The Yak Mutation That Could Help Repair the Brain (EP 56)

What can a yak living thousands of meters above sea level teach us about repairing the human brain? In Episode 56 of From First Principles, Lester Nare and Krishna Choudhary break down a new Neuron paper that traces an evolutionary adaptation found in high-altitude animals to a previously hidden pathway involved in building and repairing myelin. Summary What myelin actually does and why losing it disrupts neural communication How multiple sclerosis damages myelin and why the brain’s natural repair process eventually fails Why oligodendrocyte precursor cells can remain present in damaged tissue without successfully rebuilding myelin Why current therapies are better at slowing further damage than restoring what has already been lost The challenge of getting drugs across the blood-brain barrier while maintaining target specificity How evolutionary pharmacology has previously produced medicines from adaptations found in snakes and Gila monsters The RETSAT Q247R variant identified in animals adapted to the hypoxic environment of the Tibetan Plateau How researchers engineered the high-altitude variant into mice and tested its effect on myelin The surprising discovery that neurons — rather than the myelin-producing cells themselves — generate the key repair signal How RETSAT increases ATDR, which neurons convert into ATDRA How ATDRA activates RXR-γ in oligodendrocyte precursor cells and promotes their differentiation How administration of ATDR promoted remyelination across multiple preclinical models Why the result is scientifically promising but still far from a proven human treatment Featured Paper A gain-of-function Retsat variant from high-altitude adaptation promotes myelination via a neuronal dihydroretinoic acid-RXR-γ pathway Neuron, 2026 DOI: 10.1016/j.neuron.2026.01.013 Explore FFPffppod.comffppod.com/fundingffppod.com/transfersffppod.com/America250 Support the showffppod.com/donate Follow@FFPPod on 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?

  So we've solved the delivery mechanism. We've not solved the targeting problem.

• 0:02Krishna Choudhary?

  Yes. And there is the challenge. How do we find a molecule that is small enough to cross the blood-brain barrier? But it only activates the gamma receptor

• 0:13Lester Nare?

  Yep.

• 0:13Krishna Choudhary?

  of these stem cells, and it doesn't trigger some random catastrophic activity elsewhere in the body.

• 0:19Lester Nare?

  So we got past security, but our ticket didn't get us on the right plane.

• 0:22Krishna Choudhary?

  Yeah, no, exactly. And that's where this current paper comes in.

• 0:26Lester Nare?

  We're using nature to cheat on the test because nature's been doing the test for way longer than we have.

• 0:30Krishna Choudhary?

  Yes. Yeah. Yeah.

• 0:31Lester Nare?

  Hello, Internet. This is your captain speaking, Lester Nare, joined as always by my co-host and our resident PhD, Krishna Choudhary. After our massive two-part marathon deep dive on quantum computing in our last two episodes, we wanted to get back into our biology bag with this week's deep dive, which is going to cover a new paper published in the journal Neuron on May 20th, 2026. This research focuses on our quest to combat brain disease, something we've covered in a couple of our previous episodes,

• 1:11Lester Nare?

  stemming from an unlikely inspiration, which is the genetic adaptation of high-altitude Tibetan animals. So today, we're going to break down what myelin, which is a protective layer around nerve cell fibers, actually does, why MS, multiple sclerosis, for those who may not know, destroys it, and why the brain eventually stops repairing itself, why our current drugs can prevent the damage but cannot reverse it, how a genetic adaptation from those high-altitude Tibetan animals has led researchers to a new pathway

• 1:49Lester Nare?

  for rebuilding myelin, and how they worked backwards from that evolutionary clue to a potential drug strategy. By the end of this episode, you will be able to look at the graphical abstract from the paper and understand what exactly is happening. As always, we are going to talk about the science from the ground up today because this is from First Principles.

• 2:28Krishna Choudhary?

  Multiple sclerosis, leukodystrophies, and periventricular leukomalacia in premature infants. These are all not actually obscure conditions that are buried in the back of some medical textbook. Okay? This isn't like House, an episode where it's like some weird thing. This is actually very, very prevalent in our society. Roughly 2.8 million people worldwide live with MS alone. And for most of them, the disease is a slow, relentless war of attrition against just neurodegradation and brain damage. It's their own immune system attacking the nervous system.

• 3:12Krishna Choudhary?

  And today's best treatments, they can only really slow that immune assault. They can't really fix the problem. They can only slow it down, but if the damage has already been done, that's it. Right? And that's the gap that this particular paper steps into. And it's a new fundamental type of research that could pave the way for rebuilding that damage that's caused by these conditions. And it does so, it's coming from a very unlikely source, namely the genomes of animals that are populating the Tibetan plateau at extremely high altitudes. It turns out these animals have certain adaptations from evolution that we could borrow to maybe fix these problems in neurodegradation.

• 3:57Lester Nare?

  This would be huge. I mean, as you mentioned, this is something that impacts a huge population of people

• 4:04Krishna Choudhary?

  Yeah.

• 4:04Lester Nare?

  globally, and it's extremely pernicious because there's no rewind.

• 4:10Krishna Choudhary?

  Yes, exactly. And there's ways to slow it down, to maybe pause it, but that's the best you can do right now. The holy grail is to rewind neurodegradation, right? Nerve damage is something that is notoriously a one-way street, especially if you get all the way to where the nerves themselves are damaged. We don't grow new neurons, right? But it turns out there might be a way to grow some of the scaffolding around neurons that is the problem in MS and a lot of these other disorders. So in this episode, we're going to go over some of the fundamental neuroscience behind what is MS and these adjacent conditions, where the current therapies are lacking, and then this new paper, which uses this emerging field of evolutionary pharmacology

• 4:56Krishna Choudhary?

  to propose a possible rebuilding therapy. And what I really like about this paper is the method by which they all figure this out. It's a really nice story because it starts from very large, you know, how does a yak adapt to the Tibetan plateau? And these researchers are honing in on that mechanism, and it's like a detective work in some sense because you're going through molecular biology, cellular biology, to try and understand what is the exact mechanism that the yak genome has developed to

• 5:32Krishna Choudhary?

  let these animals survive and not only survive but thrive in this hypoxic environment where there's not a lot of oxygen. It turns out that environment is very similar to the kind of stuff that we're getting in MS. And if we can borrow that, then we could possibly have a rewind button on MS. So by the end of the episode, you should be able to fully understand this graphic. So whenever you publish in the Elsevier journals, which is like neuron, cell, they make you do not just a normal graph, a normal abstract. You know, every journal has an abstract, right? You do the abstract and then your main paper.

• 6:12Lester Nare?

  They're also being like a block of summary, executive summary in text.

• 6:15Krishna Choudhary?

  Yes, in text. So Elsevier journals also have a graphical abstract where they've got like a pictorial way of showing what exactly is happening. And my goal today is to explain that graphical abstract in a lot of detail. So by the end, you should be able to know every single one of those words, every single one of those arrows. Okay? That's the idea.

• 6:40Lester Nare?

  There's a lot of words and a lot of arrows.

• 6:42Krishna Choudhary?

  Yes. So before we do that, let's take a brief housekeeping note.

• 6:47Lester Nare?

  Yes. For those of you joining for the first time, welcome. We are very excited to have you here on the best science show on the planet. You can follow us across all of our socials at FFP Pod. It's one of the best ways to support our show, to get it to more people. Like, share, follow, subscribe. Helps us in the battle of the algorithm to get people to focus for more than 15 seconds on something that is actually going to help them learn about the world around them. We've made some huge updates to the website at FFPpod.com where you can watch all of our episodes. You can find all of the research papers we cover, like this one we just mentioned,

• 7:30Lester Nare?

  and get to our interactive apps for the Science R&D Funding Tracker, our new Science Transfer Board, where we're looking at the migration of some of the world's top scientists in and out of the country and here in the US.

• 7:45Krishna Choudhary?

  Mostly out.

• 7:46Lester Nare?

  Mostly out of the country.

• 7:47Krishna Choudhary?

  Mostly out, but we're still growing the data set. It's not looking good so far. And then we also have our America 250, looking back at 250 years of American innovation and scientific research. These are really great tools to get beyond the episode, whether you listen or you watch. And as always, you can find us on all the main platforms, YouTube and Spotify to watch. Apple Video is coming soon, but it's currently audio only. We really appreciate the support of so many of you who are just as curious and love the minutia and technical detail, science, and the way in which an expert and a layman try to work through it together. And with that, we are going to get back into why you all have come to this episode.

• 8:31Krishna Choudhary?

  And I'm excited for this because we've been on the quantum side for quite some time.

• 8:35Lester Nare?

  Yeah, we've been on the physics and math side for quite some time.

• 8:38Krishna Choudhary?

  That's true. Yeah, because we had the Riemann and the Jacobian before that.

• 8:42Lester Nare?

  Yeah.

• 8:42Krishna Choudhary?

  And so getting back into some bio work, I think, is going to be refreshing for many folks who are listening.

• 8:48Lester Nare?

  Yeah. And before we get into MS, I think we should first try and understand just some basics about the nervous system and what myelin actually is. So in a healthy nervous system, nerve fibers, which are these axons, so a nerve cell has a cell body, it's got dendrites where all of the inputs come in, and then an axon where the output goes down to postsynaptic neurons, to the neurons that this particular neuron is talking to. Now, that axon is usually wrapped up in something called a myelin sheath. And it's useful to visualize the nervous system as kind of a vast network of electrical wiring. Okay? Neurons use electricity to talk to one another. That's how they're fast.

• 9:33Lester Nare?

  If they just use diffusion, which is just like molecules moving around and bumping into each other, it wouldn't be as fast as the reflexes that we have. But there's a caveat, even with

• 9:46Krishna Choudhary?

  Electricity, neurons would not be as fast as they are now. Like, the reflexes that we have, or the reflexes that Formula One drivers have, they're pretty insane. Fractions of a second, that nerve impulses are traveling down the arm or the leg to like brake and things like that, right? That's happening because of the myelin sheath, okay? So, I want to get into a little bit of the physics here, because it's kind of cool biophysics. It's one of the first, like, biophysics things that I kind of learned about, where I was like, this is pretty cool, that, like, biology is using these principles. So here's the idea, you've got the axon, right? And you've got this myelin sheath around it. It's kind of analogous to the insulation around copper wire, okay?

• 10:31Krishna Choudhary?

  In some sense? The problem is that the membrane of the neuron is leaky. The membrane, meaning the thing that is separating the inside to the outside. The way the neuron discharges and fires off a signal is, you've got a bunch of ions on one side, and a lack of those ions on the other side. So when you open up little holes, little membrane channels on the membrane, the ions sort of discharge, it's kind of like having a capacitor, and you short-circuit it, so all of the charges flow from one place to the other.

• 11:07Lester Nare?

  The visual I think about is Black Friday, the inside of the store is locked, everyone's standing on the outside, and when you open all the doors...

• 11:14Krishna Choudhary?

  It's a rush. It's a rush, right? Usually, it's this potassium, sodium, calcium, these are the ions that we're working with. And because they're all positively charged, they want to get the hell away from each other, right? So, without insulation, the signal would actually just decay, and it wouldn't actually travel all that far down the axon terminal. But because we have this insulation, you can imagine a cable, okay? You've got spots where there's insulation, and spots where there aren't, okay? Now, the spots where there are no insulation, those are called the nodes of Ranvier, okay? That's where the actual ion transport is happening, into and out of the cell.

• 11:57Lester Nare?

  We're constricting it to specific spots where the ability to go in and out is concentrated. They're like gates, and then there's the protective layer. It visually reminds me of those, at summer camp, you'd make those beads with the little plastic rope, and you'd string the beads on top of it to put around your wrist.

• 12:13Krishna Choudhary?

  Exactly.

• 12:13Lester Nare?

  And the little gaps in between the beads is where the ions can actually go in and out.

• 12:17Krishna Choudhary?

  Yeah, and those would be the nodes of Ranvier, right? And the point is, that without, without, without the myelin sheath, there would be ion channels everywhere along this cable.

• 12:27Lester Nare?

  Yes.

• 12:27Krishna Choudhary?

  So the ions would come in, and then they'd diffuse, and then maybe they'd go out, right? On the other hand, if there is insulation, the ions are coming in, and now they're all jam-packed into this tiny little axon, so they're gonna travel really fast to the next gate, to open up that next channel.

• 12:44Lester Nare?

  That makes total sense.

• 12:45Krishna Choudhary?

  Okay? It's kind of like, I mean, if we go back to your Black Friday analogy, right? It's like, there's a, there's an entrance in the, in the front, and then when all the people come in, if there's an entrance all the way in the back, these people are gonna, they're gonna diffuse way quicker than if there's entrances all over and exits all over the place, then they're gonna sort of meander.

• 13:03Lester Nare?

  People start blocking, the traffic doesn't move very... No, that, that's, and I think the, so the idea is, this physical structure of how this is set up, amplifies the speed at which the signal can go from one point to the next.

• 13:17Krishna Choudhary?

  Exactly. And so, this means, this means you need less energy, because what you've actually done is, you know, for those who are electrical engineers, or just like undergrad physicists, capacitors, when you put them in parallel, the capacitance decreases, okay? Sorry, no, no, no, nah. When you put capacitors in series, the capacitance decreases. When you put resistors in parallel, the resistance decreases. It's the one oversea thing. Anyways, here, you've got the axon membrane, which is kind of like a capacitor, because you've got charge on one side, on the other side, so it's storing some kind of voltage difference based on the charge.

• 13:58Krishna Choudhary?

  But if you're wrapping this myelin sheath around it, that's a bunch of capacitors, and so you're decreasing the capacitance, and what that means is, you need less energy to absorb and store all of that electrical charge. Now, why is that, why is that important? You can have faster charging, right? For the same amount of voltage, you need less ions, that's always good, and the signal travels a lot faster because of what we just said, right? And between these nodes of Ranvier, that's where the signal is traveling. This mechanism is called saltatory conduction, where it goes from one node of Ranvier to the next node of Ranvier. And here, you can see a visualization of that. On the left-hand side is an axon without any myelin.

• 14:43Krishna Choudhary?

  Notice, the action potential is very slow.

• 14:46Lester Nare?

  Yeah.

• 14:46Krishna Choudhary?

  On the right-hand side, you've got these nodes of Ranvier in between these myelin cells.

• 14:52Lester Nare?

  Yep.

• 14:53Krishna Choudhary?

  Boom, boom, boom, boom, boom. The signal propagates a lot faster.

• 14:59Lester Nare?

  And, and so again, just as a, as a simple way for me to think about this, the myelin helps reduce the friction.

• 15:08Krishna Choudhary?

  In some sense, yeah.

• 15:09Lester Nare?

  Right? So things can just move.

• 15:11Krishna Choudhary?

  Yeah, it facilitates kind of like, the charge coming in, and all of that positive charge wanting to get the hell away from one another.

• 15:18Lester Nare?

  Right.

• 15:18Krishna Choudhary?

  There's not any exits, except for like, way down there.

• 15:22Lester Nare?

  And ultimately, this, I think part of the point you're trying to bring up here is it's, myelin is a very fundamental benefit to how neurons can work so efficiently, and it is a fundamental part of the effectiveness of neural communication and the signals that get sent, that are such a big part of what make us incredible creatures.

• 15:50Krishna Choudhary?

  Yes, 100%. This is why we have fast reflexes, this is why the antelope can like, see a cheetah and be like, I'm out, like, immediately, right? There's no, there's no delay between its brain sensing a cheetah and its legs being like, I'm out, right? The difference between reaching out and catching a falling glass versus like, the thing falling. I mean, we all have myelin in our hands and in our feet, that is what gives us the reflexes. Without, I mean, for example, the corticospinal tract, right? Which is the motor control pathway, goes from the brain all the way down to, let's say, the legs. That is a single cell.

• 16:28Lester Nare?

  That entire way.

• 16:29Krishna Choudhary?

  Okay? That entire thing is a single axon sometimes. There are single axons that go all the way down, okay?

• 16:36Lester Nare?

  Incredible.

• 16:36Krishna Choudhary?

  If it's a single cell, you need this kind of compartmentalization in order to get the signal all the way down to your foot so quickly, right? This is, this is how Formula One drivers can have 10 milliseconds worth of reflex time. Have you seen those, by the way, have you seen those, the, where like, they've got their trainer, like, with, with balls? And like, they're like, releasing the balls, and the, and the Formula One drivers have to like, catch them, right before the race? If you watch the races, right before the race, you'll see all of the Formula One drivers just like, doing some warm-up reflex exercises. Well, they can do that because of the myelin sheath.

• 17:14Lester Nare?

  So you're saying that Messi has a better myelin sheath than any other footballer ever?

• 17:20Krishna Choudhary?

  Yeah, maybe Ronaldo, but, you know.

• 17:25Krishna Choudhary?

  I'm gonna get a lot of hate for that. Let's, let's see what the comments say about that. Hey, let me know, I, I, I do, I am curious, how many are Ronaldo versus Messi? Yeah, I, I'm curious to see what the comments say.

• 17:38Lester Nare?

  Some have said the debate is over, but I'm not an expert.

• 17:41Krishna Choudhary?

  You know, you know, I'm certainly not an expert, but I have an opinion.

• 17:46Krishna Choudhary?

  Okay, so, the, let's talk about the myelin now in a more cellular level. What is the cell that is responsible for that myelin? It's something called the oligodendrocyte, okay? This was identified by a Spanish neuroanatomist, um, can you?

• 18:02Lester Nare?

  Pio de Rio Ortega.

• 18:04Krishna Choudhary?

  Nice, yeah. Around 1921, so that guy, he stained using the Golgi silver staining techniques, and he found that there's these cells that have a few branches that branch out and reach out to a bunch of neurons. A key discovery here is that a single cell can actually branch out to a bunch of neurons and wrap its...

• 18:27Krishna Choudhary?

  Processes around those neurons. So you know those myelin sheets that I was talking about?

• 18:31Lester Nare?

  Yes.

• 18:31Krishna Choudhary?

  The wrapping around? That's not a single cell. There's a, there's one cell that is going around and reaching out to a bunch of axons around it, kind of like Venom.

• 18:41Lester Nare?

  Yeah, yeah, yeah, yeah.

• 18:42Krishna Choudhary?

  Spider-Man, like, and it goes around and wraps around all of these axons nearby.

• 18:48Lester Nare?

  Interesting. Okay.

• 18:49Krishna Choudhary?

  Which, which is kind of cool to think about.

• 18:50Lester Nare?

  Yeah, that is.

• 18:51Krishna Choudhary?

  It's not a one-to-one sort of mapping.

• 18:53Lester Nare?

  Right.

• 18:53Krishna Choudhary?

  It's a single cell that's doing like 50 different electrical wires.

• 18:57Lester Nare?

  It has this distributed placement of its, oh, that's actually very.

• 19:03Krishna Choudhary?

  Yeah.

• 19:03Lester Nare?

  Intriguing.

• 19:04Krishna Choudhary?

  And so this maybe foreshadows some of the stuff that we're going to talk about, which is if there's a problem with these oligodendrocytes.

• 19:10Lester Nare?

  Yeah.

• 19:11Krishna Choudhary?

  It's like not a single neuron problem.

• 19:13Lester Nare?

  It, it becomes a single point of failure across multiple endpoints.

• 19:16Krishna Choudhary?

  Exactly. And that's what we're, we're sort of building towards.

• 19:19Lester Nare?

  That makes sense.

• 19:20Krishna Choudhary?

  So the precise ultrastructure of this myelin was only sort of revealed in the 1950s with the advent of electron microscopy. Here's an electron microscope image where you can see, this is a cross-section of a neuron. So that's the axon in the middle. There's a little mitochondria. You see the circle?

• 19:38Lester Nare?

  Mm-hmm.

• 19:39Krishna Choudhary?

  That's a mitochondria. The neurons have a bunch of mitochondria.

• 19:42Lester Nare?

  The powerhouse of the cell.

• 19:43Krishna Choudhary?

  It is the powerhouse of the cell and neurons need a lot of powerhouses of the cell because they need to maintain this, um, this voltage difference, which means they need to pump ions against like, you know, if there's a bunch of calcium ions on one side, it takes a lot of energy to pump even more calcium ions over there, right?

• 20:02Lester Nare?

  Even, even with the myelin sheet, you still need power.

• 20:04Krishna Choudhary?

  You still need a lot of power. And the myelin sheets, actually, it's not just something that, um, provides this capacitance trade-off of like speed. The myelin sheet is, is something that provides energy for the cell and provides like metabolic waste removal from the cell. It's kind of like a maintainer. One of the key things that it does is wrap around the cell and you can see the little layers, right?

• 20:28Lester Nare?

  Yeah, yeah, yeah.

• 20:29Krishna Choudhary?

  You can see the layers of the myelin sort of wrapping around to create a bunch of capacitors in parallel. But it does way more than just this physics argument.

• 20:39Lester Nare?

  That, that makes sense. And for the, those who are listening, if you've ever eaten nerd's rope and took a bite out of it and looked at the inside, um, or like the Twizzler things where there's an inside that's a little bit, then there's an outer layer. It looks like when you've taken a bite and looked at it, long ways.

• 20:53Krishna Choudhary?

  Yeah. No, you know what I would say? It was, it's like a Twizzler on the inside and then fruit roll-up.

• 20:57Lester Nare?

  Yeah, on the, on the, you know?

• 20:58Krishna Choudhary?

  Yeah, like wrapped, several layers.

• 21:00Lester Nare?

  Wrapped around. Yeah, it's like a fruit roll-up.

• 21:01Krishna Choudhary?

  Yeah.

• 21:02Lester Nare?

  That's a great point. Yeah.

• 21:03Krishna Choudhary?

  Yeah. We should have some fruit roll-up in the studio, actually. Anyways, so Betty Ben Garin, she graduated from Washington University and then later went to Harvard Medical School where she was doing a lot of her research. She showed in 1954 that myelin is formed from spiral wrapping of a single cell. So this oligodendrocyte wraps around and that's a single cell that's doing it. It's a living tissue. That's the main finding from this paper. Before then, it was thought that it was just like, it, it was something that maybe the neuron secreted, because we don't know, right? You don't know.

• 21:36Lester Nare?

  Right.

• 21:36Krishna Choudhary?

  But she definitively showed that there's a single cell that goes around, this oligodendrocyte goes around and wraps around, and all of that is a single process that's doing it.

• 21:47Lester Nare?

  The venom analogy is very visually compelling in the context of like the, the, how to kind of visualize what that would mean.

• 21:55Krishna Choudhary?

  Yeah.

• 21:55Lester Nare?

  Right? Like the movement of it and anyway.

• 21:58Krishna Choudhary?

  Exactly. And, and as we started learning more about the brain, we started realizing that this dichotomy between the gray matter and the white matter, right? That was already known from like the 1500s. There were like these Italian surgeons who were dissecting brains, um, Michelangelo being one of them. And they had already noticed that there were parts of the brain on the outside where there was gray matter and then on the inside, there was this white matter. It turns out that gray matter, white matter difference has to do with myelination.

• 22:26Lester Nare?

  Okay.

• 22:27Krishna Choudhary?

  Um, you've got the gray matter on the outside. That's mostly where the cell bodies are.

• 22:31Lester Nare?

  Okay.

• 22:32Krishna Choudhary?

  And then the white matter are the axons that connect different parts of the brain. And a lot of the myelin is in the axons because that's where the signal propagation is happening.

• 22:42Lester Nare?

  It's like, that's the superhighway.

• 22:44Krishna Choudhary?

  Mm-hmm.

• 22:44Lester Nare?

  And the gray matter are these islands.

• 22:46Krishna Choudhary?

  Yeah.

• 22:46Lester Nare?

  That are connected by the white matter of this, the superhighway.

• 22:49Krishna Choudhary?

  Exactly. Exactly. So this is where we get into MS, okay? 1868, French neurologist Jean Martin Charcot, I believe.

• 23:00Lester Nare?

  And people might, it might be Charcot.

• 23:02Krishna Choudhary?

  Yeah, maybe. Anyways, um, he documented

• 23:08Krishna Choudhary?

  evidence of plaques in the white matter. Okay?

• 23:13Lester Nare?

  Mm-hmm.

• 23:13Krishna Choudhary?

  And he showed that there's a correlation between those plaques when he did the autopsies of these patients and the patient's conditions at the time. The patient's conditions at the times were abnormal eye movements, intention tremors, slurred speech. This became known as Charcot's or Charcot's triad. And he recognized that these plaques in the white matter is probably what is causing these symptoms of early MS. This was the discovery of MS.

• 23:41Lester Nare?

  We saw people having these conditions. We could see, uh, these physiological, uh, happenings.

• 23:48Krishna Choudhary?

  Yeah.

• 23:49Lester Nare?

  When you then went and did an autopsy after the fact, there was something in the brain that looked different than everybody else.

• 23:55Krishna Choudhary?

  Yeah. There's a control and then there's.

• 23:57Lester Nare?

  So maybe they, these things may be connected.

• 23:59Krishna Choudhary?

  Yeah, yeah. And side note, um, Charcot was super into hypnosis. That's what he's most well-known for.

• 24:06Lester Nare?

  Funny.

• 24:06Krishna Choudhary?

  If you go back to that painting.

• 24:08Lester Nare?

  This, uh, yes.

• 24:09Krishna Choudhary?

  Uh, yeah. Yeah, there, he's, he's showing a woman who's like in hysteria is what he called it. And then he hypnotized her. And then all of these medical professionals are looking on like, oh my gosh, I can't believe you could.

• 24:21Lester Nare?

  Yeah. I can't believe you've done this.

• 24:23Krishna Choudhary?

  Yeah. Yeah. Yeah. So, uh, you know, you win some, you lose some.

• 24:29Lester Nare?

  Yeah, right.

• 24:31Krishna Choudhary?

  Um, so for, for nearly a century though, this was in 1868, for nearly a century, MS was a disease without a mechanism.

• 24:39Lester Nare?

  Yeah.

• 24:40Krishna Choudhary?

  Because we didn't actually know, okay, so there's these plaques, but you know, that's not good enough to really understand what is actually happening to create this. There was an autoimmune hypothesis that the immune system was attacking the myelin because maybe the immune system thought that it was some kind of foreign agent. And that gained traction because there was a discovery that a lot of the proteins that are around in myelin are major targets for an immune attack. Things like the myelin basic protein, the proteolipid protein. And then also with the development of MRIs, we could literally track the, the development of the white matter and the gray matter without actually, you know, doing an autopsy on a dead patient. Now there's a living patient and now what we're seeing

• 25:23Krishna Choudhary?

  with MS is that it's kind of cycling.

• 25:26Lester Nare?

  Hmm.

• 25:27Krishna Choudhary?

  There's a remission and then, and then, and then things come back to normal. And then there's a remission and then there's things coming back to normal. What does that say? That says that there is a chance, there is a mechanism inside the brain that is fixing this myelin degradation.

• 25:44Lester Nare?

  Right.

• 25:44Krishna Choudhary?

  Right?

• 25:45Lester Nare?

  Right.

• 25:45Krishna Choudhary?

  But the fixing mechanism is deteriorating with time.

• 25:50Lester Nare?

  There's a, there's an ongoing battle and the defense is, uh, losing the war of attrition.

• 25:57Krishna Choudhary?

  Exactly. Yeah. And so now that becomes kind of the focus. And with individuals suffering from multiple sclerosis, we, we now have some kind of mechanism. It is the myelin sheet and you can see now stains between, uh, normal control individual in A and, um, someone with MS in B.

• 26:15Lester Nare?

  Wow.

• 26:16Krishna Choudhary?

  The stains are the myelin sheets. You can see in A, there's so many around every single nerve fiber. There's a bunch of myelin sheet. In B, it's almost gone.

• 26:24Lester Nare?

  Yeah. And the point here is now that it's gone, it means we lose that speed. We lose the other efficiencies that it provides, not just the physics perspective of what you get out of having that myelin sheet be present.

• 26:36Krishna Choudhary?

  Yeah.

• 26:36Lester Nare?

  Um, and so now we're starting to, we're starting to, the detective work is.

• 26:41Krishna Choudhary?

  Yeah.

• 26:42Lester Nare?

  Progressing.

• 26:42Krishna Choudhary?

  We're starting to at least piece together what is going wrong.

• 26:45Lester Nare?

  Yes.

• 26:45Krishna Choudhary?

  It's definitely the myelin.

• 26:46Lester Nare?

  Yes.

• 26:46Krishna Choudhary?

  Okay?

• 26:47Lester Nare?

  Right.

• 26:48Krishna Choudhary?

  Um, now let's talk about that remission stuff, right? Because you said that there was noticing in the MRI scans, even in these early MRI studies, that it would go down and then it would go up, then it would go down, then it would go up. So certainly.

• 27:02Lester Nare?

  Which almost feels like an immune response, right? There's something that shows up and then the immune system comes and then it goes away. There's.

• 27:08Krishna Choudhary?

  Yeah. And then the immune system maybe like stops paying attention. So then.

• 27:11Lester Nare?

  Comes back.

• 27:12Krishna Choudhary?

  So then the myelin comes back. So how is the myelin actually coming back?

• 27:16Lester Nare?

  Right.

• 27:16Krishna Choudhary?

  Let's, let's, let's try to focus in on what is the repair mechanism that is working in healthy patients and what is sometimes working in patients with MS?

• 27:25Lester Nare?

  Okay.

• 27:26Krishna Choudhary?

  There are. There is a mechanism for spontaneous repair of the myelin, right? The brain and the spinal cord, they're populated by a reservoir of specialized stem cells called adult oligodendrocyte precursor cells. These are oligodendrocyte precursor cells, meaning they are stem cells that could go on to become the oligodendrocytes that create the myelin, right? So you've got the OPC and that's the abbreviation that we're going to use from now on.

• 27:59Lester Nare?

  Yeah, you know me. Down with OPC?

• 28:02Krishna Choudhary?

  What is that from?

• 28:03Lester Nare?

  Uh, it's a rap reference.

• 28:05Krishna Choudhary?

  Okay, got it. All right, well, I'm gonna look it up later. So the OPC, this oligodendrocyte precursor cell can become a myelinating oligodendrocyte cell. And there's some pathway, right? There's some signaling where the stem cell, which could become a bunch of different things, it gets specific signals from its environment to be like, oh, there's presumably, there's like myelin degradation, there's some kind of damage. I need to go lock in, become an oligodendrocyte cell and wrap myself around these axons that no longer have myelin, right? That's the idea. And that's the form of differentiation where it gets some kind of cellular signaling from its environment and then it goes and does a specific job.

• 28:49Lester Nare?

  The idea is this is a baby, it's in an egg, it hasn't yet been born, it doesn't know what it's going to be yet. It could, it's like a, you know, and then depending on the context of the environment, it can become one thing or another.

• 29:01Krishna Choudhary?

  Yeah, yeah, that's what a stem cell is. And in this case, it becomes this oligodendrocyte that becomes the myelin sheath.

• 29:07Lester Nare?

  It's what wraps the fruit roll up around the twister. And this is good. And so the point here being like, this is the mechanism by which the body is generating and when we see the cycling, the thing that is going in to then wrap again is this OPC that becomes a myelinating, uh, this oligodendrocyte.

• 29:28Krishna Choudhary?

  Oligodendrocyte cell. Yes. And, and so in healthy patients, this is happening all the time.

• 29:32Lester Nare?

  It's fine.

• 29:33Krishna Choudhary?

  Right? It's happening all the time and it's fine. So what's happening in MS? The first, the first, um, you know, hypothesis would be, okay, maybe the stem cells themselves are dying.

• 29:42Lester Nare?

  Okay.

• 29:43Krishna Choudhary?

  Right? That's a pretty easy hypothesis, right? There's, there's not enough going around. The stem cells with age die off and so you don't have them going around doing this myelinating stuff.

• 29:52Lester Nare?

  Your, your population is decreasing because you don't have enough babies that can become adults.

• 29:56Krishna Choudhary?

  Yeah, yeah, that's not the case, okay? People do studies and they actually show that, um, with histological studies where you can stain certain parts, you can actually see that there are certain lesions within someone who has MS, where certain lesions in the red arrow, the lesions are fine. They have repaired. But in other lesions, like the green arrow, in the same individual, you're getting lesions of MS where there's no myelin and there's no repair. So within the same individual, it can't really be possible that like, that like, there's, there's no oligodendrocytes, but somehow there's a repair still happening.

• 30:38Lester Nare?

  Repair still happening. Okay. As far as we're aware in this context, like that is the, that is the mechanism by which the repair happens.

• 30:43Krishna Choudhary?

  Yeah, yeah, so certainly there's oligodendrocytes that are working.

• 30:46Lester Nare?

  Right.

• 30:46Krishna Choudhary?

  There's OPCs that are working on the red. The progenitor, some stem cells.

• 30:50Lester Nare?

  Yes.

• 30:51Krishna Choudhary?

  The stem cells are working in the red area, but not in the green area.

• 30:53Lester Nare?

  Right.

• 30:54Krishna Choudhary?

  Right?

• 30:54Lester Nare?

  Right.

• 30:54Krishna Choudhary?

  And if you go and stain and actually look into it, the green areas have the stem cells. It's just that the stem cells, maybe they're not getting the correct type of signaling, or maybe they get the correct type of signaling, but they can't actually execute.

• 31:08Lester Nare?

  And so the point here is, is that it's not a lack of, of, of the, the, uh, the, the, the defense, like the workers.

• 31:17Krishna Choudhary?

  The workers.

• 31:18Lester Nare?

  The workers, they're there.

• 31:18Krishna Choudhary?

  Yeah.

• 31:19Lester Nare?

  Uh, but something is breaking down further down in the process.

• 31:23Krishna Choudhary?

  Exactly. And so they're failing to mature into these myelin producing cells.

• 31:29Lester Nare?

  Stuck in adolescence.

• 31:30Krishna Choudhary?

  Yes, yes, in some sense. So what, what's actually happening? Well, it could be some epigenetic barrier to differentiation. Here we're seeing, um, immune cells in the yellow actually attacking a myelin cell, an oligodendrocyte cell. And you can see that as it attacks, there's going to be a lot of cellular debris, there's going to be a lot of stress hormones, there's going to be a lot of like random nonsense that is happening. And perhaps that environment is making it hard for the oligodendrocytes that are around to come in and actually do the repair.

• 32:04Lester Nare?

  Right.

• 32:04Krishna Choudhary?

  Right? If there's like a battlefield, right? And there's like the, I, in some sense, there's like evidence of a battle.

• 32:11Lester Nare?

  Yeah.

• 32:11Krishna Choudhary?

  Where a bunch of your homies got knocked out.

• 32:14Lester Nare?

  Yeah.

• 32:15Krishna Choudhary?

  Like, you know, maybe you're like.

• 32:16Lester Nare?

  I might go that way.

• 32:17Krishna Choudhary?

  Yeah, I might, I might not hang out, right? Like, it, it's kind of strange to think about, but like even individual cells are feeling stress from the environment. And the macrophages that usually come in to clean up the battlefield aren't doing their jobs because maybe there's too much battlefield debris. And so perhaps this is the problem, right?

• 32:38Lester Nare?

  Yep.

• 32:39Krishna Choudhary?

  And the consequences of this failed remethylation is what it's called, where, you know, there's no methylation and then you remethylate the, the brain. The consequences of not doing this, of not remethyating are catastrophic, namely because the neurons that you have are the neurons that you have. This is why it's super important to have these mechanisms in the nervous system. In other, in other organ systems, the cells by and large can replicate. Neurons cannot. You are by and large born with the number of neurons that you have. And when a neuron dies, that's it.

• 33:19Lester Nare?

  And so just, I want to re-ground myself in kind of the circumstance we've set the table for right now. So, you know, in part, we have the, the neuron itself, right? And the neural pathway is like where the signal is being sent so we can do all of this communication.

• 33:35Krishna Choudhary?

  Yeah.

• 33:35Lester Nare?

  And function the way we do. The myelin is this wrapping.

• 33:39Krishna Choudhary?

  Yeah.

• 33:40Lester Nare?

  Around it, uh, that has a variety of benefits.

• 33:44Krishna Choudhary?

  Yeah.

• 33:45Lester Nare?

  Speed, efficiency.

• 33:48Krishna Choudhary?

  Housekeeping.

• 33:49Lester Nare?

  Housekeeping. And in MS patients specifically, there is this degradation in this myelin sheath that surrounds, uh, your neurons.

• 34:01Krishna Choudhary?

  Yeah.

• 34:02Lester Nare?

  That gives it all of these added benefits. We thought it might've been that the way, the, the way that they're born, the myelin is, the way that it was created, the, the, there's not enough resource to keep creating it.

• 34:13Krishna Choudhary?

  Yeah.

• 34:14Lester Nare?

  That did not seem to be true.

• 34:15Krishna Choudhary?

  Yep.

• 34:16Lester Nare?

  Uh, and then we moved down the, down the sort of process pipeline and now it's become this idea that, um, the, the environment, because there's this constant ebbing and flowing, uh, of myelin degradation. And then the body, uh, re- recreates its myelin sheaths in healthy patients, but in MS patients, that repair process breaks down because of this chaos that is happening in the context of the battle that creates the myelin degradation.

• 34:49Krishna Choudhary?

  Exactly.

• 34:49Lester Nare?

  In the first place.

• 34:50Krishna Choudhary?

  Yeah, yeah. And it seems that the progenitor cells, the stem cells that would go on to create the myelin and repair, they're either confused, they're not having the right signal, they're getting too much inflammatory signal, something is happening that is preventing the present workers from repairing what they should be repairing.

• 35:10Lester Nare?

  And the key idea is like, they're there.

• 35:12Krishna Choudhary?

  They're there. That's the key.

• 35:13Lester Nare?

  That's, yeah, is a big point.

• 35:15Krishna Choudhary?

  That's a big point. That's a big point. And that's the whole, yeah, that was the whole point of this whole thing.

• 35:18Lester Nare?

  Right.

• 35:19Krishna Choudhary?

  Is that they are there, we just need to equip them with perhaps the right signal. Okay?

• 35:25Lester Nare?

  Okay.

• 35:25Krishna Choudhary?

  So where do the current therapies stand? Well, they can prevent, but they cannot fix. These are called disease modifying therapies, DMTs, not to be.

• 35:36Lester Nare?

  Not that DMT.

• 35:37Krishna Choudhary?

  Not that DMT, guys. Uh, this is not the Joe Rogan podcast. But once an axon is demylinated, these disease modifying therapies cannot force the body to remylinate it, but they can perhaps force the body to stop the degradation.

• 35:53Lester Nare?

  Okay? Stop, to stop the bleeding effectively.

• 35:55Krishna Choudhary?

  Yeah, yeah. And by the 2000s, the field had identified like a bunch of different signals, there's like thyroid hormone, retinoids, um, but translating this into therapies proved kind of difficult. A big obstacle is the blood-brain barrier. This is something that we, we revisit a lot on this podcast. The blood-brain barrier is an essential barrier between the blood and the brain because the human brain is protected by this thing. It's a highly selective, semi-permeable border of endothelial cells. Endothelial cells are just, you know, cells on the lining of blood vessels, but very specific types of endothelial cells.

• 36:36Krishna Choudhary?

  And they prevent circulating blood from just freely mixing with the brain. Everywhere else it's fine, but the brain is a finicky thing. The neurons are a finicky thing. And so they want a very particular environment to actually do all of the computation that we know and love. This barrier has doomed a lot of different therapies. Okay? One of the most famous was this therapy from Biogen, which Biogen is a company, they were developing this therapy called Opisinumab.

• 37:11Lester Nare?

  I love the pharmaceutical namings of stuff.

• 37:13Krishna Choudhary?

  Yeah, I, I, Opisinumab, okay? It was developed as a monoclonal antibody that was going to target and block something called LINGO1, which is a protein that would inhibit this differentiation. So the, the idea is you've got the stem cell, the stem cell is differentiating, there's a protein called LINGO1 that would stop that differentiation, that would stop these workers. So this monoclonal antibody is going to go attack that protein. So then the protein, the workers are kind of free to, to, to do whatever.

• 37:44Lester Nare?

  Yes.

• 37:45Krishna Choudhary?

  Works in mice.

• 37:48Krishna Choudhary?

  Human Phase II trials, huge failure because these monoclonal antibodies are massive. They're complex protein structures and because of their sheer size, they couldn't actually get through the blood-brain barrier, right? In mice, the mice have a different blood-brain barrier, so perhaps it got through. This is going to come back later when we put an asterisk on the current paper. But I still think this current paper is cool because of all the methodology. So to bypass the blood-brain barrier, what do we need to do? We need to make our thingy smaller, okay? Because the blood-brain barrier has extremely tiny holes. And if I can get through that hole, then perhaps I can get into the neurons, get into the astrocytes, get into these oligodendrocytes and help out where I'm trying to help out.

• 38:33Krishna Choudhary?

  So researchers have started turning to small molecule drugs, but these molecules are tiny and they're lipophilic, meaning they're fat soluble. Lipophilic, meaning fat-loving. So they slip past the blood-brain barrier, but they're also going to slip past every other barrier.

• 38:52Lester Nare?

  Yeah.

• 38:53Krishna Choudhary?

  Right? So we want target specificity. That's not going to happen for a lot of these chemicals.

• 38:59Lester Nare?

  So this is almost, it's the problem in the opposite direction.

• 39:01Krishna Choudhary?

  Yes, because now I'm slipping through the blood-brain barrier, but because I have to be so small to get through that, I'm also getting it to the liver. I'm going to get to the kidneys. I'm going to get all over the place. And one of the big, most catastrophic and educational failures in this case was the trial of Bexarotene. So Bexarotene was an FDA-approved oral medication that was targeting something called the retinoid X receptors, which you see over here, the RXRs. These retinoid X receptors are nuclear transcription factors. We've talked about transcription factors a lot. These are the on-off switches for a bunch of genes.

• 39:41Krishna Choudhary?

  So if you can target the transcription factor, then you can influence what types of genes the cell is actually getting access to. And there you see a bit of DNA and the transcription factor is the protein that goes in and locks in on that piece of DNA, recruits, for example, RNA polymerase to make RNA that makes the protein that actually makes whatever thing that is happening. But if you can target this thing, then perhaps you can actually have a control of the on-and-off switch for something that controls whether the stem cell goes on to become a myelin. That's the idea.

• 40:13Lester Nare?

  So we're going back to the factory and the instructions of how the factory generates its stuff with the right instructions. It's like, maybe let's just reprogram at the factory to factory settings.

• 40:23Krishna Choudhary?

  Exactly. It's like, maybe the factory has some instructions and I'm just going to blackout.

• 40:27Lester Nare?

  Yeah.

• 40:28Krishna Choudhary?

  Right? I'm going to like redact a bunch of instructions. The problem is the redaction is going to happen over all the instructions because it's not specific. That's the idea that I'm trying to get to.

• 40:38Lester Nare?

  Because of this, the size problem we talked about earlier.

• 40:40Krishna Choudhary?

  Yeah.

• 40:40Lester Nare?

  And so it's going to effectively start turning off, it's going to start impacting functionality that you were not trying to change.

• 40:47Krishna Choudhary?

  Yeah, yeah.

• 40:48Lester Nare?

  Because it can't be specific.

• 40:49Krishna Choudhary?

  Exactly, yes. Because it can't be specific because it's so small. Now, before we get into the details of that failure, a brief, a brief sojourn into vitamin A, because that's going to be important later on in this episode. Vitamin A is very important and that RXR is very much tied to that vitamin A. That transcription factor is very much tied to the vitamin A. So vitamin A is a broad family of fat soluble molecules, like retinol is one specific molecule that belongs to that. And these retinoids are critical for neurodevelopment. Too much and it's bad, too little and it's bad. That's why a lot of these prenatal vitamins have vitamin A. But they have it in the form of beta-carotene and not like straight up vitamin A.

• 41:34Krishna Choudhary?

  Because beta-carotene, our body can then process and then it can decide how much vitamin A to get. If you just straight up inject yourself with retinol, that's really bad. And that's why I like the skincare products that have retinol is bad during pregnancy because then that goes into the infant and that's going to cause trouble. So the active form is something called retinoic acid. And that acts as the transcription factor for these receptors.

• 42:01Lester Nare?

  Yes.

• 42:01Krishna Choudhary?

  Okay?

• 42:01Lester Nare?

  Right.

• 42:02Krishna Choudhary?

  So, and that regulates the gene expression later on, right? Now, preclinical studies showed that these pre-genitor cells, the stem cells that go on to become the myelin.

• 42:14Lester Nare?

  The OPCs.

• 42:15Krishna Choudhary?

  Yes. Those guys, they express these RXRs, the receptors, but only a gamma kind. Okay, there's multiple types and the stem cells in the brain that become myelin, they express the gamma kind of the receptor.

• 42:35Lester Nare?

  Okay.

• 42:36Krishna Choudhary?

  Okay? And then when researchers knocked out that gamma kind, then the mice lost all the ability to re-myelinate the axons.

• 42:44Lester Nare?

  So now we have a better idea of the specific receptors that the OPCs use. Because there's a lot of options on the table. And so part of maybe what was happening before was we weren't choosing the right flavor.

• 42:56Krishna Choudhary?

  Yes.

• 42:57Lester Nare?

  And now we know, we were making lemon pepper when we needed to be making teriyaki.

• 43:02Krishna Choudhary?

  Yeah. So at least we now know that we got to make the gamma. We got to make the teriyaki, right?

• 43:07Lester Nare?

  Yeah.

• 43:07Krishna Choudhary?

  And so this clinical trial in Cambridge in the UK decided that Bexar, what is it? Bexarotene. Sorry, I'm really bad with these medical terminologies, to be honest. But Bexarotene was something that could target the gamma receptor and then perhaps reinvigorate the stem cell differentiation from stem cell to myelin. The problem turns out that there are other types of receptors. There is the RXR gamma, which is in the brain that does the myelin stuff. But there's also RXR alpha, RXR beta, and those are in the liver and in the kidneys. And this thing was going around and targeting everything. So all of a sudden, the patients got hypothyroidism.

• 43:51Krishna Choudhary?

  Ninety percent of the patients developed dangerously high levels of fat circulating in the blood, something called hypertiglyceremia.

• 44:02Lester Nare?

  This is the, yeah. And so this is, so just to double click on this, the Bexarotene, which was this potential therapeutic, right, that we were going to use, did activate RXR gamma, which is the one we know.

• 44:16Krishna Choudhary?

  That's good.

• 44:16Lester Nare?

  That the OPCs use to basically get to this point where they can re-myelinate. The problem is it didn't only reactivate RXR gamma. It reactivated RXR gamma as well as the.

• 44:27Krishna Choudhary?

  Alpha and beta.

• 44:29Lester Nare?

  And so the, all three subtypes were being activated by this therapeutic. And as such, it was effectively not targeted enough for the specific solution we were looking for, even though we solved the delivery problem of getting through the blood-brain barrier, which was the initial challenge.

• 44:46Krishna Choudhary?

  Yeah, that was the initial challenge. Okay, the monoclonal antibody is too big, it's not going to get through. Let's make the thing smaller while now it's getting through everywhere.

• 44:53Lester Nare?

  Right.

• 44:53Krishna Choudhary?

  Right?

• 44:54Lester Nare?

  And targeting too many things.

• 44:55Krishna Choudhary?

  Exactly.

• 44:56Lester Nare?

  So we've solved the delivery mechanism, we've not solved the targeting problem.

• 44:59Krishna Choudhary?

  Yes. And there is the challenge. How do we find a molecule that is small enough to cross the blood-brain barrier, but it only activates the gamma receptor?

• 45:09Lester Nare?

  Yep.

• 45:09Krishna Choudhary?

  Of these stem cells and it doesn't trigger some random catastrophic activity elsewhere in the body.

• 45:16Lester Nare?

  I want to just really briefly talk about how important it is to have done this journey because we've now set the table of like where the problem set exists.

• 45:24Krishna Choudhary?

  Exactly.

• 45:25Lester Nare?

  Today, as these research teams are looking at this problem.

• 45:28Krishna Choudhary?

  Yeah.

• 45:29Lester Nare?

  Like, why is this so pernicious? Why is it so difficult to solve?

• 45:32Krishna Choudhary?

  Yeah.

• 45:32Lester Nare?

  Well, we first had to identify the mechanisms and the mechanics of what was actually happening.

• 45:37Krishna Choudhary?

  Yeah.

• 45:38Lester Nare?

  Once we've identified what's actually happening, then we have to think about different angles of attack to solve the problem.

• 45:43Krishna Choudhary?

  Yeah.

• 45:43Lester Nare?

  Where in that chain do we go?

• 45:46Krishna Choudhary?

  Yeah.

• 45:46Lester Nare?

  Right? And so then we decided, okay, let's try to see if we can reinvigorate these OPCs, which seems to be breaking down.

• 45:52Krishna Choudhary?

  Yeah.

• 45:52Lester Nare?

  And then we have to get to the location. So that was the hardest problem at first because it doesn't matter what we think if we can't get there.

• 45:59Krishna Choudhary?

  Yeah, yeah, yeah. Let's get past security.

• 46:01Lester Nare?

  Right, right. We got to get through TSA and then we'll figure out if we can get on the plane. So we got past security, but our ticket didn't get us on the right plane.

• 46:08Krishna Choudhary?

  Yeah, no, it's every single plane.

• 46:10Lester Nare?

  It gets us on every plane and we were trying to go from London to Paris and so we need to get the London to Paris ticket.

• 46:14Krishna Choudhary?

  Exactly.

• 46:15Lester Nare?

  And so that's where we are.

• 46:16Krishna Choudhary?

  Yeah.

• 46:17Lester Nare?

  Right now, as we sort of transition into.

• 46:21Krishna Choudhary?

  This current paper, right? This is the problem set. This is where we are. And now let's talk about where this current paper comes in. This current paper introduces the, this current paper basically introduces the idea of evolutionary medicine into this fray.

• 46:40Lester Nare?

  Okay.

• 46:41Krishna Choudhary?

  Okay? Evolutionary medicine is a rapidly growing interdisciplinary field. Here's the idea. You basically apply the principles of evolutionary biology to understand, prevent and treat human diseases because biology has had about four billion years to solve random problems, okay? That have come up in every single niche that life can possibly live in, right? Life has found a way to live everywhere somehow. And to do that, it has mutated its genome. It has figured out novel mechanisms by which to solve problems. The environment applies these selective pressures and there's some way in which, in

• 47:25Krishna Choudhary?

  order to survive, a species will optimize some molecular mechanism.

• 47:31Lester Nare?

  We're using nature to cheat on the test because nature's been doing the test for way longer than we have.

• 47:35Krishna Choudhary?

  Yes, yeah, yeah. And in some sense, it would be foolish not to.

• 47:40Lester Nare?

  Right, right. The professor's not looking.

• 47:43Krishna Choudhary?

  Yeah, look, look. In fact, the professor is like, like giving us all these disorders.

• 47:50Lester Nare?

  Right, right. The professor is the problem.

• 47:52Krishna Choudhary?

  Yeah, the professor is straight up the problem. The test is rigged, right? So I'd rather try to figure out how to pass and live a good life. So there are a bunch of iconic successes in evolutionary pharmacology. The first one I want to talk about is captopril. Captopril, the first ACE inhibitor, and it was discovered in snake venom. This came from the South American pit viper. It's an active compound that was isolated from the venom of this snake. And it's the first FDA-approved ACE inhibitor that revolutionized the treatment of high blood pressure and heart failure. And it saved millions of human lives.

• 48:35Krishna Choudhary?

  Effectively, the snake has evolved a way to drop the blood pressure of its victims. That's how it kills people, okay? When it bites things, like the venom drops the blood pressure and then the thing is dead.

• 48:49Lester Nare?

  Yeah, because it can't get enough blood to.

• 48:51Krishna Choudhary?

  Right, yeah. The heart stops. I mean, it's just, yeah, obvious, right? So then modern pharmacology diluted the thing and titrated it to the point where it's just enough. To drop the blood pressure to healthy levels, right? I mean, obviously, there was more into it, but that's effectively what happened. We figured it out in the venom. And then we're like, okay, we can use this compound, things that look like this compound to then create all of the high blood pressure drugs that we see today.

• 49:20Lester Nare?

  This also goes back to this idea of looking at things that feel totally orthogonal or unrelated to problems we're trying to solve. Are actually the location of the solution sometimes. And this is a perfect example. Totally. Who knew watching the crocodile hunter and being inspired by snake venom as a child. Inspired some researcher to go and research that venom. And then that ended up being a cure to cardiovascular disease.

• 49:44Krishna Choudhary?

  Yeah, I mean, the next one is even crazier, dude. The next one is exanatide, which comes from the gila monster lizard saliva. This is how we get GLP ones. This is how we get Ozempic.

• 49:56Lester Nare?

  Oh, my goodness.

• 49:57Krishna Choudhary?

  Someone was messing around with the gila monster venom and was like, hey, hey, this could be used against diabetes. It's pretty crazy. So the groundbreaking GLP one receptor agonist is exanatide. And it was used to manage type two diabetes. The, the compound is exanadin four. It was discovered in the toxic saliva of the gila monster. It's this thing that eats only a few massive meals per year. This thing only eats like a few meals a year, right? So it needs a way to maintain stable blood sugar.

• 50:31Lester Nare?

  Oh, my God.

• 50:33Krishna Choudhary?

  Because, because it's only got a few, you know what I mean?

• 50:35Lester Nare?

  It's in this extreme environment where it doesn't have a lot to eat.

• 50:37Krishna Choudhary?

  Yeah, yeah. And so, and so humans looked at this and said, hey, this could actually be used against type two diabetes. The success of xanatide and the pathway made scientists go in and engineer Ozempic, which is structurally, it's like basically a modified form of exanatide.

• 50:56Lester Nare?

  For the human body.

• 50:57Krishna Choudhary?

  For the human body. It's like optimized for the human body, but it's, it came from the gila monster venom. Kind of hilarious.

• 51:04Lester Nare?

  If you're on Ozempic, if you're on Wegovy or any of the generics, you can thank the gila monster. Because without that, and the research people that spent the time looking at this exotic animal in this extreme environment. Because the venom. You're putting, you're putting gila monster venom derivative in your body. Okay.

• 51:25Krishna Choudhary?

  Yeah.

• 51:26Lester Nare?

  I just want you to know.

• 51:27Krishna Choudhary?

  That's what we're doing.

• 51:29Lester Nare?

  This is why science matters. It helps you lose weight, right?

• 51:32Krishna Choudhary?

  Yeah, this is finally how we're gonna get Americans to pay attention.

• 51:35Lester Nare?

  This is why basic research matters. That's how we got Ozempic, the gila monster. Everyone's gonna be like, vote, vote now.

• 51:44Lester Nare?

  That's actually so crazy, though, because, ah, that's so crazy. Do you understand how much money Ozempic is making right now and all of the GLP one? The industry is, it's literally a driver of GDP growth. They're like CEO of one of the GLP, one of the GLP one creators was like, we need to get a billion people on the planet onto GLPs because it's going to be a driver for America's GDP growth. When we're struggling to find other areas of GDP growth.

• 52:15Krishna Choudhary?

  I'm just, that's, that's, that's a crazy thing to say.

• 52:18Lester Nare?

  I'm just reminding people.

• 52:21Krishna Choudhary?

  No, that's a crazy thing to say.

• 52:22Lester Nare?

  Literally, and then he's like, the problem is, as we get more people on GLP ones, we're, we're destroying the GDP growth of like the food industry, right?

• 52:31Krishna Choudhary?

  Right.

• 52:33Lester Nare?

  People don't eat as much. So we have to find this, this is, this is what, this is where we're at. Sorry for the digression.

• 52:40Krishna Choudhary?

  That was, that, okay, that's actually hilarious. Well, gila monster snakes, this particular paper has to do with the animals of the Tibetan plateau. They live at 4,000 meters on average. Like the yak, the humble yak, where oxygen partial pressure is roughly 40% lower than at sea level. I mean, we're pretty close to sea level here in Los Angeles. Imagine 40% less oxygen. These animals like the yaks, the Tibetan antelopes, snow leopards, they've spent thousands of generations evolving solutions to that environment that would kill most mammals in hours to days.

• 53:21Krishna Choudhary?

  Okay, including humans, like chronic hypoxia, which is like low oxygen is disastrous. A lot of oxidative stress, very specifically neurodevelopmental deficits, particularly in white matter injury and demyelination. This is a known thing.

• 53:40Lester Nare?

  This is the superhighway that we talked about earlier.

• 53:42Krishna Choudhary?

  Yeah, the white matter in the brain, which has a bunch of myelin, gets demyelinated with hypoxia. So maybe there's a clue, right?

• 53:51Lester Nare?

  Very interesting.

• 53:52Krishna Choudhary?

  I mean, the brain consumes something like 20% of the body's oxygen. So it makes sense that if the oxygen is low, the brain is one of the first things that's gonna go, right?

• 54:01Lester Nare?

  It doesn't have the, the, the raw materials to do the things it normally does, part of which is this, the myelination process.

• 54:07Krishna Choudhary?

  Exactly. And that's where this current paper comes in. So it's out of Shanghai Jiaotong University. It's a bunch of researchers that have published in Neuron that show that the genomes of these creatures has a amino acid change in a gene called retstat, which is retinol saturase. We're gonna get into what exactly that is. But that mutation in that gene is a gain of function mutation. But in this case, the gain of function is a natural gain of function that is caused by evolutionary mechanisms to let yaks and snow leopards and all of these animals survive in that hypoxic environment.

• 54:51Krishna Choudhary?

  The key thing is, this is across animals. This is conserved, this single mutation is conserved, not just in the yaks, it's in the Tibetan antelope. It's in multiple, which means that there is something there.

• 55:06Lester Nare?

  Yeah, it is, the substrate has some universality to it.

• 55:10Krishna Choudhary?

  Yeah.

• 55:11Lester Nare?

  But not the substrate, but there's a fundamental that has universality.

• 55:14Krishna Choudhary?

  Exactly, and it's a missense mutation, meaning it's not a mutation where the amino acid is unchanged. This is a different amino acid that has gone into the protein. So it has changed the structure of this protein that is coming from the gene, right? So there's something that is going on. And historically, this gene, I mean, it's been studied before because we study genes all the time. This retinol saturase, it's just been studied for the context of fat storage. That's been it. Now there could be something else, right? Because now all of a sudden, we found a mutation that is very specific to species that live in hypoxia. It's been found in yaks, it's been found in Tibetan antelopes, possibly others.

• 55:57Krishna Choudhary?

  So this convergent evolution, that signal is what told these researchers that there might be something going on.

• 56:05Lester Nare?

  And so just to set the table one more time, we've identified why in multiple sclerosis, like functionally what's happening. All the research.

• 56:16Krishna Choudhary?

  Demyelination.

• 56:16Lester Nare?

  Demyelination. All the research that led to this place of, we know how we need to deliver to the source to solve the problem. But we've been unable to solve the problem because we can't target the therapeutic enough to not degrade other systems.

• 56:34Lester Nare?

  In a separate lane from that setup. This idea of studying the evolution across other animals on planet Earth has actually led to therapeutic solutions in humans and other use cases. The famous one we talked about being Ozempic, where we looked at gila monster venom. And its ability to basically make, allow you to survive with less blood sugar, which is great if you wanna manage.

• 57:03Krishna Choudhary?

  Diabetes type two.

• 57:05Lester Nare?

  And.

• 57:05Krishna Choudhary?

  Or obesity.

• 57:06Lester Nare?

  Or obesity. And so the methodology of looking at other evolutionary examples to solve problems in humans has been wildly successful already.

• 57:15Krishna Choudhary?

  Yeah.

• 57:17Lester Nare?

  And in this environment, it's notable that this is coming out of several Chinese universities.

• 57:23Krishna Choudhary?

  Yeah.

• 57:23Lester Nare?

  Who have.

• 57:24Krishna Choudhary?

  The main author is from Shanghai, but yeah.

• 57:27Lester Nare?

  Across, it's a big team. Who have proximity to Tibet.

• 57:31Krishna Choudhary?

  Yep.

• 57:32Lester Nare?

  So it's a context where they understand, they'll have, you know. Regional reference points for this.

• 57:37Krishna Choudhary?

  And there's, I think, I think there's also a government sort of effort to get the genomes of all of its exotic animals.

• 57:48Lester Nare?

  Which makes sense.

• 57:49Krishna Choudhary?

  In China, which makes sense, totally.

• 57:51Lester Nare?

  Because of exactly what we're talking about. Who knows what benefits come out of having the information? And so they've now found that in these low oxygen environments, a variety of species have been able to find a way to live.

• 58:06Krishna Choudhary?

  Yeah. And specifically combat white matter degradation.

• 58:11Lester Nare?

  Which is related to this, the problem with MS. And so we're trying to see, is there a bridge?

• 58:18Krishna Choudhary?

  Yes.

• 58:19Lester Nare?

  Now between these two things. We've defined sort of both Lego blocks of the ideas. And we're gonna try to see if we can build a bridge between these two things.

• 58:26Krishna Choudhary?

  Yes, exactly. And that's where we're going with this, okay? So the researchers said, okay, we've got this substitution at the 247 locus.

• 58:37Krishna Choudhary?

  And this is a gain-of-function mutation because clearly this thing is doing well, right? This thing is causing the individuals, the species, to actually create white matter even under environmental stress, even under the stress of low oxygen. First of all, how do they actually prove that, right? They actually proved that by engineering a genetic knock-in mouse model.

• 59:02Lester Nare?

  Okay.

• 59:02Krishna Choudhary?

  So you can take these mouse models that are in the lab and you can take the red stat Yak version and replace the red stat mouse version with the red stat Yak version. So now these genetic mouse models have the red stat Yak version.

• 59:17Lester Nare?

  We're changing the-

• 59:18Krishna Choudhary?

  So you've got the control and you've got the Yak version.

• 59:20Lester Nare?

  We're basically just changing the genetic ingredients and seeing what comes out at the end.

• 59:24Krishna Choudhary?

  Yeah, yeah. And we're trying to see, okay, does this thing play a role in protecting brain health? This is like the first thing that you do if you're a grad student that's assigned to this project. Is there a there there that can then turn into this massive neuron paper? Turns out, yes. The way they did it was really quite simple. They had the wild type, which is the control, and they had the red stat knock-in mice. And they exposed these knock-in mice and the control mice to hypoxia. They put it in a chamber where it mimicked the amount of oxygen that's there at 5,000 meters or whatever the Tibetan Plateau is.

• 1:00:03Krishna Choudhary?

  You subject it to something called a Morris Water Maze, which is the, imagine you've got like a circular sort of water tank and you've got a single spot of a platform just under the water. So the mouse can't actually see where the, where the platform is. But if it gets to the platform, it gets like cheese or something. It's got to swim around and it's only seeing the cues of the walls. Like there's like patterns on the walls that tell it where it is in the water maze. Now, pretty soon, if you're a smart mouse and everything is working, you're gonna do a random walk, random swimming to figure out where the platform is. And then, once you're on the platform, you're gonna notice, given the cues on the outside, where I am.

• 1:00:46Krishna Choudhary?

  And then the subsequent trials, I'm gonna be way faster, right? What they noticed was that the wild type, under hypoxia, did not learn. But, and that's why you see the wild type, as the days go by, the amount of time that it takes to get to the platform stays the constant. But the, the ones with the red stat-

• 1:01:07Lester Nare?

  Yeah.

• 1:01:08Krishna Choudhary?

  Very rapid learning.

• 1:01:10Lester Nare?

  Yeah.

• 1:01:10Krishna Choudhary?

  Right? So the brain is functioning normally for the ones with red stat. What this shows is, one, the red stat knock-in thing is working.

• 1:01:16Lester Nare?

  Yeah.

• 1:01:17Krishna Choudhary?

  And, two, the red stat is crucial for brain functioning in low oxygen environments. So we've done our job in creating a biological model that I can now use in the lab to manipulate and understand what exactly is going on here.

• 1:01:31Lester Nare?

  Yeah.

• 1:01:31Krishna Choudhary?

  Right?

• 1:01:31Lester Nare?

  Yep.

• 1:01:32Krishna Choudhary?

  That's, that's, that's the main idea.

• 1:01:33Lester Nare?

  We were able to replicate what happens in nature in a lab, which means we can then make it repeatable.

• 1:01:38Krishna Choudhary?

  Yeah, exactly.

• 1:01:39Lester Nare?

  For our own purposes.

• 1:01:40Krishna Choudhary?

  Yeah. Now, the second hypothesis is that the red, I mean, this was all a behavioral assay. What about the myelin? Is it actually doing the thing that the myelin is doing? And yes, you can go in and look at the, the, the brain slices and see if you stain the myelin, the wild type has, in normal oxygen environments, the wild type has certain amount of myelin.

• 1:02:00Lester Nare?

  Yes.

• 1:02:01Krishna Choudhary?

  And if you look in the hypoxia environment, the wild type does not have that myelin. So clearly, the myelin is getting degraded.

• 1:02:07Lester Nare?

  Which is what happens in MS.

• 1:02:08Krishna Choudhary?

  Which is what happens in MS and what happens in normal individuals when they go to Tibet and hang out for way too long. Like if you go to Mount Everest, that's why you need oxygen, is because this is happening, right? But for the ones with red stat, you've got normal amounts of myelin. So the second hypothesis is also making sense. That the red stat has something to do with the maintenance of myelin in low oxygen environments. Is that clear?

• 1:02:33Lester Nare?

  Very much so.

• 1:02:34Krishna Choudhary?

  Okay. So now we're gonna move on and understand how is red stat doing that? Okay, so we know that the red stat has something to do with myelin maintenance. But from what I've previously told you, that has to do with these oligodendrocytes, right? And the progenitor cells, those stem cells becoming oligodendrocytes.

• 1:02:52Lester Nare?

  OPCs.

• 1:02:53Krishna Choudhary?

  Oh, the OPCs, yeah, becoming the myelin sheets.

• 1:02:56Lester Nare?

  Yes.

• 1:02:57Krishna Choudhary?

  Does the red stat have something to do with that pathway?

• 1:03:00Lester Nare?

  Hmm, okay, okay.

• 1:03:01Krishna Choudhary?

  Right? Because that's, that's what I love about this. It's like very gradually, I was just following the figures in the main text. And they're telling a story of like, first, we established red stat has something to do with myelin survival in hypoxia. Now, does it have something to do with repairing the myelin specifically? And that's where we get into these lesion studies. What you can do is you can have LPC-induced demethylation. Basically, you take like a kind of poison and you micro-inject it into parts of the brain. And so you see like in the top row, there's like a hole-

• 1:03:35Lester Nare?

  Yes.

• 1:03:35Krishna Choudhary?

  In the green, the green is, is tagging the myelin and you've, you've created like kind of a hole, right?

• 1:03:43Krishna Choudhary?

  On the bottom row, there's no hole. The top row is the control. The hole cannot be repaired, but on the bottom row, because of the red stat, the hole was repaired. This is basically, I think this was 15 days, 14 days after the initial injury. So they've done some kind of injury and you're seeing that that injury is persisting in the control, under hypoxia. But in the red stat-

• 1:04:07Lester Nare?

  Incredible.

• 1:04:08Krishna Choudhary?

  Right? So now, now, now, now we're on to it.

• 1:04:10Lester Nare?

  Because this is, this is different than, what we're pointing to here specifically is the ability to,

• 1:04:18Lester Nare?

  for the, the regenerative, once you've created this problem-

• 1:04:22Krishna Choudhary?

  Yeah, the lesion.

• 1:04:23Lester Nare?

  The lesion.

• 1:04:23Krishna Choudhary?

  This is, and this is like simulating what MS would do.

• 1:04:26Lester Nare?

  Would do. You're actually doing the thing that MS doesn't do, which is the OPCs go through their pathway to then become the oligodendrocytes that can now re-melanate.

• 1:04:38Krishna Choudhary?

  Yeah.

• 1:04:39Lester Nare?

  And it's not happening in the control.

• 1:04:41Krishna Choudhary?

  Yes.

• 1:04:41Lester Nare?

  Which is what we would see in an MS patient. But when we have the reset, it is happening. So now we've made the connection, not only to the hypoxia environment, but specifically to this idea that the stem cell can get to its adult maturity and redo the repair process that we're actually trying to target, starting from this evolutionary inspiration.

• 1:05:03Krishna Choudhary?

  Exactly. And so we're getting down to the mechanism, but we're still not there yet.

• 1:05:07Lester Nare?

  Okay.

• 1:05:08Krishna Choudhary?

  Right? Because so far, what, what have we established? We've established that this new gene that's in Yaks, it can re-melanate lesions. How is it doing it though? Right? Now we get into the process. This is the detective work. We're digging deeper and deeper into now trying to understand what is the exact molecular pathway that is going to get us there, because that is how we get a therapy.

• 1:05:31Lester Nare?

  Right.

• 1:05:31Krishna Choudhary?

  Right? We're not gonna get a therapy by like genetically modifying patients. That's not what we're doing.

• 1:05:36Lester Nare?

  Right.

• 1:05:36Krishna Choudhary?

  We're trying to figure out what is the gene doing?

• 1:05:39Lester Nare?

  Right.

• 1:05:39Krishna Choudhary?

  And can we maybe hijack that pathway?

• 1:05:42Lester Nare?

  Yes.

• 1:05:43Krishna Choudhary?

  Right?

• 1:05:44Lester Nare?

  Yes.

• 1:05:44Krishna Choudhary?

  Okay. So let's move on. And this is where we get into a weird, weird discovery.

• 1:05:49Lester Nare?

  Okay.

• 1:05:50Krishna Choudhary?

  What you would think, based on that previous, based on that previous photo, is that the stem cells are creating the oligodendrocytes, right? Which is then populating the myelin. So this has something to do with the oligodendrocytes. This is an innate mechanism within the stem cells, within the oligodendrocytes, that is doing the repair. They did a bunch of studies, which I'm not gonna show here because, I mean, they have so many amazing figures. But one of the figures that we're gonna skip here is, they put in the gene and expressed it only in the stem cells, the precursor cells, the oligodendrocyte precursor cells.

• 1:06:30Lester Nare?

  Yes.

• 1:06:30Krishna Choudhary?

  Naively, you would think, that's all I need, right?

• 1:06:34Lester Nare?

  Right.

• 1:06:34Krishna Choudhary?

  If the oligodendrocytes have this new gene and those are the ones that are doing the repair, then it should be enough to do the repair. Nothing happens. Okay? So somehow the gene is affecting the stem cells to become myelin, but the gene has nothing to do with those stem cells. There's a intermediary.

• 1:06:57Lester Nare?

  So yeah, so you introduce it into the environment, like, but it's not a direct correlation.

• 1:07:01Krishna Choudhary?

  Yeah. If you, if you introduce it to the entire genome, that's what they did with these mouse models, right? It's like, all of the cells now have this gene, it works. If only the myelin sheath cells have this gene, it doesn't work. But that doesn't, it's kind of weird because the myelin sheath is the thing that is doing the repair, but it's not working. The next, the next figure, we're gonna see the, the kind of resolution here. They expressed the genes only in the neurons. And all of a sudden, you get a recovery of that oligodendrocyte's coming back and the myelin coming back.

• 1:07:36Lester Nare?

  As opposed to doing it in the OPCs.

• 1:07:38Krishna Choudhary?

  Yes. That's weird.

• 1:07:39Lester Nare?

  That is weird.

• 1:07:40Krishna Choudhary?

  It's weird. It's like, it's like the neurons are doing something-

• 1:07:44Lester Nare?

  That is-

• 1:07:45Krishna Choudhary?

  That is then telling the OPCs to come and help me out. Help me. Help, help me. Yeah. That's what's happening, right?

• 1:07:54Lester Nare?

  But, but that's an interesting point, which is, you know, sometimes the, the, the site of where the, the solution arises, which is these OPCs that ultimately mature and then are the ones that create the myelin sheath. It's actually could be that what is signaling it, that's really where you need to target. And this is part of, I think, what we're trying to say we're getting in here.

• 1:08:16Krishna Choudhary?

  Exactly. And I had told you earlier that like, the problem was not that the OPCs were not there.

• 1:08:21Lester Nare?

  Correct.

• 1:08:21Krishna Choudhary?

  The problem was that the signaling was not there. They didn't know what to do. Perhaps, perchance, the neurons are signaling them to do this correctly. And the retstat genome, that gene, that mutation, is giving the neurons the ability to correctly tell the oligodendrocytes, hey, I need help.

• 1:08:40Lester Nare?

  The, the, I need help signal was basically, which goes from the neurons to the OPC. There, there was a breakdown in communication.

• 1:08:48Krishna Choudhary?

  Yep.

• 1:08:49Lester Nare?

  And that seems to now be where we're centering in as like, the cause of the problem.

• 1:08:54Krishna Choudhary?

  Yeah.

• 1:08:55Lester Nare?

  And so we were looking in all the wrong places before.

• 1:08:58Krishna Choudhary?

  Yeah.

• 1:08:58Lester Nare?

  We had to do all that discovery work.

• 1:08:59Krishna Choudhary?

  Yeah, yeah, yeah.

• 1:09:00Lester Nare?

  We had to rule things out. And now it's, okay, actually, the thing that is giving the proper instruction is where the degradation is actually problematic.

• 1:09:11Krishna Choudhary?

  Yeah.

• 1:09:12Lester Nare?

  And it's in the source that needs the protection, which is the neuron.

• 1:09:15Krishna Choudhary?

  Exactly. Yeah. And so now we're honing in on this signaling, right?

• 1:09:20Lester Nare?

  Yeah, yeah, yeah.

• 1:09:20Krishna Choudhary?

  Perhaps it's something called paracrine signaling. It's simply like a chemical message or some kind of raw material that the neuron is producing. It's being secreted into the local neighborhood. And then the, the oligodendrocytes are catching it and being like, oh, this guy needs help. I need to go get there. They did, they performed, you know, because even now, what is the mechanism of this signaling?

• 1:09:44Lester Nare?

  Right.

• 1:09:44Krishna Choudhary?

  Is the signaling neuron to oligodendrocyte, straight up? Or is it something more general where the neuron just like, puts out a PSA on Twitter?

• 1:09:53Lester Nare?

  Yeah.

• 1:09:53Krishna Choudhary?

  And then, and then those who are interested come and help him, right? Is it a DM or is it a full tweet?

• 1:09:59Lester Nare?

  Or is there an intermediary?

• 1:10:01Krishna Choudhary?

  Yeah.

• 1:10:01Lester Nare?

  That is a secret, is it a back channel?

• 1:10:03Krishna Choudhary?

  Yes. Yeah. Now, these are all the possibilities, right? And we need to, we need to figure that out. So how did they, how did they figure out what, which is what?

• 1:10:11Lester Nare?

  How do we know?

• 1:10:12Krishna Choudhary?

  How do we know? Here's what they did. They took something called a conditioned medium, which is a liquid bath that surrounds the cultured cells. So here's what you do. You express the mutation, the retstat mutation, the Yak mutation in the neurons. Presumably, the neurons are going to secrete something, and then that's going to go to the oligodendrocytes. How do we know that it's not a DM and just a, just a, uh, something that I'm secreting into the environment?

• 1:10:36Lester Nare?

  A tweet.

• 1:10:37Krishna Choudhary?

  Right? What I can do is I can take the medium, the cells have like some, you know, the, the medium that they grow in. And if the neurons are really just secreting into the environment, and it's not a direct signal, then I can extract that medium. And I can now put it into another wild-type control.

• 1:10:55Lester Nare?

  And it would?

• 1:10:56Krishna Choudhary?

  And the, the precursors should see this.

• 1:11:00Lester Nare?

  The signal.

• 1:11:01Krishna Choudhary?

  The signal and start myelinating.

• 1:11:03Lester Nare?

  Because if it was a tweet to everybody, it would be.

• 1:11:06Krishna Choudhary?

  It would be in the environment.

• 1:11:08Lester Nare?

  In the, in the, yes.

• 1:11:09Krishna Choudhary?

  And that's exactly what we see.

• 1:11:10Lester Nare?

  Oh, my goodness. Okay.

• 1:11:12Krishna Choudhary?

  It's a nice, like, it's a nice progressive kind of, ah, we're getting somewhere.

• 1:11:16Lester Nare?

  Yeah, yeah, yeah, yeah.

• 1:11:17Krishna Choudhary?

  Right? The story is very cool, um, from one figure to the next. And so here on the, on the bottom, we're seeing the, the medium.

• 1:11:25Lester Nare?

  Mm-hmm.

• 1:11:25Krishna Choudhary?

  And you're seeing a lot more green dots.

• 1:11:27Lester Nare?

  Mm-hmm. Yep.

• 1:11:28Krishna Choudhary?

  And that's from, and that's from this, this, um, these neurons.

• 1:11:33Lester Nare?

  So this is so interesting. So we've now identified that the, the challenge with, uh, the, the degradation of myelin, uh, which we initially thought might have been because it wasn't going from baby OPC to these oligodendrocytes that were the thing that created and fixed myelin sheaths as things happen.

• 1:11:55Krishna Choudhary?

  Yeah.

• 1:11:56Lester Nare?

  So we thought maybe there's something in the maturity process of that that's problematic. And it ended up not being true. We looked at this evolutionary, you know, reference point from high altitude Tibetan animals. We found something that works for hypoxia that seemed like it was connected. We established that, uh, with the restat.

• 1:12:13Krishna Choudhary?

  It definitely was connected somehow.

• 1:12:15Lester Nare?

  It definitely is connected somehow, but we didn't quite know how. And back to where we started at the beginning, it wasn't clear that the problem was that, because the OPCs were present in MS patients.

• 1:12:27Krishna Choudhary?

  Yeah.

• 1:12:27Lester Nare?

  And so it wasn't that they weren't there anymore. It seemed to be that the, the trigger to do the job.

• 1:12:35Krishna Choudhary?

  Yeah.

• 1:12:35Lester Nare?

  Was breaking down.

• 1:12:37Krishna Choudhary?

  Exactly.

• 1:12:37Lester Nare?

  But we didn't know where the trigger was being triggered from.

• 1:12:40Krishna Choudhary?

  Yes.

• 1:12:40Lester Nare?

  Who's the captain that's giving orders?

• 1:12:42Krishna Choudhary?

  Yes.

• 1:12:43Lester Nare?

  Through this process that the team, this team in Shanghai did, we've now found that the neuron is the captain.

• 1:12:51Krishna Choudhary?

  Exactly.

• 1:12:51Lester Nare?

  That is triggering the instruction for the OPCs to get the proper instruction to mature, to then go to the process to recreate the myelin sheath.

• 1:13:00Krishna Choudhary?

  Yeah.

• 1:13:01Lester Nare?

  And it's sending those instructions not in a discreet way, like a DM. It's just literally blasting the signal out.

• 1:13:08Krishna Choudhary?

  Yeah. It's like, I need help.

• 1:13:09Lester Nare?

  And so what makes sense is, uh, there's a, what, the neuron is the source of the problem, and it's not tweeting, and it's private messaging itself, or it just, it sets its account on private, and no one can see its tweets.

• 1:13:23Krishna Choudhary?

  Yeah.

• 1:13:24Lester Nare?

  As a crude, annoying analogy.

• 1:13:26Krishna Choudhary?

  Hundred percent.

• 1:13:27Lester Nare?

  And that's, that's the, the functional, so now, and we know, because when we, when we took the tweet from one environment and put it around things that we're not exposed to the tweet initially, it started to do the.

• 1:13:38Krishna Choudhary?

  Started to do the thing.

• 1:13:39Lester Nare?

  So we know that that's true.

• 1:13:41Krishna Choudhary?

  We know that that's true, and now we just need to hone in on what the tweet is.

• 1:13:44Lester Nare?

  What is the tweet?

• 1:13:45Krishna Choudhary?

  What is the compound that is doing this? Because if we could make this compound.

• 1:13:50Lester Nare?

  Right. Right.

• 1:13:51Krishna Choudhary?

  Then maybe we could, maybe we could solve this problem.

• 1:13:54Lester Nare?

  Very, yes. Okay.

• 1:13:55Krishna Choudhary?

  So now we've established that there is something in that medium, in that cultured medium, that we can transfer from one to the other.

• 1:14:02Lester Nare?

  And it works.

• 1:14:02Krishna Choudhary?

  And it works.

• 1:14:03Lester Nare?

  That's, that's low-key crazy.

• 1:14:05Krishna Choudhary?

  Yeah. It's, it's, I, I think it's, it's really cool, just the, the story of this whole thing. So now what could that signal be? Well, we've got retinol, which is vitamin A, and that enters cells and gets processed in two major branches. One way is just the classical branch, which is retinol into retinal, into retinoic acid. Chemists are so annoying about this, right? It's like, come on, guys. Anyways, the other way, which is mediated by this retstat gene.

• 1:14:32Lester Nare?

  Which we, which we discovered through studying these Tibetan, the.

• 1:14:36Krishna Choudhary?

  Well, no, actually, the retstat gene is something that's been discovered before.

• 1:14:39Lester Nare?

  Before.

• 1:14:40Krishna Choudhary?

  This mutation was discovered through the, yeah.

• 1:14:42Lester Nare?

  The specific mutation of the gene.

• 1:14:44Krishna Choudhary?

  And, and we know that the, the retstat gene does this, which is it takes retinol, and then it puts it into something called ATDR, which is 13-14 dihydroretinol. It's effectively an isomer type of thing, where you take the retinol, you remove some double bonds, make them single bonds and things like that. And here, we can see that the ATDR, that retin, the, the retstat mediated thing that is coming out of the vitamin A, that is going up.

• 1:15:15Lester Nare?

  Mm-hmm.

• 1:15:16Krishna Choudhary?

  Okay? The concentration of this particular compound is going up because of this gene.

• 1:15:22Lester Nare?

  Mm-hmm. Yes.

• 1:15:23Krishna Choudhary?

  Okay.

• 1:15:23Lester Nare?

  So we're making, we've now made the causal link between the presence of this gene mutation.

• 1:15:29Krishna Choudhary?

  And now a specific compound.

• 1:15:31Lester Nare?

  Compound, this ATDR, being present.

• 1:15:33Krishna Choudhary?

  Yeah.

• 1:15:34Lester Nare?

  Which we see in these spikes in that top section with the restat and restat Q24.

• 1:15:38Krishna Choudhary?

  Yeah, yeah. And you can see that the second spike is larger than the control.

• 1:15:42Lester Nare?

  Yeah.

• 1:15:42Krishna Choudhary?

  Which means that you've got, this is that gain of function that I was talking about, right?

• 1:15:46Lester Nare?

  Right.

• 1:15:46Krishna Choudhary?

  Like, this, this particular mutation is giving me more ATDR. And perhaps that more signal.

• 1:15:52Lester Nare?

  Yes.

• 1:15:53Krishna Choudhary?

  Is telling the OPCs and the stem cells, hey, I need more myelin.

• 1:15:57Lester Nare?

  It's, it's now loud enough.

• 1:15:59Krishna Choudhary?

  Yes.

• 1:15:59Lester Nare?

  When we have the, because, so actually, this is a good point. So the, in the three top charts, right? The second and third, the restat and the restat Q24, that second, the third one, all the way to the right.

• 1:16:09Krishna Choudhary?

  That's the, that's the Yak version.

• 1:16:11Lester Nare?

  That's the mutation.

• 1:16:12Krishna Choudhary?

  Yeah.

• 1:16:12Lester Nare?

  And then the one in the middle is just like.

• 1:16:14Krishna Choudhary?

  It's control.

• 1:16:14Lester Nare?

  Standard operating procedure.

• 1:16:15Krishna Choudhary?

  Yeah.

• 1:16:16Lester Nare?

  And so potentially, it's the, unless the AT, the ATDR being at a particular level might be the tipping point.

• 1:16:24Krishna Choudhary?

  Yes.

• 1:16:24Lester Nare?

  And if it's below a particular level.

• 1:16:26Krishna Choudhary?

  In hypoxia, it might be a tipping point.

• 1:16:27Lester Nare?

  Yes.

• 1:16:28Krishna Choudhary?

  Exactly.

• 1:16:28Lester Nare?

  Okay.

• 1:16:28Krishna Choudhary?

  And perhaps in MS.

• 1:16:29Lester Nare?

  It might be a tipping.

• 1:16:30Krishna Choudhary?

  It might be a tipping.

• 1:16:31Lester Nare?

  That's the connection we're trying to, that's the bridge again from before that we're trying to draw.

• 1:16:34Krishna Choudhary?

  Yeah. So, okay, what if I just add ATDR?

• 1:16:38Lester Nare?

  Right, right.

• 1:16:39Krishna Choudhary?

  Is that going to be enough?

• 1:16:42Krishna Choudhary?

  Biology is never so kind.

• 1:16:44Lester Nare?

  It's never so simple.

• 1:16:45Krishna Choudhary?

  Right? In H, you can see that if I, if I, um, if I add the ATDR, um, all of those, all of those bars are, are about the same. There's an NS on top of them. What that means is not significant. There is no significant difference between whether I add it and whether I don't in the control or in the restat, whatever, right?

• 1:17:05Lester Nare?

  Okay.

• 1:17:06Krishna Choudhary?

  So clearly ATDR is not everything. But in the K1, if I add ATDR to the neurons and then I culture it, remember the ATDR is the stuff that came out of the red stat, right? It's the control even makes the red stat. The control even makes the ATDR. If I add that to my OPCs, then all of a sudden I get this effect.

• 1:17:29Lester Nare?

  Okay.

• 1:17:29Krishna Choudhary?

  So there is something else. This proves that ATDR is just a precursor. And the neurons are doing something else with that ATDR, right?

• 1:17:38Lester Nare?

  Yeah, yeah, yeah. Okay.

• 1:17:39Krishna Choudhary?

  So not only am I getting more of ATDR, but the neurons are doing something more with that more ATDR.

• 1:17:46Lester Nare?

  So it's almost like it's, it is a, um, just by having the neurons, it's a, it's a fundamental uh, ingredient for whatever it is the neurons are doing, but it is not the solution in and of itself.

• 1:17:59Krishna Choudhary?

  Yes. And one of the inclinations that these guys had, one of the inclinations that these guys had was, well, the ATDR, which is um, a second, you know, it's a version two of vitamin A of the retinol. There's a version three, which is ATDRA. It's just ATDR with an acid. Okay. It's the acidic version of that, that maybe this thing is maturing into.

• 1:18:22Lester Nare?

  Ah.

• 1:18:23Krishna Choudhary?

  Okay?

• 1:18:23Lester Nare?

  Okay.

• 1:18:24Krishna Choudhary?

  When they add that, they get a massive spike. They get a massive spike. So all of those columns are all of the different permutations and combinations of what I could add to my, to my cells. They were like, okay, look, I don't know.

• 1:18:38Lester Nare?

  Yes.

• 1:18:39Krishna Choudhary?

  What, what's going on? Let's just do all of the permutations and combinations. And if you look at the fifth column.

• 1:18:44Lester Nare?

  Yep.

• 1:18:45Krishna Choudhary?

  You can see a bunch of myelination happening. That is with ATDRA alone, with the acidic version of this.

• 1:18:52Lester Nare?

  So when we introduced the ATDRA.

• 1:18:55Krishna Choudhary?

  The acidic version.

• 1:18:56Lester Nare?

  We are seeing things, things happen now.

• 1:18:58Krishna Choudhary?

  Yeah.

• 1:18:59Lester Nare?

  And so we were, the ATDR base was directionally helpful.

• 1:19:03Krishna Choudhary?

  Yep.

• 1:19:04Lester Nare?

  And it's just like, it's like a slightly, it's a slightly different permutation of it.

• 1:19:09Krishna Choudhary?

  Yes. And, and the key insight here, and that's, that's effectively the punchline, is this ATDRA, this acidic version of the vitamin A derivative. That is the selective activator of the RXR gamma.

• 1:19:25Lester Nare?

  Bingo.

• 1:19:26Krishna Choudhary?

  Right?

• 1:19:27Lester Nare?

  Bingo.

• 1:19:27Krishna Choudhary?

  The, the, the failed trial.

• 1:19:29Lester Nare?

  The Bexa routine from earlier.

• 1:19:31Krishna Choudhary?

  Yes, the Bexa routine from earlier that was not only targeting gamma, but also targeting everything.

• 1:19:36Lester Nare?

  Yes.

• 1:19:37Krishna Choudhary?

  Now we've got a selective activator that is going to target only the gamma.

• 1:19:42Lester Nare?

  And, and so, and what's so, this is perfect because from, from earlier, when we talked about, we were, we had identified the uh, RXR as like the, where we needed to target.

• 1:19:53Krishna Choudhary?

  That, that's what we gotta.

• 1:19:55Lester Nare?

  Do for the therapeutic, but we couldn't target it selectively enough. We figured out the size problem for delivery. We did not figure out the targeting problem. The ATDRA is the solution to the targeting problem we defined earlier in the show.

• 1:20:07Krishna Choudhary?

  Yeah, exactly. And so how do we make sure, right? The, and this is where we get in the translational payoff of the entire study, right? We, we've established the science.

• 1:20:18Lester Nare?

  Yes.

• 1:20:19Krishna Choudhary?

  Now can this actually work as something that perhaps could combat MS and maybe even reverse the effects?

• 1:20:26Lester Nare?

  Can we deliver the actual solution?

• 1:20:28Krishna Choudhary?

  Yeah. So they, they got young mice, they exposed them to low oxygen. And then those young mice received injections of ATDR and ATDRA. Both molecules actually reduced that impact of hypoxia. Okay. So both molecules actually worked. It makes sense because a mouse brain has neurons. It got the ATDR, which it wasn't getting earlier because, I mean, this is in control, remember? Okay. This is in control that don't have that mutation. So this is normal mice.

• 1:21:01Lester Nare?

  Yep.

• 1:21:02Krishna Choudhary?

  But we're giving them the stuff that the mutation makes.

• 1:21:05Lester Nare?

  Yes.

• 1:21:06Krishna Choudhary?

  And it's working.

• 1:21:06Lester Nare?

  Yeah.

• 1:21:07Krishna Choudhary?

  You're getting re-myelination.

• 1:21:08Lester Nare?

  Yeah, yeah, yeah, yeah, yeah.

• 1:21:10Krishna Choudhary?

  Okay?

• 1:21:10Lester Nare?

  Oh my goodness.

• 1:21:12Krishna Choudhary?

  And the, the, the killer is really the next one.

• 1:21:15Lester Nare?

  Yes.

• 1:21:15Krishna Choudhary?

  The next one is, so, because this was, this was hypoxia. Now what if we straight up go in lesion?

• 1:21:21Lester Nare?

  Right. Which are the two, this is.

• 1:21:23Krishna Choudhary?

  Right. Cause hypoxia, I don't know, it could be doing other things.

• 1:21:25Lester Nare?

  Right, right.

• 1:21:26Krishna Choudhary?

  What if we, now, normal, normal environment, but we go ahead and we do a lesion. Do we get, uh, like in an MS like brain, there are these things called autoimmune encephalomyelitis, EAE. These types of mice are basically a standard model for multiple sclerosis because they mimic a lot of the, a lot of the effects. And there you can see the control has not that much myelin. But the ones that get ATDR, this particular type of mouse brand that mimics MS, if you give it ATDR, you don't have to give it ATDRA, just even ATDR, which is way simpler to make actually. You're getting a lot more myelination. The myelination volume is increased.

• 1:22:10Lester Nare?

  Which is what we want to see.

• 1:22:12Krishna Choudhary?

  Yep.

• 1:22:12Lester Nare?

  The repair process is, is reactivating. It's becoming successful again.

• 1:22:16Krishna Choudhary?

  Yep.

• 1:22:16Lester Nare?

  This is so, so, and so now we've, we've, we've weaved this story. Which is so, so good.

• 1:22:25Krishna Choudhary?

  Yeah.

• 1:22:26Lester Nare?

  To this point where we've now understood the current state of play with MS, what the limiting factors were for delivering a therapeutic, which was being able to target, target this RXR gamma.

• 1:22:39Krishna Choudhary?

  Yep.

• 1:22:40Lester Nare?

  We knew we, we needed to target RXR, but we couldn't selectively do so.

• 1:22:44Krishna Choudhary?

  Yeah, cause it was going everywhere.

• 1:22:46Lester Nare?

  We found this other pathway through looking at the evolutionary uh, progress.

• 1:22:53Krishna Choudhary?

  Yeah.

• 1:22:54Lester Nare?

  Of high altitude Tibetan animals and how they survive hypoxia, which are low oxygen environments. They're able to survive because in low oxygen environments, you see the same depletion of your myelin sheath that you do similarly in MS. And so whatever the active ingredient to their solution for the hypoxia problem, our intuition was like other evolutionary, you know, solutions, the Gila monster venom.

• 1:23:19Krishna Choudhary?

  Yeah, perhaps it's doing something.

• 1:23:20Lester Nare?

  Perhaps we can translate this into a biologic solution for humans. We've now gone to the point where we've found the selective targeting of RXR gamma through uh, uh, AD.

• 1:23:33Krishna Choudhary?

  ATDR.

• 1:23:33Lester Nare?

  ATDR slash.

• 1:23:35Krishna Choudhary?

  Slash ATDRA.

• 1:23:37Lester Nare?

  Uh, and there's some pros and cons to both.

• 1:23:39Krishna Choudhary?

  Yeah.

• 1:23:40Lester Nare?

  But like, we know how to target so that the neuron signals to the OPCs.

• 1:23:45Krishna Choudhary?

  Yeah.

• 1:23:46Lester Nare?

  To mature, to restart this process of creating the myelin.

• 1:23:49Krishna Choudhary?

  Exactly. And the ATDR, we can just put in because the neurons can take that and create.

• 1:23:54Lester Nare?

  The thing they need to do.

• 1:23:55Krishna Choudhary?

  The thing they need to do, right? We don't need to give the OPCs the, the signal in itself. We can just have the neurons do it.

• 1:24:02Lester Nare?

  Which is actually an important distinction.

• 1:24:04Krishna Choudhary?

  Yeah.

• 1:24:04Lester Nare?

  That's.

• 1:24:04Krishna Choudhary?

  Because the ATDR is a bit easier to make.

• 1:24:06Lester Nare?

  Right, right. That's an important point. Okay. Yes.

• 1:24:09Krishna Choudhary?

  Right? And so now we can finally understand the graphical abstract. We're finally here.

• 1:24:14Lester Nare?

  Okay.

• 1:24:15Krishna Choudhary?

  The wild type is on the left, the mutation is on the right. You've got a Himalayas in the background.

• 1:24:24Krishna Choudhary?

  Retinol goes to ATDR, goes to ATDRA. But on the right-hand side, the ATDRA has an up arrow. Because it's upregulated, that's that gain of function. And when that goes to the OPCs and the oligodendrocytes, the OPCs are the green cells.

• 1:24:42Lester Nare?

  Yep.

• 1:24:42Krishna Choudhary?

  When it goes to the OPCs, it creates myelin around my axon. On the left-hand side though, there's not enough signal to get the OPCs, those stem cells to become myelin. Okay? And so on the right-hand side, we're getting healthy myelin. On the left-hand side, we are not.

• 1:24:59Lester Nare?

  Not. Yeah. Yeah.

• 1:25:01Krishna Choudhary?

  And that's the graphical abstract.

• 1:25:02Lester Nare?

  And, and we, from something that was totally disconnected from anything, you'd be able to, to understand. We now have a reference point. And also like a fundamental understanding of one of the most, uh, you know, uh, impactful neurodegenerative, you know, issues we, we face as humanity, among others.

• 1:25:23Krishna Choudhary?

  Among others, yeah.

• 1:25:24Lester Nare?

  Which we've discussed.

• 1:25:26Krishna Choudhary?

  Any, any progress is good progress, right? And on the bottom, the, the, the two blue circles.

• 1:25:31Lester Nare?

  Yeah.

• 1:25:31Krishna Choudhary?

  On the left-hand side, you see a wild type mouse just doing random walks to get to the cheese, the Morse water maze. On the, on the right-hand side, it's getting there very, very quickly.

• 1:25:41Lester Nare?

  Because it's able to repair itself and maintain its cognitive functions.

• 1:25:45Krishna Choudhary?

  Very good.

• 1:25:45Lester Nare?

  Uh, in a way that the, the wild type cannot.

• 1:25:50Lester Nare?

  Oh, the bio stories, some of our best stories.

• 1:25:54Krishna Choudhary?

  Yeah. I mean, I just, it's incredibly difficult.

• 1:25:58Lester Nare?

  Yeah.

• 1:25:59Krishna Choudhary?

  To get this kind of granular understanding.

• 1:26:03Lester Nare?

  Yes.

• 1:26:04Krishna Choudhary?

  Of something so fundamental.

• 1:26:05Lester Nare?

  Yes.

• 1:26:05Krishna Choudhary?

  And it's just very cool, the amount of technology that we have in order to do this. Like so much had to, like, we know how to, we know how to stain myelin extremely well. We know how to make these mouse assays with any type of genetic mutation that we want. Not only that, we know how to express only that genetic mutation in neurons only.

• 1:26:28Lester Nare?

  Right.

• 1:26:28Krishna Choudhary?

  Or oligodendrocytes only, right? In order to establish it's not the oligodendrocytes, it's only, it's the neurons that are doing this.

• 1:26:34Lester Nare?

  Right.

• 1:26:34Krishna Choudhary?

  We had to express that gene in only the neurons, which is kind of crazy. And the way they do it is with like this kind of thing that the neuron creates a type of protein and then that protein is going to go in and trigger. Yeah, it's, I mean, incredible amounts of genetic engineering, bioengineering to get this kind of access. You know, and also just, it's just standard, like, scientific method.

• 1:27:00Lester Nare?

  It's, one would say they did it from first principles.

• 1:27:05Krishna Choudhary?

  It, one would say that, I certainly would, you know? And this is going to be incredible. The last few things I want to touch on is, you know, where this can, where this can help us. One is neonatal white matter injury. So preterm birth is highly associated with massive chronic diffuse white matter injury. Because when you have extremely low birth weight infants, the blood vessels in the brain are incredibly fragile. And so these precursor cells, these stem cells, they're very vulnerable to oxidative stress. And if the blood vessels are not properly in there, and now you've exposed this preterm infant to the world outside of the womb,

• 1:27:49Krishna Choudhary?

  you've got this risk factor where you've got severe cognitive delays, lifelong executive dysfunction. Because these stem cells, these progenitors are not getting enough oxygen. Well, maybe this ATDR, ATDRA pathway could fundamentally change that, right? Maybe you could take some of this evolutionary pressure that the Yaks have adapted to and make it some kind of therapeutic intervention.

• 1:28:17Lester Nare?

  Because in this context, it, the hypoxic stress is literally a one to one mapping.

• 1:28:23Krishna Choudhary?

  Yeah.

• 1:28:24Lester Nare?

  Uh, versus when we talked earlier about the MS, it's, it's, it's a few steps away.

• 1:28:28Krishna Choudhary?

  There's a few steps away. This one, it's like, is straight up just hypoxia. The other thing with hypoxia is a type of dementia called vascular dementia and small vessel disease. This happens in the elderly, estimated 57 million people live with dementia worldwide. Effectively, the blood vessels are getting damaged. And so if the blood vessels are getting damaged, you have oxygen deprivation in your brain. That's going to lead to neurodegradation, specifically in the white matter. Well, if you could have some kind of therapeutic retstat ATDR axis

• 1:29:06Krishna Choudhary?

  drug that mediates the same exact

• 1:29:12Krishna Choudhary?

  therapeutic axis that we've been discussing, then perhaps you have some way to slow this decay.

• 1:29:17Lester Nare?

  That would be so huge.

• 1:29:19Krishna Choudhary?

  Yeah.

• 1:29:20Lester Nare?

  I think one of the points that this brings up is the connection we've made by studying these high altitude Tibetan animals has multiple impact pathways. We started and referenced MS and some of these prenatal issues. But to your point, this like vascular dementia and potentially other things we're not even discussing in the scope of this episode have some connection points to utilizing this ADTR, ATDR, neuron, OPC, myelin sheath,

• 1:30:01Lester Nare?

  and other low oxygen regenerative benefit avenues that, you know, again, this is the idea that sometimes discoveries are discreet and have one application, and sometimes you have platforms.

• 1:30:16Krishna Choudhary?

  Yeah.

• 1:30:16Lester Nare?

  The classic example I always bring up is CRISPR.

• 1:30:19Krishna Choudhary?

  Mm hmm.

• 1:30:19Lester Nare?

  Right? Uh, you have multiple use cases for like one unlock.

• 1:30:24Krishna Choudhary?

  Yeah.

• 1:30:24Lester Nare?

  Um, and this could be a key that unlocks several doors.

• 1:30:28Krishna Choudhary?

  Yeah.

• 1:30:30Lester Nare?

  And another big, uh, another aspect to this story is the source.

• 1:30:36Krishna Choudhary?

  Yes.

• 1:30:36Lester Nare?

  Right? It was in neuron.

• 1:30:38Krishna Choudhary?

  Yeah.

• 1:30:39Lester Nare?

  But the team.

• 1:30:40Krishna Choudhary?

  Yeah.

• 1:30:41Lester Nare?

  It's from China.

• 1:30:41Krishna Choudhary?

  The team is out of China. Yeah.

• 1:30:43Lester Nare?

  Um, and as we've discussed several times on, on the pod, we're in a very different environment today than five, 10, 15 years ago, in how competitive some of these university institutions are in the frontier and not all spaces, but in some spaces.

• 1:31:00Krishna Choudhary?

  I would say most spaces, to be honest.

• 1:31:02Lester Nare?

  Right. And you can see that from the recruitment of some of the best talent across several frontier areas that are now arriving.

• 1:31:12Krishna Choudhary?

  Yeah.

• 1:31:12Lester Nare?

  In the Chinese university system. So we're going to continue to see, you know, it'd be a very competitive landscape.

• 1:31:18Krishna Choudhary?

  Yeah.

• 1:31:18Lester Nare?

  At the frontier of research.

• 1:31:20Krishna Choudhary?

  Yeah. I mean, and this was a phenomenal study. I mean, I just, I loved the narrative of it, the, the way the figures sort of told the story, just from a, from a even aesthetic and like, uh, you know, narrative point of view. I thought the paper was just very well written.

• 1:31:36Lester Nare?

  They know what they're doing.

• 1:31:37Krishna Choudhary?

  Yeah.

• 1:31:38Lester Nare?

  They're not just copying us in all ways.

• 1:31:41Krishna Choudhary?

  Yeah.

• 1:31:41Lester Nare?

  And, um, this was, you know, and for folks who may have friends or family members that are impacted by some of these things. Hopefully this may bring you a, just at least a better fundamental understanding of like what the body is doing. Uh, and why it is so difficult.

• 1:31:57Krishna Choudhary?

  Yeah.

• 1:31:57Lester Nare?

  Uh, to solve this problem. Again, frontier research and, and therapeutics, there is a large delta between these two things.

• 1:32:07Krishna Choudhary?

  Yeah. And the authors themselves make that point. There, there's a bunch of news, news articles where you can read quotes from the authors and they say, you know, there's, there's a giant delta, but you gotta do the science, you gotta do the work.

• 1:32:20Lester Nare?

  We gotta start somewhere. And so I just want to be careful about making this people's takeaway being, oh, there's going to be a solution.

• 1:32:27Krishna Choudhary?

  Yeah.

• 1:32:27Lester Nare?

  Soon for my loved one. That's not the story here.

• 1:32:30Krishna Choudhary?

  No.

• 1:32:31Lester Nare?

  But hopefully this helps you understand how we do get to these solutions.

• 1:32:34Krishna Choudhary?

  Yeah, yeah.

• 1:32:35Lester Nare?

  Um, and why they do take time. We've found a mechanism. We've not necessarily created the actual.

• 1:32:44Krishna Choudhary?

  Yeah.

• 1:32:45Lester Nare?

  End product, uh, but great story. Love the bio stuff. We will wrap up this week in half the time of the last, of the last episode. For those still listening, you can always catch our shows across all the main platforms, YouTube, Spotify, Apple Podcasts. Our clips will be on social. Instagram seems to love us. That's where we have our biggest audience. So if you want to catch these little snacks, little bite sized clips from this, uh, when you can, uh, be sure to follow us on Instagram, on Twitter, on Facebook, wherever you get your daily dose of brain rot. And hopefully we can give your feed a little bit of nice brain food.

• 1:33:31Lester Nare?

  Again, if you want to check out the website to become a donor, to check out all of our resources, ffpod.com is where you can go. We can give the listeners a prompt to let us know if they've made it to the end. Some of you, I do want to say, in the last episode, the Germany, the German clapback prompt.

• 1:33:51Krishna Choudhary?

  Those are, some of them are brutal.

• 1:33:53Lester Nare?

  Some of them were very good.

• 1:33:54Krishna Choudhary?

  Yeah, some of them.

• 1:33:56Lester Nare?

  Some of them were very good. Eventually, when we can do more production stuff, we'll pull them up live.

• 1:34:00Krishna Choudhary?

  Yeah, yeah.

• 1:34:01Lester Nare?

  It's beyond the scope of what we can do right now.

• 1:34:02Krishna Choudhary?

  Funny.

• 1:34:03Lester Nare?

  To people, so you guys did well.

• 1:34:04Krishna Choudhary?

  Yeah. Yeah, maybe I was thinking, you know, in the vein of evolutionary pharmacology, what's like one animal out there that you, you'd like want like an ability from or like, you know? Like, if we could do evolutionary pharmacology on, on an animal and like get some kind of, you know, ability, what, what, what would it be? For the gila monster, it was the low blood sugar. For the snake, it was the low blood pressure. So what, what do you guys think?

• 1:34:35Lester Nare?

  That's a great one. Uh, I am Lester Nare, joined as always by my co-host and our resident PhD, Krishna Choudhary. We are so happy for all of you who joined us for many of the new folks who may have caught some of our last four or five episodes that were super physics and math heavy. Welcome to the best general science show on earth. We cover everything and it'll just ebb and flow with what's in the news and where our timing is.

• 1:35:03Krishna Choudhary?

  And what we find interesting.

• 1:35:05Lester Nare?

  Next episode, it'll be coming up on our Labor Day weekend, so it might be a little bit more relaxed than normal. So we wanted to give you one last good, solid deep dive before we take a little bit of a half break. And we will see you all next week.