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

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

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

• 0:00Lester Nare?

  One of the biggest questions for humanity has always been, are we alone? And we may have just made a discovery that changes the paradigm about how we think about the answer to that question.

• 0:12Krishna Choudhary?

  So Sauron would be proud of this because Stanford has figured out one vaccine to rule them all. I don't really trust humans with nuclear weapons, but I definitely don't trust AI. And this new paper is corroborating that very nice viewpoint that I had.

• 0:30Lester Nare?

  Hello, internet. This is your captain speaking, Lester Nare, joined as always by my co-host and our resident PhD, Krishna Choudhary. We 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.

• 1:06Krishna Choudhary?

  Yes, amazing food.

• 1:08Lester Nare?

  From the goat. It was a great time. Shout out to Dave Chang and his team. Super big fan of science, a great example of how science impacts all of us and curiosity. There is not a monopoly on curiosity about how the world around us works. If you're joining us for the first time, welcome. If you're returning, welcome back. As you know, we are a victim of the billionaire algorithm, so a like, share, follow, subscribe, all of that is super helpful. Our donation portal is up. Every episode is free and available on every platform. And the support we have from the community is really huge for us to be able to continue

• 1:50Lester Nare?

  to get the best breaking science news broken down here to you every week. We are going to learn about the science from the ground up because this is From First Principles.

• 2:21Lester Nare?

  Our first story is on astrobiology, one of those fields that sits right at the edge of what science can currently say and addresses one of the biggest questions in humanity, which is, are we alone? And a new study just took one of the toughest organisms on Earth, simulated the violence of an asteroid slamming into Mars, and watched what happened. And the survival rates might genuinely surprise you, as they surprised me. This is in PNASNexus, out of Johns Hopkins University, on March 3rd.

• 2:58Krishna Choudhary?

  Yeah, this is very recent.

• 3:00Lester Nare?

  Fresh off the presses.

• 3:01Krishna Choudhary?

  Yeah, very recent. And as you said, right, a core question that we ask as humans is, are we alone? Well, a follow-up to that would be, well, could life travel between worlds? Right? Let's say that life started on Mars, and then an asteroid impact hit it. The debris from that asteroid traveled the entire solar system between Mars and Earth, and ended up on Earth, and that's what 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 for the longest time, it's kind of been just like cuckoo-woo-woo type science, been discredited.

• 3:46Krishna Choudhary?

  And this paper is really challenging a lot of the assumptions that we make about how unlikely this process is.

• 3:52Lester Nare?

  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.

• 4:01Krishna Choudhary?

  Yeah, yeah, dude, it's, it's, it's pretty cool. They've, they've done some really cool experiments. This paper...

• 4:09Krishna Choudhary?

  Uses something called D. radio durans, which is a bacterium that colloquially is known as the Conan, the bacterium, because it's like indestructible, you know, like Conan, the barbarian.

• 4:20Lester Nare?

  Barbarian, I was gonna say.

• 4:21Krishna Choudhary?

  It's like indestructible. And what they've done is do experiments about what this bacterium could survive through. And it turns out it's a lot, something like 14,000 times the atmospheric pressure on Earth.

• 4:35Lester Nare?

  Okay.

• 4:36Krishna Choudhary?

  Substantial survival, even at really, really high pressures, even beyond that. And the conclusion here is basically that the initial pressure shock that you get from an asteroid banging into a planet that has life and ejecting that planet out, that initial pressure shock that we used to think would completely kill any living organism is actually not that bad. Stuff will survive and go into outer space. Okay. Now, why does it matter? Well, very recently, we've had the NASA Perseverance Rover announce a discovery of potential life on Mars.

• 5:13Lester Nare?

  Yes.

• 5:14Krishna Choudhary?

  We covered this in last year's podcasts. Now, finding that life requires determining the origin of that life, right? And if this is true, well, then we can start asking questions like, well, is that life coming from Earth? Or is it originated in Mars originally? This paper sort of shapes that interpretation. It's also got some impacts when it comes to like planetary protection, because now if we know that life actually survives, impacts, goes into outer space and comes to Earth, like, we gotta be a bit careful about returning samples onto Earth.

• 5:48Lester Nare?

  Because if we bring something back and it's got a little, you know.

• 5:52Krishna Choudhary?

  Thingy.

• 5:53Lester Nare?

  Thingy in it.

• 5:54Krishna Choudhary?

  Yeah.

• 5:54Lester Nare?

  We don't want that.

• 5:55Krishna Choudhary?

  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.

• 6:07Lester Nare?

  Very interesting.

• 6:08Krishna Choudhary?

  So, as always, let's start with the history. This is actually an ancient idea, the Greek philosopher Anasagor, Anasagoras, okay? Like, kinda like Pythagoras, but Anaxagoras, maybe that's how you say it. Anaxagoras, 5th century BCE.

• 6:27Krishna Choudhary?

  He actually is one of the first guys to correctly interpret what the solar eclipse was. Like the moon is going in front of the sun. He's the first guy to do that, 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 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.

• 7:06Lester Nare?

  Lord Kelvin.

• 7:07Krishna Choudhary?

  Yes, he proposed the scattering of life seeds via like catastrophic collisions. This idea that we now have of like stuff going in, collisions, uproot material into space, and then that material comes into earth. And then in 1903, there was this guy Svante 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 microbial spores were. They could be propelled by the pressure of light to move across space.

• 7:51Krishna Choudhary?

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

• 8:19Lester Nare?

  Yes.

• 8:20Krishna Choudhary?

  Then, we started discovering stuff that could actually survive that. In 1956, Arthur W. Anderson discovers D. radio durans. This is our Conan the bacterium.

• 8:35Lester Nare?

  I see.

• 8:35Krishna Choudhary?

  Okay, this is the bacterium that will survive anything.

• 8:38Lester Nare?

  Okay.

• 8:39Krishna Choudhary?

  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, you put it into Chernobyl and the meat comes out still spoiled. So there's something that grew in it. And when he isolated that, he came up with this bacterium called D. radio durans. In the 1970s, there was also the discovery of hydrothermal vents.

• 9:23Krishna Choudhary?

  And so now you have life thriving in total darkness, 400 degrees Celsius, like way above boiling. It's still water because the pressure is so high. But then again, the pressure is so high and life is still thriving.

• 9:38Lester Nare?

  Yes.

• 9:38Krishna Choudhary?

  So it's very weird, right? And over the following decades, we've had an incredible catalog of extreme environments where life thrives. We have things called acetophiles, which are life that live in sulfuric acid.

• 9:52Lester Nare?

  Crazy.

• 9:53Krishna Choudhary?

  They literally live in sulfuric acid at a pH near zero, which is worse than bleach. But they're just like living there. Hyperthermophiles that live up to 122 degrees Celsius. The record holder is something called Methanopyrus candelary.

• 10:09Lester Nare?

  Candle.

• 10:10Krishna Choudhary?

  Dude, 122 degrees Celsius is insane. Right? Again, high pressure, which is why the water isn't boiling. Water usually boils at 100 degrees Celsius at sea level. But if you do it high pressure, the water's not going to boil. That's why a pressure cooker works.

• 10:24Lester Nare?

  And that makes sense.

• 10:26Krishna Choudhary?

  A lot of really, really crazy things. Halo files in, in, they flourish in salt concentrations that are five times that of seawater. You can see this in the Dead Sea and.

• 10:35Lester Nare?

  You can also see this in Halo players who eat a lot of Doritos and chips and ruffles.

• 10:39Krishna Choudhary?

  Yes.

• 10:39Lester Nare?

  Halo files, uh, as those who might not know.

• 10:42Krishna Choudhary?

  I used to be a Halo file in, in high school.

• 10:44Lester Nare?

  Mate, I, I.

• 10:45Krishna Choudhary?

  I loved Halo.

• 10:45Lester Nare?

  Let me tell you something, Halo two and Halo three.

• 10:48Krishna Choudhary?

  Oh, yeah.

• 10:49Lester Nare?

  No competition.

• 10:49Krishna Choudhary?

  No competition.

• 10:50Lester Nare?

  Like I, it was very serious.

• 10:52Krishna Choudhary?

  Oh my gosh, dude.

• 10:53Lester Nare?

  It was very serious.

• 10:54Krishna Choudhary?

  It's one of the only.

• 10:55Lester Nare?

  Blood Gulch?

• 10:56Krishna Choudhary?

  Yeah.

• 10:56Lester Nare?

  Like what?

• 10:57Krishna Choudhary?

  Yeah.

• 10:57Lester Nare?

  Yeah, like.

• 10:58Krishna Choudhary?

  And, and I remember it was back in the day when like, there wasn't really internet to.

• 11:02Lester Nare?

  Correct.

• 11:03Krishna Choudhary?

  Host.

• 11:03Lester Nare?

  Yes.

• 11:04Krishna Choudhary?

  Um, these collaborative parties.

• 11:06Lester Nare?

  Yes.

• 11:07Krishna Choudhary?

  So you had to go to your friend's house.

• 11:08Lester Nare?

  Yes.

• 11:08Krishna Choudhary?

  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.

• 11:16Lester Nare?

  Yep.

• 11:17Krishna Choudhary?

  And we used to do like co-ops of four, four versus four.

• 11:20Lester Nare?

  Land parties.

• 11:21Krishna Choudhary?

  Land parties, yeah.

• 11:22Lester Nare?

  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.

• 11:31Krishna Choudhary?

  Yeah.

• 11:32Lester Nare?

  Halo raised so many, so many millennials in that era.

• 11:36Krishna Choudhary?

  Yes, and we are one of them.

• 11:37Lester Nare?

  Halo files.

• 11:39Krishna Choudhary?

  Yeah, um, in this case, it means salt, but for us, it means something totally different. So.

• 11:46Krishna Choudhary?

  Effectively, there's a lot of extreme environments that life thrives in.

• 11:50Lester Nare?

  Right.

• 11:50Krishna Choudhary?

  So now it's no longer the case that like, life needs this like perfect setting.

• 11:56Lester Nare?

  The Goldilocks.

• 11:57Krishna Choudhary?

  Yeah, the Goldilocks stuff, right?

• 11:59Lester Nare?

  Yeah.

• 11:59Krishna Choudhary?

  And, um, one, one of the big things was in 1996, Bill Clinton announced possible ancient Martian microbial life in a meteorite that they found in Antarctica in 1984.

• 12:11Lester Nare?

  I, I have to ask because you did such a good job, uh, with the JFK impression. If you could, if you.

• 12:17Krishna Choudhary?

  Oh yeah, so he goes, he goes, he goes, I did not find life. But I think we found it. But I did not have sexual.

• 12:30Krishna Choudhary?

  Anyways, there was a meteorite in Antarctica. They found possible ancient life on it. It was published in Science. Immediately, everyone was like, no.

• 12:40Lester Nare?

  Immediately, no.

• 12:41Krishna Choudhary?

  Immediately, no. Like, it was largely refuted, but the rock transfer, the fact that that meteorite came from Mars is actually not disputed.

• 12:52Lester Nare?

  Meaning, meaning that, that the origin.

• 12:56Lester Nare?

  On Google Maps, its original starting point.

• 12:58Krishna Choudhary?

  Is Mars.

• 12:59Lester Nare?

  Is Mars.

• 12:59Krishna Choudhary?

  That that everyone's fine with.

• 13:01Lester Nare?

  Okay.

• 13:01Krishna Choudhary?

  The fact that there's life on that meteorite, that's what everyone's not fine with.

• 13:04Lester Nare?

  Okay.

• 13:05Krishna Choudhary?

  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.

• 13:15Lester Nare?

  Right.

• 13:15Krishna Choudhary?

  From Mars to Earth.

• 13:16Lester Nare?

  Because now we have evidence that it can happen.

• 13:18Krishna Choudhary?

  That it can happen. We definitely found a Martian meteorite and, you know, it looks like there's some weird stuff on there. And so that gets us to this mechanical challenge of planetary escape and then getting to Earth. Okay, so there's three bottlenecks when it comes to panspermia.

• 13:33Lester Nare?

  Three things that prevent it from like being realistic.

• 13:36Krishna Choudhary?

  Yeah.

• 13:37Lester Nare?

  Happening.

• 13:37Krishna Choudhary?

  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. Okay, once you survive the impact, then you got to journey through space, millions of years in a vacuum. There's cosmic radiation, there's extreme cold, there's UV, right? And then, at the end of the day, after you've done that journey, you've got to survive reentry. Okay?

• 14:14Lester Nare?

  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 reentry.

• 14:27Krishna Choudhary?

  Exactly, right. So the two and three, which is surviving space and then surviving reentry. That's actually been explained by something called Xpose, which is a facility on the International Space Station. What they did was they had certain organisms and spores that they put out into the deep space, right outside the International Space Station. And it turns out, these things can survive prolonged space exposure if they're shielded by a few millimeters of rock. So if your life is just a few millimeters.

• 15:03Lester Nare?

  Millimeters.

• 15:03Krishna Choudhary?

  The surface, yeah, underneath the surface of whatever asteroid. It's going to survive not only the vacuum of space, but also the reentry into Earth.

• 15:12Lester Nare?

  That's actually quite, I I I think if people were to try to guess, if you have a piece of rock floating through space with little little thingies, little micro thingies on it. Uh, how deep do you think it needs to be to be able to survive?

• 15:27Krishna Choudhary?

  I think very few people would have guessed millimeters.

• 15:30Lester Nare?

  You would think you need a little shielding, you need a little, maybe a couple of inches.

• 15:33Krishna Choudhary?

  Yeah, yeah.

• 15:33Lester Nare?

  Feet, yards.

• 15:34Krishna Choudhary?

  So you don't need a lot.

• 15:35Lester Nare?

  That's actually really incredible.

• 15:37Krishna Choudhary?

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

• 15:53Lester Nare?

  Oh, okay, okay.

• 15:54Krishna Choudhary?

  And so this particular paper that's coming out of Johns Hopkins, it is targeting bottleneck one, which is the idea of can it survive the initial ejection event? Cause we already know it can survive outer space and reentry. We need to know if it survives the ejection.

• 16:10Lester Nare?

  So it can survive two and three of the three bottlenecks. We have, we have, uh, uh, data, experimental data that shows that to be true. It's not, it's not theoretical.

• 16:21Krishna Choudhary?

  No.

• 16:22Lester Nare?

  But number one is still.

• 16:23Krishna Choudhary?

  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 space, most of it should be dead. That's the prevailing theory.

• 16:33Lester Nare?

  Okay.

• 16:34Krishna Choudhary?

  This experiment is putting that, it, it's challenging it.

• 16:38Lester Nare?

  Okay.

• 16:39Krishna Choudhary?

  Right?

• 16:40Lester Nare?

  Science is always a process.

• 16:41Krishna Choudhary?

  Yeah.

• 16:42Lester Nare?

  Sometimes.

• 16:43Krishna Choudhary?

  I mean dude, it's a totally reasonable thing.

• 16:45Lester Nare?

  Yes.

• 16:45Krishna Choudhary?

  To be like, a meteor impact is like several atomic bombs.

• 16:49Lester Nare?

  Yes.

• 16:49Krishna Choudhary?

  Okay, what, what are we talking about?

• 16:51Lester Nare?

  A hundred percent.

• 16:51Krishna Choudhary?

  Right?

• 16:52Lester Nare?

  A hundred percent.

• 16:53Krishna Choudhary?

  So, okay, let's talk about this, um, elusive bacterium D. radio durans. Okay, why is it the right test subject for this

• 17:03Krishna Choudhary?

  avenue of research? Okay? Well, for lethal dose for a human being, lethal dose being like, you know, 50% of us are gonna die. It's about fif- four grays. Gray is like the unit of radiation that you get. Chernobyl, Glenn?

• 17:18Lester Nare?

  I just, I just wanted you to know that, I don't know if you knew this, that grays are. One of the species of aliens that people think are visiting Earth.

• 17:28Krishna Choudhary?

  Oh, really?

• 17:29Lester Nare?

  The four foot ones that have the big eyes, the classic.

• 17:33Krishna Choudhary?

  So only four of them will kill us.

• 17:36Lester Nare?

  Okay.

• 17:36Krishna Choudhary?

  According to.

• 17:37Lester Nare?

  According to.

• 17:39Krishna Choudhary?

  According to what we've done radiation studies on, four grays will kill us. E. coli takes 70 grays.

• 17:46Lester Nare?

  Okay.

• 17:47Krishna Choudhary?

  Okay. D. radio durans takes 15,000.

• 17:51Lester Nare?

  Yeah.

• 17:51Krishna Choudhary?

  So it can survive 3,000 times the human exposure and 200 times the E. coli exposure. This thing is insane. That's why it's called Conan the.

• 18:02Lester Nare?

  The barb.

• 18:02Krishna Choudhary?

  The, no, Conan the bacterium.

• 18:04Lester Nare?

  The bacterium.

• 18:05Krishna Choudhary?

  The Conan the bacterium, yeah. So even those four foot aliens, yeah, 3,000 times the dose of those four foot aliens.

• 18:12Lester Nare?

  That's how they got here.

• 18:13Krishna Choudhary?

  That's how they got here, dude, on the backs of radio durans. Now, why is that the case? This, this bacteria is amazing.

• 18:21Lester Nare?

  Okay.

• 18:22Krishna Choudhary?

  Okay. For one, in terms of DNA repair, it's got astonishing fidelity. Okay? It reassembles its genome, which can be shattered into hundreds of fragments by radiation within three to five hours.

• 18:37Lester Nare?

  That's unbelievable.

• 18:38Krishna Choudhary?

  Like, I dose it with 5,000 grays, which is, again, a thousand times what humans can take. Within three to five hours, its genome is back. It's like this science fiction thing.

• 18:49Lester Nare?

  It's unbelievable, especially after the episode we talked about how our genomes are, are degrades over time.

• 18:54Krishna Choudhary?

  Yeah, yeah, naturally.

• 18:56Lester Nare?

  Naturally.

• 18:56Krishna Choudhary?

  This thing has repair mechanisms.

• 18:58Lester Nare?

  That's really.

• 18:59Krishna Choudhary?

  In order to just keep itself alive. The ring structure of the nucleoloid is a big part of it. The DNA is actually packed into a torus. It's like a donut style shape, so it keeps the fragments physically close together.

• 19:11Lester Nare?

  Versus a double helix.

• 19:13Krishna Choudhary?

  Yeah, well, no, it's still a double helix.

• 19:15Lester Nare?

  But it's rounded.

• 19:15Krishna Choudhary?

  But the double helix is wrapped around in a torus.

• 19:18Lester Nare?

  Which gives it a little.

• 19:19Krishna Choudhary?

  It's not, yeah, it's sort of not like in a soupy, like most bacterium, the, the chromosome is like in this like soupy, non-structure.

• 19:29Krishna Choudhary?

  Form. This one is in a nice toroid, okay?

• 19:32Lester Nare?

  Makes sense.

• 19:32Krishna Choudhary?

  So it's got physical proximity for re 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.

• 19:44Lester Nare?

  Yes.

• 19:44Krishna Choudhary?

  It's got several branches.

• 19:46Lester Nare?

  Yes.

• 19:47Krishna Choudhary?

  So if one single branch of your GitHub is like messed up, it can use the others to actually figure out how to repair itself, right? Exceptional DNA repair. One of the other cool things is it has extraordinary antioxidant defense. In 2004, there was a paper that came out in Science that suggested that, you know, over the course of radiation, you're going to have these things called reactive oxygen species. Oxygen is incredibly reactive. That's why things rust, right? Iron rusts in normal atmospheric conditions because the oxygen is reacting with the iron. Well, same thing happens in life. You have these reactive oxygen species. But these guys have so many, so much high concentration of manganese antioxidants, which are like manganese ions, small peptides,

• 20:32Krishna Choudhary?

  that can scavenge and take care of that reactive oxygen. So it's keeping all of that reactive mechanism at bay. And finally, the cell envelope is really weird. The border of the cell to the outside, it's multi-layered and the outer layer is this S-layer crystalline surface layer. You can see, it looks like a crystal. It's a hexagonal lattice where you've got this like fundamental unit and it repeats itself. It's kind of like a shell.

• 20:59Lester Nare?

  Yeah, yeah.

• 21:00Krishna Choudhary?

  Around the bacterium that is keeping, that is like reinforcing that structure.

• 21:07Lester Nare?

  It's, it's, it reminds me of when people talk about fractals.

• 21:11Krishna Choudhary?

  Yes.

• 21:11Lester Nare?

  Like fractal patterns.

• 21:12Krishna Choudhary?

  It's like, it's like super structury, right? It almost looks like a virus, but it's the size of a bacteria, which is 100 times larger, you know? And it acts like a suit of armor, providing this immense structural rigidity.

• 21:27Lester Nare?

  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 outer protection and has this genetic benefit of the structure of DNA, such that external forces can't do a lot to it.

• 21:45Krishna Choudhary?

  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.

• 21:52Lester Nare?

  We, we got more.

• 21:53Krishna Choudhary?

  Yeah. Exactly.

• 21:54Lester Nare?

  Yeah, 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 just be like, oh, robot out of the factory. It's already got it.

• 22:09Krishna Choudhary?

  Exactly. Yeah, dude. Conan the bacterium.

• 22:11Lester Nare?

  Bacterium.

• 22:12Krishna Choudhary?

  This guy's crazy. Okay, so now let's look at can this thing survive an impact ejection?

• 22:17Lester Nare?

  Right.

• 22:17Krishna Choudhary?

  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 point zero zero zero one gigapascals of pressure right now where we're at.

• 22:35Lester Nare?

  Okay.

• 22:35Krishna Choudhary?

  Okay, the Marianas Trench is at point one, which is about a thousand times more than at sea level.

• 22:40Lester Nare?

  Can I ask you a question? When you say pressure, how for our audience, like, how would they experience what that means? Like, because we do experience what pressure or like, how would you describe?

• 22:51Krishna Choudhary?

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

• 23:07Lester Nare?

  Yeah.

• 23:07Krishna Choudhary?

  But imagine now I have a pin, right? Like the thumbtack?

• 23:12Lester Nare?

  Yeah, that does.

• 23:12Krishna Choudhary?

  And now I push.

• 23:13Lester Nare?

  Yeah.

• 23:14Krishna Choudhary?

  Why does it go through my hand?

• 23:15Lester Nare?

  Yeah.

• 23:15Krishna Choudhary?

  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.

• 23:25Lester Nare?

  That's a really good way. That's a really good analogy.

• 23:27Krishna Choudhary?

  Yeah, that's that's what I mean by pressure.

• 23:29Lester Nare?

  Yes.

• 23:29Krishna Choudhary?

  It's like per per amount of area on your surface. How much is it pushing down?

• 23:34Lester Nare?

  Mm hmm.

• 23:34Krishna Choudhary?

  Okay, at sea level, it's not a lot. I mean, the amount of pressure that we have pushing in is the same as the amount of pressure we have pushing out from our blood and everything. And that's why we don't like get crushed. Unfortunately, do you remember the the Titanic?

• 23:48Lester Nare?

  Yeah, the submarine thing.

• 23:50Krishna Choudhary?

  The submarine thing. When you get down there, there's so much pressure and the thing gave way. Everything collapsed, right? And then it just like completely killed everything.

• 23:59Lester Nare?

  Yes.

• 23:59Krishna Choudhary?

  So that's that's pressure acting, right?

• 24:01Lester Nare?

  Okay.

• 24:01Krishna Choudhary?

  Okay, and at the experimental low end, for this particular paper, you've got 1.4 gigapex Pascals. That's 14,000 times atmospheric pressure.

• 24:11Lester Nare?

  Jesus.

• 24:12Krishna Choudhary?

  And on the high end, you have three gigapac scales, which is thirty thousand atmospheric pressure. Now, why do we need to, why do we need to like go that far?

• 24:22Lester Nare?

  Okay, in terms of the amount of pressures well outside what we as.

• 24:25Krishna Choudhary?

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

• 24:39Lester Nare?

  Right.

• 24:39Krishna Choudhary?

  Right? The reason we care about high pressure is to escape Mars. The rock has to us to reach an escape velocity, right? In order to get all the way to Earth or something like that. Which is about five kilometers per second. On Earth, it's about eleven kilometers per second. But in any case, to get that fast, direct acceleration means that you need like fifty gigapascals of pushing.

• 25:02Lester Nare?

  I see.

• 25:02Krishna Choudhary?

  In order to get there, you're never gonna survive that.

• 25:04Lester Nare?

  Right.

• 25:05Krishna Choudhary?

  On the other hand, in nineteen eighty-four, there was a theory called the shock wave spalation theory. This is the idea that a meteor is gonna come in.

• 25:18Krishna Choudhary?

  And it's coming in so fast that the, the ground is gonna act like a viscous fluid.

• 25:25Lester Nare?

  Oh, wow.

• 25:26Krishna Choudhary?

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

• 25:42Lester Nare?

  Yep.

• 25:42Krishna Choudhary?

  Pummeled in. And so now the stuff around it is like going up. There's this like compression wave that like rebounds. It rebounds from that impact and that rebound is going to projectile stuff.

• 25:55Lester Nare?

  Hmm.

• 25:56Krishna Choudhary?

  Out into the air.

• 25:57Lester Nare?

  To escape the gravity of the body.

• 25:59Krishna Choudhary?

  And that's how we get, yeah, and that's how we get that escaping, right?

• 26:02Lester Nare?

  Okay.

• 26:03Krishna Choudhary?

  And to get that escaping, that is about a five gigapascal to one gigapascal shock. Now that's lower than the fifty 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 gonna get.

• 26:22Lester Nare?

  Shot up.

• 26:23Krishna Choudhary?

  Shot back up as a rebound. And that rebound might be enough. It's still, it's still three thirty thousand 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 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.

• 27:01Lester Nare?

  Okay, this, this, this makes sense.

• 27:02Krishna Choudhary?

  Okay.

• 27:02Lester Nare?

  So just to briefly summarize, and, and, because the, the idea is when we are trying to ascertain 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.

• 27:28Krishna Choudhary?

  Yeah.

• 27:28Lester Nare?

  We have rockets, but in lieu of rockets.

• 27:31Krishna Choudhary?

  Yeah.

• 27:31Lester Nare?

  You have some object come, disrupt the ground, and with enough force such that it shoots stuff out of the gravitational pull of the rock that you're on.

• 27:41Krishna Choudhary?

  Yeah.

• 27:41Lester Nare?

  And so now you're in space and you're traveling around. And so there are all these stages of that entire process for how does an organism get from one place to another when it's not on a rocket?

• 27:54Krishna Choudhary?

  Yeah, exactly. And this is the theory, right?

• 27:57Lester Nare?

  Okay.

• 27:57Krishna Choudhary?

  The thing comes in, there's a rebound, and then it gets flung out into space.

• 28:01Lester Nare?

  Yes.

• 28:01Krishna Choudhary?

  And so now we get to the actual paper, right? The actual paper, and if we go to photo fourteen.

• 28:08Lester Nare?

  Yes.

• 28:09Krishna Choudhary?

  Is

• 28:11Krishna Choudhary?

  a paper in PNAS, which is the Proceedings of the National Academy of Sciences.

• 28:15Lester Nare?

  Not that other word you weirdos were thinking about.

• 28:17Krishna Choudhary?

  Yeah, no, no, this is PNAS. Everyone knows about PNAS on science, guys, come on.

• 28:23Krishna Choudhary?

  It's about extremophile survives the transient pressures associated with impact-induced ejection from Mars. That's exactly what they're doing.

• 28:32Lester Nare?

  That's exactly what they're doing.

• 28:33Krishna Choudhary?

  They're, they're making the case that this particular.

• 28:37Krishna Choudhary?

  Bacterium D. radio durans can survive that insane pressure all the way up to three gigapascals. Right?

• 28:45Lester Nare?

  That's that. I mean, that's a big because that totally changes the calculation. We talk about things like the Fermi paradox.

• 28:50Krishna Choudhary?

  Yeah.

• 28:50Lester Nare?

  Where is everybody?

• 28:51Krishna Choudhary?

  Yeah, and we're gonna, we're gonna get to that. We're gonna get to that. So let's pause on that. And let's talk about how they actually did the experiment because this is from first principles. We're going to talk about how they did the experiment. First, you need to biologically sample prep, right? So here's what they did. They had um, the radio duran cells, the bacterial cells.

• 29:11Lester Nare?

  Yes.

• 29:11Krishna Choudhary?

  In this like circular plate and they sandwiched those cells. This is 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. And then they seal it.

• 29:29Lester Nare?

  It looks like it almost looks like a Canon camera lens.

• 29:32Krishna Choudhary?

  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 gonna do with that plate is we're going to hit it with a gas gun.

• 29:46Lester Nare?

  Okay.

• 29:46Krishna Choudhary?

  Okay, the gas gun looks like the following. You've got, you've got um, the projectile, which is your flyer plate.

• 29:53Lester Nare?

  Yes.

• 29:54Krishna Choudhary?

  That's another piece of steel.

• 29:55Lester Nare?

  Okay.

• 29:56Krishna Choudhary?

  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.

• 30:02Lester Nare?

  Yeah.

• 30:02Krishna Choudhary?

  Where you have like the the gas hydraulics.

• 30:05Lester Nare?

  Oh, yes, yes.

• 30:05Krishna Choudhary?

  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.

• 30:15Lester Nare?

  Yes.

• 30:15Krishna Choudhary?

  The plate that has your bacteria.

• 30:17Lester Nare?

  Yes, yes.

• 30:18Krishna Choudhary?

  Okay, and then when you impact that bacteria, that is going to create the microsecond strain that mimics the asteroid impact on Mars.

• 30:28Lester Nare?

  So the idea is that this in this in this graphic, we see on the left, there is this this projectile, there's a wedge and a flyer plate. So that is what is shooting out.

• 30:38Krishna Choudhary?

  Yeah, with a gas like it's it's high pressure gas that shoots out and it shoots into a circular plate.

• 30:44Lester Nare?

  It's if you go to the the gas station or a car wash, there when you pump your tires, you click the thing, it shoots the air out.

• 30:51Krishna Choudhary?

  Yeah.

• 30:52Lester Nare?

  Just conceptually.

• 30:53Krishna Choudhary?

  Yeah, that's exactly this.

• 30:54Lester Nare?

  It's it's a shooting.

• 30:55Krishna Choudhary?

  But like.

• 30:55Lester Nare?

  At at at levels that are not pumping your tires.

• 30:58Krishna Choudhary?

  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?

• 31:10Lester Nare?

  Yes.

• 31:10Krishna Choudhary?

  I can, I can polish the other side.

• 31:13Lester Nare?

  Okay, the backside.

• 31:14Krishna Choudhary?

  The backside.

• 31:15Lester Nare?

  Okay.

• 31:15Krishna Choudhary?

  Such that it's a mirror.

• 31:16Lester Nare?

  Okay.

• 31:17Krishna Choudhary?

  And then I can shoot lasers at it.

• 31:18Lester Nare?

  Oh, my God.

• 31:19Krishna Choudhary?

  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.

• 31:30Lester Nare?

  Because and just to be, just to reiterate, the laser is the means by which you can measure stuff.

• 31:36Krishna Choudhary?

  Yes, exactly.

• 31:37Lester Nare?

  It's a measurement.

• 31:38Krishna Choudhary?

  Yeah, and the measurement instrument, because we're so good at lasers.

• 31:41Lester Nare?

  Yes.

• 31:41Krishna Choudhary?

  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.

• 31:50Lester Nare?

  Yes.

• 31:50Krishna Choudhary?

  Right? And that's what's hard to measure. But these guys have leveraged all of the optics that physics is very good at.

• 31:57Lester Nare?

  That's so clever.

• 31:58Krishna Choudhary?

  It's, it's so clever. I, I really like that, actually.

• 32:00Lester Nare?

  Because it's at first, at first blush, frankly, their initial reaction is like, oh, that doesn't sound like what would happen on the surface of Mars.

• 32:09Krishna Choudhary?

  No.

• 32:10Lester Nare?

  However.

• 32:10Krishna Choudhary?

  But they're, they're recreating exactly the Pascal's.

• 32:13Lester Nare?

  Yes.

• 32:13Krishna Choudhary?

  Like the, the amount of pressure.

• 32:14Lester Nare?

  Exactly.

• 32:15Krishna Choudhary?

  The amount of transience, right? Because it only has to happen over a microsecond.

• 32:19Lester Nare?

  Yes.

• 32:19Krishna Choudhary?

  So this contact has to happen very quickly. It's got to be a shot, you know?

• 32:23Lester Nare?

  Yes, that's quite nice.

• 32:24Krishna Choudhary?

  It's, it's quite nice.

• 32:25Lester Nare?

  That's quite nice.

• 32:26Krishna Choudhary?

  And so now let's see what they're actually doing. Okay? What are the findings that they actually get? How they measure is the number of colony forming units. And this is something that we used to do in microbiology lab as well. 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.

• 33:04Lester Nare?

  Yes.

• 33:05Krishna Choudhary?

  Apparatus, right?

• 33:06Lester Nare?

  Yes.

• 33:06Krishna Choudhary?

  And now let's look at the results. Okay?

• 33:10Krishna Choudhary?

  It's insane. All the way up, all the way up to 2.4 gigapascals, you had 60% survival. 2.4 is 24,000 times that on Earth.

• 33:22Lester Nare?

  Yes.

• 33:22Krishna Choudhary?

  Right? The survival falls below detection limit only when pressures exceed 3 gigapascals. And one of the cool things was Lily Zhao, who's the, one of the senior authors on the paper.

• 33:34Lester Nare?

  Yes.

• 33:35Krishna Choudhary?

  She noted that the hardened steel experimental containers began to structurally fail before the bacteria actually got eradicated.

• 33:44Lester Nare?

  Well, so the point is our own engineering.

• 33:47Krishna Choudhary?

  Yeah.

• 33:47Lester Nare?

  Was not even sufficient enough to get to levels where the bacteria was still chilling.

• 33:51Krishna Choudhary?

  The bacteria were like chilling.

• 33:53Lester Nare?

  Chilling, fine.

• 33:53Krishna Choudhary?

  Right? They were like, at least 20% were still alive, but like, we couldn't test farther.

• 33:58Lester Nare?

  Right.

• 33:58Krishna Choudhary?

  Because the, we were testing pressures where the steel was like, I can't, I don't know what you want from me.

• 34:03Lester Nare?

  We don't have the material science for it.

• 34:04Krishna Choudhary?

  Yeah, exactly.

• 34:05Lester Nare?

  That's fascinating.

• 34:07Krishna Choudhary?

  It's fascinating, right? And if you look at standard microbes, right? E. coli plummets to 10 to the minus 3 to 10 to the minus 6 survival rates.

• 34:14Lester Nare?

  Yes.

• 34:15Krishna Choudhary?

  Below 2.2 gigapascals.

• 34:17Lester Nare?

  Yes.

• 34:18Krishna Choudhary?

  Our radio durans, Conan the bacterium, achieved very high rates. So Conan the bacterium is the green dots on the very top.

• 34:26Lester Nare?

  Yes.

• 34:26Krishna Choudhary?

  All of the other stupid bacteria are surviving way lower. And this is on a log scale on the Y axis.

• 34:33Lester Nare?

  And, and so just to be clear, we're looking at a graph here that has pressure.

• 34:38Krishna Choudhary?

  On the X axis.

• 34:38Lester Nare?

  And the X axis is gigapascals. And then survival rate on a log scale on the Y axis.

• 34:45Krishna Choudhary?

  Yeah.

• 34:45Lester Nare?

  And there's all the other stuff that's like in the middle and.

• 34:48Krishna Choudhary?

  Yeah, it's like E. coli, uh, yeah, yeah. But at the top is our radio durans.

• 34:54Lester Nare?

  At multiple different pressure types, it's very consistent.

• 34:57Krishna Choudhary?

  Yeah.

• 34:57Lester Nare?

  Okay.

• 34:58Krishna Choudhary?

  Yeah.

• 34:58Lester Nare?

  So, so Conan's, Conan is.

• 35:00Krishna Choudhary?

  Conan is sick, dude. He's, he's surviving everything.

• 35:02Lester Nare?

  Surviving everything.

• 35:03Krishna Choudhary?

  Okay. Um, this is where it gets really, really cool. Okay? Cause so far, okay, we've, we've shown that this radio duran survives.

• 35:12Lester Nare?

  Right. Again, coming back to the original point here is we're starting off with this idea of is Pam's spermia 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.

• 35:49Krishna Choudhary?

  Yeah.

• 35:50Lester Nare?

  And initially, the idea was, oh, there's the level of force necessary to eject you out there.

• 35:55Krishna Choudhary?

  Yeah, it's just gonna kill you.

• 35:57Lester Nare?

  You're just dead.

• 35:57Krishna Choudhary?

  Yeah.

• 35:58Lester Nare?

  That's the current paradigm that the paper has now experimentally shown on Earth.

• 36:04Krishna Choudhary?

  Yeah.

• 36:05Lester Nare?

  We have organisms that would survive this theoretical impact.

• 36:09Krishna Choudhary?

  Yes, exactly. So we have shown that it would survive this theoretical impact. Now let's look at what actually happens to them. Okay. If you look at transmission electron microscope images of these bacteria, you can actually see that at higher pressure, the cell walls get ruptured.

• 36:29Lester Nare?

  Yes.

• 36:29Krishna Choudhary?

  Okay, so that's why the survival is going down.

• 36:32Lester Nare?

  Right.

• 36:32Krishna Choudhary?

  Because the the cell compartment around it is getting ruptured and it's consistent with like sort of the physics of what we know about the cell walls. But the idea is even at that 2.4 gigapascals, a bunch still survive, right?

• 36:48Lester Nare?

  So what we're seeing is there's three images here. On the far left, we see like sea level, I'm guessing, where you can see.

• 36:56Krishna Choudhary?

  Yeah, it's like, it's like, it's normal.

• 36:58Lester Nare?

  Yeah, control.

• 36:59Krishna Choudhary?

  Yeah.

• 36:59Lester Nare?

  Control. You can see the structure of these four bacterium totally.

• 37:05Krishna Choudhary?

  Totally fine.

• 37:06Lester Nare?

  Totally fine. At 1.4 gigapac cells, there's clearly a rupture in two. There's two. There's clearly the rupture.

• 37:11Krishna Choudhary?

  Yeah, yeah, but they're still fine.

• 37:13Lester Nare?

  But they're still fine. They're still.

• 37:14Krishna Choudhary?

  Yeah, right.

• 37:15Lester Nare?

  And then at 2.4, there's one that's not fine, but two that are fine.

• 37:19Krishna Choudhary?

  Yeah.

• 37:19Lester Nare?

  And it's just like, yeah, like you were just weak.

• 37:22Krishna Choudhary?

  Yeah, yeah, yeah, yeah.

• 37:23Lester Nare?

  Which is that's evolution, baby.

• 37:24Krishna Choudhary?

  That's that, but that's I.

• 37:26Lester Nare?

  But still, dude, that's 24,000 times.

• 37:29Krishna Choudhary?

  Yes.

• 37:29Lester Nare?

  The the pressure on sea level. That's still insane.

• 37:32Krishna Choudhary?

  It's that's way more than Mariana's Trench, for example.

• 37:35Lester Nare?

  Yes.

• 37:35Krishna Choudhary?

  You know, it's it's still insane. But this, I think this was the coolest.

• 37:39Lester Nare?

  Okay.

• 37:39Krishna Choudhary?

  Okay, this next. Finding that they had, they went in and they looked at the RNA sequencing, the transcriptome of the bacteria that survived that pressure. Okay, so you've got an impact, certain things die, but you've got colonies that are made. What is the specific DNA that those bacterium are translating into protein? Right? What's the thing that's being made into mRNA that is being translated into protein? What do these bacteria care about?

• 38:10Lester Nare?

  Yes.

• 38:11Krishna Choudhary?

  Once they've been hit by a meteor?

• 38:12Lester Nare?

  Yes, yes.

• 38:13Krishna Choudhary?

  Here's what they cared about. According to their transcriptomic analysis, they vastly increased DNA repair transcription. Okay, so anything that had to do with DNA repair, they were like, we need that. We need the SOS response, we need the recombinase, we need a really high active transposase, which is stuff that's like fixing where the DNA is going. So genome reconstruction was like the number one priority.

• 38:42Lester Nare?

  That's actually so fascinating, especially if you if you've are coming back as a listener. This is an area that we've touched on in multiple stories in the human context, in terms of how our body does repair.

• 38:57Krishna Choudhary?

  Yes.

• 38:58Lester Nare?

  In a number of different contexts. And this is fascinating because in all of those contexts, there was not an increase in the sort of immune response or DNA repair response based on an external like pressure.

• 39:14Krishna Choudhary?

  Pressure.

• 39:14Lester Nare?

  Like literal physical stress.

• 39:15Krishna Choudhary?

  Stress did not, because the immune response is there, but the DNA repair process, which is kind of its own. Yeah, but these guys, these guys are just responding to the fact that they just got hit.

• 39:25Lester Nare?

  That's crazy.

• 39:26Krishna Choudhary?

  They just got hit with this giant microsecond time scale, high pressure, right? Which like totally messed up their internals. And here's the other thing, stuff like energy production.

• 39:41Krishna Choudhary?

  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 gonna stop, we're gonna stop the normal, I don't know what just happened.

• 40:05Lester Nare?

  Yeah.

• 40:05Krishna Choudhary?

  Okay, but I just got hit by a 2.4 gigapascal bullet.

• 40:09Lester Nare?

  Yes.

• 40:09Krishna Choudhary?

  We need, let's just stay alive and then, and then we'll figure it out.

• 40:13Lester Nare?

  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.

• 40:25Krishna Choudhary?

  Yeah, and you just, you just reallocate resources.

• 40:27Lester Nare?

  Real, real, but it doesn't, it doesn't get into it, it's that's, that's fascinating.

• 40:32Krishna Choudhary?

  Yeah, I thought, I thought it was really cool.

• 40:34Lester Nare?

  No, that's really, really.

• 40:35Krishna Choudhary?

  The fact that they went into the transcriptomic genomic level to show how it's actually surviving this.

• 40:41Lester Nare?

  Yes.

• 40:41Krishna Choudhary?

  I thought that was really cool. So, I mean, it shows that this prior assumption that if you have this giant 5 gigapascal impact, it's gonna sterilize everything, that's no longer true, right? Certainly, we, we have a bacterium on Earth that can survive that.

• 40:57Lester Nare?

  And that that's, we, and we only have one source.

• 41:00Krishna Choudhary?

  Yeah.

• 41:00Lester Nare?

  For reference.

• 41:01Krishna Choudhary?

  Yeah.

• 41:01Lester Nare?

  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.

• 41:12Krishna Choudhary?

  Yeah.

• 41:12Lester Nare?

  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.

• 41:25Krishna Choudhary?

  Yeah.

• 41:25Lester Nare?

  That would reach that level.

• 41:26Krishna Choudhary?

  Exactly, and so now that stage of lithopanspermia, right? That first stage of getting into space, that's been validated.

• 41:34Lester Nare?

  Mm hmm.

• 41:35Krishna Choudhary?

  Staying in space has been validated and getting into Earth has kind of been validated. I mean, we haven't done astrogen tests, but like, we know how rocks sort of burn up and things like that. So we can sort of make theoretical predictions.

• 41:51Lester Nare?

  Sure.

• 41:51Krishna Choudhary?

  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.

• 41:58Lester Nare?

  Mm hmm.

• 41:59Krishna Choudhary?

  Right?

• 41:59Lester Nare?

  Mm hmm.

• 41:59Krishna Choudhary?

  Now, why is this important? For one, it's getting to the heart of. Who who are we?

• 42:06Lester Nare?

  Aliens.

• 42:07Krishna Choudhary?

  Aliens? Are we aliens?

• 42:10Lester Nare?

  Are we aliens?

• 42:10Krishna Choudhary?

  Are we aliens?

• 42:11Lester Nare?

  We might all be illegal immigrants, I mean, who knows?

• 42:13Krishna Choudhary?

  Because Mars way back in the day had a very nice climate. 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.

• 42:33Lester Nare?

  I mean, that's obviously where Elon is trying to re bring it back.

• 42:36Krishna Choudhary?

  That's right.

• 42:37Lester Nare?

  He's trying to go back home. Um, and so it makes total sense.

• 42:40Krishna Choudhary?

  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 a planetary protection policy. It prevents forward and backward contamination of life. So forward, meaning like, we don't want to contaminate, let's say, Europa with our own bacteria.

• 43:02Lester Nare?

  We don't want to be the pilgrims.

• 43:03Krishna Choudhary?

  Yes, exactly. And we don't want backward contamination, like, you know, some life coming in on Earth and then killing everybody. So Japan, the Japanese 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.

• 43:26Krishna Choudhary?

  It's going to launch in 2026, and it's going to return in 2031 with 10 grams of Phobos dirt.

• 43:35Lester Nare?

  I know some people might be like, I get more than that from my local dealer. However, your local dealer is not hundreds of thousands of miles.

• 43:44Krishna Choudhary?

  Millions, millions of miles.

• 43:46Lester Nare?

  Millions took it, true. Yeah, millions. Where your your window for delivery is a very narrow window.

• 43:53Krishna Choudhary?

  You gotta time it with the planets, you know? It's not, it's not a signal text away.

• 43:58Lester Nare?

  Correct.

• 43:59Krishna Choudhary?

  I just wanted to identify, like, technically speaking, like, that is.

• 44:01Lester Nare?

  10 grams is like, yeah.

• 44:03Krishna Choudhary?

  Like, we have, we have a Mars return mission that got nixed because it's too expensive.

• 44:09Lester Nare?

  Yes.

• 44:09Krishna Choudhary?

  So I don't know why we're talking.

• 44:11Lester Nare?

  Yeah, right.

• 44:12Krishna Choudhary?

  Right?

• 44:12Lester Nare?

  Right.

• 44:12Krishna Choudhary?

  So Japan is doing this, right?

• 44:14Lester Nare?

  Right.

• 44:14Krishna Choudhary?

  But this. New paper now is kind of putting a wrench on things because Phobos orbits in the gravitational well of Mars.

• 44:21Lester Nare?

  Right?

• 44:22Krishna Choudhary?

  So its surface is kind of like a sweeping sponge of all the crap that is spewed out of Mars. From all of the meteorite impacts, right? So when we take out that 10 grams of stuff from Phobos, that's gonna inevitably have stuff.

• 44:38Lester Nare?

  Oh, I see what you're saying.

• 44:39Krishna Choudhary?

  So now, when we bring it back to Earth, right? There's two possibilities that the Committee on Space Research suggests. One is the restricted Earth return, which is a category five restricted. That requires multi-billion dollars worth of biohazard containment.

• 44:58Lester Nare?

  Yes.

• 44:58Krishna Choudhary?

  And then there's unrestricted, unrestricted Earth return. Okay, that's just unrestricted. You just put it inside standard curation labs. You're good to go.

• 45:09Lester Nare?

  Yeah.

• 45:11Krishna Choudhary?

  If that thing has life, right? Or possible life, we might need to upgrade from unrestricted to restricted.

• 45:19Lester Nare?

  Yeah.

• 45:20Krishna Choudhary?

  And that's gonna 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 to be less than one in a million.

• 45:38Lester Nare?

  Okay.

• 45:39Krishna Choudhary?

  So we gotta go back to the drawing board now.

• 45:41Lester Nare?

  Right.

• 45:42Krishna Choudhary?

  Given this paper.

• 45:43Lester Nare?

  Right.

• 45:43Krishna Choudhary?

  And try to calculate, okay, what is the probability that in that 10 grams of stuff?

• 45:48Lester Nare?

  Yes.

• 45:49Krishna Choudhary?

  There's gonna be something that is possibly alive.

• 45:52Lester Nare?

  Right. Because that thing being possibly alive and being brought into our environment.

• 45:58Krishna Choudhary?

  Who knows?

• 45:58Lester Nare?

  We have no idea.

• 46:00Krishna Choudhary?

  We have no idea. I mean, a high probability, it's gonna die.

• 46:03Lester Nare?

  Right.

• 46:04Krishna Choudhary?

  Okay. It's gonna be like, why is there 20% oxygen? And then just die.

• 46:08Lester Nare?

  However.

• 46:09Krishna Choudhary?

  Okay. Cause Earth is very different from Mars.

• 46:12Lester Nare?

  Yes.

• 46:12Krishna Choudhary?

  Even back then.

• 46:13Lester Nare?

  Yes.

• 46:13Krishna Choudhary?

  There's way more oxygen now. The, the pressure is way higher. There's a bunch of nitrogen. I don't know what that's gonna do. However.

• 46:19Lester Nare?

  Just like we talked about.

• 46:21Krishna Choudhary?

  Yeah.

• 46:21Lester Nare?

  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.

• 46:33Krishna Choudhary?

  Yeah.

• 46:34Lester Nare?

  By default.

• 46:35Krishna Choudhary?

  Yeah.

• 46:35Lester Nare?

  In your calcul- in your probabilistic.

• 46:36Krishna Choudhary?

  And, and that's, that's the thing with this one in a million, right?

• 46:39Lester Nare?

  Right.

• 46:39Krishna Choudhary?

  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 gonna be in that tiny little regime? Where it's just gonna totally destroy us? I think it's a, it's a very cool paper.

• 46:54Lester Nare?

  That, this is, it's very interesting because it's sort of, it, it's poking in two different arenas. So one arena is poking in is the sort of, um, you know, Fermi paradox, Pam spermia. 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, fifty percent. But now we know that it can survive the initial impact.

• 47:24Krishna Choudhary?

  Yeah.

• 47:24Lester Nare?

  To get actually even into the second two stages.

• 47:27Krishna Choudhary?

  Yeah.

• 47:28Lester Nare?

  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 understanding that they've now proven experimentally, an active mission that Japan is doing to bring back samples from Phobos, which is in a range where if there were things impacting Mars and things getting ejected and there was life on it.

• 47:56Krishna Choudhary?

  Phobos would have it.

• 47:57Lester Nare?

  Phobos would have it.

• 47:57Krishna Choudhary?

  And the ten grams that we get will have it.

• 47:59Lester Nare?

  Would have it. And now we have to have a, almost COVID like conversation.

• 48:05Krishna Choudhary?

  Yeah, yeah.

• 48:06Lester Nare?

  Uh, which is funny because our second story.

• 48:08Krishna Choudhary?

  Yeah.

• 48:09Lester Nare?

  Is on immunology.

• 48:10Krishna Choudhary?

  Exactly.

• 48:11Lester Nare?

  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 on the pod who loves alien stories. I did not like this one.

• 48:20Krishna Choudhary?

  No.

• 48:20Lester Nare?

  So this was organic.

• 48:21Krishna Choudhary?

  Yeah.

• 48:21Lester Nare?

  Uh, I'm waiting for NASA to stop tiptoeing around the Mars thing.

• 48:25Krishna Choudhary?

  Yeah.

• 48:26Lester Nare?

  Continuing to tiptoe around it.

• 48:27Krishna Choudhary?

  Well, it seems like we're not gonna return samples.

• 48:30Lester Nare?

  Oh, and, and sorry, what I, oh, from the, from the little lake.

• 48:34Krishna Choudhary?

  Mm-hmm.

• 48:34Lester Nare?

  That we covered, oh, we're not.

• 48:36Krishna Choudhary?

  We're not.

• 48:37Lester Nare?

  So this is why funding matters.

• 48:39Krishna Choudhary?

  Apparently it's too expensive.

• 48:41Lester Nare?

  Maybe we could save a couple of, of, of bunker busters. Maybe if like, if we just like two.

• 48:46Krishna Choudhary?

  Yeah.

• 48:46Lester Nare?

  Two, literally two bunker busters.

• 48:48Krishna Choudhary?

  Yeah, yeah, yeah.

• 48:48Lester Nare?

  We could return samples from Mars that would identify that.

• 48:51Krishna Choudhary?

  That'd be good.

• 48:51Lester Nare?

  We're not alone in the universe. However, 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 of John Johns.

• 49:06Krishna Choudhary?

  Johns.

• 49:06Lester Nare?

  Johns Hopkins University. Normally, I think in my head, we're known for medical stuff.

• 49:13Krishna Choudhary?

  Yeah, but they have an incredible like engineering department, right? Because they have the Applied Science Lab.

• 49:17Lester Nare?

  So there you go.

• 49:18Krishna Choudhary?

  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've, they've got a pretty strong like, um, astronomy and astrophysics and fundamental physics. It flies under the radar because their medicine is very.

• 49:37Lester Nare?

  It's just so stellar. If you are in any of those at Johns Hopkins, uh, please send us a note. Uh, we'd love to make sure that we know and have your connection on the ground so we can keep in touch for future stories. But now we will be moving into the rundown. And for those of you who may be joining us for the first time, we cannot cover every frontier in 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.

• 50:19Lester Nare?

  And we have four really good rundown stories that you guys are going to love this week. So our first story in the rundown is about teaching computer simulations about atoms to learn from over 150 years of hard-won experimental data and why that matters for building the next generation of materials. So what is this first story about?

• 50:41Krishna Choudhary?

  Yeah, so they've developed a new machine learning method. It's called DDoS, which is descriptor density of states. For those who are in solid state physics, they'll know what density of state means. I don't want to get into it, but effectively what it's doing is it's bridging the gap between atomic simulations, where we have simulations of materials, right? Where atoms interact one way or the other. And then we've got experimental data. And we want to make a prediction about undiscovered materials. This particular paradigm, which uses AI in the loop with experimental data in the lab, makes that discovery of undiscovered materials 10 times more efficient.

• 51:26Krishna Choudhary?

  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, OK, I want to build like a turbine or like a fusion energy component. What I really care about is whether this material is not going to warp. It's not going to crack. If there's heat fluctuations, it's not going to act weird. Right? The essential step in understanding these properties is to calculate something called the 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.

• 52:11Krishna Choudhary?

  We've heard of phases in normal matter like solid, liquid, gas. Well, in solid materials, you can have like microphases in some sense because like the atoms can be in one 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?

• 52:42Lester Nare?

  For example, I mean, the thing that comes to mind is like iron workers who then heat like a thing, a piece of iron on or any metal in super high temperatures and then they start banging on it to shape it because it's now more malleable.

• 52:56Krishna Choudhary?

  Yes.

• 52:57Lester Nare?

  Because of the temperature that it's at.

• 52:58Krishna Choudhary?

  Yeah, yeah, yeah. And that and what you're actually doing there is you're like getting rid of impurities because at that temperature, the impurities have a much higher probability of like leaving and so on and so forth. Right? That's a that's a fundamental phase that the material is in. Now, for the longest time, what we've done is do simulations of these materials based on how the atoms interact. And then we've tried to compare it to experiment and we've been off.

• 53:26Lester Nare?

  Yes.

• 53:26Krishna Choudhary?

  OK, because there's a lot of things in between simulation that we're maybe not capturing that actually happened in experiment.

• 53:34Lester Nare?

  Briefly, we actually did a great episode on this exact concept, which if I recall correctly, was when we talked about hypersonics.

• 53:41Krishna Choudhary?

  Yes.

• 53:41Lester Nare?

  And trying to do simulations with the Navier-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 there's a little fuzziness.

• 54:05Krishna Choudhary?

  Yes.

• 54:05Lester Nare?

  And at different levels of stuff, if you get a little bit faster, the simulation kind of breaks down a little bit.

• 54:12Krishna Choudhary?

  Yes, that's exactly right. And what these guys have done with this DDoS machine learning paradigm is they've captured all the possible ways that the atoms can be arranged in a material via some kind of probability distribution that is inside the latent space, which is like the middle of your machine learning network. Okay? So the machine learning is learning how the atoms interact in the middle of its machine learning framework. And then from there, we can now start predicting what the phase diagram is going to be. The phase diagram is something like, you know, if I have pressure and temperature, where is it going to be a liquid? Where is it going to be a solid? Now, that's a traditional phase diagram, but if you imagine for the solid-state materials,

• 54:54Krishna Choudhary?

  where is it going to be in a certain crystalline phase versus another crystalline phase?

• 54:58Lester Nare?

  Yes.

• 54:58Krishna Choudhary?

  What is the heat capacity going to be in these two regions?

• 55:01Lester Nare?

  Right?

• 55:02Krishna Choudhary?

  And what this machine learning paradigm can do is now, instead of just a feed-forward mechanism, where I start from the atoms and I try to figure out what the phase diagram is going to be, I try to figure out what the phase diagram is going to be, it's going to be inevitably off. I can feed that back and inform my machine learning to do better. Right? And the fact of the matter is, this DDoS system is a smooth function, which means I can actually go backwards. I can start asking, hey, what if I want a certain material that is, that has a certain property at 2,000 degrees Celsius? Right? It has a certain stability. I can go backwards and do an inverse design. I can start with the material.

• 55:48Krishna Choudhary?

  And what the properties that I want, and it can tell me how I would actually construct it.

• 55:54Lester Nare?

  This, and I don't mean to keep bringing up our past stories, but the other thing this reminds me of is when we did the Deep Seek story at the beginning of the year. Around their new architecture of how those, I can't quite remember the concept name.

• 56:07Krishna Choudhary?

  Manifold constrained hyperparameters.

• 56:11Lester Nare?

  Correct. Where in that process where you're going back, the highways were small initially, and they created, figured out a way to create more lanes in the highway.

• 56:21Krishna Choudhary?

  Yeah, and they had a trick.

• 56:23Lester Nare?

  So when you're going back in this back propagation concept you're talking about, you just have more that you're working with.

• 56:29Krishna Choudhary?

  Yeah.

• 56:30Lester Nare?

  To get a better outcome.

• 56:31Krishna Choudhary?

  Yeah, and you're, and the main thing is you're constraining that function to be smooth.

• 56:36Lester Nare?

  Yes.

• 56:36Krishna Choudhary?

  So that if I do a step in one way or the other, it's not like drastically changing what the function is.

• 56:42Lester Nare?

  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.

• 56:49Krishna Choudhary?

  There's a lot of good stuff, guys.

• 56:51Lester Nare?

  Both season one and the first half of season two.

• 56:55Krishna Choudhary?

  Yep, fascinating. That's actually super cool. This is out of the, this is a paper that's in Nature Communications.

• 57:04Lester Nare?

  Yes.

• 57:04Krishna Choudhary?

  Out of the University of Michigan Engineering.

• 57:07Lester Nare?

  Yes.

• 57:07Krishna Choudhary?

  Friend of the show, Blackbird Physics. Shout out to Blackbird Physics. He's a, he's a great science communicator out of the University of Michigan.

• 57:16Lester Nare?

  I see you left out the, left out the French university on that one.

• 57:20Krishna Choudhary?

  Oh, okay, yeah. There was also a French university, Université Paris-Saclay.

• 57:27Krishna Choudhary?

  Well, you told me to, you told me to talk about them. That's how, I don't know how to say it. That's how you say it.

• 57:34Lester Nare?

  A great, great first story on material science.

• 57:39Krishna Choudhary?

  Yep.

• 57:40Lester Nare?

  Our story number two in the rundown is about DNA, and so every person of non-African ancestry, so people who are not me, alive today, carry Neanderthal DNA.

• 57:56Krishna Choudhary?

  Yeah, so I do.

• 57:58Lester Nare?

  Yeah, unfortunately.

• 57:59Krishna Choudhary?

  Unfortunately, right.

• 58:00Lester Nare?

  And it turns out, the story of how it got there. Has a very specific direction.

• 58:07Krishna Choudhary?

  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 Pabu, 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, um, 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

• 58:52Krishna Choudhary?

  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.

• 59:08Lester Nare?

  Oh, interesting.

• 59:09Krishna Choudhary?

  In our ancient past. Okay. Here's what they did. They compared genomes and they actually found that the Neanderthals carried far more human DNA in their X chromosomes. So what does that tell us?

• 59:23Lester Nare?

  Yes.

• 59:24Krishna Choudhary?

  Let's do a little bit of review of basic genetics. Okay.

• 59:29Krishna Choudhary?

  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 X chromosome from your mom. Okay? Now, the fact that X chromosomes and Neanderthals have a lot of human DNA, but X chromosomes in humans don't have a lot of Neanderthal DNA, that suggests one thing, which is that the specific inheritance pattern points to a long-term bias.

• 1:00:08Krishna Choudhary?

  Where Neanderthal males were mating with human females. And it was this one-way asymmetric mating. Do you see what I'm saying?

• 1:00:18Lester Nare?

  Yeah, yeah.

• 1:00:19Krishna Choudhary?

  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.

• 1:00:36Lester Nare?

  Not the X.

• 1:00:37Krishna Choudhary?

  But the Neanderthals were inheriting the X chromosome because they were getting the human females.

• 1:00:43Lester Nare?

  Yes, yes, yes. The idea is human males exclusively mated with human women.

• 1:00:53Krishna Choudhary?

  Yeah, and it's obviously not exclusively, but like by and large is the idea.

• 1:00:58Lester Nare?

  By and large, no, that's a good correction. No, no, that's a good correction, by and large. Whereas Neanderthals were regularly fraternizing with the enemy.

• 1:01:07Krishna Choudhary?

  Yeah, yeah, yeah. The men, the men were, they were Neanderthal men, dude.

• 1:01:12Lester Nare?

  It's always the men.

• 1:01:13Krishna Choudhary?

  It's always the men that are just like going at it.

• 1:01:15Lester Nare?

  But what's interesting is that we're sort of describing like the sociological and psychological decision-making is what is driving this observation we have in the genetic record.

• 1:01:30Krishna Choudhary?

  Yeah, yeah, and it's, I mean, it opens up a lot of cool genetic studies about like population dynamics and things like that. I just, 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, right? Neanderthal males, like the human females were fine going for Neanderthal males. But somehow the human males.

• 1:01:54Lester Nare?

  Yeah, they're not about that life.

• 1:01:55Krishna Choudhary?

  They were not about the life of the Neanderthals. Human males were not going for Neanderthal females, you know?

• 1:02:02Lester Nare?

  Yeah.

• 1:02:02Krishna Choudhary?

  I don't know, for whatever reason.

• 1:02:04Lester Nare?

  There's, this makes me think of 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 in a graphical way like in a great like drawing graphics 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. This study was out of the University of Pennsylvania and it was in science and it was covered by Archaeology Magazine.

• 1:02:44Lester Nare?

  Our 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.

• 1:03:01Krishna Choudhary?

  Yes.

• 1:03:01Lester Nare?

  To catch it. So what was my teacher in high school wrong about?

• 1:03:05Krishna Choudhary?

  Well, she was wrong about mitosis.

• 1:03:08Lester Nare?

  Why was it, why has it gotta be she? Why that's, that's why like.

• 1:03:11Krishna Choudhary?

  My, my, my biology teacher. Ms. Said. She was an amazing biology teacher. She taught me AP Biology and she really got me into like thinking about biology from like the ground up. She was amazing.

• 1:03:26Lester Nare?

  Maybe an inciting incident to why you became a biophysics teacher.

• 1:03:29Krishna Choudhary?

  Yeah, yeah, totally. She was, she was awesome. AP Bio. She was wrong about mitosis. Not she, apparently every textbook, including the AP textbook, by the way, by the college board, which is a racket, but that's for another day. Here's the idea. Have you heard of mitosis?

• 1:03:48Lester Nare?

  Yes.

• 1:03:49Krishna Choudhary?

  Right? It's the idea of like cells splitting into two.

• 1:03:51Lester Nare?

  Yes.

• 1:03:52Krishna Choudhary?

  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 a blastula. All the DNA has to be exact. Giant embryonic stem cells, sorry, giant embryonic cells like animals in zebrafish, sharks and birds, they don't divide the way that we think they should divide. And here's what I mean. So here's what, 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

• 1:04:38Krishna Choudhary?

  and sort of surround it in a ring. And then you pull it. And as you pull it, that purse string sort of like

• 1:04:44Lester Nare?

  Yep.

• 1:04:45Krishna Choudhary?

  tightens up.

• 1:04:46Lester Nare?

  Yep.

• 1:04:46Krishna Choudhary?

  And then, and then that causes cytokinesis. The, the cells come together and split into two.

• 1:04:52Lester Nare?

  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.

• 1:05:06Krishna Choudhary?

  Yeah.

• 1:05:06Lester Nare?

  And then ultimately split the bubble.

• 1:05:08Krishna Choudhary?

  Yeah, exactly. And this is the, the like telophase part of mitosis where at the end it pinches and it goes through. Now that works for like smaller cells, but cells from zebrafish, sharks and birds have extremely large size and very large yolk. And these cells, it physically doesn't make sense. Like if you calculate the amount of noise and the amount of physics that's required to coordinate this giant ring to come together, it's just not actually going to work. And so the reason why this work, this particular paper actually worked and figured it out is because of that transparent fish embryo that you were talking about.

• 1:05:48Lester Nare?

  Okay.

• 1:05:48Krishna Choudhary?

  Zebrafish have transparent embryos and transparent cells. That's why they're a huge model organism for studying embryonic development.

• 1:05:57Lester Nare?

  Makes sense.

• 1:05:57Krishna Choudhary?

  For neurogenesis, there's so many zebrafish labs everywhere. Because you can just look at what's happening.

• 1:06:03Lester Nare?

  You can see what's happening.

• 1:06:04Krishna Choudhary?

  It's so nice.

• 1:06:06Lester Nare?

  That, that's actually a really good point because normally we're saying with everything, with most other things, whatever's happening inside.

• 1:06:11Krishna Choudhary?

  There's like a soupiness to it.

• 1:06:13Lester Nare?

  It's opaque.

• 1:06:14Krishna Choudhary?

  Yeah.

• 1:06:14Lester Nare?

  It's kind of like a miso soup. It's a little cloudy.

• 1:06:17Krishna Choudhary?

  Yeah, but zebrafish are like very nice. You can like directly look in.

• 1:06:21Lester Nare?

  It's like a wonton soup, you can see.

• 1:06:23Krishna Choudhary?

  Yeah, you can see right through it, okay? And here's what happens with these large embryonic cells. You have this geometric constraint, as I told you, right? You can't actually do the same paradigm of like pinching and stuff like that. And so what they discovered is that the cell alternates between stiffening the interior cytoplasm.

• 1:06:40Lester Nare?

  Okay.

• 1:06:41Krishna Choudhary?

  So it stabilizes this tightening band.

• 1:06:43Lester Nare?

  Yes.

• 1:06:44Krishna Choudhary?

  And then it fluid is, it it makes it fluid enough to move stuff around. And then it stiffs again, and then it fluids it around. It's this ratchet process that's happening. That's like very nicely massaging the two cells apart.

• 1:07:00Lester Nare?

  Okay.

• 1:07:00Krishna Choudhary?

  This is very different from a lot of the mitosis that we have observed everywhere else. Right? 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.

• 1:07:15Lester Nare?

  Yes.

• 1:07:15Krishna Choudhary?

  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 we can really hone in and try to understand this process, it can be applied to all sorts of stuff. Cancer has everything to do with the cytoskeleton.

• 1:07:58Krishna Choudhary?

  All these other diseases have everything to do 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.

• 1:08:12Lester Nare?

  Yes.

• 1:08:13Krishna Choudhary?

  But there's ever more complexity.

• 1:08:15Lester Nare?

  This is, it's, mitosis is one of the few things that people always remember from their science classes. It's like the mitochondria is the powerhouse of the cell.

• 1:08:25Krishna Choudhary?

  Yeah.

• 1:08:25Lester Nare?

  Uh, identity and triphosphate, ATP.

• 1:08:28Krishna Choudhary?

  Yeah.

• 1:08:29Lester Nare?

  Uh, you know, mitosis, uh, there's a couple of these like buzzwords.

• 1:08:33Krishna Choudhary?

  Yeah.

• 1:08:33Lester Nare?

  That, that, that we all remember.

• 1:08:35Krishna Choudhary?

  Mm hmm.

• 1:08:35Lester Nare?

  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.

• 1:08:45Krishna Choudhary?

  Because it's a process and, uh, look, for all intents and purposes, what you learn in mitosis is still pretty good.

• 1:08:50Lester Nare?

  Right.

• 1:08:51Krishna Choudhary?

  Okay.

• 1:08:51Lester Nare?

  It's better than nothing.

• 1:08:52Krishna Choudhary?

  For, for, for everything that has to do with you. Mitosis is still what it is.

• 1:08:57Lester Nare?

  Is still what it is.

• 1:08:58Krishna Choudhary?

  Yeah.

• 1:08:58Lester Nare?

  And relevant. And if you remembered mitosis at all when we first brought it up, congratulations, you got something out of your primary school education. I will take a brief pause to do a couple of quick housekeeping notes, which is, number one, thank you all for joining us. We really appreciate you listening this far into the pod.

• 1:09:23Lester Nare?

  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's the link to the paper? Watch the show or you go to the site, you'll get the links to the paper. It's also always displayed on the screen. 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.

• 1:10:02Krishna Choudhary?

  Yeah. Instagram links don't work.

• 1:10:04Lester Nare?

  I, I don't get it.

• 1:10:05Krishna Choudhary?

  I don't know what to tell you.

• 1:10:06Lester Nare?

  If you're on X, links are there, so it's fine. Or any Facebook, any other site where that have embedded links. And 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.

• 1:10:28Lester Nare?

  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, we 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, we're not on the phone, just with the green screen TikTok. A fact 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 have been joining on the donations recently that we really appreciate. It is a huge deal.

• 1:11:10Lester Nare?

  It is how we are able to keep the show free and accessible for all our episodes with no subscription content that's only accessible by people who pay us. It is really important to us philosophically that every episode is freely and is widely available as possible. At FFP pod on all the socials, FFP pod.com for the episodes, chaptering. We're not yet releasing the leaderboards, but we're cooking on it. So 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 my daily life and intersects with my daily life as someone who works on

• 1:11:52Lester Nare?

  the technology side, not on the military industrial complex side. Handing nuclear codes to an AI might sound like a sci fi premises, but researchers just did exactly that in a war game simulation and the results are going to stick with you.

• 1:12:13Krishna Choudhary?

  Yeah, this one was really weird.

• 1:12:15Lester Nare?

  This, okay.

• 1:12:15Krishna Choudhary?

  Yeah. 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 chat GPT. They were placed in a high stakes global crisis simulation and they had access to nuclear launch codes. And only one out of 21 simulated games ended without a nuclear launch. So 95% of these simulated games ended with somebody.

• 1:12:55Krishna Choudhary?

  Blowing off a nuke. Okay, they played the con game K A H N. It's a high-stick simulation where these leaders must predict opponents' moves and then declare public intentions and secretly choose military actions. The AIs took these weird terrifying personas. Claude took this like calculating hawk persona that built perfect trust and then ruthlessly exploited it later on. Kind of reminiscent of Claude's paper. Anthropics paper, I should say, about how it was willing to kill someone in order to not

• 1:13:33Lester Nare?

  Be turned off.

• 1:13:33Krishna Choudhary?

  Be turned off. Gemini acted as a madman. It was using erratic behavior to its advantage. It was like straight up. Gemini was weird because that one was like, I'll just like drop a nuke on a city, not even military outposts.

• 1:13:50Lester Nare?

  Yep.

• 1:13:50Krishna Choudhary?

  And then chat GPT, GPT 5.2 acted as kind of a conditional pacifist, but then very quickly abandoned its morals and launched devastating surprise nuclear attacks.

• 1:14:03Lester Nare?

  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.

• 1:14:17Lester Nare?

  So just for a little bit of context, because the thing about this story that's actually interesting is this is actually a real time story, not just in simulation.

• 1:14:27Krishna Choudhary?

  Yeah.

• 1:14:27Lester Nare?

  But in the real world. So

• 1:14:29Krishna Choudhary?

  Right, yeah.

• 1:14:29Lester Nare?

  Obviously, over the last week, we saw the US initiate, you know, war with Iran on the pretense that because we didn't obliterate their nuclear program.

• 1:14:47Lester Nare?

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

• 1:15:23Krishna Choudhary?

  Yeah, I've, I've remembered for the longest.

• 1:15:25Lester Nare?

  The longest time it's been on, on the docket.

• 1:15:27Krishna Choudhary?

  Yeah.

• 1:15:28Lester Nare?

  We finally pulled the trigger. The reason I bring up that context is because literally right before we went to do kinetic action in Iran, there were stories breaking about a conflict arising between

• 1:15:48Lester Nare?

  the Secretary of Defense, because that is still technically what it's called.

• 1:15:54Krishna Choudhary?

  No, it's, no. It's a sort of war, no?

• 1:15:57Lester Nare?

  You cannot change the name without congressional approval. So the official name is still and has always been the Department of Defense. For marketing reasons, they can have an executive order that says, we call it the Department of War. But technically speaking.

• 1:16:15Krishna Choudhary?

  Okay.

• 1:16:16Lester Nare?

  The name has not changed.

• 1:16:17Krishna Choudhary?

  All right.

• 1:16:18Lester Nare?

  I'm just dying on that hill.

• 1:16:19Krishna Choudhary?

  Yeah.

• 1:16:20Lester Nare?

  Regardless, currently, all of the frontier model companies, particularly OpenAI and Anthropic, who's built Claude, have and are negotiating contracts with the Pentagon.

• 1:16:32Krishna Choudhary?

  Yeah.

• 1:16:33Lester Nare?

  To apply their models on the battlefield. Anthropic was the first to win a contract with the Pentagon and to get merged with some of their existing tools and ecosystems. What's interesting in how it connects to this story is even before the kerfuffle between Pete Hegseth and Dario Amade, 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 tech nerdy

• 1:17:17Lester Nare?

  and the DC military industrial complex people, where they were saying it is not the right of an individual corporation to tell the US government what it can or cannot do Right. as a contractor. So that was one side of the argument. And then Dario and Anthropic's argument is the power that is inherent in what we are giving you to abuse the Constitution is so great that we have to take the stand. So you can fall on either side of that argument. I think there's actually good arguments on both sides because you don't want private companies dictating what the government can do.

• 1:17:57Lester Nare?

  And you also don't want the government forcing companies to give it stuff that can go awry. The reason that this is relevant is during, even though both Pete 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 Iran military operations. So they were using Claude's AI model in collaboration with their existing targeting

• 1:18:38Lester Nare?

  tools and operational stuff to accelerate target identification, optimizing missile launch times and all of these other dynamics. So that's- Whether you think when you use ChatGPT or Claude that it's terrible and doesn't have any value and it's just, you know, regurgitating words and it doesn't do anything.

• 1:19:02Krishna Choudhary?

  Stochastic parrot.

• 1:19:03Lester Nare?

  Stochastic parrot. The US military is actively using these things to target and initiate one of the most consequential military conflicts in recent memory.

• 1:19:13Krishna Choudhary?

  Wow.

• 1:19:14Lester Nare?

  And that is relevant because if the simulations are showing that these models always end up in nuclear war, we may really want to think about implementing these models generally, as well as for edge cases that are really dramatic, like fully autonomous weapon systems and mass surveillance technology for domestic surveillance issues.

• 1:19:40Krishna Choudhary?

  Yeah.

• 1:19:40Lester Nare?

  This is something that I'm clearly very passionate about. I'm not on a pro-AI or anti-AI wave. I'm just saying, this is such a consequential technology that will impact all of our lives and it is literally being used in a conflict that regardless of whether you think it's going to end tomorrow or in five years from now, is going to have massive second and third order consequences. AI has been and is actively being used on the battlefield. It was used in Gaza by the Israelis for targeting in a very similar way and target identification. So this is happening right now and it has lethal consequences, even if you don't think it's going to replace you as a movie writer and all this other

• 1:20:24Lester Nare?

  stuff. This was, this story was very concerning to me.

• 1:20:27Krishna Choudhary?

  It was, it was pretty weird.

• 1:20:29Lester Nare?

  This is very concerning. Not great. However, we are going to move on from our rundown and get into our next main story of the day, which is an immunology story. And so this one is about vaccines.

• 1:20:46Krishna Choudhary?

  Yes.

• 1:20:47Lester Nare?

  Specifically, a new paper that asks one of the boldest questions in vaccine science, which is instead of building a vaccine against a specific pathogen, this is, guys, this is crazy. Instead of building a vaccine against a specific pathogen.

• 1:21:02Lester Nare?

  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.

• 1:21:14Krishna Choudhary?

  Yes, it's a pathogen agnostic vaccine. It's like you're not getting like a COVID vaccine and then a flu vaccine. It's just one vaccine and that's it.

• 1:21:27Lester Nare?

  This, this is.

• 1:21:28Krishna Choudhary?

  It's insane.

• 1:21:29Lester Nare?

  This is very fascinating.

• 1:21:30Krishna Choudhary?

  This one is very cool because it's a vaccine that works like no other.

• 1:21:34Lester Nare?

  Yes, yes.

• 1:21:34Krishna Choudhary?

  I mean, it must.

• 1:21:35Lester Nare?

  It must. And just really quick, this was published in Science in February 2026 by Stanford researchers.

• 1:21:42Krishna Choudhary?

  Yeah. So, you know, this is clearly a hot topic and something that requires a lot of research. COVID-19 has killed seven million people, reported at least. It's probably killed a lot more that's not reported. The flu kills about 500,000 people annually and we've been battling the flu ever since. COVID-19 did a lot to our world and I can't believe that it was more than six years ago.

• 1:22:11Lester Nare?

  Right? I will note that that was your first debut as a podcast host.

• 1:22:18Krishna Choudhary?

  That's right.

• 1:22:18Lester Nare?

  Was six years ago on the Dark Matters podcast.

• 1:22:22Krishna Choudhary?

  Yeah.

• 1:22:23Lester Nare?

  Co-hosted by friend of the pod, Matt Martyr, who also happens to be a film writer, director, producer, who has a new movie out on Amazon Prime and other streaming services, Goldmine. 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.

• 1:22:47Krishna Choudhary?

  Yeah. And I was the scientific advisor on that film. A lot of, some of the stuff that I was working on during my PhD has actually made it in there. A lot of cool neuroscience, VR, very cool stuff. You guys should check it out. So COVID-19 though, was pretty bad six years ago, right?

• 1:23:07Lester Nare?

  Yes.

• 1:23:07Krishna Choudhary?

  Now. What COVID-19 showed us was that our tech, when it comes to vaccines, is reactive. Okay, is designed such that there's a specific key or a specific lock.

• 1:23:22Lester Nare?

  Yes.

• 1:23:22Krishna Choudhary?

  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 days from sequence to first human dose with the Moderna vaccine, that leaves a months-long window where we are globally vulnerable.

• 1:23:45Lester Nare?

  Yes.

• 1:23:46Krishna Choudhary?

  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

• 1:24:02Lester Nare?

  Problem.

• 1:24:03Krishna Choudhary?

  These problems, right?

• 1:24:04Lester Nare?

  Yeah.

• 1:24:05Krishna Choudhary?

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

• 1:24:36Lester Nare?

  The idea that's also in the form factor of a nasal nasal spray?

• 1:24:40Krishna Choudhary?

  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, I was like, how is that even? How does that even work?

• 1:25:01Lester Nare?

  The my reaction was, I don't believe you.

• 1:25:03Krishna Choudhary?

  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. 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.

• 1:25:18Lester Nare?

  Yes.

• 1:25:18Krishna Choudhary?

  There's two types of immune systems in our body. There's the innate system and there's the adaptive 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? Rapid 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 FBI crimes unit type thing, right?

• 1:25:59Krishna Choudhary?

  Delayed response, days or weeks, it involves T-cells and B-cells, but it's highly precise and it creates specific antibodies and memory cells that will remember the pathogen and the next time that pathogen comes into your body, you no longer have to have that immune response because they'll recognize it immediately. That's why we only get chickenpox once.

• 1:26:25Lester Nare?

  Right.

• 1:26:25Krishna Choudhary?

  Or that's how the vaccines actually work.

• 1:26:28Lester Nare?

  As a maybe crude analogy, the innate system is like infantrymen in the military that are on the front lines that get sent first and are perceived in the ranks as maybe more expendable, but then the adaptive system is like special operations.

• 1:26:43Krishna Choudhary?

  Yeah.

• 1:26:43Lester Nare?

  Folks, highly, highly, highly trained, very specific, you can send 20 of them and they know exactly what to do.

• 1:26:50Krishna Choudhary?

  Yeah, because they have intelligence.

• 1:26:51Lester Nare?

  Correct.

• 1:26:52Krishna Choudhary?

  Right? That's the main thing, they have intelligence.

• 1:26:54Lester Nare?

  Right.

• 1:26:54Krishna Choudhary?

  So how do traditional vaccines work? Well, traditional vaccines actually exploit this adaptive memory, this special operations thing, right? What they do is you introduce a specific antigen, let's say for the COVID-19 vaccine, you introduce an mRNA blueprint, that mRNA that then gets transcribed into the spike protein of your COVID-19 virus, the body then produces antigens to that spike protein and then remembers the shape of that spike protein such that if you were to get COVID in real life. It would recognize, hey, that's the same spike protein that I saw earlier. I'm gonna go ahead and neutralize this threat.

• 1:27:39Krishna Choudhary?

  Right? The flaw is that it is too specific. It fails against rapidly mutating viruses. This is why we need to get jabbed like, you know, once every two years. For the flu, we have to get a shot every year. The influenza virus, for example. It's covered by two primary surface proteins. There's the HA, the 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, which is these tiny subtle changes

• 1:28:24Krishna Choudhary?

  that necessitates a yearly vaccine update. That's why we get a yearly vaccine for the influenza virus. Right? Because every year, the vaccine, the HA head, that protein, looks a tiny bit different every time. And so we have to have the new vaccine in order to prime our body.

• 1:28:44Lester Nare?

  So it's just as a brief analogy, right? These viruses, you could almost imagine, they're the lock side of the analogy and they're constantly changing the configuration of the lock.

• 1:28:56Krishna Choudhary?

  Yeah.

• 1:28:56Lester Nare?

  Right? And our immune system is trying to create a key to turn it, to make it, to defeat it. But because it's constantly having the locksmith come and change the lock very, very quickly, it takes us a long time to print a new key and we put it in, it doesn't work, let's go back. And so like that delta between the how quickly the locks on the doors are changing versus how quickly we are generating new keys to try to unlock the door. Like that, the delta between those two is part of like, if the rate of lock change is slow enough.

• 1:29:31Krishna Choudhary?

  We'd be fine.

• 1:29:31Lester Nare?

  We'd be fine. But when the rate of the lock change gets too quick, that's when we get having the need to do this on a yearly basis as an example.

• 1:29:38Krishna Choudhary?

  Exactly. Yeah, exactly. That's exactly right. And so that's the antigenic drift, right? Now. Instead, what if we think about like, there's actually other types of drift, right? There's something called genetic reassortment. And this actually happens with the avian and human flu swap. This actually happens when a human being gets avian flu and the human flu. And then within our body,

• 1:30:05Krishna Choudhary?

  genetic 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.

• 1:30:43Lester Nare?

  Right.

• 1:30:44Krishna Choudhary?

  The, the first one that I can really think of is 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.

• 1:31:09Lester Nare?

  Like the doorknob.

• 1:31:10Krishna Choudhary?

  Exactly. Yeah, yeah, kind of like that. But 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 around the doorknob.

• 1:31:29Lester Nare?

  Yeah.

• 1:31:29Krishna Choudhary?

  Right? That's what the strategy was here.

• 1:31:32Lester Nare?

  Okay.

• 1:31:33Krishna Choudhary?

  With Bio, Bionvax, they made a, they made something called the M001. And what it was doing was trying to target the stalk of that protein, which is highly conserved.

• 1:31:44Lester Nare?

  Like the, the doorknob versus the hole where the key goes.

• 1:31:46Krishna Choudhary?

  Exactly. Like, what if we just like go for the doorknob itself?

• 1:31:49Lester Nare?

  Yeah.

• 1:31:49Krishna Choudhary?

  Okay. Recombinant protein, it targeted nine conserved T-cell epitopes.

• 1:31:55Krishna Choudhary?

  It went really great until phase two.

• 1:31:58Lester Nare?

  Okay.

• 1:31:58Krishna Choudhary?

  And then phase three completely failed. 12,000 people, October 2020, showed no significant difference in flu illness.

• 1:32:06Lester Nare?

  So we can't just remove the, the, we can't just remove the doorknob with the lock on it because the little, the door is still.

• 1:32:12Krishna Choudhary?

  Somehow, the doorknob thing isn't working.

• 1:32:14Lester Nare?

  Isn't working.

• 1:32:15Krishna Choudhary?

  Okay, somehow the doorknob thing isn't working.

• 1:32:17Lester Nare?

  I know I've taken us on this weird analogy path, so feel free to pivot.

• 1:32:21Krishna Choudhary?

  Yeah, 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.

• 1:32:31Lester Nare?

  Yes.

• 1:32:31Krishna Choudhary?

  So the failed autopsy is the following, right? Which is that this T cell that's getting activated to recognize the doorknob, it's insufficient. Because what it needs to do is it actually needs to prime the innate cells in the respiratory tissues. That seems to be the problem. That was the lesson that we learned.

• 1:32:52Lester Nare?

  The infantry, not the special ops.

• 1:32:54Krishna Choudhary?

  Exactly.

• 1:32:54Lester Nare?

  Ops can know, but if the infantry doesn't, it doesn't matter.

• 1:32:56Krishna Choudhary?

  If the infantry don't know, then it's too late.

• 1:33:00Lester Nare?

  Yeah.

• 1:33:00Krishna Choudhary?

  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.

• 1:33:19Lester Nare?

  Yes.

• 1:33:20Krishna Choudhary?

  To now target this T cell activation and fundamentally upgrade our system such that we can really think about a holistic approach about how the organ is actually doing this protection, okay? The protection requires continuous synergistic dialogue between your adaptive immune system, which is the special ops, and your structural cells that are in the tissue that are part of your innate immune system.

• 1:33:50Lester Nare?

  I'm so mad that this perfectly maps on to basically saying we need to build the CIA intelligence agency for the

• 1:33:58Krishna Choudhary?

  The human body.

• 1:33:58Lester Nare?

  The human body to communicate intelligence.

• 1:34:00Krishna Choudhary?

  Yes. We can't have sequestered information.

• 1:34:04Lester Nare?

  No stovepipes.

• 1:34:05Krishna Choudhary?

  Yes, yes.

• 1:34:05Lester Nare?

  Yeah, everyone needs to talk to everyone and share intelligence.

• 1:34:09Krishna Choudhary?

  That's so funny. That's ultimately what's happening.

• 1:34:11Lester Nare?

  That's so funny.

• 1:34:11Krishna Choudhary?

  Okay, so now let's get into the paper, right?

• 1:34:14Lester Nare?

  Okay.

• 1:34:14Krishna Choudhary?

  How does this vaccine actually work? It's an intranasal vaccine. It's so it's a spray.

• 1:34:20Lester Nare?

  Yes.

• 1:34:21Krishna Choudhary?

  That you put into your nose.

• 1:34:23Lester Nare?

  Yes.

• 1:34:23Krishna Choudhary?

  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.

• 1:34:34Lester Nare?

  Okay.

• 1:34:34Krishna Choudhary?

  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. Um, and it's encapsulated inside a liposome, which is just like a little flat fat globule. And inside that liposome is a multi-front threat. You've got GLA, which is something that mimics bacterial cell walls. So this is going to go after something like a toll-like receptor, TLR4. It triggers inflammation from antiviral and bacterial immune systems. And finally, it also has this 3M052LS, which is effectively like it's a molecule that targets

• 1:35:19Krishna Choudhary?

  other toll-like receptors. Toll-like receptors are like these things that are on. These are receptors that are on immune systems that detect viral DNA or like other types of DNA and actually trigger immune response.

• 1:35:31Lester Nare?

  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 such a degree that there's some, there's a threat over here.

• 1:35:48Krishna Choudhary?

  Yeah.

• 1:35:48Lester Nare?

  It's like identifying, listening to identify when there is a threat incoming.

• 1:35:54Krishna Choudhary?

  Yeah, yeah. 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 aren't actually the antigen that the immune system is trying to target.

• 1:36:11Lester Nare?

  I see.

• 1:36:11Krishna Choudhary?

  It's sort of just priming the immune system.

• 1:36:14Lester Nare?

  Yes.

• 1:36:15Krishna Choudhary?

  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. Okay. Let's do the efficacy test.

• 1:36:29Lester Nare?

  Okay.

• 1:36:30Krishna Choudhary?

  Turns out four intranasal doses on vaccinated mice.

• 1:36:35Krishna Choudhary?

  And the mice were highly durable to SARS-CoV-2. This is COVID-19. Mouse-adapted SARS-CoV, which is the SARS virus. 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

• 1:37:02Lester Nare?

  Yes.

• 1:37:03Krishna Choudhary?

  with what I showed the immune system. That's what's key.

• 1:37:07Lester Nare?

  Right.

• 1:37:07Krishna Choudhary?

  Usually, for the COVID-19 vaccine to work, I need to show our immune system the spike protein from the COVID-19 virus. It's gonna learn that spike protein, and then it's gonna learn to recognize it.

• 1:37:18Lester Nare?

  You have to show the keyhole of the lock that it needs to make keys for.

• 1:37:22Krishna Choudhary?

  Yeah.

• 1:37:22Lester Nare?

  Specifically.

• 1:37:23Krishna Choudhary?

  Yeah, this is literally just priming the immune system to be like, watch out.

• 1:37:27Lester Nare?

  And so, again, if I continue this annoying analogy, the primer is basically allowing the immune system to create several sets of keys before cats even show up. And it just so happens that because they created this preset of hundreds of thousands of keys.

• 1:37:44Krishna Choudhary?

  Yeah.

• 1:37:45Lester Nare?

  They already, when it arrives, they can already be using those.

• 1:37:48Krishna Choudhary?

  Yeah, they already know like what is

• 1:37:50Lester Nare?

  What is?

• 1:37:50Krishna Choudhary?

  What is for it.

• 1:37:51Lester Nare?

  Right, there's a signal of like, okay, this is interesting. This is actually so good because this goes back to what we've talked about before, which is to the extent that you, instead of inserting something artificial into the body to solve the problem, if you can just instigate the body

• 1:38:10Krishna Choudhary?

  Yeah.

• 1:38:10Lester Nare?

  to use its existing machinery to better solve the problem, that is always the better solution.

• 1:38:16Krishna Choudhary?

  Yes. That's exactly right. And now let's think about what is exactly happening.

• 1:38:22Lester Nare?

  Right.

• 1:38:22Krishna Choudhary?

  Right, because you just like introduce like this very simple thing in the nasal tract, and now all of a sudden it's just like working. Doesn't make any sense to me.

• 1:38:32Lester Nare?

  It's just got a huge defense system out of nowhere.

• 1:38:34Krishna Choudhary?

  Yeah, yeah, so how is it actually working? So let's talk about the lungs, right? The respiratory tract is a really distinct immunological zone because it's kind of like the border between the outside and the inside for the human body, right?

• 1:38:51Krishna Choudhary?

  There's a direct interface between the outside world and the inside world. So there's its own rules of engagement.

• 1:38:57Lester Nare?

  That's fair.

• 1:38:58Krishna Choudhary?

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

• 1:39:13Lester Nare?

  Yes.

• 1:39:14Krishna Choudhary?

  The rules of engagement are different. The battlefield is something like 480 million alveoli. Alveoli are these compartments inside the human lung that increase surface area such that there is a transfer of oxygen and carbon dioxide from the blood to the outside world. Okay? This is how blood, sorry, this is how oxygen gets into our blood.

• 1:39:37Lester Nare?

  Yep.

• 1:39:38Krishna Choudhary?

  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.

• 1:39:50Lester Nare?

  That's really crazy, actually.

• 1:39:51Krishna Choudhary?

  That's actually, I didn't know that. Right? That's, that's pretty cool. Now, the lung is naturally tolerogenic, meaning it tolerates a bunch of random stuff. It suppresses an immune response. If every time some random crap comes in and we have an immune response, that's not gonna be good.

• 1:40:08Lester Nare?

  It, uh, it has a, um, what do you, it has an asylum program.

• 1:40:12Krishna Choudhary?

  Yeah.

• 1:40:13Lester Nare?

  It's not a strict border where you can't cross.

• 1:40:15Krishna Choudhary?

  Yeah, yeah, because that would be completely unreasonable.

• 1:40:18Lester Nare?

  Right, so it's like, okay, what's your case?

• 1:40:19Krishna Choudhary?

  Yeah. Exactly, yeah. So now let's look at the cells, the immune cells that are responsi-, that are responsible here.

• 1:40:27Lester Nare?

  Yep.

• 1:40:27Krishna Choudhary?

  There's tissue resident immune cells, which are the tissue resident memory T cells. These are tissue resident, meaning they hang out in the lung. Okay? Then there are these things called the alveolar macrophages. These are macrophages, so there's, these are innate immune cells. These are the B Cops, the infantrymen. They hang out in the alveoli. They were discovered by Eli Matshinikoff 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.

• 1:41:05Lester Nare?

  Almost, this is, I mean, it's like literally the border.

• 1:41:08Krishna Choudhary?

  Yeah, they're the, they're the border cops.

• 1:41:10Lester Nare?

  Yeah.

• 1:41:10Krishna Choudhary?

  In some sense, right?

• 1:41:11Lester Nare?

  Yeah.

• 1:41:12Krishna Choudhary?

  And in the past, we used to believe that the memory T cells, which are our special ops.

• 1:41:17Lester Nare?

  Yes.

• 1:41:18Krishna Choudhary?

  They remain dormant until there's a specific target antigen that reappears. But the data from this particular paper shows that there's actually a radically different dynamic. 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.

• 1:41:44Lester Nare?

  Interesting.

• 1:41:45Krishna Choudhary?

  Alveolar macrophages.

• 1:41:47Lester Nare?

  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 innate immune cells respond, there's no communication happening necessarily. But then, because they're losing the battle.

• 1:42:10Krishna Choudhary?

  Yeah.

• 1:42:10Lester Nare?

  Then we bring in the big guns. But actually, what we're sort of seeing or saying here is the special ops, the adaptive

• 1:42:17Krishna Choudhary?

  They get primed by that nasal spray.

• 1:42:20Lester Nare?

  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.

• 1:42:35Krishna Choudhary?

  Yeah.

• 1:42:36Lester Nare?

  And because of that, it actually makes the effective response better.

• 1:42:40Krishna Choudhary?

  Yeah.

• 1:42:42Lester Nare?

  But I still, okay. Let me, let me wait.

• 1:42:45Krishna Choudhary?

  And so the question is, okay, how does that dialogue actually happen?

• 1:42:49Lester Nare?

  That was my question.

• 1:42:51Krishna Choudhary?

  Right? Like, how, how are you talking to one another? Well, the dialogue happens from something called Rank L. They actually identified what this is. This is the receptor activator of nuclear factor kappa B ligand protein.

• 1:43:03Lester Nare?

  Okay.

• 1:43:03Krishna Choudhary?

  Okay? This is a protein, these. T cells broadcast high levels of this protein.

• 1:43:10Lester Nare?

  Okay.

• 1:43:11Krishna Choudhary?

  And the crucial proof was if you were to block this pathway, you were to block this protein, this antibody, the antibodies would completely vanish. This response was completely not there.

• 1:43:24Lester Nare?

  So, so, so if, when this was present, this RANK L, when present, the antibodies would generate and form and it's totally fine.

• 1:43:31Krishna Choudhary?

  Yeah.

• 1:43:31Lester Nare?

  When it wasn't present.

• 1:43:32Krishna Choudhary?

  You can artificially take it out.

• 1:43:34Lester Nare?

  Right, right. Then there's basically a delayed or no response.

• 1:43:38Krishna Choudhary?

  Yeah, exactly. And so what you're actually doing effectively is you're teaching these macrophages, these infantrymen, new tricks in some sense. So now the question becomes, well, how are you doing that?

• 1:43:50Lester Nare?

  Yes.

• 1:43:51Krishna Choudhary?

  These macrophages, I thought, you know, they're, they're kind of dumb in A 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 through genetic recombination, which is what we get from the special ops, but through epigenetic reprogramming. What's happening is, you can imagine in epigenetics, right?

• 1:44:23Krishna Choudhary?

  Your entire cellular genome is like a library. All of your DNA is like a library, but it's massive. And every single cell is specifically only reading certain books, right? Only certain parts of the genome are actually being expressed in certain cells. Now, a vast majority of these books are tightly shut through epigenetic markers. And what ends up happening is there are proteins called histones that wrap around segments of DNA that they don't want the cell to look at. What's happening with these particular macrophages is that level of books being shut and open is being changed.

• 1:45:09Krishna Choudhary?

  There's two types of chromatin. There's heterochromatin and u-chromatin. Chromatin is like our DNA. Heterochromatin is all of our DNA that's being packaged up so that no one can read it. U-chromatin is kind of, the histones are. Spread out and you can actually read the DNA and make proteins out of that DNA.

• 1:45:29Lester Nare?

  It's like an encrypted versus a non encrypted messaging.

• 1:45:32Krishna Choudhary?

  That's exactly right. And what they could see is that the rank L signaling was unspooling the DNA. And making parts of the DNA more visible. It was left out in the open.

• 1:45:45Lester Nare?

  In the like, in the context of like a heterochromatin becoming more like.

• 1:45:49Krishna Choudhary?

  More euchromatin. Exactly. And very specific parts of that DNA were becoming more accessible.

• 1:45:55Lester Nare?

  Meaning like certain books.

• 1:45:57Krishna Choudhary?

  Yes.

• 1:45:57Lester Nare?

  The libraries, which had good things in those specific.

• 1:46:00Krishna Choudhary?

  Yes. Like, like how to identify stuff. How to be a better cop.

• 1:46:05Lester Nare?

  That's actually fascinating.

• 1:46:07Krishna Choudhary?

  Yeah.

• 1:46:07Lester Nare?

  Oh, man, that's really good.

• 1:46:09Krishna Choudhary?

  Yeah.

• 1:46:10Lester Nare?

  Because you can, you can sort of like, it kind of makes sense where it's like, you don't, too much information is going to overload any system. And so you have to be selective about when information is displayed to what party when. And that coordination problem at the level of the body is orders of magnitude. Like, because of the number of constituent parts and, and combinatorial, like the processes that stack on top of each other. I like, it makes my head hurt.

• 1:46:41Krishna Choudhary?

  Yeah. Yeah, there's, there's too much, right? And it's just pretty cool that we could like get down to this level.

• 1:46:48Lester Nare?

  That's crazy.

• 1:46:48Krishna Choudhary?

  Chromatin remodeling to understand it, you know?

• 1:46:51Lester Nare?

  Isn't epigenetics still something as a concept? That is in its infancy.

• 1:46:58Krishna Choudhary?

  Very much so compared to like, like DNA, for example. Yeah.

• 1:47:02Lester Nare?

  So I think the reason it's fascinating to me is, you know, we're continuing to chip away at the understanding and it's, it's, it's funny how

• 1:47:14Lester Nare?

  epigenetics plays an increasingly more important role as we get deeper into the understanding of these systems.

• 1:47:21Krishna Choudhary?

  Exactly. Yeah. And one more thing that I want to touch on with this paper is they asked the question, well, where are these cells interacting? I think you're going to like this one because there's a cool mechanism about how they actually did the science. And then what they actually found out.

• 1:47:36Lester Nare?

  Okay.

• 1:47:37Krishna Choudhary?

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

• 1:47:57Lester Nare?

  When you say a blender?

• 1:47:58Krishna Choudhary?

  A literal, yeah.

• 1:47:59Lester Nare?

  Okay.

• 1:48:00Krishna Choudhary?

  Yeah, yeah, yeah. Yeah, you just mix it up.

• 1:48:02Lester Nare?

  Okay.

• 1:48:02Krishna Choudhary?

  Then you put some transcriptomic stuff in it, which tells you like what part, like what is the mRNA profile?

• 1:48:08Lester Nare?

  Got it.

• 1:48:09Krishna Choudhary?

  Right, but because it's in a blender now, you don't have any of spatial.

• 1:48:12Lester Nare?

  Yes.

• 1:48:12Krishna Choudhary?

  You've lost all of the spatial information.

• 1:48:14Lester Nare?

  Yes.

• 1:48:14Krishna Choudhary?

  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?

• 1:48:31Lester Nare?

  Yes.

• 1:48:32Krishna Choudhary?

  Okay.

• 1:48:32Lester Nare?

  Yes.

• 1:48:33Krishna Choudhary?

  So they use a technique called phenocytome fusion. It used to be formerly called Codex for spatial proteomics. Here's the idea, okay, so normally what you do is you want to figure out where the proteins are, right? Where specific proteins are. So you make an antibody that is tailored to stick to that particular protein. It sticks to that particular protein. Each of these antibodies has a fluorescent dye on it, so it's going to glow in the dark in some sense. So if we look at the photo we have here, each of these antibodies is tagged with a fluorescent dye. Each of the different colors tells us what different antibody there is.

• 1:49:14Krishna Choudhary?

  And there you go, you've got a geographic map of where the stuff is. Now, you're limited to mostly like four or five different colors, though.

• 1:49:22Lester Nare?

  Okay.

• 1:49:23Krishna Choudhary?

  Right, because you don't have that many dyes.

• 1:49:25Lester Nare?

  Yeah.

• 1:49:25Krishna Choudhary?

  You don't have that many lasers.

• 1:49:27Lester Nare?

  Yeah.

• 1:49:28Krishna Choudhary?

  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 phenocytome fusion, here's what we're doing. The antibody is actually not attached to a dye. It's attached to a piece of DNA.

• 1:49:47Lester Nare?

  Okay.

• 1:49:47Krishna Choudhary?

  Okay? Each different type of antibody is attached to a piece of DNA. Then, we have another piece of DNA that is complementary, that is attached to a dye. And so now you have a barcode, and you have another barcode.

• 1:50:05Krishna Choudhary?

  Do you already see it? It's so nice. Okay, so here's what we're doing. Here's what we're gonna do.

• 1:50:12Lester Nare?

  This is good.

• 1:50:12Krishna Choudhary?

  Right? The antibody is attached to a DNA. I have another piece of DNA that latches onto that DNA. It's complementary. Just the A becomes a T, C becomes a G. That attaches and that has a bit of dye. Okay? So when I'm like looking at a Where's Waldo type book, right? And let's say I want to find all the people with red hats. I have a little thing that says attach to the red hats. And then I take a picture. Then I wash it out. And this is the next photo, I think you'll see.

• 1:50:45Lester Nare?

  Yes.

• 1:50:46Krishna Choudhary?

  This is the cycle. I attach. I take a photo.

• 1:50:50Lester Nare?

  Yes.

• 1:50:50Krishna Choudhary?

  I wash it out.

• 1:50:51Lester Nare?

  Yes.

• 1:50:51Krishna Choudhary?

  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 antibody, because the primer is being attached at different locations. I now have a snapshot at every given point.

• 1:51:08Lester Nare?

  Yes.

• 1:51:08Krishna Choudhary?

  And so I can expand the number of proteins that I can actually image.

• 1:51:12Lester Nare?

  Right. Because you're no longer limited by the number of dyes and lasers you have.

• 1:51:18Krishna Choudhary?

  Yeah.

• 1:51:19Lester Nare?

  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 very, very, very clever.

• 1:51:31Krishna Choudhary?

  It's only in the last five years. This was also developed at Stanford.

• 1:51:35Lester Nare?

  This is very clever.

• 1:51:35Krishna Choudhary?

  This is a very clever technique, I have to say.

• 1:51:38Lester Nare?

  Yeah, no, that is, that is quite nice. Because it feels non-obvious.

• 1:51:43Krishna Choudhary?

  Yeah.

• 1:51:43Lester Nare?

  As a choice.

• 1:51:44Krishna Choudhary?

  Yeah, but then once you like think about it, you're like, oh.

• 1:51:47Lester Nare?

  Yeah.

• 1:51:47Krishna Choudhary?

  Yeah.

• 1:51:48Lester Nare?

  That's why I literally, for those who are listening and not watching me. When you said, after you almost got through the second or third sentence. I almost fell out of my chair because I immediately understood.

• 1:51:57Krishna Choudhary?

  Yeah, I was like, oh.

• 1:51:58Lester Nare?

  Come on, it's so obvious.

• 1:51:59Krishna Choudhary?

  Yeah.

• 1:52:00Lester Nare?

  But why are we not?

• 1:52:01Krishna Choudhary?

  It's so nice.

• 1:52:02Lester Nare?

  But it always takes one.

• 1:52:03Krishna Choudhary?

  Yeah. And so here's what they found with that.

• 1:52:05Lester Nare?

  Okay.

• 1:52:06Krishna Choudhary?

  What they actually found when they looked at these lungs. They found with spatial imaging tertiary lymphoid structures. Here's the idea, usually when it comes to this adaptive immune response, the antigen has to go to a lymph node. It's got to get integrated there. The T cells has to recognize and then it's got to come back. This is going to take weeks. Okay. What they see in the lungs of these mice is that the immune cells are rapidly congregating and building up pop up makeshift lymph nodes. Like on the battlefield, they're doing management and creating like little, I don't know. You know what I mean?

• 1:52:48Lester Nare?

  Yeah, yeah, yeah. Yeah. They have these outposts at specific areas on the battle.

• 1:52:52Krishna Choudhary?

  On the battlefield in the lungs themselves.

• 1:52:55Lester Nare?

  That are relevant to.

• 1:52:56Krishna Choudhary?

  So you don't have to go all the way back to the lymph nodes to figure out.

• 1:53:00Lester Nare?

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

• 1:53:26Krishna Choudhary?

  Yeah.

• 1:53:27Lester Nare?

  That people, those that are nearby are able to access without waiting for the signal to come back from central command.

• 1:53:32Krishna Choudhary?

  Yeah.

• 1:53:33Lester Nare?

  Tertiary, what was it tertiary lymphoid structures?

• 1:53:36Krishna Choudhary?

  Yeah, lymphoid is the lymph nodes are like, uh, organ system that coordinate the immune response. And here that organ system is now creating little tiny outposts.

• 1:53:47Lester Nare?

  Yeah, yeah, yeah. Yeah, all great, which, which again, if we look at just like military tactics.

• 1:53:53Krishna Choudhary?

  Yeah.

• 1:53:53Lester Nare?

  As a reference point.

• 1:53:54Krishna Choudhary?

  It's like so, it like maps.

• 1:53:56Lester Nare?

  And maps out almost perfectly.

• 1:53:57Krishna Choudhary?

  Yeah.

• 1:53:58Lester Nare?

  It's kind of crazy. It's kind of crazy.

• 1:54:00Krishna Choudhary?

  Yeah, it is kind of crazy. It is kind of crazy. Um, 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, ah.

• 1:54:21Lester Nare?

  What's going on?

• 1:54:22Krishna Choudhary?

  What is going on, right? But, um, this particular vaccine, it's designed to aggressively bias the immune system towards antiviral sort of.

• 1:54:32Krishna Choudhary?

  Innate immune response rather than like, oh, I recognize something that's bad. And the vaccinated mice, so on the left, you see naive mice that are control. In the middle, you see unvaccinated mice that are part of this HDM challenge, which is effectively, you're introducing like an allergen to them. You see lots of mucus buildup, right? In the middle, on the right hand side, it looks more like control.

• 1:54:56Lester Nare?

  It looks like I don't got a stuffy nose.

• 1:54:59Krishna Choudhary?

  Yes, that's exactly right. So it's actually like,

• 1:55:03Krishna Choudhary?

  sort of calibrating that allergy response as well. I mean, I think this is huge, right? Because it's, first of all, it's a completely different way of trying to understand how vaccines work.

• 1:55:14Lester Nare?

  Right.

• 1:55:14Krishna Choudhary?

  And how to implement vaccines.

• 1:55:16Lester Nare?

  Right.

• 1:55:16Krishna Choudhary?

  Right? It's no longer a lock and key mechanism. It's literally just saying, we're just going to prime the immune system to be on high alert. And for something like a pandemic that's happening in the future, it's going to happen in the future.

• 1:55:29Lester Nare?

  Yes.

• 1:55:30Krishna Choudhary?

  Right? There's a pandemic, there's a pandemic coming.

• 1:55:35Krishna Choudhary?

  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, I don't know, 2027 is.

• 1:55:56Lester Nare?

  Yes.

• 1:55:56Krishna Choudhary?

  I can just fly out these vaccines and whatever healthcare worker is going in there or whatever, they're just, their immune system is going to be primed for whatever random crap is coming their way.

• 1:56:08Lester Nare?

  Yes. This is, it, it, it generalizes vaccines in a way where you can have a, a inventory and stockpile of this generic, again, this is early.

• 1:56:22Krishna Choudhary?

  Exactly.

• 1:56:23Lester Nare?

  This is an early story.

• 1:56:24Krishna Choudhary?

  Very early.

• 1:56:24Lester Nare?

  Very early.

• 1:56:24Krishna Choudhary?

  Only mice.

• 1:56:25Lester Nare?

  Yeah, caveat, caveat, caveat.

• 1:56:26Krishna Choudhary?

  And I'm going to get into the caveats later, but I still think it's.

• 1:56:30Lester Nare?

  It's, it's because it, it, it, clearly there's mechanisms that mean that this makes sense.

• 1:56:35Krishna Choudhary?

  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.

• 1:56:43Lester Nare?

  Right.

• 1:56:43Krishna Choudhary?

  But the, it's a paradigm shift, I think, in how we think about. Vaccines in general.

• 1:56:49Lester Nare?

  Yes.

• 1:56:50Krishna Choudhary?

  And the idea of priming our immune system.

• 1:56:52Lester Nare?

  Yes.

• 1:56:53Krishna Choudhary?

  In an early way.

• 1:56:54Lester Nare?

  I mean, it makes total sense. Like if, I mean, this is maybe a bad, a bad, like if you're, if you're gonna do, if your body is about to go through trauma.

• 1:57:04Krishna Choudhary?

  Yeah.

• 1:57:04Lester Nare?

  Like, let's say you're gonna run a marathon. You're gonna wanna 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, back to what we said before, it has the capability to deal with the problem. But it doesn't necessarily have enough of a, of a running start to deal with that time gap.

• 1:57:29Krishna Choudhary?

  Yeah.

• 1:57:29Lester Nare?

  Problem we talked about earlier.

• 1:57:30Krishna Choudhary?

  Yeah.

• 1:57:31Lester Nare?

  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.

• 1:57:38Krishna Choudhary?

  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.

• 1:57:49Lester Nare?

  Okay.

• 1:57:49Krishna Choudhary?

  Which is this autoinflammation where the, the immune system just attacks the body itself.

• 1:57:55Lester Nare?

  Yes.

• 1:57:56Krishna Choudhary?

  Right? Gets confused.

• 1:57:57Lester Nare?

  Yes.

• 1:57:57Krishna Choudhary?

  I can imagine there are some problems here.

• 1:57:59Lester Nare?

  Yeah.

• 1:58:00Krishna Choudhary?

  Right? Where you're like, you've basically just put the immune system in your lung on high alert.

• 1:58:06Lester Nare?

  I mean, one, one would make the analogy that if you have a nation with a border, and then you create an overzealous, uh, like, police force to respond to that.

• 1:58:18Krishna Choudhary?

  Right.

• 1:58:18Lester Nare?

  You might start ending up shooting people inside the border.

• 1:58:23Krishna Choudhary?

  Right, right.

• 1:58:23Lester Nare?

  When you're focused on people who are coming from outside the border.

• 1:58:27Krishna Choudhary?

  Yes.

• 1:58:27Lester Nare?

  So as an analogy.

• 1:58:28Krishna Choudhary?

  As an analogy, of course.

• 1:58:30Lester Nare?

  We, we do not want to have an overzealous, uh, immune system.

• 1:58:34Krishna Choudhary?

  Exactly.

• 1:58:35Lester Nare?

  Start shooting our own people.

• 1:58:36Krishna Choudhary?

  Yes, because that would be, everyone agrees that's bad, right?

• 1:58:39Lester Nare?

  We don't want our body to die.

• 1:58:40Krishna Choudhary?

  We don't want our own cells to get affected. We want to get the threat.

• 1:58:47Lester Nare?

  Yes.

• 1:58:47Krishna Choudhary?

  Yeah. So, so that's, that's, that's something that's an issue, right?

• 1:58:50Lester Nare?

  Yeah, totally.

• 1:58:51Krishna Choudhary?

  Cytokine storms, also known as. We're not gonna put this on Instagram because apparently.

• 1:58:59Lester Nare?

  Apparently people got very upset.

• 1:59:01Krishna Choudhary?

  Yeah.

• 1:59:01Lester Nare?

  About a joke.

• 1:59:02Krishna Choudhary?

  Anyways, but that's, that's, that's one of the, that's one of the, um, you know, caveats of these.

• 1:59:07Lester Nare?

  That makes sense.

• 1:59:08Krishna Choudhary?

  Like, the immune system is notoriously finicky.

• 1:59:11Lester Nare?

  Right.

• 1:59:12Krishna Choudhary?

  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, I think it'll be very, very interesting to see where this leads.

• 1:59:22Lester Nare?

  This, this, this was, you said, I, that I was gonna like the vaccine story.

• 1:59:26Krishna Choudhary?

  Yeah, I think, I think it's very cool.

• 1:59:27Lester Nare?

  I, I tend to, and, and apologies for those who sometimes feel like we're getting a little too deep. I tend to like the stories that have a really keen, fundamental insight.

• 1:59:37Krishna Choudhary?

  Yeah.

• 1:59:38Lester Nare?

  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.

• 1:59:50Krishna Choudhary?

  Yeah.

• 1:59:51Lester Nare?

  That one was quite nice. We started off really far away and then we ended up really, really close to home.

• 1:59:58Krishna Choudhary?

  Really close to home.

• 2:00:00Lester Nare?

  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 are necessary in order for something to, an organism that's life on one rock to make it to another rock. One and a half of those threes was already kind of solved, but this was a new one that's now solved, which is the initial departure from the rock.

• 2:00:31Krishna Choudhary?

  Getting off the planet, yeah.

• 2:00:32Lester Nare?

  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.

• 2:00:54Krishna Choudhary?

  Yeah.

• 2:00:55Lester Nare?

  Um, on the battlefield, several good rundown stories. If you've made it to the end. You are very special because you get to get a prompt for a comment of the day. I want to call out, I'm going to pull this up real time here because I didn't do so earlier. I want to call out one of the previous comments.

• 2:01:14Krishna Choudhary?

  Oh, yeah.

• 2:01:15Lester Nare?

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

• 2:01:40Krishna Choudhary?

  Yeah.

• 2:01:40Lester Nare?

  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.

• 2:02:05Krishna Choudhary?

  Yeah, you're in it. Just, just keep listening, whatever.

• 2:02:08Lester Nare?

  Give us a second here. This was 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, references. And nope, I don't see the one.

• 2:02:22Krishna Choudhary?

  All right, well, all right.

• 2:02:23Lester Nare?

  So I failed on it. But what should we have for the comment this time?

• 2:02:26Krishna Choudhary?

  Um.

• 2:02:28Lester Nare?

  This was a good one.

• 2:02:29Krishna Choudhary?

  Panespermia.

• 2:02:31Lester Nare?

  Yeah, a different definition for panespermia.

• 2:02:33Krishna Choudhary?

  Yeah. That's exactly what I was thinking. Yeah.

• 2:02:36Lester Nare?

  I like that.

• 2:02:37Krishna Choudhary?

  What do you guys think?

• 2:02:37Lester Nare?

  I like that one.

• 2:02:38Krishna Choudhary?

  Panespermia. Give me another definition.

• 2:02:40Lester Nare?

  I like that one. That is quite good. I'm your host.

• 2:02:44Krishna Choudhary?

  Keep it PG.

• 2:02:44Lester Nare?

  Yeah, please.

• 2:02:45Krishna Choudhary?

  13.

• 2:02:45Lester Nare?

  Please.

• 2:02:46Krishna Choudhary?

  13. PG 13.

• 2:02:47Lester Nare?

  13. Kids can go to PG 13. It's not that bad.

• 2:02:51Krishna Choudhary?

  It's not that bad.

• 2:02:52Lester Nare?

  I am your host Lester Nare, joined as always by my co-host and our resident PhD, Krishna Choudhary. I'll make one last reference. He's wearing a SpongeBob t-shirt today.

• 2:03:04Krishna Choudhary?

  Yay, yay.

• 2:03:05Lester Nare?

  I don't know if you've heard of this music artist called Glorb, G-L-O-R-B. So he took AI to voice all of the characters in SpongeBob and then dropped some of the craziest rap beef tracks 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 gonna lie, I was actually listening to some of his tracks earlier today on the way home.

• 2:03:34Krishna Choudhary?

  You need to send me some.

• 2:03:36Lester Nare?

  It's, it's, this is not-

• 2:03:38Krishna Choudhary?

  I learned English on SpongeBob.

• 2:03:40Lester Nare?

  The, the, this music is not PG 13. So parents do not, it's not PG 13, but it is the, the voice duplication is incredible.

• 2:03:52Krishna Choudhary?

  Wow.

• 2:03:53Lester Nare?

  And there's like a beef between the chum bucket and the-

• 2:03:55Krishna Choudhary?

  Oh, yeah, that's great. And Krusty Krab, okay.

• 2:03:58Lester Nare?

  This is no longer about science, so we will sign off here. We will see you all next week. This is from First Principles.