The Peter Attia Drive - #191 - Revolutionizing our understanding of mental illness with optogenetics

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:15.500 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

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00:00:28.900 If you enjoy this podcast, we've created a membership program that brings you far more

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00:00:37.340 the end of this episode, I'll explain what those benefits are. Or if you want to learn more now,

00:00:41.740 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.780 here's today's episode. My guest this week is Carl Deseroth. Carl's a former classmate of mine

00:00:54.860 from Stanford where he received his MD and PhDs. He completed his clinical training in psychiatry,

00:01:03.180 and he also did a postdoctoral fellowship there at Stanford at the same period of time. He's

00:01:08.140 currently a professor of psychiatry and behavioral sciences and bioengineering at Stanford. Now,

00:01:13.460 over the past 16 years, Carl's lab has focused on combining neuroscience and bioengineering

00:01:20.780 to basically create a set of revolutionary tools that have done something for the first time ever in

00:01:28.280 neuroscience, which is basically to allow the use of genetic engineering to input light-sensitive

00:01:38.080 channels into very specific neurons. In fact, into any neuron that they choose to put these into.

00:01:44.860 This then allows Carl and his team, and of course now others who have been able to follow

00:01:51.200 in his footsteps, to use photons, that is to say to use light, to turn on and turn off very selective

00:01:59.140 neurons. This is something that was absolutely impossible until about a decade ago. This tool is

00:02:06.100 referred to as optogenetics. And as its name suggests, it's opto, it's light, it's genetics, it uses this

00:02:13.840 genetic engineering tool to put these channels, these light-sensitive channels into neurons. And this

00:02:20.160 has opened up a field of neurobiology that basically has allowed investigators like Carl to ask questions

00:02:27.760 that have never been asked or answered before. And in this discussion today, we go into not just how

00:02:35.920 Carl and his team came up with these unbelievable ideas and how they refine the tools, but now what they've

00:02:42.960 learned as a result of doing this. Now this work has not gone unnoticed in the scientific community.

00:02:48.160 Carl has won virtually every scientific award out there. And in fact, previously, just this month,

00:02:55.600 he was awarded the very prestigious Lasker award for his optogenetic light activated molecular research.

00:03:03.360 Now it's worth pointing out to those who might not be aware that about 50% of Lasker winners go on to

00:03:08.720 win the Nobel prize. And though I would never jinx Carl by saying this directly to his face,

00:03:14.160 I don't think there's anybody in the field who does not believe that Carl will indeed win the Nobel

00:03:18.560 prize in the not too distant future. And of course, he is entirely deserving of it when you understand

00:03:24.880 the nature of this work and how it has completely changed our understanding of the human mind. In this

00:03:32.400 episode, we talk not just about his background and how it led him to these discoveries and his chosen

00:03:38.960 career path, but we also dive into some of the deeper questions about mental illness. Remember,

00:03:44.400 Carl is a practicing psychiatrist and it's his interest in the human condition that really guides

00:03:50.960 his research. And so we dive quite deep into depression, anxiety, autism. We touch briefly on some

00:03:57.600 personality disorders, but truthfully, we kind of run out of time about two and a half hours into

00:04:03.760 this episode. And truthfully, we had really only got through about half of the material that I had

00:04:08.960 wanted to talk about. So it's safe to say that Carl will absolutely be back on this podcast because

00:04:14.800 there's still so much we want to talk about. The other thing I want to make sure you are all aware

00:04:18.640 of before we jump into this is that Carl has recently written a remarkable book called Projections,

00:04:23.440 a book that I think I mentioned in the podcast. I've read twice and his ability to write is perhaps

00:04:29.520 only rivaled by his ability to conduct Nobel Prize worthy science. He is a remarkable writer and you

00:04:37.040 don't need to be afraid of this book being written by such an esteemed scientist. It reads like a piece

00:04:42.320 of poetry and it really is a remarkable book and a remarkable journey into not just his personal journey,

00:04:51.360 but also into the eye of mental illness. So without further delay, please enjoy my conversation with

00:04:58.080 Carl Deseroth. And I think I feel safe in saying that this is a part one.

00:05:07.600 Hey, Carl, it is so good to see you today, although admittedly across video, but it's like a little blast

00:05:13.600 from the past from, I don't know, 20 years ago, right? Yeah, it's amazing. We had a good group of

00:05:18.720 friends back in the old days at Stanford and I haven't kept in touch with them as much as I'd hoped,

00:05:23.840 but it's great to see you. It really brings back a lot of memories. You look great, unchanged.

00:05:28.160 Well, yeah, that's funny. You don't look a bit different. It is funny when I think back to that

00:05:33.480 class of ours in med school, and I really feel like the overwhelming underachiever of our class.

00:05:40.140 And I remember our first day of our surgical rotation, you, me, and Josh Rabinowitz in that,

00:05:45.480 sitting in that room waiting for us to be assigned to which service we would go to.

00:05:50.660 Of course, you and Josh have gone on to do unbelievable things. I've sort of modeled along.

00:05:56.620 Now you're the star. And plus, I remember you, even though it was the start of our surgery rotation,

00:06:00.780 you already knew how to do everything, which I was impressed by. You knew all the knots and

00:06:04.920 I was like, wait, this is the first day of the rotation. How do you do that?

00:06:08.120 Well, let's pick it up back there. So you were in the MD-PhD program. So we didn't start at the

00:06:15.160 same time. We just finished at the same time. You had come in earlier, but I think the reason I

00:06:19.700 knew you even on our first day of surgery was because you had done your PhD in the same lab

00:06:24.780 as two other friends of mine, Alex Ravanis and Jason Pyle. And all kidding aside, I think that,

00:06:32.020 look, all the kids that went to med school were pretty bright, but I think the MD-PhD students were

00:06:36.300 sort of in a class of their own. And I suspect it was even harder to get into that program than it

00:06:41.400 was just the straight MD program. So thinking back to your time as an undergrad, what did you major in

00:06:47.320 again in undergrad? I did biochemical sciences. They called it at Harvard instead of biochemistry.

00:06:52.560 They had to do everything different and they didn't call it a major either. It was a concentration.

00:06:57.020 So I concentrated in biochemical sciences. So there you go. But I had a lot of other interests. All my

00:07:03.840 friends were physicists, theoretical physicists, in fact. And so I was exposed to some pretty unusual

00:07:10.180 stuff for a biochemist. And were they allowed to call it theoretical physics at Harvard?

00:07:14.200 They were. Okay. That's good. I just want to... Good question. Yes. They were allowed to name it

00:07:20.480 that. Good, good. So at what point during your biological science concentration did you know you

00:07:25.980 wanted to go into medicine? It was pretty early because I was interested in the brain early on and I

00:07:31.580 wanted to understand the brain at the level of cells. But I was also interested in the most high

00:07:38.400 level aspects of brain function. And so I thought I needed to talk to human beings. I needed some

00:07:44.160 access to the human brain. I found that interesting because I was interested in emotion and the ability

00:07:50.620 to express feelings through words. And I had this... I was torn. I liked writing and literature and the use

00:07:58.360 words. And I liked cells and biology. And I wanted to somehow fuse them. And it seemed that medical

00:08:04.180 school was the way to go because I could work with the human brain. Obviously, you could have just gone

00:08:09.560 to medical school, but you also selected into this very, very advanced program that was incredibly

00:08:14.460 selective, the MST program, the medical science training program. And so that tells me at the outset

00:08:19.700 that you also knew you wanted to do research beyond, quote unquote, just clinical medicine. Yes?

00:08:24.360 Yeah, that's right. And the nice thing about the MSTP is it lets you delay making a commitment.

00:08:30.480 So you keep both threads alive. And then there's a beautiful synergy that can happen too. And certainly

00:08:37.560 happened with me that you realize, oh, wait, I don't have to make this decision. It actually is good

00:08:43.400 to keep both threads alive in my work and in my life. And that's what happened. But it's a pretty

00:08:50.240 special thing we have in the United States. There are efforts along these lines in Europe and other

00:08:55.840 countries, but it's not nearly as institutionalized as it is here. It's a really special thing.

00:09:02.080 It really is. And again, I keep saying this, but I feel like there were maybe, what, six or eight

00:09:06.340 MSTPs per class. And I always felt like you guys had the most pressure on you, right? There was this

00:09:12.360 expectation from both the clinical side that you would go on to be great doctors. But then you were also,

00:09:18.760 especially at places like Stanford, where you had the opportunity to do your PhDs with

00:09:23.280 Nobel laureates, would-be Nobel laureates, exceptional scientists that you would also

00:09:28.700 basically be leading the charge scientifically. And for what it's worth, all of my friends in the

00:09:34.860 MSTP program, I think you're the only one that ended up doing clinical training as well. I think most

00:09:39.680 of them didn't end up doing residencies. They either went purely into academic research tracks or

00:09:47.160 actually went into industry. But before we get into the fact that you also did clinical

00:09:51.580 training, let's talk a little bit about that transition. You came into medical school pretty

00:09:55.640 hell-bent on neurosurgery, yeah?

00:09:57.780 That was the goal because, again, how do you get access to the human brain and who among the

00:10:03.300 different clinical specialties has that access? Who can, would most directly interact, study? And it

00:10:11.060 seemed to me the neurosurgeons had it all. And if one were to build an interface with the brain,

00:10:16.960 if one wanted to both communicate with a person as they were expressing feelings and emotions and

00:10:22.420 to understand at the level of cells what was going on, who could do that but a neurosurgeon was my

00:10:29.480 reasoning. And I, the neurosurgeons that my colleagues and friends, they're amazing people,

00:10:35.200 brilliant, and I saw no reason not to pursue that. And so that was the first rotation that I

00:10:42.060 selected in those second two years of medical school. Even before surgery, I did neurosurgery,

00:10:47.380 which was kind of interesting, just coming in there with no general surgical training as well. That's

00:10:52.600 how certain I was. Yeah, it's funny. Well, I had a similar experience, whereas the thing I

00:10:58.020 absolutely positively thought I was going to do, I picked as my first rotation. In my case,

00:11:03.620 I had less of a pleasant experience than you. I think you had a pleasant experience on neurosurgery.

00:11:07.860 It wasn't that in any way you didn't like it, but what was your first? I planned to do pediatric

00:11:12.380 oncology. So I went out of the gates with two months of pediatrics, which actually I didn't enjoy

00:11:18.600 largely because I just didn't feel like I didn't fit in. I think so much of your medical school

00:11:23.100 experience in terms of your clinical rotations is a function of how well do you fit in with the

00:11:27.300 residents of that specialty. And I didn't feel like I fit in with the pediatricians. They didn't,

00:11:33.620 laugh at my jokes. They thought I was probably a little too obnoxious. I probably spent too much

00:11:39.140 time imitating Dr. Evil and Fat Bastard, pretending to eat the babies, but it just,

00:11:44.640 the whole thing just didn't go well. It was a disaster. And then my next rotation was general

00:11:48.780 surgery where we connected. And even though I had no desire whatsoever to go into surgery,

00:11:54.280 that became a kind of overnight love and away we go. But so you're doing your neurosurgery rotation,

00:12:00.420 which again, yes, highly unusual that you would do that so early in your training. That's usually

00:12:05.160 something one does in the fourth year, not the third year. And I'll say this, Carl, when I did

00:12:10.680 general surgery at Hopkins, I did one month of neurosurgery as a rotation, having never been

00:12:16.720 interested in neurosurgery. So sort of saying, well, fine, I'll do this. I didn't have a choice.

00:12:20.860 I had to do this month of neurosurgery and I fell in love with it. I couldn't, I, and in fact,

00:12:27.180 I spoke to the program director at Hopkins and said, would it be ridiculous for me to try to

00:12:32.840 transfer into neurosurgery? That's how much I enjoyed it. And it turned out that he said,

00:12:38.600 I can absolutely get you in, but it won't be at Hopkins. Hopkins is the most competitive

00:12:42.380 neurosurgery program in the country. We only take three people. It's already full. You're not going

00:12:47.620 to get in here, but I can get you to another program. And I actually contemplated it for about

00:12:51.940 a month. So I can see the appeal of it. There was something about cutting open the dura and

00:12:57.180 operating on the brain. And it's a surprisingly simple organ in that sense. Like at the gross

00:13:02.220 level, it's surprisingly simple. Obviously much of what we're going to talk about today, Carl,

00:13:06.820 is not at the gross level where it's anything but simple. But what was your experience like?

00:13:11.920 I mean, it was at one level, it is an organ and it would be unfair to say that all that neurosurgeons

00:13:17.260 get to do is think about it as an organ. They do have to think about that, the blood supply and

00:13:21.780 whether the cells are receiving enough oxygen and glucose. And they have to think about it in the

00:13:29.160 context of the physicality of it, perhaps more than the mentation aspect of it. And so they do get to

00:13:37.400 think about high-level concepts. In that rotation, in that month, there was a patient who had a little

00:13:42.540 bit of a thalamic infarct as a result of the surgery and a little bit of loss of tissue in

00:13:49.100 the thalamus. And the patient had a neglect syndrome, which I spent a lot of time working

00:13:53.920 with the patient afterward, characterizing exactly how this worked. I asked the patient to draw a

00:13:59.560 clock and the patient drew just half of a clock. And it was an amazing classical thing, but amazing

00:14:06.140 to see with your own eyes as you're talking to another person. And the person said, oh, the clock

00:14:10.700 looks fine. But it was a half o'clock. And that certainly didn't diminish my interest in neurosurgery

00:14:17.560 at all. It was, you know, this was at the one level, you know, there were problems which nearly

00:14:22.500 clearly needed to be better. Aspects of neurosurgery, as with every clinical specialty,

00:14:27.520 needed to improve, needed to reduce consequences like that. And yet at the same time, it was incredibly

00:14:33.360 interesting as well. I loved the operating room. I loved the suturing, although I wasn't as good as you,

00:14:39.200 too, I think. But I was good enough. And it was particularly because it was so early. I think

00:14:44.860 the promise was there. It would have worked out. It still had a magic about it. You know, when the

00:14:50.460 dura is exposed, yes, it's an organ, but there's a spirituality to that, to know that you're actually

00:14:57.460 looking at the storehouse of a human being's thoughts and feelings and everything about them

00:15:04.460 all encapsulated in this collection of cells. It's quite an amazing thing. And so I had no

00:15:10.040 negativity at all. I did note that neurosurgeons, they didn't get a lot of free time. There was not

00:15:16.580 a lot of philosophizing. And I noticed, you know, it's a seven-year progression. And I talked to all the

00:15:23.860 neurosurgery residents and I noted a steady decline in willingness to philosophize as their progression

00:15:30.980 through the residency continued. You could almost plot that literally on a graph. And with all due

00:15:37.980 credit to them, it's the nature of the system they're in. They don't necessarily have all the

00:15:42.460 time they would like to think deeply, although they're very bright and thoughtful and certainly

00:15:46.880 could. And so I did note that. I noted that here are people who maybe don't have the freedom to do

00:15:53.640 everything I would like. And that was in the back of my mind.

00:15:56.540 Yeah. Yeah. I think back to the three people in my class. So at the entering class at Hopkins,

00:16:02.060 three of them were neurosurgery assigned. So they did the internship with us, but then they went off

00:16:06.760 and I mean, boy, they were three ridiculously smart guys. And you would think, well, they're in

00:16:14.360 neurosurgery. So how interested are they going to be in their year of general surgery? But they were

00:16:18.800 every bit the exceptional interns that the categoricals were, the ones who were going to go into general

00:16:25.720 surgery. But one of the experiences that jumps out at me from my month of general surgery in my

00:16:30.840 internship was an awake procedure we did on a patient. So under local anesthetic, the brain was

00:16:37.320 opened and the patient while wide awake was being probed in an effort to determine certain symptoms

00:16:44.320 and to see what part of the brain could be lesioned in order to ameliorate these symptoms. And I think

00:16:49.780 for anybody to see that in real life with their own eyes, even once is it's really hard to believe

00:16:56.200 what you're watching. First of all, the brain is not the same sensory organ. The fact that you can be

00:17:00.600 awake while a surgeon is probing into your brain and firing an electrical impulse into one area or

00:17:07.560 another to see how it changes this part of your visual field or this part of your, I mean, that was a

00:17:13.660 magic that I don't think I could describe otherwise. Yeah. And that, I felt that very, very strongly.

00:17:19.720 And so there was, it was all systems go after that. They, you know, surprisingly the neurosurgeons at

00:17:25.340 Stanford liked me okay after that too. I got very positive feedback from them and they said, Hey,

00:17:30.420 you know, come back and do a sub-I sub-internship and we'd love to get you down this path. That was a

00:17:37.220 green light and I was happy with that. It was, it was where I was headed. Of course, things changed after that.

00:17:42.740 Yeah. So the best laid plans, there's a set of mandatory rotations. We have to do neurosurgery,

00:17:47.620 not being one of them, but pediatrics, general surgery, internal medicine being the OBGYN. And

00:17:54.680 one of them is psychiatry, kind of this afterthought for the medical student, right? Very few people want

00:18:01.140 to go into psychiatry. And yet amazingly, two of the smartest people in my med school class,

00:18:08.040 you and Paul Conte end up picking this field ultimately. Just amazing, right? So tell me

00:18:14.900 about how did you go into your psychiatry rotation? Were you looking forward to this or did you view

00:18:19.200 it the way many of us did, which was just get me through it?

00:18:21.760 I had a get me through it attitude coming in. And again, no, no disrespect to psychiatry. Of course,

00:18:28.320 they have a hard challenge. Still, we have this challenge that there's not a,

00:18:33.580 a measurable really, you know, we have effectively questions we ask patients. It's all with words is

00:18:40.520 how we work. No biomarker. No biomarker still. Yeah. I mean, there's efforts along those lines,

00:18:46.100 looking at EEG, you know, ratios of this to that. And there's progress being made, but still

00:18:51.640 clinically, you can't make diagnoses based on measuring something about the brain and psychiatry.

00:18:57.720 You can notice that there's something else going on, a neurological or a medical problem,

00:19:01.900 but you can't define someone's psychiatric state with, with some biomarker. And that still,

00:19:08.120 amazingly to this day, still true. Yeah. So tell me about your psych rotation,

00:19:11.920 because I remember we kind of had choices. I did an entirely outpatient month,

00:19:16.340 which I ended up finding quite enjoyable. That's the irony of these things. You kind of,

00:19:20.160 I did it as one of my last rotations prior to graduation, which meant there was no chance,

00:19:24.060 even if I'd liked it, I, it was too late for me to make that choice. I had already matched,

00:19:27.880 I think in general surgery, but it was an outpatient month. So relatively low acuity,

00:19:33.280 but interesting. Nevertheless, what was your month? Like mine was the opposite of that. It was,

00:19:39.840 and this was probably a fortunate thing for me. It was in the locked unit at the VA,

00:19:45.240 at the Veterans Administration Hospital. And this was a unit where patients can't leave. And this is

00:19:51.580 due to being a danger to themselves or a danger to others or having a grave disability. And these

00:19:57.840 patients were severely ill. And I, I walked into that. I'd had typical experiences. Everybody,

00:20:04.700 you know, has friends or family who've had depression or anxiety. I, I'd seen substance

00:20:10.300 abuse and intoxicated states and dementia. And, and, and I had a fairly, I thought decently

00:20:16.680 broad understanding of, of what can go wrong on the, on the psychiatric side, but I can tell you

00:20:22.400 nothing. And you, you know this by now, but I can tell your, your viewers and listeners, there is

00:20:28.480 nothing like what you can see when you walk into the, the locked ward of a, of a psychiatric hospital.

00:20:36.240 There's a, a sort of a, a purity, not in a good way, but there's a, because there's not confounding

00:20:42.060 issues like intoxication and so on, there's a consistency and a purity to the disorders. And so

00:20:47.920 if you have someone with acute schizophrenia or schizoaffective disorder, other things that might

00:20:54.420 confound what's going on have been removed. And there's this very strong, acute, straightforward

00:21:00.120 expression of the symptoms. That's just a mind boggling to see if you haven't experienced it

00:21:04.620 before. And that was my experience and it completely changed my course. There was a, even on the, you know,

00:21:13.120 my very first day, there was a patient with schizoaffective disorder, which is a very severe

00:21:19.680 combination of mood and psychotic symptoms that are all mixed up together. And this patient accosted

00:21:27.500 me in the, in the locked unit, started screaming at me and, but it was not necessarily sort of a street

00:21:33.620 encounter that you might have in a, in a city. It was more direct and personal and evocative of something

00:21:39.580 going on in the mind of the patient that was clearly a source of immense suffering of great

00:21:45.860 disability. And yet at the same time, it was, it was tantalizing because this was a human being who

00:21:51.740 was physically intact, but whose reality was so completely different from mine. We were two people

00:21:57.600 with intact bodies and brains who were next to each other and we inhabited completely different

00:22:03.560 realities. And to experience that was a utterly transformative moment. And, and both seeing the,

00:22:10.320 the suffering and realizing I have no idea what's going on here, but it's incredibly interesting

00:22:17.180 too. How is this possible? How could this be happening to a human being? And without that direct

00:22:23.420 exposure, I don't know what would have happened, but having had it, it changed my course.

00:22:29.800 It's interesting. I mean, many people when confronted with that would be quite frightened,

00:22:34.240 especially when you realize the limitations of the tools that you have, right? So let's consider it

00:22:41.240 another analogy, which is a patient that comes in with a gunshot wound to the chest.

00:22:46.460 That's an incredibly frightening experience. There's literally a sucking chest wound. Blood could

00:22:51.740 be splaying around the room. Vital signs are crashing. The person's on the verge of death,

00:22:56.300 but that can be exciting in a way because we actually have the tools to do something, right? It might be

00:23:01.960 completely draconian. We might be doing a thoracotomy in the ER cross clamping the aorta,

00:23:06.960 but you run that patient to the OR and you know how to fix them. You're experiencing something that I

00:23:12.280 would argue is much more frightening, but compounded by the fact that what do you do? I mean, you could

00:23:20.020 temporarily give that person Haldol and sort of snow them, but that's not curing them. So was it more

00:23:26.780 the, we don't have the tools here. This is an unbelievable opportunity to learn or how did

00:23:32.640 that experience, which I think for many people could have been off-putting do the exact opposite

00:23:36.900 in you? It's a great question because I, and I would completely understand that the normal or typical

00:23:42.840 reaction would be sort of an aversive thing. You know, how this is, this is not something I want to

00:23:48.660 spend my life doing in this setting. But I had a, I had a different reaction, which surprised me.

00:23:55.120 So there were two sides to it. One was exactly what you're saying. The level of mystery here was

00:24:02.220 actually for me, it was a positive rather than an aversive thing. And maybe this was partly the,

00:24:08.120 my scientific training, you know, at that point I'd completed my, my PhD and, and I'd spent years

00:24:13.880 trying to figure things out. And we all want to figure things out. That's a natural human impulse.

00:24:19.120 Not everybody necessarily spends years and years and years trying to figure out the same thing. And

00:24:24.160 that's, that's the kind of training we get in, in the PhD program. And I saw that and I was like,

00:24:29.480 okay, got to figure this out. This is clearly a mystery that is something that it's a burden

00:24:36.280 that humanity shares. It's a terrible burden that this human being is suffering, but what's the

00:24:44.460 solution? We've got to figure it out. We've got to understand this. And, and it's a mystery that

00:24:48.600 strikes to the heart of what had always intrigued me, which is what is an emotion physically? What is

00:24:54.820 a feeling physically? How does the collection of cells in our brains, and that's what it is,

00:25:00.860 it's a collection of cells. How is it possible that that creates a feeling and emotion? And I realized

00:25:06.760 at that moment, this is, this is actually why I came to medical school. And it all made sense in,

00:25:14.380 in one moment that hadn't before. And then, you know, of course, as a physician, as you well know,

00:25:19.540 we, our instinct is to help is to heal. And we want to do that. But as you say, if we don't have

00:25:24.320 the tools, what can we do? It's a problem. And I wasn't frustrated with the inability to do anything.

00:25:31.780 And I would understand that reaction too. And the fact is we, we could do a little bit though.

00:25:38.220 So it wasn't quite nothing. And there are medications back then and still that help somewhat.

00:25:44.400 They don't come with understanding. They don't help us explain to the patient or the family or to

00:25:50.600 ourselves what's really going on, but they do help a little bit. And so I was, I knew that I could do

00:25:56.800 something, not much, but a little bit. And as time went on, hopefully, and as the science progressed,

00:26:02.920 maybe we could do more. And so that, it fit together in a moment. And I didn't have another

00:26:10.040 thought for neurosurgery after that, although it was, it was a hard process to reshape what my

00:26:19.060 trajectory was going to be. I had one set of plans. My friends and family had a set of expectations.

00:26:26.860 I can tell you, I think my, my father was pretty disappointed when I told him on the phone that I

00:26:31.840 was going to do psychiatry. I could hear it in his voice. It was, it was almost, uh, you know,

00:26:37.440 again, he, he came around in the end too. And, and I think he's happy now, but at the time I could

00:26:42.660 sense that this was not what he'd, he'd hoped for me. So yeah, it was, it was an adjustment. It was a

00:26:47.620 remapping, but it was a very compelling experience that the process of medical training and the

00:26:55.060 required psychiatry rotation made possible.

00:26:57.380 So Carl, you, you now make this decision to completely veer into this nearly orthogonal

00:27:03.120 track. I mean, psychiatry and neurosurgery of course have one thing in common, which is the

00:27:07.760 organ of interest is the brain. But at that point they basically differ. How did you decide you were

00:27:14.840 going to both pursue the clinical training, the residency for psychiatry, but also do whatever was

00:27:23.380 necessary to make sure that you could ultimately be running a lab? Because I, I think throughout this

00:27:28.660 period, you never lost sight unless I'm misremembering of the desire to be a physician

00:27:34.320 scientist and not just a physician. So residency, especially 20 years ago, when we did our residencies,

00:27:40.960 they didn't have 80 hour work week requirements and things like that. So residencies were quite

00:27:44.740 demanding. Was it a little hard for you to say, Hey, I'm going to actually have to put my research

00:27:49.380 on hold for a little while. It was hard. And there are a lot of challenges that people in this realm

00:27:56.220 face because things move so quickly in the research realm that if you step aside for even a year,

00:28:04.860 forget about four years, the world you reenter is so different and it's very hard to catch up.

00:28:09.600 And, you know, that's to some extent an old problem because that's been faced by everybody

00:28:15.420 who planned to do a residency, but it's not negligible because it's an old problem. It's that

00:28:23.020 issue exactly that ends up driving people to make this hard choice that you mentioned earlier and

00:28:28.600 saying, you know, in the end, I'm going to have to do one or the other. If I do the residency,

00:28:33.460 I'll be a doctor. I'll be a good doctor, maybe a great doctor. I'll be informed by all my scientific

00:28:40.360 training. Maybe I'll read papers better. Maybe I'll be more amenable to new ideas, new treatments

00:28:45.800 as a result of that. But ultimately I'll be a physician or on the other side saying, you know,

00:28:52.580 I'm not going to do the residency. I'm not going to drop off this fast moving train. I'm at this

00:28:58.480 moment, I've just finished my PhD. I'm a world expert in this. I can do things that nobody

00:29:03.440 else can do. Why lose that momentum? Why not speed up, add the next tool in the tool belt,

00:29:10.940 launch yourself and make great discoveries. And that is very, very tempting. I had very clear

00:29:18.540 opportunities to do that. And so that's the hard choice that the MD-PhD faces at that moment.

00:29:25.120 Now, efforts are made to ameliorate that. So residencies, again, this was the time still where

00:29:30.600 the residencies were extremely difficult. And I had some, for me, this was compounded by some

00:29:36.100 personal challenges. I was effectively a single dad at the time. And so I had to also think about

00:29:41.440 this other factor, very important. Now I've got to think about residency. I've got to think about lab.

00:29:47.660 I've got to think about family. And it was very, very challenging. And yet there are these research

00:29:54.580 track residencies and they help a little bit. So there are, and Stanford and other programs,

00:30:00.380 both in psychiatry and in other specialties, they have efforts to help people keep their scientific

00:30:06.040 mind alive during residency. And it's not great, but it's a little bit of protected time here and

00:30:11.300 there. Never quite enough to get momentum, but at least to keep a foot in the lab and try to stay

00:30:16.780 connected. And so I did that. It was a research track, psychiatry residency. And I stayed at Stanford.

00:30:23.360 And a big factor in that was that literally at the same time, and I was very fortunate in this regard,

00:30:30.440 a guy named Rob Malenka, who was a psychiatrist and a great neuroscientist, was at that moment

00:30:36.620 coming from UCSF to Stanford. He had come and was setting up his lab at Stanford. And I knew here's

00:30:44.160 somebody, a psychiatrist, but also a neuroscientist. He'll understand what's going on in my residency,

00:30:51.140 that I'm, you know, I'm taking call. I'm up all night. He'll understand why I'm never in the lab

00:30:57.700 during expected hours, why I'm never at lab meeting. And that made it work out. And I worked nights and

00:31:04.180 weekends. I maybe came to one of his lab meetings over four years, and I effectively did a combined

00:31:11.000 postdoctoral fellowship and psychiatry residency at the same time at Stanford. Some funny stories,

00:31:16.260 because Stanford's very compact, as you know, I could literally take call from the lab. I'd be

00:31:23.260 patch clamping. I'd be at the rig, you know, listening in, making measurements on currents

00:31:27.920 flying across a single cell. And I'd get paged, go walk over to the ER, admit a patient, come back,

00:31:34.880 patch clamp the next cell. And it was a pretty special moment when that happened. It felt like

00:31:40.240 the different parts of my life, they could work together. They could be compatible. And that so

00:31:44.940 many people have such a hard time, understandably, making that work, making the pieces fit together.

00:31:49.800 And I feel fortunate that I was able to make that work. Now, what year was your son born? 98?

00:31:56.040 He was actually born in 96. So he is 25.

00:31:58.860 So you're four, he is five years old, basically, when you're in the midst of this.

00:32:04.040 Yeah, that's right.

00:32:05.080 How did you manage that?

00:32:06.000 This is actually something that I touch on. I don't know, we may talk about the book I wrote,

00:32:11.420 Projections Later, but it turned out to be a theme early in my life, how my experiences with my son,

00:32:18.460 how they related to all the stressors and the patient experiences that I was having. And

00:32:24.040 in a way, psychologically, although it was difficult to make everything work, practically, it also,

00:32:30.520 it helped me a little bit to have something that mattered more than anything else in the lab or

00:32:37.860 in the clinic. There was something that was on a different scale. And it helped me not get too

00:32:45.920 stressed about things happening in the lab or the clinic. And that's a common feeling in people with

00:32:52.220 kids. For me, it was extremely important at that time. There were patchwork solutions of childcare and

00:32:58.680 so on that made things work. But it was ultimately, I think it was helpful for me in getting through

00:33:02.820 those times. And by the way, he is now an MSTP student at Baylor. So he's doing his MD, PhD in Texas,

00:33:10.560 and he's now second year. He's a cool kid. He's good at guitar, much better than I am. And he likes

00:33:17.640 computer science.

00:33:20.080 Yeah, he's got some big shoes to fill, but I and I'm positive that none of that pressure comes from you.

00:33:24.540 So no, I remember when you were finishing your residency. I just remember because of our common

00:33:32.620 friends, how exciting it was when you were now setting up your own lab. So we're talking about

00:33:39.500 what? Oh, five, oh, six ish. Yeah, the lab started to get set up in oh, four. Okay. And then it really

00:33:44.980 hit full steam between oh, six and oh, nine. But oh, four was when we were setting up.

00:33:50.360 So as you're embarking on this, what is it that you experienced during that transformation of

00:33:58.020 your clinical training, your residency? How did that shape the problems you were interested in

00:34:04.140 solving? Well, I, having just completed my psychiatry residency, I had a pretty deep understanding of

00:34:11.080 where things were clinically. I knew what, not just the medications we had, but also the brain

00:34:17.160 stimulation treatments, the interventions that we had available at the time. I did electroconvulsive

00:34:23.080 therapy, which is very effective for treatment resistant depression. It's the treatment of choice

00:34:29.180 for many people. It's incredibly effective. It's stunning to see. It has some problems. You don't want

00:34:35.580 to give it too much and there can be side effects, but it's incredibly effective. What's the durability

00:34:39.940 of it? It depends. Some patients need what we call maintenance electroconvulsive therapy. So after

00:34:46.360 three months or so, the effect will be diminished and they'll require to stay alive effectively

00:34:52.220 patients who are, for example, just acutely suicidal and they'll need every three months or so what we

00:34:59.040 call maintenance or continuation electroconvulsive therapy or ECT. So it's not a permanent fix like

00:35:05.820 so much of medicine and so much of psychiatry. It's something that moves things back into a healthy range

00:35:12.360 for a time, but we didn't know how it was working. It definitely helped, but it was, for a scientist,

00:35:17.860 it was very, it was satisfying to help the patient to take somebody who was in just horrific

00:35:24.720 psychological distress and put them into a state where they could go back and do their work and

00:35:29.720 live with their friends and family and be happy for some time. That was great, but we had no idea

00:35:34.620 and still don't, what was going on there. Why is this seizure that we give the patient? And it's done in a

00:35:40.580 pretty refined way these days. The patient's body is paralyzed, so there's no physical seizure. It's

00:35:46.420 all happening in the brain and it's a safe procedure, but still it's not specific, right?

00:35:51.820 You're causing a general pattern of activity through the brain of the patient and this astonishing

00:35:57.840 psychiatric effect is created. Clearly it was a mystery, still is, and I was unsatisfied by that.

00:36:06.940 There were early efforts at the time of other brain stimulation treatments. There was a vagus nerve

00:36:12.380 stimulation. There's a, as you know, there are the nerves that run, 10th cranial nerve that comes from

00:36:17.520 the brainstem and goes down to innervate the heart and the abdomen also sends fibers back to the brain

00:36:23.880 and you can put a little cuff around the nerve and stimulate the brain through the neck, which is

00:36:28.680 kind of interesting, a little highway to the brain. But the effects, although it became approved,

00:36:34.060 FDA approved for depression, the effects were very small on the population level, very inconsistent.

00:36:39.120 Likewise, we had transcranial magnetic stimulation, which was in its early days then as well, which was

00:36:44.520 a treatment where you can non-invasively stimulate a tiny patch of the brain by putting a rapidly

00:36:50.260 changing magnetic field near the scalp of the patient. Effects, small on the population level,

00:36:56.720 did get FDA approved, but still not fully understood. So all these treatments, and of course,

00:37:01.960 none of the medications to this day do we fully understand their mechanisms of action. So there's

00:37:06.000 a lot of mystery. And so I came from my psychiatry residency fully aware that essentially the entire

00:37:13.960 field was unmoored from scientific understanding. No fault of the practitioners, no discredit to them.

00:37:21.960 It was just not known and we didn't have the tools and techniques. We had no specific way of causing

00:37:26.880 something to happen to a particular kind of cell. All these treatments are non-specific. A seizure

00:37:33.300 all through the brain. A stimulation of a nerve, wherever that nerve may go, known, but not

00:37:40.160 specifically related to any psychiatric symptom. Transcranial magnetic stimulation, yeah, you can

00:37:46.960 stimulate a little patch of the brain, but we don't know where depression comes from, where anxiety

00:37:53.380 comes from. Is it this patch or that patch or that patch? No deep level of understanding was present.

00:37:59.020 And of course, the medications act all through the brain without cell type specificity. That was the

00:38:04.220 setting. And then to answer your question then is, you know, clearly basic science, you know, how could

00:38:10.340 you build an approach to give you some kind of precise causality? And that was the context.

00:38:16.380 Well, I want to dive really deep into this because it is essentially the skyscraper of your life. I mean,

00:38:22.900 look, if you, if you retired tomorrow for medicine and science, Carl, if you just tomorrow decided you

00:38:28.920 were going to go surfing for the rest of your life, you would have already accomplished more

00:38:33.400 than that of a hundred scientists. So I want to, I want to come to this in detail, but before I do,

00:38:39.640 I want the viewers and the listeners to get a little bit more of an understanding of the brain

00:38:45.180 structure, because we're going to be talking about structures of the brain. We're going to be

00:38:49.560 talking about the cells of the brain. And I wonder what the easiest way to do this is. Maybe we can

00:38:55.700 start about the brain and it's three layers and what, you know, we talk about them through our

00:39:01.300 evolution maybe, and how each one added to the next, but, but each one has a subset of functions.

00:39:06.880 I'll really defer to you, Carl, this is your domain and not mine, but maybe we just take a step back

00:39:12.120 and really give people a sense of, of some neuroanatomy, some neurophysiology, what neurons are,

00:39:18.040 what axons are, how chemicals get transmitted. I think investing some time in this now will really

00:39:24.180 enable people to understand the depth and breadth of your literally world-changing discovery.

00:39:31.480 Well, well, thank you for the, first of all, the gracious comments. I, we have a long way to go

00:39:35.840 though, and I'm not, and maybe it's many lifetimes ahead. There are very deep mysteries in the brain

00:39:40.660 that we have much, much work to do, exciting, fun work, but much work to do to get to where we want

00:39:46.320 to be. But, uh, it is a, an exciting moment and what we've been able to accomplish has, has been

00:39:51.840 thrilling. And it's a testament to all the amazing people that we've been able to, to get together to

00:39:57.020 work on this. And indeed the brain is, is something, it's very compelling. It's so interesting and

00:40:04.420 mysterious. The cells in the brain are more complex structurally than any other cell. They're in our

00:40:12.220 brains. There are approximately 90 billion neurons. That's with a B. Each one of them is, it's a

00:40:19.920 self-contained unit. It's covered by a membrane, but it can generate electricity. It's got little

00:40:26.940 channels, little pores in its surface that can generate little electrical impulses. And that's how

00:40:33.040 you can have a single neuron that projects from one part of the brain to another, or from one part of

00:40:38.360 the brain to the spinal cord, or it can send connections through its axon, its outgoing wire

00:40:44.560 effectively to many parts of the brain. And it sends that information in the form of electricity down

00:40:50.380 its axon, down its outgoing connection. And the connections are received by the downstream cells

00:40:57.280 through little structures called dendrites. And the interface from one cell to the next is called a

00:41:03.600 synapse. And in most cases, information gets across that little gap from one cell to another

00:41:08.420 in the form of chemicals. So the electricity triggers release of a chemical. The chemical

00:41:13.300 drifts across this tiny little gap that's some tens of nanometers. And then it acts on receptors in the

00:41:20.680 other side, the post-synaptic side. And that creates a new burst of electricity in that downstream cell.

00:41:26.860 So that's the electrochemical process of information flow. Now you've got this going on in 90 billion

00:41:32.740 neurons at the same time. Maybe they form 10,000 or even 100,000 synapses each. Their wiring is

00:41:39.920 incredibly complex. There's some structure to it. There are collections of axons that may travel

00:41:46.020 together, but then they also bifurcate and separate in incredibly complex ways. And all that's in the

00:41:52.560 brain. And then there's some structure to it, as you alluded to. And one way we can think about this

00:41:57.720 is indeed evolutionarily. We're vertebrates, okay? That means we have a backbone and we've got a

00:42:03.400 certain organization to our brain. In my lab, we have fish and we have mice and we have rats. And then

00:42:09.140 I also do clinical work. These are all vertebrates from fish to us. We all have the basic vertebrate

00:42:15.160 body plan and brain plan. But evolution has given us, obviously we have much bigger brains than fish do.

00:42:21.400 And a couple things have happened over the course of hundreds of millions of years is that, first of

00:42:27.380 all, we've scaled everything up. We've taken the same structures. We've added many more cells to them

00:42:32.340 and that lets us do more complex things. And we've also added new things on top. And so in the surface

00:42:38.120 of the brain, there's what we call the cortex, which means literally the surface of the brain.

00:42:43.960 It's like the rind of a melon, except in human beings, it's quite thin. It's just a few millimeters

00:42:49.480 thick. And within that few millimeters, there are six separate layers within that cortex or rind.

00:42:56.060 And those are layers of cells. So there are six layers of cells in this sort of

00:43:01.160 shawl or rind covering the brain. And then all the wiring coming out from that cortex goes to deep

00:43:08.300 structures. And our cortex is much more advanced. The fish don't really have something like that,

00:43:14.280 but they've got the deeper structures. They've got the interchanges and the movement control

00:43:19.420 and the arousal systems and the sleep systems. And there are structures deep in the brain like

00:43:25.620 the hypothalamus that govern all the primary needs of salt balance and avoiding danger and mating and

00:43:34.040 sleeping, thermoregulation. These deep structures are common to every vertebrate. We have a hypothalamus.

00:43:40.480 The fish has a hypothalamus. These deep structures are shared and ancestral among all vertebrates.

00:43:45.180 And so you've got these deeper structures that are conserved and ancient. In us, we've got the

00:43:49.980 surface structure that is incredibly elaborated in our lineage and is responsible for some of the

00:43:56.320 most complex and mysterious things we do. But the great thing is, and mice sort of sit somewhere in

00:44:01.580 between. They have the cortex that we have, and it's amazingly similar. It's got the same six layers.

00:44:07.420 It's got the same kinds of neurons that are connected in the same way. It's just much smaller than what we

00:44:12.200 have. And so by looking at the fish and the mice and ourselves, we can piece together a lot by studying

00:44:20.540 the cells and the connections that make things happen. And that's the context that we come to as

00:44:27.020 a neuroscientist. And what about this first layer, the brainstem, this kind of most primordial layer that

00:44:33.300 handles so many of these functions when we're not even thinking about it, like breathing? I mean,

00:44:38.040 how conserved is that across all of these models?

00:44:42.200 Yeah, the brainstem is highly, highly conserved. In the brainstem and in the midbrain, we have

00:44:48.100 clusters of neurons like the dopamine neurons and the serotonin neurons and the noradrenaline or

00:44:56.720 norepinephrine neurons. They're all clustered there in the brainstem in and around other cells that govern

00:45:04.380 the movement of the muscles of the face and the neck that send information down like the vagus nerve

00:45:13.280 that we talked about, send information down to the rest of the body. These basic structures in the

00:45:17.740 brainstem are highly conserved. Fish and mice and human beings all have them. There's a little bit of

00:45:23.600 different shaping and arrangement, but it's basically the same logic.

00:45:28.040 Are there neurons, the way you describe it, it sounds like a neuron might have mostly just

00:45:34.100 serotonin. So when that neuron fires at the end of its synapse, serotonin is the only chemical that

00:45:41.020 comes out. Is that the case for neurons that each one only can emit one neurochemical, so it's a largely

00:45:46.660 binary signal? Or are there any neurons that can secrete more than one neurotransmitter?

00:45:52.960 A relatively recent understanding has been that there are multiple neurotransmitters that can be

00:45:58.960 released by the same neuron. We still refer, for example, to the dopamine neurons as dopamine neurons

00:46:04.800 because that's what makes them special. That's what they can do that other neurons can't do.

00:46:09.660 But what we've discovered recently, what the field has discovered recently, is that dopamine neurons,

00:46:14.700 some of them also release another neurotransmitter called glutamate, which is an excitatory

00:46:20.880 neurotransmitter. It stimulates the downstream cells. Other dopamine neurons can release a

00:46:26.320 different one called GABA, which is an inhibitory neurotransmitter. It shuts down the cell that's

00:46:31.660 receiving the signal. So there's actually a great deal of complexity, and that's not all. There are

00:46:36.360 also other things that can be released at the same time, things we call neuropeptides. And there's a lot

00:46:41.700 of complexity on the other side of the synapse too. Different cells have different receptors for the

00:46:47.880 different chemicals that can do totally different things. You can have a receptor for glutamate

00:46:52.960 that makes excitation happen, or you can have another receptor for glutamate that doesn't do that,

00:46:59.440 but makes a longer pattern of modulation happen that's not even a direct excitation. So that's just

00:47:06.180 a flavor of the complexity. But broadly speaking, you'll see us still refer to things like dopamine

00:47:11.880 and serotonin neurons, because that's the first level of complexity. Prior to the work that we're

00:47:17.600 going to get into here, what tools existed to really try to establish causality between the stimulation of

00:47:29.160 one region of the brain and some sort of response, be it a phenotype or an impulse, or was there ever any

00:47:39.960 way to imagine how one part of the hypothalamus was responsible for a type of thought or emotion? I

00:47:47.900 mean, how was that probed? This was a big challenge that neuroscience faced, which is finding out what

00:47:54.680 actually matters for function. And what we did have, we had ways of listening in, we had ways of putting

00:48:01.880 in electrodes to listen, to pick up electrical patterns of activity. You can put an electrode in

00:48:07.280 the cortex or in the hypothalamus or in the brainstem, and you can pick up the chatter of neurons as these

00:48:13.400 little electrical impulses go by. And you could use the same electrode. You could also stimulate. You

00:48:18.560 could send current in through this wire effectively that you've placed. And yeah, that has an effect.

00:48:24.920 And so you can make things happen by just sending current into the brain. And at some level,

00:48:31.400 though, this is just a scaled down version of the electroconvulsive therapy we talked about,

00:48:35.700 which is also just current being put into the brain, it causes things to happen. But there's no

00:48:41.040 cell specificity. Every single neuron in the brain is electrical. And all parts of every neuron are

00:48:49.400 electrical, not just the cell body itself that has the DNA in it, but also every part of the axon,

00:48:56.860 every part of the dendrite, all electrical. And so if you send in current to a spot in the brain,

00:49:02.340 even with a tiny electrode, you're affecting every single cell near the electrode. And not just that,

00:49:09.520 every little bit of wiring that happens to be going through there. So there's no cell type

00:49:15.480 specificity because every cell is electrical. And that's still though, there's work you can do.

00:49:20.680 And so you could stimulate a region of the brain and see if that causes something to happen in the

00:49:26.600 animal. And there was a great deal of really foundational work in neuroscience going around

00:49:31.700 stimulating different parts of the brain. It was discovered that if you put an electrode in the

00:49:37.260 parts of the brain where dopamine neurons live and where the axons come out, that rodents will really

00:49:43.420 work hard for that. They like that, it seems. We can infer that because they will press a lever

00:49:50.200 thousands of times a day to get a burst of electricity to the dopamine neurons. And so that

00:49:56.100 little clues like that are built up over time. But then there was always complexity. As we dove deeper

00:50:01.960 into it, we realized, wait, this is not just the dopamine neurons. In this region of the brain, there

00:50:05.720 are a lot of other cells and connections. So is it really the dopamine neurons? It's this region.

00:50:11.780 But what really are the cells? And so there was a lot of uncertainty in the field as to which cells

00:50:16.880 were actually doing what. And so we had that, but then there was not a good way to turn things off

00:50:21.700 also. And so in science, we like to add things and see what happens. And that's testing whether

00:50:29.040 something is sufficient to cause an effect. And we like doing that. That tells you something. But

00:50:34.840 then we also like to take away something of interest and we can see what is lost with that. And that's

00:50:40.500 testing the necessity of something. How much is that needed? We would have liked to turn off

00:50:45.680 cells and say, okay, now what's different in the animal and their behavior? And there was not a great

00:50:51.280 way of doing that. Crude ways, if you stimulate really hard with an electrode, you could effectively

00:50:56.800 exhaust the cells and make them not fire anymore. And that was sort of the state of the art, both

00:51:03.200 clinically and research-wise, in trying to create a local inhibition. But again, not cell type specific

00:51:09.500 at all because all the cells are electrical. And that's the kind of situation that we found ourselves

00:51:14.200 in. Not too different clinically or basic, no cell type specificity.

00:51:18.700 Do you remember where you were, what you were doing, the very first time you learned what a

00:51:27.060 channel opsin was?

00:51:28.380 So this is an interesting thread that there are these plants and small plants, in fact,

00:51:35.700 single-celled plants that make channel rhodopsins. These are single proteins that are placed in the

00:51:43.500 surface membrane of cells, but microbial cells, not in our cells, in algae, single-celled algae.

00:51:52.000 And related molecules are present in ancient forms of bacteria. These had been known to exist for

00:51:58.620 years. And this class of protein is really interesting because they're light-activated

00:52:04.240 electricity generators. These are single bits of biology, single biomolecules that do an amazing job.

00:52:12.740 They receive a photon of light, and they move charged particles, ions, across the surface of the cell.

00:52:22.180 Now, there's a huge family of these. These are called the microbial opsins, and a subfamily of them is

00:52:29.060 called the channel rhodopsins. Now, what's amazing is that these proteins were known broadly in biology,

00:52:36.340 in biochemistry, in biochemistry for decades. They'd been discovered in 1971 by Dieter Osterhelt and Walter

00:52:43.720 Stokinius, who are at UCSF. And this was part of the training of biochemists, biologists, in

00:52:52.260 Lubert Stryer's beautiful biochemistry textbook. There's a page on the bacteria rhodopsins, and that's

00:52:58.400 where I learned about it. These proteins, they have a photo cycle, it's called. They have a

00:53:04.160 choreography of movements of the protein after the photon hits that lead to an ion, a charged particle,

00:53:10.780 moving across the membrane of the cell. So this was a class of proteins that was well-known,

00:53:17.100 and it turned out that these microbial opsins turned out to be the key for optogenetics,

00:53:24.780 the technology we developed that brought this cell-type specific causality that made it possible.

00:53:31.160 So it sounds like, okay, because I also had Lubert Stryer as a professor. I have his textbook. It's

00:53:35.340 one of the few textbooks I've still kept. First of all, I don't remember that. So, I mean, like,

00:53:40.420 that might be a page in that book, but I was not paying attention during that lecture.

00:53:43.840 So it sounds to me like you knew about these even back in medical school.

00:53:49.240 When did the idea come to you that said, wait a minute, I can now genetically insert these things

00:53:59.860 into neurons and effectively put a digital switch into a single neuron? How and when did that idea

00:54:12.220 cross your mind? Yeah. So there was a coalescence of different threads that happened

00:54:17.360 that were partly plausibility threads. And if you look at this historically, anybody in theory could

00:54:25.680 have thought about this and tried this in the late eighties or all through the nineties, these genes

00:54:31.060 were known. Somebody could have put them into neurons and tried this, but it wasn't technically

00:54:36.300 plausible for many reasons. There were not until the nineties and particularly the late nineties,

00:54:40.920 there were not good ways of introducing genes into neurons. Neurons are a little bit tricky.

00:54:47.520 They're very finicky and sensitive. And I knew this because this was a theme in my PhD work and also in

00:54:53.440 my postdoc work. How can we get genes into neurons? Even in a culture, neuron preparation, it's not easy.

00:55:00.400 That was certainly part of it, part of why nobody had tried this before. But in the late nineties,

00:55:06.280 that started to change. And I did an experiment introducing genes into neurons as part of my

00:55:11.420 postdoctoral work in the Malenka lab. And so this was something I was good at. I developed the viral

00:55:17.900 tools and the ways of introducing genes in that were plausible. Tell folks a little bit about how

00:55:22.720 that works. We're obviously, these days, I think even the lay person is somewhat familiar

00:55:28.060 with genetic modifications. People have some sense of how these have even been used to help develop

00:55:33.880 vaccines and things like that. But let's start from a place, assuming people don't even really

00:55:39.160 know the difference between DNA and RNA, and just explain how you could use this thing called a

00:55:44.620 virus to do your bidding with respect to the insertion of a foreign gene.

00:55:50.200 This is by no means a minor thing. In some ways, this is the whole ball of wax, as we say,

00:55:55.700 how do you get a gene into a neuron in a specific way? So this is the technological aspect of this

00:56:01.740 in some ways is everything. And so it's definitely worth the time to talk about this.

00:56:06.420 How do you do it? Well, DNA is the instruction manual for making proteins, things like proteins,

00:56:13.140 biomolecules that have a job. Each gene is a bit of DNA. It might be a sequence of what we call

00:56:20.180 nucleotides. They have A, G, C, and T. There's four kinds of them, and they come in different sequences.

00:56:25.800 And by the order in which these nucleotides appear, that is a code. That's the genetic code

00:56:31.420 that dictates which protein will be made, a biomolecule that has a particular structure,

00:56:37.400 and a job that comes from its structure, like being in a channel or something in the surface

00:56:43.360 of a cell that receives a photon and lets charged particles go across. That's the protein.

00:56:48.460 The instructions for making it are encoded in the DNA, in the gene.

00:56:51.640 So how do you get that gene into a cell? Well, it's not so easy. These days,

00:56:57.380 particularly with the coronavirus pandemic, I think the general public is much more aware

00:57:01.840 now of how this can be done. Viruses, and there are many kinds of viruses, they are

00:57:09.160 little bits of biology that basically exist to get DNA and RNA into cells. And so they have a little bit

00:57:18.520 of this genetic code material, DNA or RNA, and they have that encased in a coating that might have

00:57:26.620 some lipids or fats and some proteins. And then that floats through liquid, floats through the air,

00:57:34.800 hits a cell, and fuses with the cell, gets the DNA or the RNA into the cell.

00:57:41.660 And then that triggers the creation of new virus particles. And then that's how the virus spreads.

00:57:49.840 So viruses are professional introducers of genetic material in the cells. They are extremely good at

00:57:55.680 that. They are evolved for that. And this DNA-RNA distinction is interesting. Some viruses work with

00:58:02.940 DNA. Some are RNA. What is RNA? This is also something that the coronavirus pandemic has brought to

00:58:09.400 the public's attention very recently. That's the step in between DNA and protein. It turns out, for various

00:58:16.820 reasons, it's useful to have an intermediate step. First, the DNA gets turned into RNA, very similar

00:58:22.380 structure, but then that gets turned into the protein. Some viruses work with DNA, some with RNA.

00:58:28.920 So this, turns out, is then very useful for the biologist, because if you want to get a gene

00:58:34.340 into a cell, and in my case, suppose you want to get a gene for making a light-activated channel,

00:58:43.200 if you want to get that into a cell, well, how do you do it? Well, you get the DNA into the cell.

00:58:46.340 And what's the best way to do that? Well, use a virus. And there are viruses that are dangerous and

00:58:53.140 lethal, but there are also safer, weaker viruses. And then there are modified versions, even of those,

00:59:00.160 that virologists have engineered to be extremely safe, to have lost the ability to propagate from

00:59:06.280 one cell to another, but can do that first step, can bring DNA into one set of cells. And then the

00:59:12.980 life cycle, if you will, stops at that point. Those are the viruses that I had experience with

00:59:18.400 from my postdoctoral work, safe, modified viruses that can be used to shuttle bits of DNA into cells.

00:59:25.600 And so that's the core technology. And again, this was a recent, relatively recent thing,

00:59:30.660 and particularly for neurons, a relatively recent thing. It was the technology for doing that was

00:59:34.900 not so clear in the past. The other thing that I want to point out is that there were many people

00:59:40.820 who were thinking about this and trying this. And we did, from my lab, publish the first paper that

00:59:46.340 used a microbial opsin to get light sensitivity. But it was, as it turned out, quite a close call.

00:59:53.880 We published a paper from my lab in 2005, and that came out in the summer of 2005.

01:00:01.500 Within six months, several other papers came out. They all were submitted right after ours was

01:00:07.100 published. And so clearly, many people had been thinking about this. They saw our paper came out

01:00:12.780 and then rushed to submit theirs. And these were big-time labs, people who were very respected and

01:00:21.420 thoughtful, including, this is something I didn't know, but the brother of my PhD advisor,

01:00:29.380 my PhD advisor was Dick Chen. His brother, Roger Chen, was a Nobel laureate for his work with green

01:00:36.040 fluorescent protein. Turned out he was also working on this as well. I talked to him at great length

01:00:42.180 about this. Of course, he did okay. He got a Nobel Prize for other work, but this was, all this was going

01:00:46.980 on before his Nobel Prize. And so he was quite, I think, frustrated that he wasn't able to get to

01:00:52.080 this moment as quickly. So it was a broad awareness in the field that technology was now available. We

01:00:58.560 could introduce genes into neurons, that these microbial opsins existed. People had wanted to get

01:01:05.300 cell type specificity for a long time with neurostimulation. Francis Crick, of DNA double helix fame,

01:01:14.180 had been calling for this sort of technology for years. In fact, in 1999, he'd even suggested that

01:01:20.520 not only did we need a way in neuroscience to control individual cells, individual cell types,

01:01:27.740 but he said maybe light would be a good way of doing it. He didn't have an idea of how to do it,

01:01:32.300 but he said, you know, light would have some good properties. It would be fast, it would be relatively

01:01:36.340 non-invasive, photons could scatter through tissue, and most neurons don't respond to light at baseline,

01:01:43.120 unlike electricity, and so it would be a way of getting great specificity. So there was this

01:01:48.220 broad awareness that this kind of thing suddenly might be possible. I have two unrelated questions,

01:01:54.080 Carl, about this. The first is, when you introduce the virus, is it one virus that can introduce the

01:02:02.160 gene to one neuron and that's it? He said there's no replication capacity of the virus. So does that mean

01:02:08.500 that the dose of the virus you give determines how many cells will pick up the channel? That's correct.

01:02:16.700 So you can give a very high concentration of viral particles, and that will mean that you get more

01:02:23.840 cells. Also, you'll get more copies per cell. You can have multiple viral particles infecting the same

01:02:30.940 cell, and that is actually very important. Another big issue with these microbial

01:02:36.340 opsins is they generate tiny currents. They're not as professional at generating huge currents as

01:02:42.500 mammalian ion channels are, which was a big reason why I think a lot of people didn't rush to this as

01:02:48.120 well. People looked at those current sizes and said, this is not going to work. Most existing methods of

01:02:53.840 introducing genes gave you maybe one to seven copy numbers of the gene, as we say, so not enough

01:03:01.180 to control a neuron. And that was a huge issue. But with the viral technologies, you could get

01:03:07.240 hundreds or more copies of the gene per cell, and you could get much bigger currents with these

01:03:13.640 microbial opsins. And so then there again, my experience with the viral tools was critical.

01:03:20.140 Just give us a sense of the current. So when you talk about a normal mammalian neuron,

01:03:24.880 how many do we measure these in picoamps, nanoamps?

01:03:27.760 Yeah, picoamps and nanoamps are exactly right.

01:03:30.820 And action potential is how many picoamps?

01:03:33.900 A couple of ways we can look at it. So the action potential, this is this blip of electricity

01:03:38.620 that propagates down the axon of a neuron. It can be triggered by signals that are in the order of

01:03:47.140 100 to 200 picoamps. And then it becomes a voltage impulse that's about 100 millivolts,

01:03:53.860 and that propagates down the cell. So if you're in the hundreds of picoamp range, you're in business

01:04:00.160 for controlling neurons.

01:04:02.740 A single opsin is capable of what?

01:04:06.360 Vastly less than that. And so a couple issues come up. So first of all, what we found is that

01:04:12.460 if you don't have a high copy number, the currents that you're generating are on the single or less

01:04:20.000 picoamp level, we haven't done, because the currents are so small, you typically don't even do the

01:04:25.840 experiment you're asking, single channel current measurements. Since then, out of scientific

01:04:32.280 curiosity, we and others have looked at the currents that are generated, and they're extraordinarily small.

01:04:37.800 We only get to the hundreds of picoamp level by probably expressing, you know, 100,000 to a million

01:04:44.220 opsins per cell. And so this was the key issue. There was many orders of magnitude, as we say,

01:04:50.900 several factors of 10 away from where we needed to be with these opsins, unless there was a way of

01:04:56.840 introducing many genes and getting very robust, safe expression.

01:05:01.220 How do you introduce the virus? So let's just say we're talking about a mouse here,

01:05:05.240 and you decide you want to test in this particular region of the pons. So a part of the brainstem,

01:05:15.700 you want to exactly get it there. How do you direct the virus to exactly the cell you want

01:05:22.820 to get this specificity? Yeah. So this is the other technological challenge that had to be faced. It was

01:05:29.020 not obvious how this would be done. Where would the specificity come from? Yes, none of the cells

01:05:36.580 respond to light. Yes, maybe we could add a gene that makes the cells respond to light. But wait,

01:05:45.660 hang on a minute. Where's the specificity going to come from? How do we get this gene only into

01:05:51.340 the cells we're interested in? Well, all right, what could you do? You could concentrate the virus

01:05:58.740 and do a very focal injection into, let's say, the pons. And so you could create a little

01:06:05.280 hotspot of virus. And then that virus would get into all the cells that are in and around that spot in

01:06:13.780 the pons. And that's good. That gives you some spatial specificity. You're now at a spot. And that

01:06:21.700 is already a big leap beyond the electrode because the electrode and the virus both so far in how I've

01:06:31.400 described them are not cell type specific. But the electrode is going to be stimulating all the

01:06:39.160 axons that happen to be going by. If you do a viral injection at one spot, viruses are not very good

01:06:46.520 at getting into axons. They're just going to get the cells, the little spherical cell bodies that live

01:06:52.140 in that region. And so right away, that gives you some specificity. You're getting less of the cross

01:06:58.420 streams of activity being stimulated. But it's not enough because even if you're just getting the cells,

01:07:04.760 the cell bodies that are there, there are many different kinds. There are the dopamine cells, but right

01:07:09.040 next to them, there are the GABA cells. And next to them are the glutamate cells. And they're all jumbled

01:07:13.660 up together. And there you're not too different from the electrode. Now if you put in light, you're

01:07:18.640 still going to be stimulating all these cells. And so what you need is a way to make the production of

01:07:26.620 the opsin cell type specific. Okay, so how are you going to do that? Well, the virus, there were many

01:07:33.080 possibilities we could think about. And this took probably, until we'd really solved optogenetics,

01:07:38.820 probably took until 2009 because this was the critical issue. How do you get a versatile,

01:07:43.840 generalizable way of targeting specific cell types? And back in 2004, 2005, there were some

01:07:50.400 possibilities that we and others could imagine. You could try to imagine engineering the virus

01:07:56.180 capsid, this coating of the virus that has proteins on it. There were theoretical ways and even possible

01:08:03.400 practical ways of engineering capsid proteins so that they would only target one kind of cell

01:08:09.640 because that kind of cell had something else on its surface. And maybe we could create some kind

01:08:14.180 of lock and key mechanism. Yeah. So just like a coronavirus, its lock and key basically works

01:08:19.360 through the ACE2 receptor. If you knew what a potential surface protein or receptor was on the

01:08:26.840 dopaminergic neuron, that could be your entry. That would have been the first thought that would

01:08:30.820 come to my naive mind. Yep. And that was plausible. It could work. It had some drawbacks, which are that

01:08:37.260 you'd have to, first of all, we didn't have that richness of understanding. It wasn't as if there

01:08:42.760 was some lookup table. Okay. Dopamine neuron has this, so then put this on the, that didn't exist

01:08:49.220 and still doesn't, honestly. So it was more just, okay, there's going to be a lot of work. Every time you

01:08:53.400 want to target a particular cell type, you're going to have to now do some deep dive into all the

01:08:58.500 proteins it expresses and also all the cells that are nearby that you don't want to target and make

01:09:03.900 sure that whatever your strategy is, it's not, it's not giving you some cross activity. And so we

01:09:09.380 initially plausible. And then as you start to think about it more, you're like, oh, this, I mean,

01:09:14.480 this is never going to be versatile, generalizable, practical, and indeed it still isn't today. So that

01:09:21.660 wasn't it. Now, another strategy is working with DNA. Each gene, each bit of DNA in chromosomes,

01:09:32.120 in genomes, has this code for the protein, but also near it, it's got another bit of DNA that's

01:09:40.760 called a promoter or an enhancer. And this is a bit of DNA that doesn't code for a protein.

01:09:48.300 What it does is it attracts what are called transcription factors, things that decide

01:09:55.700 whether that bit of DNA gets turned into RNA and then into protein. They, by changing the structure,

01:10:02.760 by changing things around the gene, they determine whether this gene is expressed at all. It could

01:10:08.780 sit there quiet and not make the RNA and the protein, or it could be active, make the RNA and

01:10:14.440 protein. Turns out that is critical because that was a path forward. We could work with

01:10:20.680 the bits of DNA near genes, promoters and enhancers. This gave us some leverage, not all of it, but some

01:10:29.980 of the leverage. And if you think about this, well, think about a dopamine neuron again. So what is a

01:10:35.300 dopamine neuron? Well, it makes dopamine and it releases dopamine. Okay, now how does it make dopamine?

01:10:39.680 Well, it's got its own biomolecules that make dopamine. It's got enzymes that turn other precursor

01:10:47.740 chemicals into dopamine. Now those enzymes are made chiefly in dopamine neurons. And why are they only

01:10:55.460 made in dopamine neurons and not in your big toe neuron? Well, it's because-

01:11:00.580 Or more importantly, not in the serotonergic neuron right next door. I mean, that's the key insight is

01:11:05.380 you exploit the promoters that are making unique enzymes to a particular neurotransmitter.

01:11:13.440 Exactly right. And so it turns out each cell type is defined by its job, just as in many cases we are

01:11:20.340 defined by our jobs. And this is a critical thing because a professional dopamine producing cell

01:11:27.500 is going to have, by its dopamine enzyme encoding genes, it's going to have promoters or enhancers

01:11:36.360 that dictate in this cell type, this gene will be active. And so what we did was we said, okay,

01:11:41.960 let's see which of those bits of DNA, those promoters and enhancers can we borrow from,

01:11:46.960 let's say, the tyrosine hydroxylase gene. This is a gene that helps make dopamine. We could go take a

01:11:53.760 little bit of its promoter and we could put that in front of the channel rhodopsin gene,

01:11:58.680 package that whole thing up into virus infect cells. You could almost administer it systemically

01:12:03.380 at this point and it's going to go exactly, and this is a very elegant solution, Carl.

01:12:08.160 Yeah. And in fact, the systemic thing now in some ways is done in some settings. It's more costly

01:12:13.940 actually because you have to- You have to use a much higher load.

01:12:15.760 Yeah. And actually the focal injection gives us other advantages. So we still

01:12:20.460 actually prefer the focal injection, but you're right that specificity is now in large part taken

01:12:26.360 care of by the promoter. And so you can inject that in. The virus gets into all the cells,

01:12:31.460 the serotonergic cells and the dopaminergic cells, but the gene is only expressed and the

01:12:36.040 opsin is only made in the dopamine cells as a result of the promoter.

01:12:39.780 So I have another technical question, Carl. So let's go back to your garden variety cold causing

01:12:45.820 adenovirus. So you're out and about in the park or you're on an airplane and you happen to catch this

01:12:52.460 cold from somebody. That adenovirus is going to go and it's going to infect the epithelial cells

01:12:58.520 lining your trachea, probably get into your lung or something like that. It's going to incorporate

01:13:05.320 its genetic material into your machinery, which will then make its proteins. That's how it replicates.

01:13:10.340 And of course the immune system is very good at recognizing this because it's either going to put

01:13:16.900 soluble antibodies to antigens on the surface, or if it's done through class one and class two,

01:13:23.680 the T cell system is going to come and through antigen presentation will recognize foreign antigens

01:13:30.140 being presented on the surface of a cell. So in other words, the host cell, your cell will hold up

01:13:35.460 its little hand and say, look, I've got this little protein in me. The T cell will come and destroy

01:13:40.480 that cell. How do you prevent the immune system from standing by watching you do all of this very

01:13:49.360 elegant genetic engineering, and then just coming along and big footing you because it says, wait a

01:13:54.780 minute, that channel opsins not supposed to be here. Are you just getting lucky that it's not being

01:14:00.300 presented on the MHC class one or class two as a peptide or meaning pieces of it? Because obviously

01:14:05.680 it would be much larger than a nine to eight amino acid peptide, but. Yep. This is a great question.

01:14:11.720 This was another energy barrier to tackling the strategy. Everybody thought, and rightly so,

01:14:18.360 this is a potential concern, right? The immune system is going to attack the cells making this foreign

01:14:24.100 protein and kill them. Well, a couple of things helped us here. One is that we were working in the

01:14:30.180 brain, and as you know, the brain is what we call an immune privileged organ. The T cells and B cells

01:14:37.000 that patrol our bodies don't have free access to the brain. They're kept out, and that's a pretty

01:14:44.320 interesting situation. Why is that? A lot of interesting evolutionary speculations to that,

01:14:49.680 but it's a fact, and so they can't get in. And without that, no doubt things along the lines of what

01:14:55.940 you're saying would be relevant. And we've actually even recently explored this sort of thing. People

01:15:01.160 have been interested in peripheral, not central, peripheral optogenetics, and it works, but people

01:15:08.800 see loss of the expression and the cells expressing the opsins over time, over months, and the immune

01:15:15.460 response is certainly part of that. But in the brain, that doesn't happen. And so that's a great

01:15:20.400 question. And here we definitely leveraged the immune privilege. This was very helpful, Carl. I

01:15:25.740 think maybe for the listener, they thought, boy, these guys want to do a lot of detail here. But

01:15:29.920 I think this was really important because I think only now can we understand the magnitude of A, what

01:15:38.800 you and your team accomplished in what scientifically is considered a nanosecond. I mean, in four years that

01:15:46.800 you were able to do everything you just said, and now we're in 2009, 2010, you have the capacity to

01:15:55.600 introduce these opsins to very specific cells such that you could say two neurons, which are different,

01:16:05.640 I can put this gene into one and not the other. This is unparalleled. So you now have this capacity

01:16:14.100 to use photons to turn neurons on and off with precision that could never be achieved anatomically

01:16:23.680 under anatomic resolution. That's right.

01:16:26.580 So what was the first question you sought to ask using this technology from a neurobiology and

01:16:35.380 neurochemical standpoint? Yeah. We've talked about dopamine a lot. And in 2009, there was an experiment

01:16:42.640 that I and the whole field had wanted to know, which really is, is it the dopamine neurons? Is

01:16:48.880 their activity what animals are getting from this stimulation of that region? Or is it something

01:16:54.880 else, some other cell type that's nearby? Is it the gabergic or the serotonergic cells that we know

01:16:59.420 are right nearby? And in 2009, we did that experiment. So we introduced a channelrhodopsin,

01:17:06.900 an excitatory channelrhodopsin, just into the dopamine neurons of this spot in the midbrain

01:17:14.460 that's called the ventral tegmental area or VTA. It's got all these other kinds of cells, but that's

01:17:19.860 where the dopamine neurons also live. And we used a souped up form of the promoter strategy I just told

01:17:26.740 you about to get the gene into the dopamine neurons. And we asked a very simple question.

01:17:31.180 If you have a mouse and you give it a two room house to live in, it's a very simple house,

01:17:39.340 two rooms that can go back and forth from one room to the other. So kind of just like a New York

01:17:43.100 apartment. Yeah. On a good day. Yeah. Then what if you turned on the laser light, the light that

01:17:51.700 activated the channelrhodopsins on the dopamine neurons, but you did that only when the animal was in

01:17:59.880 one room and not the other room. And what we found is that if you did that, the animals preferred

01:18:06.580 to be in the room where the laser light had been applied compared to the other room, which was

01:18:16.460 equivalent in every other way. So this would be the analogy just to, sorry to interrupt, but just to

01:18:21.420 make a really crude scenario. You could have done this experiment a hundred years ago if you said,

01:18:28.500 I'm going to put sugar water in one room and not in the other, is there a preference that the animal

01:18:35.420 has for it? Presumably it would always want to go to the room with sugar water or cocaine or

01:18:39.720 something pleasurable. But yet here you were able to do that without anything other than the excitation

01:18:46.680 of a particular neuron. Exactly right. And in fact, this test, it was an old test. It's called the

01:18:52.160 conditioned place preference test. And yeah, it's a, the animal now prefers a place. And it's because of,

01:18:58.500 the conditioning is how it was done classically. Just as you're saying, you would pair something

01:19:03.740 good like cocaine or, or sugar or food or a social interaction, a mate, something like that. And you

01:19:10.140 would see later that the mouse would choose to spend time in there revealing to us by its behavior

01:19:16.500 that this thing was positive in value to it. And you can do the flip side too. You can do a negative

01:19:23.980 thing. You can make, make it feel mildly nauseous. You can give it lithium, which we give to patients

01:19:29.260 too. And one side effect you can have is mild nausea. You can give a mouse mild nausea that way,

01:19:35.620 but only in one room. And then it'll avoid that room. And that's conditioned place aversion. So the

01:19:40.440 animal can report to us the sign, if you will, the valence positive or negative of its experience by

01:19:47.540 where it chooses to spend time. And that's incredibly valuable. This harkens back to my very first,

01:19:52.960 you know, wanting to be a neurosurgeon because a human being could tell me what they were feeling.

01:19:58.640 Well, of course a human being is more eloquent, but behaviorally a mouse can report whether it's

01:20:04.640 something as a positive or negative value to it. And that test, Carl, when you're looking for the

01:20:10.240 positive valence, what's the frequency with which you would expect that to be the case? I mean,

01:20:16.300 presumably it's more than 51, 49 in favor of the dopamine firing. Just give us a sense of if you ran a

01:20:22.160 simulation of that experiment a hundred times and you always fired the dopaminergic neuron

01:20:27.360 with your opsin, how many times out of a hundred would it go to the positively valence side?

01:20:32.600 We try to keep things in, you can make this as extreme as you want. So the answer is a bit

01:20:37.700 flexible, but with typical rewards, with sugar water, with a social interaction, the number you're

01:20:44.580 looking for is sort of 70-30 or 80-20. That's kind of the level to which the mouse will prefer one

01:20:51.800 chamber versus another, one room versus another in terms of how it devotes its time. But you can

01:20:57.120 push those numbers both optogenetically using light or with stimuli up or down by making the

01:21:03.860 experience more extreme. It's quite a flexible test. And we had later versions of this. In some ways,

01:21:10.060 the animal's expressing its subjective sense, we think, by where it's choosing to spend time,

01:21:15.260 you can also make a more souped-up version of that test where the animal actually has to work

01:21:18.960 to get the light by pressing a lever or poking its nose in a little hole, a nose poke, and trigger

01:21:27.840 a pulse of light by each of its actions. So this is a slightly more advanced version where you say,

01:21:33.780 how hard will you work for light? How hard will you work for a precisely defined set of activity in

01:21:41.600 your precisely defined dopamine neurons? And if you deliver light, you can get an animal to press a

01:21:49.100 lever thousands of times a day to get that light. And so now there is no doubt that the activity of

01:21:55.860 dopamine neurons in this way is positive. And it's not just positive, it can be extremely positive.

01:22:01.900 Animals will work very, very hard to get it. It's just amazing that this could be done.

01:22:06.860 Let's keep going. I can only imagine how excited you and your colleagues were by this finding. And

01:22:13.360 of course, it probably only whets your appetite for the breadth of questions that you now want to ask.

01:22:20.660 Where was the clinical community in recognizing the value of this tool? So you have all of these

01:22:29.040 questions that have for, I think it's safe to say thousands of years been, in other words,

01:22:36.300 even before the codification of medicine as we know it today, we've always wondered things like

01:22:42.240 what regulates mood? How can two people anatomically be nearly identical and yet one be happy and one be

01:22:49.940 sad? Where do memories reside? What is a memory? What is a feeling? What is a thought?

01:22:56.740 All of these things. And yet I suspect that this experiment as simple as it was for the first time

01:23:02.880 gave you a profound sense of optimism that you now have a tool finally to ask questions. So

01:23:11.700 you're splitting your time here, right? You're still an on the ward psychiatrist. So on the one hand,

01:23:18.720 you're doing kind of the most cutting edge science in the field. And at the other end,

01:23:24.260 you're still trying to help people who are bringing these questions to your mind. How many of your

01:23:30.560 colleagues in psychiatry, not necessarily your direct colleagues at Stanford, but just, I mean,

01:23:34.580 the community more broadly, how appreciated was this tool 10 years ago?

01:23:41.100 It's actually very interesting that you ask that. The appreciation in the scientific psychiatry

01:23:48.460 realm, and these are clinicians, psychiatrists who also have some interest in the science side,

01:23:56.320 the appreciation was very quick and immediate because I think the psychiatrists know and knew

01:24:03.980 better than anyone else how much specificity was needed and wanted in their field. And,

01:24:12.040 you know, I had, this was, you know, by the time we got to 2009, the generality of that targeting

01:24:18.480 method was, was key because then people knew, okay, this wasn't just a parlor trick, a one-off,

01:24:23.840 a demonstration that you could get some kind of photosensitivity in one cell once that this was

01:24:29.700 actually a generalizable, versatile method. You could apply this principle to any cell type. It was done

01:24:36.340 freely moving mammals and mice, of course, being, having our same brain structures, our cortex, our

01:24:44.100 hypothalamus and everything in between. The significance and the opportunity was pretty clear

01:24:50.820 to everyone by 2009, particularly the psychiatrists. And so then there was a great deal of interest

01:24:57.360 and because the technique was generalizable, it was very widely adopted. And we sent the clones,

01:25:02.720 the bits of DNA to thousands of labs around the world and many thousands of discoveries were made

01:25:07.960 by other labs, which was great. After that, really showing that anybody could use it to tackle any

01:25:13.000 question, any, any disease, any symptom in diverse animals. So after 2009, it was off and running.

01:25:20.440 Between 04 and 09 though, those were hard times because we were still putting the pieces together,

01:25:26.560 solving the light delivery, solving the virus issues, getting the cell type targeting to be

01:25:31.020 generalizable and versatile. And I would say it wasn't really until 2009 that we could look at

01:25:35.740 this and say, yeah, we've done it at this point. Was this work funded by NIH?

01:25:41.200 Yeah. So early on, I had some initial trouble getting grants, but then pretty quickly,

01:25:46.840 once the opportunity became clear, both the National Institute of Mental Health and the National

01:25:53.600 Institute on Drug Abuse, two main institutes of the NIH, immediately were very supportive. And then later,

01:26:00.140 we got a great deal of support from DARPA and from the National Science Foundation. And then also from

01:26:06.680 a number of private donors, people who in many cases came through the psychiatry setting, friends or

01:26:14.140 family members who had suffered from psychiatric disease, and they had heard about what we were doing

01:26:18.700 and wanted to support it. So we ended up getting both federal and nonprofit institutions and private

01:26:25.260 donors and it all came together. But really, until we had things working in this generalizable way,

01:26:31.300 times were a little bit tough.

01:26:32.800 Well, it is, again, remarkable now as you sort of look back at it to think,

01:26:37.060 A, that it all worked out. I mean, there's a hundred steps at which this could have failed.

01:26:41.640 And again, I'm still amazed that it really only took four years, although I'm sure there were times in

01:26:47.880 there. It felt like it was taking forever. But I mean, as you know, you're such a historian of

01:26:53.080 science as well. I mean, it is a remarkable period of time. So let's talk about some of the other

01:26:58.240 questions that you wanted to probe with this technology. So what about any of the other

01:27:03.060 neurotransmitters or neurons in particular? Where did you turn to next?

01:27:07.420 Well, we were particularly interested, you know, hearkening back to my, what got me into psychiatry

01:27:13.760 in the first place. I wanted to understand internal states of mammals and how they can go

01:27:21.380 wrong and create symptoms. And if you work with animal subjects, with mice, for example, you have

01:27:27.980 to figure out what they can report that matters. And one thing they can report very well are these

01:27:34.880 universal things that all mammals experience, anxiety, social interaction, and caring for offspring,

01:27:42.500 for young. These are quintessential mammalian states that matter. They can go wrong. So I wanted

01:27:52.160 to study them and I wanted to study them in ways that were now precise and causal and had to do with

01:27:58.420 specific cell types. And so one of the first things we did was anxiety. And, you know, as a psychiatrist,

01:28:06.380 I specialize in patients who suffer from depression and also social difficulties, autism spectrum

01:28:16.320 disorders. And a common theme in both autism and in depression, anxiety is a big part of that.

01:28:23.980 Anxiety is not a small thing. Anxiety can be absolutely crushing to one's life, to one's interactions,

01:28:31.540 to occupation, to even being able to go out in the world. This is a very potentially severe disorder

01:28:42.100 in many people. Of course, anxiety, though, is also can exist in a normal healthy range, too. And it's

01:28:48.920 only it only becomes a psychiatric disorder when it exceeds that healthy range and verges into or in

01:28:57.300 many people, unfortunately, goes way beyond into a very pathological extreme.

01:29:01.900 How do you define that maladaptive transformation from normal anxiety, which I suppose you could even

01:29:08.740 make the case if a person was incapable of experiencing anxiety, they could probably

01:29:13.420 injure themselves and they might be socially quite destructive. So in other words, there must be some

01:29:19.040 evolutionary basis for anxiety and self-preservation. But as you point out, I can't imagine anybody

01:29:24.880 listening to this hasn't personally experienced or known somebody who has experienced anxiety that

01:29:29.820 has crossed too far. But I mean, is this something that falls into the DSM-5 where there's an actual

01:29:34.600 criteria? There must be, right? Yeah, there are. And in fact, it's the criterion for rising to the

01:29:41.140 level of disorder in the psychiatric literature and in the DSM-5 or a diagnostic and statistical manual

01:29:48.500 is that it's only a disorder if there's impairment in what we call social or occupational functioning.

01:29:56.280 So you could have any symptom in psychiatry, even a hallucination, for example. But if it's not

01:30:04.300 impairing your life, your social occupational function, we don't call it a disorder. And in fact,

01:30:10.000 I've had patients who were hallucinating, but it was in a way that was not disrupting their life. I had a blind

01:30:15.440 patient who had visual hallucinations, but he was fine with them. They weren't distressing to him.

01:30:21.380 And so we wouldn't say it's a disorder. It's just something happening. So that's the criterion we

01:30:26.480 use. And of course, it is somewhat flexible because different people have different social and

01:30:32.540 occupational situations. And this is a challenge we have in psychiatry. But maintaining that as a

01:30:37.560 criterion is very good because it ensures that we only treat things that need to be treated.

01:30:41.940 So then you think about anxiety. Well, if you can't function, if you can't leave your apartment

01:30:48.620 to go to work, well, that's impairing your occupational functioning. And so there are people

01:30:52.920 who have anxiety easily in that realm or far beyond. And those are people we want to help.

01:30:59.280 On the flip side, as you point out, there are people who have risk-taking behavior that's extreme

01:31:04.560 because they don't perceive or worry about threat. And that's also a problem. So anxiety,

01:31:10.520 we need to treat it in patients who are severely affected. And the problem is in anxiety,

01:31:16.660 there are medications that help, but they come with some problems. So the most effective

01:31:23.960 anti-anxiety medications are things that relate to Valium and Xanax and Ativan. As you know,

01:31:30.840 these are medications that work, but they can be addictive. They can cause the human being to adapt

01:31:37.620 to the dose and to make it very difficult to stop them. Do we think that they primarily work through

01:31:43.260 their GABA agonism? Yes. Primary belief. So you talked about GABA earlier. This is a relaxing,

01:31:50.540 for lack of a better word, neurotransmitter. This is a non-excitatory. That's right. That's exactly how

01:31:56.180 these act. They act, in fact, directly on the GABA receptor and they facilitate its action.

01:32:02.380 And they work. They just have some problems and not everybody can tolerate them. They cause some

01:32:07.880 cognitive slowing and sedation and so on. It's like they have some issues.

01:32:12.500 And which neurons in particular do we think that they're concentrated in their action in?

01:32:16.960 That is a great question. It's a subject of a lot of research. If we understood that

01:32:21.980 deeply, then we could make a separate intervention targeted to those cells.

01:32:28.260 The problem is that we don't yet know that exactly. We don't know exactly which cells

01:32:32.720 are the most anxiety-relevant cells that these medications are targeting. There are some hints,

01:32:40.260 but I would say not factually known yet. But you're getting to this key point where optogenetics was

01:32:45.020 helpful because then we could ask that and answer that question. We could say, okay, which cells govern

01:32:50.040 the different features of anxiety? And then what am I talking about here with different features?

01:32:56.000 Well, actually, this is kind of interesting when you think about it. So what is anxiety? Well,

01:32:59.820 it's actually got different parts to it. First of all, there's physiology. We've all been anxious. We

01:33:06.360 know heart beating faster, breathing faster. Okay, so there's physiology that changes. Then

01:33:12.760 there's also a behavioral change. When we're anxious, we avoid the risky situation. We have an impulse

01:33:21.680 to avoid. If we're anxious out in the open, we avoid going out in the open. And mice do this too.

01:33:29.740 And then finally, there's a negative quality to it. This is the negative valence. This is the

01:33:35.480 hardest part to put your finger on. This is the hardest part to put your finger on. And it's the

01:33:39.060 most mysterious and perhaps the most difficult, meaning perhaps the most difficult to experience.

01:33:44.540 It's the most difficult to experience. And it's also the most difficult to understand why we have

01:33:51.340 this. If we're already avoiding the risky situation, why does nature also have to make us feel bad? And

01:33:58.040 this is, there are some very interesting evolutionary discussions one can have about that. The fact is,

01:34:03.680 though, that's how it is. Anxiety feels bad. And that's what makes it, in many cases,

01:34:08.820 causes so much suffering in addition to the behavioral dysfunction that happens.

01:34:11.900 So actually, anxiety is complicated. It's got these different parts. And they all come on

01:34:16.040 together, all go away together. And then you've got to ask, okay, these are so different,

01:34:20.100 they're probably controlled by different cells, right? So you've got behavior, and you've got

01:34:24.580 breathing, and you've got inner subjective sense. These are all very different, probably different

01:34:29.780 cells are doing it. So then right away, you've got to ask, what are we going to target? So we thought

01:34:35.180 we need to figure out this. And so we used, in 2013, we did an optogenetics experiment that targeted

01:34:40.860 different parts of what we thought could be the anxiety pathway. And we found that indeed,

01:34:46.400 different cells control each of these different parts. There's a set of cells that control the

01:34:54.020 breathing changes. And there's another set of cells right nearby that control the behavioral changes,

01:34:59.860 avoiding risky situations. And there's yet a third set of cells that control the negative

01:35:05.620 valence, the internal state. Each cleanly controls separate feature of anxiety. And we

01:35:12.840 did this with optogenetics, introducing light sensitivity and light-triggered activity.

01:35:20.280 And then reproducing each of these completely distinct manifestations of anxiety.

01:35:26.840 Exactly, exactly. So we found we could turn up or down each feature in mice completely separately

01:35:33.300 from the others. We could have animals that, and this got so interesting philosophically. We could

01:35:38.380 make animals avoid the open area, the exposed realm that people and mice, but we don't, many people

01:35:47.020 don't like being out in exposed areas. Mice definitely don't because that's when they're going to get

01:35:50.680 eaten. We could make mice be much more avoidant of an open space with a specific cell type

01:36:00.180 optogenetic intervention. But the mice didn't care that this was happening. There was no negative

01:36:06.340 valence to it. And this was so interesting that we could create the behavioral avoidance of anxiety

01:36:13.420 without the mice... Without the negative feeling.

01:36:16.940 ...having this negativity. And so that, it turns out then that behavioral states that mammals have,

01:36:22.640 they can be cleanly broken apart into these features, and we could show that with optogenetics.

01:36:27.080 That was one of my, one of the,

01:36:30.180 papers from that period of time that was most interesting because it was, was so interesting

01:36:34.220 in that regard. And other people, Catherine Duloc, for example, at Harvard has done some great work

01:36:38.540 on parenting, another quintessential mammalian state using the same set of techniques, optogenetic

01:36:45.520 techniques that we've described. She did this in 2018. Mice are, are pretty good parents. They take care

01:36:51.040 of their young mostly. That can break down at times, but they care for their young. And Catherine Duloc's

01:36:57.340 lab did an amazing experiment. They optogenetically found that different parts of parenting could be

01:37:02.740 broken down into their sub features as well. And the two parts of parenting that were broken down in

01:37:11.060 this way are going out to find the young and bring them back to the nest. So go and get your kids and

01:37:19.000 bring them back home. And anybody who has kids knows that's a big part of being a parent. You got to

01:37:24.580 corral them, get them back to the safe spot. But that part of parenting that mice do very well. They

01:37:32.700 also care for the young. They groom them. That's an extremely important part of both human and mouse

01:37:39.460 parenting, of course, is grooming the offspring. Turns out there's a parenting controlling area, but the go

01:37:47.960 and get the kids' cells are different from the groom the kids' cells. And you can optogenetically

01:37:53.900 break them apart very cleanly and show how this parenting state is assembled from its features.

01:38:00.320 And this kind of thing has been, those are just two examples, but that kind of thing really gets to the

01:38:05.460 heart of what's so interesting about the brain is how do these complex states, how are they pieced

01:38:10.380 together from cells? Why does anxiety track so closely in people with autism? Have you been able

01:38:19.520 to glean any insights into that? And autism is something that interests me immensely. What do we

01:38:26.200 really understand about this disease? I think we know that it's got a significant genetic component.

01:38:32.020 It's not entirely clear what triggers it. And its phenotype, of course, exists on a pretty extreme

01:38:38.820 spectrum in terms of functionality, superpowers and super deficits. But what do we know about autism?

01:38:45.900 And then specifically, why is it that anxiety tracks so closely in people with it?

01:38:51.880 Autism is one of my main clinical focus areas. This is actually my clinic office here. I see patients

01:38:57.880 with autism spectrum disorders here. I know that they are hard to treat. There's not a medication

01:39:04.640 that treats autism. But as you say, a lot of them are very anxious. And that I can help with. I can

01:39:11.600 help them with their anxiety, with medications like the benzodiazepine class of medications that

01:39:18.220 we talked about. Those help the anxiety. They don't help the social problems per se, but they help with

01:39:25.380 the anxiety. And why is that? Why is anxiety such a comorbid symptom, as we say? Why does it show up so

01:39:31.480 much in autism? Well, the human social interaction world is very complicated. It's very fraught with

01:39:40.180 possibilities for misunderstanding, catastrophic errors of interpretation, embarrassment, humiliation,

01:39:50.920 confusion. We have a very social world that we've created. And people who have difficulty with

01:39:58.720 keeping up with the fast rate of social information and making sense of it, it's a very anxiety-provoking

01:40:07.020 situation. When you're talking to somebody, how do you know where to look, what to do? What part of

01:40:14.900 them do you pay attention to? Do you look at their eyes? Do you look at their mouth? Do you look at their

01:40:18.820 body movements? God forbid there's more than one person in a conversation with three people. How do you

01:40:25.240 know who to look at? How do people know what to say next? To someone on the autism spectrum, these are

01:40:31.320 extremely challenging situations because it's very hard to keep up with this high information rate of

01:40:39.180 the social interaction. And this is something in the book, Projections, that we've talked about. There's a

01:40:43.880 whole chapter, a story on autism and on how this might happen neurobiologically, how this information

01:40:52.020 overload might happen. We have patients who are as confused by social interaction and as overwhelmed

01:41:00.440 by it as you can imagine somebody not knowing the language, not knowing the customs of a culture and

01:41:06.800 being placed into it while extremely consequential things involving them were happening in real time.

01:41:14.080 And that's kind of the situation. And so you can understand anxiety being a big part of autism,

01:41:19.900 just being unable to predict what happens. And so these are patients who we can help with their

01:41:23.880 anxiety, still not yet with their autism. The genes that are linked to autism, there are many. It's a

01:41:30.640 very genetically determined disease, not completely, but heavily genetically. The problem is, like so many

01:41:38.040 of the psychiatric disorders, the genetic underpinnings, it's a patchwork. It's many different genes that all

01:41:44.920 contribute a little bit in most cases. And so with all the beautiful genetics, which has given us a lot

01:41:50.960 of insight, it hasn't led to treatments because there's not a single gene, single protein, single

01:41:57.340 cells intervene in yet. Are you optimistic that that's going to change? I mean, what does the treatment

01:42:02.060 for someone with autism look like in the coming decade? Let's keep it relatively short term.

01:42:07.520 Well, the exciting thing is optogenetics has given us a window now into what could be this sort of

01:42:15.260 10-year time scale of autism treatment. Because now, and again, mice are social. Not only do they

01:42:22.440 parent, but they're also social. They will choose to spend time with another even same-sex member of

01:42:29.960 their species compared to being alone. And they have complex interactions. They have a give and take.

01:42:39.980 They exchange information. And there's a lot of it. And if you make mutations in some of the genes that

01:42:47.240 are most powerfully related to autism that come from the human literature, you can make mice that have

01:42:54.120 impaired social interaction as well. And we've done this, and we've studied these in the laboratory,

01:42:58.880 and we've asked, can we correct the social deficit of these mice? And we can. And this is a whole thread

01:43:07.640 of work in my laboratory studying social interaction and asking which cells, which circuits in the brain

01:43:16.840 can improve social interaction, including in these autism mutation mice. And what's pretty interesting is

01:43:28.620 that if you think about social interaction, just like everything else, and the parenting example

01:43:34.560 made that clear, there are different parts to it. Part of a social interaction might be the motivation,

01:43:40.580 the drive to be social. And that could vary in people. Also, the cognition, the understanding,

01:43:47.440 the insight, that could be separate. That's another part of being social, is understanding what the

01:43:52.680 heck's going on. Probably different cells affect each of these. And indeed, we've found that. So

01:43:57.560 some, there are some dopamine neurons that do seem to increase the drive for social interaction.

01:44:03.860 But then, there are other cells in the front of the brain, where some of the most advanced,

01:44:08.800 complex cognitions happen, the frontal cortex, that may be more involved in the information

01:44:16.440 firehose that's coming through with a social interaction. How do you keep up with it? How do

01:44:21.600 you make sense of it? That may be more of the cognitive side. And so, just like everything else,

01:44:26.660 you've got to figure out what's most important. And we found those, though. We now know the cells that

01:44:31.360 can improve social interaction in these different areas. And now that we understand these cells better,

01:44:37.480 you can imagine designing medications that, for the first time, are aligned with a specific kind of

01:44:47.620 cell that's known to be important in social interaction. And that's the exciting opportunity

01:44:54.840 for the future. We're not there yet. But at least now, we have a causal cellular understanding. And that

01:45:00.680 opens so many doors. Is it your belief, Carl, that at least in the next decade or so,

01:45:06.780 optogenetics will be the tool for establishing cellular signal-wise causality, but not be the

01:45:16.520 mode of treatment? In other words, I'm sure people ask you this all the time. I certainly have a

01:45:20.740 thought on this, but I thought it's worth asking just to make sure everyone's on the same page.

01:45:25.720 Is it your belief that patients are going to be coming into your clinic with probes that you will be

01:45:31.700 lighting directly to actually change the neurotransmitters via the light? Or is it that

01:45:40.700 we'll just use that as the tool to establish where to target our treatments? Or do you think it's going

01:45:47.580 to be a combination of these? Yeah. Optogenetics, in my view, is by far the most important aspect of it

01:45:54.300 is it's a discovery and understanding tool. This helps us because this brings so much that we

01:45:59.680 didn't have before. Understanding what actually matters, what makes things happen in the brain

01:46:04.440 at the level of cells is the opportunity that optogenetics creates. And that understanding

01:46:10.580 then opens the door to every kind of treatment. Once you understand that, which cells are actually

01:46:15.300 causing and relieving symptoms, you can design medications that address those cells. You can design

01:46:21.560 brain stimulation treatments targeted to those cells or their axons as they project across the

01:46:27.940 brain. So it opens up every door in principle, providing this causal foundation. Now that said,

01:46:35.540 and so that I see is by far the future. It's the understanding that opens every treatment door.

01:46:40.120 That said, my friend and colleague, Botan Roska in Switzerland, just this year, was able to confer

01:46:46.780 a form of sight onto a blind person with optogenetics. And this was just published in

01:46:52.360 the journal Nature Medicine this year. Ten years ago, he and I had collaborated on a study where he

01:46:58.780 put one of our microbial opsins into a human retina, cadaveric, afterlife. So he had ways of keeping

01:47:07.620 the retina alive for some time in these donated retinas. And he was able to show optogenetics worked

01:47:14.680 perfectly well to control human retinal neurons. And he spent the next 10 years doing all, going

01:47:22.040 through all the hoops of going through primate studies and then clinical trials. And then just

01:47:27.900 this year, he's a vision scientist and he focused on retinal degeneration and was able to take a human

01:47:34.240 being who was blind from retinal degeneration. And he was able to create light sensitivity. So this

01:47:40.700 person could accurately reach for objects on a table that was not possible before. So literally

01:47:45.860 making a blind person see, at least to some extent, can happen. So I think there may be

01:47:52.000 cases like that. And of course, they're uplifting to see. But the biggest picture is that it's a

01:47:57.880 discovery tool. I want to pivot a minute to talk about your book, because I think it becomes a great

01:48:03.820 place for us to now talk about some of the mental illnesses that people will be familiar with,

01:48:09.600 depression, mania, and its sort of cousin bipolar disorder, eating disorders, all of these things

01:48:14.940 that you've written about so eloquently. First of all, I want to tell you that if I'm not already

01:48:20.460 in complete awe of your scientific achievements, I'm equally in awe of your writing achievements.

01:48:27.360 And I just don't think it's fair that one person can be so gifted on two dimensions, Carl. It's really

01:48:33.080 disappointing. And I hope there's something in life that you're horrible at so that I don't feel

01:48:37.860 even worse about myself. No, seriously. Your book is unbelievable. It's called Projections.

01:48:44.160 And I've read it twice. And I will encourage every listener to read it, because it will shatter some

01:48:52.320 of the images people have of scientists, because you don't write like a scientist. And I say that as

01:48:57.240 somebody who's in the process of sort of finishing up their book. And the biggest challenge I have in

01:49:02.240 writing is making it accessible to everybody, making it interesting enough that someone for whom this

01:49:09.460 is not their life wants to read it. You've done that in spades. This really reads like, at times,

01:49:16.880 poetry. I know you've always had an interest in writing. Did it require much effort and discipline

01:49:22.780 to write about such technical matters at times, but also to write about sort of the clinical conditions,

01:49:30.260 these psychiatric conditions that everybody's familiar with? It seemed effortless that you

01:49:35.760 were able to do this in such an easily accessible and artistic way. Well, first of all, thank you,

01:49:42.660 Pete. It means so much to hear that. You never really know when you take a step like this or a risk

01:49:49.080 like this, if it's really working. This was a risk. This was something that was very different. It's not

01:49:56.400 what people expected. As you say, not a typical scientific text at all, really. And the goal I

01:50:03.340 wanted though, the goal I had was to help everybody, whatever their background, I wanted to help them

01:50:09.840 understand and feel what these altered states are. And that's such a big part of the book is to work

01:50:18.420 with that feeling, to help people understand and feel for themselves what mania might be like,

01:50:24.540 or what the fragmentation of schizophrenia might be like, or the crushing pathological grief of

01:50:31.260 bereavement, or the incredibly complex states of eating disorders where you have these astonishing

01:50:39.560 behavioral patterns that seem so inexplicable compared to what you would think would be

01:50:45.820 what we were evolved to do. And so everything from these uplifting, exuberant states of mania to the

01:50:53.140 depths, I wanted people to feel this. And so I had to do this with the writing, with the words,

01:50:58.040 I wanted to do it with the writing and the words. And so in each chapter, the writing is adapted to

01:51:03.160 cause that feeling. In the mania story, the words are exuberant in the way that mania is. In the

01:51:11.460 schizophrenia or psychosis story, there's a fragmentation and a disorganization that happens.

01:51:17.980 And so in all of these cases, I had to work with words in ways that are not typical for a scientist.

01:51:25.020 But of course, I wanted to do it. This was my initial passion in life. And for me, it was incredibly

01:51:31.320 fulfilling, actually, to come back and be able to do this. I'd always wanted to do it. I had now not

01:51:38.500 just the desire, but I had a mission. I had something I wanted to tell, I wanted to share with

01:51:43.000 everybody. So for me, it was incredibly addictive, actually. I would, I did the bulk of the writing

01:51:50.120 over a couple of years from 2017 to 2019 or so, and then wrapped it up in 2020. And I looked forward

01:51:58.620 to this so much every day. I would block out a couple hours, but a different time each day,

01:52:03.420 depending on my schedule. You know, life's complex now. I've got five total kids. Things are hopping at

01:52:09.000 home. My wife, Michelle's an incredibly accomplished MD-PhD herself, also running clinical trials.

01:52:16.420 Also one of our classmates.

01:52:18.100 Also one of our classmates. And of course, she's in the hospital a lot. And so no day is simple or

01:52:24.240 predictable. So that the writing time would be at different times, often very late at night,

01:52:30.340 often early in the morning. I tried to block out two hours, but I would find I would look

01:52:33.560 forward to that like, like almost nothing else. And I just relish the joy of finding the right word

01:52:40.500 and spending days thinking about trying to find the right turn of phrase. And so it was, it was

01:52:46.260 incredibly uplifting, honestly, even though of course, a big challenge logistically.

01:52:52.120 One of the things I love about the book is how really try to dive into the evolutionary basis for

01:52:59.700 mental illness. This is something I'm always obsessed with. I always love trying to think

01:53:04.680 about things through an evolutionary lens. And sometimes, you know, the answers come a little

01:53:09.320 easier than others. One of the places where it comes up is in the story of Alexander. This is a

01:53:14.860 gentleman won't give away the entire story, but basically post 9-11 is triggered into what sounds

01:53:21.600 like his first manic event, correct? That's right.

01:53:24.880 Which then gets into kind of this discussion of mania. What is mania?

01:53:28.540 One of the things I found very interesting about this was the discussion about the evolutionary

01:53:34.020 basis for mania. And this is interesting to me personally, because this is a very personal

01:53:39.560 story, I guess. But when I was in residency, I was encouraged by my wife actually to see a

01:53:45.860 psychiatrist. She had some concern about some of my behaviors. And the psychiatrist, after one day,

01:53:53.240 I don't know if she was right or wrong, but she decided I was hypomanic. That was her diagnosis.

01:53:59.320 And that, of course, got me very interested in, well, why is this the case? How does she know?

01:54:04.340 Why would this be? And I began sort of examining everything I'd ever done in life. And one of the

01:54:09.940 things I came across was at the time, it was a psychiatrist at Hopkins. So this would have been

01:54:15.820 kind of 2004, 2005, had written a book suggesting that the prevalence of hypomania in North America

01:54:22.480 was higher than anywhere else in the world, because it had the highest concentration of

01:54:27.960 recent immigrants. And the argument was, well, by definition, if you have a collection of people

01:54:34.300 who are one to five generations away from people who had basically the nerve to leave a comfortable

01:54:43.120 life elsewhere, and in the case of certainly my parents and many people who came here, basically

01:54:49.140 to come to nothing. You don't know the language, you don't know the culture, you don't know the

01:54:52.040 people. It wouldn't be surprising that you could concentrate hypomania here. A, I'm curious as to

01:54:58.740 whether you have any thoughts about that theory, but perhaps more importantly, let's dive into this

01:55:03.480 evolutionary basis for mania, because the point that you get into about how there are sometimes

01:55:10.480 where traits are very valuable at the population level and not at the individual level, I found

01:55:15.880 that fascinating. Yeah. Well, first of all, that's a very interesting route into this discussion,

01:55:22.240 which is the immigrants, the recent immigrants, and the possible genetic link to have the, you know,

01:55:29.980 in recent times, to have the get up and go, to leave, to take the risks, to have the energy,

01:55:35.580 to have the motivation, to actually make it happen, to sustain it, this complex goal with so many

01:55:40.380 possible downsides. That's no small thing. Some people wouldn't want to do it, some would.

01:55:45.940 And mania, it's one of the poles of bipolar disorder, which is a very genetic, highly genetic

01:55:54.720 disorder. One of the most in psychiatry, bipolar type one disorder, extraordinarily genetically

01:56:00.900 determined. Just to be clear, Carl, does that mean that bipolar stems from bipolar or it just

01:56:07.280 clusters with other psychiatric illness? So in other words, schizophrenia or significant depression

01:56:13.420 would also be genetic precursors to it.

01:56:15.940 What it means in this case is that it's, if you look at monozygotic twins, especially those that

01:56:21.160 are raised apart, that's where the most pure information comes from. You can look at the

01:56:25.460 concordance of mania or bipolar disorder appearing in each of these twins, identical twins. It's more

01:56:32.580 than 50% for bipolar type one, in fact, verging above 70%. And so you have a very strong bipolar type

01:56:40.800 one genetic determination. Out of curiosity, what is it for autism in that same setting?

01:56:45.940 Autism also high, just maybe just a touch under that. With depression, it's like 50%. And so most of

01:56:52.900 the psychiatric disorders have strong genetic links. They tend to be less than 80%. But in this kind of

01:57:00.200 50 to 80% range for many of the severe ones, from depression to schizophrenia, to autism, to bipolar.

01:57:06.360 And so this is something we face in schizophrenia and in autism. But in bipolar, it's extremely

01:57:13.320 strong. So right away, we know there's that link. And mania is the positive pole of bipolar disorder. The

01:57:19.920 other pole is depression. People with bipolar type one have had at least one manic episode where they have a

01:57:27.200 period of time. It could be a week where they've had this very clear, discreet state of elevated mood,

01:57:34.560 increased goal-directed activity, projects, plans, spending, taking risks, faster speech, not needing

01:57:42.080 sleep, truly not needing sleep, not nearly as much. And honestly, even though this causes problems

01:57:48.880 serious problems, and not to sugarcoat it at all, mania can do terrible things. People make very poor

01:57:57.040 decisions. They can be fatal. Yeah, I was just about to say, aren't people even slightly more likely to

01:58:02.780 harm themselves during a manic phase than the depressive phase? Yes, or the transition from out

01:58:08.840 of depression to mania, that's actually probably the most risky time when they might still have some

01:58:13.540 of the negativity from the depression. But now they've got the energy to act. Yeah, exactly. It's

01:58:19.360 a problem. But yet at the same time, some of my most memorable experiences in talking with manic

01:58:23.980 patients is I actually love talking to them because there's such a charge of energy. Anything's possible.

01:58:30.660 They're funny. They're warm. They're charismatic. And it's so easy to see that this is a state that's

01:58:37.680 it's not a bunch of random things happening in the brain. This is a coherent state of

01:58:43.520 elevated mood. It's consistent. You see it in one patient. You see it in another patient.

01:58:48.260 It's something that's there that human beings have as something they can do, a sustained state

01:58:54.980 of elevated mood and energy. And you look at that and you think, okay, why? And also, what does that

01:59:03.500 mean for treatment? Is there an ethical issue with treatment? Are there cases where mania is positive?

01:59:12.380 And this is something that the story in the book and projections really made me think

01:59:17.400 so hard about. This was actually when the seed for the book was first planted in my head. It was just

01:59:22.460 20 years ago, right after 9-11. And this patient, Alexander, he had never had any psychiatric illness

01:59:29.400 at all, nor in his family. But he was flipped into a completely classic, full-blown mania after 9-11.

01:59:36.700 And he had no particular connection. In fact, he was on a sailing trip in the Mediterranean with his

01:59:42.780 wife at the time, came back home after 9-11. And a couple of weeks later, he was manic. All these

01:59:49.520 symptoms that we talked about, and it was a huge problem. But he had this appropriate or at least

01:59:56.740 aligned quality to his symptoms. He was retirement age, but he was training himself to go into battle.

02:00:03.820 He was rappelling down trees. He was running through the night. He was reading about military

02:00:09.540 strategy. And then it verged into this very difficult, emotionally challenging. He was

02:00:16.240 screaming. He was hyper-religious. Everything had become quite extreme and incompatible with his life.

02:00:23.340 And so that ended up bringing him to the hospital. But looking at this and we think, okay, this is a

02:00:27.920 state of elevated mood and energy. It was triggered by context. And this is actually the flip side of

02:00:33.400 what you're saying with the immigrants. Not only is there likely to be a set of conditions that led

02:00:40.380 to these people being able to have the energy and willingness to take the risk and meet all the

02:00:45.740 incredible challenges of moving across countries and cultures. But then that's not this fight or flight

02:00:52.200 response of a minute when you've got a threat and you have energy and then you meet the threat and then

02:00:56.400 it's gone. We're talking about you need a sustained level of energy for weeks, months, years even, and

02:01:04.400 to take a risk and a life shift like that. And so everything is on a spectrum and you've got mania and

02:01:12.280 then you've got this hypomanic state in between that makes a lot of sense that people who are able

02:01:17.540 to sustain this elevated energy state are those that would be VR immigrants. And again, you have to look

02:01:24.420 at this and think it's a spectrum. Definitely it can be bad, but we have to value the whole spectrum

02:01:32.400 and understand the whole spectrum. It's part of who we are as the human family. Why do you think that

02:01:37.140 in the bipolar condition, you have this pairing of such opposites? Is the depression a necessary part

02:01:44.980 bipolar to basically allow the recharging after this unbelievable discharge of emotional and physical

02:01:52.860 energy? Because otherwise it doesn't seem like these would, you know, like for example, why doesn't

02:01:58.240 it just go normal affect mania, normal affect mania? Yeah, that's a great question. We don't have the

02:02:04.760 answer. Some people, some fortunate people are like that. You can get a diagnosis of bipolar disorder

02:02:10.800 without ever having a depression. One episode of mania gets you that diagnosis of bipolar type 1

02:02:16.720 and those people, there are people who haven't hit a major depression yet. That said, most of the time

02:02:23.680 there is that other pole of the disorder. And what is it? Is it, we don't know. Short answer is we don't

02:02:29.440 know. But a lot of interesting ideas. One could be sort of aligned with what you're saying that there's

02:02:35.380 some resource that's exhausted. It's not a resource that we know what it is. We can't point

02:02:40.880 to it. Is it a neural circuit state of some kind, a capability of a neural circuit that can become

02:02:47.460 exhausted? We know neurons can run out of energy. This is part of how the brain stimulation to cause

02:02:53.820 inhibition works. But that's all on a very fast timescale. You can exhaust neurons on seconds to

02:02:58.420 minutes. It's not known what really could get exhausted on the weeks scale. We don't know what that

02:03:04.300 would be. Or maybe it's the termination mechanism, but it just overshoots. Or maybe it's just that

02:03:11.460 what's lost is the homeostatic thing that keeps energy in a tight range. And then it could go in

02:03:19.540 either direction because you've lost some break that's present on either side. Not known, but a

02:03:25.140 very interesting question. What is technically the most common psychiatric disorder? Is it depression?

02:03:30.100 Actually, the anxiety disorders, if you group them together, anxiety is the most common.

02:03:36.060 But depression is certainly up there. That's in the top group for sure. Anxiety disorders are

02:03:41.660 so underappreciated. A lot of people don't talk about them. A lot of people can make it through the

02:03:47.020 day with anxiety, even if they're suffering terribly. So yeah, anxiety is most common.

02:03:52.640 What has optogenetics taught us about depression?

02:03:54.720 This is my clinical specialty. I have right here in this office, we do vagus nerve stimulation.

02:04:01.020 For example, this is a VNS therapy, a radio frequency controller. We still do here electroconvulsive

02:04:07.480 therapy. We do transcranial magnetic stimulation. Clinically, though we're looking for guidance from

02:04:13.820 the science because it's still not known clinically what actually is going wrong in depression. We don't

02:04:21.240 actually know that in a way that can guide therapies in the way that we'd like. And what's

02:04:27.360 the scientific situation? Well, optogenetics has helped quite a bit because, and again, picking up

02:04:31.840 on this theme, of course, there's different parts to depression. And this is how we diagnose it. We ask

02:04:35.880 about all these different parts. There's depressed mood, and that's this negative state, okay?

02:04:44.640 There's hopelessness. So it's kind of the opposite of mania. A manic person thinks anything's possible.

02:04:49.780 Well, depressed person thinks nothing's possible. There's a deep discounting of the value of effort.

02:04:55.420 And this shows up as hopelessness. This even can lead to suicidality and certainly severe social

02:05:00.780 and occupational dysfunction. And then there are other parts to depression. There's something

02:05:04.840 called anhedonia, which is really interesting. Yeah, this is perhaps the most insidious component

02:05:09.940 of depression by far. Right, right. And it's not commonly known. People on the street don't talk

02:05:15.940 about anhedonia, right? They'll say they're depressed, but nobody talks about their anhedonia.

02:05:21.160 But it's an incredibly important symptom. It's such a core symptom of depression that actually

02:05:25.180 you can get a diagnosis of major depressive disorder without depressed mood if you also have

02:05:30.420 anhedonia. It's that important. And it's the absence of pleasure or joy from things that normally

02:05:38.080 bring pleasure or joy. And we've all had a cold and we've known that taste is gone. Food has lost all

02:05:47.020 joy. It's things even without the cold with the anhedonia of depression, all the joy of food or

02:05:54.320 social interaction or, you know, your children, your grandchildren, a book, a movie, all the joy of life

02:06:01.580 is gone. And this is a horrific thing. It leads to very serious problems. And that's something that

02:06:08.940 optogenetics has helped us understand. What do we know about that? Where do the neurons reside and

02:06:14.700 what are the neurotransmitters involved in the propagation of anhedonia? So again, you might say,

02:06:20.500 how are you going to test this? And you can set up very simple behaviors with animals that provide

02:06:26.600 some insight. First of all, you could provide a simple choice for animals. Mice like us like sugary

02:06:34.180 drinks, and you could give the animal a choice of a sugary drink or just water. And normally,

02:06:40.480 a mouse will prefer, kind of like we do, they'll prefer the sugary drink and buy a factor of, you know,

02:06:46.140 two to one or more. But a mouse that's been stressed, it's had some unpredictable events happen,

02:06:53.080 it's had its sleep disrupted. It will not prefer the sugar water nearly as much. It won't care as

02:07:01.980 much. And so it's such an interesting thing, given all the evolutionary importance of a small,

02:07:07.360 high metabolic rate mammal needing sugar. And we know the reward that we feel from sugar and presume

02:07:14.760 it's very similar for them. And then not caring, sugar water, regular water, doesn't matter now.

02:07:21.060 So in other words, if you had them going 50-50 between sugar water and regular water,

02:07:26.700 that would be even more telling than if they disproportionately went to the regular water,

02:07:31.120 right? You would be looking for a complete amelioration of the effect of the sugar water

02:07:34.820 would suggest that they have basically lost interest. That's right. That's exactly right.

02:07:39.560 And that in fact happens. And so we and others have explored this kind of thing with optogenetics.

02:07:44.840 And we found that there are pathways and coming back again to the dopamine neurons, which are

02:07:50.800 tightly linked to mood and mania and depression. But they're a complex set of cells. Some send

02:07:57.500 connections to one part of the brain, some send connections to another part of the brain.

02:08:01.900 We have found some interesting pathways that relate to those dopamine neurons where you can actually

02:08:07.900 affect how potent a normal rewarding stimulus is by something going on in the frontal cortex,

02:08:17.200 in the frontal part of the brain. An overactivity in the prefrontal cortical areas can cause anhedonia

02:08:25.540 in rodents. An overactivity seems to cause an inability of the dopamine neurons to recruit,

02:08:33.860 reward circuitry. And so this is an insight that optogenetics brought us. And it's something that

02:08:39.780 we're following up mechanistically. It's kind of an interesting thing that there's,

02:08:44.520 what we found is that again, using optogenetics, that the frontal cortex can suppress both positive

02:08:49.580 and negative things. It can suppress fear. It can suppress anxiety. This is part of how we exert

02:08:55.480 cognitive control over situations. We can enter a scenario that we know is risky. If we think about it

02:09:03.260 enough, if we frame it enough for ourselves cognitively, if we review the need for it,

02:09:10.720 for taking this action. And so our frontal cortex can help us by tamping down negative aspects,

02:09:18.480 but it also, when overactive, it turns out can tamp down positive aspects as well. And optogenetics has

02:09:24.840 given us a causal insight into this. And so that's just one example. But all the other features of

02:09:30.800 depression as well are susceptible to optogenetics study, and we've gotten insight into them.

02:09:37.620 Hopelessness being another one. And so here, again, you might ask, how do you measure hope in an

02:09:42.640 animal? Well, you can put an animal in a challenging situation that is not escapable. The animal can try to

02:09:52.400 get out of this challenging situation. And then... Would that be like a maze that doesn't have an

02:09:56.780 exit? Yeah. No way of getting out. Exactly. So it doesn't have to be painful. Just something that

02:10:02.360 an animal would want to get out of. And eventually they give up. We can do this actually in fish as

02:10:06.860 well as in mice. And that giving up is effectively, it's this hopelessness. It's this discounting

02:10:14.440 of effort. And that can be an appropriate thing, let's say. Of course, if the situation truly is

02:10:21.560 hopeless, it really is not good to keep devoting effort to it, right? If you keep flailing against

02:10:28.360 an insuperable situation, you're burning energy, you could cause physical risk, you're distracting

02:10:34.500 yourself from other things. Withdrawing, entering into a passive coping state is actually adaptive up to a

02:10:43.000 point. The problem with depression is it becomes extreme. So it becomes maladaptive. You discounted

02:10:49.240 the value of everything. And then it's got this mysterious negative balance to it too, which is of

02:10:55.380 course also part of the problem. What do you think is the evolutionary basis for depression? This is

02:11:00.800 something that is so ubiquitous. I think I can, based on what you said earlier, see the evolutionary

02:11:07.700 basis for anxiety. And maybe we could just argue that the pathologic version, well, we could discuss

02:11:15.840 why maybe it's been amplified and what it is about our environment that perhaps does that. But

02:11:20.620 depression is a less clear to me. And certainly mania is clear, right? I think we've made a very

02:11:25.060 compelling case for why mania could be, why evolutionary pressure could have favored the propagation or at a

02:11:32.920 minimum the maintenance of this. Why depression? It seems to be counter to your ability to mate,

02:11:40.100 to find food, to defend yourself. I'm struggling to come up with one evolutionarily valuable tool that

02:11:49.120 would be better in a depressed state. I think about this all the time. And part of what we've

02:11:55.440 discussed already may provide some insight, which is this withdrawal, this passivity, it is, in some

02:12:05.020 cases, you can think of it like a hibernation. Is it worthwhile for an animal to actively try to cope

02:12:12.780 with winter by running around trying to find more food all through the winter or to withdraw, to sleep

02:12:18.300 more, to not see the value or feel the value in going outside and doing anything?

02:12:23.260 And clearly, no matter what you do, you can't fight winter, right? The best thing is to conserve

02:12:29.260 your energy, ride it out on some time scale that's appropriate. Now, think about depression. It comes

02:12:37.100 with this low energy. It comes with this hopelessness, this discounting of effort, this lack of motivation

02:12:43.700 to go seek things to be enjoyed, reduced drive for social interaction. All these things can be part of

02:12:50.580 depression. The negative aspect is the one part that I can't explain. That's, of course, the clinically

02:12:56.420 significant problem. Why does it feel bad? And this is not just feeling bad. This is agony. This is psychic

02:13:02.580 pain. This is the kind of thing that drives people to seek suicide. Not to discount that at all. We don't

02:13:09.760 understand why depression feels bad. But the passivity of coping, that can be adaptive. And it's perhaps,

02:13:20.800 you could see almost depression as a hack, a bad hack. Maybe one that's not fully evolved yet. Just like

02:13:27.760 mania, not fully evolved yet, not under all the right controls to make it more generally suitable and

02:13:36.240 reasonable. Depression, easiest way to make it happen is to remove the joy, to remove the energy, to seek

02:13:49.040 out reward. And then you've got an organism that's going to be passive, that doesn't see a path to

02:13:55.840 something positive. And evolutionarily, if you take this viewpoint, maybe one way of getting to that goal

02:14:04.560 that had some at the population level, some adaptive value included having this negativity, this negative

02:14:12.480 state to it. And this is pure speculation, you know, but it's important because depression is very

02:14:19.600 genetically determined. It's common. It's biological. And at some level, we have to deal with the fact that we

02:14:29.360 have evolved to be where we are now. And we have this high rate of depression. And so we have to include in our

02:14:35.280 thinking, the biology and the evolution together. And so that would be my take on it. Of course, it's very hard. And I

02:14:41.840 wouldn't claim to have a definitive understanding. Two unrelated questions. I don't even know which

02:14:48.140 one to ask first. So I'll probably just ask them both and then let you take them whichever way you

02:14:52.300 like. The first is sort of a desire to understand where depression specifically, but even other mental

02:14:58.480 illness fits into our closest relatives, the primates, right? Do we have a sense that our primate

02:15:04.740 relatives are as afflicted by depression and or other mental illnesses as much as we are? Let's start

02:15:11.760 with that. One of the clearest things we can see is that non-human primates can certainly enter into

02:15:17.660 maladaptive states that look like grief in bereaved states. There are cases where you can have a non-human

02:15:26.280 primate who is old enough to feed itself, but who has lost a mother, let's say has lost its mother and loses the

02:15:34.200 motivation to feed and protect itself and stay with the troop and ends up dying as a result. This is a

02:15:41.740 clearly maladaptive state documented that in a non-human primate, you could call it something like

02:15:49.080 a depressed-like state deriving from bereavement and presumed to anthropomorphize something like grief

02:15:55.420 associated with bereavement. So I believe these states are shared by our non-human primates.

02:16:03.600 Any evidence of self-harm in non-human primates? Does it ever get to the level of, I mean, suicide is a top

02:16:12.040 10 cause of mortality in the developed world. It's important to make sure people understand the

02:16:19.260 significance of that statement. In the developed world, when you think about all of the problems we've

02:16:24.380 been able to solve, one of the 10 leading causes of death is self-harm. And by the way, if you really include

02:16:34.220 overdose as a subset of that, it probably leapfrogs into the top seven. Is there evidence that this occurs in

02:16:42.660 other species?

02:16:43.600 The short answer is no. And there are less suicidal forms of self-harm that can happen. Now and then

02:16:54.520 you'll see animals carrying out behaviors like headbanging and things like that. But in terms of

02:17:00.960 a true suicide, the volitional ending of the self, there is not a animal model for that. Let's say it's

02:17:10.440 not clear that that happens. And if you think about it, as much as we'd like to have that so we could

02:17:15.600 address this urgent, enormous clinical need that's not going away, we would love to have some way of

02:17:21.900 studying this. We don't have it. And if you think about it, the ending of the self is an extremely

02:17:30.140 cognitively complex thing. You think about the act of suicide, which we don't understand, and it's a

02:17:36.520 horrific thing. But you've got, there has to be some understanding of what that means, that there

02:17:42.900 is an ending of life, an ending of the self, and that the pain that's being felt now would not be

02:17:50.300 felt then. This is a level of understanding of the universe that it doesn't seem that animals that are

02:18:00.380 not us actually have. We could be wrong. I'm completely willing to admit that. There are

02:18:06.960 amazing animals, you know, dolphins and whales and elephants have incredibly complex and amazing

02:18:12.200 minds. They may be better than we are at some of these deep concepts, but they may have less clear

02:18:20.540 ways to express it. They may have not having fingers and hands to do things that we can do. They may not

02:18:28.800 have the ways to express it, even though their cognitions may be just as complex. And so I think

02:18:33.380 there are two factors. One is the things that set us apart, our brains and our hands, those two don't

02:18:39.440 come together in any other animal. And I think that's why you don't see suicide elsewhere, at least

02:18:44.480 as we understand it. Our colleague, Paul Conti, close, also a friend from medical school, who trained

02:18:50.920 with you in psychiatry, has just written a wonderful book on trauma. And so it begs the question,

02:18:57.120 what role does trauma play in the amplification of depression? We know, as you said, that depression

02:19:04.280 is highly heritable, but like most conditions that are heritable, there tends to be environmental

02:19:11.000 triggers that can bring one person to have it and one not to have it. Even if you take the most extreme

02:19:17.060 example of the monozygotic twins raised in a separate environment, one comes down with something,

02:19:22.600 there's clearly some difference. So what role do you think that early childhood trauma plays in

02:19:28.820 all mental illness, but I guess specifically depression? And do you believe that that could

02:19:34.240 be epigenetic? In other words, do you believe that this thing can irreversibly mark the gene and then

02:19:41.760 be transferred to subsequent generations?

02:19:44.640 Yeah. Subsequent generations. Yeah. So the effects of trauma, the lasting effects of early life trauma

02:19:53.140 are unfortunately very clear. These you can see in animals as well. And they extend beyond depression

02:20:02.280 for sure to include the personality disorders like borderline personality, for example.

02:20:07.480 So there's no question that early life trauma has lasting psychiatric influence on

02:20:14.640 throughout life and can cause very severe problems. Many ways to look at this, why is it happening

02:20:20.460 and how is it happening? Is there a wiring change? So is the lasting quality due to a physical

02:20:28.800 structure of the brain as a circuit? That's one level at which it could happen. And the brain is very,

02:20:35.540 brain circuitry is very tunable that way, especially in young people. And so you could imagine that

02:20:44.160 early life experience with trauma sets up the human to expect in some ways that the world is a harsh and

02:20:54.820 unpredictable place and that the value system had better be set up to deal with that because that's

02:21:02.420 how it is apparently. And so you could almost imagine an adaptive, though very unfortunate, process going

02:21:10.020 on where there's a period of youth where you're gathering statistics about the environment, deciding

02:21:16.560 what the adult should be like, and then implementing that. And so early life trauma could intersect with

02:21:22.680 such a process, very unfortunately, and create people with a lasting state of depression, for example,

02:21:29.840 expecting aversive things to be present at higher rates and negative consequences of actions to be present

02:21:37.400 at a high rate. Now, that could be for sure the case as far as an evolutionary logic, but there's no

02:21:45.340 doubt that this happens in terms of the behavioral effect and the psychiatric effect, the lasting effects

02:21:51.820 of early life trauma. Now, if it's not neural circuitry, what else could it be? It could be genetic or

02:21:57.100 epigenetic, as you say. You're not changing your genome from childhood to adulthood, but you're changing

02:22:02.780 the transcription factors, the promoters and enhancers. You could be affecting gene expression

02:22:08.920 throughout life, and that, at least through the life of that individual, we understand how that

02:22:13.600 mechanistically could work. And then finally, you raise the intergenerational aspect. In human beings,

02:22:20.460 this is very hard to separate from, you know, it's the nature-nurture thing. Of course, you've got

02:22:24.880 the parenting that's linked to what might have happened in a prior generation. And I'd say it's still

02:22:31.280 controversial how much intergenerational transfer can happen, although in animals, there are mechanisms.

02:22:38.220 You wrote about the, well, at least you wrote about your musings, your exploration of the idea of

02:22:43.900 the evolutionary basis for tears. I found this completely fascinating. A, I found it fascinating

02:22:50.200 because I'd never once considered that. And for someone like me who is often thinking about the

02:22:54.800 evolutionary basis for this feature or that feature, it was interesting to me that I hadn't considered

02:23:00.540 that. Say a little bit about that.

02:23:02.600 Well, emotional tears, and by that, the liquid coming from our tear ducts in times of emotion,

02:23:09.380 this is apparently, as far as we can tell, it's a human trait. Our great apes don't do this,

02:23:14.800 and even some human beings don't do it. So it's a special thing. It's not that we are the only ones

02:23:19.520 that grieve, but we're the ones that secrete this fluid from our eyes at these extreme moments.

02:23:24.300 And this has been studied. There are scholars of tears, as it were, and you can do things like

02:23:29.560 add or subtract tears digitally from pictures of faces, and these have enormous impacts.

02:23:36.820 The reactions of people seeing these images is much, much greater than a smile or a grimace,

02:23:43.160 and particularly creating a desire to help. When we see tears, we want to help that person. And so this

02:23:49.540 intersects very closely with the, I think, with the involuntary, largely involuntary nature of tears.

02:23:56.080 It's a truth channel. It's not so easily gameable. It reveals something that in a social grouping,

02:24:03.500 like those that we've evolved to maintain, it is an involuntary expression of something,

02:24:10.980 the world changing, of needing new systems in place, and it triggers this outreach from people

02:24:17.920 who see it in a very powerful way. And this question, can an emotional change cause something

02:24:25.380 like this to happen? It would be a very easy rewiring to happen. There are already axons that

02:24:29.900 come from emotional regions and go to the brainstem that control the breathing rate, for example, in

02:24:35.840 anxiety. And right next to those breathing rate regions, there are regions that control the tear

02:24:42.040 ducts. They're right next to each other in the brainstem. And a very tiny, tiny rewiring,

02:24:46.160 a little axon just going in one slightly different direction would create this state of expressing

02:24:52.520 this visible manifestation of an inner world. And for a social species like ours, it could be

02:24:59.240 easily evolutionarily selected for. And so there's, in the story, a storehouse of tears

02:25:04.940 in projections. This is something that a patient's story helped bring to the forefront of my mind,

02:25:10.360 and we talk about it quite a bit.

02:25:11.740 Yeah, it's a, I won't give any more away from that story because I want people to read it for

02:25:16.540 themselves. Carl, I know that we've kind of reached the limit of our time and you have another

02:25:21.220 commitment today. As you can probably imagine, I could continue this discussion for probably another

02:25:26.700 couple of hours, and I gather you could as well if it weren't for this other commitment. So

02:25:30.480 easily, yes.

02:25:31.600 I think what we should do is just commit to sitting down again next year at some point

02:25:35.140 and continuing this discussion. There are so many more questions I have about

02:25:38.960 personality disorders. And another topic that we didn't even get into today that we're both very

02:25:43.840 interested in is psychedelics, both from the traditional side, even to the non sort of

02:25:49.560 traditional side, the use of ketamine, psilocybin, LSD, MDMA, all of these things, which are an

02:25:55.840 enormous interest of yours clinically and scientifically as of mine. So I want to, again,

02:26:01.420 congratulate you on not just your recent Lasker award, which again, I'll make sure in the introduction

02:26:07.080 to explain to people what the significance of that is, but also your remarkable achievements over the

02:26:12.380 past two decades and this remarkable work that you've written projections, which I suspect many

02:26:18.140 people are going to be reading after this. So Carl, thanks very much for spending time with us today

02:26:22.260 and for educating us on this amazing journey you've been on.

02:26:26.200 Pete, it's been great. Great to reconnect with you again and an incredibly enjoyable

02:26:29.860 conversation and look forward to talking again.

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The Peter Attia Drive - January 17, 2022

#191 - Revolutionizing our understanding of mental illness with optogenetics ｜ Karl Deisseroth M.D., Ph.D.

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