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 Carl’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 for understanding

how the brain works more generally.

We also discuss issues of consciousness,

and we even delve into how somebody like Carl,

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 Carl’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 Carl 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,

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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.

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, you know, I’m married to a neurologist,

and I am a psychiatrist,

and we make fun of each other all the time.

So this is a lot of neuroscientists

and a lot of brain clinicians actually think

these two should be 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,

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 measurables.

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 hyperverbal, that you have an easier time

diagnosing them, as opposed to somebody

who’s more quiet and reserved?

Or I can 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 of reduced speech.

But ultimately, you do need something.

You need some words to help guide you.

And that, in fact, there’s challenges

that I can tell you about where patients with depression

who are 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 truly severe depression.

And this is, 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 a 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 measurables at some point.

Now, is that good or bad?

I think that will be good.

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 a quick measurement.

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 have, 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.

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 there are 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.

So how, 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.

People, here we have it,

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, you know, 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, you know, how do you,

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 these, here now you’re getting into actual things

you can talk about that are unambiguous.

If someone says, yeah, I can’t even,

I can’t even think about tomorrow.

I’m not, I don’t see how I’m gonna get to tomorrow.

That’s a nice, precise thing that, you know,

it’s sad, it’s tragic, but it’s 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 the patient’s life and in their mind.

But as you say, ultimately, you know,

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,

you know, 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 that doesn’t mean we have answers.

So in this area of trying to figure out

what’s going on under the hood through words,

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, is that, if I say, for instance,

and I won’t ask you to run a session with me here for free.

We’ll do that off camera.

Okay, right.

If I were to say, you know,

I just can’t imagine the tomorrow.

I just can’t do it.

So that’s not 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.

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 these, 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 though.

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 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.

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,

you know, I’ve heard of work that’s going on,

Sam Golden up at the University of Washington,

who works on aggression and 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 kinds of metrics

will eventually inform somebody,

hey, you know, you’re in trouble?

This is getting to this question of,

back to the statement that I heard you make

and 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 ascribed 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,

you know, just inexplicably, they’re awake.

So this is like 2 a.m., 3 a.m., type of waking?

It could start, yeah, it could start at 5 a.m.,

could go to four.

And unable to fall back asleep.

Unable to fall back asleep, exactly.

So that’s, and that, they may not know what to do with that.

It could just be, 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, you know,

needing words to self-report or machines to detect

how we feel or, and maybe inform a psychiatrist

how a patient feels, I want to 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 of examples

of great successes of psychiatry, if they exist?

Yes.

Yeah, we are fortunate in this, 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 our,

the mystery we struggle with,

many of our treatments are actually, you know,

we may be doing better than some other specialties

in terms of actually causing, you know,

the therapeutic benefit for patients.

We do help patients, you know,

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 for, on average?

For a motivated, insightful patient,

you can have a very, you know, cookbook-y series of sessions,

you know, six to 12 sessions,

or even less for someone who’s very insightful

and motivated and 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.

Antipsychotic 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 the appearance

of something abnormal.

Exactly, yeah, and 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 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, you know, this is a frustrating

and yet heartening aspect of psychiatry.

There are treatments like electroconvulsive therapy,

which is 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 seize.

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 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.

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 bins 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?

Yeah, 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.

Lithium is a good example.

Is it true that it was the urine of guinea pigs

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.

The antidepressants originally arose

as antituberculosis drugs, for example.

I did not know that.

Yeah, and so this is a classic example for,

and this is across all of psychiatry.

And of course, there’s the seizures as well

that was noticed that patients who had epilepsy,

or had a seizure, and also had depression,

that they became much, at least for a while,

they were improved after the 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 what is, 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.

Now, but, and yet when you think about autism,

to take your example, yes, we see changes,

but what is the element in the brain

that’s analogous to the pumping heart?

When we think about the symptoms of depression,

that’s maybe 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?

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 theme 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 maybe we can,

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 bin 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 portions of the body

and how they connect to one another

and what the patterns of activity are

under a normal, quote unquote, healthy interaction.

If we understand that,

then it seems that the next step,

which of course could be carried out in parallel, right?

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.

You’ve been very involved in trying to generate those tools.

So tell us about channel opsins,

why you created them,

and where they’re at now in the laboratory

and perhaps also in the clinic.

Well, this is a, first of all,

I give nature the credit for creating channel rhodopsins.

These are beautiful little proteins

that are made by algae, single-celled green algae.

And it’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 Fominzin

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 when 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 delved into this a little bit.

He identified that with microscopy,

he could see that there were little single-celled 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 it turns out, these algae achieve this amazing result

with a single gene that encodes a single protein.

What’s a protein?

It’s just a little biomolecule 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 flagellar 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 neural code in our brains

for on or off.

Sodium ions rushing into cells turns them on,

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’ve put this gene into,

turn them on.

There are other options, 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,

which is living proof that people move at different rates.

And that’s a joke at my expense, by the way.

But it’s-

You’re in the same spot.

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 is, you know, 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 Andrei Fomentsin’s work in a dish.

By 2000, that was in 2004.

In 2007, we were putting these into behaving mice,

and we were able to, with 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 were 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 and safe in 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, Botan Droska in Switzerland,

succeeded in putting channelrhodopsins

into the eyes of human beings

and making a blind person 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, Botan Droska and I

had published a paper in science in human retina,

but ex-planted, 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 neurons,

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,

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,

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,

but, and that’s direct,

what you might call direct optogenetics in patients.

Indirect is everything that comes from understanding,

you know, 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 Boton well,

and you and Boton share this incredible big vision

that I think only a clinician

can really understand, you know,

being in close contact with and 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?

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 to, I think,

to embrace 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.

I was, you know, 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, just even separate from their,

you know, 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 I was, this was always fascinating to me.

So, you know, I wanted to understand that.

And so I was interested in,

and I became interested in the brain.

And I thought, well,

I’m gonna 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

and 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

that everybody has to do.

Some are elective where you can pick what you wanna do.

I elected to do neurosurgery first,

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 so I was, 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, yes, there’s, 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 definitely use all the time.

And it’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 also turns out to be an interesting city.

So you developed methods to control neurons

with these algae proteins using light.

In 2015, there was this,

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, in the clinic,

and an interaction with a patient.

So this, as I recall, a woman who was severely depressed.

You reported in that article

some of the discussion with this patient,

and then in real time,

increase 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 channelrhodopsin 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 there are often serious side effects.

Sometimes they don’t experience relief.

But as I understand it,

channelrhodopsins 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 body and then move into the skull.

Yeah, 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,

it innervates the heart, innervates the gut.

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 superhighway to the brain then

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.

That’s the reason?

That’s the reason, yes.

Really? Yeah.

You’re not kidding.

I’m not kidding.

So stimulating the vagus to treat depression

simply because it’s accessible.

It started as actually as an epilepsy treatment

and it can help with epilepsy, but yes,

you got to love medicine.

As a scientist, I got,

this is where I get to chuckle and just say,

I’m in the field of medicine from that perspective,

from the perspective of a scientist and outsider,

the field of medicine as a field that goes in

and tickles pathways because they’re there.

It’s, I don’t know what to say.

It’s a little shocking.

And we all, 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 the vagus nerve lands on a particular spot on the brain

called the solitary tract nucleus,

which is just one synapse away from the serotonin

and dopamine and the norepinephrine.

So there’s a link to chemical systems in the brain

that make it a rational 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.

You guys would have done it anyways.

Because it’s accessible, yeah.

I see, okay.

And why?

Well, it’s not to, again, not to disparage

what’s been happening in this branch of medicine.

There’s immense suffering, treatments,

many treatments don’t work, and we try things.

And this is how so many advances in medicine happen.

You 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.

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,

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 averaged 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 voice, 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 this 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 cell starting in point A

going to point B that relieves this particular symptom.

We want to fix this key on the piano.

And then I see two other steps that are required.

One is to get the channelopsin gene into the cell.

In the case of Bhutan,

Roscoe 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,

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?

Because we’re not talking about sunlight

or standing in front of a light bulb necessarily,

but 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 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?

Yeah, yeah.

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, in solving this problem for the patient.

He had to build goggles that created much brighter light

than 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, correct?

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 could you, I’m imagining in my mind as a non-engineer,

I know you’re also a bioengineer,

I’m imagining a little tiny blue light emitting thing,

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 thousandth 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 could imagine that being put under my skin.

And then I would, what, I’d hit an app on my phone

and I’d say, I’d say, Dr. Deisseroth,

I’m not feeling great today.

Can I increase the stimulation?

And you say, go for it.

And then I 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, 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, remote control.

Through a couple steps, yeah.

And I can turn up, 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 re-dosed.

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, 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?

You know, what is your mood?

And then we talk with the patient.

We decide, oh, this is not yet where we’d like to be.

And so then I can turn up the intensity

of the stimulation real time in the office.

I don’t, 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.

And so I can get a sense,

is there a, am I in a, still in a safe side effect regime?

And then, you know, I stop at a particular point

that looks safe, and then 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,

because in your book,

you describe the incredible complexity

of social interactions.

And at one point,

you described 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.

I want to make sure that we get back

to how to maneuver and manipulate the nervous system

for sake of mental health.

But what are you looking for?

So as a vision scientist,

I think, you know, pupils dilating is a sign of arousal,

but that could be a positive arousal, positive valence,

like excitement, or it could be terror.

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.

They’re just outside the cranial vault.

So they’re not unlike the vagus,

but they’re more of a report than a control knob,

although I like to think

they could be used as control knobs too.

So without putting you on the spot,

again, to diagnose me,

something I would never ask you to do

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?

The eyes are incredibly rich in information.

And as you allude to, though,

it’s not as if any one measurable

conveys all the information you need.

It’s what we, you know,

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, you know, 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,

as if it’s,

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, you know, 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, you know, in psychiatry,

sometimes it’s over the phone

that you have to make key decisions.

And as I recall, you know, 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 eye,

you can’t see their body, 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.

You know, 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 to, whatever 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 home 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,

you know, by about half,

just by the tone of their voice.

And same with eyes,

you can, 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,

that, of course, is best.

So many theories out there

about excessive blinking and lying,

lack of blinking in sociopathy.

I like to remind people that

people have varying degrees of lubrication of the eyes,

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 it’s,

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 the,

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 bannula

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 that timescale

that I think things may start to play out.

You know, that the specificity of optogenetics

is really only useful if you have some idea

of how to use that specificity.

And it’s an 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 brain-wide-

Which looks barbaric, but as you mentioned, is effective.

I mean, it is, these days it’s much more clinically,

you know, safe and stable.

It doesn’t look like one flu,

the last seen in one flu over the cuckoo’s nest.

Now it’s a very clinically safe and stable procedure,

but where 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 has a, it’s not very specific.

You’re causing a brain-wide seizure.

How could you be less specific than that?

And we don’t know the source of the relief.

We don’t-

Presumably it’s a dump of neuromodulators

like dopamine and serotonin, but we don’t-

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 also an interesting thing.

Some of the most effective antidepressants,

some of the most effective antipsychotics

are the ones that have the most side effects.

And many examples of this, for example,

the most effective antipsychotic

is something called Clozapine,

which has, it’s unquestionably has the most side effects.

It had terrible, terrible side effects.

The D4 antagonist?

It has basically every receptor.

Does it really?

Yeah, it acts-

Interesting.

Yeah, it has prominent serotonin,

prominent muscarinic,

certainly acts on dopamine receptors,

but it causes blood cell counts to change.

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.

So the voices would go away in a good situation,

the voices would go away,

but I would feel not good in my body.

You would have, 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.

And I’m certainly not suggesting this,

but what if somebody without schizophrenia took Clozapine?

They had the same side effects, presumably, yeah.

And so it would not be something that I would recommend.

Do psychiatrists take the drugs that they prescribe?

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 a 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 really been,

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 mentioned, relate to appetite, libido and sleep,

you’re 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 a 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.

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 better be right about where we’re refining to.

And 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.

Is that it 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’ll 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,

the 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 channel ops.

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 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 channel opsense

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.

That’s fantastic.

And I realize 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 channel opsense?

I think that is, in some ways,

it’s already happening at the level of individual patients.

Here at Stanford.

Yeah, yep.

And more broadly, in terms of new drugs,

new multicenter clinical trials

that’ll 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,

I have 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.

How is what you just described compatible with

or different than brain-machine interface,

meaning devices, little probes

that are going to stimulate different patterns of activity

and ensembles of neurons?

And what are your general thoughts

about brain-machine interface as going forward?

Yeah, I mean, this is, 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.

And even, yes, it’s 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, in neurological disease,

and will give us ideas for treatment.

It is, of course, it’s 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,

almost like the prodrome or the early stage of a seizure,

maybe there are events that happen leading up to,

on some timescale, a psychiatric symptom,

we could intervene in a closed loop way,

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.

This is, I think, it’s great.

It’s something that, of course,

we’ll be grounded, again, in 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,

helping us know, okay, this pattern of activity

in these cells, in 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 gonna 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 the 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.

But, and there are a 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 channel opsins

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?

Yeah, 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.

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’t remain focused on what’s going on around them.

So their 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.

Although I have to say,

and this is a benevolent shout out to Botan Rosca,

Botan has an incredibly sharp and focused mind.

And his hand movements are extremely exact also.

So I do sometimes wonder whether or not

our body movements and our head movements are,

whether or not they’re coordinated or not,

is a readout of how directed our attention is.

I notice I have to think complex, abstract thoughts.

I notice I have to be very still.

So my body has to be almost completely unmoving

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,

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 am literally sitting almost in this position,

but without distraction and thinking.

And so it’s kind of a,

it’s almost meditative in some ways,

except it’s not true meditation.

But I am thinking while not moving.

You’re trying to structure your thoughts in that time.

Yeah, yeah. Interesting.

So, but everybody, as you say, is very different.

And so with ADHD, you have,

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 up a diagnosis

with looking at particular

externally detectable brainwave rhythms.

So skull cap with some electrodes

that don’t penetrate the skull.

That’s right.

And this can be done in an hour or two hour session.

That’s right.

Has to be done in a clinic, right?

Yeah, in the clinic, right.

You have to have the right recording apparatus and so on.

But that’s, in principle,

as increasing 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?

Meaning if 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 tick.

I used to hide it.

I actually used to hide in the closet

because my dad would make me stop.

And I used to,

I couldn’t feel any relief of my mind

until I would do this.

And actually now, if I get very tired,

if I’ve been pushing long hours,

it’ll come back.

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,

but things like skateboarding, boxing, they bring relief.

I feel clarity after a head hit, which I avoid,

but I used to say that’s the only time

I feel truly clear for a long,

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 wanna 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?

Yeah, this is a great question.

I think about it a lot.

And you mentioned this tick-like behavior in yourself.

It’s very common that people who have ticks

have this building up of something

that can only be relieved by executing the tick,

which can be a motor movement

or a localization 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, a buildup, a 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.

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 it a psychiatric diagnosis,

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 you 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.

So you bring the horizon into the unit of the day.

I do, I do.

The unit is the day, that’s right.

What I try to have in each day, as I mentioned earlier,

some, at least an hour of time where I can think.

And that can be, it can be when kids are napping,

it can be, you know, actually because I,

while driving I can do that too, because I’m sitting still.

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.

It’s, you know, so I had to add in a new block of time,

which was sort of midnight to 2 a.m. writing time.

And so that carving out these even small protected times

are very important.

There’s, of course, you know,

obligations will expand to fill the time available

and you have to be disciplined in my,

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.

I would, you know, when I was writing the book,

I would have, there’s a focus mode on the MacBook,

which kind of removes the border

and you just have your document and it’s very pure

and you don’t have a 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, yes.

So you’re actually in conversation with yourself.

Yes, and hearing literally,

I mean, not quite literally,

I don’t actually hear a phonation,

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 construction

of almost equations with words.

Complete sentences?

Complete sentences or complete-ish anyway,

mostly complete.

And then, and when writing the book,

everything about the writing,

I would always,

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?

Because 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, you know, 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, it’s aversive.

It doesn’t feel good,

but it’s not,

but there’s also a hope

because I know I can solve it too.

And so there’s this,

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 so at the end, I was like, no, I can’t put that in.

Everything you just said is entirely consistent

with my experience of you

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 tick

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 think, you know, I also, you know,

I remember the rhythms of physical work

in the laboratory very well.

My work, you know, these days as the laboratory leader,

my job has returned mostly to words now again.

And so it’s kind of coming full circle.

I was, so it’s a different mode.

I think you just have to embrace

that different stages of life come with different modes,

but you can definitely train yourself for each mode.

I was not, you know, I loved, you know,

as I mentioned, the rhythm of sewing

and suturing and surgery.

And I worked really hard on that

and became, you know, good at it.

And now I never do it, but it’s what’s the next challenge?

You know, there’s all the various experimental techniques,

the dissections of the brain.

You know, 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.

And then you developed a method

so that we don’t have to dissect brains.

As you mentioned, 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 we’re 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.

They’re at the cellular and subcellular 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.

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.

But, and you can see direct all the way through it.

That’s incredible for the,

it raises an important question,

which is again about the human brain.

I mean, 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.

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 in 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 are reporting to each other there.

Maybe they have little psychiatric sessions

with one another.

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, in 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.

A good example of that is we’ve been able to study

just in the past year,

come to an understanding of dissociation.

And both, we had a paper that came out in late 2020,

both mouse and human work,

in which we got to 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.

And so you can have someone who’s,

it’s not as if you’re numb, you’re not anesthetized.

You can still, you 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?

That is, how interesting is that?

The self-report narrative.

Yeah, yeah.

Almost 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.

Is that one way to describe it?

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.

And so we, 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 was just a, who would have 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 are 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 is 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 in mouse and human

because in the human, we could cause it to happen.

So-

And I just want to underscore the power of not just that,

I 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

the same structure or group of structures

and see the emergence.

So it’s 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,

and which gives you causality.

That’s right.

Yeah, and so, 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 that, who would have thought you could do that?

But there 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, too,

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,

playing in, providing a complex sensation

or percept that wasn’t there before.

And we can do that across species.

So we haven’t, and of course, mice are social,

and they do amazing acts of information processing,

and so 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.

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 counterculture 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 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 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 opportunity

and the peril 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 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,

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, you know,

the perception of reality is altered,

we could create 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 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 treatment,

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, you know, 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 a very,

I think about the two extremes of my experience anyway

is 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 time,

so that I’m in a micro-sliced time,

I’m 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,

it might not be.

Psychedelics seem 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,

of 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 dreamlike 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 the willingness of our brain

to accept unlikely ways of constructing the world,

unlikely hypotheses, 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, hypotheses 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.

We think how distracted we’d be

if we were constantly having to evaluate all these,

you know, 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, you know, that’s pretty interesting,

and it goes wrong in psychiatric disorders.

I think in schizophrenia,

sometimes 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 have 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.

There’s, 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, 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, they’re 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,

they will, as you say, they’ll 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, yeah, you can, 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 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.

Is that?

Exactly right, yeah.

And that probably, I’m assuming,

is still the goal of really good psychiatry also.

It’s 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 these, in many cases,

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 chord of optimism,

that where we’re headed is not just possible,

but very likely and better.

And, you know, are you an optimist?

I am, and this is, 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 in 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,

the 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

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 came through in the book.

But 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’s 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 a Twitter.

That’s where I mainly do exchange,

tell people about things that are happening.

And we’ll provide a link to it,

but that’s Karl Deisseroth, as I recall, with a K.

That’s right, yeah.

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 went into the book,

I can’t even imagine,

for the laboratory work and the development of channel ops

and 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 and 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.

It’s available on Amazon, Audible

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