Dark Galaxies, Fuzzy Dark Matter, and an Alzheimer’s Breakthrough (EP. 28)

Hosted by Lester Nare and Krishna Choudhary, this episode has two main stories: an astrophysics update on a candidate “dark galaxy” in the Perseus Cluster (a halo that’s ~99.9% dark matter), and a major Alzheimer’s mechanism paper tracing how exercise protects the brain by repairing the blood–brain barrier—with an actionable drug-like path already emerging. Summary Candidate dark galaxy — Hubble + Euclid stacking and globular clusters reveal an ultra-faint halo that could test missing satellites and the cusp–core problem (and even “fuzzy dark matter”). Exercise → Alzheimer’s mechanism — UCSF links a liver enzyme (GPLD1) to BBB repair via TNAP regulation, plus an oral TNAP inhibitor (SBI-425) that mimics the effect in mice. Rundown — Rubin Observatory’s real-time alert engine, AI-accelerated magnet discovery, a climate-corrected Easter Island history, and the Boba-Kiki effect in baby chicks. Support the showDonate: FFPod.com/donateFollow: @FFPod (X / Instagram / TikTok / Facebook)

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

• 0:00Krishna Choudhary?

  Dark matter quantum mechanics. That is what we are worried about in this particular scenario. It's a very weird way to think about it, but it might be the case.

• 0:11Lester Nare?

  So this new paper from UC San Francisco talks about links between Alzheimer's disease and exercise, but the conclusion was not what I thought it would be. Hello, internet. This is your captain speaking, Lester Nare, joined as always by my co-host and our resident PhD, Krishna Choudhary, who is today donned in his Ferrari race kit. We will get to that later in the rundown, but on this week's episode, we have two great main stories. We'll start off with an astrophysics story about dark matter and we're going to follow up with a look into the latest in Alzheimer's research. For those of you who may be new to the show, be sure to like, share and subscribe. If you want to support the show, head to our website.

• 0:52Lester Nare?

  We have a great donation portal and as you already know, we're going to learn about the science from the ground up today because this is from First Principles.

• 1:17Lester Nare?

  So we're going to begin today with an astrophysics story about dark matter, as we mentioned. Specifically, scientists think they've found a really good candidate for a dark galaxy. This is a galaxy almost completely made up of dark matter, no normal matter. That could give us a little bit of a hint into what dark matter actually is, which continues to be an enduring mystery. So let's dive in on what this story is about.

• 1:47Krishna Choudhary?

  Yeah, I mean, the central question that almost every cosmologist is trying to answer is what is the universe made out of? Okay, the current paradigm is something called Lambda cold dark matter. This is the model for what our universe is. The normal atoms that we see are only about 5% of everything in the universe. It turns out that 24% of our universe is something called dark matter, which we have no idea what it is. All we know is that it is like matter in that it interacts with gravity, but it's not like matter in that light does not care about it. The electromagnetic field does not care about it. So it's not so much as dark as it is transparent in every sense of the word.

• 2:30Krishna Choudhary?

  Like a light beam will just go through dark matter and not interact with it at all. This is very weird because atoms love interacting with photons, right? Because they're electrically charged. Obviously electromagnetism is a thing. And then finally, there's about 72% that is like dark energy, which we're not even gonna get into this time. But just to set the stage, right? Like, we only, we only know what 5% of the matter is in our universe. That's pretty, pretty insane.

• 2:58Lester Nare?

  Can you just repeat that really quick?

• 3:00Krishna Choudhary?

  It's like 5% normal matter. That's the stuff that we're made out of, atoms, baryons, is what it's called.

• 3:05Lester Nare?

  And the stuff we can see.

• 3:06Krishna Choudhary?

  Mm-hmm, yeah. And then 95% is stuff that we have no idea about. And we're trying to figure out, yeah. Weird, it's weird.

• 3:18Lester Nare?

  It is quite weird.

• 3:19Krishna Choudhary?

  And, and what this particular story is about is something called a candidate dark galaxy. This is the second candidate dark galaxy, but it's the one that like, we can, we have a lot of information on because the first one was kind of, you know? It's, it's, it's a massive dark matter halo that failed to form a population of stars. Hubble first identified it and now they've worked together with the ESA Euclid Observatory, that's also in space, to figure out some more stuff about it. It's got an extreme dark matter fraction, meaning 99.9% of this galaxy is dark matter. That's way off compared to the Milky Way, which is in the like 90s, 80s, 70s type of thing. Okay, this is, this is really weird, okay?

• 4:04Lester Nare?

  We'd actually previously done a story on, on dark matter.

• 4:08Krishna Choudhary?

  Yes, yes, on something called Cloud Nine.

• 4:11Lester Nare?

  Yes.

• 4:11Krishna Choudhary?

  And that had no stars.

• 4:14Lester Nare?

  Yes.

• 4:14Krishna Choudhary?

  This one has a few.

• 4:15Lester Nare?

  And so that was what they were, is this the first relic? Which was the abbreviation. And so, but this is different than Cloud Nine.

• 4:23Krishna Choudhary?

  This, yeah, this, this could be a proper galaxy. And there, there are differences that we're gonna highlight.

• 4:28Lester Nare?

  Okay, perfect.

• 4:29Krishna Choudhary?

  Okay, so let's give some historical context. There was this guy Fritz Vicky, he was at Caltech. He coined the term dark matter in 1933 because he observed this particular cluster called the Koma Cluster. He observed a bunch of galaxies in the Koma Cluster and he figured out what the velocities of these galaxies were. And he figured out that how fast these galaxies were moving around some central mass distribution. It didn't make any sense. They were moving way too fast. He used something called the virial theorem, which is a theorem in basic physics that connects kinetic energy to potential energy, okay? You can apply the virial theorem to the solar system, for example, and everything makes sense.

• 5:14Krishna Choudhary?

  Because the farther you are out, the slower you move. That's a, the farther you are out, the more potential energy there is, so the less you have for kinetic energy, right? When he applied it to the Koma Cluster, those observations didn't make any sense. There was way more potential energy from gravity than what he saw. And so he said, there's got to be some dark matter there that we can't see. That is providing the gravitational potential energy.

• 5:40Lester Nare?

  There has to be a source for the pull that creates these orbitals. And normally, we can see where the source of the gravity is.

• 5:49Krishna Choudhary?

  Yeah, normally it's stars, right? And it'll be bright.

• 5:51Lester Nare?

  And you can't miss it. So the thing that's weird about this is we're looking, things are moving in very fast.

• 5:58Krishna Choudhary?

  Very fast.

• 5:59Lester Nare?

  But the thing we can see that would drive that movement is not large enough to explain why they're moving so.

• 6:08Krishna Choudhary?

  Yeah, and so there's got to be some stuff there that acts like matter in that it's gravitationally bound and it creates a gravitational potential, gravitational force. But it doesn't act like matter in the sense that there's like no light coming out of it. Okay, and that's what's weird. There were other observations. Vera Rubin very famously solidified the concept in the 1970s with galaxy rotation curves. What you can do is figure out how fast stars are moving. Around a galaxy.

• 6:37Lester Nare?

  Yes.

• 6:37Krishna Choudhary?

  And what you expect is something like the solar system. Again, the farther you are out, the short, the smaller your velocity, the slower you should be going. That's why a year on Jupiter is like 15 years.

• 6:49Lester Nare?

  Right.

• 6:49Krishna Choudhary?

  Because it takes 15 years to go around the sun. That's not just because the orbit is bigger, like the circle is bigger. It's also that it's moving slower.

• 6:57Lester Nare?

  Yeah, yeah, yeah.

• 6:57Krishna Choudhary?

  It shouldn't be that long, but it's moving slower. That's why it's that long.

• 7:00Lester Nare?

  Yes.

• 7:00Krishna Choudhary?

  If it was moving as fast as the earth, it would be like five years or three years.

• 7:04Lester Nare?

  And this is, this is a similar graphic we talked about in our Verarubin deep dive. We're looking at a graph now where we see the expected, uh, the expected path for the visible disk. Sort of dissipating on the x-axis.

• 7:18Krishna Choudhary?

  Yeah, and that would be like if it was, if it was normal, if the farther I get away from the galaxy. The, the slower I should be moving. What we actually see using starlight and the 121 centimeter line, 1420 megahertz.

• 7:32Lester Nare?

  Yes.

• 7:33Krishna Choudhary?

  Is that actually you're just getting faster. So there's a bunch of invisible matter.

• 7:37Lester Nare?

  Right.

• 7:37Krishna Choudhary?

  That is pulling on you that we have no idea how to see.

• 7:39Lester Nare?

  Right.

• 7:40Krishna Choudhary?

  Okay. So the question is, what, what is, what is going on? What, what is this dark matter? Well, the more and more observations we did, the better we got. In the 1980s, people discovered something called low surface brightness objects. These became known later on in 2015 as ultra diffuse galaxies. Okay. In 2015, we made a discovery using something called the Dragonfly telephoto array. Okay. This is a new array that was built by Yale and the University of Toronto. It's very cool, actually. You as a camera guy, you're gonna love this. So each of these lenses.

• 8:16Lester Nare?

  Yes.

• 8:16Krishna Choudhary?

  So it's in a honeycomb structure, right?

• 8:17Lester Nare?

  Yes.

• 8:18Krishna Choudhary?

  And it's called Dragonfly because the dragonfly eye very much looks like this. It's a bunch of like honeycomb lenses.

• 8:24Lester Nare?

  Yep.

• 8:24Krishna Choudhary?

  Each of these lenses is just the off the shelf Canon 400 millimeter F 2.8 lens.

• 8:30Lester Nare?

  Really?

• 8:31Krishna Choudhary?

  Yeah. It's just.

• 8:32Lester Nare?

  No way.

• 8:33Krishna Choudhary?

  It's, there's, they just, they just bought a bunch of them, put them in a hexagonal array. And then they're compiling the light together to create these images.

• 8:42Lester Nare?

  That's actually incredible.

• 8:44Krishna Choudhary?

  Right? This is something you can get like on Amazon.

• 8:46Lester Nare?

  Yeah, yeah, yeah.

• 8:46Krishna Choudhary?

  But they, they put a bunch of them together. Now, the question is, why would you do this, right?

• 8:49Lester Nare?

  Yeah, yeah, yeah.

• 8:51Krishna Choudhary?

  Traditionally, you never want to use lenses because the bigger the lenses, one thing you get is aberration. Which is the idea that the bigger the lenses, the weight of the lens is going to. Deform the lens. Yes. Right, because glass is not like. Yes. Completely metal. Yes. So there's some fluid property to it. So the larger you make the glass lens, it's gonna sort of like deform. Yep. Because of the weight of its own gravity, or the other way around. And so you're gonna get image distortion that way, right? But what these guys did was a bunch of small lenses put together. Now, what is the advantage? Now, the advantage is for mirrors, right? If you have a mirror lens, which is what modern telescopes all use, they all use mirrors.

• 9:34Krishna Choudhary?

  The light has to come down and then has to get sent back up because it's a mirror. So it's gonna bounce up and there's a secondary mirror that then bounces the light back to a detector. Usually it's like warranted in some way or something. But at the end of the day, you need a secondary mirror. And that mirror needs to be held up by some kind of scaffolding. In the James Webb Space Telescope, it's hexagonal scaffolding. Yes. In the Hubble Space Telescope, it's diamond shaped scaffolding, like in a square 90 degrees. Which is why when we see the images that these telescopes produce, the mirror structure or the architecture actually dictates. For example, I remember when James Webb first came out,

• 10:15Krishna Choudhary?

  certain objects had a certain star pattern or like a certain visual representation. There's different little like little spikes. Yes. Yeah. That was different than Hubble, which is because of this has diagonal. Yeah. Versus hexagonal structure. Yeah, and those are called diffraction spikes. It happens because of scattered light from that scaffolding. Yes. Well, if you want to image really, really diffuse things, that becomes a really big problem. When you say diffuse, what do you mean? Diffuse by really dim. Okay, really dim. Like not a lot of light. Got it. As in like so little light. Yes. That we're pushing the sensitivity of the. CCD, the actual charged couple device, the thing that is collecting the light and turning it into an electrical signal, right?

• 11:00Krishna Choudhary?

  There's a bunch of silicon at the end of your detector. That's what makes up a charged couple device. And when the photon hits that silicon, it releases an electron. And then you're like, oh, I got a little photon from there, right? If you're, if you're imaging really diffuse things, even that, the scaffolding, the scattering from that scaffolding is going to be a problem. So that's why you want to use lenses. But you can't use big lenses because of the aberration, like the deformation problem. So what if these guys just figured from the dragonfly telephoto array, what if we just use a bunch, right? Like we use like 20 or 30 small lenses.

• 11:35Lester Nare?

  And the compile.

• 11:36Krishna Choudhary?

  And we compile them together, okay?

• 11:37Lester Nare?

  That makes sense.

• 11:38Krishna Choudhary?

  And it's, it was like relatively cheap, I can imagine, right? Because you're not like making custom made lenses. This is just Canon 400 millimeter, f 2.8.

• 11:47Lester Nare?

  Calling up Carl Zeiss, we need a custom giant 13 meter.

• 11:52Krishna Choudhary?

  Yeah. And he's like, uh, how about 10 million dollars? Like, no. So, so this was, this was a really cool thing. And in 2015, they came out with these extreme ultra diffuse galaxies. Dragonfly 44 is an example. This is a galaxy, you can see the faint fuzz in the middle.

• 12:11Lester Nare?

  Yes.

• 12:12Krishna Choudhary?

  Not a lot of stars.

• 12:13Lester Nare?

  Yes.

• 12:14Krishna Choudhary?

  And from what we can tell from how these things are moving around, when you do spectroscopy and you figure out the Doppler shift, so you figure out how much is the red shift in this direction, the blue shift in this direction, from there, we can figure out how fast these things are moving around.

• 12:27Lester Nare?

  Yep.

• 12:28Krishna Choudhary?

  And then you back calculate, how big does the galaxy have to be? It's like dark matter dominated. 90% of it is dark matter, 95% of it is dark matter. So it's this ultra diffuse galaxy that seems to have a lot of dark matter. Okay? It's been hard to catch before because usually with normal telescopes, the scattering takes that away. But now with this new dragonfly telephoto, we can start imaging really diffuse structures.

• 12:53Lester Nare?

  That, that makes sense. So the, the point is with the normal structure, we need bright objects for it to work well. And these sort of dark matter galaxies where it's predominantly this, this thing we don't understand is, does not interact with light. It becomes very difficult to see it or to. To image it, I should say.

• 13:12Krishna Choudhary?

  Yeah, to image it.

• 13:13Lester Nare?

  To image it, but with this lens-based architecture, it lowers, it increases the.

• 13:19Krishna Choudhary?

  Signal to noise.

• 13:20Lester Nare?

  Yes, such that we can at least get something.

• 13:24Krishna Choudhary?

  Something, yeah, exactly. And then this particular paper is candidate dark galaxy two. It is taking these ultra diffuse galaxies to a whole new level.

• 13:34Lester Nare?

  Okay.

• 13:34Krishna Choudhary?

  It's pushing that diffuse.

• 13:36Lester Nare?

  Yes.

• 13:36Krishna Choudhary?

  Into now dark, because now we're getting ninety nine point nine percent dark matter. Okay, and that's really crazy.

• 13:44Lester Nare?

  Yeah, yeah.

• 13:45Krishna Choudhary?

  Okay.

• 13:45Lester Nare?

  Yeah, yeah.

• 13:45Krishna Choudhary?

  So why do we even care, right? This intensive hunt for something like a candidate dark galaxy. It's motivated by two crises that are in the center of this cosmological model that we called Lambda CDM. You know that thing I told you before about five percent normal matter, twenty five percent dark matter, the rest being dark energy?

• 14:05Lester Nare?

  I think it was this one, yes.

• 14:06Krishna Choudhary?

  Yeah, exactly. So this is the model that we have today.

• 14:09Lester Nare?

  Yes.

• 14:09Krishna Choudhary?

  Now, fine, if if that is the model, right?

• 14:12Lester Nare?

  Right.

• 14:12Krishna Choudhary?

  There should be consequences of that model.

• 14:14Lester Nare?

  Yes.

• 14:15Krishna Choudhary?

  There are certain consequences of the model that we do not see.

• 14:19Lester Nare?

  The the point being, we have an understanding of the universe.

• 14:21Krishna Choudhary?

  Yeah, and we're like, this is our best guess. And then there's always people who are like, hmm, but that doesn't really make sense for these two reasons.

• 14:28Lester Nare?

  Got it. It doesn't, it doesn't, it it doesn't compute.

• 14:31Krishna Choudhary?

  Yeah, it doesn't compute. And these are the two things specifically.

• 14:33Lester Nare?

  Okay.

• 14:34Krishna Choudhary?

  That do not compute. The first one is the missing satellite problem, okay? These dark matter simulations, when you use that original five percent normal matter, twenty five percent dark matter, blah, blah, blah. You press play on a universe, you set it up in the computer and you press play. Simulations predict that there should be about five hundred orbiting dark matter sub halos around something that is the size of the Milky Way.

• 14:59Lester Nare?

  Okay.

• 15:00Krishna Choudhary?

  The idea is, for every big halo of dark matter condensing, right, dark matter is still gravitationally bound. So the universe is expanding, there's a bunch of dark matter, there's gonna be tiny fluctuations where there's a little bit more matter here, a little less matter here. And so it's gonna start clumping because gravity is gonna take that over-dense region, is what we call it, and we're gonna start clumping that way. Now around those big clumps, there's gonna be smaller clumps. Around those smaller clumps, there's gonna be even smaller clumps. There's like a power law structure. And what we expect is there should be a lot more small clumps.

• 15:33Lester Nare?

  Right.

• 15:34Krishna Choudhary?

  Than what we see.

• 15:35Lester Nare?

  Right.

• 15:35Krishna Choudhary?

  So that is the missing satellite problem.

• 15:37Lester Nare?

  We, we, we see big, a couple of big clumps.

• 15:40Krishna Choudhary?

  Yeah.

• 15:40Lester Nare?

  But the cascading second and third order clumps, we should be seeing are not present.

• 15:45Krishna Choudhary?

  Exactly. And that's what we're seeing over here.

• 15:47Lester Nare?

  Okay.

• 15:47Krishna Choudhary?

  Um, the, the triangles with the air bars.

• 15:51Lester Nare?

  Yes.

• 15:51Krishna Choudhary?

  That's observation.

• 15:52Lester Nare?

  Yes.

• 15:52Krishna Choudhary?

  The lines are theory. And you can see that for larger increasing mass, we're fine.

• 16:01Lester Nare?

  So when the mass increases, the observation matches the theory.

• 16:05Krishna Choudhary?

  Yes, but for the smaller clumps, these satellite galaxies, there's a massive discrepancy. Orders of magnitude.

• 16:11Lester Nare?

  Because, because of the power law, we should be seeing significantly more smaller dark matter, uh, clusters or halos. Than the large ones, but the, the rate of increase of the number from observation is very like the increase is quite low.

• 16:26Krishna Choudhary?

  Yeah, there's like, there's like a point where it's just like, we just, we just see way too few.

• 16:30Lester Nare?

  Yes.

• 16:31Krishna Choudhary?

  Okay. So the question is, I mean, maybe, maybe these smallest halos are present, but they're completely dark. Which is why you don't see them. There's no stars. So like, what are you, what are you gonna see?

• 16:39Lester Nare?

  It's a bunch of cloud nines from our, from our starless dark matter cloud.

• 16:43Krishna Choudhary?

  Exactly. And so cloud nine was trying to solve the similar problem. And this is kind of solving that similar problem too, if this is truly there, right?

• 16:50Lester Nare?

  Okay.

• 16:50Krishna Choudhary?

  Now the second, and this is something that cloud nine was not doing. So this is novel, novel. It's called the cusp core problem. Here's the idea. Dark matter does not interact electromagnetically, right?

• 17:02Lester Nare?

  Right.

• 17:03Krishna Choudhary?

  There's no like, you know, electrons, they wanna, they wanna move away from each other. And protons wanna move away from each other, even when we have atoms, these atoms, you can't just compact them. But if you have a particle like dark matter that is only interacting with gravity. That means that the closer you get to the center of the gravitational potential, the density should just get higher and higher and higher. Because gravity is just clumping everything together. There's nothing that's pushing out.

• 17:29Lester Nare?

  Right.

• 17:29Krishna Choudhary?

  Like when we think about like, like hydro- Static equilibrium and things like that, but there's nothing pushing out.

• 17:34Lester Nare?

  Right.

• 17:34Krishna Choudhary?

  So the closer you get to the center, the density of dark matter should be higher and higher. That is not what we see.

• 17:40Lester Nare?

  Interesting.

• 17:41Krishna Choudhary?

  See, instead of a cusp, which would mean in the center, we get like a little pointy.

• 17:45Lester Nare?

  Yeah.

• 17:45Krishna Choudhary?

  We get a core type where it's like at the center, the dark matter density sort of flattens out.

• 17:51Lester Nare?

  Interesting.

• 17:52Krishna Choudhary?

  That's weird.

• 17:53Lester Nare?

  That is weird.

• 17:53Krishna Choudhary?

  If dark matter is purely gravitational, why would it just flatten out?

• 17:58Lester Nare?

  It should, it could should be continuing.

• 18:00Krishna Choudhary?

  It should continue to get bigger and bigger as it gets closer and closer to the center. The density should be higher and higher. That's not what we're seeing. Now, okay, the defense that the Lambda CDM people make, like the guys who make the cosmology model and they're drinking the Kool-Aid.

• 18:15Lester Nare?

  Yes.

• 18:15Krishna Choudhary?

  Right? They're like, no, well, there's something called baryonic feedback. This is the idea that towards the center of the, of the galaxy. There's a bunch of supernova explosions.

• 18:24Lester Nare?

  Okay.

• 18:25Krishna Choudhary?

  Okay. And that supernova explosion is going to send shock waves in spacetime. And those shock waves are sort of going to diffuse the center of that galaxy. So even though the normal dark matter would create a cusp.

• 18:36Lester Nare?

  Yes.

• 18:37Krishna Choudhary?

  Right? Because there's so many explosions happening in the center of the galaxy, that's going to sort of flatten out, right? Kind of makes sense.

• 18:44Lester Nare?

  Okay.

• 18:44Krishna Choudhary?

  Right? That could work.

• 18:45Lester Nare?

  Okay.

• 18:46Krishna Choudhary?

  But this is why this particular galaxy is significant. This galaxy has no stars, basically no stars. So there's no supernova.

• 18:54Lester Nare?

  Right, right.

• 18:54Krishna Choudhary?

  Right? Which means that this should definitely have a cusp.

• 18:57Lester Nare?

  I see.

• 18:58Krishna Choudhary?

  That is why it is worth studying.

• 18:59Lester Nare?

  So, so the CDG two. It's interesting because.

• 19:05Krishna Choudhary?

  Yeah. And by the way, CDG two, CDG means candidate dark galaxy for, for those. Nope, my Siri.

• 19:15Lester Nare?

  Someone is, one of the intelligence agencies is apparently trying to hack our phones at the moment.

• 19:21Lester Nare?

  But this is interesting. So there's currently a cosmological model.

• 19:27Lester Nare?

  Of normal matter, dark matter and dark energy. Like, what is the composition of the universe?

• 19:31Krishna Choudhary?

  Yeah.

• 19:32Lester Nare?

  That model has two problems that we just talked about. The missing satellite problem and the cusp core problem. The, the folks who are in defense of this Lambda.

• 19:43Krishna Choudhary?

  CDM.

• 19:43Lester Nare?

  CDM. Believe that supernova explosions is the reason that we don't see a cusp.

• 19:51Krishna Choudhary?

  Yeah, yeah, it's like sort of like, like, you know, blurring stuff out.

• 19:54Lester Nare?

  It moves around, it moves around rather than aggregating it. Let's, let's say, for example, right?

• 19:58Krishna Choudhary?

  Yeah.

• 19:59Lester Nare?

  The problem is, observationally, we've now seen something, which is the CDG2, that has a very few amount of stars, which means very few amount of, no supernova explosions.

• 20:10Krishna Choudhary?

  Yeah, no one's dying because no one's alive.

• 20:12Lester Nare?

  So how do you, so, so, no.

• 20:14Krishna Choudhary?

  Yeah, so, so, so, this, this galaxy can now offer a test to your Lambda CDM.

• 20:21Lester Nare?

  And this is actually an interesting point about understanding the intersection between theoretical sciences and experimental sciences.

• 20:27Krishna Choudhary?

  Yeah.

• 20:27Lester Nare?

  And the experimentals are constantly in the real world looking for

• 20:31Krishna Choudhary?

  Ways to test.

• 20:32Lester Nare?

  Ways to test. You need some sort of stability, blah, blah, blah, like something that can be consistently measured. And we have something now.

• 20:41Krishna Choudhary?

  Yes, we finally found something.

• 20:42Lester Nare?

  Very interesting.

• 20:43Krishna Choudhary?

  And we haven't done spectroscopic analysis.

• 20:45Lester Nare?

  Okay.

• 20:45Krishna Choudhary?

  Because this, we, we just found it.

• 20:47Lester Nare?

  Yes, right.

• 20:47Krishna Choudhary?

  That's why it's in, that's, that's why it's interesting. Because now, we can, we can get time on the James Webb. We can get time on the Subaru. Or the giant Magellan that's going to come up and be like, I want you to stare at that thing for like, three days, straight.

• 21:00Lester Nare?

  And I just want to quickly note, you know, because getting time on these instruments is, is everyone, there's very few of them. Everyone thinks their thing that they're studying is the most important thing in the world. But this seems to be, because of the importance of dark matter generally as a concept, a good candidate

• 21:17Krishna Choudhary?

  Yeah.

• 21:18Lester Nare?

  to be able to, quote, skip the line.

• 21:19Krishna Choudhary?

  Yes.

• 21:20Lester Nare?

  Okay.

• 21:20Krishna Choudhary?

  Exactly. And so I want to make a case for why this is important. Okay. Right? And that's what these people did in this particular. Okay. Um, paper, right? The challenge is, how do you defeat sky glow? Sky glow being dark galaxies, these, these types of dark galaxies that, I mean, there's no, there's no stars. So what are you going to look at? Right? They're super faint. The signal is often so faint that there's a statistical noise limit when it comes to like your CCD, your charged couple device, the sensor in the back of your camera that is like looking at this thing. There's a noise, right? It's going to catch stray photons and that noise is going to be higher than the signal that we're getting. So we can't just like, look at the thing. Right. Right? So how do we actually find this thing? Well. This is for earth-based. Even though, this is even a Hubble, dude. Oh, interesting. Yeah. Interesting.

• 22:05Krishna Choudhary?

  Because the Hubble has a CCD on it. I see what you're saying. And even though it's in outer space, like that thing has a noise. And then there's, there's something actually called Zodiac light. Okay. There is dust in the solar system. Mm-hmm. Right? And that dust is going to scatter. I see. Sunlight. That makes sense. Into your detector. Yeah. Wherever you look, there's going to be dust from the solar system. That makes sense. And that is going to have a faint glow. That makes sense. And if the thing that you're looking at is a smaller glow than literal dust in our solar system. So what? You're, we're going to put a Hubble like outside the solar system? We're not doing that and then wait like four days to get signal back. Like, well, first of all, getting out there is like, you know, it's ridiculous. So, so. That's fair.

• 22:45Krishna Choudhary?

  So we need to figure out other proxy ways to, to look for these ultra-low-density galaxies, these candidate dark galaxies. Okay. Okay? And we, you, the proxy that comes up is called the globular cluster. These are some of my favorite objects. They're dense, ancient, they're bright, and they're point-like sources. They're way, way smaller than galaxies. They're like these old, old relics of galaxy formation. Not to be confused with the acronym relic.

• 23:16Lester Nare?

  Just to be clear.

• 23:17Krishna Choudhary?

  Yeah, yeah, yeah. Not to be confused with the acronym RELIC. There's so many of these that are around our Milky Way. They're really small, okay? They're gonna be like hundreds of solar systems to thousands of solar.

• 23:28Lester Nare?

  Wow, that's really small.

• 23:29Krishna Choudhary?

  It's really small, like, like, and the density of stars in that, in that like region.

• 23:35Lester Nare?

  Yeah.

• 23:35Krishna Choudhary?

  Is, is insanely small, like, you'll have like, like, you know, the closest star to us is like four light years away.

• 23:43Lester Nare?

  Yeah, yeah, yeah.

• 23:44Krishna Choudhary?

  Over there, I think it's like on the order of light days.

• 23:47Lester Nare?

  So it's like.

• 23:47Krishna Choudhary?

  To months.

• 23:48Lester Nare?

  It's like comparing the population density of Koreatown in Los Angeles to like Poughkeepsie, New York.

• 23:53Krishna Choudhary?

  Yes.

• 23:53Lester Nare?

  Or something else.

• 23:54Krishna Choudhary?

  Yes, yes, we are, we are that New York.

• 23:57Lester Nare?

  Yeah, yeah, we are, we are Poughkeepsie, New York.

• 24:00Krishna Choudhary?

  Yeah.

• 24:00Lester Nare?

  But these galaxies look like Koreatown.

• 24:02Krishna Choudhary?

  Yeah, yeah, yeah. You shouldn't say New York because whenever I think New York, I think New York City. It's like, so try, let's try like, uh.

• 24:09Lester Nare?

  Poughkeepsie is like the middle of New York State.

• 24:11Krishna Choudhary?

  Yeah, yeah, yeah.

• 24:11Lester Nare?

  Let's say, let's say like.

• 24:12Krishna Choudhary?

  I don't know where that is.

• 24:15Krishna Choudhary?

  I only know New York City.

• 24:17Lester Nare?

  There's only one New York.

• 24:17Krishna Choudhary?

  Yeah, you could say like.

• 24:19Lester Nare?

  You know, Nebraska.

• 24:20Krishna Choudhary?

  Right, right.

• 24:20Lester Nare?

  You know.

• 24:20Krishna Choudhary?

  Omaha.

• 24:21Lester Nare?

  Yeah, Omaha, Nebraska.

• 24:22Krishna Choudhary?

  Okay, fair, yeah, exactly.

• 24:24Lester Nare?

  Let's do that.

• 24:27Lester Nare?

  But that's an, that's a, that's a helpful reference point.

• 24:30Krishna Choudhary?

  Yeah, yeah, so these things are really small. And so imagine, and these globular clusters, they're actually really important for just history, astronomical history. Harold Shapley at Mount Wilson at the Carnegie Observatories, which we're gonna have a special coming out soon. He mapped that the sun was not at the center of our galaxy by using these globular clusters. He observed a bunch of globular clusters, their positions.

• 24:58Lester Nare?

  Yes.

• 24:58Krishna Choudhary?

  How far they were.

• 24:59Lester Nare?

  Yes.

• 24:59Krishna Choudhary?

  Relative to the galactic disk, and he could figure out we're actually off-center.

• 25:03Lester Nare?

  Uh huh.

• 25:03Krishna Choudhary?

  Right? We're not, we're not in the center of this galactic.

• 25:06Lester Nare?

  Yes.

• 25:06Krishna Choudhary?

  Um, these globular cluster distributions.

• 25:09Lester Nare?

  Yes.

• 25:09Krishna Choudhary?

  So they're really tiny little specks around them, around giant massive galaxies, right? And so they become really nice for observing a dark galaxy. Because the galaxy couldn't be there, but if we observe a bunch of globular clusters, there's got to be some. Thing that is gravitationally binding the globular clusters in that area.

• 25:31Lester Nare?

  This, this vaguely reminds me, and I know I'm always making these stretch connections. When we talked about the radius of the proton story last week. The idea that you cannot directly observe it.

• 25:44Lester Nare?

  And so we have to use these like second and third order. Reference points in order to like compute the value. And similarly, because we can't, because dark matter does not interact with light. We're using the proximity and the movement and acceleration and angular momentum and et cetera, et cetera. Of these globular clusters to derive understanding of this dark matter.

• 26:06Krishna Choudhary?

  That's exactly right. Yeah. And so this is what they finally did. They, they looked at archival data from the Piper survey. Which is of the Perseus cluster. There's a giant galaxy cluster in the Perseus constellation. Okay. And there was this survey by Hubble Space Telescope. When they looked there. They reanalyzed that data with something called DOLFOT, which is different from DAOFOT. It's like a way to analyze data from Hubble Space Telescope, taking into account like the engineering of the Hubble Space Telescope. What it's capable of, things like that. And they revealed in this Perseus cluster, they revealed a fourth globular cluster. That they hadn't seen before. If you look over there, there's three blue dots and then there's a red dot.

• 26:50Krishna Choudhary?

  That red dot is a new globular cluster that they hadn't found before. And from that, they can be like now, well, wait, if there's a new globular cluster, there's four. Four being in the same small region is really unlikely unless there's something in the middle there. That is causing them to clump.

• 27:08Lester Nare?

  I want to make a brief note here, which is this important kind of note about how the importance of data analysis. Because you have a raw data profile.

• 27:19Krishna Choudhary?

  And this is the same raw data.

• 27:20Lester Nare?

  It's the same raw data profile. Of like what had happened and it's just literally, you know, there's no interpretation on that raw data yet. However, depending on the parameters and how you filter that raw data, there's a whole spectrum of different conclusions you can make depending on what you're looking for. And so the idea here is that they change the parameters.

• 27:41Krishna Choudhary?

  Yeah.

• 27:42Lester Nare?

  And by, which is not changing the fundamental data.

• 27:45Krishna Choudhary?

  No, the raw data is the same.

• 27:46Lester Nare?

  It's like if you have a camera with a 400 millimeter lens and you're trying to look at something that's really close to you, it's just gonna look like a blur.

• 27:53Krishna Choudhary?

  Yeah.

• 27:53Lester Nare?

  Because the 400 millimeter is just trying to look at things far away, but it thinks, but if you change to a 30, whatever, 24 millimeter lens, all of a sudden, you can see the thing.

• 28:02Krishna Choudhary?

  Yeah.

• 28:02Lester Nare?

  Because you changed the way in which you're trying to analyze the information.

• 28:06Krishna Choudhary?

  Well, but I want to be cautious there because what you just talked about is actually different raw data.

• 28:12Lester Nare?

  Ah, okay.

• 28:12Krishna Choudhary?

  Right? If you're switching out lenses.

• 28:14Lester Nare?

  That's fair.

• 28:14Krishna Choudhary?

  The raw data is different.

• 28:16Lester Nare?

  Okay, that's fair.

• 28:17Krishna Choudhary?

  Right?

• 28:17Lester Nare?

  No, it's fair.

• 28:17Krishna Choudhary?

  Here, I do want to make a distinction because this is, this is important. Here, we're doing the same, we got the same photo.

• 28:24Lester Nare?

  Yes.

• 28:24Krishna Choudhary?

  Okay?

• 28:24Lester Nare?

  That's a good point.

• 28:25Krishna Choudhary?

  But we're now putting it through, like, well, like, you know, on, on your computer.

• 28:30Lester Nare?

  Yes.

• 28:30Krishna Choudhary?

  On Photoshop.

• 28:31Lester Nare?

  Yes.

• 28:31Krishna Choudhary?

  We got like Photoshop, the newest version.

• 28:33Lester Nare?

  Yes.

• 28:33Krishna Choudhary?

  Versus like the old version.

• 28:35Lester Nare?

  Okay.

• 28:35Krishna Choudhary?

  And now we can do like, oh, contrast this way and like, and like the, you know, the, you know, the color thing. And you're like, oh, I wanna, I wanna do this color more and this color less.

• 28:45Lester Nare?

  That's a very, that's a really good point.

• 28:46Krishna Choudhary?

  That's, that's the data analysis.

• 28:48Lester Nare?

  No, that, that's fair.

• 28:48Krishna Choudhary?

  If you switch out a lens, that's raw data.

• 28:50Lester Nare?

  No, no, no.

• 28:50Krishna Choudhary?

  You're, you're switching out of engineering.

• 28:52Lester Nare?

  No, that, that's, that's a very fair point. The, the, the, the Photoshop analogy is correct.

• 28:57Krishna Choudhary?

  Yeah, this is, they did like Dolphat Photoshop instead of Dauphate Photoshop.

• 29:00Lester Nare?

  It's a different Instagram filter.

• 29:02Krishna Choudhary?

  Yes, yes, yes. And they're like, oh, there's four instead of three. Yeah. And exactly.

• 29:07Lester Nare?

  Okay, yes.

• 29:07Krishna Choudhary?

  Exactly. But they did Instagram on the Hubble.

• 29:10Lester Nare?

  On the Hubble.

• 29:10Krishna Choudhary?

  Yeah.

• 29:11Lester Nare?

  Yes, okay, yes, yes, yes, yes.

• 29:12Krishna Choudhary?

  Yeah. And then, and then they found this fourth one, right? And that was critical. And when they stacked, so then they, they got their ESA colleagues.

• 29:19Lester Nare?

  Yep.

• 29:19Krishna Choudhary?

  Um, at the European Space Agency. European Space Agency has something called Euclid.

• 29:23Lester Nare?

  Okay.

• 29:24Krishna Choudhary?

  And they used the Euclid image of the same spot with the Hubble image from the Spain same spot, stacked them together. And now you could reveal a same, the same ultra faint diffuse glow in between those four globular clusters. Those four globular clusters that were there, there was actually a little bit of light coming from the middle. So there are a few stars, not that many, but there's a chance.

• 29:49Lester Nare?

  Uh huh, okay. And this, by cross referencing data sources, you can get a little more, uh...

• 29:57Lester Nare?

  Fidelity.

• 29:58Krishna Choudhary?

  Exactly.

• 29:59Lester Nare?

  Okay.

• 29:59Krishna Choudhary?

  Yeah. And so with that diffuse glow, now you can start fitting models. And you can say, okay, what is the amount of stellar mass? That's in that diffuse glow, right in the middle, right? The amount of light that I'm getting is very little. But from that, I can make an estimate, given how far I know it is, like how far away it is. Um, the Perseus cluster, we can be like, okay, that's about 10 to the six um suns. So it's about 2 million suns. Okay, it's not a lot. But from what we know about the number of globular clusters? And how luminous they are, we can also back calculate the amount of dark matter that should be there. And the dark matter is something like 10 to the 10.

• 30:45Krishna Choudhary?

  So 10 billion suns. So we've got 10 billion suns worth of dark matter and only 2 million suns worth of normal matter. Meaning that the halo mass fraction, the amount of dark matter versus normal matter is 99.94 to 99.98%.

• 31:04Lester Nare?

  This is where we get the 99.

• 31:06Krishna Choudhary?

  Yeah, yeah. The size of the dark matter halo is about that of the Large Magellanic Cloud, which is one of the, it's the biggest satellite galaxy to the Milky Way. You can only see it in the southern hemisphere. But the number of stars there is like a thousand times less than what we see in the Large Magellanic Cloud. Okay, so this is, this is like a really, really tiny, tiny fraction of what should be there. There's not that many stars. There's like one in a thousand stars of what it should be.

• 31:35Lester Nare?

  Right, and that's, and that's, and that's in, that goes in direct, that experimental data goes into direct conflict with the Lambda CDM?

• 31:48Krishna Choudhary?

  No, no, no, it doesn't, it doesn't necessarily go into direct conflict. Because the Lambda CDM does suggest that there should be a lot of dark matter galaxies.

• 31:58Lester Nare?

  Okay.

• 31:58Krishna Choudhary?

  It's just now we've found one.

• 32:00Lester Nare?

  I see.

• 32:00Krishna Choudhary?

  Right, and now, this, this is where we get into, how, how could this be possible, right?

• 32:05Lester Nare?

  Okay.

• 32:05Krishna Choudhary?

  Now, the first hypothesis is something called the failed giant hypothesis, which is something like Cloud Nine, which we covered in a very recent episode.

• 32:13Lester Nare?

  Yes.

• 32:13Krishna Choudhary?

  The idea is you've got some massive halo that's destined to be a galaxy. And then early star formation makes the globular clusters around it. But then star formation somehow abruptly just like stops. And so you just got a bunch of dark matter, a few stars and these globular clusters around, right?

• 32:30Lester Nare?

  If I recall, there's like some threshold where it's right in the sweet spot. Where it it'll maintain versus continuing.

• 32:36Krishna Choudhary?

  Yeah, yeah. The weird thing is this is bigger than that threshold, though.

• 32:39Lester Nare?

  Ah.

• 32:40Krishna Choudhary?

  I did check.

• 32:40Lester Nare?

  Okay.

• 32:41Krishna Choudhary?

  And this 10 to the 10 solar masses, so 10 billion solar masses is larger than the threshold that we had over there.

• 32:47Lester Nare?

  So it shouldn't just be like cloud nine.

• 32:49Krishna Choudhary?

  Yeah, it's not like cloud nine. Otherwise, it would be a relic and there'd be no stars. There's still a few stars.

• 32:53Lester Nare?

  Fair.

• 32:54Krishna Choudhary?

  Right? The other thing could be like something called a quenching mechanism. There's something called ram pressure. So this is a photo of the Perseus cluster.

• 33:02Lester Nare?

  Yes.

• 33:02Krishna Choudhary?

  You can see a lot of the starlight is coming from these large galaxies.

• 33:06Lester Nare?

  Yes.

• 33:07Krishna Choudhary?

  And the blue sort of haze is from the dark matter that we've mapped out because of all of the velocity measurements that we've taken. And one can imagine that in this really vibrant cluster, you had this early dark matter halo with a bunch of dark matter. And it was like it had a bunch of cold gas is what we call because cold gases like the gases are moving around. So it can clump and then form stars. So it was destined to be a galaxy, kind of like the Large Magellanic Cloud. But maybe like some other galaxy just rammed into it and then stripped it of all of the star making material. So now it didn't have any star making material and it's just stuck being like this dark galaxy.

• 33:47Lester Nare?

  That's actually interesting.

• 33:48Krishna Choudhary?

  Right?

• 33:49Lester Nare?

  Okay.

• 33:49Krishna Choudhary?

  So there's these, there's these like theories and you know, more testing and more observation is gonna tell which one is correct. What I'm really excited about is what I was telling earlier, which is this cusp and core model.

• 34:01Lester Nare?

  Right.

• 34:01Krishna Choudhary?

  Right? Like which one, why, why do, why does dark matter not form a cusp? Right? We need to do more spectroscopy. We don't have that data right now. All we have is photometric data. What we'd have to do is figure out the, the spectra to figure out the red shift and the blue shift. And all of the really nitty gritty details of what that dark matter clump looks like. Because what we'd expect, given that there's no stars, is there's no smoothing out. And because there's no smoothing out, right? Then the.

• 34:35Krishna Choudhary?

  We should have a cusp. We should have a higher density of dark matter in the center. And we should have low density out in the, in the, in the outside. We shouldn't have this flattened profile.

• 34:45Lester Nare?

  Right.

• 34:45Krishna Choudhary?

  Where in the middle, there's just a bunch of dark matter, but there's no real big over density right at the center. Right. There's no like clump of dark matter that's super dense in the center. So that is, that would be the case if we accept the current models of lambda dark matter. Which is lambda CDM, which is the idea that dark matter is some kind of particle. It doesn't interact with itself unless it's through gravity. And now we get a cusp. If we see the cusp, great.

• 35:15Lester Nare?

  Right.

• 35:15Krishna Choudhary?

  Okay. If we don't see the cusp, what does that mean?

• 35:18Lester Nare?

  So, so what we're saying is as we go out and get more data, spectroscopy data. It will further clarify, is there a core or is there a cusp?

• 35:29Krishna Choudhary?

  Yes.

• 35:30Lester Nare?

  And if there is a cusp.

• 35:32Krishna Choudhary?

  Then we're good.

• 35:33Lester Nare?

  Great. The lambda CDM, well done.

• 35:36Krishna Choudhary?

  Yeah.

• 35:37Lester Nare?

  Experimental data is now further validating the theory. If it continues to be a core, which is kind of what we, it appears to be.

• 35:48Krishna Choudhary?

  Yeah. It appears that like.

• 35:49Lester Nare?

  It appears that way.

• 35:50Krishna Choudhary?

  Yeah.

• 35:51Lester Nare?

  Then we gotta go look back at the drawing board a little bit.

• 35:54Krishna Choudhary?

  Yes. Then we gotta be like, what exactly is dark matter? Is dark matter really just like another particle, like a proton or an electron? That, fine, the only thing that's different about it is it doesn't have any charge. And it doesn't interact with electromagnetic field. It doesn't interact with light. Right. That's, that's the normal thing. And that's like, like naively, I would expect that. It's just another particle, but it doesn't interact with light, which is why we see its effects across giant times, giant scales of the universe. But not like, you know, nitty gritty stuff. This one is pretty cool. There's something called fuzzy dark matter. This is very different from lambda CDM. Okay? Fuzzy dark matter means that dark matter is not tiny little like particles.

• 36:36Krishna Choudhary?

  But it's fuzzy in the sense that it's super light, meaning billions of times lighter than the electron. And what does that mean? If it's billions, and that's, and that's some of the lightest stuff that it's going to be lighter than quarks, electrons. It's, it's at the order of like even lighter than neutrinos type of thing. It is so light that if we were to calculate the quantum mechanics of a particle that's that light, the wavelength. The de Broglie wavelength, because you know, remember in quantum mechanics, every particle is a wave and blah, blah, blah, blah, blah. Well, the larger the particle is, the shorter the de Broglie wavelength. Okay, so electrons have a wavelength that's like around like ultraviolet X-ray ish.

• 37:18Krishna Choudhary?

  This thing at 10 to the minus 22 electron volt mass would have a wavelength that is hundreds of light years big.

• 37:29Lester Nare?

  Oh, my God.

• 37:30Krishna Choudhary?

  Right? It's quantum wavelength. If you were to create a quantum wave out of it would be the size of several. Like it would be like a big chunk of the universe. I mean, sorry of the galaxy. Right? This is so, so the wavelength, the wavelength would be larger than the distance between them.

• 37:47Lester Nare?

  Right.

• 37:48Krishna Choudhary?

  Okay.

• 37:48Lester Nare?

  Yeah.

• 37:49Krishna Choudhary?

  Now, what does that remind us of? That reminds us of Bose-Einstein condensates.

• 37:54Lester Nare?

  Yes, yes.

• 37:55Krishna Choudhary?

  Because in a Bose-Einstein condensate, the wave, the waves of each particle pile on top of one another.

• 38:01Lester Nare?

  Yes.

• 38:02Krishna Choudhary?

  To create a single quantum wave.

• 38:03Lester Nare?

  Yes.

• 38:04Krishna Choudhary?

  And that's why they don't like sort of clump together.

• 38:06Lester Nare?

  Yes.

• 38:06Krishna Choudhary?

  So what this particular theory is saying is there's some kind of inherent quantum pressure.

• 38:12Lester Nare?

  Yeah.

• 38:12Krishna Choudhary?

  That's at the scale of galaxies.

• 38:15Lester Nare?

  Yeah.

• 38:15Krishna Choudhary?

  That is creating like a core with a flat density. You've got a Bose-Einstein condensate of this fuzzy dark matter particle. That is at the size of a galaxy and that's why you don't get a cuspid.

• 38:26Lester Nare?

  Yeah, that's so.

• 38:27Krishna Choudhary?

  It's so fascinating. So this, this could be, you know, this candidate dark galaxy could be a proving ground.

• 38:35Lester Nare?

  Yeah.

• 38:35Krishna Choudhary?

  For something like fuzzy dark matter. It's very interesting.

• 38:39Lester Nare?

  From my layman's perspective, I like, I like, only because we've so recently talked about Bose-Einstein condensates. So I have a mental model of what that actually means. And so I'm like, yeah, that sounds right.

• 38:51Krishna Choudhary?

  Yeah, that sounds about right. That would be so cool.

• 38:54Lester Nare?

  Yes.

• 38:54Krishna Choudhary?

  Imagine a particle whose quantum wavelength is the size of a galaxy.

• 38:59Lester Nare?

  That's unbelievable. That's unbelievable.

• 39:01Krishna Choudhary?

  Very.

• 39:02Lester Nare?

  That would be very cool.

• 39:02Krishna Choudhary?

  So I mean, so this is, this is quite a big deal in, you know, in that.

• 39:07Lester Nare?

  I'm curious, I would be curious to see how other folks and institutions

• 39:13Krishna Choudhary?

  Yeah.

• 39:14Lester Nare?

  begin to sort of digest and interpret the paper.

• 39:16Krishna Choudhary?

  Mm hmm.

• 39:17Lester Nare?

  But I think like we were talking about earlier, there are certain things that happen when it happens. It's like, okay, all the big guns point over there.

• 39:23Krishna Choudhary?

  Point over there.

• 39:24Lester Nare?

  Um, you think it has the potential to reach that threshold?

• 39:28Krishna Choudhary?

  I think so. I mean, I mean, we know where it is.

• 39:30Lester Nare?

  Yeah.

• 39:30Krishna Choudhary?

  We know, we know, like, sort of the base spectrum, spectrometry data. So I can, I can imagine there's going to be a lot of follow up studies

• 39:38Lester Nare?

  Mm hmm.

• 39:38Krishna Choudhary?

  on this from all the top telescopes and institutions.

• 39:42Lester Nare?

  Cause why not?

• 39:43Krishna Choudhary?

  Yeah, yeah, it's a, it's a testing ground for like particle physics in some sense.

• 39:47Lester Nare?

  Yes.

• 39:47Krishna Choudhary?

  Right?

• 39:48Lester Nare?

  Yes.

• 39:49Krishna Choudhary?

  Which is very cool.

• 39:49Lester Nare?

  This is very, very cool. This is very, very good. This, this was out of, uh, the Astrophysical Journal Letters.

• 39:58Krishna Choudhary?

  Mm hmm.

• 39:58Lester Nare?

  Um, and we have our institutions here. This would have been, cause I want to make sure we cover who did the paper for this.

• 40:05Krishna Choudhary?

  Yeah, yeah, yeah.

• 40:06Lester Nare?

  It was, uh, I'm just pulling this up now. Yeah. So it was in Astrophysical Journal Letters.

• 40:14Lester Nare?

  And it includes, oh, several institutions.

• 40:18Krishna Choudhary?

  Yeah, it's usually, it's usually several institutions.

• 40:20Lester Nare?

  There's a lot of.

• 40:21Krishna Choudhary?

  But if we want to name a few, University of Toronto is a big one.

• 40:24Lester Nare?

  Yes.

• 40:25Krishna Choudhary?

  Um, yeah, University of Toronto is one of the big ones.

• 40:29Lester Nare?

  Yes, and this was in collaboration.

• 40:31Krishna Choudhary?

  And Yale. And because like, you know, it's the, the, these guys love that ultra dark.

• 40:37Lester Nare?

  Oh, yeah, yeah.

• 40:38Krishna Choudhary?

  You know, diffuse stuff.

• 40:39Lester Nare?

  Yes.

• 40:39Krishna Choudhary?

  University of Santa Cruz.

• 40:40Lester Nare?

  Yes.

• 40:41Krishna Choudhary?

  California Santa Cruz. So, yeah.

• 40:43Lester Nare?

  Big shout out to all the team. This is a really interesting story. I mean, I, I still continue to be so fascinated by dark matter. I know friend of the pod, Dan Gilman has dedicated his life.

• 40:52Krishna Choudhary?

  And he, he did a postdoc at the University of Toronto. So I wonder if, um, he knows some of these guys.

• 40:57Lester Nare?

  Probably.

• 40:57Krishna Choudhary?

  I'll tell him to, I'll tell him to send them.

• 40:58Lester Nare?

  Share it, Dan, share it with the, the team. And if folks want to give us any follow ups, comments or corrections, please let us know.

• 41:04Krishna Choudhary?

  Yeah.

• 41:05Lester Nare?

  Great astrophysics first story on dark matter. A kind of continuation on our cloud nine story, which was fascinating and well worth the watch. If you haven't seen it, to get a little bit deeper into that use. Case where the cluster does not reach the level where it can produce stars.

• 41:21Krishna Choudhary?

  Yeah.

• 41:21Lester Nare?

  And so it remains sort of this like empty.

• 41:24Krishna Choudhary?

  Yeah, the relic.

• 41:25Lester Nare?

  The relics, yes.

• 41:26Krishna Choudhary?

  Cloud nine.

• 41:26Lester Nare?

  Cloud nine. So we're gonna move into the rundown now. And for those who are new to the show, we usually cover several main stories where we do a big deep dive, but the rundown allows us to talk about other breaking science research that we find interesting. We're gonna start with a follow up to a story we covered in episode four.

• 41:45Krishna Choudhary?

  Yes.

• 41:45Lester Nare?

  One of our early stories about the the Verisim Rubin Observatory. It has now launched its real time discovery engine. So this is now about eight months later.

• 41:55Krishna Choudhary?

  Yeah.

• 41:56Lester Nare?

  And it's a pretty major update.

• 41:58Krishna Choudhary?

  Yeah, yeah, this one's insane because the Verisim Rubin Observatory is unlike any other observatory out there because it's this giant thing where astronomers cannot get time on it, right? Usually, usually when there's an observatory and you you're like, oh, like in the last story, hey, I want to look at this candidate dark galaxy in the Perseus cluster, I need four nights. And that application is going to go to whoever's in charge of that telescope time. And they're gonna decide from all the applications, who is gonna get time to look at what? The Verisim Rubin Observatory is an observatory that is just taking a photo of the entire night sky every three nights.

• 42:38Krishna Choudhary?

  That is its job, like clockwork, fully automated, and that's all it's doing. It's not focusing on particular things. That's what it's doing. And what that means is it's gonna find a lot of data. Every night, there's gonna be new data. And what it can do is historically look at, what did that position in the night sky look like a month ago, a year ago, 10 years ago? Because all of the archival astronomical data of maybe the Hubble pointed at it at some point, or maybe the James Webb pointed at it six months ago. It can compare images between what it saw that particular night and what other telescopes have seen that particular night. And if there's anything different, send out an email alert. And so on its first night.

• 43:22Lester Nare?

  Jesus.

• 43:22Krishna Choudhary?

  That this real time discovery machine was operating, it sent out 800,000 alerts. It found 800,000 candidates for new stuff that scientists could look at.

• 43:36Lester Nare?

  That this is so this is incredible. And we we talked about this when we did the story because the technology behind it is. Unreal.

• 43:45Krishna Choudhary?

  Yeah.

• 43:45Lester Nare?

  In terms of the amount, the volume and the, it's like going from CRT for ADP TVs.

• 43:53Krishna Choudhary?

  Mm hmm.

• 43:54Lester Nare?

  To 4K.

• 43:54Krishna Choudhary?

  Yeah. Well, and, and, and so that's in terms of resolution.

• 43:58Lester Nare?

  Yes.

• 43:59Krishna Choudhary?

  The main thing is it's going from photographs to movies.

• 44:01Lester Nare?

  Movies, right?

• 44:02Krishna Choudhary?

  Which we talked about. And so we're seeing like motion.

• 44:04Lester Nare?

  Motion.

• 44:04Krishna Choudhary?

  We're seeing, we're seeing, for example, asteroids.

• 44:07Lester Nare?

  Mm hmm.

• 44:07Krishna Choudhary?

  Cause the asteroids will move.

• 44:09Lester Nare?

  Mm hmm.

• 44:09Krishna Choudhary?

  And so that's going to be a motion transient that the Vera Rubin can catch. We're seeing supernovae, which are going to be, oh, there was no light bulb there. And then now there's a tiny faint light bulb on that galaxy. That means a star exploded and we've got about, you know, two or three weeks to catch that star exploding. So all these transient events, these fleeting celestial events, that's what the Vera Rubin was out for, right? That's why it's called the Legacy Survey of Space and Time. The LSST, that's the program. It's for 10 years, it's going to go along. These alerts are going to be insane.

• 44:46Lester Nare?

  It's expected to generate up to seven million alerts per night.

• 44:52Krishna Choudhary?

  Yeah.

• 44:52Lester Nare?

  And we're already on track because with the first night, it was already 800,000.

• 44:56Krishna Choudhary?

  I mean, this is incredible because there's not that many astronomers out there.

• 44:59Lester Nare?

  Right.

• 45:00Krishna Choudhary?

  In the world and those astronomers don't have a lot of time.

• 45:03Lester Nare?

  Right.

• 45:04Krishna Choudhary?

  So this is really the advent, I think, of decentralized astrophysics research. Like now we can have citizen scientists, for example, if you're like in a high school or like, you know, some advanced program where you want to do scientific research, but you don't have access to data. This is an incredible resource now to do small little projects. If you, I don't know, you want to get ahead in your college application. This is something you could do. You could go on the Vera Rubin website and find data and look at some of these alerts and be like, hey, which alert do I want to like dig a little bit deeper into? Things like that. Um, you can also, I mean, this is going to be huge for machine learning.

• 45:44Lester Nare?

  A hundred percent.

• 45:45Krishna Choudhary?

  And AI because handling seven million alerts a night, no human can do that.

• 45:49Lester Nare?

  Right.

• 45:49Krishna Choudhary?

  But creating a machine learning pipeline that can, you know, sparse through all those alerts, figure out which is the one that actually might require human attention from somebody with a PhD in astrophysics and so on. It's going to be huge.

• 46:01Lester Nare?

  I, I, I, this is, this, I think when we did our end of the year episode for season one, I brought up this, uh, the episode four is one of my favorites because I still just think. Technically, from technical execution, largest camera lens in the world. The amount, the data pipeline build, like being able to actually process and make available immediately.

• 46:26Krishna Choudhary?

  Yeah.

• 46:27Lester Nare?

  That volume of data.

• 46:27Krishna Choudhary?

  Within two minutes, I think.

• 46:29Lester Nare?

  Is, is a significant technological challenge in and of itself. And then the open sourcing of it, right, out of the box. Meaning there's no gatekeeping, there's no this and that. It's, it's, it's a really, I think it's a beautiful testament, I think, to the spirit of what science

• 46:46Krishna Choudhary?

  Yeah.

• 46:47Lester Nare?

  in the modern era can look like.

• 46:48Krishna Choudhary?

  Yeah.

• 46:49Lester Nare?

  There's understandable reasons why not every system is like that.

• 46:51Krishna Choudhary?

  Yeah, and I mean, this is, this is something that I think the US taxpayer should be very proud of.

• 46:55Lester Nare?

  Yes.

• 46:56Krishna Choudhary?

  This is you, almost entirely a US effort by the US National Science Foundation and the US Department of Energy.

• 47:04Lester Nare?

  DOE, baby.

• 47:05Krishna Choudhary?

  Like, this is, this is really cool, that our taxpayer dollars are going into something like this.

• 47:10Lester Nare?

  Very cool first story. We're gonna move into our story number two. Our story number two, this one is a material science and AI story. As scientists have used AI to help them find new types of magnets, which could be used in an innumerable number of industries. So what, what exactly is going on with these new magnetic materials?

• 47:32Krishna Choudhary?

  Yeah, so finding rare earth free permanent magnets, i.e. permanent magnets that, that don't require these rare earth minerals that like we have to mine for, that are really hard to find, that maybe we have to make a deal with China with and so on and so forth. Like, that's crucial for reducing the manufacturing cost and the supply chain vulnerabilities of electric vehicles. And of electric vehicles, if we can make them cheaper, easier to make, they can be the future, right? Not just electric vehicles, I mean, batteries go on everything, right? Medical devices, renewable energy systems. And what this team at the University of New Hampshire has done is use an AI system to extract data

• 48:13Krishna Choudhary?

  from thousands of scientific reports and train a model that will predict the magnetic behavior of materials, of novel materials, right? And you, you have like now a searchable database of something like 67,000 magnetic compounds. And out of those, they found 25 new candidates that will remain magnetic at high temperatures.

• 48:35Lester Nare?

  Very interesting.

• 48:36Krishna Choudhary?

  This is big.

• 48:36Lester Nare?

  Yeah.

• 48:37Krishna Choudhary?

  The hotter you make a magnet, the more jiggling there is, which means that the local alignment between your magnetic elements, like in iron, for example, the iron has like a valence electron that creates a gross magnetic field around the atom. What, when iron becomes magnetic, like when you take a paperclip and you put it around a permanent magnet, that paperclip becomes magnetic, right? Because all of the iron atoms sort of align to be make a big magnetic field. Well, if you heat up that paperclip, you're done. But if you put that paperclip in the freezer and you come back hours later, it'll still be magnetic. The point is, we want to find magnetic materials that remain magnetic at high temperatures because that will give us industry applications.

• 49:19Lester Nare?

  Yes.

• 49:19Krishna Choudhary?

  Right?

• 49:20Lester Nare?

  Yes.

• 49:20Krishna Choudhary?

  And that's what this is doing. And it vastly accelerates material science. You know, because millions of time-consuming lab tests can now be churned through with this machine learning algorithm. And you can find like a searchable digital resource that you can then be like, okay, I want to find a particular magnetic material that does this and this. You got something.

• 49:42Lester Nare?

  This is, this is great. So this was out of nature communications. Would it be? So it, I mean, obviously, the thing that comes to my mind is, it makes me think of like a magnetic version of AlphaFold.

• 49:55Krishna Choudhary?

  Yeah, kind of.

• 49:56Lester Nare?

  Is it?

• 49:56Krishna Choudhary?

  It's like a material science version.

• 49:58Lester Nare?

  Of, of it, like directionally speaking.

• 50:00Krishna Choudhary?

  Yeah, yeah, yeah. I'm, I think it's, it's, it's still a little far from, I give you a novel material and you predict. This is still, there's all of these,

• 50:11Krishna Choudhary?

  there's all of these thousands of scientific papers that have already come out with a bunch of stuff. How do I centralize that?

• 50:17Lester Nare?

  I see.

• 50:18Krishna Choudhary?

  And create an understanding.

• 50:18Lester Nare?

  So rather, so it's more so taking the existing data and making it,

• 50:26Lester Nare?

  making someone be able to iterate on ideas based on existing data. AlphaFold was really sort of saying, here's all possible.

• 50:35Lester Nare?

  Protein structures.

• 50:36Krishna Choudhary?

  Yeah, from all of the sequences that we know, even the ones that we haven't found.

• 50:39Lester Nare?

  Which is a different thing because that's generating net new data.

• 50:42Krishna Choudhary?

  That's like, that's insane.

• 50:43Lester Nare?

  Just interpreting past data.

• 50:44Krishna Choudhary?

  Yeah.

• 50:44Lester Nare?

  Okay, so there's a, there's a difference there.

• 50:46Krishna Choudhary?

  Yeah, but it's, it's getting there, right? We're getting close.

• 50:48Lester Nare?

  That's very cool. Very, very, very, very good.

• 50:50Krishna Choudhary?

  Yeah.

• 50:51Lester Nare?

  Story number three, the climate science story with a bit of anthropology.

• 50:55Krishna Choudhary?

  Yeah.

• 50:55Lester Nare?

  Uh, there's new science about what's actually, what actually went wrong on Easter Island.

• 51:02Krishna Choudhary?

  Yes.

• 51:02Lester Nare?

  What went wrong?

• 51:03Krishna Choudhary?

  So Easter Island is very famous, right? These, this is Rapa Nui. It has those, um, giant statues of, um, these like heads with torsos that are facing out into the ocean. And for the longest time, the popular narrative was that the society collapsed there because of self-inflicted ecocide, meaning they cut down all the trees and then by the time that the European colonizers came, there was a decimated population that was like almost starving and blah, blah, blah. Okay? Um, that turns out to not be entirely true.

• 51:41Lester Nare?

  Shocking.

• 51:42Krishna Choudhary?

  Shocking that the European colonizers, um, made up a...

• 51:47Lester Nare?

  A story about the history?

• 51:48Krishna Choudhary?

  Yeah, a story about the history that is conducive, conducive to them and says, oh, the natives didn't know...

• 51:54Lester Nare?

  What they were doing.

• 51:54Krishna Choudhary?

  What they were doing. Okay, it turns out from new sediment core data, what they did was they studied hydrogen isotopes of plant leaf waxes.

• 52:03Lester Nare?

  Okay.

• 52:04Krishna Choudhary?

  And these things preserve sort of a climate history across climates, across centuries, right? So by studying the, the hydrogen isotope data there, what they actually found out was that the annual rainfall there dropped sharply by almost 24 to 31 inches during the mid 16th century. And this is right before sort of the European explorers went and like, saw what was happening, right? And so what's happening is instead of like entirely collapsing due to deforestation and conflict, which is the original theory, what probably happened is the Rapa Nui people adapted to the severe climate stress and they shifted their rituals, their power structures,

• 52:48Krishna Choudhary?

  and their ceremonial centers to respond to that climate stress, right? And it emphasizes more like human resilience. And that the history of Easter Island is way more complicated.

• 52:59Lester Nare?

  Right.

• 53:00Krishna Choudhary?

  Than what this overconsumption narrative that the colonizers had pushed. Surprise, surprise.

• 53:07Lester Nare?

  Classic, very fascinating. We could probably, I'm sure some people would be like hydrogen isotopes of plant leaf waxes being able to be analyzed over centuries in and of itself.

• 53:19Krishna Choudhary?

  Yeah.

• 53:19Lester Nare?

  I would love to understand that.

• 53:20Krishna Choudhary?

  Yeah, yeah, that's a good one for a deep dive.

• 53:22Lester Nare?

  Because it's, it, that's so curious to me.

• 53:25Krishna Choudhary?

  Yeah.

• 53:26Lester Nare?

  But clearly is hugely impactful.

• 53:29Krishna Choudhary?

  Hmm.

• 53:29Lester Nare?

  In both this like historical climate science related research, but also mapping it in this case, which is what's kind of interesting to anthropological.

• 53:37Krishna Choudhary?

  Yeah, I mean, it's, it's a technique that's like very similar to when people do ice cores. Have you heard of that?

• 53:43Lester Nare?

  No, no, no.

• 53:44Krishna Choudhary?

  They barrel like a ice cylinder in an Antarctic glacier.

• 53:48Lester Nare?

  Okay.

• 53:48Krishna Choudhary?

  And because Antarctic glaciers are like so old, layers of that are going to give you a recorded history of the climate, going back almost millions to tens of millions of years. Right? So similarly, plant waxes, like leaf waxes are stuff that are very old. Because it's not like, it's, it's not like a plant in that it was just born. It's like it created the wax and then it's, the wax has sort of persisted across centuries. It's kind of like in Jurassic Park when you have the resin, right? Resin is a plant residue. It's not wax, but it's, it's a type of residue that can last through the ages. Similarly, leaf wax is something that can last through the ages. So it gives us like a, a diary.

• 54:30Lester Nare?

  Yes.

• 54:30Krishna Choudhary?

  Of what the climate was like in that locality. If we can really analyze it at that atomic resolution, which is what these guys did at the Columbia Climate School.

• 54:39Lester Nare?

  Fascinating. This was a paper in Communications Earth. Again, I think we'll continue to see as scientific tools and instruments and the funding that goes to support those endeavors continues to grow in capability. We will be illuminating more about our, as much about our past.

• 55:00Krishna Choudhary?

  Yes.

• 55:01Lester Nare?

  As we will about where we are going as a species. Our fourth and final story in the rundown, this one's a weird story about psychology, language and baby chickens.

• 55:13Krishna Choudhary?

  Yes.

• 55:14Lester Nare?

  And I don't know much about it on purpose.

• 55:18Krishna Choudhary?

  And before we get into it. Okay. I would like to take our audience on a trip to Bahrain and ultimately Italy. Okay. We just ended Formula One testing in Bahrain. Yes. The season opener is happening in Australia at the end of this week. For F1? For Formula One. Of course, I'm talking about Formula One, the greatest sport alive today. And Ferrari is back, baby.

• 55:47Krishna Choudhary?

  Ferrari is so back. This is gonna be our year, dude. We've been, we've been, we haven't had a driver's championship since 2007. We haven't had a constructor's championship since 2008. I'm not blaming anybody. I'm just saying this is, this is the reality of the situation. But we've got Charles Leclerc, who I'm, I'm personally a fan of Charles Leclerc. Lewis Hamilton, one of the greatest of all time, so. Also, congratulations to Charles. I think he just got engaged. He did. No, he just got married. Married, married. He got married in, um, in Monaco. He's a Monagas, a native Monaco driver. Most, most drivers like go there for the tax reasons. He was born in it. I was born in it. Yeah, yeah, he was born in it. Exactly.

• 56:29Krishna Choudhary?

  Ferrari had a great testing in Bahrain. Charles Leclerc was one second clear of Mercedes George Russell. Okay. And I know, I know everyone's gonna be like, oh, during testing, everyone is like, you know, they're putting artificial masses on their, on their car. And they're like gaming the system to, to not, but a second is crazy. And what gives me, what gives me hope is that Haas, which is an American team that is a engine customer of Ferrari. So Ferrari's engine is the same engine that's in the Haas, in the Haas car. Haas is also doing really well during testing. So that's like, it's like a, you know, in science, we look for coincident data to, to suggest that there's an underlying invariant. Right.

• 57:14Krishna Choudhary?

  And as a scientist, I'm just saying Ferrari is back. Okay? And dude, we're, we're, we're, we're gonna run away with it. It's gonna be amazing. Can I ask a quick question before we continue, which is?

• 57:25Lester Nare?

  Did the wing thing get figured out?

• 57:28Krishna Choudhary?

  Oh, no, no. Ferrari has Ferrari has an amazing wing. I don't know if we're gonna.

• 57:31Lester Nare?

  The upside down thing?

• 57:32Krishna Choudhary?

  Yeah, yeah. So Ferrari has a wing that flips.

• 57:35Lester Nare?

  Yeah.

• 57:36Krishna Choudhary?

  When it goes from a curve to a straight. We don't have DRS this season because so for those who are also listening. Formula One is all about the formula, right? Which is the regulations that the Formula One gods produce, saying these are the rules for how you can build a car. And then every car manufacturer looks at those rules and says, where can we read between the lines and create little efficiencies that others might not? And Ferrari figured out that there's nothing against the building a rear wing that will entirely flip 180 degrees, depending on what part of a racetrack you're on. Because during straights, you want low drag,

• 58:21Krishna Choudhary?

  because you just want to go straight. During curves, you want high downforce, because you want more grip so that you can like take corners faster, right? And those two can be can have different wing configurations on the rear wing, based on the aerodynamics that you get and so on and so forth. And most people just have a flap that goes like this and then goes down. This thing is going is turning around 180 degrees. And all these other teams were like, yeah, we thought of that. I know you didn't. You didn't think of that. Okay, okay. You saw it and you're like, oh, we better like cover our. No, you didn't think of that. Ferrari thought of that. That's that's right. Anyways, I'm going off about Ferrari because this next, I'm gonna bring it back to science.

• 59:01Lester Nare?

  Okay, okay.

• 59:03Krishna Choudhary?

  This next rundown study is from the University of Padua in Italy. It was out in the journal Science.

• 59:09Lester Nare?

  Okay.

• 59:10Krishna Choudhary?

  And that's the connection to Italy.

• 59:14Krishna Choudhary?

  That's it. I just wanted to go on a rant about our Ferrari's win. But dude, this this paper is pretty insane.

• 59:22Lester Nare?

  Okay.

• 59:22Krishna Choudhary?

  Because it didn't make any sense to me why it should be possible. Have you ever heard of something called the Boba Kiki effect?

• 59:28Lester Nare?

  I only know about Kiki, do you love me? Are you riding? But I don't know about the Boba Kiki.

• 59:33Krishna Choudhary?

  Alright, so let's, let's pull up the, the overlay.

• 59:36Lester Nare?

  Okay, okay.

• 59:37Krishna Choudhary?

  Alright, so you see the two, um, you see the two shapes? There's a green, sort of blobby shape.

• 59:44Lester Nare?

  Yeah.

• 59:44Krishna Choudhary?

  And then there's a blue, pointed shape.

• 59:46Lester Nare?

  Okay.

• 59:47Krishna Choudhary?

  And which-

• 59:47Lester Nare?

  For listeners, so we're looking at an image that currently, can I say this?

• 59:51Krishna Choudhary?

  Yeah, go ahead.

• 59:52Lester Nare?

  Okay, okay. So it currently has what appear to be two baby chickens? Or birds of some kind, or ducks?

• 59:59Krishna Choudhary?

  Or chicks, yeah.

• 1:00:00Lester Nare?

  Uh, in the middle, and these two shapes at the top right and left-hand corners. The one on the left is a green blob, the one on the right is like a blue star kind of thing.

• 1:00:11Krishna Choudhary?

  Star kind of thing, pointy.

• 1:00:12Lester Nare?

  Pointy.

• 1:00:12Krishna Choudhary?

  Alright, so which one is Boba and which one is Kiki, for those shapes?

• 1:00:15Lester Nare?

  Oh, Boba's obviously the blob and Kiki is obviously the-

• 1:00:19Krishna Choudhary?

  Okay.

• 1:00:19Lester Nare?

  The thingy.

• 1:00:19Krishna Choudhary?

  Why did you say that?

• 1:00:21Lester Nare?

  Oh, because in my head, like, I mean, like, this is, I don't know, like-

• 1:00:25Krishna Choudhary?

  Kiki is like-

• 1:00:26Lester Nare?

  Yeah, it's like-

• 1:00:27Krishna Choudhary?

  It's pointy?

• 1:00:27Lester Nare?

  It's pointy and Boba is blobby.

• 1:00:31Krishna Choudhary?

  That's exactly right.

• 1:00:32Lester Nare?

  Like, phonetically?

• 1:00:34Krishna Choudhary?

  Yeah, and this is the Boba Kiki effect.

• 1:00:36Lester Nare?

  Oh, is it really?

• 1:00:37Krishna Choudhary?

  This, that's entirely what it is.

• 1:00:39Lester Nare?

  If anyone said the blue was, was Boba, you're crazy.

• 1:00:41Krishna Choudhary?

  No, literally nobody does. But here's what's crazy.

• 1:00:44Lester Nare?

  Okay.

• 1:00:44Krishna Choudhary?

  You know, you would think that, okay, maybe we're, we're, you know, we grew up in a western society. We are, we are, um, exposed to western language.

• 1:00:54Lester Nare?

  Yes.

• 1:00:55Krishna Choudhary?

  And so perhaps that has something to do with it.

• 1:00:56Lester Nare?

  I, I, that makes sense.

• 1:00:57Krishna Choudhary?

  No, they have done research with multiple language groups. Most famously, the Tamil language group, which is in India, South India. That is an entirely different language group from, um, English. English comes from the Indo-European family. These guys are Tamils, they're not even Hindi, because Hindi and, you know, Sanskrit still comes from the Indo-European family. The Tamil language comes from the Dravidian family, which is native to India. It is- Completely separate from Indo-European family language. And they still believe that the left is boba and the right is kiki. You go to other cultures entirely, boba kiki works. You go to infants, boba kiki works. So it was thought that this boba kiki effect, meaning boba goes to blobby, rounder things.

• 1:01:40Krishna Choudhary?

  And kiki goes to pointier, pointier things is something that is innate within human language. Okay, across human languages. And so far, so good until this paper. This paper played recordings of humans saying either boba or kiki to naive, three day old chicks. And presented them with two panels that had food behind it.

• 1:02:01Lester Nare?

  Okay.

• 1:02:02Krishna Choudhary?

  And the chicks knew which one was boba.

• 1:02:05Lester Nare?

  Shut the front door.

• 1:02:07Krishna Choudhary?

  These are, these are three day old chicks that had the boba kiki effect.

• 1:02:12Lester Nare?

  I don't believe it.

• 1:02:13Krishna Choudhary?

  No, it, but it works.

• 1:02:15Lester Nare?

  That's so, meaning there is, you know.

• 1:02:18Krishna Choudhary?

  This is not a language thing.

• 1:02:19Lester Nare?

  It's not a language thing, yeah.

• 1:02:21Krishna Choudhary?

  This is, this is like, there is something inherent in the sound of boba versus kiki. That maps onto the architecture of physical objects. Okay, and, and you can, you can start thinking like, why? And actually, it doesn't seem that weird anymore. When you start thinking about the physics of sound and the physics of boba and kiki. The word boba and the sound buh, that's lower frequency. You associate that with bass.

• 1:02:51Lester Nare?

  Yep.

• 1:02:52Krishna Choudhary?

  Right?

• 1:02:52Lester Nare?

  Yep.

• 1:02:53Krishna Choudhary?

  Kiki is like the ding, like the, the high frequencies.

• 1:02:56Lester Nare?

  Yeah.

• 1:02:57Krishna Choudhary?

  Rounder objects, when sound goes through them, the higher frequencies are gonna sort of get absorbed. Around the, the, the rounder frequencies are gonna get deflected and so forth, so on and so forth. The sharper an interface is on the physics of an object, right? The, the sharper the sound that is going to come out of that object, just because of the way sound is, alright? The sharper the thing is, the shorter the wavelength, the shorter the wavelength, the higher the frequency, the more we get that ding sound. Right? It's literally just Fourier analysis is what, what we would think if someone's a electrical or sound engineer. It's, it's like the Fourier analysis of sound around the physics of objects.

• 1:03:39Krishna Choudhary?

  The smoother an object is, the basier the sound that comes out. And so even chicks, their brains, three day old chicks, their brains, there's some innate physics calculation that's happening within them. That's saying the higher frequency has to come from a pointier object.

• 1:03:58Lester Nare?

  That is so.

• 1:04:00Krishna Choudhary?

  It's so weird.

• 1:04:01Lester Nare?

  Unbelievable, but the way that you explained it does.

• 1:04:04Krishna Choudhary?

  Yeah, then it kind of makes sense.

• 1:04:05Lester Nare?

  Kind of makes sense.

• 1:04:06Krishna Choudhary?

  What I'm, what I'm surprised about is that a three day old chick has neural mechanisms within its brain.

• 1:04:12Lester Nare?

  Right.

• 1:04:12Krishna Choudhary?

  To make that distinction, right?

• 1:04:14Lester Nare?

  Yes.

• 1:04:14Krishna Choudhary?

  That this is so invariant across um, anyone that has brains, I guess? Because this is not even a mammal.

• 1:04:21Lester Nare?

  Right.

• 1:04:21Krishna Choudhary?

  Right?

• 1:04:21Lester Nare?

  Right.

• 1:04:22Krishna Choudhary?

  This thing diverged very, very far away from us.

• 1:04:24Lester Nare?

  That's.

• 1:04:24Krishna Choudhary?

  Hundreds of millions of years ago, before the dinosaurs.

• 1:04:28Lester Nare?

  There's a, there's a deeper architecture here.

• 1:04:30Krishna Choudhary?

  Yeah.

• 1:04:31Lester Nare?

  There's, there's a deep, not architecture, there's a deeper insight um, about why that would be true.

• 1:04:37Krishna Choudhary?

  Yeah.

• 1:04:37Lester Nare?

  Not only because of the cross-species level uh, similarities, but also that you don't need brains that have developed.

• 1:04:47Krishna Choudhary?

  Yeah.

• 1:04:48Lester Nare?

  For a long amount of time to have some sort of like, you know, learned.

• 1:04:53Krishna Choudhary?

  Yeah.

• 1:04:53Lester Nare?

  Understanding of the physics of the universe.

• 1:04:55Krishna Choudhary?

  Yeah, yeah, they've just made this association because like, over the years, this is what's true, right?

• 1:05:00Lester Nare?

  Right.

• 1:05:01Krishna Choudhary?

  The buh sound comes from rounder objects and the kuh sound comes from pointier objects. Right? And it's like, even like a, a short, a small neural network that we train with reinforcement learning, for example, would come up with the Boba Kiki effect. Right? Where let's say the input of this neural network was the sound and then the output was a decision between the two. Through reinforcement learning, it would learn that the lower frequencies are the rounder things.

• 1:05:25Lester Nare?

  That, the.

• 1:05:26Krishna Choudhary?

  But the fact that like, you know, we did this going all the way back to our common ancestor, between birds and mammals, which is hundred million years plus.

• 1:05:34Lester Nare?

  And.

• 1:05:34Krishna Choudhary?

  Before the dinosaurs.

• 1:05:35Lester Nare?

  And it's still true.

• 1:05:36Krishna Choudhary?

  And it's, yeah, yeah, and it's, it's across all these animals, right? I think that's so cool.

• 1:05:41Lester Nare?

  That is.

• 1:05:42Krishna Choudhary?

  To think about. And also, what a weird experiment to run.

• 1:05:45Lester Nare?

  Yeah.

• 1:05:46Krishna Choudhary?

  Right? Like, who, who was like, hey, let's test Boba and Kiki. On Baby Chicks.

• 1:05:52Lester Nare?

  Who knew Drake was so attuned to frontier science research when he made that song? Whatever that song is called, "Do You Love Me." Four great rundown stories. We're gonna jump now back into our main story, our second story of the day, which is around Alzheimer's research.

• 1:06:12Krishna Choudhary?

  Yes, this one's very cool.

• 1:06:13Lester Nare?

  So this one is a health and medicine story about Alzheimer's disease and exercise.

• 1:06:19Krishna Choudhary?

  Yeah.

• 1:06:19Lester Nare?

  So scientists think they figured out exactly how exercise reduces the risk of Alzheimer's. It reports a new paper in Cell by a group out of the University of California, San Francisco, in this Baccarat Aging Research Institute. And so, we've, we've actually done a lot, I mean, we just did last episode, we did something on ALS. We've talked about Alzheimer's research, I think, multiple times.

• 1:06:44Krishna Choudhary?

  Yeah, multiple times.

• 1:06:44Lester Nare?

  Multiple times on the pod previously. This is clearly, you know, something that impacts millions of people, families, siblings, coworkers, etc. And so, there's, there, okay, there's a link between the disease and exercise. I'm curious what that link is.

• 1:07:01Krishna Choudhary?

  Yeah, and I mean, it's not, it's not like that surprising that exercise is good for you, right? This is something we've known, but what I love about this study is we've, again, it's about the mechanism. It's the Lego blocks that are coming together. There's a pathway from exercise to the biochemistry of Alzheimer's that these guys have traced.

• 1:07:24Lester Nare?

  Okay.

• 1:07:24Krishna Choudhary?

  From the, from me running to me not getting Alzheimer's, or getting Alzheimer's later.

• 1:07:31Lester Nare?

  Okay.

• 1:07:31Krishna Choudhary?

  And that biochemical string of Lego blocks is what is super interesting to me, okay?

• 1:07:37Lester Nare?

  There is, we potentially have a discovery of the pathway by which this is happening.

• 1:07:42Krishna Choudhary?

  Yes, because if we have a discovery of the pathway, the biochemistry of what this is happening, then perhaps we can get the benefits without the exercise.

• 1:07:50Lester Nare?

  Right, right, right, right. Because we understand the mech, the mechanistic.

• 1:07:53Krishna Choudhary?

  Yeah.

• 1:07:54Lester Nare?

  Dynamics.

• 1:07:55Krishna Choudhary?

  Yes.

• 1:07:55Lester Nare?

  That are driving the process.

• 1:07:58Krishna Choudhary?

  And, and this could be huge, because then, for people who maybe can't do exercise, but have Alzheimer's, this could be a big thing. Or for those who want to do exercise but get added benefit, you know, a boost. It's, it's huge, right?

• 1:08:09Lester Nare?

  Okay.

• 1:08:09Krishna Choudhary?

  Okay, so we're gonna start with the human brain. Eighty billion neurons. It's the most complex object in the universe. And stuff can go wrong because it is the most recent of our organs to evolve, right? Most of the mutations that create human beings have to do with brain development. And what that necessarily means is the brain is going to have a lot of stuff go wrong. Because it's still in the phase of the genetics is trying stuff out.

• 1:08:37Lester Nare?

  We're in the beta version right now.

• 1:08:38Krishna Choudhary?

  Yeah, we're still in the beta version, even though the beta version is doing really well. Like, but, but the, no one's turned off the, the code, um, like edits.

• 1:08:47Lester Nare?

  Yeah, yeah, yeah, yeah.

• 1:08:48Krishna Choudhary?

  It's like no one's frozen the main.

• 1:08:50Lester Nare?

  Yeah, yeah.

• 1:08:50Krishna Choudhary?

  You know, GitHub.

• 1:08:51Lester Nare?

  People, people are still merging branches onto main.

• 1:08:54Krishna Choudhary?

  Exactly. It's like, it's like, no, no, we're doing like, we're okay.

• 1:08:56Lester Nare?

  Can we stop? Yeah, we have some bug fixing to do.

• 1:08:58Krishna Choudhary?

  Yeah, exactly. And so the bug fixing is what's crucial and it happens a lot later on in life. And for a long time, the brain is sort of studied in isolation. There's like a, you, you imagine like the brain is an island and we think about the mind and everything that's happening in the brain is isolated to the brain. But very recently, that has progressed to be the brain, the mind and the body are connected. And we need to figure out a holistic understanding of the entire system, right? And that's where this research comes in. They've identified a biochemical pathway that links the liver to the blood to the brain. And it shows the systemic benefits of exercise and how they are transformed or transferred to the brain

• 1:09:42Krishna Choudhary?

  without actually having to do exercise. That's the idea.

• 1:09:45Lester Nare?

  Oh my goodness, okay.

• 1:09:46Krishna Choudhary?

  And it's, it's able to, it's able to trace the entire story from exercise to brain benefits. Okay, the mechanism is from a particular enzyme that I'm only going to say once. Because these biochemists and organic chemistry people, they love just making the, the world's longest word. I think that's what they're going for is like Guinness Book of World Records. Anyways, here we go. Okay, guys? It's called glycosylphosphatidylanocytol specific phospholipase D1. We are going to refer to this enzyme throughout our story as GPL D1.

• 1:10:26Krishna Choudhary?

  So whenever you hear me say that word, that is the particular enzyme that we have discovered in the liver and all of its benefits all the way up to the brain.

• 1:10:35Lester Nare?

  I just want to take a brief note to distinguish that although it has all of the same letters with a couple of extras.

• 1:10:44Krishna Choudhary?

  Yes, it's not Ozempic.

• 1:10:44Lester Nare?

  It is not a GLP1.

• 1:10:47Krishna Choudhary?

  Yes.

• 1:10:48Lester Nare?

  This is GPLD1.

• 1:10:49Krishna Choudhary?

  Exactly.

• 1:10:50Lester Nare?

  And so those are different things.

• 1:10:51Krishna Choudhary?

  Those are very different things. GPLD1, this is not Ozempic. And what it does is act on blood vessels surrounding the brain to repair age-related damage. And that's what we're going to get into.

• 1:11:02Lester Nare?

  So this is like a cleanup crew that goes in to fix stuff?

• 1:11:06Krishna Choudhary?

  Mm-hmm. But the way they fix stuff is very interesting.

• 1:11:10Lester Nare?

  Okay.

• 1:11:10Krishna Choudhary?

  Okay, and that's where the Lego blocks comes in.

• 1:11:13Lester Nare?

  Okay.

• 1:11:13Krishna Choudhary?

  And that's what I like about it. All right, so let's talk about Alzheimer's real quick. Most common cause of dementia, 60 to 70% of all cases of dementia are Alzheimer's. Globally, there's about 50 million people living with dementia right now in 2021. And if we look at a 2050 projection in the future, right? People are living longer. And if people are living longer, these age-related diseases are going to go up. And so by 2050, there's projections of 100 to 150 million individuals globally, that's nearly triple of today, living through these symptoms.

• 1:11:49Lester Nare?

  Mm-hmm.

• 1:11:49Krishna Choudhary?

  Okay? Black Americans are two times more likely. Hispanic Americans are 1.5 times more likely. Women make up approximately 2/3 of the US Alzheimer's population.

• 1:12:02Lester Nare?

  Really?

• 1:12:02Krishna Choudhary?

  Yeah. And nearly twice the risk, lifetime risk, versus men at the age of 65. So there's a lot of these disparities that go on. We still don't know much about why. I mean, you can imagine economic and social issues.

• 1:12:15Lester Nare?

  Sure.

• 1:12:15Krishna Choudhary?

  Diet issues with like black Americans and Hispanic Americans versus white people who just, I mean, they're in a different economic bracket on average, right?

• 1:12:23Lester Nare?

  On average, yeah.

• 1:12:24Krishna Choudhary?

  So these on-average statistics comes through. And it's a big crisis in medicine to figure out what is going on and how do we help it?

• 1:12:32Lester Nare?

  Okay.

• 1:12:32Krishna Choudhary?

  It was first identified in 1906 by Dr. Alois Alzheimer. He was a German doctor. He identified these extracellular amyloid plaques in patients with dementia.

• 1:12:45Krishna Choudhary?

  And since then, we've been studying these things called amyloid plaques. The idea is you've got this accumulation of a protein called beta amyloid. Okay, there are these peptides and that's the primary cause. You get a bunch of amyloid precursor proteins. So this is whatever is the precursor to amyloid. They denature in some way and they get together. Right. And when they get together, they create these plaques of amyloid. And those plaques then get in the way of all of the neural machinery.

• 1:13:20Lester Nare?

  I get you. I get it. It's there's a highway and then these roadblocks just

• 1:13:25Krishna Choudhary?

  Yeah, yeah.

• 1:13:26Lester Nare?

  Auto generating and blocking the flow of stuff.

• 1:13:28Krishna Choudhary?

  Yeah. And there was genetic link, right? Because early onset familial Alzheimer's was caused by mutations in this protein.

• 1:13:35Lester Nare?

  Got it.

• 1:13:35Krishna Choudhary?

  In the gene for this protein.

• 1:13:37Lester Nare?

  Got it.

• 1:13:37Krishna Choudhary?

  So you can imagine, okay, that seems like something that we should target.

• 1:13:43Krishna Choudhary?

  There was a big discrepancy between targeting this pathway and actual clinical advantage.

• 1:13:50Lester Nare?

  Okay.

• 1:13:51Krishna Choudhary?

  The drug failure, the drug failure rate from 2002 to 2012 is something like 99.6%. And even today, like this is a headline from last year. Nova Nordisk shares plunge after the Alzheimer's drug trial fails to hit the key target.

• 1:14:08Lester Nare?

  Interesting.

• 1:14:09Krishna Choudhary?

  Okay, so there's so much research that is going into Alzheimer's. But when we try stuff in animal studies, when we try stuff in a Petri dish, and then when we go in and try to fix the amyloid crisis in the brain of patients, it doesn't quite work. There's only a weak correlation, it turns out, the more the research we do. There's only a weak correlation between the total plaque load in the brain and cognitive severity, because the more and more that we've been able to do brain scans of healthy patients.

• 1:14:35Lester Nare?

  Yeah.

• 1:14:36Krishna Choudhary?

  We figured out that some of these healthy patients have amyloid plaques. So that can't be the whole story.

• 1:14:42Lester Nare?

  It's not, it's not a single source. It's not the single source of the problem.

• 1:14:45Krishna Choudhary?

  Yeah.

• 1:14:46Lester Nare?

  It may be part of it.

• 1:14:48Krishna Choudhary?

  Yeah, but it can't be that, oh, amyloid plaque one direction causes Alzheimer's. Because there's plenty of people that have amyloid plaques that don't have Alzheimer's. Okay. Furthermore, there's a timing problem because the amyloid plaques, they start accumulating like 20 years before the actual symptoms. So by the time you've got the symptom and you're trying to treat this thing, it's like the forest fire has already started.

• 1:15:09Lester Nare?

  Yeah, yeah.

• 1:15:10Krishna Choudhary?

  Right?

• 1:15:11Lester Nare?

  Yep, that tracks.

• 1:15:12Krishna Choudhary?

  And so there's been recent approval of certain drugs, but it only shows a modestly slow decline in early-stage patients, but it's not a cure. It doesn't reverse the effects of Alzheimer's.

• 1:15:25Lester Nare?

  Right.

• 1:15:25Krishna Choudhary?

  And sometimes it carries risks like brain swelling and hemorrhage. So this amyloid paradigm is really under pressure, right? And we need to find a new way to figure out what's going wrong in Alzheimer's brains. And is there a way to reverse the effects? Not just stop, not just slow down, but reverse.

• 1:15:44Lester Nare?

  Because, I mean, even just looking at this data, the drug failure rate that you mentioned of 99.6% was across, you know, almost over 200 programs.

• 1:15:51Krishna Choudhary?

  Yeah.

• 1:15:52Lester Nare?

  Um, in a, in a 10-year time.

• 1:15:54Krishna Choudhary?

  Yeah.

• 1:15:54Lester Nare?

  So it's not like there, if it's from a lack of trying.

• 1:15:57Krishna Choudhary?

  No, no, it's like we're trying, but like the fundamental issue we're having is maybe the philosophy with which we're going about.

• 1:16:04Lester Nare?

  Right.

• 1:16:04Krishna Choudhary?

  This.

• 1:16:05Lester Nare?

  If, if you're the Dallas Cowboys, you're like, why haven't we been to the playoffs in 30 years? It's like, you're looking at everything but the source of the problem, which might be, you know.

• 1:16:13Krishna Choudhary?

  Yeah. Or if you're Ferrari.

• 1:16:15Lester Nare?

  Yeah.

• 1:16:16Krishna Choudhary?

  Never mind, that's a, that's a source.

• 1:16:18Lester Nare?

  For another day.

• 1:16:19Krishna Choudhary?

  Yeah. We're doing well, it's gonna be fine. Anyways, so we need to change the way that we're approaching this problem.

• 1:16:26Lester Nare?

  Right.

• 1:16:26Krishna Choudhary?

  Okay, so now let's think about the brain from a mechanistic sense.

• 1:16:30Lester Nare?

  Okay.

• 1:16:30Krishna Choudhary?

  The brain is only about 2% of the body mass. But it uses up 20% of the body's energy. Okay? All of that glucose, all of that oxygen, 20% is going to our brain. Okay? It's got about 400 miles of capillaries in our brain that is supplying energy to the neurons. Now, all of that energy has to get through from the blood into the neurons. Right? And it has to go through something called the blood-brain barrier. This is an incredible plumbing system that we have in our brain. Okay? It's different from everywhere else in the body. Everywhere else in the body, normal blood vessels, they carry blood.

• 1:17:15Krishna Choudhary?

  Okay? And they've got these like. Gaps where stuff can go in, stuff can go out from the blood. So, you know, hemoglobin can go through, oxygen can go through, glucose can go through, little tiny metabolites can go through from, let's say, our muscles to the blood, back and forth.

• 1:17:38Krishna Choudhary?

  The, the junctions in the piping are loose, literally. There's, there's like gaps.

• 1:17:45Lester Nare?

  Yeah.

• 1:17:46Krishna Choudhary?

  In the blood-brain barrier, the junctions are what we call tight junctions.

• 1:17:50Lester Nare?

  Okay.

• 1:17:50Krishna Choudhary?

  Okay? These brain endothelial cells, which are the, the cells that line the blood vessels in our brain, have tight junctions, and they're so tight that 99% of large molecules and 95% of small molecules do not make it through. Not even glucose can go through unescorted. There are literally things called transport proteins that have to take glucose from the blood through a special kind of passage into the brain. It's like a clean room.

• 1:18:20Lester Nare?

  It, it, the, the analogy I think of, it's like, it's like flying, regular blood vessels were like flying back in the day where there's no TSA.

• 1:18:27Krishna Choudhary?

  Yeah, dude.

• 1:18:28Lester Nare?

  And then, but the blood-brain barrier is like TSA.

• 1:18:30Krishna Choudhary?

  Yes, it is, it is exactly like.

• 1:18:32Lester Nare?

  Take your shoes off.

• 1:18:33Krishna Choudhary?

  Yeah.

• 1:18:33Lester Nare?

  Got to scan your bags.

• 1:18:34Krishna Choudhary?

  Yeah, yeah. Random search.

• 1:18:36Lester Nare?

  Random search, come to the back room.

• 1:18:38Krishna Choudhary?

  Yeah, exactly. Yeah, exactly, exactly. The brain is like, because, because the brain is like arguably the most important thing for our humans, like, there's a lot of security between what's coming in and what's going out.

• 1:18:52Lester Nare?

  Yep, which makes, which makes sense.

• 1:18:53Krishna Choudhary?

  Totally makes sense, right? And if these blood-brain barriers fail, if these junctions fail, the tight junctions, if they become leaky, like with normal blood vessels, then that's going to lead to nonspecific leakiness. We're going to get inflammatory compounds that come in, we're going to get cytokines, that's going to drive neuroinflammation, and that's going to exacerbate any Alzheimer's-related pathology.

• 1:19:18Lester Nare?

  I see, I see.

• 1:19:19Krishna Choudhary?

  So now there's a new hypothesis here, not the amyloid hypothesis, but the vascular hypothesis. This is the hypothesis that says systematic vascular disruption caused by aging, caused by high blood pressure. That's going to loosen up the capillaries in our brain. And that's actually a primary driver for neurodegradation.

• 1:19:44Krishna Choudhary?

  Okay?

• 1:19:44Lester Nare?

  Yeah, so the the the idea is the there we have two sort of sort of thought processes here. One is this amyloid plaque accumulation is the driver of this neurodegenerative stuff. Then the other idea is that the the degradation of the blood brain barrier on on the capillaries, the 400 miles of capillaries in your brain is like the inciting incident that then enables a whole slew of derivative stuff.

• 1:20:15Krishna Choudhary?

  Yes.

• 1:20:16Lester Nare?

  Like that is a

• 1:20:16Krishna Choudhary?

  It's a precursor to the amyloid stuff.

• 1:20:18Lester Nare?

  Got it. Ah, that that's right. Got it. Yes, right. Like, it's not just that the amyloid piece is not connected at all.

• 1:20:24Krishna Choudhary?

  No.

• 1:20:25Lester Nare?

  But it's not the first.

• 1:20:26Krishna Choudhary?

  It's not the first thing. And perhaps there's something upstream that we can tackle, right? That we can put a dam on.

• 1:20:32Lester Nare?

  Okay.

• 1:20:32Krishna Choudhary?

  Okay, and usually this stuff is a hurdle, right? Because the blood brain barrier structurally prevents most drugs from reaching the brain.

• 1:20:39Lester Nare?

  Right.

• 1:20:39Krishna Choudhary?

  Right? We've we've heard about that, like, oh, this thing can cross the blood brain barrier. And then, like, the valuation goes up by a lot because it can cross the blood brain barrier. Right? People are trying to do like nanoparticles. You might have heard of like nanoparticles that go through the blood brain barrier. You can also do like sonic disruption where you like like send like high frequency sound. And that sound disrupts the blood brain barrier. But it's like, well, if we're trying to fix the blood brain barrier, we don't want to, you know, like, it's like a catch 22 type type situation.

• 1:21:07Lester Nare?

  Yes.

• 1:21:08Krishna Choudhary?

  And this particular paper is leveraging that hypothesis to actually treat the brain by targeting that blood brain barrier itself. You're not going to pass through it. We're trying to repair the the plumbing.

• 1:21:20Lester Nare?

  Yes.

• 1:21:21Krishna Choudhary?

  There.

• 1:21:21Lester Nare?

  Yes.

• 1:21:21Krishna Choudhary?

  Okay?

• 1:21:22Lester Nare?

  Yes.

• 1:21:22Krishna Choudhary?

  Now, let's get into this particular paper and this particular lab at UCSF. So they first started out by doing this technique called heterochronic parabiosis. The idea is you take old mouse and young mouse and you join up their vasculature, their blood.

• 1:21:42Lester Nare?

  Okay.

• 1:21:43Krishna Choudhary?

  And so it's kind of like that thing on Netflix. Netflix where like, you know, the old guy is getting like the

• 1:21:47Lester Nare?

  Yeah, it's what Peter Thiel's doing, right?

• 1:21:48Krishna Choudhary?

  Yeah. Like the young person's blood.

• 1:21:51Lester Nare?

  Yeah.

• 1:21:51Krishna Choudhary?

  Well, this is like the, the genesis of that.

• 1:21:54Lester Nare?

  Okay.

• 1:21:54Krishna Choudhary?

  Okay, they did this in my, my mice first and the old mice that were exposed to the young blood showed neurological rejuvenation. So new neurons, better memory. It was actually reversing the effects of dementia.

• 1:22:08Lester Nare?

  Very interesting.

• 1:22:09Krishna Choudhary?

  Okay.

• 1:22:09Lester Nare?

  The introduction of new blood was actually basically having neurological positive benefits.

• 1:22:14Krishna Choudhary?

  Exactly. And so now you can start thinking, well, okay. Maybe other interventions could make the blood young. One of the easy things is aerobic exercise, right? Like cardio. It's a potent intervention. It delays cognitive decline and maybe that cardio and exercise is doing something else to the blood that is causing that blood to rejuvenate.

• 1:22:36Lester Nare?

  Okay, I just want to pause real quick because I'm, I'm tracking. So the idea is thi- this, uh, uh, heterochronic parabiosis is this idea of a younger rodent. Uh, has better, the blood is

• 1:22:50Krishna Choudhary?

  The blood is better.

• 1:22:51Lester Nare?

  It's better. So if

• 1:22:52Krishna Choudhary?

  And it's like reversing all this like

• 1:22:53Lester Nare?

  Stuff.

• 1:22:54Krishna Choudhary?

  Yeah.

• 1:22:54Lester Nare?

  And so if you put that younger rodent blood in an older rodent, it makes the older rodent better. Like that's the first

• 1:23:01Krishna Choudhary?

  Yeah, that's the first

• 1:23:03Lester Nare?

  We know that's true.

• 1:23:04Krishna Choudhary?

  That, yeah, you did the surgery, you make them share blood, boom.

• 1:23:07Lester Nare?

  It's done.

• 1:23:08Krishna Choudhary?

  Yeah.

• 1:23:08Lester Nare?

  And so

• 1:23:11Lester Nare?

  when we look at an activity like exercise, so the, the point is it's indicating that, oh, like the blood has an impact on neurological

• 1:23:21Krishna Choudhary?

  Yeah.

• 1:23:21Lester Nare?

  Uh, maintenance.

• 1:23:22Krishna Choudhary?

  Yeah.

• 1:23:23Lester Nare?

  And growth and degradation.

• 1:23:24Krishna Choudhary?

  Exactly, yeah.

• 1:23:25Lester Nare?

  And exercise impacts the blood.

• 1:23:28Krishna Choudhary?

  Yeah.

• 1:23:30Lester Nare?

  Yeah, the more you exercise, the more it keeps it sort of, let's say, youngish.

• 1:23:33Krishna Choudhary?

  Exactly. And actually, the, the exercise impacts the blood in a very specific way because there's signaling molecules that are released by our organs during exercise. They're called

• 1:23:42Lester Nare?

  Okay.

• 1:23:42Krishna Choudhary?

  Exer kinds.

• 1:23:43Lester Nare?

  Okay.

• 1:23:43Krishna Choudhary?

  Kinds meaning like these signaling molecules, exer meaning it's coming from exercise.

• 1:23:47Lester Nare?

  Yes.

• 1:23:48Krishna Choudhary?

  And examples are like Iresin, which stimulates brain derived neurotropic factors. Neurons live longer that way. There's More synaptic plasticity, there's clustering which reduces neuroinflammation. So all of our organs are releasing this, the muscles release stuff, the heart releases stuff, the kidneys, the liver releases stuff. Even the bone releases stuff into our blood. And these are all signaling factors that facilitate like inter-organ communication. Like if the brain wants to coordinate with the liver, the liver wants to coordinate with the kidneys and so on and so forth. And all of this is happening in our blood. And so the key insight here is that, well, how do we make the blood younger? It's because of these exerkins, which are released during exercise.

• 1:24:31Krishna Choudhary?

  And what Sam, what Saul Vilada's lab in UCSF did in 2020 is they reported in Science that the exercise was actually the, the effects of exercise were happening because of this liver-derived enzyme, GPLD1. Whose name I'm not gonna say. But that is the, that's the subject of this particular paper. In 2020, they discovered this enzyme.

• 1:25:02Lester Nare?

  This is, can we just hold on this for a quick second? Cause I think this is important. So what you're saying is in this, in this 2020 paper in Science, we had this understanding that when you exercise, all your body starts sending these exerkins. And they're sort of like benefit, like the benefit of that is it helps sort of sustain. It's like, almost like this maintenance process.

• 1:25:26Krishna Choudhary?

  Yeah.

• 1:25:27Lester Nare?

  For the body where it keeps you at stable state.

• 1:25:29Krishna Choudhary?

  Yeah.

• 1:25:29Lester Nare?

  For lack of a better way to put it. We, we know that it comes from exercise, which drives a process that the body enacts.

• 1:25:38Lester Nare?

  The discovery that there is a singular protein that comes out of the liver.

• 1:25:43Krishna Choudhary?

  Yeah.

• 1:25:44Lester Nare?

  In this, in this 2020 paper.

• 1:25:45Krishna Choudhary?

  That is improving cognition.

• 1:25:47Lester Nare?

  Is, is improving cognition. Out of all the exerkins.

• 1:25:50Krishna Choudhary?

  Yeah. And other ones could be as well, right? But this one particularly found this, that is like the signal is way high.

• 1:25:56Lester Nare?

  Of all the impacts, this one is the one that has the most and is a, is a key for focus and attention. I just, I just think that's a kind of a crazy idea.

• 1:26:05Krishna Choudhary?

  That's crazy.

• 1:26:06Lester Nare?

  In and of itself.

• 1:26:06Krishna Choudhary?

  Yeah. There's, there's an enzyme coming out of the liver.

• 1:26:10Lester Nare?

  Yeah.

• 1:26:10Krishna Choudhary?

  There is an enzyme coming out of the liver that is improving cognition demonstrably.

• 1:26:16Lester Nare?

  Right.

• 1:26:16Krishna Choudhary?

  In older mice when they do exercise.

• 1:26:19Lester Nare?

  Right.

• 1:26:20Krishna Choudhary?

  Right? That's fascinating. Okay, okay. Yeah, and that was in 2020. Yes. There's a problem, though. Okay. This enzyme, GPLD1, is massive. Okay. So it's not making it through the blood-brain barrier. Uh huh, uh huh, okay. So what exactly is it doing? And that's why there's a giant, you see the question mark? Yes. BBB, and then there's a question mark and it points to the hippocampus. Like, yeah, what is going on? How is this massive GPLD1 enzyme that cannot cross the blood-brain barrier? I mean, even glucose can't pass the blood-brain barrier, let alone an enzyme of this size. Okay. So how exactly is it making my smarter and their, and their brains bigger? Because it's not going directly to the source. Exactly. Apparently, because it can't pass. Because it can't, it can't. So what is it exactly doing? Okay. And that is what this 2026 breakthrough is about. Okay. Okay?

• 1:27:05Krishna Choudhary?

  It's unpacking the mechanistic reason how that GPLD1 is affecting the brain. Okay. It's not actually going through the blood-brain barrier. It's maintaining the blood-brain barrier itself. Uh huh. Okay? Okay. It's like, it's like the gates themselves, the TSA. Yeah. Is what this thing is maintaining. Okay, I, yes, okay. Right? Very interesting. So here's the mechanism. GPLD1 is something called a phospholipase. That's what the, the, uh, D is there somehow. And what it's doing is its function is to cleave something called the GPI anchor. These are anchors that tether proteins to cell membranes. The cell has an outside.

• 1:27:50Krishna Choudhary?

  Mm hmm. That's the cell membrane. Yes. And there's a bunch of proteins that are tethered to the cell membrane. You can imagine a boat on a dock, right? The boat is not actually attached to the dock. There's like rope. Yeah. That attaches a boat to the dock and a bunch of like those, like sailor knots. Yes. Right? Yes. That's a tethering protein. Okay. And what this GPLD1 is doing is attacking that tethering protein. Okay. Now, why is that a good thing? Yeah, like, right? You would think that like if a protein is tethered to the, to the cell membrane, you want to keep it there. Yes. Right. That's exactly what I think. That's, that's what you should think. If there's too many proteins, though, on that cell membrane, what's gonna happen to your dock? Uh, dock's gonna break down.

• 1:28:33Krishna Choudhary?

  The dock's gonna break down. If there's too many boats, that's why there's like, you gotta like, pay for slips. Yeah. You can't just like, free for all dock to your, to the dock, right? Yeah. If there's too many boats, the dock is gonna float away and then, and then it's just chaos. Yes. So, you've gotta have a way to have slips and like untether boats that are causing the dock architecture to rupture. Yes. That is what GPLD1 is doing, okay? They, they, they got a target. This target must be on the blood-brain interface, and then they used actually transcriptomics to figure out that there's this specific protein called T-NAP, tissue nonspecific alkaline phosphatase. This is a boat that docks to the membrane. Yeah. Okay?

• 1:29:17Krishna Choudhary?

  And if, and this thing on its own has its own like, job. Right, sure. Okay, this particular T-NAP protein, it involves promoting bone mineralization, and in the brain it does a variety of other stuff, okay? But, in the brain, if it's anchored to the, to the cell membrane, if there's too many of that anchoring, then the cell membrane of your blood-brain barrier is gonna start breaking down. And then all of a sudden, your tight junctions start becoming loose. That was the hypothesis. Okay. Okay? Okay. And the key action was that if you circulate this GPLD1 drug, which is something that cuts, it's a scissor for the ropes that tether the boat, then what that's gonna do is act as a molecular scissor.

• 1:30:01Krishna Choudhary?

  It's gonna cut that anchor, the T-NAP is gonna go off, and you're gonna maintain the blood-brain barrier structure. And that is what is key. So, to recap. Yes. You exercise. Yes. The liver produces this GPLD1 enzyme. Yes. That GPLD1 enzyme that goes into the brain. Yes. And it maintains the blood-brain barrier by cutting...

• 1:30:27Krishna Choudhary?

  The anchor between this T nap gene and the cells that maintain that blood brain barrier.

• 1:30:34Lester Nare?

  Because the the T nap, the T nap at too much volume begins to degrade the actual structure of these tight joints.

• 1:30:43Krishna Choudhary?

  Yes.

• 1:30:44Lester Nare?

  And the blood brain barrier and they're not currently, for whatever reason, self-regulated. There are no slips.

• 1:30:50Krishna Choudhary?

  Yes. Yeah.

• 1:30:51Lester Nare?

  And so.

• 1:30:51Krishna Choudhary?

  Yeah, that the the self-regulation is the GPL D one.

• 1:30:55Lester Nare?

  Right, right, right, right.

• 1:30:57Krishna Choudhary?

  Which that's what the function.

• 1:30:58Lester Nare?

  Right.

• 1:30:59Krishna Choudhary?

  GPL D one is kind of like the boat, I guess, the dock like.

• 1:31:02Lester Nare?

  Coast Guard.

• 1:31:03Krishna Choudhary?

  Yeah, the Coast Guard. It's like you don't have a slip.

• 1:31:05Lester Nare?

  Right. But currently, at least in the context of this study.

• 1:31:10Krishna Choudhary?

  Yeah.

• 1:31:11Lester Nare?

  The only source for the GL GPL D one.

• 1:31:16Krishna Choudhary?

  Yeah.

• 1:31:17Lester Nare?

  Is exercise.

• 1:31:18Krishna Choudhary?

  Is the liver during exercise.

• 1:31:20Lester Nare?

  That is, in the context of what we're looking at, that is the only way we can generate enough Coast Guard people to patrol the docks.

• 1:31:26Krishna Choudhary?

  Yeah.

• 1:31:27Lester Nare?

  To maintain the structural integrity, the blood brain barrier, which can then be a driving force for the the the plaques we talked about earlier.

• 1:31:37Krishna Choudhary?

  Yeah, because now when when when, you know, random stuff gets in, that maybe starts denaturing the plaque proteins, which causes amyloid plaques, which causes.

• 1:31:46Lester Nare?

  Yes. Okay.

• 1:31:47Krishna Choudhary?

  Alzheimer's.

• 1:31:48Lester Nare?

  Okay.

• 1:31:48Krishna Choudhary?

  Right. It's like from the top down. And I think it's worth it's worth really like lingering on this for a bit.

• 1:31:53Lester Nare?

  Yeah.

• 1:31:54Krishna Choudhary?

  We've created a molecular cascading mechanism.

• 1:31:58Lester Nare?

  Yes.

• 1:31:58Krishna Choudhary?

  From exercise to preventing Alzheimer's.

• 1:32:02Lester Nare?

  Yes.

• 1:32:02Krishna Choudhary?

  Right. Right. There's now a link between the two.

• 1:32:04Lester Nare?

  Yes.

• 1:32:05Krishna Choudhary?

  And it it's literally exercise, the liver produces a specific exocrine, which is this GPL D one.

• 1:32:13Lester Nare?

  Yes.

• 1:32:13Krishna Choudhary?

  That then goes to maintain the blood brain barrier.

• 1:32:15Lester Nare?

  Yes.

• 1:32:15Krishna Choudhary?

  Once the blood brain barrier is maintained.

• 1:32:18Lester Nare?

  Alzheimer's gets reduced because maybe that is the key issue.

• 1:32:22Krishna Choudhary?

  Mm hmm.

• 1:32:22Lester Nare?

  Right? It's the key issues potentially, there's no TSA preventing whoever wants to come into the airport, getting into the airport.

• 1:32:30Krishna Choudhary?

  Exactly.

• 1:32:31Lester Nare?

  Um, and then what we're looking at when we had the amyloid hypothesis was a specific type of person that was getting through.

• 1:32:39Krishna Choudhary?

  Yeah.

• 1:32:39Lester Nare?

  At the airport.

• 1:32:40Krishna Choudhary?

  Yeah.

• 1:32:40Lester Nare?

  But not.

• 1:32:41Krishna Choudhary?

  And like causing problems inside the terminal.

• 1:32:43Lester Nare?

  Right.

• 1:32:43Krishna Choudhary?

  Yeah.

• 1:32:44Lester Nare?

  But that was, it's potentially just a single use case.

• 1:32:46Krishna Choudhary?

  Yeah.

• 1:32:47Lester Nare?

  Versus understanding the systemic structure.

• 1:32:48Krishna Choudhary?

  Exactly, yeah.

• 1:32:49Lester Nare?

  Okay.

• 1:32:49Krishna Choudhary?

  And let's just go through some of the experiments that they did. So they did alkaline phosphate labeling of T nap.

• 1:32:54Lester Nare?

  Yes.

• 1:32:54Krishna Choudhary?

  T nap is this thing that the boat that is docking too often.

• 1:32:57Lester Nare?

  Yes.

• 1:32:58Krishna Choudhary?

  To the blood brain barrier. And you can see on the left there is old animals. There's lots of T nap along the blood vessels. And on the right is an old animal that does exercise. The amount of T nap is drastically reduced.

• 1:33:11Lester Nare?

  That's incredible.

• 1:33:11Krishna Choudhary?

  Right?

• 1:33:12Lester Nare?

  Yeah.

• 1:33:12Krishna Choudhary?

  So there you can see just very much in the staining.

• 1:33:14Lester Nare?

  Yes.

• 1:33:15Krishna Choudhary?

  Of this particular enzyme that we're getting a lot. They also did novel object recognition and Y maze, which are these behavioral tests for old mice.

• 1:33:24Lester Nare?

  Okay.

• 1:33:24Krishna Choudhary?

  Like if, if the old mice have dementia, they can't do well on these where's the cheese type of task. But you could actually recover and reverse cognitive decline by treating old mice with GPL D one. You could treat old mice with GPL D one without having them do exercise. And then there was a profound reversal in the deficits in this particular behavioral maze, right? So they could find the cheese faster and all the other kind of stuff and remember where the cheese was.

• 1:33:53Lester Nare?

  And just to be clear, what we're, what you're saying here is, um, you can artificially introduce GPL D one.

• 1:34:02Krishna Choudhary?

  Mm hmm.

• 1:34:03Lester Nare?

  Into these aged mice who already have an accumulation of T nap happening.

• 1:34:08Krishna Choudhary?

  Yeah.

• 1:34:09Lester Nare?

  And it still works when it's not necessarily coming.

• 1:34:14Krishna Choudhary?

  From exercise.

• 1:34:15Lester Nare?

  Because it's the same enzyme.

• 1:34:16Krishna Choudhary?

  Yeah.

• 1:34:16Lester Nare?

  So it doesn't necessarily, it doesn't have to come from exercise.

• 1:34:18Krishna Choudhary?

  Yeah, it's like this, this singular benefit from exercise, we can replicate by just injecting.

• 1:34:22Lester Nare?

  Right.

• 1:34:22Krishna Choudhary?

  And then we're good to go.

• 1:34:23Lester Nare?

  And we're seeing that even when the, you don't have to do it preemptively.

• 1:34:27Krishna Choudhary?

  Mm hmm.

• 1:34:28Lester Nare?

  Or preventatively.

• 1:34:28Krishna Choudhary?

  No.

• 1:34:29Lester Nare?

  You can do it even after.

• 1:34:30Krishna Choudhary?

  This is already an old mice that has Alzheimer's like symptoms.

• 1:34:32Lester Nare?

  Yes.

• 1:34:33Krishna Choudhary?

  It's bad at the Y maze.

• 1:34:34Lester Nare?

  Right. And you artificially insert it and it's got, it gets better.

• 1:34:39Krishna Choudhary?

  It gets better. It finds the cheese. Right? So this is huge. And for blood, um, blood brain barrier repair, right? So let's look at the difference between how much leakage is happening.

• 1:34:51Lester Nare?

  Mm hmm.

• 1:34:51Krishna Choudhary?

  When you've got an aged mice.

• 1:34:53Lester Nare?

  Mm hmm.

• 1:34:54Krishna Choudhary?

  That has leakage versus one where we treat it with GPLD1. On the left, you can see the, the pink is all of where the leakage happened.

• 1:35:05Lester Nare?

  Okay.

• 1:35:05Krishna Choudhary?

  Okay. It's all over the hippocampus. This is a slice of the hippocampus. On the right, most of the pink is on that blood brain barrier in the corner. There's no huge spots in the middle of the neurons.

• 1:35:16Lester Nare?

  Yeah.

• 1:35:17Krishna Choudhary?

  Because there's not that much leakage. Because you've treated them with GPLD1, right? So I think this is, this is really, really cool.

• 1:35:24Lester Nare?

  This is this, I mean, so it's cool for a couple of reasons. It's again, understanding, you know, it's like, think what you talked about, like connecting the biochemistry processes.

• 1:35:35Krishna Choudhary?

  Yeah.

• 1:35:35Lester Nare?

  Body to these neurological, like, long-term.

• 1:35:39Krishna Choudhary?

  Symptoms.

• 1:35:40Lester Nare?

  Symptoms.

• 1:35:40Krishna Choudhary?

  Mm hmm.

• 1:35:41Lester Nare?

  And being able to trace that story.

• 1:35:46Lester Nare?

  Which again, we only talked about one of the exerkins, which is this GPLD1.

• 1:35:51Krishna Choudhary?

  There could be more.

• 1:35:52Lester Nare?

  There could be more. So again, if there's a fundamental.

• 1:35:54Krishna Choudhary?

  Yeah.

• 1:35:55Lester Nare?

  That's interesting. Independent of the specifics of them looking at Alzheimer's directly, as they're initially used to. So. And then the, then how they then, um, you know, tried to test this.

• 1:36:12Lester Nare?

  In mice.

• 1:36:12Krishna Choudhary?

  Yeah.

• 1:36:13Lester Nare?

  And saw the.

• 1:36:13Krishna Choudhary?

  They did all the right.

• 1:36:14Lester Nare?

  Things. Right? And when we compared it to the amyloid experimentation and why it didn't work. Like it clearly works or it doesn't.

• 1:36:24Krishna Choudhary?

  Yeah.

• 1:36:25Lester Nare?

  You know what I mean?

• 1:36:26Krishna Choudhary?

  Exactly.

• 1:36:26Lester Nare?

  Like, like you have a myeloid plaque in people and they're fine. But when you introduce this G P L D one into it, it's not like they just continue being ineffective at the Y maze.

• 1:36:37Krishna Choudhary?

  Exactly. Yeah. And, and you know, one could say, oh, this is, um, this is in mice. There's obviously going to be issues, right?

• 1:36:43Lester Nare?

  Always, always.

• 1:36:44Krishna Choudhary?

  That's what's cool about.

• 1:36:45Lester Nare?

  Okay.

• 1:36:46Krishna Choudhary?

  Okay. That's what's cool about this. So T nap like, okay, so how did they implement G P L D one in mice?

• 1:36:53Lester Nare?

  Yes.

• 1:36:53Krishna Choudhary?

  They've got this procedure where what you effectively do is you increase, you, you, you put the gene for G P L D one inside a viral vector or like in some kind of plasmid chunk of DNA. You stick that into mice, um, you increase the blood pressure such that the liver gets infused with this piece of DNA. And then the liver makes the G P L D one. Can't do that in humans.

• 1:37:16Lester Nare?

  Yeah.

• 1:37:17Krishna Choudhary?

  Okay. But here's what's cool.

• 1:37:19Lester Nare?

  Okay.

• 1:37:19Krishna Choudhary?

  The T nap is already something that we've been worried about.

• 1:37:23Lester Nare?

  Okay.

• 1:37:24Krishna Choudhary?

  Okay. That T nap gene, the boat that gets anchored.

• 1:37:27Lester Nare?

  Yep.

• 1:37:27Krishna Choudhary?

  That's already something that we've worried about. And there is a small molecule drug called S B I four twenty five. That is already approved.

• 1:37:36Lester Nare?

  Okay.

• 1:37:36Krishna Choudhary?

  To inhibit T nap.

• 1:37:38Lester Nare?

  Okay.

• 1:37:39Krishna Choudhary?

  The boat.

• 1:37:40Lester Nare?

  Okay.

• 1:37:40Krishna Choudhary?

  Right?

• 1:37:40Lester Nare?

  Yeah.

• 1:37:41Krishna Choudhary?

  It's already getting in the way of the boat.

• 1:37:42Lester Nare?

  Okay.

• 1:37:43Krishna Choudhary?

  And it's successfully been used in preclinical studies to prevent blood vessel calcification. Because remember T nap has to do with calcification and bone maturation. So like sometimes like there's calcification, like calcium deposits that happen in blood.

• 1:37:57Lester Nare?

  Yeah.

• 1:37:57Krishna Choudhary?

  And so this particular drug was developed in order to circumnavigate that.

• 1:38:02Lester Nare?

  Yes.

• 1:38:02Krishna Choudhary?

  But it's like, well. This thing doesn't have to cross the blood brain barrier because what it could do is go into the blood and inhibit the boats from anchoring.

• 1:38:12Lester Nare?

  Mm hmm.

• 1:38:12Krishna Choudhary?

  Right now, this is a we're we're taking our understanding from the study.

• 1:38:17Lester Nare?

  Yes.

• 1:38:18Krishna Choudhary?

  That it's about boats anchoring to the dock.

• 1:38:19Lester Nare?

  Yes.

• 1:38:20Krishna Choudhary?

  And too many boats anchoring to the dock that is then creating the physics of the dock to not be tight and be loose. And now there's leakage. Well, what if we just like messed with the boats?

• 1:38:31Lester Nare?

  Right.

• 1:38:32Krishna Choudhary?

  Right? And that's what they did.

• 1:38:34Lester Nare?

  Okay.

• 1:38:35Krishna Choudhary?

  And the oral SBI 425, it successfully mimicked this GPLD1 gene therapy.

• 1:38:44Lester Nare?

  Oh, wait, wait, wait, wait, wait, wait. This is actually probably the craziest piece of this.

• 1:38:48Krishna Choudhary?

  Yeah.

• 1:38:49Lester Nare?

  So so in the mice, we had to do gene therapy in order to to.

• 1:38:53Krishna Choudhary?

  Yeah, we had to do this like weird stuff.

• 1:38:55Lester Nare?

  Right.

• 1:38:55Krishna Choudhary?

  That we can't do in humans.

• 1:38:56Lester Nare?

  Right.

• 1:38:57Krishna Choudhary?

  But now it's like, what if we just feed the mice this this drug?

• 1:39:00Lester Nare?

  Right, which is already.

• 1:39:03Krishna Choudhary?

  Approved.

• 1:39:03Lester Nare?

  Approved for a different use case.

• 1:39:04Krishna Choudhary?

  Yeah, yeah, some some random, you know, calcification.

• 1:39:07Lester Nare?

  But the point is, it has the same it it it creates the same exact GL GPLD1. I keep saying GLP1.

• 1:39:14Krishna Choudhary?

  Yeah.

• 1:39:15Lester Nare?

  GPLD1.

• 1:39:18Lester Nare?

  Uh, generation enzyme generation.

• 1:39:21Krishna Choudhary?

  Yeah.

• 1:39:22Lester Nare?

  Just take and it's already an oral format.

• 1:39:24Krishna Choudhary?

  Yeah, it's already an oral format and it's mimicking the gene therapy.

• 1:39:27Lester Nare?

  Right.

• 1:39:28Krishna Choudhary?

  Maybe it's not doing what the gene therapy exactly is doing, but effectively.

• 1:39:32Lester Nare?

  Sure.

• 1:39:32Krishna Choudhary?

  What do we want?

• 1:39:33Lester Nare?

  Right.

• 1:39:33Krishna Choudhary?

  We want to maintain the blood brain barrier.

• 1:39:35Lester Nare?

  Yes.

• 1:39:35Krishna Choudhary?

  That is our end case.

• 1:39:36Lester Nare?

  Yes.

• 1:39:37Krishna Choudhary?

  Right?

• 1:39:37Lester Nare?

  Yes.

• 1:39:37Krishna Choudhary?

  And by whatever means necessary. Well, we already have SBI 425 that's been approved for other stuff.

• 1:39:43Lester Nare?

  Yes.

• 1:39:44Krishna Choudhary?

  And it's doing it.

• 1:39:44Lester Nare?

  Right, right.

• 1:39:46Krishna Choudhary?

  So now this is now a bioavailable pill.

• 1:39:49Lester Nare?

  Yes.

• 1:39:50Krishna Choudhary?

  That can treat Alzheimer's.

• 1:39:51Lester Nare?

  Yes.

• 1:39:52Krishna Choudhary?

  Purely by targeting the blood brain barrier.

• 1:39:54Lester Nare?

  Yes.

• 1:39:54Krishna Choudhary?

  By targeting this vascular interface.

• 1:39:57Lester Nare?

  Yes.

• 1:39:57Krishna Choudhary?

  Between the blood and the brain, maintaining that it circumnavigates this historic blood brain barrier drug delivery problem. We don't have to worry about.

• 1:40:05Lester Nare?

  Right.

• 1:40:05Krishna Choudhary?

  Does is it going to get through? Because what we're worried about is actually maintaining it in the first place.

• 1:40:10Lester Nare?

  Yes, we want to make sure that in the analogy we brought up about TSA. In the airport or the boat in the dock in the coast guard. Uh, we want to make sure that the coast guard is always patrolling the dock.

• 1:40:20Krishna Choudhary?

  Exactly.

• 1:40:21Lester Nare?

  Because what's happening is coast guard over time, people retire and then there's not enough staffing issues.

• 1:40:27Krishna Choudhary?

  Yes.

• 1:40:27Lester Nare?

  And then all of a sudden these T naps are just having a field day, kind of like the Chinese fishermen people off the coast of Chile.

• 1:40:34Krishna Choudhary?

  Yeah.

• 1:40:34Lester Nare?

  All over the place that are just totally.

• 1:40:36Krishna Choudhary?

  Exactly.

• 1:40:36Lester Nare?

  Unregulated.

• 1:40:37Krishna Choudhary?

  Yeah.

• 1:40:38Lester Nare?

  But if you had some coast guard there and then there's no less T nap and then.

• 1:40:41Krishna Choudhary?

  And the final thing I want to bring up about this paper is they did do their homework with actual human tissue. Cause so far it's always in been in um.

• 1:40:50Lester Nare?

  Rodent.

• 1:40:51Krishna Choudhary?

  In mice, in in particular mice. So in humans, they looked at autopsied cortical tissue of older adults with Alzheimer's dementia. The T nap protein levels are elevated there. Which means there's a lot of these T nap boats that are anchored to the dock of the blood brain barrier. The G P L D one levels were elevated in active, healthy elderly humans. So those who are active and healthy, the coast guard was up. So already we're seeing these like large scale correlations, right? And it's hope that this could actually work perhaps in humans. I I thought it was a very cool study because they they did a comprehensive research in mice.

• 1:41:34Lester Nare?

  Yes.

• 1:41:34Krishna Choudhary?

  And they and they didn't leave the.

• 1:41:36Lester Nare?

  The human.

• 1:41:37Krishna Choudhary?

  The human part, you know?

• 1:41:39Lester Nare?

  Because the point is the insights that were derived from the studies in mice are uh in terms of uh autopsy data. From past Alzheimer's patients, both those who are active and inactive basically mimic the levels. Both in this uh the T nap inhibitors being more present.

• 1:41:59Krishna Choudhary?

  Yeah.

• 1:42:00Lester Nare?

  On on the bus as well as um exercise increasing these this enzyme level.

• 1:42:06Krishna Choudhary?

  Yeah, this G P L D one.

• 1:42:07Lester Nare?

  That helps to maintain the structure of the blood vessels and the tight junctions of the blood being barrier. Which again seems to be as a. Competing theory to the amyloid hypothesis, a potential, it's like, it's like lower in the stack

• 1:42:26Krishna Choudhary?

  Yeah.

• 1:42:26Lester Nare?

  Of processes, because you want to basically attack a problem as close to the source as possible.

• 1:42:31Krishna Choudhary?

  Exactly.

• 1:42:32Lester Nare?

  The amyloid plaque is not the source.

• 1:42:34Krishna Choudhary?

  Yeah, it seems it's not.

• 1:42:34Lester Nare?

  It seems to be, it seems it's not, but this might be.

• 1:42:38Krishna Choudhary?

  Getting closer.

• 1:42:39Lester Nare?

  To what it's going on.

• 1:42:40Krishna Choudhary?

  Yeah.

• 1:42:40Lester Nare?

  And also, just an interesting conceptual way to think about how to look at, like, neuro degenerate, neurodegenerative diseases.

• 1:42:52Krishna Choudhary?

  Exactly, as a holistic thing.

• 1:42:53Lester Nare?

  As a holistic thing.

• 1:42:54Krishna Choudhary?

  It's like, this thing involves the liver, the blood, and the brain.

• 1:42:57Lester Nare?

  Yes.

• 1:42:58Krishna Choudhary?

  It's, the brain is no longer like an island that you have to think about.

• 1:43:01Lester Nare?

  Right.

• 1:43:01Krishna Choudhary?

  I mean, it's, it's, I think the future is looking very bright for this particular study. Of course, I don't want to do commentator's curse, but the GPLD1, which is like, you know, your coast guard, that thing targets all kinds of boats, not just T nap. It's targeting all sorts of GPI anchored proteins, hundreds of others, so there, those could be targets for new therapies.

• 1:43:22Lester Nare?

  Yes.

• 1:43:22Krishna Choudhary?

  Right? You could have a, I mean, I anticipate there's going to be a surge in peripheral T nap inhibitors, not just this SBI 425, there could be other stuff.

• 1:43:34Lester Nare?

  Right.

• 1:43:35Krishna Choudhary?

  So, yeah.

• 1:43:36Lester Nare?

  And I think that's an important point, that the, the SBI 425, already being an approved drug, like, is huge, because it sort of shows the, the drug development scaffolding.

• 1:43:47Krishna Choudhary?

  Yeah.

• 1:43:48Lester Nare?

  To get to an end result, even if you don't use exactly, like, you, you can at least reach, like, see what the pathway is to success here, around how to approach it, because, you know, there's, there's the research, but then the whole drug discovery process from stage, uh, stage one, or phase one to phase four, quite complex. You have early stage drug discovery, where they're just trying to figure out, like, the active ingredients, then you give it to the chemists, because they have to figure out, how do you actually deliver it?

• 1:44:12Krishna Choudhary?

  Right.

• 1:44:12Lester Nare?

  To the patient, is it intravenous, is it oral?

• 1:44:15Krishna Choudhary?

  Yeah.

• 1:44:15Lester Nare?

  Dosing, what is the half-life, all that kind of stuff, then you get into sort of early preclinical trials.

• 1:44:22Krishna Choudhary?

  Yeah, where it's like, okay, let's make sure it doesn't kill the mice.

• 1:44:24Lester Nare?

  Right, then you get into clinical trials. FDA approval. I mean, it is a very complex and long thing.

• 1:44:30Krishna Choudhary?

  And this is already halfway through.

• 1:44:31Lester Nare?

  It's already. So that's a huge deal.

• 1:44:33Krishna Choudhary?

  Yeah.

• 1:44:34Lester Nare?

  A fascinating story.

• 1:44:36Krishna Choudhary?

  Yeah, I thought it was very cool, actually.

• 1:44:37Lester Nare?

  It's very cool. And I think what's been so interesting in this journey on the show for me, right? Having the benefit of just having you able to really, again, having a first principles general science understanding is not super common, unfortunately.

• 1:44:51Krishna Choudhary?

  Mm hmm.

• 1:44:51Lester Nare?

  Um, and the ability for now, like me, almost thirty episodes in, to be able to make these connections across stories, because there's fundamentals about the process of this early-stage research or frontier research that track.

• 1:45:08Krishna Choudhary?

  Yeah.

• 1:45:09Lester Nare?

  I mean, we talked earlier about the proton piece and how that's like you how measurement, not of direct observation, but indirect observation is a concept and it can manifest.

• 1:45:18Krishna Choudhary?

  Yeah.

• 1:45:19Lester Nare?

  At the, when you're zooming in really, really small or when you're zooming out really, really far. I mean, this is a really, really cool story and great work. This again was from UCSF.

• 1:45:31Krishna Choudhary?

  Yeah, UCSF. They do amazing work there. Lots of Nobel prizes.

• 1:45:35Lester Nare?

  Oh, my God. Fascinating, fascinating story. And again, I just want to make a quick sort of caveat here. The point of this show is to talk about breakthrough in frontier research from first principles. There is a large delta or a big gap in between a research paper coming out and it having, you know, over the counter or prescription.

• 1:45:56Krishna Choudhary?

  Yes.

• 1:45:57Lester Nare?

  Medication available to people.

• 1:45:58Krishna Choudhary?

  Yeah.

• 1:45:59Lester Nare?

  And so just to be very clear about that point, we very much understand that, one, there needs to be replication. There's a whole process of implementation.

• 1:46:07Krishna Choudhary?

  There's a lot of stuff that can go wrong in the middle.

• 1:46:09Lester Nare?

  And so the middle is, is, there's a lot there.

• 1:46:11Krishna Choudhary?

  Mm hmm.

• 1:46:12Lester Nare?

  This show is not about the middle. It is, it is about kind of the beginning of the story, but it's important just to be clear that, that, that is, that is the case.

• 1:46:19Krishna Choudhary?

  Yeah.

• 1:46:20Lester Nare?

  Um, yeah. And so, you know, I know some folks will be, yeah, this is still early. Yes.

• 1:46:24Krishna Choudhary?

  Yeah. But isn't it cool that we figured out this coast guard boat docking thing?

• 1:46:28Lester Nare?

  It's the concepts and the ideas are really an understanding how we got there.

• 1:46:34Krishna Choudhary?

  Yeah.

• 1:46:34Lester Nare?

  Is the point.

• 1:46:35Krishna Choudhary?

  Yeah, that's the point. I mean, it's kind of cool.

• 1:46:37Lester Nare?

  Um, because there's so many things you can get from this. So in any event, um, Fantastic. We started with dark galaxies. Again, we have space and then neuroscience, some great rundown stories. I want to do a couple of quick housekeeping notes before we wrap up for the day. Number one is, if you are listening to this episode and you've made it all this way, congratulations, because some of the stuff is really hard to grok when you're just only listening. And if you are curious and want to know more, we have a video podcast, so you can watch this on YouTube, on Spotify, and soon, coming soon, because we just got the announcement email, Apple Podcasts is introducing videos. Oh, yeah.

• 1:47:21Lester Nare?

  Later this spring. So if you are an Apple Podcast listener, you are on the precipice of receiving video as a first-class object, just like we have on YouTube. Spotify, it's not our fault, that's just they haven't implemented it yet. So that's exciting. We do a ton of graphics and visuals that help really understand what's going on here. So please take a watch. If you are listening on Spotify or Apple, a five-star helps us significantly to get this out to more people. And some comments. And some comments to so many of you. Talk about how this is your favorite podcast. Go ahead and comment it on every show that you feel that way. Share it with a friend, bring it to lunch at your journal club, if you're at a lab. It's really helpful for

• 1:48:04Lester Nare?

  us. We make this show freely available. There's no subscription content. There's no exclusive backend content. It's all the episodes and all the clips are available for everybody. And so if you want to support us directly and become a patron, you can go to ffpod.com backslash donate. You can do a one-time donation, or you can do a monthly donation. That's what helps us do all the editing, get all of the equipment. Do travel for some of our special stories. Maybe, for those who have reached the end of the episode, maybe I'll do a little tease here, that, you know, you only will know, well, you might have seen it on our Instagram story, but-

• 1:48:44Lester Nare?

  We have recently had the wonderful experience of getting to be interviewed on the Dave Chang Show. With David Chang, the famous chef and owner of the Momofuku Restaurant Group. Being able to have food made for you by the goat, one of the goats is a.

• 1:49:04Krishna Choudhary?

  Yeah, it wasn't like, oh, we got takeout from Momofuku. Yeah, no, no. Dave Chang is making me, I can't say actually.

• 1:49:11Lester Nare?

  Yeah, we'll watch, you'll have to watch that episode. But that should be coming out on Netflix. Our first, our first Netflix placement as well as Spotify. By a week, probably a week from when this episode comes out, a week or 10 days. And so keep an eye on our socials at FFP Pod for when that comes out. It's a great interview. You get to see us in the real world, outside of the studio. We had a great time. Big shout out to Dave's team. David Meyer, Christine, you guys are fantastic. We had a great time and we look forward to you inviting Krishna. When you guys need the science of food or food science expertise.

• 1:49:52Krishna Choudhary?

  I will do anything for food.

• 1:49:53Lester Nare?

  Friend of the pod. Shout out to Dave Chang and Co. Really appreciate that. My name is Lester Nare.

• 1:50:00Krishna Choudhary?

  Hold on, yes.

• 1:50:03Krishna Choudhary?

  The comments. I want you guys to give me an alternate.

• 1:50:09Krishna Choudhary?

  GPLD1. What does it stand for?

• 1:50:12Lester Nare?

  Yes.

• 1:50:12Krishna Choudhary?

  Because the one that we have, which, you know, just for old times sake, I'm gonna try. Glycosylphosphatidylcholonecyl specific phospholipid D1. I would like something better. Thank you.

• 1:50:26Lester Nare?

  That's a great call. Yes. So again, listening all the way, you'll get a little couple of secret nuggets in here. Send over the comment. Keep an eye out for us on Dave Chang. And we may or may not start to do some in-pod giveaways. And so, you know, you might want to listen because he might be maybe someone who gets some special merch or. Who knows?

• 1:50:48Krishna Choudhary?

  Who knows?

• 1:50:48Lester Nare?

  Who knows? Bringing it back, I'm Lester Nare, joined as always by my co-host and our resident PhD, Krishna Choudhary. We really appreciate you guys so much, especially those who listen all the way to us ranting for two hours. We tried to do two stories this week to make it less.

• 1:51:07Krishna Choudhary?

  Yeah, and it's still two hours.

• 1:51:07Lester Nare?

  And it's still two hours.

• 1:51:08Krishna Choudhary?

  We gotta work on that.

• 1:51:10Lester Nare?

  We will be back next week with our next episode. This is From First Principles.