[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.
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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 good
2021-07-04