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

welcome to the huberman Lab podcast

where we discuss science and

science-based tools for everyday life

I'm Andrew huberman and I'm a professor

of neurobiology and Ophthalmology at

Stanford school of medicine today my

guest is Dr David Linden Dr David Linden

is a professor of neuroscience at Johns

Hopkins school of medicine his

laboratory has studied neuroplasticity

that is how Connections in the Brain

Change in response to experience much of

that work focused on a structure called

the cerebellum which is also sometimes

referred to as the mini brain because it

looks like a mini brain in the bottom

and back of the human brain and it's

responsible for an enormous number of

basic functions that we use in everyday

life including our motor behavior that

is our ability to walk and talk but also

dance play instruments and it's

responsible for an enormous number of

basic functions that we use in everyday

life including our sense of balance our

ability to learn new motor behaviors as

well as our sense of timing today we

will discuss the cerebellum and what it

does but Dr David Linden will also teach

us about the important sense of touch as

well as what makes us different as

visuals the reason today's discussion

encompasses so many important topics is

that Dr David Linden's laboratory has

focused on many of those topics and he

is also the author of five excellent

popular books about Neuroscience that

focus on for instance our sense of

pleasure and where it originates from

and what controls it in the brain as

well as our sense of touch and today we

start off our discussion by talking

about the recent discovery of a set of

neurons that have been known about for a

long period of time but that only

recently have been characterized that

are involved in sensual touch in

particular and it's a fascinating

conversation I assure you in addition to

that Dr David Linden informs us about

what makes us individuals how each and

every one of us perceives the same

things differently and it's an

absolutely fascinating conversation

which tells you for instance why some of

you think a 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

mind-body 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 Linden himself and the fact that

in 2020 he was diagnosed with a form of

heart cancer that led his Physicians to

tell him that he had six to 12 months to

live now obviously because he was in our

studio to record this conversation he

has outlived that prognosis but he lives

day to day with the knowledge that his

death may very well come soon although

it isn't clear exactly when that day

will come of course he tells us how the

initial prognosis of his cancer as well

as outliving that prognosis has informed

his day-to-day life as well as his

thinking and his relationships and that

leads to a very direct and frankly

emotional conversation that includes

advice on how all of us can get the most

out of our daily living and out of our

overall life it's an extremely powerful

conversation that I believe everyone

regardless of age or health status can

benefit from and it's one that makes

clear that not only is Dr David Linden a

spectacular scientist but also a

spectacular educator a spectacular

popular writer a spectacular Family Man

including husband and father and friend

to many people and his colleagues but he

is also a courageous and spectacularly

generous human being before we begin I'd

like to emphasize that this podcast is

separate from my teaching and research

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

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your interest in science and now for my

discussion with Dr David Linden

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 dyseroth who was the first

guest on this podcast my colleague at

Stanford and for those of you that don't

recognize Carl's name he is a absolute

Phenom he's a

active clinical psychiatrist so he's an

MD and he also is a bioengineer who's

developed a lot of the modern tools for

probing the brain and um anytime I've

met with Carl the first thing he says is

what are you most excited about lately

that's a good question it is uh so I'm

gonna steal that approach and say what

are you most excited about lately

well very very lately the most

interesting thing that I read in

Neuroscience is the answer to

a 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 intersex or gay or straight or bi or

whatever you are you know the genitals

are are a hot spot

and why and you you'd think as

biologists we'd know this by now this

would be something we could just answer

but but it's been a mystery for a long

time and if you go back to to 1860 there

was a German neuroanatomist 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 Kraus

corpuscle and there were lots of them in

these two places and so he thought well

maybe this is the cellular basis of

sexual sensation maybe these are the

particular nerve endings that are

responsible

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 on 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 distribution

doesn't quite make sense uh and so it

was never known and so if you wanted to

really test as a scientist whether these

nerve endings are responsible you want

to record their electrical signals while

the genitals are being touched you'd

want to inactivate these cells and see

if you could interfere with with uh

sexual sensation and this in a pre-print

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 corpuscles

and so you see a nerve ending in the

skin it could be convey angle kinds of

information it could be tuned for hot or

for cold or for itch or for pain or for

in or for inflammation or for mechanical

Sensations stretching vibration

indentation and sure enough when they

recorded from these Kraus corpuscles

they really are mechanical sensors as

you would expect uh 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 used genetic

tricks to express one of Carl diceroth's

uh uh molecules 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

cross 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 much less interested she's much less

likely to let him out she's much less

likely to let him finish so this is the

remarkable results

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 Krauss

corpuscle structure

we know that sexual sensation diminishes

with aging is that in part because Kraus

corpuscle density is lost from the skin

of the genitals and that's a reasonable

idea because we know for example that

fine touch sensors in the fingertips

so-called Merkel and Meisner endings

also named after German anatomists like

so many things are 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 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 Stephen Shao Michael

Katarina xinjiang dong there have been a

number of world leaders in in the

cellular basis of sensation at Hopkins

do you recall if in the pre-print that

you were describing there was an

experiment where they activated these

Kraus core particles in females it's

funny you should mention that I sent

that exact email to David ginty 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

Kraus corpuscles in female mice and

we're just kind of staring at it and

looking and see if anything happens just

there is you know does the you know does

the the body change shape is there a

color change they don't even quite know

what it is they're looking for because

it's that much on the Leading Edge of

things but it's a good question or

perhaps the female mice would be more

willing to mate outside of the usual

time frame of receptivity if uh these

Kraus corpuscles 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 make for longer

during their fertile time and I just

want to remind people because we had a

guest recently uh Dr Rina Malik who's a

urologist reproductive and sexual health

expert she's an MD and um she made clear

that the the clitoris and the penis come

from the same embryonic origin they are

analogous tissues in different

individuals

I do have one more question about this

sexual touch thing

um

these are peripheral nerves right so

these are not of the brain and spinal

cord they are in what we call the

periphery and my understanding is that

peripheral neurons regenerate and can

remodel themselves extensively in ways

that

um neurons within the brain and spinal

cord tend to remodel less especially as

one gets older out of the so-called

critical period

um is it possible that these cross

corpuscals and their patterns of

innervation within the genitals change

according to the stimulation that people

experience in other words is sexual

sensation experience dependent

that is a great question and so

we don't know because

monitoring this in people is not

technically possible Right it requires

cadaver tissue so you can only do it

once in animals it it 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 Kraus

corpuscles 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

the receptors

transiently can become less sensitive to

touch and it's well known

particularly in males that uh that

chronic masturbation can produce

sensitization of sexual sensation in the

penis and that could be as a result of a

physical change a morphological change

in the Kraus corpuscles 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 their

structure in the microscope

such an interesting topic Thanks for

opening things up with with that and

I'll have to check out this preprint I'm

also a huge fan of David 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 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 especially coming from a

neuroscientist who were trained at least

similarly to learn that sure the bumps

and ripples of the brain and the fine

wiring of the brain is different and we

are all unique and different we have

different shapes AKA morphologies but

focusing on human individuality is not

something that modern Neuroscience or

classic Neuroscience 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 prism in little little

cells which may not be a good idea and

we try to give them a similar experience

as possible they are given toys and food

and water but I agree it resembles

um a prison of sorts they aren't free to

roam they're not they have nothing like

the experience of a wild mouse let me

put it that way they're uh uh and and

yes there are as you said correctly

there are plenty of experiments where

there is enrichments uh for mice 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 two

kilometers in a night for a little time

and some of the mice are so intense they

will run 20 kilometers imagine

a mouse doing 20K but but it will happen

they really really like it they don't

like being in prison they want to

exercise and they're really bored 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 and natural

selection 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

or form but uh the place where this

really happens is in the uh olfactory

system

so we have approximately 400 functional

receptors for different odorant molecule

smells uh in our nose and if you

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 percent

of their odor receptors

and if you do as Leslie vossel 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 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 androstenone

androstenone there are some people who

can't smell it at all

for some people uh it smells like rather

Pleasant like cut 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

olfaction among other things Catherine

dulock

um I once heard say that some people

have a gene that

for them makes the smell of microwave

popcorn

they experience that smell as vomit and

other people who lack this Gene like the

smell of microwave popcorn or at least

for them it's not aversive so it can

really be a binary response well it can

actually that's a very particular funny

case so the the relevant chemical there

is butyric acid and also isovolic acid

and so uh there are uh researchers I

think Rachel Hertz uh is one of them who

have given a mixture of these two

chemicals to people 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 parmesan cheese and they

go yeah and I get another one they say

it's vomit oh yeah and then they say

well actually we fooled you it was the

same vial they said 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 very nation that

uh is responsible for our own

individual's 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 to have a very plastical factory

system that have to be very few things

that we find innately

aversive they're only a handful of odors

rotting meat odors uh molecules with the

evocative names like cadaverine and

putresine 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 happy to

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 not innate it is not innate

um there are only a few innate odor

aversions and a few innate taste or

versions 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 it's like saying it sounds

red right it's a statement about

synesthesia right and but but how did it

come to pass and do people say that

vanilla smells sweet everywhere in the

world well the answer is no

so in places in the world where vanilla

is used with sugar in in sweet foods

like desserts then people say that

vanilla smells sweet or mint similarly

uh

smell sweet if it is typically used

together with sugar but if you go to a

place like uh like Vietnam where mint is

mostly used in Savory dishes people

won't say that mint

smells sweets so there's a parrot

Association there that at least at our

level of conscious understanding feeds

back onto what we call

olfactory or smell perception but really

it's a it must be a parrot Association

at some point in development yeah it is

it absolutely is a paired Association

and it's something that goes on

continually

through your life right I mean lots of

people for example have stories of foods

that they wouldn't eat as a child but

they came to like as an adult a good

example of that is coffee

a lot of people have to overcome bitter

aversion to uh to become coffee

aficionados

so uh you know this this feeds into the

more the more General theme

that

there is no pure perception perception

is inference it's not like there is a

purely

objective world that can somehow make

its way through the senses and we can

perceive that as the truth all of our

perception through all of our senses

both the outward pointing senses of the

world like smell and taste and sight and

hearing and the inward pointing senses

like 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

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are there any examples of uniqueness of

visual perception that come to mind I

recently did a social media post

that involved it was essentially three

rings A blue ring

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 differences in two things

between individuals one is the

distribution of the cone photoreceptors

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

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's simple enough that people

understand but clearly some people see

certain colors in front of others

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 so that's the

one that I know I'm guessing you know

some others and perhaps some more robust

ones well I think you know perhaps

this is maybe not what you had in mind

but one way in which experience modifies

the visual world has to do with how much

light you're exposed to in the first

five years or so of your life and so

kids that don't get outside are much

more likely to be myopic

and it actually is excited nearsighted

yes uh 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 uh 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 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 for absolutely all

kinds of reasons and you should get

outside too especially in the mornings

yeah that circadian rhythm yeah I know

that's a famous Huber menesque 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 overrun

Thailand and Burma and they were

knocking on the gates of India and

everything was going great except the

Japanese Army had a problem there were

an enormous number of their soldiers who

became incapacitated with heat stroke

they got their core temperature got too

hot

and when the Army doctors uh examine

them they found this was much more

likely to happen in soldiers who came

from the northern part of Japan Hokkaido

where it's uh where it snows in the

winter as opposed to the southern part

of Japan like Kyushu 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 Kyushu for many

generations and you've selected four

Gene variants that allow you to tolerate

the heat better and we know actually

what this is so if you're more heat

tolerant it's because you have more of a

particular class of sweat gland called

the ekrine sweat glands the sort of salt

water sweat glands not the Liberty

stinky armpit sweat glands called the

apricorn ones the echron ones you have a

higher fraction of them that are

innervated meaning that the signals from

your brain that say your core is too hot

can then make you sweat so the total

density of sweat glands between northern

and southern

soldiers in Japan wasn't different but

the southern soldiers tend to have a

higher degree of innervation all right

so okay well this happened genetically

over many generations but if you look at

those rare cases where you had 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 innervation

they were well tolerant conversely if

you had a well-established Southern

Kyushu family and they moved to Hokkaido

and then had their child that child

developed

the northern sweat gland innervation

pattern so meaning less nerve

innervation of those sweat glands as you

mentioned before just as many sweat

glands just less nerve innervation

therefore those sweat glands could not

be activated they couldn't dump heat as

well their heat tolerance was lower

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 grandchildren will

ultimately benefit you

benefit another wonderful example of

this uh comes from field mice voles and

we were talking earlier about how we

both worked with the scientist Irv

Zucker at uh at Berkeley who was a

specialist in uh in in involves and uh

what people found is that if you take a

wild caught uh field mice and uh you

have uh 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 Zucker who has

you also mentioned was an advisor to us

both who's done incredible work in

circadian biology seasonal rhythms

hormones and behavior I have such

reverence for Irv and the experiment you

mentioned made me smile wide because

it's but one of gosh maybe hundreds of

incredible studies so if people are

interested in seasonal rhythms and

circadian rhythms and

biology of the most interesting kind

definitely check out Irving zucker's

work at Berkeley we'll I'll provide a

link to his uh PubMed uh there since

we've been taking a tour of individual

variation in olfactory 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 play it and say oh that's a

C sharp right this is a pretty rare

trait so even if you look among highly

trained musicians if you went to Peabody

conservatory at my University at 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 ten

trained musicians have perfect pitch and

parenthetically having Perfect Pitch

doesn't necessarily make you a better

musician but it's an interesting

phenomena and so the question is well is

perfect pitch heritable and the answer

is when you look at twin studies where

which is what we use to estimate

heritability the answer is it's kind of

low if there's a heritable component but

it accounts for uh my recollection is on

the on the order of 30 40 percent yes of

the variability imperfect 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

percept chin domain 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 so

if you look at human traits whether

they're 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

variants you get from your mother and

father and there are a few traits that

are absolutely unheritable but that most

fall in between so let me give an

example

everyone in the world has either wet or

dry earwax

and it turns out that this is determined

by variation in the single Gene the name

of the gene is boring it's abcc11 uh

it's a ion transporter and uh there's a

variation in this Gene gives rise to

either web or dry earwax it doesn't

matter how your parents raised you it

doesn't matter what foods you ate

growing up doesn't matter what what uh

diseases your mother had when you're on

the womb it's 100 percent

heritable well does this mean that

abcc11 we should call it the earwax type

Gene well no because it's not there just

for that like this this Gene is

expressed in cells in all parts of the

body doing all kinds of things earwax is

just something that we notice genes

don't code for traits they code for

proteins and so we have to be careful

about how we refer to them in that way

um for example the wet earwax G variant

of the abcc 11 Gene also confers a

slightly higher risk for breast cancer

uh

so clearly it's not just for earwax 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 trade is 100 heritable

at the other end of the scale speech

accent is zero percent 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 is why the children of

immigrants sound like the place where

they wound up not like their parents

and there is no evidence for any degree

of heritability not 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 is zero

percent 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 percent heritable 85 percent 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 U.S 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 percent

heritable it's only 50 percent terrible

why because

people in

these situations where they don't get

enough nourishment where they're

fighting off these diseases can't live

up to their genetic potential

for height

if you want to make things better for

the people of the world then everyone

needs to have

basic things like the ability to learn

and enough nutrition and and decent

Medical Care and schools in order to

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 IQ

tests really measure anything real and

there's been a lot of fighting in the

scientific literature about this but I

think intelligence tests aren't perfect

and they are sometimes culture bound but

they are actually quite predictive of of

of of of later success and uh much more

so than say sat tests or GRE tests or

mcats or other standardized tests

presumably those correlate in some way

they do Baidu but but but the IQ tests

are better actually they're talking

about the the classic IQ test I am

talking about the modern variants of the

classic IQ tests that are administered

by trans 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 well what is the

heritage ability for IQ test score

well the answer tends to be different

depending upon the population if you

look again in in countries like the us

or in Western Europe that are fairly

affluent where where people 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 percent

but if you look at people who don't have

those benefits who are poor and this can

be in the United States as well if you

look at 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 height because

people can't live up to their genetic

potential when they don't have the basic

things that everybody needs

so presumably if two identical twins

and I realize they aren't identical but

you're familiar with twins you have twin

children

um if two identical twins

are raised separately uh

the correlation in their IQ it can only

is it that only 60 I think you said

about 66 percent 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 and the

other one went to schools where the

instruction level was really deficient

that

one would perform far less well on an IQ

test unless of course the IQ test isn't

tapping into school-based knowledge 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 twins will share

nearly a hundred percent of their Gene

variants and on average fraternal twins

share 50 percent 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-sex fraternal twins so boys to boys

and girls to girls uh uh and uh when you

put these incidents into a formula

called Fischer's equation then you can

come up with an estimate of the

heritability of the trade but there is

an assumption

presence in that and it's called the

equal environment assumption you're

saying well two kids 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 mystra

that is really the gold standard for

assessing the heritability of many

different human traits both behavioral

traits but also disease incidents but of

course it's a small M because you know

the population of identical twins reared

apart that you can get into the lab

isn't

isn't that large they had something I

don't remember the exact numbers but

they had something like 80 some uh

identicals and 50 some fraternals 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 percent

heritable

and so okay you say right well fifty

percent 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

is

what what are are you kidding it's 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 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 well it means well

first for for some individuals 40 of

their axons will cross the midline of

the brain and for another

individual 60 will

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're relying right next

to each other in the womb and presumably

have the same or very similar

fetal environment and the reason is the

random or as we say stochastic nature of

neural development a great way to study

this is with nine banded 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

quadding

so armadillos or the nine-bounded

armadillo in particular and they're

different armadillos I'm not really an

armadillo specialist I don't know if

this holds for all of them but the nine

banded armadillo is born as identical

quadruplets

awesome awesome so you can take these

identical 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 I'm sure someone like

comments on YouTube what is the name of

a baby armadillo I know like a ferret

baby ferrets are kits uh the moms are

jills the dads are bobs I used to be

obsessed with this kind of naming it you

know it's a it's a business of ferrets

or uh 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 on on ostentation of

peacocks amazing or a murder of crows

who comes up with this stuff I know it's

a raft of otters I think that I think

that's correct but so if you have four

newborn uh identical nine founded

armadillos then this is a great model

system that biologists can use to study

uh uh stochastic differences in

development and and sure enough their

brands 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 we'll

Explore More some are will tend to hide

in the corner more and you know we know

this from the lab 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 stuck 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

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is the pseudo-random stochastic nature

of development one of the major major

excuse me driving forces for evolution

because you know we hear about mutations

and we always think where 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 a huge fan of the

X-Men 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

of individuality but there is also there

are also these other things

right that we've talked about there's

the effects of early life experience and

there is the stochastic nature 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

germline you won't pass that trait

along just a brief insert here on

germline we had ODed rashafi on the

podcast who studies

um epigenetic transmission and um and an

inheritance of uh of of it's not

lamarckian we have to point that out but

um inheritance of of uh sort of acquired

traits uh does happen and uh the

germline it's 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 germline 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 oded's work and

other people's work there is what's

called transgenerational epigenetic

inheritance which means that you can

have traits that are passed not from one

generation to the next but even two

generations to the grandchildren that

don't require modification of DNA but to

date that has been shown very

convincingly in in worms

found 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

grandmothers or great-grandmother's

trauma uh

the evidence at Presence is is poor

actually a lot of it comes from

epidemiology most of which came from

famines in the other colics region of

Northern Sweden and they had very good

medical 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 this train you're

female or 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 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 a randomly through through

luck and you have to apply a statistical

correction called a bonferoni correction

when you make many particularly post-hoc

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 inheritance

in mammals now

let's be clear

just because it hasn't been shown

convincingly now it 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 grandmas 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 I understand what you're saying

correctly

the evidence that for instance some

stress-related Gene was modified during

a trauma in my

grandparents are 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 or Excel and then contribute

to producing it in you but fragmentation

of DNA and 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 germline could be

changed by

um environmental events well right but

now I think you're starting to talk

about things that are heritable

right you're not talking about marks on

DNA you're talking about the structure

of the DNA right itself and that is its

own

separate issue now I think I want to be

really careful about this because what

is now I think fairly well established

is that you can transfer things

epigenetically over

a single generation

uh if as a result of experiences that

the mother has during pregnancy

so uh for example we know that during

the 1918 pandemic flew 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

or 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 four fold

from about one percent to about four

percent and even though autism wasn't a

term in 1918 yet uh I think came along

later what we now retrospectively would

call autism also went up by about

four-fold so there's something about mom

being stressed

and carrying the fetus at a particular

stage that seems to impact brain

development in a way that then makes

that child more likely to be

schizophrenic or autistic when they grow

up do we know that it's stress and my

recollection of this I believe this was

um the late Paul sternberg's work as

well uh maybe have that name

um incorrect but in any event that it is

if pregnant mom gets the flu

in the first trimester

you see this higher incidence of

schizophrenia and autistic Offspring

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 it could be fever could be

um some breakdown in the immune barrier

I just want to open up the the number of

variables that this could be do or do we

know that it's something in the

hypothalamic pituitary so-called stress

axis that is adrenals um so hypothalamic

pituitary adrenal axis

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 Choi at MIT

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 infect

them with virus she puts so chemical

limb that is on the code 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

guts produces a surge of a immune

signaling molecule called interleukin

17.

interleukin 17 can pass through the

placenta into the fetus and if it's

present just as you said at a particular

point in development doesn't work

anywhere during pregnancy but during

something that is sort of the mouse

equivalent of the first trimester

if that occurs it causes disorder

development of the layers of the cortex

instead of it looking like layers of a

cake you see balls and clumps of cells

and parenthetically in some but not all

postmortem 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 is

selled Vision 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 increases 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 we would want to do as a

biologist so they gave things to block

the function of of this interleukin

signaling molecule and it blocked the

phenomenon they artificially injected

the signaling molecule into fetal brain

when the mom hadn't been stressed and

they could they could reproduce it so

I'm not saying that there aren't effects

of stress hormones from the hypothalamic

pituitary axis that are important that

you mentioned but in this mouse model

system work it seems that you can

produce it through this immune signaling

pathway and and so then the question is

well like are these mice autistic well

how do you know if a mouse is autistic

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 an Autism it's a bit

of a stretch right I mean it's a

challenge to interpret mouse behavior

done in human terms but

um it's a reasonable first step

credible and uh I hope more will

continue to be done as it surrounds the

uh first trimester influenza hypothesis

because it's been around a while

and um and obviously there's a spectrum

of what we call autism Mass burgers and

nowadays people refer to it as sometimes

as 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

viruses and bacteria and fungal

infections and fighting them off we're

not fighting them off and who knows what

the variation in uh neuro immune

interactions exist in there 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 covet

right we won't know for uh for a while

or the common 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 will be very interesting and uh and

important to find out

agreed

I'd love to talk with you about mind

body but before we do that I would be

totally remiss if I didn't ask for your

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

the auditory cortex or the thalamus and

yes there's some mysterious nuclei in

the brain but to me the cerebellum is

one of the most cryptic and complicated

structures to understand and I know you

spent some time in there so

what's the cerebellum do well uh

cerebellar 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 Ceramics

that's right that's right probably over

many generations then that will happen

along with an expansion of the thumbs uh

so uh but of course everybody's going to

text with their minds in about another

10 years right you'll have elong's

implants and you won't need your thumbs

at all yeah or maybe just five or my

friend Eddie Chang is a neurosurgeon and

uh works on the auditory system he's

been on this podcast before he was

saying that if in theory and actually in

practice you could just record the

neural output to the muscles of the

speech system essentially and you could

just amplify that and you could text

without actually speaking

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 post-synaptic potential so

you're not actually moving the vocal

Machinery so that means the motor

signals are getting sent out there and

so you're speaking what you are reading

but

you just don't know it that's right it's

very analogous to what happens during

the REM phase of sleep right when you

have commands your brain is issuing

commands to your muscles to to do things

like behave in your dreams to run away

or go here or go there uh but those

signals actually are blocked and the

brainstem 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 REM 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 REM 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 rematonia 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 a 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 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 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

God 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 predictive circuitry and uh

it 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 a lot of the details of

this remain to be worked out and

understood but I would say that is in a

nutshell the modern conception of the

cerebellum thank you finally somebody

explains to me that a top Contour but

highly informed way what the cerebellum

does I couldn't be more grateful my

pleasure in all aspects of biology and

life the term nature versus nurture is

relevant but

never so much as when thinking about the

nervous system

and I know this firsthand because I've

studied neural development both the

nature side the so-called hardwired

stuff that genes just set up

neurons wire up to that neuron Etc the

cerebellum's in the back the eyes are in

the front the hard-wired stuff and then

the soft wired 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 uh as an expression it

was popularized by Francis Galton uh in

the 19th century a colleague of uh of uh

of Darwin's and I think it's wrong in or

misleading

in a lot of ways so of course the nature

in nature versus nurture is meant in

this case to me inheritability 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 guts 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 a 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

variants 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

phenylketonuria or PKU which is an

inability to uh to metabolize uh the

dietary amino acid phenylalanine 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 in

the phenylalanine if you don't it

doesn't matter that you inherited these

things right so that's a way in 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

exports 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 a

versus 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 govs the gloves don't fit

you must quit you know it's got that

kind of Snappy snare drum beats but I

think it's it's a more 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 I don't think I

can take credit for that it belongs to

other people sure but um but there's a

long history in science of of things

being 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 Linden

hypothesis but I can all right and what

I've found is as with the Galpin

equation which is now out there as a

hydration it's a formula a formula that

gives broad but

um research informed parameters as to

how much water one should drink in order

to maintain proper hydration for

physiologists Dr Andy Galpin who's a PhD

in uh physiology 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 all 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 Linden hypothesis and I'll be damned

if anyone's going to rename it uh

um faster than I'm going to propagate it

all right well I think all the the

geneticists will be gnashing their teeth

about this being named after someone who

isn't actually a geneticist quite all

right and their dentists will thank me

let's talk about Mind Body okay

I'm fascinated by this

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 mid 90s 2000s 2010 to 20 stretch was

focused on the brain piece very little

on the body there was nothing about gut

brain access in the early discussions

and coursework

um in parallels 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 complementary health and Medicine

essentially exploring things like Yoga

Nidra respiration practices even

supplements and things of that sort and

there's this understanding that oh my

goodness

the nervous system extends into the body

and the body sends neural signals back

into the brain and so this whole notion

of Mind Body has fortunately migrated

away from kind of um

California Counter Culture esselen

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 at

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 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 Mind Body

what does that mean to you and

what do you think is the potential of

the mind-body interaction it seems to me

we've just barely scratched the surface

yeah well I'm glad you asked because I

think it's a 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

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 Airy

fairy realm in the clouds that this

happens and and and I mean for for good

reason there are a lot of people who

will describe it in exactly that way

with auras or they they clop scientific

terms like resonance and energy but they

don't actually use them in scientific

ways so you know there's a lot of very

fuzzy language that surrounds this but

it shouldn't obscure the facts that when

you have a hypothesis that say some

mental state like meditation 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 initially

from my father my father was a

psychiatrist in fact kind of a talking

cure old-fashioned

psychoanalyst how does practice in uh

Los Angeles and uh we would have dinner

together every Wednesday nights and uh

he would always tell me about his

patience he was very careful to keep

confidentiality right he wouldn't

break confidentiality but you know I

would say oh this how's your narcissist

oh we had this dream you know so this

was you know this was this was normal

conversation when I was 14 15 years old

with my dad and one day I said Dad it's

really clear to me that through this

talking cure a large fraction of your

patients feel better and they conquer

their depression or or their obsessive

thoughts or things that are blocking

them how do you think it works

and he says well we don't really know

the mechanics But ultimately when it

works it's not working in some area

farrier realm it is working by changing

the biology of the brain

and when he said that it was like a

lightning bolt went off in my head

and I thought well

I don't have the kind of personality to

be a talking cure psychiatrist I'm not

nearly nice enough

but

I could understand the underlying

biology maybe I'll do that

and so

as you'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 are also talking about

how phenomena in the body affects 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 introception

right so as opposed to extra reception

your outward pointing senses these are

the senses that monitor your own body

and and while we can consciously be

aware of a lot of that information a lot

of it is happening subconsciously like

your breathing is happening

automatically most of the time without

you thinking about it and that depends

upon sensors about your blood chemistry

and the state of your lungs 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 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 cytokines and

cytokines are basically the signaling

hormones of the immune system and they

they can flow through the bloodstream

and through lymphatic fluid and reach

many parts of the body uh we've known

for a number of years that the

specialized receptors for these

cytokines are found throughout the brain

and yet we know very very very little

about

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 uh a link between

inflammation in the body whether it be

in the gut or in other places to

depression

well how might that work well it could

work either through inflammation sensing

neurons sending electrical signals to

the brain or and it's not either or it

could be both it could be

immune signaling cytokine molecules

produced at the site of inflammation

that then travel through the bloodstream

and the lymphatic system to then reach

the brain bind receptors 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

antidepressant drugs uh about a third

see very tiny benefit on about a third

scene 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 will 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 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 cytokine molecule and

when you gave it to people to treat

their hepatitis C almost everyone became

depressed

on this drug so he said 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

nor 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 cytokines including one called

interleukin-6 il-6 that's elevated

massively if you if you take a spinal

tap and you look at cerebral spinal

fluid and so that could be causative for

depression so all these real reasons to

think that inflammation is involved but

yet the idea is still a little messy so

now what if instead of looking at the

general population of depressed people

you look at the subset of people that

don't respond to SSRI antidepressants

are they helped by anti-inflammatories

and there there's a bit of a hint that

maybe they are it's not definitive yet

there are a couple of studies it's it's

right on the edge but I think this is a

really good example of how we are going

to see progress very soon in the body to

mind part of mind

body medicine that is going to be of

enormous 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 a Robin cardard Harris 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

the clinical trials on psilocybin and to

be clear so Simon's 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 2.5 gram approximately dosages

of psilocybin given separately again

with therapists present and then

follow-up therapy sessions seem to lead

to relief of depression in approximately

somewhere between 65 and 80 percent of

people in some cases total remission in

some cases some relief without remission

okay so we can kind of set that result

on the Shelf it's been repeated a number

of different times

compare that to the results of ssris

which 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 proprion

and the other antidepressants 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

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 in some cases gait

neuroplasticity that are all centers

back to changing neural circuits and so

what we're really trying to do whether

or not it's transcranial magnetic

stimulation or now we can throw ketamine

in there or psilocybin or ssris

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 disparate somewhat conflicting but it

seems like inflammation is is

anti-neuroplasticity and broadly

speaking here I realize there are many

interleukins there are many you know

some of which are inflammatory some are

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 results in these different camps

yeah I think it's a completely

reasonable hypothesis and I would be

broader and I would say honestly the

relief of any Neuropsychiatric condition

ultimately is from 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 context

between neurons as the site of

neuroplasticity 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 be-all 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 we talk about the wiring of the

brain

sometimes we're talking about literal

wiring like cell 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 another transmitter

release from cell a or it could be

something intrinsic and cell a that

makes it fire its electrical signal its

Spike more easily I think that one of

the key cell types that's going to be

important for your hypothesis

um linking inflammation to synaptic

plasticity is going to be a cell called

a microglial cell and microglial cells

are non-neuronal cells in the brain that

are motile they can crawl around they

have long processes and they can gobble

things up they can literally sort of

chew away and digest bits of the

extracellular scaffolding that surrounds

neurons and synapses and thereby renders

them plastic they can uh destroy

synapses and there is a lot of

indication that certain disease States

may involve over exuberant microglia

pruning synapses to a degree that they

shouldn't and we know that microglia are

chock-full of cytokine receptors and so

are responsive to inflammatory signals

when we're talking about inflammation

and we're talking about drugs it's

worthwhile to mention that there are a

lot of Behavioral things that also can

influence the signaling so we know and I

know you've discussed on your program

the incredibly salubrious effects of

physical exercise on mental function so

exercise is about as good an

antidepressant as ssris are and the side

effects are only good side effects as

opposed to the bad side effects of ssris

and again this isn't working through

some Airy farrier 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 microgl 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 flow into your brain so it

doesn't matter if it's reduced

transiently you're fine but as you get

older ah your blood vessels become more

occluded and less elastic and you're

closer to the to the to the trouble spot

and if you exercise regularly you can

dilate and make your blood vessels

including those in your brain more

elastic and that is almost certainly

protective against both depression and

cognitive decline uh as we age

well I am a fan of exercise but I'm

fortunate that I enjoy running and

some forms of resistance training

um

so I always assume that the good side

effects were just the positive mood

effects 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

decreases inflammation I'm delighted to

hear you say the word microglia and um

my postdoc advisor the late Ben Barris

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 drama saying we have

to pay attention to glio we have to pay

attention to glia for the longest time

glio 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

microglia and other glial cell types and

it's it's really fantastic to see that

this

actually the most abundant cell type in

the brain is the glial 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 glia are in the

spotlight for a good reason I'm not

trying to say sure that that it isn't

worthwhile but there is this phenomenon

of things being fattest and people