191 - Revolutionizing our understanding of mental illness with optogenetics

hey everyone welcome to the drive podcast i'm your host peter etia hey carl it is so good to see you today uh although admittedly across the video but uh it's like a little blast from the past from i don't know 20 years ago right yeah it's uh it's amazing we had a good group of friends back back in the old days at stanford and i haven't uh kept in touch with them as much as i'd hoped but it's great to see you it really brings back a lot of memories you look great unchanged well yeah that's funny you you don't look a bit different um it is funny when i think back to to that class of ours in med school and i really feel like the overwhelming underachiever of our class and i remember our first day of our surgical rotation uh you me and joshua benowitz in that sitting in that room waiting for us to be assigned to which service we would go to of course you and josh have gone on to do unbelievable things um i've sort of muddled along but um now you're the star and plus i remember you even though it was the start of our surgery rotation you already knew how to do everything which i was impressed about you you knew all the knots and and i was like wait this is the first day of the rotation how do you do that well let's pick it up back there so um you know i i you know you were in the md phd program so we didn't start at the same time we just finished at the same time you had come in earlier um but i think the reason i knew you even on our first day of surgery was because you had done your phd in the same lab as two other friends of mine alex rovinis and jason pyle and i mean all kidding aside i think that you know look all the kids that went to med school were pretty bright but i think the md phd students were sort of in a class of their own 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 but what did you major in again in undergrad i 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 a major either it was a concentration so i concentrated in biochemical sciences so there you go but uh i had a lot of other interest all my friends were physicists uh theoretical physicists in fact uh and so i i was exposed to some uh some pretty uh unusual stuff for biochemistry and were they allowed to call it theoretical physics at harvard they were okay well that's that's good i just i just wanna good question yes they they were allowed to name it good good so at what point during your biological science concentration did you know you wanted to go into medicine uh it was pretty early because i i was interested in the brain early on and i wanted to understand the brain at the level of cells and but i was also interested in the most high level aspects of brain function and so i thought i needed to talk to human beings i needed uh some some access to the to the human brain and i found that interesting because i was interested in emotion and the ability to express uh feelings through words and and i i had this i was torn i liked writing and literature and and uh and the use of words and i liked cells and biology and i wanted to somehow fuse them and it seemed that that medical school was the way to go because i could i could work with the human brain and um 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 um and so that tells me at the outset that you also knew you wanted to do research beyond you know quote unquote just clinical medicine yes yeah that's right and and that was the that was the you know the the nice thing about the mstp is it lets you delay making a commitment you know so you you keep both threads alive and then uh there's a beautiful synergy that can happen too and certainly happened with me that that you realize oh wait i don't have to make this decision it actually is good to keep both threads alive and in my work and my life and that that's what that's what happened but it's a it's a pretty special thing we have in the united states uh there are efforts and along these lines in europe and and other countries but it's not nearly as uh institutionalized as as it is here it's a really uh special thing well it it really is and i again i 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 you know exceptional scientists that you would also basically be leading the charge scientifically and you know for what it's worth all of my friends in the mstp program i think you're the only one that ended up doing clinical training as well i think most of them didn't end up doing residencies they either went purely into academic research tracks or actually went into industry 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 you know again how do you how do you get access to the to the human brain and who among the different clinical specialties has that uh access who can who can uh would most directly interact study and it seemed to me the neurosurgeons had it all uh and if one were to build 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 but a neurosurgeon was my was my reasoning and you know uh and i the neurosurgeons my my colleagues and friends they're amazing people you know brilliant and and i i saw no reason not to to pursue that and so that was the first rotation that i i selected in the in those second two years of medical school even before surgery i did neurosurgery and so which was kind of interesting just just coming in there with uh with no general surgical training as well that's how how certain i was yeah it's funny um well i had a similar experience whereas the thing i absolutely positively thought i was going to do i picked as my first rotation uh in my case i had less of a pleasant experience than you i think you had a pleasant experience on neurosurgery it wasn't that in any way you didn't like it but what was your first well i i planned to do pediatric oncology so i 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 residence 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 it just the whole thing just didn't go well it was a disaster and then my next rotation was general surgery where we connected uh and even though i had no desire whatsoever to go into surgery that became a a kind of overnight love and a way we go but so 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 mean 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 i in fact i spoke to the program director at hopkins and said would it be ridiculous for me to try to transfer into neurosurgery um 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 um 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 um what was your experience like i mean it was yeah at the one at one level it is an organ and and it's 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 and the whether the cells are receiving enough oxygen and and uh and glucose and they have to think about it in the in the context of the the physicality of it uh perhaps more than the the mentation aspect of it and so but they they 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 the surgery and a little bit of uh loss of tissue in the thalamus and the patient had a neglect syndrome uh which i spent a lot of time working with the patient afterward characterizing exactly how this worked uh you know i asked the patient to draw a clock and the patient drew you know just half of a clock and it was a amazing you know classical thing but amazing to see with your own eyes as you're talking to another person and that the person said the clock looks fine it's a but it was a half clock and and i that certainly didn't diminish my interest in neurosurgery at all it was you know this was at at the one level you know there were problems which nearly clearly needed to be better you know aspects of neurosurgery as with every clinical specialty needed to improve needed to reduce you know 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 i uh but i was good enough uh and it was particularly because it was so early uh i think the the promise was there it would have worked out and it was it still had a magic about it you know when you when the dura is exposed it's a it's yes it's it's an organ but it's a there's a spirituality to that to to know that that you're actually looking at the the storehouse of human beings you know thoughts and feelings and and everything about them all all encapsulated in this collection of cells it's it's quite an amazing thing and so i had no negativity at all i did note that neurosurgeons they they didn't get a lot of free time there was not a lot of you know philosophizing uh 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 in willingness to philosophize uh as their progression through the residency uh uh continued you could almost plot that you know linearly on a graph and with all you know due credit to them it's it's the nature of the system they're in that they don't necessarily have all the time they would like to to think deeply um although they certain they're very bright and thoughtful and certainly could and so i did note that i noted that you know here 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 they were three ridiculously smart guys yeah 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 but one of the experiences that jumps out at me from my month of general surgery at 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 it's really hard to believe what you're watching right 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 that was something that was a magic that i don't think i could describe otherwise yeah and and that i felt that very very strongly and so there was it was all systems go after that they you know surprisingly the neurosurgeons at stanford liked me okay after that too i got very positive feedback uh from them and and and uh they said hey you know come back and do a sub i sub internship and we'd we'd love to to to get you uh down this path um so which which was a you know that that was a that was a green light and and i was i was happy with that it was it was where i was headed um of course things changed after that yeah so the best laid plans um there was another mandatory there's a set of mandatory rotations we have to do neurosurgery not being one of them but pediatrics general surgery internal medicine being the ob gyn and one of them is psychiatry kind of this afterthought for you know 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 conte end up picking this field ultimately just amazing right so tell me about your how did you go into your psychiatry rotation were you looking forward to this or did you view it the way many of us did which was just get me through it i had a get me through it uh you know attitude coming in and again no no disrespect to psychiatry of course you know it's a they have a hard challenge still we have this challenge that there's not a a miserable really you know we have we have effectively you know questions we ask patients it's all with words is how we we work and nope no biomarker no biomarkers still yeah i mean there's efforts along those lines looking at eeg you know ratios of this to that and and there's progress being made but still clinically we can't make diagnoses uh based on measuring something about the brain and psychiatry you can you can notice that there's something else going on a neurological or a medical problem but you can't define someone's psychiatric state with with a some biomarker and that still amazingly to this day still true yeah so what 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 you kind of i did it as one of my last rotations prior to graduation which meant there was no chance even if i'd liked it 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 but interesting nevertheless what was your month like so my mine was the opposite of that it was 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 a unit where patients can't leave and this is due to you know being a danger to themselves or danger to others or having a great disability and this you know these patients were severely ill and i i walked into that uh you know i'd had typical experiences everybody you know has friends or family who've had you know depression or anxiety i i'd had uh i'd seen substance abuse and and intoxicated states and and dementia and and i had a fairly you know i thought decently broad understanding of what can go wrong on the on the psychiatric side but uh i can tell you nothing and you you know this by now but but uh i can i can tell your your viewers uh and listeners there is nothing like what you can see uh when you walk into the locked ward of a psychiatric hospital there's a there's the uh there's a sort of a purity not in a good way but there's a because there's not confounding issues like intoxication and so on there's a 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 and that's that was was my experience and it completely changed my course there was a even on the you know my very first day there was a 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 and but it was it was not uh necessarily a sort of a street encounter that you might have in a city it was more uh it was more uh direct and personal and uh evocative of something going on in the in the mind of the patient that was clearly a source of immense suffering of great disability and yet at the same time it was it was uh tantalizing because this was a human being who's physically intact but whose reality was so completely different from mine we were two people with intact bodies and and and brains who were uh you know next to each other and we inhabited completely different realities and to experience that was a utterly uh 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 and without that direct exposure i don't know what would have happened but having had it it changed my course which is interesting i mean many people when confronted with that would be quite frightened um especially when you realize the limitations of the tools that you have right so let's let's consider another analogy which is you know a patient that comes in with a gunshot wound to the chest that's an incredibly frightening experience there's literally you know a sucking chest wound blood could be splaying around the room vital signs are crashing the person's on the verge of death but that can be exciting in a way because we actually have the tools to do something right it might be completely draconian we might be doing a thoracotomy in the er cross-clamping the aorta but you run that patient to the or and you know how to fix them you're experiencing something that i would argue is much more frightening but compounded by the fact that what do you do i mean you could temporarily give that person hal doll and and sort of snow them but that's not curing them so was it which of was it more the we don't have the tools here this is an unbelievable opportunity to learn or or you know how did that experience which i think for many people could have been off-putting do the exact opposite in you i mean i had uh it's it's a great question because i i and i would completely understand that the normal uh or typical reaction would be sort of an aversive thing you know how this is this is not something i want to spend my life uh doing in this in this setting um but i had a i had a different reaction which surprised me uh and it was partly it was it was really there were two sides to it one was exactly what you're saying the level of mystery here was uh actually for me it was a positive rather than an aversive thing and maybe this was partly the my scientific training you know at that point i'd completed my my phd and and and i'd spent years trying to figure things out uh and we all want to figure things out that's a natural human impulse not everybody uh necessarily spends years and years and years trying to figure out the same thing and that's that's the kind of training we get in in in the phd program and i saw that and i was like okay gotta figure this out this is this is clearly uh a mystery that uh is something that it's a burden that humanity shares it's a terrible burden that this human being is suffering but what's the solution we've got to figure it out we've got to understand this and and it's a mystery that strikes to the heart of of what had always intrigued me which is what is what is an emotion physically what is a feeling physically how does the collection of cells in our brains and that's what it is it's a collection of cells how how is it possible that that creates a feeling and emotion and i realized at that moment this is this is actually you know why i came to medical school this and it all made sense in in one moment that it hadn't before and and then you know of course as a as a as a physician as you well know we our instinct is to help is to heal and and we want to do that but as you say if we don't have the tools what what can we do it's it's a problem uh and i wasn't frustrated with the inability to do anything and i would understand that reaction too and the fact is we we could do a little bit though 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 it fit together in a in a moment and i didn't have another thought uh for neurosurgery after that although it was it was a hard uh process uh you know to re-shape 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 my father was pretty disappointed when i told him on the phone that i was gonna do psychiatry i could hear it in his voice it was it was almost uh yeah it was a quite a and you know again he came around in the end too and and i think he's he's happy uh now but uh at the time i could i could sense that this was not what he had hoped for me um so yeah it was it was an adjustment it was a remapping uh but it was a very compelling experience that that the the process of medical training uh and the required psychiatry rotation made possible so carl you you now make this decision to completely veer into this nearly orthogonal track i mean psychiatry and neurosurgery of course have one thing in common which is the the organ of interest is the brain but at that point they basically you know differ um how did you decide you were going to both pursue the clinical training the residency for psychiatry but also do whatever was necessary to make sure that you could ultimately be running a lab because i i think throughout this period you never lost sight unless i'm misremembering of the desire to be a physician scientist and not just a physician so you know residency especially 20 years ago when we did our residencies they didn't have 80 hour work week 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 it was hard and this is uh there are a lot of uh challenges that that people in this realm face because things move so quickly uh in the research realm that if you step aside for even a year forget about four years uh you know the world you re-enter is is so different and it's very hard to catch up and this is you know that's to some extent an old problem because that's been faced by everybody who planned to do a residency but it's a 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 gonna have to do one or the other if i do the residency i'll i'll be a i'll be a doctor i'll be a good doctor maybe a great doctor i'll be i'll be informed by all my scientific training maybe i'll read papers better maybe i'll be more you know amenable to new ideas new treatments as a result of that but ultimately i'll be a 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 this fast-moving train i'm at this moment i've just finished my phd i'm a world expert in this i can do things that that nobody else can do why lose that momentum why not speed up add the next tool in the toolbelt launch yourself and make great discoveries and that is very very tempting i had uh you know very clear opportunities to do that and so that's the hard choice that that the md phd faces at that moment um now efforts are made to to ameliorate that so residencies you know again this was this was the the time still where the residencies uh were extremely difficult uh and and i had some for me this was compounded by some personal challenges i was effectively a single dad at the time and so i had to also think about this this other factor uh very important um you know now i've got i got to think about residency i've got to think about lab i've got to think about family and and it was very very uh challenging uh and yet there are these research track residencies uh and and and they they help a little bit so there are uh and stanford and other uh you know uh programs both in psychiatry and in other specialties they have efforts to help people keep their their scientific uh you know mind alive during residency and it's it's not great but it's a little bit a little bit of protected time here and there never quite enough to get momentum but at least to to keep a foot in the lab and and try to stay connected and so i did that it was a research track psychiatry residency and i i stayed at stanford and a big factor in that was that uh literally at the same time and i was very fortunate in this regard uh a 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 at stanford and i knew here's somebody a psychiatrist but also a neuroscientist he'll understand you know what's going on in my residency that i'm you know i'm taking call i'm i'm up all night uh he'll know he'll understand why i'm never in the lab during expected hours while i'm never at lab meeting and and and that made it work out and i worked nights and weekends um i i maybe came to one of his lab meetings over over four years and i effectively did a combined post-doctoral fellowship and psychiatry residency at the same time at stanford some funny stories i you know i because stanford's very compact as you know i could literally take call from you know from the lab uh i'd be patch clamping i'd be at the rig you know listening in making measurements on currents flying across a single cell and i get paged go walk over to the er admit a patient come back you know patch clamp the next cell and it was a pretty special moment uh when that happened that it felt like the different parts of my life were they they could work together they could be compatible and that with all you know so many people have such a hard time understandably making that work making the pieces fit together and i i feel fortunate that uh i was able to make that work now what year was your son born 98 uh he he was actually born in 96 so he so you're four he is five years old basically when you're in the midst of this yeah that's right so how how did you how did you manage that you know it was these this is actually uh something that that i i touch on i know we may talk about this uh the book i wrote projections later but it was a turned out to be a theme early in my in my life how my experiences with my son how they related to all the the stressors and the patient experiences that i was having and in a way psychologically although it was difficult to make everything work practically it also it helped me a little bit to have a a something that mattered more than anything else in the lab or in the in the clinic there was something that uh sort of uh was on a different scale and it helped me not get too uh stressed about things happening in the lab or the clinic and and uh that that's a a common feeling in people with kids for me it was it was extremely important at that at that time um you know and it was a they were patchwork solutions of of child care and so on that that made things work but it was ultimately i think it was helpful for me in getting through those those times and 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 a second year he's a cool kid he's he's good at guitar much better than i am and uh he likes computer science yeah he's got some big shoes to fill but i and i'm positive that none of that pressure comes from you so um yeah so i remember when you were finishing your residency um i just remember because of our common friends like how kind of exciting it was when you were now setting up your own lab so we're talking about what 0.506 ish yeah the lab started to get set up in o4 and then it really hit full steam yeah between 06 and 09 but 04 was when we were setting it up so as your embarking on this what is it that you experienced during that that transformation of your your clinical training your residency how did that shape the problems you were interested in solving well i you know having just completed my psychiatry residency i had seen 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 uh you know i did electroconvulsive therapy which uh is you know it's a it's very effective for treatment resistant depression uh it's the treatment of choice uh for many people it's incredibly effective it's stunning to see it's it has some problems 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 uh it depends up some patients need uh what we call you know maintenance electroconvulsive therapy so after three months or so uh the effect will be diminished and and they'll require uh to stay alive effectively patients who are for example just acutely suicidal uh and they'll need every three months or so what we call maintenance uh or continuation uh electroconvulsive therapy or ect so it's not a it's not a permanent uh fix uh like so so much of medicine and so much of psychiatry you know uh it's something that moves things back into a healthy range for a time uh but we didn't know how it was working it definitely helped but but it was for a scientist it was very it was satisfying to help the the patient just to have take somebody who was you know in just horrific psychological distress uh and and put them into a state where they could go back and do their work and and and live with their friends and family and be happy for some time that was great but we had no idea what and still don't uh what was going on there why is this uh seizure that we give the patient you know we and it's it's done in a pretty refined way these days the patient's body is paralyzed so there's no physical you know seizure it's it's all happening in the in the brain and it's it's a safe procedure but still it it it's not specific right we're causing a general pattern of activity through the brain of the patient and this astonishing psychiatric effect is created i i 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 a vagus nerve stimulation there's a as you know there are the nerves that run the 10th cranial nerve that comes from the brain stem and goes down to innervate the heart and the abdomen also sends fibers back to the brain and you can put a little cuff around the nerve and and stimulate the brain uh through the neck which is which is kind of interesting a little highway to the brain but the effects although it it became approved fda approved for depression the effects were very small on the population level very inconsistent likewise we had transcranial magnetic stimulation which was in its early days then as well which was a uh you know it's a it's a treatment where you can non-invasively stimulate a tiny patch of the brain by putting a rapidly changing magnetic field uh near the the scalp of the patient effects small on the population level did get fda approved but still not fully understood so all these all these treatments and of course none of the medications to this day do we fully understand their mechanisms of action so there'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 non-specific a seizure all through the brain uh you know 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 of the brain but we don't know where depression comes from where anxiety comes from is it this patch or that patch or that patch no deep level of understanding uh was present and and of course the medications act all through the brain without cell type specificity so that was the that was the setting and then you know to answer your question then as you know clearly uh basic science you know how could you build an approach to give you some some kind of uh precise causality and that was that was the the context well i want to dive really deep into this because it is essentially um the skyscraper of your life i mean look if you if you retired tomorrow for medicine and science carl if you just 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 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 what you know we talk about them through our evolution maybe and how each one added to the next but but each one has a subset of functions i'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 well thank you for the first of all the gracious uh comments i we have a long way to go though and i'm not uh maybe it's many lifetimes ahead there there are very deep mysteries in the in the brain that we have much much work to do exciting fun work but much work to do to to get to where we want to be but uh it is it is a an exciting moment and we've and and what we've been able to accomplish has has been uh thrilling um and and it's a testament to all the amazing people that that we've been able to to get together to work on this and and indeed that brain is is something it's very compelling uh it's so interesting and mysterious the cells in the brain are more complex structurally than any other cell they're in our brains there are 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 on its surface that can generate little electrical impulses and that's how you can have a single neuron that projects from one part of the brain to another or from one part of the brain to the spinal cord and or it can send connections through its axon its outgoing wire uh effectively to many parts of the brain and it sends that information in the form of electricity down its axon down its outgoing uh 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 the electricity triggers release of a chemical the chemical drifts across this tiny little gap that's some tens of nanometers and then it acts on receptors in the other side the post synaptic side and and that creates a new burst of electricity in that downstream cell so that's the electrochemical process of information flow now you've got this going on and 90 billion neurons at the same time they're all maybe they form 10 000 or even 100 000 synapses each their wiring is incredibly complex uh um there's some structure to it there are collections of axons that may travel together but then they also bifurcate and separate in incredibly complex ways and all that's in the brain and then there's some structure to it as you alluded to 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 and but evolution has given us obviously we have much bigger brains than than fish do and a couple things have happened over the course of of yeah 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 uh which means literally the the surface of of the of the brain it's like the the rind of a melon except in human beings it's it's quite thin it's just a a few millimeters uh thick and within that few millimeters there are six separate layers within that cortex or rind uh and those are layers of cells so there are six layers of cells in this sort of shawl or rind covering the brain and then all the wiring coming out from that cortex goes to deep structures and our our cortex is much more advanced the fish don't really have something like that but they've got the deeper structures they've got the interchanges and and the movement control and the the uh arousal systems and the sleep systems and and there are structures deep in the brain like the hypothalamus that govern all the primary needs of 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 this you've got these deeper structures that are that are conserved and ancient and you've got this in us we've got this uh surface structure that is uh incredibly elaborated in in our lineage and and uh is responsible for some of the most complex and and and mysterious things we do and and but the great thing is and mice sort of sit somewhere in between they have the cortex uh that we have and it's amazingly similar it's got the same six layers it's got the same kinds of neurons they're connected in the same way it's just much smaller 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 of that that we come to as a neuroscientist and what about this this first layer the brain stem this kind of most primordial layer that handles so many of these functions when we're not even thinking about it like like breathing i mean what how conserved is that across all of these models yeah the brainstem is is highly highly conserved the you know 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 and that send information down like the vagus nerve that we talked about send information down to the rest of the body these basic structures in the brain stem are are highly conserved fish and mice and human beings all have them there's a little bit of different shaping and arrangement but it's basically the same logic and are there neurons as the way you describe it it sounds like a neuron might have mostly just serotonin so when that neuron fires at the end of its synapse serotonin is the only chemical that comes out is that is that the case for neurons that each one only can emit one neurochemical so it's a largely binary signal or are there any neurons that can secrete more than one neurotransmitter a relatively recent understanding has been that it there are multiple neurotransmitters that can be released by the same neuron we still refer for example to the dopamine neurons as dopamine neurons because that's what that what's that's what makes them special that's what they can do that other neurons can't do but what we've discovered recently what the field has discovered recently is that dopamine neurons some of them also release another neurotransmitter called glutamate which is an excitatory neurotransmitter it stimulates the downstream cells other dopamine neurons can release a different one called gaba which has an inhibitory neurotransmitter it shuts down the the cell that's receiving the signal so there's actually a great deal of complexity and that's not all there are also other things that can be released at the same time things we call neuropeptides and there's a 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 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 so 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 i mean was there ever any way to imagine how one part of the hypothalamus was responsible for a type of thought or emotion i mean how how how was that probed yeah this this was a big challenge that neuroscience faced which is is finding out what actually uh matters for function and and what we did have we had ways of listening in we had uh ways of putting in electrodes to to listen uh to pick up electrical patterns of activity you can put an electrode in the cortex or in the hypothalamus or in the brain stem and you can pick up the chatter of neurons as these little electrical impulses go by and you could use the same electrode you could also stimulate you could send current in through this wire effectively that you that you've placed and yeah that that has an effect and so you can 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 can you could stimulate a region of the brain and see if that causes something to happen in the animal and there was a great deal of of really foundational work in neuroscience going around and stimulating different parts of the brain it was discovered that if you put an electrode in in the parts of the brain where dopamine neurons live and where the axons come out that 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 and so that little clues like that are built up over over time but but then there was always complexity as we dove deeper into it we realized wait this is not just the dopamine neurons in this region of the brain there are a lot of other cells and connections so is it really the dopamine neurons it's this region but what really are are the cells and so there was a lot of uncertainty in the field as to which cells were actually doing uh what and so we had that we had but but then there was not a good way to turn things off also and so in in science we like to add things and see what happens and that's testing whether something is sufficient to cause an effect and we like doing that that that tells you something but then we also like to take away uh something of interest and we can see what what is lost with that and that's that's called you know that's testing the necessity of something how much is that needed and so we would we would have liked to turn off cells and say okay now what's different in the in the animal and their behavior and there was not a great way of doing that crude ways if you stimulate really hard with an electrode you could effectively exhaust the cells and make them not fire anymore and that was sort of the state of the art both clinically and research-wise 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 situation that that we found ourselves in not too different clinically or basic uh you know no cell type specificity so do you remember where you were what you were doing the very first time you learned what a channel opsin was so this is a an interesting uh uh thread that the there are these uh plants that make and and small plants in fact single-celled plants that make uh channel rhodopsins uh these are uh single proteins that live in the that are placed in the in the surface membrane of cells but microbial cells not not in our cells in in algae single celled algae and related molecules are present in ancient forms of bacteria and these these had been known to exist for years uh and and this class of of protein is really interesting because they're light activated electricity generators uh these are single bits of biology single biomolecules that do an amazing job they receive a photon of light and they move charged particles ions across the surface of the cell now there's a huge family of these these are called the microbial opsins and a subfamily of them is called the channel rhodopsins now what's amazing is that these proteins were known broadly in biology in biochemistry for decades they'd been discovered in 1971 by dieter osterheilt and walter stakinius who are at ucsf and this was part of the training of a biochemist biologist in in lubert streier's beautiful biochemistry textbook there's a page on the bacteria rhodopsins and there's a this is that's that's where i learned about it uh you know these these proteins uh that 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 but so this was you know a class of proteins that was was well known uh and and it turned out that these microbial uh opsins turned out to be the key for for optogenetics the technology we developed that brought this cell type specific uh causality uh that made it uh possible um i want to understand this a bit more carl how cause so it sounds like okay because i also had lubertz dryer as a professor i have his textbook it's one of the few textbooks i've still kept first of all i don't remember that so i mean like that might be a page in that book but i was not paying attention during that lecture so it's it sounds to me like you knew about these even back in medical school when did the idea come to you that said wait a minute i can now genetically insert these things into neurons and effectively put a digital switch into a single neuron how and when did that idea cross your mind yeah so there was a coalition of a coalescence of different threads that happened that were partly plausibility threads um and and if you look at this historically anybody in theory could have thought about this and tried this in you know in the late 80s or all through the 90s these these genes were known somebody could have put them into neurons and tried this but it wasn't technically plausible for many reasons they were not until the 90s and particularly the late 90s there were not good ways of introducing genes into neurons neurons are a little bit uh tricky they're very finicky and sensitive and and i knew this because this was you know this was a theme in my uh phd work and also in my postdoc work you know can we how can we get genes into into neurons even in a culture neuron preparation it's not easy and so that was that was certainly part of it part of why i mean why nobody had had tried this before but in the late uh 90s uh that started to change and and i did an experiment introducing uh genes into into neurons as part of my postdoctoral work in the malenka lab that was in and so this was something i was i was good at i'd uh develop the the viral tools and the ways of introducing genes in that were that were plausible tell folks a little bit about how that works um yeah we're obviously you know these days i think even the lay person 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 so this is and this is by no means a minor thing in some ways this is this is the whole ball of wax as we say how do you get a gene into a neuron in a in a specific way so this is the technological aspect of this in some ways is everything and so it's definitely worth the time to talk about this you know how do you how do you do it well so dna is is the instruction manual for making uh 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 uh sequences and by the order in which these nucleotides appear that is a code that's the genetic code that dictates which protein will be made a biomolecule that that has a particular structure and a job that comes from its structure like being in a channel or something in the surface of a of a cell that receives a photon and lets uh charged particles go across that's the protein the instructions for making it are encoded in the dna in the gene um and so that so how do you get that that gene into a cell well it's not so easy uh you know these days um uh particularly with the coronavirus pandemic i think the general public is 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 a 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 so viruses are professional introducers of genetic material in the cells they are extremely good at that they are evolved for that and this 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 it's useful to have an intermediate step first the dna gets turned into rna very similar structure but then that gets turned into the the protein some viruses work with dna some with rna so this turns out is then very useful for the biologist because if you want to get a gene into a cell and in in my case suppose you want to get a gene for making a uh light activated uh channel if you want to get that into 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 are 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 uh bring dna into one set of cells and then the life cycle if you were if you will stops at that point and those are the so those are the viruses that that that i had experience with from my uh postdoctoral work uh safe modified uh viruses that can be used to shuttle bits of dna in into cells and so that's the core uh technology and again this was a recent relatively recent thing and particularly for neurons a relatively recent thing it was the technology for doing that was not uh so clear in the past the other thing that i want to point out is that this there were many people who who were thinking about this and trying this and we did from my lab published the first paper that used a microbial opsin to get light sensitivity but it was as it turned out quite a a close call we published the paper from my lab in in 2005 and that came out in the summer of 2005. within six months several other papers came out uh they all were submitted right after ours was was published and so clearly uh many people had been thinking about this they saw our paper came out and then then rushed to submit theirs um and these were these are big time labs uh you know people who who were very respected and thoughtful including this was something i didn't know but but uh 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 there's a i talked to him at great length about this of course he did okay he he got a nobel prize for other work and but this was all this was going on before his his nobel prize and so he was quite uh i think frustrated that he wasn't able to get to this moment as quickly so it was a it was a sort of a broad awareness in the field that the technology was now available we could introduce genes into neurons that these microbial opsins 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 there was a a broad awareness that this this kind of thing suddenly might be 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 he 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 uh 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 uh infecting the same cell and that is actually very important another big issue with these microbial opsins is they generate tiny currents they're not as you know professional at generating huge currents as mammalian ion channels are which was a big reason why i think a lot of people didn't rush to this as well people looked at those current sizes and said nah you know 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 not enough to to control a neuron and that was a huge issue but with the viral technologies you could get hundreds or more copies of of the gene per cell and you could get a much bigger current with these microbial opsins and so then i g there again my experience with the viral tools was was critical and 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 so uh an action potential is how many picoamps yeah so a couple ways we we can look at it so the the action potential this is this blip of electricity that propagates uh through the uh down the axon of a neuron it can be triggered by uh signals that are in the order of uh 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 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 what we found is that if you don't have a high copy number the currents that you're generating are are on the single or less pico amp level we haven't done because the currents are so small you typically don't even do the experiment you're asking the single channel current measurements since then out of scientific curiosity you know we and others have looked at at the uh at the currents that are generated and they're they're extraordinarily small we only get uh the to the hundreds of people level by probably expressing you know a hundred thousand uh uh or to a million uh uh opsins uh per cell and so where this this was a the key issue there was many orders of magnitude as we say you know 10 you know several factors of 10 away from where we needed to be with these uh with these options unless there was a way of 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 um and you decide you want to test in this particular region of the pons so a part of the brain stem you you want to exactly get it there how do you direct the virus to exactly the cell you want to get this specificity so this is this is the other technological challenges 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 is 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 hot spot of virus and then that virus would get into all the cells that are in and around the that spot in the ponds and that's that's good that gives you some spatial specificity you're now at a at a spot and that is already a big leap beyond the electrode because the electrode and the virus both so far in how i've described them are not cell type specific but the electrode is getting all the was 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 the cross streams of activity being stimulated but it's not enough because well 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 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 okay so how are you going to do that well the virus there there were many possibilities we could think about and this took probably do we really solved optogenetics probably took till 2009 because this was this was the critical issue how do you get a versatile generalizable way of targeting specific cell types and back in 2004-2005 there were some possibilities that we and others could imagine you could try to imagine engineering the virus 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 is uh its lock and key basically works through the ace2 receptor if you knew what a potential surface protein or receptor was on the dopa dopaminergic neuron that could be your entry that would have been the first thought that would have come to my naive mind yep and and that was plausible uh uh it could could work it had some you know some drawbacks which are that you'd have to first of all we didn't have that richness of understanding up it wasn't as if there was some lookup table okay dopamine neuron has this so then make put this on that that didn't exist it 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 uh and also all the cells that are nearby that you don't want to target and make sure you're not whatever your strategy is is not it's not giving you some cross your activity and so we you know initially plausible and then as you start to think about it more you're like oh this i mean this is this is never going to be versatile generalizable practical and indeed it still isn't today so so that wasn't it now another strategy is is is working with dna each 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 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 does a dopamine neuron well it makes dopamine and that 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 or more importantly not in the serotonin serotonergic neuron right next door i mean that's the key insight is that you exploit the promoters that are making unique enzymes to a particular neurotransmitter exactly right and so each it turns out each cell type is defined by its job just as in many cases cases we are defined by our jobs uh and and this is a a critical thing because a professional dopamine producing cell is going to have by its dopamine enzyme encoding genes it's going to have promoters or enhancers that are 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 okay now you inject you can almost administer it systemically at this point and it's going to go exactly it is a very elegant solution carl yeah yeah and and in fact the systemic thing now in some ways is is done in some settings uh it's more costly actually because you have to use a much higher level and actually the focal injection gives us other advantages so so we still uh actually prefer the local injection but you're right uh that specificity is now uh in large part taken care of by the 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 them so i have another technical question carl so let's go back to your garden variety cold causing adenovirus right so you're out and about in the park or you're on an airplane and you know you happen to catch this cold from somebody um that adenovirus is going to go and it's going to infect the epithelial cells you know 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 three 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 it's 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 channelopsin's not supposed to be here are you just getting lucky that it's not being presented on the mhc class 1 or class 2 as a peptide or meaning pieces of it because obviously it would be much larger than a 9 to 8 amino acid peptide but yep this is a great question this was another energy barrier to tackling the strategy uh 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 and kill them um well a couple things helped us here one is that we were working in the brain and 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 uh why is that a lot of interesting evolutionary speculations to that but it's a fact uh and so they they can't get in and and without that uh 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 uh you know we people have been interested in peripheral not not central peripheral optogenetics and it works but people see loss of the the expression and the cells expressing the uh opsins over time over months and the immune response is certainly part of that but in the brain that that doesn't happen and so that's a great question uh and and here we definitely leveraged the immune privilege so this was this was very helpful carl i think you know maybe for the listener they thought boy these guys went into a lot of detail here but i think this was really important because i think only now can we understand the magnitude of a what you and your team accomplished in what scientifically is considered a nanosecond i mean in four years that you were able to do everything you just said and now we're in 2009-2010 you have the capacity to introduce these options 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 from a neurobiology and neurochemical standpoint well uh you know we've talked about dopamine a lot and in 2009 there was a an experiment that that i and the whole field had wanted to to to know which really is is it the dopamine neurons is their activity what what animals are 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 are we know are right nearby and and in 2009 we did that experiment so we introduced a channelrhodopsin an excitatory channelrhodopsin just into the dopamine neurons of this spot in 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 a two-room house to live in it's a very simple house two rooms and it can go back and forth from one room to the other 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 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 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 it's a the animal now prefers a place and and it's because of its uh the conditioning is how it was done classically just as you're saying you would pair uh something good like cocaine or sugar or food or a social interaction that mate something like that and you would see later that the mouse would choose to spend time in there revealing to us by its behavior that this thing was positive in value to it and you can do the flip side too you can do a negative thing you can make make it feel mildly nauseous you can give it lithium which we give to patients too and one side effect you can have as mild nausea you can give a a mouse uh mild nausea that way it but only in one room and then it'll avoid that that room and that's condition place aversion so the animal can report to us the 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 harkens back to you know that my very first you know wanting to be a a neurosurgeon because a human being could tell me what they were feeling well of course a human being is more eloquent but behaviorally a mouse can report whether it something is a positive or negative value to it and that test carl when you're looking for the positive valence how what's the frequency with which you would expect that to be the case i mean presumably it's more than 5149 in favor of the dopamine firing just give us a sense of if you ran that experiment 100 or you ran a simulation of that experiment 100 times and you always fired the um the dopaminergic neuron with your ops and how many times out of 100 would it go to the positively valence side we try to keep things in you you can make this as extreme as you want uh and and uh so the answer is a bit flexible uh but with typical rewards with sugar water with a social interaction the sort of the number you're looking for is sort of 70 30 or 80 20. uh that's kind of the level to which uh the mouse will prefer one chamber versus another one versus another in terms of how it devotes its time but you can actually you can make that you know you can push those numbers both optogenetically using light or with with stimuli up or down by making the experience more extreme it's quite a flexible test and and we had we had later versions of this you know that that in some ways the animals expressing its its uh subjective sense we think by where it's choosing to spend time you can also make a more souped-up version of that test where the animal actually has to work to get the light by pressing a lever or poking its nose in a little hole a nose poke and trigger a pulse of light by each of its actions so this is a this is a 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 and if if you deliver uh light you can get an animal to press a lever thousands of times a day to get that that light and so now there is you know no doubt that the activity of dopamine neurons uh in this way is is positive and it's not just positive it can be extremely uh positive animals will work very very hard to get it it that's it's just amazing that this could be done let's keep going what you know i i can only imagine how excited you and your colleagues were by this finding and of course it probably only whets your appetite for the breadth of questions that you now want to ask 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 of of medicine as we know it today we've always wondered things like what regulates mood how can two people anatomically be nearly identical and yet one be happy and one be sad where do memories reside what is a memory what is a feeling what is a thought right all of these things and and yet i i suspect that this experiment as simple as it was for the first time gave you a profound sense of optimism that you now have a tool finally to ask questions so you're splitting your time here right you're still an on-the-ward psychiatrist so in the one hand you're doing kind of the the most cutting-edge science in the field and at the other end you're still trying to help people who are bringing these questions to your mind how many of your colleagues in psychiatry not necessarily your direct colleagues at stanford but just i mean the community more broadly how appreciated was this tool ten years ago you know it's it's actually uh very interesting that you ask that the appreciation in the scientific psychiatry uh realm and these are you know clinicians psychiatrists who also have some interest in in the science side the appreciation was very quick uh and immediate um because i think the psychiatrists know and knew uh better than anyone else how much specificity was was needed and wanted in in their field and you know i had this was you know by the time we got to 2009 the generality of that targeting method was was key because then people knew okay this wasn't just a parlor trick a one-off you know a demonstration that you could get some kind of photo sensitivity in one cell once that this was actually a generalizable versatile method you could apply this principle to you know any cell type it was done in freely moving mammals uh you know and mice of course being having our same brain structures our cortex our hypothalamus our all and everything in between the significance and the opportunity was was pretty clear to everyone by 2009 uh particularly the the the psychiatrist and so then there was a there was a lot of a great deal of interest and because the technique was was generalizable it was very widely adopted and we sent the the uh the clones the bits of dna to thousands of labs around the world and and many thousands of discoveries were made by other labs which was great after that uh uh really showing that that anybody could use it to tackle any question any any disease any symptom uh in diverse animals so after 2009 it was off and running the between 04 and 09 though uh that's those were those were hard times because we were still putting the pieces together solving the light delivery solving the virus uh issues getting the cell type targeting to be generalizable and versatile and i would say it wasn't really until 2009 that we could look at this and say yeah yeah we've we've done it at this point was this work funded by nih yeah so early on i had i had some initial trouble uh getting grants but then pretty quickly uh once once the opportunity became uh clear both the national institute of mental health and the national institute on drug abuse uh two main institutes of the nih uh immediately uh were were very supportive and then later we got a great deal of support from uh darpa and from the national science foundation and and then also from from a number of private uh donors people who in many cases came through the psychiatry setting friends or family members who'd suffered from a psychiatric disease and they had heard about what we were doing and wanted to support it so we ended up getting uh you know both federal and uh nonprofit institutions and private donors and it all came together but it but but you know until really until we had things working in this generalizable way uh times were a little bit tough well i mean it it is it is again remarkable now as you sort of look back at it to think that um a that it all worked out like i mean it is there's a hundred steps at which this could that could 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 yeah but i mean as you know as a you're you're such a historian of science as well i mean it is it is a remarkable period of time um so so let's talk about some of the other questions that you wanted to probe with with this technology so what about any of the other neurotransmitters or neurons in particular where where did you turn to next well we uh were particularly interested you know hearkening back to my you know what got me into psychiatry in the first place you know i i wanted to understand internal states of mammals and how they can go wrong and create symptoms and if you work with with animal subjects with mice for example you have to figure out what they can report that that that matters and one thing they can report very well are these universal things that all mammals experience anxiety uh and uh social interaction and caring for for offspring for young these are quintessential mammalian states that matter they can go wrong and so i wanted to to study them and i wanted to study them in ways that were now precise and causal and had to do with specific cell types and so one of the first things we did was anxiety and you know as a psychiatrist i i specialize in patients who suffer from depression and also social difficulties autism spectrum disorders and a common theme in both autism and 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 uh 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's only it only becomes a psychiatric disorder when it exceeds that healthy range and diverges 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 been personally experienced or hasn't personally experienced or known somebody who has experienced anxiety that has crossed too far but but it i mean is this something that falls into the dsm-5 where there's an actual criteria and there must be right yes yeah that there are and and in fact it's the it's the criterion for rising to the level of disorder in in the in the psychiatric uh literature and in the dsm-5 or our 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 who were who were hallucinating but it was in a way that was not disrupting their life i had a blind patient who had visual hallucinations but he was he was fine with them they weren't 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 you know flexible because different people have different social and occupational situations and and this is a challenge we have in psychiatry but maintaining that as a criterion is very good because it ensures that we only treat things that need to be treated so that anything about anxiety well if you can't function if you can't leave your apartment uh to go to work well that's impairing your your occupational functioning and so that that there are people who have anxiety easily in that realm or far beyond and those are people we 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 or worry about threat and and that's also a problem so anxiety we need to to to to treat it in patients who are severely affected and the problem is in anxiety there are uh medications that help but they come with uh some problems so the most effective anti-anxiety medications are things that relate to you know uh valium and xanax and ativan as you know these are medications that work uh but they can be addictive they can uh cause the human being to adapt to the dose and to to make it very difficult to stop them um do these work do we think that they primarily work through their gaba agonism is that that yes primary belief so they they you talked about gaba earlier this is a relaxing uh for lack of a better word uh neurotransmitter this is a non-excitatory that's right that's right that's exactly how these act they they act in fact directly on the gaba uh receptor and they facilitate its its action and so this is um but they they work they're just they just have some some problems and not everybody can tolerate them they cause some cognitive slowing and sedation and so on things like their 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 a subject of a lot of research if we understood that deeply then we could make a separate intervention targeted to those cells the problem is that we don't yet know that exactly we don't know exactly which cells are the most anxiety relevant cells that these these medications are are targeting um there are some some hints but i would say not factually known yet so but but you're getting to this key point where optogenetics was helpful because then we could ask that and answer that question we could say okay which cells govern the different features of anxiety and then now what am i talking about here with different features well actually this is kind of interesting when you think about it so what is anxiety well it's actually got different parts to it first of all there's physiology we've all been anxious we know heart beating faster breathing faster okay so there's physiology that changes then there's also a behavioral change we when we're anxious we avoid the risky situation we have an impulse to to avoid if we're if we're anxious out in the open we avoid going out in the open and mice do they do this too and then finally there's a negative quality to it which this is 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 perhaps the most difficult but meaning perhaps the most difficult to experience it's 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 that's how it is anxiety feels bad and that's what makes it uh in many cases so so clinically uh uh causes so much suffering in addition to the behavioral dysfunction that happens so actually anxiety is complicated it's got these different parts and they all come on together all go away together and then you've got to ask okay these these are so different they're probably controlled by different cells right so you've got behavior and you've got breathing and you've got inner subjective sense these are all very different probably different cells are doing it so then right away you've got to ask what are we going to target and so we we thought we need to figure out this and so we used in 2013 we did a 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 balance the internal state each cleanly controls separate feature of anxiety and we did this with optogenetics introducing light sensitivity and then reproducing each of these completely distinct manifestations of anxiety exactly exactly so you we could we found we could turn up or down each feature in mice completely separately from the others we could have animals that and this this got so interesting philosophically we could make animals avoid the open area the exposed realm that that people and nice boat we don't many people don't like being out in exposed areas mice definitely don't because that's when they they're going to get eaten uh we could make mice in be much more uh 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 that we could create the behavioral avoidance of anxiety without the mice without the negative feeling having this negativity and so that and it turns out then that that behavioral states that that mammals have they can be cleanly broken apart into these features and we could show that with optogenetics that was a one of my you know one of the the papers from that period of time that was most interesting because it was so interesting in that regard and other people you know catherine dulac for example at harvard has done some great work on parenting another quintessential mammalian state using the same set of techniques optogenic techniques that we described uh she did this in 2018 mice are are pretty good parents they take care of their young mostly um they that that can break down at times but but but they they care for their young and and kathryn duvox lab did an amazing experiment they optogenetically found that the different 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 go and get your 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 of both human and mouse parenting of course is grooming the the offspring turns out there's a 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 opt to genetically break them apart very cleanly and show how this this parenting state is assembled from its its features and this kind of thing has been those are just two examples but that that kind of thing really gets to the to the heart of of what's so interesting about the 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 um and and you know autism is something that interests me immensely what do we really understand about this disease i i think we know that it's it's got a significant genetic component it's not entirely clear what triggers it um but you know it's and its phenotype of course exists on a pretty extreme spectrum in terms of functionality um superpowers and super deficits uh but what do we know about autism and and then specifically why is it that anxiety tracks so closely in people with it this autism is is one of my main clinical focus areas this is actually my clinic office here i see i see patients with with autism spectrum disorders here i know that they are hard to treat there's not a medication that that treats autism but as you say a lot of them are very anxious and and that i can help with i can help them uh with with their anxiety with medications uh 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 and why is that why are these these patients with autism so why did why is anxiety such a comorbid symptom as we say why does it show up so much in autism well the the human social interaction world is very uh complicated it's very fraught with possibilities for misunderstanding catastrophic errors of interpretation embarrassment humiliation confusion we have a a very social world that we've created and people who have difficulty with keeping up with the fast rate of of social information and making sense of it it's a very anxiety-provoking situation how when you're talking to somebody how do you know where to look what to do how do you what part of them do you pay attention to do you look at their eyes do you look at their mouth do you look at their body movements god forbid there's more than one person in a conversation with three people how do you know who to look at how do people know what to say next to someone on the autism spectrum these are extremely challenging situations because it's it's very hard to keep up with this uh high information rate of of the social interaction and this is something in the book uh projections that we've talked about there's a whole chapter a story on autism and on on how this might happen uh neurobiologically how this information overload might happen we have patients who are as confused by social interaction and as overwhelmed by it as you can imagine uh you know somebody not knowing the language not knowing the customs of of a culture and being placed into it while extremely consequential things involving them were happening in 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 these are patients who we can help with their anxiety still not yet with their autism the genes that are linked to autism there are many it's a very genetically 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 what does the treatment for someone with autism look like in the coming decade let's let's keep it relatively short term well the exciting thing is is is optogenetics has given us a window now uh into what could be this sort of ten-year time scale of of autism uh 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 uh powerfully related to autism that come from the human literature you can make mice that have impaired social interaction as well and we've done this and we've studied these in the laboratory and we've asked can we correct the social deficit of these mice and we can and this is a whole thread of work in in my laboratory studying social interaction and asking which cells which circuits in the brain can improve social interaction including in these autism mutation mice and what's pretty interesting is that you know 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 the insight that could be separate that's another part of being social is understanding what the heck's going on and probably different cells affect each of these and indeed we found that so some there are some dopamine neurons that do seem to increase the drive for social interaction but then there are other cells in the front of the brain so where some of the most advanced complex cognitions happen the frontal cortex that may be more involved in the information fire hose that's that's coming through with a social interaction how do you keep up with it how do you make sense of it that may be more of the cognitive side and so just like everything else you got to figure out which 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 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 uh signal-wise causality but not be the mode of treatment in other words you know i'm sure people ask you this all the time i certainly have a thought on this but i 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 you know 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 optogenetics in my view is is by far the most important aspect of it is it's a discovery and understanding tool this helps us because this brings so much that we didn't have before understanding what actually matters what makes things happen in the brain at the level of cells is the opportunity that optogenetics creates and and that understanding then opens the door to every kind of treatment once you understand that which cells are actually causing and relieving symptoms you can design medications that address those cells you can design brain stimulation treatments targeted to those cells or their axons as they project across the brain so it opens up every door uh in principle uh under providing this this causal uh foundation now that now that said and so that i see is by far the future it's it's the understanding that opens every treatment door that said uh my friend and colleague botan raska in switzerland just this year was able to confer a form of sight onto a blind person with optogenetics and this was just published in the journal nature medicine this year ten years ago he and i you know had collaborated on a study where he put one of our microbial opsins into a human retina cataveric after life so it was a he he had ways of keeping the retina alive uh for some time in in these donated uh retinas and he was able to show optogenetics worked perfectly well to control human retinal neurons and he spent the next 10 years doing all going through all the hoops of of you know going through primate studies and then clinical trials and then just this year he focused on retinal he's a vision scientist and he focused on retinal degeneration and was able to take a human being who was blind from rental degeneration and and he was able to create light sensitivity so this person could accurately reach for objects on a table that was not uh possible before so literally you know making a blind person uh uh see at least to some extent uh uh can happen so i think there may be cases like that uh and they're of course they're uplifting this to see uh but the biggest picture is that it's a it's an it's a it's a discovery uh tool i want to pivot a minute to talk about your your book because i think it becomes a great place for us to now talk about some of the the mental illnesses that people will be familiar with depression mania and it's sort of cousin bipolar disorder eating disorders all of these things that you've written about so eloquently um first of all i want to tell you that if i'm not already in complete awe of your scientific achievements um i'm equally in awe of your writing achievements and i just don't think it's fair that one person can be so gifted on two dimensions 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 it's called projections and i've read it twice and i will encourage every listener to read it because um well it will shatter some of the images people have of scientists because you don't write like a scientist right so and i say that as somebody who's in the process of sort of finishing up their book and the biggest challenge i have in writing is making it accessible to everybody making it interesting enough that someone for whom this is not their life wants to read it um you've done that in spades this really reads like at times poetry um 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 you know sort of the clinical conditions uh these psychiatric conditions that everybody's familiar with um you it seemed effortless that you were able to do this in in such an easily accessible and artistic way well first of all thank you pete it's it's a it means so much to hear that i i uh you never really know when you when you take a step like this or a risk like this if it's really working and it this was a this was a risk this was something that was very different it's not what people expected as you say not a typical scientific uh text at all really and and the goal i wanted though the goal i had was to help everybody in the world all whatever their background i wanted to help them understand and feel what these these altered states are and that's such a big part of the the book is to 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 the the crushing you know pathological uh grief of of of bereavement or the you know the incredibly complex states of eating disorders where you have these uh astonishing uh behavioral patterns that seem so you know inexplicable uh 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 to the depths i wanted people to feel this and so i had to do this with the writing with the words i wanted to do it with the writing and the words and so in each chapter you know the the writing is adapted to cause that that that feeling and the in the mania story the the words are exuberant uh in the way that that mania is in the in the schizophrenia or psychosis story uh there's a fragmentation uh and a disorganization that happens and so in all these cases i i i had to work with with words in ways that are not typical for for a scientist and but of course i wanted to do it this was my initial uh passion in life and for me it was incredibly fulfilling actually to come back and be able to do this i'd always wanted to do it i had now not just the desire but i had a mission i had i had something i wanted to to tell i wanted to share with everybody and so for me it was incredibly addictive actually i would uh i i spent you know i did the bulk of the writing over a couple years from you know 2017 to 2019 or so and then wrapped it up in 2020 and it was uh i looked forward to this so much every day i would block out a couple hours um but a different time each day depending on my schedule you know life's complex now i've got you know five total kids things are hopping at home um you know uh my wife michelle's an incredibly accomplished uh uh md phd herself also 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 is simple or predictable uh and so that the writing time would be at different times often very late at night often early in the morning i tried to block out two hours but i would find i would look forward to that like like almost nothing else and i would i just relish the joy of finding the right word and spending days thinking about trying to find the right turn or phrase and so it was it was incredibly uh uplifting honestly uh even though uh of course a big challenge logistically one of the things i love about the book is how you really try to dive into the evolutionary basis for mental illness this is something i'm always obsessed with i always love trying to think about things through an evolutionary lens and and sometimes you know the answers come a little easier than others um one of the places where it comes up is in the story of alexander this is a gentleman 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 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 um i was encouraged uh by my wife actually to see a psychiatrist she had some concern about um 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 what why would this be and and i began sort of examining everything i'd ever done in life and and one of the things i came across was at the time i 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 the point that you get into about how there are sometimes when traits are very valuable at the population level and not at the individual level i found that i found that fascinating well first of all that's a very interesting uh route into this this discussion uh which is the the immigrants the the recent immigrants and the uh possible you know genetic link to have the you know in recent times to have the get up and go to leave to take the risks to have the energy uh to have the motivation to and uh to to actually make it happen to sustain it this complex goal with with so many possible downsides that's that's no small thing some people wouldn't want to do it some would and mania is it's one of the pulls of bipolar disorder uh which is a very genetic highly genetic disorder one of the most in in psychiatry bipolar type one disorder extraordinarily genetically determined and and what is it well and sorry 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 it's if you look at monozygotic twins especially those that are are raised apart that's where the most uh you know pure information comes from you can look at the concordance of of uh mania or bipolar disorder appearing in each of these twins and how high is it identical twins uh it's more than fifty percent uh for bipolar type one actually in fact verging above uh seventy percent so you have a very strong uh bipolar type one genetics and just out of curiosity what is it for autism in that same setting autism also high just maybe just a touch under that okay um with depression it's like 50 and so most of the psychiatric disorders have strong genetic links they tend to be less than 80 um but but in this kind of 50 to 80 range for many of the the severe ones from depression to schizophrenia uh to autism to bipolar and so this is something we we face in in schizophrenia uh and an autism uh and but in bipolar it's it's it's extremely strong so right away we know there's that link and mania is the positive pull of of of bipolar disorder the other pole is depression people with bipolar type one 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 not nearly as much and you know honestly even though this causes problems and serious problems and and not to sugarcoat it at all mania can do terrible things people make very poor decisions they it can be fatal yeah i was just supposed to say aren't people even slightly more likely to harm themselves during a manic phase than the depressive phase yes or the transition from out of depression to to mania that's actually probably the most risky time when they they may still have might still have some of the negativity from the depression but now they have the energy too yeah yeah exactly um and so that not not to say there's you know it's a it's a problem but but yet at the same time you know some of my most memorable experiences in talking with manic patients is i actually love talking to them because they're such a charge of energy anything's possible they're they're funny they're warm they're they're charismatic and it's and it's so easy to see that this is a this is a state that's it's not a bunch of random things happening in the brain this is a 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 that's there that that human beings have as something they can do a sustained state of elevated mood and energy and and you look at that you think okay you know why and and also uh you know what does that mean for treatment is there an ethical issue with with treatment is there are there cases where mania is is positive and and this is something that the story in the book in projections really made me think uh so hard about this was this was actually when the seed for the book was first planted in in my head it was just 20 years ago right after 9 11 and this patient alexander he had never had a a any psychiatric illness at all nor in his family and but he was flipped into a completely classic full-blown mania after 9 11. he had no particular connection he was in fact he was on a a a sailing uh trip in the mediterranean with his with his wife at the time came back home after 9 11 um and and a couple weeks later uh he was manic all these symptoms that we talked about and it was a huge problem um he was but his but he had this appropriate or at least uh aligned quality to his symptoms he he he wanted to he was you know he was retirement age but he was training himself uh to go into battle he was repelling down trees he was running through the night he was he was reading about military strategy and and then it verged into this you know very difficult uh emotionally challenging he was screaming he was hyper religious everything had become uh quite uh extreme and incompatible with with his life and so that ended up bringing bring him to the to the hospital but you know looking at this and we think okay this is this is a state of elevated mood and energy it was triggered by context and this is actually the flip side of what you're saying with the with the immigrants not only is there likely to be a set of conditions that led to these people being able to take that have the energy and willingness to take the the risk and meet all the incredible challenges of moving across countries and cultures but then you know that that's a that that's not that's not this fight or flight response of a minute when you've got a threat and you have to you have energy and then you meet the threat and then it's gone we're talking about you need a sustained level of energy for weeks months years even and to take a to take a risk and a life shift like that and so you know this is everything is on a spectrum and you've got mania and then you've got this hypomanic state in between that it makes a lot of sense that that people who are able to sustain this elevated energy uh state are are those that would uh be vr immigrants and it's a it's a and again you have to look at this and think it's a spectrum there definitely it can be bad but we have to value the whole spectrum and understand the whole spectrum 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 you know this unbelievable discharge of emotional and physical energy uh because otherwise i it doesn't seem like these would you know like for example why doesn't it just go normal affect mania normal affect mania that's a great question we don't have the answer some people uh some fortunate people are like that there are you can get a diagnosis of bipolar disorder without ever having a depression one one episode of mania uh gets you that diagnosis uh of bipolar type one and those people there are people who who haven't hit a major depression uh yet um that said uh uh most of the time there is there is that other poll of of the disorder and and what is it is it we don't know short answer is we don't know but a lot of interesting ideas one could be sort of aligned with what you're saying that there's some resource that's that's exhausted uh is it you know it's not a resource that we know what it is we can't point to it is it a neural circuit uh you know state of some kind a capability of a neural circuit that can become exhausted we know neurons can run out of uh energy this is part of how the brain stimulation to cause inhibition works but that's all in a very fast time scale exhaust neurons on seconds to minutes it's not known what really could get exhausted on the week's uh scale we don't know what that would be or maybe it's a it's a it's the termination mechanism but it just overshoots um or maybe it's just that what's lost is a the homeostatic thing that keeps energy in a in a tight range and then it could go in either either direction because you've lost some some break that's that's present on either side not known but a very interesting question what is technically the most common uh psychiatric disorder is it depression actually the anxiety disorders if you if you group them together anxiety is the most common and and that is um but depression is is is certainly up there that's that's that's uh uh in the top group for sure uh anxiety disorders are so underappreciated a lot of people don't talk about them um a lot of people can make it through the day with anxiety even if they're suffering uh terribly so yeah anxiety is most common what has optogenetics taught us about depression so this you know this is my clinical specialty i have you know right here in this office i have you know we do uh i do vagus nerve stimulation uh for example this is a vns therapy radio frequency controller we have 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 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 there's a deep discounting of the value of effort and this come this shows up as hopelessness this even can lead to suicidality and certainly severe social and occupational dysfunction and then there are other parts to depression there's something called anhedonia which is really interesting this is the absence of pleasure yeah this is perhaps the most insidious component of depression by far right right and it's it's it's not commonly known you don't people on the street don't talk about uh anhedonia right it's they'll say they're depressed but nobody talks about their their anhedonia but it's it's an incredibly important symptom it's a core such a core symptom of depression that actually you can get a diagnosis of major depressive disorder without depressed mood if you also have anhedonia it's that important and it's the absence of pleasure or joy from things that normally bring pleasure or joy and and we've all had a cold and we've known that taste is gone the food has lost all joy it's things even without the cold with the with the anhedonia of depression all the joy of food or social interaction or you know your children your grandchildren uh you know a book a movie all the joy of life is is is gone and this is a it's a horrific thing it leads you know to very serious problems and that's a that's something that optogenetics has helped us understand what do we know about that yeah where where do the neurons reside and what are the neurotransmitters involved in the propagation of anedonia so so again you might say how are you going to test this and you can you can set up very simple behaviors with 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 and by a factor of you know two to one or more but a mouse that's been stressed uh it'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 from sugar and presume it's very similar for them and then not caring sugar water regular water 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 so we we and others have explored this this kind of thing with with optogenetics and we found that there are uh you know pathways and coming back again to the to the dopamine neurons which are tightly linked to mood and mania and depression these but they're a complex set of cells some send connections to one part of the brain some send connections to another part of the brain we have found some interesting uh 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 uh reward uh circuitry and so this is an insight that optogenetics brought us and it's something that we're following up mechanistically it's kind of an interesting thing that there's 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 uh frame it enough for ourselves cognitively if we review the need for it for taking this action and so our 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 uh optogenetic study and we've got insight into them hopelessness being another one and so here you know again you might ask how do you how do you measure hope in an animal well you know you can you can put an animal in a challenging situation that is not escapable the animal can can try to get out of this uh challenging situation and would that be like a maze that doesn't have an exit yeah no no way of getting out exactly so it doesn't have to be painful just just something that an animal would want to get out of and eventually they give up we can do this actually in fish as well as in in mice and that giving up is effectively it's this hopelessness it's this discounting of effort and that can be 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 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 extreme so it's maladaptive yeah it becomes maladaptive you 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 um i think i can based on what you said earlier see the evolutionary basis for anxiety and maybe we could just argue that that the pathologic version well we could discuss why maybe it's been amplified and what it is about our environment that perhaps does that but depressions are less 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 the at a minimum the maintenance of this all right 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 you know and this is a great question i think about this all the time and part of what we've discussed already may provide some insight which is this this withdrawal this passivity it is in some cases you can think of it like a hibernation you know if is it is it like is it worthwhile for an animal to to actively try to cope with winter by running around trying to find more food all through the winter or to withdraw to sleep more to to not see the value or feel the value and 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 and so you think about now you think about depression uh it comes with this low energy it comes with this hopelessness this discounting of effort this lack of motivation to go seek things to to be enjoyed reduced uh uh you know drive for social interaction uh all these things can be part of depression the negative aspect is the one part that's that's that i can't explain and that's that's of course the clinically significant problem why does it feel bad and this is not just feeling bad this is agony this is psychic pain is the kind of thing that drives people to seek suicide not to discount that at all we don't understand why depression feels bad but the passivity of coping that can be adaptive and it's it's perhaps you could you could see almost depression as a as a hack a bad hack maybe one that's not fully evolved yet just like mania not fully evolved yet not under all the right controls to make it more generally suitable and reasonable depression the 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 to to something positive and evolutionarily if you if you take this 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 and this is pure speculation you know but it's it's important because depression is very genetically determined it's it's common it's biological and at some level we have to deal with the fact that we have evolved to be where we are now and we have this high rate of of depression and so we have to include in our thinking the biology and the evolution together and so that would be my my you know my my take on it of course it's very hard and i wouldn't claim to have a 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 um let's start with that yeah yeah well we can yeah one of the clearest things we can see is that you know non-human primates can certainly enter into maladaptive states that look like grief uh in bereaved states there are cases where you can have a a young non-human primate who is old enough to to feed itself but who has lost a mother let's say has lost its its mother and uh loses the motivation to feed and protect itself and stay with the the troop and ends up dying uh as a result uh this is a clearly maladaptive state documented um that in a nonhuman primate you could call it something like that a depressed-like state deriving from bereavement and presumed uh to anthropomorphize something like grief associated with with bereavement so i i believe these you know these states are are shared uh by by our any evidence of self-harm in in in non-human primates does it ever get to the level of i mean you know suicide is a top ten cause of mortality in the developed world it's important to make sure people understand the significance of that statement in the developed world when you think about all of the problems we've been able to solve one of the 10 leading causes of death is self-harm and and by the way if you really include overdose as a subset of that it probably leap frogs into the top seven is there evidence that this occurs in other species so uh really interesting question and the the short answer is uh no and uh there are uh less suicidal forms of self-harm that can happen uh now and then you'll see animals you know carrying out behaviors like you know 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 this urgent enormous clinical need that's not going away we 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 uh and and it's you think about the act of suicide which we don't understand and it's a it's a it's a horrific thing but you've got there has to be some understanding of what that means that there is an ending of life an ending of the self and that the pain that's being felt now would not be felt then this is a level of understanding of the universe that 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 than we are at some of these deep uh concepts but they may have less clear ways to express it they may have maybe not having fingers and hands to do things that we can do they may not have the ways to express it even though their cognitions may be just as complex and so i think there are two factors one is you know we the things that set us apart our brains and our hands those two don't come together in any other animal and i think that's why you don't see suicide elsewhere at least as we understand it our colleague paul conte 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 um there tends to be environmental triggers that can bring one person to heaven 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 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 subsequent generations yeah this is uh so the effects of trauma the lasting effects of early life trauma are unfortunately very clear these you can you can see in animals as well and they extend beyond depression uh for sure to include the personality disorders like borderline personality for example um so there's no question that early life trauma has lasting psychiatric influence throughout life and can cause very severe problems you know many ways to look at this you know why is it happening and how is it happening uh is there a wiring change so is the lasting quality due to a physical structure of the brain as a circuit that that's one level at which it could happen and the brain is very brain circuitry is very tunable that way especially in young people and so you could you could imagine that early life experience with trauma sets up the human to expect in some ways that the world is a harsh and unpredictable uh place and that the value system had better be set up to deal with that because that's how it is apparently and so you could almost imagine an adaptive though very unfortunate uh process going on where there's a period of of youth where you're gathering statistics about the environment deciding what the adult should be like and then implementing that and so early life trauma could intersect with such a process very unfortunately and create people with a a lasting state of 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 uh as far as a you know an evolutionary logic but there's no doubt that this happens in terms of the behavioral effect and the psychiatric effect the lasting effects of early life trauma now if it's not neural circuitry what else could it be it could be genetic or epigenetic as you say you're not changing your genome from childhood to adulthood but you're changing the transcription factors the promoters and enhancers you could be affecting gene expression throughout life and that at least through the life of that individual we understand how that mechanistically could work and then finally you raise the intergenerational uh aspect in human beings this is very hard to separate from you know it's the nature of nurture thing of course you've got the parenting that's linked to what might have happened in the prior generation um and i'd say it's still controversial to uh how much intergenerational uh transfer can happen although in animals there are mechanisms you wrote about the well at least you wrote about your your musings your your exploration of the idea of the evolutionary basis for tears i found this completely fascinating 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 it was interesting to me that i hadn't considered that but say a little bit about that emotional tears and and by that you know the the the liquid coming from our tear ducts at in times of of emotion this is apparently as far as we can tell it's it's a human trait our great apes don't do that do this and even some human beings don't don't do it so it's a it's a it's a special thing uh it's not that we are the only ones that grieve but we're we're the ones that secrete this this fluid from our eyes at these extreme moments and uh and this has been studied there are scholars of of tears as it were and you can do things like add or subtract tears digitally from pictures of faces and these have enormous impacts on 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 and so this intersects very closely with the i think with the involuntary largely involuntary nature of tears it's a truth channel it it's not so easily gameable it reveals something that in a social grouping like those that that we've evolved to maintain it it's a it's it is an involuntary expression of something the world changing of needing uh new systems in place and it triggers this outreach from people who see it in a very powerful way and you know this 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 in anxiety and right next to those breathing rate regions there are regions that control the tear ducts they're right next to each other in the brain stem and a very tiny tiny rewiring a little axon just going in one slightly different direction would create this state of expressing this visible uh uh manifestation of an inner world uh and and with for social uh species like ours that it could be easily evolutionarily selected for and so there's in this in the story uh storehouse of tears in projections this is uh something that that uh a patient's story helped bring to the forefront of my mind and we talk and we talk about it quite a bit yeah it's it's a i won't give any more away from that story because i want people to read it for themselves well 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 um i think what we should do is just commit to to sitting down again next year at some point and and and continuing this discussion there are so many more questions i have about personality disorders and another topic that we didn't even get into today that we're both very interested in is psychedelics yes both from the traditional side even to the non-sort of traditional side uh you know the use of ketamine uh psilocybin lsd mdma all of these things which are an enormous interest of yours uh clinically and scientifically as of mine so um i want to again absolutely congratulate you uh 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 you've written projections which i suspect many people are going to be reading after this so carl thanks very much for for spending time with us today and 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 uh conversation and uh look forward to talking again all right 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Channel: Peter Attia MD

Views: 23,023

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Id: anKrNnJDBZk

Length: 162min 6sec (9726 seconds)

Published: Mon Jan 17 2022