Dream Engineering, the Proton Radius Puzzle, and an ALS Breakthrough (EP. 27)

Hosted by Lester Nare and Krishna Choudhary, this episode has three main stories: interactive dream engineering (yes, two-way “communication” during lucid dreaming), the proton radius puzzle finally getting resolved by a precision lab measurement, and a sobering but hopeful look at ALS—including a breakthrough “ALS-in-a-dish” model that could finally make drug screening translate to humans. Summary Dream engineering — targeted cues + induced lucidity → dream-content biasing and measurable next-day performance gains. Proton radius puzzle — precision hydrogen spectroscopy resolves the decade-long discrepancy; normal hydrogen agrees with muonic hydrogen. ALS — a predictive iPSC motor-neuron model that correlates with patient survival and reveals a promising multi-drug synergy. Rundown — pulsar near the Milky Way center, AI decoding a Roman board game, hormones + evolution signals, and AI-in-the-loop protein engineering. Support the show Donate: FFPod.com/donate Follow: @FFPod (X / Instagram / TikTok / Facebook)

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

• 0:00Lester Nare?

  Hello, Internet. This is your captain speaking, Lester Nare, joined as always by my co-host and our resident PhD, Krishna Choudhary. We have an action-packed full episode this week with three main stories. We're going to start off with the neuroscience of dreams. We're going to follow that up with the physics of protons, and then we're going to wrap up with some of the latest advancements in the fight against ALS. We are going to learn about science from the ground up today because, as you know, this is from First Principles.

• 0:46Lester Nare?

  For our first story, we are going to get a little bit into what feels like science fiction here with interactive dream engineering as the subject. Apparently, we now have the ability to hack into people's dreams, influence and interact with them, and help them solve problems later. This is from Northwestern University in the neuroscience of consciousness, and this story is fascinating to me.

• 1:15Krishna Choudhary?

  Yeah, this one's like, pretty, pretty crazy, okay? I mean, we've all heard of the idea that, you know, if you're trying to solve a problem and you get stuck, sleep on it, right? That's the advice that we get a lot of times. There's been a lot of problem solving that's happened during sleep. Inception is in the public zeitgeist about like, you know, influencing dreams. And it turns out there's more truth to that than previously thought.

• 1:44Lester Nare?

  That's so crazy.

• 1:45Krishna Choudhary?

  Like, we're getting into the science fiction realm where we are able to now influence with dreams, interact with them, and then help the people who we interacted with in those dreams solve problems that they previously didn't solve before.

• 2:00Lester Nare?

  It's unbelievable.

• 2:00Krishna Choudhary?

  It's, it's pretty insane, dude. And the scientific evidence for like, a lot of this, like, dreams influencing your reality the next day, it's been elusive, and it's been challenging because, you know, we can't really systematically manipulate dreams until now. That's the idea. There's this new study by neuroscientists at Northwestern University, and what it does is validate the possibility of influencing dreams.

• 2:26Krishna Choudhary?

  And it's really supporting this theory that like REM sleep, which is when dreams occur, that stage of sleep when dreams occur. It might actually be especially conducive to helping individuals come up with creative solutions to problems.

• 2:40Lester Nare?

  This is so fascinating. I mean, even the idea of saying the phrase dream engineering.

• 2:45Krishna Choudhary?

  Yeah. No, that seems like something out of a Chris Nolan movie.

• 2:48Lester Nare?

  Yeah, yeah.

• 2:49Krishna Choudhary?

  But now it's like actually real.

• 2:50Lester Nare?

  Exactly.

• 2:51Krishna Choudhary?

  There's a science paper that's out, right? So as always, let's start with some of the history.

• 2:56Lester Nare?

  Yes.

• 2:56Krishna Choudhary?

  Dreams have always been viewed as sacred, as this kind of psychological gateway into the subconscious mind. The Egyptians literally had sleep temples for sleep and incubation rituals. And they used to practice these in the ancient temples with the Egyptian deity Imhotep. Do you remember the mummy?

• 3:16Lester Nare?

  Imhotep.

• 3:17Krishna Choudhary?

  Yeah, yeah, yeah, exactly. And then, I mean, it's been, it's been a thing of research for psychoanalysis for quite a while. Sigmund Freud was really into it. Carl Jung was really into it. But the modern birth really came in 1953, when Asorinsky and Kleitman discovered something called rapid eye movement sleep. Okay? And they linked that sleep stage to vivid dreams. What was really the breakthrough here is we didn't have a subjective telling of, oh, I dreamed and that was the stage that I dreamt. Because what they could do is they could hook up electrodes onto the skull and they

• 3:56Krishna Choudhary?

  could actually see signatures of dreaming that were not based on subjective reporting, right? You don't have to wake up and be like, hey, I was dreaming. You could look at the eye movement during sleep. There's a certain part of sleep called REM sleep, rapid eye movement sleep, where your eyes move very rapidly. During that part, the electrophysiological signature from the EEG electrodes is actually very distinct compared to other parts of sleep. So it was this real, actual stage in the sleep cycle. It happens about 25% of total sleep, happens about 90 minutes after you fall asleep. And then during REM, what we've realized over the years of, you know, doing research on it, the brain is highly active.

• 4:40Krishna Choudhary?

  It actually resembles the waking state. If you look at the Ephys signature, like the electrode signature of what these. Little electrodes on our skull picks up. And then you look at other stages of sleep versus when we're awake and we're like looking at stuff and and thinking about stuff.

• 4:59Krishna Choudhary?

  The electrophysiological signature during REM sleep is more similar to wakefulness than it is to other stages of sleep. Right? So when we're dreaming, it's almost like the brain is kind of awake. But obviously, we're still asleep. And it's been this really cool enigma to try to figure out.

• 5:19Lester Nare?

  So the starting point was we, you, you had the subjective experience from people saying, while I was sleeping, I saw stuff.

• 5:27Krishna Choudhary?

  Yeah.

• 5:28Lester Nare?

  But we did not at the time have a way to quantitatively track with instruments that state that people were describing that they were having until, in this historical context, we used electrodes and tracking the brain activity to see and mapping it with this rapid eye movement sleep.

• 5:47Krishna Choudhary?

  Yeah.

• 5:48Lester Nare?

  That there is a state while you are asleep. Where the brain activity looks very akin to a waking state.

• 5:56Krishna Choudhary?

  Yeah.

• 5:56Lester Nare?

  And that maps to when people are now have, you can now map the, the data with the subjective reporting from those sleeping and kind of map those two together.

• 6:06Krishna Choudhary?

  Exactly. And then, let's go even further, right?

• 6:09Lester Nare?

  Okay.

• 6:09Krishna Choudhary?

  So now we figured out that there is definitely such a thing as REM sleep.

• 6:12Lester Nare?

  Yes.

• 6:12Krishna Choudhary?

  And that's probably when you're dreaming.

• 6:14Lester Nare?

  Yes.

• 6:14Krishna Choudhary?

  Now, what if we wanted to talk about dream recall and how that affects how you solve problems the next day or

• 6:21Lester Nare?

  Right.

• 6:21Krishna Choudhary?

  day to day, right?

• 6:22Lester Nare?

  Right.

• 6:22Krishna Choudhary?

  That's still correlational still, right? Because the subject has to recall the dream. And then, there's, there's some correlation between him recalling certain dreams and the creativity that he has the next day. There's some correlation between sleep deprivation and insight. Like, there's a decorrelation, really. It's like, because like, the, the more you're sleep deprived, the less you're really gonna do novel stuff the next day. You need, you need your sleep in order to actually fully function. But these are all correlational, right? You can't do a causal Mapping.

• 6:57Lester Nare?

  Meaning like this caused that.

• 6:59Krishna Choudhary?

  Exactly. Yeah, it's always just observational studies. And this breakthrough, which was in the neuroscience of consciousness. This is a causation study between your dreams and your ability to solve problems.

• 7:14Lester Nare?

  So before we were just saying, these two things are happening at the same time. And so we think they're related.

• 7:18Krishna Choudhary?

  Yeah.

• 7:19Lester Nare?

  But we didn't really see the bridge between the two things.

• 7:21Krishna Choudhary?

  Yeah, yeah, yeah. We weren't able to literally like influence the dreams. And now this is what's happening.

• 7:25Lester Nare?

  Fascinating. Okay.

• 7:25Krishna Choudhary?

  Yeah.

• 7:26Lester Nare?

  Okay, this is getting good.

• 7:27Krishna Choudhary?

  It's pretty insane.

• 7:28Lester Nare?

  Yes.

• 7:28Krishna Choudhary?

  So let's talk about a little bit about cognitive psychology. Okay, it's divided into two domains. When when it comes to creative problem solving, there's really like two ways of thinking about it. There's the convergent thinking, which is the idea that it's like super brute force and logical. If I want to solve a problem, I start with all of my parameters. And then I sort of logically deduce how to get to the solution. Then there's divergent thinking, which is I start with some nexus of a problem. And then I just like look at relationships and try to like creatively figure out how to solve a problem. Right? Now, with the divergent thinking, there's something called the spreading activation model.

• 8:13Krishna Choudhary?

  The idea is that your memory is represented like a giant graph of like a graph like, you know, the internet is a graph. We've talked about this before on the podcast. The idea that like on the internet, each webpage is linked to other webpages. So you have webpages and you have links between them. That's what defines a graph, stuff and then links between that stuff. Now with the spreading activation model, our semantic memory can be thought of as a complex graph. Because there's nodes, which are the concepts, like for example, dog. Dog can be furry, it can be friend, it can be foe. If you're out hiking and you see a wolf, like there's all these different relationships that you can go from dog all the way to, is it an enemy or is it a friend?

• 8:58Krishna Choudhary?

  Is it my own dog? And then from there, you can start connecting nodes. So you can imagine you start with a dog and then you have that idea of a dog. And from a dog, you can now go to friend, you can go to, does he want, does he want to play? Does like all the stuff that I would think about when a dog comes up in my memory, right? There's all these connections. And the idea of the spreading activation model is that you start with some connection. And then you, if you want to solve a problem around that connection, you start exploring all the stuff that's related to that. And you try to figure out what's the best path to get to your solution.

• 9:32Lester Nare?

  So as an example, let's say I'm afraid of dogs, which I'm not because I have three of them. But let's say in this example, I'm afraid of dogs. So when I then see a dog, you know, I'm immediately now making nearby connections, which in this context might be fear, I need to run, how to like defensive, like MMA, like how to kick. Again, only because in my head, in this specific context, I'm afraid of dogs. And so I will be thinking of these associated contexts, concepts in my own head that are related to a dog. And then most adjacently fear and then all the things that come from that.

• 10:10Krishna Choudhary?

  All the stuff that comes around that, right? Exactly. And so now let's try to, let's try to take this network architecture and apply it to problem solving, right? When you're in the waking state, what ends up happening is suppose you want to solve a problem.

• 10:26Krishna Choudhary?

  Based on the brain state, what ends up happening is you, you start with the problem statement and you try to get to the solution. During the waking state, my activation of all these different concepts is tightly regulated. Okay, because there's a lot of inhibit inhibition that goes on. There's these inhibitory neurons that are firing a lot during my wake state. And so only strong, obvious connections are actually the ones that are going to pop up. And so I might get stuck in like a fixation where I'm trying to like solve a problem. And I get stuck while trying to find the solution. And it's really hard for me to get out of that. And I've had this personally in my research.

• 11:08Krishna Choudhary?

  Like when I'm trying to solve something during my work or during my research, it's like.

• 11:14Krishna Choudhary?

  I I work on it for like two hours and I'm stuck and I don't find a path forward. And that's when a lot of people stay. Why don't you just sleep on it?

• 11:21Lester Nare?

  The the idea is you have a problem. Imagine it like traffic. Like like or you're trying to drive through Los Angeles.

• 11:27Krishna Choudhary?

  Yeah.

• 11:28Lester Nare?

  But fifty percent of the roads are closed.

• 11:29Krishna Choudhary?

  Yeah.

• 11:30Lester Nare?

  In your waking state.

• 11:31Krishna Choudhary?

  Yeah.

• 11:31Lester Nare?

  And so you can't take the four oh five, you can't take the one oh one.

• 11:34Krishna Choudhary?

  That's that's really good analogy, yeah.

• 11:36Lester Nare?

  And so it's gonna you can't really it's hard to get to where you need to go. You try to go the back roads, you wind and you end up somewhere in El Segundo.

• 11:43Krishna Choudhary?

  Yeah.

• 11:44Lester Nare?

  Okay.

• 11:45Krishna Choudhary?

  Exactly. So.

• 11:47Lester Nare?

  Okay, okay.

• 11:48Krishna Choudhary?

  Maybe dreaming could fix something like this, right?

• 11:50Lester Nare?

  Yes.

• 11:51Krishna Choudhary?

  And the analogy that I want to make is actually physics analogy, something called annealing. Okay. Whenever we have a material that is in a certain state and we want to get it to a new thermodynamic equilibrium, what you can do is you can raise the temperature.

• 12:06Lester Nare?

  Okay.

• 12:06Krishna Choudhary?

  When you raise the temperature, you're raising the noise, right? And so in a physics thing, suppose I've got a potential landscape, right, which is hills and valleys. My state is stuck in a local valley, but it's not like the global minimum.

• 12:20Lester Nare?

  Yes.

• 12:20Krishna Choudhary?

  Right? It's stuck in some local solution. And I want to get to the global minimum, which is the actual solution.

• 12:26Lester Nare?

  Yes.

• 12:27Krishna Choudhary?

  If the temperature is too small, my state is only going to really jiggle around that local solution. But if I raise the temperature, then my state is able to explore a lot of different avenues because the jiggle has increased. That's the idea of annealing, right? And what people have started to figure out is perhaps the biological function of sleep and specifically dreaming is to raise the parameter of your neural network such that you start exploring different spaces in your brain.

• 13:05Lester Nare?

  Yes.

• 13:06Krishna Choudhary?

  Okay, this happens a lot of times in like artificial neural networks.

• 13:09Lester Nare?

  Yes.

• 13:09Krishna Choudhary?

  Like when you're when you're trying to. Code up an LLM or like some kind of AI. A lot of times it's going to get stuck in a local minima. And what you what you kind of do is you like increase there. There's like various tricks that you can do to make it not get stuck in that local minima. One of the ways is to increase the temperature. So you increase the jump size in your gradient descent. The other thing you can do is introduce momentum so that if it's going in one direction, even if that's local minima, it's going to have enough to like jump over that energy barrier.

• 13:41Lester Nare?

  Yep.

• 13:41Krishna Choudhary?

  And so these the same things is sort of a theory that's happening in brains. Now, is there like a neurological idea? Like, is there a mechanistic philosophy in our brain that we can actually point to here?

• 13:55Lester Nare?

  Right? Yep.

• 13:56Krishna Choudhary?

  It turns out there is. There's a lot of research on how this annealing phenomenon, this raging of temperature, is actually happening in our brain. So the REM sleep initiation.

• 14:06Lester Nare?

  And just briefly, and just because I want to make sure I'm tracking. The way you described it earlier was when you're in the waking state, there are these tight parameters around where to explore.

• 14:17Krishna Choudhary?

  Exactly. The temperature is low.

• 14:19Lester Nare?

  The temperature is low. And so we're basically trying to I we're trying to understand if, you know, is does dreaming loosen?

• 14:27Krishna Choudhary?

  Yes.

• 14:27Lester Nare?

  Those parameters. The process we made, we made the analogy that's akin to annealing in physics. But the simple way of saying it is is turning off the guardrails a little bit to expand the ability to explore into other areas.

• 14:40Krishna Choudhary?

  Yes, that's exactly right.

• 14:41Lester Nare?

  Okay.

• 14:41Krishna Choudhary?

  Yeah. And that's that's effectively what's happening. And there is actually neurological studies that show that this is happening at a cellular level.

• 14:50Lester Nare?

  Okay.

• 14:51Krishna Choudhary?

  At like the biochemistry level.

• 14:52Lester Nare?

  Okay.

• 14:52Krishna Choudhary?

  So REM sleep initiation is driven by the activation of these REM on cells in our brain. Okay. And they're located in like the LDT and the PPT. That's the lateral dorsal and tegmental nuclei in the brainstem. Okay, the brainstem is the part that connects our brain to the spinal cord and make sure our brain can talk to the rest of the body. Now, these cells, what they do is they flood the cortex and the hippocampus with massive amounts of acetylcholine. And the norepinephrine goes to zero. Norepinephrine is kind of an inhibition. Acetylcholine is an activation. Okay, during wakefulness, there's high amounts of norepinephrine. So you have a lot of inhibition.

• 15:36Krishna Choudhary?

  That's those guardrails that you were talking about. But during dreaming. That's gone. So now, without that constraint, now these cortical networks have a really high temperature. They have a lot of noise. They're able to explore all the different possibilities, right? And then, when we think about like dream phenomenology, right? All those like bizarre hallucinatory

• 15:56Lester Nare?

  Yes.

• 15:57Krishna Choudhary?

  nature of the dreams, like when you're like flying, or like you're like random crap happens during dreaming.

• 16:03Lester Nare?

  Yes.

• 16:03Krishna Choudhary?

  That might be a subjective experience of this noise.

• 16:08Lester Nare?

  I see.

• 16:09Krishna Choudhary?

  Of all of the brain sort of like getting really activated.

• 16:13Lester Nare?

  It it's so that we're sort of seeing there's like a the chemistry balance of what's happening in the brain changes.

• 16:19Krishna Choudhary?

  Yeah.

• 16:19Lester Nare?

  In between waking and sleeping state with this acetylcholine. And what was the second one? It was.

• 16:25Krishna Choudhary?

  Noradrenaline.

• 16:26Lester Nare?

  Noradrenaline.

• 16:26Krishna Choudhary?

  Yeah.

• 16:27Lester Nare?

  The noradrenaline is the is the.

• 16:29Krishna Choudhary?

  Inhibition. Yeah, that's the guardrails.

• 16:31Lester Nare?

  The guardrails. And the acetylcholine is what allows you to kind of explore a little bit more crazy.

• 16:35Krishna Choudhary?

  Yeah. And because that balances off during REM sleep.

• 16:38Lester Nare?

  That's then it's like, wow, what's over here?

• 16:40Krishna Choudhary?

  Yeah.

• 16:40Lester Nare?

  Okay, very.

• 16:41Krishna Choudhary?

  Oh, I'm flying. Oh, that's a monster. Like, crazy stuff.

• 16:45Lester Nare?

  And they.

• 16:45Krishna Choudhary?

  During your dreams.

• 16:46Lester Nare?

  And that tracks because it makes sense for anyone who's had vivid dreams before, right? This idea that, um, you know, they do kind of exist in this weird realm, a little bit beyond what is realistic.

• 16:57Krishna Choudhary?

  Yeah.

• 16:57Lester Nare?

  But still feel grounded in realism.

• 17:00Krishna Choudhary?

  Exactly. Yeah. Because it's like synthesizing all the memories that you previously have. But now it's just on overdrive. It's like trying to connect to all this other kind of stuff, right?

• 17:08Lester Nare?

  Makes total sense.

• 17:09Krishna Choudhary?

  It's it's it's it's pretty cool that we can go all the way down to the biochemistry level.

• 17:14Lester Nare?

  Yeah.

• 17:14Krishna Choudhary?

  And like still see.

• 17:15Lester Nare?

  Right.

• 17:16Krishna Choudhary?

  The subjective effects.

• 17:17Lester Nare?

  Yeah.

• 17:17Krishna Choudhary?

  All the way up. I neuroscience is like crazy. And there's just so much more that we don't know about the brain, right? And the fact that we're getting this far is already, I think, really, really cool. So now let's talk a little bit about information theory.

• 17:30Lester Nare?

  Yes.

• 17:31Krishna Choudhary?

  And the brain.

• 17:32Lester Nare?

  Okay.

• 17:32Krishna Choudhary?

  Because the brain is an information chugging machine. There's this idea of entropy, which is the same kind of idea that we have in physics, the idea of randomness. How structured is the data in our brain? If we look at the ECG signals, which is the signal, the electrical signal that we would get if we were to put electrodes on our scalp, right? You can see that the wakefulness and the REM sleep look very, very similar.

• 17:59Lester Nare?

  Yes.

• 17:59Krishna Choudhary?

  This is what I was alluding to before.

• 18:01Lester Nare?

  Okay, got it.

• 18:01Krishna Choudhary?

  Slow wave sleep, which is deep sleep.

• 18:03Lester Nare?

  Yes.

• 18:04Krishna Choudhary?

  That's the part where we're not dreaming. That's like super deep. Nothing, there's no subjective experience so far as we can tell of that. And light sleep are look very different compared to REM and wakefulness. REM is almost like we are wakeful, but our body is completely paralyzed. And the way that our body does that is our brain, our brain stem, which is the part that connects our brain to the spinal cord, completely blocks all the signal.

• 18:35Lester Nare?

  Ah, okay.

• 18:36Krishna Choudhary?

  That's why we don't act out our dreams. Well, I mean, some people do and they've got a, they've got a little.

• 18:42Lester Nare?

  We're acting out our dreams right now.

• 18:44Krishna Choudhary?

  I, I think we are actually on this show. We've talked about this for a very long time. Yeah, but you know what I mean, right? Like, like when we're dreaming and like, we're doing all the crazy stuff. Our brain stem is actually paralyzing the rest of our body. Okay, but the dream state itself looks very much like the wakeful state. That's something that I really want you to like imagine. And I think that's kind of crazy to think about.

• 19:11Lester Nare?

  Yeah, it is.

• 19:12Krishna Choudhary?

  That like during dreaming, the brain is basically simulating reality.

• 19:17Lester Nare?

  Right.

• 19:17Krishna Choudhary?

  Of being awake. It's just, we're not acting it out because the brain stem, which is the part in the back of our brain, connecting our spinal cord to the brain is just like, no, none of that signal is getting through.

• 19:27Lester Nare?

  It's, it's sort of like the brain is putting on a biological VR headset, utilizing your memory as the context by which it then projects imagery into your like mind's eye, while paralyzing your body movement. So you don't have to worry about running into your TV.

• 19:43Krishna Choudhary?

  Yeah, dude, that's exactly right. That's, I mean, it's exactly what it's doing. It's like a little VR.

• 19:48Lester Nare?

  Yeah.

• 19:49Krishna Choudhary?

  That's, that's in our head that we're making up as we go along. So given all this, given all these constraints, right?

• 19:55Lester Nare?

  Yes.

• 19:56Krishna Choudhary?

  Now let's talk about how do we do sleep engineering?

• 20:00Lester Nare?

  Right, because now we've set the basis of why we can actually look at dreaming from a quantitative perspective and understand the numbers.

• 20:11Krishna Choudhary?

  Yes.

• 20:11Lester Nare?

  And see it.

• 20:12Krishna Choudhary?

  Yeah.

• 20:12Lester Nare?

  And track it.

• 20:13Krishna Choudhary?

  Yeah.

• 20:14Lester Nare?

  But now the question is, how can we actually be more targeted? Not just read, how do we read and write?

• 20:21Krishna Choudhary?

  Yes, yes. How do we, how do we now write into the sleep itself, right? We want a deliberate manipulation.

• 20:30Krishna Choudhary?

  Of our sleep content, right?

• 20:33Lester Nare?

  And it's funny because in the waking state, we have a variety of things that manipulate our conscious waking experience.

• 20:38Krishna Choudhary?

  Yeah, yeah.

• 20:38Lester Nare?

  So theoretically, I mean, just like loosely speaking.

• 20:41Krishna Choudhary?

  Yeah.

• 20:42Lester Nare?

  If there's such a matchy-matchy.

• 20:43Krishna Choudhary?

  Yeah, then it should be possible, right?

• 20:48Krishna Choudhary?

  That's where we get into something called targeted memory reactivation.

• 20:52Lester Nare?

  Okay.

• 20:52Krishna Choudhary?

  Okay, this is something that's used not just in dream research, but just sleep research in general.

• 20:59Lester Nare?

  Okay.

• 20:59Krishna Choudhary?

  Here's the idea, okay? So we pair learning, let's say we're awake and we're learning something. We pair that learning with some kind of sensory signal. Usually it's a sound. So I'm reading something, I'm playing the piano, there's a sound that's playing, okay? Now, when we go and sleep, that same sound is going to play while we sleep. Okay, and then later on, when we wake up, because that sound is associated with the thing that we were learning, and now we heard it while we slept, it's going to sort of give that extra oomph to consolidate that into the greater brain machinery. Does that make sense?

• 21:43Lester Nare?

  It does, it's a signal that sort of triggers a hardening of the concept from your waking state in your sleeping state.

• 21:53Krishna Choudhary?

  Exactly, yeah, there's this external stimulus that's associated with the thing that you're trying to learn, either the task that you're trying to learn, or the memory that you're trying to remember. And then when you trigger it during your sleep, it like doubles down. The neurons double down because they're getting a coincidence signal. You know?

• 22:12Lester Nare?

  I wish I knew this when we were in school.

• 22:14Krishna Choudhary?

  Dude, I mean, there's a lot of cool research now that's doing this exactly right. Now, historically, this TMR, targeted memory reactivation, has focused on non-REM sleep, okay? Non-REM sleep is the slow wave sleep that we get, that's the deep sleep. And that is usually involved in memory consolidation. That's the idea of whatever short-term memory that I'm getting today, whatever is salient and I need to store into long-term memory, that's what. What happens during this deep sleep? And so if I want to store certain things into long term memory, what I can do is, um, or if I want to like have a skill that I really want to store into long term memory, I can have this targeted memory reactivation and it's actually highly effective. In ninety plus studies, this particular one by Rash and other

• 23:00Krishna Choudhary?

  authors have shown that this is like very much works.

• 23:04Lester Nare?

  Okay.

• 23:04Krishna Choudhary?

  Like those, those who learn piano, for example, with an auditory stimulus. And then you reactivate the auditory stimulus during sleep. They're going to remember that piano sequence better. Like their motor neurons literally are going to be better the next day.

• 23:18Lester Nare?

  So for all the coaches who used to say, don't play music while we were training.

• 23:23Krishna Choudhary?

  Yeah.

• 23:24Lester Nare?

  For soccer, uh, have it be known that had you let us play our rap music and then we played it during our.

• 23:30Krishna Choudhary?

  During our sleep.

• 23:32Lester Nare?

  During, during the sleep, we would have, we would have won more games.

• 23:35Krishna Choudhary?

  Yeah, yeah, yeah. That's the big one, right?

• 23:37Lester Nare?

  I'm being facetious a little bit here.

• 23:38Krishna Choudhary?

  Yeah. Um, and so here in this particular study, what they're trying to do is break that barrier and not just go into non REM sleep. They're trying to do targeted memory reactivation during dreaming. Okay. It gets a little tricky.

• 23:54Lester Nare?

  Okay.

• 23:55Krishna Choudhary?

  Okay. When we get into dreaming, right? Because what we want to do is we want to prove that the targeted memory reactivation during dreaming can buy a stream content.

• 24:06Lester Nare?

  Oh, okay.

• 24:07Krishna Choudhary?

  Right? So that's one thing.

• 24:09Lester Nare?

  Yes.

• 24:09Krishna Choudhary?

  Where like you're going to dream of certain things. And then the second thing is when you dream of those certain things, you're actually better at the task later on.

• 24:19Lester Nare?

  Interesting. So we're not just trying to harden it so that it can be reactivated when there's an external stimulus. That was just a grounding. What we're saying now is can we actually influence? What someone sees and feels when they are actively dreaming.

• 24:36Krishna Choudhary?

  Yeah.

• 24:37Lester Nare?

  And then not only that, can we then also have it so that the thing we're influencing them to see and feel while they are dreaming is functionally beneficial to like a reactivation or some functional process.

• 24:50Krishna Choudhary?

  Yes.

• 24:50Lester Nare?

  For when they're now returning to the waking state.

• 24:53Krishna Choudhary?

  Yes, exactly. And in order to really make this foolproof, they actually selected their participants.

• 24:59Lester Nare?

  Okay.

• 24:59Krishna Choudhary?

  To be 20 subjects with high lucid dreaming.

• 25:04Lester Nare?

  Okay.

• 25:04Krishna Choudhary?

  Propensity.

• 25:05Lester Nare?

  Yeah.

• 25:05Krishna Choudhary?

  Do you know about lucid dreaming?

• 25:07Lester Nare?

  I, I am from, we do live in LA.

• 25:08Krishna Choudhary?

  Yeah.

• 25:08Lester Nare?

  So, you know, there's a lot of people who love to talk about the woo woo.

• 25:12Krishna Choudhary?

  Yeah.

• 25:12Lester Nare?

  Uh, and lucid dreaming is very, it's, it's the, the idea basically that you can have agency, like you have awareness.

• 25:19Krishna Choudhary?

  During dreams.

• 25:19Lester Nare?

  During dreams and then you can make decisions.

• 25:21Krishna Choudhary?

  Yeah.

• 25:22Lester Nare?

  Not just be on a roller coaster ride through it.

• 25:24Krishna Choudhary?

  Yeah, I mean, it's, I think it's one of the coolest things that we can do as human beings is be conscious of the fact that we are in our brains simulation.

• 25:33Lester Nare?

  Yep.

• 25:33Krishna Choudhary?

  Right? And then have agency and control over that dream. Right? This is central to the plot point of inception.

• 25:40Lester Nare?

  Yes.

• 25:40Krishna Choudhary?

  And so on and so forth.

• 25:41Lester Nare?

  Yes.

• 25:41Krishna Choudhary?

  Right? So, um, here's what they did. They got 20 subjects with really high lucid dreaming propensity. Okay. 39 overnight sessions. And what these participants did was they tried to solve tasks, like little puzzles. This is like a matchstick puzzle, which is like, you, you, you, you want to move exactly five matches such that the, this like random scale that's made out of matches is exactly balanced.

• 26:10Krishna Choudhary?

  And these are all insight driven puzzles. That's, that's the key.

• 26:14Lester Nare?

  Okay.

• 26:14Krishna Choudhary?

  They're not brute force puzzles. They're not like math, algebra problems where there's a systematic, you know, algorithm that you can use to solve it. They're really like a creativity type of puzzle. Okay? And participants usually used to have some amount of puzzles that were not solved. Okay? Here's the key. Here's what they're doing. While they're solving the puzzles during the normal day, there is an auditory cue for each puzzle. Each puzzle has a unique sound associated with it. So as they're solving it, there's a unique sound that's being played in the background. So they're associating subconsciously that sound to this particular puzzle. Okay, now we get into their sleeping.

• 26:58Krishna Choudhary?

  Okay, now they're sleeping. We have something called targeted lucidity reactivation. They're able to target lucid dreaming to happen in these patients.

• 27:10Lester Nare?

  No way.

• 27:11Krishna Choudhary?

  Yeah, this is what's crazy. So at 4am, they wake up, okay? And they spend 20 minutes training their mind to associate another set of auditory clues with a critical state of mind that will provoke lucidity. So as they're falling asleep, so they wake up at 4am, and as they're falling asleep, they get played these three-tone beeps that are in ascending frequency, just like beep, beep, beep, beep, beep, beep.

• 27:38Lester Nare?

  You hear that, you hear that pitch, guys? You hear that pitch perfect over here?

• 27:42Krishna Choudhary?

  But, I mean, that's what they're doing, dude.

• 27:44Lester Nare?

  No, no, no, no, no.

• 27:45Krishna Choudhary?

  It's kind of crazy. And, and, and what they're doing is as they're lightly falling asleep, they're aware of that dun, dun, dun, dun, dun, dun, right? And they're like, oh, that's the sound, that's the sound. And they're trying to keep that lucidity. So they're trying to keep the conscious awareness of the sound while they're falling asleep.

• 28:01Lester Nare?

  The, the thing, the reason I'm kind of like giving all these facial expressions is, have you ever heard of this concept of like binaural beats?

• 28:09Krishna Choudhary?

  No.

• 28:09Lester Nare?

  So there's this whole community, like, you know, Monroe Institute and a variety of these entities have done this research into this concept of binaural beats. And there are two aspects to it. One is that it helps you, the way, the way the frequencies are tuned, it helps you like relax, but in particular, They, people use it for lucid dreaming as like the thing to fall asleep to and then like.

• 28:33Krishna Choudhary?

  Oh, okay. Yeah, that's, that's very much.

• 28:35Lester Nare?

  It puts you in the right.

• 28:37Krishna Choudhary?

  Kind of in line.

• 28:37Lester Nare?

  And state that enables or makes it more likely that you would lucid dream. It's just interesting that there is an overlap because it's very much sort of in the, you know, people who are quantitative self, self-improvement kind of universe. So it's fascinating that there's a direct overlap.

• 28:56Krishna Choudhary?

  Yeah. I mean, it's pretty crazy.

• 28:59Lester Nare?

  Yes.

• 28:59Krishna Choudhary?

  That like, I mean, dude, this stuff is just, yeah. I mean, so here, okay, so getting back to this, right? So, so they have this like ascending three-tone beep.

• 29:08Lester Nare?

  Yes.

• 29:09Krishna Choudhary?

  That then sort of like makes them sort of aware and try to lucidly dream more. And then here's the track, here's the key, right? They still have those TMR cues, the, the same targeted memory reactivation cue.

• 29:20Lester Nare?

  Right.

• 29:21Krishna Choudhary?

  Of the puzzle.

• 29:22Lester Nare?

  Yes.

• 29:23Krishna Choudhary?

  The puzzle sound is different from this lucid sound, okay? If they become lucid, right? They're gonna, and we can monitor their brain state because we have electrodes on them. So we can see when they enter REM sleep.

• 29:38Lester Nare?

  Right.

• 29:38Krishna Choudhary?

  Right? And when they enter REM sleep, I can start playing now the sound from the puzzle. And if they're lucid and they play the sound from the puzzle, and they hear the sound from the puzzle, they're going to seek out that puzzle in their hallucinated dream state. So imagine like you're dreaming and you're like out in like Yosemite or something.

• 29:56Lester Nare?

  This is so crazy.

• 29:57Krishna Choudhary?

  And like, now you hear the, you hear the dun dun dun, which is like, oh, I'm lucid. And now whatever sound was associated with a certain puzzle that they couldn't solve, they're gonna try to hallucinate that puzzle onto the granite walls of Yosemite.

• 30:12Lester Nare?

  This is unbelievable. I'm so, I'm like, we need to do a follow-up on this because I'm, I'm so excited about this.

• 30:18Krishna Choudhary?

  It's insane.

• 30:19Lester Nare?

  So just to say it back to you from the beginning, the idea is.

• 30:22Krishna Choudhary?

  And I haven't even gotten to the best part, by the way, but.

• 30:24Lester Nare?

  We, we start. I don't know if I could take which word.

• 30:27Krishna Choudhary?

  Yeah.

• 30:28Lester Nare?

  We, we, we basically have an audit, an audio cue when the participants are trying to solve a puzzle. That's an insight based puzzle.

• 30:36Krishna Choudhary?

  Yeah.

• 30:36Lester Nare?

  And the idea is to connect the puzzle to the sound for the participants.

• 30:41Krishna Choudhary?

  Yep.

• 30:41Lester Nare?

  The participants then go to sleep.

• 30:43Krishna Choudhary?

  Yeah.

• 30:43Lester Nare?

  While they're sleeping separately from that set of sounds, we have a different set of sounds. They wake up at 4am and we're trying to induce lucidity while dreaming.

• 30:53Krishna Choudhary?

  Yeah.

• 30:53Lester Nare?

  And the second set of sounds helps to facilitate that inducement of lucidity while dreaming. That lucid state while dreaming that we've now induced with our second set of sounds means we're now incepting the first set of sounds into the dream.

• 31:10Krishna Choudhary?

  Yeah.

• 31:10Lester Nare?

  Literally like the movie Inception.

• 31:12Krishna Choudhary?

  Literally, yeah.

• 31:13Lester Nare?

  Literally.

• 31:13Krishna Choudhary?

  Yeah.

• 31:13Lester Nare?

  Where they could like feel the vibrations of the car when they were crashing in the dream.

• 31:17Krishna Choudhary?

  In the dream.

• 31:18Lester Nare?

  But because the sound was previously associated with the puzzle, it will basically now instigate the brain to think about the puzzle. The point being because we've now gotten rid of those guardrails we've talked about before, the brain has more space to explore and is potentially more likely to come up with the novel solution.

• 31:37Krishna Choudhary?

  Yes.

• 31:37Lester Nare?

  That is one of the craziest, most unbelievable things that we've talked about on this pod.

• 31:43Krishna Choudhary?

  I think, I think this is absolutely insane. Here's, here's, here's the part that I thought was crazy.

• 31:50Lester Nare?

  We need a cherry on top.

• 31:51Krishna Choudhary?

  Okay, this is the cherry on top, okay? There was, so, so we've gotten to the part where it's like interactive dreaming, right?

• 31:59Lester Nare?

  Right.

• 32:00Krishna Choudhary?

  But at the end of the day, I still want to be sure that I am making this happen.

• 32:05Lester Nare?

  Right.

• 32:05Krishna Choudhary?

  Okay, I don't want subjective reporting after the patient wakes up. I want during the dream to know that this is happening.

• 32:16Lester Nare?

  Yes.

• 32:16Krishna Choudhary?

  Okay, but there's a, there's a caveat, right? This is gonna be, this is gonna be kinda difficult because as I told you, the brainstem mediated paralysis.

• 32:24Lester Nare?

  Yes.

• 32:24Krishna Choudhary?

  Is paralyzing the entire body.

• 32:26Lester Nare?

  Yes.

• 32:27Krishna Choudhary?

  But it spares the eye muscles because it's REM sleep, right? So the eye is definitely moving, that's why it's called rapid eye movement. And it's also sparing the diaphragm because you're still breathing.

• 32:38Lester Nare?

  Oh, right, yeah, yeah.

• 32:39Krishna Choudhary?

  These subjects were trained.

• 32:43Krishna Choudhary?

  If they were lucid dreaming, they would move their eye around in the dream and they would breathe, they would huff and puff during the dream, like in their dream, right? Like, so I'm in Yosemite and I'm like in my dreamscape. I start huffing and puffing in my dreamscape. Well, that's gonna transfer

• 33:02Lester Nare?

  Into your

• 33:02Krishna Choudhary?

  Into the physical body, huffing and puffing. And I could monitor that.

• 33:07Lester Nare?

  This is so crazy.

• 33:08Krishna Choudhary?

  So I have the EEG signal.

• 33:11Lester Nare?

  Yes.

• 33:11Krishna Choudhary?

  I have the signal from my breathing

• 33:15Lester Nare?

  Yes.

• 33:16Krishna Choudhary?

  Stuff. I have the signal for, from the eyes.

• 33:19Lester Nare?

  Yes.

• 33:19Krishna Choudhary?

  And I can now get a signal of the subject reporting back to me during dreaming that he is actually doing this.

• 33:28Lester Nare?

  Y'all, y'all, I want you to understand something. I want you to understand something. What you're saying is we have now experimentally shown that a patient can communicate while in a dream state, particularly when they're lucid dreaming, back to the researchers that are monitoring them across at least two modalities, eye movement and breathing.

• 33:59Krishna Choudhary?

  And breathing, yeah.

• 34:01Lester Nare?

  While, while we're trying to incept an idea to help them problem, like on top

• 34:07Krishna Choudhary?

  On top of all of that.

• 34:10Lester Nare?

  Mate, I, I'm at a loss for words because that is so, it's, it's kind of weird because literally the movie inception.

• 34:18Krishna Choudhary?

  It's not kind of happening.

• 34:19Lester Nare?

  It's kind of happening.

• 34:19Krishna Choudhary?

  Yeah, it's, it's insane. There's no sharing of dreams, fine.

• 34:22Lester Nare?

  Sure.

• 34:23Krishna Choudhary?

  But like, a lot of the stuff is, is there, right? And, and the key to this two-way communication is that there's now real-time irrefutable

• 34:32Lester Nare?

  Right.

• 34:32Krishna Choudhary?

  Proof.

• 34:33Lester Nare?

  Right.

• 34:33Krishna Choudhary?

  That the cue was heard.

• 34:35Lester Nare?

  Right.

• 34:35Krishna Choudhary?

  It was integrated into the dream.

• 34:37Lester Nare?

  Right.

• 34:37Krishna Choudhary?

  And there is a conscious response that came back.

• 34:39Lester Nare?

  Right. Because in theory, you could make the conscious response different things.

• 34:43Krishna Choudhary?

  Yeah.

• 34:43Lester Nare?

  You could say breathe like this, or breathe like that, or move your eyes like this, or move, in order to then track over multiple different

• 34:48Krishna Choudhary?

  Yeah.

• 34:49Lester Nare?

  Iteration types to be like, yeah, no, this, this is

• 34:51Krishna Choudhary?

  Definitely.

• 34:51Lester Nare?

  It's not just like, oh, it's the same single type of eye movement or breathing. Anyway.

• 34:56Krishna Choudhary?

  Yeah. Okay, so now let's see if there's actually an outcome. Were they able to solve these problems better? So for one, seventy-five percent of participants reported the queued puzzle elements in their dreams.

• 35:08Lester Nare?

  Okay.

• 35:08Krishna Choudhary?

  Okay, which is way greater than control, meaning like I I played the sound from the puzzle and the puzzle was in their dream. They were like solving it or doing whatever, right? The targeted dream efficacy, right? The the subjects reported forty percent more success on the queued puzzles versus the not queued puzzles.

• 35:30Lester Nare?

  That's so crazy. So people who got the the inception.

• 35:34Krishna Choudhary?

  Yeah.

• 35:34Lester Nare?

  To solve the puzzle, forty percent of the time were able to do so after the fact, greater than those who did not have the inception.

• 35:42Krishna Choudhary?

  Yeah.

• 35:43Lester Nare?

  So if you didn't get incepted, you got you you didn't do well.

• 35:46Krishna Choudhary?

  Yeah.

• 35:47Lester Nare?

  If you did get accepted.

• 35:47Krishna Choudhary?

  You did a little bit better because like sleep always like like natural sleep.

• 35:51Lester Nare?

  Sure.

• 35:52Krishna Choudhary?

  Will get you, you know, a little bit farther, but this is like engineered dreaming.

• 35:57Lester Nare?

  Yes.

• 35:57Krishna Choudhary?

  Is is making you like superhuman at solving these puzzles.

• 36:00Lester Nare?

  This is this is this is on I can't I just.

• 36:05Krishna Choudhary?

  It's insane, dude.

• 36:06Lester Nare?

  For those who are listening on audio, my my mouth has been mostly open slack jaw for a lot of the story.

• 36:12Krishna Choudhary?

  Dude, yeah, it's it's pretty.

• 36:13Lester Nare?

  This is quite nice.

• 36:14Krishna Choudhary?

  This is quite nice.

• 36:15Lester Nare?

  This is quite nice.

• 36:15Krishna Choudhary?

  And these studies are not in a vacuum, right? There's actually a lot of broad effort to do dream engineering.

• 36:21Lester Nare?

  Okay.

• 36:21Krishna Choudhary?

  And sleep engineering in general.

• 36:23Lester Nare?

  Okay.

• 36:23Krishna Choudhary?

  It reminded me of this study from MIT called Dormio. They were actually targeting non-REM sleep, so this is like the edge of sleep N1, which is called hypnagogia. It's like right when you're falling asleep, okay, it's this transitional state between wakefulness and sleep. And they had a sensor, they had a glove that people would put on with sensors. And then it would give a cue, like, think of a tree, right when you were going to sleep. Okay, this thing was targeting divergent creativity, which is that I the the, you know, sorry, this thing was actually targeting convergent creativity.

• 37:00Lester Nare?

  Okay.

• 37:00Krishna Choudhary?

  Which is like the the.

• 37:02Lester Nare?

  Going down the creative.

• 37:03Krishna Choudhary?

  Going down the the rabbit hole, right?

• 37:05Lester Nare?

  Yes.

• 37:06Krishna Choudhary?

  And so and so we're we're we're doing like separate, different things, and this is part of that. So I'm just saying there's like a huge modality of scientific research that is going into specifically sleep engineering.

• 37:21Krishna Choudhary?

  And this is like one of the coolest.

• 37:23Lester Nare?

  This is so cool.

• 37:24Krishna Choudhary?

  Examples that I've seen of like, yeah.

• 37:27Lester Nare?

  No, this is, this is, this is very good stuff. I mean, have you ever, have you ever had a lucid dream before?

• 37:32Krishna Choudhary?

  I've had it once. Yeah, but I haven't, I haven't been able to like, control it, you know?

• 37:37Lester Nare?

  I, I, I had, I want to say twice, but it was only awareness. It was not.

• 37:41Krishna Choudhary?

  Yeah, I wasn't able to like literally be like, I'm gonna fly now.

• 37:44Lester Nare?

  Yeah, yeah.

• 37:44Krishna Choudhary?

  You know, I wish I could do that.

• 37:45Lester Nare?

  If you've ever had a lucid dream before, it is one of the coolest things. It can be obviously very scary, like.

• 37:53Krishna Choudhary?

  Yeah.

• 37:53Lester Nare?

  Like depending on whatever's in your subconscious and stuff like that, but. Um, it is such a fascinating, mind bending thing because it's so bizarre, obviously.

• 38:04Krishna Choudhary?

  Mm hmm.

• 38:05Lester Nare?

  Um, but you're there. It, it, it's, it's like movies like Inception always maybe like, well, like, you know, what is like, do you have an opposite life, an opposite world in your dream that is consistent? Because it just kind of mirrors your own life and has different parameters and relationships that transcend time and stuff like that, but you just don't remember. It, obviously, we will find out soon because now we can incept our dreams.

• 38:28Krishna Choudhary?

  Yeah, no, no, I think this is, I think this is opening up doors for all kinds of really cool research. And there is clinical potential for this, right?

• 38:36Lester Nare?

  Makes sense.

• 38:37Krishna Choudhary?

  For example, if you can do like nighttime neuro prosthetics, that's a new and emerging field.

• 38:42Lester Nare?

  Mm hmm.

• 38:43Krishna Choudhary?

  People who have PTSD, right? PTSD can be modeled as a pathological local minimum.

• 38:48Lester Nare?

  Yep.

• 38:48Krishna Choudhary?

  In some landscape, you, you, it's like a fear network.

• 38:51Lester Nare?

  Yeah.

• 38:51Krishna Choudhary?

  And you're trapped in this local minima, right? And you can't get out. Well, if you do. Targeted memory reactivation during REM sleep and you can cue stuff, you could theoretically restructure traumatic memories.

• 39:05Lester Nare?

  That's a huge deal.

• 39:06Krishna Choudhary?

  To not be traumatic anymore.

• 39:08Lester Nare?

  Yeah, that's a huge deal.

• 39:09Krishna Choudhary?

  Right? That's a huge deal.

• 39:10Lester Nare?

  Yeah, no, I mean, for veterans, for.

• 39:12Krishna Choudhary?

  I was just thinking, yeah.

• 39:13Lester Nare?

  Victims of abuse. I mean, there's a whole swath of people who could majorly benefit.

• 39:18Krishna Choudhary?

  Yeah.

• 39:18Lester Nare?

  From that.

• 39:19Krishna Choudhary?

  Yeah. And of course, with all of this comes the ethical concern.

• 39:23Lester Nare?

  Of course.

• 39:23Krishna Choudhary?

  Right? Because.

• 39:26Krishna Choudhary?

  You're you're you're beating this sensory gate to get into dreams. Now imagine if researchers can cue puzzle solutions. What if like commercial or malicious actors attempt to embed like branded content? Or you know alter preferences, this is I I I get remembered of Tom Hardy's role in Inception as like the defense guy. He was like dream dream a little bigger and he like came up with a giant gun.

• 39:54Lester Nare?

  Yep.

• 39:55Krishna Choudhary?

  Um, it's like it's like so is dream sovereignty gonna now be the premier neuroethical challenge?

• 40:02Lester Nare?

  I mean, this and this might this what's so I didn't even think about this nexus, but while this might sound like, oh, this is early stage research and you know, there's a ways to go, which is true. Uh, if you just look at in the U. S. The recent disclosures around uh, what has been colloquially called Havana syndrome, but is what is also known as anomalous health incidents. There is real legitimate congressional hearings and restitution being provided to veterans who've been victims of what are being called microwave weapon attacks from some foreign actor. There are these diplomats who are it started in Havana, Cuba, which is why it's called Havana syndrome.

• 40:47Lester Nare?

  Where you know what the theory of the case is that there's this sort of small form factor microwave weapon. You point it at the target and it creates all kinds of nausea and you know, neurological issues. Allegedly, the the Director of National Intelligence and some of their people just went to review one of these Havana syndrome weapons recently in order to bring it into the U. S. Inventory. Uh, it's been an issue that the government is very hesitant to discuss or address. I think because it touches on the same uh, neurological sovereignty question that this issue brings up.

• 41:22Krishna Choudhary?

  Yeah.

• 41:23Lester Nare?

  Which is not an area we've really spent a lot of time thinking about, but you know, these technologies are giving us getting us to a place where we can have impact on individuals

• 41:36Lester Nare?

  external to their brain.

• 41:38Krishna Choudhary?

  Yeah.

• 41:38Lester Nare?

  But impacts their brain and that gets

• 41:42Krishna Choudhary?

  Gets tricky.

• 41:42Lester Nare?

  That gets very dicey.

• 41:43Krishna Choudhary?

  Yeah, it gets very, very tricky. It's it's a it's a frontier in neuroscience. I think it's gonna be it's gonna be incredibly. Exciting and a little bit weird.

• 41:54Lester Nare?

  I just want to also briefly note that it, you know, we talk about this is a science show. So we talk about the research and like how it, you know, what the implications are and what people are doing. Just because that's the focus of the show does not mean that we don't identify with and understand the risks and challenges that are related to these in a whole number of different ways and situations. There are a lot of people who spend a lot of time thinking about that area and do content around that. We just try to talk about the science from first principles to give everyone a frame of reference to understand where is technology going and how is it going to impact our everyday life?

• 42:29Krishna Choudhary?

  Yeah. And how does it work?

• 42:30Lester Nare?

  And how does it work? Because we need to know how these things work to know to even have the discussion about neurological sovereignty, which sounds so ridiculous.

• 42:37Krishna Choudhary?

  Yeah.

• 42:38Lester Nare?

  But once you know how it works, you get why that's important to discuss.

• 42:41Krishna Choudhary?

  Yes.

• 42:42Lester Nare?

  But we just don't yet always know how it works. So anyway.

• 42:44Krishna Choudhary?

  Yeah. And I just wanted to end this story on a lighter note.

• 42:47Lester Nare?

  Yes.

• 42:47Krishna Choudhary?

  Um, there's a movie, a little indie film that I was involved in. I was the scientific advisor on this film called Goldmine from a mutual friend of ours. He was the producer, director and writer of the film. It is being distributed on Amazon and other digital platforms, starting February 24th, 2026. I was the um, scientific advisor on the film. Lester was involved in some of the promotion of it. It's about, it's a really nice story about a father-daughter relationship. It involves virtual reality. Getting into the neural landscape of virtual reality, maybe some potential therapeutic advantages of virtual reality in the future.

• 43:30Krishna Choudhary?

  I think you guys should go check it out. It's available on Amazon. Starting pretty soon, I think this, this, this week.

• 43:37Lester Nare?

  Yes, please go watch Goldmine. Big shout out to writer-director Matt Martyr, who was one of the original co-hosts on one of your past podcast endeavors. Dark Matters.

• 43:48Krishna Choudhary?

  Yeah.

• 43:49Lester Nare?

  So friend of the pod.

• 43:50Krishna Choudhary?

  Friend of the pod.

• 43:51Lester Nare?

  Uh, really, really uh, helpful. Anyone is interested. It's fantastic. We went to the premiere. It's definitely worth a watch. So definitely check that out. One of our first friends to make it to streaming.

• 44:02Krishna Choudhary?

  Yeah.

• 44:02Lester Nare?

  Fantastic. Uh, great story. Number one neuroscience story. Dream Engineering.

• 44:09Lester Nare?

  Again, you're not, you're not gonna get these kinda stories anywhere else, folks. It's the best.

• 44:13Krishna Choudhary?

  Yeah, that was crazy, bruh.

• 44:14Lester Nare?

  Of the best, sir. And with that, we will move into our rundown. Again, we cannot cover every breaking science research story every week in the level of detail of our main stories. So we use the rundown as a way to talk about other stories we found fascinating that we wanna share with you all. You can go in and dig in on your own, but we'll just cover them topically a little bit at first. We will not go as long as last week's rundown. We will, we will keep it tight. We got a little bit excited about the AI story. But before we get there, just a couple of housekeeping notes. If you're listening to us on audio, we are a video podcast, both on Spotify and on YouTube. You can watch full episodes. We have a lot of graphics and diagrams.

• 44:59Lester Nare?

  We usually have anywhere from forty to sixty in an episode. And if you're having an issue trying to grok the subjects we're talking about, check out the video podcast version. It's a much more robust way to learn these concepts and have them sink in so we can get it reactivated when we start manipulating your dreams later.

• 45:18Krishna Choudhary?

  Okay.

• 45:18Lester Nare?

  Um, and when you're on said Spotify and YouTube, we are in our fight for our lives in the billionaire algorithm. So a five star on either is super helpful for us to get this show out to more people. Leave a comment if you want to say you have a different idea or you want us to cover something, anything. Put it in the comments.

• 45:40Krishna Choudhary?

  Or even just like random words.

• 45:41Lester Nare?

  Just anything. It's super helpful for us. Uh, share it with a friend. If you're at a research lab, bring it up during your lunch. I know you guys have coffees and lunch and learns we talk about. This is the best show for the science research community, trying to get out to more people. And if you would like to support the show, we have a new donation portal at ffpod.com backslash donate. Become a monthly patron. It helps us run this show, which again is just- The two of us. I'm gonna get better at singing, so I can sing that better. Last note, we do have a new update to the website. We now have chaptering on all of our videos, as well as all of the past both research papers and news articles related to each episode,

• 46:26Lester Nare?

  with a little bit of a more robust research papers page. We are now set up for some of our more fun features we're looking to do in the future. So please go check that out at ffpod.com. Our first story in the rundown is a possible pulsar at the Milky Way Center. This is an astrophysics story. There's a supermassive black hole at the center of our galaxy. What's going on here?

• 46:54Krishna Choudhary?

  Yes, what they're looking for with the supermassive black hole, which is a very famous supermassive black hole. It's the closest supermassive black hole to Earth. It's at the center of our Milky Way galaxy. And we finally found a pulsar, or we think at least, that we found a pulsar near that supermassive black hole, okay? A pulsar is a neutron star that extremely, extremely dense. It's about, you know, neutron stars are like the size of the sun. Sorry, no, I should say this clearly. It is, a neutron star is about the mass of the sun, if not bigger, but it's about the size of a city.

• 47:32Lester Nare?

  Okay.

• 47:33Krishna Choudhary?

  Okay, extremely dense star, where it's called a neutron star because the pressure from gravity is so high that the electrons and the protons fuse together, and it's a giant ball of neutrons. Like, not even atoms can exist at this amount of gravitational pressure, okay? What's cool about pulsars are they are specific types of neutron stars that have a really high spin, and they shoot out radio waves. And the radio waves are like a lighthouse as they're spinning. And pulsars are such that the lighthouse beam is exactly aligned with Earth.

• 48:13Lester Nare?

  Okay.

• 48:13Krishna Choudhary?

  Okay, there's plenty of neutron stars where the lighthouse beam is not aligned with Earth. But for pulsars, we just happen to be lucky enough that the lighthouse beam is aligned with Earth. So when we point our radio dish at that pulsar, we're gonna get beep beep beep beep beep metronomic radio pulses from that point in the sky. Okay, this particular pulsar that they think they found is about eight milliseconds. This is a millisecond pulsar, so every eight milliseconds, this thing is turning around. Imagine that, something the size of the sun, if not bigger, about the size of a city.

• 48:47Lester Nare?

  The mass of the sun and the size of a city.

• 48:48Krishna Choudhary?

  Yeah, sorry, I keep saying that, the mass of the sun, but the size of a city, rotating around, right? And given the conservation of angular momentum, this thing is not slowing down, okay? This thing is gonna keep going at eight milliseconds.

• 49:04Krishna Choudhary?

  That makes this a really nice clock.

• 49:07Lester Nare?

  Right.

• 49:07Krishna Choudhary?

  Okay, and if we find such a really nice clock near the galactic center, where there's a giant black hole that is warping space and time.

• 49:16Lester Nare?

  Yes.

• 49:17Krishna Choudhary?

  We can test Einstein's general relativity to unprecedented degree.

• 49:23Lester Nare?

  Right.

• 49:23Krishna Choudhary?

  That's why everyone's excited about this.

• 49:25Lester Nare?

  Is the idea that the pulsar becomes an instrument in and of itself?

• 49:29Krishna Choudhary?

  Yes, that's exactly right.

• 49:30Lester Nare?

  Yeah.

• 49:31Krishna Choudhary?

  Because a lot of things can happen. The gravitational field of the black hole itself can start influencing the pulsar, right? And maybe if it wobbles a little bit less, or if the timing is delayed, we can test Einstein's prediction that way. On the other hand, the radio signal that's coming from the pulsar is light. And light is itself, you know, affected by space and time.

• 49:56Lester Nare?

  Right.

• 49:57Krishna Choudhary?

  And if there's a lot of warping by that black hole, that light is gonna get affected.

• 50:01Lester Nare?

  Yes.

• 50:01Krishna Choudhary?

  So monitoring this thing over years is going to give us extremely nice test.

• 50:08Krishna Choudhary?

  For Einstein's general theory of relativity. That's why everyone's excited. It's not entirely foolproof, the analysis. And so, you know, there's still more stuff that needs to be done to confirm it.

• 50:19Lester Nare?

  Yes.

• 50:20Krishna Choudhary?

  But it's tantalizingly close. This was out of Columbia University and the Breakthrough Listen Project, which I don't know if you know, that's the like new SETI.

• 50:29Lester Nare?

  Yeah, yeah, yeah.

• 50:30Krishna Choudhary?

  Right? And they have this giant like Breakthrough Listen Galactic Center Survey where they conducted like the most sensitive radio search for pulsars near the galactic center. It was out in the Astrophysical Journal. It's something a lot of astrophysicists are very excited about.

• 50:47Lester Nare?

  That's very, that is very exciting. Again, it's early, as is almost every story we talk about on this podcast. So it goes without saying that we're waiting for continued further analysis, replication, etc.

• 51:00Krishna Choudhary?

  And I think it's gonna be soon. So, you know, when we get a confirmation, maybe we'll do a deep dive into it.

• 51:05Lester Nare?

  This is, this is, this is very exciting. That's actually a huge deal. Uh, that was our story number one, Columbia had Astrophysical Journey. For number two, uh, decoding an ancient Roman board game, an archaeology story about, uh, how AI has now helped us figure out the rules, uh, for this unknown board game from the Roman period.

• 51:27Krishna Choudhary?

  Yeah, this one was pretty cool. Okay, so there's a 2,000 year old limestone slab that was found in the Netherlands. And it was identified as an ancient Roman board game. It was sitting in a museum and some people who are really into board games from antiquity and from like human civilization, saw it and wanted to analyze it. The rules are lost to history, obviously. There's no like, you know, you know, the manual that comes with the board game about what the rules are. Okay, there's nothing that we can do that. But what we can do is look at that slab of limestone and figure out where the wear and tear is. And then we can use AI to play thousands of simulated games with various rules.

• 52:12Lester Nare?

  Right.

• 52:12Krishna Choudhary?

  Right? So an AI plays with itself. This is kind of like how Google DeepMind trained, um, AlphaGo.

• 52:19Lester Nare?

  Yep.

• 52:19Krishna Choudhary?

  You know?

• 52:20Lester Nare?

  Yep.

• 52:20Krishna Choudhary?

  So we've got all of these AIs that are playing thousands of different rules.

• 52:27Krishna Choudhary?

  And from those thousands of different games, tens of thousands of different games, we can figure out which games required the movement of pieces.

• 52:35Lester Nare?

  Right.

• 52:35Krishna Choudhary?

  Such that it would match the wear and tear on the limestone slab. And they figured out about like, I think there were like four, um, four to nine different games. There's, and they're all of a particular type that are still kind of played in Scandinavia. And they match the wear and tear of this thing. And it turns out it's like an asymmetric blockade game. You can actually go and play it. They, they made an online version of it. It's called Ludus Coriovali. It's played with four hounds trying to trap two hares. That's what they called it. Okay. But it's, it's very cool because it's like a use of AI to something that I literally never thought about.

• 53:19Lester Nare?

  Yeah, yeah, yeah, yeah, yeah. And it's a clever, it's a clever use case because you, you have some kind of physical indicator, which is the wear.

• 53:27Krishna Choudhary?

  Yeah.

• 53:27Lester Nare?

  And tear. And ultimately there's a finite number of options for what the rule set was for the game that would result in, especially on a limestone board, that kind of wear and tear. So like makes logical sense, but I never would have.

• 53:39Krishna Choudhary?

  I never would have thought of that. Yeah, yeah. And I mean, it's really cool because this discovery pushes the known history of these types of board games back several centuries now, you know?

• 53:50Lester Nare?

  Fantab, that's a good one.

• 53:51Krishna Choudhary?

  Very cool.

• 53:51Lester Nare?

  Uh, we, we love our archaeology. We've, we've touched on Rome a couple of times.

• 53:55Krishna Choudhary?

  And this is out of Lightning University in the journal Antiquity.

• 53:59Lester Nare?

  Yes, this is good, good, good. We are going to keep it hot with our story number three. This one is a genetics and human evolution story. How we became human might be related to, unsurprisingly, our fingers. But what about this one is particularly interesting?

• 54:16Krishna Choudhary?

  Yeah, this one was really cool because usually when we think about human evolution, we always think about brain size, right? Bigger brain size means we're smarter, means we're more human-like to modern day humans. This new research points to the fact that prenatal hormones. That we are subject to when we are in our mother's womb. That's actually a surprising driving factor to brain size and finger size. The clue lies in 2D to 4D finger ratio, okay? That's the ratio between your ring finger and your index finger, okay? And if you've got a longer index finger, that usually means that you've had higher prenatal estrogen exposure during the first trimester.

• 54:58Krishna Choudhary?

  And that's also related to larger brain size. Boo.

• 55:06Krishna Choudhary?

  For boys and not girls, too. Oh, no, I have a small brain. Now, I think, I think this is an overarching evolution story rather than individual. Fair, fair, fair, fair. You know, because, because I think, I think what they're saying is the effect is something where these two genes are correlated. Okay. Right? Okay. And it's in line with a lot of recent research that shows that there's like this, this thing called the feminization of the skeleton. And this is not like anything political or anything like that. It's not a culture war thing. No, this is not a culture war at all. It's relevant because in human evolution, increases in brain size are found alongside something called the feminization of the skeleton.

• 55:52Krishna Choudhary?

  For example, high values of this 2D to 4D in males, the, the, the ring finger to the index finger. They've been found with elevated rates of heart problems, poor sperm counts, predisposition to schizophrenia in males. I see. Okay, and it seems that this stuff is coming from prenatal hormones, from the fact that we are, we were subjected to estrogen in our first trimester. That led to heightened brain size, but it also led to all of these problems. I see. And in the course of evolution. I guess the human species decided I'll go I'll go with the large brain size, even though it comes with all of these problems.

• 56:34Lester Nare?

  That's that's fascinating. No, that that isn't the I, you know, the I'll let me not I'll leave it.

• 56:42Krishna Choudhary?

  Yeah.

• 56:42Lester Nare?

  I won't let me leave.

• 56:43Krishna Choudhary?

  This is out of the Swansia University and Istanbul University in the journal Early Human Development. I thought it was I thought it was quite interesting because, you know, we always think about how genes are related to each other. When they when they go through revolution. So so this is something that's very important.

• 56:58Lester Nare?

  I mean, you could you can also map this on to the site, you know. When people talk about quote unquote masculinity and the change in body, the body stature of like men generally over time. There's this if there's a correlation to higher brain size equals to the skeletal structure of us being slightly different.

• 57:16Krishna Choudhary?

  Yeah.

• 57:16Lester Nare?

  That is an interesting.

• 57:17Krishna Choudhary?

  That is an interesting angle. Yeah.

• 57:18Lester Nare?

  That like we kind of see manifesting unfortunately in the culture war, but has sort of this genetic basis for it. Fascinating story. Number three, our last story of the rundown combines AI with bioengineering. So no, no risk here at all. A new machine learning pipeline that is streamlining protein engineering. We've talked about AlphaFold, God knows how many times.

• 57:45Krishna Choudhary?

  Yes.

• 57:45Lester Nare?

  We've gotten comments. Yes, we understand it's not perfect. Nothing to talk about on the podcast is perfect.

• 57:51Krishna Choudhary?

  No, this is science.

• 57:52Lester Nare?

  We get that. That being said.

• 57:56Krishna Choudhary?

  That being said, AlphaFold is not everything.

• 57:59Lester Nare?

  Right.

• 58:00Krishna Choudhary?

  Right. AlphaFold means you give me a protein sequence, which is a bunch of amino acids in a line. I'll probably be able to tell you what it looks like in 3D. Okay, and how it changes shape. Okay, what if we wanted to design proteins? If we want to design proteins, the search space is incredibly big. Because if I have 100 amino acids that I want to fit into a protein, there's 20 choices for each amino acid. That's 20 to the hundredth power. There's more atoms in the universe, so I'm not gonna like I I need ways to like hone down if I want to design a new protein. Right? How to actually?

• 58:39Krishna Choudhary?

  Reduce that search space. Right. Okay. Right. So nowadays, what we can do with various techniques is get down to like tens of thousands of protein candidates. If we get down to tens of thousands of protein candidates, the bottleneck then becomes the lab. Right. Because I can only really efficiently build and test around 100 different variants. Right. Of my proteins. So what's the best way to choose which 100 I want to actually test and make in the lab? And then figure out that is what these guys at the University of California at Berkeley and the Arc Institute are doing with this particular story that came out in science. They created something called multi evolve.

• 59:21Krishna Choudhary?

  The idea is they they've created an ensemble of protein language models. And what these protein language models do is not just care about the fitness landscape of like, what is the stuff that evolution constrains me for? These models also care about stuff like, is the enzyme going to catalyze faster? Is the antibody going to bind tighter? Is the CRISPR tool going to edit better? These are things that aren't really captured by evolution. But this particular multi evolve paradigm is actually going to do. And what what's very cool about this is now we've put the lab and the AI in the loop. Right. Okay. Like it's one big loop. Yes.

• 1:00:06Krishna Choudhary?

  Of discovery where the AI is interacting with people in the lab, telling you what to what to do in the lab. The lab is going back to the AI and you can have this iteration happen even faster. Right. And the AI framework was able to accurately predict how proteins will function. Even when several of their amino acids get mutated. Because what you want to do is if you have an amino acid, you want to figure out, oh, if I replace this amino acid with a different one, it's going to make it better or is it going to make it worse? What's more is if I replace these two, is that going to make it better? Because if I just replace this one and it's good and I replace this one and it's good, that doesn't mean if I replace both. Both of them. It's good. There's some synergistic. Yes. Landscape, maybe they're antagonists. Yes.

• 1:00:49Krishna Choudhary?

  Right. And so all of these relationships are now something that I can parameterize with this multi evolve model. Right. And by bioengineers can now develop this new machine learning framework that condenses that problem of protein engineering into a single round of testing.

• 1:01:06Krishna Choudhary?

  And in their test, the model was successfully able to find combinations of mutations that outperformed the original proteins.

• 1:01:14Lester Nare?

  Yep, showing that that having it in the loop like that actually has fundamental

• 1:01:20Lester Nare?

  improvement value.

• 1:01:21Krishna Choudhary?

  Yeah, yeah. And it's very cool because the Ark Institute, which is in Silicon Valley, the whole point of it is to have like frontier AI capabilities and experimental biologists under the same physical roof. That's how they operate and closing that loop between computation and the wet lab.

• 1:01:38Lester Nare?

  Yep.

• 1:01:39Krishna Choudhary?

  This is like their first iteration. It's very exciting to see what they're going to come up with next.

• 1:01:43Lester Nare?

  This is fascinating because this is something similar that, you know, my mom works in clinical trials and there's this similar desire to find ways to incorporate tools like AI into the process to create that feedback, that that virtuous cycle and feedback loop. But you have to start somewhere. And so it's interesting to hear in a variety of these spaces across both fundamental research and application, for example, in pharmaceuticals, that people are finding ways to integrate it. That is changing outcomes.

• 1:02:18Krishna Choudhary?

  Yeah.

• 1:02:18Lester Nare?

  That is influencing.

• 1:02:19Krishna Choudhary?

  Changing, yeah.

• 1:02:20Lester Nare?

  Influencing outcomes for the positive. I get that everyone wants to say it's wrong because they tried it one time and that means that all of it is wrong. But that's just not how it works. It's not perfect, but it is it is filling in gaps that are significantly meaningful.

• 1:02:35Krishna Choudhary?

  Yeah.

• 1:02:36Lester Nare?

  Great rundown this week. I mean, it's going to be the first story, the rundown. These are some.

• 1:02:41Krishna Choudhary?

  This is cool stuff.

• 1:02:42Lester Nare?

  Fantastic stories. We're going to move on to our main story. Number two. This one is a fundamental physics story. It's about trying to measure one of the smallest things in the universe. We've talked about it a lot on this pod, the proton. It's one of the fundamental particles inside the atomic nucleus. And we've done it to super high accuracy.

• 1:03:03Krishna Choudhary?

  Yes, extremely high accuracy.

• 1:03:05Lester Nare?

  This is from the Max Planck Institute for Quantum Optics and it was published in Nature. I'm excited for this one. Let's dig in.

• 1:03:12Krishna Choudhary?

  Yeah, we'll start with the standard model.

• 1:03:15Lester Nare?

  Yes.

• 1:03:15Krishna Choudhary?

  The standard model of particle physics is the most successful model that we have to date about our universe. Okay, it's the model that.

• 1:03:26Krishna Choudhary?

  The working constituents are the fundamental particles, or I should really say the fundamental quantum fields. The Higgs boson comes out of it, the electron. The proton is actually not in the standard model. You have up and down quarks. Those are the constituents of the protons and the neutrons. And it's incredible. It is incredible, but it is incomplete. There's no dark matter. There's no dark energy. And there's no gravity. So we've always been in the search for new physics. How do we break the standard model? So we can find out what is missing? And what is the path forward to find out what is missing?

• 1:04:04Lester Nare?

  This is the idea of like unification, a grand unified.

• 1:04:08Krishna Choudhary?

  Yeah, yeah, not just unification, but also these new particles, like is dark matter a particle?

• 1:04:12Lester Nare?

  I understood, understood.

• 1:04:13Krishna Choudhary?

  That's like not even has anything to do with unifying with gravity. It's like there's just a whole set of other particles that we don't know anything about.

• 1:04:20Lester Nare?

  Most of the universe, we have no idea what it is.

• 1:04:21Krishna Choudhary?

  Yeah, yeah, exactly. So there's got to be a way for us to find out, right? And usually when we think about probing that frontier of particle physics, we think about particle accelerators, right? The most famous one is the one at CERN. The Large Hadron Collider is, you know, tens of kilometers long. They want to build like a giant future collider that's hundreds of kilometers long. They want a lot of money because they want to build these large, large colliders. Higher energy means we can probe the depths of these particles in these fields. But there's another frontier that physicists talk about

• 1:05:04Krishna Choudhary?

  when they're looking to test the standard model, and that is the precision frontier.

• 1:05:09Lester Nare?

  Okay.

• 1:05:10Krishna Choudhary?

  And it might offer an equally vital search for new physics. What you can do is instead of building giant particle colliders, you build extremely precise experiments in your lab, in a room, in a physics department. And you're able to now measure stuff so precisely that perhaps you can discern between what is known physics and what is new. This particular photograph is from the Max Planck Institute.

• 1:05:42Krishna Choudhary?

  And I saw this actually on LinkedIn from the author of the study that we're going to talk about, Lester Meisenbacher.

• 1:05:51Lester Nare?

  Okay.

• 1:05:52Krishna Choudhary?

  He posted this photo of his lab that actually made this measurement of the size of the proton.

• 1:05:57Lester Nare?

  Okay.

• 1:05:58Krishna Choudhary?

  And what it reminds me of is a colloquium that I had attended at UCLA when I was a PhD student there. It was a colloquium given by Dave Demille, who's now at University of Chicago. He used to be at Yale. He was one of these precision physicists, AMO, atomic molecular optical physicists. And he was showing, you know, the lab setup and he was trying to, he was trying to measure the dipole moment of the electron, effectively, how round is the electron? We think the electron is the roundest object in the universe. Okay. But there's a possibility that it's like got a tiny bump on the north pole.

• 1:06:36Lester Nare?

  Okay.

• 1:06:36Krishna Choudhary?

  Right? And the, and the not tiny bump on the south pole. So there, there might be a little bit of not roundedness in the electron. And he wanted to measure that. And what he was showing was, um, he showed a photo of his lab and he would, you know, the, the lab, the, the path of the laser light is, you know, a few meters, things like that. But he would put that as point zero zero one kilometers and he would do a dig at the particle accelerator guys and be like, I'm going to put this, um, in a unit of length that, you know, these particle accelerator guys can understand. So this is about point zero zero one kilometers. Um, the size of my lens is about point zero. And it was just so funny, dude, because, you know, it's just like, he's just like pulling

• 1:07:21Krishna Choudhary?

  their leg.

• 1:07:22Lester Nare?

  That's quite nice.

• 1:07:22Krishna Choudhary?

  I think it, I, it was so funny.

• 1:07:24Lester Nare?

  Look, it's okay to take the piss every once in a while.

• 1:07:26Krishna Choudhary?

  Yeah, yeah, yeah. He, he was a really funny, funny guy, really great speaker as well. So what these guys are trying to do at the Max Planck Institute, when they came out with this landmark nature paper in the February 2026, so just this, this month, is try to solve the proton radius puzzle. Okay? There's been a decade long discrepancy in how big.

• 1:07:52Krishna Choudhary?

  The proton is. Right. Okay. Right. And this particular paper in Nature is trying to put that to rest. Yes. Okay. Subpart per trillion test of the standard model with atomic hydrogen. What a great name. You know, they're testing the standard model. Yes. With just a normal hydrogen atom. Okay. Okay, this is out of the Max Planck Institute for Quantum Optics. Yes. And the precision is 0.7 parts per trillion. That's, that's, that's pretty, that's pretty small. Yeah, that's pretty small. That's pretty small. And I want to give you a sense of just how small that is and why that's like ridiculous. Okay. Okay.

• 1:08:32Krishna Choudhary?

  We're gonna start with the hydrogen atom. Okay. This is our favorite atom, every physicist's favorite atom. If you don't understand the hydrogen atom, there's no hope in understanding anything else. And it's something that we do on our first, first semester of quantum mechanics. You do the Schrodinger equation and you solve the hydrogen atom because it is, because it is the only atom that you can like perfectly solve for. Okay. The idea with quantum mechanics is the following, right? We can never observe the electron. This is something that Heisenberg said when he actually came up with quantum mechanics 100 years ago in 1925. We can never observe the electron moving around a hydrogen atom.

• 1:09:12Krishna Choudhary?

  But we, what we can observe is electrons jumping from one energy state to another energy state. Because that's when light comes out. When we make hydrogen atoms glow, certain colors are emitted by that hydrogen atom. Different atoms emit different colors. And by observing those colors of light, we can discern the structure of the atom inside. That's always the game. Okay. When it comes to quantum optics. Okay? Now, these shells are not just like simple Bohr shells. They're actually very complicated. Okay. The hydrogen wave function looks like very cool clouds. Yes.

• 1:09:57Krishna Choudhary?

  Of electrons around the central proton. This looks like some sick app icons right here. Yeah, but that's actually what the electrons are doing around a hydrogen atom. Okay. If you were to put them in certain orbitals, in certain states of angular momentum and energy, they would occupy those clouds. Those are the probability clouds that the electrons occupy. Okay? Got it. And so.

• 1:10:21Krishna Choudhary?

  What we want to do when we want to probe something like what is the size of the proton?

• 1:10:27Lester Nare?

  Yes.

• 1:10:27Krishna Choudhary?

  Is we want to probe what the colors of light are? And how those colors of light shift when the proton is yay big versus yay big?

• 1:10:37Lester Nare?

  Right, okay.

• 1:10:37Krishna Choudhary?

  Because if the proton is some size or some other size, what that is going to do is change the electron orbitals.

• 1:10:45Lester Nare?

  Right, yup.

• 1:10:46Krishna Choudhary?

  Which will then change the light that comes out.

• 1:10:49Lester Nare?

  Yes.

• 1:10:49Krishna Choudhary?

  When electrons transition from one orbital to the other.

• 1:10:52Lester Nare?

  Yes, yes.

• 1:10:53Krishna Choudhary?

  Is that perfectly clear?

• 1:10:54Lester Nare?

  Yeah, so a different sizes of the proton.

• 1:10:57Krishna Choudhary?

  Mm-hmm.

• 1:10:58Lester Nare?

  Uh, the way in which we can, uh, look at the, the way in which we understand the probabilities of where the electron will be, which is this electron cloud concept, it's going to be fundamentally different.

• 1:11:09Krishna Choudhary?

  Yes.

• 1:11:09Lester Nare?

  And we use, uh, like the, the color spectra, like the, the energy and how it appears like, as a means by which to identify what those cloud configurations will look like.

• 1:11:20Krishna Choudhary?

  Yes, if the proton is a certain size, the cloud will look a tiny bit different.

• 1:11:26Lester Nare?

  Then it-

• 1:11:26Krishna Choudhary?

  Which means that the, um, which means that the, the light that comes out.

• 1:11:31Lester Nare?

  Yes.

• 1:11:31Krishna Choudhary?

  When the electron transitions from one cloud, one energy state to another, is gonna be slightly different frequency.

• 1:11:37Lester Nare?

  Yes.

• 1:11:38Krishna Choudhary?

  And if we can measure that very precisely.

• 1:11:40Lester Nare?

  Yes.

• 1:11:40Krishna Choudhary?

  Then we can tell, back calculate what the size of the proton is.

• 1:11:44Lester Nare?

  I, I, I see what you're saying. And so, okay, yes, makes sense.

• 1:11:48Krishna Choudhary?

  Okay.

• 1:11:48Lester Nare?

  So what, what, what we're getting at is, is we're not measuring the proton.

• 1:11:52Krishna Choudhary?

  Yeah, you're not taking a ruler.

• 1:11:54Lester Nare?

  Right, and looking like, hey, here's the, it's, you know, three angstrom.

• 1:11:58Krishna Choudhary?

  Yeah.

• 1:11:58Lester Nare?

  What we're saying is, there is, there is an emission, uh, which is this electron changing energy states. That emission, if we measure that emission with a level of precision.

• 1:12:12Lester Nare?

  We can derive the size of the proton from that quote, I'm using emission as a loose

• 1:12:17Krishna Choudhary?

  Yes.

• 1:12:18Lester Nare?

  term here.

• 1:12:18Krishna Choudhary?

  Exactly, and if we look at photo number eight, right?

• 1:12:20Lester Nare?

  Yes.

• 1:12:21Krishna Choudhary?

  The electrons are in these different clouds.

• 1:12:24Lester Nare?

  Yes.

• 1:12:25Krishna Choudhary?

  There's, there's different orbitals. For those in chemistry, you guys will remember something called 1S, 1S2, 2S2, 2P6, 3S2, 3P6. It's like a rap game that we use to memorize about all the electron configurations of each of the elements on the periodic table. Each of these orbitals are shapes of the electron clouds. The 1S and the 2S are spherical.

• 1:12:48Lester Nare?

  Mm-hmm.

• 1:12:49Krishna Choudhary?

  Okay, there's no net angular momentum.

• 1:12:51Lester Nare?

  Okay.

• 1:12:51Krishna Choudhary?

  But like the 2Ps, those are when electrons are lobed in particular axes. Like there's the x-axis, the y-axis, and the z-axis, right?

• 1:12:59Lester Nare?

  Yeah.

• 1:13:00Krishna Choudhary?

  And that's that second energy level. The first energy level, there's just the sphere.

• 1:13:03Lester Nare?

  Yes.

• 1:13:04Krishna Choudhary?

  The second energy level, the electron can be in the sphere, or it can be in these like dung bell shapes.

• 1:13:09Lester Nare?

  Yes.

• 1:13:09Krishna Choudhary?

  Along the three axes, right?

• 1:13:11Lester Nare?

  Yes.

• 1:13:11Krishna Choudhary?

  Now, notice, the 1S and the 2S, those are spheres.

• 1:13:15Lester Nare?

  Yes.

• 1:13:15Krishna Choudhary?

  Those will actually interact with the proton if there's a proton in the middle of that sphere.

• 1:13:21Lester Nare?

  Okay.

• 1:13:21Krishna Choudhary?

  Okay? The 2S and the 2P, most of the time, the electron is hanging out on the outside. It's not hanging out near the nucleus of the atom.

• 1:13:30Lester Nare?

  Which in this context is where the XYZ intersects?

• 1:13:33Krishna Choudhary?

  Yeah, the center.

• 1:13:33Lester Nare?

  Yes.

• 1:13:33Krishna Choudhary?

  Right?

• 1:13:34Lester Nare?

  Yes.

• 1:13:34Krishna Choudhary?

  And so, by looking at transitions between these different energies, we can figure out what is the contribution of the proton that's in the center?

• 1:13:43Lester Nare?

  Mm-hmm.

• 1:13:44Krishna Choudhary?

  And what is not?

• 1:13:45Lester Nare?

  Because we're looking at basically the difference.

• 1:13:46Krishna Choudhary?

  Yes.

• 1:13:47Lester Nare?

  Yes.

• 1:13:47Krishna Choudhary?

  Because the difference in these energies tells us what the frequency of the light that will come out. Higher frequency means higher energy difference, okay?

• 1:13:54Lester Nare?

  Mm-hmm.

• 1:13:54Krishna Choudhary?

  But to give you a sense of the scale of what we're talking about, right?

• 1:13:58Lester Nare?

  [laughing]

• 1:13:59Krishna Choudhary?

  Because, because we're, let's not, let's not lose sight of the fact that we're talking about a hydrogen atom, and on top of that, we're talking about a proton at the center of the hydrogen atom.

• 1:14:09Lester Nare?

  Right.

• 1:14:10Krishna Choudhary?

  The proton at the center of the hydrogen atom is measured in femtometers, which is 10 to the minus 15 meters.

• 1:14:18Lester Nare?

  Okay.

• 1:14:18Krishna Choudhary?

  The hydrogen atom itself is about an angstrom, which is 10 to the minus 10. Okay, so there's a, there's a hundred thousand whole difference between the size of a hydrogen atom and the size of a proton at the center of the hydrogen atom. And to visualize this unimaginable scale, I wanted to consider an analogy, okay?

• 1:14:37Lester Nare?

  Okay.

• 1:14:38Krishna Choudhary?

  If a single hydrogen atom is expanded to the size of a professional sports stadium, then the proton that's at its center is like the size of a pea

• 1:14:47Lester Nare?

  Oh my god.

• 1:14:47Krishna Choudhary?

  at the 50 yard line.

• 1:14:48Lester Nare?

  Oh my god.

• 1:14:49Krishna Choudhary?

  That's not, that's not the worst part, though. Okay? In order to discern the size of the pea, we are looking at an electron that is in the grandstand.

• 1:15:00Lester Nare?

  Oh my god.

• 1:15:03Krishna Choudhary?

  You see what I'm saying?

• 1:15:03Lester Nare?

  Yeah, no, that's ridiculous.

• 1:15:04Krishna Choudhary?

  Because the electron is hanging out all the way out here.

• 1:15:06Lester Nare?

  Over there.

• 1:15:07Krishna Choudhary?

  We're looking at the behavior of these electrons that are hanging out at the grandstands to figure out how big is the pea on the 50 yard line?

• 1:15:16Lester Nare?

  I just, I have no, I have nothing. I just don't even, I don't even know what to say.

• 1:15:20Krishna Choudhary?

  It is insane that we can do these kinds of calculations.

• 1:15:23Lester Nare?

  That's what I'm saying. Like, that's, yeah, because I'm trying to even think about how you would do that at macro scale.

• 1:15:28Krishna Choudhary?

  Yeah, yeah, yeah. If I had a pea.

• 1:15:32Lester Nare?

  I can't have a pea.

• 1:15:32Krishna Choudhary?

  What kind of telephoto?

• 1:15:34Lester Nare?

  Yeah, right. What I even?

• 1:15:35Krishna Choudhary?

  Lens, what I need at the, at the grandstand?

• 1:15:38Lester Nare?

  To be able to?

• 1:15:39Krishna Choudhary?

  Yeah.

• 1:15:39Lester Nare?

  Okay.

• 1:15:40Krishna Choudhary?

  Okay.

• 1:15:40Lester Nare?

  So, this is something that is so infinitesimally small. And meaning the way in which we do all, like, the engineering we do to even be able to do this stuff has to be able to operate at these impossibly small

• 1:15:55Krishna Choudhary?

  Yes.

• 1:15:55Lester Nare?

  scales.

• 1:15:56Krishna Choudhary?

  Yeah, and at impossibly small error.

• 1:15:59Lester Nare?

  Right.

• 1:16:00Krishna Choudhary?

  That's the main part.

• 1:16:01Lester Nare?

  Right, right.

• 1:16:02Krishna Choudhary?

  You're chasing down, like, 12 decimal places.

• 1:16:05Lester Nare?

  Right.

• 1:16:06Krishna Choudhary?

  Okay?

• 1:16:06Lester Nare?

  Right. That's a really important, that's a really important point.

• 1:16:08Krishna Choudhary?

  Yeah.

• 1:16:09Lester Nare?

  Because not just like, oh, we got, no, it's like, to, yeah, to a level of specificity where 12 decimals is crazy.

• 1:16:14Krishna Choudhary?

  Which it's insane. It's like, no, it's not that. It's actually this.

• 1:16:18Lester Nare?

  Yeah.

• 1:16:19Krishna Choudhary?

  Okay?

• 1:16:19Lester Nare?

  Oh my god, my brain.

• 1:16:20Krishna Choudhary?

  Yeah, it's, it's, it's absolutely nuts. Okay, so, here, here's how we're gonna do it.

• 1:16:25Lester Nare?

  Okay.

• 1:16:25Krishna Choudhary?

  Okay? We are gonna calculate the transition frequency

• 1:16:28Lester Nare?

  Okay.

• 1:16:29Krishna Choudhary?

  between different

• 1:16:31Krishna Choudhary?

  Orbitals.

• 1:16:32Lester Nare?

  Okay.

• 1:16:32Krishna Choudhary?

  Okay. When we do that, this is the equation of what an electron sees when it's on the outside. This is the binding energy of atomic hydrogen. So what is the energy of an electron that's bound to the proton in the center? What I love about this is this is the first line of their paper. The binding energy of atomic hydrogen can be expressed as

• 1:16:54Krishna Choudhary?

  and it's a giant equation.

• 1:16:55Lester Nare?

  For those listening, there's like, I don't know, 23 different characters.

• 1:16:59Krishna Choudhary?

  Yeah.

• 1:16:59Lester Nare?

  It's just, it is.

• 1:17:01Krishna Choudhary?

  And it depends on, crucially, it depends on two things. Okay. It depends on something called the Rydberg constant, which is like a fundamental energy scale.

• 1:17:08Lester Nare?

  Okay.

• 1:17:08Krishna Choudhary?

  And it depends on the proton charge radius. Okay. Now, those are two different unknowns. Right? And in order to figure out what those two unknowns are, you need two different observations. You can't just rely on one. So you can't just rely on a single atomic energy spacing.

• 1:17:27Lester Nare?

  Yes.

• 1:17:27Krishna Choudhary?

  You need to observe two different transition frequencies.

• 1:17:29Lester Nare?

  I see.

• 1:17:30Krishna Choudhary?

  You need to observe two different colors.

• 1:17:32Lester Nare?

  Yes.

• 1:17:32Krishna Choudhary?

  That are coming out of my atomic hydrogen.

• 1:17:34Lester Nare?

  Okay.

• 1:17:35Krishna Choudhary?

  Okay.

• 1:17:35Lester Nare?

  That makes sense.

• 1:17:35Krishna Choudhary?

  Now, the first one

• 1:17:38Krishna Choudhary?

  is the anchor measurement. That's already been done before. Okay. This is the ultra-precise 1S to 2S transition. What they're doing in this paper is the 6P to 2S transition. The 6P orbital looks like that. It's dumbbells on top of, it's like a Russian nesting doll of dumbbells. Okay. What they're looking for is an electron in this particular energy state going down to the 2S state. Okay. What they want to do here is observe that transition frequency.

• 1:18:05Lester Nare?

  And this from the, the 2S state was the, the larger spherical state that we talked about.

• 1:18:10Krishna Choudhary?

  That we had talked about earlier. This is even bigger than that.

• 1:18:12Lester Nare?

  Okay.

• 1:18:12Krishna Choudhary?

  This is like way out in the grandstands to let's say like on the, on the sidelines.

• 1:18:18Lester Nare?

  Yep.

• 1:18:18Krishna Choudhary?

  Right? The electron is going from the grandstand all the way to like the, the really nice seats.

• 1:18:22Lester Nare?

  Yeah, yeah, yeah.

• 1:18:23Krishna Choudhary?

  And that transition is what they're trying to look for.

• 1:18:26Lester Nare?

  Got it.

• 1:18:26Krishna Choudhary?

  Okay.

• 1:18:27Lester Nare?

  Okay. Yep. Yep.

• 1:18:28Krishna Choudhary?

  Let's talk about why this is even an issue.

• 1:18:31Lester Nare?

  Right. Okay.

• 1:18:32Krishna Choudhary?

  Okay.

• 1:18:33Lester Nare?

  Yeah, yeah.

• 1:18:33Krishna Choudhary?

  Proton size.

• 1:18:34Lester Nare?

  Right. Because, because part of, uh, part of what I said earlier, which may or may not be true. It's like, you know, why do, why can't we just measure it directly?

• 1:18:44Krishna Choudhary?

  Yeah, well, I mean, how would you measure something that is a femtometer?

• 1:18:49Lester Nare?

  Right, but so like for someone who might not understand the scale of the problem set. It's like, well, why don't you just look at it?

• 1:18:55Krishna Choudhary?

  Yeah.

• 1:18:56Lester Nare?

  And it's like, well, the problem is you it's it's what are we gonna use to do that?

• 1:19:00Krishna Choudhary?

  Exactly. I mean, I mean, you could think, right? Like, what if we just like set light?

• 1:19:04Lester Nare?

  Okay.

• 1:19:05Krishna Choudhary?

  Okay, what if we just had like um light at a femtometer? How I think I think that kind of light is extremely high frequency.

• 1:19:15Lester Nare?

  Okay.

• 1:19:15Krishna Choudhary?

  Okay, like a light at a wavelength of a femtometer.

• 1:19:18Lester Nare?

  Yeah.

• 1:19:18Krishna Choudhary?

  Anything, anything larger than the obstacle? If I were to shine like visible light.

• 1:19:24Lester Nare?

  Yes.

• 1:19:24Krishna Choudhary?

  Which is like 400 nanometers.

• 1:19:26Lester Nare?

  Right.

• 1:19:27Krishna Choudhary?

  On something that is a femtometer nano 400 nanometers is 10 to the minus seven meters.

• 1:19:32Lester Nare?

  Yeah.

• 1:19:32Krishna Choudhary?

  This thing is 10 to the minus 15.

• 1:19:34Lester Nare?

  Right.

• 1:19:34Krishna Choudhary?

  Imagine a giant ocean wave.

• 1:19:36Lester Nare?

  Yeah.

• 1:19:37Krishna Choudhary?

  And then there's a pebble in the way.

• 1:19:38Lester Nare?

  Okay.

• 1:19:39Krishna Choudhary?

  Is the ocean wave gonna care?

• 1:19:40Lester Nare?

  No.

• 1:19:41Krishna Choudhary?

  No.

• 1:19:41Lester Nare?

  No.

• 1:19:41Krishna Choudhary?

  Right? The way we image things is that the the wavelength of light needs to be way smaller than the thing we're measuring. Because then the light bends and like refracts and like bounces off.

• 1:19:51Lester Nare?

  This is important.

• 1:19:52Krishna Choudhary?

  But if it's like the, you know.

• 1:19:54Lester Nare?

  The the object we're trying to measure is literally half the size of the wavelength of light we would send at it to even measure it.

• 1:20:02Krishna Choudhary?

  Yeah, not even half. No, it's it's it's a 10, 100,000th.

• 1:20:05Lester Nare?

  100,000.

• 1:20:06Krishna Choudhary?

  Or a millionth the size. So it literally is. It's a pebble.

• 1:20:09Lester Nare?

  With a tsunami.

• 1:20:10Krishna Choudhary?

  Like, no, a grain of sand versus like the Nazare.

• 1:20:15Lester Nare?

  Yeah.

• 1:20:16Krishna Choudhary?

  You know, the Portugal wave.

• 1:20:17Lester Nare?

  Yeah, yeah, yeah, the 100 foot wave in Nazare, Portugal.

• 1:20:19Krishna Choudhary?

  Yeah, Nazare, Portugal.

• 1:20:21Lester Nare?

  Yeah, yeah.

• 1:20:21Krishna Choudhary?

  Do you think the Nazare, Portugal wave cares about a tiny bit of grain of sand?

• 1:20:26Lester Nare?

  Yeah.

• 1:20:27Krishna Choudhary?

  Misplaced one way or the other?

• 1:20:28Lester Nare?

  Right, right.

• 1:20:29Krishna Choudhary?

  It really doesn't.

• 1:20:29Lester Nare?

  Right.

• 1:20:30Krishna Choudhary?

  So we gotta get really clever.

• 1:20:31Lester Nare?

  Right.

• 1:20:31Krishna Choudhary?

  With this kind of stuff.

• 1:20:32Lester Nare?

  So we can't just image it the way we normally do optical imaging.

• 1:20:36Krishna Choudhary?

  No.

• 1:20:36Lester Nare?

  It's just the scale is not, uh, it just, it doesn't even make sense.

• 1:20:39Krishna Choudhary?

  It doesn't even make sense. Yeah, exactly.

• 1:20:41Lester Nare?

  Okay.

• 1:20:41Krishna Choudhary?

  And so people have done it before. People have measured the the size of a proton before.

• 1:20:46Lester Nare?

  Yes.

• 1:20:46Krishna Choudhary?

  And it came out to about 0.8758 according to this giant consortium where where they they had like um. That would scatter off nuclei. And then they would try to figure out, okay, like, what is the, what is the size of the proton in there? They also had something called electronic hydrogen spectroscopy. It's a traditional laser measurement. Kind of similar, but like not as like insane as the one that we're going to talk about. And they got it to about zero point eight seven five eight femtometers. Then in twenty ten, there was a bombshell. Because some of the same guys in this current paper. Made an exotic hydrogen atom. They made a hydrogen atom out of muons.

• 1:21:28Krishna Choudhary?

  And they published a paper in Nature called The Size of the Proton.

• 1:21:32Lester Nare?

  This, this was fifty, sixteen, almost sixteen years ago.

• 1:21:36Krishna Choudhary?

  Sixteen years ago, these guys published a hydrogen atom where instead of an electron moving around it. They've got a muon that moves around it. A muon is the close cousin of the electron, but it's two hundred times more massive. And because it's two hundred time more, it's two hundred times more massive. The atom that you create with a proton and a muon is going to be two hundred times smaller. And we've got a little sort of like thing to show for that, right? The atom is going to be, the muonic hydrogen is going to be two hundred times smaller. If it's two hundred times smaller, that muon, effectively what we've done is take that giant stadium. And turn it into like, you know, a high, a high school stadium.

• 1:22:20Krishna Choudhary?

  Now, the, the relationship between my muon and the proton is going to be a lot closer. And my error bar is going to be smaller.

• 1:22:28Lester Nare?

  The, the, the measurement we're trying to make is the distance between the electron and the grandstands and the proton at the fifty yard line.

• 1:22:34Krishna Choudhary?

  Yeah, effectively, we're, we're trying to get like the light that comes out of this atom. The smaller the atom is. Like, the more we can sort of nail down exactly what that frequency is.

• 1:22:45Lester Nare?

  Right, the, the, the, the delta for error is much smaller.

• 1:22:49Krishna Choudhary?

  Yeah, because we've effectively make, made the atom smaller.

• 1:22:52Lester Nare?

  And this, the, the, the key idea here was the muon as the orbiting. Uh, as opposed to a standard electron.

• 1:23:00Krishna Choudhary?

  Mm hmm.

• 1:23:01Lester Nare?

  It was much more massive, which meant the proton necessarily need to be smaller, which is what

• 1:23:05Krishna Choudhary?

  The atom needs to be small.

• 1:23:06Lester Nare?

  Excuse me.

• 1:23:06Krishna Choudhary?

  Yeah.

• 1:23:07Lester Nare?

  The atom needs to be smaller, which is what collapsed the surface area of the measurement to be this.

• 1:23:11Krishna Choudhary?

  Exactly.

• 1:23:12Lester Nare?

  More deal withable.

• 1:23:14Krishna Choudhary?

  Yes.

• 1:23:14Lester Nare?

  Size.

• 1:23:15Krishna Choudhary?

  Yes. And we got a whole new number for the size of the proton there. 0.84 instead of 0.87.

• 1:23:22Lester Nare?

  Okay.

• 1:23:22Krishna Choudhary?

  Already on the second significant figure, we're off.

• 1:23:27Lester Nare?

  Okay.

• 1:23:27Krishna Choudhary?

  That is, that is unheard of for physicists. Who are doing precision measurement. They're like, this is, this is absolutely awful.

• 1:23:34Lester Nare?

  Okay.

• 1:23:34Krishna Choudhary?

  Okay.

• 1:23:35Lester Nare?

  Okay.

• 1:23:35Krishna Choudhary?

  That's like a almost, um, that's almost 5% difference.

• 1:23:40Lester Nare?

  Yeah, well, that's unacceptable.

• 1:23:41Krishna Choudhary?

  That's unacceptable. Okay. In every sense of the word. There's two, there's two possibilities.

• 1:23:48Lester Nare?

  Okay.

• 1:23:48Krishna Choudhary?

  Okay. Either our theory is wrong, meaning leptons are not universal. We used to think that the muon and the electron, the only thing that's different between them is the mass.

• 1:23:58Lester Nare?

  Mm hmm.

• 1:23:58Krishna Choudhary?

  But what if there's new physics?

• 1:24:00Lester Nare?

  Mm hmm.

• 1:24:00Krishna Choudhary?

  And the muon is actually behaving differently around my proton, which is why I'm getting this different measurement.

• 1:24:06Lester Nare?

  Okay.

• 1:24:07Krishna Choudhary?

  Yeah. Either that, or.

• 1:24:08Lester Nare?

  Okay.

• 1:24:09Krishna Choudhary?

  There's some undetected systematic error in the earlier measurement of the electron hydrogen.

• 1:24:15Lester Nare?

  Basically, the first time we did it, something was wrong.

• 1:24:17Krishna Choudhary?

  Something was wrong.

• 1:24:18Lester Nare?

  No, no one caught it at the time.

• 1:24:19Krishna Choudhary?

  Yeah.

• 1:24:19Lester Nare?

  But now we get it.

• 1:24:20Krishna Choudhary?

  Or there's literal new physics.

• 1:24:22Lester Nare?

  Right. It's one of the two.

• 1:24:23Krishna Choudhary?

  It's one of the two. And now you can see why this is such a big deal.

• 1:24:25Lester Nare?

  Yeah.

• 1:24:26Krishna Choudhary?

  We need to really figure out if that first measurement was, was actually wrong.

• 1:24:30Lester Nare?

  Correct. Cause that's, that's actually a, a, okay. Yes.

• 1:24:32Krishna Choudhary?

  Right?

• 1:24:33Lester Nare?

  That would be a big deal.

• 1:24:34Krishna Choudhary?

  That would be a big deal because if the first measurement was correct, then this is a really big deal. Because then that means there is actually new physics. The muon and the electron are actually different somehow.

• 1:24:44Lester Nare?

  Yes.

• 1:24:44Krishna Choudhary?

  And there's like, now the theorists are super happy.

• 1:24:46Lester Nare?

  Yeah.

• 1:24:47Krishna Choudhary?

  Right?

• 1:24:47Lester Nare?

  Right?

• 1:24:48Krishna Choudhary?

  Or the experimentalists are not happy.

• 1:24:51Lester Nare?

  Yeah.

• 1:24:51Krishna Choudhary?

  And these new experimentalists are happy because they, like their muonic hydrogen measurement was actually correct.

• 1:24:57Lester Nare?

  Yes.

• 1:24:58Krishna Choudhary?

  And it's like everybody else.

• 1:24:59Lester Nare?

  Now theorists, go back to the chalkboard.

• 1:25:01Krishna Choudhary?

  Yeah, yeah. It's not, it's not a field day for you guys, right? And so that's where this current experiment comes in. Oh, this is fascinating. Okay, they replicated that muon experiment. Okay, from from 2010. From 2010, they've been working on it for 10 years to try and nail down this measurement using just normal store grade hydrogen. Okay. Okay, and it's incredibly difficult. This is going back to our bigger stadium instead of our muon smaller. Now, we're trying to do the same thing. Yes. But with our bigger stadium and with a bigger stadium, there's a lot more problems. Yes, yes, okay. And it's just incredible. Some of the stuff that they were dealing with, dude. It's it's actually insane. Okay.

• 1:25:43Krishna Choudhary?

  The the transition that they were trying to figure out was the six P orbital to two S. So all the way up there to like down here, there's that transition. That transition releases violet light at 410 nanometers. Okay. That's the first issue. Okay. Violet light at 410 nanometers, that's really short wavelength. We've got lasers at like blue and green and red. We don't have lasers in violet. Okay. You can't just buy that off the shelf. You gotta make a laser at 410 nanometers. Okay. Okay. Okay. So that's something that they had to do.

• 1:26:22Krishna Choudhary?

  They actually took like a titanium sapphire laser, which operates at the infrared at 820 nanometers. And they effectively did like a trick where they stuck that inside a nonlinear optical crystal. And what this crystal did was you know how when you like play guitar? And you like strum on one of the strings. But then if you like clamp down in the middle, then you're gonna get the octave higher. Yes. Right? That's what this crystal is doing. Okay. It takes in a laser light at 820 nanometers, but then effectively squishes the wavelength by by half.

• 1:27:00Krishna Choudhary?

  So the frequency goes up by two and then I get a 410 nanometer.

• 1:27:03Lester Nare?

  For music producers who use keyboards, it's the jog wheel on the left is the same idea when you jog the wheel up.

• 1:27:10Krishna Choudhary?

  Yeah, the octave just goes up. This is just like, it's going from, you know, a C to the, uh, the C that's the do do.

• 1:27:17Lester Nare?

  Yeah.

• 1:27:17Krishna Choudhary?

  You know, it's just the octave is, is now up.

• 1:27:20Lester Nare?

  Yes.

• 1:27:20Krishna Choudhary?

  Okay.

• 1:27:20Lester Nare?

  Makes sense.

• 1:27:21Krishna Choudhary?

  So now we've got a laser.

• 1:27:23Lester Nare?

  Right.

• 1:27:24Krishna Choudhary?

  Now we've got to cool our hydrogen atoms down to five Kelvin.

• 1:27:27Lester Nare?

  Trivial, you know.

• 1:27:28Krishna Choudhary?

  Trivial. Honestly, at this rate, this is, this is pretty trivial. Okay, cooling them down to five Kelvin, but even at five Kelvin, these hydrogen atoms in your cloud of hydrogen atoms that you're trying to like, probe, those hydrogen atoms are moving at hundreds of meters per second. Which means there's going to be some moving towards you, some moving away from you. So there's going to be Doppler shifting, right?

• 1:27:49Lester Nare?

  Yes.

• 1:27:50Krishna Choudhary?

  And so if you're trying to measure the frequency of light.

• 1:27:53Lester Nare?

  Yes.

• 1:27:53Krishna Choudhary?

  Well, the guys that are coming towards you, they're going to be sensitive to shorter wavelengths. The guys that are going away from you are going to be sensitive to the longer wavelengths.

• 1:28:02Lester Nare?

  Yes.

• 1:28:02Krishna Choudhary?

  And so you're going to have a Doppler broadening of your transition line. And the whole point is I really need to measure.

• 1:28:07Lester Nare?

  Right.

• 1:28:07Krishna Choudhary?

  What frequency this transition line is at.

• 1:28:10Lester Nare?

  Yes.

• 1:28:10Krishna Choudhary?

  Okay.

• 1:28:10Lester Nare?

  Yes.

• 1:28:11Krishna Choudhary?

  So that's going to be a huge problem.

• 1:28:12Lester Nare?

  We, we don't want a range, we want an explicit.

• 1:28:15Krishna Choudhary?

  Yeah. I want like, this is the frequency.

• 1:28:18Lester Nare?

  Yes.

• 1:28:18Krishna Choudhary?

  Right?

• 1:28:19Lester Nare?

  Yes.

• 1:28:19Krishna Choudhary?

  And so here's what they, uh, very cool. What they did was Doppler free, one photon spectroscopy. Effectively, the idea is they custom built like these active fiber based retro reflectors.

• 1:28:31Lester Nare?

  Mm hmm.

• 1:28:31Krishna Choudhary?

  Okay. And what it's going to do is it's going to fire a laser at the atoms. The atoms are going to capture it and then it's going to ref- and then the atoms come back. It's going to reflect that perfectly back into the atoms.

• 1:28:44Lester Nare?

  Mm hmm.

• 1:28:44Krishna Choudhary?

  Okay. The other thing that you want is you want this beam to be perfectly straight.

• 1:28:48Lester Nare?

  Mm hmm.

• 1:28:49Krishna Choudhary?

  The beam of the lasers, it can't be like spreading out as it goes into my apparatus. And the usual optics that's built for 486 nanometer wavelengths, which is blue green.

• 1:29:01Lester Nare?

  Mm hmm.

• 1:29:01Krishna Choudhary?

  You can buy that like kind of off the shelf.

• 1:29:03Lester Nare?

  Okay.

• 1:29:04Krishna Choudhary?

  There's like specialized science companies.

• 1:29:06Lester Nare?

  Sure.

• 1:29:06Krishna Choudhary?

  Where you can buy that stuff.

• 1:29:07Lester Nare?

  Sure.

• 1:29:08Krishna Choudhary?

  If it works for 486, it's not going to work for 410. Okay, at that, at that like frequency, like it's, it's the opposite of diminishing returns. Like every nanometer is a headache. So you need to build custom optics such that my beam is like completely straight.

• 1:29:25Lester Nare?

  My new purple laser that we also had to custom make.

• 1:29:28Krishna Choudhary?

  Yes.

• 1:29:28Lester Nare?

  We have to keep it in line. And so we need these custom, like literally like optics, glass lenses that keep it in a line.

• 1:29:37Krishna Choudhary?

  Yeah.

• 1:29:37Lester Nare?

  And because it's a frequency where most optics are not built for it, that purple laser.

• 1:29:42Krishna Choudhary?

  Yeah.

• 1:29:43Lester Nare?

  It's fully, it has to be fully.

• 1:29:44Krishna Choudhary?

  Yeah, yeah. So the whole thing is like a custom apparatus, right?

• 1:29:47Lester Nare?

  We love it.

• 1:29:47Krishna Choudhary?

  And then, and then on top of that, there's like the quantum hurdle, which is you're, you're, you're putting in light in here, right? And the light is like bouncing back because of the earlier thing that I said.

• 1:29:58Lester Nare?

  Yes.

• 1:29:58Krishna Choudhary?

  Well, if the light is going there and bouncing back, now you've created a standing wave. Same thing with the guitar. When you like pluck a string, it's fastened at both ends. So the wave is going to go back and forth. It's going to create a standing wave, right? There's going to be nodes and anti nodes.

• 1:30:12Lester Nare?

  Yes.

• 1:30:12Krishna Choudhary?

  Nodes are going to be where the light piles up.

• 1:30:14Lester Nare?

  Yep.

• 1:30:15Krishna Choudhary?

  Anti nodes are going to be where there's nothing.

• 1:30:16Lester Nare?

  Yes.

• 1:30:17Krishna Choudhary?

  Now, usually you don't care.

• 1:30:19Lester Nare?

  Yes.

• 1:30:19Krishna Choudhary?

  But when we're doing a precision measurement where we've put hydrogen into the six P state, the electron orbital is a little bit like, it's not spherical.

• 1:30:28Lester Nare?

  Right.

• 1:30:29Krishna Choudhary?

  Right?

• 1:30:29Lester Nare?

  Right.

• 1:30:29Krishna Choudhary?

  And so because it's got these nodes, that electron is going to start caring about where the anti nodes and the nodes are. Because the electric field is going to be higher here, lower here, higher here. And so the, the hydrogen atom that you're trying to understand is now getting perturbed by the system itself.

• 1:30:46Lester Nare?

  Right.

• 1:30:46Krishna Choudhary?

  And so they had to make so many like Monte Carlo supercomputer simulations to model, what would the electron do?

• 1:30:54Lester Nare?

  Right.

• 1:30:54Krishna Choudhary?

  In this space.

• 1:30:56Lester Nare?

  Yes.

• 1:30:56Krishna Choudhary?

  And, and then correct for that.

• 1:31:00Lester Nare?

  Right, right. Because, because it.

• 1:31:03Krishna Choudhary?

  There's so much headache, which is why this took like 10 years.

• 1:31:06Lester Nare?

  That that makes sense. It's it's effectively you have to remove the noise.

• 1:31:11Krishna Choudhary?

  Yeah, it's called the Stark shift.

• 1:31:13Lester Nare?

  Okay, okay, right. And in order to do that, you kind of have to you have to simulate first.

• 1:31:19Krishna Choudhary?

  Yeah.

• 1:31:19Lester Nare?

  Because it's too expensive to do it experimentally all these.

• 1:31:22Krishna Choudhary?

  No, but yeah, it's like, well, it's like the experiment has this artifact.

• 1:31:25Lester Nare?

  In it, in it, so you.

• 1:31:26Krishna Choudhary?

  In itself.

• 1:31:27Lester Nare?

  I got you. You need you need. It's like um, it's like when you have a Google Photos and it's the feature where you take a photo of you and your loved one in a crowd. And then they have the Google Magic Eraser and you just select someone's head behind your head and then it's gone.

• 1:31:40Krishna Choudhary?

  And you shoot up. That's exactly what they do. Okay, right. But but they need to build it and like do the Monte Carlo simulation completely.

• 1:31:48Lester Nare?

  In order to then be able to even have the thingy that will remove the noise.

• 1:31:51Krishna Choudhary?

  Yes.

• 1:31:52Lester Nare?

  So they have to.

• 1:31:54Krishna Choudhary?

  It's nuts.

• 1:31:55Lester Nare?

  People, I love the I love the uh, the just the drive to not be beaten.

• 1:32:03Krishna Choudhary?

  Yeah.

• 1:32:03Lester Nare?

  By Mother Nature.

• 1:32:04Krishna Choudhary?

  Yeah. I will figure out what the size of the proton is. You are not going to stop me. Okay, it might take me 10 years, but I want to know how big the proton is.

• 1:32:18Lester Nare?

  That's so good. Okay, that makes sense.

• 1:32:19Krishna Choudhary?

  Yeah, it's it's absolutely nuts. And finally, after all of this, they publish their measurement.

• 1:32:27Krishna Choudhary?

  They publish their measurement.

• 1:32:28Lester Nare?

  Okay.

• 1:32:29Krishna Choudhary?

  The blue little starfighter that you see there.

• 1:32:33Lester Nare?

  Yeah, in the middle.

• 1:32:34Krishna Choudhary?

  In the middle.

• 1:32:35Lester Nare?

  Yeah.

• 1:32:35Krishna Choudhary?

  That is their measurement, 0.84.

• 1:32:39Lester Nare?

  Okay.

• 1:32:40Krishna Choudhary?

  One.

• 1:32:40Lester Nare?

  Okay.

• 1:32:41Krishna Choudhary?

  It is in line with their muon measurement that they took 16 years ago.

• 1:32:47Lester Nare?

  So the point 87, I think it was.

• 1:32:49Krishna Choudhary?

  The 0.87.

• 1:32:51Lester Nare?

  Yeah, yeah.

• 1:32:51Krishna Choudhary?

  That's all these other.

• 1:32:53Lester Nare?

  Things over to the right.

• 1:32:54Krishna Choudhary?

  Yeah.

• 1:32:56Krishna Choudhary?

  That is wrong.

• 1:32:57Lester Nare?

  You are the weakest link. Goodbye.

• 1:32:59Krishna Choudhary?

  Yeah, yeah. So so they corroborated that measurement. The muonic hydrogen is the same as the normal hydrogen. The true size of the proton is 0.84. And there is no new physics, at least in terms of the difference between the muon and the electron. They are indeed the same up to this. Significance.

• 1:33:19Lester Nare?

  Mm hmm.

• 1:33:21Krishna Choudhary?

  For all intents and purposes, the only thing that is different between the muon and the electron is their mass.

• 1:33:25Lester Nare?

  Is the mass.

• 1:33:26Krishna Choudhary?

  That's it.

• 1:33:27Lester Nare?

  That's it. And what this also means then is that the theorists have to go back to the wood shop.

• 1:33:32Krishna Choudhary?

  Yeah.

• 1:33:32Lester Nare?

  Woodshed.

• 1:33:33Krishna Choudhary?

  Yeah.

• 1:33:33Lester Nare?

  And work on it.

• 1:33:34Krishna Choudhary?

  Yeah, they're gonna, they, they need to figure out what else to try.

• 1:33:37Lester Nare?

  Right, right, right.

• 1:33:38Krishna Choudhary?

  Because they were, they were, I, I bet you there were tons of theorists that were really hoping

• 1:33:42Lester Nare?

  That this was.

• 1:33:43Krishna Choudhary?

  That this measurement was not going to fall within that error bar.

• 1:33:46Lester Nare?

  Yeah, yeah.

• 1:33:46Krishna Choudhary?

  Right?

• 1:33:47Lester Nare?

  Yeah.

• 1:33:47Krishna Choudhary?

  That, that, that the muon was gonna be here, the electron was gonna be here, and they'd be like, oh, I, I got a theory for why they're different. Turns out they're not.

• 1:33:55Lester Nare?

  This is, okay, this is actually a really great story around understanding the refinement that goes through the scientific process on something like the size of a proton, like why it's incredibly difficult.

• 1:34:07Krishna Choudhary?

  Yeah.

• 1:34:08Lester Nare?

  Uh, like fundamentally, because it's so small, like, we can't just image it the way we normally would.

• 1:34:13Krishna Choudhary?

  Yeah.

• 1:34:13Lester Nare?

  And so we have to go through this process of understanding, like, how these things interact. Because how they interact creates these derivative variables that we can measure.

• 1:34:26Krishna Choudhary?

  Exactly.

• 1:34:26Lester Nare?

  That electron piece that we just talked about. And then you can sort of now back calculate what you're looking for, because you actually have a strong understanding of these other uh, aspects of physics and the relationship between these different moving parts. And again, this tension between theory and experiment, uh, uh, and the back and forth and sort of, it's, it's sort of like a, it's sort of like a this, it's like a dance.

• 1:34:55Krishna Choudhary?

  Yeah.

• 1:34:56Lester Nare?

  Uh, where both influence and, and counter argue each other at different periods in time. However, the theorists did not win this one.

• 1:35:05Krishna Choudhary?

  No.

• 1:35:05Lester Nare?

  Um, I'm sorry, I'm sorry to say.

• 1:35:07Krishna Choudhary?

  Yeah.

• 1:35:07Lester Nare?

  Uh, maybe next time.

• 1:35:09Krishna Choudhary?

  Maybe next time, probably not.

• 1:35:10Lester Nare?

  I mean, maybe, is this why they're always looking at string theory? Because then they, the experimentalists can't.

• 1:35:14Krishna Choudhary?

  Yeah, because on string theory, they're just like, oh, well, you, I need like 10 more decimals.

• 1:35:20Lester Nare?

  And then just keep going. Let's keep going.

• 1:35:23Krishna Choudhary?

  To, to really validate my theory or not. But, like, jokes aside, I mean, you know, it seems like a relatively boring thing to talk about, just the size of the proton. But the techniques and the, the fact that this closed that door.

• 1:35:39Lester Nare?

  Right.

• 1:35:40Krishna Choudhary?

  On there being some new physics. We don't have to think about that anymore.

• 1:35:45Lester Nare?

  Right, right, right.

• 1:35:45Krishna Choudhary?

  Right? Like lepton universality is a thing. The muon and the electron are the same, except for mass.

• 1:35:51Lester Nare?

  Yes.

• 1:35:51Krishna Choudhary?

  Now, we can worry about other stuff.

• 1:35:53Lester Nare?

  Yes.

• 1:35:53Krishna Choudhary?

  Right? We can put constraints on exotic particles. Like, there's zero anomalous deviation from quantum electrodynamics rules. Right? So, like, a bunch of other stuff about dark matter. Like, oh, there's this dark sector that maybe does this. Well, if that particular way of thinking about dark matter has a different measurement, it's wrong.

• 1:36:14Lester Nare?

  Right, right.

• 1:36:15Krishna Choudhary?

  Falsifiability is everything when it comes to physics, right?

• 1:36:18Lester Nare?

  That's actually, I didn't think about that. What you're saying is, uh, this experimental result can now inform research areas that are not about, uh, like, measurements of these subatomic particles and things like that. But there's overlap, conceptually or architecturally, that if you were basing your dark matter model off of the original .087

• 1:36:43Krishna Choudhary?

  Yeah.

• 1:36:44Lester Nare?

  theoretical framework. Sorry.

• 1:36:46Krishna Choudhary?

  Sorry. Yeah.

• 1:36:51Lester Nare?

  Gotta love science. That's a good, that is a very good, very technical story.

• 1:36:54Krishna Choudhary?

  Yeah.

• 1:36:55Lester Nare?

  Um, but really, again, the, the, the fun to me is in the journey and the process.

• 1:37:02Krishna Choudhary?

  Yeah.

• 1:37:02Lester Nare?

  Um, not simply the results. Like you said, the result, okay, the size of the proton, great.

• 1:37:06Krishna Choudhary?

  Yeah.

• 1:37:07Lester Nare?

  Um, but all of those new techniques, again, also are not isolated to just this specific research question. Uh, fantastic. That was, uh, the sort of physics story on the proton size. We have this out of Max Planck Institute, and it was in, uh, quantum opt, uh, for quantum optics in nature. Uh, I, as, I, I'll ask you questions.

• 1:37:29Krishna Choudhary?

  I really liked that one.

• 1:37:30Lester Nare?

  I'll ask you questions off-air about that one, because there's, there's a couple more I have. We are going to go ahead and move into our last story, which is a medicine story about ALS. Um, it's been in the news recently, um, because of the

• 1:37:48Lester Nare?

  Recent death of Eric Dane. Many of you have maybe saw the Netflix documentary that came out. For those who may not know, Eric Dane is quite a famous and popular actor and father and husband. He was Dr. McSteamy in Grey's Anatomy. And he, while having been diagnosed with LAS, I think it was just over 10 months ago. Excuse me. When he had found out about his diagnosis, he was just wrapping up the shooting of season three of Euphoria.

• 1:38:25Lester Nare?

  Unfortunately, accelerated quite quickly. And so we just wanted to, you know, take this opportunity to, I think, cover, you know, what is the latest in the fight against ALS? Understanding it a little bit. And then we'll end with a funding piece that's related to this research area. So, you know, we know it's something that a lot of folks have been not only talking about, but have been personally impacted by because of the way in which Eric communicated. Just his, you know, worldview, his, what it's like to be a father, his message to his kids, the stories that he had to tell about life, I think, really resonated with a lot of people.

• 1:39:10Lester Nare?

  And so with that, we're going to kind of sort of look at the current landscape.

• 1:39:16Krishna Choudhary?

  Yes, I wanted to take this opportunity to talk about ALS, the disease. And one particular scientific paper that came out last year that is just, you know, one of the latest in a series of breakthroughs. Obviously, it's still very much a crisis in medicine. Amyotrophic lateral sclerosis, okay? It's a catastrophic motor neuron degradation that happens with motor neurons specifically. These are the neurons that relay signals to our muscles in order to have them contract.

• 1:39:55Krishna Choudhary?

  ALS in its most advanced phase gets so bad that even the contraction of the muscles like the diaphragm that allow you to breathe because everything, every, every bit of movement in our body is from muscular contraction, right? And like even the, the, the act of breathing becomes something that the brain cannot sustain because these motor neurons have degraded so much. The survival is really quite bad. 2.3 to five years post diagnosis is on average. One of the most famous cases is Stephen Hawking. He survived for like 50 years, but it's extremely rare to do that. Um, you know, now he's no longer the scientific hero that we, that he once was, but he's, he's

• 1:40:40Krishna Choudhary?

  one of these like rare, rare cases. Um, annual patient care is about 250,000 plus. That's so crazy. Per patient, right? And the current incidence, it's about one to two per hundred thousand. Um, by 2040, there's approximately going to be a 25% increase in the global prevalence. And if we talk about like, there's, there's really two types of ALS. There's familial ALS, which comes from genetic mutations that you inherit from your family. That's only about 10% of cases. 90% of cases are sporadic ALS.

• 1:41:19Krishna Choudhary?

  There's all these polygenetic landscapes in our genome that causes sporadic ALS and that happens just, there's no, there's no familial history of it. You know, you didn't carry a mutation from your parents. It just happened. So let's get into like, what exactly is going on? Right. Okay. In our nervous system when ALS happens. So ALS, as I, as I described, it's motor neurons, right? Yes. Motor neurons are extreme in scale. Okay. They can be about a meter long, a meadow. That's three feet. Oh, wow. A single cell is the size of like three feet. Okay. If you think about it, it kind of makes sense, right? Because, um, think about your spinal cord, like the lumber spinal cord. Oh, sure, sure, sure.

• 1:42:03Krishna Choudhary?

  A single cell body is going to be located in the spinal cord, but it's going to relay signal all the way down to the foot. Yep, that makes sense. Okay, that's a single motor neuron that's doing it. Okay. Okay? Now, maintaining this kind of architecture over an extremely long distance requires moving a massive amount of physical cargo from one end of the cell to the other, right? You're gonna have to move proteins, you're gonna have to move mRNA from your nucleus. If you wanna like, you know, make it all the way out there, you have to move mitochondria. You have to move synaptic vesicles, which are like the acetylcholine and the neurotransmitters. That's gotta move. All of that stuff has to move across a meter, a yard worth of stuff. Right.

• 1:42:49Krishna Choudhary?

  That requires a lot of energy and it requires a lot of motion from these molecular motors. They're called chinesin. These chinesin are like little tiny molecular motors that actually step in eight nanometer steps on our microtubules. They're incredible machines that literally take up ATP, which is like the energy currency of our cell. And each ATP that take up required gets them eight nanometers across. Now, eight nanometers, that's eight times 10 to the negative nine meters. If I wanna traverse a meter worth of stuff for a single molecule, that's on the order of 10 to the eight ATP molecules that I need to hydrolyze. Yep. Right? Yep.

• 1:43:34Krishna Choudhary?

  It requires a lot of energy. Okay? And when you have a lot of ATP that's being built up and something is wrong in the genetics of that neuron, you're gonna get an accumulation of misfolded proteins. Specifically, one of the main ones is TDP43. It's a misfolded protein that causes physical blockage and traffic jams on these highways Right. of transport. Right. And when you have that traffic jam, you're gonna get into an energy crisis because now your mitochondria are unhappy. They don't have the actual raw materials. There are the factories that create, you know, the powerhouse of the cell or whatever. There are the factories that actually create this ATP. You're gonna not have them being happy.

• 1:44:17Krishna Choudhary?

  Those guys are gonna create reactive oxygen species, which are just like byproducts with oxygen. Oxygen is just like something that wants to react with everything. And so it's gonna cause effectively like rust in your neurons. The same way that iron rusts in atmosphere. If you don't have the correct machinery to regulate the reactive oxygen, that reactive oxygen is gonna go and go haywire in your neurons.

• 1:44:41Lester Nare?

  The the other analogy for this would sort of be on that highway. It's just like you're getting potholes over time that never get fixed. You don't have D O, Department of Transportation coming through.

• 1:44:51Krishna Choudhary?

  Exactly.

• 1:44:51Lester Nare?

  And then it just deteriorates over time to a point where you can no longer traverse.

• 1:44:56Krishna Choudhary?

  Exactly. It's this thermodynamic breakdown, right? And ALS is like a macroscopic manifestation of that thermodynamic breakdown. You're right, the neuron can literally not maintain its highly ordered state because the mitochondria is doing all sorts of crap. The the genetics is not being good enough.

• 1:45:14Lester Nare?

  Right.

• 1:45:15Krishna Choudhary?

  To keep that low entropy state alive.

• 1:45:17Lester Nare?

  Right.

• 1:45:17Krishna Choudhary?

  Right?

• 1:45:18Lester Nare?

  Right.

• 1:45:18Krishna Choudhary?

  And so and so you're getting just massive amounts of failure everywhere. For these motor neurons.

• 1:45:25Lester Nare?

  The point is, this is something that's it's it's like it's across your your whole system.

• 1:45:29Krishna Choudhary?

  Yeah, the entire motor neuron like is just like.

• 1:45:31Lester Nare?

  Right. Yeah.

• 1:45:32Krishna Choudhary?

  Right?

• 1:45:33Lester Nare?

  Yeah.

• 1:45:33Krishna Choudhary?

  Now, the muscles not so much, but the motor neuron is like the wire.

• 1:45:37Lester Nare?

  Right.

• 1:45:37Krishna Choudhary?

  That is sending the muscle the signal.

• 1:45:39Lester Nare?

  Yeah.

• 1:45:40Krishna Choudhary?

  Right?

• 1:45:40Lester Nare?

  Yeah.

• 1:45:41Krishna Choudhary?

  It's like it like in your car when your computer goes down.

• 1:45:45Lester Nare?

  Yeah.

• 1:45:45Krishna Choudhary?

  The it you turn it however much you want.

• 1:45:48Lester Nare?

  Yeah, it's good.

• 1:45:48Krishna Choudhary?

  The engine could be fine.

• 1:45:49Lester Nare?

  The engine is still fine. It may not be, but the engine is still fine. And but the problem is you don't have.

• 1:45:53Krishna Choudhary?

  But like but like your spark plug or whatever.

• 1:45:55Lester Nare?

  Yeah, yeah, yeah, yeah.

• 1:45:56Krishna Choudhary?

  There's no electricity going there.

• 1:45:57Lester Nare?

  Yeah, that makes sense.

• 1:45:58Krishna Choudhary?

  To do anything.

• 1:45:58Lester Nare?

  Yeah, that makes sense.

• 1:45:59Krishna Choudhary?

  You know?

• 1:46:00Lester Nare?

  Yeah.

• 1:46:00Krishna Choudhary?

  So so that's that's the problem. It's the motor neurons that are that are that are really just from overuse and from degradation are not working properly. And there's been a translational chasm in drug development. It's not been good.

• 1:46:18Lester Nare?

  Okay.

• 1:46:18Krishna Choudhary?

  We've been as humanity incredible at solving medical problems. ALS is one where historically it's just been beating us.

• 1:46:27Lester Nare?

  Yeah.

• 1:46:27Krishna Choudhary?

  And it's been crazy, dude. Like, there's the example of failed drugs. Like, there's so many failed drugs because they all show preclinical promise in like rat models and mouse models. Then when you get to humans, it's all failed. These are just some of the many. There's, I think, something like a more than a hundred that fail preclinical that pass the preclinical stage in mouse models.

• 1:46:52Lester Nare?

  Yep.

• 1:46:53Krishna Choudhary?

  But then when it comes to humans, it's just all failure, failure, failure. Okay? And what does that say? What that says is we don't have a good model.

• 1:47:03Krishna Choudhary?

  In the lab to test drugs for ALS.

• 1:47:08Lester Nare?

  Right, because the point here is, is for a variety of things, we can use these rodent, mouse, rat model, we can use them as the test bed.

• 1:47:17Krishna Choudhary?

  Yeah, there's so many where it works.

• 1:47:19Lester Nare?

  It works.

• 1:47:19Krishna Choudhary?

  That's why we do research on them.

• 1:47:20Lester Nare?

  It just works fine and it's fantastic. It does not work for this.

• 1:47:23Krishna Choudhary?

  It does not work for ALS. There's something fundamentally different. And what we need is in lab, a model that we can actually test drugs on.

• 1:47:31Lester Nare?

  Right, right.

• 1:47:32Krishna Choudhary?

  Right?

• 1:47:32Lester Nare?

  That, that, that translates post, pre-clinical into actually look.

• 1:47:36Krishna Choudhary?

  Into actually the clinical trials. And this is where the, um, now we can start talking about the paper that I want to talk about.

• 1:47:43Lester Nare?

  Okay.

• 1:47:43Krishna Choudhary?

  The paper has to do with IPSCs. These are pluripotent stem cells.

• 1:47:48Lester Nare?

  Okay.

• 1:47:48Krishna Choudhary?

  Okay? These are induced pluripotent stem cells. In 2012, the Nobel Prize went to John Girdon and Shinya Yamanaka for the discovery that mature cells can be pre, can be reprogrammed to become stem cells.

• 1:48:06Lester Nare?

  Actually.

• 1:48:06Krishna Choudhary?

  Stem cells are stem, so stem cells are cells that, um, have not differentiated into like, you know, skin cells or blood cells or bone cells or whatever.

• 1:48:15Lester Nare?

  Right.

• 1:48:15Krishna Choudhary?

  They are a clean slate. They don't have a specialization.

• 1:48:18Lester Nare?

  Right.

• 1:48:18Krishna Choudhary?

  They're like you in high school.

• 1:48:19Lester Nare?

  Right.

• 1:48:20Krishna Choudhary?

  Before you went into college and then got a major and now you're stuck at whatever.

• 1:48:24Lester Nare?

  Right.

• 1:48:24Krishna Choudhary?

  You know, path of life.

• 1:48:26Lester Nare?

  Yes.

• 1:48:26Krishna Choudhary?

  Right?

• 1:48:26Lester Nare?

  Yes.

• 1:48:27Krishna Choudhary?

  And what induced pluripotent stem cells do is now we're able to reprogram someone who's, let's say, been through college and a PhD.

• 1:48:36Lester Nare?

  Yes.

• 1:48:37Krishna Choudhary?

  Preprogram their brain so that now their brain is back in high school and they can be something totally different.

• 1:48:42Lester Nare?

  Just to quickly note, like, that's like a phenomenal, like, in and of itself, this which is from the 2012 Nobel Prize. That concept is really powerful because effectively what you're saying is, uh, I'm in the college, high school, college analogy, if I get to age 45 and the world has changed and my industry has been replaced by insert whatever, uh, I can just be. Almost reset to being nineteen twenty and retrained again.

• 1:49:12Krishna Choudhary?

  Yeah.

• 1:49:13Lester Nare?

  Uh, without like with with a with a substrate that is not my forty five year old mind, but it's my twenty year old mind.

• 1:49:18Krishna Choudhary?

  Yeah, yeah, and this is really amazing for biomedical research because one, we don't have to rely on embryonic stem cells.

• 1:49:26Lester Nare?

  Yeah, that's a good point.

• 1:49:26Krishna Choudhary?

  Because embryonic stem cells are really where the stem cells are, right? Because as an embryo, you can imagine from an egg and a sperm, that egg is just like a single cell.

• 1:49:35Lester Nare?

  Right.

• 1:49:35Krishna Choudhary?

  That single cell is now becoming my nails, my my lungs, my skin, my muscles, my neurons, right? So somewhere that single cell becomes a ball.

• 1:49:46Lester Nare?

  Yes.

• 1:49:46Krishna Choudhary?

  And that ball has a bunch of embryonic stem cells. Each cell now defines, I'm gonna go become the eye. I'm gonna go become a hair cell, so on and so forth. With this technology, we don't need embryonic stem cells. We can take skin cells, graft them, put them with a genetic cocktail, and then they are gonna become stem cells on their own, right? It completely changes the landscape, and that's why they won the Nobel Prize in twenty twelve.

• 1:50:08Lester Nare?

  That makes sense.

• 1:50:09Krishna Choudhary?

  Very much deserved because it's changed biomedical research, not just for ALS, but like countless other diseases, okay? Now, as you can imagine, twenty twelve, this is a pretty old technology.

• 1:50:22Lester Nare?

  Sure.

• 1:50:23Krishna Choudhary?

  Right? We have tried to use it for ALS. There was this consortium called Answer ALS. They got a thousand lines from ALS patients, and they tried to make lines of stem cells. But they observed the same problem, which is that the drugs wouldn't, like the same drugs that don't work in clinical trials.

• 1:50:45Lester Nare?

  Yeah.

• 1:50:46Krishna Choudhary?

  They'll work in these in pluripotent stem cells.

• 1:50:49Lester Nare?

  They will.

• 1:50:49Krishna Choudhary?

  They will. So they were still missing something.

• 1:50:53Lester Nare?

  Right.

• 1:50:53Krishna Choudhary?

  Right?

• 1:50:54Lester Nare?

  Right.

• 1:50:54Krishna Choudhary?

  It's like these stem cells were not mimicking ALS motor neurons. They were they were trying, right? We got we got the stem cells from ALS patients that have the disease. But when we make them into stem cells, when we get the donor skin cells from the ALS patients, when we try to make them into stem cells, they don't mimic the disease that the patient has. And that's the whole point.

• 1:51:16Lester Nare?

  That's the whole point.

• 1:51:17Krishna Choudhary?

  So what what's going on?

• 1:51:19Lester Nare?

  Oh, which which is interesting because.

• 1:51:23Lester Nare?

  Anyway.

• 1:51:23Krishna Choudhary?

  You see, you understand what I'm saying though, right?

• 1:51:25Lester Nare?

  Yeah, because like in my head, like intuitively, I'd be like, oh, well, if you're taking my skin, I let's say I have ALS in this example, you take my skin cells, and then you try to reprogram it.

• 1:51:35Krishna Choudhary?

  Yeah, and I try to make that into a motor neuron.

• 1:51:37Lester Nare?

  Right. The problem is the motor neuron is not my body's stuff, which has it.

• 1:51:41Krishna Choudhary?

  Yeah, it's just like a normal motor neuron.

• 1:51:43Lester Nare?

  Right, because it's been re.

• 1:51:45Krishna Choudhary?

  But I, but the whole point is I want to make.

• 1:51:47Lester Nare?

  Right.

• 1:51:48Krishna Choudhary?

  A model of ALS in a Petri dish.

• 1:51:51Lester Nare?

  Correct.

• 1:51:51Krishna Choudhary?

  That I can then mess around with.

• 1:51:53Lester Nare?

  Which currently we just can't get from the boilerplate out of the box induced pluripotent stem cell process.

• 1:51:59Krishna Choudhary?

  And that is where we get to our.

• 1:52:01Lester Nare?

  I see.

• 1:52:02Krishna Choudhary?

  Study in 2025.

• 1:52:03Lester Nare?

  Okay.

• 1:52:03Krishna Choudhary?

  It's an in vitro model of sporadic ALS. It was in Nature Neuroscience, large scale drug screening. And what they did was actually figure out how to make this happen.

• 1:52:12Lester Nare?

  Okay.

• 1:52:13Krishna Choudhary?

  How to make Petri dish level.

• 1:52:15Lester Nare?

  Yes.

• 1:52:16Krishna Choudhary?

  ALS that I can mess around with in a lab and really try to understand what drugs would work and what drugs wouldn't.

• 1:52:23Lester Nare?

  Mm hmm.

• 1:52:23Krishna Choudhary?

  Right?

• 1:52:23Lester Nare?

  Mm hmm, mm hmm.

• 1:52:25Krishna Choudhary?

  It's out of the University of Melbourne and the University of Queensland, a lot of like Australian universities, actually.

• 1:52:31Lester Nare?

  There's quite a few institutions that were collaborating on this.

• 1:52:34Krishna Choudhary?

  That's right. So what they did different is the following. So they got 100 patients with sporadic ALS. They got 11 patients with familial ALS. They got 25 healthy controls. They got skin cells from the dermal fibroblasts. They extracted from skin biopsies from these patients and from these 25 controls. And they used something called non-integrating epizomal vectors. So usually when we try to make stem cells, like pluripotent stem cells from whatever donor like skin cells that we got, I need to, I need to change the genetics of that skin cell to now forget everything about being a skin cell and go back to being a stem cell, right?

• 1:53:17Krishna Choudhary?

  Usually when, or we, how we do that is we use a retrovirus.

• 1:53:22Lester Nare?

  Okay.

• 1:53:22Krishna Choudhary?

  So a virus that has a piece of RNA.

• 1:53:24Lester Nare?

  Yep.

• 1:53:25Krishna Choudhary?

  The RNA goes into the cell that becomes reverse transcribed into DNA. The DNA then goes and gets mixed in. With the native DNA of the cell. With these specific non-integrating epizomal vectors, this is DNA that that just goes into the nucleus and hangs out. It doesn't get inserted into the chromosome of the cell.

• 1:53:45Lester Nare?

  Okay.

• 1:53:46Krishna Choudhary?

  And what that does is prevent any random, you know, like off-target stuff from happening.

• 1:53:52Lester Nare?

  It's exactly what we want.

• 1:53:54Krishna Choudhary?

  Yeah, it's just, it's not messing with anything.

• 1:53:56Lester Nare?

  Right.

• 1:53:57Krishna Choudhary?

  That's already there because the cell is already in this sort of, it's from an ALS patient. So it already has the mutations.

• 1:54:04Lester Nare?

  Right.

• 1:54:04Krishna Choudhary?

  That are causing ALS. We don't want to mess with that because we want to replicate the ALS in my Petri dish. So if I want to reprogram the cell to become a motor neuron.

• 1:54:13Lester Nare?

  Yes.

• 1:54:13Krishna Choudhary?

  I just get my DNA, I put it in the nucleus and I just have you hang out.

• 1:54:17Lester Nare?

  Yes.

• 1:54:17Krishna Choudhary?

  Do not go inside the house.

• 1:54:19Lester Nare?

  Yeah.

• 1:54:19Krishna Choudhary?

  Just hang out.

• 1:54:20Lester Nare?

  Yeah, okay, okay, okay. Because previously the retrovirus insertion.

• 1:54:24Krishna Choudhary?

  Yeah, it would insert.

• 1:54:26Lester Nare?

  And then.

• 1:54:26Krishna Choudhary?

  And then that changes whatever's happening inside the house.

• 1:54:28Lester Nare?

  And because this is such a comensurate problem.

• 1:54:30Krishna Choudhary?

  Yeah.

• 1:54:31Lester Nare?

  We have no idea. We don't know.

• 1:54:32Krishna Choudhary?

  Yeah, we don't know what happened.

• 1:54:34Lester Nare?

  But now we have total control. We're trying to have total control over each of the sort of second and third order.

• 1:54:40Krishna Choudhary?

  Yeah.

• 1:54:40Lester Nare?

  Steps that happen after we introduce it into the environment.

• 1:54:43Krishna Choudhary?

  Exactly, yeah. And they did a lot of other, other stuff that I'm not going to totally get into, but like they, the, the way that they um grew the stem cells, they actually withdrew a bunch of growth factors. That would prevent artificial masking of this phenotype of ALS because we want that phenotype to actually happen.

• 1:55:00Lester Nare?

  Yes.

• 1:55:01Krishna Choudhary?

  They also like cultured it under strict 5% oxygen, which is this hypoxic condition that happens in the spinal cord. So it's something that you want to mimic when you want to make modern neurons that are like ALS.

• 1:55:14Lester Nare?

  So we removed stuff that would potentially make it so that the thing would, like the system would make it go away. And we also created the environment that is almost identical to the environment that exists.

• 1:55:23Krishna Choudhary?

  Yeah.

• 1:55:24Lester Nare?

  To remove again, any possibility that we're missing the mark.

• 1:55:28Krishna Choudhary?

  Yes.

• 1:55:28Lester Nare?

  In terms of the, like the variables that need to be present in order to generate the results we're looking for with this new in lab. They'd be able to basically replicate it in a Petri dish.

• 1:55:39Krishna Choudhary?

  Yes, we want ALS motor neurons in a Petri dish. Right? And finally, the resulting purity that they got, it was exceptionally pure. Motor neurons, 90% were co-expressing the, the gene that, that we wanted.

• 1:55:52Lester Nare?

  Okay.

• 1:55:52Krishna Choudhary?

  Um, very low contamination. So there's not that many astericides, there's not that many microglia. They're all motor neurons and they're all, they all look great.

• 1:56:01Lester Nare?

  This is a, okay, so this is, this is a very big deal.

• 1:56:04Krishna Choudhary?

  Yes, so finally, we might have our ALS in a Petri dish.

• 1:56:09Lester Nare?

  Yes.

• 1:56:09Krishna Choudhary?

  And now, we can start doing preclinical trials in our Petri dish with some confidence that it might work at the clinical stage.

• 1:56:20Lester Nare?

  The point here is we're saying this ALS in a Petri dish is going to increase the conversion rate of preclinical targets to those that actually can make it into clinical trials. Because we are basically saying, we're basically recreating the environment that would be an actual human in the trials, not using the rodent, mouse, rat model, which can work in a lot of other cases.

• 1:56:44Krishna Choudhary?

  Yeah.

• 1:56:45Lester Nare?

  But just in this one, it does not.

• 1:56:46Krishna Choudhary?

  Exactly.

• 1:56:47Lester Nare?

  Okay, yes.

• 1:56:48Krishna Choudhary?

  And when they created these, when they created these motor neurons in the Petri dish, those motor neurons would exhibit the same kind of damage that we got in ALS.

• 1:56:58Lester Nare?

  Good.

• 1:56:58Krishna Choudhary?

  They, they came up with this metric called the lethal day 50%, so it's the exact day when the total length of the neurites degrades by 50%, the maximum peak length. So it's like, imagine, like, you made the motor neuron, and then you, like, press play, and then, you know, because of degradation, it's gonna get shorter and shorter.

• 1:57:16Lester Nare?

  Yes.

• 1:57:16Krishna Choudhary?

  They came up with this metric, that metric was correlated, and this is, this is kind of the nail in the coffin, that we have replicated in the Petri dish. It's kind of an unfortunate metric, but at the same time, it's a lot of hope for the future, because here's what they did. That metric is correlated with the actual clinical patient survival time.

• 1:57:39Lester Nare?

  Oh, interesting.

• 1:57:40Krishna Choudhary?

  Do you see what I'm saying?

• 1:57:41Lester Nare?

  Yes.

• 1:57:41Krishna Choudhary?

  So, the patient that I got my donation from, of the skin cells?

• 1:57:45Lester Nare?

  Yes.

• 1:57:46Krishna Choudhary?

  That I made my pluripotent stem cells from to make into a motor neuron?

• 1:57:49Lester Nare?

  Yeah.

• 1:57:50Krishna Choudhary?

  The survival of that culture?

• 1:57:52Lester Nare?

  Yes.

• 1:57:53Krishna Choudhary?

  Is correlated with the patient, him or herself.

• 1:57:56Lester Nare?

  The, the, you know, the unfortunate point being here is that the real world outcome for the patient, in terms of time?

• 1:58:03Krishna Choudhary?

  Yeah.

• 1:58:04Lester Nare?

  Is correlated with our ALS in a Petri dish.

• 1:58:08Krishna Choudhary?

  Yes.

• 1:58:08Lester Nare?

  Meaning, it is, it is replicating. The problem that the patient had to a degree that it's it's matching.

• 1:58:16Krishna Choudhary?

  It's matching. Exactly. Yeah. And it's unfortunate, but at the same time, very encouraging because now we have the model.

• 1:58:22Lester Nare?

  Yeah.

• 1:58:23Krishna Choudhary?

  In our Petri dish. Now we can finally start getting to the bottom of how do we fix this?

• 1:58:29Lester Nare?

  Yes. Right. That's actually a really, really big deal.

• 1:58:32Krishna Choudhary?

  Yeah. And we didn't have this before.

• 1:58:34Lester Nare?

  Yeah, right. Right.

• 1:58:35Krishna Choudhary?

  Right. This like we were working with like rats and mice that were just like awful.

• 1:58:39Lester Nare?

  Right.

• 1:58:40Krishna Choudhary?

  Just didn't work.

• 1:58:41Lester Nare?

  Right.

• 1:58:41Krishna Choudhary?

  Right. And now we finally got a model.

• 1:58:43Lester Nare?

  We were throwing darts at the board, but the board was behind us.

• 1:58:45Krishna Choudhary?

  Yeah, exactly.

• 1:58:46Lester Nare?

  It's and it's like.

• 1:58:47Krishna Choudhary?

  What are we doing?

• 1:58:48Lester Nare?

  What are we doing?

• 1:58:49Krishna Choudhary?

  Yeah.

• 1:58:49Lester Nare?

  But but the challenge here is, is again, to your point, you know, the model, the the sort of rodent model works in so many other arenas. It was fair to have extrapolated it to this one.

• 1:59:00Krishna Choudhary?

  Totally.

• 1:59:00Lester Nare?

  But after some time.

• 1:59:01Krishna Choudhary?

  Yeah, you're just like, OK, we need something else.

• 1:59:03Lester Nare?

  We need something else. Yeah.

• 1:59:05Krishna Choudhary?

  This is totally not working.

• 1:59:06Lester Nare?

  Yes.

• 1:59:06Krishna Choudhary?

  Right. So here's what they did. They they made a screening library. A hundred and seven commercially available drugs from phase one to three ALS trials. So this is preclinical.

• 1:59:17Lester Nare?

  Yes.

• 1:59:17Krishna Choudhary?

  Right. Pretty sure, right? Phase one to three is is, I think, preclinical. And then ninety seven percent of the tested drugs failed.

• 1:59:25Lester Nare?

  Yeah.

• 1:59:26Krishna Choudhary?

  And this is sort of what we want.

• 1:59:29Lester Nare?

  Right. That's because.

• 1:59:30Krishna Choudhary?

  Because that's what we're seeing. We're seeing them pass the preclinical and then only when they get to clinical stage in a human being, they're failing.

• 1:59:36Lester Nare?

  Yes.

• 1:59:37Krishna Choudhary?

  Now they're failing in the Petri dish.

• 1:59:38Lester Nare?

  Yes.

• 1:59:39Krishna Choudhary?

  I don't have to waste time and resources like actually doing a clinical trial if it's failing in the Petri dish.

• 1:59:44Lester Nare?

  So.

• 1:59:45Krishna Choudhary?

  That's the whole point.

• 1:59:45Lester Nare?

  Just to say it back to you, we took what was working in preclinical before, but failing in humans. We took our Petri dish platform. We applied the already commercially available options. And ninety seven percent of them failed in our Petri dish when they were passing in the preclinical in the prior regime.

• 2:00:03Krishna Choudhary?

  Yeah.

• 2:00:03Lester Nare?

  And so the point here is, is the, again, not only are we seeing in patients this the the the one to one on survival time. We are also seeing a one to one on efficacy in testing in this sort of pretrial environment. In in this in lab environment.

• 2:00:25Krishna Choudhary?

  Yeah.

• 2:00:25Lester Nare?

  Not even in the in lab.

• 2:00:27Krishna Choudhary?

  Yeah.

• 2:00:27Lester Nare?

  Meaning we can feel, we can have some level of confidence. That we are actually in a new 2.0 foundation.

• 2:00:37Krishna Choudhary?

  For lab testing.

• 2:00:38Lester Nare?

  Lab testing.

• 2:00:39Krishna Choudhary?

  Yeah.

• 2:00:40Lester Nare?

  For lab testing.

• 2:00:41Krishna Choudhary?

  Exactly. And out of the 107, three actually did pretty good.

• 2:00:45Lester Nare?

  Okay.

• 2:00:46Krishna Choudhary?

  Riluzole, um, Mementine and Bar Baricitinib. I think that's how you pronounce it. Okay? So let's get into, let's get into what these, what each of these things are.

• 2:00:58Lester Nare?

  Yep.

• 2:00:59Krishna Choudhary?

  Riluzole is actually something that people are already testing nowadays. It was dose dependent. There was significant rescue of this lethal day 50% metric that I was telling you about. And if we look at the physical effect on these neurons, there was restored electrical coherence. So on the top row, you see just, um, control.

• 2:01:22Lester Nare?

  Yes.

• 2:01:23Krishna Choudhary?

  On the bottom row, they're treated with Riluzole. The new, the neurons are healthier.

• 2:01:27Lester Nare?

  Yeah.

• 2:01:28Krishna Choudhary?

  Right? They just look better.

• 2:01:29Lester Nare?

  Yep.

• 2:01:29Krishna Choudhary?

  And it inverted the disease vector. So there was a negative correlation with like the effect and like how, how much time? The, the neurons actually stay alive. So it was all a good thing, right?

• 2:01:40Lester Nare?

  Yeah.

• 2:01:41Krishna Choudhary?

  The other two, they did not confer statistically significant population level benefit.

• 2:01:47Lester Nare?

  Okay.

• 2:01:48Krishna Choudhary?

  So you think, okay, maybe they're a dud, right? Not so fast.

• 2:01:51Lester Nare?

  Okay.

• 2:01:51Krishna Choudhary?

  What if we combine the drugs, the three drugs that we had a positive effect on? What if we combine them? Is it a synergistic multiplication effect?

• 2:02:01Lester Nare?

  Yeah.

• 2:02:02Krishna Choudhary?

  Right? And that is what they found. They found that so each of these, each of these columns now.

• 2:02:07Lester Nare?

  Yeah.

• 2:02:08Krishna Choudhary?

  Is individual drugs and then you add the two, right? Like there's Riluzole and Mementine.

• 2:02:13Lester Nare?

  Yeah.

• 2:02:14Krishna Choudhary?

  There's Baricitinib and Mementine. And then there's all three. The more you added, the three were somehow working together.

• 2:02:21Lester Nare?

  Yeah.

• 2:02:22Krishna Choudhary?

  To create a much better lasting effect.

• 2:02:25Lester Nare?

  I mean, the, the, I mean, the, the visuals here are, are just astonishing.

• 2:02:29Krishna Choudhary?

  From left to right, right? It's just like healthier and healthier neurons.

• 2:02:32Lester Nare?

  Yeah. And then the, basically on the, the one with all three, at all levels, it's, it basically maintains its structure.

• 2:02:40Krishna Choudhary?

  Yes.

• 2:02:41Lester Nare?

  Where whereas when we were just having untreated by the time we get to that.

• 2:02:46Krishna Choudhary?

  Yeah, but by the by the time, I mean, it's just like the time axis is on the on the Y axis.

• 2:02:50Lester Nare?

  Yep.

• 2:02:50Krishna Choudhary?

  So it's like it's like the earliest and then as time goes on, they just start dying, right?

• 2:02:55Lester Nare?

  I mean, this.

• 2:02:55Krishna Choudhary?

  But at the right most with all three of them, it's like they're still alive.

• 2:02:59Lester Nare?

  That's astonishing.

• 2:03:00Krishna Choudhary?

  Yeah.

• 2:03:00Lester Nare?

  I mean, I mean, the the level of impact.

• 2:03:02Krishna Choudhary?

  Yeah, the level of impact is crazy.

• 2:03:03Lester Nare?

  On the combinatorial piece.

• 2:03:05Krishna Choudhary?

  Yes. And then and then if you wanted to do, okay, so what is the ultimate zenith, right? Is it all three? Is it just two? You can actually test. Now that we've got a Petri dish.

• 2:03:14Lester Nare?

  Right.

• 2:03:15Krishna Choudhary?

  We can do A B testing.

• 2:03:16Lester Nare?

  Right.

• 2:03:16Krishna Choudhary?

  Right?

• 2:03:17Lester Nare?

  Yeah, yeah, yeah.

• 2:03:17Krishna Choudhary?

  On all the different patient donors, like all the different profiles. Is it only for sporadic? Is it only for familial? We can do all of these different categorical tests and figure out that the triple combination is actually the best. Right? Each of those cells actually lasted for thirty more days. Thirty might not seem like a lot, but it's actually a six point five times greater than just Riluzol alone.

• 2:03:42Lester Nare?

  Right.

• 2:03:43Krishna Choudhary?

  Right?

• 2:03:43Lester Nare?

  Right.

• 2:03:43Krishna Choudhary?

  And it's it's, I mean, this is something that we can now take to clinical trials, right?

• 2:03:48Lester Nare?

  Right.

• 2:03:48Krishna Choudhary?

  Like, why don't we just try all three?

• 2:03:50Lester Nare?

  Right.

• 2:03:50Krishna Choudhary?

  At the same time.

• 2:03:51Lester Nare?

  Right, right.

• 2:03:51Krishna Choudhary?

  Right?

• 2:03:52Lester Nare?

  Let alone the fact that you have the new in lab test bed.

• 2:03:55Krishna Choudhary?

  Yeah, that's the proof of concept now.

• 2:03:57Lester Nare?

  Then do whatever.

• 2:03:58Krishna Choudhary?

  Yeah.

• 2:03:58Lester Nare?

  To do, e- even if you say, let's not use these three, let's let's now try something totally different.

• 2:04:02Krishna Choudhary?

  Yeah, the fact that we can now try something totally different, right? It creates a scalable, robust and like pharmacologically predictive model.

• 2:04:10Lester Nare?

  Yes.

• 2:04:11Krishna Choudhary?

  Of ALS.

• 2:04:12Lester Nare?

  That's a really big deal.

• 2:04:13Krishna Choudhary?

  Yeah, I think I think it's a really big deal. I thought it was a really cool paper. And the clinical advantage is clearly there, right? Like, all three drugs, you do a cocktail of all three drugs. These drugs are already FDA approved for other indications.

• 2:04:26Lester Nare?

  Okay.

• 2:04:27Krishna Choudhary?

  With known safety profiles.

• 2:04:28Lester Nare?

  Okay.

• 2:04:28Krishna Choudhary?

  So they've got known safety profiles. Now we can actively start. Like prescribing these to patients. The next step is to rapidly move to human clinical trials. But I think it's got a potential to like fundamentally alter.

• 2:04:43Lester Nare?

  ALS. Yeah, no, that's a. Therapy and projections, right? That's. I think I thought it was very cool. It's very clearly a step function change. Yeah. In, in what can be done in therapeutics for ALS. Yeah. And research in this area. Um, the, the area we wanted to just end on here, uh, just given Congress actually just approved new funding for this. Right. This month is related to, uh, federal funding, uh, for ALS research. So for those who might not be super familiar with like how, who pays for fundamental science? And like, how do we actually get the money to do a lot of this stuff? You know, there are a variety of sources, but the federal government has been a huge

• 2:05:28Lester Nare?

  funder of, uh, fundamental science research since the constitution. Let me, I don't know if you know that, did you know this? In the constitution, the word science is used. And I think like in the, in the, in article one, which is establishing the powers of the legislative branch. Uh, I think it's section eight, clause eight is that, uh, they, Congress must, uh, you know, basically promote the investment and, you know, uh, work in the sciences and related arts. Wow. And like the word science is an article one of the constitution. That's really cool. That's gotta be either Benjamin Franklin or Thomas Jefferson. Hundred percent.

• 2:06:13Lester Nare?

  One of those two. Hundred percent. And, and so it's, it is a part of the ethos of. That's cool. Of even the founding document for our, our nation. It's a great document, by the way. It is a, they were so ahead of the time. Yeah, the constitution is a amazing document. It's quite nice. If you have not read it, I encourage you because we now need to understand it now more than ever. Yeah. But on February 3rd of this year, Congress approved new ALS funding for the fiscal year of 2026. So that means for the year that we're in fiscal year of 2026, every year, all these federal agencies and projects, they need to go, they need to be appropriated new funding by Congress. This is what Congress is always fighting about, among other things,

• 2:06:56Lester Nare?

  is where should money be allocated? So for fiscal year 2026, meaning next year, they're gonna have to, you know, all of the folks who are supporting and doing the nonprofit work to, you know, make sure Congress does continue to appropriate money, are consistently advocating for this to be true. This year was a total of $315 million, which is the highest level of funding ever for ALS research. It's a lot of money. It's a lot of money. And I just briefly want to break down what the different categories of where this is going is. So $90 million is going for accelerating access to critical therapies for ALS. It's sort of called ACT4ALS at the NIH, the National Institutes of Health,

• 2:07:38Lester Nare?

  which is a $15 million increase over fiscal year 2025. They're gonna do $30 million for Advanced Research Projects Agency for Health. This is like ARPA-H, it's like DARPA, but for health. And so this is net new funding. This $30 million is net new that didn't exist previously. $145 million for NIH general ALS research, not specific to critical therapies, which is a sort of a subsidiary under NIH. $40 million for Department of Defense ALS research through their directed medical research programs. And then $10 million for the Center for Disease Control, CDC, and Prevention of National ALS Registry. So, you know,

• 2:08:21Lester Nare?

  this funding is super important to generate outcomes. It is not just private pharmaceutical companies and all these things that are kind of working in these areas, especially in areas that are not perceived to be financially lucrative. Like, my dad works, you know, used to work in neglected diseases. So this is a lot of things that have impacted, you know, the You know, Sub-Saharan African population, et cetera. There is no market.

• 2:08:51Krishna Choudhary?

  Yeah.

• 2:08:51Lester Nare?

  For leshmania or African sibling sickness, et cetera, et cetera. And so it is, it can be difficult to actually get the funding to do this work. That does impact. So kudos to Congress for being able to not only continue funding ALS research, but increasing it. And I think applying it in ways that are going to be impactful. And again, we are seeing the results of, because through NIH, et cetera, they give grants out to universities and research labs. And so this money flows through the system in order to reach the experts, like the folks we just talked about in the previous story.

• 2:09:25Krishna Choudhary?

  Yeah. Yeah, incredibly important work. The US has always been at the forefront, not always, but since post-war, we have been at the forefront of scientific research because our government has used our incredible economy to bankroll amazing scientific research. And that shouldn't stop.

• 2:09:47Lester Nare?

  It should not. It's incredibly important. We had a fantastic, big, chunky, over two hours. I think we're just over two hours.

• 2:09:57Krishna Choudhary?

  We had a little, we had some pretty good stories.

• 2:10:00Lester Nare?

  I mean, we started with the dream engineering, which I still want to follow up on. That was out of Northwestern in the neuroscience of consciousness. We followed up that up with understanding measuring protons, where we actually confirmed the previous experimental measurement. This was from Max Planck Institute for Quantum Optics. That was in Nature. We ended with a sort of high level overview of ALS research generally. And the rundown, we had a bunch of stories in there as well. We are going to go ahead and wrap this up. Again, if you are still here listening, you are one of the core FFP nation. You are so important to us. We really appreciate those of you who find this interesting and valuable in your busy

• 2:10:45Lester Nare?

  day. There's so many ways you could spend your time. There's so much infinite amounts of content. You're choosing to spend your time with us and we are grateful to you. We must do our comment for our late show listeners.

• 2:10:58Krishna Choudhary?

  Yes.

• 2:10:58Lester Nare?

  I think you said you had an idea.

• 2:11:01Krishna Choudhary?

  Did I? I'm sorry.

• 2:11:03Lester Nare?

  Brain fried, though. Look, this is.

• 2:11:04Krishna Choudhary?

  It's been two hours. Hey, what would you, what would, if you could dream engineer?

• 2:11:09Lester Nare?

  Oh, yeah.

• 2:11:10Krishna Choudhary?

  Yeah. What would you, what would you want to dream engineer in your dreams?

• 2:11:13Lester Nare?

  Yes, that's a good one, because that's, we're gonna get some interesting answers. So let us know in the comments below. Again, if you're listening, make sure you check us on video, on Spotify and YouTube. We're on all the socials where we put out all of our clips. The clips don't always have the full context, so it's always encouraged to listen to the full podcast. If you would like to support the show, you can become a patron by going to ffpod.com/donate. Follow, like, subscribe, as always.

• 2:11:46Lester Nare?

  My name is Lester Nare, joined as always by my co-host and our resident PhD Krishna Choudhary. We are just so grateful for you all. We will see you all next week. And I now forget what I'm supposed to say with this is from First Principles at the end of the episode.

• 2:12:03Krishna Choudhary?

  So something like that, yeah.

• 2:12:04Lester Nare?

  Something, something. Uh, this is from First Principles. Cue exit music.