Where are the darkest places you've ever gone in your life?
The following is a conversation with Carl Diceroth, professor of bioengineering, psychiatry,
and behavioral sciences at Stanford University.
He's one of the greatest living psychiatrists and neuroscientists in the world.
He's also just a fascinating human being.
We discuss both the darkest and most beautiful places that the human mind can take us.
He explores this in his book called Projections, A Story of Human Emotions.
I highly recommend it.
It's written masterfully.
This is the Lex Friedman podcast.
To support it, please check out our sponsors in the description.
And now, dear friends, here's Carl Diceroth.
You open your book called Projections, A Story of Human Emotions with a few beautiful words
to summarize all of humanity.
The book draws insights about the human mind from modern psychiatry and neuroscience.
So if it's okay, let me read a few sentences from the opening.
You got to give props to beautiful writing when I see it.
Quote, In the art of weaving, warp threads are structural and strong and anchored at
the origin, creating a frame for crossing fibers as the fabric is woven.
Moving across the advancing edge into free space, warp threads bridge the formed past
to the ragged present to the yet featureless future.
Yet featureless future.
Well done.
Well done, sir.
The tapestry of the human story has its own warp threads, rooted deep in the gorges of
East Africa, connecting the shifting textures of human life over millions of years, spanning
pictographs backdropped by crevice ice, by angulated forestry, by stone and steel and
by glowing rare earths.
The inner workings of the mind give form to these threads, creating a framework within
us upon which the story of each individual can come into being.
Personal grain and color arise from the cross threads of our moments and experiences, the
fine weft of life, embedding and obscuring the underlying scaffold with intricate and
sometimes lovely detail.
Here are stories of this fabric fraying in those who are ill, in the minds of people
for whom the warp is exposed and raw and revealing.
What have you learned about human beings, human nature and the human mind, from those
who suffer from psychiatric maladies, for those for whom this fabric is warped?
The one thing we learn as biologists is that when something breaks, you see what the original
unbroken part was for.
And we see this in genetics, we see this in biochemistry.
It's known that when you have a mutated gene, sometimes the gene is turned up in strength
or turned down in strength, and that lets you see what it was originally for.
You can infer true function from dysfunction.
And this is a theme that I thought needed to be shared and needed to be made communicable
to the lay public, to everybody, people who, which is, I think, almost all of us who think
and care about the inner workings of our minds, but who also care for those who have been
suffering, who have mental health disorders, who face challenges.
But then more broadly, it's a very much larger story than the present.
There's a story to be told where the protagonist really is the human mind, and that was one
thing I wanted to share as well in projections, is that broader story, but still anchored
in the moment of patience, of people, of experiences of the moment.
Is there a clear line between dysfunction and function, disorder and order?
This is always debated in psychiatry, probably more so than any other medical specialty.
I'm a psychiatrist.
I treat patients still.
I see acutely ill people who come to the emergency room where there's no doubt that this is
not something that's working well, where the manifestation of disease is so powerful, where
the person is suffering so greatly where they cannot continue as they are.
But of course, it's a spectrum, and there are people who are closer to the realm of
being able to work okay in their jobs, but suffer from some small dysfunction.
And everywhere in between.
In psychiatry, we're careful to say we don't call it a disease or a disorder unless there's
a disruption in social or occupational functioning.
But of course, psychiatry has a long way to go in terms of developing quantitative tests.
We don't have blood draws.
We don't have imaging studies that we can use to diagnose.
And so that line ultimately that you're asking about between order and disorder, function
and dysfunction, it's operational at the moment.
How are things working?
Can we just like linger on the terms for a second?
So this disease, dysfunction, how careful should we be using those words?
Can we just, even in this conversation, from a sort of technical perspective, but also
human perspective, how quick should we be in saying that schizophrenia, depression,
autism, as we kind of go down across the spectrum of different maladies, just to use the word
dysfunction and disease?
I would say to give ourselves a license to capture the whole spectrum, let's say disorder,
because that captures truly, I think, the essence of it, which is we need to talk about
it when it's not working, when there's disorder.
And that's the fairest and most inclusive term to use.
So is it fair to assume that basically every member of the human species suffers from a
large number of disorders then?
Well, we just have to pick which ones are debilitating for each person.
If you look at the numbers, if you look at how our mental health disorders are currently
defined, you can look at population prevalence values for all these disorders.
And you can come up with estimates that somebody will have a lifetime prevalence of having
a psychiatric disorder that approaches 25% or so.
And in some studies, it could be more, some studies, it could be less.
Now, what do we do with that number?
What does that mean?
And in some ways, that's the essence of what I was hoping to approach with the book, is
to reflect on this spectrum that exists for all the disorders.
There is taking nothing away from the severity and the suffering that comes at the extreme
end of these illnesses.
But nearly every one of them exists on a spectrum of severity, from nearly functional to completely
dysfunctional, life-threatening, and even fatal.
And so that number 25%, more or less, it doesn't capture that spectrum of severity.
Looking at that number, where do those numbers come from?
Is it self-report?
Is it people who show up and say, I need help?
Is it somebody else that points out that person needs help?
Or is it like estimates that even go beyond that for people who don't ask for help or
are suffering quietly alone?
When you look at self-report numbers, then those numbers get even higher, beyond 25%
or more.
The most rigorous studies are done with structured psychiatric interviews where people who are
trained in eliciting symptoms carefully do complete psychiatric inventories of individuals.
And these are time-consuming, laborious studies that are not often repeated.
When they're done, they're done well.
But very often you'll see a report or something in the news of a very high number for some
disorder or symptom, and very often if it's shockingly high, that's coming from a self-report
of a person.
And so that's another issue that we have, again, take nothing away from the severity
and reality and biological nature of these disorders, which are very genetic.
We understand that these are very biological, and yet we lack, right now, the lab tests
and the blood draws to make the diagnoses.
But we'll talk about it, just how biological they are, because that, too, is a mystery.
In terms of from our perspective of how to probe into the disease, how to understand
it, how to help it, so some of it could be neurobiological.
Some of it could be just the dance of human emotion and interaction, and it's love when
it works and it's love when it breaks down, biological or is it something else?
So we're going to talk about it, but let me just linger in terms of disorder.
What about genius?
You know that sort of cliche saying like the madness and genius that they kind of dance
together?
What about if the thing we see as disorder is actually genius, unheard or misunderstood?
Well, here, again, the numbers help us, and here's where being rigorous and quantitative
actually really helps.
If you look at disorders like autism and bipolar disorder and eating disorders, anorexia nervosa,
for example, these, particularly bipolar and anorexia, these can be fatal, they can cause
immense suffering, but they are heavily genetic, all three of these, and what's very interesting
is each one of these three is actually correlated positively, positively, with measures of intelligence,
of educational attainment, and even of income.
And so you look at this, severe disorders in many cases, causing quite immense morbidity
and mortality, and yet they are positively correlated at the population level with positive
things.
Can you say the three again, autism, anorexia and bipolar?
Bipolar disorder.
Bipolar.
What's that book?
I forgot the book name, but is intelligence a burden?
Well, people can get into trouble when they think they're smarter than they are, I will
say that.
I don't know.
Sometimes in the deepest meaning of that statement, I think ignorance is bliss.
I'm a big fan of Prince Michigan from The Idiot and Ardosh from Brother Karamazov.
It can be seen as naivety and dumbness, but I think it's a kind of deep intelligence,
maybe inability to reason about the mechanics of the world, but instead kind of feel the
world.
And it seems like that's one of the paths to happiness.
There is, how much you think versus how much you feel, this comes up all the time.
In medicine, we encounter this all the time.
And day after day, you encounter the abyss of suffering from patients.
How much do you let yourself feel?
Or how much do you make it abstract and objective and try to make it clinical?
And that range, how you're able to move yourself on that spectrum is very important for survival
as a physician.
And the way you protect yourself and your feelings turns out to be very important.
You quote Finnegan's Wake, Mad Props for that James Joyce book.
It's like a class on James Joyce in college.
I think I read parts of Finnegan Wake, it might have been on drugs or some kind, or
I somehow got an A in that class, which probably refers to some kind of curve where nobody
understood anything.
The only thing I understood and really enjoyed is his short stories, The Dead.
And then Ulysses, I kind of, I think, read a few Cliff Notes that kind of got to the
point and Finnegan's Wake was just a hopeless, for people who haven't looked at it, maybe
you can elucidate to me better.
But I felt like I was reading things, words, and the words made sense, like standing next
to each other.
But when you kind of read for a while, you realize you didn't actually understand anything
that was said.
Right.
But did you have a feeling though?
Yeah, that's one thing I found interesting about Finnegan's Wake.
I never fully understood it, but the words caused feelings in me, which I found fascinating.
And sometimes I couldn't predict it from the semantic black and white context of what I
was seeing in front of me on the page.
But the rhythm or the melody would make me feel certain ways.
And that was what I always was intrigued by with Joyce.
Of course, that was his, he existed on a spectrum too, and he wrote, as you say, more accessible
works.
I learned a lot about Irish history from a portrait of the artist as a young man, and
there was just, he could be as objective as he wanted to be, but then when he let himself
loose, he was in this realm where the words had their own purpose separate from semantic
meaning from their dry dictionary definition.
There's a funny story that I was told, doesn't matter if it's true or not, but they said
that James Joyce, when he was young, when he was in his teen years, will go around sort
of Ireland drinking and so on and telling everybody that he's going to be one of, if
not the greatest writers of the 20th century.
And he turned out to be that.
So I always think about that little story that somebody told me, because I have a lot
of people come up to me, including myself, I'm a bit of a dreamer.
And you get into certain moods where you say, I'm going to be the greatest anything ever.
You get people tell you this, especially young people, and it kind of, it makes me feel all
kinds of ways, but that story reminds me that you just might be one of the greatest writers
of the 21st century, for example, if somebody were to tell me that, and don't immediately
disregard that.
Because one of the people that say that, that's almost like a precondition that's a good requirement
just to believe in yourself.
Maybe it's not a full requirement, but it's an interesting story.
Well, I think when someone tells you that, then it creates one season opportunity, and
then it would be a tragedy if the opportunity weren't captured, right?
And so then that creates some impetus, some motivation to do something good.
I think the mind, it's like, you know, I guess that's what like books like the books or whatever,
I don't even know if it's a book, the secret plugs into, they kind of make a whole industry
out of it.
But there is something about the mind believing something, making it a reality.
It is just time and time again with Steve Jobs, like your belief in yourself, your belief
in an idea, sort of embracing the me versus the world, embracing the madness of this idea
and making it a life pursuit, somehow more reality for some tiny fraction of the population,
for everybody else, you descend into all the beautiful ways that failure materializes in
our lifetime.
You mentioned love earlier, I mean, that's a great example of how belief in something
makes it real, right?
It's not reasonable on the face of it, but because you believe it's reasonable, then
it actually does become reasonable and then it is real, and so that's a good example.
That doesn't happen.
I'm also in a bioengineering department.
We don't imagine that a bridge is soundly built and then it is soundly built.
That's something that, it doesn't come up in too many realms of human existence, but
love is one of them and the ability to have a fixed idea and to say it's true and then
it is true.
A bridge is a kind of manifestation of love, so maybe it does work a little bit, but you
know, it can break down like Chernobyl did, you can't just say it's safe, you have to
also prove it's safe.
But on Finnegan's Wake, I think, maybe correct me if I'm wrong, you're using kind of Finnegan's
Wake to give one perspective on what madness is, of what's going on in the mind.
How much of that is, that we're simply unable to communicate with the person on the other
side of their mind?
Like, there's almost like a little person inside the brain and they have some circuitry
that's used to communicate emotion, communicate ideas to the outside world and there's something
about that circuitry that makes it difficult to communicate with the little person on the
other side.
So, if you look at what shows up in schizophrenia, with many cases, what we call thought disorders,
what we call the individual speech symptoms of schizophrenia, Finnegan's Wake is loaded
with them and it's just full of them.
We talk about clang associations in schizophrenia where the word that is said echoes in some
way the previous word and we call that a clang association because there's no other reason
than the similarity of the sound, like a clang of a garage door being hit and sometimes it's
not even a word and we call that a neologism, a new word being created and of course Finnegan's
Wake is full of that and then we also, in schizophrenia there's what we call loose associations
or tangential thought processes, of course full of that where things just go off in
directions that are not linear or logical and you can't read Finnegan's Wake, I think
without, certainly as a psychiatrist you can't read it without thinking about schizophrenia
and then when we look at the families of people with schizophrenia and Joyce was no exception,
there very often are people within the family who are on the spectrum, some have it, some
are able to see it from a distance, from a safe distance, there's an association between
schizophrenia and what we call schizotypal personality disorder where people are not
quite in this severe state of schizophrenia but have some magical thinking, have some
unusual thought patterns, very often those are family members of people with schizophrenia.
So this points again to this idea that there is a range even along this very severe, very
genetic biological illness that human beings dwell on different spots along that spectrum.
I should mention that we have my friend Sergei pulling up stuff, young Sergei or old Sergei,
I don't know what to call you, but there's drafts of Finnegan's Wake, yeah I actually
saw pictures of this from, I think it was on Instagram or something.
These are early drafts of Finnegan's Wake and it's so beautiful to see.
For people who are just listening, there's just random paragraphs and writing all over
the page with stuff crossed out and it's great to see that Joyce himself was thinking in
this kind of way as you're putting it together.
How much do you think he was thinking about schizophrenia, the schizophrenic mind?
I think a lot.
I think it's known that his daughter suffered from schizophrenia and this is what's depicted
here on the page is something that I'm sure he either felt himself in some level was able
to access this nonlinearity of processing or had seen enough in family that he knew
what it was and was able to reflect it down in black and white on the paper.
So what he was able to do was quite authentic in that sense.
Of course, I don't want to pigeonhole him, he was doing much more than that.
It was much more than talking about altered human thought processes and thought disorders,
but that was an aspect that he was so good at representing that it had to be intentional
to some extent.
At Tiny Tangent, what does your own writing look like for this book?
Because it's extremely well written.
How many edits did you just drink some whiskey and like I'm imagining Hemingway style?
It's a very different, the writing is very different, I mean, it's really, really well
written, which was like, I was reading it, it makes you realize, because I was expecting
sort of a science kind of, which it is like, you know, elucidating something about the
human mind kind of thing, but you could also probably write really strong like novels.
So maybe that's in the future, but anyway, what is your, how many edits, how many, what's
your style?
What's like that?
Is it more structured to organize?
Unfortunately, I used a laptop, so I didn't have this sort of beautiful record of-
No typewriter, cigarette and whiskey.
I did explore, you know, which was their particular altered state that would help me to be most
creative and I found actually, I actually did the best while sober, but slightly disinhibited
in the late hours of the night or early morning, particularly late hours of the night there.
And I have a friend who would tell me that she thought that very early in the morning,
her inner critic was still asleep and she could write more effectively before her inner
critic woke up.
Yeah.
And I actually found that outstanding advice for me that I often found that there was, I
was looser and could write more in the morning.
But the other interesting thing is each chapter, each story, it's about a different human being
with a different class of psychiatric disorder, that's what each story, each chapter is anchored
in.
But I'm trying to use words and style of writing and, you know, diction that captures the feeling
of the disorder.
And so it's different in each story.
In the story about mania, which is a very expansive, exuberant, at least briefly uplifting
state where the words come out in a torrent and they're complex and pressured and elaborate,
I try to capture that feeling with the words used in that chapter.
And then in the schizophrenia or psychosis chapter, where things slowly fragment over
time and become looser and separated, I try to capture that in the writing too.
So for each, it wasn't as if there was a single mode I could be in for the whole book.
For each chapter, I had to put myself into a different mode to capture that inner feeling
of the disorder.
When you put yourself in that mode, does that change you?
Yeah.
I couldn't turn it on and off right away.
I had to, first, I would start by thinking about the person or the people, one or two
people based on real patients and the stories that are put forth, the symptom descriptions
are real.
They're from the patients.
Of course, all details change to protect privacy, but the actual symptom descriptions
are real.
And I would sit with them and really try to inhabit the space of the mind of that person
that I knew.
And that's not instantaneous.
It would take some time.
I needed quiet.
I needed to be still.
That's another reason late at night is good.
Sergei posted that draws in his gifts, creativity boosts according to Andrew Huberman.
Thank you, Andrew.
He's not wrong.
He's not wrong.
Why projections, instead of putting words into your mouth, because I can imagine a lot.
To me, I will start putting words in your mouth, despite what I just said.
To me, projections, working on neural networks, for example, from an artificial neural networks
from a machine learning perspective, it's often, that's exactly what you're doing.
You're having an incredibly complex thing and you're trying to find simple representations
in order for you to make sense of it.
So I was kind of thinking about it in that way, which is like this incredibly complex
neural neural network that is kind of projecting itself onto the world through this low bandwidth
expression of emotion and speech and all that kind of stuff.
And the way it's, we only have that window into your soul, the eyes and the speech and
so on.
So in that way, when there's any kind of disorder, we get to only see that disorder through that
narrow window as opposed to the full complexity of its origins.
The word projections definitely serves that purpose here, but it's got a few other really
appropriate other connotations as well.
So the first thing is a projection in terms of neuroscience is this long range connection
that goes from one part of the brain to another.
And so it's what binds two parts of our brain together.
There are projections, long range connections of axons.
These are the outgoing threads that connect one part of the brain to another part.
There's a projection that links, for example, auditory cortex where we hear things to reward
centers where we can feel, where feelings of pleasure and reward are initiated.
And it's been shown that if you have reduced connectivity along that dimension, you are
less able to enjoy music.
And so these connections, these projections matter.
They define how effectively two parts of the brain can engage with each other and join
together to form a joint representation of something.
So that's one meaning.
It's pure neuroscience.
The word projection is used all the time, and it happens to be something that optogenetics,
a technique that maybe we'll talk about a little later, works particularly well with.
We can use light to turn on or off the activity along these projections from one spot of the
brain to another.
And this is particularly referring to the long range connections?
Yeah, it's particularly straightforward along these long range projections that connect
different parts of the brain, but it works over a shorter range too.
But then there's this other meaning of projections which you were bringing up, which is very
relevant, which is at some point you can reduce something from one level of dimensionality
to another, and you can project down into a lower dimensional space, for example.
And then finally there's a psychiatric term projections, which comes up all the time,
which is we very often will look at our internal states and to understand somebody else, we'll
project them onto somebody else, we'll try to understand someone else's behavior and
make sense of it by projecting our own inner feelings, our own sort of narrative onto them
and use that as a way to help us understand them better.
And we'll do the reverse too.
We'll take things we see in the outside world and we'll bring them into ourselves and see
how well they map, how well they align, and that's called introjection.
So projections turns out to be a really rich word.
And finally, of course, there's the very common sense of it as a projector that illuminates
by conveying information across space with light.
So for English, for English language, perfect word to use for this book, but what's funny
is not every, there are a lot of international translations now and all those rich connotations
aren't captured in other languages and so for some translations, connections is used
instead of projections.
In fact, even in England, the British version is connections instead of projections because
apparently projections doesn't have the full connotation I was told there.
So you have to sacrifice some of the rich ambiguity of meaning with connections.
That's interesting.
I mean, words are so interesting, they have so many meanings.
I love language and how much is lost in translation.
I'm very fortunate enough to be able to speak.
I'm not good at languages.
I was just, I guess, forced to, by less circumstance, to learn two languages, Russian and English,
and it's just so interesting to watch how much of culture, how much of people, how much
of history is lost in translation.
The poetry, the music, the history, the pain, the way the scientists actually express themselves,
which is funny.
I mean, just, it's so sad to see how much brilliant work that was written in Russian.
There's a whole culture of science in the Soviet Union that is not lost.
It makes me wonder in the modern day how much incredible science is going on in China that
is lost in translation and I'll never, I mean, that makes me very sad because I'll never
learn Chinese in the same way that I've learned English and Russian.
Maybe whenever I say stuff like that, people are like, well, there's still time, but yeah,
that's actually fair.
I think the 21st century, both China and US will have very important roles in the scientific
development, and we should actually bridge the gap through language.
That doesn't just mean convincing Chinese to speak English, that means also learning
Chinese.
When we need these bridge people who can do both, Nabokov, for example, writing in English
beautifully, one of my favorite poets, Borges, who I mentioned earlier, he wrote both in
English and in Spanish, I think beautifully in both.
We need those people who can serve as bridges across cultures who really can do both.
You mentioned Borges.
You opened your book with a few lines from a poem by Jorge Luiz Borges, a love poem.
I'm going to read parts of it because it's a damn good poem.
Yeah.
It's called Two English Poems.
I mean, I'd like to understand why you used it and the specific parts you used, which
is interesting.
But then when I read the full thing, so I think you used it as a beautiful description
of what it means to delve deep into understanding, offering yourself to the task of understanding
another human being.
But if you look at the full context of the poem, it's also a damn good description of
being hit by love and overtaken by it and trying to figure out how to make sense of
the world now that you've been stricken by it.
It says a bunch of things about chatting and significantly with friends and all those kinds
of things.
And then the poem reads, the big wave brought you.
This is the moment, I guess, of the universe where the two people you fall in love.
Maybe I'm totally misreading this poem, by the way.
It doesn't matter.
You can't misread the poem.
So it goes on, words, any words, your laughter, and you so lazily and incessantly beautiful,
we talked and you have forgotten the words.
The shattering dawn finds me in a deserted street of my city, your profile turned away,
the sounds that go to make your name, the lilt of your laughter.
These are the illustrious toys you have left me.
So these little memories of these peculiar little details, he remembers, those are the
illustrious toys.
I apologize to mix my own words with the poem, but you should definitely read it.
I turn them over in the dawn, I lose them, I find them.
I tell them to the few stray dogs and to the few stray stars of the dawn.
Your dark, rich life, I must get at you somehow.
I put away those illustrious toys you have left me.
I want your hidden look, your real smile, that lonely mocking smile your cool mirror
knows.
I want your hidden look, your real smile.
So this is the first part of the poem.
And then it goes on, which is some of the parts that you reference.
Second part is, what can I hold you with?
I offer you lean streets, desperate sunsets, the moon of the jagged suburbs.
I offer you the bitterness of a man who has looked long and long in a lonely moon.
I offer you my ancestors, my dead men, the ghosts that living men have honored in bronze.
My father's father killed in the frontier of Buenos Aires, two bullets through his lungs
and so on and so on.
I offer you whatever insights my books may hold, whatever manliness of humor my life.
I offer you the loyalty of a man who has never been loyal.
I offer you that kernel of myself that have saved somehow the central heart that deals
not in words, traffic's not with dreams and is untouched by time, my joy and adversities.
And I think this is where the part they include in the book.
I offer you the memory of a yellow rose seen as sunset, years before you were born.
Damn, that's a good line, okay.
I offer you explanations of yourself.
Stories about yourself, authentic and surprising news of yourself.
I can give you my loneliness, my darkness, the hunger of my heart.
I'm trying to bribe you with uncertainty, with danger, with defeat.
That is a man who's in love and longing, but I just want to go back to, maybe you could
say why you wanted to include that poem, but also your dark rich life, I must get at you
somehow.
I put away those illustrious toys you have left me at.
I want your hidden look, your real smile, that lonely mocking smile, your cool mirror
nose.
Well, sometimes I meet a stranger and I just, it's like a double take.
It's like, who are you?
Have we met before somewhere?
Who's that person behind there?
And I want to get at that, whatever that is.
And of course, maybe that's what love is because maybe that's the whole pursuit, like a lifelong
pursuit of getting at that person.
Maybe that's what that is, and that insatiable curiosity to keep getting to it, like, well,
who is that person in your private life?
Yeah.
So that, absolutely, I think that it was a beautiful description of what you just said
when there's that first moment, and then you want to dive deeper.
You want to know what the hidden mysteries are.
In a way, it's a love poem.
As a scientist, though, it's a bit of how a scientist can love science.
And that wanting to dive deeper is, it's almost like, again, where it could be a love affair
with investigating the human mind, for example.
And that was one reason it spoke to me also, again, thinking about the broader sweep of
where the human mind came from, the steps it took to get where it is today, what was
given up along the way, what compromises were made.
And here's where the darkness of the poem starts to come in a little bit too.
It doesn't shy away from the negativity, from the confusion, from the danger.
And then at the very end, the Board of Haces is offering up scenes from his life, parts
of himself.
And this is how we connect with people.
We offer up parts of ourselves.
Just here it is.
And then we see, how well does that map onto what you have?
And it's that offering up that I liked, and not the good stuff, or not only the good stuff.
The yellow rose is nice, but he's offering up the bad stuff too.
And that, to me, was important for the book because I'm offering up hard stuff too, in
fact, a lot of it.
And also, hard stuff from within me, from my own personal side too.
And that was, there's a lot of vulnerability that comes with that, but that comes with
love, that comes with writing, you have to be open, you have to be vulnerable.
And so, I thought that reflected what I was trying to do, and I thought it was as an epigraphic
kind of made it clear how vulnerable I was in taking this step, but also what could come
out of it.
And also, in a metaway, because I was not familiar with this poem, it may be curious
of the poem itself to pull at that thread of finding out more.
You picked a very particular part that kind of means you want to pull at that thread and
see where did this, where did these few lines come from?
Because I read it as a curiosity of a scientist, those lines alone.
And also, as a desperate human being searching, like offering himself for understanding or
connection with another human being, and then, because I wasn't sure if it's a love poem
or not, or if it's desperation or if it's curiosity, whatever it is, and then you see
the love poem.
I mean, I don't know, that's going to stick with me for a while, your dark, rich life.
And then a few lines in here are just, I mean, those are, I'm going to just use them as pick-up
lines at a bar.
I offer you the memory of a yellow rose seen at sunset years before you were born.
No, that's a pick-up line if I've ever heard one.
Anyway, sorry.
But this is universal.
You see it in so many forms of art, like we're in Texas now, you see this in country and
western songs.
It's often a list of things, like here's how I describe myself.
There's this and there's that, and there's the other thing, and here you are.
These things matter to me, and I hope they matter to you too.
It's a pretty universal form, but he did it in this very artful and very vulnerable way.
It was both beautiful and you could feel the hurt coming from him too, and that was important.
The dark stuff too.
I offer you my ancestors, my dead men, the ghosts that living men have honored in bronze
and talking about two bullets through his lungs, bearded and dead, wrapped by his soldiers
in the height of a cow.
My mother's grandfather, just 24, heading a charge of 300 men in Peru, now ghosts on
vanished horses, so all of it, the whole history of it.
Since it is a love poem, what do you think about love, Carl?
What's the role of love in the human condition?
We'll talk about the dark stuff, but maybe love is the dark stuff too.
It's the most powerful connection we can form, and that's what makes it so important to us.
It's the strongest and most stable connection that we can form with another person, and
that matters immensely.
It matters for the human family to have evolved, to be something that could survive against
the odds that we've faced over the years of that unreasonable bond that becomes reasonable
by virtue of its own existence, and of course, that joy, the wild, raw joy of love is not
a bad thing either.
So, you put these together, the strongest bridge we can form, and the reward and the
joy that it brings.
That's what love is to me, and from my perspective, this is something that – it can be hard
to capture fairly because you want to talk about the positive and the negative sides
at once.
They need to be wrapped up together for a full, honest description of what it is, and that's
hard to do in a compact form.
So, you have to take time to talk about love, you have to take time to do it justice.
It takes a book, or at least a poem, or several thousands of them.
I don't know, could you pull up – there's a video I saw, yeah, like right here.
So can you pause for a second?
So there's March of the Penguins, so you always see like penguins huddling together
against – I mean, sorry if I see just metaphors and everything, but them huddling together
against the harshness of the conditions around them.
That's very kind of – that's like a metaphor for life, like finding this connection.
That's kind of what love is, it's like it allows you to forget whatever the absurdity,
whatever the suffering of life is, together you get to like huddle for warmth.
And that's why I love sort of just the honesty and the intensity of the way penguins, just
in the middle of like the cold do this.
And then this video I saw, a lonely – this is misinformation.
So the name of the video is Lonely Deranged Penguin, I don't know if he's deranged.
So if you play it, so he left his pack, and there's a nice like voiceover and you don't
need to play it, but he for some reason left the pack and journeyed out into the mountains.
And so the narrator says that he's deranged, he's lost his mind.
Now I'd like to project the idea that he's actually – there's so many stories you
could think of.
He's returning to his homeland, he's an outsider thinking, journeying out into the
unknown, thinking he may be able to discover something greater than the tribe, he might
be looking for lost love.
Why is he deranged immediately?
Why is he lost his mind anyway?
But people should look up this video because to me, I might be the only one who romanticizes
this, but it's such a nice kind of – it's both a picture of perhaps a mental disorder,
which is what the video kind of describes, and it may be some deeper explanation that's
not – that has to do with the motivation of a mind.
Yeah, I don't know if you have a deeper analysis on this, Penguin.
Well, I –
Like you.
The psychiatrist.
I would want to sit down with the Penguin and go through – I want to see the notes
from his prior therapist, but this actually is relevant.
Not knowing what was that Penguin's motivation, we have very clear situations where there
are both within an individual, we go through periods of time when we stay in one place
and we reap the benefits from what we've built, and then we go through periods of foraging,
of wandering, even if there may be resources where we are.
We have periods of time in our lives where we wander, where we go in an exploratory mode,
and different people express that trait in different ways.
This is not a human-specific trait.
If you go down to the tiny little nematode worm, C. elegans with 302 nervous system cells,
they go through these phases of foraging and rest, and different individuals have different
propensity to forage or to rest and stay in one place.
At the level of the species, that's really good that there's that diversity in their
willingness to forage.
Some stay where they are, the species is somewhat on a firm footing then, but some carry a burden,
a risk for themselves, but it's good for the species that they're explorers and they
will venture out.
The migration patterns that different species blunder into and that turn out to be really
good, they weren't logically derived.
They most certainly started from something like this, an exploration.
If humans do this too, you think?
And we do it too.
In fact, it's something we do extremely well.
Let's talk about psychiatry a little bit.
So in my book, you're a rock star.
First of all, for people who don't know, aside from sort of the neurological view of the
brain and neuroscience view of the brain, you're also one of the great psychiatrists
of our time.
I've always, not always, but when I was younger, I dreamed about being a psychiatrist.
So it's like getting to meet your heroes and also getting to meet the people at the top
of the world at the thing you've failed to pursue.
So I'm getting a free therapy session on top of that.
So what big picture, what is the practice to go the hope of modern psychiatry?
If you could try to describe the discipline as you see it, maybe historically throughout
the 20th century in contrasting to what it is today, or maybe if you want to describe
to what you hope psychiatry becomes or longs to become in the 21st century.
It's been an interesting journey.
Psychiatry started out pretty firmly grounded in neurology and pathology.
Only initial founders effectively of the field were very well grounded in microscopy, looking
at cells, working with patients, particularly on the neurological side, and this certainly
included Freud and some of his contemporaries.
But they rapidly discovered that what they could work with at the level of cells and
microscopy was so far from the realm of what they could get from a human being and what
they were getting from the human being was so much more interesting and had so mysterious
and so unknown that many of them just said, we're going to inhabit this domain and we're
going to work with the people, with their words and understand what we can based on
verbal communication because that was the only tool that people really had.
And that was a very important step for the field.
I would say one of the interesting things that came from the early decades of psychiatry
really was this distinction between the conscious and the unconscious mind and paying particular
attention to the unconscious mind as something that was worthy of consideration that might
be important in explaining people's actions and that perhaps even insight into that was
valuable in its own right.
And out of that psychoanalysis became a practice that was not always focused on cures or treatment
but was more focused on insight.
What does it mean?
How can we help people understand why they're feeling something or thinking something or
dreaming something?
And that insight separate even from treatment was an interesting thing as long as one was
honest about that and said, we're going for understanding, we're going for insight.
Maybe it's useful to just pause on that.
If you look at the father of psychoanalysis, Zygmunt Freud, what do you make of the ideas
that he had?
So you mentioned taking the unconscious, the subconscious seriously.
That's like step one, like that there could be worlds we do not have direct access for
and we probe at them through conversation or is that too simplistic to call psychoanalysis
conversation?
That's not too simplistic.
But that's right.
And I think that was valuable where Freud ended up breaking from some of his contemporaries.
He was very focused on this unconscious as being so tightly linked to libido.
And really, from his perspective, you couldn't really separate the operation of the unconscious
mind from these aspects of the libidinous aspects.
And that was one reason.
What's libidinous aspects?
Sexual related drives.
Carl Jung, who was contemporary, that's one factor that led to them separating was Carl
Jung felt there was a lot more to the unconscious than this libidinous aspect of it.
And he saw it as a much more complete alternate representation of the conscious self, one
that maybe reflected a whole range of different motivations and desires, and to properly treat
it when had to consider all of them rather than the ones that that Freud was hooked on.
Yes, Carl Jung, thank you for the high level of images that Sergei is pulling up for people
who are just listening.
You pulled up as a quote from Sigmund Freud's meme, your mom quote, Freud.
So the shadow, the Carl Jung shadow encompasses everything, not just the desire to have sex
with your mother or sex period.
If you look at those two folks en masse, I mean, there's a kind of, it's almost like
a technique for philosophical exploration of human mind, human motivations.
So it's not even like necessarily, it's also doubles as a methodology for helping people,
but it's almost like a, it's a kind of philosophical method.
Right.
This is the fascinating thing about psychoanalysis, and even though it's, I would say, mostly
not considered a treatment today, it persists for a couple of reasons.
One is, it's thought that it gives people some insight, but second, there's been a huge
influence on literature, on philosophy, on art, and the opening up of discussion about
what was below our conscious mind was so fertile in the implications that it sort of reverberated
and still does throughout all these different realms of human endeavor from different artistic
experiences that people have can be colored by this concept of the unconscious.
Now the other thing that was interesting is this distinction, what are the parts of the
unconscious?
And so there were these id and ego and superego subdivisions that Freud, for example, would
talk about them.
And the id was the primary, the primal drives that an infant would have, or that a very
young child just warmth and feeding, and then later the sexual or libidinous aspects.
And for Freud, the later happened very quickly.
Just the controversial thing about him, I think, I guess he thought even children had
sexual desires that they're dealing with, contending with.
So it's the full thing, hungry, wanting to eat, wanting to poop, wanting to have sex.
And he was extremely focused on that aspect.
But then there was the superego which brought on these later sort of moralistic sort of codes
of conduct.
And that, of course, was very often intention, but all this could play out subconsciously.
And then the ego, this third aspect was mediating, and Freud's conception mediated this tension
between the different parts.
Now I think that's interesting.
I will say that in some ways it's maybe unnecessary from the perspective of modern neuroscience
to divide things up that way from the moralistic drives and the primal gratification drives.
In some ways they're all drives, and maybe they're even all primal drives.
The moralistic drives, they're taught in ways that ultimately relate back to survival, and
you could even say selfish aspects of health and life for the self and family.
And so this is, I think it's maybe an artificial distinction.
The concept of the unconscious is very valuable and very interesting.
But these categorizations of id and superego may not map onto neurobiology in any particular
way, if there's a town hall of competing drives and desires, and they interrelate to
each other, they involve different aspects of the brain and the history of the person.
And actions and choices come out of the result of that overall shouting in the town hall.
So in some sense Carl Jung was a step into the direction of liberating yourself from
such harsh categorizations.
I mean, you have Daniel Kahneman with system one and system two, there's just these very
compelling categorizations of the human mind that seem to be sticky in the superego, how
we talk about these ideas and so on.
Do you think those are helpful or did they get in the way?
Is it some kind of balance in terms of deeper understanding of how the mind actually works?
Yes, from modern neuroscience, whenever we seem to get closer to addressing a question
like this at the level of cells, it seems to get farther away and I'll give you an example
of what I mean by that.
So one thing I'm doing in my laboratory and many people are doing is we are listening
in on the activity of cells, neurons in the brain of mice or rats or fish or monkeys.
Individual cells.
Individual cells, exactly.
Of which there are in our brain many billions and when we do and we try to predict what
action will be taken by an animal to address this question, where does the choice arise?
Where does the impetus to make a particular selection of one action versus another action?
Where does that start in the brain?
If you're recording, listening in on the activity of cells all across the brain, where
is the earliest spot you can pick up a choice being made?
That's so awesome.
At one level, you might think, how excited would Jung have been to see this or Freud
or the early psychoanalysts to see where this starts?
But it's not so simple because an emerging theme in very recent neuroscience, literally
over the last few years, is that things sort of all start together all across the brain
and so you can be recording from the cortex, this rim of cells at the surface of the brain,
or you can be recording deeper in a structure called the striatum, which is a little older.
It's more tightly linked to action and then structures called the thalamus, other parts
of the brain and if you record from these, these all sort of represent the action and
the choice more or less all at about the same time, very close and so you can't point to
a particular spot and say, here's where the choice or the action originates, it's a group.
Finding the free will, Neuron.
It's relevant to that question.
Nobody is close to being able to point to such a thing.
Well, close is a relative term and nobody, what I tweet today, all generalizations are
wrong.
So including this one.
Let's actually talk about that, sort of the study of individual cells.
If you can linger on your sense that as you get closer to that understanding, it feels
like you're getting farther away.
Why is that?
Because that often is the feeling until you're actually there.
So that's when I'm running and I know there's only a mile left, it just feels like that
mile is just getting longer and longer, but eventually you finish.
So maybe we're getting close to cracking open these beginnings of a sense, like we'll talk
about consciousness or these very difficult, big questions about the human mind.
Where do they start?
You're right to say we shouldn't generalize or make absolutist statements, but I would
say right now, the reason things are looking even harder to crack than we had initially
thought.
We now have the data streams that we've wanted for so long in terms of activity patterns
all across the brain at the level of cells.
We can literally see what cells are doing, immense data sets.
These are time series of one individual cell with sub-second resolution and you can collect
this from enormous numbers of cells across the brain.
So very rich data sets that we've wanted for a long time and yet having these has not
led to an understanding of truly where actions initiate in terms of regions or locations.
I'll ask you a few questions on that.
Is the answer high level question by your intuition, is the answer within the data
or do we need different kind of data?
So we should also say that when you collect data about the brain, there's like the richness
of information you're collecting, but there's also human doing stuff and information.
So static information about the human and dynamic information about the human and you
can get them to do different stuff and you can select different humans and that's part
of the collection of data aspect.
So when you're collecting data about the brain, there's some truths that you can, you
know, in machine learning like annotations, like supervised learning, there's some true
things you can hold on to before you look at the full rich mess complexity of the human
mind.
So given the data you've looked at, do you think the answer for the origin of free will
in the human mind can be found?
Well, one amazing thing is that nobody's found it, but we have these rich data sets.
And then there's a conundrum, which is, is it in the data and we just don't know how
to look at it.
Maybe we don't know the right scale, the right projection to make of the data, the right
way to interpret it.
And here's where causal testing becomes very valuable because then instead of just passively
observing, well, here are the activity patterns and then here's the choice made by the animal.
As we've gotten more powerful at reaching in and causing things to happen in the brain,
turning up or down the activity of certain types of cells or defined populations of
cells and seeing how that affects actions.
These causal perturbations have turned out to be very valuable.
We're just now getting to the point where we can apply these in very wide swaths of
the brain at cellular resolution.
And so we're going to be able hopefully to make some headway on this question with causality.
And those, that's the one thing that Optogenetics provides us this way of using light that we
developed to control cells.
This is an untapped, relatively untapped at this broad brain-wide scale and hopefully
we can get there in the near future.
But I would say that the answer may be, maybe in the data, but we don't know how to find
it.
Well, there's this interactive element like where you can cause stuff that's really powerful
because you get to, I mean, as opposed to collecting data passively, you're collecting
data actively.
So can you maybe describe one of the many things you're known for?
One of the big things is called Optogenetics.
What is it?
Optogenetics is a way of causing things to happen.
It's a way of determining what actually matters in terms of the activity of the brain for
the amazing things.
It does sensation, cognition, action, and what it does is it provides activity.
It's a way of playing in, if you will, activity patterns into precisely defined cells.
And the way we do it is pretty cool, I think, right away there's a problem, if you think
about how do we do this, how could we play in well-defined activity patterns and provide
a stream of activity into this cell and that cell and that cell, but not these other cells?
For context, we're talking about the brains of mice, monkeys, humans, and then the goal
is to try to control accurately the behavior of a single neuron and then to be able to
monitor single collection of single neurons to then say, well, to draw some deeper insight
about the origins, first of all, the function of different parts of the brain, different
neurons, different kinds of neurons, but also the origins of the big things, the flap
of the butterfly wing that leads to an actual behavioral thing.
So if you could, exactly.
So if you could turn on or off the brain or parts of the brain or cell types or individual
cells at the natural rate and rhythm and timing of normal brain activity, that would be immensely
valuable because you could determine what actually mattered, what could cause complex
things to happen and what could prevent complex things from happening in a specific way.
But right away, you've got a problem if you want to do this and neuroscientists have wanted
to do this for a long time.
Francis Crick of Double Helix of DNA fame, he wrote a famous paper in 1999.
He got interested in neuroscience later in life.
And he said, what we need in neuroscience is a way that we could turn on or off the
activity of individual types of neurons in a behaving animal.
And he even said the ideal signal would be light because it would be fast, it could penetrate
through the brain to some extent.
And he had no idea how to do it.
He said this would probably be very far-fetched, but it would be a good thing.
And so that's what you're actually saying, like if you want to do this kind of thing
and you imagine like, how do I get inside the brain?
It's pretty difficult to do.
Pretty difficult.
And then even once you get in, it's hard because all brain cells are electrical, all neurons
are electrically activated.
And so if you wanted to use electricity as what you were putting in, you won't have
any specificity at all.
If you have an electrode, a wire, and you put it in the brain and you send current through
it, all the cells near the electrode will be stimulated.
That's like trying to control fish by spraying them with water.
Yeah, right.
Because there's already a lot of electricity going around anyway, and you're adding more.
But there's no specificity even among the different kinds of cells either because all
around the wire that you've put in, there are going to be so many different cells doing
totally different things.
Many of them in opposition to each other.
We know that's one way the brain is set up.
There are parts of the brain that where neurons side by side are doing completely different
things and maybe even antagonistic to each other.
So what do you do?
How do you play in activity with any kind of specificity?
Well, what you do is use, what we found is what you can do is make some cells responsive
to light.
So normally, no cells deep in the brain really respond to light.
They're not built for that.
There's no reason for them to respond to light in there, which is a great situation to start
with because any light sensitivity you can provide to some cells will be a huge signal
above the noise.
And so that's what we do with optogenetics.
We take genes, bits of DNA from microbes, single-celled organisms, and these single-celled
organisms like algae, they make little proteins that sit in the surface of their cells that
receive light, capture a photon of light, and open up a little hole in the membrane
of the cell and let charged particles, ions like sodium and potassium, flow across the
membrane of the cell.
And that, these algae and bacteria, they do this for their own reasons because that helps
them move, it helps them make and use energy.
But that's a beautiful thing for neuroscience because movement of ions charge particles
across the membrane of the cell is exactly the kind of electricity that neurons work
with.
So if we can take this bit of DNA that encodes this beautiful protein that turns light into
electricity from algae, and if we can put it into some neurons, but not other neurons,
which we can do using genetic tricks, then you've got a situation, then you can shine
on the light and only the cells that have the gene and that are expressing the gene
will be the initial direct cells that are activated by the light.
And so that's the essence of optogenetics is the ability to do that.
We get that initial specificity that you could never get with an electrode.
First of all, let me say that this is, recently got the Alaska Prize for this, is a brilliant
idea.
So I talked to Andrew Huberman, who's a friend of yours, friend of mine, not to jinx things,
but he believes that you deserve the Nobel Prize for this.
So I do too, but what my votes, anyway, the thing is, it doesn't matter, prizes will
be all forgotten, all of us will be forgotten.
When the cool idea is a cool idea, there's a really powerful idea.
It's actually the origins of it you might be interested in are even are very deep.
There was a botanist in St. Petersburg named Andre Femenson in 1866.
He published a paper on the single celled green algae, and he was the botanist who first
noticed that they moved in response to light.
These are tiny single celled algae that have flagella, so they swim through the water.
And he noticed this, he was a botanist, and he published this as a paper.
He wrote in German, but he published it in a French journal, and he was doing it from
St. Petersburg, so it was a very international effort.
But you have to go back to 1866, and I like to highlight how far back that discovery goes
is back to Andre Femenson.
And it highlights the value of just pure basic science discovery.
That always originates somewhere in the Eastern European bloc.
But I don't think he expected the splicing of genetic material from the algae into the
human brain.
And one of the cool things we've been able to do now with modern methods is to really
study these proteins.
And so we've discovered some of these proteins other groups have as well.
We've dived deep into their structure, just like the double helix structure of DNA was
uncovered with x-ray crystallography.
We used the same method, x-ray crystallography, to see how these beautiful little proteins
work.
We re-engineered them for all kinds of function.
We can make them, instead of responding to blue light, we can make them respond to red
light.
We can speed them up, slow them down.
We can make them, with genetic engineering, we can make them have different ions flow
through them.
And so it's this convergence, as you said, like the botanist in 1866 couldn't have predicted
what we could do with this, and the fact that we've been able to discover how these beautiful
proteins work and then apply them to neuroscience is really a thrilling story.
Is it possible to achieve scale, do you think, with this, meaning like what is the progress
of the next 50 years, 100 years looks like, in terms of the precision and the scale of
control using light?
It's going so fast.
It's hard to predict.
I'll give you a sense of it, though, in first paper, we published in 2005, that was just
in cultured neurons, by 2007, so that was in a dish.
By 2007, we had it working in behaving mice.
By 2009, we had it pretty general, so we had methods to really make it a versatile method.
It could be applied to essentially any cell.
By 2012, we could get to single cell resolution.
We used light guidance strategies to target individual cells in the brain of a living
mouse.
By 2019, we were able to control up to 20 to 50 individually specified single cells in
the brain of a mouse in ways that specifically changed its behavior, that could bias its
decisions one way or the other.
In fact, we could take a mouse and without any visual stimulus at all, we could make
it act as if it had seen a particular visual stimulus by playing in, using the single cell
resolution optogenetics, a specific pattern of activity into 20 or 25 individually specified
cells.
That's 2019.
It's your question of scale now, in 2022, we're controlling hundreds of individually
specified single cells over all of visual cortex of a mouse, all the part of the brain
that is the initial direct target of the incoming information from the retina.
Are you constrained to specific types of cells currently?
Like you mentioned, long range is easier.
Is there constraints on which cells?
Now that we have this individual cell guidance, we can target any individual kind of cell
very reliably.
Now to your question of scale, how far can we go?
Well, things are moving quickly.
It's hard to say.
We can access individual cells across the entire brain now.
If you look 10, 20 years in the future, I think we'll surprise ourselves, but the fact
that we're already able to cause specific perceptions to happen and specific actions
means we're essentially where we want to be and now it's a matter of just more experiments,
more discoveries, but the basic principles are clear now.
The basic capability is there.
Is there a pathway to doing the same for humans?
Optogenetics is primarily, it's a discovery tool that really is well suited for use in
mice and rats and monkeys because it involves putting in a gene and also delivering light.
Those are two things that you can do in human beings, but you'd want to do in a very careful
way.
Now that said, there is actually just less than a year ago, my friend Botan Roska in
Switzerland, he did the first human optogenetics therapy and he published this in the journal
Nature Medicine.
So about 10, 12 years ago, he and I published a paper together where we gave him one of
our optogenetic tools, one of these light-activated regulators of ion flow, these are called microbial
opcins, by the way, opcins, and he put one of those into an extracted retina from a human
being who had died, so it was a cataviric retina, and he was able to show that optical control
in this paper was able to turn on or off individual cells in the human retina.
So that was a while back.
He spent about 10 years of going through all the regulatory hoops and hurdles and going
through primate studies, and finally, he was able to take a human being with a retinal
degeneration syndrome, so someone who was blind in both eyes.
And he gave one of these opcins into one eye of this human being who was blind and with
the goal of conferring light sensitivity onto this retina that was not able to see light,
and he was able to make this person see through that eye.
So he took a blind person, and the blind person could see, now, could reach for objects selectively
on a table, and he published this in Nature Medicine, and it was, you know, that's an
amazing thing.
Do you know the title of the paper?
What's his name again?
Rosca, R-O-S-K-A.
Can you look up the nature paper?
Yeah, Nature Medicine.
Nature Medicine.
So that's sort of proof of principle.
Now, the retina is very accessible.
It's near the surface.
You can use natural light, or you can use brighter natural light.
I'm, myself, I see optogenetics as a discovery tool.
It's a way to figure out the principles by which the brain works and how it operates.
Partial recovery, visual function in a blind patient after optogenetic therapy.
So he went through the full process of doing primates and then going, well, that's dedication,
and that's really exciting to see.
As beautiful as that is, and I'm glad he did all that work, there are so many other
ways that optogenetics could help with therapies.
Once you know the principles, then any kind of therapy can become more powerful.
Once you know the causal cells in a symptom, like in lack of motivation or inability to
enjoy things or altered sleep or altered energy, once you know the cells that are causal, then
you can make medications that address those cells, you could address brain stimulation
treatments that might address those cells.
Also diagnosis, very effective systematic way of diagnosing, or at least providing you
rich data to some of these deep questions about schizophrenia, about bipolar, all those
kinds of things that are, the tools are low resolution currently for determining the degree
to which you have a thing and whether you have a thing at all.
Yeah, exactly.
And so the hope is, that's a great example of how you can cure, or you can provide some
relief for a symptom of a person who has a serious degenerative disease, but the principles
are what we're after, and that's why I spend, even though I'm a psychiatrist, even though
I still see patients, I'm not myself trying to drive any clinical trials in the lab.
I'm trying to discover, and then any kind of therapy could result from that.
What do you think about my friend Elon Musk and his efforts with Neuralink?
So this is another, there's a lot of things to say here, because there's a lot of ideas
under the umbrella of Neuralink, but one of them is to use electrical signals to stimulate
and then you also record, you collect electrical signals from the brain at a higher and higher
resolution, and you go implant surgically the methods by which you do the stimulation
and the data collection.
So it's possible for the ideas of optogenetics to play well with this, and we can even zoom
out outside of just Neuralink and just the whole idea of brain-computer interfaces.
What are your thoughts?
Well, I think the engineering that they've done is actually pretty cool.
So I like the robots, from the design perspective, and it was a design approach that wasn't being
taken in academia, and it's great that they did it, and I think it's pretty cool.
So I'll say that.
Also, there are many ways that you can record from many thousands of neurons, and that's
not the only way, it's a very interesting way.
We and others are using brain-penetrating electrodes that actually get quite deep.
The whole structure of the brain is very interesting.
There's the surface cortex, where it's the most recently emergent part of the brain
in evolution, mammals have it, reptiles have something a little bit like it, but it's not
really the whole thing.
This is a very recent thing.
That's what we can access with some of these, like the Neuralink approach and with some
of these short electrodes.
This part of the brain in the cortex is only a few millimeters thick.
There's so much that's deep, though, that's so important.
There's the striatum, there's the thalamus.
There are the parts of the brain that drive motivation, that drive hunger and thirst and
social interaction and parenting and flight and fear and anxiety.
All these things are, there's so much that's deep that these surface approaches are not
getting to.
We and others are using these very long electrodes that help us get deep, and we can still record
for many cells, many thousands of cells.
We can have multiple of these at once in the same animal.
There's a diversity of methods to get to this goal.
I think it's great that people coming from outside academia will bring ideas that weren't
being worked on, at least approaches.
They may turn out to be synergistic.
These things do work very well with optogenetics because all these electrical recording methods,
that's one channel of information flow.
Light delivery is a separate, more or less independent.
There can be some artifacts that happen, but if you're careful, that's another independent
pathway of information flow.
We've done really fun experiments in mice where we play in patterns of activity with
light and we record activity from all across the brain of a mouse, electrically.
Using optical and electrical together is extremely powerful.
Optoelectric brain computer interfaces, which by the way, there's efforts on the computing
side to build optoelectric servers, where you have both.
Optics is really interesting.
Light is a very interesting method of communication that's, like you said, orthogonal in many
ways.
It doesn't have some of the constraints of bandwidth that electricity does go into wires,
but you're able to, but it's less ability to control precisely at scale.
There's challenges and there's benefits and having those two interplays really, really
fascinating, especially when obviously on the other side of your signal is a biological
mesh, mush, mushy mesh.
Well, the mushy mesh is kind of interesting because we have, there are problems with
light scatters in the brain, so the photons don't just go, you know, linearly through.
Whenever they hit an interface between fat and water, lipid and water, they bounce off
in different directions.
And so you can come in with all the resolution you want.
You could play in an incredibly detailed high-resolution pattern of light, but the photons start
scattering quite quickly and by the time you've gone a couple of millimeters deep, you've
lost almost all that fine spatial information.
So, but we've developed workarounds.
The longer wavelength light you use, if you get into the infrared, there's less scattering.
You can use two photon methods or three photon methods where the photons have to arrive all
together at the same time.
You can put in fiber optics.
We developed these fiber optic methods in 2007 where you can access these deep structures
with fiber optic methods and you can put in many of these fiber optics at the same time
in an animal.
We've used holographic methods, 3D holograms to play in, hundreds of individual cell-sized
spots of light and we can change those quickly.
And so there are a lot of tricks, a lot of interesting optics engineering that has come
together with neuroscience in a pretty exciting way.
I don't know if it is engineering too, it was just super, super, super exciting.
I should mention, because I remember, I mentioned Elon.
I recently got, for the first time ever, got COVID.
How did I go so long without the, finally, so I'm all vaccinated and everything like
that.
And so I got, because I think he mentioned it publicly so I can mention it, but I won't
mention anybody else involved, but hanging out, we all got, Elon got COVID and the interesting
thing about, maybe you can comment about this.
So I was only sick for like a half a day.
I got a fever of like 104, I just went up and then crashed and then I was, now maybe
I'm just seeing the silver lining of everything, but afterwards, I have like a greater clarity
about the world.
You just think it's greater clarity.
Maybe I just, it was so, maybe so intensely, the mind fog kind of thing for such a short
amount of time, but the people were involved were also reporting this.
It's kind of interesting because like, because I do know like the immune system is involved
with the brain in very interesting ways.
So like the human mind also incorporates all these other, it's not just the, it's not
just the nervous system and I just wanted, because everyone always says, no, not like,
everyone always says like COVID does all these bad things or whatever the disease is or whatever
the virus, but I wonder like, I hate to be a Steven Pinker on this, but like, I wonder
what the benefits of certain disease are if you're like, what is there's some like, again
don't want to romanticize it, but if your system goes to some kind of hardship and you
come out on the other end, I wonder sometimes if there's a greater, maybe killed off a bunch
of neurons that I didn't need anyway, and they were actually getting in the way.
There were the hater neurons.
I don't know.
Well, that was your inner critic that I was talking about.
Exactly.
You killed off your critic.
Well, you know, there are mechanisms for what, the potential mechanisms for what you're
talking about.
There are, there's actually been a fair bit of research on post COVID neurological function.
Actually my wife, Michelle Manje, who's at Stanford, she's done a lot of this work, Akiko
Iwasaki, Yeo has done a lot of this, but what they found is that there's a loss of myelin.
This is the coding of those long range projections that go from one part of the brain to another.
Myelin is this sort of insulator that coats these long range projections and makes the
impulses go faster and more reliably.
And there's altered function of the myelin producing cells and altered myelin in the case
of COVID.
They've looked in both mouse and human brains.
And but of course it could be very idiosyncratic.
Many people have cognitive problems post COVID.
You're definitely aware of that.
So many people report this persistent brain fog and ability to function, but it depends
on where the inflammation was.
You know, maybe the people who have dysfunction post COVID, they had a global effect.
But you lost some of these projections that were restraining you in some way, and these
plausibly exist.
And it's known that there are cell populations in the prefrontal cortex that actively restrain
deeper structures from expressing what they do.
And it's theoretically possible that you had a lucky focal point.
Somebody has to get lucky, right?
Somebody has to get lucky.
Why not me?
All right.
I'd like to go back to this idea of trying through optogenetics to find origins of when
the way first starts, origins of a decision, origin of idea, origin of maybe consciousness
or the subjective experience or origin of things in the mind.
So one thing is Carl Jung, is there a God neuron?
Is there a belief neuron?
Is there, so through this methodology of optogenetics, can you start getting to like where a belief
begins or an idea begins and especially looking at the strongest of our beliefs, maybe beliefs
of love and hate, but religious belief into something like really grand, the grandest
of scale?
Yeah.
Neuroscience and neurology point us a little bit.
We don't have an answer to that.
But for example-
Yeah.
A lot of these questions I'm going to ask you, there's no good answer, but you're providing
the tools that give us hope to find the answer one day.
Yeah.
There are some clues.
So for example, when patients with epilepsy have experiences of religiosity as part of
their seizure or the aura before their seizure, very often those are in the temporal lobe
in these parts of the brain that are at the side.
And so that's initial clue.
There are also parts of the brain that are involved in the definition of the self and
defining the borders or boundaries of the self.
And we know this, this is some experiments that we did in my lab.
There's a part of the brain where if there's a rhythm of a particular type, you can cause
a separation of the sense of self from the sense of the body.
It's normally bound up and unitary.
We normally think of ourself and our body as pretty tightly bound up together.
Those can be separated, it turns out.
We can't take that for granted and there are certain conditions, certain patterns of activity
in one part of the brain called the retro splenial cortex where you can actually separate those
two out.
And so if you think about these very big questions, where are the origins of religiosity?
How do we define the boundaries of who we are relative to others and to the world?
How do we link ourself to our body and how can that become separated?
These are actually, believe it or not, now accessible and rigorously and quantitatively
so.
We did an experiment with optogenetics where we provided this abnormal rhythm to this particular
part of the mouse brain and we saw this separation of detection of a stimulus and caring about
it.
So that's like stimulating something about the mouse brain that affects these neurons
that give the conception of self.
So you're able to dissociate the experience from the impact of the experience unto you.
That's right.
Exactly right.
So like these are the goals of meditation.
These are the goals whenever I get drunk, pretty much effective.
That's not a scientific statement, just an experiential anecdotal one.
Also psychedelics seek to attain this kind of state.
That's so interesting.
Well, you mentioned psychedelics, DMT and 5MEO, DMT.
These create this religious experience, this connection.
People describe them as a strong connection to God.
In theory, these are accessible with modern methods.
Now that we have these rich recording methods, we can explore what are the precise millisecond
resolution, cellular resolution, brain-wide manifestations of these altered states.
So like you could look at an altered state like on DMT, record it across many people
and then from there see where do these experiences originate in the brain in terms of single
neurons and then how do they propagate and interact with everything else and if there's
some kind of common signal.
How do you narrow down the set of neurons that are responsible for particular experience
or for a particular behavioral effect?
Here's where optogenetics is so useful because anytime you give an agent like ketamine or
PCP, which we used for our dissociation experiments that I was mentioning, or you have a psychedelic,
LSD or DMT for this altered perceptual state, if you give either of those, these change
everything across the brain.
Just the fact that you maybe give them to a mouse, let's say, or eventually to a human,
you won't know yet which cells to home in on as the causal players in all this just by
recording the activity, but then what we found is that optogenetics providing a causal pattern
of activity guided by what you see can let you test hypotheses and we saw this rhythm
with ketamine and PCP for dissociation and then we said, okay, let's test what's causal.
We came in and provided that rhythm, we tried a few different things, but only one of the
causal tests we tried actually caused the behavioral dissociation and so that's how
we home in on what actually matters.
Is it repeatable once you see the causality?
That's one definition of causality is you try and it repeats across different mice and
all that kind of stuff.
You could do that for DMT, you could do that for the really fascinating mind-expanding
draw, thank you, so the meme for people just listening, this is again another disagreement
between Freud and Carl Jung, religion and spirituality.
This is the, I guess, the ring scene from Lord of the Rings.
Religion and spirituality, Freud says, cast it into the fire, destroy it.
Carl Jung says, no, so for people who don't know, Sergei is the Slavic Lord of the meme.
Thank you, I appreciate that.
So what we're talking about, so there is, I mean, I think a connection between DMT and
religious experiences or some of these psychedelics, do you think it's possible to sort of stimulate
religious experiences?
So religious experiences are one of the most deep kind of experiences and so here you could
first understand where they originate, how they propagate to the brain and then to stimulate
them.
And so this is, and these that can happen in people who had no predisposition, people
who are as agnostic or atheistic as you'd like, they can feel connected to God in these
states.
Now, to be clear, I'm not advocating these, we don't know what's safe in human beings,
but we definitely had not yet, but we definitely can do these experiments in mice and that
was already very productive in understanding dissociation.
So we can already imagine making headway on these methods.
And then I had a, and this does map onto the non-psychedelic human experience.
I had a patient who's actually described in the book, Projections.
This was the patient that's in the maniac chapter, the bipolar chapter.
Here was a guy who had never had a psychiatric illness or symptom in his life.
He was a retirement age gentleman and nobody in his family either.
So no family history, no personal history of any psychiatric illness and he had never
been religious particularly before either, certainly no passionate type of religion.
But he, not through any psychedelic or drug, he had a stressful experience, actually a
post-911 change in how he was thinking and he was pushed into a mania, a manic state
revealing that he had bipolar, never before known in this case, in this person.
And his mania, his elevated state in bipolar included this profound religiosity which he
had never had before.
And he was preaching in an elevated, vigorous way to his family.
And so this state can be created in people even late in life who had no predisposition
for it and no, even without a neurochemical.
So the causality of that is very interesting to explore.
How did the manic state unleash this religiosity?
But you see that in other realms of psychiatry too, OCD can manifest as religiosity also.
You can take people who never really had a, a religion never played a powerful role in
their life, but then when their obsessive compulsive symptoms become severe, they can
manifest in this.
I think I'm in that group, so I'm a bit OCD.
We have, there's, I think these subreddits, when there's oddly satisfying things.
So there's certain things that are really satisfying to my OCD, maybe my mild OCD.
I think it's pretty much a religious experience.
So I understand that there's, if it's not directed, it's at least rhymes.
So maybe can you speak to the, as Sergei is probably desperately scrambling to pull up
oddly satisfying.
Thank you.
People can check it out themselves.
It is, as, as the subreddit promises, oddly satisfying.
Can we talk about bipolar and maybe depression?
Well, let's talk about, I mean, I don't know if there's a nice way to discuss the differences
in the full landscape of suffering that's here, but maybe what is depression and what
are the types of depression?
What kind of depression have you seen and experienced and researched and how can people
overcome it?
How can humans overcome it and deal with it, live with it and overcome it?
So this is my clinical specialty.
I see patients in my outpatient clinical work with treatment resistant depression.
So very hard to treat severe illness where medications haven't been been working.
I also see patients with autism spectrum disorders.
These are my two clinical focal areas, but then I do emergency room work as well.
But the depression, why do I focus on that?
One feels tantalizingly close to helping these people who are suffering so deeply.
That's why I focused on it is these are people who, there may not even be anything situational
that's difficult or challenging in their life.
You can have people who seem to have everything that you would want.
Every objective measure of the life is fine, and yet they can be just hit with this unstoppable
hopelessness and inability to see into the future, a discounting of the value of their
own action, anything they can imagine themselves doing seems worthless or they are unable to
enjoy things.
We call this anhedonia.
There's no reward, no pleasure, not in food, social interaction, movies, books, anything
that they would enjoy, positivity gone.
They can have a profound negative internal state, psychic pain, and these things can
seem and in the severe cases are inescapable.
So what is going on?
Why is this state part of the human existence?
It's got a strong biological genetic link.
We know that.
It's been linked to certain genes, certain regions of the chromosome, and twin studies.
There's a clear genetic link.
It doesn't explain everything, but it's a big part of it.
Genetics are a strong contributor.
Although you can have depression without anything terrible going on in your life, the symptoms
can be made worse by stressors, by trauma.
But at a very deep level, there's nothing we can measure in a person objectively.
So we don't have, there's not a known chemical, not a known structure that's different, not
a known brain activity pattern that we can pick up with EEG.
A lot of people are exploring this, but right now we have no objective measures.
All we do is talk to people and we elicit these symptoms.
We explore them, distinguish them from other possible causes, and then what do we do?
Well, we have a range of treatments.
We have medications that can help people, do help people, but not everybody.
And if they don't work, then we can go to brain stimulation methods.
We can do things even like electroconvulsive therapy, which is very effective, but it's
sort of the final thing we go to in the end.
And so we have treatments, they work for some people, they don't do everything we'd like,
but here's the problem is at a very deep level, we don't understand really what's going on
in the brain.
We don't have a physical interpretation of the problem.
We have all these symptoms, but we can't yet point to a set of cells or a set of circuits
or an activity pattern that is causing major depression, this disease state per se in human
beings.
Why do you think you can't yet, from an optogenetics perspective, is it because there's so many
possible causes?
Is it so much, so many things involved?
So I think the answer is there are many things involved and all these different symptoms that
I've mentioned, those we can study and those we can fix, the individual symptoms.
And we can do this in animals to be clear.
So in a mouse, for example, we can instantaneously and precisely turn up or down the motivation
of an animal to overcome a challenge, we can turn up or down its ability to be motivated
by or we think experience reward from situations or actions.
We can increase its apparent energy level, its drive to meet challenges.
We can turn up or down social interaction.
All these individual features of depression, individual symptoms, we now can point to exact
projections and cells that are causal in meeting these.
But we don't know is why all these different symptoms show up together in major depression
in the human disease syndrome.
And that's the mystery.
It's sort of in other fields of medicine, someone with congestive heart failure who
comes into the clinic.
They have very different symptoms.
They have shortness of breath and they have swollen feet, couldn't be two more different
across the body sets of symptoms, neither one obviously related to the heart, but they're
both happening because the heart is not working as a pump.
And now, thankfully in cardiology, we understand these disparate symptoms that seem totally
unrelated can be completely understood because there's an altered pump action of the heart.
That's what we are hoping for in psychiatry and in the study of depression or any disease.
These different symptoms, the inability to enjoy things, the hopelessness, what's the
unifying principle?
Unifying.
I mean, is there some truth to that, the Tolstoy quote, that all happy families are alike and
each unhappy family is unhappy in its own way?
So basically, I mean, this is the human condition and basically that might, you know, the physicist
long to find the theory of everything, isn't understanding depression essentially require
you to really have the big theory of everything for the human mind?
I think we, it would certainly be nice to have that theory though, don't get me wrong.
I don't think we need it.
The other state of the surgery, it would be nice.
It's also a good question if it's possible.
Yeah.
Well, that I have some thoughts on too.
But to this specific question, I don't think we need a theory of everything.
I think there will be unifying principles we can get to.
But even shy of that, if we can treat symptoms and that's a big step and as you say, different
unhappy families are different, different unhappy people are different.
If we have somebody who comes to the clinic and I see someone with a profound anhedonia
as one of their main symptoms, inability to enjoy things, and if I know based on optogenetics
work and animal work that a particular medication can treat anhedonia, even if it doesn't fix
major depression in everybody.
If I treat that one symptom in that one person, that's a good thing.
And so we don't need the theory of everything and we don't even need the unifying principle
to help people with insights that come from optogenetics.
How much does talking help for diagnosis and for treatment, would you say, for depression?
It's a big part of what we do.
Every good psychiatrist should be a pretty adept in these verbal communications and
talk therapy as part of what they do.
I give medications, I deliver brain stimulation treatments, but a big, big part of everything
I do with every patient is talk therapy because it works so well together with these other
modalities.
Even alone, it can help people with moderate or mild depression by itself.
People with severe depression, people with other psychiatric illnesses that are severe,
you don't want to do talk therapy alone.
It's not going to do it, but it still is crucial to do together with the others.
And it's critical because it's part of how you reshape cognitions, complex activity patterns,
and you won't get to that with a medication or brain stimulation treatment.
Do you have advice for people who suffer from mild forms of depression or feel as they might,
both for those people and do you have advice for people who love the people who suffer
from depression and want to help?
One of the incredibly frustrating things about depression is the very nature of it makes
it hard for the people who suffer to get treatment because they're hopeless, so they don't think
treatment will help.
They have low energy, so they're not motivated to participate in treatment in many cases.
Sometimes they're actively suicidal, that certainly doesn't help.
They have all these things that seem to prevent treatment from being effective.
So the loved ones, that's where the loved ones are so important, is helping them overcome
these barriers to treatment, the motivation, the safety, and the insight.
That's critical, and particularly for the severe cases.
For the mild cases where people still have some insight and motivation and energy to get
something done.
There are many things you can do.
Exercise is extremely important in mood maintenance.
Regulation of sleep and getting sufficient and regular enough sleep is very important.
And talk therapy can be helpful in those mild or moderate cases.
Just looking at cognitions, looking at patterns of thought that people may have fallen into,
where they catastrophize, where they spiral from small things into big things.
A little bit of talk therapy, 10-12 sessions, can help people identify those patterns they
may have in themselves that are taking occasional negative thoughts, which everybody has, and
magnifying those into more persistent negative states.
If you work at this, and it's kind of like homework, this is what we call cognitive behavioral
therapy, it's very structured, very organized, you work hard, it requires insight and motivation
and you have to be motivated.
But if you are, then you can identify these triggers that send you down particular pathways
and work to intercept them.
And that is amazingly very effective in mild to moderate cases.
So you basically have to train yourself to see the world as a collection of triggers.
And you have to first understand, like collect the data, like basically see every experience
as a thing that creates a follow on emotion of feeling.
And I've learned this on social media, where early on, like all of us, I'll say something,
I'll kind of respond to negativity with negativity, and then you observe the results of that.
Over time, you think, wait a minute.
This thing that I've been doing where when somebody says, you suck and you say, no, you
suck, that never produces the result you thought it might.
And so I might not want to just don't say you suck back.
And I do this through a lot of things in life.
I'm very fortunate to not suffer from depression, but I, first of all, I have had and have people
in my life who do.
And also, all of us have depression, who don't suffer from depression, have depression out.
Like it's always knocking on the door, and so you have mild, I mean, if you're very careless
with the triggers all around you, then you're just, I think all of us have the capacity
to really suffer from that kind of chemical or psychological or philosophical existential
crisis.
But then it raises a question, why are we built this way?
It seems like it doesn't make sense, right?
And here's where some of us thinking about where we came from as the human family is
kind of interesting.
It doesn't make sense that somewhere on that spectrum that it's good to detect that there's
an array of adverse forces out there in the world right now at this moment.
And to withdraw, to hunker down, to not fight, not strive, not try to meet the challenge,
and outweigh these negative forces that are present out there.
And that makes a lot of sense.
And all animals that have been studied in one form or another show this, even the worm
that I mentioned earlier, C. elegans with 302 neurons, it can effectively give up in
challenging situations.
We've done this with zebrafish, tiny little transparent fish.
You can give them a challenging situation and they will give up.
But then if you stimulate a couple of very specific brain regions in particular ways,
you can motivate them to overcome the challenge.
And if you inhibit those regions, they give up much more easily than they would otherwise.
You can do this in mice, you can do this in rats.
So this is an ancestral conserved pattern to detect that things are pretty bad out there.
And to conserve energy, to hunker down, to weight out the storm.
So as use, unfortunately, many of our maladies have useful roots in our, that contribute to
our survival.
So both depression and motivation have uses and sometimes it's nice to just shut the hell
up and huddle with the penguins versus, for some unknown reason, venture out on your own
into the mountains like a David Goggins type character.
So what's the difference to you between, you see patients between sort of rigorous psycho
analysis.
And if you consider we talk therapy and psycho analysis, are they neighbors, are they overlapping?
They're neighbors.
Psycho analysis is, they're relatively, it's not nearly done as much as the talk therapy,
like the cognitive behavioral therapy I mentioned.
The psycho analysis is a little more niche now and partly because it's not data isn't,
in terms of actual treatment of actual therapeutic effects, data not as supportive as for cognitive
behavioral therapy.
But it's still interesting as for insight, people, a lot of people still do it to gain
insight into themselves.
And in general, it's a good sort of conversation starter.
Those methods is, you know, they're good for getting things out, you know, we don't focus
on dreams, typically these days in psychiatry, but they're great conversation starters.
They're great ways to get things out if people have, and so we like to use those methods
just to get the ball rolling sometimes, get people to open up a little bit.
But the actual treatment tends not to involve these psychoanalytic approaches where you
are really probing the unconscious mind and its manifestation through dreams, for example,
as the goal.
That's not the goal.
Modern talk therapy, we're really focusing on treatment, how to get people to feel better.
See, I use that as a conversation opener, the Freudian thing where I try to delve at
a bar of the deep sexual desires in a person's subconscious, and I find that opens up possibilities
very quickly.
No, I mean, this is a silly sounding question, but what's the difference between cognitive
behavioral therapy and conversation?
So because I personally, as a fan of conversations, as a fan of just listening to podcasts versus
like audio book, I like both, but they're very different, and I like conversation.
It makes me personally very anxious, so I like to be the listener, like a third wheel, like
overhearing a conversation kind of thing.
But it's a really powerful method for humans to explore each other's mind, just raw conversation.
So do you think it can be more productive to be very systematic about it, or is conversation
itself the art form of helping each other, understanding each other and helping each
other?
There are forms of talk therapy that are essentially conversational, or they much more approach
pure conversation.
There's a befriending therapy.
There's interpersonal therapy.
These are approaches that are purely talk therapy, but they're not as structured as
cognitive behavioral therapy.
Cognitive behavioral therapy, as there are manuals, there are guidelines, you can almost
go through it in a very cookbook-y way, there's homework that you get done.
So it's in its fullest form, it's very different from these more conversational strategies.
But what's interesting is sometimes people compare them, and so you'll see almost like
randomized controlled studies comparing cognitive behavioral therapy with interpersonal therapy,
for example.
And they both can work, and actually in some studies, they look comparable.
So to your point, conversation and insights that come from conversation, if done well,
if done artfully, can be as powerful.
This reminds me of Robin Williams.
I have to ask you several questions here on that, but one of my favorite movies is Good
Dwell Hunting.
I don't know if you've seen it with Robin Williams.
So as a psychiatrist yourself, can you do a deep analysis of this other famous psychiatrist,
which is the movie character played by Robin Williams at Good Dwell Hunting?
Is it just a caricature between a psychiatrist and patient relationship, or is there something
to you that was moving about his ability to connect to this obviously struggling young
kid?
I think you've hit on the key thing there, which is the depth of the connection.
If there's too powerful a connection, that can impair therapy because it could impair
open communication.
If a patient sees the relationship in a particular way, like in a friendly way, maybe, or like
a parental child type way, that can cause problems because then what they choose to share, what
they choose to bring up is selected to be appropriate for that view of the relationship.
And so I and many other talk therapists actually prefer not to let the connection get that
deep.
You want to have trust, you want to have a therapeutic alliance, we sometimes call it,
but it's got to be enough of a blank slate that the patient is not consciously or unconsciously
constrained in what they choose to share.
And so great movie, great actors, all good, no complaints except realistically the relationship
should be a little more arm's length than that.
Let's pretend this is real life.
Sometimes can't you leave a little bit of yourself in the interaction with the patient?
I mean, it's another human being.
So it's a balance and actually you do need some of it because let's say this person is
having challenges, interpersonal challenges in their life.
The best way to notice what those are and to identify them and to work with them is if
you can elicit some of those problems in the office, in the therapeutic interaction.
And this is really powerful.
As long as you're alert to it, aware of it, and you don't let it get out of hand, this
transference, we call it, is when you transfer in between the current therapeutic relationship
and external relationships that the patient may have had with others.
And so if the therapist starts to feel an inner feeling like anger, let's say, so let's
say you have a patient who is stirring frustration in you or even in extreme cases, anger, the
best thing for the therapist to do in that case is to recognize it and to realize that's
probably being stirred by other people in the patient's life.
And that could be the source of a lot of problems.
And so instead of trying to wall it off and say, oh, I shouldn't be feeling that, I better
be a better therapist instead and recognize it and use it and help the patient that way.
And so you've got to be a human being.
You've got to be a person who feels you've got to be open.
To be in control of it and be aware of it.
If I may, I just want to read the, because this is my favorite scenes, probably one of
the greatest scenes, one of the greatest scenes in movie history because Robin Williams does
a single take.
Is that right?
I didn't know.
So this is a very interesting interaction between them.
So Will, and I'm sure this is a common interaction, maybe with a therapist and a patient, maybe
with a father and son, where Will, the young character, they're a young, brilliant mathematician
and Sean is the therapist, the older therapist, where Will looks at a painting that Sean painted
and then does like a deep critical analysis of the painting that basically describes pretending
as if he can understand another human being completely, but just looking at their painting.
And then Sean gives this whole speech that contrasts sort of raw intelligence and the
wisdom of experience.
And Sean says, single take.
He says, you've never been out of Boston, right?
And Will says, nope.
All this in a sexy Boston accent, by the way.
And then Sean gives the speech.
If I asked you about art, you'd probably give me this skinny and about every art book I've
written, Michelangelo, you know a lot about him, life's work, political aspirations, him
and the Pope, sexual orientation, the whole works, right?
But I bet you can't tell me what it smells like in the Sistine Chapel.
You never actually stood there and looked up at that beautiful ceiling, seen that.
If I asked you about women, you'll probably give me a syllabus of your personal favorites.
You may have even been laid a few times.
The language here is just beautiful, but you can't tell me what it feels like to wake up
next to a woman if you're truly happy.
You're a tough kid.
If I asked you about war, you'd probably throw Shakespeare at me, right?
Probably not, but let's say.
Once more into the breach, dear friends, but you've never been near one.
You've never held your best friend's head on your lap and watched him gasp his last breath,
looking to you for help.
If I asked you about love, you'd probably quote me a sonnet, but you've never looked
at a woman and be truly vulnerable, known someone who can level you with her eyes, feeling
like God put an angel on earth just for you, who could rescue you from the depths of hell
and you wouldn't know what it's like to be her angel.
To have that love for her, be there forever, through anything, through cancer, and you
wouldn't know about sleeping, sitting up in a hospital room for two months, holding her
hand because the doctors could see in your eyes the terms visiting hours don't apply
to you.
You don't know about real loss because that only occurs when you love something more than
you love yourself.
I doubt you've ever dared to love anybody that much.
I look at you.
I don't see an intelligent, confident man.
I see a cocky, scared, shitless kid.
But you're a genius, Will.
No one denies that.
No one can possibly understand the depths of you, but you presume to know everything
about me because you saw a painting of mine, you ripped my fucking life apart.
You're an orphan, right?
Do you think I know the first thing about how hard your life has been, how you feel
who you are because I read Oliver Twist?
Does that encapsulate you?
Personally, I don't give a shit about all that because you know what?
I can't learn anything from you that I can't read in some fucking book unless you want
to talk about you, who you are.
And I'm fascinated.
I'm in.
But you don't want to do that, do you, sport?
You're terrified of what you might say.
Your move, chief.
Well done, sir.
I know it's a movie.
It's interesting, right?
So some of that conversation is at some intellectual level, too.
It's not just emotional.
It's something, it's like, the reason I kind of connect with that is that's a lot of work
for a therapist, like to really understand another, because he's, I mean, from, okay,
I know this is fictional, but just there's calculation happening.
He deeply cares to say the words that the other person needs to hear, but also a little
bit loses himself in the pride, but then catches himself again, switches from anger
to connection.
Yeah.
A lot is brought up there.
You're right.
There has to be some emotion in the therapist to care enough to keep going, to keep probing,
to open up as he's doing so, right?
He revealed a lot about himself, his own vulnerabilities, but that gave him authenticity.
He had to open himself up so that the kid would see the authenticity and open himself
up in return.
So how do you do that as a psychiatrist, as a therapist?
You have to be careful.
You don't want to do too much, but opening up a little bit does help.
It does create a chance.
You're offering up something, and that helps the patient come back in return, and it gives
you that believability and authenticity.
Do you pay the price for that, for opening it up?
You can.
You have a family, you have an incredibly difficult research, you're doing a lot of
things in your world.
I mean, it's the price you pay for like.
This was one of the terrifying things about writing the book was, I do open up in a little
bit about my own personal life, my own personal challenges, and that was a considered decision
because I could have done the patient work and the science work and the history of the
human family work and tied it all together, but it wasn't, in an early draft, it was like
that, but it wasn't real yet.
It wasn't something that everybody could connect with, and I said, then I realized, look, if
I'm going to do this, I've got to open up myself, and then people can connect with me
and see what I'm really saying.
So I did, and that was not something that I'd gone in planning to do.
In retrospect, I learned a lot about myself.
It was actually really, I think, a good thing that I did, but it was scary.
Where are the darkest places you've ever gone in your life?
I had things haven't always been easy personally or professionally.
I had moments, I was effectively a single dad for a while, a number of years, and these
came at probably the hardest, also, professional lifetimes for me, too.
The absolute hardest days of late medical school internship, taking a call, getting
up at 3 a.m., surgery, medicine, rounds, unforgiving environments, and then all the
while, personal life, stripped down to the bare.
These were low moments, and then I was hit particularly hard by just experiences on the
clinical ward connecting to deeply with patients, like a child with a brain tumor and feeling
it too strongly.
When you get down to those lowest of the low moments when everything is stripped away
and there's only this raw core, well, that's pretty hard.
That was probably the lowest moment, and you learn a lot about yourself in those moments.
It's left, and then what are the roots out from there, and that can be powerful to see
in yourself.
Have you thought about killing yourself?
I have not.
Have you seen that thought in the distance?
I am fortunate that that has not come to my mind, and I have not seen it even in the distance.
In some ways, I've wondered if that's made me, am I a less effective psychiatrist because
of that.
I've felt everything stripped away.
I've been at the lowest of the low, and yet that can't-
There's still hope.
There's a light of hope still at the end of the tunnel.
You never lost, even for brief moments, that-
I never did.
I don't know why.
You don't know why.
There was no reason-
You don't know why.
No reason to feel hope at that moment, honestly.
Yeah.
So it was just a light without reason.
Yeah, that's right.
What wisdom do you draw from that time about-
So first of all, you said something funny, which is I wonder if it-
That it's somehow not having thoughts of suicide limits your capacity to truly understand somebody
who is having those thoughts.
So how many demons must the psychiatrist have in order to be a good psychiatrist?
This is a really interesting question.
I think everybody knows, and I can say this, that psychiatrists can be a little unusual.
We think about ourselves, right?
We think about our brains.
That may be one reason why we become psychiatrists is we think, oh, that's interesting going
on in there.
What's that about?
So a little introspective, a little introverted, maybe.
And that's what can make us good when we're good.
But also that may select for people who have some unusual aspects.
But you don't have to have all of them.
There's a lot that can go wrong in the psychiatric realm.
I think having some of those, some of it, but not all of it, is enough.
You get to see how low things can get, you get empathy from that, even if the symptoms
are not the same.
Just empathy for struggle, for suffering.
That's right.
That's right.
Do you yourself have to practice observing triggers just as a human operating in this
world?
I've definitely, those skills that have come from therapy, I've found them useful.
If I noticed that, we've all been through experiences where we wonder, oh, I got really
mad in that interaction.
Why did I get that mad?
Yeah, sure, maybe I could have been irritated, but man, why did I?
And then thinking about it and realizing, OK, back up here, think about the broader context.
Think about how that relates to prior events in my life.
OK, yeah, so this is a thing for me when something of this class happens, then it triggers me.
So going forward, I'm going to be aware of that.
And I've definitely used that because you don't want to be out of control of those emotions.
You want to identify them, you want to know where they come from, and you want to head
them off as a civilized human being living on this earth, trying to get along with other
people.
You want to understand those moments.
Give me a return to Robin Williams for a second and looking at Robin Williams, the actor, sorry,
the human, because you mentioned, for depression, you can have everything going well.
And I think there's just famous cases of just public figures because a lot of people know
them where they suffer quietly, and it seems like from the outside perspective that they
have everything going for them, that they're atop of their career.
Two people that come to mind are Robin Williams and Anthony Bourdain.
What insight do you have in why either of those have taken, why Robin Williams, a comedian,
kind of sort of the most jolly humans, obviously there's always the darkness that he was channeling
in order to present the happiness, but it feels like that that realness is only possible
when you're deeply self-honest and analytical, and then if you're deeply self-honest, you're
going to realize that there's a lot of beautiful things about life that you can discover.
And if you do that, how can you possibly then take your own life?
I mean, you go through all of these thoughts, and I think a lot of people really loved Robin
Williams, which is why it was really difficult to see how can even him, how can even Robin
Williams take his own life?
So I don't know if there's something to be said about the nature of depression from
just looking at his case.
I think the action of suicide is not well understood.
It doesn't always, although often is correlated with depression, there are cases of suicide
where there is not clear depression, that's in the minority.
By the way, if I just, because you said it's so interesting, action of suicide, because
there's also thoughts of suicide, and probably those, they're probably somewhat understood,
but it's an interesting, because you can think of suicide, if you have suicidal ideation,
you can think of that for so many reasons.
And the thoughts sometimes, like painful thoughts, angry thoughts, or thoughts in general can
be very different, like fantasies, for example, you can fantasize, like sexual fantasies, you
can fantasize, I was just for humor's sake, wanted to mention stuff, but then people think
I'm serious, I'm not going to mention anything.
But sexual fantasies, and then there's, I know there's people that have sexual fantasies
and they don't want to actually do that in real life, that sexual fantasies serve some
kind of purpose in imagination only.
In that same way, suicide might serve a purpose in imagination, only is very unlikely to lead
to action.
And yet there's other thoughts that maybe are more amorphous that do lead to action.
And that leap, yeah, oh boy, that's a facet, and that's such a philosophically powerful
thought to not exist.
Like that question, that's this, is it Sartre, or Camus, Camus, or the mythosophist Camus,
who says like basic question of why live, good question.
Yeah, right.
So that's a great question, actually.
And there are other related questions.
Some people may have the thought of suicide because there seems no point, there's no joy
in life, that's one reason that some people can put forward.
Sometimes it's not just the absence of joy, there's an active pain, an active psychic
pain in some people.
And that, the inescapability of that is enough to drive the thoughts of suicide.
And then there are interpersonal and cultural reasons as well that can show up.
But the act, this act of ending of the self is in all these cases, there's no real way
to study this in animals, no other animal as far as we know that we can study has this
concept of this is myself, the situation is not tolerable, therefore I will end the self.
To our knowledge, this is not something that can be studied in another animal.
So it remains this very poorly understood action.
And in predicting it, so what do we do as psychiatrists, we have this challenge, people
come to the emergency room, they say they're suicidal or their friends say they're suicidal
or they've taken some action that didn't lead to death.
What do we do?
Well, there's a whole range of options, was it a suicidal gesture in the sense of not
intending death, or was it was the intent death?
And if it was the intent was death, what were the reasons are the reasons transient?
Are they gone now?
What's the probability that it'll be repeated?
So we do all these things just to decide what sort of treatment should be carried out.
But nowhere is there a deep understanding of the biology of the cells and circuits and
activity patterns that underlie the action to end the self.
It's a very, it's this frustrating thing.
It's so timely, it's so common, it shows up in veterans, it shows up in kids, it shows
up in people at every stage of life.
And yet we're very bad at understanding it and we're relatively poor at predicting it
and our tools are not very powerful.
We can put people in a locked unit, we can give them care or therapy for a while.
At some point, we release them and there's only so much we can do.
It's one of the most frustrating things about the suffering that is linked to suicidality.
But it is a decision and it is an action.
And if you look at optogenetics, you should be able to one day sort of understand the
dynamics of such weighty decisions.
The individual causes then, if someone is anhedonic, if there is no joy in life, that
very likely is addressable by optogenetics.
We know how to turn that dial very robustly in animals.
The motivation to overcome challenges, that we have some hope of understanding.
Psychic pain, internal negative states, we have actually a handle on that as well.
There's a structure in the brain called the habenula and some linked structures around
it that seems to generate this negative internal state.
It's active when a state of acute disappointment, acute outcomes that go wrong, not as expected.
Moments of unexpected pain.
Habenula is there, it seems, it's active to report on internal negativity with its action.
And so you could imagine strategies to target this brain structure that might have the effect
of reducing psychic pain, reducing the negativity of internal states.
That is a very concrete hope.
It's precise, it's anatomical.
Optogenetics has given us all the firm foundation we need to go after that question.
So I think there is hope.
If you look at the individual causes, the individual symptoms relating to suicide, and then it's
like a puzzle, you put together the puzzle pieces.
By the way, I do think my habenula is very functioning very actively.
And I wonder if it's like, because you can also learn to channel these things, right?
Some of the things we suffer from, I mean, there's degrees of suffering, can be a source
of progress and personal growth and development and all those kinds of things.
I mean, what is it, Nietzsche suffered from stomach issues?
I wonder if he's written some of those things, if his stomach was all great.
I kind of think that a difficult life in some form, you get to choose in some regard and
some you don't, the difficulties you have and the ones you do have, it's nice to use
if possible.
It's sometimes it's nice to treat, sometimes it's nice to use.
Well, the way you phrase it, I think you're using it.
I could be wrong, but if you phrase it in this semi-humorous way about your habenula,
it seems to me that you're using that to good effect now.
But one never really knows what someone else's internal state is.
As I look at you, I don't know the depths of what's going on.
And it's possible that it's a much harder situation in there.
Yes.
So I actually worry about this a lot.
So I'm extremely self-critical in the privacy of my own mind, which is an interesting thing
when you get to meet the internet and the internet will tell you, you suck.
But for now, this is what I worry about and I'm very paying attention.
For now, I just have this very negative voice, but that voice seems to be very useful for
productivity.
And so I channel it.
I just put it on the table and let that voice talk to me.
But I'm monitoring that voice because looking at Robin Williams, you get older, your brain
changes and then that voice can now all of a sudden grow.
And then where you can't control is my shift, you're very careful with these kinds of things.
You're very right about that.
So my negativity, I never think I've done enough is sort of where my negativity comes
from inside.
I never think that I've met the potential of the moment.
I haven't made the most of the opportunities that are available.
Real early, I haven't progressed as far as I should.
And exactly as you're saying, that works for a while.
But then what happens as you get later in life and there's less runway to fix that.
And then maybe then that negative voice is a problem.
But also at that point, the negative voice starts having more and more of a point.
When you're being very successful, it's easy to be like, no, okay, well, later in life,
you're really literally just sitting there on a rocking chair doing nothing.
Or maybe any kind of tragedy happens, loss of a loved one, loss of a job, loss, or you
get screwed over in some kind of way, I don't know.
And then all of a sudden the negative voice is just you in the negative voice for days
and days and days.
And so I don't know, to go back to your example of Robin Williams, I don't know what was going
on inside him.
I don't know the nature of his internal state.
Was it active psychic pain that...
May I mention, may I interrupt to just say that Sergei posted an examination of Robin
Williams' brain tissue suggested that he suffered from, quote, diffuse L-E-W-Y, lewey body dementia,
L-B-D.
A depression is a symptom of L-B-D, and it's not about psychology, it's rooted in urology.
This is words from Sergei.
His brain was falling apart.
Yeah.
L-E-W-Y body dementia, this is a very interesting neurological disorder where, among other things,
there's neuron death indeed.
So you've got Frank, neuron loss, it's not just a matter of some longstanding psychic
pain, but you've got a progressive loss.
And so clearly, you've got a situation where he could have finally reached a point where
the balance that he'd worked out between negativity and positivity was disrupted due to loss,
the wrong cells died, the wrong projections were cut by the lewey body dementia, certainly
dopamine neurons die in lewey body dementia.
Those are neurons that give rise to much of the feelings of reward and pleasure that
we experience, among other roles.
So clearly, in his case, there could have been a very concrete cellular neurological
issue that was progressive and pushed him to that point.
But were you about to make a point about broader that if there isn't enough in your
logical degeneration?
Yeah.
So in his case, not knowing that, it could have been simply that, let's say he had an
internal psychic pain state, and he was in sort of a compensated mode for much of his
life, able to generate enough joy from his comedy and his social interactions.
And then, but eventually later in life, those things drop away, the balance shifts, you
get tired of fighting the pain for that long.
And then, so you've got this time dependent non-stationarity that happens, and then the
same symptom becomes no longer tolerable in the end.
What is autism?
What do we know about autism?
Human beings exist on a spectrum of how social we can be.
And this is pretty interesting, actually, scientifically, but also very important clinically.
There are hyper-social states where people are almost too social, there are chromosomal
deletion states where people have instant affinity and bonding and rich, deep, seeming
connections with people, very verbal.
On the other end, people with autism spectrum disorder are not able to keep up with social
interactions, and it's a spectrum.
Some have mild to moderate difficulties, they may have inability to understand what the next
thing to do in a social situation is, but may have perfectly good language abilities.
And then as you progress further along the spectrum, that gets more and more severe,
so they can't make eye contact because it's too overwhelming to think about what has to
be done next if a person looks in a particular way.
And then as you go farther, then language and social communication themselves break down,
so there's no reciprocity, there's no shared enjoyment, and that this gets very hard then
as you get to this far end of the spectrum where there's really an absence of social
cognition at all and social bonding.
So why does this exist?
What is it?
It's very genetic.
As I mentioned, it's one of the top three or four most biological in a sense of most
genetically determined of the psychiatric illnesses.
It does have these interesting positive correlations, slight positive correlations with intelligence
and education.
And the reason for that is kind of interesting to think about.
Is there something good about it just like or at least with at least part of the spectrum
is there's something good about it just as we were talking about for depression, as you
could say for mania, as you could say for schizophrenia.
And here it's kind of interesting to think about the underlying science of what it means
to be good at a social interaction.
Someone who's very good at a social interaction is incredibly good at dealing with unpredictable
information, is able to handle this torrent of information coming through rapidly changing
model of the other person and of the interaction and their model of you, your model of them
with each word that changes with each new bit of information that comes in through the conversation,
each bit of body language.
All this is rapidly changing and some people are able to keep up with that fire hose information
perfectly well.
But that's a special brain state to be in.
That's working with unpredictability.
The only way that can be done is most likely by constantly running models of what the other
person might be about to say.
So you can't stop and think, oh, what did that word mean?
What did that shift in eye contact mean?
What did they mean together?
There has to be some advanced work going on where you're predicting what's going on if
you're to keep up with a rich and fast social interaction.
Now on the flip side, there are brain states that maybe don't have to work so fast that
are extremely important still.
Dealing with something that's not moving or that's predictable, still complex like mathematical
proof or a very complex arrangement of geometrical shapes, a large number of individual non-moving
things, there's possibly a way of being that's particularly good at dealing with these static
unmoving or predictable situations and less so with these rapidly changing social situations.
And so the way I conceptualize autism is these are people whose brains are not so good with
the high bit rate, unpredictable information, but maybe quite good at given enough time,
given the grace to work with the system to look at it from different angles, to take
different perspectives with a confidence that it's not changing in between perspectives.
That's a brain state that's valuable.
It's something that has contributed to a lot of the success of the human family, being
able to design something, being able to consider all the different contributions to a static
predictable system.
So autism in a sense is a spectrum that has identifiable characteristics about the way
people deal with dynamic information often expressed itself as like social dynamic information.
But you critically, your use of the word often there is really, I think, smart because it's
not just social interaction that is a challenge in autism.
And so many people conceptualize it purely as a social dysfunction disorder.
But it's really any unpredictable information that's a problem, that's a challenge for people
on the spectrum.
They react very negatively to unexpected sounds, even if not social sounds, unexpected
lights, unexpected touches.
And so it's really unpredictable information that is, in my view, the core problem with
the processing in autism, not just social.
Social just shows up because it's so unpredictable.
Yeah, it's so interesting.
I mean, I tried to not to think about that stuff.
I'm afraid of thinking about the sorters and things like that because just like I don't
like economics or game theory, I wouldn't be careful with it because whenever you have
a category or a model, it's too easy to just, for everything, I mean, it's the OCD thing.
I like models too much.
I like categories too much.
The moment you acknowledge yourself, well, I have an eating disorder, for example, or
something like that, as opposed to just being a, well, I'll just leave it at that for my
own critical understanding of myself.
Let's just say I don't know how to moderate eating fruit.
People make fun of me.
They think all fruit is healthy.
I'd know.
Well, I don't know how to moderate anything, but even fruit, this apples and cherries is
a nightmare.
Interesting.
Anyway, that's such a psychiatrist thing to say.
Very interesting.
But there's characteristics, and it's interesting to think about, for example, I have trouble
making eye contact, but actually, as you said it now, it's not that I'm shy at all in that
sense.
It's literally, I'm getting way too much information, it's distracting me.
I need to just close my eyes so I can, like all the things that people seem to be able
to do in parallel, it's just, you just asked me a question.
For me to think about the answer to that question, I can't have all this cool, rich, visual
information coming my way.
That's literally, because I often close my eyes to think.
It's not because I'm afraid of something, whatever, it's just like too much information
happening here.
Well, that's a beautiful description.
It's amazing that that is how you experience the eye contact aspect.
I think that's, I mean, you've articulated what captures it for so many people, which
is that it's overwhelming.
There's just too much information just coming in through the eyes, and to keep up with it,
to know you're going to be expected to keep up with it, first of all, so there's that
aspect.
You know, you learned socially that there's going to be an expectation if you're making
eye contact, people are going to think you're keeping up with it and you don't want to because
you want to focus on other things and make progress in other dimensions.
Yeah.
And so then there's a strong desire to look away or to close the eyes because it's overwhelming,
it's a distraction, and it's going to cause errors of understanding.
And of course, our eyes, that's part, the way we use our eyes as part of the human
communication, so you have to kind of be aware of that element of it.
So yeah, I mean, but it's fascinating.
You should be aware of your own self and those little characteristics, whether it's classified
on some aspect of the autism spectrum or just in general, whether it's eating, whether
it's depression, whether it's even like schizophrenia that would, I hope we get a chance to talk
to a little bit.
Yeah, but those things are all made up of different symptoms and characteristics.
And use them as a superpower, I suppose, is the best we can hope for in mild cases, I
guess.
I do think both brain states can't coexist at the same time.
The way of dealing with something unpredictable and dealing with something predictable, those
are different ways of being, here's a huge opportunity for very creative model building
in theoretical neuroscience and linking that to these data streams we're getting across
the brain that we talked about earlier, these immense data sets of activity across the brain.
Here's where I think there could be a real convergence of theoreticians and experimentalists
to say, okay, given what we know about wiring of the brain, here is what the brain state
is likely to be that deals well with unpredictable information.
Here's the brain state that deals with predictable information.
Here's why they're incompatible at least at the same time.
Here's why you've got to be able to detect which state you should be in.
Here's how you could switch between them.
Here's the kind of cells that you would predict almost like predicting the Higgs boson.
Here's the kind of circuitry that I would predict should govern the switching or might
make one state too sticky, too hard to get out of.
That is a huge opportunity for an interaction from the theoretical and experimental side
together.
Make one state too sticky, sort of measure the stickiness of the state and how to lessen
the stickiness.
That's right.
Get some oil in the machine.
Yes.
What would predict the kind of oil that would work well?
What in your practice is treatment or advice for people on the autism spectrum?
Right now, there's no real medical treatment.
There are behavioral treatments that are most effective early in life.
They make sure people don't fall too far behind.
If you're not interacting socially, you create this vicious cycle where you fall farther
and farther behind because you're not interacting.
These therapies which are applied early in life, therapists work with the kids, train
them to deal with these things that otherwise would be aversive to them, teach them how
to predict things and interact.
That has a big effect, but it's behavioral therapy.
There's no medicine that works.
There are ways of reducing individual symptoms though that sometimes come along with autism
and those do respond to medications.
One thing, very often, my patients with autism are very anxious because they live in a world
that they have a really hard time predicting what's going to happen.
Some of these are high-functioning Silicon Valley types who they may make great livings,
but they're very unhappy because they're on the spectrum.
They don't understand how social interactions really work.
They're very anxiety-provoking because they don't know what to say.
They don't have any clue how anybody else knows what to say.
They're constantly worried they're going to say something that's completely inappropriate
and so they're very anxious.
I can treat their anxiety.
It doesn't touch the autism per se, but I can help them with their anxiety.
What I just talked about eye contact, I am rich that even with the eyes closed and all
those kinds of things, I'm richly experiencing the world.
It's not like you're afraid of the world or you're not able.
I don't know what to do.
No, I know everything.
In fact, I know way too much.
There's so many cool options.
Like at any one moment, there's all the stuff happening and it's all beautiful and in any
one moment, you can do anything you want.
You can take off your clothes.
You can punch that guy over there.
You can run away.
You can go in for a hug.
You can say something profound and deep or you can say something generic or you could
use so many things you can say.
And then it'll unravel in all these kinds of ways and this moment could be completely
life changing or it can be mundane and meaningless and all of those options are before you at
any one moment.
Isn't that amazing?
It's amazing and overwhelming if you allow yourself to think about it, which whatever
exactly.
Like, unfortunately with chess, you have a few set options, two-dimensional constraints.
There is unlimited possibilities and unlimited beautiful things happening all around you.
So I don't think there's a kind of sense that somehow you're limited in the places of,
in the way you can see the world and how you can interact with that world.
I am overwhelmed by the lack of limit that all of us should be, have you looked around?
You can do whatever the hell you want.
If you will remember you anyway, all of us will be dead one day.
You could do anything.
You can, I don't know, you can get naked and run around the city as long as you're not
hurting anybody and it doesn't matter.
Austin, I mean.
Austin.
Exactly.
Seems like a to-do item for anybody living in Austin for sure.
But the spectrum is an interesting concept because that is, when I say, when I refer
to the spectrum, I'm actually referring to, it's a precise clinical term, but you're
right, it's been co-opted more broadly and it is widely used and it can be an unfair
categorization of someone who's socially and occupationally very healthy.
And that is critical because we don't define a disorder unless there's social or occupational
dysfunction.
It doesn't matter what the symptoms are.
I've had patients who are pleasantly hallucinating, so frankly, psychotic, but doesn't affect
their lives.
So I don't give that person as diagnosis because there's not social or occupational
dysfunction.
Same with anything on this, any of the diverse symptoms of autism spectrum disorder.
If someone has them, but they're successful socially and occupationally, we don't say
that there's a disorder, but then you're right that the concept of the spectrum does
become a useful pigeon-holing device, which is maybe not the best thing.
Yeah, and eye contact is interesting one, is interesting one.
I'm torn on it.
I'm torn about the usefulness of eye contact because people kind of make fun of it, but
let me just say one thing about eye contact and about life in general.
It's okay to be weird, but some people, when you have your eyes closed and there's that
weird, what is happening to this creature?
You see a weird creature on the side of the road.
It's interesting.
Yeah.
I mean, the weird stuff, I'm going to go back to Robin Williams, that's the good stuff.
He has that whole speech about him and his wife and what he loves, all the little peculiarities,
all the weird stuff, and let those flourish, let those celebrate those in yourself.
Not in some kind of woke way, but in some very human way.
This is what makes us, this is the weirdness.
I'm 100% on board with that.
I don't think people who are happy and who have people in their lives who are happy with
them, these are, I think, let the weirdness flourish.
Let all the different ways, members of the human family can be different.
Let's see them all.
That's one of the joys of being alive, is seeing all the ways we can be human.
I think about it all the time, why do we have all these ways of being human?
Even within one individual, you go through phases of life where you express different
sides of your way of being, which is also a pretty fun opportunity.
You can go through phases where you're in one mode and phases when you're in another mode,
and let that flourish too.
Let the ways that you can be you vary as well.
I think that's important for people to explore.
Because if you can address the internet, but I would like to ask the internet to celebrate
the weirdness of people.
The Robin Williams, people call these imperfections, but they're not.
That's the good stuff.
For any one individual person, find the weird stuff and celebrate it, as opposed to what
the internet often does, which is find the weird stuff and criticize it.
Because when you criticize the weird stuff, you're creating conformity, which is another
human thing, but that conformity creates a boring world.
You want the weird.
You want the crazy.
That's what fun is made of.
That's the foundation of humor and all of the ways in which we deal with the suffering
in the world, with the injustices in the world, is this huge variety of weird.
I don't know.
That's what, at the depth of psychiatry, you want to acknowledge the weird, celebrate
the weird, step around it to find the particular aspects of weird that are debilitating, like
you said.
They're somehow negatively affecting your ability to function in the world, as opposed
to trying to shut it all down.
That's right.
Well, on that topic, I'd love to talk to you about schizophrenia.
What is schizophrenia?
From your research and from your general understanding, and what is the full landscape
of suffering and wisdom that schizophrenia explores?
Schizophrenia is a state where there is a break from reality, and so this can show up
as we call them the positive symptoms of schizophrenia.
These include hallucinations, hearing something or seeing something that's not there, usually
auditory hallucinations, paranoia.
People can have complex fears, delusions, which we call fixed false beliefs.
People get an extremely unshakable but completely implausible idea about something, sometimes
relates to themselves, sometimes to the world.
These we call the positive symptoms, break from reality as we know it.
Then there are the negative symptoms that come with it, and these are progressive.
These are flattening of emotion as we call it, so starting to express less and less.
Positive emotion ending more in a neutral or flat state.
Thought disorder, inability to work with complex patterns of planning or thinking, so you can't
make plans.
You'd have poor working memory.
You can't keep track of where you were in a conversation, in a sequence of actions.
Poor and impaired working with the thoughts of oneself and then these positive symptoms
of break from reality.
Okay.
Now, why do these come together?
What's the neurobiology of it?
Again, we don't know.
Schizophrenia, extremely genetically determined.
If you look at the numbers, it could be upwards of 80%, genetically determined.
1% of the human population around the world, it's universal.
It's not confined to any one culture, not even really biased in one culture or another,
about 1% around the world.
Has this progressive quality to it untreated?
It's very interesting.
There's a break that happens.
We call it first break when someone experiences their first disruption of reality.
They can have a completely typical life up until that point.
You might have a, and I've seen just heartbreaking cases of like this in the Stanford emergency
room where a kid who's come there has been extremely high functioning in that sense of
academic achievement and athletic and interpersonal and then comes to college.
Usually in men, it's around 18, 19 when the first break happens.
Some terrifying paranoia hits or some auditory hallucinations start.
They're getting screamed at by a voice in their head.
So devastating.
With women, comes on also often a little later, sometimes in the 20s, and it can be progressive.
If it's not treated, it just progresses and progresses.
The voices become overwhelming, the delusions and paranoia extend and expand.
And negative symptoms particularly become more and more severe.
So one can't even maintain thoughts in any sort of ordered fashion.
And then eventually, it can be fatal, can lead to suicide, it can lead to erratic behavior
that leads to accidents.
Now, it can be treated.
There are medications that help, fortunately.
They have side effects, so they're not perfect.
They can have movement problems and actually a whole host of different side effects that
come from the medications.
But we can help people now with schizophrenia very, very significantly.
But the amazing thing, and this is emblematic of where psychiatry stands, we don't have
the deep understanding just like with depression.
We don't have that heart as a pump level of understanding that we'd like to have with
schizophrenia despite it being so biological, so genetic in its nature.
So is there a way to return to the other side of the first break?
So when you have a break with reality, is there a way to kind of stitch it together?
So some people, that works, but we don't really know how.
So medications, anti-psychotic medications we call them, they block a particular neurotransmitter
receptor called the serotonin 2A receptor.
And they modulate dopamine as well and other neurotransmitters.
These can take someone who's actively hallucinating, actively paranoid, put them back in a completely
normal state, and some people stay that way indefinitely.
So you can bring people back from that back to the other side, have it stitched together.
More typically, you'll end up in some intermediate state where there's symptoms are reduced powerfully,
but there might be still something there and you've got a drop down and functioning that
may be persistent for a while.
But concepts, what physically is going on?
One idea is that it's communication within the brain.
One part of the brain is not able to tell other parts of the brain what it's doing.
And so the auditory hallucinations are very interesting in this regard.
They often have this conversational inner monologue-like quality.
As we're walking along the street, we may have an inner monologue thoughts about what's
going on.
If we see somebody we don't like, we may have a thought where somebody would punch that
guy, something like that, or maybe I should punch that guy.
But these are so far below where we would ever act or even think of acting, but they're
just things that come up and in people with schizophrenia, those inner thoughts, that
inner monologue is not recognized as the inner monologue of the self.
And so it's perceived as something coming from the outside or from inside, but from
another entity.
Oh, another entity.
I thought you meant like another room inside the same building.
Another room inside there, yeah.
And so it could be conceptualized as a communication within the brain problem, notifying another
part of the brain what's going on.
And there's some evidence consistent with that.
I don't know if you can help with this, but sometimes I've been talking to quite a few
homeless folks recently.
Just what I do is I hang out at night and talk to interesting people.
And some of them, and I've known people in the past who suffer from schizophrenia and
some of them like self will describe as that as something they suffer from.
And they seem to understand something deeply about this world.
I don't know if it's correlated or maybe it's another aspect of like depression, all those
things that I've encountered in my own life is maybe just the struggle and the suffering
has taken you through a life where you think deeply about life.
There's self reflection that society forces on you because it's a disorder of some kind.
It's interesting, I guess my only sort of anecdotal observation is people who suffer
from schizophrenia seem to be very interesting and very thoughtful in the non-linear way
about the world.
I've noticed that it's not always positive, the unusual ways they view the world, but
it's always interesting.
It could be conspiratorial thinking too, but the theories they have about the way the
world functions, often very well read, which is also interesting because they're almost
like looking for helpful answers from somewhere.
And so there might be citing some very interesting literature and then using that there's a stickiness
in their mind to different models of the world and trying to make sense of that world.
And those models could include conspiracy theories.
They're very attuned to complexity and they come up with unlikely explanations, which
is one of the things that makes it hard for them to function in the world is how unlikely
their explanations are.
But you're right, there's a depth of consideration of the complexity of the world and a concern
about it and an impulse to work to understand it that is actually quite refreshing.
But the first case in the medical literature, there was a classical schizophrenia.
There was a patient named James Tilly Matthews who had this, he sketched out for his doctor
the experiences he was sensing and he drew himself as a cowering figure on the ground
controlled by a loom, a weaving device that was sending threads, long threads, projections
across space from the loom to him, to his arms and to his body and controlling him from
afar.
And he called us the air loom, a loom in the air.
And it was such an evocative thing because this was the start of the Industrial Revolution
or mid and it was where really industrial strength looms and weaving devices were really
kind of the emblematic of the most complex, powerful technological achievements of the
time.
And so that was the explanation available to him to explain how his body was seemingly
moved without his volition.
And these days, of course, people with schizophrenia will have more technology-appropriate interpretations.
They'll have delusions of satellite or alien control or beamed information very, very common
to have this delusion of a government agency sending electromagnetic or radio frequency
information to control their limbs.
But it's the same thing, whether it's a thread from an Industrial Revolution loom or RF radiation.
It's the same thing just adapted to the moment explaining, trying to explain the world they
live in and their relationship to the world.
But unconstrained by sort of the thing that's socially acceptable, which is both refreshing
and dangerous.
I wrote down a question, why do we cry?
Are tears a window to some depths that we ourselves don't know?
I almost want to make fun of myself for that question, but you do talk seriously about
crying in the book.
In fact, the whole first chapter really tussles with crying as why do we do it?
What does it mean?
Why is it involuntary?
It seems like a weakness because it's so involuntary and it's reflecting something true and inside
at the level of the individual, that seems like a problem.
Wouldn't it be better if we could control it, if we could not show that emotion when it's
not useful, show it when it's useful, but it's largely involuntary.
There's a value to it, I think, as an honest reporter of a need, of hope and frailty at
the same time.
I'm a human being.
There's a frailty to myself or my situation where I need social help, I need help from
my community.
I have hope that that is possible, but I'm not enough for myself, I need the community.
That I think is what the social signal of crying is.
People have studied crying, it's an extreme, you can quantify the extent to which the presence
of tears on a face triggers reactions and onlookers.
You can show the same face in the presence or absence of tears and show that to people
under quantifiable and rigorous psychological conditions and tears are much more powerful
at stirring the desire to help in viewers than any other facial feature, which is pretty
interesting that it's the honest one that's also the most powerful.
It kind of indicates there's a certain logic to our design as social beings that we have
an honest report.
That's hard to control on, but is it well understood how that connects to the internal
state of emotion?
There are long range projections that come, so where is crying generated?
This is the confusing thing about it, so that we have a little tear dock to the lacrimal
gland that leads the release of fluid, it ejects fluid and it comes out in those, of
course.
That whole system was designed to keep the eye clean, to wash out particulate irritants,
so it's a long standing, as long as we've had eyes and have been out of the water in
our evolution, we've needed this sort of thing, so long standing biological structure recently
co-opted, it seems, by our evolution as social primates.
Now, how could that happen?
Well, the lacrimal gland is controlled by structures in the ponds, which is a structure
deep in our, just above our neck, between our neck and our head, and reflecting its
ancient origin, as you go farther down toward the spinal cord.
These are the more basic, early evolved structures, and in the ponds, that's where breathing
is controlled, tear, duct contraction.
What we found, and with Optogenetics, we helped sort this out, there are long range projections
from fear and anxiety regions in the forebrain that project all the way to the ponds in and
around those areas.
The reason those are there, we think, is to regulate the respiratory rate changes, the
breathing changes of fear and anxiety.
We know when we're in a state of fear and anxiety, we need, we cope better if we have
elevated heart rate, elevated respiratory rate, more blood pumping around, more oxygenated
blood, we're ready to meet the threat if it happens.
All those cells are down there in the ponds too, right next to the lacrimal duct, the
tear gland neurons.
And so, almost certainly, this fear, anxiety induced crying arose from a very slightly misdirected
long range projection that was there to regulate breathing, and a little twist, just a little
misdirection, a little missing of one signpost to stop here going on a little farther, getting
to the lacrimal gland neurons gave us crying.
And that's, and we just have it, that peculiar sort of structure, neuronal structure that
resulted in that, that's what we're stuck with, and then ends up being, in terms of
social interaction, one of the more important authentic involuntary displays of interstate.
That's right.
So communication.
Oh, yeah, is there other stuff like that?
I mean, do you, yeah, I mean, the human face is fascinating as a display of emotion, as
a display of truth and lying and all those kinds of things.
I personally, I mean, we're all, I suppose, have different sensors that are sensitive to
certain aspects of the human face.
But to me, it seems like the eyes are really important communication or something.
I've talked to a few sort of girls about botox and stuff like that, and it always bothers
me when, I guess guys can do this too, but when women speak negatively of, I guess you
can call them wrinkles at the tips of an eye, but to me, when you smile, when you not wink,
but like narrow the eyes to, something is communicated, and those, that stuff is really
useful, the human face, and when it's gone, that something is missing.
And a lot of little stuff, it feels like it can really, it's almost involuntary, I guess,
but it's harder to describe as the presence or absence of tears.
It's like something about this person, you can tell they're not bullshitting you.
And so that was what made, presumably, that tear recruitment so powerful, is it just
landed in this very high value real estate for social communication.
If it had gone to, there's a lot of neurons in the ponds that control movement of large
muscles elsewhere, that would have been much less effective as a social signal than something
around the eye.
So it was, however, that little misdirection happened, it landed in a great area for social
communication.
And because it was coming from the fear and anxiety circuits that regulate that necessary
involuntary change in heart rate and respiratory rate, it also was involuntary, and that became
valuable as a truth signal as social beings.
So very interesting when you think about the origins of the human family, the origins of
social structures and our ability and need to call for help when there's hope, but need
at the same time.
What is consciousness?
So you're actually using techniques, I mean, even putting psychiatry aside, just looking
at optogenetics, you're trying to understand some of these deep aspects of the human mind.
And maybe this is a good time to return to a question you mentioned you might have an
opinion on if there are such a thing as a theory of everything for the human mind.
Just surely answering of what is consciousness is as, well, that's not sure, but it seems
like it's a fundamental part of the human experience in the human mind and solving that
question will result in solving the bigger thing about the human mind.
The flip side could be consciousness is just the few neurons that are generating some useful
thing, it's like the sense of self that you talked about in the mice, maybe it's a subset
of those cells that are just creating a richer sense of self and that's it.
So this is a great question.
All neuroscientists think about this and a lot of non neuroscientists too, it's the reason
a lot of people came to the study of the brain is to think about consciousness and not just
being awake or alert, but really what's sometimes called the hard problem of consciousness which
is what is that nature of that inner subjective sense we have, not just information processing
but feeling something about the information, what is that inner state of subjectivity physically,
what is it?
And that's called the hard problem of consciousness.
And it's not an extremely well-defined question, everybody has sort of a sense of what it means,
but it's such a hard problem because you run into paradoxes quite quickly the more you
think about it and that is exciting also because it makes us think, actually there's some fundamental,
there's a big thing that we're missing.
The brain is not just a collection of little tricks, there is a big, big concept.
So that's your sense because a flipside could be with optogenetics, there's an engineering
question, can you turn consciousness on and off like a light switch?
So here's where exactly consciousness frames the problem extremely well and it frames it
the following way.
So I told you earlier that we can stimulate 20 or 25 cells in the visual cortex of a mouse
and we can make it behave and we can make its brain act as if it's seeing something that
isn't there.
We have that level of control now.
We can pick out 25 neurons, play in activity and both behavior and in the brain, it's as
if it's seeing something specific.
Okay, now let's do a thought experiment, a gandhakan experiment and let's play this out.
Let's say we could do the same thing for every single neuron in the brain of a human being.
Let's say we had total control and I could do something like I could show you a rich
deep color red and you could look at it and you would be aware that it's red but also
you might have some feelings about it, something would be stirred in you, some subjective sense
as you looked at that rich color red.
And then I would take away the visual stimulus and in this thought experiment I would, using
some hyperoptogenetics, I would play in exactly the same pattern of activity in every cell
in your brain for as long as it was needed, whatever, 15 seconds, something like that,
that exactly matched what was going on when you were feeling that inner subjective sense.
Okay, so in that thought experiment, a question for you is, would you be feeling that same
inner subjective sense?
Stimulus is gone, every neuron is doing the same thing because I'm controlling it.
There's a philosophical question there.
If you ask me specifically, I would say yes.
Okay.
Most people would say that because it's hard to say no, right?
It's very hard to say no.
If every cell in your brain is doing what it was doing, what else could be different?
How could...
Well, most normal people would say yes.
Of course, philosophers would then start saying no.
They're the ones that say, I'm sort of parallel and sorry if it's a bit of an interruption
but if there's a robot that's conscious in front of you, if it appears conscious, then
it's conscious.
Like to me, of course, philosophers again speak up and say, well, no, how do you know
it's conscious?
Well, how do you know anything is conscious and sort of as normal humans, we tend to
lean on the experience versus some kind of philosophical concept.
So the great thing about what you just said, the Turing test is it's very practical if
it acts conscious, it is conscious.
But I think that's limiting.
I like the thought experiment.
I think it's actually more informative and so I'm halfway to the conclusion there.
But let's take it as your answer was yes, that you would be feeling the same thing.
Okay.
Now, here's where it gets fun.
Now that every cell in your brain knows what it has to do in the sense that we know it
and we're providing it, your brain cells don't need to be in your head anymore at all.
The only reason they're next to each other, the only reason they're wired together is
to affect each other, to stimulate or inhibit each other.
But we don't need that anymore because optogenetically, we're providing that activity pattern for
as long as needed.
We're providing the effect of the communication.
They don't need to be connected anymore.
They don't even need to be in your head.
I could spread your neurons all over the continent, all over the galaxy and I could still provide
the same stimulus pattern over 10 or 15 seconds to all those neurons and somewhere Lex Friedman
would have to be, even though no longer existing as a physical object anymore, would be feeling
that subjective feeling.
And it's inescapable because it's exactly the same as the previous situation.
All the neurons have to be spatially, like the locality constraint, they have to be spatially
close to each other.
And you talk about light, opto, which is funny because light is the fastest traveling thing
that we know of.
Maybe let's not put them all over the universe because we might get relativistic problems
then.
Let's just keep them out.
Let's keep all your neurons.
Let's keep them out over North America and let's play them out.
Same pattern of activity.
It seems absurd.
There's no way that could be true.
There's no way that Lex would be feeling that internal sense if his neurons were spread
all over North America.
And yet it's exactly the same as the previous situation where you said, sure.
So we've got a paradox.
And this is what makes people think-
Is this a paradox though, sir?
Yeah, yeah.
Maybe paradox is the wrong word.
We've got a problem.
We've got a problem because it reveals that there's something big about that internal
subjective state that we're not explaining.
And we don't really have a hope of explaining in the near future.
But don't you think we would still have that?
It's just the word internal loses meaning, but don't you think we would still have that
internal subjective state?
If not, then where the heck is the magic coming from?
Okay.
What I just think, I think one of the problems that I think we need to let go of is we tend
to, outside of the experience of consciousness, the hard problem of consciousness, we tend
to think that we individual humans are really special.
Not the subjective experience, but the entirety of it, like the body that contains the things.
So the local, the constraint of all the stuff has to be together and it's all mine.
I don't know if that has anything to do with the mechanisms that are creating this.
So in fact, one really nice way to break through that is to either observe or create consciousness
that spans multiple organisms, sort of like, let's say it's not, it's not an organism dependent
phenomena that the phenomena can, that's just a peculiar way it has evolved on earth.
But it's a phenomena that doesn't have anything to do with a specific biological system.
All right, so and we have different parts of our brain exist and sometimes create complex
awarenesses of things that involve different neurons that are distributed widely and that
need to communicate with each other to form this joint representation, this state of consciousness.
But indeed, why do they have to be in the same head?
We don't know why that would be the case that they do.
And so that's a huge unanswered question in the field is, what is it that binds the activity
of neurons together so they can form a joint representation?
And actually this comes back to the dissociation experiment we talked about before where your
sense of self becomes separated from your body.
Those things that were fused in a joint representation, the same concept, unitary, are now separate.
And in late 2020, we published a paper in Nature showing how this could be, we used
optogenetics to drive this rhythm that ketamine and PCP cause in retrosplenial cortex and
we got different parts of the brain to be out of sync and when they were active, never
able to be active at the same time, never able to form a joint representation at the
same time.
And so we've got a toehold into these questions.
We don't have the answers, but-
And that mimics the dynamics of ketamine effects.
Exactly, exactly.
And you're able to find that kind of oscillation to, wow, wow, wow.
And so if you get even greater and greater control with more control over individual
neurons and understanding, like if you think of certain neurons that having some role to
play in the sense of self, you can play like an orchestra that to create the certain degrees
of consciousness, degrees of subjectivity and thereby understand what is consciousness
by having a very complicated light switch essentially.
And here's the challenge is the nice thing about the thought experiment is that it kind
of highlights that we're going to hit a point where we're addressing some very, very fundamental
questions.
What allows the activity of two sets of neurons to become mutually relevant to each other?
This is, in some ways, maybe one of the deepest remaining questions in neuroscience is what
allows activity patterns to become relevant to each other.
Do they have to be in sync temporarily?
Do they need to be...
Is there some other quality that we don't know about that also needs to be present to
allow cells to fuse together into a joint representation?
So I understand because it feels close to some very, very deep idea.
So there's a bunch of semi-distributed signals going on in the brain and you're saying there
could be something like a theory of everything if one to exist is to understand why how and
why signals close to each other start becoming relevant to each other as part of some very
much bigger signal that they're producing, how they coordinate essentially because it's
very distributed.
I mean, that's a kind of... within a distributed system, how is order achieved?
And this is a very specific kind of distributed system that is one of the most intelligent
that we're aware of in the known universe.
In that will maybe be something also an understanding of the full conscious experience too, that
this kind of coordination.
How does the coordination between different neurons that are responsible for sense of
self?
How do they begin to form a big picture that we see as a human experience?
That's really, really interesting.
So uniting the small and the...
That's actually literally theory of everything.
Uniting the small, the sort of the theory of the neuron, the functioning of the neuron
with the big, just the functioning of the entire mind.
That's right.
Keeping a toehold in both at the cellular level of resolution and the brain-wide resolution
will be critical.
If you lose touch with either, I think you'll miss the big insight.
So that's what we're trying to do, keeping our... keeping grounded in the cellular resolution,
trying to keep the broadest brain-wide perspective and meet in the middle.
Do you think you'll see it in your lifetime?
A major breakthrough in that dimension?
I have hope.
I have hope.
I'm... it's very hard to predict what will happen with big things like this.
If we don't get there, there'll be plenty of other exciting stuff, so it's okay.
But the other aspect of this whole thing is that your life is pretty short.
That's true.
So first of all, you can die any day.
I tend to try to think about that, that it ends... you can end at any moment because
it really, really can, and if not, it'll be soon anyway.
Do you think about that?
Do you think about your mortality?
I do.
Yeah.
It comes back to what we talked about earlier.
I never think I've done enough, and it's relevant to that, for sure.
There's a deadline.
Yeah.
Do you think there's ever going to be a feeling where you sit back and you're really proud
of yourself?
I hope so.
Like I've done enough.
I've done everything there is.
Because the thing is, a warrior has some number of battles in them, and at a certain point,
if you're deeply honest, it's like, well, that was a pretty good run.
As far as runs goes, that was pretty good.
You can hang up your helmet and then go sort of drink some ale, listen to some music with
the old lady and say, I did pretty good.
You think you'll get there?
You know, with nature, it always has surprises for us.
The curious mind is always after more.
But biology gives us other rewards, children and family, community, and one can feel good
about those things.
Biology is full of rewards, but do you think about those rewards?
What do you think is the why of those rewards?
What's the meaning of life and this existence?
What's the why of biology?
What does it want from us?
Why are all these cells very busy putting together an organism that seems to want to
just be in a hurry to do stuff and survive, but it also just doesn't, it's not happening
being survived.
Like I said, it's curious.
It keeps wanting to get into more trouble.
Why?
Yeah.
That, you know, that we're clearly designed for that, right?
This is, we're clearly designed to ask why and to answer.
And that I think is, I don't know the meaning of all life, I think a meaning of our lives
is that, and you know, this is the Aristotelian, you know, happiness.
This is, an organism is happy, an animal's happy if it's performing to its design, right?
If it's doing what it was made for.
Yeah.
Well, you have to understand, what's the design?
And, you know, who is the designer and what were they up to and how hard is it, do you
have to build the whole universe?
And does the design even know what the hell they're doing?
Because, you know, maybe the designer built humus to find out about themselves.
That's what I would do.
Like if I had the power to build clones, I would build a lot of clones and I would get
them to different trouble to understand, like, what am I designed, what's this body designed
to do?
How far can I go that way?
Exactly.
And then, and I dissociate myself completely from having any way to know, like that I know
that person.
That's good.
I mean, I suppose you could do that in a single person's body by dissociation.
You could, yeah, why, but I do wonder what, if you, if you look at earth as a collection
of humans, as a collection of biological organisms, it seems that we're busy doing something.
And it just seems too beautiful and too special to be a random, a random experiment.
It seems like it's an experiment that's cleverly designed by some forces of nature that are
beyond our current understanding.
And maybe that's part of our design is to keep asking why, I said answer.
I'm not sure that's part of the design, the answer.
I think we're given just the sufficiently limited cognitive capability that we know
how to long to find the answer and we lack the ability to find the answer.
That's basically a summary of your career.
No, I'm just kidding.
And then we give each other Nobel prizes for, for having even an inkling of a good step
towards the right direction.
Carl, you're an incredible human being.
I'm a huge fan of who you are as a person, who you are as a scientist, who you are as
a writer.
I just thank you so much.
I'm so honored that you would sit down and talk to me today.
It was amazing.
It's been incredibly fun.
Let's do it again sometime.
Let's do it again.
It's been really great.
Your insights and wit and modesty are really quite rewarding.
Thanks so much, man.
Thanks for listening to this conversation with Carl Diceroth.
To support this podcast, please check out our sponsors in the description.
And now, let me leave you with some words from Carl Jung.
Knowing your own darkness is the best method for dealing with the darkness of other people.
Thank you for listening and hope to see you next time.