105__transcript.txt

[gentle upbeat music]
- [Andrew] Welcome
to the Huberman Lab Podcast,
where we discuss science,
and science-based tools for everyday life.
I'm Andrew Huberman, and I'm
a professor of neurobiology
and ophthalmology at
Stanford School of Medicine.
Today, I have the pleasure of
introducing the first guest
of the Huberman Lab Podcast.
My guest is Dr. Karl Deisseroth.
Dr. Karl Deisseroth is a medical doctor,
he's a psychiatrist and
a research scientist
at Stanford School of Medicine.
In his clinical practice, he sees patients
dealing with a range of
nervous system disorders,
including obsessive
compulsive disorder, autism,
attention deficit disorders,
schizophrenia, mania,
anxiety disorders, and eating disorders.
His laboratory develops and explores tools
with which to understand
how the nervous system works
in the healthy situation,
as well as in disorders of the mind.
Dr. Deisseroth's laboratory
has pioneered the development
and use of what are called channelopsins,
proteins that come from algae,
which can now be introduced
to the nervous systems
of animals and humans, in
order to precisely control
the activity of neurons
in the brain and body
with the use of light.
This is a absolutely
transformative technology,
because whereas certain drug treatments
can often relieve certain
symptoms of disorders,
they often carry various side effects.
And in some individuals,
often many individuals,
these drug treatments simply do not work.
The channelopsins and their
related technologies stand
to transform the way that we
treat psychiatric illness,
and various disorders of
movement and perception.
In fact, just recently,
the channelopsins were
applied in a human patient,
to allow an adult fully blind
human being to see light,
for the very first time.
We also discuss Dr. Deisseroth's
newly released book,
which is entitled "Projections:
A Story of Human Emotions".
This is an absolutely remarkable book,
that uses stories about his
interactions with his patients,
to teach you how the brain works
in the healthy and diseased state,
and also reveals the
motivation for and discovery
of these channelopsins
and other technologies
by Karl's laboratory,
that are being used now
to treat various disorders
of the nervous system,
and that in the future,
are certain to transform
the fields of psychiatry,
mental health, and health in general.
I found our conversation to be
an absolutely fascinating one
about how the brain functions
in the healthy state,
and why and how it breaks
down in disorders of the mind.
We also discuss the
current status and future
of psychedelic treatments
for psychiatric illness,
as well as we're understanding
how the brain works more generally.
We also discuss issues of consciousness,
and we even delve into
how somebody like Karl
who's managing a full-time
clinical practice
and a 40 plus person laboratory,
and a family of five children
and is happily married,
how he organizes his internal landscape,
his own thinking in order to
manage that immense workload
and to progress forward
for the sake of medicine
and his pursuits in science.
I found this to be an
incredible conversation,
I learned so much.
I also learned, through the course
of reading Karl's book, "Projections",
that not only is he an
accomplished psychiatrist,
and obviously an accomplished
research scientist
and a family man, but he's
also a phenomenal writer.
"Projections" is absolutely
masterfully written.
It's just beautiful, and
it's accessible to anybody,
even if you don't have
a science background.
So, I hope that you'll
enjoy my conversation
with Karl Deisseroth as much as I did,
and thank you for tuning in.
Before we begin, I want to point out
that this podcast is
separate from my teaching
and research roles at Stanford.
In my desire and effort to bring zero cost
to consumer information about science
and science related tools
to the general public,
I'd like to acknowledge the
sponsors of today's podcast.
Our first sponsor is Roka.
Roka makes eyeglasses and sunglasses
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And now, my conversation
with Dr. Karl Deisseroth.
Well, thanks for being here.
- Thanks for having me.
- It's been a long time coming for me,
because you may not know this,
but one of the reasons
I started this podcast
was actually so I could
have this conversation.
[Karl laughs]
It's but one, there are other reasons,
but one of the goals is to
be able to hold conversations
with colleagues of mine that
are doing incredible work
in the realm of science,
and then here we also have
this really special opportunity
because you're also a clinician.
You see patients and have for a long time.
So for people that
might not be so familiar
with the fields of
neuroscience, et cetera,
what is the difference between
neurology and psychiatry?
- Well, I'm married to a
neurologist and I am a psychiatrist
and we make fun of each
other all the time.
A lot of neuroscientists and
a lot of brain clinicians
actually think these two
should be in the same field
at some point in the future,
they were in the past,
they started together.
Psychiatry though, focuses on disorders
where we can't see something
that's physically wrong,
where we don't have a measurable,
where there's no blood test
that makes the diagnosis,
there's no brain scan that
tells us this is schizophrenia,
and this is depression
for an individual patient.
And so psychiatry is much more mysterious,
and the only tools we have are words.
Neurologists are fantastic physicians.
They see the stroke on brain scans,
they see the seizure and
the pre-seizure activity
with an EEG, and they can measure
and treat based on those measureables.
In psychiatry, we have
a harder job, I think.
We use words, we have
rating scales for symptoms,
we can measure depression and
autism with rating scales,
but those are words still.
And ultimately, that's what
psychiatry is built around.
It's an odd situation because
we've got the most complex,
beautiful, mysterious,
incredibly engineered
object in the universe,
and yet all we have are
words to find our way in.
- So, do you find that if
a patient is very verbal or
hyper-verbal, that you have an
easier time diagnosing them,
as opposed to somebody who's
more quiet and reserved?
Or it's, I could imagine the
opposite might be true as well.
- Well, because we only have words,
you've put your finger on a key point.
If they don't speak that much,
in principle, it's harder.
The lack of speech can be a symptom.
We can see that in depression,
we can see that in the negative
symptoms of schizophrenia,
we can see that in autism.
Sometimes by itself, that is
a symptom, reduced speech,
but ultimately you do need something.
You need some words to help guide you
and in fact, there's challenges
that I can tell you about
where patients with depression
were so depressed, they can't speak.
That makes it a bit of a challenge
to distinguish depression
from some of the other reasons
they might not be speaking.
And this is sort of the art
and the science of psychiatry.
- Do you find that there are patients
that have, well, let's call
them comorbidities or conditions
where they would land in both
psychiatry and neurology,
meaning there's damage to a
particular area of the brain
and therefore they're depressed?
And how do you tease that
out as a psychiatrist?
- Yeah, this happens all the time.
Parkinson's disease is a great example.
It can be debilitating in so many ways.
People have trouble moving,
they have trouble walking,
they have trouble swallowing,
and they can have a
truly severe depression.
And this is where you
might say, "Oh, well,
they've got a life-threatening illness",
but there are plenty of
neurological disorders
where depression is not a
strongly comorbid symptom,
like ALS, Lou Gehrig's
disease, for example,
depression is not strongly
comorbid in that disease,
but in Parkinson's, it
is extremely common.
And as you know, in Parkinson's disease,
we have loss of the dopamine
neurons in the midbrain.
And this is a very specific
population of cells
that's dying, and probably that leads
to both the movement
disorder and the depression.
There are many examples of that
where these two fields come together
and you really need to work as a team.
I've had patients in my clinic,
that I treat the depression
associated with their Parkinson's,
and a neurologist treats the movement
associated with the Parkinson's
and we work together.
- Do you think we will
ever have a blood test
for depression or schizophrenia or autism?
And would that be a good or a bad thing?
- I think ultimately there
will be quantitative tests.
Already, efforts are being made
to look at certain rhythms in
the brain using external EEGs
to look at brain waves effectively,
look at the ratios of certain frequencies
to other frequencies,
and there's some progress
being made on that front.
It's not as good as it could be.
It doesn't really give you the confidence
for the individual patient
that you would like,
but ultimately, what's
going on in the brain
in psychiatric disease is physical,
and it's due to the
circuits and the connections
and the projections in the
brain that are not working
as they would in a typical situation.
And I do think we'll have those
measureables at some point.
Now, is that good or bad?
I think that will be good,
and one of the challenges
we have with psychiatry
is it is an art as well as a science
to elicit these symptoms in a precise way.
It does take some time,
and it would be great
if we could just do quick measurements.
Could it be abused or misused?
Certainly.
But that's I think true,
for all of medicine.
- I want to know, and I'm
sure there are several,
but what do you see as
the biggest challenge
facing psychiatry and the
treatment of mental illness today?
- I think we're making progress
on what the biggest challenge is,
which I think there's
still such a strong stigma
for psychiatric disease
that patients often don't come to us,
and they feel that they
should be able to handle this
on their own.
And that can slow treatment.
It can lead to worsening symptoms.
We know, for example,
patients who have
untreated anxiety issues.
If you go for a year or more
with a serious untreated anxiety issue,
that can convert to depression.
You can add another problem
on top of the anxiety.
And so it would be...
Why do people not come for treatment?
They feel like this is
something they should be able
to master on their own, which can be true,
but usually, some help is a good thing.
- That raises a question
related to something
I heard you say many
years ago at a lecture,
which was that, this
was a scientific lecture
and you said, "We don't
know how other people feel.
Most of the time, we don't
even really know how we feel."
- [chuckles] Yeah.
- [Andrew] Maybe you could
elaborate on that a little bit
and the dearth of ways that we
have to talk about feelings.
I mean, there's so many words.
I don't know how many,
but I'm guessing they're more
than a dozen words to describe
the state that I call sadness,
but as far as I understand,
we don't have any way of comparing that
in a real objective sense.
As a psychiatrist, when
your job is to use words
to diagnose, words of
the patient to diagnose,
do you maneuver around that?
And what is this landscape
that we call feelings or emotions?
- This is really interesting.
Here there's a tension between
the words that we've built up
in the clinic that mean
something to the physicians,
and then there's the
colloquial use of words
that may not be the same,
and so that's the first
level we have to sort out
when someone says, "I'm depressed",
what exactly do they mean by that?
And that may be different
from what we're talking about
in terms of depression.
So part of psychiatry is
to get beyond that word,
and to get into how
they're actually feeling,
get rid of the jargon and
get to real world examples
of how they're feeling.
So, how much do you look
forward into the future?
How much hope do you have?
How much planning are
you doing for the future?
So here now you're
getting into actual things
you can talk about that are unambiguous.
If someone says, "Yeah, I can't
even think about tomorrow.
I don't see how I'm going
to get to tomorrow".
That's a nice, precise
thing that you know,
it's sad, it's tragic, but
also, that means something.
And we know what that means.
That's the hopelessness
symptom of depression.
And that is what I try to do
when I do a psychiatric interview.
I try to get past the jargon,
and get to what's actually
happening in a patient's life
and in their mind.
But as you say, ultimately,
[chuckles] and this shows up across...
I address this issue every day in my life,
whether it's in the lab where
we're looking at animals,
whether fish or mice or rats
and studying their behavior,
or when I'm in a conversation
with just a friend
or a colleague, or when
I'm talking to a patient,
I never really know what's going on
inside the mind of the other person.
I get some feedback, I get words,
I get behaviors, I get actions,
but I never really know.
And as you said at the very
beginning of the question,
often we don't even have
the words and the insight
to even understand what's
going on in our own mind.
I think a lot of psychiatrists
are pretty introspective.
That's part of the reason
they end up in that specialty,
and so, maybe we spend a little more time
than the average person
thinking about what's going on within,
but it doesn't mean we have the answers.
- So in this area of trying to figure out
what's going on under
the hood through words,
it sounds like certain words would relate
to this idea of anticipation and hope.
Is it fair to say that
that somehow relates
to the dopamine system in the sense
that dopamine is involved
in motivated behaviors?
I mean, if I say for instance,
and I won't ask you to
run a session with me here
[chuckles] for free.
[Karl laughs]
- We'll do that off camera.
- [Andrew] Off camera. Right.
If I were to say, "I just
can't imagine tomorrow.
I just can't do it."
So that's not an action-based,
that's purely based on
my internal narrative,
but I could imagine things like, you know,
I have a terrible time
sleeping, I'm not hungry,
I'm not eating, so statements
about physical actions,
I'm guessing also have validity.
- Absolutely.
- And there are now ways to measure
the accuracy of those statements.
Like for instance, if
I gave you permission,
you could know if I slept last night,
or whether or not I was just saying
I had a poor night's sleep.
- Yes. That's right.
- So in moving forward through 2021
and into the next 10 and
100 years of psychiatry,
do you think that the body
reporting some of the actions
of a human are going to become useful
and mesh with the words in a way
that's going to make your job easier?
- I do think that's true.
And the two things you've
mentioned, eating and sleeping,
those are additional criteria
that we use to diagnose depression.
These are the vegetative signs,
we call them of depression,
poor sleep, and poor eating.
And if you have a baseline for somebody,
that's the real challenge there.
What's different in that person?
Some people with
depressed, they sleep more.
Some people who are
depressed, they sleep less.
Some people who are depressed,
they're more physically agitated,
and they move around more.
Some people who are depressed,
they move less even while they're awake.
And so you need...
Here's the challenge is
that you can't just look
at how they are now.
You have to get a baseline,
and then see how it's changed.
And that can be a challenge
that raises ethical issues,
and how do you collect
that baseline information
from someone healthy?
I don't think that's
something we have solved.
Of course, with phones and
accelerometers and phones,
you could in principle,
collect a lot of baseline
information from people,
but that would have to be treated
very carefully for privacy reasons.
- And in terms of measuring
one's own behavior,
I've heard of work that's going on.
Sam Golden up in the
University of Washington
who works on aggression in animal models
was telling me that there's
some efforts that he's making,
and perhaps you're involved
in this work as well,
I don't know, of devices
that would allow people
to detect, for instance,
when they're veering
towards a depressive episode
for themselves, that they
may choose or not choose
to report that to their clinician,
maybe they don't even have a clinician.
Maybe this person that you
referred to at the beginning,
this person who doesn't feel comfortable
coming to talk to you,
maybe something is measuring
changes in the inflection
of their voice, or the speed
at which they get up from a chair.
Do you think that those kind of metrics
will eventually inform
somebody, "Hey, you know,
you're in trouble"?
This is getting to back to the statement
that I heard you make and
it rung in my mind now,
I think for more than a decade,
which is, "Oftentimes, we
don't even know how we feel."
- Yeah.
You know, that I do like,
because that gives the
patient the agency to detect
what's going on, and even
separate from modern technology,
this has been part of
the art of psychiatry
is to help patients realize
that sometimes other people observing them
can give them the earliest
warning signs of depression.
We see this very often in family.
They'll notice when
the patient is changing
before the patient does.
And then there are things
the patient may notice,
but not correctly ascribe
to the onset of depression.
And a classic example of that
is what we call 'early morning awakening'.
And this is something
that can happen very early
as people start to slide into depression.
They start to wake up earlier and earlier,
just inexplicably, they're awake at-
- This is like 2:00 AM, 3:00 AM awakening?
- It could start...
Yeah, it could start at
5:00 AM, could go to four,
and three-
- And are unable
to fall back asleep?
- Unable to fall back asleep. Exactly.
And they may not know
what to do with that.
It could just be, [chuckles]
from their perspective,
it's just something that's happening.
But if you put enough of
that information together,
that could be a useful
warning sign for the patient
and it could help them seek treatment.
And I think that is something
that could be really valuable.
- Interesting.
So, in this framework of
needing words to self-report
or machines to detect how we feel
and maybe inform a psychiatrist
how a patient feels,
touch on some of the technologies
that you've been involved in building,
but as a way to march into that,
are there any very good treatments
for psychiatric disease?
Meaning, are there currently
any pills, potions,
forms of communication that
reliably work every time,
or work in most patients?
And could you give a couple
examples of great successes
of psychiatry if they exist?
- Yes.
Yeah, we are fortunate.
And this [chuckles] coming
back to my, you know,
the joking between my wife and myself
in terms of neurology and psychiatry,
we actually in psychiatry,
despite the depths
of the mystery we struggled with,
many of our treatments are actually...
We may be doing better
than some other specialties
in terms of actually
causing therapeutic benefit
for patients.
We do help patients, the
patients who suffer from...
By the way, both
medications and talk therapy
have been shown to be extremely
effective in many cases,
for example, people with panic disorder,
cognitive behavioral therapy,
just working with words,
helping people identify the early signs
of when they're starting to
move toward a panic attack,
what are the cognitions
that are happening?
You can train people to derail that,
and you can very potently
treat panic disorder that way.
- How long does something
like that take on average?
- For a motivated, insightful patient,
you can have a very
cookbooky series of sessions,
that's six to 12 sessions, or even less
for someone who's very
insightful and motivated
and it can have a very
powerful effect that quickly.
And that's just with words,
there are many psychiatric medications
that are very effective for the conditions
that they're treating.
Anti-psychotic medications,
they have side effects,
but boy, do they work!
They really can clear up
particularly the positive symptoms
of schizophrenia for example,
the auditory hallucinations,
the paranoia, people's lives
can be turned around by these-
- We should clarify positive symptoms.
You mean not positive in
the qualitative sense,
you mean positive meaning
that the appearance
of something abnormal.
- Exactly. Yeah.
Thank you for that clarification.
When we say positive symptoms,
we do mean the addition of something
that wasn't there before,
like a hallucination or a paranoia,
and that stands in contrast
to the negative symptoms
where something is taken away,
and these are patients who are withdrawn.
They have what we call thought blocking.
They can't even progress forward
in a sequence of thoughts.
Both of those can be
part of schizophrenia,
the hallucinations and the paranoia
are more effectively treated right now,
but they are effectively treated.
And then, this is a frustrating,
and yet heartening aspect of psychiatry.
There are treatments like
electroconvulsive therapy,
where it's extremely
effective for depression.
We have patients who
nothing else works for them,
where they can't tolerate medications,
and you can administer under a very safe,
controlled condition,
where the patient's body is not moving.
They're put into a very safe situation
where the body doesn't move or cease,
it's just an internal process
that's triggered in the brain.
This is an extraordinarily
effective treatment
for treatment-resistant depression.
At the same time, I find it [chuckles]
as heartening as it is to
see patients respond to this
who have severe depression,
I'm also frustrated by it.
Why can't we do something
more precise than this,
for these very severe cases?
And people have sought
for decades to understand,
how is it that a seizure is leading
to the relief of depression?
And we don't know the answer yet.
We would love to do that.
People are working hard on that,
but that is a treatment
that does work too.
In all of these cases
though in psychiatry,
the frustrating thing
is that we don't have
the level of understanding
that a cardiologist has
in thinking about the heart.
You know, the heart is,
we now know it's a pump.
It's pumping blood. and so
you can look at everything
about how it's working or not working,
in terms of that frame,
it's clearly a pump.
We don't really have that level
of, what is the circuit really
there for in psychiatry?
And that's what is missing.
That's what we need to find,
so we can design truly effective
and specific treatments.
- So, what are the pieces
that are going to be required
to cure autism, cure
Parkinson's, cure schizophrenia?
I would imagine there are several
elements and 'beens here',
understanding the natural biology,
understanding what the
activity patterns are,
how to modify those, maybe
you could just tell us
what you think, what is the
Bento Box of the perfect cure?
- I think the first thing
we need is understanding.
Almost every psychiatric treatment
has been serendipitously identified,
just noting by chance that
something that was done
for some person also had a side effect-
- Like lithium or something-
- Like lithium, is a good example.
- Is it true that it was
the urine of guinea pigs
[Karl laughs]
given lithium
that was given to manic patients
that made them not manic?
Is that true?
- I don't have firsthand
knowledge of that,
but I would defer that,
but it's true for
essentially every treatment,
that the antidepressants originally arose
as anti-tuberculosis drugs, for example.
- I did not know that.
- Yeah, and so this is a
classic example for illnesses
across all of psychiatry,
and of course there's
the seizures as well.
That was noticed that
patients who had epilepsy,
they had a seizure there
and also had depression,
that they became much,
at least for awhile,
they were improved after that seizure.
- That's amazing.
I don't want to take you
off course of the question
answering the question I asked,
but I've heard before that if
autistic children get a fever,
that their symptoms improve, is that true?
- I've done a fair bit
of work with autism.
In my clinical practice,
I work with adult autism
and I have heard statements like that
and descriptions like that from
patients and their families.
That is very hard to study quantitatively
because often with the
children, you have this
not as quantitative as you'd like
collection of symptom
information from home.
But I have heard that enough that I think
there may well be something to that.
And anytime you have a
fever, what's going on?
Well, we know all the cells in the brain,
and I know this as an electrophysiologist,
if you just change the
temperature by a few degrees,
everything changes about how neurons work
and that's even just a single neuron.
It's even more likely to
be complex and different
with a circuit of neurons that
are all affecting each other.
Just elevate the temperature a little bit,
everything's different.
And so, it's plausible for sure,
that things like that
could happen and do happen.
And yet, when you think about
autism, to take your example,
yes, we see changes,
but what is the elements of
the brain that's analogous
to the pumping heart?
When we think about the
symptoms of depression,
we think about motivation
and dopamine neurons.
When we think about autism,
it's a little more challenging.
There's a deficit in social interaction
and in communication.
And so where is that?
[chuckles] Where is that situated?
What is the key principle
governing the social interaction?
This is where we need the basic science
to bring us a step forward,
so we can say okay, this is
the process that's going on.
This is what's needed for
the incredibly complex task
of social interaction,
where you've got incredibly
rich data streams of sound
and meaning, eye contact, body movement,
and that's just for one person.
What if there's a group of people?
This is overwhelming
for people with autism.
What's the unifying thing there?
It's a lot of information,
and that maybe is unmatched
in any realm of biology,
the amount of information coming in
through a social interaction,
particularly with words and language.
And so then, that turns our
attention as neuroscientists,
we think, okay, let's think
about the parts of the brain
that are involved in dealing with merging
complex data streams that
are very high in bit rate
that need to be fused together
into a unitary concept.
And that starts to guide us,
and we know other animals
are social in their own way,
and we can study those animals.
And so that's how I think about it.
There's hope for the future,
thinking about the symptoms
as an engineer might,
and trying to identify the
circuits that are likely working
to make this typical behavior happen,
and that will help us understand
how it becomes atypical.
- So that seems like the first to me,
the first been of this,
what I call the Bento Box
for lack of a better analogy,
that we need to know the circuits.
We need to know the cells
in the various brain regions
and end portions of the body
and how they connect to one another,
and what the patterns of activity are
under a normal 'healthy interaction'.
- [Karl] Yeah.
- If we understand that, then
it seems that the next step,
which of course could be
carried out in parallel, right?
Though that work can
be done alongside work
where various elements within
those circuits are tweaked
just right, like the tuning
of a piano in the subtle way,
or maybe even like the
replacement of a whole set of keys
if the piano is lacking keys, so to speak.
- Right.
- You've been very involved
in trying to generate those tools.
Tell us about channelopsins,
why you created them,
and where they're at now
in the laboratory and
perhaps also in the clinic.
- Well, first of all, I
give nature the credit
for creating channelrhodopsins.
These are beautiful little
proteins that are made by algae,
single-celled green algae.
And there's a great story in basic science
that our understanding of animal behavior,
sensation, cognition
and action in our brains
all the way back to a botanist
in the 1850s and 1860s
in Russia, is where the story begins.
So this was a botanist
named Andrei Famintsyn
who worked at St. Petersburg,
and he had noticed in the
river near his laboratory,
that there were algae
that he could look at
in a dish, in a saucer.
He could put them there and he had light
shining from the side.
The green tinge in the saucer of water
would move to a particular
distance from the light
that he was shining from the side,
which was an amazing thing.
If he made the light brighter,
the green tinge would
back off a little bit
to a more optimal location,
so just the right light level.
So this was plant behavior.
It was light-driven plant behavior,
and he delves into this a little bit.
He identified that with microscopy,
he could see that there were
little single-cell algae
with flagella that were swimming
to the right light level.
So behaving plants, and
this has been the secret
that's helped us unlock so many principles
of animal behavior.
So turns out,
these algae achieve this amazing results
with a single gene that
encodes a single protein.
What's a protein?
It's just a little bio-molecule
that does a job in a cell.
And these are proteins that
sit in the surface of cells
in their surface membrane,
and when a photon, a
light particle hits them,
they open a little pore, a
little hole in the membrane
and charged particles, ions like sodium
rush across the pore.
Now, why do they do that?
They do that to guide their
flagella, that signal coming in,
those ions coming in through the pore
in response to light,
guide their flagella motor,
that guides them to a
particular spot in the saucer.
Now, that's plant
behavior, but it turns out,
as you know, this movement
of ions across the membrane,
this happens to also be a neural code
in our brains for on or off.
Sodium ions rushing into
the cells, turns them on.
It makes them fire away, fire
action potentials communicate
to the next cell down the chain,
and this is an amazing opportunity
because we can borrow these proteins.
In fact, we can take the gene
that directs the creation of the protein,
and we can use genetic
tricks, modern genetic tricks
to put that gene into neurons
in the brains of mammals,
and then use light to turn those cells,
the specific cells that
we put this gene into,
turn them on.
There are other opsins, we call them,
that you can use to turn cells off.
It's all fast, real time.
You can play in patterns
of activity in real time
into cells or kinds of
cells, just as a conductor
elicits the music from the orchestra,
the strings and the woodwinds.
And you can see what matters.
What matters for sensation,
what matters for cognition,
what matters for action, and
we call this optogenetics.
- Beautiful, and I must
say it was quite an honor
and a privilege to watch optogenetics move
from idea to discovery to the laboratory.
I think we were postdocs at the same time,
- We were, huh?
- which is living proof that
people move at different rates,
because [laughs] it's a joke
at my expense by the way,
[Karl laughing]
but it's really-
- We end up in the same spot. [laughs]
- That's right, [laughs]
yeah, more or less.
Physically, if not professionally,
but nonetheless, it's been
a marvelous story thus far.
And I'd like to...
Maybe you could give us...
I'd like to just touch
on a couple examples
of where the technology
resides in laboratories now,
so maybe the range of animals
that it's being used in,
and some of the phenomenon
that channelrhodopsins
and their related genes
and proteins are starting
to elicit, what you've seen,
and then I'd like to talk
about their applicability
to the clinic, which is I
think the bigger mission,
if you will.
- Yeah.
So this whole thing, you know,
it's been about, now going on 17 years
that we've been putting
channelrhodopsins into neurons.
It started just like Andre
Famintsyn's work in a dish,
that was in 2004.
In 2007, we were putting
these into behaving mice,
and we were able to with
a flick of a switch,
cause them to move one
direction or another,
by 2009-
- So basically, you're
controlling the mouse's behavior?
- Yeah, exactly. In real time.
So we could make a mouse
that was just sitting there
doing nothing, to then turn
left very consistently,
in fact, go around in a circle
and as soon as we turn off
the light, it would stop.
That was an eye-opening moment.
It took really a few years
to make optogenetics work.
There was a lot of putting all the...
There are a lot of problems
that had to be solved.
These channelrhodopsins
actually don't move many ions.
They have a small current,
small conductance, as we say.
And so we had to figure out
ways to pack a lot of them
into cells without damaging cells,
and still make them targetable,
so we don't want them to
just be in all the cells,
'cause then it becomes
just like an electrode.
You're just stimulating all
the cells that are nearby.
We had to keep that specificity,
make them targetable to just
one kind of cell or another,
while still packing in
large numbers of them
into those cells.
And we had to get in the light
in safe and specific ways,
and so it took probably
about four or five years
to really create optogenetics
between 2004 and 2009.
By the end of that time though,
we had all the basic light
delivery, gene delivery,
principles worked out, and
people started to apply
the technology to fish, to rats, to mice,
to non-human primates like monkeys,
and just a couple months ago,
my colleague, Botond Rosca in Switzerland,
succeeded in putting channelrhodopsins
into the eyes of human beings
and making a blind person to see.
And so that's pretty cool.
This was a patient with
retinal degeneration,
and he provided a channelrhodopsin
into the eye of this patient
and was able to confer
some light sensitivity
onto this patient that
wasn't there before.
- An amazing paper and discovery.
I realize it was one patient,
but it's such an important milestone.
- Well, as you say, it's
a very important milestone
and the history of that is very deep.
Almost 10 years earlier,
Botond Rosca and I
had published a paper in
science in human retina,
but X plants taken from cadavers
from someone who had died,
the living retina taken out,
opsins put into this retinal tissue
and showing that it worked,
recording from the cells
showing that in these
human retinal neurons,
that you could get light responses.
But then, from that moment,
almost 10 years of how
clinical development goes,
and this is a gene therapy
and so you've got all the regulations
and concerns and all that.
It took almost 10 years
to get to this point now
where a living human being
has a new functionality
that wasn't there before.
Now, that's incredibly inspiring,
and it's a beautiful thing.
I would say though,
that the broader
significance of optogenetics
is really still understanding,
because once you understand
how the circuitry works and
which cells actually matter,
then any kind of treatment
becomes more grounded and logical
and specific and principled.
And whether it's a
medication, or a talk therapy
or brain stimulation treatment
with electrical or magnetic means,
if you actually know what matters,
[chuckles] that is incredibly powerful.
And I think,
not intended to disparage
the beautiful retinal work
and conferring vision on
someone who couldn't see,
of course that's wonderful,
and that's direct what you might call
direct optogenetics in patients.
Indirect is everything that
comes from understanding.
Okay, we know these cells
matter now, for this symptom.
Well, how can we target those cells
and help them work better
in patients by any means?
And I think that's the
broader significance
of optogenetics, clinically.
- I know Botond well,
and you and Botond share
this incredible big vision,
that I think only a clinician
can really understand,
being in close contact within
the suffering of patients
as a ultimate motivator of
developing technologies,
which makes me have to ask,
did you decide to become a scientist
to find cures for mental disease?
- [chuckles] No, I didn't.
It's a really important
question to actually look back
and see the steps that brought
you to a particular place.
And that was not what brought
me initially to science
and it's okay I think,
to embrace [chuckles]
the twists and turns
that life brings to you,
but I was always interested in the brain.
And so, that was something
that for me started
from a very early age.
We talked about being introspective.
I noticed very early on I
had a deep love of poetry
and stories, and I was a voracious reader,
and I was amazed by how
words could make me feel
in particular ways.
Even separate from their, of
course, dictionary meanings,
the rhythm, and how they work together,
even separate from meaning.
And I was stunned by poets that
could use words in new ways
that were even divorced
from their meaning at all,
and yet could still
trigger specific emotions.
And this was always fascinating to me.
So, I wanted to understand that,
and so I was interested and I
became interested in the brain
and I thought, well, I'm
going to to have to study
the human brain, because only
human beings can describe
what's going on inside enough.
So in college, I began to
steer myself toward medicine,
with the idea of becoming a neurosurgeon.
And so I came here to medical school,
and did an MD PhD program,
planning neurosurgery all the way through.
The first rotation I did at
the end of medical school,
as you know, you do rotations,
you go through different specialties,
and some of these are required rotations,
everybody has to do this summary elective
where you can pick what you want to do.
I elected to do the
neurosurgery first, [chuckles]
even before regular surgery.
I was that sure I wanted
to do it, and I loved it.
I had a fantastic time.
There was an amazing patient
who had a thalamic damage,
and there was a neglect syndrome
where the patient was not
able to be aware of something
that was right in front of him-
- Even though their
vision was perfectly fine?
- Even though their vision
was perfectly fine, exactly.
And I loved the operating room,
I loved the rhythm of suturing
and the precision of it,
and I loved being able to
help patients immediately,
but then a required
rotation was in psychiatry,
which I was not looking forward to at all.
And that completely reset my whole life,
that experience in psychiatry.
And it was at that moment that I saw
this is first of all, the greatest need,
the depth of suffering
and the depth of the mystery together.
And also it was, I almost feel
a little guilty about this.
It's so interesting too.
Yes, we can help.
Yes, there's need, but as a scientist,
this is amazing, that someone's
reality can be different
from my own, with everything physically,
as far as we can tell the same
with the measures we have,
and yet we've got a different reality.
That is an amazing thing,
and if we can understand that
and help these people,
that would be just more
than anybody could ask for.
And so that's how I ended
up taking this path,
just a required rotation in psychiatry.
- It all started with poetry?
- And it started with poetry.
- Out of respect for poetry,
are there any favorites
that you spend time with
on a regular basis?
- I mean, the ones who
got me down this path
early on, I remember in
childhood and high school,
Borges had an immense influence on me.
I studied Spanish all the way
through and reading his work.
He was a great writer.
He wrote both in English and in Spanish
and being able to appreciate his poetry
both in English and in Spanish
was a pretty amazing thing.
Not many poets can do that.
- You're bilingual?
- I'm not, I wouldn't say.
Now I became, at one point
I was effectively fluent
in Spanish, and I'm pretty
good with medical Spanish still
because we use Spanish all
the time in the clinic here.
I wouldn't claim full fluency,
but it's something I can
definitely use all the time.
And that's been very
helpful in the clinic.
- Yeah, Borges is wonderful.
As the son of an Argentine,
I grew up hearing about it
and I learned that Borges'
favorite city was Geneva.
So I spent time in Geneva
only for that reason.
It's also turns out
[Karl laughs]
to be an interesting city.
- Yes.
- So you developed
methods to control neurons
with these algae proteins using light?
- Yeah.
- In 2015, there was what I
thought was a very nice article
published in the New
Yorker, describing your work
and the current state of your work
in the laboratory and the clinic,
and an interaction with a patient.
So this as I recall, a woman
who was severely depressed,
and you reported in that article
some of the discussion with this patient,
and then in real time,
increased the activation of
the so-called vagus nerve,
this 10th cranial nerve that
extends out of the skull
and innervates many of
the viscera and body.
What is the potential
for channelrhodopsins
or related types of algae engineering
to be used to manipulate the vagus?
Because I believe in that instance,
it wasn't channelopsin stimulation,
it was electrical stimulation, right?
Or to manipulate for instance,
a very small localized
region of the brain?
Let me frame it a little bit differently
in light of what we were talking
about a couple minutes ago.
My understanding is that if
somebody has severe depression
and they take any number
of the available pharmaceutical
agents that are out there,
SSRI, serotonergic agents,
increased dopamine,
increased whatever, that
sometimes they experience relief,
but they're often serious side effects.
Sometimes they don't experience relief,
but as I understand it,
channelopsins and their related
technology, in principle,
would allow you to turn on
or off the specific regions
of the brain that lead to
the depressive symptoms,
or maybe you turn up a happiness circuit,
or a positive anticipation circuit.
Where are we at now in terms
of bringing this technology
to the nervous system?
And let's start with the body,
and then move into the skull.
- Yup.
So starting with the
body is a good example
because it highlights the opportunity
and how far we have to go.
So let's take this example
of vagus nerve stimulation.
So the vagus nerve, it's
the 10th cranial nerve.
It comes from the brain, it goes down
and innervates the heart
and innervates the gut.
And by innervate, I mean it
sends little connections down
to help guide what happens in these organs
in the abdomen and chest.
It also collects information back,
and there's information coming
back from all those organs
that also go through this vagus nerve,
the 10th cranial nerve, back to the brain.
And so this is somewhat of a
super highway to the brain,
and it was the idea.
And maybe the idea is maybe
we could put a little cuff,
a little electrical device
around the vagus nerve itself,
and maybe have just like
a pacemaker battery,
have a little power source
here under the clavicle,
everything under the skin,
and have a little cuff
and drive signals, and maybe
they'll get back to the brain.
So a way of getting into the brain
without putting something
physical into the brain.
- And why the vagus?
I mean, it's there and it's accessible-
- That's the reason.
- [chuckles] That's the reason?
- [chuckles] That's the reason, yes.
- Really?
- Yeah.
- You're not kidding?
- [Karl] I'm not kidding.
- So stimulating the
vagus to treat depression,
simply because it's accessible.
- It started actually
as an epilepsy treatment
and it can help with epilepsy,
but yes, it's simple.
- God, you got to love medicine.
As a scientist, this is
where I get to chuckle
and you say, I'm in the field of medicine
from that perspective.
From the perspective of
a scientist and outsider,
the field of medicine
is a field that goes in
and tickles pathways
because they're there.
I don't know what to say.
It's a little shocking.
- Yeah.
And at least in my laboratory,
I always say you never do an
experiment because you can,
you do an experiment to
test a specific hypothesis.
- Yeah. Yeah.
I mean, there are stories people tell
so that the vagus nerve
lands on a particular spot
on the brain called the
solitary tract nucleus,
which is just one snaps
away from the serotonin
and dopamine and the norepinephrine-
- So there's a link to
chemical systems in the brain-
that make an irrational choice?
- Yes.
It's not irrational,
but I can tell you that
even if that were not true,
the same thing would have been tried.
[Andrew laughs]
- You guys would have done it anyway.
- Because it's accessible. Yeah.
- [Andrew] I see. Okay.
- And why?
Well, it's again, not to disparage
what's been happening in
this branch of medicine.
There's immense suffering,
many treatments don't work,
and we try things.
And this is how so many
advances in medicine happen.
When think about kidney dialysis
which has kept many people alive,
that was just started by someone saying,
"Hey, let's try this.
Maybe there's something
building up in the blood
and maybe we can dialyze
something and help them."
Yeah, it worked.
And it was just sort of
a test pilot mentality.
We can access the blood,
let's run it across a dialysis membrane,
put it back in the body, oh
my God, that actually works.
And sometimes you do need
that test pilot mentality,
of course, to do it in a rigorous, safe,
controlled way-
- Sure.
- which is what we do.
And so, anyway, that's how we ended up,
but still with the vagus
nerve stimulation, okay,
so what is it? Does it work?
It has, it's FDA approved for depression,
this vagus nerve stimulation,
but on a population level,
if you average across all people,
the effect sizes are pretty small.
Some patients it has an amazing effect in,
but some patients it doesn't work at all,
and average across everybody,
the effect size is pretty small.
- How do you think it's
working when it does work?
Is it triggering the activation of neurons
that release more serotonin or dopamine?
- It could be, but I would
say we don't have evidence
for that and so I just don't know.
But what is clear, is
that it's dose-limited
in how high and strongly we can stimulate
and why, it's because it's an electrode,
and it's stimulating everything nearby.
And when you turn on the
vagus nerve stimulator,
the patient's voice becomes
strangulated and hoarse,
they can have trouble swallowing,
they can have trouble speaking for sure,
even some trouble breathing,
because everything in the neck,
every electrically responsive cell
and projection in the
neck is being affected
by this electrode.
And so you can go up just
so far with the intensity,
and then you have to stop.
So, to your initial question,
could a more precise stimulation
method like optogenetics
help in the setting?
In principle, it could,
because if you would target
the light sensitivity
to just the right kind of cell,
let's say cell X that goes
from point A to point B
that you know, causes symptom
relief of a particular kind,
then you're in business.
You can have that be the only
cell that's light sensitive.
You're not going to affect
any of the other cells,
the larynx and the pharynx
and the projections passing through.
So that's the hope,
that's the opportunity.
The problem, is that we
don't yet have that level
of specific knowledge.
We don't know, okay, it's
the cells starting at point A
going to point B, that relieves
this particular symptom.
- We want to fix this key on the piano?
- Yeah.
- And then I see two other
steps that are required.
One is to get the channelopsin
gene into the cell.
In the case of Botond Rosca and colleagues
rescuing vision in this patient,
they did that by an injection of a virus
that doesn't damage the neurons.
The virus itself is fairly innocuous,
but carries a cargo, and
it's a one-time injection,
the cells express, and then
they used light to stimulate.
So, let's say I'm depressed,
which I don't think I am,
although now sitting in
front of a psychiatrist,
[Karl laughs]
you probably can see signs that maybe I am
or maybe I'm not, but let's
say we put channelopsin
into a specific branch of
the vagus that we understand
is responsible for mood,
how are we going to get it in there?
And, then how are we going
to deliver the light?
'Cause we're not talking about sunlight
or standing in front of
a light bulb necessarily,
what are the mechanisms for the body?
- Yeah.
So we had to solve exactly
these questions you're saying.
How do you get the light in?
How do you get the gene in,
in a potent and robust and safe way?
And that's now solved, and
that's not a challenge.
So there are very safe,
well-tolerated gene delivery mechanisms
that are called
adeno-associated viruses, AAVs,
and these are things that are associated
with the common cold.
They themselves don't cause any symptoms.
They've been engineered, and
there's been a broad community
of viral engineering that's
been going on for decades
making these safer,
well-tolerated, and so on.
We can put the channelrhodopsin
gene into these
viral vectors that deliver the gene
and we can have little
bits of additional DNA
that govern expression
only in one kind of cell,
but not another.
These are called promoters and enhancers,
all genetic tricks built up
by a very broad community
of great scientists over the decades.
We can put these different bits of DNA,
package them into this
AAV, this little virus,
and that can be then injected
into a particular part of the body,
and sticking with this
vagus nerve example,
we know that there are
particular clumps of neurons.
There's one called the nodose ganglion
that has a clump of cells
related to the vagus nerve,
and you could for example,
target a little injection
into that ganglion-
- Would that be an outpatient procedure?
- Yep. Yep.
- So you come in in the
morning, get your injection,
maybe walk out a few hours later?
- Yeah. That's right.
And so that's the gene,
then the light delivery,
this is also something
that we've worked out.
We've worked on making very,
very light-sensitive opsins.
One challenge, and Botond would
be the first to state this
in fact, [chuckles] in solving
this problem for the patient,
he had to build goggles that
created much brighter light
than the normal ambient light delivery,
because as I mentioned earlier,
you have to pack a lot of
these channelrhodopsins in,
they don't have much current.
You have to really make sure
that you've got a tense enough light
to activate enough of them
to cause a stimulation-
- And it has to be the
right wavelength, right?
- It has to be the right wavelength-
- And going back to your
example of the algae
moving toward or away the light,
it has to be tuned just right.
So I'm imagining in my
mind as a non-engineer,
I know you're [chuckles]
also a bioengineer,
I'm imagining a little tiny
blue light-emitting object,
that's a little bigger
than a clump of cells,
or maybe about the size
of a clump of cells.
And for those that don't know,
your credit card is about 200
microns thick on the side,
and a micron is a
thousandths of a millimeter,
and so we're talking
about a little tiny stamp
that's basically half a
millimeter in size all around.
Each edge, half a millimeter in size.
I can imagine that
being put under my skin,
and then I would what, I'd
hit an app on my phone,
and I'd say, "Dr. Deisseroth,
I'm not feeling great today.
Can I increase the stimulation?"
And you'd say, "Go for it."
And then I'd ramp it up.
Is that how it would go?
- I mean, that's effectively
what we already do
with the vagus nerve stimulation.
The doctor in this case, and I have this
in some of my patients in the clinic,
I do vagus nerve stimulation.
I talk to them, I say, "How are you?"
I go through the symptoms, I
use the psychiatric interview
to elicit their internal states,
and then I have a radio
frequency controller
that I can dial in-
- Right there in real time?
- Right there in real time.
- You're holding the remote control
essentially to their brain,
although it's remote controlled?
- Yeah, through a couple
of steps, but yeah.
And I can turn up the frequency,
I can turn up the intensity,
all with the radio frequency and control,
and then it's reprogrammed or redosed,
and then the patient can then
leave at this altered dose.
- So this is happening now?
- This is happening
right now, electrically.
- You do this routinely?
- I do it routinely in my
clinic, electrically, yeah.
- And you're getting the verbal content,
which as you described
earlier, is the indication
of how well something
is working in real time?
- Yes.
- So this is what, maybe
you could just describe
a little bit of the interaction
with that particular patient
or another patient, what's a typical arc
of narrative as you go from no stimulation
to increased stimulation?
- In most patients, the
actual therapeutic effects,
the benefits actually
take many days to weeks,
and so what I'm mostly
focusing on in the office
in real time, is making sure
I'm in a safe, low side effect regime.
And so first I talk to the patient
who has been on a particular
dose of the stimulation
for weeks or longer, and
I talk about symptoms,
how were things over the past month?
How was your hope?
How was your energy level?
Sleep? What is your mood?
And then we talk with the patient
and we decide, well, this is
not yet where we'd like to be.
And so then, I can turn up the
intensity of the stimulation
in real time in the office.
In most patients, I don't
expect an immediate mood change.
What I do, is I increase the
dose until a next level up,
while asking the patient for side effects.
Can you still breathe? Okay.
Can you still swallow? Okay.
And I can hear their voice as well.
And I can get a sense-
- And you're looking at their face?
- And I'm looking at their face.
- Yeah.
- And so I can get a sense,
am I still on a safe side effect regime?
And then, I stop at a particular
point that looks safe,
and then the patient goes
home, comes back a month later,
and I get the report on how
things were over that month.
- I asked if you're looking at their face,
'cause in your book,
you describe the incredible complexity
of social interactions.
And at one point,
you describe the incredible
amount of information
that the eyes inform about the brain
and the context of
somebody's inner experience,
whether depressed or happy or otherwise.
- Yeah.
- I want to make sure that we
get back to how to maneuver
and manipulate the nervous system
for the sake of mental health.
But, what are you looking for?
So as a vision scientist,
I think pupils dilating
is a sign of arousal,
but that could be a positive
arousal, positive valence,
like excitement, or it could be terror.
- Yeah.
- You're going to get the
same dilation of the pupils.
And I'm always reminding people
that these two little goodies
are two pieces of brain,
basically,
[Karl chuckles]
they're just outside the cranial vault.
So they're not unlike
the vagus in that sense,
but they're more of a
report than a control knob,
although I'd like to
think they could be used
as control knobs too.
So, without putting you on the spot,
again, to diagnose me,
[Karl laughs]
that's something I would
never ask you to do
[Karl laughing]
with the cameras rolling,
but what are you looking for
that the patient might not be aware of?
In other words, can you see
depression in somebody's eyes?
And if you know a patient or if you don't,
can you see it in their body
posture when they walk in?
Realizing of course, that
a trained psychiatrist
like yourself, develops an intuitive sense
that's aggregating lots of
different features of a patient,
but what about the eyes?
What's going on there?
- Yeah.
The eyes are incredibly
rich in information.
And as you alluded to though,
it's not as if any one measurable
conveys all the information you need.
It's what an engineer would
say, joint statistics.
It's many things all at once,
whether they're in synchrony
or out of synchrony,
that actually turns out to matter.
And the eye contact question,
we all know eye contact
is incredibly important.
You don't feel you've
connected with somebody,
unless there's eye contact, but
eye contact can go awry too.
It can be too intense,
or it can be mistimed, or if
there's someone with autism,
it can be barely there at all.
And this is one of the most
striking symptoms of autism,
is the avoidance of eye contact,
almost as if it's a harmful quantity.
And so there's an immense
amount of information
you get from the eyes,
but it's the pairing of
what's going on in the eyes,
with everything else going
on, the body language,
the verbal content of what's coming out.
All that together is the art of psychiatry
and social interaction.
But sometimes you don't
have the eye contact.
And this is an amazing thing
and I do talk about this
in the book as well.
In many cases in psychiatry,
sometimes it's over the phone
that you have to make key decisions.
And as I recall, vividly
being as a resident,
very often you have to
take these phone calls
from people who are not in the hospital,
people you can't see,
you can't see their eyes,
you can't see their body
or anything about them,
just the sound of their voice.
And you can ask them questions,
and you have to make, in some cases,
life or death decisions.
Is this person truly suicidal?
Something like that, as
it comes up all the time.
And so I developed over
the course of training,
and I think all psychiatrists do this,
is you develop a way that
data stream you have,
whether it's the eyes or
whether it's just the sound
of a voice coming over the phone,
you learn to hone in on
that data stream you have
and focus on it and identify changes
and it's quite amazing.
I found that you can actually...
If you know a patient, you can
detect very precise changes
in mood, just from the sound of the voice.
And you can have a realization
that oh, this patient's
depression has improved
by about half, just by
the tone of their voice.
And same with eyes, with enough practice,
you can get enough information
from a single data stream
to give you some information,
but when you do have the whole picture
of that, of course, is best.
- So, so many theories out
there about excessive blinking
and lying, lack of
blinking and sociopathy.
I like to remind people
that people have varying degrees
of lubrication of the eyes,
[Karl laughs]
which also influence
the frequency of blinking and
presumably have nothing to do
with whether or not what
they're saying is true or not.
But incredible, nonetheless,
that the eyes are a portal
to overall arousal state.
I'm fascinated by the effects
of light on circadian biology
and just overall desire to be
awake or asleep, et cetera.
So the eyes are on the
outside of the cranial vault.
The vagus is outside the
cranial vault, obviously.
What about the goodies in here?
Parkinson's, we know at
least one of the major sites
of degeneration and failure
that lead to those symptoms.
I can name off any number of other things.
In your book, you talk about
the beautiful work done
with optogenetics of active
versus passive coping,
that there are areas of
the brain like the habenula
that when active, make
animals and presumably people,
passive and unwilling, or
uninterested in fighting back
against pressures of life,
whereas another region,
the raphe, you stimulate
that, and they actively cope.
They get their grit going,
and they are able to lean into life.
So, how does one get to those
structures in a focused way?
And what does the next two to
five, to 10 years look like?
- Well, this is the promise on that,
and it is on a timescale
that I think things may start to play out.
The specificity of optogenetics
is really only useful
if you have some idea of
how to use that specificity.
And actually, it's a
frustrating aspect of psychiatry
that in many cases, the most
effective treatments we have,
have the least specificity,
electroconvulsive therapy
being a great example,
where you're causing a brainwide-
- Which looks barbaric, but
as you mentioned is effective.
- I mean, it is.
These days, it's much
more clinically safe-
- It doesn't look like one
fluid there last seen in the lab
[indistinct]
- No it doesn't.
Now it's a very clinically
safe and stable procedure,
but I would say yeah,
it's got this almost
medieval lack of specificity,
even if the procedure is
well-controlled and clinically safe
and stable, and it's not very specific.
You're causing a brainwide seizure.
How could you be less specific than that?
- And we don't know the
source of the relief.
- [Karl] We don't know-
- Presumably it's a
dump of neuromodulators
like dopamine and serotonin,
but we don't really know-
- There certainly is a
dump of neuromodulators.
We don't know that that's
the cause for the relief.
And likewise with medications,
this is an awesome and interesting thing.
Some of the most
effective antidepressants,
some of the most effective anti-psychotics
are the ones that have
the most side effects
and there are many examples of this.
For example, the most
effective anti-psychotic
is something called clozapine,
which unquestionably has
the most side effects.
It has terrible, terrible side effects.
- The D4 antagonist?
- It has basically
every receptor. [laughs]
- Does it really?
- Yeah.
- Interesting.
- Yeah, it has prominent
serotonin, prominent muscarinic,
certainly acts on dopamine receptors,
but it causes blood cell
counts change- [laughs]
- How do people feel?
So if I were schizophrenic
and I was getting auditory
hallucinations, et cetera,
and I took clozapine, what
could I expect to feel?
- Well, so you would notice side effects,
and you would notice resolution
of symptoms both and-
- So the voices would go away?
- Yeah.
- But in a good situation,
the voices would go away?
- That's right.
- But I would feel not good in my body?
- You might have dizziness,
you might have drooling,
you might have any number
of physical sensations
that would be due to these
off target effects, the medication acting
on these other receptors-
- I'm certainly not suggesting this,
but what if somebody without
schizophrenia took clozapine?
- They'd have the same side
effects presumably, yeah.
And so it would not be something
that I would recommend.
- Yeah.
Do psychiatrists take the
drugs that they prescribe?
[Karl laughs]
I just finished for the third time,
Oliver Sacks' autobiography
which is marvelous
and I highly recommend to people.
He certainly took a lot of drugs,
not as part of his professional role,
but just out of curiosity,
what is the interest
or kind of role of drugs
in the field of psychiatry?
Because I would imagine for a group
of very curious introspective people
who are making recommendations
about what to take,
there could actually be some
benefit for understanding
what the experience of
those drugs was like
for their patients.
- I think that's true.
And I will say that probably
many or most psychiatrists
have sampled the number of
these for exactly the reason
that you're saying is to understand better
and to help treat their patients better.
And I've spoken to people
who have found this very helpful to know,
okay, this sleep disruption
caused by this medication
or the libido disruption caused
by this other medication.
Wow, that is a big effect.
And it really helps with empathy
for the patients to understand.
- I'm not suggesting that
physicians or anybody
experiment with drugs, but
I am relieved to hear that,
because I think that when you're talking
about accessing somebody's mind
and their basic physiology,
as you've mentioned, relate
to appetite, libido and sleep,
really, one is acting as a mechanic
of the person's whole experience.
They walk out of the office
and they have a life experience
that extends beyond the script.
- Yeah.
And so at the same time though,
you can't let that completely
guide your clinical decisions,
because as I mentioned,
some of these medications
that have the most side effects,
they are also the most effective
and clozapine is a great example.
That will work in patients
where nothing else works.
And believe me, we don't take the step
of clozapine prescription lightly,
because of all these side effects.
You have to come in for
a weekly blood cell,
or every few weeks of blood cell check,
to make sure that the blood
counts are not off for example,
but there are patients where
no other medication works
for the schizophrenia and
clozapine works amazingly well-
- That's marvelous.
- And so we do it, even though
there are the side effects.
And so then this comes
back to your question,
what if we had better
and better specificity?
Well, only if we know exactly
what we're doing is the point.
And so because as we become more refined,
we'd better be right about
where we we're refining to..
- And do you imagine
a day where it will be
a single, maybe even
outpatient neurosurgery,
would go in through the
skull or the back of the ear,
deliver a small viral injection
of one of these adenoviruses,
a little sticker of light-emitting diode,
deep in the brain, is that
how you envision this someday?
- That certainly could happen.
What I actually prefer as a
vision is still medications,
because those are minimally invasive.
If we knew what we were doing,
we could make them more specific,
have fewer side effects,
but optogenetics, that will arm us
with true causal understanding.
And so we'll know,
and we're already moving
rapidly toward this point,
we'll know okay, this symptom,
loss of pleasure in life
that we call anhedonia,
or the loss of motivation or energy
to overcome challenges, active coping,
these are largely subserved,
largely controlled
by this circuit or that
circuit or the cell
that inhabits this other circuit.
- And we will know that
because of the work done
with channelopsins?
- Exactly.
- Yeah. I agree.
- In ways that we never could
have the confidence otherwise.
And so we'll know that this is the circuit
that underlies the
symptom or its resolution.
And then we'll get to understand
these cells very deeply,
okay, these cells that are
causal, that do matter,
who are they? What's their wiring?
What are the proteins that they make?
What are the little things
that are on the surface
of the cell that could be
receptors for specific medications
or combinations of receptors
that would give us the
specificity we need?
And then, armed with
that causal and precise
and rigorous knowledge,
then you can imagine
medication development
becoming totally different,
no longer serendipitous, but
truly grounded in causality.
- I see.
So using channelopsins as a
way to probe the circuitry
and figure out the sites
that are disrupted,
what patterns of activity are required?
And then, by understanding the
constituents of those cells,
like what they express and what they make,
then developing drugs that
could target those cells,
not necessarily putting
light-inducing diodes
into the brain, or walking
around with wire packs
attached to our skull
or something like that.
- [Karl] Right. Exactly.
- That's fantastic.
And I realized no one has a crystal ball,
but what do you think the arc of that is?
Meaning, are we going
to see that in a year?
In two years? Three years?
Let me reframe that.
How soon will a pill-based treatment
for a psychiatric disease be available,
that targets a specific set of cells
that we know are important
because of the work done
with channelopsins?
- I think that in some
ways it's already happening
at the level of individual patients-
- Here at Stanford?
- Yeah. Yup.
And more broadly in terms of new drugs,
new multi-centered clinical
trials that will play out
over the next few years.
And these could be drugs
that are already safe
and approved for other purposes,
but we might say okay, now we know
that this medication,
based on what we know
from causal optogenetics,
this could be useful
for this other purpose,
this psychiatric symptom.
And so the path to helping patients
could be relatively swift.
- That's very exciting.
What are your thoughts about
brain machine interface
and Neuralink always comes up,
although I do want to point
out a tremendous respect
for the folks at Neuralink
including someone who
came up through my lab,
is now there as a neurosurgeon,
but the brain machine
interface is something
that's been happening for a long time now,
some of the best work, among
the best work being done here
at Stanford and elsewhere too of course,
is what you just described compatible with
or different than brain machine interface,
meaning devices, little
probes are going to stimulate
different patterns of activity
and ensembles of neurons?
And what are your general thoughts
about brain machine
interfaces going forward?
- I mean, first of all,
it's an amazing scientific
discovery approach,
as you mentioned, we and
others here at Stanford
are using electrodes,
collecting information
from tens of thousands of neurons-
- In humans, I should
add. Yeah. [chuckles]
- And even, yes, it is quite even separate
from the Neuralink work as you point out,
many people have been
doing this in humans,
as well as in non-human primates.
And this is pretty
powerful, it's important.
This will let us understand
what's going on in the brain,
in psychiatric disease
and neurological disease,
and will give us ideas for treatment.
It is, of course still invasive.
You still are talking about
putting a device into the brain.
And that has to be treated
as a situation that has some risks,
and a step that has to be taken carefully.
I see that as something
that will be part of
psychiatry in the long run,
already with deep brain
stimulation approaches,
we can help people with
psychiatric disorders.
And that's putting just
a single electrode,
not even a complex closed loop system
where you're both playing in
and getting information back,
even just a single stimulation
electrode in the brain
can help people with OCD, for
example, quite powerfully.
And that will become much more powerful
when we get to a true
brain machine interface,
collecting information back,
stimulating only when you need to.
If we could identify a
pathological activity pattern,
a particular, almost like the prodrome
or the early stage of a seizure,
maybe there are events
that happened leading up to
on some timescale, a psychiatric symptom
that we could intervene
in a closed loop way
to detect what's happening,
what's starting to go wrong,
feed that back to the brain
stimulation electrode,
have it be in that way more
efficient and more principled.
I think it's great.
It's something that of
course will be grounded again
and causal understanding,
we'll need to know,
what is that pathological
pattern that we're detecting?
And we need to know that it matters.
And so again, that's where
optogenetics is helping us.
It's helping us know, okay,
this pattern of activity
in these cells and these
circuits, this does mean
that there's a particular kind
of symptom that's happening.
But armed with that knowledge, absolutely,
even the simple closed loop
device detect and stimulate
is going to be part of
psychiatry in the future.
And then of course, as
you get to more cells,
more connections, the ability
that we have to help people
will become more powerful.
- One of the questions I get
asked a lot is about ADHD
and attention deficit of various kinds.
I have a hunch, that one
reason I get asked so often
is that people are feeling
really distracted and challenged
in funneling their attention
and their behavior.
And there are number of
reasons for that, of course,
but what is true ADHD, and
what does it look like?
What can be done for it?
And what if any role for channelopsins
or these downstream technologies
that you're developing,
what do they offer for
people that suffer from ADHD
or have a family member
that suffers from ADHD?
- This is a pretty interesting
branch of psychiatry.
There's no question that
people have been helped
by the treatments, there's active debate
over what fraction of people
who have these symptoms
can or should be treated?
- This is typically Adderall
or stimulants of some kind?
- Yeah, for example the
stimulants, that's right.
So ADHD as its name
suggests, it has symptoms of,
it can have either a hyperactive state
or an inattentive state,
and those can be completely
separate from each other.
You could have a patient who effectively
is not hyperactive at all,
but can remain focused
on what's going on around them-
- So the body can be still,
but their mind is darting around?
- That's right.
- Or they can be very
hyperactive with their body.
- Yeah, it happens both ways.
- Probably rarely is somebody
hyperactive with their body
but their mind is still,
[Karl laughs]
although I have to say,
and this is a benevolent
shout out to Botond Rosca,
Botond has an incredibly
sharp and focused mind.
- Yeah.
- And his hand movements
[Karl laughs]
are extremely exact also,
so I do sometimes wonder, whether or not
our body movements and our head movements,
whether or not they're coordinated or not
is a readout of how
directed our attention is.
- I noticed, I have to think
complex, abstract thoughts.
I noticed I have to be very still.
So my body has to be
almost completely on moving
for me to think very
abstractly and deeply.
Other people are different.
Some people, when they're running,
they get their best thoughts.
I can't even imagine that.
My brain does not work that way at all.
I have to be totally motionless, [laughs]
which is kind of interesting.
- How do you go about that?
- I sit much like this, I
try to have time in each day
where I'm literally sitting
almost in this position,
but without distraction and thinking,
and so it's almost
meditative in some ways,
except it's not true meditation,
but I am thinking, well, I'm not moving-
- You're trying to structure
your thoughts in that time?
- Yeah.
- Interesting.
- Yeah.
So, but everybody, as you
say is very different.
And so with ADHD, the key
thing is we want to make sure
that this is present across
different domains of life,
school and home, to show that it really
is a pervasive pattern,
and not something specific
to the teacher or the home
situation or something.
And then you can help patients.
It's interesting that ADHD
is one of those disorders
where people are trying to work
on quantitative EEG-based diagnoses,
and so there's some progress
toward making a diagnosis
looking at particular,
externally detectable brainwave rhythm-
- So skullcap with some electrodes
that don't penetrate the skull?
- That's right.
- And this can be done in
an hour or two-hour session?
- Yeah, that's right.
- It has to be done in a clinic, right?
- Yeah, in the clinic, right,
and you have to have the
right recording apparatus
and so on,
but in principle, increase
in confidence comes
in exactly which measurements
one could even imagine
moving toward home tests,
but we're not there yet.
- Amazing.
I think one of the reasons
I get asked about it so much
is a lot of people
wonder if they have ADHD.
Do you think that some
of the lifestyle factors
that inhabit us all these days,
could induce a subclinical
or a clinical-like ADHD?
I look at people's phone
use including my own,
and I don't think of it like addiction,
it looks to me and feels
to me more like OCD.
And I'll come clean here by
saying when I was younger,
when I was a kid, I had a grunting tic.
I used to hide it.
I actually used to hide in the closet,
'cause my dad would make me stop.
And I couldn't feel any relief of my mind
until I [grunts] would do this.
And actually now, if I get very tired,
if I've been pushing long
hours, it'll come back.
- Interesting.
- I was not treated for it,
but I will confess that
I've had the experience
of, I always liked sports where
I involved a lot of impact,
fortunately not football,
because I went to a high school
where the football team was terrible.
Maybe that would have avoided more impact,
[Karl laughs]
but things like skateboarding, boxing,
they bring relief.
I feel clarity after a
head hit, which I avoid,
[Karl laughs]
but I used to say that's the only time
I feel truly clear for a while.
And then eventually it dissipated.
By about age 16, 17, it just disappeared.
So I have great empathy
for those that feel
like there's something contained in them
that won't allow them to focus
on what they want to focus on.
And these days, with the phone
and all these email, et cetera, I wonder
and I empathize a bit
when I hear people saying
like, "I think I might have ADHD or ADD".
Do you think it's possible
that our behaviors
and our interaction
with the sensory world,
which is really what phones
and email really are,
could induce ADD or reactivate it?
- This is a great question.
I think about it a lot,
and you mentioned this
tic-like behavior in yourself,
it's very common that people who have tics
have this building up of something
that can only be relieved
by executing the tic which
can be a motor movement
or a vocalization or even a thought.
And people do, I think
these days, do have this.
If they haven't checked
their phone in a while,
they do have a buildup
and buildup and buildup
until they can check it and relieve it.
And there's some similarities,
there is a little reward
that comes with the checking.
But the key question in all of psychiatry,
what we do is we don't diagnose something
unless it's disrupting what we call social
or occupational functioning.
Like you could have
any number of symptoms,
but literally every
psychiatric diagnosis requires
that it has to be
disrupting someone's social
or occupational functioning.
And these days, checking your
phone is pretty adaptive.
That pretty much helps your social
and occupational functioning.
And so we can't make [chuckles]
it a psychiatric diagnosis.
- Interesting.
- At least in the world of today.
- Yeah, opting out of communication now,
makes you in some ways less adaptive,
though I would point to you as an example
of somebody who is quite good
at managing his interactions,
at least from the outsider perspective,
I do want to ask you a
little bit about you.
And first of all, and I realize
this is only a partial list,
but you're a clinician, you see patients,
you run a big laboratory,
how many people are in
your laboratory now?
That's a huge laboratory.
From experience, I can say
that's an enormous laboratory.
You have a family of five children,
and you're happily married to
a wonderful colleague of ours
as well, who does incredible work.
How do you organize at a
kind of conceptual level,
the day and the week?
And I should say, what stress
mitigation practices if any,
do you incorporate?
I've received emails from
you at three in the morning.
I sometimes send emails
at three in the morning,
but that's when I wake
up, maybe I'm depressed,
but I go back to sleep.
So, maybe just describe
the arc of the blocks
of the day, not hour by hour,
necessarily the details of
what are in those blocks,
but how do you conceptualize the day?
How do you conceptualize the week?
And how do you feel
about how that's lined up
with your larger goals
of making sure these five
young people flourish?
Which I hear they are,
but how do you go about
this, what for most people
would just be an
overwhelming set of items?
- Well, of course sometimes
it's just take it day by day,
and so I don't claim-
- So you bring the horizon
into the unit of the day?
- I do, I do.
The unit is the day, that's right.
And I try to have in each
day, as I mentioned earlier,
at least an hour of
time where I can think,
and it can be when kids are napping,
actually, because while
driving I can do that too,
because I'm sitting still, [clears throat]
but that's the one
thing I try to preserve.
When I was writing the
book, I adapted that time
to be my writing time,
but it wasn't enough,
so I had to add in a new block of time
which was sort of midnight
to 2:00 AM, writing time.
[chuckles] And carving out
these, even small protected times
are very important.
Of course, obligations will expand
to fill the time available and
you have to be disciplined.
At least I found I had to be disciplined
in truly protecting those
times where one can think.
- So that means no phone?
- That means no phone,
no checking of the phone.
When I was writing the book,
there's a focus mode on the MacBook
which kind of rules the border,
and you just have your
documents and it's very pure,
and you don't have the
temptation of distraction.
- I'm a big believer in because
the vision and the eyes play
such a prominent role in
directing our cognition,
something you talk about in the book,
really beautifully, and with
a lot of depth and rigor,
using visual tools
to harness one's complete
mental attention.
When you do this practice of
sitting and just thinking,
sitting still and thinking,
you said your eyes are open.
Are you hearing your own verbal voice,
although in your head?
- Yes.
- So you're actually in
conversation with yourself?
- Yes.
And hearing literally, I
mean, not quite literally,
I don't actually hear information,
but I'm hearing words,
and so I discovered this about myself.
Other people, I think
may operate differently,
but I'm extremely verbal in how I think.
That's how all my reasoning is done.
It's with sentences and
[chuckles] construction
of almost equations with words.
- Complete sentences?
- Complete sentences
or complete-ish anyway,
mostly complete, and
when writing the book,
everything about the writing,
every sentence was always
played out in my mind,
listening for rhythm and timing,
and I would obsess over
exact placement of words
to get the right rhythm of the
spoken sentence in my mind.
- I don't mean to interrupt your flow,
but when you do that, and
having experienced this process
a bit, although differently,
do you experience any kind
of welling up of anxiety
when you're hitting the friction points?
And if so, do you have tools or ways
that you quell that anxiety in real time?
'Cause what we're really
talking about here is your mind.
But what we're really
talking about is this process
of converting the activity of neurons,
into something physically
concrete in the world.
And these intermediate steps
are so mysterious to everybody.
We hear, "Just write the book",
"Just do it", whatever that means.
In fact, statements like that to me
are kind of empty and meaningless,
but when you hear your voice
and you're trying to find the correct word
and you keep hitting, it
doesn't sound quite right,
what is the experience in your body?
- Yeah, when it's not right,
it's definitely evasive,
it doesn't feel good,
but there's also a hope because
I know I can solve it too,
and it's almost like you're almost there.
There's a path that you know is there,
you don't quite see it, but it's there.
And I keep that in mind,
and so there's this
propulsive force forward
because I know that the solution is there.
And that said, there were single words
that I would spend days on,
because I was just not
happy until I got it right.
And there were some things
that I never quite got perfect,
and so I left out of the book entirely
because it was so close,
but not quite there.
And I was like, no, I can't put that in.
- Everything you just said
is entirely consistent
with my experience of you,
[both laughing]
and the way you go about everything.
I have to ask, are your kids writers?
Do they like books and words and poetry?
I know one of your children is going on
to a career in medicine and science.
- Yeah.
They're each different which is amazing,
yet they all, I think do
have some appreciation
or a lot of appreciation for reading,
but some are very musical.
Two of the five are extremely musical,
very, very talented with
guitar and singing and vocal,
impressions, it's just astonishing.
And some of them are great
with drawing and artistry
and some are very physical and vigorous
and are never happy
except when leaping about.
And so, it's just amazing how
different they are, honestly.
But I think there is a shared
appreciation for language.
- Do you think that one
can train their mind
in using these practices?
I really like your description
of the staying physically still
and learning to grapple
with those challenges.
It's something that, especially
in laboratory science,
we aren't really trained to do.
Like many professions
we're taught to come in
and just get into motion, and
I found that very relaxing
as someone who probably
has an underlying tic
[Karl chuckles]
or something like that,
it felt great to be in motion.
One of the hardest things
about becoming a university
professor and running a lab,
was that I no longer
working with my hands.
And it felt like some big
important part of my life
had been amputated.
But what sorts of practices
do you incorporate there?
And do you think people can
learn to get better at focusing
through a dedicated practice
of the sort that you described?
- I remember the rhythms of physical work
in the laboratory very well.
My work these days as
the laboratory leader,
my job has returned mostly
to words now, again.
And so it's kind of coming full circle.
So it's a different mode.
I think you just have to
embrace the different stages
of life, come with the different modes,
but you can definitely train
yourself for each mode.
I loved, as I mentioned,
the rhythm of sewing
and suturing and surgery,
and I worked really hard on
that and became good at it.
And now, I never do it, but
it's what's the next challenge.
There's all the various
experimental techniques
the dissections of the brain,
I can't tell you how many
thousands of brain dissections
I've done in my life, and
now I don't do them at all.
[Karl laughs]
- And then you developed a method
so that we don't have to dissect brains.
- That's right. [chuckles]
- As you mentioned there,
maybe tell us for a moment about clarity,
and for people who will
probably never set foot
into a laboratory, what an incredible,
yet another incredible discovery
and development clarity is,
and why it helps us understand
how the brain is structured.
- Yeah.
So this is a different technology
also developed in my lab
here, and it's part of a broader approach
that we call hydrogel-tissue chemistry.
And what this is, is it's building a gel,
like a clear jello-like substance
from within all the cells
of a tissue or even an
animal, all at once.
So you're effectively building a gel
inside all the cells at once.
Now, that's an odd thing to do.
Why do we do it?
Well, we do it to transform the tissue
into a more tractable accessible object.
And the reason that works
is having built this gel,
this new infrastructure inside the tissue,
we can then use chemical tricks,
and we can link the
molecules we care about,
like proteins or RNAs
which are the things,
as you know, right before
they become proteins,
we can link them, physically
anchor them to this gel,
which is a scaffold basically,
it's an interlocking network of polymers.
We can link all these
interesting molecules in place,
lock them in where they were
initially in the tissue,
in the cell, in all the cells.
And then we can remove very vigorously,
everything we don't care about
that's blocking our light,
that's blocking our molecules,
coming in to exchange
information with the tissue.
We can get rid of everything
else, like the lipids,
the fats, we can
effectively use detergents
to get them all out,
and then we can see in
all the things that were
absorbing or scattering light
are gone, you can have a brain
that's completely transparent,
and yet, all the interesting
molecules are still locked
into place there, at the
cellular and sub cellular level.
And so this is hydrogel-tissue chemistry.
The first form we described
was called clarity.
We use that quite a bit still,
but there are many variants now,
that we and others have
developed on this basic concept
of building this gel within the tissue
and anchoring molecules into place.
- Literally glass-clear brains.
I've done this, I've taken a
brain cleared with this method,
and looked at somebody through it,
[Karl laughing]
and although you don't want to
get it too close to your eye,
you don't want to touch
it to your own eye,
and you can see direct
all the way through it.
- [Karl] Yeah.
- That's incredible for it
raises an important question,
which is again, about the human brain,
and as somebody who essentially
started out in neuroanatomy
and then got into other things,
I always am bothered by the
fact that we actually know
very little about the
microstructure of the human brain,
compared to the brains of other organisms.
- Yeah.
- And in thinking about
understanding the circuitry
and the piano, so to speak
and how to manipulate it
in order to relieve suffering,
one wonders, are the structures
in these animal brains
and how they behave, and
active coping, passive coping,
ADD, et cetera, those models,
how well they translate
to the human condition.
Do you think it's fair to say
that there are entire regions
of the human brain that
aren't just bigger,
but that exist only in
the brains of humans?
Especially given that we have this speech,
although I do wonder sometimes
if animals report in to each other there.
Maybe they have little
psychiatric sessions
with one another.
- You know, I'm always
careful to not assume
we do things better.
We certainly understand what we're doing
better than we understand
what animals are doing,
and they certainly do
things better than we do.
That said, we do have
amazing, wonderful brains
and many structures that
are very highly developed
in our brains that are
not nearly so developed
in mice and fish for example.
Now, that said, when I
look at the big picture,
what is the mammalian brain really doing?
There are things that you
would never have thought
we could study in animals and
laboratory mammals like mice,
that it turns out you can, actually,
and so I would never draw the line
and say, here's something
you can't study in mice,
or here's something that
has no parallel in mice.
I would be very careful
before making any statement like that.
And a good example of that
is we've been able to study
just in the past year,
come to an understanding
of dissociation, and we had a paper
that came out in late 2020,
both mouse and human work,
in which we got to the
sort of the circuit basis
for dissociation.
Now, what is dissociation?
A lot of people might
not have experienced it,
but it's actually very common.
More than 70% of people
who've been through trauma
experience dissociation,
it shows up in borderline
personality, it shows up in PTSD.
What it is, is a separation
of the sense of self,
from the body.
So you can have someone who,
it's not as if you're numb,
you're not anesthetized.
You can still know that
something's happening to the body,
but you just don't care,
because you don't ascribe it to yourself,
which is very interesting, right?
How interesting is that?
- The cells report narrative.
- Yeah. Yeah.
- In your book, you touch on this.
And I will say is the most precise,
and meaningful and eloquent description
of what might be consciousness,
this narrative toward
the self or of the self,
and where it might reside.
So in dissociative conditions,
people are feeling as kind
of an absence of a merge
between mind and body.
- Right.
- Is that one way to describe it?
- That's right.
- And as I recall,
this paper involved an
exploration of ketamine.
- Ketamine was a big part of it.
Yeah, that's right.
And so ketamine is
another one of those cases
where people can experience dissociation.
Ketamine or PCP, we call
these the dissociative drugs.
They cause it just like these
other psychiatric conditions
can cause it.
But we were able to manifest this in mice,
administering these
dissociative agents in mice.
We could make them still
able to detect stimulus,
but not care that it was happening.
All the while we were recording
the activity of individual
cells in the brain
to see what was going on,
what was happening along
with this dissociation,
and then use optogenetics
to see that it mattered
to actually provide
that pattern of activity
and see, oh, that actually
causes the dissociation.
So we could do all that in mice,
which who would've thought
that you could study something
like this in mice?
And we were able to go back
and forth with human work
because here in our Stanford
Comprehensive Epilepsy Center,
there's a lot of what we
call Stereo EEG Recording.
Patients who come in
and in the course of normal clinical care,
they have electrodes
recording in their brain
to identify where the seizure is,
so they can be candidates
for removing a little patch
of the brain that's causing the seizure.
This has done for patients who
medications are not helping
their seizure disorder.
And there was a patient who
had a dissociative state
before every seizure, so
this was a human being
who was really dissociating,
who could tell us literally
as it was happening.
And we could see this
pattern, the same pattern
that was happening in the
mice, in the same patch
of the brain, we could see that happening
in the human being at
exactly the right time,
in the same patch of the
brain that's homologous
across these immense
evolutionary distances.
And we knew that it mattered
to both the mouse and human
because in the human we
could cause it to happen.
- I just want to underscore the power
of optogenetics and the ability
to not just remove a particular
experience or behavior
by lesioning or destroying,
but then to go back
and actually activate same
structure or group of structures
and see the emergences.
So essentially, these days you hear a lot
about gain of function research
in the context of viral manipulation,
but gain of function is something
that we do in the laboratory
and you do in patients, to
both take away something
and put it back, which
gives you causality.
- That's right.
Yeah, and exactly.
And so with optogenetics,
we were able to provide
in animals without being
on any ketamine or any drug
and we could cause the dissociative state
by playing in a precise
pattern of activity.
And who would have
thought you could do that?
But that was a combined
mouse and human paper.
Likewise, we've been able
to play in visual sensations
into the brains of mice,
and by observing which cells
in the visual part of
the brain, visual cortex,
are naturally responsive to
for example, vertical bars,
instead of horizontal
bars in the visual world,
we could see which cells
were normally reporting
on vertical bars, and then
we could use optogenetics
to come and play in activity
just to those cells.
- So these animals are
not viewing anything?
- Not viewing anything at all.
And we could activate just
the vertical bar cells,
and not only did the animal act
as if it was seeing a vertical bar,
behaviorally, it was trained
to do a particular thing
if it saw a vertical bar, and it did that,
just as if it was seeing
something visually.
But everything in the brain
that we were recording
to the internal representation
of this external world
was naturalistic too.
It looked like the brain
was seeing something visual.
So that's gain of function too, you know,
playing in, providing a
complex sensation or percept
that wasn't there before.
And we can do that across species.
So, and of course mice are social,
and they do amazing acts
of information processing
and I try not to disparage
our cousins too much.
- They certainly have helped
the field of neuroscience
and medicine I should mention,
and I know that people
have various sensitivities
about animal research, but the
work that's been carried out
in mice has been absolutely
vital and instructional
for treatment of human disease.
- That's right.
- Since we talked about
dissociation and dissociative states
rather and ketamine,
I'd love your thoughts
on psychedelic medicine.
You know, I sort of half joke
having grown up in this area
in Northern California when it
was much more counter-culture
than it is now, that many of the things
that we're hearing about now,
at least from my read
of the history books,
happened before.
There was a movement
aimed at taking the very
same compounds essentially,
putting them into patients
or people who were obviously
using them recreationally,
but putting them into patients,
and seeing tremendous positive effects,
but also tremendous examples
of induced psychiatric illness.
In other words, many
people lost their minds
as a consequence of
overuse of psychedelics.
I'll probably lose a few people out there,
but I do want to talk
about, what is the state
of these compounds?
And I realize it's a huge
category of compounds,
but LSD and psilocybin, as I
understand trigger activation
of particular serotonin
receptor mechanisms,
may or may not lead to
more widespread activation
of the brain that one
wouldn't see otherwise.
But when you look at the clinical
and experimental literature,
what is your sort of top contour sense
of how effective these
tools are going to be
for treating depression?
And then if we have the time,
we could talk about trauma
and MDMA and some of that work.
- Well, you're right to
highlight both the opportunity
and the parallel that is there.
And of course we want to help patients
and of course we want to explore anything
that might be helpful,
but we want to do it in
a safe and rigorous way.
But I do think we should
explore these avenues.
These are agents that alter reality
and alter the experience
of reality I should say,
in relatively precise ways.
They do have problems,
they can be addictive,
they can cause lasting
change that is not desirable,
but we have to see these as opportunities.
We have to first of all,
study in the laboratory,
and I'm doing this here.
You know we have [chuckles] big...
We have safes with many
interesting psychedelics
that are all very carefully regulated.
We get inspections from the DEA and so on.
- If anyone's hoping to find these labs,
[Karl laughing]
they exist in outer space,
so you need to be on board
one of the SpaceX missions
in order to access them.
So don't try and come find them.
- No, that's exactly true. Yes.
And we're doing exactly this.
We're saying this is an
incredible opportunity.
If we could understand how
the perception of reality is altered,
we could be creating new
kinds of intervention
that don't have the risks
and the problems of causing
lasting change or addiction.
Now, that said, even as
these medications exist now,
as you know, there's
an impulse to use them
in very small doses and to use
them as adjunctive treatments
for the therapy of various kinds.
And I'm also supportive
of that if done carefully
and rigorously, of course there's risk,
but there's risk with many
other kinds of treatments.
And I'm not sure that the
risks for these medications
vastly outweigh the risks
that we normally tolerate
in other branches of medicine.
- Why would they work?
I mean, let's say that
indeed their main effect
is to create more connectivity,
at least in the moment
between brain areas.
So the way I think about the two extremes
of my experience anyways,
a high degree of stress and
focus for whatever reason,
is going to create
changes in my visual field
and changes in the way
that I perceive times,
so that I'm on a micro-sliced time,
I might be in a very contracted view
of whatever my experience is,
whereas on the opposite
extreme in a dream or in sleep,
space and time are very fluid,
and I'm essentially relaxed,
although it might be a
very interesting dream,
or it might not be.
Psychedelics seemed to be a trajectory.
I'm not too far off from the dream state
where space and time are
essentially not as rigid.
And there is this element of synesthesia,
blending of the senses, you know,
feeling colors and hearing
light and things of that sort.
You hear these reports, anyway.
Why would having that
dream-like experience
somehow relieve depression, long-term?
Do we have any idea why that might be?
- Yeah.
We have some ideas, and
no deep understanding.
One way I think about the psychedelics
is they increase our willingness to...
They increase the willingness of our brain
to accept unlikely ways
of constructing the world,
unlikely hypothesis, as it
were, as to what's going on.
The brain, in particular
our cortex, I think,
is a hypothesis generation
and testing machine.
It's coming up with
models about everything.
It's got a lot of bits of data coming in,
and it's making models
and updating the models
and changing them, theories,
hypothesis for what's going on.
And some of those never
reach our conscious mind.
And this is something I
talk about in "Projections"
in the book quite a bit, is
many of these are filtered out
before they get to our
conscious mind, and that's good.
Think how distracted we'd be
if we were constantly
having to evaluate all these
hypotheses about what
kinds of shapes or objects
or processes were out there.
And so a lot of this is handled
before it gets to consciousness.
What the psychedelics seem to do,
is they change the threshold
for us to become aware
of these incomplete hypotheses
or wrong hypotheses,
or concepts that might be
noise but are just wrong,
and so are never allowed to
get into our conscious mind.
Now, that's pretty interesting,
and it goes wrong in
psychiatric disorders.
I think in schizophrenia
there's some of the times
the paranoid delusions that people have
are examples of these poor models
that escape into the conscious mind
and become accepted as reality
and they never should've gotten out there.
Now, how could something
like this in the right way,
help with something like depression?
Patients with depression often are stuck.
They can't look into the
future world of possibilities
as effectively.
Everything seems hopeless.
And what does that really mean?
They discount the value
of their own action,
they discount the value of the world
at giving rise to a future that matters.
Everything seems to run out like a river
just running out into
a desert and drying up,
and what these agents may do
that increase the flow through
circuitry, if you will,
the percolation of
activity through circuitry
may end up doing for depression
is increasing the escape of some tendrils
of process of forward
progression through the world.
That's a concept, that's
how I think about it.
There are ways we can make that rigorous.
We can indeed identify in
the brain by recording,
we can see cells that
represent steps along a path
and look into the future,
and we can rigorously define these cells
and we can see if these are
altered on psychedelics.
And so that's one of the reasons
that we're working with these
agents in the laboratory
to say, all right, is
this really the case?
Are these opening up new paths
or representations of
paths into the future?
- MDMA, ecstasy is a unique compound
in that it leads to big increases
in brain levels of dopamine
and serotonin simultaneously.
And I realized that the neuromodulators
like dopamine and serotonin
often work in concert,
not alone, the way
they're commonly described
in the more general popular discussions.
However, it is a unique compound,
and it's different than
the serotonergic compounds,
like LSD and psilocybin.
And there are now data,
still emerging that it might be,
and in some cases can be useful
for the treatment of trauma,
PTSD and similar things.
Why would that work?
And a larger question, perhaps
the more important question
is, psychedelics, MDMA,
LSD, all those compounds,
in my mind there are two components.
There's the experience you
have while you're on them,
and then there's the
effect they have after.
People are generating
variations of these compounds
that are non-hallucinatory variations.
But, how crucial do you think it is
to have, let's stay with MDMA,
the experience of huge levels of dopamine,
huge levels of serotonin,
atypical levels of dopamine
and serotonin released,
having this highly abnormal experience
in order to be normal again?
- Yeah.
I think the brain learns
from those experiences.
That's the way I see
it, and so for example,
people who have taken MDMA,
as you say, there will be the acute phase
of being on the drug
and experiencing this
extreme connectedness
with other people for example,
and then the drug wears off,
but the brain learned
from that experience.
And so what people will report is,
yeah, I'm not in that state,
but I saw what was possible.
I saw it. Yeah.
There don't need to be barriers,
or at least not as many
barriers as I thought.
I can connect with more people
in a way that that is helpful.
And so I think it's the learning
that happens in that state,
that actually matters.
- And as you described that,
that sounds a lot like what I understand
to be the hallmark feature of
really good psychoanalysis,
that the relationship between
patient and therapist,
hopefully evolves to the point
where these kinds of tests can be run
within the context of that relationship,
and then exported to other relations.
- Exactly right. Yeah.
- And that probably, I'm assuming
is still the goal of really
good psychiatry also.
- As a part of-
- Intimacy, really.
- It should be.
When we have time, I think
all good psychiatrists
try to achieve that level
of connection and learning,
try to help patients create
a new model that is stable,
that is learned, and that can
help instruct future behavior.
- One of the things that I
took from reading your book,
in addition to learning so much science
and the future of psychiatry
and brain science was,
amidst this very tragic cases and sadness,
and a lot of the weight that
that puts on the clinician,
on you also, that there's
a central cord of optimism,
that where we're headed
is not just possible
but very likely, and better.
- Yeah.
- And, are you an optimist?
- [chuckles] I am.
And by the way, this was a
really interesting experience
in writing "Projections",
because I had a dual goal.
I wanted it to be for everybody,
literally everybody in the
world who wants to read it.
And yet at the same time,
I wanted to stay absolutely
rigorously close to the science,
what was actually known, when
I was speaking about science.
When I was speaking about
the neurobiology of the brain
or psychiatry, I wanted to not have
any of my scientific colleagues
think, oh, he's going too
far, he's saying too much.
And so I had these two goals
which I kept on my mind the entire time.
And a lot of this trying to
find exactly the right word
we talked about was, on this path
of staying excruciatingly
rigorous in the science
and yet, letting people see the hope,
where things were, have everybody see
that we've come a long way,
we have a long way to go,
but the trajectory and
the path is beautiful.
And so that was the goal, I think.
Of course that sounds almost impossible
[chuckles] to jointly
satisfy those two goals,
but I kept that in my mind
the whole way through.
And yes, I am optimistic
and I hope that it came
through in the book
- It certainly did, and at
least from this colleague,
you did achieve both.
And it's a wonderful, it's
a masterful book, really,
and one that as a scientist
and somebody who is a
fellow brain explorer,
hits all the marks of rigor
and is incredibly interesting
and there's a ton of storytelling.
I don't want to give
away too much about it,
but people should definitely
check out the book.
Are you active on social media?
If people want to follow you
and connect with what you're
doing now and going forward?
- Yeah. I have Twitter.
That's where I mainly do exchange,
tell people about things
that are happening.
- We'll provide a link to it,
but that's Karl Deisseroth,
as I recall, with a K?
- That's right.
- Yeah.
- That's right.
- And so you're on Twitter,
and people will hear this,
definitely check out the book.
There are other people in our community
that of course are going to be
reaching out on your behalf,
but it's incredible that you juggle
this enormous number of things,
perhaps even more important however,
is that it's all in service
to this larger thing
of relieving suffering.
So thank you so much for your time today,
for the book, and the
work that [chuckles] went
into the book, I can't even imagine,
[Karl laughs]
for the laboratory work
and the development of
channelopsins, clarity,
and all the related technologies
and for the clinical work you're doing
and for sharing with us.
- Well, thank you for all
you're doing in reaching out.
I'm very impressed by it.
It's important and it's so valuable,
and thank you for taking the time
and for all your gracious
words about the book.
Thank you.
- I hope you enjoyed today's
discussion with Dr. Deisseroth
as much as I did.
Be sure to check out his new book,
"Projections: A Story of Human Emotions".
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