From First Principles - 3I/ATLAS Explained, Forensic Fingerprints & Alzheimer’s Breakthrough (EP. 18)

Episode Date: November 27, 2025

Hosted by Lester Nare and Krishna Choudhary, this episode spans astrophysics, forensic chemistry, and neuroimmunology. We begin with a deep dive into 3I/ATLAS, only the third confirmed interstellar object to ever pass through our solar system — larger and stranger than ‘Oumuamua and Borisov, with new imagery released as NASA reopened operations. Then we break down a true-crime forensic breakthrough from Maynooth University that reveals how to recover fingerprints from fired bullet casings — a technique that could radically accelerate criminal investigations. And we close with a Max Planck Institute discovery identifying a regulatory microglial state in the brain that may finally clarify why Alzheimer’s develops — and how immune dysfunction, not just plaques, drives the disease.SummaryThe third interstellar visitor — 3I/ATLAS joins ‘Oumuamua and Borisov as only the third object ever observed entering the solar system from interstellar space, with new NASA imagery revealing structure, trajectory, and compositional clues.A forensic chemistry breakthrough — researchers at Maynooth University develop a technique to retrieve latent fingerprints from fired shell casings, combining heat-stable organic residues with spectroscopic imaging.A new model of Alzheimer’s — Max Planck Institute scientists uncover a microglial “regulatory” state (a T-reg–like analogue) activated through CD28-dependent pathways, reshaping how the field thinks about plaques, neuroinflammation, and therapeutic targets.Show Notes3I/ATLAS — Interstellar Object Updates (NASA / JPL)Forensic Chemistry: Fingerprints on Fired Casings (Maynooth University)Alzheimer’s Microglia Study — Max Planck Institute / Univ. of Cologne

It's peak pollination season, and my business is scaling fast. To keep the nectar flowing, I need a phone plan with top priority data speed. That's why I chose GoogleFi Wireless. My connections stay strong even when the hive is buzzing. Plus, unlimited plans start at $35 a month. Now, that's a deal that doesn't stay. Explore GoogleFi Wireless plans today. Plus taxes and government fees.

GoogleFi Wireless is not subject to data traffic deprioritization during times of high network usage. You said this place was steps from the water. We just haven't found the steps yet. How much did we save? Enough. Enough to get lost. Or you could book a stay with Hilton. Welcome to your oceanfront room.

Just steps from the water. The Hilton sale is on now. Book on Hilton.com or the Hilton app and save up to 20% to get the stay you expected. When you want savings, not surprises. It matters where you stay. Hilton for the stay. Hello, Internet. This is your captain speaking. Lester Nare, joined as always by my co-host and our resident PhD Krishna Chowdery. My friend, how are you?

Pretty good. You have any exciting Thanksgiving plans for the week? Yeah, I'm actually going to go to Maui with my parents. It's going to be great. That's awesome. Yeah. Hopefully I'm going to get to see the Daniel K. Inouye telescope. I was actually going to ask you're going to make a trip out to the. Yeah, yeah. We're definitely going to make a trip out.

I don't know if the telescope is operating, but, you know, it'd be nice to see whatever I can. Absolutely. Absolutely. And it's an interesting dovetail, at least on the observatory piece for the story we're going to spend a lot of time on today, which is we're going to talk about the Reyes Atlas. We now have the observations. Yep. We've had time to put it together. We did touch on this once before.

Yes. So we're doing a little bit of an update based on all the latest and greatest. Yeah. greatest. It's been in high demand. We're going to start off with 3-Ey Atlas today, followed up by a new story that's going to be at a Minuth university in Ireland. It was in forensic chemistry

around a new technique for taking fingerprints off of fired bullet casings. So this is a new forensic technique that will help us catch the bad guys even better. Ending with a new Alzheimer's sort of discovery around

microglia or immune cells that are in our brain. Yeah. This is a combination of a couple of universities in nature. Icon School of Medicine at Mount Sinai, Max Plaque Institute of Biology and Aging, and the University of Cologne. So three incredible stories. We're going to touch on all the details.

Yep. This is from first principles. So our first story of the day is 3i Atlas. Yes. This is the one that obviously everyone keeps asking us about because the government is back open. Yeah. And so NASA has now released.

least new imagery. Yes. So let's sort of just start right from the top here. Yeah, I mean, it's, it's a, it's an interstellar visitor, as we all know. It's the third interstellar object. There's been two predecessors that it's had. The first one was Amuamua. The second one was two Iborysov.

And this is the third and the largest one that we have by far. Okay. Okay. Um, um, um, um, um, um, was a really strange words. It was an inert, highly elongated object that was flying through. Then we had two eye Borisov, which was basically just like a normal comet, like any other comet that we'd seen. The only thing that was really different was that it was moving so fast that it wasn't

trapped by the sun's gravity, right? And then now we've got finally this guy, three eye Atlas. The eye stands for interstellar. The three stands for the fact that it's the third. and the Atlas stands for the fact that it was discovered by the Atlas system, which is the asteroid terrestrial impact last alert system. These are a bunch of telescopes all over the world. The one that actually discovered this was in Chile.

And the whole point of this telescope system is to find near-Earth objects or objects that are coming through and going to be a little bit close in our solar system. It preferentially looks in the plane of, the planets. Okay. Right. So meaning meaning so if the sun is here, all of the planets revolve around the sun in the same sort of plate. It's not like the Big Bang Adam. Okay. From the show where it's like, you know, there's one going this way. There's another going the other way. They're all sort of along the same plane. Makes sense. Right. Yes. And that's because when the solar system first formed, there was some angular momentum of that cloud. So when it collapsed, you know,

everything has to be on that plane to preserve the angular momentum. Makes sense. So that's actually why we discovered this thing. And one of the reasons why it's sort of taking a tour of the planetary systems, right? It's kind of by design that Atlas finds objects that are along this plane, right? So it begs the question, there might be other objects that are not in the plane that we're not really sensitive to. But perhaps with the new Veraruban telescopes and things like that, we will be. But in any case, that's how it got its name, right?

It's inbound. It's got an extremely hyperbolic orbit. So an eccentricity of approximately 6.2, the Earth is basically out of one. It looks like a circle, right? But this thing is extremely hyperbolic. You can see that it's going so fast, 58 kilometers per second, that it barely even changes its orbit as it passes the sun, right? Unlike the, you know, the wicked movie, there's that one of my favorite songs is like a comet pulled from orbit as it passes the sun. This is not doing that.

It is not changed in any, in any real sense, for the better or the worse. But it's 58 kilometers per second, right? That's a velocity that's three times higher than what's expected for a usual star encounter. So this thing's moving extremely. extremely quickly. Yeah, yeah. And it begs the question like, what even gave it its speed?

How did it reach that? Yeah. How does something move that fast through the solar system? And the orientation is it's also retrograde. The other weird thing is, you know, in the Milky Way, the sun is moving around the Milky Way, right?

Yeah. And the plane of the planets is about perpendicular to the motion. So are the, our entire sort of solar systems moving through the Milky Way galaxy, like, let's say, on the X access. But then the orbit of the planets in that context, while we're doing that, is on the Y-S. Yeah, is in the, isn't this Y, right? And so, and so when 3-I Atlas, when we say that it's taking a tour of the solar system,

what it's really doing is it's like going piercing through the Milky Way in some sense, right? It's not moving. I mean, obviously it has some direction. along the Milky Way's rotation as well, but it's going through the plate of the Milky Way as well. That's why it's going through all the planets in the plane of our ecliptic.

Which is sort of a cosmic... The cosmic serendipity there is... Yeah. It's kind of a mystery where it came from and things like that, and we're going to get into some of that later. So there's been some milestones that have happened since the last time we talked.

It flew by Mars on October 3rd, 2025, that was when it got as close as it possibly could. And that was a really cool way of providing a local observation, right? Because we have the Mars reconnaissance orbiter around Mars, the ESA, the European Space Agency has a bunch of stuff around there. And it's about 28 million kilometers away from these guys. So you can get at least some close-ups, you know. It's still far away.

28 million kilometers. Yeah, yeah, yeah. It's like, it's close enough, right? Yep. And then on October 30th, 29th, it had its closest approach to the sun, which was at a distance of 1.36 astronomical units. One astronomical unit is the orbit of the Earth. So it didn't even get closer than Earth is to the Sun. Got it. Okay. A lot of comets, you know, the really bright ones get within Earth's orbit, sometimes even like as close as Mercury. Right. Right. As close as like between Venus and Mercury. And those are the ones that glow

and you can see with your naked eye. This one, not so much, right? It wasn't that close. And then finally, in December 19th, it's going to be well outside the Earth's orbit, but that's when it's actually going to be the closest to Earth. It's going to be 80% of the distance between Earth and the sun, but it's going to be in the other side.

Yep. So the Sun will be in front of us. The comet will be kind of behind us. That's when it's going to get closer. Okay. So I told you that it's got a really, weird orbit, right? It's coming through really fast and it's going along the plane of the planets. It's unclear whether it's coming from a part of our Milky Way called the thin disk, which is really

what you see when you look out in the night sky and you see the Milky Way or from the thick disk. Because if you trace back, the yellow trajectory here shows where the comet is and the red trajectory is where we are, where the sun is. And it's sort of like playing tag. and go with our sun because it's about the same distance away from the center of the Milky Way as we are. And so it's going to be kind of sharing our orbit, the same way that, you know, you can imagine the Trojan asteroids outside of Jupiter. They share the same orbit with Jupiter and they move around with Jupiter. The James Webb Telescope is orbiting the sun with the Earth, right? Because it's feeling the same gravitational pull from the sun that the Earth is and the moon is.

So the question is where did it come from? The idea is as we are traveling through the Milky Way, we're going on a particular orbit. And the way that Therai Atlas moves through the Milky Way is in that similar circular orbit. Exactly. In the radius of that orbit is almost identical. It's almost identical, right?

I mean, hence it's right here. And the Milky Way just has a gravitational potential because of all the stars and gas in it. And the sun is feeling the same gravitational potential that the comet is. And because of Newton's law of gravitation, the acceleration that we feel is independent of our mass. So even though the comet 3A Atlas

is really, really small compared to the sun, all objects fall at the same rate, according to Galileo, right? So it doesn't mean like in terms of the orbit, it's not really going to matter if it's the sun or the sun. Or a star, right? Yep, that's a good distinction.

That's the point. Yep. That's why the James Webb telescope is moving around the sun the same way that we are. Right, even though it's obviously smaller than the Earth. Right. So the first paper that tried to answer this was from Oxford in the Astrophysical Journal letters. This was in July. And they said that it's from the thick disk.

The thick disk is the part of the Milky Way that's just above all of the stars and the real gas. So the stuff that we see in the night sky when we look up, that's the thin disk. The thick disk is the part that's right above or below. That's an old population of stars. We know that because we can look at the spectral signatures of the stars that are above there. And, you know, there are these very red, long-lasting stars with lots of metal, which means they've been doing fusion for a while. It depends, actually.

It depends on whether it's high metal or low metal. High metal could also mean that you're you're the second or third generation of stars that are coming from the ashes of the older stars that have made the metal. And then low metallicity could mean that, okay, you just have hydrogen and helium. So like it's like from the Big Bang. You got nothing else. You know? So there's ways of quantifying it. But in any case, they've quantified that a lot of these stars are between 7 to 14 billion years old.

Right. So it's much older than the sun, which is about 5 billion years old, right? Right. So that was the first one. Then there's some new work that came out in September. This is not in a journal, but it's on the archive. And it was from the Tenerife Observatory, a bunch of people there in Spain. They were trying to trace back the object's origins in a similar way.

And they used this Python package called Milky Way Potential 2022, which basically, what, it can do is it can take your object and then run back the clock for however long that you want given the Milky Way potential. And what they found was that if you integrate over the millions of stars in that database and you go back, at least in the last 10 million years, there's no close encounter that's going to cause this giant velocity. Okay. If you go through all of the, And those are the stars that it had close encounters with. Yep. And none of them were close enough to really add any velocity to this thing.

The point being, 3-I Atlas had to get its acceleration from an encounter with some celestial object at some point in its history. Yeah. And from... But it can't be the recent history. But it can't be the recent history. Yeah. Okay. And then when we look in this Milky Way potential 20th,

22 and trace back the journey that it had made and the stars that it would have passed, these celestial objects would have passed on the way. None of those are of sufficient mass and size. Yeah, and it wasn't close enough to generate the acceleration that we're seeing. That's what the paper is trying to say. That's what the paper is trying to say, right. So then they say, okay, what we can do is we can really just run back the clock, right? And we can say, okay, if it's not in our recent history,

let's just treat the Milky Way as this like potential landscape and ask how far does it deviate away from the thin disc, right? Because what it could do, what the original paper was saying was that, you know, because it's got such a high velocity perpendicular to the disc, it must be coming from up there. Yeah. Right. But the potential landscape is such that when it goes above the disc, the disc is going to start pulling back. And so there's going to be some oscillation through the disc, right? It's going to go up and then it's going to come back down. It's going to go down.

Then it's going to get pulled back up again. Right. So how big is that amplitude? Right. Yeah. Of that oscillation. Basically how high, how far above and below the thin disk? Yes.

Is it going, right? Is it going all the way to the thick disk? Because we also have velocity profiles of the stars that are up there. There's some typical trajectories that those guys take. And there's some typical trajectories that the thin disc takes. Which one does this thing? belong to. Got it.

Right. And so that's what they did. And what they think is happening is that it stayed basically within the thin disc. And they're ruling out the fact that it could be in that upper thick disk. Okay. They found where the velocity profile of this comet is compared to the stars in these two regions. And it's more aligned with the thin disk. Interesting.

So this is kind of a clap back to the Oxford paper. Which was that original one. Which was that original one. So we're going to have to see if Oxford comes back and says, nah. This is good because when we first covered this, the Oxford paper was the only one. It was the only one. And everyone was like, okay, that's got to be it. But the process of science is extremely dynamic.

There's a bunch of researchers vying for the spotlight. Right. So, you know, someone's going to say this. The other person's going to say that. This is very good. So we now are in a position in terms of the locational origin of, of 3A Atlas, which initially was believed to be coming from above where we are on the thin disc in the thick disk.

But there's at least now a rebuttal. Yes. There's at least now a rebuttal to that that can explain away the thickness origin hypothesis. Yeah, yeah, exactly. And now it calls into question whether it is as old as they say they are. Because it used to be, we were really excited, right? There's going to be the oldest thing in the solar system. It's going to be older than 7 billion years old because all of the,

The stars that are up there are super old. And if it came from there, then it's got to be super old too. Now, well, if it's just one of these thin-disc populations that just got bumped maybe a bunch, a long, long time ago, right? It's no longer maybe that old. Right. Maybe it is quite contemporary. So there's a bunch of, you know, very cool science that is still happening, trying to figure this out.

Trying to trace back its location, origin location. Yeah. So that's the origin story. It's still in question. Yes. Now let's talk about what it actually is and why it is so interesting. It is quite a bizarre comet. Okay.

Okay. If we're completely honest, there's a typical comet that we see in our solar system. And this is a pretty bizarre one. It's not unprecedented. We have seen comets that do the weird things that this thing is doing, but it's been like one or two. Got it. Okay. So it's rare, but it's not like totally unprecedented.

Unprecedented. Yep. Okay. So it's got a nucleus. The radius is about anywhere between 0.22 kilometers to 2.8 kilometers. That's how we constrained it. There's a lot of activity on this thing. It's called a hyperactive comet.

Okay? As the comet gets closer and closer to the sun, the solar radiation and the photons from the sun start creating chemical reactions and physical reactions on the comet surface. and that's going to just make it glow and do all of the cool things that it does. And a lot of the weird stuff that it does has, it's been implied that, you know, maybe there's something weird going on, if there's a techno signature, blah, blah, blah. A lot of this actually came from Avi Loeb at Harvard. But then in September or sorry, October of this year, he came out with this model,

which is a physical model for the Icecoma of 3i Atlas with Avi Loeb and one of his collaborators. Eric Kito. And this one is trying to suggest how the physics of a comet could produce all of the weird stuff that we're seeing. Just normal comet, maybe not a normal comet,

but kind of a weird comet, but just ordinary physics. Stuff that we know. Okay, one of the things that it tries to explain is something called the anti-tail. This was very weird, right? There was a...

If you can see over there, this is from the Hubble Space Telescope. On the right is where the sun is, and there's some... projection, there's like a jet from the comet coming out towards the sun. Which is counterintuitive because

the idea would be if the comet is traveling at high velocity towards the sun, you would imagine the quote unquote jet would be pointing in the opposite direction. And there is one. Yeah, and there is one. There is an anti-suntail. And because of the way that we're looking, right, it's coming at us.

So the anti-suntail is kind of behind the comet and the sun facing one is towards us. So because of our vantage point, it looks like the sun facing emission is that much brighter, but that's not actually true. But in any case, there is a sun facing emission, right?

Okay. And then when it went past post-perihelian, so it went past the sun on the other side, now there's no anti-suntail. Sorry, now there's no towards the suntale. There's only the anti-suntail. Okay, so it disappeared. This is from the very large array,

sorry, the very large telescope, the VLT in Chile. So the nucleus has been, has done this thing where it had jets pointing in both directions. And then on the other side of the sun, it no longer has that. Yes. So what's going on? The model that Kito and Loeb proposed is the following. Okay.

So when the comet is coming towards the sun, there's going to be something called sublimation. Sublimation is what happens with dry ice where you go directly from a solid form to gas form. There's no in between of liquid because the temperature, the energy is enough to cause the CO2 molecule to just free itself from the gas, not transition through that liquid phase. Now, when it's happening and it's coming towards us, that sublimation is actually going to cause chunks of CO2 to sort of shoot out from the comet. Okay? And if you're far enough away, those chunks of CO2 are going to shoot out. But, they're going to follow with the comet because of the same thing that I said earlier, right?

They're falling towards the sun the same way the comet is, even though the comet is this giant mountain of stuff. And let's say a chunk of CO2 is, you know, centimeters to meters to maybe tens of meters big. That thing is still feeling the sun's gravity. So it's going to follow in the same sort of path, but maybe a little bit ahead because it got shot towards the sun. Yep, yep, got it. And the solar radiation out there, far away, is not enough to quickly melt these chunks.

Okay? So it's sort of like the comet is here. You've got these chunks of CO2 ahead. And it's moving along the sun, right? Now, as it gets close to the sun, there's going to be so much pressure, radiation pressure and ionization pressure, that these chunks, as soon as they get out of the comet,

they're just going to immediately evaporate. And so that's why we're seeing that loss. Yeah, that makes sense. Yeah, yeah. of the front facing tail, right? Because the closer you get, the more, the, the shorter the lifespan of the stuff that's getting ejected. At, when it, at distance, we're seeing these large chunks break off, right?

But they're in such large size and the pressure is not high enough yet, that they maintain its structure. Yeah, and they just follow along. Right. At this slightly, you know, again, because it's basically getting broken off. from the front side as it's making its way over. But as you get so close, the radiation is so high that the lifespan of that tail that is appearing in front

basically doesn't have enough time to exist before it evaporates into going from that sublimation process from solid to liquid, which if I recall correctly was also part of the original walkthrough we did about where the origins of this could have been, where it could have been around a star that had this. accumulation of ice and things and then then it broke up.

So in that first episode, it's interesting, that same process was discussed well before even this keto loan paper came out. Yeah. And that was, that was in how it formed. And how it formed in the snow line. Yes. In that ice line, right? Where the CO2 goes from gas to being able to freeze.

So there's a bunch of frozen stuff right at this ice line. And maybe the comet formed there, which is why there's so much CO2 compared. to water. And which is basically the opposite process on the formation. Now we're seeing it. Now we're seeing it on the other side. And so if you go back and watch that episode, it does a good job. We go into detail about the concept of sublimation and that formation process that actually

kind of dovetails to what you just talked about quite nicely. Exactly. Yeah. So so that's the that's sort of the keto lobe hypothesis. Right. Or why we're seeing a tail sometimes and not other times. The sunward extension. Yeah.

specifically the thing that was weird. Yeah, yeah. So I wanted to highlight that that paper because I thought that was a quite interesting physical model. Yep.

That's out of Harvard Astronomy. So now let's get into some of the observations that have been happening. So the James W. Space Telescope, infrared chemical frame fingerprinting. So this is in the

infrared range. The space telescope took that photo. The coma is highly dominated by a mission that's coming from CO2 and H2O. And one can see that the mixing ratio between the CO2 and H2O is 7.6, which is way higher than the typical solar system comets, right?

The typical solar system comets are at 0.1 to 0.2. 3A Atlas is all the way up there. So, yeah, so we're looking at this graph. It's a plot. It's a plot. And then we see basically that 3A Atlas is well above

the trend line. The trend line, well, well above the trend line. Yeah, there are a few that, like the C-2016 R2. That's another comet that's local, and that's even more above than three-outlists. But these are exceptions, that's the point. These are very much exceptions. And the fact that, you know, we've had two interstellar visitors. One is typical.

The other is crazy. Of course, like n equals two is a very small sample size, but it begs the question, are most interstellar comets atypical? Right, right, right. It's kind of an interesting question because we don't know where they formed and how they formed around what stars they formed and things like that. The other thing that's kind of weird about throughout this is there's a lot of nickel and there's not a lot of iron. This is very strange because those two usually come side by side together. Okay.

They're formed at the core of stars during explosions, things like that. And one can imagine that whenever they form in a dust cloud and they're in summer environment, they have typically the same. kind of elemental mass. So they're going to be forming together. It's not unprecedented again, but it's definitely unusual. That there's a lot of nickel. There's not a lot of iron.

The ratio between these two is so. Yeah. The delta is so large. Yeah, yeah, yeah. So that, again, there's another question mark there. How did you get a lot of nickel on a comet, but no iron? So we, the one of the questions is like the velocity question, which goes to origin.

One of the questions is the XO2. The Sunward extension, C. Oh, yeah. Yeah. And then this is now like the, like a third question, which is the, um, the composition itself. Yeah. Just to try to like quickly summarize those, those three key points that are quote in question.

Yeah. Okay. Exactly. Um, another really cool local view that we got. I was telling you about the Mars fleet that we had. Yes. So the Maven, um, probe, which is on Mars, imaged three Atlas. We found a massive neutral hydrogen corona using the,

Lyman Alpha line, which is one of the spectral lines of hydrogen that this Maven instrument actually had access to. So from that, we can actually derive a water production rate, and there's a lot of water sublimation that's happening on that comet, okay? Which is kind of cool, but that's not really that unprecedented. Comets have a lot of water. It used to be thought, actually, that and it still is thought, that a lot of the Earth's water came from comets, because when Earth was forming, probably all the water just got evaporated, and then comets came and deposited their water during the early bombardment of Earth when it was forming. And one can actually look at the isotopic ratios of different isotopes in water and comets and in the ocean, and they're the same. So that suggests

that there is a link. The last piece from Mars that I want to highlight is the Mars reconnaissance orbiter high rise. This confirmed that there is a nuclear diameter, which is probably less than 30 kilometers. That's the limit of the high resolution imager. I mean, we've had tighter constraints before. Actually, I saw a interview of Avilob on like NBC where he was just like this, this, like there's nothing new here. Like the data kind of sucks. It's like, you know, I mean, give him a break. They were supposed to, they were supposed to image Mars with this thing. They didn't know that they were going to have like a comet on their hand that's like a astronomical unit away. But I just thought it was funny because like everybody's like really excited about this data. But because the orbiters

around Mars are built for Mars, right? As as like, you know, within hundreds of kilometers to thousands of kilometers. Now you're asking them to image something that's 30 million kilometers away that's much smaller than Mars. They're not going to have a good time. I think this is this is this is an important sort of side note because I think this has been the one thing that a lot of people have been like leaning on which is like we spend billions of dollars and like you know why is it that you know we can't capture imagery that is you know equivalent to like this and they just bring up an example of something else and I think for the Mars specific for the Mars orbiter specifically you know it would be like asking you to take a picture of someone holding a penny on the Empire State

Building from Los Angeles with your iPhone. phone, you know, and it's like, it's not built for that. It's not built for that, yeah. You know, maybe you could use a specialized tool to do so, but that just wasn't what was up there at the time. Yeah, exactly. Like, wildlife photographers use giant telephoto lenses, right? To get those shots.

They spend thousands of dollars on that. They don't just all go up with an iPhone. As someone who's had to take photos of my little brother at sports games and having video lenses, not a telephoto lens. Yeah. Yeah, yeah. There's a reason why the lens matters. Like, it's a hardware problem.

at some point, right? The other really cool way of monitoring this thing was with something called Stereo A, which is solar conjunction monitoring. This is a really cool set of satellites we have on two sides of Earth's orbit that monitor the sun all the time. Because the Earth only sees the side of the sun

that it's seeing. Right, right? What we'd like to do is see all of the sun all the time. Right. So what they do is as the Earth is revolving around the sun, they have two satellites that share Earth's orbit, but are on 180 degrees away from each other. So they're imaging the sun from two different sides. One is leading the Earth. The other is trailing behind us.

And so with this, we can actually track 3A Atlas as it goes behind the sun, right? Because when it was coming towards Earth, it actually went behind the sun and we could no longer see it. Well, with these two satellites, we can. We can track it. And we were tracking it and the object kept its structural integrity. Okay. Again, this thing is built for imaging the sun, not comets. But at least it could see that, okay, this thing still exists on the other side.

Right. It didn't like totally disintegrate, like some comets sometimes do. Yep, yep. And then finally, I want to mention that Isro, the Indian Space Research Organization, did some observations with the 1.2 meter Mount Abu Infrared Observatory. I have actually been to that observatory because my dad used to work there. Look at this guy.

Yeah, that's me when I was probably like nine, nine or ten years old. That's awesome. Taking a photo with that 1.2 meter telescope. Yes, yes. So that was pretty cool that I saw that, you know, one of these observatories that my dad did a lot of research at

back when we were in India, did some things. They've got a really nice spectrometer there. So they found some key molecules in that spectrum. They found the Swan, bands, which are C2 and C3, that's two carbons and three carbons. And they also found cyanogen, which is carbon and nitrogen. Like those bonds have very specific spectra. And from that spectrum, we can actually find that, okay, these molecules do exist. And it sort of refutes any lingering

claims that there's some like inert or artificial composition, because, again, comets very typically have these kinds of carbon spectral lines. So that's sort of where we're at in terms of 3-Ey Atlas, the current data, all of the current observations. Not all of them. I mean, we still keep doing a bunch. There's a lot of actually amateur astronomers that are taking really great photos of this thing, which I find really awesome. It's a weird comet for sure.

Probably came from a metal-rich star system. That's why it's got a bunch of nickel. the fact that it doesn't have a lot of iron it's kind of weird but there's a lot of stuff that we can do with it, right? I'm really excited for the Vera Rubin Observatory that's going to come online. I'm also really excited for an ESA mission

called the Comet Interceptor. It's this new type of mission where it's scheduled for 2029. It's designed for high-speed flybys. Okay? And this thing is the highest speed possible, right? So now we've got sort of a parameter space on how high we think flybys should be capable of. Right, right, right, right.

Because we have a real world data point now with the Atlas of knowing like, okay, we are going to see objects that are moving this quickly. Yeah, yeah, yeah. And so now we need to meet those expectations of, okay, we found this thing in July or in a, yeah, in July we found it. We've got like a few months to scramble the fighter jets, to scramble the rockets and get this thing going. that's the capability that we need in order to really study these things really up close. Yep. So now we have some data points to actually, you know,

give us that ballpark estimate. It basically gives like a sort of a mission orientation. Yes. For the, like, you know, how fast do we need to set up a rapid response? Yeah. And what are the sort of implement, like what are the keys to implementation

in order to be able to accomplish it and do so? Yeah. And I cannot wait for, I keep thinking about how with Vera Rubin, the number of these interstellar objects is going to just balloon and explode. If they are there to be discovered, if they are there to be discovered,

it will be discovered. It will be discovered by the Vera Rubin. Yeah. 100%. The Verra Rubin would have discovered this thing, had it gone online three weeks earlier. Which is so crazy. Right.

It's so crazy. And the quality of that data would have been fantastic. You know, again, this being a tool that is built for that type of observation. Yeah. In contrast to the Mars orbiters, which just happened to be closer in proximity and also able to see it at a time where we were on the other side of the sun. So very would have been, would not have been helpful during that window of time. Yeah, yeah, definitely not.

Just that window of time. Fascinating. So we still, jury still out on origins. Yep. Locationally, like where it is coming from. Yeah. We have. And that's jury still out on age.

Oh, which is location is tied to age. So we still don't know like where and how old. Yeah. We have an interesting explanation for the Sunward extension. Mm-hmm. But that still is being developed. Yeah. Again, that's an archive that's not been peer reviewed and published.

Right. Right. And we, you know, don't quite have the explanation for the nickel-iron ratio. No. So these are still open questions. Yeah. Which is fair and understandable. And it's interesting to see the inner process.

I mean, this thing's a few months old. Right. Right. Right. Right. Right now we're still in the capture all the data you can. It's going to, in December, it's going to be close to Jupiter. Right.

So that'll be interesting. We have some probes there that perhaps can go, you know, orientations. and take a look. Well, I don't know what the plans are there. I think what is interesting is it's, you know, it hasn't been clear or we haven't had a lot of these. So we've never had the opportunity to say, hey, we have all these instruments in our solar system now,

which we didn't have before. No, yeah. We have a ton of stuff that's just out there. And when there is a, these ephemeral events, these events that happen, you know, in a moment in time, where are these tools going to be used to capture, this data or not. And this is like proof positive that like everyone understands the import and the unique opportunity and chose to do so. So another update on the Atlas, I'm sure we'll do

another one once it's all gone. Once it's all gone and everyone's really doing that deep dive. Or once it, once it puts probes in Jupiter. Right, right. Apparently. We'll know it a month. December 19th. It's still not done yet. So we're waiting for quote unquote, whatever, December 19th. That was our story number one, which was, again, a quick update on 3A Atlas. We're going to now move on to story number two, which is a very different context. We're going into a forensic story. Yeah, we've never done a forensic story. I think it's our first.

I thought this was really cool. A true crime. So if you're a fan of true crime, we're going to love this one. This is out of forensic chemistry, research out of Maynooth University in Ireland, for fingerprints from fired bullet casings. So I think the top line is there's a new technique that is making it more efficient to figure out who done it. Yeah, yeah.

And from fired bullet casings, which is really quite something. Because it's kind of the holy grail of modern forensics, okay, is to find fingerprints from bullet cases that have already been fired, right? Because then you can tie a suspect to actually loading,

the gun rather than just possession of the firearm. That's actually, that's an important decision. That's pretty big. Yes. It's a really cool methodology involving electro deposition. The paper is out in forensic chemistry by Maynooth University in Ireland. The fingerprints are typically destroyed whenever a firearm discharges, right? Because you have stuff like 500 degrees Celsius, pressures of 50,000 pounds per square inch.

And this method exploits some organ. residue that remains even after all of this stress. And it like amplifies that organic residue to create a fingerprint. And it's very cool that the electrochemical techniques that they're using to do this. Okay. And the significance is, as I was saying, right, the print on the casing links individuals to the act of loading the gun. And before we really only have the possession of the firearm.

But it could somebody else could have done it. somebody could have taken the fireman, done something. Yep, yep, yep. And the prevailing consensus is the violent process of actually firing a bullet would destroy the fingerprint on the casing. Right. The theory of the case is you're never going to get the fingerprint off of the fired bullet. Exactly.

Yeah. And it is a pretty violent process, right? I fired a gun only once. I went to a shooting range. And it was like one of the craziest exhilarating experiences I've ever. had. I've never done it again. So I don't, I don't, I had to do a lot of research on how the gun works and the physics of the gun. But this is my two minute summary. Yes. Of, of the process. This whole thing happens

in under two milliseconds. You've got a casing that has gunpowder and then you've got the bullet, which is the projectile in the front. You've got a firing pin. And when you hit the firing pin with the trigger, that causes a chemical reaction, which raises the temperature inside of the casing, all of that gun powder or whatever goes up in temperature around something like you can get as much as 2,000 degrees Celsius. And then that's going to expand a lot of air, which is going to shoot the gun forward. Okay. That's not the end, though, because afterwards, you have to take out the casing and replace it

with the next one, right? So there's like a thing that grabs the case, pulls it back, throws it away, and then loads up the next one, right? So all of that stuff is going to mess with the fingerprint that's on the outside. Because when the bullet is fired, that expansion of the air is also going to, first of all, it's going to heat up everything. So any organic residue that you have like the proteins or any carbon, that's just going to burn up. Then the casing itself is going to expand into the chamber.

And when you pull it back, that friction is going to then again destroy any residue. of a fingerprint that's on the outside. Yep. Right. So there's all of these different things that are happening that will completely mess with the fingerprint that's on the outside. Right. Okay.

So the recovery relies on some persistence of like a decomposition product that's on the outside, okay? And what this particular paper is focusing on is the carbonized ash. So there's going to be some inorganic salts that are left by our sweat and our oils that is going to remain. it's going to get burned up, but the ash is going to remain on the outside. There's the idea being, the theory of the case is there's no organic residue that will be left after the bullet is fired because it's just going to get burned up.

Yeah, like the proteins, the oils and the lipids, it's gone. But their hypothesis was there's going to be a little indicator still left despite all of that. Yeah. And it should be the burned up ash of all of that stuff. Of all of that stuff. And there should be a little bit left. Right. And if there's even a little bit left, there's a chance.

So you're saying there's a chance. Exactly. And so that's what they're doing here. This isn't completely unprecedented. Okay. So in 2008, there was a guy, Dr. John Bond. He came up with a mechanism to actually figure out these casings. That's crazy that his name is Bond.

Yeah, yeah. And I thought it was like part of the bond when I was reading it because my summary just had Bond. And even the news articles about this just have Bond. And I'm like like James Bond. Like this is, you know, maybe this is one of cues like the weird techniques that he's made. But no, this is Dr. John Bond. And he came up with a way of using really high voltage 2.5 kilovolts. Right. And what you do is you realize that most of these. casings are made out of brass, which is copper and zinc. Okay. And the zinc and the copper are going to react with the oils on my finger in different ways. Okay. Okay. So where the fingerprint was, that's actually going to create a chemical reaction and a corrosion of the zinc part, not the copper part. Okay. Okay. So there's going to be different resistance. There's going to be different tiny layer of different metals. And what I'm going to do is subject this casing to really high voltage. People are crazy. And then put a fine conducting powder on top. And then that powder is going to be attracted to the corrosion sites because that's going to be higher,

more conductive than the rest, right? And then I can, I can make a fingerprint out of that. That's so brilliant. It's pretty brilliant. So in 2008, this has already happened. This is going one step further. Okay. And so we've identified that we can basically put like current into

a substrate and it will basically reveal this red, like this pattern which is the fingerprint we're looking for because the zinc interacts. Yeah, the metal itself. The metal itself interacted differently with the organic residue which is just us

touching outside of the brass bullet casing. Where he's like, let's just pump it. and then it just shows up. I know that's like a bastard, but that's so... I think that's pretty cool. That's pretty cool. In and of itself.

Yeah, the problem is it works on brass because it requires this alloy, right, of copper and zinc. Yep. Well, now, I mean, I think there are now casings made out of steel, stainless steel and things like that. It's not going to work there, right?

It's not a universal solution. The chemistry is not going to work with the iron. Yep. And the carbon that's in the steel. Okay. So what these guys did was use a process called cyclic volatometry. So you start with an electrochemical cell, which is a three electrode setup.

You've got a working electrode. In this case, this is going to be our brass casing, the thing that we want to actually test on. There's going to be a counter electrode, which basically completes the circuit. And then there's a reference electrode that keeps the circuit at a certain voltage. And you've got, so imagine you take your brass casing, you put it in a chamber with a bunch of electrolyte around it. So chemically conducting water effectively. you attach a electrode lead to it, you have other leads,

and now what you can do is start turning on the voltage very gradually. Okay? And that's called cyclic voltometry. You turn on the voltage extremely gradually, and what you do is you measure the current. There's going to be a blip in the current. There's going to be a peak in the current, and that corresponds to something called the oxidation potential.

Effectively, there's some current that is going to allow a chemical reaction to take place on that surface. Okay? Once you tune it to that peak current, you can keep that current as low as possible. So you don't make any other weird chemistry that's happening. And really tune it to that residue that you want. Right.

And this is the ash that's been left over after the casings come out. Right. So you're at a low enough voltage where you're not destroying anything, you're not causing anything else to start destroying the ash that's there. You're only tuning it barely to that ash itself. Okay? Barely to that ash itself. And what ends up happening is you get these two polymers called E dot and P.E.

It doesn't matter what they are. The effect is they're polymers that are long chains, but still really, really small in terms of, you know, every day. But they're like a single chemicals. And what those single chemicals are going to do is, When this chemical reaction is happening, this oxidation reaction, the chemicals are going to get deposited on the ash. Okay? Oh, actually, no, sorry.

They're going to get deposited on the metal, and they're going to leave the ash alone. Okay. Because the ash is going to be insulating. I got you. I should say that again. You stick the electrode in, you charge up the casing. Yes.

That's going to have a bunch of carbon ash and residue on it. That ash is going to be insulating compared to the metal. So the chemicals are going to get deposited on the metal, but leave holes where the ashes. It's like the opposite of the tracer stuff that they put in mice when they're trying to test them to follow it. It's like the opposite imprint of like that content. Exactly. Exactly. What's left is what we're looking for. Yes, exactly.

And so now we have a way of actually doing this, right? Now, why is this better than the 2008 method? Okay. For one, I can do this on steel. Okay. Right? I don't need the brass, zinc,

and all that stuff. The other is you get a lot higher resolution on this. Okay? This E. Dot thionine method consistently yields grade three visualization.

I didn't know this about fingerprints. With fingerprints, there's level one pattern, which is the fingerprint itself. The level two pattern is the detail on the ridges. And the level three pattern is within each of our ridges.

There's little pores. That's crazy. where the pattern of that poor is also unique to each individual. Okay. And so to really like start getting something that I can admit in court and all of this other kind of stuff, it would be really nice to get level three patterns because sometimes level two patterns. Like let's say you have like just the edge of someone's fingerprint. Well, that edge could maybe match to somebody else's fingerprint and things like that.

But if you have the edge of someone's fingerprint and you have the pattern of the holes, that's now extremely hard to match to erroneously. Yeah, yeah, right? And so this current method actually lets you resolve those pores with these micro deposits, right? You've got a mechanism to now actually visualize those pores with those electrolyte contacts. And this is from the paper, you can see very clearly,

the pores and the ridges. Yeah, right? And this is at tens of microns of resolution. That's the other key that's very different. In the 2008 method from Dr. Bond, he used a conductive powder. That powder, the size of the powder is bigger than the pores. That's your limiting factor for resolution. Here we're doing single molecule deposition.

Right, right, right, right. It makes total sense. This is so, I'm just like been out of shape at how clever. conceptually. Like people think about this stuff. Yeah. Yeah. Yeah.

And then put it in a, and then put some electrolytes around it. Yeah. And then we know, because we know the other aspects of this chemistry, we can just into it, right? Yeah. This should probably work.

Yeah. And then when you do it and you see the, you know, the example image we just looked at. That's a sick image. Where it's getting the level of detail. Oh, sorry, not this one, but not number eight. Where we now see in the real world, that detail difference.

Yeah. I mean, like, again, even as sort of someone who's maybe not in France, you could understand why you would want something with this, the level of fidelity on the right. Yeah. Versus on the left. Yeah, yeah, exactly.

And then it's pretty awesome. It's pretty cool. Yeah. The other cool thing that they did was actually like, so, you know, your casing goes in. Yep. In order to maintain a uniform electric field around that casing during this electrochemical reaction,

they had a custom built cylindrical chamber that would sort of make a uniform electric field. Because if you put it inside a box, then the edges, the edge effects are going to be different, and you're not going to get the complete fingerprint around the thing. So now it moves to a place where, okay, if we want to implement this in industry, for each different size of casing, we should have different size chambers to actually do this reaction. The other cool thing about this is the Dr. Bond method took 2.5 kilovolts. that's not something that I can like

hook up to my car battery and like right this thing takes less than one 0.1 volts so this could be handheld by the crime fighting units yeah yeah yeah I wouldn't think if you do it on site you wouldn't necessarily have to send it to a lab

yes and then you know with that stuff timing is everything yeah that's actually a really big deal so so there's a lot of really new stuff that's happening now before it actually gets implemented it needs to passed something called the Dobert standard, which is the standard that they have in forensics

before you can admit something in court. Like DNA testing had to go through this, things like that. It relies on testability. You got to have peer review. They already have peer review with this paper. You got to figure out what the error rates are among a general population, like not just, let's say, white males, but okay, how does it work with women? How does it work with different races?

things like that. And generally to accept everything, all of these things have to be checked. So that's the next step. It's sort of like the regulatory process or the governing standard for this moving from being something that is interesting and people could utilize but not then be admissible in court to it being able to be used

to actually say, you know, as evidence that someone is the shooter. Yeah, exactly. And one last thing that I want to talk about is the fact that they can actually do old casings as well. They tried to do a fingerprint from a 16-month-old casing, and they were actually able to recover a fingerprint.

Which is, you know, so this isn't like just now. They could be going back. This is okay. Yeah. Look. So if you thought you got away, I don't know. Yeah. That's actually a very important detail.

Yeah. Because it kind of, you know, I think because, for example, if for all the fans of true crime, podcast, etc., With the advent of DNA testing, a lot of cold cases have been reopened. Yeah. And, you know, people have started to, you know, get caught for stuff they did ages ago. Yeah. This is another.

There's another one. Another lever that could unlock a lot of stuff there. Yeah. I mean, there's a lot of recent cases I can think of where this existing would have been value. I mean, Meg the stallion and had a case with that little rapper that I can't remember his name right now who's in jail. And like it has this issue of they fingerprinted the gun, but, uh, they, not the casings.

Oh. Okay. Yeah. And so like that would be a case where it would be interesting. Another one is obviously the recent unfortunate assassination of Charlie Kirk. Like, yes. That would be an example. Yeah.

Where like this would really go. Because there's a lot of issue. Right. About the weapon and the suspect and all of the kind of the timeline doesn't. Yeah. quite, yeah, yeah. So, I mean, this would be another, you know, an empirical thing that would be valuable in that context. Yeah, I think, I think, it's a very cool use of just fundamental electrochemistry or a problem that's been around for ages. Tori Lanes. I had to say the name

because I was going to be mad if I couldn't remember it. That was, yeah, it's a stallion and Torilands. Yeah, okay. I didn't forget, guys, it's a little brain fart. I got it, I got it. I don't know I don't know who either of those people are. It's funny because it was very, on TikTok, it was a very, anyway, story number two, our first forensic story, we should do more. Yeah, we should do. Yeah. That was, that was cool.

A nice little true crime vibe. And so again, we have now a new way to identify fingerprints from fired bullet casings. This is out of my new university in Ireland, and it was in forensic chemistry. We're going to move on to our last story. We've done a lot of health-related or health care-related stories just because science is having an absolute just tear, I think, on just some of these new... Wishing you could be there live for the big game,

soaking up the atmosphere in the crowd. But too often, life gets busy. Or the price holds you back. Price Line is here to help. you make it happy. With millions of deals on flights, hotels, and rental cars, you can go see the game live. Don't just dream about the trip. Book it with Priceline. Download the Priceline app or visit Priceline.com. Actual prices may vary, limited time offer. When you need to build up your team to handle the growing chaos at work, use Indeed sponsor jobs. It gives your job post

the boost it needs to be seen and helps reach people with the right skills, certifications, and more. Spend less time searching and more time actually interviewing candidates who check all your boxes. Listeners of this show will get a $75-sponsored job credit at Indeed.com slash podcast. That's Indeed.com slash podcast. Terms and conditions apply. Need a hiring hero? This is a job for Indeed sponsored jobs. Models, new detection mechanisms.

And so this last story is about Alzheimer's. Yes. And we have sort of a paper in nature, icon school of medicine at Mount Sinai, Max Planck Institute for Biology of Aging and the University of Cologne seem to have a new detection? Yeah, it's a new type of immune system. It's a new type of immune cell that they found in the brain. And even that is kind of, let me be very careful.

It's not a new type of immune cell because we already knew the microglia existed, but it's a state that the cell is in, that is very important for mitigating Alzheimer's. And we're honing in on what exactly that cell needs to be in order to help Alzheimer's not happen. Okay. Got it. Got it.

Alzheimer's is an incredibly difficult disease. Okay? Incredibly difficult. There used to be this thing called amyloid hypothesis, where the basic idea was there's a protein in our brain called beta amyloid that misfolds, starts aggregating, and then starts creating clumps. And then those clumps are what get in the way of neurons. They start killing neurons.

They start killing synapses. And then that is what leads to Alzheimer's. That's been sort of shut out by a lot of recent evidence, suggesting that that might not actually be the case. Okay. So the hypothesis is basically there's a blockage that starts growing. Yeah. And then that's what impacts the brain activity.

this growth of this blockage. Exactly. And now we're slowly shifting from there's this like protein blockage to there might be an innate immune system in the brain that might be failing at doing its job. That's the shift that we're sort of in the middle of actually right now as more and more papers come out. I think I know where this is going. Okay.

And so the core study that came out in nature, first author Ayata, lymphoid gene expression supports neuroproductive microglia function. What they've, what they found is a novel immune-like microglial state that, and they've identified exactly the transcription factor that is required. They've identified exactly the genes that are involved in this microglial state. And they've identified how those genes and those transcription factors create the downstream effect of mitigating Alzheimer's. So it's top down all the way.

They have a full map. They have a full map of how it's happening. And it's very, very cool. Very interesting. Okay. So let's start with Alzheimer's, right? It's an evolving landscape. Alwaal Alzheimer's 1906 described these senile plaques and neurofibrillate tangles. And the field of neurodegradation has been intellectually sort of focused on these plaques.

You can see the really dark plaque in the middle of brain tissue. That's going to just get in the, way of stuff, right? Then we started targeting immunotherapies that were capable of stripping the brain of these amyloid plaques, right? And those had only modest effects on cognitive decline. And that suggests that these plaques are like kind of a match that starts a much larger fire. Okay?

There's something else downstream of the plaques that's really the cause. There's something more fundamental. Yes, exactly. And that thing that is more fundamental, people thought, could be neuroinflammation, which is the inflammation of the brain because of stress, because of an immune response. Effectively, it's kind of like an autoimmune response, but local to our brain. Okay. Okay. There's the immune system itself that's supposed to be cleaning everything is now in a stage where it's just attacking all the time.

Okay. So there's some genetic evidence for this because a vast majority of the same. the late onset Alzheimer's genetic risk. Like, we can tell because some people have Alzheimer's and others don't. We can look at what the genetic mutations are. All of those are targeted on these things called microglia, not neurons. Okay. Those genetic loci are activated in microglia and not in neurons.

So that's telling us that the riskiness of the Alzheimer's, at least from a genetic standpoint, is happening in the cells that are the microglia, not on the neurons, right? Not on the computation, but on these housekeeping cells that might be acting up. Yep, yep, yep. Microglear are a specific type of cell. They actually originate in the yolk sac, the stem cells in the yolk sack back when we're in embryo.

They colonize the brain act before the blood brain barrier forms. Oh, okay. So they get inside and then the blood brain barrier forms, and then they maintain themselves within the blood brain barrier. So they don't come from the bone marrow, like, other immune cells do. Okay. They're sort of innate in the brain and they stay in the brain. Okay. Okay. So another big reason why it's hard to access these things is they're inside the blood brain barrier, right? Right. So you can't really like poke it with drugs and things like that.

And a lot of times they're basically in homeostasis. So they're doing their normal thing where they're moving around. They're cleaning up byproducts. They have these things called processes, which are, if you've ever seen immune cells like in real time, they'll like protrude out. They'll have these arms that stick out. And they're basically just surveying, right? They don't have eyes. So they're using these protrusions to increase their surface area and sense the chemical environment. And if they sense something that's bad, then they go into a state of response, where they try to eat whatever thing is bad or they try to deal with the plaques and stuff like that.

But if you have too much of that, then that's going to destroy the neurons around you as well. Right? So if you have too much upregulation of that state, that's pretty bad. Right? And what ends up happening is you've got this aggressive amyloid deposition that happens in, let's say, mice models, right? Yep.

This is something that mimics the Alzheimer's. so you've got a neuron in the middle and all of these plaques that are sort of getting in the way of the neuron trying to do everything. Yes. And if your microgle cell, like actually senses some of these plaques, senses too much of the plaques, or just has this upregulation and can't downregulate, then it's a runaway reaction of immune stuff that's happening in our brain. So what we're sort of getting at here is this idea that these immune cells might be overactivated based on some stimuli. And that overactivation is actually the driver for the neurodegeneration.

Yeah, it could be one of the drivers. One of the drivers of the decline in cognition because now it's these arms that are going to pick up stuff are just everywhere. Yeah. Doing too much. Too much. Doing too much. Yeah.

Pick up too many people off the street. Yeah. And when they're doing too much, they're not doing their original job. Of like cleaning the plaque and like compacting it and all this other kind of stuff. It's like if the janitor became a vigilante at night at the building. And so instead of doing the normal janitor stuff. Yeah. Now the building's falling apart while the janitor's going to be a vigilante.

Yeah. Yeah. And he's not going to have vigilante either. It's like, bro. You know? Okay. So they had a bunch of different methodologies that they used, which was quite cool. They used a mouse model, and the mouse model mimics the adult Alzheimer's.

They also have this Kree-Lox recombination system, which what you can do is you can induce gene deletion four to six weeks after they're born, right? Usually you imagine with gene deletion, the deletion needs to happen, and then you create the life. form. Yes. But then you have problems because, like, what if the development is perturbed, right? Then you've created this defective life form. You're making conclusions and you don't know if it's the development or the actual gene

that's happening in the adult population. So here, this is a way to delay deleting a gene. And then it ensures that any phenotypes that are observed and anything that we observe in the experiment is due to a loss of gene function in the adult deceased brain. Because Alzheimer's is the adult. Yeah, right, right, right. It's not something that, you know, this gene is doing something bad once you're getting old. Right.

Right. And so that's what we want to mimic. So they were able to do that. They also have this, they, the other really cool thing that they could do was something called trap, which is translating ribosome affinity purification. The idea is I want to prove that the transcripts, the MRNA that's getting translated in the microglia. like so the instructions from the DNA into making protein those instructions that the microglia is paying attention to it's coming from the actual microglia and not because the microglia is like let's say eating another immune cell right because if the microglia eats another

immune cell well that immune cell is going to have its own mRNA and when I sequence I don't know if this mRNA came from me doing my own thing or me eating something else and then that food is what's getting transcribed. Right? So how do we make that distinction? There's this incredible way of doing it called GFP tagging where you take this green fluorescent protein. You tag a ribosome with it.

Okay? So the ribosome has attached this green fluorescent protein. And now the ribosome is going along and it's transcribing your MRI. You take that, you take those cells in that culture. and you have another part that attaches to the GFP, that green fluorescent protein, but that thing is attached to a magnetic bead. Okay.

And now with a magnetic field, I can rip only the ribosomes from the microglia, right? Because the magnetic bead is something I can use a force on. Right, right, right, right. And then I have, and the ribosome is going to have an MRI-N-A attached. Because it's in the middle of doing some job. Right. Now all of a sudden you like pick it up.

So it's like dragging the mRNA with it. And then you're like, okay, now I'm going to sequence this MRI. Right. That gives me an insight into the actual transcriptome of the immune cell rather than all of the mRNA in the immune cell. That makes sense. I'm actively looking at only the mRNA that is being transcribed into protein that's actually being put.

Yes. Yes. Yes. Right. I thought that's a really cool technique. I just, who, the way that folks think about this,

um, as like the solution to the problem. Mm-hmm. Because like, it makes sense you want to be able to know what is actively being translated. Yeah. Yes. And so you need to be able to track.

Like in order to be able to validate, like what is your process by which you can actually do validation? And it's a very clever. It's very clever. It's like, just like, do that. Yeah, basically tag the factory. Right. That's making the stuff.

Right. And so any product. And then drag the factory out. Right, right, right. And then see what's inside the factory. Right. So if you want only the cars in that particular, like, let's say city and you don't want all the cars that are right.

Being ridden around by the general population. You just tag the factory. Drag out the factory. No, yeah, that's, that's really good. You know? That's really good. It was very cool. So now let's get into.

It's funny. They call it trap too. Yeah. They literally call it trap. Yeah. A lot of times with these acronyms, they come, they, I'm pretty sure they start with the acronym. And then they're like, okay, what are the words? 100% that like can make it happen.

I like trap. Yeah. And then they put down, okay, in the lab meeting, trap. Translating. Okay, that works. Yeah. Rivas. Yeah.

Yeah. Exactly. So, fun. So let's get into what they actually found. Okay. Okay. They focused on a transcription factor called PU1. Okay.

A transcription factor is basically something that gets attached to the DNA and promotes RNA polymerase, which is the factory that creates M RNA to actually transcribe a gene. Okay. So this is how we get from gene to MRNA. RNA to protein. That first step, you need something called the transcription factor to get where that DNA is, bring in an RNA polymerase and be like, all right, you need to start here, look for that start code on, and then start transcribe. The transcription factors like identifying

like where the things need to happen, like where the polymerase needs to come in to do stuff. Yes. And each gene usually has different transcription factors. So this particular one, this gene, SPI-1, has a transcription factor. P.U. 1. Okay. And different genes have different transcription factors. These transcription factors have different affinities, right? There's some that'll bind immediately. So even at low concentration, it's going to find that bit of DNA and bind. Those are usually the housekeeping genes that you can't live without. Okay. Those are the ones that like, it's like, how do I, how do I make sure that I stay alive as a cell? Okay. Then there's stuff that have to do with function,

specific states. Like this P.U.1 gene is the one that is controlling whether microglia go are chilling or if they're doing the vigilante stuff, right? And what they found was that when microglia were in the plaque environment, that plaque environment actively enforces low PU1. Okay. It's very counterintuitive. Okay.

You would think that, you know, I want like super a lot of inflammation and a lot of police around my plaques. That's not what's happening. What's happening is near the plaques, there's a downregulation of P.U.1 of that transcription factor, which is already a first clue that perhaps we don't fully understand this ecosystem of what's happening, right? So then they actually used, they used a bunch of tools to figure out what is the signal transduction pathway that goes from, I sense a myeloid, I sense my plaques, to I downregulate PU1.

And they use some knockout versions of mice to actually link all of these signal transduction pathways together. They also showed that there is an upregulation of a T-cell associated gene. Okay. Okay. In those low P-U-1 populations. So when there's low P-U, right?

Yeah. Right. There's this, there's a T-cell gene. There's a T-cell gene that now more frequently arises or is, or proliferates because of that low population environment. Exactly. And what they think is happening is when you don't have that transcription factor or when you don't have a lot of that transcription factor, the chromatin around that part sort of relaxes. And it exposes some of the genes. And one of these genes that is exposes is CD28, which is a neuroprotective master switch.

You might recognize CD28 from our Nobel Prize videos. I was literally going to say. OK, CD28 is the gene that sort of regulates T cells from becoming normal T cells to T regulatory cells. Right. So that same gene, that same part of the gene is also having a role in microglia in the brain. That's actually crazy. So it's like the brain is, the, these cells are borrowing a motif from innate immunity elsewhere in the body and saying, well, I can actually use this for my own gains over here. Right, right.

For this, this function, which ultimately sort of generates this new protective master switch. Yeah. And so, so the idea is because if we come back in it, because I just want to make sure I'm tracking here. Yeah. So we have this, we have this mechanism by which the, you. The microglia is, we don't want, when it's close to these plaque regions, it is less active. Yeah, it's the PU1. The PU1 is less active.

There's not enough PU1 in the cell. Right. And that, because of that, that induces. Yeah, then the chromatin sort of relaxes. And now parts of the DNA get exposed and one of the parts that gets exposed is the CD28. And that one is sort of This is that neuroprotective master switch Which is so like we can sort of it's like the Tylenol button

It's like go fix and make all my problems go away Right and because of that low PU It is what helps to release more of that Yeah And so what you don't want to happen is that process to get Prevented Yes Because that is potentially then what is causing the neurodegeneration

Exactly Because we're not basically, you know, releasing the Tylenol response. Yeah. Yeah. And so, exactly. That master switch is the switch that is controlling the cell fate of these microglia. That's turning it vigilante, janitor. That's okay.

You know? Yeah. And so if we can control that and we can have therapies that now that we understand this entire chain of all of the stuff that's happening, we can actually, you know, maybe do something. Right. Right. And so these microglia are now, you know, they're calling it the T-Regs of the brain. T-Regs being, again, the thing that won these three scientists, the Nobel Prize in. The military police. Yes. The police of the police, right? The system that by which that regulates the things that regulate your body can in and of itself break down. Exactly. And maybe that's what's happening in these Alzheimer's brains, which is causing these, these.

runaway effects that we see as symptoms. But maybe this is the cause, right? This is, or one of the causes. Obviously, Alzheimer's is extremely complicated, right? And there's probably multifaceted genes that are happening all in an environment. But, you know, step by step, we're getting, you know, closer to understanding what is really going on. And they are called the T-Regs of the brain because it's very similar. They've got a very small population, just like regulatory T-cells, dominant suppressive effects.

So they suppress immune responses. just like the T-Rex. And then they're also dependent on the CD-28. The same gene. The same gene is in both. I understand the connection to T-Regs because the deep dive we did for the Nobel Prize, we went really, really deep on.

And it is definitely worth watching in the context. We have so many throwback connections to past episodes in this one. Because I can now much more intuitively translate in my head the idea of it being T-regs of the brain because of understanding the function of regulatory T cells and the immune response and why a breakdown in the regulatory T cells can sort of be a driver for like problems that we see arise. So like you can map it's a very direct. Yeah, very directly map to this

problem set. Just in terms of the framework of how to think about it. Yeah. Obviously understanding I think it's as a combinatorial problem set. There's multiple blah, blah, blah. Exactly, yeah. But very, very interesting. But it is, it is very cool. And they use not only mouse models. They also had human brain tissue.

Okay. And the same results were in the human brain tissue, which is very important. Obviously, you can't do the in vivo effects and things like that. But on the tissue as much as you can sort of express one thing, express the other thing, all of this stuff tracks, even in humans, right? The one really cool thing that I thought they did, was they used hippocampal tissue, and they looked at something called LTP,

which is long-term potentiation. This is the idea that synapses will grow and shrink based on how the neurons are talking to one another. This is the physical mechanism by which we learn. Like when we say the connections are strengthening, literally what's happening is the size of the synapses, the connections, is getting bigger and smaller. It's increasing in surface area,

and that's causing the connection to get, Strengthened. This is something that doesn't happen in Alzheimer's. Okay? So what they did was they used these brain slices and they showed that if they have these manipulations where they downregulate PU1 and then the CD28 comes on, stuff like that.

You can restore this LTP. You can restore this ability of the hippocampus to start forming connections and have a dynamic way of expanding connections, contracting connections, and so on and so forth. That is very intriguing. So there was a mechanistic link here. Right, right.

To straight up learning. Right. That is tied to this process. And the hippocampus is the center for consolidation of memories, right? And the access to the long-term memories and things like that, right? So having this happen in hippocampal slices is also super, super important to show that, you know, this could be a target for therapies in the future. And because, you know, the idea would be.

you want to try to target to the lowest level of abstraction possible. Yeah. And because of like this, again, analogy of T-Rex with the brain, this seems to be an interesting place to target because it has so many derivative. Like it's like it's at the foundation and then that is going to impact processes that happen at a higher order's and all that. So that is interesting. Yeah, yeah. So now when we look at translational horizons, it's promising, but we have to be very, very

careful. Okay. One way to think about it was, okay, what if we just, okay, it depends on CD28, right? What if we just like stimulate CD28 and we boost these populations? Yep. That sounds simple and biology is never that simple. There's actually this really famous disaster that happened in 2006 when it went to phase one trials of doing exactly this.

This wasn't in the brain, but this was in the body. They were trying to stimulate CD28 to get the autoimmunity to go away and things like that, get the T-Regs to come back. This is called a TGN-1412 disaster. Six patients, it resulted in cytokine release syndrome in all six volunteers, multiple organ failures, because basically all the T-cells just got activated. And then it didn't care that usually the T-cell is presented with some kind of antigen, and then they act.

They just started acting. And it was really bad, right? So we have to be very careful with messing with the immune. system, right? And you could have something called specific antibodies, like by specific antibodies, where it targets not just CD28, but it also targets something that is very specific to microglia. And you need both. It's an and, not an ore that, like, makes this thing. Yeah, activate. Activate. Perhaps that's one way of doing it. You got to have brain penetrating vectors that go through the blood brain barrier. That's always like, if you know,

because now something's in my brain. I don't, like, the brain is, if that thing also matches in shape to some other random thing in my neurons, then what's going to happen? So, like, trying to create translational therapies is one thing, and that's its own, like, bag of, yeah, can of worms. But understanding the mechanism itself is the first step, right? The fundamental science needs to happen first, before we start saying, okay, what part of this pathway can I poke?

We have to figure first define the treasure map and then we can figure out the plan of how we're going to go get the treasure. And now we have an interesting treasure map that is specific issue that again also might have insights that are connected to other related topics. This is such a great piggyback off of our T-Regs episode. Yeah. Yeah. I think it's a pretty good story. Right. It shows just how complicated the brain is.

Right, right. Like the brain is not just neurons. It's blood vessels. It's immune cells. Those immune cells have been there since forever. Since we were born, right? All of these microglia are just hanging out in our brain. And we're not getting any new ones.

Right, right. Because they can't go through the blood brain barrier. Right, right. Because it stops at some point of that development. Yeah. It's so good. This is so good. So this was a, and,

And kudos to, you know, another multi-institution. Yes. Nature paper. Yeah, multi-institution, multi-country. Multi-country. Yeah. You know, again, with Icon School of Medicine at Mount Sinai, Max Plaque Institute for Biology of Aging and the University of Cologne.

I mean, this is, again, people are working really hard. Like, obviously, we lose a lot of people to. Yeah. Alzheimer's every year. Yeah. It's the next frontier. It's the next frontier. it's going to be hugely impactful if we can sort of take this and continue to iterate to the

point where hopefully we again we don't want to have another TN you know issue. Yeah, disaster. But we have better tools now. We have better understandings. Yeah. And I think we learned a lot from that disaster on how to start phase one trials for immunology. Maybe we do a lot more testing in vitro before going in vivo into a human at least, you know. But the other thing with this kind of stuff is it's incredibly hard to, because this is such a unique sort of late stage evolution problem.

And what I mean by that is a lot of these problems with Alzheimer's is something that happens because the human brain is the most recent organ to have evolved. A lot of the mutations that are different that make us different from the chimpanzees. have to do with neurodevelopment. I mean, uh, duh, right? But what that also means is the locations, the location,

the part of our genome and the part of our brain that is so new also means there's a lot of stuff that can go wrong, right? Because it's kind of by design. Right. We're still evolving this thing. Yeah, yeah, yeah. Right?

All of a sudden, we kind of put evolution on pause because survival of the fittest isn't the same in the classical sense anymore. We're not having 20 kids and then the smartest ones like, you know, we're a completely different animal now where the evolution that's happening in humans

is now not something that is in Darwin's origin of the species. But the genetics doesn't know that. Right, right. Our genome doesn't know that. And so the mutation rate is still really high and the genome is still kind of experimenting with what the brain is doing, right? And that's going to cause all of these failure mechanisms. Right.

So it's really hard to find, you know, you can't just, with heart disease, you can sometimes even take a pig's heart, put it into a human and it'll work, right? Can't do that with the brain. Yeah, right, right, right, right. It's like, it's actually a really good. Like it's, you know, it's because it's by design the most recent organ, it's going to have these failure modes that are just way more complicated than normal. God.

Yeah. And also the accessibility problem. Yeah. Like, it's kind of hard to get in there. Yes. As compared to the rest of the body. That's just another layer of complexity. Three great stories this week.

We touched on a review of Three-Eye Atlas, which is the most demanded story. Yeah, yeah. And it is what... I hope you're happy now. Another wicked reference. And it is very similar to what we said in our original coverage of it. Yeah. It basically...

It's a weird comment. It's panned out exactly the way we described it the first time. What are the things that were going to be weird? What were the areas that still needed more information? We discussed about why we would be able to get stuff on from the Mars orbiters. Why it wouldn't be that good. Yeah, we talked about it. The guys were like, guys, you guys know it's not going to be that good.

We brought it up. This was months ago at this point. But again, still so much to be learned. Yeah. We followed that up with the fingerprint story, which is so clever. Yeah, that's clever. That one is this clever. We can now pull fingerprints off of fired bullet casings.

Yeah. And it works retroactively. Old stuff does, works for that too. Yeah. At least 16 months. At least 16 months. And they, I don't know. We haven't pushed it.

And they're going to push it. Oh, there are. They're going to push it. And then we finally ended with a great story about a better understanding of the different states that are helping us. better understand how Alzheimer's, sort of the process by which it begins and a potential pathway for us to think about therapeutics to try to address what is one of the most prevalent

neurodegenerative diseases that we're seeing in the human population. I'm ready for some good food this week. I'm going to eat a lot. Thanksgiving is always, you know, my birthday is that. the same week as Thanksgiving. And so it's always a little bit of,

I have to be thankful when we're supposed to be celebrating me. Right. That's funny. Like, why am I, this week is supposed to be about me. Yeah. But I get food. They should be thankful for you. Yeah, that's exactly right. But it'll be, it'll be good.

I'm excited to travel. You're going to have a little bit of time. Hawaii. Good time in Hawaii. That's going to be great. After three weeks of rain here or whatever it was, to get to some nice weather for a little bit. As always, we really appreciate the listeners,

especially those of you who get to the banter at the end, who reach us all the way here. We are going to have a couple of more episodes through the end of the year, and we may do some best of coverage for the end of year wrap-up. So if you're interested in us choosing our favorite stories from the year and doing like a huge summary,

kind of top 10, top five, kind of video in the comments wherever you see this put that we want to see best of if you made it this if you made it this far you know put some stuff in the comments yeah yeah give us ideas for the next month yeah we we want to try to do something for the holidays we think we want to do top 10 or a top best of kind of list to wrap up the year but let us know in the comments I'm your host Lesterneri joined as always by my co-host and our resident PhD Krishna Chowdry for another fantastic episode this is from First principles.

Enjoy more ways to save at Ralph's, like low prices in every aisle. And when you download the Ralph's app, you can clip and save more with digital coupons every week. Plus, you can earn fuel points to save up to $1 per gallon at the pump. At Ralph's, you can enjoy more ways to save and more rewards every time you shop. So it's always easy to save big every day with savings and rewards. Ralph's SoCal for over 150 years, savings may vary by state fuel restrictions. apply. See site for details.

Own it all. Pay off your home, travel for life, drive a Ferrari. In celebration of the world premiere of the Monopoly Big Board Buckslot machine by aristocrat gaming, Yamava Resort and Casino at San Manuel is giving one person a $1.6 million dream package. The biggest prize in Yamava's history. Club Serrano members

can earn daily instant prizes and secure a spot in the finale May 29. Don't pass go and own it all. Only at Yamava celebrating its 40th anniversary. You win? Details at Yamava.com must be 21-20. Please gamble responsibly. Monopoly is a trademark of Hasbro. Hasbro is not a sponsor of this promotion.