of the heart muscle faster than it should and so if you thread through a catheter in your in your in your in your groin up uh up through blood vessels you can put in a little needle and use that to quize and to ablate a tiny little strip of cells in the heart that will produce a barrier that will prevent that aarant return of electrical activity and will cure atrial fibrillation so I had that process that ablation surgery and sure enough it it cured my atrial fibrillation and I was feeling terrific and they said oh as a followup come back uh a few months later and we'll do an echo cardiogram to see how your heart looks and they did and they went oh my God there's this huge mass pressing against your heart it's like the size of a Coke can uh here's what we think it is we think it's a hadal hernia we think your stomach has poked up through the diaphragm muscle and it's nestling next to your heart so the way we diagnose this it's 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 chugged it I got up there oh nope it's not your stomach I said oh okay well what we think this is is a Teratoma and a Teratoma is a developmental uh 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 a tooth that grows hair in their abdomen Sometimes women have these 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 had 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 it lasted two days wow um they had 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 John's 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 stop and they so the surgery was a be and then uh 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 sovial saroma and sovial saroma 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 Tes testicular cancer or breast cancer there are huge tables of Statistics from millions of patients on what's been tried and what works and what the prognosis is for sovial saroma of the heart they're only individual case reports oh there's a guy in Kenya and he got it and this is what happened there's there's there there's there's a woman in Minnesota and this is what happened with her right there are 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 uh about uh now 27 months ago so I've fortunately uh exceeded that lifespan estimate and I think we got to be clear also that you know being 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 inform you can't just say I won't do it right you got to 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 um so so you know I got this information and I was Furious I was so angry heart cancer who the hell gets heart cancer is that even a thing have you ever heard of somebody with heart cancer not until now no heart cancer what the f I've got heart cancer this is this is crazy time I was 59 years old I I got a lot to 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 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've had a good career uh it's been a fairly easy run of it um 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 my family and I have a wonderful wife named Dena and she's just the best how do I deserve this I don't deserve her you know honestly um 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 are you relaxed are you fleeing or are you approaching you know it's it's like a single axis well but it isn't you know and I think most people understand that but but dumb me I I I didn't until that moment really understand that I could feel profoundly grateful and profoundly angry in the very in the very same moment and you know having cancer and getting the kind of treatments the 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 the radiation burned my esophagus I couldn't eat for weeks it was months it was painful to swallow you know bad stuff lots of people have have had to have bad stuff like this and and what I it realize you know this is It's a deeply um unempowered situation to be a medical patient particularly when there's something serious you have you have a limited sense of agency things are being done to you drugs go in you that make you feel really bad and there isn't there isn't that much to do and I realized that for me the sense of agency came 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 uh so for example I'm getting the ch Mo and uh I should just say as background I'm fortunate I I don't have a tendency for depression I'm a pretty upbeat guy I don't take any credit for that I think I was just born lucky and and raised lucky right but day after day of feeling bad in your body from chemo boy it's hard to be positive it really is I could not overcome it my mood got 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 a wash in interlan six and I couldn't overcome it I felt really low but at the same time I was sort of out of remove being a nerd about going like huh I bet these cyto kindes 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 it 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 gone oh no no no no no no I'm 59 years old I should get way more than 5 years I got a lot of things to do uh professional things personal things family things I got all things to do no that wouldn't be right I'd be very upset but you know if you told me after my diagnosis of 6 to 18 months oh you get five years I'd be like five years yeah that's pretty good I can do a lot in five years I can finish up in the 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 do 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 realize 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 genuinely engaging with my own demise I really find that as much as I try I really can't do that and I first I thought well that's just your own lack of imagination Lyon it's just because you know you're not very good at this but the more I thought about it I thought actually no this is a human thing this is a fundamental human thing and and 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 it triggers some things you you think you make decisions and then you make an action that goes out to your muscles or or or and that's the loop and that's what the brain does and what we have known in more recent years 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 there'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 is everywhere in the world if you ask anthropologists is there any society that doesn't have religious ideas both say no they said they don't always have the word religion they might just say well yeah in this place everybody knows that you know the world's on the back of a turtle and that you know this and this happened there are these rules they may not call it religion but every place in the world has religion not everyone is religious but it is across cultural Universal and most religions not absolutely every single one but almost every single one has stories of afterlife or reincarnation in which your Consciousness endures well why would that be and and and in 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 that's a very a very general idea or punished in the afterlife or punished in the afterlife right and you know in some religions you meld with the Divine in other religions you're reincarnated is this or that heaven or hell right there's there's variance but but they share that your Consciousness endures 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 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 um my undergraduate graduate and post talk advisors all sadly died earlier early really um by pretty much any standard um and I was fortunate enough to be in communication with the the last two as they were going through that process um both of them described um 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 um that makes me conclude that something about the knowledge of one's impending death however far off that might be um 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 with the little things or things that we previously overlooked um there's this sense of slowing down and we know from uh basic uh videography photography that slowing down means an increase in frame rate M right that uh you know you know shooting at um strobe frame rates gives you the perception of uh strobe um shooting at very high frame rates allows you to see things in very slow motion you're noticing subtle variations that normally you overlook um I not trying to be overly reductionist about this uh this process of enhanced gratitude um that's uh that you describe 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 um and with this kind of openend did 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 um 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 course I know that I've hopefully have more than 12 months but it's not infinite yes so you know this this idea of of the the Finish Line the cliff leaving aside whatever might happen afterwards I don't know haven't been there um it changes what we notice by way of changing our perception of time um I mean this is a this is a profound tuning of our perception what are your thoughts on that and 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 um 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 perception of time is 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 uh you know my wife and I have taken 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 sensient 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 choke up the profound love that I've felt from my wife and my children you know it's all the little stuff it's the big stuff that I think about when I think about gratitude it's not noticing the sip of tea it's it's the big issues and you know for me I you know I don't I want to delay my death as much as possible of course but uh 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 um I've had a lot of it I'm 61 I'd 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 and have wonderful loving interconnected experiences and so the negative part is about what I leave behind certainly what you've left behind is enormous um and has been the consequence of actions long before your diagnosis which I think is a is a clear lesson to everyone um I can't speak for you but don't wait for the diagnosis um you've mentioned the sense of agency uh that you felt um by being able to pay attention to and explore your experience of let's call it what it is impending death um and at the same time you as you mentioned you've Amplified and uh accelerated the number of things that you've put into the world recently writing incredible um articles about your experience of life and death and we will of course link to those so people can read them um I've read them all and they are uh profound and they don't just feel important they clearly are important so very few people have uh your insight into the nervous system at the mechanistic level but also at this more holistic level that um you've clearly displayed to us here and and in your research and in your book writing and public speaking um you know I think it's a it's a risky thing to ask uh somebody for advice um but I can't help myself because um I think it's a it's a real opportunity um if you had advice um to give to any and all of us um based on the whole experience yeah uh all of it from go as they say right um if if you're willing and feel free to pass but if you're willing um what is your advice well I would say the advice that is really Universal is what everybody already knows and is a bit trait 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 and your own medical situation can be empowering and and useful but I don't think that should be broad advice I think that's only for a fraction of people that's probably the worst thing they could do and there's nothing wrong with that everybody's everybody's different 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 and all of that is absolutely true in the case of you being here today and the work you've done but I think it's self-evident how much you've uh not just accomplish but how much knowledge you've put into the world and not just scientific knowledge but knowledge about The Human Experience um 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 um so great to still have you here and to have this conversation and I hope it goes longer and no matter when it ends uh you've done an enormous service to humanity well thank you that's very kind it's been a it's been a pure pleasure to have this discussion 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 zeroc cost way to support us in addition please subscribe to the podcast on Spotify and and on both Spotify and apple you can leave us up to a f-star review if you have questions for me or 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interest in science [Music]