#191 - Revolutionizing our understanding of mental illness with optogenetics | Karl Deisseroth M.D., Ph.D.

Hey everyone. Welcome to the Drive podcast. I'm your host, Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop. And we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in depth content. If you want to take your knowledge of this space to the next level, at the end of this episode, I'll explain what those benefits are. Or if you want to learn more now, head over to peterattiamd.com subscribe Now without further delay, here's today's episode. My guest this week is Karl Dezeroth. Carl's a former classmate of mine from Stanford where He received his MD and PhDs. He completed his clinical training in psychiatry, and he also did a postdoctoral fellowship there at Stanford at the same period of time. He's currently a professor of psychiatry and behavioral sciences and bioengineering at Stanford. Now, over the past 16 years, Carl's lab has focused on combining neuroscience and bioengineering to basically create a set of revolutionary tools that have done something for the first time ever in neuroscience, which is basically to allow the use of genetic engineering to input light sensitive channels into very specific neurons, in fact, into any neuron that they choose to put these into. This then allows Carl and his team, and of course now others who have been able to follow in his footsteps, to use photons, that is to say, to use light to turn on and turn off very selective neurons. This is something that was absolutely impossible until about a decade ago. This tool is referred to as optogenetics. And as its name suggests, it's opto, it's light, it's genetics. It uses this genetic engineering tool to put these channels, these light sensitive channels into neurons. And this has opened up a, a field of neurobiology that basically has allowed investigators like Carl to ask questions that have never been asked or answered before. And in this discussion today, we go into not just how Carl and his team came up with these unbelievable ideas and how they refine the tools, but now what they've learned as a result of doing this. Now, this work has not gone unnoticed in the scientific community. Carl has won virtually every scientific award out there. And in fact, previously, just this month, he was awarded the very prestigious Lasker Award for his optogenetic light activated molecular research. Now, it's worth pointing out to those who might not be aware that about 50% of Lasker winners go on to win the Nobel Prize. And though I would never jinx Carl by saying this directly to his face, I don't think there's anybody in the field who does not believe that Carl will indeed win the Nobel Prize in the not too distant future. And of course he is entirely deserving of it. But when you understand the nature of this work and how it has completely changed our understanding of the human mind. In this episode we talk not just about his background and how it led him to these discoveries in his chosen career path, but we also dive into some of the deeper questions about mental illness. Remember, Carl is a practicing psychiatrist and it's his interest in the human condition that really guides his research. And so we dive quite deep into depression, anxiety, autism. We touch briefly on some personality disorders. But truthfully, we kind of run out of time about two and a half hours into this episode. And truthfully, we had really only got through about half of the material that I had wanted to talk about. So it's safe to say that Carl will absolutely be back on this podcast because there's still so much we want to talk about. The other thing I want to make sure you are all aware of before we jump into this is that Carl has recently written a remarkable book called Projections, a book that I think I mentioned in the podcast I've read twice. And his ability to write is perhaps only rivaled by his ability to conduct Nobel Prize worthy science. He is a remarkable writer and you don't need to be afraid of this book being written by such an esteemed scientist. It reads like a piece of poetry and it really is a remarkable book and a remarkable journey into not just his personal journey, but also into the eye of mental illness. So without further delay, please enjoy my conversation with Karl Deseroth. And I think I feel safe in saying that this is a part one. Hey, Carl. It is so good to see you today. Although admittedly across video, but it's like a little blast from the past, from, I don't know, 20 years ago, right?

Yeah, it's amazing. We had a good group of friends back in the old days at Stanford and I haven't kept in touch with them as much as I'd hoped. But it's great to see you. It really brings back a lot of memories. You look great, unchanged.

Well, yeah, that's funny. You don't look a bit different. It is funny when I think back to that class of ours in med school and I really feel like the overwhelming underachiever of our class. And I remember our first day of our surgical rotation. You, me, and Josh Rabinowitz sitting in that room, waiting for us to be assigned to which service we would go to. Of course, you and Josh have gone on to do unbelievable things. I've sort of muddled along.

Now you're the star. And plus, I remember even though it was the start of our surgery rotation, you already knew how to do everything, which I was impressed by. You knew all the knots and. And I was like, wait, this is the first day of the rotation? How do you do that?

Well, let's pick it up back there. So you were in the MD PhD program. So we didn't start at the same time. We just finished at the same time. You had come in earlier, but I think the reason I knew you, even on our first day of surgery was because you had done your PhD in the same lab as two other friends of mine, Alex Rovanis and Jason Pyle. And all kidding aside, I think that. Look, all the kids that went to med school were pretty bright, but I think the MD PhD students were sort of in a class of their own. And I suspect it was even harder to get into that program than it was just the straight MD program. So thinking back to your time as an undergrad, what did you major in again? In undergrad?

I did biochemical sciences. They called it at Harvard, instead of biochemistry, they had to do everything different. And they didn't call it a major either. It was a concentration. So I concentrated in biochemical sciences. So there you go. But I had a lot of other interests. All my friends were physicists, theoretical physicists, in fact. And so I was exposed to some pretty unusual stuff for a biochemist.

And were they allowed to call it theoretical physics at Harvard?

They were. Okay, that's good.

I just wanted.

Good question. Yes, they were allowed to name it that.

Good, good. So at what point during your biological science concentration did you know you wanted to go into medicine?

It was pretty early, because I was interested in the brain early on, and I wanted to understand the brain at the level of cells, but I was also interested in the most high level aspects of brain function. And so I thought I needed to talk to human beings, I needed some access to the human brain. I found that interesting because I was interested in emotion and the ability to express feelings through words, and. And I was torn. I liked writing and literature and the use of words, and I liked cells and biology, and I wanted to somehow fuse them. And it seemed that medical school was the way to Go. Because I could work with the human brain.

Obviously, you could have just gone to medical school, but you also selected into this very, very advanced program that was incredibly selective, the MST program, the medical science training program. And so that tells me at the outset that you also knew you wanted to do research beyond just clinical medicine. Yes.

Yeah, that's right. And the nice thing about the MSTP is it lets you delay making a commitment, so you keep both threads alive. And then there's a beautiful synergy that can happen, too, and certainly happened with me, that you realize, oh, wait, I don't have to make this decision. It actually is good to keep both threads alive in my work and in my life. And that's what happened. But it's a pretty special thing we have in the United States. There are efforts along these lines in Europe and other countries, but it's not nearly as institutionalized as it is here. It's a really special thing.

It really is. And again, I keep saying this, but I feel like there were maybe, what, six or eight MSTPs per class. And I always felt like you guys had the most pressure on you. Right. There was this expectation from both the clinical side that you would go on to be great doctors, but then you were also, especially at places like Stanford, where you had the opportunity to do your PhDs with Nobel laureates, would be Nobel laureates, exceptional scientists, that you would also basically be leading the charge scientifically. And for what it's worth, all of my friends in the MSTP program, I think you're the only one that ended up doing clinical training as well. I think most of them didn't end up doing residencies. They either went purely into academic research tracks or actually went into industry. But before we get into the fact that you also did clinical training, let's talk a little bit about that transition. You came into medical school pretty hell bent on neurosurgery.

Yeah, that was the goal. Because again, how do you get access to the human brain? And who, among the different clinical specialties, has that access? Who can most directly interact? Study. And it seemed to me the neurosurgeons had it all. And if one were to build an interface with the brain, if one wanted to both communicate with a person as they were expressing feelings and emotions, and to understand at the level of cells what was going on, who could do that. But a neurosurgeon was my reasoning. And the neurosurgeons, my colleagues and friends, they're amazing people, brilliant. And I saw no reason not to pursue that. And so that was the first rotation that I selected. In those second two years of medical school, even before surgery, I did neurosurgery, which was kind of interesting, just coming in there with no general surgical training as well. That's how certain I was.

Yeah, it's funny. Well, I had a similar experience, whereas the thing I absolutely, positively thought I was going to do, I picked as my first rotation. In my case, I had less of a pleasant experience than you. I think you had a pleasant experience on neurosurgery. It wasn't that in any way. You didn't like it, but what was your first? I planned to do pediatric oncology. So I went out of the gates with two months of pediatrics, which actually I didn't enjoy, largely because I just didn't feel like I didn't fit in. I think so much of your medical school experience in terms of your clinical rotations is a function of how well do you fit in with the residents of that specialty. And I didn't feel like I fit in with the pediatricians. They didn't laugh at my jokes. They thought I was probably a little too obnoxious. I probably spent too much time imitating Dr. Evil and Fat Bastard pretending to eat the babies. But the whole thing just didn't go well. It was a disaster. And then my next rotation was general surgery, where we connected. And even though I had no desire whatsoever to go into surgery, that became a kind of overnight love. And away we go. So you're doing your neurosurgery rotation, which, again, yes, highly unusual that you would do that so early in your training. That's usually something one does in the fourth year, not the third year. And I'll say this, Carl. When I did general surgery at Hopkins, I did one month of neurosurgery as a rotation, having never been interested in neurosurgery. So sort of saying, well, fine, I'll do this. I didn't have a choice. I had to do this month of neurosurgery, and I fell in love with it. I couldn't. In fact, I spoke to the program director at Hopkins and said, would it be ridiculous for me to try to transfer into neurosurgery? That's how much I enjoyed it. And it turned out that he said, I can absolutely get you in, but it won't be at Hopkins. Hopkins is the most competitive neurosurgery program in the country. We only take three people. It's already full. You're not going to get in here. But I can get you to another program. And I actually contemplated it for about a month. So I can see the appeal of it. There was something about cutting open the dura and operating on the brain. And it's a surprisingly simple organ in that sense. Like at the gross level, it's surprisingly simple. Obviously, much of what we're going to talk about today, Carl, is not at the gross level, where it's anything but simple. But what was your experience like?

I mean, it was at one level, it is an organ. And it would be unfair to say that all that neurosurgeons get to do is think about it as an organ. They do have to think about that, the blood supply and whether the cells are receiving enough oxygen and glucose. And they have to think about it in the context of the physicality of it, perhaps more than the mentation aspect of it. And so they do get to think about high level concepts in that rotation. In that month, there was a patient who had a little bit of a thalamic infarct as a result of the surgery and a little bit of loss of tissue in the thalamus. And the patient had a neglect syndrome, which I spent a lot of time working with the patient afterward, characterizing exactly how this worked. You know, I asked the patient to draw a clock, and the patient drew, you know, just half of a clock. And it was an amazing, you know, classical thing, but amazing to see with your own eyes as you're talking to another person. And the person said, oh, the clock looks fine, but it was a half a clock. And that certainly didn't diminish my interest in neurosurgery at all. It was, you know, this was at the one level, you know, there were problems which nearly clearly needed to be better Aspects of neurosurgery, as with every clinical specialty, needed to improve, needed to reduce consequences like that. And yet at the same time, it was incredibly interesting as well. I loved the operating room. I loved the suturing, although I wasn't as good as you, I think. And I. But I was good enough. And it was particularly because it was so early, I think it was the promise was there. It would have worked out. It still had a magic about it. When the dura is exposed, yes, it's an organ, but there's a spirituality to that. To know that you're actually looking at the storehouse of a human being's thoughts and feelings and everything about them all encapsulated in this collection of cells. It's quite an amazing thing. And so I had no negativity at all. I did note that neurosurgeons, they didn't get a lot of free time. There was not a lot of philosophizing. And I noticed, you know, it's a seven year progression. And I talked to all the neurosurgery residents and I noted a steady decline and willingness to philosophize as their progression through the residency continued. You could almost plot that linearly on a graph. And with all due credit to them, it's the nature of the system they're in. They don't necessarily have all the time. They would like to think deeply, although they're very bright and thoughtful and certainly could. And so I did note that. I noted that here are people who maybe don't have the freedom to do everything I would like. And that was in the back of my mind.

Yeah, I think back to the three people in my class. So at the entering class at Hopkins, three of them were neurosurgery assigned, so they did the internship with us. But then they went off and, I mean, boy, they were three ridiculously smart guys. And you would think, well, they're in neurosurgery, so how interested are they going to be in their year of general surgery? But they were every bit the exceptional interns that the categoricals were, the ones who were going to go into general surgery. One of the experiences that jumps out at me from my month of general surgery in my internship was an awake procedure we did on a patient. So under local anesthetic, the brain was opened and the patient, while wide awake, was being probed in an effort to determine certain symptoms and to see what part of the brain could be lesioned in order to ameliorate these symptoms. And I think for anybody to see that in real life with their own eyes even once is it's really hard to believe what you're watching. First of all, the brain is not the same sensory organ. The fact that you can be awake while a surgeon is probing into your brain and firing an electrical impulse into one area or another to see how it changes this part of your visual field or this part of your. I mean, that was a magic that I don't think I could describe otherwise.

Yeah. And I felt that very, very strongly. And so it was all systems go after that. Surprisingly, the. The neurosurgeons at Stanford liked me. Okay. After that too. I got very positive feedback from them and they said, hey, come back and do a sub Ia sub internship and we'd love to get you down this path. That was a green Light. And I was happy with that. It was where I was headed. Of course, things changed after that.

Yeah. So the best laid plans there are a set of mandatory rotations. We have to do neurosurgery, not being one of them, but pediatrics, general surgery, internal medicine being the obgyn, and one of them is psychiatry. Kind of this afterthought for the medical student. Right. Very few people want to go into psychiatry, and yet, amazingly, two of the smartest people in my med school class, you and Paul Conti, end up picking this field ultimately. Just amazing. Right? So tell me about. How did you go into your psychiatry rotation? Were you looking forward to this?

What?

Or did you view it the way many of us did, which was just get me through it.

I had a get me through it attitude coming in. And again, no disrespect to psychiatry, of course, they have a hard challenge still. We have this challenge that there's not a measurable, really. We have effectively questions we ask patients. It's all with words is how we work.

No biomarker.

No biomarker still? Yeah. I mean, there's efforts along those lines looking at EEG ratios of this to that, and there's progress being made. But still, clinically, we can't make diagnoses based on measuring something about the brain. In psychiatry, you can notice that there's something else going on, a neurological or medical problem, but you can't define someone's psychiatric state with some biomarker. And that still, amazingly, to this day, still true.

Yeah. So tell me about your psych rotation, because I remember we kind of had choices. I did an entirely outpatient month, which I ended up finding quite enjoyable. That's the irony of these things. I did it as one of my last rotations prior to graduation, which meant there was no chance, even if I'd liked it. It was too late for me to make that choice. I had already matched, I think, in general surgery, but it was an outpatient month, so relatively low acuity, but interesting nevertheless. What was your month like?

Mine was the opposite of that. And this was probably a fortunate thing for me. It was in the locked unit at the VA at the Veterans Administration Hospital. And this was a unit where patients can't leave. And this is due to being a danger to themselves or a danger to others or having a grave disability. And these patients were severely ill. And I walked into that. I'd had typical experiences. Everybody has friends or family who've had depression or anxiety. I'd seen substance abuse and intoxicated states and Dementia. And I had a fairly, I thought, decently broad understanding of what can go wrong on the psychiatric side. But I can tell you nothing, and you know this by now, but I can tell your viewers and listeners there is nothing like what you can see when you walk into the locked ward of a psychiatric hospital. There's a sort of a purity, not in a good way, but because there's not confounding issues like intoxication and so on. There's a consistency and a purity to the disorders. And so if you have someone with acute schizophrenia or schizoaffective disorder, other things that might confound what's going on have been removed. And there's this very strong, acute, straightforward expression of the symptoms that's just mind boggling to see if you haven't experienced it before. And that was my experience, and it completely changed my course. There was a. Even on the, you know, my very first day, there was a patient with schizoaffective disorder, which is a very severe combination of mood and psychotic symptoms that are all mixed up together. And this patient accosted me in the, in the locked unit, started screaming at me and. But it was not necessarily sort of a street encounter that you might have in a city. It was more direct and personal and evocative of something going on in the mind of the patient that was clearly a source of immense suffering, of great disability. And yet at the same time, it was tantalizing, because this was a human being who was physically intact, but whose reality was so completely different from mine. We were two people with intact bodies and brains who were next to each other, and we inhabited completely different realities. And to experience that was a utterly transformative moment. And both seeing the suffering and realizing, I have no idea what's going on here, but it's incredibly interesting too. How is this possible? How could this be happening to a human being? And without that direct exposure, I don't know what would have happened. But having had changed my course, just interesting.

I mean, many people when confronted with that, would be quite frightened, especially when you realize the limitations of the tools that you have. So let's consider another analogy. Rich is a patient that comes in with a gunshot wound to the chest. That's an incredibly frightening experience. There's literally a sucking chest wound. Blood could be splaying around the room, vital signs are crashing, the person's on the verge of death. But that can be exciting in a way because we actually have the tools to do something right. It might be completely draconian. We Might be doing a thoracotomy in the er, cross clamping the aorta, but you run that patient to the OR and you know how to fix them. You are experiencing something that I would argue is much more frightening, but compounded by the fact that what do you do? I mean, you could temporarily give that person Haldol and sort of snow them, but that's not curing them. So was it more the. We don't have the tools here. This is an unbelievable opportunity to learn or how did that experience, which I think for many people could have been off putting, do the exact opposite in you?

It's a great question because. And I would completely understand that the normal or typical reaction would be sort of an aversive thing. This is not something I want to spend my life doing in this setting. I had a different reaction which surprised me. There were two sides to it. One was exactly what you're saying. The level of mystery here was actually, for me, it was a positive rather than an aversive thing. And maybe this was partly my scientific training at that point. I'd completed my PhD and I spent years trying to figure things out. And we all want to figure things out. That's a natural human impulse. Not everybody necessarily spends years and years and years trying to figure out the same thing. And that's the kind of training we get in the PhD program. And I saw that and I was like, okay, got to figure this out. This is clearly a mystery. That is something that. It's a burden that humanity shares. It's a terrible burden that this human being is suffering. But what's the solution? We've got to figure it out. We've got to understand this. And. And it's a mystery that strikes to the heart of what had always intrigued me, which is what is an emotion physically? What is a feeling physically? How does the collection of cells in our brains. And that's what it is, it's a collection of cells. How is it possible that that creates a feeling and emotion? And I realized at that moment, this is actually why I came to medical school. And it all made sense in one moment that it hadn't before. And then of course, as a physician, as you well know, our instinct is to help, is to heal, and we want to do that. But as you say, if we don't have the tools, what can we do? It's a problem. And I wasn't frustrated with the inability to do anything. And I would understand that reaction too. And the fact is we could do a little bit, though, so it wasn't quite nothing. And there are medications back then and still that help somewhat. They don't come with understanding. They don't help us explain to the patient or the family or to ourselves what's really going on. But they do help a little bit. And so I was, I knew that I could do something. Not much, but a little bit. And as time went on, hopefully, and as the science progressed, maybe we could do more. And so that it fit together in a moment. And I didn't have another thought for neurosurgery after that. Although it was a hard process to reshape what my trajectory was going to be, I had one set of plans. My friends and family had a set of expectations. I can tell you, I think my father was pretty disappointed when I told him on the phone that I was going to do psychiatry. I could hear it in his voice. It was almost. Again, he came around in the end too, and I think he's happy now. But at the time I could sense that this was not what he'd hoped for me. So, yeah, it was an adjustment, it was a remapping, but it was a very compelling experience that the process of medical training and the required psychiatry rotation made possible.

So, Carl, you now make this decision to completely veer into this nearly orthogonal track. I mean, psychiatry and neurosurgery of course have one thing in common, which is the organ of interest is the brain. But at that point they basically differ. How did you decide you were going to both pursue the clinical training, the residency for psychiatry, but also do whatever was necessary to make sure that you could ultimately be running a lab? Because I, I think throughout this period you never lost sight, unless I'm misremembering of the desire to be a physician scientist and not just a physician. So residency, especially 20 years ago when we did our residencies, they didn't have 80 hour workweek requirements and things like that, so residencies were quite demanding. Was it a little hard for you to say, hey, I'm going to actually have to put my research on hold for a little while?

It was hard and there are a lot of challenges that people in this realm face because things move so quickly in the research realm that if you step aside for even a year, forget about four years, the world you re enter is so different and it's very hard to catch up. And that's to some extent an old problem because that's been faced by everybody who planned to do a residency. But it's not negligible because it's an Old problem. It's that issue exactly. That ends up driving people to make this hard choice that you mentioned earlier and saying, you know, in the end I'm going to have to do one or the other. If I do the residency, I'll be a doctor, I'll be a good doctor, maybe a great doctor, I'll be informed by all my scientific training. Maybe I'll read papers better, maybe I'll be more amenable to new ideas, new treatments as a result of that. But ultimately I'll be a physician or on the other side saying, you know, I'm not going to do the residency, I'm not going to drop off this fast moving train. I'm at this moment, I've just finished my PhD. I'm a world expert in this. I can do things that nobody else can do. Why lose that momentum? Why not speed up, add the next tool in the tool belt, launch yourself and make great discoveries? And that is very, very tempting. I had very clear opportunities to do that. And so that's the hard choice that the MD PhD faces at that moment. Now efforts are made to ameliorate that. So residencies again, this was the time still where the residencies were extremely difficult. And I had some. For me, this was compounded by some personal challenges. I was effectively a single dad at the time. And so I had to also think about this other factor very important now I've got to think about residency, I've got to think about lab, I've got to think about family. And it was very, very challenging. And yet there are these research track residencies and they help a little bit. So there are and Stanford and other programs both in psychiatry and in other specialties, they have efforts to help people keep their scientific mind alive during residency. And it's not great, but it's a little bit of protected time here and there. Never quite enough to get momentum, but at least to keep a foot in the lab and try to stay connected. And so I did that. It was a research track, psychiatry residency and I stayed at Stanford. And a big factor in that was that literally at the same time, and I was very fortunate in this regard. A guy named Rob Malenka, who was a psychiatrist and a great neuroscientist, was at that moment coming from UCSF to Stanford. He had come and was setting up his lab at Stanford. And I knew, here's somebody, a psychiatrist, but also a neuroscientist, he'll understand what's going on in my residency that I'm taking call, I'm up all night. He'll understand why I'm never in the lab during expected hours while I'm never at lab meeting. And that made it work out. And I worked nights and weekends. I maybe came to one of his lab meetings over four years. And I effectively did a combined postdoctoral fellowship and psychiatry residency at the same time at Stanford. Some funny stories, because Stanford's very compact, as you know. I could literally take call from the lab. I'd be patch clamping, I'd be at the rig listening in, making measurements on currents flowing across a single cell. And I get paged, go walk over to the er, admit a patient, come back, patch clamp the next cell. And it was a pretty special moment. When that happened. It felt like the different parts of my life, they could work together, they could be compatible. And that so many people have such a hard time understandably making that work, making the pieces fit together. And I feel fortunate that I was able to make that work.

Now, what year was your son born? 98.

He was actually born in 96. So he is.

So you're four. He is five years old, basically, when you're in the midst of this.

Yeah, that's right.

How did you manage that?

This is actually something that I touch on. I know we may talk about the book I wrote, Projections later, but it turned out to be a theme early in my life. How my experiences with my son, how they related to all the stressors and the patient experiences that I was having. And in a way, psychologically, although it was difficult to make everything work practically, it also. It helped me a little bit to have something that mattered more than anything else in the lab or in the clinic. There was something that was on a different scale and it helped me not get too stressed about things happening in the lab or the clinic. And that's a common feeling in people with kids. For me, it was extremely important at that time. There were patchwork solutions of childcare and so on that made things work. But ultimately, I think it was helpful for me in getting through those times. And by the way, he is now an MSTP student at Baylor, so He's doing his MD PhD in Texas, and he's now second year. He's a cool kid. He's good at guitar, much better than I am, and he likes computer science.

Yeah, he's got some big shoes to fill. And I'm positive that none of that pressure comes from you.

So, no.

I remember when you were finishing your residency. I just remember, because of our common friends, how exciting it was when you were now setting up your own lab. So we're talking about what, 05, 06 ish? Yeah.

The lab started to get set up in 04 and then it really hit full steam between 06 and 09. But 04 was when we were setting it up.

So as you're embarking on this, what is it that you experienced during that transformation of your clinical training, your residency? How did that shape the problems you were interested in solving?

Well, having just completed my psychiatry residency, I had a pretty deep understanding of where things were clinically. I knew what, not just the medications we had, but also the brain stimulation treatments, the interventions that we had available at the time. I did electroconvulsive therapy, which is very effective for treatment resistant depression. It's the treatment of choice for many people. It's incredibly effective. It's stunning to see it has some problems. You don't want to give it too much and there can be side effects, but it's incredibly effective.

What's the durability of it?

It depends. Some patients need what we call maintenance electroconvulsive therapy. So after three months or so, the effect will be diminished and they'll require to stay alive, effectively, patients who are, for example, just acutely suicidal. And they'll need every three months or so what we call maintenance or continuation electroconvulsive therapy, or ect. So it's not a permanent fix like so much of medicine and so much of psychiatry. It's something that moves things back into a healthy range for a time. But we didn't know how it was working. It definitely helped, but it was. For a scientist, it was very. It was satisfying to help the patient, to take somebody who was in just horrific psychological distress and put them into a state where they could go back and do their work and live with their friends and family and be happy for some time. That was great, but we had no idea and still don't what was going on there. Why is this seizure that we give the patient? And it's done in a pretty refined way these days. The patient's body is paralyzed, so there's no physical seizure. It's all happening in the brain. And it's a safe procedure, but still it's not specific. Right. You're causing a general pattern of activity through the brain of the patient, and this astonishing psychiatric effect is created. Clearly it was a mystery, still is. And I was unsatisfied by that. There were early efforts at the time of other brain stimulation treatments. There was vagus nerve stimulation. There's a. As you know, there are the nerves that run 10th cranial nerve that comes from the brainstem and goes down to innervate the heart and the abdomen, also sends fibers back to the brain. And you can put a little cuff around the nerve and stimulate the brain through the neck, which is kind of interesting, a little high away to the brain. But the effects, although it became approved, FDA approved for depression, the effects were very small on the population level, very inconsistent. Likewise, we had transcranial magnetic stimulation, which was in its early days then as well, which was a treatment where you can non invasively stimulate a tiny patch of the brain by putting a rapidly changing magnetic field near the scalp of the patient. Effects small on the population level did get FDA approved, but still not fully understood. So all these treatments and of course none of the medications to this day do we fully understand their mechanisms of action. So there's a lot of mystery. And so I came from my psychiatry residency fully aware that essentially the entire field was unmoored from scientific understanding. No fault of the practitioners, no discredit to them. It was just not known. And we didn't have the tools and techniques. We had no specific way of causing something to happen to a particular kind of cell. All these treatments are nonspecific. A seizure all through the brain, a stimulation of a nerve, wherever that nerve may go. Known, but not specifically related to any psychiatric symptom. Transcranial magnetic stimulation. Yeah, you can stimulate a little patch of the brain, but we don't know where depression comes from, where anxiety comes from. Is it this patch or that patch or that patch? No deep level of understanding was present. And of course the medications act all through the brain without cell type specificity. That was the setting. And then to answer your question then is clearly basic science. How could you build an approach to give you some kind of precise causality? And that was the context.

Well, I want to dive really deep into this because it is essentially the skyscraper of your life. I mean look, if you retired tomorrow from medicine and science, Carl, if tomorrow decided you were going to go surfing for the rest of your life, you would have already accomplished more than that of 100 scientists. So I want to come to this in detail, but before I do, I want the viewers and the listeners to get a little bit more of an understanding of the brain structure. Because we're going to be talking about structures of the brain, we're going to be talking about the cells of the brain. And I wonder what the easiest way to do this is. Maybe we can start about the brain and its Three layers and we talk about them through our evolution maybe, and how each one added to the next, but each one has a subset of functions. I'll really defer to you, Carl. This is your domain and not mine. But maybe we just take a step back and really give people a sense of some neuroanatomy, some neurophysiology, what neurons are, what axons are, how chemicals get transmitted. I think investing some time in this now will really enable people to understand the depth and breadth of your literally world changing discovery.

Well, thank you for the first of all the gracious comments. We have a long way to go though, and I'm not maybe it's many lifetimes ahead. There are very deep mysteries in the brain that we have much, much work to do, exciting, fun work, but much work to do to get to where we want to be. But it is an exciting moment and what we've been able to accomplish has been thrilling. And it's a testament to all the amazing people that we've been able to get together to work on this. And indeed the brain is something, it's very compelling. It's so interesting and mysterious. The cells in the brain are more complex structurally than any other cell. In our brains there are approximately 90 billion neurons. That's with a B. Each one of them is, it's a self contained unit, it's covered by a membrane, but it can generate electricity. It's got little channels, little pores in its surface that can generate little electrical impulses. And that's how you can have a single neuron that projects from one part of the brain to another, or from one part of the brain to the spinal cord. Or it can send connections through its axon, its outgoing wire effectively to many parts of the brain. And it sends that information in the form of electricity down into its axon, down its outgoing connection. And the connections are received by the downstream cells through little structures called dendrites. And the interface from one cell to the next is called a synapse. And in most cases, information gets across that little gap from one cell to another in the form of chemicals. So the electricity triggers release of a chemical. The chemical drifts across this tiny little gap that's some tens of nanometers. And then it acts on receptors in the other side, the post synaptic side, and that creates a new burst of electricity in that downstream cell. So that's the electrochemical process of information flow. Now you've got this going on in 90 billion neurons. @ the same time, they're all, Maybe they form 10,000 or even 100,000 synapses each. Their wiring is incredibly complex. There's some structure to it. There are collections of axons that may travel together, but then they also bifurcate and separate in incredibly complex ways. And all that's in the brain, and then there's some structure to it, as you alluded to. And one way we can think about this is indeed, evolutionarily. We're vertebrates, okay? That means we have a backbone, and we've got a certain organization to our brain. In my lab, we have fish, and we have mice and we have rats. And then I also do clinical work. These are all vertebrates. From fish to us, we all have the basic vertebrate body plan and brain plan. But evolution has given us, obviously, we have much bigger brains than fish do. And a couple things have happened over the course of hundreds of millions of years is that, first of all, we've scaled everything up. We've taken the same structures, we've added many more cells to them, and that lets us do more complex things. And we've also added new things on top. And so in the surface of the brain, there's what we call the cortex, which means literally the surface of the brain. It's like the rind of a melon, except in human beings, it's quite thin. It's just a few millimeters thick. And within that few millimeters, there are six separate layers within that cortex or rind, and those are layers of cells. So there are six layers of cells in this sort of shawl or rind covering the brain. And then all the wiring coming out from that cortex goes to deep structures. And our cortex is much more advanced. The fish don't really have something like that, but they've got the deeper structures. They've got the interchanges and the movement control and the arousal systems and the sleep systems. And there are structures deep in the brain, like the hypothalamus, that govern all the primary needs of salt balance and avoiding danger and mating and sleeping thermoregulation. These deep structures are common to every vertebrate. We have a hypothalamus. The fish has a hypothalamus. These deep structures are shared and ancestral among all vertebrates. And so you've got these deeper structures that are conserved and ancient in us. We've got this surface structure that is incredibly elaborated in our lineage and is responsible for some of the most complex and mysterious things we do. But the great thing is, and mice sort of sit somewhere in between. They have the cortex that we have, and it's amazingly similar. It's got the same six layers, it's got the same kinds of neurons. They're connected in the same way. It's just much smaller than what we have. And so, by looking at the fish and the mice and ourselves, we can piece together a lot by studying the cells and the connections that make things happen. And that's the context that we come to as a.

Neuroscientist. And what about this first layer, the brain stem, this kind of most primordial layer that handles so many of these functions when we're not even thinking about it, like breathing? I mean, how conserved is that across all of these.

Models? Yeah, the brainstem is highly, highly conserved. In the brainstem and in the midbrain, we have clusters of neurons like the dopamine neurons and the serotonin neurons and the noradrenaline or norepinephrine neurons. They're all clustered there in the brain stem, in and around other cells that govern the movement of the muscles of the face and the neck, that send information down, like the vagus nerve that we talked about, send information down to the rest of the body. These basic structures in the brainstem are highly conserved. Fish and mice and human beings all have them. There's a little bit of different shaping and arrangement, but it's basically the same.

Logic. Are there neurons? The way you describe it, it sounds like a neuron might have mostly just serotonin. So when that neuron fires at the end of its synapse, serotonin is the only chemical that comes out. Is that the case for neurons, that each one only can emit one neurochemical? So it's a largely binary signal, or are there any neurons that can secrete more than one.

Neurotransmitter? A relatively recent understanding has been that there are multiple neurotransmitters that can be released by the same neuron. We still refer, for example, to the dopamine neurons as dopamine neurons, because that's what makes them special. That's what they can do that other neurons can't do. But what we've discovered recently, what the field has discovered recently, is that dopamine neurons, some of them, also release another neurotransmitter called glutamate, which is an excitatory neurotransmitter. It stimulates the downstream cells. Other dopamine neurons can release a different one called gaba, which is an inhibitory neurotransmitter. It shuts down the cell that's receiving the signal. So there's actually a great deal of complexity. And that's not all. There are also other things that can be released at the same time, things we call neuropeptides. And there's a lot of complexity on the other side of the synapse, too. Different cells have different receptors for the different chemicals that can do totally different things. You can have a receptor for glutamate that makes excitation happen, or you can have another receptor for glutamate that doesn't do that, but makes a longer pattern of modulation happen. That's not even a direct excitation. So that's just a flavor of the complexity. But broadly speaking, you'll see us still refer to things like dopamine and serotonin neurons, because that's the first level.

Of complexity prior to the work that we're going to get into here. What tools existed to really try to establish causality between the stimulation of one region of the brain and some sort of response, be it a phenotype or an impulse or was there ever any way to imagine how one part of the hypothalamus was responsible for a type of thought or emotion? I mean, how was that.

Probed? This was a big challenge that neuroscience faced, which is finding out what actually matters for function. And what we did have, we had ways of listening in, we had ways of putting in electrodes to listen to, pick up electrical patterns of activity. You can put an electrode in the cortex or in the hypothalamus, or in the brain stem, and you can pick up the chatter of neurons as these little electrical impulses go by. And you could use the same electrode, you could also stimulate, you could send current in through this wire, effectively that you've placed. And, yeah, that has an effect. And so you can make things happen by just sending current into the brain. And at some level, though, this is just a scaled down version of the electroconvulsive therapy we talked about, which is also just current being put into the brain. It causes things to happen, but there's no cell specificity. Every single neuron in the brain is electrical, and all parts of every neuron are electrical. Not just the cell body itself that has the DNA in it, but also every part of the axon, every part of the dendrite, all electrical. And so if you send in current to a spot in the brain, even with a tiny electrode, you're affecting every single cell near the electrode. And not just that, every little bit of wiring that happens to be going through there. So there's no cell type specificity because every cell is electrical. And that's still, though there's work you can do. And so you could stimulate a region of the brain and see if that causes something to happen in the animal. And there was a great deal of really foundational work in neuroscience going around and stimulating different parts of the brain. It was discovered that if you put an electrode in the parts of the brain where dopamine neurons live and where the axons come out, that rodents will really work hard for that. They like that. It seems we can infer that because they will press a lever thousands of times a day to get a burst of electricity to the dopamine neurons. And so that little clues like that are built up over time. But then there was always complexity. As we dove deeper into it, we realized, wait, this is not just the dopamine neurons in this region of the brain. There are a lot of other cells and connections. So is it really the dopamine neurons? It's this region, but what really are the cells? And so there was a lot of uncertainty in the field as to which cells were actually doing what. And so we had that, but then there was not a good way to turn things off also. And so in science, we like to add things and see what happens. And that's testing whether something is sufficient to cause an effect. And we like doing that. That tells you something. But then we also like to take away something of interest and we could see what is lost with that. And that's testing the necessity of something. How much is that needed? We would have liked to turn off cells and say, okay, now what's different in the animal and their behavior? And there was not a great way of doing that. Crude ways. If you stimulate really hard with an electrode, you could effectively exhaust the cells and make them not fire anymore. And that was sort of the state of the art, both clinically and research wise, and trying to create a local inhibition. But again, not cell type specific at all, because all the cells are electrical. And that's the kind of situation that we found ourselves in. Not too different clinically or basic. No cell type.

Specificity. Do you remember where you were, what you were doing the very first time you learned what a channel opsin.

Was. So this is an interesting thread that there are these plants, and small plants, in fact, single celled plants that make channel rhodopsins. These are single proteins that are placed in the surface membrane of cells, but microbial cells, not in our cells. In algae, single celled Algae and related molecules are present in ancient forms of bacteria. These had been known to exist for years. And this class of protein is really interesting because they're light activated electricity generators. These are single bits of biology, single biomolecules that do an amazing job. They receive a photon of light and they move charged particles, ions, across the surface of the cell. Now, there's a huge family of these. These are called the microbial opsins, and a sub family of them is called the channelrhodopsins. Now, what's amazing is that these proteins were known broadly in biology, in biochemistry, for decades. They'd been discovered in 1971 by Dieter Osterhelt and Walter Stoichenius, who are at UCSF. And this was part of the training of biochemists, biologists. In Lubert Stryer's beautiful biochemistry textbook, there's a page on the bacteria rhodopsins. And that's where I learned about it. These proteins, they have a photo cycle, it's called. They have a choreography of movements of the protein after the photon hits that lead to an ion, a charged particle, moving across the membrane of the cell. So this was a class of proteins that was well known. And it turned out that these microbial opsins turned out to be the key for optogenetics, the technology we developed that brought this cell type specific causality that made it.

Possible. So it sounds like, okay, because I also had Lubrich Dreyer as a professor. I have his textbook. It's one of the few textbooks I've still kept. First of all, I don't remember that. So, I mean, like, that might be a page in that book, but I was not paying attention during that lecture. So it sounds to me like you knew about these even back in medical school. When did the idea come to you that said, wait a minute, I can now genetically insert these things into neurons and effectively put a digital switch into a single neuron. How and when did that idea cross your.

Mind? Yeah, so there was a coalescence of different threads that happened that were partly plausibility threads. And if you look at this historically, anybody in theory could have thought about this and tried this. In the late 80s or all through the 90s, these genes were known. Somebody could have put them into neurons and tried this, but it wasn't technically plausible for many reasons. There were not until the 90s, and particularly the late 90s, there were not good ways of introducing genes into neurons. Neurons are a little bit tricky. They're very finicky and sensitive. And I knew this, because this was a theme in my PhD work and also in my postdoc work. How can we get genes into neurons? Even in a culture neuron preparation, it's not easy. That was certainly part of it, part of why nobody had tried this before. But in the late 90s, that started to change. And I did an experiment introducing genes into neurons as part of my postdoctoral work in the Malenka lab that was in. And so this was something I was good at. I developed the viral tools and the ways of introducing genes in that were.

Plausible. Tell folks a little bit about how that works where, obviously these days, I think even the layperson is somewhat familiar with genetic modifications. People have some sense of how these have even been used to help develop vaccines and things like that. But let's start from a place assuming people don't even really know the difference between DNA and rna, and just explain how you could use this thing called a virus to do your bidding with respect to the insertion of a foreign.

Gene. This is by no means a minor thing. In some ways, this is the whole ball of wax, as we say. How do you get a gene into a neuron in a specific way? So this is the technological aspect of this, in some ways is everything. And so it's definitely worth the time to talk about this. How do you do it? Well, DNA is the instruction manual for making proteins, things like proteins, biomolecules that have a job. Each gene is a bit of DNA. It might be a sequence of what we call nucleotides. They have A, G, C and T. There's four kinds of them, and they come in different sequences. And by the order in which these nucleotides appear, that is a code. That's the genetic code that dictates which protein will be made. A biomolecule that has a particular structure and a job that comes from its structure, like being in a channel or something in the surface of a cell that receives a photon and lets charged particles go across. That's the protein. The instructions for making it are encoded in the DNA in the gene. So how do you get that gene into a cell? Well, it's not so easy these days, particularly with the coronavirus pandemic. I think the general public is much more aware now of how this can be done. Viruses, and there are many kinds of viruses. They are little bits of biology that basically exist to get DNA and RNA into cells. And so they have a little bit of this genetic code material, DNA or rna, and they have that encased in a coating that might have Some lipids or fats and some proteins. And then that floats through liquid, floats through the air, hits a cell and fuses with the cell, gets the DNA or the RNA into the cell and then that triggers the creation of new virus particles and then that's how the virus spreads. Viruses are professional introducers of genetic material in the cells. They are extremely good at that. They are evolved for that. This DNA RNA distinction is interesting. Some viruses work with DNA, some are rna. What is rna? This is also something that the coronavirus pandemic has brought to the public's attention very recently. That's the step in between DNA and protein. It turns out for various reasons, it's useful to have an intermediate step. First the DNA gets turned into rna, very similar structure, but then that gets turned into the protein. Some viruses work with DNA, some with rna. This turns out is then very useful for the biologist because if you want to get a gene into a cell, and in my case, suppose you want to get a gene for making a light activated channel. If you want to get that into a cell, well, how do you do it? Well, you get the DNA into the cell. And what's the best way to do that? Well, use a virus. And there are viruses that are dangerous and lethal, but there are also safer, weaker viruses. And then there are modified versions, even of those that virologists have engineered to be extremely safe, to have lost the ability to propagate from one cell to another, but can do that. First step, can bring DNA into one set of cells and then the life cycle, if you will, stops at that point. Those are the viruses that I had experience with from my postdoctoral work. Safe modified viruses that can be used to shuttle bits of DNA into cells. That's the core technology. And again, this was a relatively recent thing, and particularly for neurons, a relatively recent thing. The technology for doing that was not so clear in the past. The other thing, though, I want to point out, is that there were many people who were thinking about this and trying this, and we did, from my lab, publish the first paper that used a microbial opsin to get light sensitivity. But it was, as it turned out, quite a close call. We published the paper from my lab in 2005 and that came out in the summer of 2005. Within six months, several other papers came out. They all were submitted right after ours was published. And so clearly many people had been thinking about this. They saw our paper came out and then rushed to submit theirs. And these were, these were big time labs, people who were very respected and thoughtful including, this is something I didn't know, but the brother of my PhD advisor, my PhD advisor was Dick Chen, his brother Roger Chen, was a Nobel Laureate for his work with green fluorescent protein. Turned out he was also working on this as well. I talked to him at great length about this. Of course he did okay. He got a Nobel Prize for other work. But this was all this was going on before his Nobel Prize. And so he was quite, I think, frustrated that he wasn't able to get to this moment as quickly. So it was a broad awareness in the field that technology was now available. We could introduce genes into neurons, that these microbiopsins existed. People had wanted to get cell type specificity for a long time with neurostimulation. Francis Crick of DNA double helix fame had been calling for this sort of technology for years. In fact, in 1999, he'd even suggested that not only did we need a way in neuroscience to control individual cells, individual cell types, but he said maybe light would be a good way of doing it. He didn't have an idea of how to do it, but he said, you know, light would have some good properties, it would be fast, it would be relatively non invasive. Photons could scatter through tissue, and most neurons don't respond to light at baseline, unlike electricity. And so it would be a way of getting great specificity. So there was this broad awareness that this kind of thing suddenly might be.

Possible. I have two unrelated questions, Carl, about this. The first is when you introduce the virus, is it one virus that can introduce the gene to one neuron and that's it? You said there's no replication capacity of the virus. So does that mean that the dose of the virus you give determines how many cells will pick up the.

Channel? That's correct. So you can give a very high concentration of viral particles, and that will mean that you get more cells also, you'll get more copies per cell. You can have multiple viral particles infecting the same cell, and that is actually very important. Another big issue with these microbial opsins is they generate tiny currents. They're not as professional at generating huge currents as mammalian ion channels are, which was a big reason why I think a lot of people didn't rush to this as well. People looked at those current sizes and said, this is not going to work. Most existing methods of introducing genes gave you maybe one to seven copy numbers of the gene, as we say, so not enough to control a neuron. And that was a huge issue. But with the viral technologies, you could get hundreds or more copies of the gene per cell. And you could get much bigger currents with these microbial opsin. And so then there again, my experience with the viral tools was.

Critical. Just give us a sense of the current. So when you talk about a normal mammalian neuron, how many do we measure these in? Picoamps.

Nanoamps. Yeah, picoamps and nanoamps are exactly.

Right. An action potential is how many.

Picoamps? A couple ways we can look at it. So the action potential, this is this blip of electricity that propagates down the axon of a neuron. It can be triggered by signals that are in the order of 100 to 200 picoamps, and then it becomes a voltage impulse that's about 100 millivolts and that propagates down the cell. So if you're in the hundreds of picoamp range, you're in business for controlling.

Neurons. A single opsin is capable of.

What vastly less than that. And so a couple issues come up. So first of all, what we found is that if you don't have a high copy number, the currents that you're generating are on the single or less picoamp level. We haven't done. Because the currents are so small, you typically don't even do the experiment. You're asking single channel current measurements. Since then, out of scientific curiosity, we and others have looked at the currents that are generated, and they're extraordinarily small. We only get to the hundreds of picoamp level by probably expressing 100,000 to a million opsins per cell. And so this was the key issue. There was many orders of magnitude, as we say, several factors of 10 away from where we needed to be with these opsins. Unless there was a way of introducing many genes and getting very robust, safe.

Expression. How do you introduce the virus? So let's just say we're talking about a mouse here, and you decide you want to test in this particular region of the pons. So a part of the brainstem, you want to exactly get it there. How do you direct the virus to exactly the cell? You want to get this.

Specificity. Yeah. So this is the other technological challenge that had to be faced. It was not obvious how this would be done. Where would the specificity come from? Yes, none of the cells respond to light. Yes. Maybe we could add a gene that makes the cells respond to light. But wait, hang on a minute. Where's the specificity going to come from? How do we get this gene only into the cells we're interested in? Well, all right, what could you do, you could concentrate the virus and do a very focal injection into, let's say, the pons. And so you could create a little hotspot of virus and then that virus would get into all the cells that are in and around that spot in the pons. And that's good. That gives you some spatial specificity. You're now at a spot, and that is already a big leap beyond the electrode, because the electrode and the virus both, so far in how I've described them, are not cell type specific. But the electrode is getting all the, is going to be stimulating all the axons that happen to be going by if you do a viral injection at one spot. Viruses are not very good at getting into axons. They're just going to get the cells, the little spherical cell bodies that live in that region. And so right away that gives you some specificity. You're getting less of the cross streams of activity being stimulated, but it's not enough. Because even if you're just getting the cells, the cell bodies that are there, there are many different kinds. There are the dopamine cells, but right next to them there are the GABA cells, and next to them are the glutamate cells, and they're all jumbled up together. And there you're not too different from the electrode. Now if you put in light, you're still going to be stimulating all these cells. And so what you need is a way to make the production of the opsin cell type specific. How are you going to do that? Well, the virus, there were many possibilities we could think about. And this took probably till we really solved optogenetics, probably took till 2009, because this was the critical issue. How do you get a versatile, generalizable way of targeting specific cell types? Back in 2004, 2005, there were some possibilities that we and others could imagine. You could try to imagine engineering the virus capsid, this coating of the virus that has proteins on it. There were theoretical ways and even possible practical ways of engineering capsid proteins so that they would only target one kind of cell, because that kind of cell had something else on its surface. And maybe we could create some kind of lock and key.

Mechanism. Yeah, so just like a coronavirus, its lock and key basically works through the ACE2 receptor. If you knew what a potential surface protein or receptor was on the dopaminergic neuron, that could be your entry. That would have been the first thought that would have come to my naive.

Mind. Yep. And that was plausible. It could work. It had Some drawbacks, which are that you'd have to. First of all, we didn't have that richness of understanding. It wasn't as if there was some lookup table. Okay, dopamine neuron has this. So then put this on the. That didn't exist and still doesn't, honestly. So it was more just, okay, there's going to be a lot of work. Every time you want to target a particular cell type, you're going to have to now do some deep dive into all the proteins it expresses and also all the cells that are nearby that you don't want to target and make sure that whatever your strategy is not giving you some cross reactivity. And so initially plausible. And then as you start to think about it more, you're like, oh, this, I mean, this is never going to be versatile, generalizable, practical. And indeed it still isn't today. So that wasn't it. Now, another strategy is working with DNA. Each gene, each bit of DNA in chromosomes, in genomes has this code for the protein. But also near it, it's got another bit of DNA that's called a promoter or an enhancer. And this is a bit of DNA that doesn't code for a protein. What it does is it attracts what are called transcription factors, things that decide whether that bit of DNA gets turned into RNA and then into protein. They, by changing the structure, by changing things around the gene, they determine whether this gene is expressed at all. It could sit there quiet and not make the RNA and the protein, or it could be active, make the RNA and the protein. Turns out that is critical because that was a path forward. We could work with the bits of DNA near genes, promoters and enhancers. This gave us some leverage. Not all of it, but some of the leverage. And if you think about this. Well, think about a dopamine neuron again. So what is a dopamine neuron? Well, it makes dopamine and it releases dopamine. Okay, now how does it make dopamine? Well, it's got its own biomolecules that make dopamine. It's got enzymes that turn other precursor chemicals into dopamine. Now, those enzymes are made chiefly in dopamine neurons. And why are they only made in dopamine neurons and not in your big toe neuron? Well, it's.

Because. Or more importantly, not in the serotonergic neuron right next door. I mean, that's the key insight is you exploit the promoters that are making unique enzymes to a particular.

Neurotransmitter. Exactly right. And so it turns out each cell type is defined by its job, just as in many cases we are defined by our jobs. And this is a critical thing because a professional dopamine producing cell is going to have, by its dopamine enzyme encoding genesis, it's going to have promoters or enhancers that dictate in this cell type, this gene will be active. And so what we did was we said, okay, let's see which of those bits of DNA, those promoters and enhancers can we borrow from. Let's say the tyrosine hydroxylase gene. This is a gene that helps make dopamine. We could go take a little bit of its promoter and we could put that in front of the channelrhodopsin gene, package that whole thing up into virus infect.

Cells. You can almost administer it systemically at this point and it's going to go. Exactly. And this is a very elegant solution.

Carl. Yeah, and in fact, the systemic thing now in some ways is done in some settings. It's more costly actually, because you.

Have to, you have to use a much higher voltage. Yeah.

Yeah. And actually the focal injection gives us other advantages. So we still actually prefer the local injection. But you're right, that specificity is now in large part taken care of by the promoter. And so you can inject that in. The virus gets into all the cells, the serotonergic cells and the dopaminergic cells. But the gene is only expressed and the opsin is only made in the dopamine cells as a result of the.

Promoter. So I have another technical question, Carl. So let's go back to your garden variety cold causing adenovirus. So you're out and about in the park, or you're on an airplane and you happen to catch this cold from somebody, that adenovirus is going to go and it's going to infect the epithelial cells lining your trachea, probably get into your lung or something like that. It's going to incorporate its genetic material into your machinery, which will then make its proteins. That's how it replicates. And of course the immune system is very good at recognizing this because it's either going to put soluble antibodies to antigens on the surface, or if it's done through class one and class two, the T cell system is going to come and through antigen presentation will recognize foreign antigens being presented on the surface of a cell. So in other words, the host cell, your cell, will hold up its little hand and say, look, I've got this little protein in me The T cell will come and destroy that cell. How do you prevent the immune system from standing by, watching you do all of this very elegant genetic engineering and then just coming along and bigfooting you because it says, wait a minute, that channel opsin is not supposed to be here. Are you just getting lucky that it's not being presented on the MHC Class I or Class 2 as a peptide, or meaning pieces of it, because obviously it would be much larger than a 9 to 8amino acid.

Peptide. But yep, this is a great question. This was another energy barrier to tackling this strategy. Everybody thought, and rightly so. This is a potential concern, right? The immune system is going to attack the cells making this foreign protein and kill them. Well, a couple things helped us here. One is that we were working in the brain, and as you know, the brain is what we call an immune privileged organ. The T cells and B cells that patrol our bodies don't have free access to the brain. They're kept out. And that's pretty interesting situation. Why is that? A lot of interesting evolutionary speculations to that, but it's a fact. And so they. They can't get in. And without that, no doubt, things along the lines of what you're saying would be relevant. And we've actually even recently explored this sort of thing. People have been interested in peripheral, not central, peripheral optogenetics, and it works. But people see loss of the expression in the cells expressing the opsins over time, over months, and the immune response is certainly part of that, but in the brain, that doesn't happen. And so that's a great question. And here we definitely leverage the immune.

Privilege. This was very helpful, Carl. I think maybe for the listener, they thought, boy, these guys went into a lot of detail here. But I think this was really important because I think only now can we understand the magnitude of a. What you and your team accomplished in what scientifically is considered a nanosecond. I mean, in four years that you were able to do everything you just said, and now we're in 2009, 2010, you have the capacity to introduce these opsins to very specific cells, such that you could say, two neurons which are different, I can put this gene into one and not the other. This is unparalleled. So you now have this capacity to use photons to turn neurons on and off with precision that could never be achieved anatomically under anatomic.

Resolution. That's.

Right. So what was the first question you sought to ask using this technology from a neurobiology and neurochemical.

Standpoint. Yeah, we've talked about dopamine a lot. And in 2009 there was an experiment that I and the whole field had wanted to know which really is, is it the dopamine neurons? Is their activity what animals are getting from this stimulation of that region? Or is it something else, some other cell type that's nearby? Is it the GABAergic or the serotonergic cells that we know are right nearby? And in 2009 we did that experiment. So we introduced a channelrhodopsin and excitatory channelrhodopsin just into the dopamine neurons of this spot in the midbrain that's called the ventral tegmental area or vta. It's got all these other kinds of cells, but that's where the dopamine neurons also live. And we used a souped up form of the promoter strategy I just told you about to get the gene into the dopamine neurons. And we asked a very simple question. If you have a mouse and you give it a two room house to live in, it's a very simple house, two rooms. I can go back and forth from one room to the.

Other. So kind of just like a New York.

Apartment. Yeah, on a good day, yeah. Then what if you turned on the laser light, the light that activated the channelrhodopsins on the dopamine neurons. But you did that only when the animal was in one room and not the other room. And what we found is that if you did that, the animals preferred to be in the room where the laser light had been applied, compared to the other room, which was equivalent in every other.

Way. So this would be the analogy just to. Sorry to interrupt, but just to make a really crude scenario, you could have done this experiment 100 years ago. If you said, I'm going to put sugar water in one room and not in the other. Is there a preference that the animal has for it? Presumably it would always want to go to the room with sugar water or cocaine or something, something pleasurable. But yet here you were able to do that without anything other than the excitation of a particular.

Neuron. Exactly right. And in fact, this test is an old test. It's called the conditioned place preference test. And yeah, the animal now prefers a place, and it's because of the conditioning is how it was done. Classically, just as you're saying you would pair something good like cocaine or sugar or food or a social interaction, a mate, something like that, and you would see later that the mouse would choose to spend time in there, revealing to us by its behavior that this thing was positive in value to it. And you can do the flip side, too. You can do a negative thing. You can make it feel mildly nauseous. You can give it lithium, which we give to patients, too. And one side effect that you can have is mild nausea. You can give a mouse mild nausea that way, but only in one room, and then it'll avoid that room. And that's conditioned place aversion. So the animal can report to us the sign, if you will, the valence, positive or negative of its experience by where it chooses to spend time. And that's incredibly valuable. This hearkens back to my very first wanting to be a neurosurgeon because a human being could tell me what they were feeling. Well, of course, a human being is more eloquent, but behaviorally, a mouse can report whether something is of positive or negative value to it in that.

Test. Carl, when you're looking for the positive valence, what's the frequency with which you would expect that to be the case? I mean, presumably it's more than 51, 49 in favor of the dopamine firing. Just give us a sense of if you ran a simulation of that experiment 100 times and you always fired the dopaminergic neuron with your opsin, how many times out of a hundred would it go to the positively valence.

Side? We try to keep things in. You can make this as extreme as you want. So the answer is a bit flexible. But with typical rewards, with sugar water, with a social interaction, the number you're looking for is sort of 70, 30, or 80, 20. That's kind of the level to which the mouse will prefer one chamber versus another, one room versus another in terms of how it devotes its time. But you can push those numbers both optogenetically using light or with stimuli up or down by making the experience more extreme. It's quite a flexible test, and we had later versions of this. In some ways, the animal's expressing its subjective sense, we think, by where it's choosing to spend time. You can also make a more souped up version of that test where the animal actually has to work to get the light by pressing a lever or poking its nose in a little hole, a nose poke and trigger a pulse of light by each of its actions. So this is a slightly more advanced version where you say, how hard will you work for light? How hard will you work for a precisely defined set of activity in your precisely defined dopamine neurons. And if you deliver light, you can get an animal to press a lever thousands of times a day to get that light. And so now there is no doubt that the activity of dopamine neurons in this way is positive. And it's not just positive. It can be extremely positive. Animals will work very, very hard to get.

It. It's just amazing that this could be done. Let's keep going. I can only imagine how excited you and your colleagues were by this finding. And of course, it probably only whets your appetite for the breadth of questions that you now want to ask. Where was the clinical community in recognizing the value of this tool? So you have all of these questions that have, for, I think it's safe to say, thousands of years, been, in other words, even before the codification of medicine as we know it today. We've always wondered things like what regulates mood? How can two people anatomically be nearly identical and yet one be happy and one be sad? Where do memories reside? What is a memory? What is a feeling? What is a thought? Right? All of these things. And yet I suspect that this experiment, as simple as it was, for the first time, gave you a profound sense of optimism that you now have a tool, finally to ask questions. So you're splitting your time here, right? You're still an on the ward psychiatrist. So on the one hand, you're doing kind of the most cutting edge science in the field, and at the other end, you're still trying to help people who are bringing these questions to your mind. How many of your colleagues in psychiatry, not necessarily your direct colleagues at Stanford, but just, I mean, the community more broadly, how appreciated Was this tool 10 years.

Ago? It's actually very interesting that you ask that. The appreciation in the scientific psychiatry realm, and these are clinicians, psychiatrists, who also have some interest in the science side, the appreciation was very quick and immediate because I think the psychiatrists know and knew better than anyone else how much specificity was needed and wanted in their field. And, you know, I had this was, you know, by the time we got to 2009, the generality of that targeting method was key because then people knew, okay, this wasn't just a parlor trick, a one off, a demonstration that you could get some kind of photosensitivity in one cell once, that this was actually a generalizable, versatile method. You could apply this principle to any cell type. It was done in freely moving mammals and mice, of course, having our same brain structures, our cortex, our hypothalamus, and everything in between. The significance and the opportunity was pretty clear to everyone by 2009, particularly the psychiatrists. And so then there was a great deal of interest. And because the technique was generalizable, it was very widely adopted. And we sent the clones, the bits of DNA, to thousands of labs around the world, and many thousands of discoveries were made by other labs, which was great after that, really showing that anybody could use it to tackle any question, any disease, any symptoms in diverse animals. So after 2009, it was off and running. Between 04 and 09, though, those were hard times because we were still putting the pieces together, solving the light delivery, solving the virus issues, getting the cell type targeting to be generalizable and versatile. And I would say it wasn't really until 2009 that we could look at this and say, yeah, we've done it at this.

Point. Was this work funded by.

Nih? Yeah. So early on, I had some initial trouble getting grants. But then pretty quickly, once the opportunity became clear, both the National Institute of Mental Health and the National Institute on Drug Abuse, two main institutes of the nih, immediately were very supportive. And then later we got a great deal of support from DARPA and from the National Science foundation, and then also from a number of private donors, people who in many cases came through the psychiatry setting, friends or family members who had suffered from psychiatric disease, and they had heard about what we were doing and wanted to support it. So we ended up getting both federal and nonprofit institutions and private donors, and it all came together. But really, until we had things working in this generalizable way, times were a little bit.

Tough. Well, it is again, remarkable now, as you sort of look back at it, to think a that it all worked out. There's a hundred steps at which this could have failed. And again, I'm still amazed that it really only took four years, although I'm sure there were times in there it felt like it was taking forever. But I mean, as you know, you're such a historian of science as well. I mean, it is a remarkable period of time. So let's talk about some of the other questions that you wanted to probe with this technology. So what about any of the other neurotransmitters or neurons in particular? Where did you turn to.

Next? Well, we were particularly interested hearkening back to what got me into psychiatry in the first place. I wanted to understand internal states of mammals and how they can go wrong and create symptoms. And if you work with animal subjects, with mice, for example, you have to figure out what they can report that matters. And one thing they can report very well are these universal things that all mammals experience, anxiety, social interaction and caring for offspring, for young. These are quintessential mammalian states that matter. They can go wrong. So I wanted to study them and I wanted to study them in ways that we're now precise and causal and had to do with specific cell types. One of the first things we did was anxiety. As a psychiatrist, I specialize in patients who suffer from depression and also social difficulties. Autism spectrum disorders, a common theme in both autism and in depression. Anxiety is a big part of that. Anxiety is not a small thing. Anxiety can be absolutely crushing to one's life, to one's interactions, to occupation, to even being able to go out in the world. This is a very potentially severe disorder in many people. Of course, anxiety, though, is also can exist in a normal healthy range too. And it only becomes a psychiatric disorder when it exceeds that healthy range and verges into or in many people, unfortunately goes way beyond, into a very pathological.

Extreme. How do you define that maladaptive transformation from normal anxiety, which I suppose you could even make the case if a person was incapable of experiencing anxiety, they could probably injure themselves and they might be socially quite destructive. So in other words, there must be some evolutionary basis for anxiety and self preservation. But as you point out, I can't imagine anybody listening to this, hasn't personally experienced or known somebody who has experienced anxiety that has crossed too far. But I mean, is this something that falls into the DSM 5 where there's an actual criteria? There must be.

Right? Yeah, there are. And in fact, it's the criterion for rising to the level of disorder in the psychiatric literature and in the DSM 5 or Diagnostic and Statistical Manual is that it's only a disorder if there's impairment in what we call social or occupational functioning. So you could have any symptom in psychiatry, even a hallucination, for example. But if it's not impairing your life, your social occupational function, we don't call it a disorder. And in fact, I've had patients who were hallucinating, but it was in a way that was not disrupting their life. I had a blind patient who had visual hallucinations, but he was fine with them. They weren't distressing to him. And so we wouldn't say it's a disorder, it's just something happening. So that's the criterion we use. And of course it is somewhat flexible because different people have different social and occupational situations. And this is a challenge we have in psychiatry. But maintaining that as A criterion is very good because it ensures that we only treat things that need to be treated. So then you think about anxiety. Well, if you can't function, if you can't leave your apartment to go to work, well, that's impairing your occupational functioning. And so there are people who have anxiety easily in that realm or far beyond. And those are people we want to help. On the flip side, as you point out, there are people who have risk taking behavior that's extreme because they don't perceive or worry about threat. And that's also a problem. So anxiety, we need to treat it in patients who are severely affected and the problem is in anxiety. There are medications that help, but they come with some problems. So the most effective anti anxiety medications are things that relate to Valium and Xanax and Ativan. As you know, these are medications that work, but they can be addictive. They can cause the human being to adapt to the dose and to make it very difficult to stop.

Them. Do we think that they primarily work through their GABA agonism? Yes, primary belief. So you talked about GABA earlier. This is a relaxing, for lack of a better word, neurotransmitter. This is a non.

Excitatory. That's right. That's exactly how these act. They act in fact directly on the GABA receptor and they facilitate its action. They work. They just have some problems and not everybody can tolerate them. They cause some cognitive slowing and sedation and so on, have some.

Issues. And which neurons in particular do we think that they're concentrated in their action.

In? That is a great question. It's subject of a lot of research. If we understood that deeply, then we could make a separate intervention targeted to those cells. The problem is that we don't yet know that exactly. We don't know exactly which cells are the most anxiety relevant cells that these medications are targeting. There are some hints, but I would say not factually known yet. But you're getting to this key point where optogenetics was helpful because then we could ask that and answer that question. We could say, okay, which cells govern the different features of anxiety? And then what am I talking about here with different features? Well, actually this is kind of interesting when you think about it. So what is anxiety? Well, it's actually got different parts to it. First of all, there's physiology. We've all been anxious, we know heart beating faster, breathing faster. Okay, so there's physiology that changes. Then there's also a behavioral change. When we're anxious, we avoid the risky situation. We have an impulse to avoid. If we're anxious out in the open, we avoid going out in the open. And mice do this too. And then finally there's a negative quality to.

It. This is the negative valence. This is the hardest part to put your finger.

On. This is the hardest part to put your finger on. And it's the most mysterious.

And. And perhaps the most difficult, meaning perhaps the most difficult to.

Experience. It's the most difficult to experience. And it's also the most difficult to understand why we have this. If we're already avoiding the risky situation, why does nature also have to make us feel bad? And this is. There are some very interesting evolutionary discussions one can have about that. The fact is, though, that's how it is. Anxiety feels bad and that's what makes it, in many cases causes so much suffering in addition to the behavioral dysfunction that happens. So actually, anxiety is complicated. It's got these different parts and they all come on together, all go away together. And then you've got to ask, okay, these are so different. They're probably controlled by different cells, right? So you've got behavior and you've got breathing and you've got inner subjective sense. These are all very different. Probably different cells are doing it. So then right away you've got to ask, what are we going to target? So we thought we need to figure out this. And so we used. In 2013, we did an optogenetics experiment that targeted different parts of what we thought could be the anxiety pathway. And we found that indeed different cells control each of these different parts. There's a set of cells that control the breathing changes, and there's another set of cells right nearby that control the behavioral changes, avoiding risky situations. And there's yet a third set of cells that control the negative valence, the internal state. Each cleanly controls a separate feature of anxiety. And we did this with optogenetics, introducing light sensitivity and light triggered activity.

And then reproducing each of these completely distinct manifestations of.

Anxiety. Exactly, exactly. So we found we could turn up or down each feature in mice completely separately from the others. We could have animals that. And this got so interesting, philosophically, we could make animals avoid the open area, the exposed realm that people and mice, but many people don't like being out in exposed areas. Mice definitely don't, because that's when they're going to get eaten. We could make mice be much more avoidant of an open space with a specific cell type optogenetic intervention. But the mice didn't care that this was happening. There was no negative balance to it. And this was so interesting that we could create the behavioral avoidance of anxiety without the mice, without the negative feeling having this negativity. It turns out then that behavioral states that mammals have, they can be cleanly broken apart into these features. And we could show that with optogenetics. That was one of the papers from that period of time that was most interesting because it was so interesting in that regard and other people. Catherine Dulac, for example, at Harvard, has done some great work on parenting, another quintessential mammalian state, using the same set of techniques, optogenetic techniques, that we described. She did this in 2018. Mice are pretty good parents. They take care of their young. Mostly that can break down at times, but they care for their young. Catherine Duoc's lab did an amazing experiment. They optogenetically found that different parts of parenting could be broken down into their sub features as well. And the two parts of parenting that were broken down in this way are going out to find the young and bring them back to the nest. So go and get your kids and bring them back home. And anybody who has kids knows that's a big part of being a parent. You gotta corral them, get them back to the safe spot. But that part of parenting that mice do very well, they also care for the young, they groom them. That's an extremely important part. Both human and mouse parenting, of course, is grooming the offspring. Turns out there's a parenting controlling area, but the go and get the kids cells are different from the groom the kids cells. And you can optogenetically break them apart very cleanly and show how this parenting state is assembled from its, its features. And this kind of thing has been, those are just two examples. But that kind of thing really gets to the heart of what's so interesting about the brain, is how do these complex states, how are they pieced together from.

Cells? Why does anxiety track so closely in people with autism? Have you been able to glean any insights into that? And autism is something that interests me immensely. What do we really understand about this disease? I think we know that it's got a significant genetic component. It's not entirely clear what triggers it. And its phenotype, of course, exists on a pretty extreme spectrum in terms of functionality, superpowers, and super deficits. But what do we know about autism? And then specifically why is it that anxiety tracks so closely in people with.

It? Autism is one of my main clinical focus areas. This is actually my clinic office here. I See, patients with autism spectrum disorders here. I know that they are hard to treat. There's not a medication that treats autism. But as you say, a lot of them are very anxious and that I can help with. I can help them with their anxiety with medications like the benzodiazepine class of medications that we talked about. Those help the anxiety. They don't help the social problems per se, but they help with the anxiety. And why is that? Why is anxiety such a comorbid symptom, as we say? Why does it show up so much in autism? Well, the human social interaction world is very complicated. It's very fraught with possibilities for misunderstanding, catastrophic errors of interpretation, embarrassment, humiliation, confusion. We have a very social world that we've created and people who have difficulty with keeping up with the fast rate of social information and making sense of it. It's a very anxiety provoking situation. When you're talking to somebody, how do you know where to look, what to do? What part of them do you pay attention to? Do you look at their eyes? Do you look at their mouth? Do you look at their body movements? God forbid there's more than one person in a conversation with three people. How do you know who to look at? How do people know what to say next to someone on the autism spectrum? These are extremely challenging situations because it's very hard to, to keep up with this high information rate of the social interaction. And this is something in the book Projections that we've talked about. There's a whole chapter, a story on autism and on how this might happen neurobiologically, how this information overload might happen. We have patients who are as confused by social interaction and as overwhelmed by it as you can imagine somebody not knowing the language, not knowing the customs of a culture and being placed into it, while extremely consequential things involving them were happening in real time. And that's kind of the situation. So you could understand anxiety being a big part of autism, just being unable to predict what happens. And so these are patients who we can help with their anxiety, still not yet with their autism. The genesis that are linked to autism, there are many. It's a very genetically determined disease. Not completely, but heavily genetically. The problem is, like so many of the psychiatric disorders, the genetic underpinnings, it's a patchwork, it's many different genes that all contribute a little bit in most cases. And so with all the beautiful genetics which has given us a lot of insight, it hasn't led to treatments because there's not a single gene, single Protein, single cell to intervene in.

Yet. Are you optimistic that that's going to change? I mean, what does the treatment for someone with autism look like in the coming decade? Let's keep it relatively short.

Term. Well, the exciting thing is optogenetics has given us a window now into what could be this sort of 10 year timescale of autism treatment. Because now and again, mice are social. Not only do they parent, but they're also social. They will choose to spend time with another, even same sex member of their species, compared to being alone. And they have complex interactions, they have a give and take, they exchange information, and there's a lot of it. And if you make mutations in some of the genes that are most powerfully related to autism, that come from the human literature, you can make mice that have impaired social interaction as well. We've done this and we've studied these in the laboratory and we've asked, can we correct the social deficit of these mice? And we can. This is a whole thread of work in my laboratory studying social interaction and asking which cells, which circuits in the brain can improve social interaction, including in these autism mutation mice. What's pretty interesting is that if you think about social interaction, just like everything else, and the parenting example made that clear, there are different parts to it. Part of a social interaction might be the motivation, the drive to be social, and that could vary in people. Also the cognition, the understanding, the insight that could be separate, that's another part of being social, is understanding what the heck's going on. Probably different cells affect each of these. And indeed we found that. So there are some dopamine neurons that do seem to increase the drive for social interaction. But then there are other cells in the front of the brain where some of the most advanced complex cognitions happen, the frontal cortex, that may be more involved in the information fire hose that's coming through with a social interaction. How do you keep up with it? How do you make sense of it? That may be more of the cognitive side. And so just like everything else, you got to figure out what's most important. And we found those, though we now know the cells that can improve social interaction in these different areas. And now that we understand these cells better, you can imagine designing medications that for the first time are aligned with a specific kind of cell that's known, known to be important in social interaction. And that's the exciting opportunity for the future. We're not there yet, but at least now we have a causal cellular understanding and that opens cells so many.

Doors. Is it your Belief, Carl, that at least in the next decade or so, optogenetics will be the tool for establishing cellular signal wise causality, but not be the mode of treatment, in other words. I'm sure people ask you this all the time, I certainly have a thought on this. But I thought it's worth asking just to make sure everyone's on the same page. Is it your belief that patients are going to be coming into your clinic with probes that you will be lighting directly to actually change the neurotransmitters via the light? Or is it that we'll just use that as the tool to establish where to target our treatments? Or do you think it's going to be a combination of.

These? Yeah. Optogenetics, in my view is by far the, the most important aspect of it is it's a discovery and understanding tool. This helps us because this brings so much that we didn't have before. Understanding what actually matters, what makes things happen in the brain at the level of cells, is the opportunity that optogenetics creates. And that understanding then opens the door to every kind of treatment. Once you understand that which cells are actually causing and relieving symptoms, you can design medications that address those cells. You can design brain stimulation treatments targeted to those cells or their axons as they project across the brain. So it opens up every door in principle under providing this, this causal foundation. Now that said, and so that I see as by far the future, it's the understanding that opens every treatment door. That said, my friend and colleague Botond Roska in Switzerland just this year was able to confer a form of sight onto a blind person with optogenetics. This was just published in the journal Nature Medicine this year. Ten years ago, he and I had collaborated on a study where he put one of our microbial opsins into a human retina cadaveric after life, he had ways of keeping the retina alive for some time in these donated retinas. And he was able to show optogenetics worked perfectly well to control human retinal neurons. And he spent the next 10 years doing all, going through all the hoops of going through primate studies and then clinical trials. And then just this year he's a vision scientist and he focused on retinal degeneration and was able to take a human being who was blind from retinal degeneration. And he was able to create light sensitivity so this person could accurately reach for objects on a table. That was not possible before. So literally making a blind person see at least to some extent can happen. So I think there may be cases like that. And of course, they're uplifting to see. But the biggest picture is that it's a discovery.

Tool. I want to pivot a minute to talk about your book because I think it becomes a great place for us to now talk about some of the mental illnesses that people will be familiar with during depression, mania, and its sort of cousin, bipolar disorder, eating disorders, all of these things that you've written about so eloquently. First of all, I want to tell you that if I'm not already in complete awe of your scientific achievements, I'm equally in awe of your writing achievements. And I just don't think it's fair that one person can be so gifted on two dimensions. Carl, it's really disappointing, and I hope there's something in life that you're horrible at so that I don't feel even worse about myself. No, seriously, your book is.

Unbelievable. Thank.

You. It's called Projections, and I've read it twice. And I will encourage every listener to read it because it will shatter some of the images people have of scientists, because you don't write like a scientist. And I say that as somebody who's in the process of sort of finishing up their book. And the biggest challenge I have in writing is making it accessible to everybody, making it interesting enough that someone for whom this is not their life wants to read it. You've done that in spades. This really reads like, at times, poetry. I know you've always had an interest in writing. Did it require much effort and discipline to write about such technical matters? At times, but also to write about sort of the clinical conditions, the psychiatric conditions that everybody's familiar with. It seemed effortless that you were able to do this in such an easily accessible and artistic.

Way. Well, first of all, thank you, Pete. It means so much to hear that you never really know when you take a step like this or a risk like this, if it's really working. This was a risk. This was something that was very different. It's not what people expected, as you say, not a typical scientific text at all, really. And the goal I wanted, though, the goal I had was to help everybody, whatever their background. I wanted to help them understand and feel what these altered states are. And that's such a big part of the book, is to work with that feeling, to help people understand and feel for themselves what mania might be like or what the fragmentation of schizophrenia might be like, or the crushing pathological grief of bereavement or the incredibly complex states of eating disorders where you have these astonishing behavioral patterns that seem so inexplicable compared to what you would think would be what we were evolved to do. And so everything from these uplifting, exuberant states of mania to the depths, I wanted people to feel this. And so I had to do this with the writing, with the words. I wanted to do it with the writing and the words. And so in each chapter, the writing is adapted to cause that feeling. In the mania story, the words are exuberant in the way that mania is. In the schizophrenia or psychosis story, there's a fragmentation and a disorganization that happens. And so in all these cases, I had to work with words in ways that are not typical for a scientist. But of course, I wanted to do it. This was my initial passion in life. And for me, it was incredibly fulfilling, actually, to come back and be able to do this. I'd always wanted to do it. I had now not just the desire, but I had a mission. I had something I wanted to tell, I wanted to share with everybody. So for me, it was incredibly addictive, actually. I would. I did the bulk of the writing over a couple years from 2017 to 2019 or so, and then wrapped it up in 2020. And I looked forward to this so much. Every day I would block out a couple hours, but a different time each day depending on my schedule. You know, life's complex now. I've got five total kids. Things are hopping at home. My wife Michelle's an incredibly accomplished Maryland. PhD, herself, also running clinical trials. Also one of our classmates, also one of our classmates. And of course, she's in the hospital a lot. And so no day is simple or predictable so that the writing time would be at different times. Often very late at night, often early in the morning. I tried to block out two hours, but I would find I would look forward to that like almost nothing else. And I just relished the joy of finding the right word and spending days thinking about trying to find the right turn of phrase. And so it was incredibly uplifting, honestly, even though, of course, a big challenge.

Logistically. One of the things I love about the book is how really try to dive into the evolutionary basis for mental illness. This is something I'm always obsessed with. I always love trying to think about things through an evolutionary lens. And sometimes the answers come a little easier than others. One of the places where it comes up is in the Story of Alexander. This is a Gentleman won't give away the entire story, but basically post 911 is triggered into what sounds like his first manic event.

Correct? That's.

Right. Which then gets into kind of this discussion of mania. What is mania? One of the things I found very interesting about this was the discussion about the evolutionary basis for mania. And this is interesting to me personally, because this is a very personal story, I guess. But when I was in residency, I was encouraged by my wife actually to see a psychiatrist. She had some concern about some of my behaviors. And the psychiatrist, after one day, I don't know if she was right or wrong, but she decided I was hypomanic. That was her diagnosis. And that, of course, got me very interested in, well, why is this the case? How does she know? Why would this be? And I began sort of examining everything I'd ever done in life. And. And one of the things I came across was at the time, it was a psychiatrist at Hopkins. So this would have been kind of 2004, 2005. Had written a book suggesting that the prevalence of hypomania in North America was higher than anywhere else in the world because it had the highest concentration of recent immigrants. And the argument was, well, by definition, if you have a collection of people who are one to five generations away from people who had basically the nerve to leave a comfortable life elsewhere, and in the case of certainly my parents and many people who came here basically to come to nothing, you don't know the language, you don't know the culture, you don't know the people. It wouldn't be surprising that you could concentrate hypomania here. A. I'm curious as to whether you have any thoughts about that theory. But perhaps more importantly, let's dive into this evolutionary basis for mania. Because the point that you get into about how there are some times when traits are very valuable at the population level and not at the individual level, I found that.

Fascinating. Yeah. Well, first of all, that's a very interesting route into this discussion, which is the immigrants, the recent immigrants and the possible genetic link to have the. In recent times, to have the get up and go, to leave, to take the risks, to have the energy to have the motivation to actually make it happen, to sustain it. This complex goal with so many possible downsides, that's no small thing. Some people wouldn't want to do it, some would. And mania, it's one of the poles of bipolar disorder, which is a very genetic, highly genetic disorder, one of the most in psychiatry, bipolar type 1 disorder, extraordinarily genetically.

Determined. Just to be clear, Carl, does that mean that bipolar stems from bipolar, or it just clusters with other psychiatric illness. So in other words, schizophrenia or significant depression would also be genetic precursors to.

It. What it means in this case is that if you look at monozygotic twins, especially those that are raised apart, that's where the most pure information comes from. You can look at the concordance of mania or bipolar disorder appearing in each of these twins, identical twins. It's more than 50% for bipolar type 1. In fact verging above 70%. And so you have a very strong bipolar type 1 genetic.

Determination. Out of curiosity, what is it for autism in that same.

Setting? Autism also high, maybe just a touch under that. With depression, it's like 50%. And so most of the psychiatric disorders have strong genetic links. They tend to be less than 80%, but in this kind of 50 to 80% range for many of the severe ones, from depression to schizophrenia to autism to bipolar, this is something we face in schizophrenia and in autism, but in bipolar, it's extremely strong. Right away we know there's that link. Mania is the positive poll of bipolar disorder. The other poll is depression. People with bipolar type 1 have had at least one manic episode where they have a period of time, could be a week, where they've had this very clear, discrete state of elevated mood, increased goal directed activity, projects, plans, spending, taking risks, faster speech, not needing sleep, truly not needing sleep, not nearly as much. And honestly, even though this causes problems and serious problems, and not to sugarcoat it at all, mania can do terrible things. People make very poor decisions. They can be.

Fatal. Yeah, I was just about to say, aren't people even slightly more likely to harm themselves during a manic phase than a depressive.

Phase? Yes. Or the transition from out of depression to mania. That's actually probably the most risky time when they might still have some of the negativity from the.

Depression. But now they've got the energy to.

Attack. Yeah, exactly. It's a problem. But yet, at the same time, some of my most memorable experiences in talking with manic patients is I actually love talking to them because there's such a charge of energy. Anything's possible. They're funny, they're warm, they're charismatic. And it's so easy to see that this is a state that it's not a bunch of random things happening in the brain. This is a coherent state of elevated mood. It's consistent. You see it in one patient, you see it in another patient. It's something that's there that human beings have as something they can do. A Sustained state of elevated mood and energy. And you look at that and you think, okay, why? And also, what does that mean for treatment? Is there an ethical issue with treatment? Are there cases where mania is positive? And this is something that the story in the book and projections really made me think so hard about. This was actually when the seed for the book was first planted in my head. It was just 20 years ago, right after 9 11. And this patient, Alexander, he had never had any psychiatric illness at all, nor in his family, but he was flipped into a completely classic full blown mania after 9 11. He had no particular connection. In fact, he was on a sailing trip in the Mediterranean with his wife at the time. Came back home after 911 and a couple weeks later he was manic. All these symptoms that we talked about and it was a huge problem. But he had this appropriate or at least aligned quality to his symptoms. He was retirement age, but he was training himself to go into battle. He was rappelling down trees, he was running through the night, he was reading about military strategy. And then it verged into this very difficult, emotionally challenging. He was screaming, he was hyper religious. Everything had become quite extreme and incompatible with his life. And so that ended up bringing him to the hospital. But looking at this, and we think, okay, this is a state of elevated mood and energy. It was triggered by context. And this is actually the flip side of what you're saying with the immigrants. Not only is there likely to be a set of conditions that led to these people being able to have the energy and willingness to take the risk and meet all the incredible challenges of moving across countries and cultures, but then that's not this fight or flight response of a minute when you've got a threat and you have to, you have energy and then you meet the threat and then it's gone. We're talking about you need a sustained level of energy for weeks, months, years even, and to take a risk and a life shift like that. And so everything is on a spectrum and you've got mania and then you've got this hypomanic state in between. That makes a lot of sense that people who are able to sustain this elevated energy state are those that would be VR immigrants. And again, you have to look at this and think it's a spectrum. Definitely it can be bad, but we have to value the whole spectrum and understand the whole spectrum. It's part of who we are as the human.

Family. Why do you think that in the bipolar condition you have this pairing of such opposites? Is the depression a necessary part of bipolar to basically allow the recharging after this unbelievable discharge of emotional and physical energy. Because otherwise it doesn't seem like these would. For example, why doesn't it just go normal affect mania? Normal affect.

Mania? Yeah, that's a great question. We don't have the answer. Some people, some fortunate people are like that. You can get a diagnosis of bipolar disorder without ever having a depression. One episode of mania gets you that diagnosis of bipolar type 1. And those people there are people who haven't hit a major depression yet. That said, most of the time there is that other pole of the disorder. And what is it? Is it? We don't know. Short answer is we don't know. But a lot of interesting ideas. One could be sort of aligned with what you're saying, that there's some resource that's exhausted. It's not a resource that we know what it is. We can't point to it. Is it a neural circuit state of some kind, capability of a neural circuit that can become exhausted? We know neurons can run out of energy. This is part of how the brain stimulation to cause inhibition works. But that's all on a very fast timescale. You can exhaust neurons on seconds to minutes. It's not known what really could get exhausted on the week's scale. We don't know what that would be. Or maybe it's the termination mechanism, but it just overshoots. Or maybe it's just that what's lost is the homeostatic thing that keeps energy in a tight range and then it could go in either direction because you've lost some break that's present on either side. Not known. But a very interesting.

Question. What is technically the most common psychiatric disorder? Is it.

Depression? Actually, the anxiety disorders, if you group them together, anxiety is the most common, but depression is certainly up there. That's in the top group for sure. Anxiety disorders are so underappreciated, a lot of people don't talk about them. A lot of people can make it through the day with anxiety even if they're suffering terribly. So, yeah, anxiety is most.

Common. What has optogenetics taught us about.

Depression? This is my clinical specialty. I have right here in this office. We do vagus nerve stimulation, for example. This is a VNS therapy, radio frequency controller. We still do here, electroconvulsive therapy. We do transcranial magnetic stimulation. Clinically though, we're looking for guidance from the, the science because it's still not known clinically what actually is going wrong in depression. We don't actually know that in a way that can guide therapies in the way that we'd like. And what's the scientific situation? Well, optogenetics has helped quite a bit because. And again, picking up on this theme, of course, there's different parts to depression, and this is how we diagnose it. We ask about all these different parts. There's depressed mood, and that's this negative state. Okay. There's hopelessness. So it's kind of the opposite of mania. A manic person thinks anything's possible. Depressed person thinks nothing's possible. There's a deep discounting of the value of effort. And this shows up as hopelessness. This even can lead to suicidality and certainly severe social and occupational dysfunction. And then there are other parts to depression. There's something called anhedonia, which is really.

Interesting. Yeah. This is perhaps the most insidious component of depression by.

Far. Right, right. And it's not commonly known. People on the street don't talk about anhedonia. Right. They'll say they're depressed, but nobody talks about their anhedonia. But it's an incredibly important symptom. It's such a core symptom of depression that actually you can get a diagnosis of major depressive disorder without depressed mood. If you also have anhedonia, it's that important. And it's the absence of pleasure or joy from things that normally bring pleasure or joy. And we've all had a cold, and we've known that taste is gone. Food has lost all joy. It's things even without the cold, with the anhedonia of depression, all the joy of food or social interaction, or your children, your grandchildren, a book, a movie, all the joy of life is gone. And this is a horrific thing. It leads to very serious problems. And that's something that optogenetics has helped us.

Understand. What do we know about that? Where do the neurons reside? And what are the neurotransmitters involved in the propagation of.

Anhedonia? So again, you might say, how are you going to test this? And you can set up very simple behaviors with animals that provide some insight. First of all, you could provide a simple choice for animals. Mice like us like sugary drinks. And you could give the animal a choice of a sugary drink or just water. And normally a mouse will prefer, kind of like we do, they'll prefer the sugary drink and by a factor of, you know, two to one or more. But a mouse that's been stressed, that's had some unpredictable events happen, it's had its sleep disrupted, it will not prefer the sugar water nearly as much. It won't care as much. And so such an interesting thing, given all the evolutionary importance of a small, high metabolic rate mammal needing sugar, and we know the reward that we feel from sugar and presume it's very similar for them, and then not caring. Sugar water, regular water, it doesn't matter.

No. So in other words, if you had them going 50, 50 between sugar water and regular water, that would be even more telling than if they disproportionately went to the regular water. Right. You would be looking for a complete amelioration of the effect of the sugar water, would suggest that they have basically lost.

Interest. That's right. That's exactly right. And that in fact happens. And so we and others have explored this kind of thing with optogenetics, and we found that there are pathways, and coming back again to the dopamine neurons, which are tightly linked to mood and mania and depression. But they're a complex set of cells. Some send connections to one part of the brain, some send connections to another part of the brain. We have found some interesting pathways that relate to those dopamine neurons where you can actually affect how potent a normal rewarding stimulus is by something going on in the frontal cortex in the frontal part of the brain. And overactivity in the prefrontal cortical areas can cause anhedonia in rodents, an overactivity seems to cause an inability of the dopamine neurons to recruit reward circuitry. This is an insight that optogenetics brought us, and it's something that we're following up mechanistically. It's kind of an interesting thing that what we found is that again, using optogenetics, that the frontal cortex can suppress both positive and negative things. It can suppress fear, it can suppress anxiety. This is part of how we exert cognitive control over situations. We can enter a scenario that we know is risky if we think about it enough, if we frame it enough for ourselves cognitively, if we review the need for it, for taking this action. And so our frontal cortex can help us by tamping down negative aspects, but it also, when overactive, it turns out, can tamp down positive aspects as well. And optogenetics has given us a causal insight into this. And so that's just one example. But all the other features of depression as well are susceptible to to optogenetic study. And we've gotten insight into them, hopelessness being another one. And so here again, you might ask, how do you Measure hope in an animal. Well, you can put an animal in a challenging situation that is not escapable. Animal can try to get out of this challenging situation and then would.

That be like a maze that doesn't have an.

Exit? Yeah, no way of getting out. Exactly. So it doesn't have to be painful, just something that animal would want to get out of and eventually they give up. We can do this actually in fish as well as in mice. And that giving up is effectively. It's this hopelessness, it's this discounting of effort. And that can be an appropriate thing. Let's say, of course, if the situation truly is hopeless, it really is not good to keep devoting effort to it. Right. If you keep flailing against an insuperable situation, you're burning energy, you could cause physical risk, you're distracting yourself from other things, withdrawing, entering into a passive coping state is actually adaptive up to a point. The problem with depression is it becomes an extreme, so it becomes maladaptive. You've discounted the value of everything and then it's got this mysterious negative balance to it too, which is of course also part of the.

Problem. What do you think is the evolutionary basis for depression? This is something that is so ubiquitous, I think I can, based on what you said earlier, see the evolutionary basis for anxiety and maybe we could just argue that the pathologic version. Well, we could discuss why maybe it's been amplified and what it is about our environment that perhaps does that. But depression's a less clear to me. And certainly mania is clear. Right. I think we've made a very compelling case for why mania could be why evolutionary pressure could have favored the propagation or at a minimum, the maintenance of this. Why depression? It seems to be counter to your ability to mate, to find food, to defend yourself. I'm struggling to come up with one evolutionarily valuable tool that would be better in a depressed.

State. I think about this all the time and part of what we've discussed already may provide some insight, which is this withdrawal, this passivity. It is, in some cases, you can think of it like a hibernation. Is it worthwhile for an animal to. To actively try to cope with winter by running around trying to find more food all through the winter, or to withdraw to sleep more, to not see the value or feel the value in going outside and doing anything? And clearly, no matter what you do, you can't fight winter. Right. The best thing is to conserve your energy, ride it out on some time scale that's appropriate. Now think about Depression, it comes with this low energy, it comes with this hopelessness, this discounting of effort, this lack of motivation to go seek things to be enjoyed, reduced drive for social interaction, all these things can be part of depression. The negative aspect is the one part that I can't explain. That's of course the clinically significant problem. Why does it feel bad? And this is not just feeling bad, this is agony, this is psychic. Pain is the kind of thing that drives people to seek suicide. Not to discount that at all. We don't understand why depression feels bad. But the passivity of coping, that can be adaptive. And it's. Perhaps you could see almost depression as a hack, a bad hack, maybe one that's not fully evolved yet, just like mania, not fully evolved yet, not under all the right controls to make it more generally suitable and reasonable. Depression, easiest way to make it happen is to remove the joy, to remove the energy, to seek out reward. And then you've got an organism that's going to be passive, that doesn't see a path to something positive. And evolutionarily, if you take this viewpoint, maybe one way of getting to that goal that had some at the population level, some adaptive value included, having this negativity, this negative state to it. And this is pure speculation, but it's important because depression is very genetically determined, it's common, it's biological. And at some level we have to deal with the fact that we have evolved to be where we are now and we have this high rate of depression. And so we have to include in our thinking the biology and the evolution together. And so that would be my take on it. Of course. It's very hard and I wouldn't claim to have a definitive understanding two.

Unrelated questions, I don't even know which one to ask first. So I'll probably just ask them both and then let you take them whichever way you like. The first is sort of a desire to understand where depression specifically, but even other mental illness fits into our closest relatives, the primates. Right. Do we have a sense that our primate relatives are as afflicted by depression and or other mental illnesses as much as we are? Let's start with.

That. One of the clearest things we can see is that non human primates can certainly enter into maladaptive states that look like grief in bereaved states. There are cases where you can have a non human primate who is old enough to feed itself, but who has lost a mother, let's say, has lost its mother and loses the motivation to feed and protect itself. And so stay with the troop and ends up dying as a result. This is a clearly maladaptive state. Documented that in a non human primate. You could call it something like a depressed like state, deriving from bereavement and presumed to anthropomorphize. Something like grief associated with bereavement. So I believe these states are shared by our non human.

Primates. Any evidence of self harm in non human primates? Does it ever get to the level of. I mean, suicide is a top 10 cause of mortality in the developed world. It's important to make sure people understand the significance of that statement. In the developed world. When you think about all of the problems we've been able to solve, one of the 10 leading causes of death is self harm. And by the way, if you really include overdose as a subset of that, it probably leapfrogs into the top seven. Is there evidence that this occurs in other.

Species? The short answer is no. And there are less suicidal forms of self harm that can happen now and then you'll see animals carrying out behaviors like head banging and things like that. But in terms of a true suicide, the volitional ending of the self, there is not a animal model for that. Let's say it's not clear that that happens. And if you think about it, as much as we'd like to have that so we could address this urgent, enormous clinical need, that's not going away. We would love to have some way of studying this. We don't have it. And if you think about it, the ending of the self is an extremely cognitively complex thing. If you think about the act of suicide, which we don't understand and it's a horrific thing, but you've got. There has to be some understanding of what that means, that there is an ending of life, an ending of the self, and that the pain that's being felt now would not be felt, then this is a level of understanding of the universe that it doesn't seem that animals that are not us actually have. We could be wrong. I'm completely willing to admit that there are amazing animals. You know, dolphins and whales and elephants have incredibly complex and amazing minds. They may be better then we are at some of these deep concepts, but they may have less clear ways to express it. They may have maybe not having fingers and hands to do things that we can do. They may not have the ways to express it, even though their cognitions may be just as complex. And so I think there are two factors. One is the things that set us apart, our brains and our hands, those two don't come together in any other animal. And I think that's why you don't see suicide elsewhere, at least as we understand.

It. Our colleague Paul Conti, close also friend from medical school who trained with you in psychiatry, has just written a wonderful book on trauma. And so it begs the question, what role does trauma play in the amplification of depression? We know, as you said, that depression is highly heritable. But like most conditions that are heritable, there tends to be environmental triggers that can bring one person to have it and one not to have it. Even if you take the most extreme example of the monozygotic twins raised in a separate environment, one comes down with something. There's clearly some difference. So what role do you think that early childhood trauma plays in all mental illness, but I guess specifically depression? And do you believe that that could be epigenetic? In other words, do you believe that this thing can irreversibly mark the gene and then be transferred to subsequent.

Generations? Yeah, subsequent generations, yeah. So the effects of trauma, the lasting effects of early life trauma are unfortunately very clear. These you can see in animals as well, and they extend beyond depression, for sure, to include the personality disorders, like borderline personality, for example. So there's no question that early life trauma has lasting psychiatric influence throughout life and can cause very severe problems. Many ways to look at this. Why is it happening and how is it happening? Is there a wiring change? So is the lasting quality due to a physical structure of the brain as a circuit? That's one level at which it could happen. And the brain is very. Brain circuitry is very tunable that way, especially in young people. And so you could imagine that early life experience with trauma sets up the human to expect in some ways that the world is a harsh and unpredictable place and that the value system had better be set up to deal with that, because that's how it is, apparently. And so you could almost imagine an adaptive, though very unfortunate process going on where there's a period of youth where you're gathering statistics about the environment, deciding what the adult should be like, and then implementing that. And so early life trauma could intersect with such a process, very unfortunately, and create people with a lasting state of depression, for example, expecting aversive things to be present at higher rates and negative consequences of actions to be present at a high rate. Now, that could be for sure the case as far as an evolutionary logic, but there's no doubt that this happens in terms of the behavioral effect and the psychiatric effect. The Lasting effects of early life trauma. Now, if it's not neural circuitry, what else could it be? It could be genetic or epigenetic, as you say. You're not changing your genome from childhood to adulthood, but you're changing the transcription factors, the promoters and enhancers. You could be affecting gene expression throughout life, and that, at least through the life of that individual, we understand how that mechanistically could work. And then finally, you raise the intergenerational aspect in human beings. This is very hard to separate from. It's the nature, nurture thing, of course. You've got the parenting that's linked to what might have happened in the prior generation. And I'd say it's still controversial how much intergenerational transfer can happen, although in animals there are.

Mechanisms. You wrote about the. Well, at least you wrote about your musings, your exploration of the idea of the evolutionary basis for tears. I found this completely fascinating. A. I found it fascinating because I'd never once considered that. And for someone like me who is often thinking about the evolutionary basis for this feature or that feature, it was interesting to me that I hadn't considered that. Say a little bit about.

That. Well, emotional tears. And by that, the liquid coming from our tear ducts in times of emotion, this is apparently, as far as we can tell, it's a human trait. Our great apes don't do this, and even some human beings don't do it. So it's a special thing. It's not that we are the only ones that grieve, but we're the ones that secrete this fluid from our eyes at these extreme moments. And this has been studied. There are scholars of tears, as it were. And you can do things like add or subtract tears digitally from pictures of faces. And these have enormous impacts, the reactions of people seeing these images much, much greater than a smile or a grimace. And particularly creating a desire to help. When we see tears, we want to help that person. And so this intersects very closely with the, I think with the involuntary, largely involuntary nature of tears. It's a truth channel. It's not so easily gamble. It reveals something that in a social grouping like those that we've evolved to maintain, it is an involuntary expression of something, the world changing, of needing new systems in place. And it triggers this outreach from people who see it in a very powerful way. And this question, can an emotional change cause something like this to happen? It would be a very easy rewiring to happen. There are already axons that come from emotional regions and go to the brain stem that control the breathing rate, for example, in anxiety. And right next to those breathing rate regions, there are regions that control the tear ducts. They're right next to each other in the brainstem. And a very tiny, tiny rewiring little axon just going in one slightly different direction would create this state of expressing, this visible manifestation of an inner world. And for a social species like ours, it could be easily evolutionarily selected for. And so in the story about Storehouse of Tears and Projections, this is something that a patient story helped bring to the forefront of my mind and we talk about it quite a.

Bit. Yeah, I won't give any more away from that story because I want people to read it for themselves. Carl, I know that we've kind of reached the limit of our time and you have another commitment today, as you can probably imagine. I could continue this discussion for probably another couple of hours and I gather you could as well if it weren't for this other commitment so easily. Yes, I think what we should do is just commit to sitting down again next year at some point and continuing this discussion. There are so many more questions I have about personality disorders. And another topic that we didn't even get into today that we're both very interested in is psychedelics, both from the traditional side, even to the non sort of traditional side, the use of ketamine, psilocybin, lsd, mdma, all of these things which are an enormous interest of yours, clinically and scientifically as of mine. So I want to again congratulate you on not just your recent Lasker Award, which again I'll make sure in the introduction to explain to people what the significance of that is, but also your remarkable achievements over the past two decades and this remarkable work that you've written, projections which I suspect many people are going to be reading after this. So, Carl, thanks very much for spending time with us today and thank you for educating us on this amazing journey you've been.

On. Pete, it's been great, great to reconnect with you again and an incredibly enjoyable conversation and look forward to talking.

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