From First Principles - The Yak Mutation That Could Help Repair the Brain (EP 56)

Episode Date: September 7, 2026

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.SummaryWhat myelin actually does and why losing it disrupts neural communicationHow multiple sclerosis damages myelin and why the brain’s natural repair process eventually failsWhy oligodendrocyte precursor cells can remain present in damaged tissue without successfully rebuilding myelinWhy current therapies are better at slowing further damage than restoring what has already been lostThe challenge of getting drugs across the blood-brain barrier while maintaining target specificityHow evolutionary pharmacology has previously produced medicines from adaptations found in snakes and Gila monstersThe RETSAT Q247R variant identified in animals adapted to the hypoxic environment of the Tibetan PlateauHow researchers engineered the high-altitude variant into mice and tested its effect on myelinThe surprising discovery that neurons — rather than the myelin-producing cells themselves — generate the key repair signalHow RETSAT increases ATDR, which neurons convert into ATDRAHow ATDRA activates RXR-γ in oligodendrocyte precursor cells and promotes their differentiationHow administration of ATDR promoted remyelination across multiple preclinical modelsWhy the result is scientifically promising but still far from a proven human treatmentFeatured PaperA gain-of-function Retsat variant from high-altitude adaptation promotes myelination via a neuronal dihydroretinoic acid-RXR-γ pathwayNeuron, 2026DOI: 10.1016/j.neuron.2026.01.013Explore FFPffppod.comffppod.com/fundingffppod.com/transfersffppod.com/America250Support the showffppod.com/donateFollow@FFPPod on X / Instagram / TikTok / Facebook

So we've solved the delivery mechanism. We've not solved the targeting problem. 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 of these stem cells? And it doesn't trigger some random catastrophic activity elsewhere in the body. So we got past security, but our ticket didn't get us on the right plane.

Yeah, no, exactly. And that's where this current paper comes in. We're using nature to cheat on the test. Yes. Nature's been doing the test for way longer than we have. Yes, yeah, yeah. Hello, Internet. This is your captain speaking, Lester Nare, joined as always by my co-host and our resident PhD, Krishna Chowdery.

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, 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 for rebuilding myelin and how they worked backwards from that evolutionary clue to a potential drug strategy by the end of this episode. You'll 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. Multiple sclerosis, leukodistrophies, 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, um, the disease is a slow, relentless war of attrition against just neurodegradation and brain damage. It's, there. own immune system attacking the nervous system. 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. This would be huge.

I mean, as you mentioned, this is something that impacts a huge population of people globally. And it's extremely pernicious. because there's no rewind. 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, 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, very low, 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 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 l severe journals which is like neurons 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. They also... Being like a block of executive summary in text. 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. There's a lot of words and a lot of arrows. Yes. So before we do that, let's take a brief housekeeping note. 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. a like, share, a follow, a 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 ffpod.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 and get to our interactive apps

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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 is 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. And I'm excited for this because we've been on the quantum side for quite some time. Yeah, we've been on the physics and math side for quite some time.

That's true, yeah, because we had the Riemon and the Jacobian before that. And so getting back into some bio work, I think, is going to be refreshing for many folks who are listening. 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 dentistry, where all of the inputs come in, and then an axon where the output goes down to post-synaptic 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. Neurons use electricity to talk to one another. That's how they're fast.

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 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 and impulses are traveling down the arm or the left. to like break 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? 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.

The visual I think about is Black Friday, the inside of the store is locked. Everyone's standing on the outside. Yeah, yeah, yeah. And when you open all the doors. It's a rush. It's a rush, right? Usually it's this potassium, sodium, 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. So we're sort of into and out of the cell.

We're constricting it to specific spots where the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, the, 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 string the beads on top of it to put it on your wrist. Exactly. And the little gaps in between the beads is where the ions can actually go in and out. Yeah, and those would be the nodes of Ranvier.

Okay. Right? And the point is that without, without the myelin sheath, there would be ion channels everywhere along this cable. Yes. 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 going to travel really fast to the next gate to open up

that next channel. That makes total sense. Okay? It's kind of like, I mean, if we go back to your Black Friday analogy, right? It's like there's a entrance 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 going to, they're going to diffuse way quicker than if there's entrances all over and exits all over the place, then they're going to sort of meander. People start blocking. Yeah. 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. 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. When you put capacitors in series, the capacitance decreases. When you put resistors in parallel, the resistance decreases.

It's the one-over-sea 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. 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 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.

Notice the action potential is very slow. Yeah. On the right-hand side, you've got these nodes of Ranvier in between these myelin cells. Yep. boom boom boom boom boom boom the signal propagates a lot faster and and so again just as a simple way for me to think about this the myelin helps reduce the friction in some sense like right so things can just move yeah it it facilitates kind of like the charge coming in and all of that positive charge wanting to get the hell away from one another right there's not any

exits except for like way down there. 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. 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 immediately.

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 fallen 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. That entire way.

Okay? That entire thing is a single axon sometimes. There are single axons that go all the way down. Okay? It's incredible. 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 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 driver. It's just like doing some warm up reflex exercises. Well, they can do this. that because of the myelin sheath. So you're saying that Messi has a better mile in sheath than any other footballer ever. Yeah, maybe Ronaldo, but you know, I'm going to get a lot of hate for that. Let's see what the comments say about that. Hey, let me know. I am curious. How many are Ronaldo versus Messi? Yeah, I'm curious to see what the comments say. Some have said the goat debate is over,

but I'm not an expert. You know, you know, I'm certainly. not an expert, but I have an opinion. Okay, so 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 oligo dendrocyte.

This was identified by Spanish neuroanatomist. Can you... Pio de Rio Ortega. 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 processes around those neurons. So you know those myelin she's that I was talking about? Where 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. Yeah, yeah, yeah. In, Spider-Man, like, and it goes around and wraps around all of these axons nearby. Interesting. Okay.

Which is kind of cool to think about it. It's not a one-to-one sort of mapping. It's a single cell that's doing like 50 different electrical wires. It has this distributed placement of its, oh, that's actually very intriguing. And so this may be foreshadows some of the stuff that we're going to talk about, which is if there's a problem with these oligodendro sites, it's like not a single neuron problem. It becomes a single point of failure across multiple endpoints. Exactly. And that's what we're sort of building towards. That makes sense. Okay. 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. That's a mitochondria. The neurons have a bunch of mitochondria. powerhouse of the cell. It is the powerhouse of the cell and neurons need a lot of powerhouses of the cell because they need to maintain 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? Even with the mileage, you still need power. You still need a lot of power. And the myelin sheets actually, it's not just something that provides this capacitance tradeoff of like, like speed, the myelin sheath 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? Yeah, yeah, yeah.

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. That makes sense. For those who are listening, if you've ever eaten nerds rope and took a bite out of it and looked at the inside 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. Yeah, you know what I would say? It's like a Twizzler on the inside and then fruit roll up. Yeah, on the, you know?

Yeah, like wrapped around. Yeah, that's a great. Roll up. Yeah, that's a great point. Yeah. Yeah. We should have some fruit roll up in the studio. Actually.

Yeah. Anyways. So, Betty Ben Garen, 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 was something that maybe the neuron secreted because we don't know, right? You don't know. But she definitively showed that there's a single cell that goes around, this oligodendron side goes around and wraps around. And all of that is a single process that's doing it. The venom analogy is very visually compelling in the context of how to kind of visualize what that would mean.

Yeah. Right? Like the movement of it. And anyway. Exactly. 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, 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. You've got the gray matter on the outside.

That's mostly where the cell bodies are. 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. It's like that's the super highway and the gray matter are these islands that are connected by the white manner of this, the super highway system. Exactly. Exactly. So this is where we get into MS. Okay. 1868, French neurologist Jean Martin Charcot, I believe. And people might, it might be Charcot. Yeah, maybe. Anyways, he documented evidence of plaques in the white matter.

Okay? 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 time were abnormal eye movements, intention tremors, slurred speech. This became known as Sharcot's or Sharco'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. We saw people having these conditions we could see, these physiological happenings. Yeah. When you then went and did an autopsy after the fact, there was something in the brain that looked different than everybody else. Yeah, there's a control, and then there's...

So maybe these things may be connected. Yeah, yeah. And side note, Charcot was super into hypnosis. That's what he's most well known for. If you go back to that painting, this, uh, yes. Uh, yeah. Yeah,

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,

yeah. I can't believe you've done this. Yeah. Yeah. Yeah. So, uh, you know, you win some, you live some. Yeah, right.

Right. Um, so funny. So for, for nearly a century, though, this was in 1868. For nearly a century, MS was a disease without a mechanism. Yeah, yeah.

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 proteolypid protein. And then also with the development of MRIs, we could literally track the development of the white matter and the gray matter without actually doing an autopsy

on a dead patient. Now there's a living patient. And now what we're seeing with MS is that it's kind of cycling. There's a remission 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. Right. Right.

But the fixing mechanism is deteriorating with time. There's an ongoing battle and the defense is losing the war of attrition. Exactly. Yeah. And so now that becomes kind of the focus. And with individual suffering from multiple sclerosis, we now have some kind of mechanism. It is the myelin sheath.

And you can see now stains between normal control individual in A and someone with MS in B. 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 sheath. In B, it's almost gone. 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 sheath be present. Yeah. And so now we're starting to, we're starting to, the detective work is progressing. We're starting to at least piece together what is going wrong. Yes. It's definitely the myelin. Yes. Okay.

Right. Now let's talk about that remission stuff, right? Because you said 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. 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. Yeah.

And then the immune system maybe like stops paying attention. So then the myelin comes back. So how is the myelin actually coming back? Right. 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. Okay. 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. Yeah, you know me. Now with OPC? What is that from? It's a rap reference.

Okay, got it. All right. Well, I'm going to look it up later. So the OPEC, this oligodendrocyte precursor cell, can become a myelanating 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 illegal dendrozyte 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.

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's like a, you know, and then depending on the context, of the environment, it can become one thing or another. Yeah. Yeah, that's what a stem cell is. Right. And in this case, it becomes this oligodendrocyte that becomes the myelin sheet.

It's what wraps the fruit roll up around the twistler. 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 myelinating. this oligo dendricide cell. Yes. And so in healthy patients, this is happening all the time. It's fine.

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

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. Your population is decreasing because you don't have enough babies that can become adults. Yeah, yeah. That's not the case. Okay. People do studies, and they actually show that with histological studies where you can stay in 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 no oligodendrocytes, but somehow there's repair still happening. Because as far as we're aware in this context, like that is the mechanism by which the repair happens. Yeah, yeah. So certainly there's oligodendicitis that are working. Right. There's OPCs that are working on the red. The pregenitor, some stem cells.

Yes. The stem cells are working in the red area, but not in the green area. Right. Right. Right. 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. And so the point here is that it's not a lack of the defense. Yeah, the workers. The workers, they're there. Yeah. But something is bringing down further down in the process. Exactly. And so they're failing to mature into these myelin-producing cells.

Stuck in adolescence. Yes, yes, in some sense. So what's actually happening? Well, it could be some epigenetic barrier to differentiation. Here we're seeing immune cells in the yellow actually attacking a myelin cell and a lego dendrocyte 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 illegal dendrocytes that are around to come in and actually do the repair. Right. If there's like a battlefield, right? And there's like the, in some sense, there's like evidence of a battle. Yeah. Where a bunch of your homies got knocked out.

Yeah. Like, you know, maybe you're like, I might go that way. Yeah, I might not hang out. Right. Like, 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? And the consequences of this failed remethylation is what it's called, where, you know, there's no methylation and then you remethelate the brain.

the consequences of not doing this, of not remethylating 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 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. And so just I want to reground myself in kind of the circumstance we've set the table

for right now. So, you know, in part we have the neuron itself, right, and the neural pathway is like where the signal is being sent so we can do all of this communication. Yeah. And function the way we do. The myelin is this wrapping. Yeah. Around it that has a variety of benefits.

Yeah. speed, efficiency, housekeeping. And in MS patients specifically, there is this degradation in this myelin sheath that surrounds your neurons. Yeah. That gives it all of these added benefits. We thought it might have been that the way that they're born, the myelin is, the way that it was created, there's not enough resource to keep creating it. Yeah. That did not seem to be true.

Yep. And then we moved down the sort of process pipeline, and now it's become this idea that the environment, because there's this constant ebbing and flowing of myelin degradation, and then the body 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 in the first place. Yeah, yeah. And it seems that the pregenitor 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. And the key idea is like, they're there. They're there. That's the key. That's a big point. 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. Right. Is that they are there. We just need to equip them with perhaps the right signal. Okay. Okay. So where do the current therapy stand? Well, they can prevent, but they cannot fix.

These are called disease modifying therapies, DMTs, not to be... Not that DMT, guys. This is not the Joe Rogan podcast. But once an axon is demilinated, these disease-modifying therapies cannot force the body to remilinate it, but they can perhaps force the body to stop the degradation. Okay? To stop the bleeding effectively. Yeah.

Yeah. And by the 2000s, the field had identified like a bunch of different signals. There's like thyroid hormone, retinoids. But translating this into therapies proved kind of difficult. A big obstacle is the blood-brain barrier. This is something that 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. 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. One of the most famous was this therapy from Biogen, which Biogen is a company. They were developing this therapy called Opisinumab.

I love the pharmaceutical namings of stuff. Yeah, Opposanumab. Okay. It was developed as a monoclonal antibody that was going to target and block something called Lingo 1, which is a protein that would inhibit this differentiation. So the idea is you've got the stem cell. The stem cell is differentiating. There's a protein called Lingo 1 that would stop that differentiation, that would stop

these workers. So this monoclonal antibody is going to go attack that protein. So then the workers are kind of free to do whatever. Yes. Works in mice. Human phase two 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. 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. 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. Yeah. Right? So we want target specificity. That's not going to happen for a lot of these chemicals. So this is like

almost, it's the problem in the opposite direction. 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 Bexa Routine. 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. 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. 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. Exactly. It's like maybe the factory has some instructions and I'm just going to black out.

Yeah, yeah. 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. Because of the size problem we talked about earlier. And so it's going to effectively start turning off, it's going to start impacting functionality that you were not trying to change. Yeah.

Because it can't be specific. 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 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 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 retinodes 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. 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 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 retinoric acid. And that acts as the transcription factor for these, for these, receptors. Yes. Okay. Right. So, and that regulates the gene expression later on, right? Now, pre-clinical studies showed that these pre-genitor cells, the stem cells that go on to become the myelin. The OPCs. Yes. Those guys, they express these RXRs, the, the, the, the, the, the receptors,

but only a gamma kind. Okay. There's, there's multiple types. And the stem, cells in the brain that become myelin, they express the gamma kind of the receptor. Okay. And then when researchers knocked out that gamma kind, then the mice lost all the ability to remilinate the axons. So now we have a better idea of the specific receptors necessary, 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. Yes. And now we know, we were making lemon pepper when we needed to be making terriaki. Yeah. So at least we now know that we got to

make the gamma. We got to make the terriarchy, right? Yeah. And so this clinical trial in Cambridge in the UK decided that Bexar, what is it, Bexorotene. 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's 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. 90% of the patients developed dangerously high levels of fat circulating in the blood, something called hyper triglyceridemia. This is the, yeah. And so this is, so just a double click on this, the Bexorotene, which was this potential

therapeutic, right, that we were going to use, did activate RxR Gamma, which is the one we know that the OPCs used to basically get to this point where they can remilinate. The problem is it didn't only reactivate RXR Gamma. It reactivated RXR Gamma as well. as the alpha and beta. And so 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. 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. Well, now it's getting through everywhere. Right.

Right. And targeting too many things. Exactly. So we've solved the delivery mechanism. We've not solved the targeting problem. Yes. New from Nespresso. Blend wellness into your coffee routine with the coffee plus range, infused with functional benefits.

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but it only activates the gamma receptor of these stem cells? And it doesn't trigger some random catastrophic activity elsewhere in the body. 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. Exactly. Today, as these research teams are looking at this problem, why is this so pernicious? Why is it so difficult to solve? Well, we first had to identify the mechanisms and the mechanics of what was actually happening. Once we've identified what's actually happening, then we have to think about different

angles of attack to solve the problem. Where in that chain do we go? Yeah. Right. And so then we decided, okay, let's try to see if we can reinvigorate these OPCs, which seems to be breaking down. Yeah. 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. Yeah, yeah, yeah. Let's get past security. 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. Yeah, no. It's every single plane. 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.

And so that's where we are right now as we sort of transition into 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, the, this current paper basically introduces the idea of evolutionary medicine into this fray. Okay.

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 order to survive, a species will optimize some molecular mechanism. We're using nature to cheat on the test because nature's been doing the test for way longer than we have. Yes. Yeah. Yeah. And in some sense, it would be foolish not to.

Not to. Right. Right. The professor's not looking. Yeah. Look. In fact, the professor is like giving us all these disorders. Right.

Right. The professor is the problem. 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 capto-pril.

Capto-prill, the first A-C-E 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's saved millions of human lives. 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. Yeah, because it can't get enough blood to it. Right. Yeah. The heart stops. I mean, it's just, yeah, obviously.

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. 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. Yeah. And this is a perfect example. Totally. Who knew watching the crocodile hunter and being expired by snake venom as a child? Yeah. Inspired some researcher to go and research

that venom. Yeah. And then that ended up being a cure to cardiovascular disease. Yeah. I mean, the next one is even crazier, dude. The next one is exanatide, which comes from the giller monster lizard saliva. This is how. we get GLP ones. This is how we get OZempic. Oh my goodness. Someone was messing around with a Gila monster venom and was like, hey, hey, this could be used against diabetes. It's pretty crazy. So the groundbreaking GLP1 receptor agonist is exanitide and it was used to manage type 2 diabetes. The compound is exanidin 4. It was discovered in the toxic

saliva of the Gila monster. It's this thing that eats only a few massive meals per year. year. This thing only eats like a few meals a year, right? So it needs a way to maintain stable blood sugar. Oh my God. Because it's only got a few, you know what I mean? It's in this extreme environment where it doesn't have a lot to eat. 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 Zanetide and the pathway made scientists go in and engineer Ozempic, which is structurally, it's like basically a modified form of exanatide for the human body for the human body it's like optimized for the human body but it's it came from the gillam monster venom kind of hilarious if you're on ozempic if you're on

we govi or any of the generics you can thank the gila monster yeah because without that and the research people that spent the time looking at this exotic animal in this extreme environment because the venom yeah you're putting you're putting gila monster venom direction in your body. Okay. Yeah. That's what you to know. That's what we're doing.

This is why science matters. It helps to lose weight, right? Yeah, this is finally how we're going to get Americans to pay attention. This is why basic research matters. That's how we got OZemping. The GILO monster. Everyone's going to be like, vote. Vote now.

That's actually so crazy, though, because, oh, that's so great. Do you understand how much money OZemPEC is making right now and all of the GLP? Can you imagine. The industry is, it's literally. It's literally. a driver of GDP growth. But like CEO of one of the GLP, one of the GLP one of the GLP one of the GLP one, creators was like, we need to get a billion people on the planet onto GLP's

because it's going to be a driver for America's GDP growth when we're struggling to find other areas of GDP growth. I'm just, that's, that's a crazy thing to say. I'm just reminding people. No, that's a crazy thing to say. But that's literally. And then he's like, the problem is, as we get more people on GLP-1s, we're destroying the GDP growth of like the food industry, right? Right.

Oh, I see. People don't eat as much. So we have to find this. This is what, this is where we're at. Sorry for the digression. That was that. Okay, that's actually hilarious. Well, Gila Monster's 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. Yeah. 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. This is the superhighway that we talked about earlier.

Yeah. The white matter in the brain, which has a bunch of myelin, gets demyelanated with hypoxia. So maybe there's a clue, right? Very interesting. 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 going to go. It doesn't have the raw materials to do the things it normally does, part of which is the myelination process. Exactly.

And that's where this current paper comes in. So it's out of Shanghai Giao Tong University. It's a bunch of researchers that have published in Neuron that show that the genomes of these creatures, has an amino acid change in a gene called retstat, which is retinol saturates. We're going to 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. The key thing is this is across animals. This is conserved. This single mutation is conserved not just in the axe. It's in the Tibetan antelope. That's multiple. Which means that there is something there.

Yeah. It is, the substrate has some universality to it. Yeah. Not the substrate, but there's a fundamental that has universality to it. Exactly. And it's a mis-sense 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 retinal 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. So this convergent evolution, that signal is what told these researchers that there might be something going on. And so just to set the table one more time, we've identified why in multiple sclerosis, like functionally what's happening,

demylination, demylination, all of the research, all of the researches 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. 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 in other use cases, the famous one we talked about being OZempe, where we looked at Gila Monster Venom and its ability to basically allow you to survive with less blood sugar,

which is great if you want to manage diabetes type 2 or obesity. And so the methodology of looking at other evolutionary examples to solve problems in humans has been wildly successful already. And in this environment, it's notable that this is coming out of several Chinese universities. Yeah, yeah.

The main author is from Shanghai, but yeah. Across, it's a big team. Yeah. Who have proximity to Tibet. Yep. So it's a context where they'll have, you know, regional reference points for this. And there's, I think there's also a government sort of effort to get the genomes of all of its exotic.

animals in China, which makes sense, totally. 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. Yeah. And specifically combat white matter degradation.

Which is related to the problem with MS. And so we're trying to see is there a bridge now between these two things. We've defined sort of both Lego blocks of the ideas. And we're going to try to see if we can build a bridge between these two things. 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. 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. Okay. So you can take these mouse models that are in the lab, and you can take the retstat yak version and replace the retstat. mouse version with the RETSTAT YAC version.

So now these genetic mouse models have the RETSTAT YAC version. We're changing the control and you've got the yak version. We're basically just changing the genetic ingredients and seeing what comes out at the end. 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 RET-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. 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 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 going to do a random walk random swimming to figure out where the platform is. And then once you're on the platform, you're going to notice, given the cues on the

outside, where I am, and then the subsequent trials, I'm going to 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 ones with the RETSTAT, very rapid learning. Yeah. Right? So the brain is functioning normally for the ones with the RETTAT.

What this shows is one, the RETTAT knock-in thing is working. Yeah. And two, the RET 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. Yeah. Right? Yeah.

That's the main idea. We were able to replicate what happens in nature in a lab, which means we can then make it repeatable. Yeah, exactly. For our own purposes. Yeah. Now, the second hypothesis is that the ret-I-I-I-I-I-I-L 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 brain slices and see if you stay in the myelin, the wild type has in normal oxygen environments, the wild type has a certain amount of myelin. Yes. And if you look in the hypoxia environment, the wild type does not. not have that myelin. So clearly the myelin is getting degraded. Which is what happens in MS. 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.

Because this is happening, right? But for the ones with Redstat, you've got normal amounts of myelin. So the second hypothesis is also making sense that the Redstat has something to do with the maintenance of myelin in low oxygen environments. Is that clear? Very much so. Okay. So now we're going to move on and understand how is RETSTAT doing that. Okay. So we know that the RETSTAT 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 pregenitor cells, those stem cells becoming oligodendrocytes. OPCs. Oh, the OPCs, yeah, becoming the myelin sheets. Yes. Does the RETT have something to do with that pathway? Okay, okay. Right? Because 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, RETStat 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 microinject it into parts of the brain.

And so you see, like, in the top row, there's like a hole in the green. The green is tagging the myelin. And you've created, like, kind of a hole, right? 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, right? So now we're on to it. Because this is different that what we're pointing to here specifically is the ability to, for the regenerative, once you've created this problem. Yeah, the lesion. This is like simulating what MS 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 agalodentricites that can now remelinate. Yeah. And it's not happening in the control, 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. Exactly.

And so we're getting down to the mechanism, but we're still not there yet. Okay. Right? Because so far, what have we established? We've established that this new gene that's in yaks, it can remilinate 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. Right. Right. We're not going to get a therapy by like genetically modifying patients. That's not what we're doing.

Right. We're trying to figure out what is the gene doing. Right. And can we maybe hijack that pathway? Yes. Right? Yes. Okay.

So let's move on. And this is where we get into a weird, weird discovery. Okay. 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 going to show here, because, I mean, they have so many amazing figures. But one of the figures that we're going to skip here is they put in the gene and expressed it only in the stem cells, the precursor cells. the oligodendrocyte precursor cells. Yes.

Naively, you would think, that's all I need. Okay, right. 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 an intermediary. So you introduce it into the environment, but it's not a direct correlation. 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 figure we're going to see the kind of resolution here. they expressed the genes only in the neurons.

And all of a sudden, you get a recovery of that oligodendrocytes coming back and the myelin coming back. As opposed to doing it in the OPCs. Yes. That's weird. That is weird. It's weird. It's like the neurons are doing something that is then telling the OPCs to come and help me out. Help me.

Help me. Yeah. That's what's happening. Right? But that's an interesting point, which is, you know, sometimes the site of where the solution arises, which is these OPCs that ultimately mature and then are the ones that create the myelin sheets. It 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. And I had told you earlier that, like, the problem was not that the OPCs were not there.

Correct. The problem was that the signaling was not there. They didn't know what to do. Perhaps, per chance, 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. The I need help signal was basically, which goes from the neurons to the OPC. There was a breakdown in communication. Yep.

And that seems to now be where we're centering it. as like the cause of the problem. Yeah. And so we were looking in all the wrong places before. Yeah. We had to do all that discovery work. Yeah, yeah, yeah. 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. Yeah. And it's in the source that needs the protection, which is the neuron. Exactly. Yeah. And so now we're holding in on this signaling, right? 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 oligodendrocytes are catching it and being like, oh, this guy needs help. I need to go get there. They performed, you know, because even now, what is the mechanism of this signaling? Is the signaling neuron to oligodendrocytes straight up? Or is it something more general where the neuron just like, puts out a PSA on Twitter. Yeah.

And then those who are interested come and help him. Right? Is it a DM or is it a full tweet? Or is there an intermediary? Yeah. That is a secret. Is it a back channel? Yes.

Yeah. These are all the possibilities. Right. And we need to figure that out. So how did they figure out, which is what? How do we know? 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 red stat mutation, the yak mutation in the neurons. Presumably the neurons are going to secrete something and then that's going to go to the illegal dendrocytes. How do we know that it's not a DM and just something that I'm secreting into the environment? A tweet. What I can do is I can take the medium. The cells have like some, you know, 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. And it would,

and the precursors should see this signal, this signal and start myelanating. Because if it was a tweet to everybody, it would be in the environment. Yes, it would be in the network. And that's exactly what we see. Oh my goodness. It's a nice, like, it's a nice progressive kind of, ah, we're getting somewhere. Yeah, yeah, yeah, right? The story is very cool. From one figure to the next. And so here on the bottom, we're seeing the medium, and you're seeing a lot more green dots. Yep. And that's from these neurons.

So this is so interesting. So we've now identified that the challenge with the degradation of myelin, which we initially thought might have been because it wasn't going from baby OPC to these elite. egotendro sites that were the thing that created and fixed myelin sheaths as things happened. Yeah. So we thought maybe there's something in the maturity process of that that's problematic. It ended up not being true. We looked at this evolutionary, you know, reference point from high altitude to bent animals. We found something that works for hypoxia that seemed like it was connected. We established that with the restat. It definitely was connected somehow. 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. And so it wasn't that they weren't there anymore. It seemed to be that the trigger to do the job was breaking down. But we didn't know where the trigger was being triggered from. Who's the captain that's giving orders? Yes. Through this process that the team and this team,

in Shanghai did, we've now found that the neuron is the captain that is triggering the instruction for the OPCs to get the proper instruction to mature to then go to the process to recreate the mile and sheath. And it's sending those instructions not in a discrete way, like a DM. It's just literally blasting the signal out. It's like, I need help. And so what makes sense is there's a, the neuron is the source of the problem. and it's not tweeting and it's private messaging itself or just it sets account on private

and no one can see its tweets as a crude, annoying analogy. And that's that that's the functional. So now, and we know because 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 thing. So we know that that's true. We know that that's true. And now we just need to hone in on what the tweet is. What is the tweet?

What is the compound that is doing this? Because if we could make this compound, then maybe we could solve this problem. Very, yes. 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. And it works.

That's low-key crazy. Yeah. I think it's really cool just the story of this whole thing. So now what could that signal be? Well, we've got retinal, 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 retinol, into retinolic 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, which we discovered through studying these Tibetan. Well, no, actually, the retstad gene is something that's been discovered before. This mutation was discovered through the, yeah. the specific mutation of the gene. And we know that the retstad gene does this,

which is it takes retinol, and then it puts it into something called ATDR, which is 1314 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 retostat mediated thing that is coming out of the vitamin A, that is going up. Okay? The concentration of this particular compound is going up because of this gene. Yes. Okay. So we've now made the causal link between the presence of this gene mutation and now a specific

compound, this ATDR being present, which we see in these spikes in that top section with the restat and the rest at Q24. Yeah, yeah. And you can see that the second spike is larger than the condition. control. Yeah. Yeah. This is that gain of function that I was talking about.

Yes. Right. Right. Like this, this particular mutation is giving me more ATDR. And perhaps that more signal is telling the OPCs and the stem cells, hey, I need more myelin. It's, it's now loud enough. Yes.

When we have, because, so actually this is a good point. So 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. That's the, that's the Yak version. That's the mutation. Yeah. And then the one in the middle is just like standard operating procedure. Yeah.

And so potentially it's the, unless the ATDR being at a particular level might be the tipping point. Yes. And if it's below a particular level. In hypoxia, it might be a tipping point. Exactly. Okay. And perhaps in MS. It might be a tipping.

That's the connection we're trying to. That's the bridge again from before that we're trying to. Yeah. Yeah. So, okay, what if I just add ATDR? Right. Right. Is that going to be enough?

biology is never so kind. It's never so simple. Right? In H, you can see that if I, if I add the ATDR, all of those, all of those bars are about the same. There's an N.S 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? So clearly, ATDR is not everything. But in the K one, 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 step. The control even makes the ATDR. If I add that to my OPCs, then all of a sudden I get this effect. So there is something else. This proves that ATDR is just a precursor, and the neurons are doing something else with that ATDR.

Yeah, yeah, yeah, yeah, yeah, okay. So not only am I getting more of ATDR, but the neurons are doing something more with that more ATDR. So it's almost like it is just by having the neurons, it's a fundamental ingredient for whatever it is the neurons are doing, but it is not the solution in and of itself. Yes. And one of the inclinations that these guys had, one of the inclinations that these guys had was, well, the ATDR, which is a second, you. You know, it's a version two of vitamin A of the retinal. There's a version three, which is ATDRA. It's just ATDRA. It's just ATDR with an acid.

Okay? It's the acidic version of that that maybe this thing is maturing into. Ah. Okay. Okay. 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 cells.

They were like, okay, look, I don't know. know what's going on. Let's just do all of the permutations and combinations. And if you look at the fifth column, you can see a bunch of myelination happening. That is with ATDRA alone, with the acidic version of this. So when we introduce the ATDRA, the acidic version, we are seeing, things happen now. Yeah. And so we were, the ATDR base was directionally helpful. Yep. And it's just like, it's like a slightly, it's a slightly different permutation of it. Yes. And the key insight here, and 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. Bingo. Right? Bingo. The fail trial. The Bexarotene from earlier. Yes. The Bexarotene from earlier that was not only.

targeting gamma but also targeting everything. Yes. Now we've got a selective activator that is going to target only the gamma. And so, and what's so, this is perfect because from earlier when we talked about, we were, we had identified the RXR as like the where we need to target for. That's what we got to 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. Yeah, exactly. And so how do we make sure, right? And this is where we get in the translational payoff of the entire study. Right? We've established the science. Yes.

Now, can this actually work as something that perhaps could combat MS and maybe even reverse the effects? Can we deliver the actual solution? Yeah. So 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, but we're giving them the stuff that the mutation makes. Yes. And it's working.

Yeah. You're getting remilination. Yeah, yeah, yeah, yeah, yeah. Okay? Oh, my goodness. And the killer is really the next one. Yes. The next one is, so, because this was hypoxia.

Now, what if we straight up go in lesion? Right. Which are the two. Right. Because hypoxia, I don't know. It could be doing other things. Right. Right.

What if we, now normal environment, but we go ahead and we do it. lesion, do we get, like in an MS-like brain, there are these things called autoimmune encephalomyletus, EAE. These types of mice are basically a standard model

for multiple sclerosis because they mimic 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, which is what we want to see. The repair process is reactivating. It's becoming successful again. This is so, and so now we've we've weaved this story, which is so, so good 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 this RXR gamma. Yep. We knew we needed the target RXR, but we couldn't selectively do so.

Yeah, because it was going everywhere. We found this other pathway through looking at the evolutionary progress 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. Yeah, perhaps it's doing something. 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 our, are gamma through ADR ATDR slash ADDRA. And there's some pros and cons to both.

Yeah. But like we know how to target so that the neurons signals to the OPCs to mature to restart this process of creating the mileage sheet. Exactly. And the ATDR we can just put in because the neurons can take that and create the thing they need to do. The thing they need to do, right? We don't need to give the OPCs the signal in itself.

We can just have the neurons do it, which is actually an important distinction. Yeah. Because the ATDR is a bit easier to make. Right, right. That's an important point. Okay. Yes.

All right. And so now we can finally understand the graphical abstract. We're finally here. Okay. The wild type is on the left. The mutation is on the right. You've got a Himalayas in the background. Retinal goes to ATDR.

goes to ATDRA, but on the right-hand side, the ATDRA has an up arrow because it's up-regulated. That's that gain of function. And when that goes to the OPCs and the oligodendrocytes, the OPECs are the green cells. 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.

Yeah. Yeah. And that's the graphical abstract. And we, from something that was totally disconnected from anything you'd be able to understand, we now have a reference point. And also like a fundamental understanding of one of the most, you know, impactful neurodegenerative, you know, issues we face as humanity, among others. Among others, yeah. Which we've discussed. Any progress is good progress.

And on the bottom, the two blue circles, on the left-hand side, you see a wild-type mouse just doing random walks to get to the cheese in the Morse water maze. On the right-hand side, it's getting there very, very quickly. Because it's able to repair itself and maintain its cognitive functions. Very good. In a way that the wild-type cannot. Oh, the bio stories.

Some of our best stories. Yeah. I mean, I just, it's, it's incredibly difficult. Yeah. To get this kind of granular understanding. Yes. Of something so fundamental. Yes.

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

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. It's, one would say they did it from first principles. 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 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 intermed. to the world outside of the womb, 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. Because in this context, the hypoxic stress is a one-to-one mapping. Yeah. Versus when we talked earlier about the MS, it's there's a few steps away. Yeah, 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 drug that mediates the same exact

therapeutic axis that we've been discussing, then perhaps you have some way to slow this decay. That would be so huge. Yeah. 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, ATDR, neuron, OPC, myelin sheath, 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. A classic example I always bring up is CRISPR, right? You have multiple use cases for like one unlock. Yeah. And this could be a key that unlocks several doors. Yeah.

And another big, another aspect to this story is the source. Yes. Right. It was in neuron. Yeah. But the team. Yeah. It's from China.

The team is out of China, yeah. And as we've discussed several times 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. I would say most spaces, to be honest. Right, right. And you can see that from the recruitment of some of the best talent across several frontier areas that are now arriving. in the Chinese university system. So we're going to continue to see, you know, it'd be a very competitive landscape at the frontier of research.

Yeah, I mean, and this was a phenomenal study. I mean, I just, I love the narrative of it, the way the figures sort of told the story. Just from a even aesthetic and like, you know, narrative point of view, I thought the paper was just very well written. They know what they're doing. Yeah. They're not just copying us in all ways.

And 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 and why it is so difficult. Yeah. To solve this problem. Again, frontier research and end therapeutics. There is a large delta between these two things. And the authors themselves make that point. There's a bunch of news articles where you can read quotes from the authors, and they say, you know, there's a giant delta. But you got to do the science.

You got to do the work. We got to 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 soon for my loved one. That's not the story here. No. But hopefully this helps you understand how we do get to these solutions. Yeah, yeah. And why they do take time.

We've found a mechanism. we've not necessarily created the actual end product. But great story. Love the bio stuff. We will wrap up this week in half the time 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.

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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 German clapback prompt, some of them are brutal. Some of them are very good. Yeah. Some of them are very good.

Eventually when we can do more production stuff, we'll pull them up live. That's beyond the scope of what we can do right now. That's pretty funny. So you guys did well. Do you have any thoughts? Yeah, maybe I was thinking, you know, in the vein of

evolutionary pharmacology, what's like one animal out there that you'd like want like an ability from? Or like, you know, like if we could do evolutionary pharmacology on an animal and like get some kind of, you know, ability, what would it be? For the Gillam monster, it was the low blood sugar. For the snake, it was the low blood pressure. So what do you guys think? That's a great one. I am Lester Nare, I joined as always by my co-host and our resident PhD, Krishna Chowdhury. 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. And what we find interesting. Next episode, it will be coming up on our... 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.