Andrew Huberman - The Frontier of Neurotechnology - [Invest Like the Best, EP.494]

Andrew Huberman is a neuroscientist and professor at Stanford, the host of the Huberman Lab podcast, and the author of Protocols. Most of our conversation is about where neuroscience goes next. For decades the field has focused on reading from the brain, and Andrew believes the next era is about writing to it with precise control over specific brain states. He explains why he thinks the leading AI companies are really building toward this, and why understanding our waking brain states is the problem he most wants to see solved. Please enjoy my conversation with Andrew Huberman. For the full show notes, transcript, and links to mentioned content, check out the episode page ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠here⁠⁠⁠⁠⁠. ----- Become a Colossus member to get our quarterly print magazine and private audio experience, including exclusive profiles and early access to select episodes. Subscribe at ⁠colossus.com/subscribe⁠. ----- ⁠Ramp’s⁠ mission is to help companies manage their spend in a way that reduces expenses and frees up time for teams to work on more valuable projects. Go to⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ ⁠ramp.com/invest⁠⁠ to sign up for free and get a $250 welcome bonus. ----- Trusted by thousands of businesses, ⁠Vanta⁠ continuously monitors your security posture and streamlines audits so you can win enterprise deals and build customer trust without the traditional overhead. Invest Like the Best listeners get a special offer of $1,000 off Vanta when you go to ⁠vanta.com/invest⁠. ----- WorkOS⁠ is the infrastructure B2B and AI-native companies use to sell to enterprise. It covers everything enterprise security requires: SSO, SCIM, RBAC, Audit Logs, AI governance, and more. Trusted by 2,000+ fast-growing companies, including OpenAI, Anthropic, Cursor, and Vercel. ----- Rogo is the AI platform for finance. They're building agents for Wall Street that are trained to understand how bankers and investors actually do work: from diligence and modeling, to turning analysis into deliverables. To learn more, visit rogo.ai/invest. ----- ⁠Ridgeline⁠ has built a complete, real-time, modern operating system for investment managers. It handles trading, portfolio management, compliance, customer reporting, and much more through an all-in-one real-time cloud platform. Visit⁠ ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ridgeline.ai⁠. ----- Editing and post-production work for this episode was provided by The Podcast Consultant. Timestamps: (00:00:00) Energy as the Bottleneck for Top Performers (00:06:20) How to Downshift and Fall Asleep (00:14:06) Neurotech for Sleep and Focus (00:17:57) The State of Public Health Discourse (00:22:07) The Biggest Problem in Neuroscience (00:23:30) Why AI Companies Will Become Biotech Companies (00:26:18) How We Read Brain Activity (00:42:07) Crossing the Cyborg Line (00:43:30) Measuring the Nervous System Directly (00:57:34) The CRISPR Babies Story (01:00:24) Embryo Screening and Genetic Engineering (01:03:01) Understanding Waking Brain States (01:06:12) Technologists Becoming Neuroscientists (01:09:35) The Kindest Thing

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Patrick O'Shaughnessy?

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• 0:45Patrick O'Shaughnessy?

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• 1:29Patrick O'Shaughnessy?

  Every action feeds Rogo Intelligence, the firm's context layer, turning years of deal experience into a secure, governed institutional memory that makes each new transaction stronger than the last. To learn more, visit rogo.com/invest. There's a very interesting thing happening that relates to a piece of your work, which I haven't seen you talk about as much, and so maybe it's a fun place to begin, which is that it feels like we're now bandwidth-limited on the most talented people's ability to do work. Like, it used to be that the rest of the world couldn't keep up with the most talented people, and so they would get frustrated that no one was moving as fast or as efficiently as they were. There seems to be something flipping, which is, actually, some of these people would

• 2:14Patrick O'Shaughnessy?

  earn a really high return if they could generate more energy, maintain more energy, not burn out. I heard this from several great entrepreneurs this summer, that, I think maybe Elon has just gotten into everyone's head, that the real greats are going to run multiple companies. Technology unlocks so much potential for the most talented people, and so this seems like an actual bottleneck, is like, these people's energy. And I'd be curious, in all your research and study, what you've learned about the component parts of this, like generating energy, maintaining it, clean versus dirty fuel, long-term performance, like, all of these things are fascinating and I think actually important to the degree of progress, and so I would love you to just riff on all that for a while.

• 2:55Speaker 01

  With the caveat that Elon represents the apex of being able to do multiple huge things simultaneously, and I don't think he has any peers in that regard. In fact, one of the best multi-billionaire investors from the Bay Area who may have gone to Stanford and been part of the PayPal early team, has asked me, "How is it that Elon does this?" I'm like, "I can't tell you."

• 3:19Patrick O'Shaughnessy?

  Like physiologically?

• 3:20Speaker 01

  Physiologically. I mean, there are examples throughout history of people who seem to require less sleep, they just have more energy, and most people can get their energy up. There are a lot of healthy ways to do that now, and I think now we've undergone this huge shift whereby everyone understands you have to sleep eventually, and you have to know your own sleep requirements. So to delude oneself into thinking you only need four or five hours because Elon only needs four or five hours, that's ridiculous. An honest self-assessment about how much sleep one actually needs to perform well, and perhaps best, and what you can get by on, if you can't get that, that's an important thing to understand. But most people know, like, for me, it's seven hours, I feel great. Eight, probably puts me into the day a little bit groggy. Six, I can manage just fine. Five, for one day or a sleepless night, I'm good.

• 4:05Speaker 01

  Two nights like that, of four to zero hours of sleep, and I'm cratered. And I think most people are similar. What's really changed is that we have effective, healthy ways to build our energy up. We know to sleep, we can talk about exercise, caffeine, some people are using nicotine, yes, it's addictive, it raises blood pressure, but it does put people into that focused but relaxed mode. I always say, if you really want the benefits of nicotine, don't use it very often. If you want the actual cognitive-enhancing effects or the focus-enhancing effects, then you have to not be a chronic user and then spike your system with nicotine at low amounts every once in a while. Setting Elon aside, with the understanding that he represents that extreme in terms of energy and sleep requirements being very low, I think what's really happening now

• 4:50Speaker 01

  is people are hopefully doing this self-assessment. Like, I would hope people would have an honest conversation about themselves and say, "At this point in my life, with or without kids, at this stage of my company, at this stage of my career, whatever it is, at this age, how much sleep do I need in order to feel awesome, good enough, or it's not enough?" And I think most people know that. Okay, so that's step number one. The next one is something most people don't ever talk about, which is, some people actually just have more energy. They can focus for long, long periods of time. They have a ton of energy to run, they have a ton of energy to then go work, but what we never ask is, what is that person's internal state? So I know people that can do all of that, but they're kind of redlining, and they're using a lot of stimulants to do it.

• 5:35Speaker 01

  Or they're not using stimulants to do it, but they're redlining. And then at night, they're having a hard time switching it off, and so they're not resetting their system. Some people, however, are these, like, wake up at 4:00 AM, work out, handle business, deal with family, go off to work, back to business, come home, and they pivot and task switch really fast. I don't think these things are necessarily stable features throughout our entire life. Seems to be a lot of young guys come up to me, they're like, "What should I do?" The Oracle said it best, like, know thyself. You really have to be honest with yourself about what you need in order to do something for a long period of time. Now that said, I do recall working 80, even 100-hour weeks in graduate school, and that served me well. I mean, eventually led me to tenure at Stanford, et cetera.

• 6:15Speaker 01

  I do think that if you can pull it off, I think from zero to maybe first four years of starting a company, or if you're in medical school, the goal is, don't die. Get as much done as you can and don't impair yourself with an injury or chronic disease. We don't really define this thing optimization. And then you start to pivot into, how can I insert components of rest along the way, maybe during the day or across the week or the month, that really allow me to access my best levels of focus and creativity? But I'd be naive and I'd be lying if I said, somebody's starting a company in the AI realm in the Bay Area or elsewhere these days, you're going to sit them down and you go, "Listen, you really need eight hours of sleep, you gotta do your resistance training, should do some breath work." Like, no, none of that.

• 7:00Speaker 01

  What they should determine is how much energy they actually have. And you've met these people, right? Occasionally, you'll run into, like, Jimmy Iovine or some of the folks doing AI at Meta, and they just seem to have an extra gear. Some people have this extra gear. Now, there's one other component, we can deep dive into any of these, that nobody talks about, and that's the ability to switch off your thoughts, your planning and your concerns at the end of your day and drop into sleep.

• 7:23Patrick O'Shaughnessy?

  Yeah, can we go deeper in that one? Because to be very selfish about it, if I was to self-diagnose, the biggest problem I have is downshifting. Sometimes it'll take literally four hours to go from a crazy, exciting, awesome day to literally even be able to fall asleep or just, like, stop the mind. If I could bestow myself with any gift, it would be what you're describing. So what is the research there of how to do that?

• 7:45Speaker 01

  So, in terms of sleep, there are a couple of prerequisites for sleep. There are a bunch of don'ts. So obviously, you don't want to drink caffeine too late, being under too much bright light late in the day can make it difficult, but a lot of us can't control that. Alcohol, cannabis, these things impair the quality of your sleep, help you get to sleep, we all know that by now. But in terms of being able to turn your thoughts off, this is a very, very difficult thing for people, for good reasons. The brain wants to think, plan, remember and organize itself around what's coming next, because it's such a huge aspect of brain function, is prediction of what's happening next. So, first requirement, turn your thoughts off. Second requirement is, slow your heart rate down. Okay, so that's purely of body.

• 8:28Speaker 01

  And then third is, you need to forget about the position of your limbs in space. So let's work through each one systematically. For the first one, turning your thoughts off is a skill. We can think, we can predict, we can remember, but we also can get into pure sensation, and that's the gateway to turning off your thoughts. And this doesn't come from Eastern tradition per se, although this has been discussed for a long time in those traditions, but there's a neuroscience correlate to all of this, of course, and we can talk about those. So, how do you do that? You have to focus on pure sensation. So you start focusing on the surface of your body, if you can detect your heart rate. Some people are very good at what's called interoception, they can actually get pretty accurate measurements of their heart rate without pressing on a vein or artery, and

• 9:13Speaker 01

  they're just listening to their own breathing, they're listening to the sounds in the room, they're sort of bringing their conscious awareness just to the body, and it generally helps, and this relates to the second thing, to slow the heart rate down by just doing long exhales. Now, this might sound very woo, but I want to be very clear, this is not meditation. Because meditation has you do something very different. Meditation has you focus all of your attention on your breathing, or all of your attention on some region behind your forehead, or your hands, or whatever. In this sort of practice, what you do is you actually migrate your attention to your feet, to your legs, to your breathing, to sounds in the room, then back again. Now, this might sound really squishy, but you're moving away from thinking and planning to pure sensation and perception, and you're literally bringing your perception into the present.

• 9:57Speaker 01

  Remember, this is one door in front of turning off your To actually turn off your thoughts, your heart rate actually has to drop a certain amount. Those long exhales drop your heart rate through something called respiratory sinus arrhythmia. Arrhythmia makes it sound dangerous or bad, but it's actually very good. As you're breathing, the size of your heart is literally changing based on the amount of space it has because of the movement of the diaphragm and the filling of the lungs. And when we inhale, our heart rate actually speeds up a bit. When we exhale, the heart actually gets a little bit smaller, volume-wise, and the blood, therefore, that's in it moves a little bit quicker per unit volume. And the brain sends a signal to slow the heart down. So when you exhale, you're slowing the heart rate down through this thing that we call the vagus nerve.

• 10:41Speaker 01

  So if you want to slow your heart rate down anytime in waking to de-stress or just bring your level of activation down, or if you want to fall asleep, it really helps to do some long exhales until lungs are empty and then just passive inhales. Normally, when we're really activated, we're doing a lot of inhaling, we're passively exhaling. And then the last piece is to be able to turn off your perception of your limbs relative to you. It's something that we call proprioception. The three ways to do this, one is old school, everyone accepts it. One is pretty wacky sounding, and then there's a new technology that's coming out that I wish I had developed that I think is going to make people more comfortable with the second one. So here goes. Believe it or not, there have been studies of what puts babies to sleep and what puts adults to sleep without pharmacology.

• 11:26Speaker 01

  It turns out that the rocking pacing that we do with babies at a certain rate, parents figure this out on their own, puts them to sleep. Turns out that you can build, and they've done this for studies, a bed that rocks at a certain frequency, and adults will fall asleep very quickly. What it has to do with is the fact that when you're moving side to side, your eyes are generating, under your closed eyelids, compensatory eye movements. Our eye movements all the time are communicating through our brainstem to our cerebellum to control balance and proprioception. So when people are rocked this way, somehow, they fall asleep more quickly. That's interesting, actually. And the frequency at which that works best and fastest is known. Now, I don't have a rocking bed.

• 12:09Speaker 01

  I don't know anyone large enough to rock me and hold me, and if they did, I'm not sure I'd feel comfortable with that. Can't imagine you would either. So there are two ways to approach this. One is something that looks kind of wacky but works, which is to mimic the eye movements under closed eyelids that help you forget about your limb position. I've been talking about this a lot in public education recently, and I confess it makes me feel really weird as a neuroscientist. Somebody just prefaced this by saying, please don't just put the part out into the world about the eye movement thing without just allowing me to first say that this confuses the circuit between, for the aficionados, these direction selective cells in the retina, the accessory optic nuclei of the brainstem and the cerebellum, and you forget about body position. And basically, what you do is, under closed eyelids, you move your eyes to one side, then

• 12:54Speaker 01

  the other, slowly or fast, doesn't really matter, then up, then down. You can roll them counterclockwise and clockwise. You can do a long exhale, but really what you're doing is confusing this system. The reason I got so interested in this, and the reason I went to the literature on rocking of babies and adults to fall asleep, is because a group out of MIT approached me and they said, we'd like you to try this eye mask. The eyes are two pieces of brain, they're just not in the cranial vault, which makes them unusual in terms of parts of brain. So the eyes are an amazing gateway to the rest of the brain. Everyone knows about eye masks to get the darkness out. These guys have developed eye masks that measure rapid eye movement, because right now, your whoop, your aura, your eighth sleep, they're not measuring REM directly. This can measure REM directly, but they designed this mask specifically to make people fall

• 13:39Speaker 01

  asleep faster. Like, I want that thing. So I got to try it, and it works very well in the daytime or at night. And what does it do? It generates these slow back and forth, up and down eye movements through a small amount of stimulation behind your ears, because it turns out you can access the extraocular muscles well enough from that location. So it's just an eye mask with some straps. You sometimes feel a little bit of the stimulation, and you're out. And then, once REM sleep starts, it actually helps amplify the REM stage, you can get much more REM. So I wish I had a stake in this company, I don't. These technologies are about seven to 12 months from release. I'm super excited about them. I'm also super excited about the fact that people can just do this on their own, and obviously, babies get rocked.

• 14:23Speaker 01

  You could do the non-mask tool approach, or you could use the mask. I will say, and I don't want to take us too far off course, but for those interested in emerging technologies in AI, in particular neural technologies, I do think that in sleep, reading from and writing to the brain is going to be a huge area. But of course, I'm also interested in reading from and writing to the nervous system in waking states. Like, you can imagine that within 12 months, or a year, of the release of the technology that I just described, you can imagine somebody developing eyeglasses like this that are stimulating some component of the autonomic nervous system so that I'm exceptionally focused at certain times of day, and then when I'm walking home, I'm sort of in a slightly more relaxed state to capture some more of that energy.

• 15:08Speaker 01

  We're going to start shifting brain states into focus, into modes for learning, and we're going to start doing it with technologies. Right now, we're doing cold showers, caffeine, exercise, we're doing inhale emphasized breathing versus exhale emphasized breathing to get more alert or calm. If you think about it, all breathing exercises can be summarized as inhale emphasized or exhale emphasized. So, yes, we can do that stuff deliberately, but you can imagine that pretty soon, there will be non-invasive stimulation devices that will allow people to do this, but it will start in sleep, because we're all kind of comfortable with the idea now of measuring our physiology in sleep, little bit in waking states, but this is where this is going. So to return to this in sequence, you need to learn to turn your thoughts off, you need

• 15:52Speaker 01

  to forget about your body position and slow your heart rate down. And the order in which you do that doesn't really matter. You ideally want to combine all three, but I think that's going to be a significant achievement for humanity, because if you look at recovery from illness, healing, learning, stress control, burnout, right? If you're going through grief or psychological stress or trauma healing, if you're trying to start a company and you've got kids, or even if you're just trying to work the maximum number of hours and you've got four hours to sleep and you're somebody who needs six, you want to be able to hit the pillow and shut it off. And we don't have good ways to do that, except the tools I described. So I think we are starting to go about things in a more healthy way, but what I'm talking

• 16:33Speaker 01

  about is people doing a thorough self-assessment of sleep need, ability to turn off thoughts, and then training those things. In fact, a lot of hard-driving people will come to me and say, like, what workout should I do? I'm like, look, how much time do you have? In graduate school, I worked out twice a week. I don't talk about this, but I lifted weights and I ran really far, because I just wanted to maintain while I worked my ass off, publishing as many great papers as I could. And then later, I'm doing, you know, three workouts a week with the weights, I do cardio three times a week, long, medium, and short, take a day off, maybe do some sauna and cold. My life's a little bit different now, or a lot different. But I do think those first years, you're trying to just not die while you create this thing. Then you start moving into some quote-unquote "balance and optimization."

• 17:16Speaker 01

  And then you get the people who have really achieved some level of mastery or virtuosity in their craft, and you really get an assessment of how accurately their schedule matched who they really were at a physiological level by looking at them and going like, they look like shit, they have a chronic illness, they look 10 years older than they were supposed to, or there are certain people who are like phenoms, like an Elon, or you look at some people and you just go, holy crap, they just got an extra gear. And I'm speculating here, but I'm guessing that Jack Dorsey was always a pretty calm, thoughtful guy. That's what people tell me of him, and that's how I experience him too. But I'm guessing he's also put some work into it. He's figured out that staying alert and calm all day and sleeping well at night is the

• 17:59Speaker 01

  key to having a really long, successful arc.

• 18:02Patrick O'Shaughnessy?

  Since you've been covering it for so long, I'm curious what you think the biggest challenge or problem or issue is facing your whole field. Like, if I think about this as the quest to learn and teach, to understand our health and our well-being and ways of making it better, what is the biggest challenge facing the field today, do you think?

• 18:21Speaker 01

  I mean, I feel like the public discourse around health and longevity is a fucking disaster. It is a bunch of clowns, and people are doubling and tripling down on the theatrics. I'm not saying I get everything right or that I have all the answers, I'm definitely not saying that. I got into this at the right time, but the downside is that it was so devoid of anyone else. There were people talking about health only in their area that they worked on in their lab, but not broadly, that, you know, the bar for entry in public discourse around health is basically zero. You know, it's like, you show your abs, and you admit you're on steroids, you have a following. Some dude shows his abs, or some woman like shows her glutes and claims to be all natural, and we believe them then, and suddenly they have a following.

• 19:02Speaker 01

  So, I mean, if that's the bar for entry, I come from a field where having a PhD isn't even nearly sufficient. It's necessary, but not even nearly sufficient to say that you've contributed something to the understanding of the brain. Like, if we could take somebody like, Tim Ferriss was talking about a lot of this stuff early on, that biohacking, self-optimization. And what I love about Tim is he's remained Tim. There was this period where he experimented, he had some things that he felt probably weren't a good idea, you know, he talks about those, like, things that he wishes he hadn't done and things that he's happy he did. And then, he's also invested in all these other things. I think Tim's fantastic, because he's being Tim. So I'm not referring to that. And then you started getting these more and more extreme versions where people were coming in with basically no science or health training and saying,

• 19:46Speaker 01

  hey, like, here's how you optimize the mind and body. And I know this because I'm doing all these things and I used to be fat and I'm not fat anymore. And I think that's fine in principle, but then it just keeps getting crazier and crazier. And so what you've seen now is there's a big gap between, if I'm just honest, between the A tier public health educators and what used to be the B tier public educators is just getting bigger and bigger and bigger. Because one has to be true to self, but you also have to take the endeavor seriously. It's very easy to get attention. It's very hard to keep respect. So I do think that the public health discourse is harmed when it becomes about the theatrics. And I'm not trying to not name names here. I mean, I think everyone can look out on the landscape of everyone from Brian to me to Gary Brekka to Asprey to anyone else.

• 20:31Speaker 01

  There are a lot in the space and just go like, whose persona resonates, not just what captures the entertainment value. So what I would expect will happen next, now that we've gone from high amounts of interest in this to this optimization, optimization. Now it's turned into, are we over optimizing? I think we're going to see a downturn in the number of things that people are willing to do each day. They're like, this is just too much. It's gotten kind of kooky. It's kind of crazy. And the characters, I need more serious peers. I need serious peers with training. You need either science or medicine, maybe pharmacology, and they're out there. But I think those people are going to rise to the surface. We haven't seen them yet. So I look forward to having colleagues like that. And then I think what's going to happen is we're going to get many, many more people trained as PhDs, trained as MDs,

• 21:16Speaker 01

  who are going to be doing serious science, health discourse, not regressing to the TikTok dance model, the focus on me model and really educating people in a way that's unique that I, I'm certain I haven't even tapped into. Someone's going to come along that's better than me. So I think this field is going to go into a downturn now. The public education around health and optimization, longevity, et cetera, is going to go into a bit of a downturn. And then I think we're going to get an influx of a lot of great people. And then it will be where I would like to see it.

• 21:47Patrick O'Shaughnessy?

  How about on the research side? Biggest problem facing the field?

• 21:50Speaker 01

  Well, I think the coolest problem, that's also the biggest problem, is how we can non-invasively write to the nervous system in sleep and waking states. So my best friend from childhood, Eddie Chang, is chair of neurosurgery at UCSF. He's a bioengineer. He's doing things similar-ish to what Neuralink is doing, but removing brain tumors and this kind of thing. I've been with him to surgeries, like right up there next to the tumors. Patient is awake, he's probing areas of the brain. He has permission to map areas related to speech and language, et cetera. So breaching the skull is a big deal. The neurosurgeons say, well, you know, a titanium plate would be better. It's stronger, it lasts longer, but most people don't want to have to do that. They do it because they need something taken out, like a tumor or an epileptic foci.

• 22:29Speaker 01

  I think the big one now is who can develop, it will probably be ultrasound, but a non-invasive way of selectively activating or quieting brain areas with high amounts of temporal precision. Like getting people who are in locked in syndrome to speak, as Eddie has done, or getting people who have a spinal injury to walk, which Neuralink and Eddie and others are trying to develop technologies to do. That is, that's heroic, right? But ultimately, and I'll go on record saying this, anyone who thinks that Meta, OpenAI, Anthropic, or Elon's got Neuralink as his stated neural interest, anyone that thinks that those are LLM AI companies is perhaps going to be surprised at this prediction.

• 23:13Speaker 01

  Every single one of those is going to be a biotech company. They're all interested in the brain. You talk to any of those guys, they may not have formal training in it, but they understand a lot of neuroscience. And they will all tell you, here's the goal, right? The goal is to be able to read and write from your brain, non-invasively. And there are straightforward ways to do that. So the big thing is, how can you stimulate a brain area with temporal and spatial precision? How can you quiet that brain area with spatial and temporal precision? How can you dial up or down the level of quieting? Because it's one thing to say silent versus activated, but the nervous system has a lot of graded signals in it. And we don't think about those signals, but the communication between areas is gated, it's graded, thresholds for activation change, even just for things like drive and motivation.

• 23:54Speaker 01

  A non-invasive device where you could literally crank up your level of motivation by stimulating the nucleus accumbens and related pathways while engaging in a particular learning task or in hard work and then turning it off so that you can capture more energy. You have more of a square wave function on your energy output. That's coming. And those companies are all about that. That's what the real arms race of AI is about. So I sort of chuckle when I think like, okay, like the LLMs are great or terrible, depending on who you are. And I believe they're great. I'm a big fan of AI. But the dynamic modulation of your own neural activity using non-invasive technologies, not pharmacology, but then using AI to be able to understand, okay, this level of activation in this brain area for you, Patrick,

• 24:38Speaker 01

  is related to a hypermotivated brain state that makes it very hard for you to do anything else the rest of the day. And it will just learn to titrate. But you say, well, that sounds kind of science fiction. How far off is it? I mean, my eight sleep changes the temperature throughout the night to give me more REM sleep or deep sleep. It's already doing that. It's just, we're okay with these things in sleep. And it's doing that through a powerful but indirect method, temperature change. But it's no small thing to dynamically change and measure the degree of change in the nervous system in order to access a given state, sleep or otherwise, better. And that's what these companies want to do. So my field of neuroscience has to embrace this.

• 25:20Speaker 01

  And they are, that the people are trying to figure out, what are the natural signals occurring in the brain when people think? When people see, when people move their limbs in a particular way? That's been the last 30, 40 years. That's all reading from the nervous system. Now it's about writing to the nervous system, non-invasive.

• 25:35Patrick O'Shaughnessy?

  I have a stupid basic question. What is the method by which we can read and how precise is our ability to read activity? And what does activity even mean in different parts of the brain?

• 25:44Speaker 01

  Great questions. So it depends on how invasive you want to get. So most people understand, or if you haven't, no big deal, that neurons communicate through action potentials, electrical signals. And we were taught, and it's still in the textbooks, that they're always the same size and shape for a given neuron. Turns out that's not even true. So there's variability there, but we sort of have this all or none, like a neuron either fires or it doesn't. But there are graded potentials. You get to a threshold, the neuron fires, communicates with the next neuron, depending on the milieu there, how many other inputs, what they're doing, the next neuron fires. You sort of set off a chain or not. So you can record from neurons by putting an electro, close to them, extracellular recordings. You can put a bed of nails nearby, record lots of those extracellular signals. You can impale a neuron, record intracellularly.

• 26:28Speaker 01

  All of that requires breaching the skull, sticking wires basically down into the brain. The methods that are really exciting are things like ultrasound, transcranial magnetic stimulation, which is used for the treatment of depression and other things. The spatial control there of, that's for stimulation, is not great. The recording from the nervous system, you can go from what I just described, intracellular recording at the most extreme, then extracellular recording, and then you go all the way to like FMRI or EEG. When people see these like heat maps of the brain, where you really can only measure signals in the surface, like at the cortex, which is interesting, but you're not going to get to the deeper layers. A big problem now is how important is it to understand the natural patterns of activity in detail

• 27:12Speaker 01

  before we start poking around and stimulating with writing? And obviously there are two ways to write, at least two. You can use pharmacology. So what does most pharmacology do? Whether it's alcohol, barbiturates, sedatives of some kind, what are you doing? You're increasing the threshold for activation. You're quieting the brain by just increasing the threshold for activation. You're doing it indirectly by increasing inhibitory release. So there's less excitation overall. You think about Adderall, caffeine, nicotine, speed, modafinil, and you're talking about lowering the threshold. Because those generally work by increasing neuromodulators that increase the likelihood that neurons will fire. So you're just kind of ramping up that baseline. You're sort of creating higher RPM across the brain and body.

• 27:55Speaker 01

  That's why they lead to some shaking, some agitation, like everything's like primed to move, primed to fire, primed to think. It's hard to shut off your mind when you're under the influence of stimulants. Easier when you're under the influence of these other drugs that increase inhibition. So the real question for trying to get to better reading and writing to the nervous system is about spatial and temporal precision and how willing you are to put something underneath the skin. I say skin because you don't necessarily have to go under the skull. Like, let's take vagal stimulation, for example. Vagal stimulation, most people think about as a way to calm down, but most of the vagal pathways are excitatory. And so common treatments for depression now, if somebody's willing, is to put a small, a little smaller than a penny sized stimulator

• 28:39Speaker 01

  under the skin of the neck and stimulate the vagus in order to overcome this sort of sedation that accompanies depression. So vagal stimulation increases alertness. Neuroscientists have known this for a long time and a lot of people are getting pretty good results in their treatment of their depression by increasing vagal stimulation. And it's dynamic. You can say, how do you feel? Ah, I feel okay. You can actually see this in real time. There's an amazing thing that my colleague Carl Deisseroth, one of the greatest bioengineers alive, has talked about where he's talking to a patient and she's suicidally depressed. And then he starts increasing the stimulation on her vagus and she starts moving from that to a discussion about how she feels willing enough to go out and apply for a job in real time. That just tells you that these excitatory mechanisms and these depressive mechanisms

• 29:24Speaker 01

  or inhibitory mechanisms are profound in terms of our perception of the outside world, our perception of ourself. So this would be very nice to have. The question is, are you willing to go under the skin? I am. A guy that came up, not mainly through my lab, but he spent some time in my lab. He's now the head neurosurgeon at Neuralink, Matt McDougall, amazing guy, has a little receiver implanted under the skin of his hand, between his thumb and his index finger. And his wife does too, and it opens their door to their home, to keys. Like, I was like, what are you doing? He's like, it's a sort of biohacking Bay Area-ish kind of stuff. He's like, yeah, like, I'm just playing with the idea of what is it like to have a small device under your skin that can do stuff in the world for you? That's very Neuralink-ish and obviously they have much bigger aspirations than that.

• 30:07Speaker 01

  But I think within 12 months, 20% of the entrepreneur, real world, will be asking, huh, if it's only as invasive as getting a piercing, yeah, maybe I want a little vagal stimulator. And that's coming next. People are thinking like peptides, what are we gonna do? I'm not worried about peptides. I'm thinking implantable devices is where it's gonna go next. The commercially available vagal stimulators, some have shown some promise. They're not super impressive to my neurosurgeon colleagues who like to get it under the skin and under the skull. But I will say there's some interesting results there, but we're not quite there. But think about 10 years ago, if I told you, listen, you're gonna be wearing a ring or

• 30:50Speaker 01

  a band on your wrist that measures your sleep and HRV, that's pretty out there.

• 30:56Patrick O'Shaughnessy?

  I'm so fascinated by this. So there's reading, the underlying activity of the brain at different levels of fidelity. There's writing. You talked about ultrasound stimulation. I think there's electrical. I think there's magnetic stimulation potentially of these areas of the brain. One central part that I don't really know much about is the model of the brain itself. How far along in our understanding of that we even are? I know there's some things that we can say, activation of this area produces this thing. But like, it feels like we need those three things, like good input modalities, good reading methods and a model.

• 31:26Speaker 01

  Yeah. I'm glad you're asking. I mean, these are my favorite topics. It's just that usually people are like, what peptide should I take?

• 31:32Patrick O'Shaughnessy?

  Which peptide should we take, by the way?

• 31:34Speaker 01

  I mean, it depends on what your pain points are. So at the periphery, the retina, the cochlea, the tongue, the olfactory system, the skin, neuromuscular control, which isn't at the periphery, but I think we know pretty darn well how the nervous system works. And we know how different wavelengths of light are transformed into visual images at a, not even a first approximation, but we understand that in significant detail, how motion is processed. We understand a fair amount about memories, although I want to put that on the shelf for a moment because there's an important finding in the memory field that will make you feel like it's in kind of twilight zone, perhaps in neuroscience. It worries me all the time. The hypothalamus, so circuits that are deep in the brain that control hunger, anger,

• 32:19Speaker 01

  sexual appetite, lack thereof, hormone secretion, those are switches. So do we understand those? Yes. Do we understand everything? No. But we understand them. I mean, one of the reasons the GLPs are so effective and one of the reasons they got so much velocity is because we understand where they bind in the brain and they bind to these hypothalamic and other areas, of course, that activate neurons that are involved in the suppression of appetite. And so it's a very simple equation, really. Ramp these GLP levels up thousandfold, people aren't as hungry, but turns out they're not as driven for other things too, if you get beyond a certain level. I think Sam Altman talked about his experience with that at one point and why he decided to either back off the dosage or stop taking them.

• 33:03Speaker 01

  So as you move in from the periphery of the sensory organs, right? And as you move up from the base of the brain, the deeper limbic structures and hypothalamic structures to the prefrontal cortex, we can say, yeah, like your prefrontal cortex, we know based on lesion studies in humans, activation studies, is really important for contextual learning, for strategy setting in different environments, for suppression of impulse, what we call top-down suppression. So do we understand what the prefrontal cortex is doing? Yeah. The place where it starts to get murky is at the level of memory. We'll talk about that in a moment. And at the level of thoughts. You won't find a chapter in a neuroscience textbook that says, this is how thoughts are made.

• 33:46Speaker 01

  And we can talk about what's starting to emerge there, these dynamic attractor states. We'll get to those in a moment. But here's the eerie results from the study of the hippocampus and memory that freak me out and a lot of neuroscientists don't want to talk about this because it throws all the read-write stuff that we were talking about earlier, all the technologies and pharmacology into a complicated place because it doesn't allow for clean matching of conceptual understanding of the brain from experiments to levers that actually allow us some control. The experiments are like this. Mark Mayford's lab has done this, so down at Scripps. Tsushimo Tonagawa, who won a Nobel for his work on immunoglobulins, but then became a very successful neuroscientist, they've done these experiments where they have an animal

• 34:29Speaker 01

  do some sort of learning task, could either learn that they get shocked over here and not there, they get a reward over here and not there, or they learn a maze, or they learn a lever press combination that gets them a reward, you know? They can learn pretty sophisticated things for a mouse. Monkeys can do this too. Humans can do this too. Because ways to read from the brain, including the hippocampus, a deep-ish brain structure, have gotten pretty good. You can say, okay, these are the patterns of signals that happened as the animal learned. And here are the patterns of signals that occur every time the animal expresses this thing. We imagine there's a corlet where every time somebody serves a tennis ball, the way they perfected it, that the same cluster of neurons is activated in the brain, they're communicating with each other, the same circuit rather, and in a particular sequence, A leads to

• 35:14Speaker 01

  B leads to C, and so on and you get the tennis serve. The data tell us that if you tag the neurons that were involved in this behavior and then reactivate them, you expect the behavior, right? And indeed, that's what you find. Hypothetically, you serve the tennis ball. I'm able to measure, let's just say with the highest degree of fidelity, that the patterns of activation from start to finish that occurs as you toss the ball in the air and you serve. Great. Now I stamp those neurons with a chemical tag. This has been done. Then I come back later and I activate those neurons in the same sequence and you do the serve perfectly. And I say, great. But then they did the important control experiment. What if I activate those neurons in the opposite sequence?

• 35:58Speaker 01

  What if I activate all those neurons at once, like banging on the keys of the piano? It's not the same as playing the song. If I just say, what are all the keys involved in this motif of music? And instead I just bang on them all at once, you get a very different sound coming out of the piano. Turns out you get the exact same behavior. This is problematic for the field of neuroscience because what it says is that this notion of these circuits firing in a particular sequence, at least for memory, it's probably not true. So now if I want to write to your nervous system, maybe I'm better off because all I have to do is activate these same neurons. And it doesn't matter what sequence I activate them in. That's kind of cool, right? Like you want someone to walk, maybe you just need to activate the brain areas involved in walking and the body and the other brain circuits will figure it out. But here's the problem.

• 36:43Speaker 01

  First of all, it's very hard to activate these select sets of neurons with high spatial and temporal fidelity to begin with. But the other problem is these neurons, I didn't tell you, are all also involved in lots of other perceptions and behaviors. So it's not like you have a circuit for serving a tennis racket that isn't also used for some aspect of thinking and remembering about something from your childhood. I mean, that's one of the beauties of the nervous system is it repurposes different neurons to participate in different circuits depending on the perceptions and behaviors that you're experiencing, that you're engaging in. Our model of the brain works at the level of the periphery, at the deeper brain structures. But once you start getting into memory and thinking, it's complicated because we don't

• 37:26Speaker 01

  yet have a good model of whether or not the temporal ordering of firing of neurons matters. And every textbook says it does. And the flow from like eyes to the thalamus up to the cortex to create a visual perception, we know that direction of flow is critical. If you cut that off at the level of this deeper brain structure of the thalamus, there's no perception. We know this from human patients. But memory, thinking, brain plasticity, these things all rest on the assumption that the temporal order matters. And apparently it doesn't. And that's one of the unspoken, like, mm, within our field. And people are trying to understand that and what it means, but it's going to present a serious problem for the neurotechnologies.

• 38:09Speaker 01

  Again, it's going to alleviate some problems because maybe you don't need as much spatial fidelity. But in my mind, this is a huge gap in understanding. And then the other piece is that we don't really understand what a thought is. And so if you're gonna get in there and start stimulating neurons in even just motor cortex to generate movement, without the acknowledgement that these neurons are extensively interconnected with structures involved in thinking and planning, you could send the system into haywire. That said, if there's a goal in mind, like drink the glass of water, the brain generally figures it out. And that's what's incredible. I mean, there are people working on brain damaged patients that are finding that if you just go to the areas of the brain where the signals are generated to inform the action

• 38:54Speaker 01

  output ends of the brain, then you can do pretty well. That's how my friend Eddie Chen gets people with Lockton syndrome to speak through a computer. He's not measuring from the speech production areas. He's carefully characterized for many years, decades, the signals coming out of the speech planning areas. And because the signals can't get down to the pharynx and larynx, because speech is just, the pharynx and larynx controlling exhales, what he's doing is he's just transforming those signals into electrical signals so that the person can talk through a computer. So there's advantages and disadvantages to this nonspecificity. I think that's the big one. That's the really big one.

• 39:30Patrick O'Shaughnessy?

  What about all this excites you most and scares you most? Like, some of this, it feels to sort of strip me of my humanity or my identity in some weird way. If, if I knew that you could just like play me like a piano or something like this, given high-precision technology that's underneath the skull or something. The bigger question is like, where do you actually think we're going? Like five, 10 years from now, what kinds of things you think we'll have? But I'm also just curious about the cyborg line here that we're probably going to cross that gets philosophically weird.

• 39:58Speaker 01

  I have to acknowledge I was born and raised in Palo Alto and I have friends in the technology medical sector. So sometimes I get a little bit of the blinders on about how other, you know, a lot of people are terrified of AI. And I'm told lately that I'm not scared enough.

• 40:09Patrick O'Shaughnessy?

  Yeah.

• 40:09Speaker 01

  But I acknowledge that people are concerned, afraid they don't understand it. But I remember the same discussions about computers, which is not to say that we don't need to be careful, but people are okay now with reading from the nervous system. People are okay now with the fact that our phones are recording everything that we're saying. Remember while we're like, is it really listening? How could it really know? It's a little bit like the autonomous driving in San Francisco. Like I got in a Waymo, I didn't even think about it. I just like got in. I think measurement of the nervous system directly in waking states is the next mental hurdle. And I think it's going to be a healthy one to cross. Right now we get heart rate, HRV, and a few other things, but mostly heart rate and HRV. And from that, we get told how stressed we are, how well recovered we are, how well we are sleeping.

• 40:53Speaker 01

  None of that is direct readout from the autonomic nervous system. I actually have a former postdoc of mine who did her undergraduate, Stanford graduate work at Harvard. And I was at Caltech briefly. Her name is Melissa Olmes. She's a brilliant neuroscientist and now biotechnologist. She's developing a tool. It's like a little cuff that actually directly measures activity from the autonomic nervous system. And then gives you a readout. This is so cool. I got to try it. It gives you a readout at the end of the day of how different activities and different patterns of speech and breathing in you related to levels of distress versus use stress. Right now, we just think all levels of increased heart rate and decreased levels of HRV are bad. But she's discovering that there are certain things in your day, like when you're stressed out doing things that you love,

• 41:37Speaker 01

  that actually sets you up for better sleep, more focus, that the data have hinted in that direction for a while. But these devices are the sort that she's developed and she's brought this to police departments, first responders. And eventually this will be a broadly available technology. Direct measurements from the nervous system of how stressed are you when you are stressed? Or are you actually doing great? You just are in a high arousal state. That might change your perception of how stressed you are. I think accurate feedback about those things will have a real positive effect on our health metrics. Maybe you'll discover that there are a lot of things in your day that really stress you out, that you weren't aware of. You'll also learn how long is the tail on your stress from a given stressful interaction, stress in air quotes.

• 42:21Speaker 01

  How well are you focusing will probably need to be picked up from measurements of pupil size changes. This is how it's done in animals. This is why I think confidently it'll be done from eyeglasses. So you need a lot of access from a wristband and eyeglasses or an eye mask and sleep. I think people are going to be really comfortable with that. The big one is how willing are people going to be to set up their entire brain for a vulnerability to non-invasive control? So we're not going to drop wires into people's brains for a while, unless they have a clinical issue. Maybe something under the skin, but you still don't have access to all the neurons. What I want for me is I want access to all the neurons where I can turn things up or turn them down, at least by brain structure. And I have control over it.

• 43:05Speaker 01

  There has to be some benevolence written into that, you know, and vaulted into the device, right? We can't have things that are just like, and you just suddenly you're in a rage. You would hope that the companies building these things would put safeguards in place. They have them for vagal stimulators. Why wouldn't they have them for brain stimulators? And so the vulnerability, or let's call it accessibility that I'm talking about would be the following. My lab, when I was running a lab and a lot of people tickle neurons, right? To neurons, increase their activity a little or a little bit more or a lot these days, not through electrical stimulation, but by putting some sort of gene in them that isn't normally expressed in them. Typically, these are genes that express channels that come from either algae or other things like non-human little things.

• 43:50Speaker 01

  It sounds scary, right? But the way this is done is you can do it locally by making one injection. Okay, problem, got to breach the skull. Or what a lot of people do is they will inject an animal with an adenoid-associated virus or some sort of virus that can stably express genes in all the types of cells that you want. You can direct them to neurons, you can direct them to immune cells. You do this by putting specific promoters. Sounds fancy, but straightforward in primates and mice and so on. You can do this in humans. They've done it in humans for other purposes, but it's more localized, like into the eyes. So here's where we're going. This is where we're going to end up. I know it sounds scary, but at some point in the not-too-distant future, if you're willing and it can be done safely, you get an injection of a virus. Everyone goes, oh my God, it's going to make me sick. No, it's not going to make you sick. It's not the active virus.

• 44:34Speaker 01

  The virus is just a vector, it's just a carrier for some genetic cargo that puts into your brain a channel such that if you have a hat on, wool cap or baseball cap, that it can direct stimulation of only those neurons because it will cast a non-specific stimulus, like a cone of maybe light that can go through the skull, like long wavelength light. That seems the most likely, or ultrasound. In a non-specific way, so not illuminating or activating the whole brain, but it'll sort of send a beam of sound or light onto these neurons that if they express that tag, will be active. You can increase the intensity of the light. You could flicker the light. We'll work through all the different parameters that allow you to turn those neurons from inactive to active,

• 45:18Speaker 01

  to more active, to hyperactive and dial it down. And then with, most likely through AI, you're not going to be turning a knob. You, if you're somebody who is suffering from severe motivational issues or you have healthy levels of motivation, you want to ramp it up, we'll just increase the stimulation. Now, does this open up into people cranking the circuit for themselves? Yeah. But we also have this thing called caffeine and we also have this thing called methamphetamine. Methamphetamine is a problem. 90% plus of the adult world population drinks caffeine every day, which increases excitability in the brain, basically.

• 45:53Patrick O'Shaughnessy?

  Yeah, it's like a blunt.

• 45:54Speaker 01

  Yeah, it blocks the thing that's, that shuts down excitation. But you know, the net effect is more excitation. So you know how much coffee you can drink at a given time of day, given how much sleep you've had. You'll decide how much alertness you want to have. I don't have a better word for it. The opportunity or vulnerability of a given set of neurons will be set by some genetic thing that will be introduced through a virus. Maybe it's an and gate. Maybe you also have to take a pill. So you can't just have the virus and the ultrasound. You need a third factor there. So it could be an and gate. It could have any number of different safeguards in there. But these people with vagal stimulators can unplug them too. I know it sounds scary, but it's absolutely going to happen for the people that want to do it. I think not everyone's going to want to do it.

• 46:39Speaker 01

  And right now, the reading and measurement from the brain and body are freaking some people out. I put out a post on X a few weeks ago, like, oh, if the cost of whole body MRI comes down, I can imagine most people would want it. I know people who have told me they've saved patients' lives because they went and got this done and saw a tumor and we took it out. And the neurosurgery community did not like that. I thought it'd be like, oh, more business for them, but they did not like it. The public gaining more access to their own health data is scaring some sectors of medicine. Dermatologists, ophthalmologists love the AI and the more measurements, better. But I think the Wall Street Journal just put something out saying like, whole body MRI is, basically says it's bad. But you don't have to do it.

• 47:22Speaker 01

  Assuming it's safe, if the cost is low enough or insurance coverage, like, I just don't get the logic. But my friends in medicine tell me, we all know within 20 months, I don't know why 20 and not 24, but within 20 months, it's going to be commonplace because the cost is coming down, just like blood testing. Everyone was resistant to blood testing and to genetic testing. I'm old enough to remember the eighties when it was like, will you get your genome mapped? It was like, what if you have the Huntington's gene? What if you're going to get, would you want to know? They had like episodes of 60 Minutes about this. Now it's very simple. You want to know, you go take the test. You don't want to know, you don't take the test. No one's talking about whether or not getting your genetics done is worthwhile or not, or scary or not. It's up to you. Same thing with your blood.

• 48:03Patrick O'Shaughnessy?

  It's so interesting to me that through all this, so many of the things that you've written about, or I've seen you talk about are indirect ways to affect these same end states. And it sounds like what you think the arc is, is just away from the blunt tools and towards direct, highly precise tools through technology over time.

• 48:21Speaker 01

  More and more specificity. That's what you want as an experimental neurobiologist. The early days of neurobiology were like lesion this, or find a patient who had a spike through his head. And oh, that's what the orbital frontal cortex does? It's involved in morality? No, it's involved in contextual decision-making, strategy. That's Phineas Gage. Certainly not the whole story, but it goes through HM. He's got lesions in his hippocampus, can't remember new things. We now are at the level of tickling specific neurons that are involved in a particular memory or expression of a particular behavior, using chemical genetic tags, using light, using sound. I mean, we only have so many different ways to manipulate neurons. But in the health realm, I love that you bring this up because it really bridges the two areas

• 49:02Speaker 01

  that we've been talking about, public health discourse and neuroscience, reading, writing to the nervous system. And it bridges the two because what are we talking about? Get morning sunlight. Why? To set your circadian rhythm, spike your cortisol. It seems like a blunt tool, but there's a circuit in place from your eye to your hypothalamus and on and on, that is there for that purpose. So it's not biohacking, right? This is important. It's not like using a paperclip to fix my glasses. That's not what the paperclip was designed for. It's not a good solution. It's a temporary solution. The problem with a lot of pharmacology, like SSRIs, believe it or not, helped so many people with true clinical-grade OCD. They were over-prescribed for depression. And really what they do is increase serotonin, which allows for more neuroplasticity.

• 49:45Speaker 01

  Now everyone's down on SSRIs, understandably so, although they have their place. But everyone's really excited about psilocybin. What is psilocybin? It increases serotonin and massively so. It unmasks lateral connections in the brain, allows you to form new associations in a very condensed timeframe. Sometimes it works great, sometimes not, but it's interesting. Same thing with MDMA. Create really massive increases in neuromodulators in a specific context of we're going to work on this thing, this pain, this issue, this trauma, this depression. And you get more plasticity than you do if you're just lathing away at the problem through talking about it day in, day out. You need the therapy, but what did you really do to create plasticity? You put serotonin through the roof with psilocybin.

• 50:27Speaker 01

  Or in the case of MDMA, you increase serotonin and dopamine and you have this heightened opportunity for plasticity. Okay, TMS. Or what I think will soon happen is combine transcranial magnetic stimulation and pharmacology in order to work through a clinical issue that is of, you know, emotions or mind, like depression, like PTSD. So these two things are going to start to intersect. ADHD with stimulants, yep, ramps up activity in the prefrontal cortex. And you can focus better on things that you normally wouldn't be able to focus on. It's just a nonspecific focus enhancer because it increases activity there. You could also do sleep creatine, in particular when sleep deprived. Is it like Adderall?

• 51:09Speaker 01

  No, but those two things, great night's sleep, plus some caffeine. You're pretty close to Adderall level effects. It's just that the people taking Adderall aren't getting great sleep. And so we're really talking about tools of different types, different margins of safety. But they are all very blunt because all these receptors are expressed everywhere. So you get sexual side effects, weight gain or excessive weight loss with certain antidepressants or hypersexuality with certain drugs, et cetera. Because these receptors are all over the brain. The same thing with electrical stimulation. You just want more spatial and temporal specificity. It has to go that way. Neuroscience went that way in terms of reading and understanding the nervous system. And you talk about Dario's work, for instance, Don talks about his work in this realm.

• 51:53Speaker 01

  But he was recording in Mike Berry's lab from retina is usually a salamander retina or some other creature, and they record as many neurons as you could. And then you knew what visual signals you were giving the retina. So you knew the input, you knew the responses at the lower photoreceptors, the output cells, what we call ganglion cells, the signals going off to the brain. And the goal was get as much information about the total collection of neurons responding to an image so we can move from image to perception deep in the brain. Now, you're still a few steps away from the actual perception, which takes place in the brain, but those and the guys that they were trained under, Marcus Meister, those were heroes of our field because dropping electrodes in an area and buzzing and like the animal goes into a rage or it starts mating or whatever, that's super cool.

• 52:35Speaker 01

  But then you have to move to like, what's the nature of the switch in real life? And people are studying those things. What moves an animal from exploring mating to actual mating? What moves an animal from exploring an aggressive interaction to an actual aggressive interaction? But these are all still very low level behaviors and motivations. And we're just starting to understand those. So the cyborg thing, like, can I increase your creativity? We're not even close to that. We don't even know what circuit.

• 53:04Patrick O'Shaughnessy?

  Or IQ or something.

• 53:06Speaker 01

  Yeah, I mean, you could imagine stimulating more memory capacity, but you might give up something. You want to hear something super creepy? This might freak out your audience, but it's true. So a few years back, there was a guy, his first name is He, that's how you pronounce it, H E, I can't pronounce his last name. He actually had done his postdoctoral training at Stanford and then he moved on to his own lab in China. He announced to the world at a meeting that he had done CRISPR in twin babies. He had deleted the HIV receptor. And the story was, and I don't know if it's true or not, but that the father of these children was HIV positive and he wanted to save these kids from getting HIV AIDS. There was this moment in the medical science community where no one knew how people would react.

• 53:49Speaker 01

  Were they going to give them a Nobel Prize or throw them in jail? He went to like the end experiment. We know how to do this now, the technologies exist, but he just did it. And there was this really weird sociology around this in the science community where people who had worked with him prior, who had exchanged emails with him, their emails now were like, people were digging into the emails. And it was clear that the communications from a lot of these people were sort of the hey, be careful, but like, is it working? Is it working? But everyone was waiting, like if he gets in trouble, I didn't know the guy, right? And I didn't know the guy for the record. I didn't know the guy, I knew of him because, you know, I knew the lab he worked in. But it's like, am I going to be a part of this? Like, was I important for this important discovery or should I dissociate myself from this?

• 54:32Speaker 01

  It turns out the world decided like, no, ethically this is bad. The Chinese government came out and said that his lab would be taken away and he'll be punished in some way. I don't know how he was going to be punished.

• 54:41Patrick O'Shaughnessy?

  Disappeared.

• 54:42Speaker 01

  Yeah, do you know what that guy's doing right now? He has a laboratory purportedly in Austin, Texas. Okay, now I don't know if that's true or not. So my first reaction is like, how did that happen? My second reaction is, wait, of course he wasn't the only person doing this. Like you know, this is happening in labs all over the world. It's just no one's talking about it because he proved that it's dangerous to talk about. Now, I think it's very important to have the ethics and the committees set up for this kind of technology. But then you take a step back and you say like, where are we in the world of genetic engineering humans? And you say, okay, well, they do testing of amniotic fluid in pregnant women, babies. It's commonplace, people can refuse it, I believe, but in general, that's done. People are screening embryos for IVF.

• 55:26Speaker 01

  There are companies like Heracite and Orchid. Some are more focused on trying to see if there are any diseases. Some are trying to link certain genetic patterns of expression to autism, but also to IQ, to height, et cetera. So you can see where this is going. And then of course, there's this thing that we call partner selection. People choose in most cases, not always, but they choose who to get sperm from or eggs from in the context of a relationship, right? Or if people are using a sperm donor or something, they're choosing on the basis of like, you look at the criteria and the criteria are like height, where they go to school, what do they look like, you know? So the lines between these haven't been cleanly defined, but you can see there's a gradation there.

• 56:06Speaker 01

  Now, I don't know if he is actually in Austin, Texas, or if he's actually doing these experiments. I don't know that, I want to be very clear. But I find it fascinating and important to understand that people are going to run with these technologies. How fast they run, where they get implemented isn't clear. What about memory? The HIV receptor supposedly is also linked to some aspects of neural circuit formation that are linked to memory. So there was this other layer of those experiments that everyone knew in the neuroscience community, but wasn't talking about, which was, was he actually trying to both render those kids immune from HIV infection, but also make them super smart? And no one's been able to answer that question conclusively.

• 56:49Speaker 01

  But there is this idea that maybe people are genetically engineering people that have some gene expression or lack of gene expression, which renders them more cognitively or physically capable. And you go, oh, that sounds crazy. Yeah, and the folistatin gene has been mutated in animals and there are people doing gene therapy for folistatin to try and build more muscle. So if this was 15 years ago and you and I were having this conversation, you'd be like.

• 57:15Patrick O'Shaughnessy?

  Guys out of his mind.

• 57:15Speaker 01

  Guys out of his mind. Everything I just described has happened. Why it happened, exactly what they were trying to do, unclear. Whether or not it's still ongoing, whether or not this guy's actually in Austin, Texas, doing these experiments or he's someplace else, or he's sitting in a prison someplace in China, I don't know. Okay, I think it'll be interesting, the internet will tell us.

• 57:34Patrick O'Shaughnessy?

  Yeah.

• 57:34Speaker 01

  I guess I'm more excited than concerned, provided people are talking about it and people are thinking about it really carefully. One of the beautiful things about social media is nothing stays a secret for very long, if at all. Nothing stays a secret. There are no secrets anymore. You can have a vaulted conversation with somebody, that absolutely is true. But as soon as more than two people know about something, like you can't exist in this world without leaving a digital footprint. So sooner or later, we'll hear.

• 58:02Patrick O'Shaughnessy?

  It seems like the arc of all this is just control, like control of genetics, control of brain states, control of all these things through technology over time. And this is very much like a William Gibson, future is here, just not evenly distributed yet. And these are all the futures here type things. What excites you most of all this stuff? If you had to pinpoint, like if I forced you to go start a company or something and just focus on one thing?

• 58:28Speaker 01

  I spend a lot of time thinking about media and culture and just humans generally. So to me, the most exciting thing is that because of social media, we're all in the same campus. X is that campus, Instagram to some degree, but those are the campuses for the communication about these things. And so what I'm excited about is the idea that we've got so many more people learning about things in their field and adjacent to their field, that there are a bunch of things that we can't predict that are going to happen. Like someone in the human gene therapy space, who's an amazing educator, has the charisma and the ability to talk about these things, but also has the chops, really understands

• 59:09Speaker 01

  it, is going to move that space forward at tremendous velocity at some point. The issue is that he was a scientist, just like doing his thing and he just kind of went rogue and did it. He didn't check with anybody. When I was coming up, you did experiments at night and the goal was like, don't kill yourself, don't burn down the lab, don't break protocol, but like do experiments. Now it's changed a little bit. Everyone's a little bit more paranoid. I'm excited that somebody, and they're starting. I think that people are thinking about neurotechnologies to read and write from the nervous system in awake states. My own interest right now is really understanding the waking states. We understand slow wave sleep, deep sleep, N1, N2, N3 sleep. I wrote a whole chapter in the book about sleep, its architecture, how temperature changes one or the other, heat up the bed in the morning or the room in the morning, you get

• 59:54Speaker 01

  more REM. We know all that stuff. We know so much about sleep and how to measure and now nudge and maybe even dial in sleep really precisely with these eye mask type tools. Changing the room temp is pretty crude compared to that, but it's also helpful. I want to understand waking brain states. I don't know how to describe the state that we're in. REM is not language about how you feel in REM. It's rapid eye movements. There's something associated with the state that we're in right now. Like I'm alert, I'm focused, I'm enjoying our discussion. What is this state? We need much better understanding of waking states and which waking states lend themselves better to which activities. Then we can start writing to the nervous system to generate those states with a lot of temporal and spatial precision.

• 1:00:37Speaker 01

  That to me seems like the most important thing to resolve right now, and it's totally doable. I'm not the person to do it because I'm no longer running a lab. The problem with neuroscience as a field is a little bit of a problem with academia, but even the biotech sector related to neuroscience is that people tend to work on things that are like four degrees off from what their training was. Actually, even though I've never met him, I think Dario, even though I disagree with a lot of things I hear from him about AI, I think that it's interesting someone came up through neurosciences in this quite different but related field. Sam I've spoken to is extremely smart about the neuroscience, extremely smart, as is Zuck, as is Andreessen. And Elon obviously understands what he's trying to achieve with Neuralink, and he's

• 1:01:22Speaker 01

  extremely savvy with respect to like what can be done now, where we need to go. So in a lot of ways, the technologists who used to just engineer stuff, like they're becoming neuroscientists. And I love that because neuroscience has always benefited from bringing people in from other fields. You can't give them the whole problem entirely because as soon as they sink their hands into a brain, they realize this is not a computer. It's something a whole lot more complicated. But bioengineers are getting very, very good. And people like Eddie Chang, obviously Neuralink's doing this, Matt McDougall and the folks there, and Sam Zuck and Dario, like that's a pretty killer lineup. And Elon, those four, those are the big four. Those are the athletes of brain exploration now. I think most people don't realize that.

• 1:02:07Speaker 01

  And I'm not sitting here like, what are the kids saying? I'm not trying to like glaze it. I think it's just awesome. You want people coming in who have outside expertise and can leverage the best minds, like the best neuroscientists and engineers. So I'm all excitement about it, frankly. But I think we need better definition of waking brain states. I think that's the biggie. And the reason I mentioned those different silos that I've touched into is that anytime you see a field, whether or not it's action sports, or it's science, or it's medicine, take a big leap forward, there's always this thing that we talked about earlier where people get into it, some people go public facing, they kind of push the margins a little bit, then it gets too crowded, people start getting wacky to get more signal to noise on them. And then the thing kind of dies down. And then there's this surge of really accessible, useful technologies and information.

• 1:02:50Speaker 01

  So I think 2027, 28 are going to be a low level noise in my estimation around the health space. I mean, that's what the book Protocols was about. That's my thesis. We got it. I'm not going to keep talking about morning light. For God's sake, I'm starting to tire myself out, you know? So the reason I can move on from is because I know it for certain. What's in the book are the things I know for certain. So now that my thesis is turned in and people can do with it what they will, I think it has things of value, certainly information, but hopefully things of value to people. Now it's time to move into some other realm. And you can probably tell from today's conversation, I didn't realize this was going to come up. I am very, very interested in reading and writing from the awake nervous system. Eddie Chang and I talk three times a week for hours at a time. We take walks. Where is neuroscience? What's next?

• 1:03:35Speaker 01

  I'm just super excited. It's going to be great. I promise you, there's safeguards we need in place, but like the best people are on these problems, the best people. And that's why it pisses me off when the traditional media tries to slow these people down, like, okay, everybody make your public statement about how you're not going to blow up the world. It's like, of course, like you want them to do that. Also, by the way, it doesn't pacify anybody. Of course, we need the ethics, we need the safeguards in place, but I'm nothing but excitement about this. But then again, I'm born and raised in Palo Alto.

• 1:04:03Patrick O'Shaughnessy?

  I did not exactly expect our discussion to focus so much on neurotech and waking brain states and things like this, but I honestly hope you and I could do this once a year to check in on the state of this stuff. It does seem like if you really think ahead from the current stuff in AI to where this is all going, of course, inevitably the intimacy of technology into us is going to increase. And this is like the final frontier. So incredibly fun to talk to you about. When I do this, and I hope it's the first of many, I ask the same traditional closing question. What is the kindest thing that someone's done for you?

• 1:04:35Speaker 01

  The kindest thing? All right, this is a bit of a weird one, but I've carried the message that I got forward through basically everything. Once people hear it, if they thread it back through portions of today's conversation, I think they'll, they'll know how I've done that. So when I was in graduate school, I initially joined a different laboratory. You do rotations. And I joined a laboratory doing excellent work that was very popular at the time, that was really on the cutting edge of molecular genetic techniques for looking at neurons. And it was all the rage at the time. But I had this absolute love obsession for the work that I had done in my second rotation on stuff and in a field that was pretty crowded.

• 1:05:17Speaker 01

  And I found myself having joined this other lab and sneaking into the lab that interested me more at night and doing experiments. And the woman who ran that lab, who's my graduate advisor, Barbara Chapman, she came to me one day and she just said, listen, I'm totally okay with the fact that you didn't join my lab. Her lab was already very successful anyway, publishing papers in science, et cetera. And she said, but you just seem to really love this stuff. And the only thing that's really going to determine your success is how badly do you want to know the answers to the questions that you're working on? I was like, okay. So I broke up with the other lab, I joined her lab, we published eight first author papers, my career went. But that was all the consequence of working on things to try and answer questions that

• 1:06:02Speaker 01

  I was most curious about. That was an incredibly kind thing to do. It also required a lot of humility and boldness on her part because she was basically saying like dump them, come back to me. And I had to trust that it wasn't because of some sense of rejection in her. And it wasn't, she had extremely strong ego. Honestly, I think that's the kindest thing anyone's ever done for me because it showed a belief in me, it showed that she understood that I didn't have enough self-understanding and enough, frankly, enough guts to just say, I don't want to do the thing that everyone else is super excited about. I want to focus on the thing that I'm most excited about, which takes a strong mind and is much easier to do once you've had some significant success in a field. It's easy to do when you're like, oh yeah, everyone said that, that was done, that area

• 1:06:46Speaker 01

  was done, no one listens to that music, but then we had like two platinum albums. It's easy to just carry on. But when you're making the decision to go into this area that you know, most people are like, why would you go there? Like, no one works on that anymore. And it turns out that the wheel of the field rotated too. And I found myself exiting my PhD lab with the skills that were best suited to what was most important in the field next. And I had to be very careful because now the landscape matched my internal curiosity. And now I had to make sure, yes, I'm going into this for the right reasons. And it was true. And likewise, with starting a podcast, I loved running a lab, I truly did, loved teaching at Stanford, I still do. But it was really, I just have this itch, I've got this knowledge in me that I know people can benefit from.

• 1:07:30Speaker 01

  I did not anticipate what came with being public facing, that was like not anticipated. I had no training in that, in being media. And I'm like, fuck it, I want to do this. And I just pulled all the stops out and just went for it.

• 1:07:43Patrick O'Shaughnessy?

  Here we are. Can you say that line one more time? Was it her phrasing of it?

• 1:07:47Speaker 01

  Success is determined by how precisely you match your genuine curiosity to the work that you do. You do have to understand the field you're in and pay attention to it because all experiments are so hard. Building any company is hard. Doing any podcast, if it's done right, is hard. So you have to make sure that it's really true to you. And not to puff him up too much, but I think one of the reasons why Elon is admired by so many people, yeah, some people dislike him, but I think one of the reasons why deep down, people either greatly admire him or envy him is not his money. It's his ability to ignore what people say about what he should be doing. I had a guy come on my podcast who I actually like and respect, and he was telling me all the things that Elon and the top technologists should be doing. They should be helping people this way and that way.

• 1:08:31Speaker 01

  And I'm like, wait, electric cars? And I do think OpenAI is heading to some very interesting things that relate to medicine and benevolence there and on and on. And he's like, yeah, that's what they should be doing, not this other stuff, not Mars. That's like telling Metallica to play The Grateful Dead. Metallica are Metallica because that's what they love, that's the music they fucking love. And The Grateful Dead are The Grateful Dead because that's the music they love. Like you have to be yourself. The big tragedy is when people don't go in the direction of their genuine curiosity because they're trying to quote unquote succeed. So the kindest thing someone did for me was to gently, but very clearly tell me, follow your curiosity, answer the question, solve the problems related to that, and you can't go wrong.

• 1:09:15Speaker 01

  And to not do that is kind of a slow death, frankly.

• 1:09:18Patrick O'Shaughnessy?

  A wonderful, awesome place to close. Andrew, thank you so much for your time.

• 1:09:21Speaker 01

  Thanks.

• 1:09:22Patrick O'Shaughnessy?

  If you enjoyed this episode, visit colossus.com. You'll find every episode of this podcast complete with hand-edited transcripts. You can also subscribe to Colossus, our quarterly print, digital, and private audio publication featuring in-depth profiles of the founders, investors, and companies that we admire most. Learn more at colossus.com/subscribe.

• 1:09:43Speaker 02

  Patrick O'Shaughnessy is the CEO of Positive Sum. All opinions expressed by Patrick and podcast guests are solely their own opinions and do not reflect the opinion of Positive Sum. This podcast is for informational purposes only and should not be relied upon as a basis for investment decisions. Clients of Positive Sum may maintain positions in the securities discussed in this podcast. To learn more, visit psum.vc.