From First Principles - Astrobiology’s Biggest Survival Test + A Vaccine Against Everything? (EP. 29)

Episode Date: March 12, 2026

Hosted by Lester Nare and Krishna Choudhary, this episode starts in astrobiology with a fresh experimental challenge to one of the biggest objections to lithopanspermia: can life actually survive the violence of being blasted off a planet by an asteroid impact? Then, after a packed Rundown, we pivot hard into immunology with a radical Stanford paper asking whether we could build one nasal vaccine that doesn’t target a specific pathogen at all—but instead makes the lung itself a stronger fortress against whatever shows up.SummaryLithopanspermia gets less crazy — a Johns Hopkins / PNAS Nexus study tests whether extremely resilient microbes can survive the initial shock of ejection from a planet, potentially closing the last major bottleneck in rock-to-rock transfer of life.The universal-vaccine idea — instead of training the adaptive immune system on one pathogen, Stanford asks whether the lung itself can be preconditioned to respond broadly and rapidly to many threats.The Rundown — AI for materials science, orbital nuclear conflict simulations, and other frontier stories the guys wanted to hit even without full deep dives.Support the showDonate: FFPod.com/donateFollow: @FFPod (X / Instagram / TikTok / Facebook)Show NotesLithopanspermia / impact survival (PNAS Nexus, Johns Hopkins)https://academic.oup.com/pnasnexus/article/5/3/pgag018/8503064Pathogen-agnostic nasal vaccine (Science, Stanford)https://www.science.org/doi/10.1126/science.aea1260

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Fit for your ambition for Citizens Bank. One of the biggest questions for humanity has always been, Are We Alone? And we may have just made a discovery that changes the paradigm about how we think about the answer to that question. So Sauron would be proud of this because Stanford has figured out one, vaccine to rule them all. I don't really trust humans with nuclear weapons, but I definitely don't trust AI. And this new paper is corroborating that very nice viewpoint that I had.

Hello, internet. This is your captain speaking. Lester Nare, joined as always by my co-host and our resident PhD Krishna Chowdery. We are back for another week of Science News. This week we have two phenomenal stories that we're going to talk. touch on. First, we're going to hit an astrobiology story, followed up by an immunology story. And this week, there's a little bit of a special surprise as our episode on the Dave Chang show, which will be on Netflix. We'll be dropping this week. So be sure to check that out.

We got some phenomenal food. Yes, from the goat. It was a great time. Shout out to Dave Chang and his team. Super big fan of science. A great example of how science is a great example of how science impacts all of us in curiosity. There is not a monopoly on curiosity about how the world around us works. If you're joining us for the first time, welcome. If you're returning, welcome back. As you know, we are a victim of the billionaire algorithm. So a like, share, follow, subscribe. All of that is super helpful. Our donation portal is up. Every episode is free and available on every platform and the support we have from the community is really huge for us to be able to continue to get the best breaking science news broken down here to you every week.

We are going to learn about the science from the ground up because this is from first principles. Our first story is on astrobiology, one of those fields that sits right at the edge of what science can currently say and addresses one of the biggest questions in humanity, which is, are we alone? And a new study just took one of the toughest organisms on Earth, simulated the violence of an asteroid slamming into Mars, and watched what happened. And the survival rates might genuinely surprise you, as they surprised me. This is in PNAS Nexus out of John Hopkins University on March 3rd. Yeah, this is Very recent. Fresh off the presses.

Yeah, very recent. And as you said, right, a core question that we ask as humans is, are we alone? Well, a follow-up to that would be, well, could life travel between worlds, right? Let's say that life started on Mars and then an asteroid impact hit it. The debris from that asteroid traveled the entire solar system between Mars and Earth and ended up on Earth. And that's what ceded life on Earth. this is the idea of lithopanspermia. Litho meaning rock, panpspermia, meaning this sort of like life everywhere type thing, right?

And for the longest time, it's kind of been just like cuckoo-woo-woo type science, been discredited. And this paper is really challenging a lot of the assumptions that we make about how unlikely this process is. The idea that life can generate in one place and then travel through the vacuum of space. to another place and then continue to flourish. Yeah, yeah, dude, it's, it's, it's pretty cool. They've, they've done some really cool experiments. This paper uses something called D. Radio Durans, which is a bacterium that colloquially is known as the Conan the bacterium,

because it's like indestructible. You know, like Conan the Barbarian? It's like indestructible. And what they've done is do experiments about what this bacterium could survive through. and it turns out it's a lot. Something like 14,000 times the atmospheric pressure on Earth. Substantial survival, even at really, really high pressures, even beyond that. And the conclusion here is basically that the initial pressure shock that you get from an asteroid banging into a planet that has life and ejecting that planet out, that initial pressure shock that we used to think would completely kill any living organism is actually not that.

bad. Stuff will survive and go into outer space. Okay. Now, why does it matter? Well, very recently, we've had the NASA Perseverance rover announce a discovery of potential life on Mars. Yes. We covered this in last year's podcasts. Now, finding that life requires determining the origin of that life, right? And if this is true, well, then we can start asking questions like, well, is that life coming from Earth or is it originated in Mars originally? This paper sort of shapes that interpretation. It's also got some impacts when it comes to like planetary protection. Because now if we know that life actually survives impacts,

goes into outer space and comes to Earth, like we got to be a bit careful about returning samples onto Earth. Because if we bring something back and it's got a little, you know, thingy in it, we don't want that. Yeah, and there's like plenty of science fiction movies about that, about how it can go really, really wrong. Hollywood has its ways of, you know, aggrandizing things, but it turns out it might actually be a real phenomenon. Very interesting. So, as always, let's start with the history.

This is actually an ancient idea, the Greek philosopher Anazagoras, Annazagoras, okay? Kind of like Pythagoras, but Anaxagoras. Maybe that's how you say it. Anaxagoras, 5th century. BCE. He actually is one of the first guys to correctly interpret what the solar eclipse was, like the moon is going in front of the sun. He's the first guy to do that. Fifth century BCE, so 2,500 years ago. He proposed the idea of spermata, which is seeds of life that are scattered throughout the universe. Now, the Greeks had a very rudimentary understanding of what the universe was,

but I still think it's quite cool that somebody that far ago was, you know, coming up with these kinds of ideas. The historical basis for the idea of panspermia really comes from William Thompson in the 1870s. This is Lord Kelvin. Lord Kelvin. Yes. He proposed the scattering of life seeds via like catastrophic collisions, this idea that we now have of like stuff going in, collisions, uproot material into space and then that material comes into Earth.

And then in 1903, there was this guy Svante Arrinius. I think any chemist in the audience would know about the Arrinius equation and all the great things that Svante Arrhenius did. But one of the things that he formalized was this idea of

radio panpspermia, which is the idea that microbial spores, which are small enough, at that time they had figured out how small in mass these microbial spores were. they could be propelled by the pressure of light to move across space. And so that was his idea, radio panspermia.

Now, in the 1900s, this idea was completely invalidated because in deep space, we now know, we didn't know about radiation back when Arrhenius came up with his thing. But now we know about cosmic rays and the solar wind and all the radiation and the dangers in space. So everyone was like, okay, unshielded deep space, you're going to have ultraviolet radiation. You're going to have this vacuum. it's rapidly going to sterilize DNA, so there's no hope. Right? Yes.

Then we started discovering stuff that could actually survive that. In 1956, Arthur W. Anderson discovers D. Radio Durans. This is our Conan the bacterium. I see. Okay. This is the bacterium that will survive anything. Okay. He was actually at the Oregon Agricultural College, and he was studying canned meat that he was trying to sterilize with gamma radiation. Gamma radiation is extremely short wavelength radiation,

extremely high energy photons. And so that should just kill anything. It should break every chemical bond known. And these, and the meat that he was studying spoiled anyway. And it didn't make any sense, right? It's like you put it into a freezer or like, you put it into Chernobyl and the meat comes out still spoiled. So there's something that grew in it. And when he isolated that, he came up with this bacterium called D-Radio-Durans. In the 1970s, there was also the discovery of hydrothermal vents. And so now you have life thriving in total darkness, 400 degrees Celsius, like way above boiling. It's still water because the pressure is so high.

But then again, the pressure is so high and life is still thriving. Yes. So it's very weird, right? And over the following decades, we've had an incredible catalog of extreme environments where life thrives. We have things called acetophiles, which are life that live in sulfuric acid. That's crazy.

They literally live in sulfuric acid at a pH near zero, which is worse than bleach, but they're just like living there. Hyperthermophiles that live up to 122 degrees Celsius. The record holder is something called metanopyrus candelary. Dude, 122 degrees Celsius is insane. I... Right. Again, high pressure, which is why the water isn't boiling. Water usually boils at 100 degrees Celsius at sea level, but if you do it at high pressure, the water's not going to boil. That's why a pressure cooker works.

That makes sense. A lot of really, really crazy things. Halo files, they flourish in salt concentrations that are five times out of sea water. You can see this in the Dead Sea. You can also see this in Halo players who eat a lot of Doritos and chips and ruffles. Yes. Halo files, as those who might not know. I used to be a halo file in high school Mate, I loved Halo Let me tell you something

Halo 2 and Halo 3 Oh yeah No competition No competition Like I, it was very serious Oh my gosh dude It was very serious It's one of the only games

Blugolch Yeah, like what? Yeah, yeah And I remember it was back in the day When like there wasn't really internet To host Yes These collaborative parties

So you had to go to your friend's house Yes And I remember in the valley there was a friend's house that I used to go to. And he had a TV in one room and a TV in another room. And we used to do like co-ops of four, four versus four. Oh, my gosh. Land parties?

Land parties? Yeah. Before Xbox Connect, before Xbox Live, we'll go back to the story. But this is our history. So we will give it the due respect. Yeah. Halo raised so many, so many millennials in that era. Yes.

And we are one of them. Halo files. Yeah. In this case it means salt, but for us it means something totally different. So effectively, there's a lot of extreme environments that life thrives in. Right. So now it's no longer the case that life needs this like perfect setting. The Goldilocks.

Yeah, the Goldilocks stuff, right? Yeah. And one of the big things was in 1996, Bill Clinton announced possible ancient Martian microbial life in a meteorite that they found in Antarctica. in 1984. I have to ask because you did such a good job with the JFK impression. If you could,

oh yeah. So he goes, he goes, he goes, I did not find life, but I think we found it. But I did not have sexual relations. USAA knows dynamic duos can save the day like superheroes and sidekicks or auto and home insurance.

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You can watch the record-breaking phenomenon at home. You're clearly. We're going to add. Zootopia 2. Now available on Disney Plus rated PG. Anyways, there was a meteorite in Antarctica. They found possible ancient life on it. It was published in science.

Immediately everyone was like, no. Immediately no. Immediately no. Like, it was largely refuted. But the rock transfer, the fact that that meteorite came from Mars is actually not disputed. Meaning, meaning that the origin on Google Maps, its original starting point is Mars. That everyone's fine with. The fact that there's life on that meter right, that's what everyone's not fine with.

Okay. They saw little structures that kind of looked like bacteria and so on and so forth. They didn't have enough evidence. But it really started this question of could life survive the journey from Mars to Earth? Because now we have evidence that it can happen. That it can happen. We definitely found a Martian meteorite. And, you know, it looks like there's some weird stuff on there.

And so that gets us to this mechanical challenge of planetary escape and then getting to Earth. Okay. So there's three bottlenecks when it comes to panspermia. Three things that prevent it from being realistic. Yeah, happening. Yeah, exactly. The first one is the impact ejection event, right? You get an initial shock, an asteroid impacts you.

That's going to cause a bunch of pressure over Microsoft. seconds, and it's going to eject stuff into space. You've got to survive that impact. Okay. Once you survive the impact, then you've got to journey through space. Millions of years in a vacuum, there's cosmic radiation, there's extreme cold, there's UV, right? And then at the end of the day, after you've done that journey, you've got to survive reentry. Okay? So you have to be big and bulky to survive impact. You have to have endurance to last a long time and maybe more also endurance

and being big to survive reentry. Exactly, right. So the two and three, which is surviving space and then surviving reentry, that's actually been explained by something called Expose, which is a facility on the International Space Station.

What they did was they had certain organisms and spores that they put out into the deep space. right outside the International Space Station. And it turns out these things can survive prolonged space exposure if they're shielded by a few millimeters of rock.

So if your life is just a few millimeters underneath the surface, yeah, underneath the surface of whatever asteroid, it's going to survive not only the vacuum of space but also the reentry into Earth. That's actually quite... I think if people were to try to guess, if you have a piece of rock floating through space

with little thingies, little micro-thingies on it, how deep do you think it needs to be to be able to survive? I think very few people would have guessed millimeters. You would think you need a little shielding, you need a little shielding, maybe a couple inches, maybe a couple feet yards. So you don't need a lot. That's actually really incredible.

The interior of the rock actually heats minimally when you go into atmospheric entry. That's the idea. Okay. And they actually found that this particular bacterium D-Radio Durands, it was already, it's like survived space-like conditions and it's the best at it. Okay. Okay.

And so this particular paper that's coming out of Johns Hopkins, it is targeting bottleneck one, which is the idea of can it survive the initial ejection event? Because we already know it can survive outer space and re-entry. We need to know if it survives the ejection. So it can survive two and three of the very bottlenecks. We have every... data, experimental data, that shows that to be true. It's not theoretical.

No. But number one is still... Number one is still, yeah. Like, it's like, if there's life on Mars and I hit it with an asteroid, by the time it gets out into outer space, most of it should be dead. That's the prevailing theory. Okay. This experiment is putting that...

It's challenging it. Okay. Right? Science is always a process. Yeah. Sometimes... I mean, dude, it's a totally reasonable thing. Yes.

A meteor impact is like several atomic bombs. Yes. Okay. What are we talking about? 100%. Right. 100%. So, okay, let's talk about this elusive bacterium D-Radio durands.

Okay? Why is it the right test subject for this avenue of research? Okay. Well, for lethal dose for a human being, lethal dose being like, you know, 50% of us are going to die. It's about four grays. Gray is like the unit of radiation that you get. Chernobyl Glenn. I just wanted you to know that,

I don't know if you knew this, that grays are one of the species of aliens that people think are visiting Earth. Oh, really? The four-foot ones that have the big eyes. The classic. So only four of them will kill us. Okay. According to...

According to... According to what we've done radiation studies on. Four grays will kill us. E. coli takes 70 grays. Okay. Okay. D-Radio Durant's takes 15,000. Yeah. So it can survive 3,000 times the human exposure and 200 times the E. coli exposure.

This thing is insane. That's why it's called Conan the... The Barbarian. No, Conan the Bacterium. The Cone and the Bacterium. Yeah. So even those four-foot aliens, yeah, 3,000 times the dose of those four-foot aliens. Yeah, that's how they got here. That's how they got here, dude, on the backs of Radio Durants. Now, why is that the case?

This bacteria is amazing. Okay. Okay. For one, in terms of DNA repair, it's got astonishing fidelity. Okay. It reassembles its genome, which can be shattered into hundreds of fragments by radiation within three to five hours. That's unbelievable. Like, I dose it with 5,000 grays, which is, again, a thousand times what humans can take.

within three to five hours its genome is back. It's like this science fiction thing. It's unbelievable, especially after the episodes we talk about how our genomes are DNA degrades over time. Yeah, yeah, naturally. Naturally.

This thing has repair mechanisms in order to just keep itself alive. The ring structure of the nucleoloid is a big part of it. The DNA is actually packed into a torus. It's like a donut-style shape. So it keeps the fragments physically close together. Versus a double helix.

Yeah, well, no, It's still a double helix. But it's rounded. Double helix is wrapped around in a torus. Which gives it a little extra. Yeah, it's sort of not like in a soupy. Like most bacterium, the, the chromosome is like in this like soupy non-structure form. This one is in a nice toroid.

Okay. So it's got physical proximity for easy reassembly. It also has multiple genome copies. Every single one of its cells has four to ten copies per cell. It's like that stuff we were talking about with GitHub. Yes. It's got several branches. Yes.

So if one single branch of your GitHub is like messed up, it can use the others to actually figure out how to repair itself, right? Exceptional DNA repair. One of the other cool things is it has extraordinary antioxidant defense. In 2004, there was a paper that came out in science that suggested that, you know, over the course of radiation, you're going to have these things called reactive oxygen species. Oxygen is incredibly reactive. That's why things rust.

right, iron russes in normal atmosphere conditions because the oxygen is reacting with the iron. Well, same thing happens in life. You have these reactive oxygen species. But these guys have so many, so much high concentration of manganese antioxidants, which are like manganese ions, small peptides, that can scavenge and take care of that reactive oxygen.

So it's keeping all of that reactive mechanism at bay. And finally, the cell envelope is really weird. the border of the cell to the outside. It's multi-layered, and the outer layer is this S-layer, crystalline surface layer. You can see it looks like a crystal. It's a hexagonal lattice where you've got this like fundamental unit and it repeats itself. It's kind of like a shell around the bacterium that is keeping, that is like reinforcing that structure. It reminds me of when people talk about fractals.

Yes. Like fractal patterns. It's like super structurally, right? It almost looks like a virus, but it's the size of a bacteria, which is 100 times larger, you know? And it acts like a suit of armor providing this immense structural rigidity. So there's a, there's a, there's the physical structure of this bacterium is such that it gets this extra layer of outer protection and has this genetic benefit of the, of the structure of DNA such that external forces can't do a lot to it. Yeah, exactly.

Like when radiation comes in and like messes up its DNA, it's got repair mechanisms. You just be like, oh, right on it. We got more. Yeah, exactly. Yeah, it's like the robots. When we replace humans with robots, it's just like where you can manufacture them quickly. Yeah, and it's not unique, you know, and all the time it takes to have a human grow to be an adult and stuff. Like, you just be like, oh, robot out of the factory, it's already got it.

Exactly. Yeah, dude, Conan the bacterium. Bacterium. This guy's crazy. Okay, so now let's look at can this thing survive an impact ejection, which is the idea of like a meteor comes in, slams into the earth at insane energy, several atomic bombs. Can it survive this? So at sea level, we've got about 0.0001 gigapascals of pressure right now where we're at. Okay.

The Marianas trench is at point one, which is about a thousand times more. more than at sea level. Can I ask a question? When you say pressure, how for our audience, how would they experience what that means? Because we do experience what pressure. Or like, how would you describe?

Yeah, pressure is, yeah, that's a good point. So pressure is force per unit area. That's how it's defined in physics, right? It's the amount of force that you're pushing on some amount of area. Now you can imagine if I'm pushing hand to hand, there's not a lot of pressure. But imagine now I have a picture.

Right? Like the thumbtack? Yeah, that does... And now I push. Yeah. Why does it go through my hand? Yeah, yeah. Because there's a lot of pressure. The same amount of force is being concentrated on a tiny bit of area and that pressure

is enough to pierce my skin and cause a lot of damage. That's a really good way. That's a really good analogy. That's what I mean by pressure. Yes. It's like per per amount of area on your surface, how much is it pushing down? Mm-hmm. Okay?

At sea level, it's not a lot. I mean, the amount of pressure that we have pushing in. is the same as the amount of pressure we have pushing out from our blood and everything, and that's why we don't get crushed. Unfortunately, do you remember the Titanic? Yeah, the submarine thing. The submarine thing. When you get down there, there's so much pressure, and the thing gave way, everything

collapsed, right? And then it just completely killed everything. So that's pressure acting, right? Okay, okay. And at the experimental low end for this particular paper, you've got 1.4 gigapes, That's 14,000 times atmospheric pressure. And on the high end, you have three gigapaxeals, which is 30,000 atmospheric pressure. Now, why do we need to, why do we need to like go that far?

Okay, in terms of the amount of pressure is well outside what we as humans. Well, we as humans, right? Like, even on Mars, Mars is actually low pressure. It's way lower pressure atmospherically because Mars is smaller, so it doesn't have a big enough atmosphere. So the atmosphere isn't like actually pushing down. So why do we care about these high pressures? Right. Right.

The reason we care about high pressure is to escape Mars, the rock has to reach an escape velocity, right, in order to get all the way to Earth or something like that, which is about five kilometers per second. On Earth, it's about 11 kilometers per second. But in any case, to get that fast, direct acceleration means that you need like 50 gigapascals of pushing in order to get there. You're never going to survive that. Yeah, right. On the other hand, in 1984, there was a theory called the shockwave spolation theory. This is the idea that a meteor is going to come in, and it's coming in so fast that the ground is going to act like a viscous fluid.

Oh, wow. And that's actually what happens when meteor's impact. They're coming in so fast with so much energy that the ground, the shock wave is no longer a solid. It's like this viscous fluid. So the meteor comes in and then the stuff around it bounces up, right? Because you've pummeled in. And so now the stuff around it is like going up. There's this like compression wave that like rebounds.

It rebounds from that impact. And that rebound is going to projectile stuff out into the air. To escape the gravity of the body. And that's how we get, yeah. And that's how we get that escaping, right? Okay. And to get that escaping. escaping, that is about a 5 gigapascal to 1 gigapascal shock.

Now, that's lower than the 50 gigapascals that we thought what's going on, right? So the idea is the meteor comes in, hits it, there's stuff around, and that stuff that's around is going to get shot back up as a rebound. And that rebound might be enough. It's still 30,000 times the atmosphere of the Earth. But it still, it might be enough that the... things survive. The other clue as to why it would survive is because it's not really a sustained pressure. This is transient. This happens over like a microsecond. This thing impacts. This thing goes in. The pressure that this thing, that the ground fields is over a microsecond, right? It's extremely

short. So maybe that brief shock will leave the cells mechanically intact. That's the question that they're trying to answer. Okay. This makes sense. Okay. So just to briefly summarize, rise in because the idea is when we are trying to ascertain if pan-spermia is a thing, which means life arises on one rock and then moves to another rock that's orbiting around a star. The life on rock number one needs to be able to have enough to escape the atmosphere. We have rockets, but in lieu of rockets, you have some object come, disrupt the ground, ground and with enough force such that it shoots stuff out of the gravitational pull of the rock that you're on. Yeah. And so now you're in space and you're traveling around. And so there are

all these stages of that entire process for how does an organism get from one place to another when it's not on a rocket? Yes, exactly. And this is the theory, right? Okay. The thing comes in, there's a rebound and then it gets flung out into space. Yes. And so now we get to the actual paper, right? The actual paper, and if we go to photo 14, is a paper in PNAs, which is the proceedings of the National Academy of Sciences. Not that other word, you weirdos were thinking about. No, no, this is PNAs. Everyone knows about Pinaz on science, guys, come on.

It's about extremophile survives the transient pressures associated with impact-induced ejection from Mars. That's exactly what they're doing. That's exactly what they're doing. They're making the case that this particular bacterium, deradurans, can survive that insane pressure all the way up to three gigapascals, right? I mean, that's a big, because that totally changes the calculation. When we talk about things like the Fermi paradox, where is everybody? Yeah, and we're going to get to that.

We're going to get to that. So let's pause on that. And let's talk about how they actually did the experiment, because this is from first principles. We're going to talk about how they did the experiment. First, you need to biologically sample prep, right? So here's what they did. They had the radioduran cells, the bacterial cells in this circular plate, and they sandwiched those cells. This is about a billion cells that they put inside like a Petri dish, but it's like a circular Petri dish.

They sandwiched those cells between two large steel plates, and then they seal it. It almost looks like a cannon camera lens. Yeah, totally. We're in the center. Yeah, in the center you have your biological sample and then you're sort of like collapsing a bunch of steel plates on top, right? Now, what we're going to do with that plate is we're going to hit it with a gas gun. Okay. Okay.

The gas gun looks like the following. You've got the projectile, which is your flyer plate. Yes. That's another piece of steel. Okay. And that piece of steel is going to be propelled by getting. It's the same like kind of like you know in like car mechanic shops where you have like the the gas hydraulics.

Oh yes. Yes. It's I mean it's obviously more sophisticated than like the car. But it's the same thing. Yeah. It's like a gas gun that is like propelling a fly a flyer plate to impact. Yes. The plate that has your bacteria.

Yes. Okay. And then when you impact that bacteria, that is going to create the microsecond strain that mimics the asteroid impact on Mars. So the idea is that this, in this graphic we see on the left, there is this projectile. There's a wedge in a flyer plate. So that is what is shooting out. Yeah, with a gas.

Like, it's high pressure gas that shoots out and it shoots into a circular plate. If you go to the gas station or a car wash, when you pump your tires, you click the thing, it shoots the air out. Yeah. Just conceptual. Yeah, that's exactly this. It's shooting. But like, you know, at levels that are not pumping your tire. Yeah, yeah, yeah. This is much higher pressure.

And the advantage here is that, so I'm shooting my gas plate and interacting with this plate that has my sample, right? Yes. I can polish the other side. Okay. The backside. The backside. Okay. Such that it's a mirror.

Okay. And then I can shoot lasers at it. Oh, my God. And then I can really hone in on what the dynamics of the trajectory is. Like how much pressure was there, how much strain was there in each direction? because I can monitor how the laser is coming out. Because, and just to be, just to reiterate, the laser is the means by which you can measure stuff.

Yes, exactly. It's a measurement instrument. Yeah, and the measurement instrument, because we're so good at lasers. Yes. Right? And measuring like frequency and all this other kind of stuff. We can measure exactly the amount of pressure

that was imparted in that microsecond. Yes. Right. That's what's hard to measure. But these guys have leveraged all of the optics that physics is very good at. That's so clever. It's so clever. I really like that, actually.

Because it's at first, at first blush, frankly, their initial reaction is like, oh, that doesn't sound like what would happen on the surface of Mars. No. However. But they're recreating exactly the Pascal's, like the amount of pressure, the amount of transients, right? Because it only has to happen over a microsecond. So this contact has to happen very quickly.

It's got to be a shot, you know? Yes. That's quite nice. It's quite nice. That's quite nice. And so now let's see. they're actually doing. Okay.

What are the findings that they actually get? How they measure is the number of colony forming units. And this is something that we used to do in microbiology lab as well, is you basically like swab and put it into a petri dish with like agar, which is like a solution that grows bacteria. And then if there's a single bacteria that survived, that's going to create a colony because it's going to replicate over some time. And you can count the number of colony forming units.

and that will give you a proxy for how many survived. Because you knew the initial concentration of how many bacteria you put in into that apparatus, right? Yes. And now let's look at the results. Okay. It's insane. All the way up, all the way up to 2.4 gigapak scales, you had 60% survival. 2.4 is 24,000 times that on Earth.

Yes. Right? The survival falls below detection limit. only when pressures exceed three gigapascals. And one of the cool things was Lily Zhao, who's one of the senior authors on the paper, she noted that the hardened steel experimental containers began to structurally fail before the bacteria actually got eradicated. So the point is, our own engineering was not even sufficient enough to get to levels

where the bacteria were like chilling. Chillin, fine. Right? They were like at least 20% were still alive, but like we couldn't test farther because we were testing pressures where the steel was like, I can't, I don't know what you want for me. We don't have the material science. Yeah. Yeah, exactly. It's fascinating, right? And if you look at standard microbes, right? E. coli plummets to 10 to 10 to minus 3 to 10 to minus 6 survival rates. below 2.2 gigapascals. Our radio durands, Conan the bacterium, achieved very high rates. So con in the bacterium

is the green dots on the very top. Yes. All of the other stupid bacteria are surviving way lower. And this is on a log scale on the y-axis. And so just to be clear,

we're looking at a graph here that has pressure on the x-axis. And the x-axis is gigapascals and then survival rate on a log scale on the y-axis. access. Yeah. And there's all the other stuff that's like in the middle and love. Yeah, it's like

E. coli and yeah, but at the top is our radio durands. At multiple different pressure types, it's very consistent. Yeah. Okay. Yeah. So, so Conan's, Conan is sick. He's surviving everything. Okay. Um, this is where it gets really, really cool. Okay. Because so far, okay, we've, we've shown that this radio durand survives. Right. Again, coming back to the original. point here is we're starting off with this idea of is PAMPSpermia a thing which is life going from one rock

through the vacuum of space to another rock and part of the current paradigm was that in order for an organism not powered by rockets or some advanced technology would require an impact

on that planetary body of a level of force such that it would eject it into the vacuum of space. Yeah. And initially the idea was, oh, there's no way. The level of force necessary to eject you out there. Yeah. You're dead.

You're dead. Yeah. That's the current paradigm that the paper has now experimentally shown on earth. Yeah. We have organisms that would survive this theoretical impact. Yes, exactly. So we have shown that it would survive this theoretical impact. Now let's look at what actually happens to them.

Okay. If you look at transmission electron microscope images of these bacteria, you can actually see that at higher pressure, the cell walls get ruptured. Yes. Okay? So that's why the survival is going down. Right. Because the cell compartment around it is getting ruptured. And it's consistent with like sort of the physics of what we know about the cell walls.

But the idea is even at that tool. 2.4 gigapascals, a bunch still survive. Right? So what we're seeing is there's three images here. On the far left, we see like sea level, I'm guessing. Where you can see that... Yeah, it's like, it's normal. Control, yeah.

Control. You can see the structure of these four bacterium. Totally fine. At 1.4 gigapaxiles, there's clearly a rupture. There's two. There's clearly the rupture that's happening. Yeah, but they're still fine. But they're still fine.

They're still fine. Yeah. Right. And then at 2.4, there's one that's not fine, but two that are fine. Yeah. And it's just like, yeah, like you were just weak. Yeah, yeah, yeah. That's evolution, baby.

That's that, but that's, I, I want to. Dude, that's 24,000 times the pressure on sea level. That's still insane. That's way more than Marianas Trench, for example. Yes. You know, it's still insane. But this, I think this was the coolest. Okay.

This next finding that they had. They went in and they looked at the RNA sequencing, the transcriptome of the bacteria that survived that pressure. Okay? So you've got an impact. Certain things die, but you've got colonies that are made. What is the specific DNA that those bacterium are translating into protein? What's the thing that's being made into MRNA that is being translated into protein? What do these bacteria care about once they've been hit by?

a meteorist. Yes. Yes. Here's what they cared about. According to their transcriptomic analysis, they vastly increased DNA repair transcription. Okay? So anything that had to do with DNA repair,

they were like, we need that. We need the SOS response. We need the recombinase. We need a really high active transposase, which is stuff that's like fixing where the DNA is going. So genome reconstruction was like the number one priority. That's actually so fascinating. Especially if you are coming back as a listener, this is an area that we've touched on in multiple stories.

Yes. In the human context in terms of how our body does repair. Yes. In a number of different contexts. And this is fascinating because in all of those contexts, there was not an increase in the sort of immune response or DNA repair response based on an external. like pressure like literal physical stress did not because the immune response

is there but the DNA repair process which is kind of its own yeah but these guys are just responding to the fact that they just got hit that's they just got hit with this giant microsecond time scale high pressure right which like totally messed up their internals

and here's the other thing stuff like energy production lipid metabolism cell cycle, so that's like the reproduction, that's deregulated. So the idea is the cell halts growth. It's like, I'm not trying to replicate. I'm just trying to stay alive.

So all of my ATP, all of my energy is going to go into structural and genomic repair. Okay? We're going to stop the normal. I don't know what just happened. Yes. Okay. But I just got hit by a 2.4 gigapascal bullet. Yes.

Let's just stay alive. and then we'll figure it out. There's such a clear analogy here to economics and society where it's like, you know, despite any shocks to the system, capitalism keeps trucking along. Yeah. And you just reallocate resources. But it doesn't get into it. That's fascinating.

Yeah. I thought it was really cool. I mean, the fact that they went into the transcriptomic genomic level to show how it's actually surviving this. I thought that was really cool. So, I mean, it shows that this prior assumption that if you have this giant 5 gigapascal impact, it's going to sterilize everything. That's no longer true, right? Certainly, we have a bacterium on Earth that can survive that.

And that's, we only have one source for reference in an infinite galaxy. I'm sorry, infinite universe, excuse me, an almost infinite galaxy in comparison. And on the first place, we have the thing. Yeah. And so it's like clearly, you know, or statistically speaking, it is likely true that across the universe, there are other things that if they were to arise, that would reach that level. Exactly. And so now that stage of lithopanspermia, right, that first stage of getting into space, that's been validated. Staying in space has been validated.

and getting into Earth has kind of been validated. I mean, we haven't done astringent tests, but we know how rocks sort of burn up and things like that so we can sort of make theoretical prediction. Sure. But at the end of the day, this significantly increases the probability mathematically that there's life that could migrate from one planet to the other, right?

Now, why is this important? For one, it's getting to the heart of who are we? Aliens. Aliens. Are we aliens? Are we aliens? We might all be illegal immigrants. Right.

Because Mars way back in the day had a very nice climate. Right? When the solar system formed, Mars had oceans, had lakes, had water, had an atmosphere, and could be the perfect place to start life. And so it's not completely crazy that perhaps life started there and came to Earth. It's peak pollination season, and my business is. is scaling fast. To keep the nectar flowing, I need a phone plan with top priority data speed.

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He's trying to go back home. And so it makes total sense. But in today's world, why does it matter? Well, this is, I thought was really cool. Okay. So there's a committee on space research. It's called Kospar. And they have this thing called a planetary protection policy.

It prevents forward and backward contamination of life. So forward meaning like we don't want to contaminate, let's say, Europa, with our own bacteria. We don't want to be the pilgrims. Yes, exactly. And we don't want backward contamination like, you know, some life coming in on Earth and then killing everybody. So Japan, the Japanese Airspace Agency, has a mission called the Martian Moons Exploration, which is going to go to Phobos, which is one of the big Martian moons. It's going to launch in 2026, and it's going to return in 2013 with 10 grams of Phobos dirt. I know some people might be like, I get more than that from my local dealer.

However, your local dealer is not hundreds of thousands of miles. Millions of miles. Millions of miles. Millions took it. Sure. Millions. Yeah. Where your window for delivery is a very narrow window. Yeah, yeah, yeah.

You've got to time it with the planets, you know? It's not a signal text away. Correct. I just wanted to identify, like, technically speaking like that is. Yeah. Ben Grants is like, we have a Mars return mission that got nixed because it's too expensive. So I don't know why we're talking. Yeah, right?

Right. Right. So Japan is doing this, right? Right. But this new paper now is kind of putting a wrench on things. Because Phobos orbits in the gravitational well of Mars, right? So its surface is kind of like a sweeping sponge of all the crap that is spewed out of Mars from all of the meteorite impacts, right? So when we take out that 10 grams of stuff from Phobos, that's going to inevitably have stuff from Mars.

Oh, I see what you're saying. So now when we bring it back to Earth, right, there's two possibilities that the Committee on Space Research suggests. One is the restricted Earth return, which is a category 5 restricted. That requires multibillion dollars worth of biohazard containment. And then there's unrestricted, unrestricted. unrestricted Earth return. Okay?

That's just unrestricted. You just put it inside standard creation labs. You're good to go. Yeah. If that thing has life, right? Or possible life,

we might need to upgrade from unrestricted to restricted. And that's going to increase the cost of the mission. And it's something that we have to grapple with. Like, what is the probability? Because the threshold is

for unrestricted, it requires the probability of viable, unstarized Martian organism to be less than one in a million. Okay. So we got to go back to the drawing board now, given this paper, and try to calculate, okay, what is the probability that in that 10 grams of stuff,

there's going to be something that is possibly alive. Right. Because that thing being possibly alive and being brought into our environment, who knows? We have no idea. I have no idea. I mean, high probability, it's going to die. Right. It's going to be like, why is there 20% oxygen and then just die? However.

Okay. Because Earth is very different from Mars. Yes. Even back then. Right? There's way more oxygen now. The pressure is way higher. There's a bunch of nitrogen. I don't know what that's going to do. However, just like we talked about, on Earth, we have things that have the ability to live in conditions that are way more extreme than Earth's environment. So why is the inverse not true by default in your probabilistic? And that's the thing with this one in a million, right? We have to do that mathematical calculation and say, okay, given the span of all the organisms, what is the chance that this thing that came out of Mars is going to be in that tiny little regime where it's just going to totally destroy us?

I think it's a very cool paper. It's very interesting because it's sort of, it's poking in two different, arenas. So one arena is poking in is the sort of you know, Fermi paradox, Pamspermia, can life go from one rock to another? We already had kind of two,

one and a halfish of the three where we felt like we have it. It can travel through space, fine. Reentry to Earth, 50%. But now we know that it can survive the initial impact to get actually even into the second two stages. Yeah.

So at least in terms of referencing something we can know as life here on Earth. That is huge. Not only that, based on an active mission coming back, because of that understanding that they've now proven experimentally, an active mission that Japan is doing to bring back samples from Phobos, which is in a range where if there were things impacting Mars and things getting ejected and there was life on it, Phobos would have it. Fobos would have it. And the 10 grams that we get will have it. would have it. And now we have to have a almost COVID-like conversation. Yeah, yeah. Which is funny because our second story is on immunology.

Exactly. Which we'll get to in a moment. But fast, you know, for those of you know, I'm the one on the pod who loves alien stories. I did not select this one. No. So this was organic. Yeah. I'm waiting for NASA to stop tiptoeing around the Mars thing. Yeah. Continuing to tiptoe around it. Well, it seems like we're not going to return samples. Oh, and sorry. Oh, from the little lake that we cover. Oh, we're not. We're not. So this is why funding matters. Funding.

It's too expensive. Maybe we could save a couple of bunker busters. Maybe if we just like two, literally two bunker busters, we could return samples from Mars that would identify that. We're not alone in the universe. However, we will not see that at the moment, but we may. may see in the future in terms of funding. Fascinating story. Our first story of the day, astrobiology, out of John Johns. Johns Hopkins University. Normally, I think in my head, we're known for medical stuff. Yeah, but they have an incredible engineering department, right?

Because they have the applied science lab. So there you go. The applied, is it applied physics laboratory? I think it's the applied physics laboratory. And they also are in charge of the space Telescope Institute. They've got a pretty strong like astronomy and astrophysics and fundamental physics. It flies under the radar because their medicine is very good. It's just so stellar. If you are in any of those at Johns Hopkins, please send us a note. We'd love to make sure that we know and have your connection on the ground so we can

keep in touch for future stories. But now we will be moving into the rundown. And for those of you who may be joining us for the first time, we cannot cover every frontier and breaking science research story every week because there is so much happening in every aspect and every vertical. However, we reserve the rundown to cover briefly some stories that we are fascinated by but do not have the time to always cover in full in the way that we want to on the pod. And we have four really good rundown stories that you guys are going to love this week.

So our first story in the rundown is about teaching computer simulations about atoms to learn from over 150 years of hard-won experimental data. And why that matters for building the next generation of materials. So what is this first story about? Yeah. So they've developed a new machine learning method. It's called DDoS, which is descriptor density of states. For those who are in solid state physics, they'll know what density of state means. I don't want to get into it, but effectively, what it's doing is it's bridging the gap between atomic simulations, where we have simulations of materials, right, where atoms interact one way or the other. And then we've got experimental data, and we want to make a prediction about undiscovered materials. This particular paradigm, which uses AI in the loop with experimental data in the lab, makes that discovery of undiscovered materials.

covered materials 10 times more efficient. It's very cool. The idea is, you know, when you're in search of a metallic alloy, let's say for like, okay, I want to build like a turbine or like a fusion energy component, what I really care about is whether this material is not going to warp, it's not going to crack, if there's heat fluctuations, it's not going to act weird, right? The essential step in understanding these properties is to calculate something called a vibrational free energy, is the idea of these atoms sort of vibrating at certain energies, and whether that is going to rattle the crystal lattice that the atoms are positioned in, right? That crystal lattice and that vibrational energy strongly influences something called phase stability. We've heard of phases

in normal matter, like solid liquid gas. Well, in solid materials, you can have like micro phases in some sense, because like the atoms can be in one configuration, in one configuration, in the crystal lattice and then at certain temperatures they can transition to another configuration and that's going to change stuff like heat capacity or like the

stress or the bending ability of these materials and that's really important to figure out right? For example I mean the thing that comes to mind is like iron workers who then heat like a thing a piece of iron on or any metal

in super high temperature and then they start banging on it to shape it because it's now more malleable. Yes. Because of the temperature that it's at. Yeah, yeah, yeah. And what you're actually doing there is you're like getting rid of impurities. Because at that temperature, the impurities have a much higher probability of like leaving and so on and so forth. Right.

That's a fundamental phase that the material is in. Now, for the longest time, what we've done is do simulations of these materials based on how the atoms interact. And then we've tried to compare it to experiment. And we've been off. Yes. Okay? Because there's a lot of things in between simulation that we're maybe not capturing that actually happened in experiment.

Briefly, we actually did a great episode on this exact concept, which, if I recall correctly, was when we talked about hypersonics. Yes. And trying to do simulations with the Navier-Stokes equation. And where for supersonic, white, our interpretation, which is not real-world accurate, it to the actual environment because it's so complex that we can't actually model it to the level of sophistication necessary to do a direct real-world sim. So there's a little fuzziness.

Yes. And at different levels of stuff, if you get a little bit faster, the simulation kind of breaks down a little bit. Yes, that's exactly right. And what these guys have done with this DDoS machine learning paradigm is they've captured all the possible ways that the atoms can be arranged in a material. via some kind of probability distribution that is inside the latent space, which is like the middle of your machine learning network. Okay?

So the machine learning is learning how the atoms interact in the middle of its machine learning framework. And then from there, we can now start predicting what the phase diagram is going to be. The phase diagram is something like, you know, if I have pressure and temperature, where is it going to be a liquid? Where is it going to be a solid? Now, that's a traditional phase diagram. But if you imagine for these solid state materials, where is it going to be in a certain crystalline phase versus another crystalline phase? What is the heat capacity going to be in these two regions, right? And what this machine learning paradigm can do is now instead of just a feed forward mechanism where I start from the atoms and I try to figure out what the phase diagram is going to be, I try to figure out what the phase diagram is going to be.

It's going to be inevitably off. I can feed that back and inform my machine learning to do better, right? And the fact of the matter is this DDoS system is a smooth function, which means I can actually go backwards. I can start asking, hey, what if I want a certain material that has a certain property at 2,000 degrees Celsius, right? It has a certain stability. I can go backwards and do an inverse design. I can start with the material and what the properties that I want, and it can tell me how I would actually construct it.

And I don't mean to keep bringing up our past stories, but the other thing this reminds me of is when we did the Deep Seek story at the beginning of the year around their new architecture of how I can't quite remember the concept name. Manifold constrained hyperparameters. Yeah, correct. where in that process where you're going back, the highways were small initially and they figured out a way to create more lanes in the highway. Yeah, and they had a trick. So when you're going back in this back propagation concept

you're talking about, you just have more that you're working with to get a better outcome. And the main thing is you're constraining that function to be smooth. Yes. So that if I do a step in one way or the other, it's not like drastically changing what that. the function is. Yes. I'm just trying to prove the point that our episodes do build

on each other. So if you haven't watched the library, there's a lot of great stuff. There's a lot of good stuff guys. Both season one and the first half of season two. Yep. Fascinating. That's actually super cool. And this is out of the, this is

a paper that's in nature of communications. Yes. Out of the University of Michigan engineering. Friend of the show, Blackbird Physics. Shout out to Blackbird physics. He's a he's a great science communicator out of the University of Michigan I see his friend of the show

left out the French University on that one. Oh, okay, yeah. There was also a French university. Universite Paris Sacclae. Well, you told me to talk about them. That's how I don't know how to say it. That's how you say it.

A great, great first story on material science. Yep. Our story number two in the rundown is about DNA. And so every person of non-African ancestry, so people who are not me, alive today carry Neanderthal DNA. Yes, I do. Yeah.

Unfortunately. Unfortunately. And it turns out the story of how it got there has a very specific direction. Yeah, this one was pretty funny. So for decades, we've all wondered why modern human X chromosomes are completely devoid of Neanderthal DNA. We can sequence human DNA and then we can sequence Neanderthal DNA. Svante Pabo very famously, I think maybe two or three years ago, won the Nobel Prize in Medicine for actually doing that, for sequencing ancient genomes that were human adjacent. And from that, we can figure out that the human XVI.

X chromosome is almost completely devoid of Neanderthal DNA. Okay? But Neanderthal DNA exists everywhere else. So how come the X chromosome, which is a giant chromosome with, you know, millions of base pairs, how come that has almost none of it? And this new study that uses computer modeling is suggesting that it's not because of bio-incombatability, but it's because of mating habits. Oh, interesting. In our ancient past. Interesting.

Here's what they did. They compared genomes, and they actually found that the Neanderthals carried far more human DNA in their X chromosomes. So what does that tell us? Yes. Let's do a little bit of review of basic genetics, okay? The female gender has X, X, and then the male has an X, Y. Right? So when females are born, you get an X chromosome from the dad and an X chromosome from the mom.

But when males are born, you get a Y chromosome from your dad and X chromosome from your mom. Okay? Now, the fact that X chromosomes and Neanderthals have a lot of human DNA, but X chromosomes and humans don't have a lot of Neanderthal DNA, that suggests one thing, which is that the specific inheritance pattern, points to a long-term bias where Neanderthal males were mating with human females. And it was this one-way asymmetric mating. Do you see what I'm saying? Yeah, yeah. It's the only way to explain this discrepancy between why the X chromosome is only one way.

The Neanderthals have the humans, but the humans don't have the Neanderthals. Because the humans were only inheriting the Y chromosome from the Neanderthal. the Neanderthals, not the X. Not the X. But the Neanderthals were inheriting the X chromosome because they were getting the human females. Yes, yes, yes. The idea is human

males exclusively mated with human women. Yeah. And it's obviously not exclusively, but like by and large is the idea. By and large. No, that's a good correction. No, no, that's a good correction. By and large.

Whereas Neanderthals, were regularly frattenizing with the enemy. Yeah, yeah, men. The men were, the men were, they were, it's always the men, they were Neanderthal men, dude. It's always the men. It's always the men that are just like going at it.

But, but what's interesting, we're sort of describing like the sociological and psychological decision making is what is driving this observation we have in the genetic record. Yeah, yeah. And it's, I mean, it opens up a lot of cool genetic studies, about like population dynamics and things like that. I just find it really cool that we can actually trace back

and look at mating patterns like that and be like, oh, it's actually sex-specific. Yes. Right? Neanderthal males, like the human females were fine going for Neanderthal males. But somehow the human males... Yeah, not about that life. They were not about the life of the Neanderthal.

Like human males were not going for Neanderthal females. You know? Yeah. I don't know, for whatever reason. There's a, there's a, this makes me think of the, the channel H-O-Math, which I will not pronounce because this is a family-friendly show. But this channel talks about dating dynamics stuff and, in a graphical way, like in a, like drawing graphics and like kind of creating a formula. I'm not going to opine on the accuracy or lack of accuracy of H-O-Math. However, if any of you have participated in consuming that media, please feel free to add your comment.

below. This study was out of the University of Pennsylvania, and it was in science, and it was covered by Archaeology magazine. Our third story in the rundown is something biology teachers have been comfortably getting wrong for decades, and it just got a serious reality check. And it took, of all things, transparent fish embryos to catch it. So what was my teacher in high school wrong about. Well, she was wrong about mitosis. Why was it, why has it got to be she? Why that's why like my, my, my biology teacher. Miss Saeed. She was an amazing biology teacher. She taught me AP biology and she really got me into

like thinking about biology from like the ground up. She was amazing. Maybe an inciting incident to why he became a bio physics. Yeah, yeah, totally. She was she was awesome. AP bio. She was wrong about mitosis. Not she, apparently every textbook, including the AP textbook, by the way, by the college board, which is a racket. But that's for another day. Here's the idea. Have you heard of mitosis?

Yes. Right? It's the idea of like cells splitting into two. Yes. They replicate their DNA. They split into two and then they split into two. This happens a lot during embryonic development, right? Because you start from a single cell.

you make like a balustula, all the DNA has to be exact. Giant embryonic stem cells, sorry, giant embryonic cells like animals in zebrafish, sharks, and birds, they don't divide the way that we think they should divide. And here's what I mean. So here's what we think is how mitosis happens. You've got a cell. The DNA, the chromosomes line up in the middle. And there's this kind of purse string.

So there's a bunch of cytoskeleton with actin and myosin filaments that grab the DNA and sort of surround it in a ring. And then you pull it. And as you pull it, that purse string sort of like tightens up. And then that causes cytokinesis. The cells come together and split into two. The analogy I'm thinking of is imagine you have a bubble in the middle and you have a string over the top and a string over the bottom. and you put your fingers to pinch the strings on both ends, and then you pull those strings,

the string will pinch and then ultimately split the bubble. Yeah, exactly. And this is the telephase part of mitosis where at the end it pinches and it goes through. Now, that works for like smaller cells, but cells from zebrafish, sharks, and birds, have extremely large size and very large yolk. And these cells, it physically doesn't make sense.

Like if you calculate the amount of noise and the amount of physics that's required to coordinate this giant ring to come together, it's just not actually going to work. And so the reason why this particular paper actually worked and figured it out is because of that transparent fish embryo that you were talking about. Zebrafish have transparent embryos and transparent cells. That's why they're a huge model organism for studying embryonic development for neurogenesis. there's so many zebrafish labs everywhere because you can just look at what's happening. You can see what's happening. It's so nice.

That's actually a really good point because normally we're saying with everything, with most other things, whatever's happening inside. There's like a soupiness to it. It's opaque. It's kind of like a miso soup. It's a little cloudy. Yeah, but zebra fish are like very nice.

You can like directly look in. It's like a wonton soup. You can see. Yeah, you can see right through it. Okay. And here's what happens. With these large embryonic cells, you have this geometric constraint, as I told you, right? You can't actually do the same paradigm of pinching and stuff like that.

And so what they discovered is that the cell alternates between stiffening the interior cytoplasm. So it stabilizes this tightening band. And then it makes it fluid enough to move stuff around, and then it stiffs again, and then it fluids it around. It's this ratchet process that's happening. that's like very nicely massaging the two cells apart. This is very different from a lot of the mitosis that we have observed everywhere else. Right?

I think it's really cool because it's a part of mitosis that we do read about in high school biology. But it's now a completely different process because there's like this mechanical ratchet that I think is going to open up a lot of very cool technology. I think this has the opinion. Like, I think this has the potential to be something that is extraordinary if we were to really hone in and try to figure out what's going on. Because it's going to tell us a lot about how the cytoskeleton works. The cytoskeleton is the part

of the cell that gives it structure and coordinates movement. If we can really hone in and try to understand this process, it can be applied to all sorts of stuff. Cancer, has everything to do with the side of skeleton. All these other diseases have everything to do with the cytoskeleton. It could give us new tools to figure out how to manipulate the side of skeleton. So that's why I was really excited about this because it's something that as biologists, I think, a lot of people take for granted. Yes.

But there's ever more complexity. This is, it's mitosis is one of the few things that people always remember from their science classes. It's like the mitochondria is the powerhouse of the cells. Identicine Trifosphate, ATP, you know, mitosis. There's a couple of these, like, buzzwords that we all remember. And so it's great to know that we wasted our time

with no child left behind by learning something that's not true. I'm being facetious. I'm being facetious because it's a process. Because it's a process. And look, for all intents and purposes, what you learn in mitosis is still pretty good. Right. Okay.

It's better than nothing. For everything that has to do with you, mitosis is still what it is. It's still what it is. And relevant. And if you remembered mitosis at all when we first brought it up, congratulations. You got something out of your primary school education. I will take a brief pause to do a couple of quick housekeeping notes, which is number one. Thank you all for joining us.

We really appreciate you listening this far into the pod. As you all know, we have our website, FFPpod.com. All of our episodes are up on that website. We have full chaptering as well as all of the links to the papers we cover on the show. Are itemized by episode with a summary and key details and TLDRs and all of that stuff. So many are commenting on our social posts. Where is the link to the paper? You watch the show or you go to the site.

you'll get the links to the paper. It's also always displayed on the screen. I'm not quite sure why that's... Yamava Resort and Casino at San Manuel is California's number one entertainment destination for today's superstars. Catch the Jonas Brothers return to the Yamava Theater stage on April 30th, the powerful vocals of Demi Lovato

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We're going to move into our last story of the rundown, which is something that's sort of interesting in my daily life and intersects with my daily life as someone who works on the technology side, not on the military, industrial complex side. Handing nuclear codes to an AI might sound like a sci-fi premises, but researchers just did exactly that in a war game simulation, and the results are going to stick with you. Yeah, this one was really weird.

Okay? Yeah. It came out of the King's College London. It's only on archive, so it's not peer-reviewed or whatever. But here's what's happening. They put leading frontier models. This was Claude, Gemini, and Chachybti. They were placed in a high-stakes global crisis simulation,

and they had access to nuclear launch codes. And only one out of 21 simulated games ended without a... nuclear launch. So 95% of these simulated games ended with somebody blowing off a nuke. Okay. They played the con game, K-A-H-N. It's a high-stakes simulation where these leaders must predict opponents moves and then declare public intentions and secretly choose military actions. The AIs took these weird, terrifying personas. Claude took this like calculating hawk persona, that built perfect trust and then ruthlessly exploited it later on, kind of reminiscent of Claude's paper,

Anthropics paper, I should say, about how it was willing to kill someone in order to not be turned off. Be turned off. Gemini acted as a madman. It was using erratic behavior to its advantage. It was like straight up. Gemini was weird because that one was like, I'll just like drop a nuke on a sift.

city, not even military outposts. And then chat GPT, GPD 5.2 acted as kind of a conditional pacifist, but then very quickly abandoned its morals and launched devastating surprise nuclear attacks.

It's so incredible to me that the conclusions of these models so closely almost mimic the perceived personality of the leaders of each of the companies. So just for a little bit of context, because the thing about this story that's actually interesting is this is actually a real-time story, not just in simulation, but in the real world. So obviously over the last week, we saw the U.S. initiate war with Iran on the pretense that because we didn't obliterate their nuclear.

program when we bombed them to oblivion last year, that now they are almost close again in six months to another nuclear weapon, so we have to go back in and finish the job. That is the, and the reasoning has changed literally every day since the war has started. But it's obviously one of the most dramatic geopolitical military conflicts in our lifetime. You know, the idea of going to war with Iran has been on the playbook for a variety of... Yeah, I've remembered for the longest time. The longest time it's been on the docket. Yeah.

We've finally pulled the trigger. The reason I bring up that context is because literally right before we went to do kinetic action in Iran, there were stories breaking about a conflict, a right? between the Secretary of Defense, because that is still technically what it's called. No, you cannot... You cannot change the name without congressional approval. So the official name is still and has always been the Department of Defense. For marketing reasons, they can have an executive order that says we call it the Department of War.

but technically speaking, the name has not changed. All right. I'm just dying on that hell. Yeah. Regardless, currently, all of the frontier model companies, particularly Open AI and Anthropic, who's built Claude, have and are negotiating contracts with the Pentagon to apply their models on the battlefield. Anthropic was the first to win a contract with the Pentagon and to get murder.

merged with some of their existing tools and ecosystems. What's interesting in how it connects to this story is even before the kerfuffle between Pete Hagseth and Dario Amadeh, who's the CEO at Anthropic, Anthropic basically came out and said, our principles are that our models can be used for everything, but not for autonomous weapons and not for mass surveillance. And this sparked a huge debate between a lot of, the sort of San Francisco Technorati and the D.C. military industrial complex people where they were saying it is not the right of an individual corporation to tell the U.S.

government what it can or cannot do as a contractor. So that was one side of the argument. And then Dario and Anthropics argument is the power that is inherent in what we are giving you to abuse the Constitution is so great that we have to take the stand. So you can fall on either side of that argument. I think there's actually good arguments on both sides

because you don't want private companies dictating what the government can do. And you also don't want the government forcing companies to give it stuff that can go awry. The reason that this is relevant is during, even though both Pete Higgseth and President Trump have been arguing that they're going to,

to list Anthropic as a high-risk vendor and basically cancel their Pentagon contract, it's been now confirmed by multiple sources that Claude was actually used during the initial days of the Iran incursion, like the Iran military operations. So they were using Claude's AI model in collaboration with their existing targeting tools and operational stuff.

to accelerate target identification, optimizing missile launch times, and all of these other dynamics. So that's whether you think when you use chat GPT or Claude that it's terrible and doesn't have any value and it's just, you know, regurgitating words and it doesn't do anything. Stochastic parrot.

Stochastic parrot. The U.S. military is actively using these things to target and initiate one of the most consequential military conflicts in recent memory. Wow. And that is relevant because if the simulations are showing that these models always end up in nuclear war, we may really want to think about implementing these models generally, as well as for edge cases that are really dramatic, like fully autonomous weapon systems and mass

surveillance technology for domestic surveillance issues. Yeah. This is something that I'm clearly very passionate about. I'm not on a pro-AI or anti-AI wave. I'm just saying this is such a consequential technology that will impact all of our lives. And it is literally being used in a conflict that regardless of whether you think it's going to end tomorrow or in five years from now is going to have massive second and third order consequences. AI has been and is actively being used on the battlefield. It was used in Gaza by.

the Israelis for targeting in a very similar way and target identification. So this is happening right now and it has lethal consequences, even if you don't think it's going to replace you as a movie writer and all this other stuff. This was, this story was very concerned to me. It was pretty weird. This is very concerning. Not great. However, we are going to move on from our rundown and get into our next main story of the

day, which is an immunology story. And so this one is about vaccines. Yes. Specifically, a new paper that asks one of the boldest questions in vaccine science, which is instead of building a vaccine against a specific pathogen, this is, guys, this is crazy. Instead of building a vaccine against a specific pathogen, what if you could make the lung itself a better fortress against any threat that shows up?

It's like in the Lord of the Rings, we may have one vaccine to rule them all. Yes. It's a pathogen agnostic vaccine. It's like you're not getting like a COVID vaccine and then a flu vaccine. It's just one vaccine. And that's it. This is. It's insane.

This is very fascinating. This one is very cool because it's a vaccine that works like no other. Yes. Yes. And just really quick. It must. And just really quick. This was published in science.

February, 2026 by Stanford researchers. Yeah. So, you know, this is clearly a hot topic and something that requires a lot of research. COVID-19 has killed 7 million people, reported at least. It's probably killed a lot more that's not reported. The flu kills about 500,000 people annually. And we've been battling the flu ever since COVID-19 did a lot to our world and I can't believe that it was more than six years ago. Right. I will note that that was your first debut as a podcast host. That's right. It was six years ago on the Dark Matters podcast. Yeah. Co-hosted by Friend of the Pod, Matt Martyr, who also happens to be a film writer, director, producer who has a new movie out. on Amazon Prime and other streaming services,

Goal Mine. We talked about it in our last episode. I'll do a brief plug here. It's absolutely worth a watch. If you heard it here first, you know you have to watch it. So definitely check that out. Yeah.

And I was the scientific advisor on that film. A lot of some of the stuff that I was working on during my PhD has actually made it in there. A lot of cool neuroscience, VR. Very cool stuff. You guys should check it out. So COVID-19, though,

was pretty bad six years ago, right? Yes. Now, what COVID-19 showed us was that our tech, when it comes to vaccines, is reactive, okay? It's designed such that there's a specific key or a specific lock. We'll get into what that actually means. But ultimately, that comes into a timeline problem, right? Because even the miraculous modern speed that we had with the Moderna vaccine, which was 63 days from sequence to first human dose with the Moderna vaccine, that leaves a months-long window where we are globally vulnerable. It would be really nice to switch from a reactive to a proactive type of, you know, what's the word I'm looking for?

a reactive versus a proactive type of procedure on how to tackle these problems, right? This new paper that came out of Stanford, it's asking a very radical question. It's saying, can we train the lung itself or organs in general to broadly, durably, and be more capable of fighting off whatever shows up? It doesn't matter if it's COVID. It doesn't matter if it's a bacteria, not just one virus, not just one bacteria. diverse viruses, even allergens, simultaneously with a single vaccine, a single nasal spray that's going to last for months.

The idea that's also in the form factor of a nasal spray is crazy. It's not even a jab. It's not even a jab. It's a nasal spray that is going to vaccinate you against several different pathogens. I think that's really cool to even think about. And when I first heard the story, I was like, how does that even work? My reaction was, I don't believe you. Yes.

Because I sort of know how conventional vaccines work. It's this lock and key mechanism that we're going to get into in a little bit. It just didn't make any sense. So let's get into just immunology 101. Okay? Let's prime ourselves with a little bit of understanding. There's two types of immune systems in our body. There's the innate system and there's the adaptive system.

The innate system has to do with rapid response. These are your beat cops that are on your neighborhood. Not a lot of memory. Okay? Rapid response, these macrophrages, neutrophils, they recognize broad patterns and they lack long-term memory. But they're very responsive. They're very quick.

The adaptive system, these are your detectives. These are your more sophisticated sort of, what's the FBI crimes unit type thing, right? Delayed response, days or weeks. It involves T cells and B cells, but it's highly precise, and it creates specific antibodies

and memory cells that will remember the pathogen, and the next time that pathogen comes into your body, you no longer have to have that immune response because they'll recognize it immediately. That's why we only get chickenpox once. Right. Or that's how the vaccines actually work. As a maybe crude analogy, the innate system is like infantrymen in the military that are on the front lines that get sent first and are perceived in the ranks as maybe more expensive.

But then the adaptive system is like special operations. Yeah. Folks highly, highly, highly trained, very specific. You can tend 20 of them and they know exactly what to do. Yeah, because they have intelligence. Correct. Right. That's the main thing. They have intelligence. Right. So how do traditional. vaccines work. Well, traditional vaccines actually exploit this adaptive memory, this special operations thing, right? What they do is you introduce a specific antigen, let's say for the COVID-19 vaccine, you introduce an mRNA blueprint, that mRNA that then gets transcribed into the spike protein of your COVID-19 virus. The body then produces antigens to that spike protein. and then remembers the shape of that spike protein such that if you were to get COVID in real life,

it would recognize, hey, that's the same spike protein that I saw earlier. I'm going to go ahead and neutralize this threat, right? The flaw is that it is too specific. It fails against rapidly mutating viruses. This is why we need to get jabbed like, you know, once every two years. For the flu, we have to get a shot every year. The influenza virus, for example, it's covered by two primary surface proteins. There's the HA, the hemaglutinin, and then there's the NA.

The HA is usually the one that actually allows the virus to bind and enter human respiratory cells. So it's the primary target for the immune system. And the challenge is that HA head, it undergoes constant antigenic drift, which is these tiny subtle changes that necessitates a yearly vaccine update. That's why we get a yearly vaccine for the influenza virus, right? Because every year the vaccine, the HA head, that protein, looks a tiny bit different every time. And so we have to have the new vaccine in order to prime our body. So just as a brief analogy, right, these viruses, you could almost imagine they're the

lock side of the analogy and they're constantly changing the configuration of the lock. Yeah. Right. And our immune system is trying to create a key. Yeah. To turn it, to make it to defeat it. But because it's constantly having the locksmith come and change the lock very, very quickly, it takes us a long time to print a new key. And we put it in.

It doesn't work. Let's go back. And so like that delta between the how quickly the locks on the doors are changing versus how quickly we are generating. versus how quickly we are generating new keys to try to unlock the door. Like the delta between those two is part of like, if the rate of lock change is slow enough, we'd be fine. We'd be fine.

But when the rate of the lock change gets too quick, that's when we get having the need to do this on a yearly basis as an example. Exactly. Yeah, exactly. That's exactly right. And so that's the antigenic drift, right? Now, instead, what if we think about, like, there's actually other types of drift, right?

There's something called genetic reassortment. And this actually happens with the avian and human flu swap. This actually happens when a human being gets avian flu and the human flu. And then within our body, genetic elements get reshuffled. And now you have an entirely novel H.A. protein on the outside of the virus. This is what actually happened in 1918 with the Spanish flu. You had this driver where a human being had a swapping of elements inside that created this incredibly different virus that no one had ever seen. And that's why nobody was immune to it.

So we've been trying to figure out a universal vaccine that just like is, it stays invariant across all of this nonsense. Okay? Right. The first one that I can really think of is one that targeted conserved internal proteins. Here's what I mean by that. The H.A., which is this protein that is in our analogy, the lock, so to speak, it's on the very outside of the virus. There's a little stalk that protrudes out, that presents this to the outside, such that the virus can actually get into our human cells. Like the doorknop.

Exactly. Yeah, yeah, kind of like that. But, okay, let's continue with the analogy, right? We've got the lock. The lock is really the hole that the key is in. What if I could make a little thing that recognizes the shape of the lock itself, like the little round that goes around the doorknob, right? That's what the strategy was here with bi-on Vax.

They made something called the M-ZO-1, and what it was doing was trying to target the stock of that protein. which is highly conserved. Like the doorknob versus the hole where the key goes in. Exactly. Like what if we just like go for the doorknob itself? Yeah. Okay. Recomitant of protein.

It targeted nine conserved T-cell epitopes. It went really great until phase two. Okay. And then phase three completely failed. Mm-hmm. 12,000 people, October 2020, showed no significant difference in flu illness. So we can't just remove the,

we can't just remove the doorknob with the lock on it because the little door still is still. Somehow the doorknob thing isn't working. Okay? Somehow the doorknob thing isn't working. I know I've taken us on this weird analogy path, so feel free to pivot. Yeah, no, no, no, no. Now we're stuck, baby.

But let's go. So somehow, somehow the idea of like this invariant thing that I want to recognize is no longer working. Yes. So the failed autopsy is the following, right, which is that this T-cell that's getting activated to recognize the doorknob, it's insufficient. because what it needs to do is it actually needs to prime the innate cells in the respiratory tissues. That seems to be the problem. That was the lesson that we learned.

The infantry, not the special ops. The special ops can know, but if the infantry doesn't, it doesn't matter. If the infantry don't know, then it's too late by the time that the infection actually progresses. Okay? And that's where we get into the paper that we have here. Okay. out of Stanford, it's by the lab of

Balipulandran Integrated organ immunity. It's this idea that we need to shift from specific antigen matching to now target this T-cell activation and fundamentally upgrade our system

such that we can really think about a holistic approach about how the organ is actually doing this protection, okay? The protection requires continuous synergistic dialogue between your adaptive immune system, which is the special ops, and your structural cells that are in the tissue that are part of your innate immune system. I'm so mad that this perfectly maps on to basically saying we need to build

the CIA intelligence agency for the human body to communicate intelligence. Yes. We can't have sequestered information. No stove pipes. Yes. Yes. We can't have stuff pipes. Everyone, needs to talk to everyone and share intelligence. That's ultimately what's happening. That's so funny. So now let's get into the paper, right? Okay. How does this vaccine actually work? It's an intranasal vaccine. It's a spray. Yes. That you put into your

nose. Yes. The payload is the following. You've got ovalbumin. This is OVA. This is a model antigen that's encapsulated in this is an antigen that actually just comes out of egg whites. Okay. Okay. So it has nothing to do to do with humans. It's kind of just there to prime

the immune system. To be like, that's weird. I don't know what that is. Okay. Okay. And it's encapsulated inside a liposome, which is just like a little fat globule. And inside that liposome is a multi-front threat. You've got GLA, which is something that mimics bacterial

cell walls. So this is going to go after something like a toll-like receptor, TLR4. it triggers inflammation from antiviral and bacterial immune systems. And finally, it also has this 3M-052 LS, which is effectively like it's a molecule that targets other toll-like receptors. Toll-like receptors are like these things that are on. These are receptors that are on immune systems that detect viral DNA or like other types of DNA

and actually trigger immune response. It's like our radar systems or... any of our signals, intelligence systems to figure out if someone shoots a hypersonic missile, we have all these satellites that will, like, know, oh, the heat over here changed to such a degree that there's a threat over here. Yeah. It's like identifying, listening to identify when there is a threatening coming. Yeah.

Yeah. Yes, exactly. And what's crucial about it is these two things, they're actually synthetic adjuvents. Okay. Adjuvants are little helen. that help the immune system but aren't actually the antigen that the immune system is trying to target. I see. It's sort of just priming the immune system to be on alert in some sense.

Okay? Now, let's see if this actually works. And to be honest, even the lead author was like, I'm surprised at this point. Okay. Let's do the efficacy test. Okay. Turns out four intranasal doses on vaccinated mice And the mice were highly durable

To SARS COVID-2 This is COVID-19 Mouse adapted SARS-Cove Which is the SARS virus A coronavirus that was bat derived A gram positive bacteria And another gram-negative bacteria So like five-drengthenative bacteria

So like five different things that had nothing to do with what I showed the immune system. That's what's key. Usually for the COVID-19 vaccine to work, I need to show our immune system the spike protein from the COVID-19 virus. It's going to learn that spike protein and then it's going to learn to recognize it. You have to show the keyhole of the lock that it needs to make keys for. Yeah, this is literally just priming the immune system to be like, watch out. And so again, if I continue this annoying analogy. The primer is basically allowing the immune system to create several sets of keys before

cats even show up. And it just so happens that because they created this preset of hundreds of thousands of keys. Yeah. They already, when it arrives, they can already be using those. Yeah, they already know like what is what is for it. Right. There's a signal of like, okay, this is interesting. This is actually so good because this goes back to what we've talked about before,

which is to the extent that you, instead of inserting something artificial into the body to solve the problem, if you can just instigate the body to use its existing machinery to better solve the problem, that is always the better solution. Yes. That's exactly right. And now let's think about what is exactly happening. Right. Right, because you just like introduce like this very simple thing in the nasal tract.

And now all of a sudden it's just like working. It doesn't make any sense to me. It's just got a huge defense system out of nowhere. Yeah, yeah. So how is it actually working? So let's talk about the lungs, right? The respiratory tract is a really distinct immunological zone because it's kind of like the border between the outside and the inside or the human body, right? there's a direct interface between the outside world and the inside world.

So there's its own rules of engagement. That's fair. It's like this is not the blood, right? Where the blood is shielded by the skin and the heart and the capillaries. The lung is like where the outside world is coming in and I need to get oxygen and release carbon dioxide, right? So there's a lot of stuff coming in. Yes. The rules of engagement are different.

The battlefield is something like 480 million. Alveoli. Alveoli are these compartments inside the human lung that increase surface area such that there is a transfer of oxygen and carbon dioxide from the blood to the outside world. Okay? This is how blood, sorry, this is how oxygen gets into our blood. Every single lung has 70 square meters of surface area, which is roughly half a tennis court. So if you were to take our lungs that actually lay it out flat, that would be half a tennis court worth of surfacing. That's really crazy, actually. I didn't know that. Right? That's pretty cool. Now, the lung is naturally tolerogenic. Meaning, it tolerates a bunch of random stuff. It suppresses an immune response.

If every time some random crap comes in and we have an immune response, that's not going to be good. It has an asylum program. Yeah. It's not a strict border where you can't cross. Yeah, because that would be completely unreasonable. Right. So it's like, okay, what's your case? Yeah. Exactly, yeah. So now let's look at the cells, the immune cells that are responsible here.

There's tissue resident immune cells, which are the tissue resident memory T cells. These are tissue resident, meaning they hang out in the lung. Okay. Then there are these things called the alveolar macrophages. These are macrophages. So these are innate immune cells. These are the beet cops, the infantrymen. They hang out in the alveoli They were discovered by Eli Metcinov In the 1880s He won the Nobel Prize in 1908 for it They basically hang out in the alveoli Which are these compartments

The interface between the blood and the outside world I mean it's like literally the border Yeah they're the border cops Yeah yeah yeah And in the past we used to believe that the memory T cells Which are our special ops they remain dormant until there's a specific target antigen that reappears. But the data from this particular paper shows that there's actually a radically different dynamic.

When you put that nasal spray in, those tissue resident memory T cells, they actually broadcast training signals to these infantrymen, these alveolar macrophages. So the special operations people actually have an active channel of communication at the beginning of the inciting incident. Initially, the thought was the inciting incident happens. The infantrymen, the innate immune cells respond. There's no communication happening necessarily. But then because they're losing the battle, then we bring in the big guns.

But actually what we're sort of seeing or saying here is the special ops, the adaptive. primed by that nasal spray. Right. And so now they because they got primed by the nasal spray, they're already presending information to the border where we have these innate immune cells to say

hey, be on alert. There might be a caravan coming through. And because of that, it actually makes the effective response better. Yeah. No one goes to Hank's for his spreadsheets. They go for a darn good pizza. Lately though, the shop's been

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While supplies last, selection varies by location. See associate or Lowe's.com for details. But I still... Okay. Let me wait. And so the question is, okay, how does that dialogue actually happened. That was my question. Right? Like, how are you talking to one another? Well, the dialogue happens from something called rank L. They actually identified what this is. This is the receptor activator of nuclear factor Kappa B ligand protein. Okay. Okay. This is a protein. These T-cells

broadcast high levels of this protein. Okay. And the crucial proof was if you were to block this pathway, you were to block this protein, this antibody, the antibodies would completely vanish. This response was completely not there. So when this was present, this rank L, when present, the antibodies would generate and form and it's totally fine. When it wasn't present. You can artificially take it out.

Right, right. Then there's basically a delayed or no response. Yeah, exactly. And so what you're actually doing effectively is you're teaching these macrophages, these infantry men, new tricks in some sense. So now the question becomes, well, how are you doing that? Yes.

These macrophages, I thought, you know, they're kind of dumb, innate immunity. How are you training them to be immune and really select certain things and like become this more effective cop in some sense? Well, it turns out that they acquire biological memory, not through genetic recombination, which is what we get from. the special ops, but through epigenetic reprogramming. What's happening is, you can imagine in epigenetics, right, your entire cellular genome is like a library. All of your DNA is like a library, but it's massive. And every single cell is specifically only reading certain books, right? Only certain parts of the genome are actually being expressed in certain cells.

Now, a vast majority of these books are tightly shut through epigenetic markers, and what ends up happening is there are proteins called histones that wrap around segments of DNA that they don't want the cell to look at. What's happening with these particular macrophages is that level of books being shut and open is being changed. There's two types of chromatin. There's heterochromatin and eukromatin. Chromatin is like our DNA. Heterochromatin is all of our DNA that's being packaged up so that no one can read it. Echromatin is kind of the histones are spread out, and you can actually read the DNA and make proteins out of that DNA. It's like an encrypted versus a non-encrypted messaging channel.

That's exactly right. And what they could see is that the rank L signaling was unspooling the DNA. DNA and making parts of the DNA more visible. It was left out in the open in the context of like a heterochromatine becoming more like more eukromatine. Exactly. And very specific parts of that DNA were becoming more accessible. Meaning like certain books in the libraries, which had good things in those specific books.

Like how to identify stuff. How to be a better cop. That's actually fascinating. Yeah. Oh, man. really good. Yeah. Because you can you can sort of imagine like it kind of makes sense where it's like you don't too much information is going to overload any system. And so you have to be selective about what information is displayed to what party you when. And that coordination problem at the

level of the body is orders of magnitude like because of the number of constituent parts and and combinatorial product like the processes that stack on top of you. each other. It makes my head hurt. Yeah. Yeah. There's too much, right? And it's just pretty cool that we could like get down to this level. That's crazy. Of chromatin remodeling who understand it, you know? Isn't epigenetics

still something as a concept that is in its infancy? Very much so. Compared to like DNA for example? Yeah. So I think the reason it's fascinating to me is you know, we're continuing to chip away. at the understanding.

And it's funny how epigenetics plays an increasingly more important role as we get deeper into the understanding of these systems. Exactly, yeah. And one more thing that I want to touch on with this paper is they ask the question, well, where are these cells interacting? I think you're going to like this one. Okay. Because there's a cool mechanism about how they actually did the science and then what they actually found out.

Okay. Okay. So the question is, where are these immune responses actually happening? Okay? So usually when you want to answer that question, what you do is you take a bunch of lung tissue, you put it into a blender, and then you run some transcriptomics, and you try to figure out what part of the genome is being read. When you say a blender?

A literal, yeah. Okay. Yeah, just mix it up. Okay. Then you put some transcriptomic stuff in it, which tells you like what part, like what is the MRNA profile. Got it. Right?

But because it's in a blender now, you don't have any of spatial. Yes. You've lost all of the spatial information. Yes. Right. What we'd want to do is try to figure out where the genes are being transcribed. Like in a tissue. I take a slice of lung, let's say, from my mouse.

And I want to figure out where is the immune response happening geographically? Yes. Okay. Yes. So they used a technique called phenociter. fusion. It used to be formerly called codex for spatial proteomics. Here's the idea. Okay, so normally what you do is you want to figure out where the proteins are, right? Where specific proteins are. So you make an antibody that is tailored to stick to that particular protein. It sticks to that

particular protein. Each of these antibodies has a fluorescent dye on it. So it's going to glow in the dark in some sense. So if we look at the photo we have here, each of these antibodies, antibodies is tagged with the fluorescent dye. Each of the different colors tells us what different antibody there is. And there you go. You've got a geographic map of where the stuff is. Now, you're limited to mostly like four or five different colors, though. Okay.

Right? Because you don't have that many dyes. You don't have that many lasers. Yeah, yeah. So what if we want to do like hundreds of different types of proteins? How am I going to actually do this? Well, with Codex, with this. phenocidal or fusion,

here's what we're doing. The antibody is actually not attached to a dye. It's attached to a piece of DNA. Okay. Okay? Each different type of antibody is attached to a piece of DNA. Then we have another piece of DNA that is complementary that is attached to a die.

And so now you have a barcode and you have another barcode. Do you already see it? It's so nice. Okay, so here's what we're doing. Here's what we're going to do. This is good. Right? The antibody is attached to a DNA.

I have another piece of DNA that latches onto that DNA. It's complementary. Just the A becomes a T, C becomes a G. That attaches and that has a bit of dye. Okay? So when I'm like looking at a Where's Waldo type book, right? And let's say I want to find all the people with red hats. I have a little thing that says attached to the red hats

and then I take a picture. Then I wash it out and this is the next photo I think you'll see. This is the cycle. I attach, I take a photo, I wash it out, I attach with another barcode, I take a photo. The key is I can take a photo with the same color of light.

But because the primer is being attached at different locations, I now have a snapshot at every given point. Yes, yes. And so I can expand the number of proteins that I can actually image. Right. Because you're no longer limited by the number of dyes and lasers you have. Yeah. Because the mechanism to make the connection is now, it's one part of DNA connected,

the other part of DNA. On the other side of it, it can have a whole range of stuff. That's very, very, very, very clear. It's only in the last five years. This was also developed at Stanford. This is a very clever. This is a very clever technique, I have to say. Yeah, no, that is, that's quite nice.

Because it feels non-obvious as a choice. Yeah, but then once you think about it, you're like, oh, yeah, yeah, yeah. That's why I literally, for those who are listening and not watching me, when you said after you almost got through the second or third sentence, I almost fell out of my chair because I immediately understood. Yeah, I was like, oh. Come on, it's so obvious. Yeah, but why I mean?

It's so nice. It always takes one. Yeah. And so here's what they found with that. Okay. What they actually found when they looked at these lungs, they found with spatial imaging, tertiary lymphoid structures. Here's the idea.

Usually, when it comes to this adaptive immune response, the antigen has to go to a lymph node. It's got to get integrated there. The T cells has to recognize. And then it's got to come back. This is going to take weeks. Okay? What they see in the lungs of these mice,

is that the immune cells are rapidly congregating and building up pop-up makeshift lymph nodes. Like on the battlefield, they're doing management and creating like little, I don't know, you know what I mean? Yeah, yeah, yeah. Yeah, they have these outposts at specific areas on the battlefront.

On the battlefield, in the lungs themselves. That are relevant to the middle. So you don't have to go all the way back to the lymph nodes to figure out. So in this analogy, if you have a central command that houses the core intelligence pieces, what's happening is we're actually getting

these satellite outposts that have localized intelligence and relevant information so that people who are nearby don't need to wait because they already have basically, you know, preloaded, not preloaded, but they already have the relevant

information that those that are nearby are able to access without waiting for the signal to come back from central command. Yeah. Tertiary, what was it? Tertiary lymphoid structures. Yeah, lymphoid is the lymph nodes are like an organ system that coordinate the immune response. And here that organ system is now creating little tiny outposts.

Yeah, yeah, yeah. Yeah, all crazy. Which, which again, if we look at just like military tactics as a reference point. It's like so, it like maps on almost perfectly. Yeah, it's kind of crazy. It's kind of crazy. Yeah, it is kind of crazy. It is kind of crazy.

The one that I got really kind of excited about was the idea that it could actually help allergies and allergy asthma. Because it turns out that allergies are basically a maladaptive response to harmless allergens, right? It's like the immune system just kind of going, ah, what's going on? What is this? What's going on, right? But this particular vaccine, it's designed to aggressively bias the immune system towards antiviral sort of. innate immune response rather than like, oh, I recognize something that's bad. And the vaccinated mice, so on the left, you see naive mice that are control.

In the middle, you see unvaccinated mice that are part of this HDM challenge, which is effectively you're introducing like an allergen to them. You see lots of mucus build up, right, in the middle. On the right hand side, it looks more like control. It looks like I don't got a stuffy nose. Yes, that's exactly right. So it's actually like sort of calibrating

that allergy response as well. I mean, I think this is huge, right? Because it's, first of all, it's a completely different way of trying to understand how vaccines were. Right. And how to implement vaccines. Right. Right. It's no longer a lock and key mechanism. It's literally just saying we're just

going to prime the immune system to be on high alert. And for something like a pandemic that's happening in the future, it's going to happen in the future. Yes. Right? There's a pandemic coming.

This can be kind of a stopgap because imagine there's a pandemic that comes out of wherever. You can fly out these vaccines that don't need a sequence of whatever pathogen there is. I don't need to know what COVID-19 is or what COVID, I don't know, 2027 is. I can just fly out these vaccines and whatever health care worker is going to, going in there or whatever, their immune system is going to be primed for whatever random crap is coming in their way. Yes. This is, it generalizes vaccines in a way where you can have an inventory and stockpile of this generic.

Again, this is early. Exactly. This is an early. Very early. Very early. Only in my. Cava caveat, caveat. Yeah.

And I'm going to get into the caveats later. but I still think it's because it clearly there's mechanisms that mean that this makes sense. Yes, yes, exactly. That's the big thing, right? Clearly it worked in mice,

which means that we're just mammals. Like maybe this might not work. Right. But it's a paradigm shift, I think, in how we think about vaccines in general. Yes. And the idea of priming our immune system

in an early way. I mean, it makes total sense. Like if, I mean, this is maybe a bad a bad. Like if you're if you're going to do, if your body is about to go through trauma. Yeah. Like let's say you're going to run a marathon. You're going to want to train before the marathon. And this is sort of a means by which for us to arbitrarily activate the immune system because it has the capability. Like back to what we said before. It has the capability to deal with the problem. But it doesn't necessarily have enough of a running start to deal. with that time gap problem we talked about earlier.

Yeah. And if we just give it an extra little bit of a head start, its natural response will be better at taking care of the situation. Exactly, yeah. And I mean, there's caveats, right? Like, I think the researchers, when they go into human trials, they need to make sure that it doesn't cause these things called cytokine storms, which is this auto-inflammation where the immune system just attacks the body itself, right?

Gets confused. Yes. I can imagine there are some problems here, right? Where you're like, you've basically just put the immune system in your lung on high alert. I mean, one would make the analogy that if you have a nation with a border, and then you create an overzealous police force to respond to that, you might start ending up shooting people inside the border. Right, right.

When you're focused on people who are coming from outside the border. Yes. So as an analogy, of course. We do not want to have an overzealous immune system. Exactly. We're going to start shooting our own people. Yes, because that would be, everyone agrees that's bad, right? We don't want our body to die.

We don't want our own cells to get affected. We want to get the threat. Yes. Yeah. So that's something that's an issue, right? Yeah, totally. Scytokine storms, also known as. Nice.

We're not going to put. this on Instagram because apparently people got very about a joke. Anyways, but that's one of the that's one of the you know caveats of these like the immune system is

notoriously finicky right so we don't know but at the end of the day I think it's a lot of very cool fundamental research that's happening I think it'll be very very interesting to see where this leads this this this was you said that I was going to like the vaccine

story I think it's a very I tend to, and apologies for those who sometimes feel like we're getting a little too deep, I tend to like the stories that have a really keen, fundamental insight about something that was non-obvious and required a little bit of creativity or outside of the box thinking to problem solve from an experimental design and solution perspective. So that one was quite nice. Yeah. That one was quite nice.

We started off really far away, and then we ended up. Really, really close to home. Our first story was our astrobiology story out of PNASNexis, Johns Hopkins University. This was on our idea of understanding panspermia and the three aspects that are necessary in order for something to an organism that's life on one rock to make it to another rock.

One and a half of those threes was already kind of solved, but this was a new one that's now solved, which is the initial departure from the life. Getting off the planet. On high impact. We ended with this immunology story about the one vaccine to rule them all

in a different approach. Instead of going after a pathogen specifically, can we prime the pump in the immune system to just have a better, more generalized response with some interesting dynamics of understanding how adaptive and innate immune cells communicate with each other on the battlefield. Several good rundown stories.

If you've made it to the end, you are very special because you get to get a prompt for a comment of the day. I want to call out, I'm going to pull this up real time here because I didn't do so earlier. I want to call out one of the previous comments from last week's episode,

which I think there were two that were, one at least, was quite good. The second one might be okay. And I think this one came right before we started recording. And so please bear with me. Okay, yes. So two days ago, this was for our last episode. We asked for come up with a better acronym for GPLD1.

Yeah. And so one of them was garlic pepper lemon dip because apparently we made someone hungry. So garlic pepper lemon dip sounds actually quite nice. And then we had another one earlier today, which, I guess may have been on YouTube because I'm not seeing it here. And so this is now bad and a bad plug and I don't have it pulled up. Let me pull up YouTube really quick. If you listen this long, you're in it for the long haul.

Yeah, you're in it. Just keep listening. Just give us a second here. This is bad pre-production prep by me. But I want to make sure people get there just desserts here on some of these really clever references. And nope, I don't see the one. All right. So I failed on it.

But what should we have for the comment this time? This was a good one. Penspermia. Yeah, a different definition for Panspermia. Yeah. That's exactly what I was thinking. Yeah. I like that one.

What do you guys think? I like that one. Give me another definition. I like that one. That is quite good. I'm your host. Yeah, please. 13.

13. P.G. 13. Kids can go to PG 13. It's not that bad. Yeah, it's not that bad. I am your host, Lester Nare, joined as always by my co-host and our resident PhD, Krishna Chowdary. I'll make one last reference. He's wearing a SpongeBob t-shirt today.

I don't know if you've heard of this music artist called Glorb, G-L-O-R-B. So he took AI to voice all of the characters in SpongeBob and then dropped some of the craziest rap beef tracks, two or three years ago where it's like SpongeBob and Patrick and Sandy and Mr. Craves and Plankton voices are rapping on trap beats and I'm not going to lie I was actually listening to some of his tracks earlier today on the way home and you need to send me so it's this is not I learned English on SpongeBob the this music is not PG 13 so parents and we do not it's not PG 13 but it is the the voice duplication is incredible.

Wow. And there's like a beef between the chum bucket and the... Oh yeah. It's great. And crusty crab? It's great.

This is no longer about science, so we will sign off here. We will see you all next week. This is from First Principles. Did you know if your windows are bare, indoor temperatures can go up 20 degrees? Get ahead of summer with custom window treatments like solar roller shades from blinds.com

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