Dr. Karl Deisseroth, MD, PhD, is a Clinical Psychiatrist and scientist
who directs a bioengineering research laboratory at Stanford
University School of Medicine. His work aims to understand and develop
treatments for disorders of the mind such as depression, attention
deficit disorders (ADHD & ADD), autism, schizophrenia, anxiety, eating
disorders, borderline personality and obsessive-compulsive disorder
(OCD). We discuss his experience treating his patients and his
laboratory’s mission to find and develop cures for mental disease and
tools for probing how the brain works.
[gentle upbeat music] - [Andrew] Welcome to the Huberman Lab Podcast,
where we discuss science, and science-based tools for everyday life.
I'm Andrew Huberman, and I'm a professor of neurobiology and
ophthalmology at Stanford School of Medicine. Today, I have the
pleasure of introducing the first guest of the Huberman Lab Podcast.
My guest is Dr. Karl Deisseroth. Dr. Karl Deisseroth is a medical
doctor, he's a psychiatrist and a research scientist at Stanford
School of Medicine. In his clinical practice, he sees patients dealing
with a range of nervous system disorders, including obsessive
compulsive disorder, autism, attention deficit disorders,
schizophrenia, mania, anxiety disorders, and eating disorders. His
laboratory develops and explores tools with which to understand how
the nervous system works in the healthy situation, as well as in
disorders of the mind. Dr. Deisseroth's laboratory has pioneered the
development and use of what are called channelopsins, proteins that
come from algae, which can now be introduced to the nervous systems of
animals and humans, in order to precisely control the activity of
neurons in the brain and body with the use of light. This is a
absolutely transformative technology, because whereas certain drug
treatments can often relieve certain symptoms of disorders, they often
carry various side effects. And in some individuals, often many
individuals, these drug treatments simply do not work. The
channelopsins and their related technologies stand to transform the
way that we treat psychiatric illness, and various disorders of
movement and perception. In fact, just recently, the channelopsins
were applied in a human patient, to allow an adult fully blind human
being to see light, for the very first time. We also discuss Dr.
Deisseroth's newly released book, which is entitled "Projections: A
Story of Human Emotions". This is an absolutely remarkable book, that
uses stories about his interactions with his patients, to teach you
how the brain works in the healthy and diseased state, and also
reveals the motivation for and discovery of these channelopsins and
other technologies by Karl's laboratory, that are being used now to
treat various disorders of the nervous system, and that in the future,
are certain to transform the fields of psychiatry, mental health, and
health in general. I found our conversation to be an absolutely
fascinating one about how the brain functions in the healthy state,
and why and how it breaks down in disorders of the mind. We also
discuss the current status and future of psychedelic treatments for
psychiatric illness, as well as we're understanding how the brain
works more generally. We also discuss issues of consciousness, and we
even delve into how somebody like Karl who's managing a full-time
clinical practice and a 40 plus person laboratory, and a family of
five children and is happily married, how he organizes his internal
landscape, his own thinking in order to manage that immense workload
and to progress forward for the sake of medicine and his pursuits in
science. I found this to be an incredible conversation, I learned so
much. I also learned, through the course of reading Karl's book,
"Projections", that not only is he an accomplished psychiatrist, and
obviously an accomplished research scientist and a family man, but
he's also a phenomenal writer. "Projections" is absolutely masterfully
written. It's just beautiful, and it's accessible to anybody, even if
you don't have a science background. So, I hope that you'll enjoy my
conversation with Karl Deisseroth as much as I did, and thank you for
tuning in. Before we begin, I want to point out that this podcast is
separate from my teaching and research roles at Stanford. In my desire
and effort to bring zero cost to consumer information about science
and science related tools to the general public, I'd like to
acknowledge the sponsors of today's podcast. Our first sponsor is
Roka. Roka makes eyeglasses and sunglasses that in my opinion, are the
very highest quality out there. The company was founded by two All-
American swimmers from Stanford, and everything about the eyeglasses
and sunglasses was developed with performance in mind. One of the
things I really love about Roka sunglasses, is that unlike other
sunglasses that make it hard to see when there's a lot of cloud cover,
or when the shadows change or environmental conditions change, with
Roka sunglasses, they clearly understand the signs of the visual
system, because when I put them on for the first time, I noticed that
as I moved into shadows or the cloud cover changed or the day got
brighter or dimmer, everything was still crystal clear. And that's
also because the lenses are tremendously high optical clarity, and the
glasses are really lightweight. You don't even notice that they're on.
The other thing is that the eyeglasses, I wear readers at night,
they're incredibly lightweight, and for both the sunglasses and
eyeglasses, the aesthetic is terrific. Unlike a lot of performance
eyewear, which frankly can look kind of cyborg-like and kind of
ridiculous, the aesthetic of the glasses is such that you could really
wear them anywhere, indoors or outdoors. If you'd like to try Roka
eyeglasses, you can go to Roka, that's R-O-K-A.com, and enter the code
"Huberman", to save 20% on your first order. That's Roka, R-O-K-A.com,
and enter the code "Huberman", at checkout. Today's podcast is also
brought to us by InsideTracker. InsideTracker is a personalized
nutrition platform that analyzes data from your blood and DNA, to help
you better understand your body and reach your health goals. I'm a big
believer in getting regular blood work done. And now with the advent
of good genetic DNA tests, I'm also a believer in analyzing your DNA.
The simple reason for this is that many of the factors that impact our
immediate and longterm health, can only be measured and evaluated with
a quality blood test. And now, the DNA tests further inform our
immediate and long-term health. One of the problems with a lot of DNA
tests and blood tests out there however, is that you get the
information back, and you don't know what to do with that information.
With InsideTracker, you get the numbers back of different metabolic
factors, hormones, et cetera, but it also provides simple directives,
as to how perhaps you might want to change your nutritional intake or
your exercise regimen, or other lifestyle factors, to bring those
numbers into alignment with where you'd like them to be. InsideTracker
also makes this really easy. They have a dashboard that makes
organizing that all very simple, and they can even have someone come
to your house to take the blood and DNA test. If you'd like to try
InsideTracker, you can visit insidetracker.com/huberman, to get 25%
off any of InsideTracker's plans. Just use the code "Huberman", at
checkout. Today's episode is also brought to us by Athletic Greens.
Athletic Greens is an all-in-one vitamin mineral probiotic drink. I
started taking Athletic Greens way back in 2012, and I've taken it
ever since, so I'm delighted that they're sponsoring the podcast. The
reason I started taking Athletic Greens and that I continue to take
Athletic Greens, is that it covers all my vitamin and mineral bases,
and it covers my probiotic needs. There's now a wealth of data showing
that probiotics support a healthy gut microbiome, and that a healthy
gut microbiome supports the gut brain access for healthy mood. It also
supports metabolism, immune function, endocrine, that means hormone
function, and a host of other important biological functions. I drink
it once or twice a day. I mix it with water and a little bit of lemon
juice or some lime juice, and it's absolutely delicious. If you'd like
to try Athletic Greens, you can go to athleticgreens.com/huberman, and
if you do that, you can claim a special offer, where they will give
you a year's supply of vitamin D3. In addition, they'll give you five
free travel packs. Vitamin D3 as we all know, is very important for a
huge range of biological functions and health. Again, that's
athleticgreens.com/huberman, for your Athletic Greens, the five free
travel packs, and the year's supply of vitamin D3. And now, my
conversation with Dr. Karl Deisseroth.
Well, thanks for being here. -- Thanks for having me. -- It's been
a long time coming for me, because you may not know this, but one of
the reasons I started this podcast was actually so I could have this
conversation. [Karl laughs] It's but one, there are other reasons, but
one of the goals is to be able to hold conversations with colleagues
of mine that are doing incredible work in the realm of science, and
then here we also have this really special opportunity because you're
also a clinician. You see patients and have for a long time. So for
people that might not be so familiar with the fields of neuroscience,
et cetera, what is the difference between neurology and psychiatry?
-- Well, I'm married to a neurologist and I am a psychiatrist and we
make fun of each other all the time. A lot of neuroscientists and a
lot of brain clinicians actually think these two should be in the same
field at some point in the future, they were in the past, they started
together. Psychiatry though, focuses on disorders where we can't see
something that's physically wrong, where we don't have a measurable,
where there's no blood test that makes the diagnosis, there's no brain
scan that tells us this is schizophrenia, and this is depression for
an individual patient. And so psychiatry is much more mysterious, and
the only tools we have are words. Neurologists are fantastic
physicians. They see the stroke on brain scans, they see the seizure
and the pre-seizure activity with an EEG, and they can measure and
treat based on those measureables. In psychiatry, we have a harder
job, I think. We use words, we have rating scales for symptoms, we can
measure depression and autism with rating scales, but those are words
still. And ultimately, that's what psychiatry is built around. It's an
odd situation because we've got the most complex, beautiful,
mysterious, incredibly engineered object in the universe, and yet all
we have are words to find our way in. -- So, do you find that if a
patient is very verbal or hyper-verbal, that you have an easier time
diagnosing them, as opposed to somebody who's more quiet and reserved?
Or it's, I could imagine the opposite might be true as well. --
Well, because we only have words, you've put your finger on a key
point. If they don't speak that much, in principle, it's harder. The
lack of speech can be a symptom. We can see that in depression, we can
see that in the negative symptoms of schizophrenia, we can see that in
autism. Sometimes by itself, that is a symptom, reduced speech, but
ultimately you do need something. You need some words to help guide
you and in fact, there's challenges that I can tell you about where
patients with depression were so depressed, they can't speak. That
makes it a bit of a challenge to distinguish depression from some of
the other reasons they might not be speaking. And this is sort of the
art and the science of psychiatry. -- Do you find that there are
patients that have, well, let's call them comorbidities or conditions
where they would land in both psychiatry and neurology, meaning
there's damage to a particular area of the brain and therefore they're
depressed? And how do you tease that out as a psychiatrist? -- Yeah,
this happens all the time. Parkinson's disease is a great example. It
can be debilitating in so many ways. People have trouble moving, they
have trouble walking, they have trouble swallowing, and they can have
a truly severe depression. And this is where you might say, "Oh, well,
they've got a life-threatening illness", but there are plenty of
neurological disorders where depression is not a strongly comorbid
symptom, like ALS, Lou Gehrig's disease, for example, depression is
not strongly comorbid in that disease, but in Parkinson's, it is
extremely common. And as you know, in Parkinson's disease, we have
loss of the dopamine neurons in the midbrain. And this is a very
specific population of cells that's dying, and probably that leads to
both the movement disorder and the depression. There are many examples
of that where these two fields come together and you really need to
work as a team. I've had patients in my clinic, that I treat the
depression associated with their Parkinson's, and a neurologist treats
the movement associated with the Parkinson's and we work together.
-- Do you think we will ever have a blood test for depression or
schizophrenia or autism? And would that be a good or a bad thing? --
I think ultimately there will be quantitative tests. Already, efforts
are being made to look at certain rhythms in the brain using external
EEGs to look at brain waves effectively, look at the ratios of certain
frequencies to other frequencies, and there's some progress being made
on that front. It's not as good as it could be. It doesn't really give
you the confidence for the individual patient that you would like, but
ultimately, what's going on in the brain in psychiatric disease is
physical, and it's due to the circuits and the connections and the
projections in the brain that are not working as they would in a
typical situation. And I do think we'll have those measureables at
some point. Now, is that good or bad? I think that will be good, and
one of the challenges we have with psychiatry is it is an art as well
as a science to elicit these symptoms in a precise way. It does take
some time, and it would be great if we could just do quick
measurements. Could it be abused or misused? Certainly. But that's I
think true, for all of medicine.
-- I want to know, and I'm sure there are several, but what do you
see as the biggest challenge facing psychiatry and the treatment of
mental illness today? -- I think we're making progress on what the
biggest challenge is, which I think there's still such a strong stigma
for psychiatric disease that patients often don't come to us, and they
feel that they should be able to handle this on their own. And that
can slow treatment. It can lead to worsening symptoms. We know, for
example, patients who have untreated anxiety issues. If you go for a
year or more with a serious untreated anxiety issue, that can convert
to depression. You can add another problem on top of the anxiety. And
so it would be... Why do people not come for treatment? They feel like
this is something they should be able to master on their own, which
can be true, but usually, some help is a good thing. -- That raises
a question related to something I heard you say many years ago at a
lecture, which was that, this was a scientific lecture and you said,
"We don't know how other people feel. Most of the time, we don't even
really know how we feel." - [chuckles] Yeah. - [Andrew] Maybe you
could elaborate on that a little bit and the dearth of ways that we
have to talk about feelings. I mean, there's so many words. I don't
know how many, but I'm guessing they're more than a dozen words to
describe the state that I call sadness, but as far as I understand, we
don't have any way of comparing that in a real objective sense. As a
psychiatrist, when your job is to use words to diagnose, words of the
patient to diagnose, do you maneuver around that? And what is this
landscape that we call feelings or emotions? -- This is really
interesting. Here there's a tension between the words that we've built
up in the clinic that mean something to the physicians, and then
there's the colloquial use of words that may not be the same, and so
that's the first level we have to sort out when someone says, "I'm
depressed", what exactly do they mean by that? And that may be
different from what we're talking about in terms of depression. So
part of psychiatry is to get beyond that word, and to get into how
they're actually feeling, get rid of the jargon and get to real world
examples of how they're feeling. So, how much do you look forward into
the future? How much hope do you have? How much planning are you doing
for the future? So here now you're getting into actual things you can
talk about that are unambiguous. If someone says, "Yeah, I can't even
think about tomorrow. I don't see how I'm going to get to tomorrow".
That's a nice, precise thing that you know, it's sad, it's tragic, but
also, that means something. And we know what that means. That's the
hopelessness symptom of depression. And that is what I try to do when
I do a psychiatric interview. I try to get past the jargon, and get to
what's actually happening in a patient's life and in their mind. But
as you say, ultimately, [chuckles] and this shows up across... I
address this issue every day in my life, whether it's in the lab where
we're looking at animals, whether fish or mice or rats and studying
their behavior, or when I'm in a conversation with just a friend or a
colleague, or when I'm talking to a patient, I never really know
what's going on inside the mind of the other person. I get some
feedback, I get words, I get behaviors, I get actions, but I never
really know. And as you said at the very beginning of the question,
often we don't even have the words and the insight to even understand
what's going on in our own mind. I think a lot of psychiatrists are
pretty introspective. That's part of the reason they end up in that
specialty, and so, maybe we spend a little more time than the average
person thinking about what's going on within, but it doesn't mean we
have the answers. -- So in this area of trying to figure out what's
going on under the hood through words, it sounds like certain words
would relate to this idea of anticipation and hope. Is it fair to say
that that somehow relates to the dopamine system in the sense that
dopamine is involved in motivated behaviors? I mean, if I say for
instance, and I won't ask you to run a session with me here [chuckles]
for free. [Karl laughs] -- We'll do that off camera. - [Andrew] Off
camera. Right. If I were to say, "I just can't imagine tomorrow. I
just can't do it." So that's not an action-based, that's purely based
on my internal narrative, but I could imagine things like, you know, I
have a terrible time sleeping, I'm not hungry, I'm not eating, so
statements about physical actions, I'm guessing also have validity.
-- Absolutely. -- And there are now ways to measure the accuracy of
those statements. Like for instance, if I gave you permission, you
could know if I slept last night, or whether or not I was just saying
I had a poor night's sleep. -- Yes. That's right. -- So in moving
forward through 2021 and into the next 10 and 100 years of psychiatry,
do you think that the body reporting some of the actions of a human
are going to become useful and mesh with the words in a way that's
going to make your job easier? -- I do think that's true. And the
two things you've mentioned, eating and sleeping, those are additional
criteria that we use to diagnose depression. These are the vegetative
signs, we call them of depression, poor sleep, and poor eating. And if
you have a baseline for somebody, that's the real challenge there.
What's different in that person? Some people with depressed, they
sleep more. Some people who are depressed, they sleep less. Some
people who are depressed, they're more physically agitated, and they
move around more. Some people who are depressed, they move less even
while they're awake. And so you need... Here's the challenge is that
you can't just look at how they are now. You have to get a baseline,
and then see how it's changed. And that can be a challenge that raises
ethical issues, and how do you collect that baseline information from
someone healthy? I don't think that's something we have solved. Of
course, with phones and accelerometers and phones, you could in
principle, collect a lot of baseline information from people, but that
would have to be treated very carefully for privacy reasons.
-- And in terms of measuring one's own behavior, I've heard of work
that's going on. Sam Golden up in the University of Washington who
works on aggression in animal models was telling me that there's some
efforts that he's making, and perhaps you're involved in this work as
well, I don't know, of devices that would allow people to detect, for
instance, when they're veering towards a depressive episode for
themselves, that they may choose or not choose to report that to their
clinician, maybe they don't even have a clinician. Maybe this person
that you referred to at the beginning, this person who doesn't feel
comfortable coming to talk to you, maybe something is measuring
changes in the inflection of their voice, or the speed at which they
get up from a chair. Do you think that those kind of metrics will
eventually inform somebody, "Hey, you know, you're in trouble"? This
is getting to back to the statement that I heard you make and it rung
in my mind now, I think for more than a decade, which is, "Oftentimes,
we don't even know how we feel." -- Yeah. You know, that I do like,
because that gives the patient the agency to detect what's going on,
and even separate from modern technology, this has been part of the
art of psychiatry is to help patients realize that sometimes other
people observing them can give them the earliest warning signs of
depression. We see this very often in family. They'll notice when the
patient is changing before the patient does. And then there are things
the patient may notice, but not correctly ascribe to the onset of
depression. And a classic example of that is what we call 'early
morning awakening'. And this is something that can happen very early
as people start to slide into depression. They start to wake up
earlier and earlier, just inexplicably, they're awake at- -- This is
like 2:00 AM, 3:00 AM awakening? -- It could start... Yeah, it could
start at 5:00 AM, could go to four, and three- - And are unable to
fall back asleep? -- Unable to fall back asleep. Exactly. And they
may not know what to do with that. It could just be, [chuckles] from
their perspective, it's just something that's happening. But if you
put enough of that information together, that could be a useful
warning sign for the patient and it could help them seek treatment.
And I think that is something that could be really valuable. --
Interesting. So, in this framework of needing words to self-report or
machines to detect how we feel and maybe inform a psychiatrist how a
patient feels, touch on some of the technologies that you've been
involved in building, but as a way to march into that, are there any
very good treatments for psychiatric disease?
Meaning, are there currently any pills, potions, forms of
communication that reliably work every time, or work in most patients?
And could you give a couple examples of great successes of psychiatry
if they exist? -- Yes. Yeah, we are fortunate. And this [chuckles]
coming back to my, you know, the joking between my wife and myself in
terms of neurology and psychiatry, we actually in psychiatry, despite
the depths of the mystery we struggled with, many of our treatments
are actually... We may be doing better than some other specialties in
terms of actually causing therapeutic benefit for patients. We do help
patients, the patients who suffer from... By the way, both medications
and talk therapy have been shown to be extremely effective in many
cases, for example, people with panic disorder, cognitive behavioral
therapy, just working with words, helping people identify the early
signs of when they're starting to move toward a panic attack, what are
the cognitions that are happening? You can train people to derail
that, and you can very potently treat panic disorder that way. --
How long does something like that take on average? -- For a
motivated, insightful patient, you can have a very cookbooky series of
sessions, that's six to 12 sessions, or even less for someone who's
very insightful and motivated and it can have a very powerful effect
that quickly. And that's just with words, there are many psychiatric
medications that are very effective for the conditions that they're
treating. Anti-psychotic medications, they have side effects, but boy,
do they work! They really can clear up particularly the positive
symptoms of schizophrenia for example, the auditory hallucinations,
the paranoia, people's lives can be turned around by these- -- We
should clarify positive symptoms. You mean not positive in the
qualitative sense, you mean positive meaning that the appearance of
something abnormal. -- Exactly. Yeah. Thank you for that
clarification. When we say positive symptoms, we do mean the addition
of something that wasn't there before, like a hallucination or a
paranoia, and that stands in contrast to the negative symptoms where
something is taken away, and these are patients who are withdrawn.
They have what we call thought blocking. They can't even progress
forward in a sequence of thoughts. Both of those can be part of
schizophrenia, the hallucinations and the paranoia are more
effectively treated right now, but they are effectively treated. And
then, this is a frustrating, and yet heartening aspect of psychiatry.
There are treatments like electroconvulsive therapy, where it's
extremely effective for depression. We have patients who nothing else
works for them, where they can't tolerate medications, and you can
administer under a very safe, controlled condition, where the
patient's body is not moving. They're put into a very safe situation
where the body doesn't move or cease, it's just an internal process
that's triggered in the brain. This is an extraordinarily effective
treatment for treatment-resistant depression. At the same time, I find
it [chuckles] as heartening as it is to see patients respond to this
who have severe depression, I'm also frustrated by it. Why can't we do
something more precise than this, for these very severe cases? And
people have sought for decades to understand, how is it that a seizure
is leading to the relief of depression? And we don't know the answer
yet. We would love to do that. People are working hard on that, but
that is a treatment that does work too. In all of these cases though
in psychiatry, the frustrating thing is that we don't have the level
of understanding that a cardiologist has in thinking about the heart.
You know, the heart is, we now know it's a pump. It's pumping blood.
and so you can look at everything about how it's working or not
working, in terms of that frame, it's clearly a pump. We don't really
have that level of, what is the circuit really there for in
psychiatry? And that's what is missing. That's what we need to find,
so we can design truly effective and specific treatments.
-- So, what are the pieces that are going to be required to cure
autism, cure Parkinson's, cure schizophrenia? I would imagine there
are several elements and 'beens here', understanding the natural
biology, understanding what the activity patterns are, how to modify
those, maybe you could just tell us what you think, what is the Bento
Box of the perfect cure? -- I think the first thing we need is
understanding. Almost every psychiatric treatment has been
serendipitously identified, just noting by chance that something that
was done for some person also had a side effect- -- Like lithium or
something- -- Like lithium, is a good example. -- Is it true that
it was the urine of guinea pigs [Karl laughs] given lithium that was
given to manic patients that made them not manic? Is that true? -- I
don't have firsthand knowledge of that, but I would defer that, but
it's true for essentially every treatment, that the antidepressants
originally arose as anti-tuberculosis drugs, for example. -- I did
not know that. -- Yeah, and so this is a classic example for
illnesses across all of psychiatry, and of course there's the seizures
as well. That was noticed that patients who had epilepsy, they had a
seizure there and also had depression, that they became much, at least
for awhile, they were improved after that seizure. -- That's
amazing. I don't want to take you off course of the question answering
the question I asked, but I've heard before that if autistic children
get a fever, that their symptoms improve, is that true? -- I've done
a fair bit of work with autism. In my clinical practice, I work with
adult autism and I have heard statements like that and descriptions
like that from patients and their families. That is very hard to study
quantitatively because often with the children, you have this not as
quantitative as you'd like collection of symptom information from
home. But I have heard that enough that I think there may well be
something to that. And anytime you have a fever, what's going on?
Well, we know all the cells in the brain, and I know this as an
electrophysiologist, if you just change the temperature by a few
degrees, everything changes about how neurons work and that's even
just a single neuron. It's even more likely to be complex and
different with a circuit of neurons that are all affecting each other.
Just elevate the temperature a little bit, everything's different. And
so, it's plausible for sure, that things like that could happen and do
happen. And yet, when you think about autism, to take your example,
yes, we see changes, but what is the elements of the brain that's
analogous to the pumping heart? When we think about the symptoms of
depression, we think about motivation and dopamine neurons. When we
think about autism, it's a little more challenging. There's a deficit
in social interaction and in communication. And so where is that?
[chuckles] Where is that situated? What is the key principle governing
the social interaction? This is where we need the basic science to
bring us a step forward, so we can say okay, this is the process
that's going on. This is what's needed for the incredibly complex task
of social interaction, where you've got incredibly rich data streams
of sound and meaning, eye contact, body movement, and that's just for
one person. What if there's a group of people? This is overwhelming
for people with autism. What's the unifying thing there? It's a lot of
information, and that maybe is unmatched in any realm of biology, the
amount of information coming in through a social interaction,
particularly with words and language. And so then, that turns our
attention as neuroscientists, we think, okay, let's think about the
parts of the brain that are involved in dealing with merging complex
data streams that are very high in bit rate that need to be fused
together into a unitary concept. And that starts to guide us, and we
know other animals are social in their own way, and we can study those
animals. And so that's how I think about it. There's hope for the
future, thinking about the symptoms as an engineer might, and trying
to identify the circuits that are likely working to make this typical
behavior happen, and that will help us understand how it becomes
atypical. -- So that seems like the first to me, the first been of
this, what I call the Bento Box for lack of a better analogy, that we
need to know the circuits. We need to know the cells in the various
brain regions and end portions of the body and how they connect to one
another, and what the patterns of activity are under a normal 'healthy
interaction'. - [Karl] Yeah. -- If we understand that, then it seems
that the next step, which of course could be carried out in parallel,
right? Though that work can be done alongside work where various
elements within those circuits are tweaked just right, like the tuning
of a piano in the subtle way, or maybe even like the replacement of a
whole set of keys if the piano is lacking keys, so to speak. --
Right. -- You've been very involved in trying to generate those
tools.
Tell us about channelopsins, why you created them, and where they're
at now in the laboratory and perhaps also in the clinic. -- Well,
first of all, I give nature the credit for creating channelrhodopsins.
These are beautiful little proteins that are made by algae, single-
celled green algae. And there's a great story in basic science that
our understanding of animal behavior, sensation, cognition and action
in our brains all the way back to a botanist in the 1850s and 1860s in
Russia, is where the story begins. So this was a botanist named Andrei
Famintsyn who worked at St. Petersburg, and he had noticed in the
river near his laboratory, that there were algae that he could look at
in a dish, in a saucer. He could put them there and he had light
shining from the side. The green tinge in the saucer of water would
move to a particular distance from the light that he was shining from
the side, which was an amazing thing. If he made the light brighter,
the green tinge would back off a little bit to a more optimal
location, so just the right light level. So this was plant behavior.
It was light-driven plant behavior, and he delves into this a little
bit. He identified that with microscopy, he could see that there were
little single-cell algae with flagella that were swimming to the right
light level. So behaving plants, and this has been the secret that's
helped us unlock so many principles of animal behavior. So turns out,
these algae achieve this amazing results with a single gene that
encodes a single protein. What's a protein? It's just a little bio-
molecule that does a job in a cell. And these are proteins that sit in
the surface of cells in their surface membrane, and when a photon, a
light particle hits them, they open a little pore, a little hole in
the membrane and charged particles, ions like sodium rush across the
pore. Now, why do they do that? They do that to guide their flagella,
that signal coming in, those ions coming in through the pore in
response to light, guide their flagella motor, that guides them to a
particular spot in the saucer. Now, that's plant behavior, but it
turns out, as you know, this movement of ions across the membrane,
this happens to also be a neural code in our brains for on or off.
Sodium ions rushing into the cells, turns them on. It makes them fire
away, fire action potentials communicate to the next cell down the
chain, and this is an amazing opportunity because we can borrow these
proteins. In fact, we can take the gene that directs the creation of
the protein, and we can use genetic tricks, modern genetic tricks to
put that gene into neurons in the brains of mammals, and then use
light to turn those cells, the specific cells that we put this gene
into, turn them on. There are other opsins, we call them, that you can
use to turn cells off. It's all fast, real time. You can play in
patterns of activity in real time into cells or kinds of cells, just
as a conductor elicits the music from the orchestra, the strings and
the woodwinds. And you can see what matters. What matters for
sensation, what matters for cognition, what matters for action, and we
call this optogenetics. -- Beautiful, and I must say it was quite an
honor and a privilege to watch optogenetics move from idea to
discovery to the laboratory. I think we were postdocs at the same
time, -- We were, huh? - which is living proof that people move at
different rates, because [laughs] it's a joke at my expense by the
way, [Karl laughing] but it's really- -- We end up in the same spot.
[laughs] -- That's right, [laughs] yeah, more or less. Physically,
if not professionally, but nonetheless, it's been a marvelous story
thus far. And I'd like to... Maybe you could give us... I'd like to
just touch on a couple examples of where the technology resides in
laboratories now, so maybe the range of animals that it's being used
in, and some of the phenomenon that channelrhodopsins and their
related genes and proteins are starting to elicit, what you've seen,
and then I'd like to talk about their applicability to the clinic,
which is I think the bigger mission, if you will. -- Yeah. So this
whole thing, you know, it's been about, now going on 17 years that
we've been putting channelrhodopsins into neurons. It started just
like Andre Famintsyn's work in a dish, that was in 2004. In 2007, we
were putting these into behaving mice, and we were able to with a
flick of a switch, cause them to move one direction or another, by
2009- -- So basically, you're controlling the mouse's behavior? --
Yeah, exactly. In real time. So we could make a mouse that was just
sitting there doing nothing, to then turn left very consistently, in
fact, go around in a circle and as soon as we turn off the light, it
would stop. That was an eye-opening moment. It took really a few years
to make optogenetics work. There was a lot of putting all the... There
are a lot of problems that had to be solved. These channelrhodopsins
actually don't move many ions. They have a small current, small
conductance, as we say. And so we had to figure out ways to pack a lot
of them into cells without damaging cells, and still make them
targetable, so we don't want them to just be in all the cells, 'cause
then it becomes just like an electrode. You're just stimulating all
the cells that are nearby. We had to keep that specificity, make them
targetable to just one kind of cell or another, while still packing in
large numbers of them into those cells. And we had to get in the light
in safe and specific ways, and so it took probably about four or five
years to really create optogenetics between 2004 and 2009. By the end
of that time though, we had all the basic light delivery, gene
delivery, principles worked out, and people started to apply the
technology to fish, to rats, to mice, to non-human primates like
monkeys, and just a couple months ago, my colleague, Botond Rosca in
Switzerland, succeeded in putting channelrhodopsins into the eyes of
human beings and making a blind person to see.
And so that's pretty cool. This was a patient with retinal
degeneration, and he provided a channelrhodopsin into the eye of this
patient and was able to confer some light sensitivity onto this
patient that wasn't there before. -- An amazing paper and discovery.
I realize it was one patient, but it's such an important milestone.
-- Well, as you say, it's a very important milestone and the history
of that is very deep. Almost 10 years earlier, Botond Rosca and I had
published a paper in science in human retina, but X plants taken from
cadavers from someone who had died, the living retina taken out,
opsins put into this retinal tissue and showing that it worked,
recording from the cells showing that in these human retinal neurons,
that you could get light responses. But then, from that moment, almost
10 years of how clinical development goes, and this is a gene therapy
and so you've got all the regulations and concerns and all that. It
took almost 10 years to get to this point now where a living human
being has a new functionality that wasn't there before. Now, that's
incredibly inspiring, and it's a beautiful thing. I would say though,
that the broader significance of optogenetics is really still
understanding, because once you understand how the circuitry works and
which cells actually matter, then any kind of treatment becomes more
grounded and logical and specific and principled. And whether it's a
medication, or a talk therapy or brain stimulation treatment with
electrical or magnetic means, if you actually know what matters,
[chuckles] that is incredibly powerful. And I think, not intended to
disparage the beautiful retinal work and conferring vision on someone
who couldn't see, of course that's wonderful, and that's direct what
you might call direct optogenetics in patients. Indirect is everything
that comes from understanding. Okay, we know these cells matter now,
for this symptom. Well, how can we target those cells and help them
work better in patients by any means? And I think that's the broader
significance of optogenetics, clinically. -- I know Botond well, and
you and Botond share this incredible big vision, that I think only a
clinician can really understand, being in close contact within the
suffering of patients as a ultimate motivator of developing
technologies, which makes me have to ask, did you decide to become a
scientist to find cures for mental disease?
- [chuckles] No, I didn't. It's a really important question to
actually look back and see the steps that brought you to a particular
place. And that was not what brought me initially to science and it's
okay I think, to embrace [chuckles] the twists and turns that life
brings to you, but I was always interested in the brain. And so, that
was something that for me started from a very early age. We talked
about being introspective. I noticed very early on I had a deep love
of poetry and stories, and I was a voracious reader, and I was amazed
by how words could make me feel in particular ways. Even separate from
their, of course, dictionary meanings, the rhythm, and how they work
together, even separate from meaning. And I was stunned by poets that
could use words in new ways that were even divorced from their meaning
at all, and yet could still trigger specific emotions. And this was
always fascinating to me. So, I wanted to understand that, and so I
was interested and I became interested in the brain and I thought,
well, I'm going to to have to study the human brain, because only
human beings can describe what's going on inside enough. So in
college, I began to steer myself toward medicine, with the idea of
becoming a neurosurgeon. And so I came here to medical school, and did
an MD PhD program, planning neurosurgery all the way through. The
first rotation I did at the end of medical school, as you know, you do
rotations, you go through different specialties, and some of these are
required rotations, everybody has to do this summary elective where
you can pick what you want to do. I elected to do the neurosurgery
first, [chuckles] even before regular surgery. I was that sure I
wanted to do it, and I loved it. I had a fantastic time. There was an
amazing patient who had a thalamic damage, and there was a neglect
syndrome where the patient was not able to be aware of something that
was right in front of him- -- Even though their vision was perfectly
fine? -- Even though their vision was perfectly fine, exactly. And I
loved the operating room, I loved the rhythm of suturing and the
precision of it, and I loved being able to help patients immediately,
but then a required rotation was in psychiatry, which I was not
looking forward to at all. And that completely reset my whole life,
that experience in psychiatry. And it was at that moment that I saw
this is first of all, the greatest need, the depth of suffering and
the depth of the mystery together. And also it was, I almost feel a
little guilty about this. It's so interesting too. Yes, we can help.
Yes, there's need, but as a scientist, this is amazing, that someone's
reality can be different from my own, with everything physically, as
far as we can tell the same with the measures we have, and yet we've
got a different reality. That is an amazing thing, and if we can
understand that and help these people, that would be just more than
anybody could ask for. And so that's how I ended up taking this path,
just a required rotation in psychiatry. -- It all started with
poetry? -- And it started with poetry. -- Out of respect for
poetry, are there any favorites that you spend time with on a regular
basis? -- I mean, the ones who got me down this path early on, I
remember in childhood and high school, Borges had an immense influence
on me. I studied Spanish all the way through and reading his work. He
was a great writer. He wrote both in English and in Spanish and being
able to appreciate his poetry both in English and in Spanish was a
pretty amazing thing. Not many poets can do that. -- You're
bilingual? -- I'm not, I wouldn't say. Now I became, at one point I
was effectively fluent in Spanish, and I'm pretty good with medical
Spanish still because we use Spanish all the time in the clinic here.
I wouldn't claim full fluency, but it's something I can definitely use
all the time. And that's been very helpful in the clinic. -- Yeah,
Borges is wonderful. As the son of an Argentine, I grew up hearing
about it and I learned that Borges' favorite city was Geneva. So I
spent time in Geneva only for that reason. It's also turns out [Karl
laughs] to be an interesting city. -- Yes. -- So you developed
methods to control neurons with these algae proteins using light? --
Yeah.
-- In 2015, there was what I thought was a very nice article
published in the New Yorker, describing your work and the current
state of your work in the laboratory and the clinic, and an
interaction with a patient. So this as I recall, a woman who was
severely depressed, and you reported in that article some of the
discussion with this patient, and then in real time, increased the
activation of the so-called vagus nerve, this 10th cranial nerve that
extends out of the skull and innervates many of the viscera and body.
What is the potential for channelrhodopsins or related types of algae
engineering to be used to manipulate the vagus? Because I believe in
that instance, it wasn't channelopsin stimulation, it was electrical
stimulation, right? Or to manipulate for instance, a very small
localized region of the brain? Let me frame it a little bit
differently in light of what we were talking about a couple minutes
ago. My understanding is that if somebody has severe depression and
they take any number of the available pharmaceutical agents that are
out there, SSRI, serotonergic agents, increased dopamine, increased
whatever, that sometimes they experience relief, but they're often
serious side effects. Sometimes they don't experience relief, but as I
understand it, channelopsins and their related technology, in
principle, would allow you to turn on or off the specific regions of
the brain that lead to the depressive symptoms, or maybe you turn up a
happiness circuit, or a positive anticipation circuit. Where are we at
now in terms of bringing this technology to the nervous system? And
let's start with the body, and then move into the skull. -- Yup. So
starting with the body is a good example because it highlights the
opportunity and how far we have to go. So let's take this example of
vagus nerve stimulation. So the vagus nerve, it's the 10th cranial
nerve. It comes from the brain, it goes down and innervates the heart
and innervates the gut. And by innervate, I mean it sends little
connections down to help guide what happens in these organs in the
abdomen and chest. It also collects information back, and there's
information coming back from all those organs that also go through
this vagus nerve, the 10th cranial nerve, back to the brain. And so
this is somewhat of a super highway to the brain, and it was the idea.
And maybe the idea is maybe we could put a little cuff, a little
electrical device around the vagus nerve itself, and maybe have just
like a pacemaker battery, have a little power source here under the
clavicle, everything under the skin, and have a little cuff and drive
signals, and maybe they'll get back to the brain. So a way of getting
into the brain without putting something physical into the brain. --
And why the vagus? I mean, it's there and it's accessible- -- That's
the reason. - [chuckles] That's the reason? - [chuckles] That's the
reason, yes. -- Really? -- Yeah. -- You're not kidding? - [Karl]
I'm not kidding. -- So stimulating the vagus to treat depression,
simply because it's accessible. -- It started actually as an
epilepsy treatment and it can help with epilepsy, but yes, it's
simple. -- God, you got to love medicine. As a scientist, this is
where I get to chuckle and you say, I'm in the field of medicine from
that perspective. From the perspective of a scientist and outsider,
the field of medicine is a field that goes in and tickles pathways
because they're there. I don't know what to say. It's a little
shocking. -- Yeah. And at least in my laboratory, I always say you
never do an experiment because you can, you do an experiment to test a
specific hypothesis. -- Yeah. Yeah. I mean, there are stories people
tell so that the vagus nerve lands on a particular spot on the brain
called the solitary tract nucleus, which is just one snaps away from
the serotonin and dopamine and the norepinephrine- -- So there's a
link to chemical systems in the brain- that make an irrational choice?
-- Yes. It's not irrational, but I can tell you that even if that were
not true, the same thing would have been tried. [Andrew laughs] --
You guys would have done it anyway. -- Because it's accessible.
Yeah. - [Andrew] I see. Okay. -- And why? Well, it's again, not to
disparage what's been happening in this branch of medicine. There's
immense suffering, many treatments don't work, and we try things. And
this is how so many advances in medicine happen. When think about
kidney dialysis which has kept many people alive, that was just
started by someone saying, "Hey, let's try this. Maybe there's
something building up in the blood and maybe we can dialyze something
and help them." Yeah, it worked. And it was just sort of a test pilot
mentality. We can access the blood, let's run it across a dialysis
membrane, put it back in the body, oh my God, that actually works. And
sometimes you do need that test pilot mentality, of course, to do it
in a rigorous, safe, controlled way- - Sure. - which is what we do.
And so, anyway, that's how we ended up, but still with the vagus nerve
stimulation, okay, so what is it? Does it work? It has, it's FDA
approved for depression, this vagus nerve stimulation, but on a
population level, if you average across all people, the effect sizes
are pretty small. Some patients it has an amazing effect in, but some
patients it doesn't work at all, and average across everybody, the
effect size is pretty small. -- How do you think it's working when
it does work? Is it triggering the activation of neurons that release
more serotonin or dopamine? -- It could be, but I would say we don't
have evidence for that and so I just don't know. But what is clear, is
that it's dose-limited in how high and strongly we can stimulate and
why, it's because it's an electrode, and it's stimulating everything
nearby. And when you turn on the vagus nerve stimulator, the patient's
voice becomes strangulated and hoarse, they can have trouble
swallowing, they can have trouble speaking for sure, even some trouble
breathing, because everything in the neck, every electrically
responsive cell and projection in the neck is being affected by this
electrode. And so you can go up just so far with the intensity, and
then you have to stop. So, to your initial question, could a more
precise stimulation method like optogenetics help in the setting? In
principle, it could, because if you would target the light sensitivity
to just the right kind of cell, let's say cell X that goes from point
A to point B that you know, causes symptom relief of a particular
kind, then you're in business. You can have that be the only cell
that's light sensitive. You're not going to affect any of the other
cells, the larynx and the pharynx and the projections passing through.
So that's the hope, that's the opportunity. The problem, is that we
don't yet have that level of specific knowledge. We don't know, okay,
it's the cells starting at point A going to point B, that relieves
this particular symptom. -- We want to fix this key on the piano?
-- Yeah. -- And then I see two other steps that are required.
One is to get the channelopsin gene into the cell. In the case of
Botond Rosca and colleagues rescuing vision in this patient, they did
that by an injection of a virus that doesn't damage the neurons. The
virus itself is fairly innocuous, but carries a cargo, and it's a one-
time injection, the cells express, and then they used light to
stimulate. So, let's say I'm depressed, which I don't think I am,
although now sitting in front of a psychiatrist, [Karl laughs] you
probably can see signs that maybe I am or maybe I'm not, but let's say
we put channelopsin into a specific branch of the vagus that we
understand is responsible for mood, how are we going to get it in
there? And, then how are we going to deliver the light? 'Cause we're
not talking about sunlight or standing in front of a light bulb
necessarily, what are the mechanisms for the body? -- Yeah. So we
had to solve exactly these questions you're saying. How do you get the
light in? How do you get the gene in, in a potent and robust and safe
way? And that's now solved, and that's not a challenge. So there are
very safe, well-tolerated gene delivery mechanisms that are called
adeno-associated viruses, AAVs, and these are things that are
associated with the common cold. They themselves don't cause any
symptoms. They've been engineered, and there's been a broad community
of viral engineering that's been going on for decades making these
safer, well-tolerated, and so on. We can put the channelrhodopsin gene
into these viral vectors that deliver the gene and we can have little
bits of additional DNA that govern expression only in one kind of
cell, but not another. These are called promoters and enhancers, all
genetic tricks built up by a very broad community of great scientists
over the decades. We can put these different bits of DNA, package them
into this AAV, this little virus, and that can be then injected into a
particular part of the body, and sticking with this vagus nerve
example, we know that there are particular clumps of neurons. There's
one called the nodose ganglion that has a clump of cells related to
the vagus nerve, and you could for example, target a little injection
into that ganglion- -- Would that be an outpatient procedure? --
Yep. Yep. -- So you come in in the morning, get your injection,
maybe walk out a few hours later? -- Yeah. That's right. And so
that's the gene, then the light delivery, this is also something that
we've worked out. We've worked on making very, very light-sensitive
opsins. One challenge, and Botond would be the first to state this in
fact, [chuckles] in solving this problem for the patient, he had to
build goggles that created much brighter light than the normal ambient
light delivery, because as I mentioned earlier, you have to pack a lot
of these channelrhodopsins in, they don't have much current. You have
to really make sure that you've got a tense enough light to activate
enough of them to cause a stimulation- -- And it has to be the right
wavelength, right? -- It has to be the right wavelength- -- And
going back to your example of the algae moving toward or away the
light, it has to be tuned just right. So I'm imagining in my mind as a
non-engineer, I know you're [chuckles] also a bioengineer, I'm
imagining a little tiny blue light-emitting object, that's a little
bigger than a clump of cells, or maybe about the size of a clump of
cells. And for those that don't know, your credit card is about 200
microns thick on the side, and a micron is a thousandths of a
millimeter, and so we're talking about a little tiny stamp that's
basically half a millimeter in size all around. Each edge, half a
millimeter in size. I can imagine that being put under my skin, and
then I would what, I'd hit an app on my phone, and I'd say, "Dr.
Deisseroth, I'm not feeling great today. Can I increase the
stimulation?" And you'd say, "Go for it." And then I'd ramp it up. Is
that how it would go? -- I mean, that's effectively what we already
do with the vagus nerve stimulation. The doctor in this case, and I
have this in some of my patients in the clinic, I do vagus nerve
stimulation.
I talk to them, I say, "How are you?" I go through the symptoms, I use
the psychiatric interview to elicit their internal states, and then I
have a radio frequency controller that I can dial in- -- Right there
in real time? -- Right there in real time. -- You're holding the
remote control essentially to their brain, although it's remote
controlled? -- Yeah, through a couple of steps, but yeah. And I can
turn up the frequency, I can turn up the intensity, all with the radio
frequency and control, and then it's reprogrammed or redosed, and then
the patient can then leave at this altered dose. -- So this is
happening now? -- This is happening right now, electrically. --
You do this routinely? -- I do it routinely in my clinic,
electrically, yeah. -- And you're getting the verbal content, which
as you described earlier, is the indication of how well something is
working in real time? -- Yes. -- So this is what, maybe you could
just describe a little bit of the interaction with that particular
patient or another patient, what's a typical arc of narrative as you
go from no stimulation to increased stimulation? -- In most
patients, the actual therapeutic effects, the benefits actually take
many days to weeks, and so what I'm mostly focusing on in the office
in real time, is making sure I'm in a safe, low side effect regime.
And so first I talk to the patient who has been on a particular dose
of the stimulation for weeks or longer, and I talk about symptoms, how
were things over the past month? How was your hope? How was your
energy level? Sleep? What is your mood? And then we talk with the
patient and we decide, well, this is not yet where we'd like to be.
And so then, I can turn up the intensity of the stimulation in real
time in the office. In most patients, I don't expect an immediate mood
change. What I do, is I increase the dose until a next level up, while
asking the patient for side effects. Can you still breathe? Okay. Can
you still swallow? Okay. And I can hear their voice as well. And I can
get a sense- -- And you're looking at their face? -- And I'm
looking at their face. -- Yeah. - And so I can get a sense, am I
still on a safe side effect regime? And then, I stop at a particular
point that looks safe, and then the patient goes home, comes back a
month later, and I get the report on how things were over that month.
-- I asked if you're looking at their face, 'cause in your book, you
describe the incredible complexity of social interactions. And at one
point, you describe the incredible amount of information that the eyes
inform about the brain and the context of somebody's inner experience,
whether depressed or happy or otherwise. -- Yeah. -- I want to
make sure that we get back to how to maneuver and manipulate the
nervous system for the sake of mental health. But, what are you
looking for? So as a vision scientist, I think pupils dilating is a
sign of arousal, but that could be a positive arousal, positive
valence, like excitement, or it could be terror. -- Yeah. --
You're going to get the same dilation of the pupils. And I'm always
reminding people that these two little goodies are two pieces of
brain, basically, [Karl chuckles] they're just outside the cranial
vault. So they're not unlike the vagus in that sense, but they're more
of a report than a control knob, although I'd like to think they could
be used as control knobs too. So, without putting you on the spot,
again, to diagnose me, [Karl laughs] that's something I would never
ask you to do [Karl laughing] with the cameras rolling, but what are
you looking for that the patient might not be aware of? In other
words, can you see depression in somebody's eyes? And if you know a
patient or if you don't, can you see it in their body posture when
they walk in? Realizing of course, that a trained psychiatrist like
yourself, develops an intuitive sense that's aggregating lots of
different features of a patient, but what about the eyes? What's going
on there? -- Yeah. The eyes are incredibly rich in information. And
as you alluded to though, it's not as if any one measurable conveys
all the information you need. It's what an engineer would say, joint
statistics. It's many things all at once, whether they're in synchrony
or out of synchrony, that actually turns out to matter. And the eye
contact question, we all know eye contact is incredibly important. You
don't feel you've connected with somebody, unless there's eye contact,
but eye contact can go awry too. It can be too intense, or it can be
mistimed, or if there's someone with autism, it can be barely there at
all. And this is one of the most striking symptoms of autism, is the
avoidance of eye contact, almost as if it's a harmful quantity. And so
there's an immense amount of information you get from the eyes, but
it's the pairing of what's going on in the eyes, with everything else
going on, the body language, the verbal content of what's coming out.
All that together is the art of psychiatry and social interaction. But
sometimes you don't have the eye contact. And this is an amazing thing
and I do talk about this in the book as well. In many cases in
psychiatry, sometimes it's over the phone that you have to make key
decisions. And as I recall, vividly being as a resident, very often
you have to take these phone calls from people who are not in the
hospital, people you can't see, you can't see their eyes, you can't
see their body or anything about them, just the sound of their voice.
And you can ask them questions, and you have to make, in some cases,
life or death decisions. Is this person truly suicidal? Something like
that, as it comes up all the time. And so I developed over the course
of training, and I think all psychiatrists do this, is you develop a
way that data stream you have, whether it's the eyes or whether it's
just the sound of a voice coming over the phone, you learn to hone in
on that data stream you have and focus on it and identify changes and
it's quite amazing. I found that you can actually... If you know a
patient, you can detect very precise changes in mood, just from the
sound of the voice. And you can have a realization that oh, this
patient's depression has improved by about half, just by the tone of
their voice. And same with eyes, with enough practice, you can get
enough information from a single data stream to give you some
information, but when you do have the whole picture of that, of
course, is best. -- So, so many theories out there about excessive
blinking and lying, lack of blinking and sociopathy. I like to remind
people that people have varying degrees of lubrication of the eyes,
[Karl laughs] which also influence the frequency of blinking and
presumably have nothing to do with whether or not what they're saying
is true or not. But incredible, nonetheless, that the eyes are a
portal to overall arousal state. I'm fascinated by the effects of
light on circadian biology and just overall desire to be awake or
asleep, et cetera.
So the eyes are on the outside of the cranial vault. The vagus is
outside the cranial vault, obviously. What about the goodies in here?
Parkinson's, we know at least one of the major sites of degeneration
and failure that lead to those symptoms. I can name off any number of
other things. In your book, you talk about the beautiful work done
with optogenetics of active versus passive coping, that there are
areas of the brain like the habenula that when active, make animals
and presumably people, passive and unwilling, or uninterested in
fighting back against pressures of life, whereas another region, the
raphe, you stimulate that, and they actively cope. They get their grit
going, and they are able to lean into life. So, how does one get to
those structures in a focused way? And what does the next two to five,
to 10 years look like? -- Well, this is the promise on that, and it
is on a timescale that I think things may start to play out. The
specificity of optogenetics is really only useful if you have some
idea of how to use that specificity. And actually, it's a frustrating
aspect of psychiatry that in many cases, the most effective treatments
we have, have the least specificity, electroconvulsive therapy being a
great example, where you're causing a brainwide- -- Which looks
barbaric, but as you mentioned is effective. -- I mean, it is. These
days, it's much more clinically safe- -- It doesn't look like one
fluid there last seen in the lab [indistinct] - No it doesn't. Now
it's a very clinically safe and stable procedure, but I would say
yeah, it's got this almost medieval lack of specificity, even if the
procedure is well-controlled and clinically safe and stable, and it's
not very specific. You're causing a brainwide seizure. How could you
be less specific than that? -- And we don't know the source of the
relief. - [Karl] We don't know- -- Presumably it's a dump of
neuromodulators like dopamine and serotonin, but we don't really know-
-- There certainly is a dump of neuromodulators. We don't know that
that's the cause for the relief. And likewise with medications, this
is an awesome and interesting thing.
Some of the most effective antidepressants, some of the most effective
anti-psychotics are the ones that have the most side effects and there
are many examples of this. For example, the most effective anti-
psychotic is something called clozapine, which unquestionably has the
most side effects. It has terrible, terrible side effects. -- The D4
antagonist? -- It has basically every receptor. [laughs] -- Does
it really? -- Yeah. - Interesting. -- Yeah, it has prominent
serotonin, prominent muscarinic, certainly acts on dopamine receptors,
but it causes blood cell counts change- [laughs] -- How do people
feel? So if I were schizophrenic and I was getting auditory
hallucinations, et cetera, and I took clozapine, what could I expect
to feel? -- Well, so you would notice side effects, and you would
notice resolution of symptoms both and- -- So the voices would go
away? -- Yeah. -- But in a good situation, the voices would go
away? - That's right. -- But I would feel not good in my body? --
You might have dizziness, you might have drooling, you might have any
number of physical sensations that would be due to these off target
effects, the medication acting on these other receptors- -- I'm
certainly not suggesting this, but what if somebody without
schizophrenia took clozapine? -- They'd have the same side effects
presumably, yeah. And so it would not be something that I would
recommend.
-- Yeah. Do psychiatrists take the drugs that they prescribe? [Karl
laughs] I just finished for the third time, Oliver Sacks'
autobiography which is marvelous and I highly recommend to people. He
certainly took a lot of drugs, not as part of his professional role,
but just out of curiosity, what is the interest or kind of role of
drugs in the field of psychiatry? Because I would imagine for a group
of very curious introspective people who are making recommendations
about what to take, there could actually be some benefit for
understanding what the experience of those drugs was like for their
patients. -- I think that's true. And I will say that probably many
or most psychiatrists have sampled the number of these for exactly the
reason that you're saying is to understand better and to help treat
their patients better. And I've spoken to people who have found this
very helpful to know, okay, this sleep disruption caused by this
medication or the libido disruption caused by this other medication.
Wow, that is a big effect. And it really helps with empathy for the
patients to understand. -- I'm not suggesting that physicians or
anybody experiment with drugs, but I am relieved to hear that, because
I think that when you're talking about accessing somebody's mind and
their basic physiology, as you've mentioned, relate to appetite,
libido and sleep, really, one is acting as a mechanic of the person's
whole experience. They walk out of the office and they have a life
experience that extends beyond the script. -- Yeah. And so at the
same time though, you can't let that completely guide your clinical
decisions, because as I mentioned, some of these medications that have
the most side effects, they are also the most effective and clozapine
is a great example. That will work in patients where nothing else
works. And believe me, we don't take the step of clozapine
prescription lightly, because of all these side effects. You have to
come in for a weekly blood cell, or every few weeks of blood cell
check, to make sure that the blood counts are not off for example, but
there are patients where no other medication works for the
schizophrenia and clozapine works amazingly well- -- That's
marvelous. -- And so we do it, even though there are the side
effects. And so then this comes back to your question, what if we had
better and better specificity? Well, only if we know exactly what
we're doing is the point. And so because as we become more refined,
we'd better be right about where we we're refining to.. -- And do
you imagine a day where it will be a single, maybe even outpatient
neurosurgery, would go in through the skull or the back of the ear,
deliver a small viral injection of one of these adenoviruses, a little
sticker of light-emitting diode, deep in the brain, is that how you
envision this someday? -- That certainly could happen. What I
actually prefer as a vision is still medications, because those are
minimally invasive. If we knew what we were doing, we could make them
more specific, have fewer side effects, but optogenetics, that will
arm us with true causal understanding. And so we'll know, and we're
already moving rapidly toward this point, we'll know okay, this
symptom, loss of pleasure in life that we call anhedonia, or the loss
of motivation or energy to overcome challenges, active coping, these
are largely subserved, largely controlled by this circuit or that
circuit or the cell that inhabits this other circuit. -- And we will
know that because of the work done with channelopsins? -- Exactly. -
Yeah. I agree. -- In ways that we never could have the confidence
otherwise. And so we'll know that this is the circuit that underlies
the symptom or its resolution. And then we'll get to understand these
cells very deeply, okay, these cells that are causal, that do matter,
who are they? What's their wiring? What are the proteins that they
make? What are the little things that are on the surface of the cell
that could be receptors for specific medications or combinations of
receptors that would give us the specificity we need? And then, armed
with that causal and precise and rigorous knowledge, then you can
imagine medication development becoming totally different, no longer
serendipitous, but truly grounded in causality.
-- I see. So using channelopsins as a way to probe the circuitry and
figure out the sites that are disrupted, what patterns of activity are
required? And then, by understanding the constituents of those cells,
like what they express and what they make, then developing drugs that
could target those cells, not necessarily putting light-inducing
diodes into the brain, or walking around with wire packs attached to
our skull or something like that. - [Karl] Right. Exactly. -- That's
fantastic. And I realized no one has a crystal ball, but what do you
think the arc of that is? Meaning, are we going to see that in a year?
In two years? Three years? Let me reframe that. How soon will a pill-
based treatment for a psychiatric disease be available, that targets a
specific set of cells that we know are important because of the work
done with channelopsins? -- I think that in some ways it's already
happening at the level of individual patients- -- Here at Stanford?
-- Yeah. Yup. And more broadly in terms of new drugs, new multi-
centered clinical trials that will play out over the next few years.
And these could be drugs that are already safe and approved for other
purposes, but we might say okay, now we know that this medication,
based on what we know from causal optogenetics, this could be useful
for this other purpose, this psychiatric symptom. And so the path to
helping patients could be relatively swift. -- That's very exciting.
What are your thoughts about brain machine interface and Neuralink
always comes up, although I do want to point out a tremendous respect
for the folks at Neuralink including someone who came up through my
lab, is now there as a neurosurgeon, but the brain machine interface
is something that's been happening for a long time now, some of the
best work, among the best work being done here at Stanford and
elsewhere too of course, is what you just described compatible with or
different than brain machine interface, meaning devices, little probes
are going to stimulate different patterns of activity and ensembles of
neurons? And what are your general thoughts about brain machine
interfaces going forward? -- I mean, first of all, it's an amazing
scientific discovery approach, as you mentioned, we and others here at
Stanford are using electrodes, collecting information from tens of
thousands of neurons- -- In humans, I should add. Yeah. [chuckles]
-- And even, yes, it is quite even separate from the Neuralink work as
you point out, many people have been doing this in humans, as well as
in non-human primates. And this is pretty powerful, it's important.
This will let us understand what's going on in the brain, in
psychiatric disease and neurological disease, and will give us ideas
for treatment. It is, of course still invasive. You still are talking
about putting a device into the brain. And that has to be treated as a
situation that has some risks, and a step that has to be taken
carefully. I see that as something that will be part of psychiatry in
the long run, already with deep brain stimulation approaches, we can
help people with psychiatric disorders. And that's putting just a
single electrode, not even a complex closed loop system where you're
both playing in and getting information back, even just a single
stimulation electrode in the brain can help people with OCD, for
example, quite powerfully. And that will become much more powerful
when we get to a true brain machine interface, collecting information
back, stimulating only when you need to. If we could identify a
pathological activity pattern, a particular, almost like the prodrome
or the early stage of a seizure, maybe there are events that happened
leading up to on some timescale, a psychiatric symptom that we could
intervene in a closed loop way to detect what's happening, what's
starting to go wrong, feed that back to the brain stimulation
electrode, have it be in that way more efficient and more principled.
I think it's great. It's something that of course will be grounded
again and causal understanding, we'll need to know, what is that
pathological pattern that we're detecting? And we need to know that it
matters. And so again, that's where optogenetics is helping us. It's
helping us know, okay, this pattern of activity in these cells and
these circuits, this does mean that there's a particular kind of
symptom that's happening. But armed with that knowledge, absolutely,
even the simple closed loop device detect and stimulate is going to be
part of psychiatry in the future. And then of course, as you get to
more cells, more connections, the ability that we have to help people
will become more powerful. -- One of the questions I get asked a lot
is about ADHD and attention deficit of various kinds.
I have a hunch, that one reason I get asked so often is that people
are feeling really distracted and challenged in funneling their
attention and their behavior. And there are number of reasons for
that, of course, but what is true ADHD, and what does it look like?
What can be done for it? And what if any role for channelopsins or
these downstream technologies that you're developing, what do they
offer for people that suffer from ADHD or have a family member that
suffers from ADHD? -- This is a pretty interesting branch of
psychiatry. There's no question that people have been helped by the
treatments, there's active debate over what fraction of people who
have these symptoms can or should be treated? -- This is typically
Adderall or stimulants of some kind? -- Yeah, for example the
stimulants, that's right. So ADHD as its name suggests, it has
symptoms of, it can have either a hyperactive state or an inattentive
state, and those can be completely separate from each other. You could
have a patient who effectively is not hyperactive at all, but can
remain focused on what's going on around them- -- So the body can be
still, but their mind is darting around? -- That's right. -- Or
they can be very hyperactive with their body. -- Yeah, it happens
both ways. -- Probably rarely is somebody hyperactive with their
body but their mind is still, [Karl laughs] although I have to say,
and this is a benevolent shout out to Botond Rosca, Botond has an
incredibly sharp and focused mind. -- Yeah. -- And his hand
movements [Karl laughs] are extremely exact also, so I do sometimes
wonder, whether or not our body movements and our head movements,
whether or not they're coordinated or not is a readout of how directed
our attention is. -- I noticed, I have to think complex, abstract
thoughts. I noticed I have to be very still. So my body has to be
almost completely on moving for me to think very abstractly and
deeply. Other people are different. Some people, when they're running,
they get their best thoughts. I can't even imagine that. My brain does
not work that way at all. I have to be totally motionless, [laughs]
which is kind of interesting. -- How do you go about that? -- I
sit much like this, I try to have time in each day where I'm literally
sitting almost in this position, but without distraction and thinking,
and so it's almost meditative in some ways, except it's not true
meditation, but I am thinking, well, I'm not moving- -- You're
trying to structure your thoughts in that time? -- Yeah. --
Interesting. - Yeah. So, but everybody, as you say is very different.
And so with ADHD, the key thing is we want to make sure that this is
present across different domains of life, school and home, to show
that it really is a pervasive pattern, and not something specific to
the teacher or the home situation or something. And then you can help
patients. It's interesting that ADHD is one of those disorders where
people are trying to work on quantitative EEG-based diagnoses, and so
there's some progress toward making a diagnosis looking at particular,
externally detectable brainwave rhythm- -- So skullcap with some
electrodes that don't penetrate the skull? -- That's right. -- And
this can be done in an hour or two-hour session? -- Yeah, that's
right. -- It has to be done in a clinic, right? -- Yeah, in the
clinic, right, and you have to have the right recording apparatus and
so on, but in principle, increase in confidence comes in exactly which
measurements one could even imagine moving toward home tests, but
we're not there yet. -- Amazing. I think one of the reasons I get
asked about it so much is a lot of people wonder if they have ADHD. Do
you think that some of the lifestyle factors that inhabit us all these
days, could induce a subclinical or a clinical-like ADHD? I look at
people's phone use including my own, and I don't think of it like
addiction, it looks to me and feels to me more like OCD. And I'll come
clean here by saying when I was younger, when I was a kid, I had a
grunting tic. I used to hide it. I actually used to hide in the
closet, 'cause my dad would make me stop. And I couldn't feel any
relief of my mind until I [grunts] would do this. And actually now, if
I get very tired, if I've been pushing long hours, it'll come back.
-- Interesting. -- I was not treated for it, but I will confess that
I've had the experience of, I always liked sports where I involved a
lot of impact, fortunately not football, because I went to a high
school where the football team was terrible. Maybe that would have
avoided more impact, [Karl laughs] but things like skateboarding,
boxing, they bring relief. I feel clarity after a head hit, which I
avoid, [Karl laughs] but I used to say that's the only time I feel
truly clear for a while. And then eventually it dissipated. By about
age 16, 17, it just disappeared. So I have great empathy for those
that feel like there's something contained in them that won't allow
them to focus on what they want to focus on. And these days, with the
phone and all these email, et cetera, I wonder and I empathize a bit
when I hear people saying like, "I think I might have ADHD or ADD". Do
you think it's possible that our behaviors and our interaction with
the sensory world, which is really what phones and email really are,
could induce ADD or reactivate it? -- This is a great question. I
think about it a lot, and you mentioned this tic-like behavior in
yourself, it's very common that people who have tics have this
building up of something that can only be relieved by executing the
tic which can be a motor movement or a vocalization or even a thought.
And people do, I think these days, do have this. If they haven't
checked their phone in a while, they do have a buildup and buildup and
buildup until they can check it and relieve it. And there's some
similarities, there is a little reward that comes with the checking.
But the key question in all of psychiatry, what we do is we don't
diagnose something unless it's disrupting what we call social or
occupational functioning. Like you could have any number of symptoms,
but literally every psychiatric diagnosis requires that it has to be
disrupting someone's social or occupational functioning. And these
days, checking your phone is pretty adaptive. That pretty much helps
your social and occupational functioning. And so we can't make
[chuckles] it a psychiatric diagnosis. -- Interesting. -- At least
in the world of today. -- Yeah, opting out of communication now,
makes you in some ways less adaptive, though I would point to you as
an example of somebody who is quite good at managing his interactions,
at least from the outsider perspective, I do want to ask you a little
bit about you.
And first of all, and I realize this is only a partial list, but
you're a clinician, you see patients, you run a big laboratory, how
many people are in your laboratory now? That's a huge laboratory. From
experience, I can say that's an enormous laboratory. You have a family
of five children, and you're happily married to a wonderful colleague
of ours as well, who does incredible work. How do you organize at a
kind of conceptual level, the day and the week? And I should say, what
stress mitigation practices if any, do you incorporate? I've received
emails from you at three in the morning. I sometimes send emails at
three in the morning, but that's when I wake up, maybe I'm depressed,
but I go back to sleep. So, maybe just describe the arc of the blocks
of the day, not hour by hour, necessarily the details of what are in
those blocks, but how do you conceptualize the day? How do you
conceptualize the week? And how do you feel about how that's lined up
with your larger goals of making sure these five young people
flourish? Which I hear they are, but how do you go about this, what
for most people would just be an overwhelming set of items? -- Well,
of course sometimes it's just take it day by day, and so I don't
claim- -- So you bring the horizon into the unit of the day? -- I
do, I do. The unit is the day, that's right. And I try to have in each
day, as I mentioned earlier, at least an hour of time where I can
think, and it can be when kids are napping, actually, because while
driving I can do that too, because I'm sitting still, [clears throat]
but that's the one thing I try to preserve. When I was writing the
book, I adapted that time to be my writing time, but it wasn't enough,
so I had to add in a new block of time which was sort of midnight to
2:00 AM, writing time. [chuckles] And carving out these, even small
protected times are very important. Of course, obligations will expand
to fill the time available and you have to be disciplined. At least I
found I had to be disciplined in truly protecting those times where
one can think. -- So that means no phone? -- That means no phone,
no checking of the phone. When I was writing the book, there's a focus
mode on the MacBook which kind of rules the border, and you just have
your documents and it's very pure, and you don't have the temptation
of distraction. -- I'm a big believer in because the vision and the
eyes play such a prominent role in directing our cognition, something
you talk about in the book, really beautifully, and with a lot of
depth and rigor, using visual tools to harness one's complete mental
attention. When you do this practice of sitting and just thinking,
sitting still and thinking, you said your eyes are open. Are you
hearing your own verbal voice, although in your head? - Yes. -- So
you're actually in conversation with yourself? -- Yes. And hearing
literally, I mean, not quite literally, I don't actually hear
information, but I'm hearing words, and so I discovered this about
myself. Other people, I think may operate differently, but I'm
extremely verbal in how I think. That's how all my reasoning is done.
It's with sentences and [chuckles] construction of almost equations
with words. -- Complete sentences? -- Complete sentences or
complete-ish anyway, mostly complete, and when writing the book,
everything about the writing, every sentence was always played out in
my mind, listening for rhythm and timing, and I would obsess over
exact placement of words to get the right rhythm of the spoken
sentence in my mind. -- I don't mean to interrupt your flow, but
when you do that, and having experienced this process a bit, although
differently, do you experience any kind of welling up of anxiety when
you're hitting the friction points? And if so, do you have tools or
ways that you quell that anxiety in real time? 'Cause what we're
really talking about here is your mind. But what we're really talking
about is this process of converting the activity of neurons, into
something physically concrete in the world. And these intermediate
steps are so mysterious to everybody. We hear, "Just write the book",
"Just do it", whatever that means. In fact, statements like that to me
are kind of empty and meaningless, but when you hear your voice and
you're trying to find the correct word and you keep hitting, it
doesn't sound quite right, what is the experience in your body? --
Yeah, when it's not right, it's definitely evasive, it doesn't feel
good, but there's also a hope because I know I can solve it too, and
it's almost like you're almost there. There's a path that you know is
there, you don't quite see it, but it's there. And I keep that in
mind, and so there's this propulsive force forward because I know that
the solution is there. And that said, there were single words that I
would spend days on, because I was just not happy until I got it
right. And there were some things that I never quite got perfect, and
so I left out of the book entirely because it was so close, but not
quite there. And I was like, no, I can't put that in. -- Everything
you just said is entirely consistent with my experience of you, [both
laughing] and the way you go about everything. I have to ask, are your
kids writers? Do they like books and words and poetry? I know one of
your children is going on to a career in medicine and science. --
Yeah. They're each different which is amazing, yet they all, I think
do have some appreciation or a lot of appreciation for reading, but
some are very musical. Two of the five are extremely musical, very,
very talented with guitar and singing and vocal, impressions, it's
just astonishing. And some of them are great with drawing and artistry
and some are very physical and vigorous and are never happy except
when leaping about. And so, it's just amazing how different they are,
honestly. But I think there is a shared appreciation for language.
-- Do you think that one can train their mind in using these
practices? I really like your description of the staying physically
still and learning to grapple with those challenges. It's something
that, especially in laboratory science, we aren't really trained to
do. Like many professions we're taught to come in and just get into
motion, and I found that very relaxing as someone who probably has an
underlying tic [Karl chuckles] or something like that, it felt great
to be in motion. One of the hardest things about becoming a university
professor and running a lab, was that I no longer working with my
hands. And it felt like some big important part of my life had been
amputated. But what sorts of practices do you incorporate there? And
do you think people can learn to get better at focusing through a
dedicated practice of the sort that you described? -- I remember the
rhythms of physical work in the laboratory very well. My work these
days as the laboratory leader, my job has returned mostly to words
now, again. And so it's kind of coming full circle. So it's a
different mode. I think you just have to embrace the different stages
of life, come with the different modes, but you can definitely train
yourself for each mode. I loved, as I mentioned, the rhythm of sewing
and suturing and surgery, and I worked really hard on that and became
good at it. And now, I never do it, but it's what's the next
challenge. There's all the various experimental techniques the
dissections of the brain, I can't tell you how many thousands of brain
dissections I've done in my life, and now I don't do them at all.
[Karl laughs] -- And then you developed a method so that we don't
have to dissect brains. -- That's right. [chuckles] - As you
mentioned there, maybe tell us for a moment about clarity, and for
people who will probably never set foot into a laboratory, what an
incredible, yet another incredible discovery and development clarity
is, and why it helps us understand how the brain is structured. --
Yeah. So this is a different technology also developed in my lab here,
and it's part of a broader approach that we call hydrogel-tissue
chemistry. And what this is, is it's building a gel, like a clear
jello-like substance from within all the cells of a tissue or even an
animal, all at once. So you're effectively building a gel inside all
the cells at once. Now, that's an odd thing to do. Why do we do it?
Well, we do it to transform the tissue into a more tractable
accessible object. And the reason that works is having built this gel,
this new infrastructure inside the tissue, we can then use chemical
tricks, and we can link the molecules we care about, like proteins or
RNAs which are the things, as you know, right before they become
proteins, we can link them, physically anchor them to this gel, which
is a scaffold basically, it's an interlocking network of polymers. We
can link all these interesting molecules in place, lock them in where
they were initially in the tissue, in the cell, in all the cells. And
then we can remove very vigorously, everything we don't care about
that's blocking our light, that's blocking our molecules, coming in to
exchange information with the tissue. We can get rid of everything
else, like the lipids, the fats, we can effectively use detergents to
get them all out, and then we can see in all the things that were
absorbing or scattering light are gone, you can have a brain that's
completely transparent, and yet, all the interesting molecules are
still locked into place there, at the cellular and sub cellular level.
And so this is hydrogel-tissue chemistry. The first form we described
was called clarity. We use that quite a bit still, but there are many
variants now, that we and others have developed on this basic concept
of building this gel within the tissue and anchoring molecules into
place. -- Literally glass-clear brains. I've done this, I've taken a
brain cleared with this method, and looked at somebody through it,
[Karl laughing] and although you don't want to get it too close to
your eye, you don't want to touch it to your own eye, and you can see
direct all the way through it. - [Karl] Yeah. -- That's incredible
for it raises an important question, which is again, about the human
brain, and as somebody who essentially started out in neuroanatomy and
then got into other things, I always am bothered by the fact that we
actually know very little about the microstructure of the human brain,
compared to the brains of other organisms. -- Yeah. -- And in
thinking about understanding the circuitry and the piano, so to speak
and how to manipulate it in order to relieve suffering, one wonders,
are the structures in these animal brains and how they behave, and
active coping, passive coping, ADD, et cetera, those models, how well
they translate to the human condition.
Do you think it's fair to say that there are entire regions of the
human brain that aren't just bigger, but that exist only in the brains
of humans? Especially given that we have this speech, although I do
wonder sometimes if animals report in to each other there. Maybe they
have little psychiatric sessions with one another. -- You know, I'm
always careful to not assume we do things better. We certainly
understand what we're doing better than we understand what animals are
doing, and they certainly do things better than we do. That said, we
do have amazing, wonderful brains and many structures that are very
highly developed in our brains that are not nearly so developed in
mice and fish for example. Now, that said, when I look at the big
picture, what is the mammalian brain really doing? There are things
that you would never have thought we could study in animals and
laboratory mammals like mice, that it turns out you can, actually, and
so I would never draw the line and say, here's something you can't
study in mice, or here's something that has no parallel in mice. I
would be very careful before making any statement like that. And a
good example of that is we've been able to study just in the past
year, come to an understanding of dissociation, and we had a paper
that came out in late 2020, both mouse and human work, in which we got
to the sort of the circuit basis for dissociation. Now, what is
dissociation? A lot of people might not have experienced it, but it's
actually very common. More than 70% of people who've been through
trauma experience dissociation, it shows up in borderline personality,
it shows up in PTSD. What it is, is a separation of the sense of self,
from the body. So you can have someone who, it's not as if you're
numb, you're not anesthetized. You can still know that something's
happening to the body, but you just don't care, because you don't
ascribe it to yourself, which is very interesting, right? How
interesting is that? -- The cells report narrative. -- Yeah. Yeah.
-- In your book, you touch on this. And I will say is the most
precise, and meaningful and eloquent description of what might be
consciousness, this narrative toward the self or of the self, and
where it might reside. So in dissociative conditions, people are
feeling as kind of an absence of a merge between mind and body. -
Right. -- Is that one way to describe it? -- That's right. - And
as I recall, this paper involved an exploration of ketamine. --
Ketamine was a big part of it. Yeah, that's right. And so ketamine is
another one of those cases where people can experience dissociation.
Ketamine or PCP, we call these the dissociative drugs. They cause it
just like these other psychiatric conditions can cause it. But we were
able to manifest this in mice, administering these dissociative agents
in mice. We could make them still able to detect stimulus, but not
care that it was happening. All the while we were recording the
activity of individual cells in the brain to see what was going on,
what was happening along with this dissociation, and then use
optogenetics to see that it mattered to actually provide that pattern
of activity and see, oh, that actually causes the dissociation. So we
could do all that in mice, which who would've thought that you could
study something like this in mice? And we were able to go back and
forth with human work because here in our Stanford Comprehensive
Epilepsy Center, there's a lot of what we call Stereo EEG Recording.
Patients who come in and in the course of normal clinical care, they
have electrodes recording in their brain to identify where the seizure
is, so they can be candidates for removing a little patch of the brain
that's causing the seizure. This has done for patients who medications
are not helping their seizure disorder. And there was a patient who
had a dissociative state before every seizure, so this was a human
being who was really dissociating, who could tell us literally as it
was happening. And we could see this pattern, the same pattern that
was happening in the mice, in the same patch of the brain, we could
see that happening in the human being at exactly the right time, in
the same patch of the brain that's homologous across these immense
evolutionary distances. And we knew that it mattered to both the mouse
and human because in the human we could cause it to happen. -- I
just want to underscore the power of optogenetics and the ability to
not just remove a particular experience or behavior by lesioning or
destroying, but then to go back and actually activate same structure
or group of structures and see the emergences. So essentially, these
days you hear a lot about gain of function research in the context of
viral manipulation, but gain of function is something that we do in
the laboratory and you do in patients, to both take away something and
put it back, which gives you causality. -- That's right. Yeah, and
exactly. And so with optogenetics, we were able to provide in animals
without being on any ketamine or any drug and we could cause the
dissociative state by playing in a precise pattern of activity. And
who would have thought you could do that? But that was a combined
mouse and human paper. Likewise, we've been able to play in visual
sensations into the brains of mice, and by observing which cells in
the visual part of the brain, visual cortex, are naturally responsive
to for example, vertical bars, instead of horizontal bars in the
visual world, we could see which cells were normally reporting on
vertical bars, and then we could use optogenetics to come and play in
activity just to those cells. -- So these animals are not viewing
anything? -- Not viewing anything at all. And we could activate just
the vertical bar cells, and not only did the animal act as if it was
seeing a vertical bar, behaviorally, it was trained to do a particular
thing if it saw a vertical bar, and it did that, just as if it was
seeing something visually. But everything in the brain that we were
recording to the internal representation of this external world was
naturalistic too. It looked like the brain was seeing something
visual. So that's gain of function too, you know, playing in,
providing a complex sensation or percept that wasn't there before. And
we can do that across species. So, and of course mice are social, and
they do amazing acts of information processing and I try not to
disparage our cousins too much. -- They certainly have helped the
field of neuroscience and medicine I should mention, and I know that
people have various sensitivities about animal research, but the work
that's been carried out in mice has been absolutely vital and
instructional for treatment of human disease. -- That's right.
-- Since we talked about dissociation and dissociative states rather
and ketamine, I'd love your thoughts on psychedelic medicine. You
know, I sort of half joke having grown up in this area in Northern
California when it was much more counter-culture than it is now, that
many of the things that we're hearing about now, at least from my read
of the history books, happened before. There was a movement aimed at
taking the very same compounds essentially, putting them into patients
or people who were obviously using them recreationally, but putting
them into patients, and seeing tremendous positive effects, but also
tremendous examples of induced psychiatric illness. In other words,
many people lost their minds as a consequence of overuse of
psychedelics. I'll probably lose a few people out there, but I do want
to talk about, what is the state of these compounds? And I realize
it's a huge category of compounds, but LSD and psilocybin, as I
understand trigger activation of particular serotonin receptor
mechanisms, may or may not lead to more widespread activation of the
brain that one wouldn't see otherwise. But when you look at the
clinical and experimental literature, what is your sort of top contour
sense of how effective these tools are going to be for treating
depression? And then if we have the time, we could talk about trauma
and MDMA and some of that work. -- Well, you're right to highlight
both the opportunity and the parallel that is there. And of course we
want to help patients and of course we want to explore anything that
might be helpful, but we want to do it in a safe and rigorous way. But
I do think we should explore these avenues. These are agents that
alter reality and alter the experience of reality I should say, in
relatively precise ways. They do have problems, they can be addictive,
they can cause lasting change that is not desirable, but we have to
see these as opportunities. We have to first of all, study in the
laboratory, and I'm doing this here. You know we have [chuckles]
big... We have safes with many interesting psychedelics that are all
very carefully regulated. We get inspections from the DEA and so on.
-- If anyone's hoping to find these labs, [Karl laughing] they exist
in outer space, so you need to be on board one of the SpaceX missions
in order to access them. So don't try and come find them. -- No,
that's exactly true. Yes. And we're doing exactly this. We're saying
this is an incredible opportunity. If we could understand how the
perception of reality is altered, we could be creating new kinds of
intervention that don't have the risks and the problems of causing
lasting change or addiction. Now, that said, even as these medications
exist now, as you know, there's an impulse to use them in very small
doses and to use them as adjunctive treatments for the therapy of
various kinds. And I'm also supportive of that if done carefully and
rigorously, of course there's risk, but there's risk with many other
kinds of treatments. And I'm not sure that the risks for these
medications vastly outweigh the risks that we normally tolerate in
other branches of medicine. -- Why would they work? I mean, let's
say that indeed their main effect is to create more connectivity, at
least in the moment between brain areas. So the way I think about the
two extremes of my experience anyways, a high degree of stress and
focus for whatever reason, is going to create changes in my visual
field and changes in the way that I perceive times, so that I'm on a
micro-sliced time, I might be in a very contracted view of whatever my
experience is, whereas on the opposite extreme in a dream or in sleep,
space and time are very fluid, and I'm essentially relaxed, although
it might be a very interesting dream, or it might not be. Psychedelics
seemed to be a trajectory. I'm not too far off from the dream state
where space and time are essentially not as rigid. And there is this
element of synesthesia, blending of the senses, you know, feeling
colors and hearing light and things of that sort. You hear these
reports, anyway. Why would having that dream-like experience somehow
relieve depression, long-term? Do we have any idea why that might be?
-- Yeah. We have some ideas, and no deep understanding. One way I
think about the psychedelics is they increase our willingness to...
They increase the willingness of our brain to accept unlikely ways of
constructing the world, unlikely hypothesis, as it were, as to what's
going on. The brain, in particular our cortex, I think, is a
hypothesis generation and testing machine. It's coming up with models
about everything. It's got a lot of bits of data coming in, and it's
making models and updating the models and changing them, theories,
hypothesis for what's going on. And some of those never reach our
conscious mind. And this is something I talk about in "Projections" in
the book quite a bit, is many of these are filtered out before they
get to our conscious mind, and that's good. Think how distracted we'd
be if we were constantly having to evaluate all these hypotheses about
what kinds of shapes or objects or processes were out there. And so a
lot of this is handled before it gets to consciousness. What the
psychedelics seem to do, is they change the threshold for us to become
aware of these incomplete hypotheses or wrong hypotheses, or concepts
that might be noise but are just wrong, and so are never allowed to
get into our conscious mind. Now, that's pretty interesting, and it
goes wrong in psychiatric disorders. I think in schizophrenia there's
some of the times the paranoid delusions that people have are examples
of these poor models that escape into the conscious mind and become
accepted as reality and they never should've gotten out there. Now,
how could something like this in the right way, help with something
like depression? Patients with depression often are stuck. They can't
look into the future world of possibilities as effectively. Everything
seems hopeless. And what does that really mean? They discount the
value of their own action, they discount the value of the world at
giving rise to a future that matters. Everything seems to run out like
a river just running out into a desert and drying up, and what these
agents may do that increase the flow through circuitry, if you will,
the percolation of activity through circuitry may end up doing for
depression is increasing the escape of some tendrils of process of
forward progression through the world. That's a concept, that's how I
think about it. There are ways we can make that rigorous. We can
indeed identify in the brain by recording, we can see cells that
represent steps along a path and look into the future, and we can
rigorously define these cells and we can see if these are altered on
psychedelics. And so that's one of the reasons that we're working with
these agents in the laboratory to say, all right, is this really the
case? Are these opening up new paths or representations of paths into
the future?
-- MDMA, ecstasy is a unique compound in that it leads to big
increases in brain levels of dopamine and serotonin simultaneously.
And I realized that the neuromodulators like dopamine and serotonin
often work in concert, not alone, the way they're commonly described
in the more general popular discussions. However, it is a unique
compound, and it's different than the serotonergic compounds, like LSD
and psilocybin. And there are now data, still emerging that it might
be, and in some cases can be useful for the treatment of trauma, PTSD
and similar things. Why would that work? And a larger question,
perhaps the more important question is, psychedelics, MDMA, LSD, all
those compounds, in my mind there are two components. There's the
experience you have while you're on them, and then there's the effect
they have after. People are generating variations of these compounds
that are non-hallucinatory variations. But, how crucial do you think
it is to have, let's stay with MDMA, the experience of huge levels of
dopamine, huge levels of serotonin, atypical levels of dopamine and
serotonin released, having this highly abnormal experience in order to
be normal again? -- Yeah. I think the brain learns from those
experiences. That's the way I see it, and so for example, people who
have taken MDMA, as you say, there will be the acute phase of being on
the drug and experiencing this extreme connectedness with other people
for example, and then the drug wears off, but the brain learned from
that experience. And so what people will report is, yeah, I'm not in
that state, but I saw what was possible. I saw it. Yeah. There don't
need to be barriers, or at least not as many barriers as I thought. I
can connect with more people in a way that that is helpful. And so I
think it's the learning that happens in that state, that actually
matters. -- And as you described that, that sounds a lot like what I
understand to be the hallmark feature of really good psychoanalysis,
that the relationship between patient and therapist, hopefully evolves
to the point where these kinds of tests can be run within the context
of that relationship, and then exported to other relations. --
Exactly right. Yeah. -- And that probably, I'm assuming is still the
goal of really good psychiatry also. -- As a part of- -- Intimacy,
really. -- It should be. When we have time, I think all good
psychiatrists try to achieve that level of connection and learning,
try to help patients create a new model that is stable, that is
learned, and that can help instruct future behavior.
-- One of the things that I took from reading your book, in addition
to learning so much science and the future of psychiatry and brain
science was, amidst this very tragic cases and sadness, and a lot of
the weight that that puts on the clinician, on you also, that there's
a central cord of optimism, that where we're headed is not just
possible but very likely, and better. -- Yeah. -- And, are you an
optimist? - [chuckles] I am. And by the way, this was a really
interesting experience in writing "Projections", because I had a dual
goal. I wanted it to be for everybody, literally everybody in the
world who wants to read it. And yet at the same time, I wanted to stay
absolutely rigorously close to the science, what was actually known,
when I was speaking about science. When I was speaking about the
neurobiology of the brain or psychiatry, I wanted to not have any of
my scientific colleagues think, oh, he's going too far, he's saying
too much. And so I had these two goals which I kept on my mind the
entire time. And a lot of this trying to find exactly the right word
we talked about was, on this path of staying excruciatingly rigorous
in the science and yet, letting people see the hope, where things
were, have everybody see that we've come a long way, we have a long
way to go, but the trajectory and the path is beautiful. And so that
was the goal, I think. Of course that sounds almost impossible
[chuckles] to jointly satisfy those two goals, but I kept that in my
mind the whole way through. And yes, I am optimistic and I hope that
it came through in the book -- It certainly did, and at least from
this colleague, you did achieve both. And it's a wonderful, it's a
masterful book, really, and one that as a scientist and somebody who
is a fellow brain explorer, hits all the marks of rigor and is
incredibly interesting and there's a ton of storytelling. I don't want
to give away too much about it, but people should definitely check out
the book.
Are you active on social media? If people want to follow you and
connect with what you're doing now and going forward? -- Yeah. I
have Twitter. That's where I mainly do exchange, tell people about
things that are happening. -- We'll provide a link to it, but that's
Karl Deisseroth, as I recall, with a K? -- That's right. -- Yeah.
- That's right. -- And so you're on Twitter, and people will hear
this, definitely check out the book. There are other people in our
community that of course are going to be reaching out on your behalf,
but it's incredible that you juggle this enormous number of things,
perhaps even more important however, is that it's all in service to
this larger thing of relieving suffering. So thank you so much for
your time today, for the book, and the work that [chuckles] went into
the book, I can't even imagine, [Karl laughs] for the laboratory work
and the development of channelopsins, clarity, and all the related
technologies and for the clinical work you're doing and for sharing
with us. -- Well, thank you for all you're doing in reaching out.
I'm very impressed by it. It's important and it's so valuable, and
thank you for taking the time and for all your gracious words about
the book. Thank you. -- I hope you enjoyed today's discussion with
Dr. Deisseroth as much as I did. Be sure to check out his new book,
"Projections: A Story of Human Emotions". It's available on Amazon,
Audible, and all the other standard places where books are found. If
you'd like to support this podcast, please subscribe to us on YouTube.
As well, you can subscribe to us on Apple or Spotify. At Apple, you
also have the opportunity to leave us a five-star review, and to give
us feedback. Please put any questions you have in the comment section
below the YouTube video, if you'd like us to address certain things in
future episodes, or if you have questions about this particular
episode. In addition, please check out our sponsors. That's a terrific
way to support us. We also have a Patreon, it's
patreon.com/andrewhuberman. There you can support us at any level that
you'd like. Last but not least, if you're interested in understanding
more about how the brain works and how it functions, and how it breaks
down in various conditions, check out the first episode of the
"Huberman Lab Podcast". The title of that episode is "How your nervous
system works and changes". If you're watching this right now on
YouTube, you can simply click on the title card for that episode. And
last but not least, [upbeat music] thank you for your interest in
science.
Dr. Karl Deisseroth
Twitter: https://twitter.com/KarlDeisseroth
New book: https://amzn.to/3diiKHG
Lab Website: https://web.stanford.edu/group/dlab/
Thank you to our sponsors
ROKA - https://www.roka.com - code: huberman
InsideTracker - https://www.insidetracker.com/huberman
Athletic Greens - https://www.athleticgreens.com/huberman
Our Patreon page:
* https://www.patreon.com/andrewhuberman
Supplements from Thorne:
* http://www.thorne.com/u/huberman
Social:
* Instagram - https://www.instagram.com/hubermanlab
* Twitter - https://twitter.com/hubermanlab
* Facebook - https://www.facebook.com/hubermanlab
Website: https://hubermanlab.com
Join the Neural Network: https://hubermanlab.com/neural-network
Please note that The Huberman Lab Podcast is distinct from Dr.
Huberman's teaching and research roles at Stanford University School
of Medicine. The information provided in this show is not medical
advice, nor should it be taken or applied as a replacement for medical
advice. The Huberman Lab Podcast, its employees, guests and affiliates
assume no liability for the application of the information discussed.
Title Card Photo Credit: Mike Blabac - https://www.blabacphoto.com
HubermanLab #KarlDeisseroth #AndrewHuberman