The Yak Mutation That Could Help Repair the Brain

Intro

0:00So, 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 bloodb 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 because nature's been doing the test for way longer than we have. >> Yes. Yeah. Yeah. >> Hello internet. This is your captain speaking, Lester Nar, joined as always by my co-host and our resident PhD, Krishna Chowdery. After our massive

0:43two-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

1:24layer around nerve cell fibers, actually does, why MS, multiple scerosis, 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

2:06happening. As always, we are going to talk about the science from the ground up today because this is from first

Why lost myelin matters

2:14principles,

2:28multiple sclerosis, lucodistrophies and perventricular luccom malaysia 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 neuroderadation and brain damage. It's their own immune

3:10system 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

3:52borrow to maybe fix these problems in neuroderadation. This would be huge. I mean, as you mentioned, this is something that impacts uh a a huge population of people. >> Yeah. >> Globally and it's extremely pernitious 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. Mhm. >> The holy grail is to rewind neuro degradation, 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.

The search for a way to rebuild

4:29>> 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. Um where the current therapies are lacking and then this new paper which uses this emerging field of evolutionary pharmarmacology >> to propose a possible rebuilding therapy. And what I really like about this paper is the method by which they all figured this out. It's a really nice story because it starts from very large, you know, what how does a yak adapt to

5:10the Tibetan plateau and these researchers are honing in on that mechanism and it's like a detective work in some sense because you're you're going through molecular biology, cellular biology to try and understand what is the exact mechanism that the Yak genome has developed to um let these animals survive and not only survive but thrive in this hypoxic environment where there's lot 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

5:53the episode you should be able to fully understand this graphic. So whenever you publish in the El Seavier journals which is like neuron cell um they make you do not just a normal graph a normal abstract you know that's every journal has an abstract right you do the abstract and then your main paper >> meaning like a block of sum executive summary in text >> yes in text um the so elvier 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.

6:34>> Um 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, a 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

7:16help 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 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. Mostly out >> mostly out of the country. mostly out, but we're still growing the data set. Uh, it's not looking good so far. Uh, and then we also have our America 250 looking back at 250 years of American

7:58innovation 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 of 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.

8:38>> That's true. Yeah, cuz we had the the remon and the the Jacobian before that

What myelin actually does

8:42and so uh getting back into some bio work I think is going to be uh 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 dendrites 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

9:24system as kind of a vast network of electrical wiring. Okay, 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 1 drivers have, >> they're pretty insane. fractions of a second that nerve impulses are traveling down the arm or the leg to like break and things like that, right?

10:06>> Um, that's happening because of the myelin sheath. Okay. So, I want I want to get into a little bit of the physics here because it's kind of cool biohysics. It's one of the first like bioysics 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 um discharges and fires off um a signal is

10:48you'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 on the membrane, the ions sort of discharge. It's kind of like having a capacitor and you shortcircuit it. So all of the charges flow from one place to the other. >> The 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, >> it's it's a rush. >> It's a rush. >> It's a rush, right? Usually it's this um 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

11:29actually 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 >> into and out of the cell. >> We're constricting it to specific spots where the the the the ability to go in and out is concentrated. Uh they're like gates and then there's the protective layer. It's it visually reminds me of those at summer camp. You'd make those beads with the little plastic rope and

12:11you string the beads on top of it to put on your wrist. Exactly. And the little gaps in between the beads is where the ions could actually Yes. >> go in and out. >> Yeah. And those would be the nodes of Ranvir. Right. And the point is that without >> without without the myelin sheath, >> there would be ion channels everywhere along this cable. So the ions would come in and then they 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 there's a entrance in the in the front and then

12:52when all the people come in, if there's an entrance all the way in the back, these people are going to Yes. 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 meander. People start blocking and 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. >> Exactly. And so this means this means you need less energy because what you've actually done is um you know for those who are electrical engineers or just like undergrad physicists um capacitors when you put them in parallel the

13:33capacitance decreases. Okay. Sorry. No no no. When you put capacitors in series the capacitance decreases. When you put resistors in parallel the the resistance decreases. It's the one over C thing. Anyways, here you've got the axon membrane, which is kind of like a capacitor because you've got charge on one side and the other side. So, it's storing some kind of voltage difference based on the charge. But if you're wrapping this myin 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

14:14is 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? >> Um, >> and between these nodes of Ranvir, that's where the signal is traveling. This mechanism is called saltatory conduction where it goes from one node of Ranvir to the next node of Ranvir. And here you can see a visualization of that. On the left hand side >> is an axon without any myelin. M >> notice the action potential is very slow. >> Yeah. >> On the right hand side you've got these nodes of raanvier in between these myelin cells. >> Yep. >> Boom boom boom boom boom. The signal

14:57propagates a lot faster. >> Mhm. And and so again just as a a a simple way for me to think about this, the myelin helps reduce the friction >> in some sense. >> Right. So things can just move. It 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. There's not any exits except for like way down there. >> Mhm. Mhm. 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. Um, and it is a fundamental part of the

15:40effectiveness 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, 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? um 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 >> um without I mean for example the corticospinal tract right which is the

16:22motor 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 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 1 drivers can reflex time. Have you seen those? Uh, by the way, have you seen those the where like uh they've got their trainer like with with balls and like they're like releasing the balls and the and the Formula 1 drivers have to like catch

17:02them right before the race. If you watch the races, right before the race, you'll see all of the Formula 1 drivers just like doing some warm-up reflex exercises. Well, they can do that because of the milein sheath. >> So, you're saying that Messi has a better milein 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 let's see what the comments say about that. Hey, let me know. I I I I do I am curious how many are Ronaldo versus Messi >> versus Messi. I I'm curious to see what the comments say. >> Some have said the goat debate is over, but I I'm not an expert. >> You know, you know, I'm certainly not an

17:43expert, but I have an opinion.

Oligodendrocytes and white matter

17:46Okay, 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 oligodendrite. Okay. This was identified by Spanish neuroanatomist um I'm can you >> P Rio Ortega. >> Nice. Yeah. Around 1921. So that guy he stained using the GGI 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

18:28processes around those neurons. So you know those myin sheets that I was talking about where the 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 >> in in Spider-Man like and it goes around and wraps around all of these axons nearby. >> Interesting. Okay. >> Which is which is kind of cool to think about. It's not a one one sort of mapping. It's a single cell that's doing like 50 different >> electrical wires. >> It has this distributed >> um placement of its that Oh, that's actually very >> Yeah. >> intriguing. And so this maybe foreshadows some of the stuff that we're going to talk about which is if there's

19:08a problem with these oligodendrites. >> Yeah. >> It's like not a single neuron problem. >> It's it it becomes a single point of failure across multiple end points. >> Exactly. And that's what we're we're sort of building towards. That makes sense. Okay. So the precise ultra structure 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

19:50um 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 and so >> even even with the milein sheet you still need power >> 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 myin sheath 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? >> You can see the layers of the myelin

20:31sort of wrapping around to create a bunch of capacitors in parallel. But it does way more than just this physics argument. >> 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 outer layer. It looks like when you've taken a bite and look at it long ways. So >> yeah. No, you know what I would say it was? It's like a Twizzler on the inside and then fruit roll up. >> Yeah. On the on the Yeah. Like wrapped wrapped around. Yeah. It's like fruit roll up. >> Yeah, that's a great point. >> Yeah. Yeah. We should have some fruit roll up in the studio >> actually. Anyways, so um Betty Bengarin, she graduated from Washington University

21:12and 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 oligo dendrite 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 neurons secreted cuz we don't know, right? You don't know. But she definitively showed that there's a single cell that goes around. This oligo dendrite 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 like the the how to kind of visualize what that

21:54would mean. >> Yeah. >> Right. Like the movement of it and anyway. >> 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 mileelination. >> Okay. Um, you've got the gray matter on the outside. That's mostly where the cell bodies are. >> Okay? >> And then the white matter are the axons

22:34that 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 superighway and the gray matter are these islands. Yeah. >> That are connected by the white matter of this the superighway system. >> Exactly. Exactly. So this is where we get into MS. Okay. 1868 French neurologist Jean Martin Charott I believe >> and people might it might be charcoal. >> Yeah, maybe. Anyways, um he documented evidence of plaques in the white matter. >> Okay. And he showed that there's a

How multiple sclerosis was discovered

23:14correlation between those plaques when he did the autopsies of these patients and the patients conditions at the time. The patients conditions at the times were abnormal eye movements, intention tremors, slurred speech. This became known as shark cuts or sharos 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 >> uh these physiological uh >> 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.

23:55>> Yeah. There's a control and then there's >> So maybe they these things may be connected. >> Yeah. Yeah. And side note, um Charco 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. 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 couldn't believe you've done this." >> Yeah. Yeah. Yeah. So, you know, you win some, you lose some, >> right? >> Um, so for for nearly a century though, this was in 1868. For nearly a century,

24:37MS 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 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

25:18know, 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 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 milein degradation. >> Right. >> Right. Right. >> But the fixing mechanism is deteriorating with time. >> The there's a there's an ongoing battle and the defense is uh losing the war of attrition. >> Exactly. Yeah. And so now that becomes

26:00kind of the focus. And with individuals suffering from multiple sclerosis, we 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 um 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 milein 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 milein sheath be present. Yeah. >> Um and so now we're starting to >> we're starting to the detective work is

26:42>> progressing. >> We're starting to at least piece together what is going wrong. It's definitely the myelin. Yes. >> Okay. >> Right.

Why remyelination fails

26:48>> Um now let's talk about that remission stuff, right? Because you said the 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. So there's >> Yeah. And then the immune system maybe like stops paying attention. So then >> comes back. >> So then the myelin comes back. >> So how is the myelin actually coming back right? >> Right. 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. >> Okay, >> there are there is a mechanism for

27:30spontaneous repair okay >> of the myelin right the brain and the spinal cord they are populated by a reservoir of specialized stem cells called adult oligodendrite precursor cells. These are oligodendrite precursor cells, meaning they are stem cells that could go on to become the oligodendritty 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. You know what OPC? >> What is that from? >> Uh, it's a rap reference. >> Okay, got it. We could. >> All right. Well, I'm going to look it up later. So the OPC this oligodendrite

28:12precursor cell >> can become a mileinating oligodendrite cell >> and there's some pathway right there's some signaling where the stem cell which could become 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 oligodendrite 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

28:52know 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. >> Yeah. Yeah. That's what a stem cell is. And in this case, it becomes this oligodendrite that becomes the myin. It's what's 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 me 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 uh mileinating uh this oloend >> olodendrite cell. Yes. And and so in healthy patients this is happening all the time.

29:32>> It's fine, >> 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. >> Okay. >> 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 mileinating stuff. >> Your 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 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

30:15the lesions are fine. >> Mhm. >> 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 oligo dendrites. >> Mhm. >> But somehow there's repair still. >> The repair is still happening because as far as we're aware in this context like that is the that is the mechanism by which the repair happens. >> Yeah. Yeah. So certainly there's oligodendrites that are working, right? >> There's OPC's that are working on the red the progenitor stem cells. The stem cells are working in the red area but not in the green area. Right. >> Right. And if you go and stain and

30:56actually 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 is that it's not a lack of of of the the the uh the the the defense like the workers, they're there. >> Yeah. >> Uh but something is breaking 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. Um so what's actually happening? Well, it could be

31:36some epigenetic barrier to differentiation. Here we're seeing um immune cells in the yellow actually attacking a myelin cell, an ilodendrite 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 dendrites that are around to come in and actually do the repair. Right. >> Right. If there's like a battlefield, >> right? And there's like the I 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

32:16>> I might go that way. >> Yeah. I might I might not hang out. Right. there the like it's kind of strange to think about but like even individual cells are feeling stress >> from the environment and the macrofasages 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 rethylation 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 remethylating are catastrophic. Namely because

32:57the 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. >> And so just I want to regground 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 >> and function the way we do.

33:37>> The myelin is this wrapping >> Yeah. >> around it. Uh that has a variety of benefits. >> Yeah. speed, efficiency, >> housekeeping, >> housekeeping. And in MS patients specifically, there is this degradation in this myelin sheath >> that surrounds uh your neurons that gives it all of these added benefits. >> We thought it might have 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. >> Yeah. that did not seem to be true. Y >> uh and then we moved down the down the

34:18sort 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 sheath in healthy patients but in MS patients that repair process breaks down because of this chaos that is happening in the context text of the battle that creates the mile myelin degradation in the first place. >> Yeah. Yeah. And it seems that the pregentor cells, these stem cells that would go on to create the myelin and repair, they're either confused, they're

34:59not 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 Yeah. is 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 therapies stand? Well, they can prevent, but they

Why current MS therapies cannot rebuild myelin

35:30cannot fix. These are called disease modifying therapies, DMTs. Not to be >> not that DMT. >> Not that DMT, guys. Uh this is not the Joe Rogan podcast. Um but once an axon is deminisinated these disease modifying therapies cannot force the body to reminonate it but they can perhaps force the body to stop the degradation. >> Okay. >> Stop to stop the bleeding effectively. >> 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 bloodb brain barrier. Mhm. >> This is something that we we revisit a

36:12lot on this podcast. The bloodb 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

36:53love. This barrier has doomed a lot of different therapies. Okay, one of the most famous was this therapy from Biogen, which I Biogen is a company. They were developing this therapy called opposumab. >> I love the pharmaceutical namings of stuff. >> Yeah, I I opposumab. Okay. Um it was developed as a monoconal antibbody that was going to target and block something called lingo 1, 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 lingo one that would stop that differentiation. that

37:35would stop these workers. So this monoconal antibbody is going to go attack that protein. So then the pro the workers are kind of free to >> to to do whatever. >> Yes. >> Works in mice. Human phase 2 trials huge failure because these monoconal antibodies are massive. They're complex protein structures and because of their sheer size, they couldn't actually get through the bloodb brain barrier. >> Right? In mice, the mice have a different bloodb 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

The blood-brain barrier problem

38:15bloodb brain barrier, what do we need to do? We need to make our thingy smaller. >> Okay? Because the bloodb 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 astroytes, get into these oligodendrites 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 lipopilic meaning they are fat soluble. Lipophilic meaning fat loving so they slip past the blood bloodb brain barrier but they're also going to slip past every other barrier. >> Yeah. >> Right. So we want target specificity.

38:56That'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 Beexa Rotine. So, Beexin 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

39:36transcription factors a lot. These are the onoff 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 p 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 andoff switch for something that controls whether the stem cell goes on to become a milein. That's the idea. >> So we're going back to the factory and the instructions of how the factory

40:17generates its stuff with the right instructions. It's like maybe let's just reprogram at to 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. >> 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 this 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. Yeah. because it can't be specific. >> Exactly. Yes. Because it can't be specific because it's so small. Now, um before we get into the details of that failure, >> um a brief

40:58a 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. The that transcription factor is very much tied to the vitamin A. So vitamin A is a broad broad family of fats soluble molecules like retinol is one specific molecule that belongs to that and these retinoids are critical for neuro development. Too much and it's bad, too little and it's bad. That's why a lot of these prenatal vitamins have vitamin A. Um but they have it in the form of betaarotene and not like straight up vitamin A because betaarotene our body can then process and then it can decide how much vitamin A to get. If you just

41:40straight up inject yourself with retinol, that's really bad. And that's why like the skinincare products that have retinol is bad during pregnancy because then that goes into the infant and then that that's going to cause trouble. >> So um the active form is something called retinoic acid and that acts as the transcription factor for these for these um receptors. >> Yes. >> Okay. >> Right. >> So and that regulates the gene expression later on. >> Right. Now, pre-clinical studies showed that these pregentor cells, the stem cells that go on to become the myelin, >> the OPC's, >> yes, those guys, they express these RXRs, the um the the the

42:24receptors, 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. >> Okay. And then when researchers knocked out that gamma kind then the mice lost all the ability to reminate the axons. So now we have a better idea of the specific receptors necessary that that the OPC's use cuz 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 we were making lemon pepper when we needed to be making uh teriyak. >> Yeah. So at least we now know that we

43:04got to make the gamma, we got to make the teriyak, right? And so >> this um clinical trial in Cambridge in the UK decided that be um beexa, what is it? Beexa protein, sorry, I'm really bad with these medical terminologies to be honest, but beexin 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

43:45thing 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 hypertlymia. >> This is the Yeah. And so this is so just to uh double click on this the beexotin which was this potential therapeutic right that we were going to use um did activate uh RXR gamma which is the one we know >> that the OPC's use to to basically get to this point where they can reminate. The problem is it didn't only reactivate RXR gamma. It reactivated RXR gamma as

44:27well as the alpha and beta. >> 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 bloodb brain barrier which was the initial challenge. >> Yeah, that was the initial challenge. Okay, the monoconal antibbody 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. And there is the challenge. How do we find a molecule that is small enough to cross the bloodb brain barrier, >> but it only activates the gamma receptor

45:09of 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 like why is this so pernicious? Why is it so difficult to solve? >> Well, we first had to identify >> the the mechanisms and the mechanics of what was actually happening. Yeah. >> 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

45:50these 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 cuz it doesn't matter what we think if we can't get there. >> Yeah. Yeah. Yeah. Let's get past security, >> 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. >> Yeah. No, it's every single plane. >> It's every it gets us on every plane. And we we we're trying to go from London to Paris and so we need to get the London to Paris. Exactly. >> And so that's where we are. >> Yeah. >> 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

46:33this current paper basically introduces the idea of evolutionary medicine into this fray. Okay. Okay. Evolutionary

Evolutionary medicine

46:42medicine 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 4 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

47:24in order to si 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.

Learning from nature

47:41>> Right. Right. The professor is not looking. >> Yeah. Look look. >> In fact the professor is like 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 um and live a good life. So there are a bunch of iconic successes in evolutionary pharmarmacology. The first one I want to talk about is um Captoril. Captopril, the first ACCE inhibitor and it was discovered in snake venom. >> Mhm.

Snake venom and modern medicine

48:17>> 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. 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 >> right yeah the heart stops I mean it's just yeah obvious right um so then modern pharmacology diluted the thing

48:58and 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 um 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. Like who knew watching the crocodile hunter and being inspired by snake venom as a child inspired some researcher to go and

49:40research that venom 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 exanide which comes from the Giller Monster lizard saliva. This is how we get GLP1s. This is how we get ompic. >> Oh my goodness. >> Is someone was messing around with a Gillam monster venom and was like, "Hey,

Gila monsters and GLP-1 drugs

50:02hey, this could be used against diabetes." >> It's pretty crazy. So the the groundbreaking GLP-1 receptor agonist is exanide and it was used to manage type 2 diabetes. The the compound is exanin 4. It was discovered in the toxic saliva of the gilla 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. >> 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

50:43diabetes." The success of Xanide and the pathway made scientists go in and engineer osmpic, which is structurally it's like basically a modified form of exanide >> 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 OMIC, if you're on Wiggoi, 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 put you're putting Gila monster

51:23venom derivative in your body. Okay. >> Yeah. That what we're doing. Yeah. >> This is why science matters. It helps you lose weight, right? >> Yeah. This is finally how we're going to get Americans to pay attention. This is why basic research matters. This how we got OPEC the Gilo monster. Everyone's going to be like, "Vote, vote." Now, that's actually so crazy though because Oh, that's so crazy. >> Do you understand how much money Ozmpic is making right now and all of the GLP? The industry is so It's literally a driver of GDP growth. the like CEO of um one of the GP GLP uh um one of the GLP1 creators was like we need to get a

52:04billion people on the planet onto GLPs because it's going to be a driver for America's GDP growth uh when we're struggling to find other areas of G GDP growth. I'm just >> that's that's that's a crazy thing to say. >> I'm just reminding people. >> No, that's a crazy thing to That's literally. And then he's like, "The problem is as we get more people on GLP1s, >> we're we're destroying the GDP growth of like the food industry, right? Because people don't eat as much. So, we have to find is this is this is what this is where we're at. >> Sorry for the digression. >> That was that." Okay, that's actually hilarious. Um, well, Gila Monsters,

52:46Snakes. This particular paper has to do

Why the Tibetan Plateau matters

52:49with the animals of the Tibetan plateau. They live at 4,000 m on average. Um, 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. Um, 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. Okay? >> Including humans like chronic hypoxia, which is like low oxygen, is disastrous, >> a lot of oxidative stress, very

53:30specifically neurodedevelopmental deficits, particularly in white matter injury. and demyelination. This is a known thing. >> This is the superighway that we talked about earlier. >> Yeah. The white matter in the brain which has a bunch of myelin gets demyelinated with hypoxia. >> Mhm. >> So maybe there's a clue, right? >> Very interesting. Okay. >> 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, right? >> It doesn't have the the the raw materials to do the things it normally does. Part of which is this the mileination process. >> Exactly. And that's where this current paper comes in. So it's out of Shanghai

The RETSAT mutation

54:12Gaiaong 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 retat 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

54:54this is across animals. >> This is conserved. This single mutation is conserved not just in the axe, it's in the Tibetan antelope. >> It's multiple which means that there is something there. >> Yeah. It is the the substrate is has some universality to it. >> Yeah. >> Not the substrate but there's a fundamental that has universality to it. >> 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

55:35all the time. This retinol saturates it's just been studied for the context of fat storage. >> That's been it. >> Mhm. >> 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. >> Mhm. 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. >> Mhm. All the research demilination

56:18>> 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 >> in a separate lane from that setup. >> Yeah. Uh this idea of um 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 ompic where we looked at Gila Monster Venom. >> Yeah. >> Uh and its ability to basically make

56:59allow you to survive with less blood sugar which is great if you want to manage >> diabetes. diabetes, type two or obesity >> or obesity. And so the methodology of looking at other evolutionary examples to solve problems in humans >> has been wildly successful already. >> Yeah. >> And in this environment, it's notable that this is coming out of uh several Chinese universities. >> Yeah. >> Who have a proximity >> the main author is from Shanghai, but yeah. >> Uh you know across it's a big team. >> Um who have proximity to Tibet. >> Yep. Um, so it's a context where they they'll have, you know, regional reference points for this. >> And there's, I think, I think there's

57:39also a a government sort of effort to >> get the genomes of all of its exotic animals, >> which makes sense 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 uh low oxygen environments, a variety of of species have been able to find a way to live. >> Yeah. >> Um >> and specifically combat white matter degradation, >> which is related to this the problem with MS. >> And so we're trying to see is there a bridge

58:19>> now between these two things. Lego blocks >> and we're going to try to see if we can build a bridge between 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? Um, 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

Putting the yak mutation into mice

58:56do they actually prove that, right? They actually prove that by engineering a genetic knockin mouse model. Okay. >> So, you can take these mouse models that are in the lab and you can take the redstat yak version >> and replace the redstat mouse version with the redstat yak version. So now these genetic mouse models have the redstat yak version. You got a control and you've got the 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 can then

59:36turn 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 statin 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 m 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

1:00:16actually 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 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 um 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 and that

1:00:57that's why you see um 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 >> Yeah. >> very rapid learning. >> Yeah. >> Right. So the brain is functioning normally for the ones with red stat. What this shows is one, the rat statin thing is working and two, the rat 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. >> That's that's the 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.

1:01:38>> Yeah. Exactly. >> For our own purposes. >> Yeah. Now the second hypothesis is that the ret 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 stay in the myelin >> the wild type has in normal oxygen environments the wild type has certain amount of myelin. Yes. >> And if you look in the hypoxy environment the wild type does 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 is because this is happening, right? But for the

1:02:19ones 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? >> Very much so. >> Okay. So now we're going to move on and understand how is RESTAT doing that. Okay. So we know that the red stat has something to do with myelin maintenance

Can RETSAT repair damaged myelin?

1:02:43>> but from what I've previously told you that has to do with these oligodendritty right and the pregentor cells those stem cells becoming oligodendrites >> OPC's >> oh the OPC's yeah becoming the myelin sheets >> yes >> does the retat have something to do with that pathway >> right cuz >> 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

1:03:23do 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 um in the top row there's like a hole. Yes. In the green the green is is tagging the myelin and you you've created like kind of a hole, right? Um on the bottom row there's no hole. >> Mhm. >> 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 um 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

1:04:04under hypoxia but >> in the red stat right so now now now now we're on to it because this is this is different that what we're pointing to here specifically is the ability to uh for the the regenerative once you've created a uh this problem >> yeah the lesion this is and this is like simulating what MS would do >> would do you're actually doing the thing that MS doesn't do which is the OPC's go through their pathway to then become the algalaentric sites that can now rem uh remlanate. >> 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

1:04:45happening. And 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 uh inspiration. >> Exactly. And so we're getting down to the mechanism, >> but we're still not there yet. Okay. >> Right. Because so far what what have we established? We've established that this new gene that's in Yaks, it can reminate 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

1:05:27pathway 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. >> 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.

The unexpected neuron discovery

1:05:50>> What you would think based on that previous um based on that previous photo is that the stem cells are creating the oligodendrittes, right? Which is then populating the myelin. >> So, this has something to do with the oligoendritty. This is an innate mechanism within the stem cells within the iloenderytes 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 oligo dendrite precursor cells. Naively you would think

1:06:32>> that's all I need. >> Right? If the oligodendrites 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. >> So yeah, so you introduce it into the environment like uh but it's not a direct correlation. If you if you introduce it to the entire genome, that's what they did with these mouse models, right? Is like all of the cells now have this gene, it works. If only the myelin sheath cells have this gene,

1:07:13it doesn't work. But that doesn't it's kind of weird because the myin sheath is the thing that is doing the repair, but it's not working. The ne the next figure we're going to see the the kind of resolution here. They expressed the genes only in the neurons. >> Mhm. And all of a sudden you get a recovery >> of that oligodendrites coming back and the myelin coming back >> as opposed to doing it in the OPC's. >> Yes. That's weird. >> Say that is weird. >> It's weird. It's like it's like the neurons are doing something >> that is >> that is then telling the OPC's to come and help me out. >> Help me. >> Help. Help me. >> Yeah, that's what's happening, right?

1:07:54But but that's an interesting point which is you know sometimes the the the site of where the the solution arises which is these OPC's that ultimately mature and then are the ones that create the myelin sheets. >> It it's 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 at here >> and and and I had told you earlier that like the problem was not that the OPC's 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 red stat genome that that gene that mutation is giving the

1:08:35neurons the ability to correctly tell the oligodendrites, hey, I need help. >> The the I need help signal >> was basically which goes from the neurons to the OPC. There there was a breakdown in communication. Yep. >> And that seems to now be where we're centering in as like the cause of the problem. >> And so we were looking in all the wrong places before. >> We had to do all that discovery work. >> We had to rule things out. >> And now it's okay. Actually, the thing that is giving the the proper instruction

How neurons signal for help

1:09:09>> is where the degradation is actually problematic. >> And it's in the source that needs the protection, which is the neuron. >> Exactly. Yeah. And so now we're honing 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 the oligodendrittes are catching it and being like, "Oh, this guy needs help. I need to go get there." They did they performed, you know, cuz even now what is the mechanism of this signaling? Right. >> Is the signaling neuron to illegal dendrite straight up or is it something more general where the neuron just like

1:09:50puts out a PSA on Twitter? >> Yeah. >> And then 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 a is it a back channel? >> Yes. Yeah. 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? >> 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 start mutation, the yak mutation in the neurons. Presumably, the neurons are going to secrete something and then that's going to go to the oligodendritty. How do we know that it's

1:10:31not a DM and just a just a uh something that I'm secretreting into the environment? That's sweet. >> 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 secretreting 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 the precursors should see this signal >> this signal and start mileating >> because if it was a tweet to everybody it would be >> it would be in the environment >> in the in the Yes. It would be >> and that's exactly what we see. >> Oh my goodness.

1:11:11>> It's it's a nice like it's a nice progressive kind of ah we're getting somewhere >> 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 >> and you're seeing a lot more green dots. >> Mhm. >> Yep. >> And that's from and that's from this this um these neurons. 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 illegalodendrites that were the thing that created and fixed

1:11:53>> myin sheath as things happen. >> 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 Tibetan animals. We found something that works for hypoxia that seemed like it was connected. We established that uh with the rest, >> 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 cuz the OPC's were present in MS patients. And so it wasn't that they weren't there anymore. >> It seemed to be that the the trigger to

1:12:34do the job >> Yeah. >> was breaking down. >> Exactly. >> But we didn't know where the trigger was being triggered from. >> Yes. >> Who's the captain that's giving orders? >> Yes. >> Through this process that the team in this team in Shanghai did, we've now found that the neuron is the captain. >> Exactly. that is triggering the instruction for the OPC's to get the proper instruction to mature to then go to the process to recreate the myelin sheath >> and it's sending those instructions not in a discrete way like a DM it's just literally blasting the signal out >> yeah it's like I need help >> and so what makes sense is uh there's a what the neuron is the source of the

1:13:15problem and it's not tweeting and it's private messaging itself or just it's it set its account on private and no one can see its tweets as a crude annoying analogy >> and that's that that's the 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 were not exposed to the tweet initially it started to do the >> 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, >> right? >> Right. >> Then maybe we could maybe we could solve this problem >> very Yes. Okay. >> So now we've established that there is

1:13:56something in that medium in that cultured medium that we can transfer from one to the other >> and it works. >> And it works. >> That's that's lowkey crazy. >> 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

What is the signal?

1:14:14gets processed in two major branches. One way is just the classical branch which is retinol into retinel into retinoic acid. Chemists are so annoying about this, right? It's it's like come on guys. Anyways, the other way which is mediated by this red stat gene >> which we discovered through studying these Tibetan the >> well no actually the red stat gene is something that's been discovered before this mutation was discovered the specific mutation of the gene >> and and we know that the the redstat gene does this which is it takes retinol and then it puts it into something called ATDR which is 1314 dihydro retinol. It's effectively an isomer type

1:14:57of 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 ret the the rstat 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. >> Mhm. >> Yes. Okay. >> So, so we're we've now made the causal link >> between the presence of this gene mutation and >> now a specific compound >> compound this ATDR being present which we see in these spikes in that top section with the rest and Q24.

1:15:38>> Yeah. Yeah. And you can see that the second spike is larger than the control which means that you've got this is that gain of function that I was talking about, right? like this this particular mutation is giving me more ATDR and perhaps that more signal is telling the OPC's and the stem cells hey I need more myelin >> it's it's now loud enough when we have the because so actually this is a good point so the the in the three top charts right the second and third the rest and the rest Q24 that second the third one all the way to the right >> that's the that's the yak version >> that's the mutation >> and then the one in the middle is just like standard operating procedure And so potentially it's the unless the

1:16:18AT the ATDR being at a particular level might be >> the tipping point. And if it's below a particular level >> in hypoxia it might be a tipping point. Exactly. >> And perhaps in MS >> it might be a tipping point. >> Might be a tipping point. >> That's the connection we're trying to that's the bridge again from before that we're trying to >> Yeah. So okay, what if I just add ATDR,

Is ATDR enough?

1:16:38>> 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 um if I add the ATDR um all of those all of those bars are are about the same. There's a NS on top of them. What that means is not significant. There's no significant difference between whether I add it and whether I don't in the control or in the rest whatever. Right? So clearly ATDR is not everything. M but in the K one if I add ATDR to the neurons and then I culture it

ATDRA and RXR-γ

1:17:17remember 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 OPC's then all of a sudden I get this effect >> okay >> so there is something else >> this proves that ATDR is just a precursor >> Mhm. And the neurons are doing something else with that ATDR. Right. >> Yeah. Yeah. Yeah. Okay. >> So, not only am I getting more of ATDR, but the neurons are doing something more with that more ATDR is. So, it's almost like it's a it is a um just by having the neurons need it's a it's a fundamental uh ingredient for whatever it is the neurons are doing, but it is

1:17:58not 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 um a second, you know, it's a version two of vitamin A of the retinol. There's a version three, which is ATDR A, 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 to my cells. They were like okay look I don't know

1:18:38>> yes >> what what's going on let's just do all of the permutations and combinations and if you look at the fifth column >> y >> you can see a bunch of mileelination happening >> that is with ATDR alone with the acidic version of this >> so when we introduced the ATDR >> the acidic version we are seeing things things happen now >> and so we were the ATDR base was directionally helpful >> and it's just like it's like a a slightly It's a diff slightly different permutation >> of it. >> Yes. And and the key insight here and that's that's effectively the punch line is this ATDRA this acidic version of the vitamin A derivative.

1:19:21>> Mhm. >> That is the selective activator of the RXR gamma. >> Bingo. >> Right. >> Bingo. >> The the the failed trial. >> The beexotin from earlier. >> Yes. the beexa protein 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 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 >> that that's what we got to >> do for the therapeutic but we couldn't target it selectively enough. We've figured out the size problem for delivery. We did not figure out the

1:20:02targeting problem. The ATDR is the solution to the targeting problem we defined earlier in the show. >> 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. >> 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 they got young mice, they exposed them to low oxygen and then those young mice received in injections of ATDR and ATDRA. Both molecules actually reduced that impact of hypoxia.

1:20:44>> Okay, so both molecules actually worked. It makes sense because uh 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. >> You're getting remination. >> Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. >> Okay. >> Oh my goodness. >> And the the the killer is really the next one. >> Yes. >> The next one is so because this was this was hypoxia. >> Mhm. >> Now, what if we straight up go in lession? >> Right. which are the two this >> because hypoxia I don't know it could be

1:21:24doing other things >> right right >> what if we now normal normal environment but we go ahead and we do a lesion um do we get like with in an MS- like brain there are these things called um autoimmune ancilitis E AE 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 ATD, just even ATDR, which is way simpler to make,

1:22:05actually. >> You're getting a lot more mileelination. The mileination volume is increased, which is what we want to see. >> The repair process is is reactivating. It's becoming successful again. This is so so and so now we've 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 target this RXR gamma. >> Yep. >> Um we knew we we needed to target RXR but we couldn't selectively do so. >> Yeah. Cuz it was going everywhere. We

1:22:46found this other pathway through looking at the evolutionary uh

Testing the pathway in disease models

1:22:53>> progress. Yeah. >> 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 to >> it's doing something. >> Perhaps we can translate this into uh a biologic solution for humans. We've now gotten to the point where we've found the selective targeting of RXR gamma through uh uh AD uh

1:23:33>> ATDR ATDR/ AD and there's some pros and cons to both. >> Yeah. >> But like we know how to target so that the neurons signals to the OPC's to mature to restart this process of creating the mileage. >> 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 OPC's the the signal in itself. We can just have the neurons >> do it. Which is actually an important distinction. Yeah. That's >> because the ATDR is a bit easier to make. >> Right. Right. That's an important point. Okay. Yes.

Understanding the graphical abstract

1:24:09>> 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. Um retinol goes to ATDR goes to ATDR. But on the right hand side, the ATDR has an up arrow >> because it's upregulated. That's that gain of function. >> And when that goes to the OPC's and the oligodendritty, >> the OPC's are the green cells. >> When it goes to the OPC's, it creates myelin around my axon. On the left hand side though, there's not enough signal.

1:24:49>> Mhm. >> To get the OPC's, 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 >> not. Yeah. Yeah. >> And that's the graphical abstract. Yes, that's and and we from something that was totally disconnected from anything you'd be able to to understand. We we now have a reference point and also like a fundamental understanding of one of the most uh you know uh impactful neurodeenerative you know issues we we face as humanity among others. among others. Yeah, which we've discussed. >> I mean, >> any any progress is good progress, right? And on the bottom, the the the

1:25:29two blue circles 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 >> because it's able to repair itself and maintain its cognitive functions. >> Very good. >> Uh in a way that the the wild type cannot. >> There it Oh, the 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. And it's just very cool the amount of technology that we have in order to do this. Like

1:26:09so much had to like we know how to we we know how to stain myelin extremely well. We know how to make these um 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 oligodendrites only, right? In order to establish it's not the oligodendrites, it's only it's the neurons that are doing this. We had to express that gene in only the neurons, which is kind of crazy. And 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

1:26:51genetic 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 uh did it from first principles. >> It one would say that I certainly would

Other possible applications

1:27:08you know um 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 birthw weightight 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 pren preterm infant to the world outside of the womb, you've got this

1:27:50risk 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 ATDR 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 it the the hypoxic stress literally it's a onetoone mapping. >> Yeah. >> Uh versus when we talked earlier about the MS it's 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.

1:28:32The other thing with hypoxia is a type of dementia called vascular dementia and small vessel disease. This happens in um 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 neuroderadation specifically in the white matter. Well, if you could have some kind of therapeutic rstat ATDR axis drug that mediates the same exact um therapeutic axis that we've been

1:29:13discussing, then perhaps you have some way to slow this decay. That would be so huge. >> Yeah. I 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 uh impact pathways. We started and referenced MS and some of these prenatal uh 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 ADT, ADTR, ATDR,

1:29:58neuron, 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 the classic example I always bring up is crisper right uh you have multiple use cases for like one unlock >> um and this could be a key that unlocks >> several doors yeah >> um and another big Another aspect to this story is the

The Chinese research team

1:30:36source. Yes. Right. It was in Neuron. >> Yeah. >> But the team >> Yeah. >> It's from China. >> The team is out of China. Yeah. Um, and as we've discussed several times on on the pod, we're in a very different environment today than 5, 10, 15 years ago in how competitive some of these university institutions are in the frontier and not all spaces >> but in some spaces were >> I would say most spaces to be honest. >> Right. And you can see that from the recruitment of some of the best talent across several frontier areas that are now arriving. >> Yeah. in the Chinese university system. So, we're going to continue to see, you

1:31:16know, it'd be a very competitive landscape. >> Yeah. >> At the frontier of research. >> Yeah. I mean, and this this was a phenomenal study. I mean, I just I love 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. >> They know what they're doing. >> Yeah. >> Um they're not just copying us in all

What this discovery actually means

1:31:40ways. 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 just at least a better fundamental understanding of like what the body is doing >> uh and why it is so difficult. Yeah. >> Uh to solve this problem. Um again, frontier research and and therapeutics, there is a large delta between these two things. 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 got to do the science. You got to do the work. We got to start somewhere. And so

1:32:21I 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. um and why they do take time. Um we've found a mechanism. We've not necessarily created the actual >> end product. Uh but great story. Love the bio stuff. We will wrap up this week in half the time >> of the last episode. Uh, for those still listening, you can always catch our shows across all the main platforms,

1:33:02YouTube, 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 uh snacks, little bite-siz 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. Um, 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

1:33:44they've made it to the end. Some of you I I do want to say in the last episode, the Germany the German clapback prompt, >> those are some of them are brutal. >> Some of them were very good. Yeah, some of them were >> some of them were 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. Two people. So, you guys did well. Do you have any thoughts? Yeah, maybe I was thinking, you know, in the vein of ev evolutionary pharmarmacology, 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 pharmarmacology on on an animal and like get some kind of, you know, ability, what what what would it

1:34:25be? For the Gillum monster, it was the low blood sugar. For the snake, it was the low blood pressure. So, what what do you guys think? That's a great one. Uh I am Lester Nar joined as always by my co-host and our resident PhD Krishna Chowdery. 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 eb and flow with what's in the news and where our timing is >> and what we find interesting.

1:35:05>> 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.

1:35:28Hey,