Astrobiology’s Biggest Survival Test + A Vaccine Against Everything?

Intro — astrobiology, immunology, and the Dave Chang / Netflix shoutout

0:00One 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 have. Hello internet, this is your captain speaking, Lester Narai, joined as always by my co-host and our resident PhD, Krishna Chaudhary.

0:40We are back for another week of science news. This week we have two phenomenal stories that we're going to 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, will be dropping this week. So, be sure to check that out. We got some phenomenal food. Yes, amazing food. From the goat. It was a great time. Shout out to Dave Chang and his team. Uh super big fan of science. A great example of how science impacts all of us and curiosity. There is not a monopoly on curiosity

1:23about 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

2:04first principles.

Story 1 begins — can life survive being blasted off Mars?

2:21Our 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 Johns Hopkins University on March 3rd. Yeah, this is very recent. >> Fresh off the presses. Yeah, very

3:02recent. 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 seeded life on Earth. This is the idea of lithopanspermia. Litho meaning rock, panspermia meaning this sort of like life everywhere type thing, right? And um for the longest time, it's kind of been

3:42just like kooky 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 Deinococcus radiodurans, which is a bacterium that colloquially is known as the Conan the bacterium because it's like indestructible. You know, like Conan the >> Barbarian. >> Yeah. It's like indestructible. And what

4:24they've done is do experiments about what this bacterium could survive through, and it turns out it's a lot.

Lithopanspermia explained: life traveling rock-to-rock

4:30Something like 14,000 times the atmospheric pressure on Earth. >> Okay. Um 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. >> Mhm. Okay? Now, why does it matter? Well, very recently, we've had the NASA Perseverance rover announce a discovery

5:11of 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? Mhm. Um 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 You to be a bit careful about returning samples onto Earth. Because if we bring something back and it's got a little,

5:52you know, thingy thingy in it, we don't 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 Anaxag Anaxagoras. Okay, like 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

6:33front of the sun. He was the first guy to do that, 5th 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 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 had now have of like

7:14stuff going in, collisions uproot material into space and then that material comes into Earth. And then in 1903 there was this guy Svante Arrhenius. I think any chemist in the audience would know about the Arrhenius equation and all the great things that Svante Arrhenius did. But one of the things that he formalized was this idea of radio panspermia, which is the idea that microbial spores, which are small enough, at that time they had figured out how small in mass these these microbial spores were, they could be propelled by the pressure of light Mhm. to move across space. And so that was his idea, radio panspermia. Now, in the 1900s,

7:55this 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 Deinococcus radiodurans. This is our Conan the Bacterium. >> I see. Okay? This is the bacterium that

8:37will 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 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 a you put it into Chernobyl and the meat still spoiled. So there's something that grew in it. And when he isolated that, he came up with this bacterium called Deinococcus

9:18radiodurans. Um in the 1970s, there was also the discovery of hydrothermal vents. Yes. >> now you have life thriving in total darkness, 400° C, 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 acidophiles, which are life that live in sulfuric acid. >> They literally live in sulfuric acid at a pH near zero, which is worse than

9:58bleach, but they're just like living there. Hyperthermophiles that live up to 122° C. The record holder is something called Methanopyrus kandleri. Kandler? Dude, 122° C is insane. I I I Right? Again, high pressure, which is why the water isn't boiling. Water usually boils at 100° C at sea level, but if you do it high pressure, the water's not going to boil. That's why a pressure cooker works, right? >> That That makes sense. >> Um A lot of really really crazy things. Halophiles in in They flourish in salt concentrations that are five times that of seawater. You can see this in the Dead Sea and You can also see this in Halo players who eat a lot of Doritos and chips and Ruffles. Halophiles as

10:40those who might not know. I used to be a halophile in in high school. >> Mate, I I Let me tell you something. Halo 2 and Halo 3 in 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 >> Blood Gulch? Like what? And and I remember it was back in the day when like there wasn't really internet to host these collaborative parties. So, you had to go to your friend's house and I remember I in the valley there was a 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-op. So, four four versus four. Oh my

11:20gosh. LAN parties. >> LAN parties? 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. Um, 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 like >> So, now it's no longer the case that like life needs this like perfect setting. The Goldilocks >> Yeah, the Goldilocks stuff, right? Yeah. >> And um, one one of the big things was in

12:021996 Bill Clinton announced possible ancient Martian microbial life in a meteorite that they found in Antarctica in 1984. I I have to ask because you did such a good job uh with the JFK impression, if you could if you could do the voice. >> he goes he goes he goes I did not find life, but I think we found it. But, I did not have sexual relations 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

12:43was largely refuted, but the rock transfer, the fact that that meteorite came from Mars is actually not disputed. Meaning meaning that that the origin on Google Maps its original starting point >> is Mars. >> is Mars. >> Not Not everyone's fine with. >> Okay. The fact that there's life on that meteorite, that's what everyone's not fine with, okay? They 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 Right. >> 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

The three bottlenecks: ejection, space travel, reentry

13:24mechanical challenge of planetary escape and then getting to Earth. Mhm. >> Okay? So, there's three bottlenecks when it comes to panspermia. Three things that prevent it from be like being realistic happening. >> Yeah. Yeah, exactly. There's 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 microseconds and it's going to eject stuff into space. You got to survive that impact. >> Mhm. Okay. Once you survive the impact, then you got a journey through space, millions of years in a vacuum, there's cosmic radiation, there's extreme cold,

14:05there's UV, right? And then at the end of the day, after you've done that journey, you've got to survive re-entry. Mhm. Okay? Mhm. So, You have to be big and bulky to survive impact, you have to have endurance to last a long time, and and and you maybe more also endurance and being big to survive re-entry. >> Exactly, right. So, the two and three, which is surviving space and then surviving re-entry, that's actually been a 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

14:48outside the International Space Station, and it turns out these things can survive prolonged space exposure. >> Mhm. If they're shielded by a few millimeters of rock. Interesting. >> So, if your life is just a few millimeters millimeters the surface, yeah. Underneath the surface of whatever asteroid, it's going to survive not only the vacuum of space, but also the re-entry into Earth. That's actually quite I I I think if people were to try to guess, if you have a a piece of rock floating through space with the little little thingies, little micro thingies on it, Uh how deep do you think it needs to be to be able to survive? I think very few people would have said

15:28guessed millimeters. >> Guessed millimeters. >> You would think you need a little shielding, you need a little maybe a couple inches, maybe a couple feet, yards. >> you don't need a lot. That's actually really cool. The interior of the rock actually heats minimally when you go into atmospheric entry. >> Oh, yeah. Okay. That's that that's the idea, right? And they actually found that this particular bacterium, D. radiodurans, Mhm. it was already It's like survived space-like conditions and it's the best at it. Oh, okay. Okay. >> 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? Cuz we already know it can survive outer space and re-entry. We need to know if

16:09it survives the ejection. >> So, it can survive two and three of the three bottlenecks. We have ev- we have uh uh uh data, experimental data, that shows that to be true. It's not It's not theoretical. >> Yeah. But number one is still Number one is still yeah. Like it's 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

What we already knew: survival in space + survival on reentry

16:30space, most of it should be dead. That's the prevailing theory. This experiment is putting that it it's challenging it. Okay. Right? All right. Science is always a process. >> Yeah. And sometimes things get >> it's a totally reasonable thing >> Yes. to be like, "Hey, a meteor impact is like several atomic bombs. >> Yes. Okay. What what are we talking about? >> 100%. >> Right? 100%. So, okay, let's talk about this um elusive bacterium, D. radiodurans. Okay? Why is it the right test subject for this avenue of research? Okay? Well, for a lethal dose for a human being, lethal dose being like, you know, 50% of us are going to die,

17:12it's about four grays. Gray is like the unit of radiation that you get. Chernobyl, Glenn. I just I just want to 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 4-ft ones that have the big eyes. The classic. So, only four of them will kill us. Okay. Yes. >> According to >> According to According to the study. Uh according to um what we've done radiation studies on, four grays will kill us. E. coli takes 70 grays. >> Okay. Okay? D. radiodurans takes 15,000. Yeah, that's a So, it can survive 3,000

17:53times the human exposure and 200 times the E. coli exposure. This thing is insane. That's why it's called Conan the the bar barbarian >> the No, Conan the bacterium. >> The Conan the bacterium, yeah. So, even those 4-ft aliens, yeah, 3,000 times the dose of those 4-ft aliens. >> That's how they got here. That's how they got here, dude. On the backs of radiodurans. Now, why is that the case? This This bacteria is amazing. 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

18:34radiation, within 3 to 5 hours. That's unbelievable. >> Like I dose it with 5,000 grays, which is again 1,000 times what humans can take, >> Yeah. within 3 to 5 hours, its genome is back. It's like the science fiction thing, That's unbelievable, especially after

The new question: surviving the initial impact shock

18:50the episode we talked about how our genomes our DNA degrades over time. >> Yeah, yeah, naturally. Naturally, this thing has repair mechanisms >> really cool. >> in order to just keep itself alive. The ring structure of the nucleoid 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. But the double helix is wrapped around in a torus. Which gives it a little extra help. >> 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,

19:31okay? So, it's got physical proximity for easy reassembly. It also has multiple genome copies. Every single one of its cells has four to 10 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. Um 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

20:13rust, right? Iron rusts in normal atmospheric conditions cuz 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

20:53got this like fundamental unit and it repeats itself. Yeah, yeah. It's kind of like a shell Yeah, yeah, yeah. around the bacterium that is keeping that is like reinforcing that structure. It's it's It reminds me of when people talk about fractals. Yes. Like fractal patterns. >> It's like super structure-y, right? It almost looks like a virus, but it's the size of a bacteria, which is 100 times larger, you know? Um and it acts like a suit of armor providing this immense structural rigidity. So, there's there's a there's a There's the physical structure of this bacterium is such that it gets this extra layer of

21:36outer protection and has this genetic benefit 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 that'll just get right on it. >> we we got more." Yeah. Exactly. >> They got It's It's like the robots. When we replace humans with robots, it's just like where you can manufacture them quickly and it's not unique, you know, and all the the time it takes to have a human grow to be an adult and stuff like that. You can just be like, "Oh, robot out of the factory. It's already got it. We're ready to >> Exactly. Yeah, dude. Conan the bacterium. >> bacterium This guy is crazy. Okay, so now let's look at Can this thing survive

Deinococcus radiodurans — “Conan the bacterium”

22:16an 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 .0001 gigapascals of pressure right now. Where we're at. Okay. Okay. The Mariana's Trench is at .1, which is about 1,000 times more than at sea level. >> Okay, can I ask you a question? When you say pressure, how for our audience, like how would they experience what that means? Like cuz we do experience what 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

22:56defined 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, >> Mhm. there's not a lot of pressure. >> Yeah, yeah. But imagine now I have a pin. Mhm, yeah. >> Right? Like the thumb tack. >> Yeah, that does it. >> And now I push. Yeah. Why does it go through my hand? 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 really good analogy. Yeah. >> That's That's what I mean by pressure. It's like per per amount of area on your surface, how much is it pushing down? >> Mhm. Okay? At sea level, it's not a lot.

23:37I 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 like get crushed. Um unfortunately, do you remember the the Titanic? Yeah, it was the submarine thing. >> submarine thing? When you get down there, there's so much pressure, and the thing gave way, everything collapsed, right? And then it just like completely killed everything. >> Yes. >> So, that's That's pressure acting, right? >> Okay, okay. >> And at the experimental low end for this particular paper, you've got 1.4 gigapascals. That's 14,000 times atmospheric pressure. >> Jesus. And on the high end, you have 3 gigapascals, which is 30,000 atmospheric pressure. Now, why do we need to

24:19Why do we need to like go that far? Okay? >> In terms of the amount of pressure is well outside what we as humans >> as humans, right? Like like even on Mars, Mars is actually low pressure. >> Mhm. 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? The reason we care about high pressure is to escape Mars, the rock has to es- to reach an escape velocity, right? In order to get all the way to Earth or something like that, which is about 5 km per second. Okay. On Earth, it's about 11 km per second. But in any case, to get that fast, direct acceleration means that you need like 50

25:00gigapascals of pushing I see. >> in order to get there. You're never going to survive that. On the other hand, in 1984, there was a theory called the shockwave spallation theory. This is the idea that an a meteor is going to come in and it's coming in so fast that the the ground is going to act like a viscous fluid. Oh wow. >> And that's actually what happens when meteors impact. They're coming in so fast with so much energy that the ground, the shockwave 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

25:41you've Yep. 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 project tile stuff Mhm. >> 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, that is about a 5 gigapascal to 1 gigapascal shock. Now, that's lower than the 50 gigapascals that we thought was going on, right? So, 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 up.

26:23>> shot back up as a rebound. And that rebound might be enough. So, it's still it's still 330,000 times the atmosphere of the Earth, but it's still it might be enough that these things survive. The other clue as to why it would survive is because it's not really a sustained pressure. This is transient. This is This happens over like a microsecond. This thing impacts, this thing goes in, the the pressure that this thing that the ground feels 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 this this makes sense. So so

27:03just to briefly summarize and cuz the the idea is when we are trying to ascertain uh if panspermia is a thing, which means life arises on one rock and then moves to another rock that's orbiting around a star. The the life on rock number one needs to be able to have enough to escape the atmosphere. Yeah. We have rockets. But in lieu of rockets, you have some object come, disrupt the ground and it with enough force such that it shoots stuff out of the gravitational pull of the rock that you're on. And so now you're in space and you're traveling around. And so

27:45there 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 and this is the theory, right? The thing comes in, there's a rebound, and then it gets flung out into space. And so now we get to the actual paper, right? The actual paper, and if we go to photo 14 >> Yes. is a paper in PNAS, which is the Proceedings of the National Academy of Sciences. Um not that other word you weirdos were thinking about. >> No, this is PNAS. Everyone knows about PNAS on science, guys. Come on. Um it's about extremophile survives the

28:25transient pressures associated with impact-induced ejection from Mars. That's exactly what they're doing. They're making the case that this particular bacterium, D. radiodurans, can survive that insane pressure all the way up to 3 gigapascals. Right? >> That's that I mean, that's a big because that totally changes the calculation when we talk about things like the Fermi paradox. Where is everybody? >> And we're going to we're going to get to that. We're going to get to that. So let 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

29:07um the radio duran cells, the bacterial cells in this like circular plate Mhm. and they sandwich those cells, this about a billion cells that they they put inside like a petri dish, but it's like a circular petri dish. They sandwiched those cells between two large steel plates >> Mhm. and then they seal it. It looks like it almost looks like a Canon 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 are going to hit it with a gas gun. Okay.

Why this matters for Mars sample return and planetary protection

29:46>> Okay? The gas gun looks like the following. You've got You've got um the projectile which is your flyer plate. Yes. That's another piece of steel. Okay. And that that piece of steel is going to be propelled by gas. It's the same like kind of like, you know, in like car mechanic shops where you have like the the gas hydraulics. >> Yes. >> It's I mean it's obviously more sophisticated than like the car but it's the same thing, right? It's like a gas gun that is like propelling a fly a flyer plate to impact the plate that has your bacteria, okay? And then when you impact that bacteria, that is going to create the microsecond strain that mimics the asteroid impact on Mars. So so the

30:29idea is that this in this in this graphic we see on the left, there is this this this projectile, there's a wedge and a flyer plate. So that is what is shooting out. >> Yeah, with a gas like it's it's high high gas that shoots out and it shoots into a a circular plate. It if you go to the the gas station or a car wash, there when you pump your tires, you click the thing and shoots the air out. >> Yeah. >> Yeah. Just conceptual. >> Yeah, that's exactly this. >> It's it's shooting at at levels that are not pumping your tire. >> Yeah, yeah, yeah. This is this is much higher pressure. And and the advantage here is that so I'm shooting my gas plate and interacting with this plate that has my sample, right?

31:10>> Yes. I can I can polish the other side. Okay. The back side. >> side. Okay. Such that it's a mirror. Okay. >> 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 to reiterate, the laser is the means by which you can measure stuff. >> Yes, exactly. >> measurement instrument. >> measurement instrument because we're so good at lasers, 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, right?

31:51>> And 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 it's so clever. I I really like that actually. Cuz 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, >> they're recreating exactly the Pascals, like the amount of pressure, the amount of transient, 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 it's quite nice. And so now let's see what they're actually doing, okay? What are the findings that they actually get?

32:31How they measure is the number of colony forming units. And this is something that we used to do in microbiology lab, as well. Um 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'll give you a proxy for how many survived because you knew the initial concentration of how many bacteria you put in into that like Yes. apparatus, right? And now let's look at the results, okay? It's insane. All the way up all the way

33:12up to 2.4 gigapascals, you had 60% survival. 2.4 is 24,000 times that on Earth, right? The survival falls below detection limit only when pressures exceed three gigapascals. And one of the cool things was um Lily Zhao, who's the one of the senior authors on the paper, >> Yes. she noted that the hardened steel experimental containers began to structurally fail before the bacteria actually got eradicated. >> What? So the point is our own engineering was not even sufficient enough to get to levels where the bacteria were >> bacteria were like chilling,

33:53right? They were like at least 20% were still alive, but like we couldn't test further because the we were testing pressures where the steel was like, "I can't I don't know what you want me to >> the material science for it. >> Yeah, exactly. It's fascinating, right? And if you look at standard microbes, right? E. coli plummets to 10 to the minus three to 10 to the minus six survival rates below 2.2 gigapascals. Yes. Our radio durans, Conan the Bacterium, achieved very high rates. So Conan the Bacterium is the green dots on the very top. All of the other stupid bacteria are surviving way lower. And this is on a log scale on the Y axis. And then so

34:33just to be clear, we're looking at a graph here that has pressure on the X axis. >> And X axis is gigapascals, and then survival rate on a log scale on the Y axis. >> Yeah. And there's all the other stuff that's like in the middle and like >> Yeah, it's like E. coli and yeah, yeah. But at the top is our radio durans at multiple different pressure types, it's very consistent. Okay. So so Conan's Conan Conan is sick, dude. He's He's surviving everything. Okay. Um this is where it gets really, really cool. Okay? Cuz so far, okay, we've we've shown that this radio duran survives. Right. Again, coming back to the original point

35:14here is starting off with this idea of is panspermia 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 There's no way. >> There's the level of force necessary to eject you out there. It's just going to

35:56kill you. You're You're You're dead. >> Yeah. That's the current paradigm that the paper has now experimentally shown on Earth 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 um transmission electron microscope images of these bacteria, you can actually see that at higher pressure >> Mhm. the cell walls get ruptured. Yes. >> Okay? So, that's why the survival is going down. >> Right. >> Because the the cell compartment around it is getting ruptured.

36:37>> Mhm. 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 2.4 gigapascals, a bunch still survive. >> Mhm. Right? Mhm. So, so what we're seeing is there's three images here. On the far left, we see like sea level, I'm guessing. >> Mhm. Uh where you can see the >> like it's like it's normal. Yeah. Control yeah. >> The You can see the structure of these four bacterium. >> Mhm. Totally Totally fine. Totally fine. >> At 1.4 gigapascals, there's clearly a rupture in two There's two There's clearly the rupture that's happening. >> But, they're still fine. >> But, they're still fine. They're still right. Right. And then at 2.4, there's one that's not fine, but two that are

37:18fine. >> Yeah. And it's just like, "Yeah, like you you were just weak." >> Yeah. Yeah. Yeah. Yeah. It's That's evolution baby. >> That's That, but that's I I I want to say >> that's 24,000 times the the pressure on sea level. That's still insane. That's way more than Mariana's Trench, for example, you know? It's 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 >> Mhm. of the bacteria that survived that pressure, okay? So, you've got an impact. >> Mhm. Certain things die, but you've got colonies that are made. What is the specific DNA that those

38:01bacterium are translating into protein, right? What's the thing that's being made into mRNA that is being translated into protein? What do these bacteria care about >> Yes. >> once they've been hit by a meteorite? >> 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 um 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.

38:42>> That's actually so fascinating, especially if you if you've uh are coming back as a listener, this is an area that we've touched on in multiple stories and in the human uh context in terms of how our body does repair. >> Yes. Um in a number of different contexts. And this is fascinating cuz in all of those contexts, there was not an increase in the sort of immune response it's like or or DNA repair response based on an external like pressure. >> pressure >> Like literal physical stress. >> did not cuz the immune response is there, but the DNA repair process, which is kind of its own Yeah, but these guys these guys are just

39:23responding to the fact that they just got hit. >> That's cool. They just got hit with this giant microsecond timescale high pressure, right? Which like totally messed up their internals. And what here here's the other thing. Stuff like um 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 We're going to stop the normal I don't know what just

40:04happened, okay? But I just got hit by a 2.4 gigapascal bullet. >> Yes. We need Let's just stay alive and then 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 you just reallocate resources. >> reallocate, but it doesn't it doesn't get into it. That's that's fascinating. >> Yeah, I thought it 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

40:46this giant 5-gigapascal impact it's going to sterilize everything. That's no longer true, right? Certainly, we we have a bacterium on Earth that can survive that. And that that's we have and we only have one source for reference in a in an infinite galaxy. I'm sorry, infinite universe, excuse me. Um an almost infinite galaxy in comparison. And it on the first place, we have the thing. Yeah, 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.

41:26>> 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 like we know how rocks sort of burn up and things like that. So, we can sort of make theoretical predictions. 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 who are we? Aliens! Aliens? Are we

42:09aliens? Are we aliens? >> Are we aliens? >> We might all be illegal immigrants. so I mean who knows? >> Right. Because Mars, way back in the day, had a very nice climate. Mhm. Right? When the when 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. I mean, that's obviously where Elon is trying to re-bring it back. I mean, he's trying to go back home. >> Um and so it makes total >> Yeah. 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 COSPAR, and they have this thing called

42:49a 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. >> to be the colon- the pilgrims. Yes, exactly. And we don't want backward contamination like, you know, some life coming in on Earth and then killing everybody. Yes. Japan, the Japanese Aerospace Agency, has a mission called the Martian Moons Exploration, which is going to go to Phobos, which is one of the big Martian moons. >> Mhm. Um it's going to launch in 2026, and it's going to return in 2031 with 10 g

43:32of 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 >> millions millions of miles. >> Millions to get, true. Yeah, millions. Yeah. Where your your window to for delivery is a very narrow window. >> yeah. You got to time it with the planets, you know? Uh it's not it's not a signal text away. >> I just want to identify like technically speaking like that is >> g is like Yeah. Like we have we have a Mars return mission that got nixed because it's too expensive. Yes. So, I don't know why we're talking. >> Yeah, right. Right. Right. So, Japan is

44:13doing 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 g of stuff from Phobos, that's going to inevitably have stuff from Mars. >> see what you're saying. >> 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 five restricted. That requires multi-billion

44:55dollars worth of biohazard containment. >> Yes. >> And then there's 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. >> yeah. 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 unsterilized Martian organism Mhm. to be less than

45:37one 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 g of stuff >> Yes. 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. no >> I mean, a high probability it's going to die. Right. Okay? It's going to be like, "Why is there 20% oxygen?" And then just die. However, >> Okay. cuz Earth is very different from Mars, even back then, right? There's a way more oxygen now. The the pressure is way higher. There's a bunch of nitrogen. I

46:18don'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 calcula- in your probabilistic framework of >> the thing with this one in a million, right? We have to do that mathematical calculation and say, "Okay, given the 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 it's a very cool paper. >> That this is it's very interesting because it sort of it it's poking in two

46:59different arenas. So, one arena is poking in is the sort of um you know, Fermi paradox, panspermia, can life go from one rock to another? We already had kind of two one and a half-ish 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. Yeah. >> To get actually even into the second two stages. Yeah. Uh 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

47:40understanding 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. >> Phobos would have it. >> 10 g that we get will have it. >> Would have it. And now we have to have a almost COVID-like conversation. >> Yeah. Yeah. Uh which is funny because our second story >> Yeah. is on immunology. Exactly. >> Which we'll get to in a moment. But fast, you know, for those of you who know, I'm the I'm the one in the pod who loves alien stories. I did not select this one. >> No. So this was organic.

48:21>> Yeah. Uh I'm waiting for NASA to stop tiptoeing around the Mars thing. Yeah. They're continuing to tiptoe around it. Well, it seems like we're not going to return samples. Oh, and and sorry. What I'm Oh, from the from the little lake that we covered Oh, we're not. >> We're not. So this is why funding matters. >> Funding is too expensive. >> Maybe we could save a couple of of of bunker busters. Maybe if like if we just like two Yeah. >> two literally two bunker busters >> Yeah. we could return samples from Mars that would identify that we're not alone in the universe. However, uh we will not see that at the moment, but we may see in the future in terms of funding. Fascinating story. Our first story of the day, astrobiology out

49:03of John John's John's. Johns Hopkins University. Uh normally I think in my head we're known for medical stuff. >> Yeah, but they have an incredible like engineering department, right? Cuz they have the Applied Science Lab. >> So there you go. Um the Applied Is it Applied Physics Laboratory? I think it's the Applied Physics Laboratory. Um and they also are in charge of the Space Telescope Institute. They have they they've they've got a pretty strong like um astronomy and astrophysics and fundamental physics. It it flies under the radar because their medicine is very good. >> just so stellar. If you are in any of those at John Johns Hopkins, uh please send us a note. Uh we'd love to make

49:44sure 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

Story 1 wrap-up — one more bottleneck may now be solved

50:19we 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

50:59simulations 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 10 times more efficient. It's 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

51:40going 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, which 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

52:20one figuration 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, that I mean the thing that comes to mind is like iron workers >> Mhm. who then heat like a thing a piece of iron on or any metal in super high temperatures 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 that And what you're actually doing there is you're

53:01like 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 That's a fundamental phase that the material is in. Mhm. 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 happen in experiment. That I'd just briefly We actually did a great episode on this exact concept, which if I recall correctly was when we talked about hypersonics >> Yes. trying to do simulations with the

53:43Navier-Stokes equation and where for supersonic flight our interpretation which is not real world accurate 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, it's there's a little fuzziness. Yes. And at different levels of stuff if you get a little bit faster the the simulation kind of breaks down a little bit. >> Yes, that's exactly right. And and what these guys have done with this D-DoS machine learning paradigm is they've captured all the possible ways that the atoms can be arranged in a material via

54:24some 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

55:05of a 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. >> Mhm. I can feed that back and inform my machine learning to do better. Mhm. Right? And the fact of the matter is this D-DoS 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 is that has a certain property at 2000° C, right? It has a certain stability. I can go backwards and do an inverse design. I can start

55:46with the material and what the properties that I want and

AI teaching atomic simulations from 150+ years of data

55:50it can tell me how I would actually construct it. The this and I don't need 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 uh around their new architecture of how they was I can't quite remember the concept name. Manifold uh uh constrained >> Yeah, hyper parameters. >> Yeah, correct. W- where in that process where you're going back the the the highways were small initially and they created figured out a way to create more lanes in the highway. Yeah, and they had a trick. W- so when you're going back in this back propagation concept you're talking about, you you just have more that you're working with uh to get a

56:30better outcome. And so And you're and you're 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 >> Yes. what 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 >> of good stuff, guys. in both season 1 and the first half of season 2. >> Mhm. Yep. >> Fas- fascinating. Th- that that that's actually super cool. >> is out of the This is um a paper that's in Nature Communications >> Yes. out of the University of Michigan engineering. Yes. >> Friend of the show, Blackbird Physics. Shout out to Blackbird Physics. He's a

57:11He's He's a great science communicator out of the University of Michigan. Um >> I I see that you left out the the left out the French university on that one. Oh, okay. Yeah, there was also a French university, Université Paris-Saclay. Well, you told me to uh told me to talk about them. That's how I I don't know how say it. That's how you say it. A great great first story uh on material science. Yep. Our story number two in the rundown um is about DNA. And so every person of non-African ancestry so people who are not me

57:54alive today carry Neanderthal DNA. Yeah, so I do. Yeah. Yeah, unfortunately. Unfortunately. All right. And it turns out the story of how it got there has a very specific direction. Yeah, this one was 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 uh human DNA and then we can sequence Neanderthal DNA. We've Svante Pääbo 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

58:36um from that we can figure out that the human 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-incompatibility, 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

59:19in their X chromosomes. So what does that tell us? >> Yes. Let's do a A bit of review of basic genetics okay? Um the female gender has XX and then the male has an XY, 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 an X chromosome from your mom okay? Now, the fact that X chromosomes in Neanderthals have a lot of human DNA, but X chromosomes in humans don't have a lot of don't have a lot of Neanderthal DNA, that suggests one thing, which is that

1:00:02the 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? 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 Neanderthals, not the X. But the the Neanderthals were inheriting the the X chromosome because they were they were

1:00:42getting the human female. >> Yes, yes, yes. The idea is human males exclusively mated with human women. Yeah. It's obviously not exclusively, but like by and large is the idea. By and large. That's a good correction. No, no, that's a good correction. By and large. Whereas Neanderthals were regularly fraternizing with the enemy. The men The men were The men were They were Neanderthal men, dude. >> It's always the men. It's always the men that are just like going at it. But but but this but what's interesting is we're we're sort of describing like the sociological and psychological uh decision-making

1:01:24>> Mhm. is what has is driving this observation we have in the genetic record. >> Yeah, yeah. And it's I mean it it opens up a lot of cool genetic studies about like population dynamics and things like that. I just 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, specific right? >> Neanderthal males like the human females were fine going for Neanderthal males. >> Yeah. But somehow the human males >> Yeah, they're 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.

1:02:04There's a there's a this makes me think of the the channel HO Math, which I will not pronounce because this is a family-friendly show, but this channel talks about dating dynamic stuff and and a and a graphical way like in a great like drawing graphics and and like kind of creating a formula. >> I'm not going to opine on the accuracy or lack of accuracy of HO Math. However, if any of you have participated in consuming that media, please feel free to add your comments below. >> Yeah. This study was out of the University of Pennsylvania and it was in science and it was covered by Archaeology magazine.

1:02:44Our third story in the rundown is something biology teachers have been constantly getting wrong for decades and it just got a serious reality check and it took, of all things, transparent fish embryos >> Yes. to catch it. So, what was my teacher in high school wrong about? Well, she was wrong about um mitosis. Why was it Why is it got to be a she? Why that's that's why I like Why >> My my my biology teacher, Miss Saeed. She was She was an amazing biology teacher. Um she taught me AP biology and she really got me into um like thinking about biology from like the ground up. She was an amazing

1:03:26>> maybe an inciting incident to why you became a biophysics teacher. >> Yeah, yeah, totally. She was She was awesome. Um 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. Um here's the idea. Have you heard of mitosis? Yes. Right? It's the idea of like cell splitting into two. They um 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 about blastula, all the DNA has to be exact.

1:04:07Um giant embryonic stem cells, sorry, giant embryonic cells like animals in zebra fish, 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 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 Yep. tightens up >> Yep. and then and then that causes

1:04:47cytokinesis. The the cells come together and split into two. The 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 The string will pinch Yeah. >> and then ultimately split the bubble. >> Yeah, exactly. And this is the the like telophase part of um mitosis where at the end it pinches and it goes through. >> Mhm. 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.

1:05:29>> Mhm. 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 this particular paper actually worked and figured it out

Military AI, escalation, and nuclear-conflict simulations

1:05:45is because of that transparent fish embryo that you were talking about. >> Okay. >> Zebrafish have transparent embryos and transparent cells. That's why they're a huge model organism for studying embryonic development or neurogenesis. There's so many zebrafish labs everywhere because you can just look at what's happening. >> see what's happening. >> it's so nice. >> That's actually really good point cuz normally what you're saying with everything with most other things whatever's happening inside >> There's like a soupiness to it. >> It's opaque. It's It's kind of like a miso soup. It's a little cloudy. >> but zebrafish 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

1:06:26these large embryonic cells you have this geometric constraint as I told you, right? You can't actually do the same paradigm of like pinching and stuff like that. And so what they discovered is that the cell alternates between stiffening the interior side of the cytoplasm. Okay. So it stabilizes this tightening band. >> Yes. And then it fluid is it makes it fluid enough to move stuff around and then it stiffens 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. >> Okay. This is very different from a lot of the mitosis that we have observed everywhere else.

1:07:06>> Mhm. Right? >> Mhm. I think I think it's really cool because it's it's a part of mitosis that, you know, we do read about in high school biology. >> Yes. 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 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

1:07:48we 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 cytoskeleton. All these other diseases have everything to do with with the cytoskeleton. It could give us new tools figure out how to manipulate the cytoskeleton. So that's why I was like really excited about this because it's something that as biologists I think a lot of people take for granted, but there's ever more complexity. This is it's mitosis is one of the few things that people always remember from their >> Mhm. science classes. It's like the mitochondria is the powerhouse of the cell. Yeah. >> Uh adenosine triphosphate, ATP. Yeah. Uh

1:08:29you know, mitosis. Uh there's a a couple of these like buzzwords that that that we all remember. Mhm. Um 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 uh look, for all intents and purposes, what you learn in mitosis is still pretty good. Right. >> Okay? It's better than nothing. >> for for everything that has to do with you, Yeah. >> mitosis is still what it is. >> what it is. >> Yeah. 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

1:09:12of quick housekeeping notes, which is number one, thank you all for joining us. We really appreciate you listening this far into the pod. Um as you all know, we have our website ffpod.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.

1:09:54It's also always displayed on the screen. Not quite sure why that's I I I don't I don't know. You can't even copy a link out of Instagram. So >> Instagram links don't work. >> I I don't get it. >> what to tell you guys. >> If you're on X, links are there, so it's fine. Or any Facebook, any other site where that have embedded links. Um and the last note here is if you if this is your first episode and you're just smitten and you think this is the best podcast that you've heard is top five, top three and it's not three. We we love that you're here. We do this show with just the two of us. And if you want to support the channel,

1:10:35we have a great donation portal where there's different levels for monthly donations or you can do a one-time. It really helps us sustain all this equipment. The production value is kind of high. It's not low. We're not We're not just on the We're not on the phone just with a a green screen Tik Tok uh effect behind us yelling at you to try to get the hook. We really try to focus on substance and content, and it does take a lot to do the show. We have a couple of key supporters who've been joining in on the donations recently that we really appreciate. It is a huge deal. Um, it is how we're able to keep the show free and accessible for all our episodes with no subscription

1:11:15content that's only accessible by people who pay us. It is really important to us philosophically that every episode is freely and as widely available as possible. At ffpod on all the socials, ffpod.com for the episodes chaptering. We're not yet releasing the leaderboards, but we're cooking on it. So, the the site's going to have a lot of great stuff. We're going to move into our last story of the rundown, which is something that's sort of interesting in in my daily life and intersects with my daily life as as someone who works on the technology side. Um, not on the

1:11:56military-industrial complex side. Uh, handing nuclear codes to an AI might sound like a sci-fi premises, but researchers just did exactly that in a wargame simulation, and the results are going to stick with you. Yeah, this one was really weird, okay? >> It came out of the King's College London. It's only on archive, so it's not, you know, peer-reviewed or whatever, but here's what's happening, okay? They put leading frontier models. This was Claude, Gemini, and ChatGPT. They were placed in a high-stakes global crisis simulation, and they had access

1:12:38to 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 Khan 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

1:13:18perfect trust and then ruthlessly exploited it later on. Kind of reminiscent of Claude's paper Mhm. Anthropic's paper, I should say, about how it was willing to kill someone in order to not be turned off. Be turned off. Um Gemini acted as a madman. It was using erratic behavior to its advantage. It was like straight-up It Gemini was weird because that one was like I'll just like drop a nuke on a city, not even military. Right. pose. And then ChatGPT, GPT-5.2, acted as kind of a conditional pacifist, but then very quickly abandoned its

1:13:58morals and launched devastating surprise nuclear attacks. It's so incredible to me that the conclusions of these models so closely almost mimic the the perceived personality of the leaders of each of the companies. Um so just for a little bit of context cuz the thing about this story that's actually interesting is this is actually a real-time story, not just in simulation, Yeah. but in the real world. So I obviously over the last week we saw the US initiate uh you know, war with Iran

1:14:39on the pretense that uh because we didn't obliterate their nuclear program when we bombed them to oblivion last year. Uh that now they have nuc they are almost close again in 6 months to another nuclear weapon, so we have to go back in and finish the job. Um that is the And the the reasoning has changed literally every day since the war has started. Um but it's obviously uh one of the most dramatic geopolitical military conflicts uh in our lifetime. >> Mhm. Um you know, the the idea of going to war with Iran has been on the

1:15:20playbook for a variety of >> Yeah, I've I've remember for the longest time. >> time it's been on on the docket. >> Yeah. Uh we finally pulled the trigger. Uh the reason I bring up that context is because literally right before we went to do kinetic action in Iran, um there were stories breaking about a conflict arising between the Secretary of Defense because that is still technically what it's called. Because >> it's No, you cannot war, no? You cannot change the name without congressional approval.

1:16:01So 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 Okay. Okay. the name has not changed. >> All right. I'm just dying on that hill. Yeah. Regardless. Currently, all of the frontier model companies, particularly OpenAI and Anthropic who's built Claude, have and are negotiating contracts with the Pentagon. Yeah. Uh to apply their models uh on the battlefield. Anthropic was the first to win a contract with the Pentagon and to get merged with some of

1:16:43their existing tools and ecosystems. What's interesting in how it connects to this story is even before the kerfuffle between Pete Hegseth and Dario Amodei, 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 uh and the DC military-industrial complex people, where they were saying it is not the right of an individual corporation to

1:17:25tell the US government what it can or cannot do as a contractor. Uh so, that was one side of the argument. And And then Dario and Anthropic's argument is "The power that is inherent in what we are giving you to abuse the Constitution uh 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, cuz 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

1:18:07both Pete Hegseth and President Trump have been arguing that they're going 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 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

1:18:49of these other dynamics. So, that's whether you think when you use ChatGPT or Claude that it's terrible and doesn't have any value and it's just a a you know, regurgitating words and it doesn't do anything. Stochastic parrot. >> Stochastic parrot. The US 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

1:19:30are really dramatic like fully autonomous weapon systems >> Yeah. 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 5 years from now is going to have massive second and third-order consequences. AI is has been and is actively being used on the battlefield. It was used in Gaza uh by the Israelis for targeting in a

1:20:12very 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 concerning to me. >> Yeah. It was It was pretty weird. >> very concerning. Um 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. Um, 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

1:20:53vaccine 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 you you're not getting like a COVID vaccine and then a flu vaccine. It's just one vaccine. And that's it. >> This this is It's insane. This one is very cool because it's a vaccine that works like no other. Yes. Yes. And just

1:21:35really quick, it must. And just really quick, this was published in Science in 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 6 years ago. Right? >> I will note that that was your first

1:22:15debut as a podcast host. >> That's right. >> Was 6 years ago on the Dark Matters podcast, co-hosted by friend of the pod Matt Marder, who also happens to be uh uh film writer, director, producer who has a new movie out on Amazon Prime and other streaming services, Gold 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. But >> Yeah. And I was the um 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

1:22:55there. A lot of cool neuroscience, VR very cool stuff. You guys should check it out. So, COVID-19 though was pretty bad 6 years ago, right? >> Yes. Now, what what COVID-19 showed us was that our tech when it comes to vaccines is reactive. Mhm. Okay? It's designed such that there's a specific key for a specific lock. Yes. >> We'll get into what that actually means, but what ultimately that comes into a timeline problem, right? Because even the miraculous modern speed that we had with the Moderna vaccine, which was 63

1:23:36days from sequence to first human dose with the Moderna vaccine, that leaves a month-long window where we are globally vulnerable. >> Yes. 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 problem >> these problems, right? >> Yeah. There 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,

1:24:16durably, 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 nasal spray that's going to last for months. The idea that's also in the form factor of a nasal nasal spray >> Yes, it's not even a jab. It's not even a jab. It's a nasal spray that is going to vaccinate you against like several different pathogens. I think that's really cool to even think about. And when I first heard the story,

1:24:57I was like, how is that even How does that even work? And then my reaction was, I don't believe you. Yes. Yeah, because 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. Um 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 adapt 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 um memory okay?

1:25:37Rapid response. These macrophages, 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 um what's the 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 comes into your body, you

1:26:17no longer have to have that immune response because they'll recognize it immediately. That's why we only get chickenpox once. Or that's how the vaccines actually work. Mhm. 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 and are perceived in the ranks as maybe more expendable. But then the adaptive system is like special operations folks. >> Highly highly highly trained, very specific. You can send 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. So, how do traditional vaccines work? Well, traditional vaccines actually exploit

1:26:58this adaptive memory, this special operations thing, right? What they do is you would 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." Mhm. Right?

1:27:40>> Mhm. 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 2 years for the flu. We have to get Right. >> a shot every year. The influenza virus, for example, um it's covered by two primary surface proteins. There's the HA, the hemagglutinin, 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,

1:28:22which is these tiny subtle changes that necessitates a yearly vaccine update. That's why we get a yearly vaccine for

Story 2 begins — a pathogen-agnostic vaccine out of Stanford

1:28:31the influenza virus, right? Because every year the vaccine the 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, it's just as a brief analogy, right? That these these viruses you could almost imagine they they're they have they're the lock side of the analogy and they're constantly changing the the configuration of the lock. Yeah. Right? Um and our immune system is trying to create a key Yeah. to turn it to to make it to to defeat it. Mhm. But because it's constantly having the locksmith come and change the lock very very quickly, it takes us a long time to

1:29:11print 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 new keys to try to unlock the door, like that the delta between those two is part of like if 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 >> Exactly. Exactly. >> 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

1:29:52reassortment 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

“One vaccine to rule them all” — why this idea is so radical

1:30:05genetic elements get reshuffled and now you have an entirely novel HA 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, right? 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 The first one that I can really think of

1:30:47is one that targeted conserved internal proteins. Here's what I mean by that. The HA, which is this protein that is in 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 doorknob. >> Exactly. Yeah, yeah, kind of like that. But it it Okay, let's 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 um What if I could make a little thing that recognizes the shape of the lock itself? Like the little round that goes

1:31:28around the doorknob, >> Yeah. right? >> Yeah. That's what the strategy was here

Why current vaccines are reactive, not proactive

1:31:33with Bio BioNTech. They They made a They made a They made They made something called the M-001, and what it was doing was trying to target the stalk of that protein, which is highly conserved. Like the the doorknob versus the hole where the key goes in. >> Exactly. Like what if we just like go for the doorknob itself, okay? Recombinant protein, it targeted nine conserved T-cell epitopes. It went really great until phase two. Okay. And then phase three completely failed. 12,000 people, October 2020, showed no significant difference in flu illness. So, we can't just remove the the We can't just remove the door knob with the lock on it because the the little door is still is still

1:32:13>> the the door knob thing isn't working. Isn't working. Okay? Somehow the door knob thing isn't working. >> I've got to take us on this weird analogy path, so feel free to pivot if we need to. >> no no no no no now we're stuck, baby. But, let's go. So, somehow somehow the idea of like this this invariant thing that I want to recognize is no longer working. So, the failed autopsy is the following, right? Which is that this T-cell that's getting activated to recognize the door knob, 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

1:32:54special 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. Out of Stanford, it's by the lab of Bali Pulendran, 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 pro- protection, okay? The

1:33:36protection 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 the human body body >> communicate intelligence. >> Yes. Uh we can't have sequestered

Innate vs adaptive immunity — the key distinction

1:34:03information. >> No stovepipes, right? Yes, we can't have stovepipes. >> needs to talk to everyone and share intelligence. That's so hot. That's ultimately what's happening. Okay? So now let's get into the paper, right? How does this vaccine actually work? It's an intranasal vaccine. It's So 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 a 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. Um and it's encapsulated inside a

1:34:45liposome, which is just like a little flat fat globule. Mhm. 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. Um 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

1:35:25>> Mhm. 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 our our our signals intelligence systems to 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 a such a degree that there's some There's a threat over here. Yeah. >> It's like identifying, listening to identify when there is a threat incoming. >> Yeah, yeah. And Yes, exactly. And and what's crucial about it is these two things, they're actually synthetic adjuvants, okay? Adjuvants are little helpers that help the immune system, but

1:36:06aren't actually the antigen that the immune system is trying to target. 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 that this works."

Why flu/COVID-style vaccines keep falling behind mutation

1:36:26Okay? Let's do the efficacy test. >> Okay. Turns out, four intranasal doses on vaccinated mice and the mice were highly durable to SARS-CoV-2, this is COVID-19. Mouse-adapted SARS-CoV, which is the SARS virus. Um a coronavirus that was bat-derived. A gram-positive bacteria. And another gram-negative bacteria. So, like five different things that had nothing to do >> Yes. with what I showed the immune system. That's what's key. Usually, for

1:37:08the 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. >> keyhole of the lock that it needs to make keys for. Yeah, this is Yeah, this is literally just priming the immune system to be like, "Watch out." And so, for 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, they already when it arrived, they can already be using those and >> Yeah, they already know like what is

1:37:50what is what is foreign. Right. There's a There's a signal like oh, okay, this is interesting. Um, 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? Cuz you just like introduced like this very simple thing in the nasal tract and now all of a sudden it's just

1:38:30like working. Doesn't make any sense to me. >> It just got a huge defense system out of nowhere. Yeah, yeah. So 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 of the human body, right? Um there's a direct interface between the outside world and the inside world. So there's its own rules of engagement. >> That's that's fair. It's like this is not the blood, right? Where the blood is shielded by the skin and the heart and and and the capillaries. The lung is like where the outside world is coming in and I need to get oxygen and release

1:39:10carbon 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 Oh, sorry, this is how oxygen gets into our blood. >> Yep. 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 and actually lay it out flat, that would be half a tennis court worth of surface area. >> That's really crazy, actually.

1:39:51>> I didn't know that. >> Right? That's that's pretty cool. >> It's massive. Now, the lung is naturally tolerogenic, meaning it tolerates a bunch of random stuff. It suppresses an immune response.

The real target: making the lung itself a stronger fortress

1:40:03If every time some random crap comes in and we have an immune response, it's not going to be good. It uh it has a um what do you It has an asylum program. Yeah. Yeah. Yeah. Yeah. In some sense. It's not a strict border where you can't cross the border. >> 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 respon- 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. Mhm. Okay? Then, there are these things called the alveolar macrophages. These are macrophages, so there's These

1:40:44are innate immune cells. These are the beat cops, the infantrymen. Mhm. They hang out in the alveoli. They were discovered by Élie Metchnikoff in the 1880s. He won the Nobel Prize in 1908 for it. They basically hang out in the alveoli, which are these compartments that interface between the blood and the outside world. >> This is I mean, it's like literally the border. >> Yeah, they're the they're the border. Yeah. >> Yeah. In some sense, right? >> Yeah. Yeah. Yeah. And in the past, we used to believe that the memory T cells, which are our special ops, >> Yes. they remain dormant until there's a specific target antigen that reappears. But, the data from this particular paper

1:41:26shows that there's actually a radically different dynamic. The when we when when you put that nasal spray in, those tissue resident memory T cells, they actually broadcast training signals to these infantrymen. Interesting. Alveolar macrophages. So the 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 the innate immune cells respond. There's no communication happening necessarily.

1:42:07But 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, uh, the adaptive immune cells >> by that nasal spray. Right? And so now they, because they got primed by the nasal spray, they're already pre-sending information to the border, where we have these innate immune cells to say, "Hey, be on alert. There might be a caravan coming through." Yeah. And because of that, it actually makes the effective response better. Yeah. But I still, okay. Let me Let me wait. And so the question is, okay, how does that dialogue

1:42:47actually happen? That That was my question. Right? Like how how are you talking to one another? Well, the dialogue happens from something called RANKL. 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. >> Mhm. This response was completely not there. So so so if when this was present, this RANKL, when present, the antibodies

1:43:29would generate and form and it's totally fine. Yeah. When it wasn't present >> artificially take it out. >> Right. Right. Then the 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 infantrymen, new tricks >> Mhm. in some sense. So now the question becomes, well, how are you doing that? >> Yes. These macrophages I thought, you know, they're they're kind of dumb in innate immunity. How are you training them to be immune and really select certain things and like and like become this more effective cop in some sense. Well, it turns out that they acquire biological memory not

1:44:11through 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? Um 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

1:44:51called 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 euchromatin. Chromatin is like our DNA. Heterochromatin is all of our DNA that's being packaged up so that no one can read it. Euchromatin 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.

1:45:32>> That's exactly right. And what they could see is that the RANKL signaling was unspooling the DNA Mhm. >> and making parts of the DNA more visible. I It was left out in the open. In the like in the context of like a heterochromatin heterochromatin becoming more like >> More euchromatin. Exactly. And very specific parts of that DNA >> Mhm. were becoming more accessible. Mhm. Meaning like certain books in the libraries which had good things in those specific books. >> Yes. Like how like how to identify stuff. How to be a better cop. >> That's actually fascinating. Yeah. Oh man, that's really good. >> Yeah. Cuz because you can you can sort of like it kind of makes sense

1:46:14where 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 part of you when. And that coordination problem at the level of the body is orders of magnitude. Yeah. >> Like because of the number of constituent parts and Mhm. combinatorial pro like the processes that stack on top of each other. I like it makes my head hurt. >> Yeah. Yeah, there's there's too much, right? Um and it it's just pretty cool that we could like get down to this level >> That's crazy. >> of chromatin remodeling to understand it, you know? Is isn't epigenetics still something as a concept

1:46:55>> Mhm. that is in its infancy? Very much so. Compared to like like DNA, for example. Yeah. So I think it the reason it's fascinating to me is you know we're continuing to chip away at the understanding and it's it's it's

Why a nasal spray changes the game

1:47:11funny 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

1:47:52figure out what part of the genome is being read. When you say a blender? A little yeah. >> Okay. Yeah, yeah, yeah, you just >> Yeah, you just mix it up. >> Okay. Then you put some transcriptomics 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,

1:48:34they use the technique called phenocycler fusion. It used to be formally called codex for a 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 is tagged with a fluorescent dye. Each of the different colors tells us what different antibody there is, and

1:49:14there 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. 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 PhenoCycler 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

1:49:55that is complementary that is attached to a dye. 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 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 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.

1:50:35I have a little thing that says attach to the red hats and then I take a picture. Then, I wash it out and this is the next next photo I think you will see. Yes. 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 anti because the primer is being attached at different locations, I now have a snapshot at every given point. And so I can expand the number of proteins that I can actually image. >> Right. Because you're you're no longer limited by the number of dyes and lasers

1:51:17you have. >> Yeah. Because the mechanism to make the connection is now this one part of DNA connected to the other part of DNA. On the other side of it, it can have a whole range of stuff. That's It's such a nice idea. It's only in the last 5 years. This was also developed at Stanford. This is very clever. >> This is a very clever technique, I have to say. >> Yeah, no, that is that is that's quite nice. Cuz it's it it feels non-obvious >> Yeah. as a choice. >> Yeah, but then once you like think about you're like, "Oh, duh." Yeah. >> Yeah, 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 cuz I immediately understood what they >> Yeah, I was like, "Oh,

1:51:58come on, it's so obvious." >> Yeah. Yeah. But why have we not >> It's so nice. >> Um but 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 um 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.

1:52:40Like on the battlefield, they're doing management and creating like little I don't know. You know what I mean? >> yeah, yeah. Yeah, they have these outposts at specific areas on the battle front. >> On the battlefield in the lungs themselves. >> that are relevant to the >> have to go all the way back to the lymph nodes to figure out So so in this analogy, if you have a central if you have a central command that has like houses the core intelligence pieces, what you're What's happening is we're actually getting these satellite outposts that have uh localized intelligence and relevant information. So that people who are nearby don't need to wait because they already have

1:53:22basically, you know, preloaded not preloaded but they already have the relevant information that people those that are nearby are able to access without waiting for the signal to come back from central command. Tertiary, what was it? Tertiary lymphoid structures. >> Yeah, lymphoid is the the lymph nodes are like uh organ system that coordinate the immune response. And here that organ system is now creating little tiny outposts. >> Yeah, yeah, yeah, yeah. Yeah, all which which again if we look at just like military tactics as a reference point. >> so it like maps out almost perfectly. >> kind of crazy. Dude, that Yeah. >> of crazy. Yeah, it is kind of crazy. It

1:54:02is kind of crazy. The one that I I got really kind of excited about was the idea that it could actually like help allergies and allergy asthma because um it turns out that allergies are basically a maladaptive response to harmless allergens, right? It's like the immune system just kind of going 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

1:54:43middle 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 I 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 work 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

1:55:26like a pandemic that's happening in the future, it's going to happen in the future, yes, right? There's a pandemic There's a pandemic coming. Um 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 I don't need to know what COVID-19 is or what COVID, you know, I don't know, 2027 is. I can just fly out these vaccines and whatever health care worker is going in there or whatever, they're just their immune system is going to be primed for whatever random

Benefits, caveats, and the cytokine-storm risk

1:56:06crap is coming their way. This is it generalizes vaccines in a way where you can have a inventory and stockpile of this generic Again, this is this is an early stage. Very early only in mice. caveat caveat caveat And I'm going to get into the caveats later, but I still think it's It's because it it 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, but the it's a paradigm shift, I think, in how we

1:56:47think about vaccines in general 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 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 train before the marathon. And and and this is sort of a a means by which for us to arbitrarily activate the immune system because it has the capability to go back to what we said before. It has the capability to deal with the problem, but it doesn't necessarily have enough of a a running start

1:57:28to deal with that time gap problem we talked about earlier. Yeah. Um and if we just give it an extra little bit of a head start, its natural response will like will be better at taking care of the situation. >> Exactly, yeah. And I mean, there's there's caveats, right? Like, I think the researchers when we 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 the immune system just attacks the body itself, right? Gets confused. I can imagine there's 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 one would make the analogy that if you have a nation with a

1:58:10border and then you create an overzealous uh like police force to respond to that, >> Right. >> you might start ending up shooting people inside the border >> Right, right. >> when you're focused on people who are coming from outside >> border. Yes. >> So, as an analogy, >> of course. we we do not want to have an overzealous uh immune system cuz we don't want 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, so that's that's that's something that's an issue, right?

1:58:50>> Yeah, totally. Cytokine storms, also known as Nice. Well, I'm going to put this on Instagram because apparently >> Yeah, apparently people got very People got very Yeah. about a joke, guys. Anyways, but that's that's one of the that's one of the um you know, caveats of these. Like, the immune system is notoriously finicky. Right. So, we 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. >> Um I think it'll be very very interesting to see where this leads. This this this was a you said I that I was going to like the vaccine story. >> I I think it's it's very cool. >> I I tend to and and apologies for those who sometimes feel like we're getting a

1:59:31little too deep. I tend to like the stories that have a really keen fundamental insight >> Yeah. 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. >> to home. Uh our first story was our astrobiology story out of PNAS Nexus Johns Hopkins University. This was on our idea of understanding panspermia and the three aspects that

2:00:15are necessary in order for something to an organism that's life on one rock to make it to another rock. One and half of those threes of was already kind of solved. But, this was a new one that's now solved, which is the initial departure from Getting off the planet, yeah. 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. >> Yeah. Um on the battlefield. Several

2:00:57good rundown stories. If you've made it to the end, you are very special cuz you get to get a prompt for uh comment of the day. I want to call out uh I'm going to pull this up real time here cuz I didn't do so earlier. I want to call out one of the previous comments Oh, yeah. from last week's episode which uh I think there were two that were quite that were one at least was quite good. Uh 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 So 2 days ago, this was for our last episode. We asked for uh come up with a better acronym for G-

2:01:38GPLD1. Um and so one of them was garlic pepper lemon dip um because apparently we made someone hungry. Um 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. >> You're Yeah, you're in it. Just just keep listening. Whatever. >> give us a second here. This is bad pre-production prep by me. So but I want to make sure people get their just desserts here on some of these really clever uh

2:02:19references. And nope, I don't see the one the second one. >> So I failed on it. But what should we have for the comment this time? >> Um This This was a good >> Panspermia. Yeah, a different definition for panspermia. >> Yeah. That's what exactly what I was thinking. Yeah. >> that one. >> What do you guys think? Panspermia. Give me another definition. >> I like that one. That is quite good. I'm your host >> Yeah, please. Please. 13. PG-13. >> 13. Kids can go to PG-13. It's not that bad. >> not that bad. Um I'm your host Lester Nare, joined as always by my co-host and our resident PhD Krishna Choudhury. I'll make one

2:03:01last reference. He's wearing a SpongeBob t-shirt today. Yeah. Yeah. 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 wrath rap beef tracks like two or three years ago, where it's like SpongeBob and Patrick and Sandy and Mr. Krabs 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. You need to send me some. It's It's This is not >> English on SpongeBob. The The This music is not PG-13.

2:03:44So, parents do not It's not PG-13, but it is the the voice um duplication is incredible. Well, And there's like a beef between the Chum Bucket and the Oh, yeah. That's right. That's right. And Krusty Krab, okay. This is no longer about science, so we will sign off here. We will see you all next week. This is from First Principles.