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Peter Attia MD191 - Revolutionizing our understanding of mental illness with optogenetics
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EVERY SPOKEN WORD
140 min read · 27,658 words- 0:00 – 0:10
Intro
- PAPeter Attia
[upbeat music] Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Attia.
- 0:10 – 14:51
Karl’s journey through medical school and interest in the brain
- PAPeter Attia
Hey, Karl. It is so good to see you today, uh, although admittedly across video, but, uh, it's like a little blast from the past from, I don't know, 20 years ago, right?
- KDKarl Deisseroth
Yeah, it's, uh, it's amazing. We, uh, had a good group of friends back, uh, back in the old days at, at, at Stanford, and I haven't, uh, kept in touch with them as much as I'd hoped, but it's great to see you. It really brings back a lot of memories. You look great, unchanged.
- PAPeter Attia
Well, uh, yeah, it's funny, you, you don't look a bit different. Um, it, it is funny when I think back to, to that class of ours in med school, and I really feel like the overwhelming underachiever of our class. Um, [clears throat] and I, I remember our first day of our surgical rotation, uh, you, me, and Josh Rabinowitz in that, sitting in that room waiting for us to be assigned to which service we would go to. Of course, you and Josh have gone on to do unbelievable things. Um, I've sort of muddled along. But, um-
- KDKarl Deisseroth
Ah. No, you're the star. And plus, I remember you-- even though it was the start of our surgery rotation, you already knew how to do everything, which I was impressed by.
- PAPeter Attia
[laughs]
- KDKarl Deisseroth
You, you knew all the knots and, and I was like, "Wait, this is the first day of the rotation. How do you do that?"
- PAPeter Attia
[laughs] Well, let's pick it up back there. So, um, you know, I, I... Y- you know, you were in the MD-PhD program, so we didn't start at the same time. We just finished at the same time. You had come in earlier. Um, but I think the reason I knew you even on our first day of surgery was because you had done your PhD in the same lab as two other friends of mine, Alex Ravenels and Jason Pyle. Um, and I mean, all kidding aside, I think that, you know, look, all the kids that went to med school were pretty bright, but I think the MD-PhD students were sort of in a class of their own. Um, and I suspect it was even harder to get into that program than it was just the straight MD program. So, uh, thinking back to your time as an undergrad, what, what did you major in again in, in undergrad?
- KDKarl Deisseroth
I, uh, I, I did biochemical sciences, they called it at, at Harvard, instead of biochemistry. They had to do everything different, and, and they didn't call it a-
- PAPeter Attia
[laughs]
- KDKarl Deisseroth
... a major either. It was a concentration. So I, I concentrated in biochemical sciences.
- PAPeter Attia
[laughs]
- KDKarl Deisseroth
So there you go. But, uh, I had a lot of other interests. All my friends were physicists, uh, theoretical physicists, uh, in fact, uh, and so I, I was exposed to some, uh, some pretty, uh, unusual stuff for a biochemist.
- PAPeter Attia
And were they allowed to call it theoretical physics at Harvard?
- KDKarl Deisseroth
They were. [laughs]
- PAPeter Attia
Okay. That's, that's good. I just, I just wanna... [laughs]
- KDKarl Deisseroth
Good question.
- PAPeter Attia
Yeah.
- KDKarl Deisseroth
Yes. They, they, they were allowed to, to name it that, yes.
- PAPeter Attia
Good, good. So at what point during your biological science concentration did you know you wanted to go into medicine?
- KDKarl Deisseroth
Uh, it was pretty early because I, I was interested in the brain early on, and I, I wanted to understand the brain at the level of cells and-- But I was also interested in the most high-level aspects of brain function, and so I thought I needed, uh, to talk to human beings. I needed, uh, some, some access to the, to the human brain. Uh, I found that interesting because I was interested in emotion and the ability to express, uh, feelings through words and, and I, I had this-- I was torn. I liked writing and literature and, and, uh, and the use of words, and I liked cells and biology, and I wanted to somehow fuse them, and it seemed that, that medical school was the, the way to go because I could, I could work with the human brain.
- PAPeter Attia
And, um, obviously, you could have just gone to medical school, but you, you also selected into this very, very advanced program that was incredibly selective, the MST program, the Medical Science Training Program. Um, and so that tells me at the outset that you also knew you wanted to do research beyond, you know, quote-unquote, just clinical medicine, yes?
- KDKarl Deisseroth
Yeah, that's right. And, and that was the, that was the... You know, the, the nice thing about the MSTP is it lets you delay making a commitment, you know. So you, you keep both threads alive. And then, uh, there, there's a beautiful synergy that can happen too, and certainly happened with me, that, that you realize, oh, wait, I don't have to make this decision. It actually is good to keep both threads alive in, in, in my work and my life. And that, that's what, that's what happened. But it's a, it's a pretty special thing we have in, in the United States. Uh, there are efforts in, along these lines in, in Europe and, and, and other countries, but it's not nearly as, uh, institutionalized as, as it is here. It's really a special thing.
- PAPeter Attia
Well, it, it really is. And I, again, I, I keep r- saying this, but I, I feel like there were maybe, what, six or eight MSTPs per class. Um, and I always felt like you guys had the most pressure on you, right? There was this expectation from both the clinical side that you would go on to be great doctors, but then you were also, especially at places like Stanford, where you had the opportunity to do your PhDs with Nobel laureates, would-be Nobel laureates, you know, exceptional scientists, that you would also basically be leading the charge scientifically. And, you know, for what it's worth, all of my friends in the MSTP program, I think you're the only one that ended up doing clinical training as well. I think most of them didn't end up doing residencies. They either went purely into academic research tracks or actually went into industry. Um, but before we get into-
- KDKarl Deisseroth
Mm-hmm
- PAPeter Attia
... the fact that you also did clinical training, let's talk a little bit about that transition. You came into medical school pretty hell-bent on neurosurgery, yeah?
- KDKarl Deisseroth
That was the goal because, you know, again, how do you, how do you get access to the, to the human brain, and who among the different clinical specialties has that, uh, access? Who can, who can, uh, would most directly interact, study? And it seemed to me the neurosurgeons had it all. Uh, and if one were to build, uh, an interface with the brain, uh, if one wanted to both communicate with a person as they were expressing feelings and emotions and to understand at the Level of cells, what was going on, who could do that, but a neurosurgeon was my reasoning. And, you know, uh, and I-- the neurosurgeons that my, that my colleagues and friends that are amazing people, you know, brilliant, and, and I, I saw no reason not to, to pursue that. And so that was the first rotation that I, I selected in the, in those, uh, second two years of medical school. Even before surgery, I did neurosurgery. And so, which was kind of interesting, just, just coming in there with, uh, with no general surgical training as well. That's how, how certain I was.
- PAPeter Attia
Yeah, it's funny. Um, [chuckles] well, I, I had a similar experience, whereas the thing I absolutely positively thought I was going to do, I picked as my first rotation. Uh, in my case, I had less of a pleasant experience than you. I think you had a pleasant experience on neurosurgery. It wasn't that in any way you didn't like it, but-
- KDKarl Deisseroth
What was your first?
- PAPeter Attia
Well, I, I, I planned to do pediatric oncology, so I, I went out of the gates with two months of pediatrics, um, which, which actually I didn't enjoy, um, largely 'cause I just didn't feel like I didn't fit in. I think so much of your medical school experience in terms of your clinical rotations is a function of how well do you fit in with the residents of that specialty. And-
- KDKarl Deisseroth
Yep
- 14:51 – 25:07
A profound medical school experience that changed Karl’s career path to psychiatry
- PAPeter Attia
amazing, right? So tell me about your... How, uh, how did you go into your psychiatry rotation? Were you looking forward to this, or did you view it the way many of us did, which was, "Just get me through it"?
- KDKarl Deisseroth
I had a get me through it, uh, you know, attitude coming in, um, and again, no, no disrespect to, to psychiatry, of course. Uh, you know, it's a, they have a hard challenge. Still, we have this challenge that there's not a, uh, a measurable really. You know, we have, we have s- effectively, you know, questions we ask patients. It's all with, with words is, is how we, we work. And, and-
- PAPeter Attia
Yeah, no, no biomarker
- KDKarl Deisseroth
... [laughs] no biomarker still. Yeah, I mean, there's efforts along those lines looking at EEG, you know, ratios of, of this to that and, and there's progress being made, but still clinically, we can't make diagnoses, uh, based on measuring something about the brain in psychiatry. You can, you can notice that there's something else going on, uh, a neurological or a medical problem, but you, you can't, uh, de- define someone's psychiatric state with, with, uh, some biomarker, and that still amazingly to this day is still true.
- PAPeter Attia
Yeah, so what, tell me about your psych rotation 'cause I remember we kind of had choices. I did an entirely outpatient month, um, which I ended up finding quite enjoyable. That's the irony of these things. You kind of... I did it as one of my last rotations prior to graduation, which meant there was no chance, even if I'd liked it, I c- it was too late for me to make that choice. I had already matched, I think, in general surgery. Um, but it was an outpatient month, so relatively low acuity, um, but, but interesting nevertheless. What, what was your month like?
- KDKarl Deisseroth
[clicks tongue] So my, mine was the, uh, opposite of that. It was, and this was probably a fortunate thing for me. It was in the locked unit at the, uh, VA, at the Veterans-
- PAPeter Attia
Mm
- KDKarl Deisseroth
... Administration Hospital, and this was a, uh, a unit where patients, um, uh, can't leave, uh, and this is due to, you know, being a danger to themselves or a danger to others or having a, a grave disability. Uh, a- and this, uh, uh, you know, these patients were, uh, severely ill, uh, and I, I walked into that. [clicks tongue] Uh, you know, I'd, I'd had typical experiences. Uh, everybody, you know, has friends or family who've had, you know, depression or anxiety. I'd, I'd, I'd had, uh, I'd seen substance abuse and, and intoxicated states and, and dementia and, and, and I had a, a fairly, you know, I thought decently broad understanding of, of what can go wrong on the, on the psychiatric side. But, uh, I can tell you nothing, a- and you, you know this by now, but, but, uh, I can, I can tell your, your viewers, uh, and listeners there is nothing like what you can see, uh, when you walk into the, the locked ward of a, of a psychiatric hospital. There's a, there's the i- uh, uh, there's a, a sort of a, a purity, uh, not in a good way, but there's a, a, a, the, because there's not confounding issues like intoxication and so on, there's a, there's a, a, a consistency and a purity to the disorders. And so if you have someone with acute schizophrenia or schizoaffective disorder, other things that might confound what's going on have been removed, and there's this very strong, acute, uh, um, uh, straightforward expression of the symptoms that's just, uh, mind-boggling to see if you haven't experienced it before. And, and that's, that was, was my experience, and it completely changed my course. There was a... Even on the, you know, my very first day, there was a, uh, a patient with schizoaffective disorder, which is a very severe combination of mood and psychotic symptoms that are all mixed up together. And this patient, uh, accosted me in the, in the locked unit, started screaming at me and, and, but it was, it was not, uh, necessarily sort of a street encounter that you might have in a, in a city. It was more, uh, it was more, uh, direct and personal and, uh, evocative of something going on in the, in the mind of the patient that was clearly a source of immense suffering, o- of great disability. And yet at the same time, it was, it was, uh, tantalizing because this was a, you know, human being who was physically intact, but whose reality was so completely different from mine. We are two people with intact bodies and, and, and brains who are, uh, you know, next to each other, and we inhabited completely different realities. And to experience that was a utterly, uh, transformative moment. And, and both seeing the, the suffering and realizing I have no idea what's going on here, but it's incredibly interesting, too. How is this possible? How could this be happening to a, a human being? And, and without that direct exposure, uh, I don't know what would have happened. But having had it, it, it changed my course.
- PAPeter Attia
Which is interesting. I mean, uh, many people when confronted with that would be quite frightened, um, especially when you realize the limitations of the tools that you have, right? So let- let's, let's consider a- another analogy, which is, you know, a patient that comes in with a gunshot wound to the chest. That's an incredibly frightening experience. There's literally, you know, a, a sucking chest wound. Blood could be splaying around the room. Vital signs are crashing. The person's on the verge of death. But that can be exciting in a way because we actually have the tools to do something, right? It might be completely draconian. We might be doing a thoracotomy in the ER, cross-clamping the aorta, but you run that patient to the OR and you know how to fix them. You're experiencing something that I would argue is much more frightening, but compounded by the fact that what do you do? I mean, you, you could temporarily give that person Haldol and, and sort of snow them, but that's not curing them. So w- was it-- Which of-- Was it more the, we don't have the tools here, this is an unbelievable opportunity to learn, or, or, or, you know, h- how did that experience, which I think for many people could have been off-putting, do the exact opposite in you?
- KDKarl Deisseroth
I mean, I had, uh... It's, it's a great question because I, I... And I would completely understand that the normal, uh, or typical reaction would be sort of an aversive thing. You know, how this is, this is not something I wanna spend my life, uh, doing in this, in this setting. Um, but I had a, I had a different reaction, which surprised me. Uh, and it was, partly it was, it, it was really there were two sides to it. One was exactly what you're saying. Uh, the, the level of mystery here was, uh... Actually, for me, it was a, a positive rather than an aversive thing. And maybe this was partly the, my scientific training. You know, at that point, I'd completed my, my PhD and, and, and I'd spent years trying to figure things out. Uh, and we all want to figure things out. That's a natural human impulse. Not everybody, uh, necessarily spends years and years and years trying to figure out the same thing, and that's, that's the kinda, uh, training we get in, in, in, in the PhD program. And I saw that and I was like, "Okay, gotta figure this out." This is, this is clearly, uh, a mystery that, uh, is something that it's a burden that humanity shares. It's a terrible burden that this human being is suffering. But what's the solution? We've got to figure it out. We've got to understand this. And, and it's a, a mystery that strikes to the heart of, of what had always intrigued me, which is what is, what is an emotion physically? What is a, a feeling physically? How does the collection of cells in our brains, and that's what it is, it's a collection of cells, how, how is it possible that that creates a feeling, an emotion? And I realized at that moment, this is [laughs] , this is actually, you know, why I came to medical school. This... And it all made sense in, in, in one moment that, that hadn't before. And, and then, you know, of course, as a, as a, as a physician, as you well know, we-- our instinct is to help, is to heal, and, and we want to do that. But as y- as you say, if we don't have the tools, what, what can we do? It's, it's a problem. Uh, and I wasn't frustrated with the inability to do anything, and I would understand that reaction too. And the fact is we, we could do a little bit though, uh, so it wasn't quite nothing. Uh, and there are medications back then and still that help somewhat. They don't come with understanding. They don't help us explain to the patient or the family or to ourselves what's really going on, but they do help a little bit. And so I was-- I knew that I could do something, not much, but a little bit, and as time went on, hopefully, and as the science progressed, maybe we could do more. And so that, it, it, it fit together in a, i- in a moment and I didn't have another thought, uh, uh, for neurosurgery after that. Although it was, it was a hard, uh, process, uh, you know, to reshape what my trajectory was gonna be. I had one set of plans. My friends and family had a set of expectations. I can tell you, I think my, my father was pretty disappointed when I told him on the phone that I was gonna do psychiatry. I could hear it in his voice. It was, it was almost, uh, yeah, it was a quite a... And, and, you know, again, he, he came around in the end too, and, and I think he's, he, he's happy, uh, now. But, uh, at the time I could, I could sense that this was not what he'd, he'd hoped for me. Um, so yeah, it was, it was an adjustment. It was a, a remapping, uh, but it was a, a very compelling experience that, that the, the process of medical training, uh, and the required psychiatry rotation made possible.
- 25:07 – 32:43
Karl’s commitment to research and challenges overcome early in his career
- PAPeter Attia
So Karl, you, you now make this decision to completely veer into this nearly orthogonal track. I mean, psychiatry and neurosurgery of course have one thing in common, which is the, the organ of interest is the brain, but at that point they basically f- you know, differ. Um, how did you decide you were going to both pursue the clinical training, the residency for psychiatry, but also do whatever was necessary to make sure that you could ultimately be running a lab? Because I, I think throughout this period you never lost sight, unless I'm misremembering, um, of the desire to be a physician scientist and not just a physician. So, you know, residency, especially 20 years ago when we did our residencies, they didn't have 80-hour workweek requirements and things like that, so residencies were quite demanding.
- KDKarl Deisseroth
Mm-hmm.
- PAPeter Attia
Was it a little hard for you to say, "Hey, I'm gonna actually have to put my research on hold for a little while"?
- KDKarl Deisseroth
It was, it was hard, and this is, uh, [chuckles] there are a lot of, uh, challenges that, that people in this realm face because things move so quickly, uh, in the research realm that if you step aside for even a year, forget about four years, uh, you know, the world you reenter is, is so different and it's very hard to catch up. And this is, you know, that's to some extent a- an old problem because that's been faced by everybody who planned to do a residency. Uh, but it's a, it's not negligible because it's an old problem. It's that issue exactly that ends up, uh, driving people to make this hard choice that you mentioned earlier and saying, "You know, in the end I'm gonna have to do one or the other. If I do the residency, I'll, I'll, I'll be a, I'll be a doctor. I'll be a, a good doctor, maybe a great doctor. I'll be, I'll be informed by all my scientific training. Maybe I'll read papers better. Maybe I'll be more, you know, amenable to new ideas, new treatments as a result of that, but ultimately I'll be a, a, a physician." Or on the other side saying, "You know, I'm not gonna do the residency. I'm not gonna drop off this, this fast-moving train. I'm, at this moment I've just finished my PhD. I'm a world expert in this. I can do things that, that nobody else can do. Why lose that momentum? Why not speed up? Add the next tool in the tool belt, launch yourself, and make great discoveries," and that is very, very tempting. I had, uh, you know, very clear opportunities to do that, and so that's the hard choice that, that the, the MD-PhD faces at that moment. Um, now efforts are made to, to ameliorate that, so residencies, you know, again, this was, this was the, the, the time still where the residencies, uh, were extremely difficult. Uh, and, and I had some... For me, this was compounded by some personal challenges. I was, uh, effectively a single dad at the time, and so I had to also think about this, this other factor, uh, very important. Um, you know, I, now I've got, I've gotta think about residency, I've gotta think about lab, I've gotta think about family and, and it was very, very, uh, challenging. Uh, and yet there are these research track residencies, uh, and, and th- and they, they help a little bit. So there are, uh, in, in Stanford and other, uh, pr- you know, uh, programs both in psychiatry and in other specialties, they have efforts to, to help people keep their, their scientific, uh, you know, mind alive during residency. And it's, it's not great, but it's a little bit, uh, a little bit of protected time here and there. Never quite enough to get momentum, but at least to, to keep a foot in the lab and, and, and try to stay connected. And so I did that. It was a research track psychiatry residency, and I, I, I stayed at Stanford, and a big factor in that was that, uh, literally at the same time, and I was very fortunate in this, uh, regard, uh, a, uh, a guy named, uh, Rob Malenka, who was a psychiatrist and a, and a great neuroscientist, was at that moment, uh, coming from UCSF to Stanford. Uh, he had come and was setting up his lab, uh, at, at Stanford, and I knew here's somebody, a psychiatrist, but also a neuroscientist. He'll understand, uh, you know, what's going on in my residency, that I'm, you know, I'm taking call. I'm, I'm up all night. Uh, he'll know, he'll understand why I'm never [chuckles] in the lab during expected hours, why I'm never at lab meeting a- and, and, and that made it work out. And I worked nights and weekends. Um, I, I maybe came to one of his lab meetings over, over four years, and I effectively did a combined, uh, postdoctoral fellowship and psychiatry residency at the same time at Stanford. Some funny stories, I, you know, I, I... Because Stanford's very compact, as you know, I could literally take call from, you know, from the lab. Uh, I'd be patch clamping. I'd be at, at the rig, you know, listening in, me- making measurements on currents flowing across a single cell, and I'd get paged Go walk over to the ER, admit a patient, come back, you know, patch clamp the next cell. And it was a pretty special moment, uh, uh, when that happened. It, it felt like the different parts of my life were... They, they could work together. They could be compatible. And that with all... You know, so many people have such a hard time understandably making that work, making the pieces fit together, and I, I feel fortunate that, uh, I, I was able to make that work.
- PAPeter Attia
Now, what year was your son born? '98?
- KDKarl Deisseroth
Uh, he, he was actually born in '96, so he is, uh-
- PAPeter Attia
So you're four-
- KDKarl Deisseroth
25
- PAPeter Attia
... he is five years old basically when you're-
- KDKarl Deisseroth
Yes
- PAPeter Attia
... in the midst of this.
- KDKarl Deisseroth
Yeah, that's right.
- PAPeter Attia
So how, how did you, how did you manage that?
- KDKarl Deisseroth
You know, it was... Th- these... This is actually, uh, something that, that I, I touch on. Uh, I know we may talk about this, uh, the, the book-
- PAPeter Attia
Mm-hmm
- KDKarl Deisseroth
... I wrote, Projections, later, but it was a... turned out to be a theme early in my, in my life, how my experiences with my son, how they related to all the, the stressors and the patient experiences that I was having. And in a way, psychologically, although it was, was difficult to make everything work, uh, uh, practically, um, it also, uh, it, it helped me a, a little bit to have a, uh, a, a, a something that mattered more than anything else in the lab or in the, in the clinic. There was something that, uh, sort of, uh, was on a different scale, and it helped me not get too, uh, stressed about things happening in the lab or the clinic. Uh, and, and, uh, that, that's a, a common feeling in, in people with kids. For me, it was, it was extremely important at that, at that time. Um, you know, and it was a... There were patchwork solutions of, of, of, of childcare and so on that, that made things work, but it was... Ultimately, I think it was helpful for me in, in getting through those, those times. And, and by the way, he is now, uh, an MSTP student at Baylor, so he's doing his MD-PhD, uh, in Texas, and he's now second-year. He's a cool kid. He's, he's good at guitar, much better than I am, and, uh, he likes computer science.
- PAPeter Attia
[laughs] Yeah, he's got some big shoes to fill, but I... and I'm positive that none of that pressure comes from you, so,
- 32:43 – 38:13
The state of psychiatry and mental health therapies when Karl started his lab in 2004
- PAPeter Attia
um-
- KDKarl Deisseroth
No.
- PAPeter Attia
So I remember when you were finishing your residency, um, I just remember, because of our common friends, like, how kind of exciting it was when you were now setting up your own lab. So we're talking about, what, '05, '06-ish?
- KDKarl Deisseroth
Yeah, the lab started to get set up in '04.
- PAPeter Attia
Okay.
- KDKarl Deisseroth
Uh, and then it really hit full steam, yeah, between '06 and '09. But it, '04 was when we were setting it up.
- PAPeter Attia
So as you're embarking on this, what is it that you experienced during that, that transformation of your, your clinical training, your residency? How did that shape the problems you were interested in solving?
- KDKarl Deisseroth
Well, I, you know, having just completed my psychiatry residency, I had seen... I, I had a pretty deep understanding of where things were clinically. Uh, I knew what, not just the medications we had, but also the brain stimulation treatments, the interventions that we had available at the time. I did a l- uh, you know, I did electroconvulsive therapy, which, uh, is, you know, it's a... it's very effective for treatment-resistant depression. Uh, it's the treatment of choice, uh, for many people. It's incredibly effective. It's stunning to see. It's... It has some problems. Uh, you don't want to give it too much, and there, there can be side effects, but it's incredibly effective.
- PAPeter Attia
What's the durability of it?
- KDKarl Deisseroth
Uh, it depends. Uh, some patients need, uh, what we call, you know, a, a maintenance, uh, electroconvulsive therapy. So after three months or so, uh, the effect will be diminished, and, and they'll, they'll, uh, uh, require, uh, to stay alive effectively, patients who are, for example, just acutely suicidal. Uh, and they, they'll need every three months or so what we call maintenance, uh, or continuation, uh, electroconvulsive therapy or ECT. So it's not a, it's not a permanent, uh, fix. Uh, like so, so much of medicine and so much of psychiatry, you know, uh, it's something that moves things back into a healthy range for a time. Uh, but we didn't know how it was working. It, it definitely helped, but, but it was... For a scientist, it was very... It was satisfying to help the, the patient, to s- to h- take somebody who was, you know, in, uh, just horrific psychological distress, uh, and, and put them into a, a, a state where they could go back and do their work and, and, and, and live with their friends and family and be happy for some time. That was great, but we had no idea what, and still don't, uh, what was going on there. Why is this, uh, seizure that we give the patient, you know, we... and it's, it's done in a pretty refined way these days. The, the patient's body is paralyzed, so there's no physical, you know, seizure. It's, it's all happening in the, in the brain, and it's, it's a safe procedure, but still, it, it, it's not specific, right? Where you're causing a general pattern of activity through the brain of the patient and y- and this astonishing psychiatric effect is created. I, I, I... Clearly it, it was a, a mystery, still is, and I was unsatisfied by that. There were early efforts at the time of, of other brain stimulation treatments. There was, uh, vagus nerve stimulation. There's a... As you know, there are the nerves that run, uh, the 10th cranial nerve that comes from, uh, the brain stem and goes down to innervate the heart, and the abdomen. Also sends fibers back to the brain, and you can put a little cuff around the, the nerve and, and stimulate the brain, uh, through the neck, which, which is kind of interesting, a little, little highway to the brain. But the effects, uh, although it, it became approved, FDA approved for depression, the effects were very small on the population level, very inconsistent. Likewise, we had transcranial magnetic stimulation, which was in its early days then as well, which was a Uh, you know, it's a, it's a treatment where you can noninvasively stimulate a tiny patch of the brain by putting a, a rapidly changing magnetic field, uh, near the, the, the s- the scalp of the patient. Effects small on the population level, did get FDA approved, but still not fully understood. So all these, all these treatments, and of course, none of the medications to this day do we fully understand their mechanisms of action, so there are a lot of mystery. And so I came from my psychiatry residency fully aware that, that essentially the entire field was unmoored from scientific understanding. No fault of the practitioners, no discredit to them. It was just not known, and we didn't have the tools and techniques. We had no specific way of causing something to happen to a particular kind of cell. All these treatments are, are nonspecific, a seizure all through the brain. Uh, you know, a, a stimulation of a nerve wherever that nerve may go, known, but not specifically related to any psychiatric, uh, uh, symptom. Uh, transcranial magnetic stimulation, yeah, you can stimulate a little patch of, of the brain, but we don't know where depression comes from, where anxiety comes from. Is it this patch or that patch or that patch? No deep level of understanding, uh, uh, was present and, and of course, the medications act all through the brain without cell type specificity. So that was the, that was the setting. And then, you know, to answer your question then is, you know, clearly, uh, basic science, you know, how could you build an approach to give you s- some, some kind of, uh, precise causality? And that was, that was the, the context.
- 38:13 – 48:05
Neuroscience 101: fundamentals of neuroanatomy and neurophysiology
- PAPeter Attia
Well, I want to dive really deep into this because it is essentially, um, the skyscraper of your life. I mean, look, if you, if you retired tomorrow from medicine and science, Karl, if you dec- tomorrow decided you were going to go surfing for the rest of your life, you would have already accomplished more than that of 100 scientists. Um, so I want to, I want to come to this in detail. But before I do, I want the viewers and the listeners to get a little bit more of an understanding of the brain structure because we're going to be talking about structures of the brain. We're going to be talking about the cells of the brain. And, um, I, I wonder what the easiest way to do this is. Maybe we can start about the brain and its three layers and what... You know, we talk about them through our evolution maybe and how each one added to the next, but, but each one has a subset of functions. I, I'll really defer to you, Karl. This is your domain and not mine. But, um-
- KDKarl Deisseroth
Mm-hmm
- PAPeter Attia
... maybe we just take a step back and really give people a sense of, of some neuroanatomy, some neurophysiology, what neurons are, what axons are, how chemicals get transmitted.
- KDKarl Deisseroth
Mm-hmm.
- PAPeter Attia
I think investing some time in this now will really enable people to understand the depth and breadth of your literally world-changing discovery.
- KDKarl Deisseroth
Well, well, thank you for the, first of all, the, the gracious, uh, uh, comments. I, we have a long way to go though, and I'm not, uh, and maybe it's many lifetimes, uh, ahead. There, there are very deep mysteries in the, in the brain that we have much, much work to do. Exciting, fun work, but much work to do to, to get to where we want to be. But, uh, it is, it is a, an exciting moment, and we've, and, and what we've been able to accomplish has, has been, uh, thrilling. Um, and, and it's a testament to all the amazing people that, that we've been able to, to, to get together to work on this. And, and indeed, the brain is, is something that's very compelling. Uh, it's so interesting and mysterious. The cells in the brain are more complex structurally than any other cell. They're in our brains. There are, uh, approximately 90 billion neurons. That's with a B. Each one of them is, it's a self-contained unit. It's covered by a, a membrane, but it can generate electricity. It's got little channels, little pores in its surface that can generate little electrical impulses, and that's how you can have a single neuron that projects from one part of the brain to another or from one part of the brain to the spinal cord and, or it can send connections through its axon, its outgoing wire, uh, effectively to many parts of the brain. And it sends that information in the form of electricity down its axon, down its outgoing, uh, uh, connection. And the connections are received by the downstream cells through little structures called dendrites, and the interface from one cell to the next is called a synapse. And in most cases, information gets across that little gap from one cell to another in the form of chemicals. So the e- the electricity triggers release of a chemical. The chemical drifts across this tiny little gap that's some tens of nanometers, and then it acts on receptors in the other side, the post-synaptic side, and, and that creates a new burst of electricity in that downstream cell. So that's the electrochemical process that, of information flow. Now, you've got this going on in 90 billion neurons at the same time. They're all, maybe they form 10,000 or even 100,000 synapses each. Their wi- wiring is incredibly complex. Uh, uh, um, there's some structure to it. There are collections of axons that may travel together, but then they also bifurcate and separate in incredibly complex ways. And all that's in the brain. And then there's some structure to it, as you alluded to. Uh, and one way we can think about this is, is indeed evolutionarily. We're vertebrates, okay? That means we have a backbone, and we've got a certain organization to our brain. Uh, in my lab, we have fish, and we have mice, and we have rats, and then I also do clinical work. These are all vertebrates from fish to us. We all have the basic vertebrate body plan and brain plan. And But evolution has given us, obviously we have much bigger brains than, than fish do. And a couple things have happened over the course of, of, you know, hundreds of millions of years, is that first of all, we've scaled everything up. We've taken the same structures, we've added many more cells to them, uh, and that lets us do more complex things. And we've also added new things on top. And so in the surface of the brain, there's what we call the cortex, uh, uh, which means literally the, the surface of, of the, of the brain. It's like the, the rind of a melon, except in human beings, it's, it's quite thin. It's just a, a, a few millimeters, uh, uh, thick. And within that few millimeters, there are six separate layers within that cortex or rind, uh, and those are layers of cells. So there are six layers of cells in this sort of shawl or, or rind covering the, the brain. And then all the wiring coming out from that cortex, uh, goes to deep structures. Uh, and our, our cortex is much more advanced. The fish don't really have something like that, but they've got the deeper structures. They've got the interchanges and, and the movement control and the, the, uh, uh, arousal systems and the sleep systems and, and there are structures deep in the brain like the hypothalamus that govern all the primary needs of, of salt balance and, uh, avoiding danger and mating and sleeping, uh, thermoregulation. These deep structures are common to every vertebrate. We have a hypothalamus. The fish has a hypothalamus. These deep structures are shared and ancestral among all vertebrates. And so you've got this, you've got these deeper structures that are, that are conserved and ancient, and you've got this, uh, in, in us, we've got this, uh, surface structure that is, uh, in- incredibly elaborated in, in our lineage and, and, uh, is responsible for some of the most complex and, and, and mysterious things we do. And, and, but the great thing is, and mice sort of sit somewhere in between. They have the cortex, uh, that we have, and it's amazingly similar. It's got the same six layers. It's got the same kinds of neurons. They're connected in the same way. It's just much smaller, uh, than what we have. And so by looking at the fish and the mice and ourselves, uh, we can, uh, piece together a lot by studying the cells and the connections that make things happen. And, and that's the context of, that, that we come to as a neuroscientist.
- PAPeter Attia
A- and what about this, this first layer, the brain stem, this kind of most primordial layer that handles so many of these functions when we're not even thinking about it, like, like breathing? I mean, what, w- how conserved is that across all of these models?
- KDKarl Deisseroth
Yeah, the brain stem is, is highly, highly conserved. The, you know, in the brain stem and in the midbrain, we have clusters of neurons, uh, like the dopamine neurons and the serotonin neurons and the, uh, noradrenaline or norepinephrine neurons. They're all, uh, uh, clustered there in the brain stem in and around, uh, other cells that govern, uh, the movement of the, uh, muscles of the face and the, the neck and that send information down, like the vagus nerve that we talked about, send information down to the rest of the body. These basic structures in the brain stem are, are highly conserved. Fish and mice and human beings, uh, all have them. There's a little bit of different shaping and arrangement, but it's basically the same logic.
- PAPeter Attia
And are there neurons, as the way you describe it, it sounds like a neuron might have mostly just serotonin. So when that neuron fires at the end of its synapse, serotonin is the only chemical that comes out. Is that, is that the case for neurons, that each one only can emit one neurochemical, so it's a largely binary signal? Or are there any neurons that can secrete more than one neurotransmitter?
- KDKarl Deisseroth
A relatively recent understanding has been that it, there, there are multiple neurotransmitters that can be released by the same neuron. We still refer, for example, to the dopamine neurons as dopamine neurons because that's what that, what's, that's what makes them special. That's what they can do that other neurons can't do. But what we've discovered recently, what the field has discovered recently is that dopamine neurons, some of them also release another neurotransmitter called glutamate, uh, which is an excitatory neurotransmitter. It stimulates the downstream cells. Other dopamine neurons can release, uh, a different one called GABA, which is an inhibitory neurotransmitter. It shuts down the, the cell that's receiving the signal. So there's actually a great deal of complexity, and that's not all. There are also other things that can be released at the same time, things we call neuropeptides, and there's a, a lot of complexity on the other side of the synapse too. Different cells have different receptors for the different chemicals that can do totally different things. You can have a, a receptor for glutamate that makes excitation happen, or you can have another receptor for glutamate that doesn't do that, but makes a, a longer pattern of modulation happen that's not even a direct excitation. So that's just a, a, just a flavor of the complexity. Uh, but broadly speaking, you'll see us still refer to things like dopamine and serotonin neurons because that's the first level of complexity.
- 48:05 – 52:30
Traditional techniques for identifying the brain regions involved in specific behaviors
- PAPeter Attia
So prior to the work that we're gonna get into here, what tools existed to really try to establish causality between the stimulation of one region of the brain and some sort of response, be it a phenotype or an impulse or... I mean, was there ever any way to imagine how one part of the hypothalamus was responsible for a type of thought or emotion? I mean, how, how, how was that probed?
- KDKarl Deisseroth
Yeah, this, this was a big challenge that neuroscience faced, which is, is finding out what actually, uh, matters for function. And, and what we did have, we had ways of listening in, we had, uh, ways of, of putting in electrodes to, to listen, uh, to pick up electrical patterns of activity. You can put an electrode in the cortex or in the hypothalamus or in the brain stem, and you can pick up the chatter of neurons as these little electrical impulses go by. And you could use the same electrode, you could also stimulate. You could send current in through this wire effectively that you've, that you've placed. Um, and yeah, that, that has an effect. And so you can, you can make things happen by just sending current into the brain. Uh, and at some level though, this is just a scaled down version of the electroconvulsive therapy we talked about, which is also just current being put into the brain. It causes things to happen, but there's no cell specificity. Every single neuron in the brain is electrical, and all parts of every neuron are electrical, not just the cell body itself that has the DNA in it, but also every part of the axon, every part of the dendrite, all electrical. And so if you send in current to a spot in the brain, even with a tiny electrode, you're affecting every single cell near the electrode, and not just that, every little bit of wiring that happens to be going through there. So there's no cell type specificity because every cell is electrical. And that's still though, there, there, there's work you can do. And so you can, you could stimulate a region of the brain and see if that causes something to happen in the animal. And there was a great deal of, of really foundational work in, in neuroscience going around and stimulating different parts of the brain. It was discovered that if you put an electrode in, in the parts of the brain where dopamine neurons live and where the axons come out, that, uh, rodents will really work hard for that. They, they like that, uh, it seems. Uh, we can infer that because they will, uh, press a lever thousands of times a day, uh, to get a burst of electricity to the dopamine neurons. And, and so that little clues like that are built up over, over time. But, but then there was always complexity. As we dove deeper into it, we realized, wait, this is not just the dopamine neurons. In this region of the brain, there are a lot of other cells and connections. So is it really the dopamine neurons? It's, it's this region, but what really are, are the cells? And so there was a lot of, um, uncertainty in the field as to which cells were actually doing, uh, what. And so we had that. We had, but, uh, and, but then there was not a good way to turn things off also. And so in, in science, we like to add things and see what happens, and that's testing whether something is sufficient to cause an effect, and we like doing that. That, that tells you something. But then we also like to take away, uh, something of interest, and we can see what, what is lost with that. And that's, that's called, you know, that's testing the necessity of something. How much is that needed? And so we would, we would've liked to turn off cells and say, "Okay, now what's different in the, in the animal and their behavior?" And there was not a great way of doing that. Crude ways, if you stimulate really hard with an electrode, you could effectively exhaust the cells and make them not fire anymore. And that was sort of the state-of-the-art, both clinically and research-wise in trying to create a local inhibition. But again, not cell type specific at all because all the cells are electrical. And that's the kind of situ- situation that, that we found ourselves in. Not too different clinically or basic, uh, you know, no cell type specificity.
- 52:30 – 1:04:50
Intro to optogenetics and how to get a gene into a neuron
- PAPeter Attia
So do you remember where you were, what you were doing the very first time you learned what a channel opsin was?
- KDKarl Deisseroth
So this is a, an interesting, uh, uh, uh, thread that the-- there are these, uh, plants that make... and, and small plants, in fact, single-celled plants that make, uh, channel rhodopsins. Uh, these are, uh, single proteins that live in the, that are placed in the, in the surface membrane of cells, but microbial cells, not, not in our cells, in, in algae, single-celled algae, and related molecules are present in ancient forms of bacteria. And these, these had been known to exist for years. Uh, and, and this class of, of protein is really interesting because they're light-activated electricity generators. Uh, these are single bits of biology, single biomolecules that do an amazing job. They receive a photon of light, and they move charged particles, ions across the surface of the cell. Now, there's a huge family of these. These are called the microbial opsins, and a subfamily of them is called the channel rhodopsins. Now, what's amazing is that these proteins were known broadly in biology, in biochemistry for decades. They'd been discovered in 1971, uh, by Dieter Oesterhelt and Walter Stöckenius, uh, who are at UCSF. And this was part of the training of, uh, biochemists, biologists in, in Lubert Stryer's beautiful biochemistry textbook. There's a page on the bacteria rhodopsins, and there's a-- this was-- that's, that's where I learned about it. Uh, you know, these, these proteins, uh, the, the-- they have a photo cycle it's called. They have a, a choreography of movements of the protein after the photon hits that lead to an ion, a charged particle moving across the membrane of the cell. So this, but th- th-- so this was, you know, a, a class of proteins that was, was well-known, uh, and, and it turned out that these microbial, uh, opsins turned out to be th- the key for, for optogenetics, the technology we developed that brought this cell type-specific, uh, causality, uh, that made it, uh, possible. Um...
- PAPeter Attia
Uh, I wanna understand this a bit more, Karl.
- KDKarl Deisseroth
Yeah.
- PAPeter Attia
How-- 'cause, so it sounds like, okay, 'cause I also had Lubert Stryer as a professor. I have his textbook. It's one of the few textbooks I've still kept. First of all, I don't remember that, so I mean, like, that might be a page in that book, but I was not paying attention during that lecture. So it's, it sounds to me like you knew about these even back in medical school. When did the idea come to you that said, "Wait a minute, I can now genetically insert these things into neurons and effectively put a digital switch into a single neuron"? How and when did that idea cross your mind?
- KDKarl Deisseroth
Yeah, so there was a coalition of, uh, a coalescence of different threads that happened, uh, that were partly plausibility threads. Um, and, and if you look at this, uh, historically, anybody in theory could have thought about this and tried this in, you know, in the late '80s or all through the '90s. These, these genes were known. Somebody could have put them into neurons and tried this, but it wasn't technically plausible for many reasons. There were not, until the '90s, and particularly the late '90s, there were not good ways of introducing genes into neurons. Neurons are a little bit, uh, tricky. They're very finicky and sensitive, and, and I knew this because this was, you know, it was, this was a theme in my, uh, PhD work and also in my postdoc work. You know, can we, uh, how can we get genes into, into neurons? Even in a, a cultured neuron preparation, it's not easy. And so that was, that was certainly part of it, part of why, I mean, why nobody had, had, had tried this before. But in the late, uh, '90s, uh, uh, that started to change and, and I did an experiment introducing, uh, genes into, into neurons as part of my postdoctoral work in the Malenka lab. That was in-- And so this was something I was, I was good at. I'd, I'd, uh, developed the, the viral tools and the ways of introducing genes in that were, that were plausible.
- PAPeter Attia
[lips smack] Tell, tell folks a little bit about how that works. Um-
- KDKarl Deisseroth
Yeah
- PAPeter Attia
... we're obviously, you know, these days, I think even the layperson is somewhat familiar with genetic modifications. People have some sense of how these have even been used to help develop vaccines and things like that. But, um, l- let's start from a place assuming people don't even really know the difference between DNA and RNA, and just explain how you could use this thing called a virus to do your bidding with respect to the-
- KDKarl Deisseroth
Yeah
- PAPeter Attia
... insertion of a foreign gene.
- KDKarl Deisseroth
So this is, and, uh, this is by no means, uh, a minor thing. In some ways, this is, this is the whole ball of wax, as we say. How do you get a gene into a neuron in a, in a specific way? So this is, the technological aspect of this in, in some ways is, is everything, and so it's definitely worth the time to, to talk about this. Um, you know, how do you, how do you do it? Well, so, uh, DNA is, is the instruction manual for making, uh, uh, proteins, uh, things like proteins, uh, biomolecules that have a job. Each gene is a bit of DNA. Uh, it might be, uh, a, a sequence of what we call nucleotides. They have A, G, C, and T. There's four kinds of them, and they come in different, uh, uh, sequences, and by the order in which these nucleotides appear, that is a code. That's the genetic code that dictates which protein will be made, a biomolecule that, that has a particular structure and, and a job that comes from its structure, like being in a channel or something in the surface of a, of a cell that receives a photon and lets, uh, charged particles go across. That's the protein. The instructions for making it are encoded in the, in the DNA, in the gene. Um, and so that, so how do you get that, that gene into a cell? Well, it's not so easy. Uh, you know, these days, um, uh, particularly with the, uh, coronavirus, uh, pandemic, I think the general public is, is much more aware now of how this, uh, can be done. Viruses, uh, and there are many kinds of viruses, they are, uh, little bits of biology that basically exist to get DNA and RNA, uh, into cells. And so they have a little bit of this genetic code material, DNA or RNA, and they have that encased in a coating that might have some lipids or fats and some proteins. And then that f- floats through, uh, uh, liquid, floats through the air, hits a cell, and fuses with the cell, gets the DNA or the RNA into the cell, and then that triggers the creation of new virus particles, and then that's how the virus, uh, spreads. So viruses are professional introducers of genetic material into cells. They are extremely good at that. They are evolved, uh, for that. Um, and this, this DNA-RNA distinction is, is interesting. Some viruses work with DNA. Some are RNA. What is RNA? This is also something that the coronavirus pandemic has brought to the public's, uh, uh, attention, uh, very recently. That's the, uh, step in between DNA and protein. It turns out, for various reasons, it's, it's useful to have an intermediate step. First, the DNA gets turned into RNA, very similar structure, but then that gets turned into the, the protein. Some viruses work with DNA, some with RNA. So this, it turns out, is, uh, then very useful for the biologist because if you want to get a gene into a cell, and, and, and in my case, suppose you want to get a gene for making a, uh, light-activated, uh, channel, if you want to get that into a cell, well, how do you do it? Well, you get the DNA into the cell, and what's the best way to do that? Well, uh, use a virus. And there are viruses that are dangerous and, uh, lethal, but there are also, uh, safer, weaker viruses. And then there are modified versions even of those that are, that, that, uh, virologists have engineered, uh, to be extremely safe, to have lost the ability to propagate from one cell to another, but can do that first step, can, uh, bring DNA into one set of cells, and then the life cycle, if you were, if you will, stops at that point. And those are the cell-- those are the viruses that, that, uh, that I had experience with from my, uh, uh, uh, postdoctoral work, uh, safe, modified, uh, viruses that can be used to shuttle bits of DNA in-into cells. And so that's the core, uh, technology. And again, this was a, a recent, uh, relatively recent thing, and particularly for neurons, uh, a pa- a relatively recent thing. It was-- the technology for doing that was not, uh, uh, so clear in, in the past. The other thing, though, I want to point out is that this, um, uh, the, there were, uh, many people, uh, who, who were thinking about this and trying this, and we did, uh, from my lab, publish the first paper that used a microbial opsin to get light sensitivity. But it was, as it turned out, uh, quite a, a, a close call. Uh, we published, uh, the paper from my lab in, in, uh, 2005, and that came out in the summer of 2005. Uh, within, uh, six months, uh, uh, several other papers came out. Uh, they all were submitted right after ours was, was published, and so clearly, uh, many people had been thinking about this. They saw our paper came out and then, then rushed to submit theirs. Um, and these were, these were big-time labs, uh, you know, people who, who were very respected and, and thoughtful, including, this is something I didn't know, but, but, uh, the, uh, brother of my PhD advisor. My PhD advisor was Dick Chen. His brother, Roger Chen, was a Nobel laureate, uh, uh, for his work with green fluorescent protein. Turned out he was also working on this, uh, as well. Uh, there's a-- I talked to him at great length about this. Of course, he did okay. He, he got a Nobel Prize for, for other work and, but this was-- all this was going on before his, his Nobel Prize, and so he was quite, uh, I think, frustrated that he wasn't able to get, uh, uh, uh, to this moment as, as quickly. So it was a, it was a sort of a, a broad, uh, uh, awareness in the field that the, the technology was now available. We could introduce, uh, genes into neurons, that these microbial opsins existed. People had wanted to get cell type specificity, uh, for a long time, um, with neurostimulation. Francis Crick of, uh, DNA, uh, double helix, uh, fame had been calling for this sort of technology for years. In fact, in 1999, he'd even suggested that not only did we need a way in neuroscience to control individual cells, individual cell types, but he said maybe light would be a good way of doing it. He didn't have an idea of how to do it, but he said, you know, light would have some good properties. It would be fast. It would be relatively non-invasive. Photons could scatter through, uh, tissue, and most neurons don't respond to light at baseline, unlike electricity, and so it would be a way of, of getting great specificity. So there was this, there was a, a, a broad, uh, awareness that this, this kind of thing suddenly might
- 1:04:50 – 1:19:41
How viruses helped make optogenetics possible
- KDKarl Deisseroth
be, might be possible.
- PAPeter Attia
I, I have two unrelated questions, Karl, about this. Uh, the first is, when you introduce the virus, is it one virus that can introduce the gene to one neuron, and that's it? But you said there's no replication capacity of the virus.
- KDKarl Deisseroth
That's right.
- PAPeter Attia
So does that mean that the dose of the virus you give determines how many cells will pick up the channel?
- KDKarl Deisseroth
Uh, that's correct. So you can give, uh, uh, a, uh, very high concentration of viral particles, and that will mean that you get more cells. Also, you'll get more copies per cell. You can have multiple-
- PAPeter Attia
Mm-hmm
- KDKarl Deisseroth
... viral particles, uh, infecting the same cell, and that is actually very important. Another big issue with these microbial opsins is they generate tiny currents. They're not as, uh, you know, professional at generating huge currents as mammalian ion channels are, which was a big reason why I think a lot of people didn't, uh, rush to this as well. People looked at those current sizes and said, "Nah, you know, this is not gonna work." Most existing methods of, of introducing genes, uh, gave you maybe one to seven copy numbers of the gene, as we say, so not, not enough to, to control a neuron, and that was a huge issue. But with the viral technologies, you could get hundreds or more copies of, of the gene per cell, and you could get, uh, much bigger currents with these microbial, uh, opsins. So then ag- there again, my experience with the viral tools was, was, was critical.
- PAPeter Attia
Uh, just give us a sense of the current. So when you talk about a normal mammalian neuron, how many do we measure these in picoamps, nanoamps?
- KDKarl Deisseroth
Yeah, picoamps and nanoamps are exactly right. So, uh, a, a typical-
- PAPeter Attia
An action potential is how many picoamps?
- KDKarl Deisseroth
Yeah. So, uh, a couple ways we, we, we can look at it. So the, so the action potential, this is this blip of electricity that, uh, propagates, uh, through the, uh, down the axon of a neuron. It can be triggered by, uh, signals that are in, are in the order of, uh, 100 to 200 picoamps. And then it becomes a, a voltage impulse that's about 100 millivolts, and that propagates down the cell. So if you're in the hundreds of picoamp range, you're, you're in business for, uh, controlling, uh, neurons.
- PAPeter Attia
A single opsin is capable of what?
- KDKarl Deisseroth
Um, vastly, uh, less than that. And so a, a couple issues come up. So first of all, what we, what we found is that, uh, if you don't have, um, a, a high copy number, the currents that you're generating are, are, uh, on the single or less, uh, picoamp level. We haven't done ... Because the currents are so small, y- you typically don't even do the experiment you're asking, the, uh, single channel, uh, current measurements. Since then, out of scientific curiosity, you know, we and others have looked at, at the, uh, at the currents that are generated, and they're, they're extraordinarily small. We only get, uh, the, to the hundreds of picoamp level by probably expressing, you know, 100,000, uh, uh, or to a million, uh, uh, opsins, uh, per cell. And so we're ... This, this was, uh, the, the key issue. There was many orders of magnitude, as we say, you know, 10, you know, several, uh, factors of 10 away, uh, from where we needed to be with these, uh, with these opsins, unless there was a way of, of, of introducing many genes and getting very robust, safe expression.
- PAPeter Attia
How do you introduce the virus? So let's just say we're talking about a mouse here, um, and you decide you want to test in this particular region of the pons, so a part of the brainstem. You, you want to exactly get it there. How do you direct the virus to exactly the cell you want to get this specificity?
- KDKarl Deisseroth
So this is, this is the other, uh, technological challenge that had to be faced. It was not obvious how this would be done. Uh, where would the specificity come from? Yes, uh, none of the cells respond to light. Yes, maybe we could add a gene that makes the cells respond to light. But wait, hang on a minute. Where is the specificity gonna come from? How do we get this gene only into the cells we're interested in? Well, all right, what could you do? You could concentrate the virus and do a very focal injection into, let's say, the pons. And so you could create a little hotspot of virus, uh, and then that virus would get into all the cells that are in and around the, uh, that spot in the pons. And that's, that's good. That gives you some spatial specificity. You're now at a, at a spot, and that is already a big leap beyond the electrode because the electrode and the virus both, so far in how I've described them, are not cell type specific. But the electrode is getting all the, was gonna be stimulating all the axons that happen to be going by. If you do a viral injection at one spot, viruses are not very good at getting into axons. They're just gonna get the cells, the little spherical cell bodies that live in that region. And so right away, that gives you some specificity. You're, you're getting less of the, the cross streams of activity being stimulated. But it's not enough because even if you're just getting the cells, the cell bodies that are there, there are many different kinds. There are the dopamine cells, but right next to them-
- PAPeter Attia
Mm-hmm
- KDKarl Deisseroth
... there are the GABA cells, and next to them are the glutamate cells, and, and they're all jumbled up together. And there you're not too different from the electrode. Now, if you put in light, you're still gonna be stimulating all these cells. And so what you need is a way to make the p- uh, production of the opsin cell type specific. Okay, so how are you gonna do that? Well, the virus, there, there were many possibilities we, we could think about, and this took probably ... Till we, till we really solved optogenetics probably took till 2009 because this was, this was the critical issue. Um, how do you get a, a versatile, generalizable way of targeting specific cell types? And back in 2004, 2005, there were some possibilities that we and others could imagine. You could try to imagine engineering the virus, uh, capsid, this coating of the virus that has proteins on it. There were theoretical ways and even possible practical ways of engineering capsid proteins so that they would only target one kind of cell because that kind of cell had-
- PAPeter Attia
Right
- KDKarl Deisseroth
... something else on its surface, and maybe we could create some kind of lock and key mechanism.
- PAPeter Attia
Yeah, so just like a coronavirus is, uh, its lock and key basically works through the ACE2 receptor.
- KDKarl Deisseroth
Yeah.
- PAPeter Attia
If you knew what a potential surface protein or receptor was on the dopamer- dopaminergic neuron, that could be your entry. That would've been the first thought that would've come to my naive mind.
- KDKarl Deisseroth
Yep. And, and that was plausible. Uh, uh, it could, could work. It had some, you know, some drawbacks, which are that you'd have to ... First of all, we didn't have that richness of understanding up ... It wasn't as if there was some lookup table. Okay.
- PAPeter Attia
[laughs] Right.
- KDKarl Deisseroth
Dopamine neuron has this, so then make, put this on that. That, that didn't exist, and still doesn't, honestly. So it was more just, okay, there's gonna be a lot of work. Every time you want to target a particular cell type, you're gonna have to now do some deep dive into all the proteins it expresses, uh, and also all the cells that are nearby that you don't want to target and make sure-
- PAPeter Attia
You're not crossing that
- KDKarl Deisseroth
... that whatever your strategy is-
- PAPeter Attia
Yep
- KDKarl Deisseroth
... is not, is not giving you some cross activity. And so we, you know, initially Plausible, and then as you start to think about it more, you're like, "Oh, this... I mean, this is, this is never gonna be versatile, generalizable, practical," and, and indeed, it still isn't today. So, so that wasn't it. Now, another strategy is that... is, is working with DNA. Uh, each, each gene, each bit of DNA in chromosomes, in genomes, uh, has this code for the protein, but also, near it, it's got another bit of DNA that's called a promoter or an enhancer, uh, and this is a bit of DNA that doesn't code for a protein. What it does is it attracts, uh, what are called, uh, transcription factors, things that decide whether that bit of DNA gets turned into RNA and then into protein. They, by changing the structure, by changing things around the gene, they determine whether this gene is expressed at all. It could sit there quiet and not make the RNA and the protein, or it could be active, make the RNA and the protein. Turns out, that is critical because that was a, a, a, a path forward. We could work with the bits of DNA near genes, promoters, and enhancers. This gave us some leverage, not all of it, but, but some of the leverage. And if you think about this, well, think about a dopamine neuron again. So what is a dopamine neuron? Well, it makes dopamine, and it releases dopamine. Okay. Now, how does it make dopamine? Well, it's got its own biomolecules that make dopamine. It's got enzymes that turn other precursor chemicals into dopamine. Now, those enzymes are made chiefly in dopamine neurons, and why are they only made in dopamine neurons and not in your big toe neuron? Well, it's because-
- PAPeter Attia
Or, or more importantly, not in the serotonoji- serotonergic neuron right next door. I mean, that's the key insight is-
- 1:19:41 – 1:27:02
How optogenetics was used to investigate the effects of dopamine neurons
- PAPeter Attia
So this was, this was very helpful, Karl. I think, you know, maybe for the listener, they thought, "Boy, these guys went into a lot of detail here," but I think this was really important because I think only now can we understand the magnitude of, A, what you and your team accomplished in what scientifically is considered a nanosecond. I mean, in four years that you were able to do everything you just said, and now we're in 2009, 2010, you have the capacity to introduce these opsins to very specific cells, such that you could say two neurons, which are different, I can put this gene into one and not the other. This is unparalleled. So you now have this capacity to use photons to turn neurons on and off with precision that could never be achieved anatomically, under anatomic resolution.
- KDKarl Deisseroth
That's right.
- PAPeter Attia
So what was the first question you sought to ask using this technology from a, from a neurobiology and neurochemical standpoint?
- KDKarl Deisseroth
Well, uh, you know, we, we've talked about dopamine a lot, and in 2009, there was a, an experiment that, that I and the whole field had, had wanted to, to, to know, which really is, is it the dopamine neurons, is their activity what, what animals are, are, uh, getting from this stimulation of that region? Or is it something else, some other cell type that's nearby? Is it the GABAergic or the serotonergic cells that are, we know are, are right nearby? And, and in 2009, we did that experiment. So we introduced, uh, a channelrhodopsin, an excitatory channelrhodopsin just into the dopamine neurons of this spot in, in, uh, the midbrain that's called the ventral tegmental area, or VTA. It's got all these other kinds of cells, but that's where the dopamine neurons also live. And we used a, a souped-up form of the promoter strategy I just told you about, um, to get the gene into the dopamine neurons, and we asked a very simple question. If you have a mouse and you give it a, a two-room house to live in, it's a very simple house, two rooms, and it can go back and forth from one room to the other.
- PAPeter Attia
So kind of just like a New York apartment.
- KDKarl Deisseroth
[laughs] Yeah. Yeah, on a good day.
- PAPeter Attia
[laughs]
- KDKarl Deisseroth
Yeah. Um, then what if you turned on the laser light, the light that activated the channelrhodopsins on the dopamine neurons, but you did that only when the animal was in one room and not the other room? And what we found is that if you did that, the animals preferred to be in the room where the laser light had been applied compared to the other room, which was equivalent in every other way. And that-
- PAPeter Attia
So, so this would be the analogy, just to... Sorry to interrupt, but just to make a really crude scenario, you could have done this experiment 100 years ago if you said, "I'm gonna put sugar water in one room and not in the other. Is there a preference that the animal has for it?" Presumably, it would always wanna go to the room with sugar water or cocaine or something pleasurable. But yet here you were able to do that without anything other than the excitation of a particular neuron.
- KDKarl Deisseroth
Exactly right. And, and in fact, this test is an old test. It's called the conditioned place preference test. And yeah, it's a, the animal now prefers a place. And, and it's because of its, uh, the, the conditioning is how it was done classically, just as you're saying. You would pair, uh, something good like cocaine or, or sugar or food or a social interaction, a mate, something like that, and you would see later that the mouse would choose to spend time in there, revealing to us by its behavior that this thing was positive in value to it. And you can do the flip side too. You can do a negative thing. You can make, make it feel mildly nauseous. You can give it lithium, which we give to, to patients too, and one side effect you can have is mild nausea. You can give a, a mouse, uh, mild nausea that way, it- but only in one room, and then it'll avoid that, that room, and that's conditioned place aversion. So the animal can report to us the, the sign, if you will, the, the valence, positive or negative, of its experience by where it chooses to spend time, and that's incredibly valuable. This hearkens back to, you know, the, my very first, you know, wanting to be a, a neurosurgeon because a human being could tell me what they were feeling. Well, of course, a human being is more eloquent, but behaviorally, a mouse can report whether it, it, something is of positive or negative, uh, value, uh, to it.
- PAPeter Attia
And, and that test, Karl, when you're looking for the positive valence, how... What's the frequency with which you would expect that to be the case? I mean, presumably it's more than 51/49 in favor of the dopamine firing. Just give us a sense of if you ran that experiment, uh, 100, or you ran a simulation of that experiment 100 times, h- and you always fired the, um, the dopaminergic neuron with your opsin, how many times out of 100 would it go to the positively valenced side?
- KDKarl Deisseroth
We try to keep things in... You, you can make this as extreme as you want, uh, a- and, and, uh, so the answer is a bit flexible. Uh- But w- with typical rewards, with sugar water, with a social interaction, peop- the sort of, the number you're looking for is, is sort of 70/30 or, or 80/20. Uh, that's kind of the level to which, uh, the mouse will prefer one chamber versus another, one room versus another in terms of how it devotes its time. But you can actually, you can make that... You know, you can push those numbers both optogenetically using light or with, with stimuli, uh, up or down, uh, by making the experience more extreme. Um, it's, it's quite a flexible test. And, and we had, we had later versions of this, you know, that, that in some ways the animal's expressing its, its, uh, subjective sense, we think, by where it's choosing to spend time. You can also make a more souped-up version of that test where the animal actually has to work to get the light by pressing a lever or poking its nose in a, in a, in a little hole, a nose poke, and trigger a pulse of light by each of its actions. So this is a, this is a, a, a slightly more advanced version where you say, "How hard will you work for light? How hard will you work for a, a precisely defined set of activity in your precisely defined dopamine neurons?" And, and if y- if you deliver, uh, light, you can get an animal to press a lever thousands of times a day, uh, to get that, that light. And so now there is, you know, no doubt that the activity of dopamine neurons, uh, in this way is, is positive, and it's not just positive, it can be extremely, uh, positive. Animals will work very, very hard to get
- 1:27:02 – 1:32:42
Appreciating the power of optogenetics
- KDKarl Deisseroth
it.
- PAPeter Attia
It, it, that's, it's just amazing that this could be done. Let's keep going. What... You know, I, I can only imagine how excited you and your colleagues were by this finding, and of course, it probably only whets your appetite for the breadth of questions that you now want to ask. Um, w- where was the clinical community in recognizing the value of this tool? So you have all of these questions that have for, I think it's safe to say, thousands of years been... I- in other words, even before the codification of, of, of medicine as we know it today, we've always wondered things like what regulates mood? How can two people anatomically be nearly identical and yet one be happy and one be sad? Where do memories reside? What is a memory? What is a feeling? What is a thought, right? All of these things. Y- and, and yet I, I suspect that this experiment, as simple as it was, for the first time gave you a profound sense of optimism that you now have a tool finally to ask questions. So you're splitting your time here, right? You're still an on-the-ward psychiatrist. So on the one hand, you're doing kind of the, the most cutting-edge science in the field, and at the other end, you're still trying to help people who are bringing these questions to your mind. How many of your colleagues in psychiatry, not necessarily your direct colleagues at Stanford, but just, I mean, the community more broadly, how appreciated was this tool 10 years ago?
- KDKarl Deisseroth
You know, it's, it's actually, uh, very interesting that you ask that. The appreciation in the, the scientific psychiatry, uh, realm, and these are, you know, clinicians, psychiatrists who also have some interest in, in the, the science side, the appreciation was very quick, uh, and immediate, um, because I think the psychiatrists know and knew, uh, better than anyone else how much specificity was, was needed and wanted in, in, in their field. And, you know, I had... This was, you know, by the time we got to 2009, the generality of that targeting method was, was key because then people knew, okay, this wasn't just a, a parlor trick, a one-off, you know, a demonstration that you could get some kind of photosensitivity in one cell once, that this was actually a generalizable, versatile method. You could apply this principle to, you know, any cell type. It was done in freely moving mammals, uh, you know, and mice, of course, being, you know, having our same brain structures, our cortex, our hypothalamus, our all, and everything in between. The significance and the opportunity was, was pretty clear to everyone by 2009, uh, particularly the, the, the psychiatrists. And so then there was a, there was a lot of, uh, a great deal of interest, and because the technique was, was generalizable, uh, it was very widely adopted. And we sent the, the, uh, the clones, the, the bits of DNA to thousands of labs around the world, and, and, and many thousands of discoveries were made by other labs, which was great after that, uh, uh, really showing that, that anybody could use it to tackle any question, any, any disease, any symptom, uh, in, in diverse animals. So after 2009, it was off and running. The, between '04 and, and '09, though, uh, that's, those were, those were hard times because we were still putting the pieces together, solving the light delivery, solving the virus, uh, issues, getting the cell type targeting to be generalizable and versatile. And I would say it wasn't really until 2009 that we could look at this and say, "Yeah, yeah, we've, we've, we've done it at this point." Um, so it-
- PAPeter Attia
Was this work funded by NIH?
- KDKarl Deisseroth
Yeah. So early on, I had, uh, I had some initial trouble, uh, getting grants, but then pretty quickly, uh, once, once the opportunity became, uh, clear, both the National Institute of Mental Health, uh, and the National Institute on Drug Abuse, uh, two main, uh, institutes of the NIH Uh, immediately, uh, were, were very supportive. And then later we got a, a great deal of support from, uh, DARPA and from the National Science Foundation and, and then also from a, from a number of private, uh, donors, people who in many cases came through s- the psychiatry setting, friends or family members who had suffered from a psychiatric disease, and they had heard about what we were doing and, and wanted to support it. So we ended up getting, uh, you know, both federal and, uh, nonprofit institutions and, and private donors, and it all came together. But it, but it... but, you know, until, really until we had things working in this generalizable way, uh, times were a little bit tough. [laughs]
- PAPeter Attia
Well, I mean, it, it is, it is again remarkable now as you sort of look back at it to think that, um, A, that it all worked out. Like, I mean, it is... there's 100 steps at which this could, that c- this could have failed. Um-
- KDKarl Deisseroth
That's right
- PAPeter Attia
... and again, I'm still amazed that it really o- only took four years, although I'm sure there were times in there it felt like it was taking forever, but-
- KDKarl Deisseroth
Yes. [laughs]
- PAPeter Attia
But I mean, as you know, as a... you're, you're such a historian of science as well, I mean, it is, it is a remarkable period of time.
- 1:32:42 – 1:45:12
Investigating and treating anxiety with optogenetics
- PAPeter Attia
Um, so, so let's talk about some of the other questions that you wanted to probe with, with this technology. So what about any of the other neurotransmitters or neurons in particular? Where, where, where did you turn to next?
- KDKarl Deisseroth
Well, we, uh, were particularly interested, you know, hearkening back to my, you know, what got me into psychiatry in the first place. You know, I, I wanted to understand internal states of mammals and how they can go wrong and, and create symptoms. And if you work with, with, uh, animal subjects, with mice, uh, for example, you have to figure out what they can report that, that, that matters. And one thing they can report very well, uh, are these universal things that all mammals experience: anxiety, uh, and, uh, social interaction, and caring for, for offspring, for young. These are quintessential mammalian states that matter. They can go wrong. Uh, and so I wanted to, to study them, and I wanted to study them in ways that were now precise and causal and had to do with specific cell types. And so one of the first things we did was anxiety. And, you know, as a psychiatrist, I, I specialize in patients who suffer from depression and also social difficulties, autism spectrum disorders. And a common theme in both autism and in depression, uh, anxiety is a big part of that. Uh, anxiety is not a small thing. Anxiety can be absolutely crushing to one's life, to one's interactions, to occupation, uh, to even being able to go out in the world. Um, this is a very potentially severe disorder in many people. Of course, anxiety, though, is also can exist in a normal healthy range, too. Uh, and it's only, it only becomes a psychiatric disorder when it exceeds that healthy range and verges into or in many people unfortunately goes way beyond into a, a very pathological extreme.
- PAPeter Attia
H- how do you define that maladaptive transformation from-
- KDKarl Deisseroth
Yeah
- PAPeter Attia
... uh, n- normal anxiety, which I, I suppose you could even make the case if a person was incapable of experiencing anxiety, they could probably injure themselves, and they might be socially quite destructive. So in other words, there must be some evolutionary basis for anxiety and self-preservation.
- KDKarl Deisseroth
Yes. Yes.
- PAPeter Attia
Uh, but as you point out, uh, I can't imagine anybody listening to this hasn't been personally experienced, uh, or hasn't personally experienced or known somebody who has experienced anxiety that has crossed too far. But, but it... I mean, is this something that falls into the DSM-5, where there's an actual criteria? Um, there must be, right?
- KDKarl Deisseroth
Yes. Yeah. Th- there are. And, and in fact, it's the s- it's... the, the criterion, uh, th- for rising to the level of disorder in, in the, in the psychiatric, uh, uh, literature and in the DSM-5 or, or, or Diagnostic and Statistical Manual, is that it's only a disorder if there's impairment in what we call social or occupational functioning. So you could have any symptom in psychiatry, even a hallucination, for example, but if it's not impairing your life, your social or occupational function, we don't call it a disorder. And in fact, I've had patients who, who were, who were hallucinating, but it was in a way that was not disrupting their life. I had a blind patient who had visual hallucinations, but he was, he was fine with them. They weren't, uh, distressing to him, and so we wouldn't say it's a disorder.
- PAPeter Attia
Mm.
- KDKarl Deisseroth
It's just something happening. So that's the criterion we use. And of course, it, it, uh, is somewhat, uh, you know, flexible because different people have different social and occupational situations. And, and this is a challenge we have in psychiatry, but maintaining that as a criterion is, is very good because it ensures that we only treat things that, that need to be treated. So that... then you think about anxiety. Well, if you can't function, if you can't leave your apartment, uh, to go to work, well, that's impairing your, your occupational functioning. And so that, that... there are people who have anxiety easily in that realm or far beyond, and those are people we, we want to help. On the flip side, as, as you point out, there are people who have i- risk-taking behavior that's extreme because they don't perceive or, or worry about threat, and, and that's also a problem. So anxiety, we, we need to, to, to To treat it in patients who are severely affected. And the problem is, in anxiety, there are, uh, medications that help, but they come with, uh, some problems. So the most effective anti-anxiety medications are things that relate to, you know, uh, Valium and Xanax and, and Ativan. As you know, these are m- medications that work, uh, but they can be addictive. They can, uh, cause the human being to adapt to the dose and to, to make it very difficult to stop them. Um, and they also can cause-
- PAPeter Attia
And these, do these work... Do, do we think that they primarily work through their GABA agonism? Is that the-
- KDKarl Deisseroth
Yes. That's right
- PAPeter Attia
... primary belief?
- KDKarl Deisseroth
Yeah.
- PAPeter Attia
So they, they... You, you talked about GABA earlier. This is a relaxing, uh, for lack of a better word, uh, neuro- neurotransmitter. This is a non-excitatory.
- KDKarl Deisseroth
That's right. That's right. And that's exactly how these act. They, they act, in fact, directly on the GABA, uh, uh, receptor, and they facilitate its, its action. And so this is, um... But they, they work. They're just, they just have some, some problems, and not everybody can tolerate them. They cause some cognitive slowing and sedation and, and so on. It's like they're have some issues.
- PAPeter Attia
And which neurons in particular do we think that they're concentrated in their action in?
- KDKarl Deisseroth
That is a great question. It's s- subject of a lot of research. If we understood that deeply, then we could make a separate intervention targeted to those cells. The problem is that we don't yet know that exactly. We don't know exactly which cells are the most anxiety-relevant cells that these, these medications are, are targeting. Um, there are some, some hints, but I would say not factually known yet, so. But, but you're getting to this key point where optogenetics was helpful because then we could ask that and answer that question. We could say, "Okay, which cells govern the different, uh, features of anxiety?" And then, now, what am I talking about here with different features? Well, actually, this is kind of interesting when you think about it. So what is anxiety? Well, it's actually got different parts to it. First of all, there's physiology. We've all been anxious. We know heart beating faster, breathing faster, okay? So there's physiology that changes. Then there's also a behavioral change. We, when we're anxious, we avoid the risky situation. We have an impulse to, to avoid. If we're, if we're anxious out in the open, we avoid going out in the open, and mice do this, do this too. And then finally, there's a negative quality to it, which may sound trivial.
- PAPeter Attia
This is, this is the negative valence. This is the hardest part-
- KDKarl Deisseroth
This is the negative valence
- PAPeter Attia
... to put your finger on.
- KDKarl Deisseroth
This is the hardest part to put your finger on, and it's the most mysterious and kind of seems-
- PAPeter Attia
Perhaps the most difficult.
- KDKarl Deisseroth
I think it's the most difficult
- PAPeter Attia
Meaning perhaps the most difficult to experience.
- KDKarl Deisseroth
It's the most difficult to experience, and it's also the most difficult to understand why we have this. If, if we're already avoiding the risky situation, why does nature also have to make us feel bad?
- PAPeter Attia
Mm-hmm.
- KDKarl Deisseroth
And, and this is... There are some very interesting evolutionary, uh, uh, discussions one can have about that. The fact is, though, that's, that's how it is. Anxiety feels bad, and that's what makes it, uh, in many cases, so, so clinically, uh, uh, causes so much suffering in addition to the behavioral dysfunction that happens. So actually, anxiety is complicated. It's got these different parts, and they all come on together and all go away together. And then you've got to ask, okay, these, these are so different, they're probably controlled by different cells, right? So you've got behavior, and you've got breathing, and you've got inner subjective sense. These are all very different. Probably different cells are doing it. So then right away you've got to ask, "Well, what are we gonna target?" And so we, we thought we, we need to figure out this. And so we used... In 2013, we did a, an optogenetics experiment that targeted, uh, different, uh, parts of what we thought could be the anxiety pathway, and we found that indeed different cells control each of these different parts. There's a set of cells that control the breathing changes, and there's another set of cells right nearby that control the behavioral changes, avoiding risky situations. And there's yet a third set of cells-
- PAPeter Attia
Hmm
- KDKarl Deisseroth
... that control the negative valence, the internal state. Each cleanly controls a separate feature of anxiety, and we did this with optogenetics i- introducing light sensitivity.
- 1:45:12 – 1:52:41
Autism and autism-related anxiety, and the potential of optogenetics in treating autism
- PAPeter Attia
Why does anxiety track so closely in people with autism? Have you been able to glean any insights into that? Um-
- KDKarl Deisseroth
Yeah
- PAPeter Attia
... and, and, and, you know, autism is, is something that interests me immensely. What, what do we really understand about this disease? Uh, I think we know that it's, it's got a significant genetic component. It's not entirely clear what triggers it. Um, but, you know, it's ... And its phenotype, of course, exists on a pretty extreme spectrum in terms of functionality, um-
- KDKarl Deisseroth
Yeah
- PAPeter Attia
... superpowers and super deficits. Uh, but what, what do we know about autism? And, and then specifically, why is it that anxiety tracks so closely in people with it?
- KDKarl Deisseroth
This, autism is, is one of my main clinical focus areas. This is actually my clinic office here. I see, I see patients with, with autism, uh, spectrum disorders here. I know that they are hard to treat. There's not a medication that, that treats autism, but as you say, a lot of them are very anxious, and, and that I can help with. I can help them, uh, uh, with, with their anxiety with medications, uh, like, uh, the benzodiazepine class of medications that we talked about. Those help the anxiety. They don't help the social problems per se, but they help with the anxiety. And, and why is that? Why are these, these patients with autism so, uh, why did, why is anxiety such a comorbid symptom, as we say? Why does it show up so much in autism? Well, the, the human social interaction world is very, uh, complicated. It's very fraught with possibilities for misunderstanding, catastrophic errors of interpretation, embarrassment, uh, humiliation, confusion. We have a, a very social world that we've created, and people who have difficulty with keeping up with the fast rate of, of social information and making sense of it, it's a very anxiety-provoking situation. H- how ... When you're talking to somebody, how do you know where to look, what to do? How do you ... What part of them do you pay attention to? Do you look at their eyes? Do you look at their mouth? Do you look at their body movements? God forbid there's more than one person. In a conversation with three people, how do you know who to look at? How do people know what to say next? To someone on the autism spectrum, these are extremely challenging situations because it's, it's very hard to, to keep up with this, uh, high information rate of, of the social interaction, and this is something in the book, uh, Projections, that, uh, we- we've talked about. There's a whole chapter, a story on autism and on, on how this might happen, uh, neurobiologically, how this information overload might happen. We have patients who are as confused by social interaction and, and as overwhelmed by it as you can imagine, uh, you know, somebody not knowing the language, not knowing the customs of, of a culture and being, uh, placed into a, uh, while extremely consequential things involving them were happening in, in real time, and that's kind of the situation. So you can understand anxiety being a big part of, of, of autism, just being unable to predict what happens. And so these are, these are, uh, patients who we can help with their anxiety, still not yet with their autism. The genes that are linked to autism, there are many. It's a very genetically, uh, determined disease, not completely, but heavily genetically. The problem is, like so many of the psychiatric disorders, the genetic underpinnings, it's a patchwork. It's many different genes that all contribute a little bit in most cases. And so with all the beautiful genetics, which has given us a lot of insight, it hasn't led to treatments because there's not a single gene, single protein, single cell to intervene in yet.
- PAPeter Attia
Are you optimistic that that's going to change? I mean, what does, what does the treatment for someone with autism look like in the coming decade? Let's, let's keep it relatively short term.
- KDKarl Deisseroth
Well, the exciting thing is, is, is optogenetics has given us a window now i- uh, into what could be this sort of 10-year timescale of, of, of autism, uh, treatment. Because now, and again, mice are, are social. Not only do they parent, but they're also social. They will choose to spend time with another Even same-sex member of their species compared to being alone. Uh, and they have complex interactions. They have a give and take. They exchange information, and there's a lot of it. And if you make mutations in some of the genes that are most, uh, powerfully related to autism that come from the human literature, you can make mice that have impaired social interaction as well. And we've done this, and we've studied these in the laboratory, and we've asked, "Can we correct the social deficit of these mice?" And we can. And this is a whole thread of work in, in my laboratory studying social interaction and asking which cells, which circuits in the brain can improve social interaction, including in these autism mutation, uh, mice. And what's pretty interesting is that, you know, if you think about social interaction, just like everything else, and, and the parenting example made that clear, there are different parts to it. Part of a, a social interaction might be the motivation, the drive to be social, and that could vary in people. Also, the cognition, the understanding, the, the insight, that could be separate. That's another part of, of being social is understanding what the heck's going on. And probably different cells affect each of these, and indeed, we found that. So some... There are some dopamine neurons for, that do seem to increase the drive for social interaction. But then there are other cells in the front of the brain, some, where some of the most advanced complex cognitions happen, the frontal cortex, that may be more involved in the information fire hose that's, that's coming through with a social interaction. How do you keep up with it? How do you make sense of it? That may be more of the cognitive side. And so just like everything else, you gotta figure out which, what's most important, and we, we found those though. We now know the cells that can, uh, improve social interaction in, in these different areas. And now that we understand these cells better, you could imagine designing medications that, for the first time, are aligned with a specific kind of cell that's known, known to be important in social interaction, and that's the exciting opportunity for the future. Uh, we're not there yet, but at least now we have a causal cellular understanding, and that opens so many doors.
- 1:52:41 – 1:55:59
Optogenetics as a powerful tool for the discovery and creation of medical treatments
- PAPeter Attia
I- is it your belief, Karl, that at least in the next decade or so, optogenetics will be the tool for establishing cellular, uh, signal-wise causality, uh, but not be the mode of treatment? In other words, d- you know, I'm sure people ask you this all the time. I, I certainly have a, a, a thought on this, but I, I, I thought it's worth asking just to make sure everyone's on the same page. Is it your belief that patients are gonna be coming into your clinic with, you know, probes that w- you will be lighting directly to actually change the neurotransmitters via the light? Or is it that we'll just use that as the tool to establish where to target our treatments? Or do you think it's gonna be a combination of these?
- KDKarl Deisseroth
Optogenetics i- in my view is, is by far the most important aspect of it is it's a discovery and understanding tool. This helps us because this brings so much that we didn't have before. Understanding what actually matters, what makes things happen in the brain at the level of cells is the opportunity that, that optogenetics creates, and, and that understanding then opens the door to every kind of treatment. Once you understand that, which cells are actually causing and relieving symptoms, you can design medications that address those cells. You can design brain stimulation treatments targeted to those cells or their axons as they, uh, project across the brain. So it opens up every door, uh, uh, in principle, uh, under s- h- providing this, this causal, uh, foundation. Now, n- now that said, and so that I see is by far the future. It's, it's the understanding that opens every treatment door. That said, uh, my friend and colleague, uh, Botond Roska in Switzerland just this year was able to confer, uh, a form of sight onto a blind person with optogenetics, and this was just published in the journal Nature Medicine, uh, this year. 10 years ago, he and I, uh, you know, had collaborated on a study where he put, uh, one of our microbial opsins into a human retina, cadaveric, after life, so it was a... He, he had ways of keeping the retina alive, uh, for some time in, in these donated, uh, retinas. And he was able to show optogenetics worked perfectly well to control human retinal neurons. And he spent the next 10 years doing all... going through all the, the hoops of, of, you know, going through primate studies and then clinical trials, and then just this year, he, he focused on retinal... He's a vision scientist, and he focused on retinal degeneration and was able to take a human being who was blind from retinal degeneration, and, and he was able to create light sensitivity so this person could accurately reach for objects on a table that was not, uh, possible before. So literally, you know, making a, a blind person, uh, uh, see, at least to some extent, uh, uh, can happen. So I, I think there may be cases like that, uh, and they're... of course, they're uplifting to s- to see. Uh, but the biggest picture is that it's a, it's an, it's a, it's a discovery, uh, tool.
- 1:55:59 – 2:01:44
Karl’s inspiration to write his book, Projections
- PAPeter Attia
I want to pivot a minute to talk about your your book because I think it becomes a great place for us to now talk about some of the, the mental illnesses that people will be familiar with. Depression, uh, mania and its sort of cousin, bipolar disorder, eating disorders, all of these things that you've written about so eloquently. Um, first of all, I wanna tell you that if I'm not already in complete awe of your scientific achievements, um, I'm equally in awe of your writing achievements, and I just don't think it's fair that one person can be so gifted on two dimensions, Karl. It's really disappointing, and I hope there's something in life that you're horrible at so that I don't feel even worse about myself. No, seriously, your book is unbelievable. Um, it's called Projections, and I've read it twice.
- KDKarl Deisseroth
Wow.
- PAPeter Attia
Um, and I will encourage every listener to read it because, um, well, it, it will shatter some of the images people have of scientists because you don't write like a scientist. Right? So, and I say that as somebody who's in the process of sort of finishing up their book, and, um, the biggest challenge I have in writing is making it accessible to everybody, making it interesting enough that someone for whom this is not their life wants to read it. Um, y- y- you've done that in spades. This really reads like, at times, poetry. Um, I know you've always had an interest in writing. Uh, did it require much effort and discipline to write about such technical matters at times, but also to write about, you know, sort of the clinical conditions, uh, these psychiatric conditions that everybody's familiar with? Um, y- y- it seemed effortless that you were able to do this in, in such an easily accessible and artistic way.
- KDKarl Deisseroth
Well, first of all, thank you, uh, Pete. It's, it's, uh, it means so much to hear that. I, I, uh, you never really know when you, when you take a step like this or a risk like this if it's really working, and it... This was a, this was a, a risk. This was something that, uh, was very different. It's not what people expected. As you say, not a typical, uh, scientific, uh, text at all, really. Uh, and, and the goal I wanted, though, the goal I had was to help everybody in the world, all, what- whatever their background, I wanted to help them understand and feel what these, these altered states are, and that's such a, a big part of the, the book is to, is to work with that feeling to help people understand and, and feel for themselves what mania might be like, or what the fragmentation of schizophrenia might be like, or the, the, the crushing, you know, pathological, uh, grief of, of, of, of bereavement or the, you know, the in- incredibly, uh, complex states of eating disorders where you have these, uh, astonishing, uh, behavioral patterns that seem so, uh, you know, inexplicable, uh, uh, compared to what you would think would be, uh, what we were evolved, uh, to do. And so everything from these uplifting, exuberant states of mania to the, to the depths, I wanted people to feel this, and so I had to do this with the writing, with the words. I wanted to do it with the writing and the words. And so in each chapter, you know, the, the writing is adapted to cause that, that, that feeling. In the, in the mania story, the, the words are, uh, exuberant, uh, in the way that, that mania is. In the, in the schizophrenia or psychosis story, uh, there's a fragmentation, uh, and a, and a, a disorganization that happens. And so i- in all these cases, I, I, I, I had to work with, with words in ways that are not typical for a, for a scientist, and... But of course, I wanted to do it. This was my initial, uh, passion in life, and for me, it was incredibly fulfilling actually to come back and be able to do this. I'd always wanted to do it. I had now not just the desire, but I had a mission. I had, I had something I wanted to, to tell, I wanted to share with everybody. And so for me, it was incredibly addictive actually. I would, uh, I, I spent... You know, I, I did the bulk of the writing over a couple years from, you know, 2017 to 2019 or so and, and then wrapped it up in 2020, and it was, uh, it... I looked forward to this so much every day. I, I would block out a couple hours, um, but a different time each day depending on my schedule. You know, life's complex now. I've got, you know, five total kids. Things are hopping at home. Um, you know, uh, my wife Michelle's an incredibly accomplished, uh, uh, MD PhD herself, also running a clinical trial.
- PAPeter Attia
Also one of our classmates.
- KDKarl Deisseroth
Also one of our classmates, and of course, she's in the hospital a lot, and so no day is, is simple or predictable. Uh, and so that, the writing time would be at different times, often very late at night, often early in the morning. I tried to block out two hours, but I would find I would look forward to that like, like almost nothing else. And I would... I, I just relished the joy of finding the right word and spending days thinking about trying to find the right turn of phrase. And so it was, it was in- incredibly, uh, uh, uplifting honestly, uh, even though, uh, of course, a big challenge logistically.
- PAPeter Attia
One of the things
- 2:01:44 – 2:13:50
Mania and bipolar disorder: evolutionary basis, symptoms, and the high prevalence in North America
- PAPeter Attia
I love about the book is how you really try to dive into the evolutionary basis for mental illness. This is something I'm always obsessed with. I always love trying to think about things through an evolutionary lens and, and sometimes, you know, the answers come a little easier than others. Um, One of the places where it comes up is in the story of Alexander. This is a gentleman, uh, won't give away the entire story, but basically post 9/11 is triggered into what sounds like his first manic event, correct?
- KDKarl Deisseroth
That's right. Mm-hmm. That's right.
- PAPeter Attia
Which then gets into kind of this discussion of mania. What is mania? Uh, one of the things I found very interesting about this was the discussion about the evolutionary basis for mania. Um, and, and this is interesting to me personally because, you know, this is a very personal story I guess, but when I was in residency, um, I was encouraged, uh, by my wife actually to see a psychiatrist. She had some concern about, um, some of my behaviors. [smacks lips] And the psychiatrist, after one day, uh, I don't know if she was right or wrong, um, but she decided I was hypomanic. That was her diagnosis. Um, and that of course got me very interested in, well, why is this the case? How does she know? What... Why would this be? And, and I began sort of examining everything I'd ever done in life and, and one of the things I came across was at the time, uh, it was a psychiatrist at Hopkins, so this would've been kind of 2004, 2005, had written a book suggesting that the prevalence of hypomania in North America was higher than anywhere else in the world because it had the highest concentration of recent immigrants. [smacks lips] And the argument was, well, by definition if you have a collection of people who are one to five generations away from people who had basically the nerve to leave a comfortable life elsewhere, and in the case of certainly my parents and many people who came here, basically to come to nothing. You don't know the language, you don't know the culture, you don't know the people, um, it wouldn't be surprising that you could concentrate hypomania here. Uh, A, I'm curious as to whether you have any thoughts about that theory, but perhaps more importantly, let's dive into this evolutionary basis for mania because the, the point that you get into about how there are some times wherein traits are very valuable at the population level and not at the individual level, I found that ver- I found that fascinating.
- KDKarl Deisseroth
Well, first of all, that's a very interesting, uh, uh, uh, route into this, this discussion, uh, which is the, the, uh, immigrants, the, the recent immigrants and the, uh, possible, you know, genetic, uh, link. To have the, you know, in recent times to have the get up and go, to leave, uh, to take the risks, to have the energy, uh, to have the motivation to, and, uh, to, to, to actually make it happen, to sustain it, this complex goal with, with so many, uh, possible downsides, that's, that's no small thing. Some people wouldn't wanna do it, some would. And mania is, it's one of the poles of bipolar disorder, uh, which is a very genetic, highly genetic, uh, disorder, one of the most in, in psychiatry, bipolar type 1 disorder, uh, extraordinarily genetically determined. And, and what is it? Well, it's got these two poles-
- PAPeter Attia
And sorry, just to be clear, Karl, does that mean that bipolar stems from bipolar or it just clusters with other psychiatric illness? So in other words, uh, schizophrenia or, uh, significant depression would also be genetic precursors to it.
- KDKarl Deisseroth
What it means in this case is that it's, uh, if you look at, uh, monozygotic twins, uh, especially those that are, are raised apart, that's where the most, uh, re- uh, you know, pure information comes from. You can look at the concordance of, of, uh, m- mania or bipolar disorder appearing in each of these twins-
- PAPeter Attia
And how high is it?
- KDKarl Deisseroth
... uh, identical twins. Uh, it's more than 50%, uh, for bipolar type 1, act- in fact verging above, uh, 70%.
- PAPeter Attia
Wow.
- KDKarl Deisseroth
And so you have a, a very strong, uh, bipolar type 1 genetic determination. So first of all-
- PAPeter Attia
And, and just out of curiosity, what is it for autism in that same setting?
- KDKarl Deisseroth
Autism, also high. Um, just maybe just a touch under that.
- PAPeter Attia
Okay.
- KDKarl Deisseroth
Um, with depression it's like 50%. Uh, and so, uh, most of the psychiatric disorders have, uh, strong genetic links. They tend to be less than 80%, um, uh, but, but in this kind of 50 to 80% range-
- PAPeter Attia
Wow
- KDKarl Deisseroth
... for many of the, the severe ones, uh, from depression to schizophrenia, uh, to autism, to, to bipolar. And so this is something we, we face in, in schizophrenia, uh, and, and in autism, uh, and in... But in bipolar it's, it's, it's extremely strong. So right away we know there's that link. And mania is the positive pole of, of, of bipolar disorder. The other pole is depression. People with bipolar, uh, type 1 have had at least one manic episode where they've have a period of time, could be a week, uh, where they've had this very clear discrete state of elevated mood, increased goal-directed activity, projects, plans, spending, taking risks, faster speech, not needing sleep, truly not needing, uh, sleep, not, not nearly as much. Um, uh, and you know, honestly even though this causes problems, and serious problems, and, and not to sugarcoat it at all, mania can do terrible things. People make very poor decisions. They, it can be fatal.
- PAPeter Attia
Are... Yeah, I was just gonna say, aren't people even slightly more likely to harm themselves during a manic phase than in a depressive phase?
- KDKarl Deisseroth
Yes, or the transition from out of depression to, to mania, that's actually probably the most risky time-
- PAPeter Attia
Mm
- KDKarl Deisseroth
... when they, they may still ha- might still have some of the negativity from the depression, but now they've got the-
- PAPeter Attia
They have the energy to act.
- KDKarl Deisseroth
Energy. Yeah.
- PAPeter Attia
Yeah.
- KDKarl Deisseroth
Yeah, exactly. Um, and so that, not, not to say there's, you know, it's a, it's a problem, but, but yet at the same time, you know, some of my most memorable experiences in talking with manic patients is I actually love talking to them because there's such a, a charge of, of energy, anything's possible, they're, they're funny, they're warm, they're, they're charismatic. Uh, and it's, and it's so easy to see that this is a, this is a state that's, it's not a bunch of random things happening in the brain. This is a, a coherent state of elevated mood. It's consistent. You see it in one patient and you see it in another patient. It's something that's, that's there that, that human beings have as something they can do, a sustained state of elevated mood and energy. And, and you look at that and you think, "Okay." You know, why? And, and also, uh, you know, what does that mean for treatment? Is there an ethical issue with, with treatment? Is there, are there cases where mania is, is positive? And, and this is something that the story in the book, in Projections, really made me think, uh, so hard about. This was, this was actually when the seed for the book was first planted in, in my head. It was just 20 years ago, um, right after 9-11, and this patient, Alexander, he had never had a, a, any psychiatric illness at all, nor in his family. And, but he was flipped into a completely classic full-blown mania after 9-11. He had no particular connection. He was, in fact, he was on a, a, a sailing, uh, trip in the Mediterranean with his, with his wife at the time, came back home after 9-11. Um, and, and a couple weeks later, uh, he was manic. All these symptoms that we talked about, and it was a huge problem. Um, he was... But his, but he, he had this appropriate or at least, uh, aligned quality to his symptoms. He, he, he wanted to, he was, you know, he was retirement age, but he was training himself, uh, to go into battle. He was rappelling down trees. He was running through the night. He was, he was reading about military strategy. And, and then it verged into this, you know, uh, uh, very difficult, uh, emotionally challenging. He was screaming. He was hyper-religious. He, everything had become, uh, uh, quite, uh, extreme and incompatible with, with his life. And so that ended up bringing, bringing him to the, to the hospital. But, you know, looking at this and we think, okay, this is, this is a state of elevated mood and energy. It was triggered by context. And this is actually the flip side of what you're saying with the, with the immigrants. Not only is there likely to be a, a set of conditions that led to these people being able to take, have the energy and willingness to take the, the risk and, and meet all the incredible challenges of, of moving across countries and, and cultures. But then, you know, that, that's a sus- that, that's not, that's not this fight or flight response of a minute when you've got a threat and you have to, you have energy and then you meet the threat and then it's gone. We're talking about you need a sustained level of energy for weeks, months, years even, and to take a, to, to take a, a risk and a, and a life shift like that. And so, you know, this is, everything is on a spectrum and you've got mania and then you've got this hypomanic state in between that makes a lot of sense that, that people who are able to sustain this elevated energy, uh, state are, are those that would, uh, be, be our immigrants. And it's a, it's a, a- and again, you have to look at this and think it's a spectrum. There definitely it can be bad, but we have to value the whole spectrum and understand the whole spectrum as part of who we are as, as the human family.
- PAPeter Attia
W- why do you think that in the bipolar condition you have this pairing of such opposites? Is the depression a necessary part of bipolar to basically allow the recharging after, you know, this unbelievable discharge of emotional and physical energy? Uh, because otherwise I, it doesn't seem like these would... You know, like for example, why doesn't it just go normal affect, mania, normal affect, mania?
- KDKarl Deisseroth
That's a great question. Uh, we don't have the answer. Some people, uh, some fortunate people are like that. There are, you can get a diagnosis of bipolar disorder without ever having a depression. One, one episode of mania, uh, gets you that diagnosis, uh, of bipolar type one. And those people, there are people who, who haven't hit a major depression, uh, yet. Um, that said, uh, uh, most of the time there is, there is that other pole of, of the disorder. And, and what is it? Is it, we don't know. Short answer is we don't know. But a lot of interesting ideas. One could be, uh, sort of aligned with what you're saying, that there's some resource that's, that's exhausted. Uh, is it, you know, it's not a resource that we know what it is. Uh, we can't point to it. Is it a neural circuit, uh, you know, state of some kind? Uh, uh, a capability of a neural circuit that can become exhausted. We know neurons can run out of, uh, energy. This is part of how the brain stimulation to cause inhibition works, but that's all on a very fast timescale.
- PAPeter Attia
Right.
- KDKarl Deisseroth
You can exhaust neurons on seconds to minutes. It's not known what really could get exhausted on the weeks, uh, scale. We don't know what that would be. Or maybe it's a, it's a, it's the, it's the termination mechanism, but it just overshoots.
- PAPeter Attia
Mm.
- KDKarl Deisseroth
Uh, or maybe it's just that what's lost is a, the homeostatic thing that keeps energy in a, in a tight range, and then it, it could go in either, either direction because you've lost some, some brake that's, that's present on either side. Not known, but a very interesting question.
- 2:13:50 – 2:31:03
Depression: evolutionary basis and insights from optogenetics
- PAPeter Attia
What is technically the most common, uh, psychiatric disorder? Is it depression?
- KDKarl Deisseroth
Actually, the anxiety disorders, if you, if you group them together, anxiety is the most common, and, and that is, um, but depression is, is, is certainly up there. That's, that's, that's, uh, uh, in, in the top group for sure. Uh, anxiety disorders are so underappreciated. A lot of people don't talk about them. Um, uh, a lot of people can make it through the day with anxiety, even if they're suffering, uh, terribly. So yeah, anxiety is most common.
- PAPeter Attia
What has optogenetics taught us about depression?
- KDKarl Deisseroth
So this, you know, this is my clinical specialty. I have, you know, right here in this office, I have, you know, we do, uh I do vagus nerve stimulation, uh, for example. This is a, a VNS therapy, a radio frequency controller. Uh, we have, uh, we still do here electroconvulsive therapy. We do transcranial magnetic stimulation. Clinically, though, we're looking for guidance from the, the science because it's still not known clinically what actually is going wrong in depression. We don't actually know that, uh, in a way that can guide therapies in the way that we'd like. And what's the, what's the scientific situation? Well, optogenetics has helped quite a bit because... And again, picking up on this theme, of course, there's different parts to depression, and this is how we diagnose it. We ask about all these different parts. There's depressed mood, and that's this negative state, okay? There's hopelessness, so it's kind of the opposite of mania. A mania- manic person thinks anything's possible. Depressed person thinks nothing's possible. There's, there's a deep discounting of the value of effort, and this come... this shows up as hopelessness. This even can lead to suicidality and certainly severe social and occupational dysfunction. And then there are other parts to depression. There's something called anhedonia, which is really interesting. This is the absence of pleasure.
- PAPeter Attia
Yeah, this is perhaps the most insidious component of depression by far.
- KDKarl Deisseroth
Right. Right. And it's, it's, it's not commonly known. You don't... People on the street don't talk about, uh, anhedonia, right? It's... They'll, they'll say they're depressed, but nobody talks about their, their anhedonia. But it's, it's an incredibly important symptom. It's a, a core, such a core symptom of depression that actually you can get a diagnosis of major depressive disorder without depressed mood if you also have anhedonia. It's that important. And it's the absence of pleasure or joy from things that normally bring pleasure or joy. And, and we've all had a cold, and we've known that taste is gone. The food has lost all, all joy. It's things even without the cold, with the, with the anhedonia of depression, all the joy of food or social interaction or, you know, your children, your grandchildren, uh, you know, a book, a movie, all the joy of life is, is, is gone. And this is a, it's a horrific thing. It, it leads, you know, to very serious problems, and that's a, that's something that optogenetics has helped us understand.
- PAPeter Attia
What, what do we know about that? Yeah, t- where, where, where do the neurons reside, and what are the neurotransmitters involved in the propagation of anhedonia?
- KDKarl Deisseroth
So, so again, you might say, "How are you gonna test this?" And, and you can, you can set up very simple behaviors with, with animals that, that provide some insight. Uh, first of all, uh, you could provide a simple choice for animals. Mice, like us, like sugary drinks, and you could give the animal a choice of a sugary drink or just water, and normally, a mouse will prefer, kind of like we do, they'll prefer the sugary drink and, and by a factor of, you know, two to one or, or more. Uh, but a mouse that's been stressed, uh, it's had some unpredictable events happen, um, it's had its sleep disrupted, um, it will not prefer the sugar water nearly as much. Uh, it won't care as much. And so such an interesting thing, given all the evolutionary importance of a small, high metabolic rate mammal needing sugar, and we know the reward that we feel from, from sugar and presume it's very similar for them, and then not caring, sugar water, regular water.
- PAPeter Attia
So in other words, if you had them going 50/50 between sugar water and regular water, that would be even more telling than if they disproportionately went to the regular water, right? You would be looking for a complete amelioration of the effect of the sugar water would suggest that they have basically lost interest.
- KDKarl Deisseroth
That's right. That's exactly right. And that, in fact, happens. And so, so we, we and others have explored this, this kind of thing with, with optogenetics, and we've found that there are, uh, you know, pathways, a- and coming back again to the, to the dopamine neurons, which are tightly linked to mood and mania and depression. These... But they're a complex set of cells. Some send connections to one part of the brain. Some send connections to another part of the brain. Uh, we have found some interesting, uh, pathways that relate to those dopamine neurons where you can actually, uh, affect how potent a normal rewarding stimulus is by something going on in the frontal cortex, in the frontal part of the brain. And overactivity in the prefrontal cortical areas can cause anhedonia in rodents.
- PAPeter Attia
Hmm.
- KDKarl Deisseroth
An overactivity seems to cause an, an inability of the dopamine neurons to recruit, uh, reward, uh, circuitry. And so this is an insight that optogenetics brought us, and it's something that we're following up mechanistically. It's kind of an interesting thing that there's... W- what we've found is that, again, using optogenetics, that the frontal cortex can suppress both positive and negative things. It can suppress fear. It can suppress anxiety. This is part of how we exert cognitive control over situations. We can enter a scenario that we know is risky. If we think about it enough, if we, uh, frame it enough for ourselves cognitively, if we review the need for it, for taking this action, and so our, our, our frontal cortex can help us by tamping down, uh, negative aspects, but it also, when overactive, it turns out, can tamp down, uh, positive, uh, uh, aspects as well. And optogenetics has given us an, a causal insight in, in, into this. And so that's just one example, but all the other features of Depression as well are susceptible to, uh, optogenetic study and we've gotten insight into them. Hopelessness being another one. And so here, you know, again, you might ask, "How do you, how do you measure hope in an animal?" Well, you know, you can, you can put a, an animal in a challenging situation that is not escapable. The animal can, can try to get out of this, uh, challenging situation, and then-
- PAPeter Attia
Would, would that be like a maze that doesn't have an exit?
- KDKarl Deisseroth
Yeah. No, no way of getting out. Exactly. So it does- doesn't have to be painful, just, just something that an animal would want to, to get out of and, and eventually they, they give up. We can do this actually in fish as well as in, in mice, and that giving up is effectively, it's this hopelessness, it's this discounting of effort, and that can be a, an appropriate thing, let's say. Of course, if the situation truly is hopeless, it, it really is not good to keep devoting effort to it, right? If you, if you keep flailing against an insuperable situation, you're burning energy, you could cause physical risk, you're distracting yourself from other things. Withdrawing, entering into a passive coping state is actually adaptive up to a point. The problem with depression is it becomes an extreme, so-
- PAPeter Attia
It's maladaptive. Yeah
- KDKarl Deisseroth
... mm-hmm, becomes maladaptive. You've discounted the value of everything, and then of- it's got this mysterious negative valence to it too, which is of course also part of the problem.
- PAPeter Attia
What do you think is the evolutionary basis for depression? This is something that is so ubiquitous. Um, I think I can, based on what you said earlier, see the evolutionary basis for anxiety, and maybe we could just argue that, that the pathologic version, well, we could discuss why maybe it's been amplified and what it is about our environment that perhaps does that. But depression's a less c- less clear to me and, and certainly mania's clear, right? I think we've made a very compelling case for why mania w- could be, why evolutionary pressure could have favored the propagation or at the m- at a minimum the maintenance of this.
- KDKarl Deisseroth
Right.
- PAPeter Attia
Why depression? It seems to be counter to your ability to mate, to find food, to defend yourself. I'm, I'm struggling to come up with one evolutionarily valuable, uh, tool that would be better in a depressed state.
- KDKarl Deisseroth
You know, and this is a great question. I think about this all the time. Um, and part of what we've discussed already may provide some insight, which is this, this withdrawal, this passivity. It is, in some cases you can think of it like a hibernation. You know, i- if, is it, is it like, is it worthwhile for an animal to, to actively try to cope with winter by running around trying to find more food all through the winter or to withdraw, to sleep more, to, to not see the value or feel the value in going outside and doing anything? And clearly, no matter what you do, you can't fight winter, right? The best thing is to conserve your energy, ride it out on some timescale that's appropriate. And so you think about, uh, now you think about depression. Uh, it comes with this low energy. It comes with this hopelessness, this discounting of effort, this lack of motivation to go seek things to, to be enjoyed. Reduced, uh, uh, you know, drive for social interaction. Uh, all these things can be part of depression. The negative aspect is the one part that's, that's, that I can't explain, and that's, that's of course the clinically significant problem. Why does it feel bad? And this is not just feeling bad. This is agony. This is psychic pain. This is the kind of thing that drives people to seek suicide. Not to discount that at all. We don't understand why depression feels bad, but the passivity of coping, that can be adaptive and it's, it's perhaps y- you could, you could see almost depression as a, as a hack, a bad hack, maybe one that's not fully evolved yet, just like mania, not fully evolved yet, not under all the right controls to make it m- more generally suitable and reasonable. Depression, it, easiest way to make it happen is to remove the joy, to remove the energy to seek out reward, and then you've got an organism that's gonna be passive, that doesn't see a path to, to, to, to something positive, and evolutionarily, if you, if you take this, this viewpoint, maybe one way of, of getting to that goal, uh, that had some, at the population level, some adaptive value included having this negativity, this negative state to it. And, and this is pure speculation, you know, but it's, it's important because depression is very genetically determined. It's, it's common, it's biological, and at some level we have to deal with the fact that we have evolved to be where we are now, and we have this high rate of, of, of, of depression. And so we have to include in our thinking the biology and the evolution together, and so that would be my, my, you know, my, my take on it. Of course, it's very hard and I wouldn't claim to have a, a definitive understanding.
- PAPeter Attia
Two unrelated questions. I don't even know which one to ask first, so I'll probably just ask them both and then let you take them whichever way you like. The first is, um, sort of a desire to understand where depression specifically, but even other mental illness fits into our closest relatives, the primates, right? Do we have a sense that our primate relatives are as afflicted by depression and/or other mental illnesses as much as we are. Um-
- KDKarl Deisseroth
Mm-hmm
- PAPeter Attia
... w- l- let's start with that. Yeah.
- KDKarl Deisseroth
Yeah. Well, we can, y- one of the, the clearest things we can see is that, you know, a, a pr- non-human primates can certainly enter into maladaptive states that look like grief, uh, in bereaved states. There are cases where you, you can have a, a, a young, a non-human primate who i- is old enough to, to feed itself, but who has lost a, a mother, let's say, has lost its, its mother, and, uh, loses the motivation to feed a- and protect itself and stay with the, the troop and ends up dying, uh, as a result. Uh, this is a clearly maladaptive state documented, um, that in a non-human primate, you could call it something like that, d- a d- a depressed like state, uh, deriving from bereavement and presumed, uh, to anthropomorphize something like grief associated with, with bereavement. So I, I, I believe these, you know, these states are, are shared, uh, by, by our, our non-human
- PAPeter Attia
A- any evidence of self-harm in, in, in, um, non-human primates? Does it ever get to the level of... I mean, you know, suicide is a top 10 cause of mortality in the developed world. It's important to make sure people understand the significance of that statement. In the developed world, when you think about all of the problems we've been able to solve, one of the 10 leading causes of death is self-harm. And, and by the way, if you really include overdose as a subset of that, it probably leapfrogs into the top seven. Is there evidence that this occurs in other species?
- KDKarl Deisseroth
So, uh, really interesting question, and the, the short answer is, uh, no. And, uh, there are, uh, less suicidal forms of self-harm that can happen. Uh, now and then you'll see animals, you know, carrying out behaviors like, you know, h- head banging and, and things like that. But in terms of a true suicide, the volitional ending of the self, [lips smack] there is not a animal model for that, let's say. It's not clear that that happens. And if you think about it, uh, a- as much as we'd like to have that so we could address this, this urgent, enormous clinical need that's not going away, uh, we, we would love to have some way of studying this. Uh, we don't have it. And if you think about it, the ending of the self is an extremely cognitively complex thing. Uh, and, and it's... Y- you think about the act of suicide, which we don't understand, and it's a, it's a, it's a horrific thing, but you've got... There has to be some understanding of what that means, that there is an ending of life, an ending of the self, and that the pain that's being felt now would not be felt then. This is a level of understanding of the universe that w- it doesn't seem that animals that are not us, uh, actually have. Uh, we could be wrong. I'm completely willing to admit that. There are amazing animals. You know, dolphins and whales and elephants have incredibly complex and amazing minds. They may be better than we are at some of these deep, uh, concepts, but they may have less clear ways to express it. They may have... Maybe not having fingers and hands to do things that we can do, they may not have the ways to express it, even though their cognitions may be just as complex. And so I think there are two factors. One is, you know, we, the things that set us apart, our brains and our hands, those two don't come together in any other animal, and I think that's why you don't see suicide elsewhere, at least as we understand it.
- 2:31:03 – 2:42:05
The effects of trauma early in life
- PAPeter Attia
Our colleague, Paul Conti, close also friend from medical school, who trained-
- KDKarl Deisseroth
Yeah
- PAPeter Attia
... with you in psychiatry, has just written a wonderful book on trauma. Um, and so it begs the question, what role does trauma play in the amplification of depression? We know, as you said, that depression is highly heritable. Um, but like most conditions that are heritable, um, there tends to be environmental triggers that can bring one person to have it and one not to have it. Even if you take the most extreme example of the, uh, monozygotic twins raised in a separate environment, one comes down with something, there's clearly some difference. [lips smack] Um, so what role do you think that, that early childhood trauma plays in all mental illness, but I guess specifically depression and, and do you believe that that could be epigenetic? In other words, do you believe that this thing can irreversibly mark the gene and then be transferred [lips smack] to subsequent generations?
- KDKarl Deisseroth
Subsequent generations. Yeah. This is, uh... So the effects of trauma, the lasting effects of early life trauma are unfortunately very clear. These you can, you can see in animals as well, and they extend beyond depression, uh, for sure, to include the personality disorders like borderline personality, for example. Um, so there's no question that early life trauma has lasting psychiatric influence, uh, throughout life and can cause very severe, uh, problems. You know, many ways to, to look at this, you know, why is it happening and how is it happening? Uh, is there a, a wiring change? So is, is the lasting quality due to a, a physical structure of the brain as a circuit? That- that's one level at which it could happen, and the brain is very... brain circuitry is very tunable that way, especially in young people. And so you could, you could imagine that early life experience with trauma sets up the human-
- PAPeter Attia
Mm
- KDKarl Deisseroth
... to expect, in some ways, that the world is a, is a harsh and unpredictable, uh, place, and that the value system had better be set up to deal with that because that's how it is apparently. And so you could almost imagine an adaptive, though very unfortunate, uh, process going on where there's a, a period of, of youth where you're gathering statistics about the environment, deciding what the adult should be like, and then implementing that. And so early life trauma could ins- intersect with such a process very unfortunately and create people with a, a lasting state of, uh, of depression, for example, expecting aversive things to be present at, at higher rates, and negative consequences of actions to be present at a high rate. [lip smack] Now, that could be for sure the case, uh, as far as a, you know, an evolutionary logic, but there's no doubt that this happens in terms of the behavioral effect and the psychiatric effect, the lasting effects of early life trauma. Now, if it's not neural circuitry, what else could it be? It could be genetic or epigenetic, as you say. You're not changing your genome from childhood to adulthood, but you're changing the transcription factors, the promoters and enhancers. You could be affecting gene expression throughout life, and that, at least through the life of that individual, we understand how that mechanistically could work. And then finally, you raise the intergenerational, uh, aspect. In human beings, this is very hard to separate from, you know, it's the nature-nurture thing. Of course, you've got the parenting that's linked to what might have happened in a prior generation. Um, and I'd say it's still controversial to, uh, how much intergenerational, uh, transfer can happen, although in animals there are mechanisms.
- PAPeter Attia
You wrote about the... Well, at least you wrote about your, your musings, your, your exploration of the idea of the evolutionary basis for tears. I found this completely fascinating. Um, A, I found it fascinating 'cause I'd never once considered that, and for someone like me who is often thinking about the evolutionary basis for this feature or that feature, it, it was interesting to me that I hadn't considered that. W- w- Say a little bit about that.
- KDKarl Deisseroth
Emotional tears, and, and by that, you know, the, the, the liquid coming from our tear ducts at, in, in times of, of emotion, this is apparently, as far as we can tell, it's, it's a human trait. Our great apes don't do the, do this, and even some human beings don't, don't do it. So it's a, it's a, it's a special thing. Uh, it's not that we are the only ones that grieve, but we're, we're the ones that sec- secrete this, this fluid from our eyes at these extreme moments. And, uh, and this has been studied. There are scholars of, of tears, as it were. And, and-
- PAPeter Attia
[laughs]
- KDKarl Deisseroth
... and you can do things like add or subtract tears digitally from pictures of, of faces, and these have enormous impacts on the reactions of people seeing these images much, much greater than, uh, a smile or a grimace, and particularly creating a desire to help. Uh, uh, when we see tears, we wanna help, uh, that person. And, and so this intersects very closely with the, I think, with the involuntary, largely involuntary nature of tears. It's a truth channel. It, it, it's not so easily gameable. It reveals something that in a social grouping like those that, that we've evolved, uh, to maintain, it, it's a, it's, it is an involuntary expression of something, the world changing, of needing, uh, uh, new systems in place, and it triggers this outreach from people who see it in a, in a very powerful way. And, you know, this, this question, can a, an emotional change cause something like this to happen? It would be a very easy rewiring to happen. There are already axons that come from emotional regions and go to the brain stem that control the breathing rate, for example, in, in anxiety. And right next to those breathing rate regions, there are regions that control the tear ducts. They're right next to each other in the brain stem. And a very tiny, tiny rewiring, a little axon just going in one slightly different direction, would create this state of expressing this visible, uh, uh, manifestation of an inner world. Uh, and, and with it, for a social, uh, species like ours, it, it could be easily evolutionarily selected for. And so there's, in the s- in the story, uh, Storehouse of Tears in Projections, this is, uh, something that, that, that, uh, a patient's story helped bring to the forefront of my mind, and we talk, and we talk about it quite a bit.
- PAPeter Attia
Yeah. It's a, it's a... I won't give any more away from that story because I, I want people to read it for themselves. Well, Karl, I know that, uh, we've kind of reached the limit of our time, and you have another commitment today. Um, as you can probably imagine, I could continue this discussion for probably another couple of hours, and I gather you could as well if it weren't for this other commitment.
- KDKarl Deisseroth
Easily, yes. I would.
- PAPeter Attia
So, um, I think what we should do is just commit to, to, to sitting down again next year at some point and, and, and continuing this discussion. There are so many more questions I have about personality disorders. And, and another topic that we didn't even get into today that we're both very interested in is psychedelics-
- KDKarl Deisseroth
Yes
- PAPeter Attia
... both from the traditional side, even to the non-sort of traditional side, uh, you know, the use of ketamine, uh, psilocybin, LSD, MDMA, all of these things which are an enormous interest of yours, uh, clinically and scientifically as of mine. So, um-
- KDKarl Deisseroth
Yeah
- PAPeter Attia
... I want to again-
- KDKarl Deisseroth
Absolutely
- PAPeter Attia
... congratulate you-
- KDKarl Deisseroth
Let's do it
- PAPeter Attia
On, on not just your recent Lasker Award, which, uh, again, I'll make sure in the introduction to explain to people what the significance of that is, uh, but also your remarkable achievements over the past two decades and, uh, this remarkable work that you've, you've written, Projections, which I suspect many people are gonna be reading after this. So Karl, thanks very much for, for spending time with us today and for educating us on this amazing journey you've been on.
- KDKarl Deisseroth
Pete, it's been great. Great to reconnect with you again on a incredibly enjoyable, uh, conversation, and, uh, look forward to talking again.
- PAPeter Attia
All right. Bye for now.
- KDKarl Deisseroth
All right. Take care.
- PAPeter Attia
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Episode duration: 2:42:05
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