Karl Deisseroth: Depression, Schizophrenia, and Psychiatry | Lex Fridman Podcast #274

Lex Fridman 0:01 Where are the darkest places you've ever gone in your life? The following is a conversation with Karl Deisseroth, professor of bioengineering, psychiatry, and behavioral sciences at Stanford University. He's one of the greatest living psychiatrists and neuroscientists in the world. He's also just a fascinating human being. We discuss both the darkest and the most beautiful places that the human mind can take us. He explores this in his book called Projections: A Story of Human Emotions. I highly recommend it. It's written masterfully. This is the Lex Fridman Podcast. To support it, please check out our sponsors in the description, and now, dear friends, here's Karl Deisseroth.

Lex Fridman 0:48 You open your book called Projections: A Story of Human Emotions with, uh, a few beautiful words that summarize all of humanity. The book draws insights about the human mind from modern psychiatry and neuroscience. So if it's okay, let me read a few sentences from the opening.

Karl Deisseroth 1:04 Go ahead.

Lex Fridman 1:05 You gotta give props to beautiful writing when I see it. Quote, "In the art of weaving, warp threads are structural and strong and anchored at the origin, creating a frame for crossing fibers as the fabric is woven. Projecting across the advancing edge into free space, warp threads bridge the formed past, to the ragged present, to the yet featureless future. Yet featureless future. Well done. Well done, sir. "The tapestry of the human story has its own warp threads, rooted deep in the gorges of East Africa, connecting the shifting textures of human life over millions of years, spanning pictographs back-dropped by creviced ice, by angulated forestry, by stone and steel, and by glowing rare earths. The inner workings of the mind give form to these threads, creating a framework within us upon which the story of each individual can come into being. Personal grain and color arise from the cross-threads of our moments and experiences, the fine weft of life, embedding and obscuring the underlying scaffold with intricate and sometimes lovely detail. Here are stories of this fabric fraying in those who are ill, in the minds of people for whom the warp is exposed and raw and revealing." What have you learned about human beings, human nature, and the human mind from those who suffer from psychiatric maladies, for those for whom this fabric is warped?

Karl Deisseroth 2:41 Yeah. One thing we learn as biologists is that when something breaks, you see what the original unbroken part was for, and we see this in genetics, we see this in biochemistry. It's known that when you have a, a mutated gene, sometimes the gene is turned up in strength or turned down in strength, and that lets you see what it was originally for. You can infer true function from dysfunction, and this is a theme that I thought needed to be shared and needed to be made communicable to the, to the lay public, to everybody, people who... which is, I think, uh, almost all of us who think and care about the inner workings of our mind, but who also care for those who have been suffering, who have mental health disorders, who face challenges. But then more broadly, it's a very much larger story than the present. There's a, a story to be told where the protagonist really is the human mind, and that was one thing I wanted to share as well in Projections, is that broader story, but still anchored in the moment of patients, of people, of experiences of the moment.

Lex Fridman 3:54 Is there a clear line between dysfunction and function, disorder and order?

Karl Deisseroth 3:59 This is always debated in psychiatry, probably more so than any other, you know, medical specialty. I'm a psychiatrist. I'm, I treat patients still. Uh, I see acutely ill people who come to the emergency room where there's no doubt that this is not something that's working well, where the manifestation of disease is so powerful, where the person is suffering so greatly where they cannot continue as they are. But of course, it's a spectrum and there are people who are closer to the, to the realm of being able to, to work okay in their jobs, but suffer from some small dysfunction and everywhere in between. In psychiatry, we're careful to say we don't call it a disease or a disorder unless there's a disruption in social or occupational functioning, but, of course, psychiatry, uh, has a long way to go in terms of developing quantitative tests. We don't have, uh, blood draws. We don't have imaging studies that we can use to diagnose. And so that line ultimately that you're asking about between order and disorder, function and dysfunction, it's operational at the moment how are things working.

Lex Fridman 5:08 Can we just, like, linger on the terms for a second? So this, uh, disease, uh, dysfunction, how careful should we be using those words? Can we just... e- even in this conversation, um, from a sort of technical perspective but also a human perspective, how, uh, quick should we be in saying that schizophrenia, uh, depression, autism-

Karl Deisseroth 5:38 Yeah.

Lex Fridman 5:38 ... as we kind of go down this, uh, the, the, uh, across the spectrum of different maladies, like, th- th- just to use the word dysfunction and d- and disease?

Karl Deisseroth 5:48 I would say, to give our- ourselves license to capture the whole spectrum, let's say disorder because that, that captures truly, I think, the essence of it, which is we need to talk about it when it's not working, when there's disorder, and that, that's the fairest and, and, uh, you know, most, uh, inclusive term to use.

Lex Fridman 6:08 So, is it fair to assume that basically every member of the human species suffers from a large number of disorders then?

Karl Deisseroth 6:17 Well-

Lex Fridman 6:17 And we just have to pick which ones are (laughs) are, uh, debilitating and, uh, for each person?

Karl Deisseroth 6:23 You know, if you, if you look at the numbers, there are... Uh, you know, if, if you look at how our, our mental health disorders are currently defined, you can, uh, look at population prevalence values for all these disorders, and you can come up with estimates that, uh, somebody will have a lifetime prevalence of having a psychiatric disorder that a- approaches 25% or so. And so that's... And in some studies it could be more, in some studies it could be less. Now, what do we do with that number? What does that mean? And in some ways that's the essence of what I was hoping to approach with, uh, the book, is to reflect on this spectrum that exists for all the disorders. There is... And, and taking nothing away from the severity and the suffering that comes at the extreme end of, of these illnesses, but nearly every one of them exists on a spectrum of severity, uh, from nearly functional to completely dysfunctional, life-threatening and, and even fatal. And so that, that, that number, 25%, more or less, it doesn't capture, uh, that, that spectrum of in- of, of, uh, severity.

Lex Fridman 7:27 So looking at that number, where do those numbers come from? Is it self-report? Is it people who show up and say, "I need help"? Is it somebody else that points out that person needs help? Uh, or is it like estimates that even go beyond that for people who don't ask for help but are suffering quietly, uh, alone?

Karl Deisseroth 7:45 When you look at self-report numbers that, that then those numbers get even higher, beyond 25% or more. Uh, those... The most rigorous studies are done with structured psychiatric interviews where people, uh, who are trained in eliciting symptoms, uh, carefully do complete psychiatric inventories of, of individuals. And these are, uh, time-consuming, laborious studies. They're not often repeated. When they're done, they're, they're done well. Uh, but, uh, very often you'll see a report or something in the news of a very high number for some disorder or, or symptom, and very often if it's shockingly high, that's coming from a self-report of, of a person. And so that's another, another issue that we have. Again, take nothing away from the severity and reality and, and biological nature of these disorders, which are very genetic, very... You know, we, we understand that these are very biological, and yet we lack right now the lab tests and the blood draws to make the diagnoses.

Lex Fridman 8:45 Well, we'll talk about it, just how biological they are 'cause it's a... That too is a mystery. Uh, j- you know, in terms of from a perspective of how to probe into the disease, how to understand it, and how to help it. So some of it could be neurobiological, some of it could be, uh, just the hu- the dance of human emotion and interaction and, uh... It's like, uh... Well, uh, is love when it works and is love when it breaks down, uh, biological or is it something else? So we're, we're, we're gonna talk about it. But, well, let me just like... To linger in terms of disorder,

Lex Fridman 9:21 what about genius? You know that sort of, uh, cliche saying like the madness and genius, that they kind of dance together. Uh, what about if the thing we see as disorder is actually genius unheard or misunderstood?

Karl Deisseroth 9:37 Yeah. Well, here again, the numbers help us, and here's where being rigorous and quantitative actually really helps. If you look at disorders like autism and bipolar disorder and eating disorders, anorexia nervosa, for example, these... Uh, you know, particularly bipolar and anorexia, these can be fatal. They can cause immense suffering, but they are heavily genetic, all three of these, and what's very interesting is each one of these three is actually correlated positively, positively with measures of intelligence, of educational attainment, and even of income. And so you look at this, it's severe disorders in many cases causing quite an immense morbidity and mortality and yet they are positively correlated at the population level with positive things.

Lex Fridman 10:31 Can you say the, the three again?

Karl Deisseroth 10:33 Yeah.

Lex Fridman 10:33 Autism-

Karl Deisseroth 10:33 Autism, anorexia, and bipolar disorder.

Lex Fridman 10:37 Bipolar, right. What's that book? Forgot the book name, but, uh, Is Intelligence a Burden?

Karl Deisseroth 10:43 (laughs)

Lex Fridman 10:44 Uh... (laughs)

Karl Deisseroth 10:45 Well, you know, people can get into trouble when they think they're smarter than they are. I will say that.

Lex Fridman 10:51 I don't know. Sometimes, like, uh, uh, in the deepest meaning of that statement, I think ignorance is bliss. I'm a big fan of Prince Myshkin from The Idiot and, um, Alyosha from Brother Karamazov.

Karl Deisseroth 11:04 Mm-hmm.

Lex Fridman 11:04 Optimism can be seen as naivete and, and dumbness, but I think it's a, it's a kind of deep intelligence (laughs) . Maybe inability to reason, uh, sort of about the mechanics of the world, but instead kind of feel the world. And it seems like that's a pa- one of the paths to happiness.

Karl Deisseroth 11:24 There is. How much you think versus how much you feel, this comes up all the time. In medicine, we encounter this all the time. When you... Uh, day after day you encounter this, you know, the, the, the abyss of suffering from patients. How much do you let yourself feel or how much do you make it abstract and, and objective and, and try to make it clinical? And that range, how you're able to move yourself on that, on that spectrum is very important for survival as a physician (laughs) . Uh, and the way you, you protect yourself and your feelings turns out to be

Karl Deisseroth 11:59 very important.

Lex Fridman 12:00 So you quote Finnegans Wake. Uh, mad props for that James Joyce book. I took a class on James Joyce in college. I, uh, think I read parts of Finnegans Wake-... I might have been on drugs or some kind of, or-

Karl Deisseroth 12:12 (laughs)

Lex Fridman 12:13 ... I, um, I somehow got an A in that class-

Karl Deisseroth 12:15 (laughs)

Lex Fridman 12:15 ... which probably refers to some kind of curve where nobody understood anything. The only thing I understood and really enjoyed is his short stories, The Dead. And then Ulysses, I kind of, uh, I think read a few cliff notes that kind of got to the point, and then Finnegan's Wake was just a hopeless pers-... I, it's a, you, you, uh, for people who haven't looked at it, maybe you can, uh, elucidate to me better, but I felt like I was reading things, words, and the words made sense, like standing next to each other, but when you kind of read for a while you realize you didn't actually understand anything that was said.

Karl Deisseroth 12:54 Right. But did you have a feeling though? That's one, that's one thing I found interesting about Finnegan's Wake. I, I never fully understood it, but the words caused feelings in me, which I found fascinating. And, and sometimes I, I, I couldn't predict it from the, the semantic, you know, black and white context of what I was seeing in, in front of me on the page. But the rhythm or the melody would, would make me feel certain ways, and that's, that was what I always was intrigued by with Joyce. Of course, that was his... He, he existed on a spectrum too, and he wrote, uh, as you say, you know, more accessible, uh, works, you know. I learned a lot about Irish history from, you know, Portrait of the Artist as a Young Man, and there was just... He, he could be as objective as he wanted to be, but then when he let himself loose, he was in this realm where words had their own purpose separate from, from, you know, semantic meaning, from their, their dry, uh, you know, dictionary definition.

Lex Fridman 13:46 You know, there's a funny story that I was told, doesn't matter if it's true or not, but they, they said that, uh, James Joyce when he was young, when he was in his teen years would go around sort of Ireland drinking and so on and telling everybody that he's going to be one of if not the greatest writers of the 20th century, and, uh, he turned out to be that.

Karl Deisseroth 14:06 Mm-hmm.

Lex Fridman 14:07 So the... Uh, that, I always think about that little story that somebody told me because I have a lot of people come up to me including myself, I'm a bit of a dreamer, I'll, and I'm, you know, you get into certain moods where you say, "I'm going to be the greatest anything ever." You get, you get, like, people tell you this, uh, young, especially young people, and it kind of, and it makes me feel all kinds of ways but that story reminds me that, like, you just might be one of the greatest (laughs) writers of the 21st century, for example, if somebody were to tell me that, and, like, don't dis-... Don't immediately disregard that 'cause one of the people that say that, that's almost like a pre, uh, condition that's like a requirement just to believe in yourself. Maybe it's not a full requirement, but it's, it's an interesting story. (laughs) So...

Karl Deisseroth 14:56 Well, I think when someone tells you that, then it creates a... You, one sees an opportunity and then it would be a tragedy if the opportunity weren't captured, right? And so then that creates a, um, some, some impetus, uh, some motivation to do something, something good.

Lex Fridman 15:12 I think the mind, it's like, uh, you know, I guess that's what, like, books like The... Or books or whatever, I don't even know if it's a book, The Secret plugs into. Uh, they kind of make a whole industry out of it, but there is something about the mind believing something, making it a reality. It is just time and time again with Steve Jobs, like, your belief in yourself, your belief in an idea, sort of embracing the me versus the world, embracing the madness of this idea and making it a life pursuit, somehow morphs reality around for some tiny fraction of the population. For everybody else, you descend into, um, uh, you know, all, all the beautiful ways that failure, uh, materializes in our lifetime. (laughs)

Karl Deisseroth 15:59 Well, you know, the... You mentioned love earlier. I mean, that's, that's a great example of how belief in something makes it real, right? It's, it's not reasonable on the face of it, but because you believe it's reasonable, then it actually does become reasonable and then it is real. And so that's a, that's a good example. That doesn't happen... I'm also in a bioengineering department. We don't imagine that a bridge is soundly built and then it is soundly built. That's, um, something that it doesn't come up in too many realms of human existence, but love is, is one of them and, and these, the ability to, to have a fixed idea and to say it's true and then it is true.

Lex Fridman 16:32 A bridge is a kind of manifestation of love so maybe it does work a little bit, but, you know, they can break down like Chernobyl did. You can't just say it's safe. It, you have to (laughs) also prove it safe. Uh, but on Finnegan's Wake, I think, maybe correct me if I'm wrong, you're using kind of Finnegan's Wake to give one perspective on what madness is, of what's going on in the mind. How much of that is, uh, that we're simply unable to communicate with the person on the other side-

Karl Deisseroth 17:02 Yeah.

Lex Fridman 17:02 ... of, of their mind? Like, there's almost like a, a little person inside the brain and they have some circuitry that's used to communicate emotion, communicate ideas to the outside world, and there's something about that circuitry that makes it difficult to communicate with the little person on the other side.

Karl Deisseroth 17:18 So if you look at what shows up in schizophrenia with many cases the, the, what we call thought disorders, what we call, uh, the, the individual speech symptoms of, of schizophrenia, Finnegan's Wake is, is loaded with them and it's just, just full of them. We, we talk about, uh, clang associations in schizophrenia where the word that is said is, echoes in some way the previous word and it's, we call that a clang association 'cause there's no other reason than the similarity of the sound like a, like a clang of a, of a, of a garage door being hit. And it has a, uh, and sometimes it's not even a word and we call that a neologism, uh, a new word being created, and of course Finnegan's Wake is, is full of that, and then, uh, we, we also, in schizophrenia there's what we call loose associations or tangential thought processes. Of course full of that, where things just go off in directions that are not, uh, linear or logical. And you can't read Finnegan's Wake I think without, um...... uh, certainly as a psychiatrist, you can't read it without thinking about schizophrenia. And then when we look at the families of people with schizophrenia, and, and Joyce was no exception, there very often are people within the family who are on the spectrum. Some have it, some are able to see it from a distance, from a safe distance. There's an association between schizophrenia and what we call schizotypal personality disorder, where people are not quite in this severe state of schizophrenia, but have some magical thinking, have some unusual, uh, thought patterns. Very often, those are family members of people with schizophrenia. So this points to this, again, to this idea that, that there is a, a range, even along this very severe, very genetic biological illness, that human beings dwell on different spots along that spectrum.

Lex Fridman 19:11 I should mention that we have my friend Sergei pulling up stuff, young Sergei or old Sergei, I don't know what to call you. But, uh, there's drafts (laughs) of Finnegans Wake. Yeah, I, I actually saw pictures of this from, um, I think it was on Instagram or something. These are early drafts of Finnegans Wake. And it's so beautiful to see for people who are just listening. There's just random paragraphs and writing all over the page with stuff crossed out, and it's great to see that Joyce himself was thinking in this kind of way as, um, as you're putting it together. How much do you think he was thinking about schizophreni- uh, the schizophrenic mind?

Karl Deisseroth 19:48 I think a lot. I think, you know, it's, it's known that his, his daughter suffered from, from schizophrenia, and, uh, the, this is, what, what's depicted here on the page is something that I'm sure he either felt himself in some, some level was able to access this non-linearity of, of processing or had seen enough in family, uh, that he, he knew what it was and w- and was able to, to reflect it down in black and white on the paper. So it was... What he was able to do was, was quite authentic in that sense. Of course, I don't wanna pigeonhole him. He was doing much more than that. It was much more than, than talking about altered human thought processes and thought disorders. But that was an aspect that he was so good at representing that it had to be

Karl Deisseroth 20:36 intentional to some extent.

Lex Fridman 20:37 A tiny tangent. What does your own writing look like for this book? 'Cause it's extremely well-written. How many edits? Did you just drink some whiskey and, uh, like, I'm imagining Hemingway style? What's a very different... The, the writing is very diff- I mean, it's really, really well-written, which was like, I (laughs) ... I was reading it. Um, it makes you realize, 'cause I was expecting sort of a, a science kind of, which it, it is like a, a, you know, uh, elucidating something about the human mind kind of thing. But you could also probably write really strong, like, novels. Uh, so maybe that's in the future. But anyway, what is your... How many edits? How many... What's your style? Does it look like that? Is it more structured, organized?

Karl Deisseroth 21:22 Unfortunately, I, I used a laptop, so I didn't have this sort of, uh, beautiful record of-

Lex Fridman 21:26 No typewriter-

Karl Deisseroth 21:27 ... the process. (laughs)

Lex Fridman 21:27 ... and cigarette and whiskey?

Karl Deisseroth 21:29 I did explore, I, I was, you know, which... Was there a particular altered state that would help me to be most creative? And, and I, uh, I found actually I, I actually did the best while, uh, you know, sober, but slightly disinhibited in the l- late hours of the, of the night or early morning.

Lex Fridman 21:46 Oh.

Karl Deisseroth 21:46 Yeah. Particularly late hours of the night there. You know, I, I, uh, I have a friend who, who would, would tell me that she thought that very early in the morning, her inner critic was still asleep, and she could write more effectively (laughs) -

Lex Fridman 21:59 (laughs) .

Karl Deisseroth 21:59 ... before her inner critic woke up.

Lex Fridman 22:01 Yeah.

Karl Deisseroth 22:01 And I actually found that, uh, outstanding advice for me that I, I often found that there was... I, I was looser and could write more in, in the morning.

Lex Fridman 22:09 Wow.

Karl Deisseroth 22:09 But the other interesting thing is, is each, each chapter, each story, it's about a different, uh, human being with a different class of, of, of psychiatric disorder. That's what each story, each ank- each, uh, chapter is anchored in. But I'm trying to use words that... And style of, of writing and, and, uh, you know, diction that captures the feeling of the disorder. And so it's different in each story. In the story about mania, which is a very expansive, exuberant, uh, at least briefly uplifting state, uh, where the words come out in a torrent and they're complex and pressured and elaborate, I try to capture that feeling with the, the words used in that chapter. And then in the schizophrenia or, or psychosis chapter, where things slowly fragment over time and, and become looser and, and, and, and separated, I try to capture that in the writing too. So for each, it wasn't as if there was a single mode I could be in for the whole book. For each chapter, I had to put myself into a, a different mode to, to capture that, uh, inner feeling of the disorder.

Lex Fridman 23:14 When you put yourself in that mode, does that change you?

Karl Deisseroth 23:17 Yeah. I couldn't turn it on and off right away. I had to... First, I would start by thinking about the person, uh, or the people, one or two people based on real patients and the, and the stories that are, that are put forth. Uh, the symptom descriptions are real. They're from the patients. Of course, all details changed to protect, uh, privacy, but the actual symptom descriptions are real. And I would sit with them and really try to inhabit the space of the mind of, of that person, uh, that I knew. And that's not instantaneous. It would take, take some time. I needed quiet. I needed to be (laughs) still. That's another reason late at night is, is good.

Lex Fridman 23:53 Sergei posted that drowsiness gives creativity a boost according to Andrew Huberman.

Karl Deisseroth 23:58 (laughs) .

Lex Fridman 23:58 Thank you, Andrew. (laughs)

Lex Fridman 24:01 Uh-

Karl Deisseroth 24:01 He's not wrong. He's not wrong.

Lex Fridman 24:03 Why projections? Is it, uh, I mean, there's emu- uh, in- instead of putting words into your mouth 'cause I can imagine a lot... I mean, I, to me... Uh, no. I will start putting words in your mouth, despite what I just said.

Karl Deisseroth 24:17 (laughs) .

Lex Fridman 24:18 Uh, (laughs) so, I mean, so, so to me projections, w- working on neural networks, for example, from an artificial neural networks, fr- uh, machine learning perspective, it's often... That's exactly what you're doing. You have an incredibly complex thing, and you're trying to, uh, find simple representations in order for you to make sense of it. So I was kind of thinking about it in that way, which is like, um...... this incredibly complex ne- neuronal network that is kind of projecting itself onto the world through this s- low bandwidth expression of emotion, and speech, and all that kind of stuff, and the way it's, we only have that window into your soul. The eyes, and the speech, and so on, so that, uh, i- in that way, we're, um, when there's any kind of disorder, we get to only see that disorder through that narrow window-

Karl Deisseroth 25:08 Mm-hmm.

Lex Fridman 25:08 ... as opposed to the full complexity of its origins.

Karl Deisseroth 25:11 The word projections s- definitely serves that purpose here, but it's, it's got a few other really, uh, appropriate other connotations as well. So the first thing is p- a projection, in terms of neuroscience, is this long-range connection that goes from one part of the brain to another-

Lex Fridman 25:26 Mm-hmm.

Karl Deisseroth 25:26 ... and so it's what binds two parts of our brain together. Y- there are projections, long-range connections of axons, these are the outgoing threads that connect one part of the brain to another part. There's a, there's a projection that links, for example, auditory cortex, where we hear things, to reward centers, where we can feel, where feelings of, of pleasure and reward are initiated. And it's been shown that if you have reduced connectivity along that dimension, you are less able to enjoy music. And so these connections, these projections matter. They define how effectively two parts of the brain can engage with each other and join together to form a, a joint representation of something. So that's one meaning. It's pure neuroscience, the word projection is used all the time, and it happens to be something that optogenetics, a technique that we, maybe we'll talk about a little later, works particularly well with. We can use light to turn on or off the activity along these projections from one spot of the brain to another.

Lex Fridman 26:22 And this is particularly referring to the long-range connections?

Karl Deisseroth 26:25 Yeah. It's particularly straightforward along these long-range projections that connect different parts of the brain, but you can... It works over a shorter range too. But then, there's this other meaning of projections, which you were bringing up, which is very relevant, which is, at some point, you, you can reduce something from one level of dimensionality to another. You can project down into a lower dimensional space, for example. And then finally, there's a psychiatric, uh, term projections, which comes up all the time, which is, uh, we very often, uh, will look at our internal states, and to understand somebody else, we'll project them onto somebody else. We'll try to understand someone else's behavior and, and make sense of it by projecting our own inner feelings, our own, uh, sort of narrative onto them, and use that as a way to help us understand them better. And we'll do the reverse too. We'll take things we see in the outside world and we'll bring them into ourselves and see how well they map, how well they align. That's called introjection. So, projections is a, turns out to be a really rich word. Then finally, of course, there's the very common sense of it as y- as a projector that, that (laughs) illuminates by, uh, conveying information across space with, uh, with

Karl Deisseroth 27:35 light. So, for English, for English language, perfect word to use for this book.

Lex Fridman 27:40 (laughs)

Karl Deisseroth 27:40 But what was funny is, not every ... There are a lot of international translations now, and, and all those rich connotations aren't captured in, in other languages. And so, for some translations, uh, connections is used, uh, instead of projections. In fact, even in England, the British version is connections instead of projections, because apparently projections doesn't have the full connotation, I was told by our-

Lex Fridman 28:02 So you have to sacrifice some of the rich, um, ambiguity of meaning, uh, with connections? That's interesting.

Karl Deisseroth 28:09 Yeah.

Lex Fridman 28:09 I mean, connect- Yeah, man, words are so interesting. They could have so many mean- I love language and how much is lost in translation. I'm very fortunate enough to be able to speak ... I'm not good at languages. I was just, I guess, forced to, by life circumstance, to learn two languages.

Karl Deisseroth 28:25 Mm-hmm.

Lex Fridman 28:26 Russian and English, and it's just so interesting to watch how much of culture, how much of people, how much of history is lost in translation.

Karl Deisseroth 28:34 Yep.

Lex Fridman 28:35 Uh, the poetry, the, the music, the history, the pain, uh, the way scientists actually express themselves, which is funny. I mean, just, I- it's so sad, um, to see how much brilliant work that was written in Russian, there's a whole culture of science in the Soviet Union-

Karl Deisseroth 28:56 Yeah.

Lex Fridman 28:56 ... that is now lost. It makes me wonder, in the modern day, how much incredible science is going on in China that is lost in translation.

Karl Deisseroth 29:06 Yeah.

Lex Fridman 29:06 And I'll never ... I mean, that makes me very sad, because I'll never learn Chinese in the same way that I've learned English and, and Russian. Maybe. Uh, whenever I say stuff like that, people are like, "Well, there's still time."

Karl Deisseroth 29:19 (laughs)

Lex Fridman 29:19 But, uh, you know, uh, yeah. That's, it's, uh, that's actually fair, that, uh, I think the 21st century, uh, both China and US will have very important roles in the scientific development, uh, and we should actually bridge the gap through language. And that, that doesn't just mean convincing Chinese to speak English.

Karl Deisseroth 29:40 (laughs)

Lex Fridman 29:40 That means also learning Chinese.

Karl Deisseroth 29:43 Well, we need these bridge people who can do both, you know? The, um, you know, Nabokov, for example, writing in, in English beautifully. Uh, uh, you know, one of my favorite poets, Borges, who, uh, you know, I mentioned earlier, he wrote both in English and in Spanish. I think, you know, beautifully in both. We need those people who can serve as, as bridges across cultures, who really can do both.

Lex Fridman 30:07 (inhales) You mentioned Borges. So, you open your book with a few lines from a poem by Jorge Luis Borges, a love poem. I'm gonna read parts of it 'cause it's a damn good poem.

Karl Deisseroth 30:18 Yeah.

Lex Fridman 30:18 It's called Two English Poems. (laughs) I mean, th- there's ... I'd like to understand why you used it, and the specific parts you used, which is interesting. But then when I read the full thing ... So I think you used it as, as a, as a sort of beautiful description of what it means to delve deep into understanding-... uh, offering yourself to the task of understanding another human being. But if you look at the full context of the poem, it's also a damn good description of being hit by love and overtaken by it, and, uh, uh, sort of ... Uh, and trying to fi- (laughs) trying to figure out how to make sense of the world now that you've been, uh, stricken by it. It says a bunch of things, uh, about chatting insignificantly with friends and all those kinds of things, and then the poem reads, "The big wave brought you." Like, this is the moment, I guess, of the universe where two people ... You fall in love. Maybe I'm totally misreading this poem, by the way.

Karl Deisseroth 31:18 No. (laughs)

Lex Fridman 31:18 It doesn't matter.

Karl Deisseroth 31:19 No.

Lex Fridman 31:19 You can't misread a poem.

Karl Deisseroth 31:20 (laughs) That's right.

Lex Fridman 31:22 So it goes on, "Words, any words. Your laughter. And you're so lazily and incessantly beautiful. We talked, and you have forgotten the words. The shattering dawn finds me in a deserted street of my city. Your profile turned away. The sounds that go to make your name. The lilt of your laughter. These are the illustrious toys you have left me." So these little memories of these peculiar little details he remembers, those are the illustrious toys. I apologize to mix my own words with the poem, but, uh, you should definitely read it. "I turn them over in the dawn. I lose them, I find them. I tell them to the few stray dogs and to the few stray stars of the dawn. Your dark, rich life. I must get at you somehow. I put away those illustrious toys you have left me. I want your hidden look, your real smile, that lonely mocking smile your cool mirror knows. I want your hidden look, your real smile." I, I've n- I, so I ... This is the first part of the poem. And then it goes on, which is some of the parts that you reference. Second part is, "What can I hold you with? I offer you lean streets, desperate sunsets, the moon, or the jagged suburbs. I offer you the bitterness of a man who has looked long and long at a lonely moon. I offer you my ancestors, my dead men, the ghosts that living men have honored in bronze. My father's father killed in the frontier of Buenos Aires, two bullets through his lungs," and so on, so on. "I offer you whatever insights my books may hold, whatever manliness or humor in my life. I offer you the loyalty of a man who has never been loyal. I offer you that kernel of myself that I have saved somehow, the central heart that deals not in words, traffics not with dreams, and is untouched by time, by joy and, uh, adversities." And I think this is where y- the part that you include in the book.

Karl Deisseroth 33:21 Mm-hmm.

Lex Fridman 33:22 "I offer you the memory of a yellow rose seen as sunset years before you were born. I ..." Damn, that's a good line. Okay. "I off-" (laughs) "I offer you explanations of yourself, theories about yourself, authentic and surprising news of yourself. I can give you my loneliness, my darkness, the hunger of my heart. I am trying to bribe you with uncertainty, with danger, with defeat." That is a man who's in love and longing. If I've taken ... But I just wanna go back to, maybe you could s- say why you wanted to include that poem, but also ... "Your dark, rich life. I must get at you somehow. I put away those illustrious toys you have left me. I want your ... I want your hidden look, your real smile, that lonely mocking smile your cool mirror knows." What ... Sometimes I meet a stranger, and I just ... It's like, I ... It's like a double take.

Karl Deisseroth 34:15 Mm-hmm.

Lex Fridman 34:15 It's like, "Who are you? Have we met before somewhere? Who's that person behind there?"

Karl Deisseroth 34:21 Yeah.

Lex Fridman 34:22 And I wanna get at that, whatever that is. And of course, maybe that's what love is, because maybe, uh, maybe that's the whole pursuit, like a lifelong pursuit of getting at that person. Maybe that's what that is. And like that, uh, insatiable sort of curiosity to keep getting, to have like, "Well, who is that person in your own private life?"

Karl Deisseroth 34:40 Yeah. So that, absolutely, I think that it was a beautiful description of what you just said, when there's that first moment and then you wanna dive deeper. You want to know what the, what the hidden mysteries are. In a way, it's, it's a, it's a love poem. As a, as a scientist though, it also ... It's a bit of how a scientist can love science, and, and that wanting to, to dive deeper is ... It's almost like, uh, again, where the ... It could be a, a love affair with investigating the human mind, for example. And, and that was one reason it, it spoke to me also. Again, thinking about the broader sweep of where the human mind came from. Uh, the steps it took to get where it is today, what was given up along the way, what compromises were made. And here's where the darkness of the poem starts to come in a little bit too. It doesn't shy away from the negativity, from the confusion, from the danger. And then at the very end, the Borges is offering up scenes from his life, parts of himself. And this is how we connect with people. We offer up parts of ourselves, just, "Here it is," and then we see, how well does that map onto what you have? And it's, it's that offering up that I liked. And not, not the good stuff, or not only the good stuff.

Lex Fridman 36:00 Mm-hmm.

Karl Deisseroth 36:00 The yellow rose is nice but, but he's offering up the bad stuff too. And that, that to me was important for the, for the book because I'm offering up hard stuff too. Uh, in fact, a lot of it. And also hard stuff from within me, from my, my own personal side too, and that was ... There's a lot of vulnerability that comes with that. But that's, that comes with love, that comes with writing. You have to be, be open, you have to be vulnerable. And so I thought that reflected what I was trying to do, and I thought it was a ... As an epigraphic, kind of made it clear, uh, how vulnerable (laughs) I was in, in taking this step, but also what, what could come out of it.

Lex Fridman 36:38 And also in a meta way, because I was not familiar with this poem, it, uh, it made me curious ...... of the poem itself to pull at that thread, of finding out more. See, you picked a very (laughing) particular part that kinda made you want to, um, pull at that thread and, and, and, and see where did this... where did these few lines come from?

Karl Deisseroth 37:02 Yeah.

Lex Fridman 37:02 'Cause I, I, I read it as a curiosity of a scientist, those lines, uh, alone, and also as a d- desperate, uh, human being searching, like offering himself for an, uh, understanding or connection with, with another human being. And then, 'cause I wasn't sure if it's a love poem or not, or if it's desperation or if it's curiosity, whatever it is, and then you see the love poem. I mean, I don't know. That, that's gonna stick with me for a while, the, "You're a dark rich life." And then a few lines in here are just, I mean, those are... I'm gonna just use them as, as, as pickup lines at a bar.

Karl Deisseroth 37:39 (laughs)

Lex Fridman 37:40 "I offer you the memory of a yellow rose seen at sunset years before you were born." (laughs) Now that's a pickup line I've never heard, if, if, if I've ever heard one. Anyway, sorry. (laughs)

Karl Deisseroth 37:51 But this is universal, you know, you see it in so many forms of, of art, you know, like, you know, we're in Texas now, you see this in country, uh, country and western songs, it's, it's often a, a list of things. Like, "Here, here's how I describe myself. There's this and there's that and there's the other thing, and, and here you are. These things mattered to me and I hope they matter to you too." It's a, it's a pretty universal form. But it's... but he did it in this very artful, uh, and very vulnerable way. It was, it was both, both beautiful and you could, you could feel the hurt coming from him too, and that was important.

Lex Fridman 38:23 The dark s- stuff too, "I offer you my ancestors, my dead men, the ghosts that living men have honored in bronze." And talking about two bullets through his lungs, bearded and dead, wrapped by his soldiers in the hide of a cow. "My mother's grandfather just, 24, heading a charge of 300 men in Peru. Now ghosts, on vanished horses." So all of it, the whole history of it.

Lex Fridman 38:49 Um, since it is a love poem, what do you think about love-

Karl Deisseroth 38:55 (laughs)

Lex Fridman 38:55 ... Carl? What's, what's the role of love in the human condition? We'll talk about the dark stuff-

Karl Deisseroth 39:00 Yeah.

Lex Fridman 39:00 ... but, uh, maybe love is the dark stuff too.

Karl Deisseroth 39:03 I mean, it's, it's the most powerful connection we can form, and that's, that's its... that's what makes it so important to us. It's the, it's the strongest, uh, and most stable connection that we can form with another person, and that matters immensely. Uh, it matters for, for the human family to have evolved to be something that could survive against the odds that, that, that we've faced over the years, uh, that unreasonable bond that becomes reasonable by virtue of its own existence. And, of course, that joy, the, the wild raw joy of love is not a bad thing either. So you put these together, the form- the strongest bridge we can form, and the reward and the joy that it, that it brings. That's, that's what love is to me. And from, you know, my perspective, this is something that, you know (laughs) it, it can be hard to capture fairly because you wanna talk about the positive and the negative sides at once. They need to be wrapped up together for a full honest description of, of what it is, and that, that's hard to do in a, in a compact form. And so you have to take time to talk about love. You have to take time to, to, to do it justice. Um, it takes a book or at least a poem.

Lex Fridman 40:26 (laughs) Or, or several thousands of them. I don't know. So is there... could you pull up, there's a video I saw, yeah, like right here. So can you pause for a second? Uh, so, so there's March of the Penguins. So you always see, like, penguins huddling together against... I, I mean, sorry, if I see just metaphors in everything, but, uh, them huddling together against the harshness of the conditions around them. That's very kind um... that's like a metaphor for life, like finding this connection. That's kind of what love is, is like it allows you to forget whatever the absurdity, whatever the suffering of life is, together you get to like huddle for warmth. And that's why I love the, uh, sort of just the, uh, the honesty and the intensity of the way penguins, just in the middle of, like, the cold do this. And then this video I saw (laughs) a lonely... this, this is, this is misinformation. So the name of the video is Lonely Deranged Penguin.

Karl Deisseroth 41:23 (laughs)

Lex Fridman 41:24 I don't know if he's deranged. So if you play it. So he left his pack and, uh, and there, there, there's a nice, like, voiceover in it, you don't need to play it, but he for some reason left the pack and journeyed out into the mountains. And so the, the narrator says that he's deranged, he's lost his mind. Now I'd like to project the idea that he's actually... there's so many stories you could think of. He's returning to his homeland. He's an outsider thinking, journeying out into the unknown, thinking he may be able to discover something greater than the tribe. He might be looking for a lost love. Why is he deranged immediately? (laughs) Why has he lost his mind? Anyway, but th- this... people should look up this video 'cause to me, I might be the only one who, uh, romanticizes this, but it's such a nice kind of a... it's both a picture of perhaps a mental disorder, which is what the video kind of describes, and maybe some deeper explanation that's not... that, that has to do with the motivation of a, uh, of a mind. Per- per- yeah, I don't know if... (laughs) I don't know if you have a deeper analysis on this penguin-

Karl Deisseroth 42:36 Well, I, I, as a psychia-

Lex Fridman 42:37 ... like you (laughs) as a psychiatrist. (laughs)

Karl Deisseroth 42:39 (laughs) I, I would, I would want to sit down with the penguin-

Lex Fridman 42:41 (laughs) And, and and go through... I wanna see the notes from his prior therapist and... but-

Karl Deisseroth 42:49 ... this, this actually is, is r-relevant. I, uh, not knowing what was that penguin's motivation, we have very clear situations where there are, both within an individual, we go through periods of time when we stay in one place and we reap the benefits from what we've built, and then we go through periods of, of foraging, of, of, of wandering. Even if there may be resources where we are, we, we have periods of time in our lives where we wander, where we, where we, uh, go in a exploratory mode. And different people express that trait in different ways. This is not a human-specific trait. If you go down to, to the tiny little nematode worm, C. elegans, with 302 nervous system cells, they go through these phases of foraging and rest, and different individuals have different propensity to forage or, or to rest and, and stay in one place. At the level of the species, that's really good that there's that diversity in their willingness to forage. Some stay where they are. The species is somewhat on a firm footing then, but some carry a burden, a risk for themselves, but it's good for the species that they are explorers and they will venture out. The migration patterns that different species blunder into and that turn out to be really good, they weren't logically derived. Uh, they most certainly started from something like this, uh, an exploration.

Lex Fridman 44:18 And humans do this too you think?

Karl Deisseroth 44:19 And we do it too. In fact, it's, it's something we do extremely well.

Lex Fridman 44:23 Let's talk about psychiatry a little bit. (sighs) So in my book, you're a, a, a rock star. First of all, for people who don't know your work, aside from sort of, um, the neurological view of the brain and neuroscience view of the brain, you're also one of the great psychiatrists of our time. I've always... not always, but when I was younger, I dreamed about being a psychiatrist.

Karl Deisseroth 44:47 Mm-hmm.

Lex Fridman 44:49 Um, so it's like, it's like getting to meet your heroes and also, um, you know, getting to meet the people who, uh, the best... at the top of the world at the thing you've failed to pursue. So there, uh, so there's, uh, I'm getting a free therapy session on top of that. Okay, so what, um, big picture, what is the practice, the goal, the hope of modern psychiatry? If you could try to describe the discipline as you see it, maybe historically throughout the 20th century, uh, in contrasting to what it is today, or maybe if you wanna describe to what you hope psychiatry becomes or longs to become in the 21st century.

Karl Deisseroth 45:32 Yeah. It's been an interesting journey. Uh, it... psychiatry started out, uh, pretty firmly grounded in neurology, in pathology. Some of the initial, uh, founders effectively of the field were very well-grounded in, uh, microscopy, looking at cells, uh, uh, working with patients, uh, particularly on the neurological side, and this certainly included, you know, Freud and, and some of his contemporaries. And, uh, but they rapidly discovered that what they could work with at the level of cells and microscopy was so far from the realm of what they could get from a, a human being, and what they were getting from the human being was so much more interesting and had... was so mysterious and so unknown that many of them just said, "We're gonna inhabit this domain, and we're gonna work with the people, with their words, and un- understand what we can, uh, based on verbal communication." Because that was the only tool that, that people really had. And that was a very, uh, important step for the field. I would say one of the interesting things that came from the early decades of, of psychiatry really was this distinction between the conscious and the unconscious mind, and paying particular attention to the unconscious mind as something that was worthy of consideration, uh, that, that might be important in explaining people's actions, and that perhaps even insight into that was valuable in its own right. And o- out of that, psychoanalysis, uh, became, uh, a practice that was not always focused on cures or treatment, but was more focused on insight. What does it, what does it mean? How can we help people understand why they're feeling something or thinking something or, or dreaming something? And that insight, separate even from treatment, was, was an interesting thing, as long as one was honest about that and said, "You know, we're, we're going for understanding. We're going for insight."

Lex Fridman 47:32 Maybe it's useful to just pause on that.

Karl Deisseroth 47:34 Yeah.

Lex Fridman 47:34 Let's... if

Lex Fridman 47:35 we look at the father of psychoanalysis, Sigmund Freud, (deep inhale) what do you make of the ideas that he had? So you mentioned taking the unconscious, the subconscious seriously. That's like step one. Like that there could be worlds we did not have direct access for and we probe at them through conversation or... um, is that too simplistic to call psychoanalysis conversation? (laughs)

Karl Deisseroth 48:03 That's not too simplistic, but that's right, and I think that was valuable. Where, where Freud ended up breaking from some of his contemporaries, he was very focused on this unconsciousness being so tightly linked to libido and, and really he cr-... from his perspective, you couldn't really separate the operation of the unconscious mind from these aspects, the l- libidinous aspects, and, and that was one reason.

Lex Fridman 48:25 What's the libidinous aspect? Sex?

Karl Deisseroth 48:25 You know, sex- sexual, sexually related, uh, you know, drives. Carl Jung, who was his, you know, uh, uh, you know, contemporary, that's one factor that led to them separating was, you know, Carl Jung felt there was a lot more to the unconscious than, than this libidinous, uh, aspect of it, and he saw it as a much more complete, uh, uh, alternate representation of the, the conscious self, one that maybe reflected a whole range of different...... motivations and- and desires, um, and to- to properly treat it, one had to consider all of them rather than the ones that- that Freud was focused on.

Lex Fridman 49:06 Yeah, so Carl Jung's sh- your mom (laughs) -

Karl Deisseroth 49:08 (laughs)

Lex Fridman 49:08 Thank you for... (laughs) Thank you for the high level of, uh, of images that Sergey is pulling up. For people who are just listening, he pulled up a- it's a quote from, uh, Sigmund Freud. It's a meme. Your mom, quote, uh, Freud. Uh, so the- the shadow, the Carl Jung shadow, encompasses everything, not just the desire to have sex with your mother or sex period. That's-

Karl Deisseroth 49:33 That's right. That's right.

Lex Fridman 49:34 ... if you look at those two folks on mass, I mean there's a kind of- it's almost like a technique for philosophical exploration of human mind, human motivations. So it's not even like necessarily, it's also doubles as a methodology for helping people, but it's almost like a, um, it's a kind of philosophical method.

Karl Deisseroth 50:00 Right. This is the fascinating thing about- about psychoanalysis and- and it, even though it's- it's, I would say, mostly not considered a treatment today, it persists for a couple reasons. One is, it- it's- it's thought that it gives people some insight. But second, there's been a huge influence on- on literature, on philosophy, on art, and the- the opening up of discussion about what was below our conscious mind was, uh, so- so fertile in- in the implications that it- it sort of reverberated and still does throughout all these different realms of- of human endeavor from art- art- different artistic, uh, you know, experiences that people have, uh, can be colored by this- this, uh, concept of the unconscious. Now, the other thing that was interesting is- is- is this distinction, you know, what- what are the parts of the unconscious? And- and so there were these id and ego and super ego, uh, subdivisions that, you know, that- that Freud, for example, would- would- would talk about them and- and the- the id was the primary, the primal drives that an infant would have, uh, or- or that a very young child, just warmth and feeding and then- and later the, you know, the sexual or libidinous aspects.

Lex Fridman 51:22 And for Freud, the later happened very quickly.

Karl Deisseroth 51:26 (laughs)

Lex Fridman 51:26 (laughs) That's the- the controversial thing about him, I think. I guess he thought like even children had sexual desires that they're like dealing with, contending with, so it's the full thing. Hungry, wanting to eat, wanting to poop, wanting to have sex.

Karl Deisseroth 51:39 Yeah. And he was extremely focused on that- on- on that aspect. But then there was- then there was this, the super ego, which brought on these later sort of moralistic, uh, uh, sort of codes of- of conduct and- and that, of course, was very often in- in tension. But all this could play out subconsciously and then the ego, this third aspect, was mediating and- and for its conception, mediated this tension between the different, uh, parts. Now, I think that's interesting. Uh, I will say that in some ways it's maybe unnecessary from the perspective of modern neuroscience to divide things up that way from the, you know, the- the moralistic, uh, drives and the- the primal, uh, gratification drives. In some ways, they're all drives and maybe they're even all primal drives. You know, the- the moralistic drives, they're- they're taught and they're taught in ways that ultimately relate back to survival and, uh, you could even say selfish aspects of- of health and life for the self and family. And so this is, uh, I don't, I think it's maybe an artificial distinction. The concept of the unconscious is very valuable and very interesting, um, but these categorizations, uh, of id and- and super ego may not map onto neurobiology in any particular way. If there's a town hall of- of competing drives and desires and they're, they- they interrelate to each other, they involve different aspects of the- of the brain and the- and the history of the person and actions and choices come out of the result of that overall, you know, shouting in the town hall.

Lex Fridman 53:25 So in some sense, Carl Jung was a step into the direction of liberating yourself from such harsh categorizations.

Karl Deisseroth 53:32 Yep.

Lex Fridman 53:32 Do you think, I mean you have, uh, Daniel Kahneman with System One and System Two, there's just these very compelling categorizations of the human mind that seem to be sticky in our, uh, in the super ego. No, uh, in the, you know, in the- the how we talk about these ideas and so on.

Karl Deisseroth 53:52 Yeah.

Lex Fridman 53:52 Uh, do you think those are helpful or did they get in the way? Is it some kind of balance in terms of deeper understanding of how the mind actually works?

Karl Deisseroth 53:59 You know, it's from the- from modern neuroscience, uh, whenever we seem to get closer to addressing a question like this at the level of cells, it seems to get farther away. And I'll give you an example of- of what I mean by that. So one thing I'm doing in my laboratory and many people are doing is we are listening in on the activity of cells, neurons in the brain of mice or rats or fish or monkeys.

Lex Fridman 54:27 Individual cells.

Karl Deisseroth 54:28 Individual cells, exactly. Of which there are, you know, in our brain many billions. And when we do and we try to predict what action will be taken by an animal to address this question where does the choice arise? Where does the impetus to make a particular selection of one action versus another action? Where does that start in the brain? If you're recording, listening in on the activity of cells all across the brain, where's the earliest spot you can pick up?... a choice being made. Well-

Lex Fridman 55:00 (laughs) That's so awesome.

Karl Deisseroth 55:02 Yeah. At one level, you might think how excited would- would Jung have been to see this, or- or Freud, or the early, you know, psychoanalysts to see where this starts, but it's not so simple because an emerging theme in very recent neuroscience, literally over the last few years, is that things sort of all start together all across the brain. And so you can be recording from the cortex, this rim of cells at the surface of the brain, or you can be recording deeper in a structure called the striatum, which is a little older. It's more tightly linked to- to- to action. And then, structures called the thalamus, other parts of the brain. And if you record from these, these all sort of represent the action and the choice more or less all at about the same time, very close. And so it's, it- you can't point to a particular spot, uh, and say, "Here's where the choice or the action originates." It's a- it's a group-

Lex Fridman 56:00 It's- it's, uh, finding the free will neuron. (laughs)

Karl Deisseroth 56:03 It's- it's relevant to that question. Nobody is- is close to being able to point to such a thing.

Lex Fridman 56:08 Well, close is a relative term. And nobody ... Uh, what'd I, what'd I tweet today? Uh, all generalizations are wrong. (laughs)

Karl Deisseroth 56:18 (laughs)

Lex Fridman 56:19 So including this one. Let's actually talk about that. So to the study of individual cells, uh, if you could linger on your sense that as you get closer to that understanding, it feels like you're getting farther away. Why is that? 'Cause that- that often is the feeling until you're actually there. (laughs) So- so like, uh, you know. See, that's how when I'm running and I know there's only a mile left, it just feels like that mile is just getting longer and longer, but eventually you finish. So maybe we're getting close to cracking open these, like, beginnings of a ce- Like, we'll talk about consciousness or these very difficult big questions about the human mind. Where do they start?

Karl Deisseroth 57:02 You're right to say we shouldn't, uh, generalize or make absolutist statements, but it- I would say right now, the reason things are looking even, uh, (laughs) harder to crack than we had initially thought, we now have the data streams that we've wanted for so long, uh, in terms of activity patterns all across the brain at the level of cells. We can literally see what cells are doing. Immense datasets, you know. We- we get, these are, you know, time series of one individual cell with, you know, sub-second resolution. And you can collect this from, you know, enormous numbers of cells across the brain. So very rich datasets that we've wanted for a long time, and yet having these, uh, has not led to an understanding of truly where actions, uh, initiate, um, in terms of- of regions or locations.

Lex Fridman 57:52 Ask you a few questions on that.

Karl Deisseroth 57:54 Yeah.

Lex Fridman 57:54 Is the answer ... High- high level question about your intuition. Is the answer within the data or do we need different kind of data? So we- we should also say that when you collect data about the- the brain, there's like the richness of information you're collecting, but there is also human doing stuff. Um, like (laughs) and information, so static information about the human and dynamic information about the human, and you can get them to do different stuff and you can select different humans. And that's part of the collection of data aspect. So like when you're collecting data about the brain, there's some truths that you can ... You know, machine learning is like annotations, like supervise learning. There's some true things you can hold onto before you look at the full rich mess complexity of the human mind. So given the data you've looked at, do you think the answer for the- for the origin of free will in the human mind is- can be found?

Karl Deisseroth 58:58 Well, one- one amazing thing is that, uh, nobody's- nobody's found it, but we have these rich datasets. And- and then there's a- a conundrum, uh, which is, uh, is it in the data and we just don't know how to look at it? Maybe we don't know the right scale, the right projection to make of the data, the right way to interpret it. And here's where, uh, causal testing becomes very valuable 'cause then instead of just passively observing, well, here are- here are the activity patterns and then here's the choice made by the animal, as we've gotten more powerful at reaching in and causing things to happen in the brain, turning up or down the activity of certain types of cells or defined populations of cells and seeing how that affects actions, these causal perturbations have turned out to be very valuable. We're just now getting to the point where we can apply these in- in very, uh, wide swaths of the brain at cellular resolution, and so we're gonna be able, uh, hopefully to make some headway on this question with- with, uh, causality. And those- that's th- the one thing that optogenetics provides us, this way of using light that we developed to control cells. This is an untapped- relatively untapped at this broad brain wide scale, and hopefully we can get there in the near future. But I- I would say that the answer may be- may be in the data, uh, but we don't

Karl Deisseroth 1:00:23 know how to find it.

Lex Fridman 1:00:24 Well, there's this interactive element like where you can cause stuff that's really powerful 'cause you get to, I mean, uh, as opposed to collecting data passively, you- you're collecting data actively. So can- can you maybe describe one of the many things you're known for, one of- one of the big things is called optogenetics. What is it?

Karl Deisseroth 1:00:43 Optogenetics is a way of- of causing things to happen. It's a way of determining what- what actually matters in terms of the activity of the brain for the amazing things it does, sensation, cognition, action, and-... what it does is it provides activity. It's a way of playing in, if you will, activity patterns into precisely defined cells. And the way we do is pretty cool, I think. It's- it- you know, right away there's a problem, if you think about how do we do this? How could we play in well-defined activity patterns and provide a stream of- of activity into this cell and that cell and that cell, but not these other cells?

Lex Fridman 1:01:22 But just for c- for context, we're talking about the brains of mice, uh, monkeys, humans, and then the goal is to try to control accurately the behavior of a single neuron, and then to be able to monitor single collection of single neurons to then say, well, to- to get- draw some deeper insight about the origins, first of all, the function of different parts of the brain, different neurons, different kinds of neurons, but also the origins of the big things, the, uh, the- the flap of the butterfly wing that leads to an actual behavioral thing.

Karl Deisseroth 1:02:03 Yeah. So if you could... Exactly. So if you could turn on or off the brain or parts of the brain or cell types or individual cells at the natural rate and rhythm and timing of normal brain activity, that would be immensely valuable because you could determine what actually mattered, what- what could cause complex things to happen, and what could prevent complex things from happening in a specific way. But right away, you've got a problem if- if you wanna do this, and- and scientists, uh, neuroscientists have wanted to do this for a long time. Francis Crick of double helix of DNA fame, he wrote a famous paper in 1999. He got interested in neuroscience later in life, and he said, "What we need in neuroscience is a way that we could turn on or off the activity of individual types of neurons in a behaving animal." And he even said, uh, the ideal signal would be light because it would be fast, it could, uh- uh, penetrate through the, uh, brain to some extent. And he had no idea how to do it. He said this would probably be very far-fetched, but it would be a good thing.

Lex Fridman 1:03:15 And so that's what you're actually saying here. Like, if you wanna do this kind of thing and then it's- you imagine like, "How do I get inside the brain?" It's pretty difficult (laughs) to do.

Karl Deisseroth 1:03:24 It's pretty difficult. And then even once you get in, it's hard because all brain cells are electrical. All neurons are electrically activated. And so if you wanted to use electricity as what you were putting in, you won't have any specificity at all. If you pu- have an electrode, a wire, and you put it in the brain and you send current through it, all the cells near the electrode will be stimulated.

Lex Fridman 1:03:48 That's like trying to control f- fish by spraying them with water.

Karl Deisseroth 1:03:52 (laughs) Yeah, ri- yeah, right, because there's already a lot of-

Lex Fridman 1:03:55 (laughs)

Karl Deisseroth 1:03:55 ... electricity going around anyway-

Lex Fridman 1:03:57 Yeah.

Karl Deisseroth 1:03:57 ... and you're adding more. But there's no, uh, specificity even among the different kinds of cells either because all around the wire that you've put in, there are gonna be so many different cells doing totally different things, many of them in opposition to each other. We know that's one way the brain is set up. There are parts of the brain that- where neurons side-by-side are doing completely different things and maybe even antagonistic to each other. So what do you do? How do you play in activity with any kind of specificity? Well, what you do is use... What- what we found is what- what you can do is make some cells responsive to light. Now normally, no cells deep in the- in the brain really respond to light. They're not built for that. There's no reason for them to respond to light in there, which is a great situation to start with because any light sensitivity you can provide to some cells will be a huge signal above the noise. And so that's- that's what we do with optogenetics. We take genes, bits of DNA from microbes, single-celled organisms, and these single-celled organisms like algae, they, uh, make, uh, little proteins that sit in the surface of their cells that receive light, capture a photon of light, and open up a little hole in the membrane of the cell and let charged particles, ions like sodium and potassium, flow across the membrane of the cell. And that, they- these algae and bacteria, they do this for their own reasons because that helps them move, it helps them m- u- make and use energy. But that's a beautiful thing for neuroscience because movement of ions, charged particles across the membrane of the cell, is exactly the kind of electricity that neurons work with. So if we can take this bit of DNA that encodes this beautiful protein that turns light into electricity from algae and if we can put it into some neurons but not other neurons, which we can do using genetic tricks, then you've got a situation, then you can shine on the light and only the cells that have the gene and that are expressing the gene will be the initial direct, uh, cells that are activated by the light. And so that's the essence of optogenetics is- is the ability to do that. We get that initial specificity that you could never get with an electrode.

Lex Fridman 1:06:15 First of all, let me say that this is, um... That you recently got, uh, the Lasker Prize for this is a brilliant idea. Um, so I talked to, um, Andrew Huberman, who's a friend of yours, a friend of mine, um, to not- not to jinx things, but he believes that you deserve the Nobel Prize for this. So (laughs) , um, I do too, but what, uh, my votes ...

Karl Deisseroth 1:06:42 Well-

Lex Fridman 1:06:42 Anyway, the thing is, it doesn't- doesn't matter. Prizes will be all forgotten. All of us will be forgotten. When a cool idea is- cool idea is a cool idea. This is a really powerful idea.

Karl Deisseroth 1:06:51 It's actually the- the origins of it you might be interested in are even- are- are very deep. Uh, there was a botanist in St. Petersburg named Andrei Famintsyn. In 1866, he published a paper ...... on these single celled green algae, and he was the botanist who first noticed that they moved in response to light. These are tiny single-celled algae that have flagella, so they swim through the water.

Lex Fridman 1:07:16 Mm-hmm.

Karl Deisseroth 1:07:17 And he noticed this, he was a botanist, and he published this, it was as a paper, you know, h- he wrote in, in German but he published it in a French journal, and he was doing it from St. Peters- Petersburg so it was a very international effort. But you have to go back to 1866, and that, I just, I like to highlight how far back the, that discovery goes is back to, to Andrei Svinustin. And this is a, it, it highlights the value of, of just pure basic science discovery.

Lex Fridman 1:07:45 That always originates, uh, somewhere in the Eastern European block.

Karl Deisseroth 1:07:50 (laughs)

Lex Fridman 1:07:50 Uh, but I don't think he, uh, expected the splicing of genetic material- (laughs)

Karl Deisseroth 1:07:55 Right.

Lex Fridman 1:07:55 ... from the algae- (laughs)

Karl Deisseroth 1:07:56 Yeah, yeah.

Lex Fridman 1:07:56 ... into the human brain.

Karl Deisseroth 1:07:58 And one of the cool things we've been able to do now with modern methods is to really study these, these proteins. And so we, we've discovered some of these proteins, other, other groups have as well. We've dived deep into their structure, just like the double helix structure of DNA was uncovered with x-ray crystallography. We used the same method, x-ray crystallography, to see how these beautiful little proteins work. We've re-engineered them for all kinds of function. We can make them, instead of responding to blue light, we can make them respond to red light, we can speed them up, slow them down, we can make them with genetic engineering, we can make them have different ions flow through them. And so it's, it's this convergence, as you said, like, the botanist in 1866 couldn't have predicted what we could do with this, uh, and, and the fact that we've been able to discover how these beautiful proteins work and then, uh, apply them to neuroscience is really a, a thrilling story.

Lex Fridman 1:08:46 Is it possible to achieve scale, do you think, with this? Meaning, like greater ... Like, what is the progress of the next 50 years, 100 years looks like in terms of the precision and the scale of control using light?

Karl Deisseroth 1:08:59 It's going so fast it's hard to, to predict but I'll give you a sense of it though. In, you know ... First paper, you know, we published be- in 2005, that was just in cultured neurons, by 2007, so that was in a dish. By 2007, we had it working in behaving mice. By 2009, we had a pretty general, uh, so w- we had methods to really make it a versatile method, it could be applied to essentially any cell. By 2012, we could get to single cell resolution. We used light guidance strategies to target individual cells in the brain of a, of a living mouse. By 2019, we were able to control up to 20 to 50 individually specified single cells in the brain of a mouse and in ways that specifically changed its behavior that could bias its decisions one way or the other. In fact, we could take a, a mouse and without any visual stimulus at all, we could make it act as if it had seen a particular visual stimulus by playing in, using the single cell resolution optogenetics, a specific pattern of activity into, you know, 20 or 25 individually specified cells. That's 2019. To your question of scale, now in 2022, we're controlling hundreds of individually specified single cells over all of visual cortex of a mouse, all the part of the, of the, of the brain that, that is the initial direct target of the incoming information from the, from the retina.

Lex Fridman 1:10:31 Are you constrained to specific types of cells currently? Like you mentioned long range is easier. Is, is there constraints on which cells?

Karl Deisseroth 1:10:39 Uh, now there, there really isn't. Now that we have this individual cell guidance, we can target any individual kind of cell, uh, very reliably. Um, and so now, to your question of scale, uh, how far can we go? Well, um, things are moving quickly, it's, it's hard to say. Uh, we, we can access individual cells across the entire brain now. If you look 10, 20 years in the future, um, you know, I think we'll, (laughs) we'll surprise ourselves but the fact that we're already able to-

Lex Fridman 1:11:13 Yeah.

Karl Deisseroth 1:11:14 ... to cause specific perceptions to happen and specific actions means we're essentially where we wanna be, and now it's a matter of, of just, uh, you know, more experiments, more discoveries, but the, the basic principles are clear now. The basic capability is, is there.

Lex Fridman 1:11:32 Is there pathway to doing s- uh, the same for humans?

Karl Deisseroth 1:11:36 Optogenetics is primarily, it's a discovery tool. It really is well-suited for use in, in mice and rats and, and, and monkeys because it's, uh, um, it involves putting in a gene, uh, and also delivering light, and those are two things that you can do in human beings, but you'd wanna do in a very careful way. Now that, that said, there is, actually just less than a year ago, uh, my friend Botond Roska in Switzerland, he did the first human optogenetics, uh, therapy, and he published this in the journal Nature Medicine. So about, uh, uh, 10, 12 years ago, he and I published a paper together where we gave him one of our, uh, optogenetic tools, one of these light activated, um, regulators of ion flow, um, these are called microbial opsins, by the way, opsins, and he put one of those into an extracted retina from a human being, uh, who had died, and so it was a cadaveric, uh, retina, and he was able to show that optical control in this, in this paper, uh, was able to turn on or off individual cells in the human retina. So that was a while back. He spent about 10 years of going through all the regulatory, you know, hoops and hurdles and going through primate studies, and finally he was able to take a human being with a retinal degeneration syndrome, so someone who's blind in both eyes-... and he gave a, one of these opsins into one eye of this human being who was blind a- and with the goal of conferring light sensitivity onto this retina that was not able to see light. And he was able to- to make this person see through that eye (laughs) . So he took a blind person and the blind person could- could see now, could reach for objects selectively on a table, uh, uh, and he published this in Nature Medicine. And it was, you know, that's an amazing thing. Um-

Lex Fridman 1:13:39 Do you know the title of the pa- what's his name again?

Karl Deisseroth 1:13:41 Uh, Roska, R-O-S-K-A.

Lex Fridman 1:13:43 Can you look up the Nature paper?

Karl Deisseroth 1:13:45 Yeah, Nature Medicine.

Lex Fridman 1:13:46 N- Nature Medicine.

Karl Deisseroth 1:13:47 So that- that's sort of proof of principle. Now, the retina is very accessible. It's near the- the surface, you can use natural light, or you can use brighter natural light. Um, I'm, myself, I see optogenetics as- as a discovery tool.

Lex Fridman 1:14:02 Mm-hmm.

Karl Deisseroth 1:14:02 It's a way to figure out the principles by which the brain works and how it operates.

Lex Fridman 1:14:05 Partial recovery-

Karl Deisseroth 1:14:06 Yeah.

Lex Fridman 1:14:06 ... of visual function in a blind patient after optogenetic therapy, so he went through the full process of doing primates studies and then- and then going, wow, that's dedication and that- that's really exciting to see.

Karl Deisseroth 1:14:19 Yeah. As- as beautiful as that is, and I'm glad he did all that work, there- there are so many other ways that optogenetics could help with therapies. Once you know the principles, then any kind of therapy can become more powerful. Once you know the causal cells in a symptom, like in lack of motivation, or inability to enjoy things-

Lex Fridman 1:14:41 Yeah.

Karl Deisseroth 1:14:41 ... or altered sleep or altered energy-

Lex Fridman 1:14:43 Yeah.

Karl Deisseroth 1:14:44 ... once you know the cells that are causal, then you can make medications that address those cells, you could address, uh, brain stimulation treatments that might address those cells.

Lex Fridman 1:14:53 Also diagnosis. You maybe-

Karl Deisseroth 1:14:55 Diagnosis, yeah.

Lex Fridman 1:14:55 ... be a very effective systematic way of diagnosing, or at least g- providing you rich data to some of these deep questions about schizophrenia, about bipolar, all of those kinds of things that our tools are low resolution currently for determining wh- like the degree to which you have a thing and whether you have a thing at all.

Karl Deisseroth 1:15:18 Yeah, and exactly. And so the- the- the hope is, you know, that's a, that's just a great example of how, uh, you- you can cure or you can, you know, provide some relief for a- a symptom of a person who has a- a serious degenerative disease. But- but the principles are what- what we're after, and that's why I spend, even though I'm a s- a psychiatrist, even though I- I still see patients, I'm not myself trying to drive any clinical trials in the lab, I'm trying to discover and then any kind of- of therapy could result from

Karl Deisseroth 1:15:50 that.

Lex Fridman 1:15:50 What do you think about, uh, my friend Elon Musk and his efforts with Neuralink? So this is another, um, there's a lot of things to say here because there's a lot of ideas under the umbrella of Neuralink, um, but one of them is to use electrical signals to stimulate and then you also record, you collect electrical signals from the brain at a higher and higher resolution and you go, uh, implant surgically the methods by which you do the stimulation and the da- the data collection. So it's possible for the ideas of optogenetics to play well with this, um, and we can even zoom out outside of just Neuralink and just the whole idea of brain computer interfaces. What- what are your thoughts?

Karl Deisseroth 1:16:41 Well, I think the engineering that they've done is actually pretty cool, so I-

Lex Fridman 1:16:45 Yeah.

Karl Deisseroth 1:16:45 ... I like the uh (laughs) -

Lex Fridman 1:16:46 Robots.

Karl Deisseroth 1:16:47 Yeah. From the- from the design perspective, and it was an a- it was a design approach that wasn't being taken in academia, and it's great that they did it, and I think it's- it's pretty cool, um, so I'll say that. Also, there are many ways that you can record from many thousands of neurons, um, and, uh, that's not the only way. It's a- it's a very interesting way. We and others are using, um, uh, brain penetrating electrodes that actually get quite deep. The- this whole structure of the brain is very interesting. We, the- there's the surface cortex where it's the most recently emergent part of the brain in evolution, uh, mammals have it, reptiles have something a little bit like it but it's not really the- the full thing. It's a, this is a very recent thing. That's what we can access with some of these, you know, like the Neuralink approach and with some of these, uh, short electrodes. This part of the brain, the cortex, is only a few millimeters thick, but there's so much that's deep though that's so important. There's the striatum, there's the thalamus, there are the parts of the brain that drive, uh, motivation, that drive hunger and thirst and- and social interaction and parenting and- and flight and fear and anxiety. All these things are, there's so much that's deep that these surface approaches are not getting to. And so we and others are using these very long, uh, electrodes that help us get deep and we can still record from many cells, many thousands of cells. Uh, we can have multiple of these at once in the same animal, and so there's a diversity of methods to get to this goal. Um, I think it's great that- that people coming from, you know, the- the, you know, outside academia will bring, uh, ideas that weren't being worked on, uh, at least approaches, they may turn out to be synergistic. These things work very, do work with very well with optogenetics because all these electrical recording methods, that's one channel of information flow. Light delivery is a separate, you know, more or less independent, there can be some- some artifacts that happen, but if you're careful that's another independent pathway of information flow. And we've done really, uh, fun experiments in mice where we play in patterns of activity with light and we record activity from all across the brain of a mouse electrically. And so using optical and electrical together is extremely, uh, powerful.

Lex Fridman 1:19:04 So like opto-electric brain computer interfaces?

Karl Deisseroth 1:19:08 Yeah, exactly.

Lex Fridman 1:19:09 ... which, by the way, there's, uh, efforts on the computing side to build optoelectric, uh, servers. So like, where you have both electricis- so because optics is really interesting. Light is a very interesting method of communication that's, li- like you said, orthogonal in many ways.

Karl Deisseroth 1:19:25 Yeah.

Lex Fridman 1:19:26 It doesn't have some of the constraints of bandwidth that electricity does going through wires, but you're able to, but it's less ability to control precisely at scale. Uh, so like there's challenges and there's benefits and having those two interplay is really, really, really fascinating.

Karl Deisseroth 1:19:43 Yeah.

Lex Fridman 1:19:44 Especially when obviously on the other side of your signal is a biological m- mesh-

Karl Deisseroth 1:19:50 Yep.

Lex Fridman 1:19:50 ... m- mush-

Karl Deisseroth 1:19:51 (laughs)

Lex Fridman 1:19:52 ... mushy mesh.

Karl Deisseroth 1:19:53 Well, the- the mushy mesh is kind of interesting 'cause we have, there are problems with light, light scatters in the brain. So the- the- the photons don't just go, you know, linearly through, they, whenever they hit an interface between fat and water, lipid and water, they- they- they bounce off in different directions. And so you can come in with all the resolution you want, you could play in an incredibly detailed high resolution pattern of light, but the photons start scattering, uh, quite quickly. And by the time you've gone a couple of millimeters deep, it, you've lost almost all that fine spatial information. So, but we've developed workarounds, the longer wavelength light you use, if you get into the infrared, there's less scattering. You can use two photon methods or three photon methods where the photo- tones have to arrive all together at the same time. You can put in fiber optics, we developed these fiber optic methods in 2007 where you can access these deep structures with- with fiber optic methods, and you can put many of these fiber optics at the same time in an animal. We've used, uh, holographic methods to, uh, 3D holograms to play in hundreds of individual cell sized spots of light. And we can, and we can change those quickly. And so there are a lot of tricks, a lot of interesting optics engineering that has come together with neuroscience in a pretty exciting way.

Lex Fridman 1:21:04 Well, it is engineering too, which is super, super, super exciting. I should mention, 'cause I remember, I mentioned Elon, um, I recently got, for the first time ever, got COVID.

Karl Deisseroth 1:21:15 Oh.

Lex Fridman 1:21:17 Um, (laughs) how did I go so long without ... But finally, so I'm all vaccinated and everything like that. And so I got, uh, 'cause I think he, he mentioned it publicly so I can mention it, but I won't mention anybody else involved. But hanging out, we all got, Elon got COVID, and the interesting thing about, maybe you can comment about this, so I was only sick for like a half a day. I got a fever of like 104, it just went up and then crashed, and then I was ... Now, maybe I'm just, uh, seeing the silver lining of everything, but afterwards, uh, I have like a greater clarity about the world (laughs) .

Karl Deisseroth 1:21:57 (laughs) You just think it's greater clarity.

Lex Fridman 1:21:58 Maybe.

Karl Deisseroth 1:21:59 (laughs)

Lex Fridman 1:21:59 Maybe I just, it was so, uh, maybe so intensely the m- mind fog kind of thing for such a short amount of time, but the people who were involved were also reporting this.

Karl Deisseroth 1:22:11 Oh.

Lex Fridman 1:22:12 It's kind of interesting 'cause like, uh, because I- I do know like the immune system, uh, is involved with the brain in very interesting ways. So like, the human mind also incorporates all these other ... It's not just the, it- it's not just the nervous system. And I- I just wonder 'cause everyone always says, no, not like, everyone always says like COVID does all these bad things or whatever the disease is or whatever the virus, but I wonder like, uh, I hate to be a Steven Pinker on this, but like, I wonder what the benefits of certain disease are if you're able to recover? (laughs)

Karl Deisseroth 1:22:43 (laughs)

Lex Fridman 1:22:43 Like, what, is there some like, uh, again, don't want to romanticize it, but if your system goes through some kind of hardship and you come out on the other end, I wonder sometimes if there's a greater, um, maybe killed off a bunch of neurons that I didn't need anyway and they were actually getting in the way. They were the hater neurons.

Karl Deisseroth 1:23:00 Well, that-

Lex Fridman 1:23:00 I don't know.

Karl Deisseroth 1:23:01 ... is your inner critic that I was talking about there.

Lex Fridman 1:23:02 Exactly. (laughs)

Karl Deisseroth 1:23:03 You killed off your, uh, your critic.

Lex Fridman 1:23:05 Yeah.

Karl Deisseroth 1:23:05 Well, you know, there- there are mechanisms for what you, the potential mechanisms for what you're talking about. There are, uh, there's actually been a fair bit of research on post COVID neurological function. Uh, actually my wife Michelle Manje, who's at Stanford, she's done a lot of this work. Uh, Akiko Iwasaki at Yale has done a lot of this. But what- what they found is that there's a loss of myelin. This is the coating of those long range projections that go from one part of the brain to another. Myelin is this sort of insulator that coats these long range projections and makes the impulses go faster and more reliably. And there's altered, uh, uh, function of the myelin producing cells, uh, and altered myelin in the case of- of COVID. They've looked in both mouse and- and human, uh, brains. And, but of course it could be very idiosyncratic. Many people have cognitive problems post COVID, you're- you're definitely aware of that. So many people report this persistent brain fog, inability to function, but it depends on where the inflammation was, you know, maybe the people who have dysfunction post COVID, they had a global effect. Maybe you lost some of these projections that were restraining you in some way and- and these plausibly exist and it's known that there are, uh, cell populations in the prefrontal cortex that actively restrain deeper structures from expressing what they do. And it's- it's theoretically possible that you had a lucky-

Lex Fridman 1:24:40 (laughs)

Karl Deisseroth 1:24:40 ... uh, focal-

Lex Fridman 1:24:41 Somebody has to get lucky, right?

Karl Deisseroth 1:24:42 Somebody has to get lucky, yeah.

Lex Fridman 1:24:43 (laughs) Why not me? All right, if we can actually, uh, go back to this idea of trying through optogenetics to find origins of, uh, when the wave first starts, origins of, uh, a decision, origin of, uh, idea, origin of maybe, uh, consciousness or, uh, the subjective experience, the origin of things in the mind. Uh, so one thing is Carl Jung-Um, is there a God neuron? Is there a belief neuron? Is there... So through this methodology of optogenetics, can you start getting to like where a belief begins, or an idea begins?

Karl Deisseroth 1:25:36 Mm-hmm.

Lex Fridman 1:25:37 And especially looking at the strongest of our beliefs, maybe beliefs of love and hate, but re-