AI Supercharges CRISPR & LIGO (Nobel Prize Week Preview) (EP. 10)

Hosted by Lester Nare and Krishna Choudhary, this two-story, 2.5-hour special sets the table for Nobel Prize Week with deep dives into two recent Nobel-winning domains—gene editing (CRISPR) and gravitational waves (LIGO)—and how AI is accelerating both. We trace CRISPR from bacterial immunity to Stanford’s new “CRISPR-GPT” lab co-pilot, then pivot to how machine learning upgrades are pushing LIGO past its noise limits to capture new classes of gravitational waves. Summary • CRISPR, from bacterial immune memory to RNA-programmable genome editing • The 2012 Science breakthrough: guide RNAs unlock programmable editing • The patent saga and the 2020 Nobel Prize in Chemistry • Stanford’s CRISPR-GPT: an AI “co-pilot” trained on expert lab threads and papers • Experiment planning, guide design, and safety guardrails for CRISPR-GPT • Biosecurity and ethical guardrails around AI in biology • LIGO’s foundations: Einstein’s equations, binary pulsars, and interferometer engineering • The “noise budget”: seismic, environmental, and quantum limits • AI-driven denoising and template generation: unlocking earlier inspirals and tougher detections • Funding, leadership, and the global policy race to keep LIGO competitive • Big picture: AI as an amplifier of discovery in both medicine and physics Show Notes Stanford Medicine — AI + CRISPR Breakthrough Nature Biomedical Engineering — AI-CRISPR Original Paper Caltech — AI Helps LIGO Science — LIGO Machine Learning Paper

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

• 0:00Lester Nare?

  Hello, Internet. This is your captain speaking, Lester Nare, joined as always by my co-host and our resident PhD, Krishna Choudhary. This is From First Principles. We have an exciting episode. It'll be a little bit of a special episode this week as we gear up for Nobel Prize Week, which is going to be our episode next week. We're going to do full coverage all week long, all three days, detailed deep dives. So be sure to subscribe to catch our Nobel Prize Week coverage. But in advance of that, we wanted to cover two of our favorite recent Nobel Prizes in a little bit of a grab bag of coverage that is anchored by two new papers about how AI is

• 0:42Lester Nare?

  being used for these two fundamental discoveries that got the Nobel. The first of which is going to be how AI-powered CRISPR could possibly lead to faster gene therapies. This is out of Stanford Medicine, and they put their paper in Nature. And then the second story is going to be about LIGO. Again, how can we apply new algorithms to hush the noise, which may lead to more black hole discoveries? This is out of our favorite Caltech, The Legends, and it was published in Science. So this is going to be a great prep episode for Nobel Prize Week. You're going to love it. This is From First Principles.

• 1:35Lester Nare?

  My friend.

• 1:36Krishna Choudhary?

  How's it going?

• 1:38Lester Nare?

  Episode 10. We've made it to double digits.

• 1:40Krishna Choudhary?

  Double digits, baby.

• 1:41Lester Nare?

  Thanks for everyone who's tuned in.

• 1:43Krishna Choudhary?

  We're also on Double Digits on Instagram and TikTok.

• 1:46Lester Nare?

  It's, it's just-

• 1:47Krishna Choudhary?

  Get us there on YouTube, though.

• 1:48Lester Nare?

  Yes. Yeah, we are on YouTube, so definitely check us out on YouTube if you're not watching this on YouTube. We really appreciate all, all the support. I think people really like Science content.

• 1:58Krishna Choudhary?

  Yeah.

• 1:59Lester Nare?

  We do have Nobel Prize Week coming up next week. That's going to be huge. You're going to get so much content from us. We know you guys like the history and the current, so we're going to be combining both. But this week, in preparation-

• 2:14Lester Nare?

  We're going to talk about CRISPR and LIGO.

• 2:16Krishna Choudhary?

  Yeah.

• 2:17Lester Nare?

  Are two of our favorite recent Nobel Prizes, let's say in the last 10 years.

• 2:21Krishna Choudhary?

  Yep.

• 2:21Lester Nare?

  And our first story comes out of Stanford Medicine. And this is related to their new CRISPR GPT, a large language model that is accelerating gene editing processes and increasing accessibility to CRISPR. So we've talked about CRISPR, CRISPR Cas9 on the podcast quite a bit.

• 2:43Krishna Choudhary?

  Yeah.

• 2:44Lester Nare?

  Um, and.

• 2:45Krishna Choudhary?

  Yeah, and this one is like, it's an AI co-pilot.

• 2:48Lester Nare?

  Yes, for for for CRISPR.

• 2:50Krishna Choudhary?

  For like CRISPR researchers. So you know how like, you know, um, all the coders out there probably know about co-pilot?

• 2:58Lester Nare?

  Yes.

• 2:58Krishna Choudhary?

  And you can just like verbally tell it what to code and then it'll just code it.

• 3:05Lester Nare?

  This is our, our, our favorite new term vibe coding.

• 3:07Krishna Choudhary?

  Vibe coding, yeah. Now you can vibe code with CRISPR research. Which, okay, it sounds funny, but it's actually going to be like really, really good for the scientific community and for the medical computer, community in terms of finding new therapies, all sorts of stuff. It's very cool.

• 3:24Lester Nare?

  Vibe gene editing.

• 3:26Krishna Choudhary?

  Yeah.

• 3:27Lester Nare?

  And so we, we talked in previous episodes, you, you made this kind of reference to

• 3:34Lester Nare?

  this idea of like a bacterial immune system as a way to think about CRISPR.

• 3:40Krishna Choudhary?

  That's how it started, yeah.

• 3:41Lester Nare?

  And, and so help me, can you like re-explain? Like what you meant by that as we kind of talk about this combination of AI and CRISPR?

• 3:51Krishna Choudhary?

  Yeah, I mean, you know, in preparation for Nobel Prize week, I think it's fitting that we talk about the Nobel Prize winners and how they got that discovery and how they got there. And it's, it's an incredible story of like.

• 4:05Krishna Choudhary?

  Collaboration in science and also in curiosity driven research, not application driven research.

• 4:14Lester Nare?

  Right.

• 4:15Krishna Choudhary?

  Right, because CRISPR now, obviously, it has so many applications, therapeutic, agricultural, all of these other things, but you know, it really started off as a curiosity driven scientific research program.

• 4:28Lester Nare?

  So, let's briefly start with what the new paper is about, and then we can sort of tell the story about how we got here.

• 4:37Krishna Choudhary?

  Okay, so the new paper is basically taking this pretty mature technology, which is CRISPR Cas9, which is this ability for us to snipe and cut DNA at wherever we want, and it's, it's taking that technology and it's putting it, it's training an AI to do that technology. And then, and then it's letting all of these researchers who might be novices in the technology, but want to use it, have a helping hand, and that's where this co-pilot thing comes in.

• 5:12Lester Nare?

  It's like, I can, as a researcher, speak in my natural language. And it will then convert that natural language into sort of the technical implementation.

• 5:21Krishna Choudhary?

  Yeah, yeah, exactly. And that's, that's what the, that's, that's what that current paper that came out in Nature Biomedical Engineering.

• 5:29Lester Nare?

  Yes, yes.

• 5:30Krishna Choudhary?

  Is doing.

• 5:31Lester Nare?

  Yes, and so how did, so, so how did we get here?

• 5:33Krishna Choudhary?

  Yeah, the question is, how did we get here?

• 5:35Lester Nare?

  Because this is crazy, we're playing God at this point.

• 5:38Krishna Choudhary?

  We're playing God at this point, and CRISPR lets us play God, right? And I think, I think it's, I think it's, um, it's nice to see how it gets there and what the human stories are. So, we're actually going to start back in 1987.

• 5:51Lester Nare?

  Oh, good year.

• 5:52Krishna Choudhary?

  Okay, why is that a good year?

• 5:54Lester Nare?

  I don't know.

• 5:55Krishna Choudhary?

  Okay, the eighties, baby, the eighties. Everything was good in the eighties.

• 5:59Lester Nare?

  That's what they say.

• 6:00Krishna Choudhary?

  Everything was good in the eighties.

• 6:01Lester Nare?

  That's what they say.

• 6:02Krishna Choudhary?

  Yeah, we were winning in the Cold War.

• 6:03Lester Nare?

  Yeah, that's true.

• 6:04Krishna Choudhary?

  You know, Ronald Reagan was president. So, everyone was like, oh, it's fine.

• 6:10Lester Nare?

  Take one for the gipper.

• 6:12Krishna Choudhary?

  You know, even though he had Alzheimer's at the time, whatever, you know, nineteen eighty seven, he he had full blown Alzheimer's.

• 6:18Lester Nare?

  Well, he shouldn't have used Tylenol because that's probably the reason why.

• 6:21Krishna Choudhary?

  Right, yeah, yeah, yeah, it turns out, turns out anyways, nineteen eighty seven, okay.

• 6:28Lester Nare?

  Okay.

• 6:28Krishna Choudhary?

  Um, gene editing is not a thing, really, okay.

• 6:32Lester Nare?

  Right.

• 6:33Krishna Choudhary?

  There are these things called restriction enzymes, restriction endonucleases. And what they do is they target a specific. Um, motif of DNA, so a specific sequence. And whenever you have that specific sequence, it'll go in and cut it.

• 6:51Lester Nare?

  Yep.

• 6:51Krishna Choudhary?

  Okay. The problem with that is it requires that specific sequence.

• 6:55Lester Nare?

  Mm hmm.

• 6:55Krishna Choudhary?

  Okay, so it was it was really in its nascent, nascent. State. At the time, and in nineteen eighty seven. Some scientists in Japan led by Yoshizumi Ishiuni, okay.

• 7:12Krishna Choudhary?

  I'm gonna say that again, because that was wrong. It was Yoshizumi Ishino. I got the vowels mixed up there, but in nineteen eighty seven. He discovered.

• 7:25Krishna Choudhary?

  This segment of DNA in E. coli, E. coli is sort of the bread and butter of biomedical research.

• 7:30Lester Nare?

  Yes.

• 7:31Krishna Choudhary?

  At least when it comes to, you know. This sort of researching bacteria as a as a model organism.

• 7:39Lester Nare?

  Mm hmm.

• 7:39Krishna Choudhary?

  To try to understand just basic molecular biology. E. coli is like the goat for that kind of stuff. And what he noticed was, he was sequencing parts of the E. coli genome. At that point, you didn't really have the technology to sequence the whole thing now, obviously, we have the whole E. coli genome. But back then, he noticed that there were the, there was this part of the genome. That had a very weird structure, okay? What it had was, it had these repeating sequences, okay? And in between these repeating sequences were non-repeating, unique sequences. Okay, so it was kinda like, there was like A, which is the repeating.

• 8:21Krishna Choudhary?

  And then it would be A B, and then A C, and then A D, and then A E, and so on and so forth. Okay, and each of these, each of these parts were about thirty base pairs long.

• 8:31Lester Nare?

  Okay.

• 8:31Krishna Choudhary?

  It was very weird.

• 8:32Lester Nare?

  Yes.

• 8:33Krishna Choudhary?

  Highly structured.

• 8:34Lester Nare?

  Right.

• 8:34Krishna Choudhary?

  The A was always the same.

• 8:36Lester Nare?

  Yes.

• 8:36Krishna Choudhary?

  Okay, and at this point, this is very new, like, research, where we're, we're starting to sequence large parts of genomes of organisms. And whenever you find this kind of nice mathematical repeating structure, it always like raises flags.

• 8:52Lester Nare?

  Right.

• 8:52Krishna Choudhary?

  Right? So you're, so this guy, he publishes a paper in nineteen eighty-seven where he's like, you know, I find these consistently repeating segments, and then with non-repeating segments. And everyone started focusing on the repeating segment, because that's the part that gets highest signal.

• 9:08Lester Nare?

  Right.

• 9:09Krishna Choudhary?

  Right? Whenever you're doing any kind of thingy.

• 9:11Lester Nare?

  Yes.

• 9:12Krishna Choudhary?

  On the genome, you're gonna get some signal on, like, how much of a match you're getting.

• 9:17Lester Nare?

  Right.

• 9:17Krishna Choudhary?

  And the repeating part is getting this higher signal. So the repeating part is kinda crazy, because it's also a palindrome. You know what a palindrome is?

• 9:27Lester Nare?

  Yes.

• 9:27Krishna Choudhary?

  It's like a race car.

• 9:28Lester Nare?

  Yes.

• 9:29Krishna Choudhary?

  Race car is a palindrome, because you read it front or from the back, it's the same thing.

• 9:34Lester Nare?

  Yep.

• 9:34Krishna Choudhary?

  Well, the same thing was happening with these repeats, okay?

• 9:37Lester Nare?

  Interesting.

• 9:37Krishna Choudhary?

  These repeats had, if you, you know, DNA is double-stranded.

• 9:42Lester Nare?

  Yes.

• 9:42Krishna Choudhary?

  So there's a top segment, for example, and then there's a bottom segment.

• 9:46Lester Nare?

  Yes.

• 9:46Krishna Choudhary?

  And the top segment, you'll read from left to right.

• 9:49Lester Nare?

  Yes.

• 9:49Krishna Choudhary?

  That's what they call from the three prime to the five prime. And that'll be, you know, some sequence of ACTGs. But if you read the bottom segment from the other way, it'll be the same exact

• 10:00Lester Nare?

  Hmm.

• 10:01Krishna Choudhary?

  thing.

• 10:01Lester Nare?

  Hmm.

• 10:02Krishna Choudhary?

  So it's already like, not only is it repeating and has this highly conserved structure.

• 10:07Lester Nare?

  Yes.

• 10:07Krishna Choudhary?

  But it's also, within the repeats, there's this structure.

• 10:11Lester Nare?

  It's this palindromic structure.

• 10:13Krishna Choudhary?

  Yeah, yeah, yeah, and it's already, so already, it's like, you know, E. coli.

• 10:17Lester Nare?

  Yeah, yeah, yeah, yeah, yeah.

• 10:18Krishna Choudhary?

  E. coli has this, it's like, that's crazy.

• 10:20Lester Nare?

  Yeah, right, right.

• 10:21Krishna Choudhary?

  And people thought it was interesting, but didn't really think anything of it.

• 10:27Lester Nare?

  Hmm.

• 10:27Krishna Choudhary?

  Okay?

• 10:29Krishna Choudhary?

  Then came Francisco Mojica. From Spain.

• 10:34Krishna Choudhary?

  This is back when bioinformatics was just a nascent field and people had, you know, started to sequence not just E. coli. But they were starting to sequence viruses. Specifically, these things called bacteriophages. Have you ever heard of these things?

• 10:50Lester Nare?

  Yes, I, yes, I remember from my.

• 10:51Krishna Choudhary?

  They do, they look like alien motherships.

• 10:54Lester Nare?

  Yeah, with these little like long, fatty long legs.

• 10:56Krishna Choudhary?

  Exactly, like, um, they look like the, the Martians that come down. But they're, but they're at the molecular level.

• 11:04Lester Nare?

  It's just like the, the aliens in War of the Worlds.

• 11:07Krishna Choudhary?

  Exactly.

• 11:07Lester Nare?

  When they come down, they look very similar to that.

• 11:09Krishna Choudhary?

  Exactly. Bacteriophages look exactly like that. They've got this capsule, which is this really nice polygon. And that has the DNA material and then it's got the, the neck or the shaft and then it's got these like prongs, these legs that attach to the bacteria.

• 11:24Lester Nare?

  Yes.

• 11:25Krishna Choudhary?

  And they're viruses that attack bacteria, hence bacteriophage. Okay, people started, um, finding the DNA sequences of the stuff that's inside bacteriophages. And what they noticed, Francisco Mojica specifically, what he noticed was the stuff that people weren't thinking about in CRISPR, which are, you've got the repeats, the AAAA, but you also have these B, C, D.

• 11:50Lester Nare?

  Right.

• 11:50Krishna Choudhary?

  Which has low signal.

• 11:52Lester Nare?

  Right.

• 11:52Krishna Choudhary?

  Those interspaced

• 11:55Lester Nare?

  Yes.

• 11:56Krishna Choudhary?

  unique parts were exactly the same DNA as the stuff that we were finding in bacteriophages. Okay, so now it's like, and, and he comes up with this, with this really cool hypothesis, which is that CRISPR, which, okay, I'm, I'm not gonna say CRISPR because right now we don't have the acronym yet.

• 12:16Lester Nare?

  Sure.

• 12:16Krishna Choudhary?

  Historically.

• 12:17Lester Nare?

  Sure.

• 12:17Krishna Choudhary?

  But what he comes up with is, he says this, this segment of DNA of this A, B, A, C, A, D. This is some type of bacterial immune system.

• 12:27Lester Nare?

  Okay.

• 12:27Krishna Choudhary?

  Because how does, how does our immune system work? Okay? We get, we get struck with a virus, let's say the flu or the COVID or whatever, right?

• 12:35Lester Nare?

  The COVID.

• 12:35Krishna Choudhary?

  The COVID, yeah. What ends up happening is you've got these T-cells, which create antigens.

• 12:42Krishna Choudhary?

  Or that that try to, no, they create antibodies that try to bind to the antigens of whatever pathogen that comes in, right? And the the way that um our adaptive immune system works is the T cells create these sort of antibodies that try to match with the antigens.

• 13:03Lester Nare?

  This is that lock and key.

• 13:04Krishna Choudhary?

  Exactly, it's the lock and key, where the antigen has a specific key or specific lock, we try to make the key that fits. And the ones that get the right fit, those are the ones that actually proliferate and create more of themselves. You have the sort of mini evolution that goes on within your body to try and remember the stuff that came in, so the next time it comes in, you can be ready and you don't have to have a fever. It can immediately recognize that pathogen and kill it.

• 13:32Lester Nare?

  Yes.

• 13:32Krishna Choudhary?

  Right? It can tag it and then other stuff comes in and kills it.

• 13:35Lester Nare?

  Yes.

• 13:36Krishna Choudhary?

  Okay, so that's this adaptive immune system that we have as humans.

• 13:39Lester Nare?

  Yes.

• 13:40Krishna Choudhary?

  So Mohica had this crazy idea of what if we had an adaptive immune system for bacteria? Where this is a way, because obviously you've got these DNA segments, right? That are natively found in viruses. But now you're you you've got a memory mechanism.

• 14:00Lester Nare?

  Yes.

• 14:00Krishna Choudhary?

  Where you're keeping track of the stuff that you maybe saw in the past in your own DNA. And maybe maybe that serves as a kind of template where you can compare it to stuff that comes in and be like, that's bad.

• 14:13Lester Nare?

  Yes.

• 14:13Krishna Choudhary?

  I'm I'm gonna get rid of that.

• 14:14Lester Nare?

  Yes.

• 14:15Krishna Choudhary?

  Okay, so so he had this idea that it's a bacterial immune system, this this A B A C.

• 14:20Lester Nare?

  This repeating pattern that that we are seeing that has repeating components interspersed with non repeating components.

• 14:28Krishna Choudhary?

  Yes, exactly. And he was like, he was like, you know, the fact that they match means that this is some kind of adaptive immune system. A funny story, though. He he found this thing in 2001 and he tried to get it published, all the big ones, nature, science, we always talk about nature in science papers, all rejected him.

• 14:45Lester Nare?

  Oh, my goodness.

• 14:45Krishna Choudhary?

  You know, because it was either like, uh, you're wrong, or like bioinformatics was so new, it's like, you're probab-

• 14:52Lester Nare?

  We don't, we don't have enough of.

• 14:53Krishna Choudhary?

  Yeah, so he finally published in two thousand and five in a journal that's way lower tier than nature and science, but it's a fundamental discovery because that's what led to all of this CRISPR research.

• 15:04Lester Nare?

  With this little insight.

• 15:06Krishna Choudhary?

  Yeah, well, it's a little insight into, okay, the fact that this matches and the fact that the bacteria keeps track of this, like, why would it keep track of this unless it was for remembering the stuff in the past, right, and making sure that it doesn't get duped again, right? And now we know actually that it is a bacterial immune system. What ends up happening is, you know, you have a pathogen, let's say, that comes in and infects a population of E. coli, ninety-nine percent of them are gonna die. In fact, only one in a million are gonna survive. But that one in a million that's gonna survive is gonna be like, that was, that was awful. I don't want that again. So it's gonna take, it's

• 15:48Krishna Choudhary?

  gonna take, like, you know, after it survives, it's gonna take whatever part of the viral genome that is left, and it's gonna integrate it into this A, B, A, C, A, D. Now it's gonna make it A, E, or A, F.

• 16:00Lester Nare?

  It's adding to this chain of history of, next time you see, we've added this new component part, so we know what to do. We have that lock and key mechanism in order to, it's like this.

• 16:10Krishna Choudhary?

  Yeah, it's like now I can be like, oh, this matches with you. That means you are not me.

• 16:16Lester Nare?

  Bad guy.

• 16:17Krishna Choudhary?

  Which means you're a bad guy, right?

• 16:18Lester Nare?

  Where's your citizenship?

• 16:20Krishna Choudhary?

  Yeah, yeah.

• 16:20Lester Nare?

  You don't belong here.

• 16:21Krishna Choudhary?

  Exactly. And you have to remember, like, in biology, especially with E. coli, right, they don't have eyes, they don't have like.

• 16:27Lester Nare?

  It's a really good point.

• 16:28Krishna Choudhary?

  Reading mechanisms, right? So the way that, the way that, you know, at a molecular level, you can actually sense whether something is different and whether something requires intervention, is to actually have a template of DNA that matches the thing that you're trying to. To get rid of.

• 16:51Lester Nare?

  Yes, yes.

• 16:52Krishna Choudhary?

  Right?

• 16:53Lester Nare?

  The idea is the lack of a sensory system.

• 16:55Krishna Choudhary?

  Yeah, this is their sensory.

• 16:56Lester Nare?

  This is their, it's stor-, it's memorializing, you know, in the DNA layer because they don't have sight, smell.

• 17:04Krishna Choudhary?

  Yeah, yeah, they, this is what they got.

• 17:06Lester Nare?

  Yes.

• 17:06Krishna Choudhary?

  Right? It's like, it's like if I recognize, then it can create a cascade of other processes that then takes care of that.

• 17:13Lester Nare?

  Hundred percent.

• 17:13Krishna Choudhary?

  Right? Which is, which is kinda, which is kinda cool to even think about. So now Francisco Mojica establishes that this thing is a bacterial immune system.

• 17:23Lester Nare?

  Yes.

• 17:23Krishna Choudhary?

  And this is around where we start getting the acronym CRISPR.

• 17:26Lester Nare?

  Okay.

• 17:26Krishna Choudhary?

  Okay, um, or CRISPR, sorry guys. Um, someone's gonna.

• 17:31Lester Nare?

  Yeah, we've got enough comments about it.

• 17:33Krishna Choudhary?

  Someone's gonna, someone's gonna say something, but CRISPR stands for clustered, because it's clustered, it's all in the same genetic locus.

• 17:41Lester Nare?

  Okay.

• 17:42Krishna Choudhary?

  Regularly interspaced.

• 17:44Lester Nare?

  Yeah, cuz of that spacing.

• 17:45Krishna Choudhary?

  The regular interspacing.

• 17:46Lester Nare?

  Yes.

• 17:48Krishna Choudhary?

  Short palindromic repeats.

• 17:50Lester Nare?

  Which is literally what you just described.

• 17:52Krishna Choudhary?

  Yes, which is the idea that the A, which is the part that's repeating is palindromic.

• 17:57Lester Nare?

  Yes.

• 17:57Krishna Choudhary?

  So it's regularly interspaced and it's interspaced with these viral genomes.

• 18:02Lester Nare?

  And it's short.

• 18:03Krishna Choudhary?

  Yeah, it's short, it's only about thirty, thirty base pairs.

• 18:06Lester Nare?

  Yep.

• 18:06Krishna Choudhary?

  Right?

• 18:06Lester Nare?

  Yep, yep.

• 18:07Krishna Choudhary?

  So that's sort of how CRISPR is established. And CRISPR is really this bacterial part.

• 18:13Lester Nare?

  Conceptually, this is the birth, this is the origin of the idea.

• 18:18Krishna Choudhary?

  Yeah, but when, yeah, and when people say CRISPR, what they really mean is CRISPR Cas9. Or Cas13, or Cas any of these other.

• 18:26Lester Nare?

  Yes.

• 18:27Krishna Choudhary?

  Technologies.

• 18:28Lester Nare?

  Yes.

• 18:28Krishna Choudhary?

  And the Cas9, the Cas13 part, that's where our two heroes come in.

• 18:33Lester Nare?

  Got it.

• 18:34Krishna Choudhary?

  All right, Emmanuel Sharpentier and Jennifer Doudna, or Doudna.

• 18:39Lester Nare?

  Doudna.

• 18:40Krishna Choudhary?

  Sorry.

• 18:40Lester Nare?

  No, no, that, that, that's, so, so this is, this is interesting.

• 18:43Krishna Choudhary?

  Does that make sense?

• 18:44Lester Nare?

  It does make sense. And there's a whole, we'll get to it in a moment, but yes, I'm tracking.

• 18:51Krishna Choudhary?

  Yeah, you're tracking so far. Okay, so now let's talk about our, um, our two Nobel Prize winners.

• 18:58Lester Nare?

  Yes.

• 18:59Krishna Choudhary?

  So we got Emmanuel Sharpentier.

• 19:01Lester Nare?

  Yes.

• 19:01Krishna Choudhary?

  So she did her PhD at the Louis Pasteur Institute in Paris, founded in the late eighteen hundreds by Louis Pasteur himself.

• 19:11Krishna Choudhary?

  You know, one of the foremost.

• 19:14Krishna Choudhary?

  People to do life science research at a nitty gritty sort of quantitative level. He's the guy who actually established that life doesn't come from nothing. You need life in order to make life. There's no such thing as spontaneous generation. Cause people used to think like, you know, oh, I like, I let rotting food.

• 19:32Lester Nare?

  Yeah.

• 19:33Krishna Choudhary?

  Like out and then all of a sudden there's flies. So it must just be like, you know, just sprouts. And now we're like, like, it's like, it's like, that's so stupid. But like back then, I mean, yeah, the observation is I let out rotting food and now there's randomly there's flies.

• 19:49Lester Nare?

  Right.

• 19:50Krishna Choudhary?

  Right?

• 19:50Lester Nare?

  Right.

• 19:51Krishna Choudhary?

  The, the amount of experiments that he had to do to actually like

• 19:54Lester Nare?

  Convince.

• 19:55Krishna Choudhary?

  Convince people that it's not that. It was actually insane and I think we should do a separate episode on that.

• 20:01Lester Nare?

  This is, this is people forget that it takes a very long time for new ideas that come from sort of scientific research to actually permeate and settle.

• 20:10Krishna Choudhary?

  Yeah.

• 20:10Lester Nare?

  In the zeitgeist and in most cases it is a very aggressively pushed back.

• 20:18Krishna Choudhary?

  Yeah, yeah, yeah. Exactly. And so Louis Pasteur Institute, she gets her PhD. Um, she starts a lab at University of Vienna. And that's where she gets really into um, studying the streptococcus pyogenes bacteria, which is a pathogenic bacteria. It causes tonsillitis and um, it's known as a flesh eating disease. Because it causes strep throat and it actually starts damaging the soft tissue.

• 20:48Lester Nare?

  Mm hmm.

• 20:49Krishna Choudhary?

  And she was really interested in trying to find some way to, you know, circumnavigate this pathogen. And while she's working, she actually discovers that there's small RNA molecules that are part of this streptococcus bacterium that are doing something very close to what the CRISPR sequence is doing.

• 21:13Lester Nare?

  Okay.

• 21:14Krishna Choudhary?

  Okay, they match very closely and.

• 21:19Krishna Choudhary?

  The the function, because they match very closely, right? The function should be about the same. Because in biology, the the structure means that your three dimensional structure is about the same, which means you're probably doing the same thing. So she's she's trying to do this research, right? At the same time, we've got Jennifer Doudna.

• 21:39Lester Nare?

  Yes.

• 21:40Krishna Choudhary?

  She actually grew up in Hawaii. Um, did her um, college in Pomona College, which is

• 21:47Lester Nare?

  Oh, it's Sun Street.

• 21:48Krishna Choudhary?

  In in uh, Southern California and, you know, thank goodness for her French professor.

• 21:53Lester Nare?

  Okay.

• 21:53Krishna Choudhary?

  Because she was majoring in chemistry and it was getting hard as science gets hard.

• 22:00Lester Nare?

  It does sometimes.

• 22:01Krishna Choudhary?

  Science gets hard and she went to her French professor and and she was talking about, you know, maybe switching her her major from chemistry to French. And her French professor was like, no, no, no.

• 22:14Krishna Choudhary?

  Which is pretty awesome.

• 22:15Lester Nare?

  Shout out to Jennifer Doudna's French professor. Thank you.

• 22:19Krishna Choudhary?

  Yeah, shout out to the humanities French professor at Pomona College to be like, no, stick with chemistry, chemistry is dope, because that's how we get the Nobel Prize, yes. And so um, she stuck with chemistry. She did her um, PhD with um, the Harvard Medical School Professor Jack Sostak, who also won a Nobel Prize in two thousand and nine for his research in telomeres, which is the the stuff that it's at the end of chromosomes.

• 22:50Lester Nare?

  Yes.

• 22:51Krishna Choudhary?

  It's at the end of your DNA, basically. There's a bunch of repeating A T A T A T A T that just goes on forever. And that's basically a way to circumnavigate the fact that when you age, your DNA gets shorter and shorter.

• 23:05Lester Nare?

  It's a little buffer.

• 23:06Krishna Choudhary?

  Yeah, it's a little buffer that's like, it's it's a bunch of nonsense DNA. Not really nonsense, because obviously it's got functions, but like, it's a bunch of like, stuff that doesn't really code for anything to secure the stuff in the middle, right? It's like when you're copying stuff, the stuff at the very ends is gonna get wrecked.

• 23:21Lester Nare?

  Right.

• 23:21Krishna Choudhary?

  So you wanna have a giant buffer.

• 23:23Lester Nare?

  Yes.

• 23:24Krishna Choudhary?

  So he was um, he he was really instrumental in that kind of research. She did her Um, research, PhD research under this guy.

• 23:34Lester Nare?

  Yes.

• 23:34Krishna Choudhary?

  And she was really in interested in RNA interference. Okay, which is this idea of like small types of RNA actually interfering with DNA. And influencing gene expression, shutting stuff down, things like that. So she's already in this sort of, you know, molecular biology mindset.

• 23:53Lester Nare?

  The idea is that there's these cases where this RNA is almost acting like a mechanic of some kind. You know, it's coming in, uh, house cleaning.

• 24:01Krishna Choudhary?

  Yeah.

• 24:02Lester Nare?

  Moving stuff around, like, okay.

• 24:04Krishna Choudhary?

  Yeah, and this was brand new research back in the day.

• 24:06Lester Nare?

  Yeah.

• 24:06Krishna Choudhary?

  Because, you know, uh, uh, we, they'd all been grown up in the days of the central dogma.

• 24:13Lester Nare?

  Right.

• 24:14Krishna Choudhary?

  Right? DNA makes RNA makes protein.

• 24:16Lester Nare?

  Yes.

• 24:17Krishna Choudhary?

  And the RNA is just a messenger.

• 24:19Lester Nare?

  Yes.

• 24:19Krishna Choudhary?

  That is an intermediate between the DNA that's inside the nucleus. And the part that makes the protein, which is the ribosome, which is outside the nucleus. So this RNA becomes a messenger. But she was sort of growing up in her academic career at the time when RNA was finding all of these new uses. That people had not really tried to figure out before.

• 24:40Lester Nare?

  It's not simply that RNA is a translator and a transporter. It had.

• 24:44Krishna Choudhary?

  It has active.

• 24:46Lester Nare?

  Function.

• 24:46Krishna Choudhary?

  Function within the cell. So she's, she's researching um RNA interference at the time. Um, she's at Yale at the time. And, yeah, boo Yale. She ditched Yale.

• 24:58Lester Nare?

  Good.

• 24:58Krishna Choudhary?

  She ditched Yale for Cal Berkeley because um Berkeley solved the two body problem. Do you know about the famous two body problem in academics? It's basically, you're married, your spouse is an academic. And it's, it's one of the toughest problems to solve in academia, the two body problem. But Berkeley solved it by hiring both her husband and her. And good for them.

• 25:22Lester Nare?

  Yeah.

• 25:23Krishna Choudhary?

  You know, so.

• 25:24Lester Nare?

  They are winning.

• 25:25Krishna Choudhary?

  So they, so they switched to Cal Berkeley.

• 25:28Lester Nare?

  Yes.

• 25:29Krishna Choudhary?

  In the, I think, early 2000s.

• 25:31Lester Nare?

  Very good choice.

• 25:32Krishna Choudhary?

  Good choice. Um, I think they also liked the fact that, you know, Berkeley compared to the eastern institutions, which we went to one of them.

• 25:40Lester Nare?

  Yes.

• 25:40Krishna Choudhary?

  The eastern institutions are very formal, if I may say, right? They're very, you know, um, formal.

• 25:49Lester Nare?

  Uh, upright and straight.

• 25:51Krishna Choudhary?

  Right, they've got, they've got. Something in there, but, um, you know, in California, we're a little bit laid back.

• 25:57Lester Nare?

  Yeah.

• 25:58Krishna Choudhary?

  Yeah, and, and they liked that. And, um, so they, they came to California. And that's where Jennifer Dodna first encountered CRISPR.

• 26:09Lester Nare?

  Okay.

• 26:09Krishna Choudhary?

  Okay. She had a brief sojourn into actually, um, private tech. So she was, she was, um, she worked for Genentech, which is this company, it's a big company. She worked for Genentech. She wanted to like, see like what private industry research would be like. She lasted two months. She wrote, she wrote this like article about her and she was like, it was just like, no.

• 26:32Krishna Choudhary?

  But because she had left, right, she had sort of left all of her, um, teaching and administrative obligations behind. So when she came back, she could just focus fully on her research.

• 26:44Lester Nare?

  Freedom.

• 26:45Krishna Choudhary?

  Right, freedom. And this is when one of her colleagues, Gillian Banfield.

• 26:50Lester Nare?

  Yes.

• 26:50Krishna Choudhary?

  Contacted her. Gillian Banfield was a professor at Berkeley. She was working with, trying to sequence sort of the metagenomes of samples. So she'd go to like mines and try to collect bacteria there or like thermophils and try to collect bacteria there, soil samples and try to do a metagenomic analysis where you sequence a bunch of genomes and you try to find.

• 27:17Krishna Choudhary?

  You know?

• 27:17Lester Nare?

  Yes.

• 27:17Krishna Choudhary?

  Stuff in the genome.

• 27:18Lester Nare?

  Yes.

• 27:19Krishna Choudhary?

  Okay.

• 27:19Lester Nare?

  Thingies.

• 27:19Krishna Choudhary?

  And what she had noticed was, and this is something that was in the literature as well. You kept coming up with this CRISPR sequence.

• 27:27Lester Nare?

  Mm hmm.

• 27:27Krishna Choudhary?

  Okay.

• 27:28Lester Nare?

  Mm hmm.

• 27:28Krishna Choudhary?

  She found it in bacteria in the mines. She found it in bacteria here, there. Not only did she find it in bacteria, she also found it in archaea, which is kind of like bacteria. They're, you know, sort of indistinguishable from bacteria. If you look at it in a microscope, they kind of look like bacteria, single celled organisms. But if you look at the phylogenetic tree of life, you know, where you have some primordial first life ancestor and then that fans out. Um, the, one of the first two things that fanned out was actually bacteria and archaea.

• 28:01Lester Nare?

  Hmm, okay.

• 28:02Krishna Choudhary?

  And then from bacteria outcrop the eukarya.

• 28:06Lester Nare?

  Right.

• 28:06Krishna Choudhary?

  Which is us.

• 28:07Lester Nare?

  Right.

• 28:07Krishna Choudhary?

  Eukaryotes are the multicellular organisms that have mitochondria living in them and chloroplast living in them and a nucleus living in them.

• 28:15Lester Nare?

  The powerhouse of the cell.

• 28:16Krishna Choudhary?

  Yes, and all of these, so, so the higher complex organisms.

• 28:20Lester Nare?

  Yes.

• 28:20Krishna Choudhary?

  Came out of the bacteria, but very early on in the evolution of life came out bacteria and archaea.

• 28:26Lester Nare?

  Mm hmm.

• 28:27Krishna Choudhary?

  And the fact that the CRISPR sequence.

• 28:30Lester Nare?

  Exists.

• 28:30Krishna Choudhary?

  Exists in both bacteria and archaea is very, very interesting.

• 28:34Lester Nare?

  Cause this means this happened very, very early evolutionarily.

• 28:38Krishna Choudhary?

  Yeah.

• 28:38Lester Nare?

  Very, very, very.

• 28:39Krishna Choudhary?

  It says two things. One is viruses were out like, even back then viruses were like, oh, I gotta get in on that.

• 28:46Lester Nare?

  Yeah, yeah, yeah, yeah.

• 28:47Krishna Choudhary?

  And, and the other thing is this thing, this thing is preserved, which means it really might have this immune capability. And it might be nice to figure out how it works.

• 28:57Lester Nare?

  Yes.

• 28:58Krishna Choudhary?

  Now, Gillian Banfield at Berkeley, she thought it was something to do with RNA interference.

• 29:03Lester Nare?

  Okay.

• 29:03Krishna Choudhary?

  It's some kind of interference mechanism where it creates an RNA and then that RNA interferes with these.

• 29:09Lester Nare?

  Yes.

• 29:10Krishna Choudhary?

  Um, viral DNA to sort of stop it from happening.

• 29:13Lester Nare?

  Yeah.

• 29:13Krishna Choudhary?

  So what she literally did was she Googled RNAi Berkeley.

• 29:18Lester Nare?

  Okay.

• 29:19Krishna Choudhary?

  And out pops Jennifer Doudna's.

• 29:22Krishna Choudhary?

  Web page.

• 29:23Lester Nare?

  Yeah.

• 29:24Krishna Choudhary?

  Right?

• 29:24Lester Nare?

  Yeah.

• 29:24Krishna Choudhary?

  She's like, okay, this is someone who works in RNAi. It's at Berkeley. So gives them a call.

• 29:30Lester Nare?

  Yes.

• 29:30Krishna Choudhary?

  Um, and they set up a meet cute at the cafe, which is the free speech movement cafe.

• 29:38Lester Nare?

  Yes, yes.

• 29:39Krishna Choudhary?

  Very famous.

• 29:40Lester Nare?

  Very famous.

• 29:40Krishna Choudhary?

  Cafe in um, one of the libraries in Berkeley, you know, it commemorates the free speech movement back in the nineteen sixties and seventies.

• 29:48Lester Nare?

  A movement we are trying to reinvigorate here in the United States.

• 29:51Krishna Choudhary?

  Yeah.

• 29:52Lester Nare?

  It is.

• 29:52Krishna Choudhary?

  Yeah, it's probably, it's probably like on its, on its high tails right now, right? We really need that. But they met at this free speech movement cafe.

• 30:00Lester Nare?

  Yes.

• 30:01Krishna Choudhary?

  They have a little bit of banter and then um, Gillian Banfield gets right into CRISPR. It's like, this is what CRISPR is. It's kind of crazy. Jennifer Doudna is like immediately hooked.

• 30:11Lester Nare?

  Yes.

• 30:12Krishna Choudhary?

  Like, this is crazy.

• 30:13Lester Nare?

  Yeah.

• 30:13Krishna Choudhary?

  Right? Palindromic.

• 30:14Lester Nare?

  Yeah.

• 30:15Krishna Choudhary?

  Regularly interspersed because people had seen these sort of regular structures before, or these palindromic structures before, but not in this sort of nice, like organized form.

• 30:28Lester Nare?

  It was too perfect.

• 30:29Krishna Choudhary?

  It was too perfect for it to be just some random thing.

• 30:32Lester Nare?

  Yes.

• 30:32Krishna Choudhary?

  Okay?

• 30:33Lester Nare?

  Yes.

• 30:33Krishna Choudhary?

  So that's when Jennifer Doudna starts thinking about CRISPR, okay? And she starts investigating the CRISPR system. She starts mapping it. And what at the time people end up finding is there's the CRISPR part of the genome, which is this A B A C A D. And then there's another part of the genome that's always there right next to it. Okay, we talked about how promoters are right next to the part of the genome.

• 30:58Lester Nare?

  Yes.

• 30:59Krishna Choudhary?

  So this is kind of like that. It's not a promoter, but it was an associated region because it would always be there right next to the CRISPR system.

• 31:08Lester Nare?

  It was a crony.

• 31:08Krishna Choudhary?

  Because crony would always be hanging out right before.

• 31:11Lester Nare?

  Yes.

• 31:11Krishna Choudhary?

  Um, they started calling it CRISPR associated.

• 31:16Krishna Choudhary?

  And it became CAS. So now we're getting CRISPR CAS.

• 31:20Lester Nare?

  So the CRISPR is that, you know, regularly repeating interspace sequence. And then the crony that's always with the, you know, little mob boss.

• 31:32Krishna Choudhary?

  That's the CAS.

• 31:33Lester Nare?

  That's the CRISPR associate.

• 31:35Krishna Choudhary?

  Yes, and it becomes the CAS.

• 31:37Lester Nare?

  Yes, that becomes where CAS and CRISPR CAS nine sort of, okay.

• 31:42Krishna Choudhary?

  Yeah, so now we gotta get to the nine. Because we've already, we fixed the puzzle with CRISPR.

• 31:47Lester Nare?

  Yes.

• 31:47Krishna Choudhary?

  We fixed CAS.

• 31:48Lester Nare?

  Yes.

• 31:49Krishna Choudhary?

  Now we gotta get to the nine.

• 31:50Lester Nare?

  Right, this bacterial immune system. And this associate of that sort of immune system structure. Okay, yes.

• 32:00Krishna Choudhary?

  So now, so she starts researching these CAS systems. It turns out there's two types. There's a class one system, and that requires many different proteins to function. They figured that out. And then there's a class two system that was sort of simpler. Okay, now let's get back to Emmanuel Sharpen-Tier.

• 32:19Lester Nare?

  Yes.

• 32:20Krishna Choudhary?

  Okay, so meanwhile, while Daudna is doing this in her lab, Sharpen-Tier starts looking at the streptococcus genome.

• 32:27Lester Nare?

  Yes, the soft tissue eating.

• 32:30Krishna Choudhary?

  And she starts, yeah, the soft tissue streptococcus, tensillitis-causing bacteria. And she starts discovering a previously unknown RNA molecule that was very closely associated with CRISPR. Okay, and she called it the tracker RNA for transactivating CRISPR RNA. It's something that was required for the CRISPR RNA, which is the RNA that is made from transcribing the CRISPR DNA, right? CRISPR, remember, this ABA, ACA, AD thing.

• 33:03Lester Nare?

  Yes.

• 33:03Krishna Choudhary?

  This is in the DNA.

• 33:04Lester Nare?

  Yes.

• 33:05Krishna Choudhary?

  But that gets transcribed by RNA polymerase to become an RNA molecule, right? And then that RNA molecule, presumably for all the other gene stuff, that RNA molecule goes outside and makes a protein. But in this case, what it was doing was it's mediating this immune system. Okay, and what she realized was there's this other RNA molecule called tracker RNA that is required to make that bigger CRISPR RNA work.

• 33:29Lester Nare?

  Got it.

• 33:30Krishna Choudhary?

  And do its thing.

• 33:31Lester Nare?

  Okay.

• 33:32Krishna Choudhary?

  Okay, so she starts. She starts um looking at this tracker RNA and she's like, okay, this thing is essential for making whatever CRISPR is doing.

• 33:41Lester Nare?

  Right.

• 33:41Krishna Choudhary?

  Work.

• 33:42Lester Nare?

  It.

• 33:42Krishna Choudhary?

  She publishes that in 2011.

• 33:44Lester Nare?

  Okay, got it.

• 33:44Krishna Choudhary?

  Okay. And then we have the chance meeting in Puerto Rico.

• 33:49Lester Nare?

  Ah, look, great, great.

• 33:50Krishna Choudhary?

  In San Juan, Puerto Rico.

• 33:51Lester Nare?

  In the US.

• 33:52Krishna Choudhary?

  Mm hmm. In the US, um, they meet at a, they meet at a conference and um, they get introduced to each other with one of Dowden's colleagues. They have a, a short meet cute and then they decide to explore the city together, the old, old San Juan city together the next day.

• 34:14Lester Nare?

  Yeah.

• 34:15Krishna Choudhary?

  And on this walk in the old San Juan city, they talk about what they've been working on and Sharpen TA says, okay, let's, why don't we collaborate? Because you're a biochemist, I'm sort of the structural person who does um, bacteria research, perhaps we can help each other. They, they agree. And so Jennifer Dowden and now they, they start like collaborating via Skype.

• 34:40Lester Nare?

  Mm hmm.

• 34:40Krishna Choudhary?

  And their postdoc start collaborating.

• 34:42Lester Nare?

  R I P Skype, recently shut down.

• 34:44Krishna Choudhary?

  Yeah, yeah, now it's called Zoom, but I guess I still use Skype, that just shows how old I am. Um, but they, they start collaborating on the interweb.

• 34:52Lester Nare?

  Yes.

• 34:53Krishna Choudhary?

  And um, they start focusing on a class two system, remember Dowden was focused on class one.

• 35:01Lester Nare?

  The more complex.

• 35:02Krishna Choudhary?

  Sharpen TA is like, no, I got a class two.

• 35:04Lester Nare?

  Yeah, yeah.

• 35:04Krishna Choudhary?

  It's quite nice.

• 35:05Lester Nare?

  Yes.

• 35:06Krishna Choudhary?

  Um, it's this thing in Disruptococcus and it requires only a single protein.

• 35:11Lester Nare?

  Mm hmm.

• 35:11Krishna Choudhary?

  Not the multiple that you need.

• 35:12Lester Nare?

  Mm hmm.

• 35:13Krishna Choudhary?

  And the single protein, they're calling it Cas9.

• 35:16Lester Nare?

  Mm hmm, I see.

• 35:18Krishna Choudhary?

  So now we're getting to Cas9.

• 35:20Lester Nare?

  It's the ninth associate.

• 35:21Krishna Choudhary?

  It's the ninth associate, i- it's sort of named on the, the um, order in which it was discovered.

• 35:28Lester Nare?

  Which makes sense.

• 35:29Krishna Choudhary?

  So it's CRISPR Cas9, she's like, the, the single protein that's required, okay? And they suspected the Cas9 was a scissor that cut viral DNA.

• 35:39Lester Nare?

  Mm.

• 35:39Krishna Choudhary?

  So what, what CRISPR would do is CRISPR would be this record.

• 35:42Lester Nare?

  Yes.

• 35:43Krishna Choudhary?

  Of all the viral DNA.

• 35:44Lester Nare?

  Yes.

• 35:44Krishna Choudhary?

  That the, the bacteria had seen in its past.

• 35:47Lester Nare?

  It would be like a historical map.

• 35:48Krishna Choudhary?

  Yes, and or in its ancestors past.

• 35:50Lester Nare?

  Yes.

• 35:51Krishna Choudhary?

  Right, that had been passed down genetically.

• 35:52Lester Nare?

  Yes.

• 35:53Krishna Choudhary?

  And. The Cas9 system would take this, match it to a viral protein.

• 35:59Lester Nare?

  Yes.

• 35:59Krishna Choudhary?

  And then cleave it.

• 36:00Lester Nare?

  Yes.

• 36:01Krishna Choudhary?

  Okay, so they did an experiment where they combined the Cas9 protein. They combined the CRISPR RNA, which is the thing that gets transcribed from the A B A C A D.

• 36:10Lester Nare?

  Yes.

• 36:11Krishna Choudhary?

  And then they combined the target DNA and they're like, okay, it should work.

• 36:15Lester Nare?

  Mm hmm.

• 36:15Krishna Choudhary?

  Didn't work.

• 36:16Lester Nare?

  Okay.

• 36:16Krishna Choudhary?

  Okay, they're like, what the hell?

• 36:18Lester Nare?

  Yes.

• 36:20Krishna Choudhary?

  And then after a lot of soul searching and everything, um, Charpentier is like, well, you know, the the tracker RNA that I had earlier, I thought I was just doing this job of like preparing the CRISPR RNA for this task, but what if it's like needed for something else? So they put in the tracker RNA.

• 36:38Lester Nare?

  Ah, this other thing you were talking about.

• 36:40Krishna Choudhary?

  Other thing that I was talking about that was sort of just like.

• 36:42Lester Nare?

  On the side, yeah, yeah.

• 36:44Krishna Choudhary?

  Right in the sidelines, they put in the tracker RNA and all of a sudden we're getting.

• 36:49Lester Nare?

  Scissors.

• 36:50Krishna Choudhary?

  Yes. We're getting scissors that are like actually cutting stuff.

• 36:55Lester Nare?

  Yes.

• 36:56Krishna Choudhary?

  They're like, oh, okay, so we got something that cuts.

• 37:00Lester Nare?

  And this is meaningful because still in and around this time, this idea that RNA has this active

• 37:09Lester Nare?

  like aspect to it.

• 37:11Krishna Choudhary?

  Mm hmm.

• 37:11Lester Nare?

  Is is in its na- like it's still kind of being worked out.

• 37:15Krishna Choudhary?

  Yeah.

• 37:16Lester Nare?

  Like it's not quite obvious.

• 37:18Krishna Choudhary?

  It's not quite obvious that like that like RNA would be such a huge part.

• 37:23Lester Nare?

  Right.

• 37:23Krishna Choudhary?

  Of the activity of an enzyme.

• 37:25Lester Nare?

  Right.

• 37:25Krishna Choudhary?

  Like Cas9 is a protein.

• 37:27Lester Nare?

  Right.

• 37:27Krishna Choudhary?

  But like it needs this tracker RNA to actually do its job.

• 37:30Lester Nare?

  Yes.

• 37:30Krishna Choudhary?

  Right?

• 37:31Lester Nare?

  Yes.

• 37:31Krishna Choudhary?

  And um, now it gets interesting.

• 37:34Lester Nare?

  Mm hmm.

• 37:35Krishna Choudhary?

  Because the way that this Cas9 system is identifying the thing that it needs to cut.

• 37:43Lester Nare?

  Mm hmm.

• 37:43Krishna Choudhary?

  Is through the CRISPR RNA.

• 37:45Lester Nare?

  Right.

• 37:47Krishna Choudhary?

  But the next question is, what if I just make the CRISPR RNA whatever I want?

• 37:53Lester Nare?

  So, okay, now.

• 37:55Krishna Choudhary?

  That is the key insight.

• 37:57Lester Nare?

  We've discovered that CRISPR is this repeating pattern, that's kind of this historical, this historical map of past interactions that bacteria were having that helped it to remember how to fight back. We have this, these associates, these cronies, the bag men.

• 38:13Krishna Choudhary?

  Yes.

• 38:13Lester Nare?

  That go out and kind of do stuff, one of which is Cas9.

• 38:17Krishna Choudhary?

  Yeah.

• 38:17Lester Nare?

  Right, right, uh, and, and Cas9 had one job.

• 38:21Krishna Choudhary?

  Mm hmm.

• 38:22Lester Nare?

  And that one job was to.

• 38:23Krishna Choudhary?

  Was to actually cut people, yeah.

• 38:25Lester Nare?

  Cut them.

• 38:25Krishna Choudhary?

  But how did it know what to cut?

• 38:27Lester Nare?

  Right, right. And could you change its instructions of what to cut?

• 38:32Krishna Choudhary?

  Yeah, because it's like, it's almost like, like, as you say, okay, well, let's go with the cronies thing, right?

• 38:37Lester Nare?

  Yes.

• 38:37Krishna Choudhary?

  Like, the cronies got a photo.

• 38:39Lester Nare?

  Yeah, right, right?

• 38:40Krishna Choudhary?

  I'm like, who he needs to have cut.

• 38:42Lester Nare?

  Yeah, this is, this is who you gotta go after.

• 38:44Krishna Choudhary?

  And, and then he looks around, right? What if I just replace the photo with whatever I want?

• 38:48Lester Nare?

  Yes, put a little deep fake.

• 38:49Krishna Choudhary?

  Yeah, right, exactly. And that's what they figured, right?

• 38:52Lester Nare?

  That is so fascinating.

• 38:53Krishna Choudhary?

  The first insight, the first insight was, okay, we can, we can, maybe we can give it our own version.

• 39:00Lester Nare?

  We can repeal and replace the initial CRISPR sequence with something else, so that Cas9 goes after what we tell it to go after.

• 39:08Krishna Choudhary?

  Yeah.

• 39:08Lester Nare?

  Not what it was maybe historically X, Y, and Z.

• 39:11Krishna Choudhary?

  Yeah. The other thing that they did that was, again, huge and part of the discovery, because already this would be a crazy discovery.

• 39:18Lester Nare?

  Yeah.

• 39:18Krishna Choudhary?

  Okay, already, the fact that a Cas9 system, what it's doing is it's matching this DNA with whatever DNA that comes in, and then it's cutting it out that place, already, that's insane.

• 39:28Lester Nare?

  Yes.

• 39:28Krishna Choudhary?

  Okay, the next thing they did was, they noticed that, well, tracker RNA, which is the, the sort of helper that comes in.

• 39:35Lester Nare?

  Yes, let's say, let's say in the crony example, it's the driver.

• 39:38Krishna Choudhary?

  It's the driver, yeah.

• 39:39Lester Nare?

  Which get, like, just as a, as a loose analogy.

• 39:41Krishna Choudhary?

  Exactly, yeah, it's the driver, right, that comes in, and, um, and then you've got the photo.

• 39:47Lester Nare?

  Yes.

• 39:48Krishna Choudhary?

  Which is the, which is the thing that lets it recognize, right? These are two separate components.

• 39:53Lester Nare?

  Right, right, which are important.

• 39:55Krishna Choudhary?

  Yeah, which are important. So what they figured was, what if we made them a single component?

• 40:01Lester Nare?

  Oh, okay.

• 40:01Krishna Choudhary?

  Called a guide RNA.

• 40:03Lester Nare?

  Okay.

• 40:04Krishna Choudhary?

  This was a big one.

• 40:05Lester Nare?

  Okay.

• 40:05Krishna Choudhary?

  Because what they did, well, well, cause now it's just way simpler.

• 40:08Lester Nare?

  It was one.

• 40:08Krishna Choudhary?

  Anyone in a lab can just make a single piece of guide RNA. It's a single piece of RNA.

• 40:13Lester Nare?

  Yes.

• 40:13Krishna Choudhary?

  That I can just make.

• 40:14Lester Nare?

  Yes.

• 40:15Krishna Choudhary?

  I know how to make RNA.

• 40:16Lester Nare?

  Yes.

• 40:17Krishna Choudhary?

  And I can just make that and be like this part of the RNA is the thing that I wanna cleave.

• 40:20Lester Nare?

  Yes.

• 40:21Krishna Choudhary?

  That's what they did. They they combined, they they added a nucleotide sequence.

• 40:26Lester Nare?

  Yes.

• 40:26Krishna Choudhary?

  That sort of stitched these two together, the CRISPR RNA, which is the part that's recognizing what I want to cleave.

• 40:33Lester Nare?

  Yes.

• 40:33Krishna Choudhary?

  And the tracker RNA, which is what's sort of preparing the Cas9 protein to do the cleaving. They combined these into a single thing and it's it's not as trivial as just like, oh, I just like staple them together. Because if I staple them together, that's gonna change the morphology of them.

• 40:49Lester Nare?

  Yes.

• 40:49Krishna Choudhary?

  And then the Cas9 protein, your crony is not gonna be happy.

• 40:52Lester Nare?

  Right.

• 40:52Krishna Choudhary?

  He's like, I don't know what to do with this. I can't recognize this photo.

• 40:55Lester Nare?

  Yes.

• 40:55Krishna Choudhary?

  Right?

• 40:56Lester Nare?

  Yes.

• 40:56Krishna Choudhary?

  But they they did it in such a way that the tracker RNA part of the of the structure was intact and the CRISPR RNA part of the structure was intact. But they were connected together in a way that didn't get in the way of the Cas9.

• 41:11Lester Nare?

  Yes.

• 41:11Krishna Choudhary?

  Right? That's what they did. They created a guide RNA.

• 41:14Lester Nare?

  It's it's so, and again, to continue this really bad analogy. Whenever you're trying to commit crimes, you wanna minimize the amount of people.

• 41:22Krishna Choudhary?

  Yes.

• 41:23Lester Nare?

  Who are your co-conspirators.

• 41:24Krishna Choudhary?

  Exactly.

• 41:24Lester Nare?

  And so instead of having a driver and then the crony who's doing the cutting.

• 41:28Krishna Choudhary?

  Yeah.

• 41:29Lester Nare?

  You just have the driver and the crony be the same person as one more or less point of failure. And you know, it's hard to find that person.

• 41:36Krishna Choudhary?

  Yeah.

• 41:37Lester Nare?

  That can do both things.

• 41:38Krishna Choudhary?

  Yeah.

• 41:38Lester Nare?

  And this.

• 41:38Krishna Choudhary?

  And it's hard to make that person and train him, but but you got it. That's exactly right.

• 41:43Lester Nare?

  Yeah.

• 41:44Krishna Choudhary?

  And so that is what became the CRISPR Cas9 system.

• 41:48Lester Nare?

  Okay.

• 41:48Krishna Choudhary?

  Okay? It's it's really the guide RNA.

• 41:50Lester Nare?

  That was the that was the.

• 41:52Krishna Choudhary?

  That was the.

• 41:52Lester Nare?

  That was the the the the sort of key aspect that made it move from an observation of something that's happening naturally to a programmable platform or concept or system.

• 42:04Krishna Choudhary?

  Yes.

• 42:04Lester Nare?

  That could then effectuate specific instructions dictated by.

• 42:09Krishna Choudhary?

  Yes, very good point. And to that point, in 2012, they published in Science.

• 42:13Lester Nare?

  Yes.

• 42:13Krishna Choudhary?

  And in their abstract, they could already tell this was gonna be big.

• 42:16Lester Nare?

  Right.

• 42:16Krishna Choudhary?

  Because they wrote in their abstract that this is an RNA programmable genome editing technology.

• 42:22Lester Nare?

  It's so funny, because I mean, that's immediately what I think of. It's just like, well.

• 42:25Krishna Choudhary?

  You can, you can now, because before, before, we used to have these, these things called zinc finger nucleases.

• 42:31Lester Nare?

  Okay.

• 42:32Krishna Choudhary?

  Right? That was the best we could do, where you have these like zinc fingered domains of proteins.

• 42:38Lester Nare?

  Yes.

• 42:38Krishna Choudhary?

  That would recognize three nucleotides at a time.

• 42:41Lester Nare?

  Mm-hmm.

• 42:42Krishna Choudhary?

  And then actually like try and cleave stuff. And that was the best we could do with programmable stuff. It was really hard to make, dude. It's really hard. Like, you, for each zinc or zinc finger is like attached to three. You gotta make, if you want to do a much larger recognition, you gotta do three times, three times, three. And they've got to be the right structure. And like making these proteins is really hard. Making RNA is super easy now.

• 43:04Lester Nare?

  Mm-hmm.

• 43:04Krishna Choudhary?

  Right? Even back then, it was like way easier. Which goes to show, like right after they published this, right? Then there was an MIT group.

• 43:12Lester Nare?

  Yes.

• 43:13Krishna Choudhary?

  From Feng Zhang, who published how to do this with mammalian cells and human cells.

• 43:17Lester Nare?

  Yes.

• 43:18Krishna Choudhary?

  And then since then, I mean, the, the technology is just completely blown up.

• 43:21Lester Nare?

  Yes, 100%.

• 43:22Krishna Choudhary?

  Now we're, now we're, we're, we're making crops that can withstand drought.

• 43:27Lester Nare?

  Yes.

• 43:27Krishna Choudhary?

  We've got, um.

• 43:28Lester Nare?

  Shout out David Freiberg and the All In Boys.

• 43:30Krishna Choudhary?

  Exactly. We've got, we've got, um, Christopher Technologies that do genome editing in humans. And like, but, but like, it's happening. It's, I mean, it's curing sickle cell disease, which is really nice.

• 43:45Lester Nare?

  Big for black people.

• 43:46Krishna Choudhary?

  Yeah, it's, it's also, um, you know, being used by the Chinese, or in one instance, I'll give them that. It was one.

• 43:53Lester Nare?

  That we know of!

• 43:54Krishna Choudhary?

  That we know of, yeah. But like, they, they literally like, they said they took out a genome that gives.

• 44:02Krishna Choudhary?

  HIV a leg up in trying to infect someone. But I know at the end of the day, you like you edited the genome of like a human being and now that human being is out there, you know, like like reproducing and stuff. That's kind of crazy. Like I did not sign up for that. But like in any case, like CRISPR, I I hope you now see the sort of the thread of discovery, right? Where it starts from just curiosity driven.

• 44:29Lester Nare?

  Yes.

• 44:29Krishna Choudhary?

  What is A B A C A D doing in E. coli? Why is it an archaea?

• 44:34Lester Nare?

  Yes.

• 44:35Krishna Choudhary?

  To now we've got a technology that that lets us play God.

• 44:39Lester Nare?

  This what's so important about this story. There's so many important aspects of the story, but I think the thing that sticks out for me is a lot of times folks don't understand how a scientist in a lab with an electron microscope or doing looking at really tiny stuff. They don't get the through line for how that ends up creating something that is going to be one of the most profound scientific discovery terms that impact on medical outcomes for people.

• 45:10Krishna Choudhary?

  Yeah.

• 45:11Lester Nare?

  That we've ever.

• 45:12Krishna Choudhary?

  Yeah.

• 45:12Lester Nare?

  Made. I mean, like, this is like having a programming language with infinite, you know, like idea space.

• 45:19Krishna Choudhary?

  Yeah, yeah, yeah.

• 45:20Lester Nare?

  For the fundamentals of like what makes us.

• 45:23Krishna Choudhary?

  Yeah.

• 45:23Lester Nare?

  And like it it's it is.

• 45:25Krishna Choudhary?

  The blueprint. We can now edit blueprints of buildings. The buildings are us.

• 45:29Lester Nare?

  And the buildings are us.

• 45:30Krishna Choudhary?

  It's insane.

• 45:31Lester Nare?

  It's it's it's it's insane. There's an interesting before we get to.

• 45:38Krishna Choudhary?

  The paper.

• 45:39Lester Nare?

  The paper. Because now we've because now we've created the the base.

• 45:42Krishna Choudhary?

  Yeah.

• 45:42Lester Nare?

  Of understanding, how did we get to this new paper that's coming out of Stanford Medical?

• 45:48Krishna Choudhary?

  That's right.

• 45:48Lester Nare?

  About creating CRISPR GPT, which just feels like yoga babble of new thing CRISPR, new thing chat GPT, just smash it together. It doesn't actually mean anything.

• 45:58Krishna Choudhary?

  Yeah, yeah.

• 45:58Lester Nare?

  But but now that we have that background, it's there's an interesting side story to these characters that you just talked about and touched on at the end. The President of the United States and his good friend Jeffrey Epstein are not the only ones who have suffered from years of long legal battles over who came first. Two of America's most elite research universities have been locked in a legal dispute over who was first to file.

• 46:27Krishna Choudhary?

  Yes.

• 46:27Lester Nare?

  That's file, F I L E, file. And we're talking about patents.

• 46:32Krishna Choudhary?

  Yes.

• 46:32Lester Nare?

  The other P word.

• 46:34Krishna Choudhary?

  Yeah, cuz whenever you, you make something big like this.

• 46:37Lester Nare?

  The immediate reaction from people who are capitalistic is like, that's multi-trillion dollar market.

• 46:43Krishna Choudhary?

  Yeah.

• 46:43Lester Nare?

  Uh, in terms of personalized medicine, gene editing, I mean, we're talking, it's like at least one or two Nvidia's. And so just as a brief kind of sidecar to the background you just gave, the, we talked about this, let's start at the beginning, which is the discovery. Uh, so Doudna and Charpentier, they make this discovery in 2012.

• 47:03Krishna Choudhary?

  Yeah, published it in Science.

• 47:05Lester Nare?

  Published in Science. And then months later in early 20, uh, 2013.

• 47:09Krishna Choudhary?

  Yeah.

• 47:09Lester Nare?

  Uh, Fang Zhang at the Broad Institute at MIT is the one who made the leap to show that CRISPR worked in eukaryotes. This was some mammalian cells, animal cells, which matters because that's how you can create a product.

• 47:22Krishna Choudhary?

  Yes.

• 47:22Lester Nare?

  For, for, and, and market.

• 47:24Krishna Choudhary?

  Now it becomes something that, that, that health people want.

• 47:26Lester Nare?

  Right. It's not just this observation about our natural environment, you can actually productize it.

• 47:30Krishna Choudhary?

  Yeah.

• 47:30Lester Nare?

  So the idea here is that, you know, Berkeley proved that the tool worked and then the Broad showed that it can work in cells that matter for medicine.

• 47:37Krishna Choudhary?

  Yeah.

• 47:38Lester Nare?

  That's when the patent race begins.

• 47:40Krishna Choudhary?

  Right, right.

• 47:40Lester Nare?

  So it gets, gets a little bit messy. So Berkeley filed their patent application first in May of 2012.

• 47:46Krishna Choudhary?

  Right.

• 47:47Lester Nare?

  Covering CRISPR broadly. No pun intended. And then, then the Broad filed later in December of 2012, so just a couple of months apart.

• 47:55Krishna Choudhary?

  Right.

• 47:55Lester Nare?

  But, but MIT fast-tracked their application, uh, with the Patent Office, which meant they actually got the first CRISPR patent in 2014, covering use in human and animal cells while Berkeley's application was still making its way through.

• 48:11Krishna Choudhary?

  Oh my gosh.

• 48:11Lester Nare?

  Which is like, okay, okay, okay. So now Burke, the first legal challenge, Berkeley challenged that, obviously.

• 48:17Krishna Choudhary?

  Yeah.

• 48:17Lester Nare?

  So now in 2016, fast forward to, forward two years after MIT got that initial patent for human and animal cells.

• 48:24Krishna Choudhary?

  Yeah.

• 48:25Lester Nare?

  The Patent Office held this special interference trial, not to be confused with RNA interference, to decide if the Broad's patent overlapped with Berkeley's patent. And then in 2017, the ruling was a little bit of a surprise where the board, the patent board said both can stand. Right? Both patents can stand. And it was because they argued that CRISPR moving from a test tube to human cells was not obvious. Like, this is sort of the term of use with patents. Like, is it obvious?

• 48:55Krishna Choudhary?

  Yeah, yeah, yeah. I see.

• 48:56Lester Nare?

  So they were arguing that it's not obvious and it counted as a separate invention.

• 48:59Krishna Choudhary?

  Alright.

• 49:00Lester Nare?

  Uh, so this obviously gave MIT the upper hand for commercial applications.

• 49:05Krishna Choudhary?

  Yeah, yeah, because like, that's where the big money is. I mean, sure, you can use it for agricultural stuff, but like...

• 49:10Lester Nare?

  You know, which is important.

• 49:12Krishna Choudhary?

  Yeah, which is important, yeah.

• 49:14Lester Nare?

  But it didn't end there. Not satisfied, right? So round two.

• 49:17Krishna Choudhary?

  Round two.

• 49:17Lester Nare?

  So Berkeley went, came out with new filings aimed at this eukaryotic cells issue.

• 49:23Krishna Choudhary?

  Right.

• 49:24Lester Nare?

  Um, and they got a second interference case. Now, in 2022, uh, Berkeley lost the claim outright because they were arguing that the Broad hadn't in fact shown that they were able to make it work in human cells, but they were. So it's kind of like, eh, didn't really... So the loss then had this big financial and reputational hit because it's like, you're begging now. Right, right. Like, you lost. Take your L and go, take your toys and go home. But, obviously, this is worth hundreds of millions, billions of dollars, licensing fees. So like, you know.

• 49:56Krishna Choudhary?

  Yeah.

• 49:56Lester Nare?

  Okay. Here's what's interesting, and this goes back to our Nobel Prize discussion.

• 50:01Krishna Choudhary?

  Yeah.

• 50:03Lester Nare?

  In 2020, right, the Nobel Prize ultimately went to...

• 50:06Krishna Choudhary?

  Jennifer Doudna, Emmanuel Shapantia.

• 50:09Lester Nare?

  Yeah, at Berkeley despite not getting the patent. So the credit for the discovery

• 50:14Krishna Choudhary?

  Yeah.

• 50:15Lester Nare?

  went to the original founders, but...

• 50:17Krishna Choudhary?

  And they didn't, you know, the Nobel Prize committee could have easily done it for three people because the three is the limit, according to Alfred Nobel's will

• 50:27Lester Nare?

  Yep.

• 50:27Krishna Choudhary?

  of how many people can win a Nobel Prize, but they chose to give it to Shapantia and Doudna, right?

• 50:33Lester Nare?

  Which is like, look, the OGs. He refers.

• 50:36Krishna Choudhary?

  I mean, as I was saying, right? It's like patents are, I think, local in time, but Nobel prizes are forever.

• 50:42Lester Nare?

  Yes.

• 50:42Krishna Choudhary?

  You know?

• 50:43Lester Nare?

  Yes, unlike diamonds. No, I'm kidding. So there was a split between who got the glory.

• 50:47Krishna Choudhary?

  Yeah.

• 50:48Lester Nare?

  Like the prestige, right? To be immortalized forever.

• 50:51Krishna Choudhary?

  Yeah.

• 50:51Lester Nare?

  And who's gonna make their shareholders hundreds of millions of dollars.

• 50:54Krishna Choudhary?

  Exactly, yeah.

• 50:55Lester Nare?

  So this kind of has shaped the biotech startup playing field in terms of developing CRISPR therapies, because you had likely had to license it with.

• 51:04Krishna Choudhary?

  Right.

• 51:05Lester Nare?

  The Broad Institute and all of Berkeley's allies were kind of boxed in, at least commercially.

• 51:10Krishna Choudhary?

  Yeah.

• 51:11Lester Nare?

  Now, just this year.

• 51:12Krishna Choudhary?

  Oh.

• 51:13Lester Nare?

  In 2025, this is still ongoing.

• 51:16Krishna Choudhary?

  It is.

• 51:17Lester Nare?

  Because a federal appeals, a federal appeals court actually reopened the case.

• 51:22Krishna Choudhary?

  Oh, my God.

• 51:23Lester Nare?

  Saying that the patent office may have applied the wrong legal standard back in the 2022 case. So this is not entirely over.

• 51:32Krishna Choudhary?

  Wow, it's not even over.

• 51:33Lester Nare?

  In terms of, you know, who owns CRISPR in human cells.

• 51:39Krishna Choudhary?

  Yeah.

• 51:39Lester Nare?

  It's still being litigated. And again, I think hundreds of millions and billions is underestimating the total addressable market impact.

• 51:48Krishna Choudhary?

  Easily.

• 51:49Lester Nare?

  When these gene therapies get to scale, not only in, you know, US and other Western, but globally. So it was just this.

• 51:58Krishna Choudhary?

  Dude, that's crazy. I mean, to think, I don't even know. So all of these people who have been using CRISPR, there's so many companies that have been using CRISPR on the MIT license, right? Let's say for sake of argument that Berkeley wins this appeal in 2025. What's gonna?

• 52:14Lester Nare?

  This is, this is, we're gonna start our new, our new from first legal principles sideshow.

• 52:18Krishna Choudhary?

  Yeah, yeah.

• 52:19Lester Nare?

  No, there's a really interesting point there, but.

• 52:21Krishna Choudhary?

  Right? It's like.

• 52:21Lester Nare?

  Is it retro, what are the, what are the retroactive?

• 52:24Krishna Choudhary?

  Yeah.

• 52:24Lester Nare?

  Remedies for Berkeley saying, look, we've lost out on, you know, existing revenues. It could potentially be a very big landmark case if ultimately Berkeley is, you know, ends up winning this reopening of the case, which is.

• 52:40Krishna Choudhary?

  I'd love to see MIT just like pay Berkeley out of pocket, because I just hate MIT.

• 52:47Lester Nare?

  Look, I mean, we are the best university on the East Coast, so they're always chasing us. We get it. We get it. It's hard to be the best all the time.

• 52:54Krishna Choudhary?

  But, but, I mean, it's, you know, to Doudna's credit, though, I saw a. Interview of her with Dan Rather.

• 53:02Lester Nare?

  Yes.

• 53:02Krishna Choudhary?

  Back in twenty seventeen, back when, you know, this was at the height of it and um Dan Rather in his journalistic voice, he's like, I wouldn't be doing my job if it weren't, if I wasn't asking about the legal dispute. And and she said very, very calmly and and quite nicely that, you know, that legal dispute is between the two institutions.

• 53:22Lester Nare?

  Right.

• 53:23Krishna Choudhary?

  MIT and Berkeley. Right. And her opinion was that science shouldn't slow down because of a legal dispute. So she was totally for all of these companies using the existing MIT patent to go and forge ahead.

• 53:37Lester Nare?

  Mm hmm.

• 53:38Krishna Choudhary?

  You know?

• 53:38Lester Nare?

  Yeah, yeah. Which is how it should be.

• 53:40Krishna Choudhary?

  Which is, which is, I think, I think that was really cool to see that.

• 53:43Lester Nare?

  And in good spirit of, I think, what we all mean when those of us who are passionate about science and research, experimental design and growth of this understanding of the fundamentalology of the world around us and applying it in a way that like impacts people's lives every day.

• 53:59Krishna Choudhary?

  Yeah.

• 53:59Lester Nare?

  Not to, you know, poo poo on the theorists. We love you two.

• 54:03Krishna Choudhary?

  Yeah.

• 54:03Lester Nare?

  But.

• 54:04Krishna Choudhary?

  You guys are important.

• 54:05Lester Nare?

  Important, we get it. Practical applications are nice.

• 54:07Krishna Choudhary?

  Yeah, yeah. And and yeah, she's, I thought it was a really cool answer.

• 54:11Lester Nare?

  That, that's good. No, that's good. Institutions are always gonna battle over the dead carcasses.

• 54:16Krishna Choudhary?

  Yeah, yeah, yeah.

• 54:17Lester Nare?

  That's kind of how it goes.

• 54:17Krishna Choudhary?

  Yeah. I mean, I, to me personally, I think Berkeley won because they got the Nobel.

• 54:22Lester Nare?

  Yeah.

• 54:22Krishna Choudhary?

  You know?

• 54:23Lester Nare?

  What, what really matters?

• 54:24Krishna Choudhary?

  And now, and now she gets a, you know, at Berkeley, the tradition is every Nobel Prize winner gets a really nice parking spot right next to their building.

• 54:31Lester Nare?

  Look.

• 54:32Krishna Choudhary?

  Like, everybody else has to park in the parking structure and then walk.

• 54:35Lester Nare?

  Yeah.

• 54:35Krishna Choudhary?

  But like, there's a, it says reserved for Nobel Prize winner. Oh, it's so great.

• 54:40Lester Nare?

  Just like that.

• 54:41Krishna Choudhary?

  And she could just like roll up and park right next to it.

• 54:43Lester Nare?

  There's a whole studio episode about a parking spot, like, just this exact same story. That's great.

• 54:48Krishna Choudhary?

  Yeah. But I love that in academic institutions, they're like, no, it's, she won Nobel.

• 54:54Lester Nare?

  Yeah, no, she's not going to the garage.

• 54:56Krishna Choudhary?

  Yeah.

• 54:57Lester Nare?

  What? She's not a peon?

• 54:58Krishna Choudhary?

  Yeah.

• 54:59Lester Nare?

  Not for you PhDs and lab rats. Uh, okay, so we've now, we have a really strong foundational understanding from first principles. About what it is, what are we talking about when we say CRISPR Cas9?

• 55:13Krishna Choudhary?

  Yeah.

• 55:14Lester Nare?

  And kind of the history of how this osmosis and collaborative nature brings us to a point of like actual application. So now Stanford Medicine put out this new paper.

• 55:22Krishna Choudhary?

  Yeah.

• 55:22Lester Nare?

  About CRISPR GPT.

• 55:24Krishna Choudhary?

  Yes.

• 55:24Lester Nare?

  Which is now taking all of this decades, all the way back to nineteen eighty seven, where we started the story of understanding.

• 55:32Krishna Choudhary?

  Yeah.

• 55:32Lester Nare?

  To now applying something that's relatively new in the zeitgeist.

• 55:36Krishna Choudhary?

  Mm hmm.

• 55:36Lester Nare?

  Large language models and applying it to this Cas9 use case. So what does that look like?

• 55:41Krishna Choudhary?

  Yeah, so, you know, now it's been about thirteen years since the discovery of CRISPR Cas9. And it's been used in a variety of different applications, but at the end of the day, it's actually quite intricate. Right? The whole technology requires intricate decisions. By now we have Cas9, we also have Cas thirteen, we have all of these different associated proteins that you can use in these different use cases. And it's hard for a novice to know which one to use. There's a high failure rate, there's safety concerns. Um, you can get bottlenecked in all sorts of little tiny things that happen in the scientific process. And to actually make that better for researchers.

• 56:26Krishna Choudhary?

  Stanford, along with Princeton and Google Deep Mind.

• 56:29Lester Nare?

  Woo woo!

• 56:30Krishna Choudhary?

  Yay yay! They actually developed this co-pilot, which is CRISPR GPT, that's what they're calling it. It's a co-pilot for gene editing experiments where researchers can literally talk to the CRISPR GPT and be like, you know, I want to use CRISPR on this human lung cancer cell line, and I want to target these locations. How should I do my experiment? And the GPT will output all of the steps that you should do, how you should design your experiments, what to look out for, how you should analyze the data. All of that, right? It becomes like this sort of lab mate.

• 57:11Lester Nare?

  Yes.

• 57:12Krishna Choudhary?

  That, you know, you wish you had, I wish I had.

• 57:15Lester Nare?

  Yeah, I was gonna say.

• 57:16Krishna Choudhary?

  Back in my PhD days, right? Um, and it can really expedite and democratize the use of CRISPR.

• 57:24Lester Nare?

  Yes.

• 57:24Krishna Choudhary?

  In all of these systems by researchers who might not be totally versed in how to do it in the first place, right? And I think that's really cool.

• 57:35Lester Nare?

  Yes.

• 57:36Krishna Choudhary?

  Um, it was, it was trained, so the training is pretty, pretty interesting. It was trained on four thousand real world discussion threads. So there was this thing called the CRISPR-focused Google group, which is around three thousand question and answer sessions with really talented CRISPR scientists. And what this GPT did, it was, it was actually a CRISPR-Lama three, so it's, it's based on the Lama three from Meta.

• 58:00Lester Nare?

  Yes.

• 58:01Krishna Choudhary?

  I believe. And, um, it was a specialized model that was trained on these discussion threads, along with a lot of scientific papers that were out about CRISPR.

• 58:10Lester Nare?

  Lama three is old, they could have used, uh, that might be, anyway.

• 58:12Krishna Choudhary?

  Yeah, I mean, they, um, it was probably like something that they started way back.

• 58:16Lester Nare?

  A hundred percent.

• 58:16Krishna Choudhary?

  It's probably something that required, you know, less compute resources and all this other kind of stuff.

• 58:21Lester Nare?

  Hundred percent.

• 58:22Krishna Choudhary?

  Um, it's kind of interesting that DeepMind was involved in this, but they still use Lama three.

• 58:26Lester Nare?

  Yeah.

• 58:28Krishna Choudhary?

  Um, the, but the, the AI was trained on these nuances of scientific discourse that you don't really get with reading papers. Like, you don't get troubleshooting.

• 58:40Lester Nare?

  Right.

• 58:40Krishna Choudhary?

  You don't get problem solving. You don't get like, this is what I tried and it didn't work. That's something that you get in these discussion threads.

• 58:48Lester Nare?

  Yes.

• 58:48Krishna Choudhary?

  Right?

• 58:48Lester Nare?

  So similar to how the normal chat GPT that everyone uses is trained on all of the internet, including all these Reddit threads.

• 58:54Krishna Choudhary?

  Yeah.

• 58:55Lester Nare?

  All we're saying is the training data for this specialized model used a version of a Reddit thread with only very high level experts that are talking about this outside of the explicitly data-driven or experimental context. It's sort of this.

• 59:10Krishna Choudhary?

  Yeah.

• 59:10Lester Nare?

  Like gray area that, like the human, this is that, that human element.

• 59:14Krishna Choudhary?

  Yes. And, and then, and then you get an AI that sort of talks and thinks like a human scientist.

• 59:20Lester Nare?

  It approximates that context.

• 59:22Krishna Choudhary?

  Exactly, yeah. And they compared it against just, you know, GPT three point five, GPT four O, because obviously, I mean, I can ask. GPT four O about CRISPR and it'll be pretty good, right? Is this any better? It's a lot better. Okay, like when it comes to experiment planning, this was near perfect.

• 59:39Lester Nare?

  That's crazy.

• 59:40Krishna Choudhary?

  Okay, and um, I've actually tried experiment planning.

• 59:44Lester Nare?

  Yes.

• 59:44Krishna Choudhary?

  With GPT four O and it's very, very bad. It's not good.

• 59:48Lester Nare?

  It's a lot of noise.

• 59:49Krishna Choudhary?

  Yeah, it's not, it's a lot of like, it's stuff that an undergraduate.

• 59:52Lester Nare?

  Yeah.

• 59:53Krishna Choudhary?

  Would like come up with, that's like, oh, that's cute. But like, no, that's just, there's, there's like five reasons why that experiment won't work. Um, but thi- this one was very good at it. Um, it was also really good at guide RNA design, you know, the guide RNA that we were talking about. It's, it's not as simple as just, oh, this is the sequence that I want, right? You want to design a sequence that will only go to your specific location in the genome and not get misidentified with other parts of the genome, right? Because at the end of the day, it's a lock and key.

• 1:00:24Lester Nare?

  Right.

• 1:00:24Krishna Choudhary?

  But if the lock and key closely matches elsewhere, then you're going to start cutting other parts of the genome.

• 1:00:29Lester Nare?

  Right.

• 1:00:29Krishna Choudhary?

  And then your whole experiment fails. So it's really good at guide RNA design. And it's also really good at um, scientific question and answer. Like if you want to learn more about how this stuff works, or what is the logic behind a certain experimental step? You can ask it and it actually gives it back to you. Um, so the Stanford lab that developed this is actually already using it with its PhD students. And now it's out like in the open. And I think it's going to be really cool for expanding the broader impact of CRISPR, Cas9 and these like CRISPR technologies, you know? There's something like seven thousand to 10,000 single gene disorders out there.

• 1:01:07Lester Nare?

  Mm hmm.

• 1:01:07Krishna Choudhary?

  Right? And

• 1:01:10Krishna Choudhary?

  in order to work on them, if you can make it easier for the researcher.

• 1:01:13Lester Nare?

  Right.

• 1:01:14Krishna Choudhary?

  That's a huge win.

• 1:01:15Lester Nare?

  There, there's gonna be, and again, you know, obviously, we will be remiss and get escorted in the comments if we don't talk about the obvious like third rail related to all this stuff, which is you're combining these two extremely powerful, but also extremely dangerous frontier technologies. And they have this accelerant effect when they're now combined.

• 1:01:40Krishna Choudhary?

  Yeah.

• 1:01:40Lester Nare?

  And also open sourced. And so the obvious kind of the safety, you know, this is why people talk so much about AI safety. It's it's not always the most obvious like, like, oh, it's just gonna be in a robot. And then we're gonna have drones with computer vision killing everybody. It is more so if you have, you know, in some place, a group of expert scientists who are in this arena, but maybe are under a repressive regime that wants to do crazy stuff. And now they have accessibility to better tools of discovery.

• 1:02:18Krishna Choudhary?

  Yeah.

• 1:02:18Lester Nare?

  Um, there, there's a whole like human piece to it. There is this technology piece in its entirety, like, how do you decide? How does Stanford decide to release it or not release it?

• 1:02:29Krishna Choudhary?

  That's right. I mean, they did. So to be fair, they did have like guardrails in place. Um, one of the guardrails was like, you know, if you're, if you're trying to like do CRISPR on like COVID or HIV, it'll just be like, no, what are you doing?

• 1:02:43Lester Nare?

  Yeah.

• 1:02:43Krishna Choudhary?

  Why, why are you doing that? If, if, if you give it um, an identifiable DNA sequence, so like something that's more than like thirty base pairs long, which is something that you can maybe identify with individuals. If you want patient confidentiality, again, it'll lock down. I mean, obviously there's ways to get around this, right? And it is concerning.

• 1:03:04Lester Nare?

  I just wanna make sure we at least touch on that.

• 1:03:07Krishna Choudhary?

  And I agree with you. Like, I think it's a very important point.

• 1:03:10Lester Nare?

  It, it, it's not the focus of this discussion.

• 1:03:13Krishna Choudhary?

  Yeah.

• 1:03:13Lester Nare?

  But, you know, as we talk about all these things, everything has is sort of this double edged sword. And it goes back to the whole kind of quote where every technology is agnostic. It's about how ultimately we as humans choose to implement it. So it's a human, uh, CRISPR doesn't kill people, people kill people.

• 1:03:35Krishna Choudhary?

  Sure, bro.

• 1:03:35Lester Nare?

  But it is, it is a worthwhile discussion point. And if there's interest in this topic of CRISPR, and it's kind of continuing on the, the sort of safety conversation, just let us know in the comments and we'll definitely come back to touch on this.

• 1:03:47Krishna Choudhary?

  Yeah.

• 1:03:47Lester Nare?

  This is, I think, the fourth or fifth time. And we've talked about safety every single time.

• 1:03:50Krishna Choudhary?

  Yeah, every time.

• 1:03:51Lester Nare?

  Uh, maybe not as in-depth, but these are things that, again, folks at the frontier do have to start thinking about. Um, because, you know, we've, we already seen, seen what happened with nukes. And so it's the same story.

• 1:04:05Krishna Choudhary?

  Yeah.

• 1:04:05Lester Nare?

  History doesn't repeat, but it rhymes.

• 1:04:07Krishna Choudhary?

  Yes, exactly.

• 1:04:08Lester Nare?

  But this is really, really fascinating.

• 1:04:10Krishna Choudhary?

  Yeah. And I'm, you know, 2020, so five years ago, the Nobel Prize went to them. One of my favorite Nobel Prizes over the past 10 years, definitely.

• 1:04:19Lester Nare?

  Yes.

• 1:04:19Krishna Choudhary?

  Is CRISPR. I, I actually remember, um, you know, in 2012, um, at Princeton as an undergrad, I was just having a conversation at a dinner table with a friend of mine who was in molecular biology. And she was talking about this paper that had just come out in Science about programmable DNA. And that's where I, at the dinner table is when I first heard the word CRISPR.

• 1:04:45Lester Nare?

  Yes.

• 1:04:45Krishna Choudhary?

  I was like, like CRISPR, like crispier.

• 1:04:48Lester Nare?

  Yeah, yeah, yeah, yeah.

• 1:04:48Krishna Choudhary?

  Like, you know, like food. And then she was like, no. And then she described it to me and I was like, oh, oh, oh shit.

• 1:04:56Lester Nare?

  Yeah, yeah, this is.

• 1:04:57Krishna Choudhary?

  This is insane.

• 1:04:59Lester Nare?

  We're gonna start referring to people like KFC Chicken. Are you original or CRISPR?

• 1:05:02Krishna Choudhary?

  Yeah.

• 1:05:03Lester Nare?

  Because people, it's gonna start being.

• 1:05:04Krishna Choudhary?

  Yeah, yeah. And I still remember that day when it was like, it was sophomore year, 2012. And I was like, whoa.

• 1:05:10Lester Nare?

  Yeah, no, big deal.

• 1:05:11Krishna Choudhary?

  Whoa, this is a big deal.

• 1:05:12Lester Nare?

  Big deal.

• 1:05:13Krishna Choudhary?

  Yeah.

• 1:05:13Lester Nare?

  Very, very big deal. This is our first Nobel Prize reference story of the day. Again, Nobel Prize week is next week. Be sure to tune in. We're gonna be doing crazy coverage. The best coverage from First Principles. Nowhere is gonna be better.

• 1:05:28Krishna Choudhary?

  The best is gonna be the greatest.

• 1:05:31Lester Nare?

  The best coverage.

• 1:05:32Krishna Choudhary?

  They say, they, they say it's the best.

• 1:05:35Lester Nare?

  Okay, so we just finished talking about CRISPR, which was our first favorite Nobel Prize. We're gonna talk about our second one, a great achievement for American science.

• 1:05:46Krishna Choudhary?

  This was all America.

• 1:05:47Lester Nare?

  This was us, America, and which is the sort of LIGO. And again, we're tying it from the AI story that just came out this year to the history of this project and how AI is making this initial tool and kind of area of research even better. So the headline on this LIGO story, "New Algorithm Hushes Unwanted Noise in LIGO, May Lead to More Black Hole Discoveries." So this is from researchers at Caltech, and their idea was we want to make it easier for LIGO to find black holes with eccentric or oblong orbits, as well as catch mergers earlier in the coalescing process.

• 1:06:25Krishna Choudhary?

  Yes.

• 1:06:25Lester Nare?

  They published their paper in Science, which is this AI kind of context. But we've talked about LIGO on the podcast before, and I remember you talking about how this is sort of this like long tail of this initial contribution of what Einstein predicted 100 years ago.

• 1:06:45Krishna Choudhary?

  100 years ago, yeah.

• 1:06:46Lester Nare?

  And so we're gonna do the same thing again, which is kind of look at this story of the scientific curiosity journey from that initial prediction now to how all these new AI things are actually making LIGO better.

• 1:07:04Krishna Choudhary?

  Better, yeah. It's kind of crazy. 100 years ago, actually more than 100 years ago, so 1915.

• 1:07:11Lester Nare?

  Okay.

• 1:07:12Krishna Choudhary?

  Einstein publishes his General Relativity, which is a new way of thinking about gravitation, not as a force in the sense of Newton, where there's a force between two bodies, but actually as a disturbance in the actual fabric of space and time where...

• 1:07:30Krishna Choudhary?

  Now you have this unified quantity called space and time.

• 1:07:33Lester Nare?

  Yes.

• 1:07:34Krishna Choudhary?

  Which he had sort of already unified in nineteen oh five with special relativity. But special relativity dealt with inertial reference frames, which means. A reference frame here, let's say us sitting. Stationary and then um a frame of someone in a car that's moving in a straight line. With constant velocity. The idea is any experiment that he does in there is the same as any experiment that we do stationary. This is kind of, he's taking Galilean relativity from Galileo's time and taking it very, very seriously. Right? And he's combining that with the fact that the speed of light is constant.

• 1:08:11Lester Nare?

  Right.

• 1:08:11Krishna Choudhary?

  To get special relativity, all these consequences about how time is really relative, space is really relative. And there's this metric that is a combination of the two that is the thing that is invariant. Okay. So now we get special relativity, general relativity is where he generalizes it. To say, what about accelerating reference frames? What if the, what if that train was not moving in a, in a constant velocity?

• 1:08:36Lester Nare?

  Yes.

• 1:08:36Krishna Choudhary?

  But was moving around, was, was turning, was speeding up or slowing down? How would that affect? These calculations that I've been making and he comes up with general relativity, which is the, this idea that. Gravity and acceleration, gravity and this change in space and time are actually the same thing. We don't have to get into the whole details, but at the end of the day, it created this sort of. Nice.

• 1:09:03Krishna Choudhary?

  Mathematical framework for how we identify and understand space and time in a very nitty gritty, precise way.

• 1:09:11Lester Nare?

  Which impacts us, you know, every day.

• 1:09:13Krishna Choudhary?

  Every day. And I mean, um, you know, GPS, for example, is impacted by general relativity. The fact that GPS satellites are so far up. Means that they have a s- um, a smaller gravitational field due to the earth compared to us down here. Um, which means that their clocks actually run a little bit faster.

• 1:09:34Krishna Choudhary?

  than ours do.

• 1:09:35Lester Nare?

  Right.

• 1:09:35Krishna Choudhary?

  You would think because of special relativity that their clocks would run slower.

• 1:09:39Lester Nare?

  Yes.

• 1:09:40Krishna Choudhary?

  Right, because they're moving so fast.

• 1:09:42Lester Nare?

  Yes.

• 1:09:42Krishna Choudhary?

  But actually, the general relativistic effect is something like four times. The effect from special relativity. So special relativity, the fact that they're moving so fast means that the clock is slowing down. But the fact that they're in such a smaller gravitational environment, right, where the gravity is so less. Means that they're actually moving faster.

• 1:10:02Lester Nare?

  Which is why there's a correlation, that's like these things matter like.

• 1:10:04Krishna Choudhary?

  Yeah, and and so and so and actually like measuring that and accounting for that is essential to how GPS works. Yeah, because at the like GPS can like. Localize me to within a few meters of where I actually am, right? That few meters, if you think about it. The way they actually do it is from the. Light traveling between us and the satellite and the time delay between us and several different satellites, right? And then triangulating from those several different satellites to where we are. Well, in order to actually measure that time difference, you need to have extremely precise clocks.

• 1:10:40Lester Nare?

  Yes.

• 1:10:40Krishna Choudhary?

  On that. GPS satellite.

• 1:10:43Lester Nare?

  Yes.

• 1:10:44Krishna Choudhary?

  That precise clock is gonna be so precise that it is going to feel these relativistic effects. And so you need to have an active mechanism that accounts for the fact that that clock is going faster than this clock. By exactly the amount that Einstein's field equations say that they will go faster by. And then you do the math and then you like, oh, you're here, you know, and you need to go over there and so on and so forth.

• 1:11:06Lester Nare?

  That's actually a really good.

• 1:11:07Krishna Choudhary?

  So it's it's very much like involved in.

• 1:11:09Lester Nare?

  Right, right. It's a good example of how GR uh like. Relates to a very everyday use case that everyone can under- understand.

• 1:11:17Krishna Choudhary?

  Everyone, yeah. Everyone's used GPS.

• 1:11:19Lester Nare?

  Yes.

• 1:11:20Krishna Choudhary?

  Okay, so now we're getting to the fact that um Einstein publishes these field equations. Um, people start trying to find solutions to the field equations, okay, which means to say. The field equations give us a way to understand what matter does to space. And what space does to matter. The the great. Saying by um John Wheeler, who we'll get to later on, is that um.

• 1:11:46Krishna Choudhary?

  Space tells matter how to move and matter tells space how to curve.

• 1:11:51Lester Nare?

  Hmm.

• 1:11:52Krishna Choudhary?

  Okay, that's effectively what Einstein's field equations are. They're a way for us to mathematically describe the stretching and turning of spacetime, okay? So spacetime becomes this sort of like field in some sense. Okay, it's like everywhere and it's got a, it's got a way to stretch and stuff. And one can imagine people start asking, can I make waves?

• 1:12:18Lester Nare?

  In that, in this.

• 1:12:19Krishna Choudhary?

  In this field.

• 1:12:20Lester Nare?

  Field of spacetime.

• 1:12:21Krishna Choudhary?

  In this sort of field of spacetime, you can imagine, right, like if I've got ropes or if I've got a rubber band, right? I can create waves in my rubber band. If I have a bunch of rubber bands lined up together and I stretch one and then that sort of propagates on the rest. You, you can create these waves in rubber bands and if spacetime is this sort of elastic thing, then I should be able to create waves in spacetime.

• 1:12:43Lester Nare?

  The thought, my initial thought on that is, uh, you, you, you must need an immense amount of energy.

• 1:12:53Krishna Choudhary?

  Energy, yes.

• 1:12:54Lester Nare?

  In order to.

• 1:12:54Krishna Choudhary?

  Insane amount of energy.

• 1:12:55Lester Nare?

  In order to, you know, disrupt the fabric of.

• 1:12:58Krishna Choudhary?

  Of spacetime. Yeah, yeah, I mean, and you're exactly right. You do need an insane amount of energy to disrupt the fabric of space and time. But before we even try to think about what could cause waves in space and time, you got to first show that the Einstein field equations admit a solution that looks like the wave equation.

• 1:13:22Lester Nare?

  Okay.

• 1:13:22Krishna Choudhary?

  Okay, the wave equation is something that's been around for hundreds of years and it's very well defined, you know, signs and cosines, traveling. Um, the wave equation is, is a very simple second order differential equation. That's basically saying that the, the amount of curvature that I have in space tells me how much acceleration I have in time. And that's basically how the wave equation works, right? There's a second derivative in space. There's a second derivative in time and they're related by the velocity of propagation. So. Einstein sets out to see if this works in his um in his equations of special relativity in his field equations. So at this point, it's in the nineteen thirties.

• 1:14:04Lester Nare?

  Yep.

• 1:14:04Krishna Choudhary?

  Einstein's already at Princeton.

• 1:14:06Lester Nare?

  Mm hmm.

• 1:14:07Krishna Choudhary?

  Woo woo. New Jersey, he's already um at the Institute for Advanced Study. At this point, I don't think the institute had actually been made and so he was, he had an office in Frist.

• 1:14:17Lester Nare?

  Yeah.

• 1:14:17Krishna Choudhary?

  Campus center.

• 1:14:18Lester Nare?

  Yes.

• 1:14:18Krishna Choudhary?

  Um, which used to be the old physics building and the math building.

• 1:14:21Lester Nare?

  Yes.

• 1:14:22Krishna Choudhary?

  On campus, so.

• 1:14:23Lester Nare?

  Spent a lot of two AM nights.

• 1:14:24Krishna Choudhary?

  Yeah, yeah, yeah, yeah, with the late meal.

• 1:14:26Lester Nare?

  Yeah, late meal was classic.

• 1:14:28Krishna Choudhary?

  Uh, so he, he's sitting there and he tries to find a solution to the wave equation in his field equations.

• 1:14:39Krishna Choudhary?

  He does the math and he actually comes up with the fact that wha- what he notices, what he notices are these things called singularities, which he can't quite get rid of when he's trying to do this analysis. And so he writes a paper saying that the wave equations, the, the field equations do not admit, admit wave solutions, okay? He writes this up and he sends it over to the physical review, okay? The physical review at this point was um, the editor was John Tate. And he is kind of a stickler for the peer review process. At this point Einstein had already sent in a bunch of papers to the peer review.

• 1:15:22Krishna Choudhary?

  There was the very famous EPR paper Einstein Podolsky Rosen, which is the one that was talking about local variables solving quantum mechanics. He was saying that, you know, this whole quantum stuff is weird, maybe there's some like hidden variable that explains quantum mechanics. That was the famous EPR paper. There was also the Einstein Rosen Bridge paper that he had published in the peer, uh, Physical Review. So he's had a pretty good relationship with the Physical Review.

• 1:15:51Lester Nare?

  Yes.

• 1:15:51Krishna Choudhary?

  He sends this one in. And he says that, you know, uh, my equations do not allow for wave-like solutions. Um, John Tate sends it over to his buddy, um, H P Robertson, who's also in the Princeton Physics Department. So, you know, Einstein sends it to John Tate, John Tate sends it back to Princeton. And Robertson finds an error.

• 1:16:15Lester Nare?

  Okay.

• 1:16:16Krishna Choudhary?

  In the paper, okay? He finds that the singularities that Einstein is so worried about and the reason why he thinks that wave equations won't exist are actually just coordinate singularities. They're not actually real physical singularities. Coordinate singularities are something like, you know, trying to find the longitude of the North Pole. Something like that. It's it's an artifact of like our version of how we're keeping track of latitude and longitude. Right? But the North Pole could be anywhere.

• 1:16:44Lester Nare?

  Yeah, yeah, yeah.

• 1:16:45Krishna Choudhary?

  Right? It's just we we we like the North Pole at the top because that's how it's spinning. But you can easily imagine a coordinate system where the North Pole and the South Pole are on the opposite sides of the equator. And we just have really convoluted equations of mechanics for how the how physics on the earth works, right? But at the end of the day, it's a choice that we've made as humans on where to put the zero of our coordinate system, right? It's it's an artifact of the coordinate system. So Robertson actually looks at Einstein's paper and he's like, actually, these these these singularities are coordinate singularities. They're not physical singularities. So he writes back to Tate. Tate then pushes back on Einstein and he's like, hey, I got these peer reviews. I was wondering if, very nicely, the the the letters are still there.

• 1:17:29Lester Nare?

  Not like reviewer number one.

• 1:17:31Krishna Choudhary?

  No, not like reviewer number one from the Mars paper.

• 1:17:33Lester Nare?

  Yes.

• 1:17:33Krishna Choudhary?

  Where it's like you need to, this needs to get rejected. It's like, this is Einstein we're talking about. So obviously you have to be like, you know, they have these comments. Can you take a look? Um. And Einstein is just livid.

• 1:17:49Krishna Choudhary?

  He's like, I can't believe you showed my paper. To someone without my consent. Um, given this, I'm just gonna publish somewhere else. He retracts his paper.

• 1:18:01Lester Nare?

  The goat.

• 1:18:02Krishna Choudhary?

  He never publishes in Physical Review again. And John Tate goes down as the guy who editorialized Einstein. But he, he was, he was true, a man true to his word. He was like, I don't care if you're Einstein or God. You're gonna go through the same peer review. And hey, if Robertson, who's a great mathematical physicist in his own right, says something is wrong, maybe you need to pay attention, right?

• 1:18:26Lester Nare?

  Seems reasonable.

• 1:18:27Krishna Choudhary?

  Reasonable. Einstein retracts his paper. He gets word from his assistant elsewhere about Robertson, cause Robertson goes to his assistant and is like, you know, you guys are having trouble with these singularities. Like, you know, there's one way that you can just like, do this and then blah, blah, blah, and then you're, the math trick works out. And so Einstein gets word from his assistant that, you know, there's a way to counteract it. He goes back to the drawing board. And Einstein, true to his physics side, right? He sets aside his ego and he's like, okay, that was, that was bad. And, and he corrects his paper and he publishes it in um, a Philadelphia journal. I think of the Benjamin Franklin Society or something, some random journal. Um, you know, not the Physical Review.

• 1:19:12Krishna Choudhary?

  Right? Um, and it's a totally new paper. And it's a new paper that admits that gravitational waves can in fact, be allowed in the space time of Einstein's field equations. It's so funny, right? Because it's like this guy, like he, he, he, you should have just read the peer review. Right? He could have just read the peer review and like, but, but he had to go through all this.

• 1:19:38Lester Nare?

  He chose violence.

• 1:19:38Krishna Choudhary?

  He chose violence and like, at the end of the day, he even admitted to himself that he was wrong. And like corrected his paper, but he never went back to the peer review.

• 1:19:49Krishna Choudhary?

  Yeah, it's like, I know I'm wrong, but how dare you? That's Einstein dude, you don't, yeah anyways, he never published in the peer reviewer, the, the physical reviewer ever again. But that paper sort of established this idea that, okay.

• 1:20:04Krishna Choudhary?

  We can have gravitational.

• 1:20:05Lester Nare?

  You can have waves. Uh, in the system of spacetime where spacetime is this fabric.

• 1:20:11Krishna Choudhary?

  Yeah, that governs the dynamics of all things. Okay. So, alright, fine. Now, now we've got a paper that says gravitational waves do exist.

• 1:20:20Lester Nare?

  Right.

• 1:20:20Krishna Choudhary?

  Okay, just like electromagnetic waves.

• 1:20:23Lester Nare?

  Yes.

• 1:20:24Krishna Choudhary?

  Okay, and just like electromagnetic waves, in order to create gravitational waves, you need accelerating bodies. So you can't have a thing that's just moving at constant velocity.

• 1:20:34Lester Nare?

  Cause it's not gonna disturb.

• 1:20:35Krishna Choudhary?

  Because it's not gonna disturb space in the way that it propagates out.

• 1:20:39Lester Nare?

  Yes.

• 1:20:39Krishna Choudhary?

  Okay, it's gonna create a disturbance, but that disturbance is just gonna, like, sort of be local.

• 1:20:44Lester Nare?

  Yes.

• 1:20:44Krishna Choudhary?

  To it.

• 1:20:45Lester Nare?

  Yes.

• 1:20:45Krishna Choudhary?

  Okay, and you're not gonna get this like radiating effect.

• 1:20:48Lester Nare?

  It's like if you're in a boat and you're stationary, you don't create a wake.

• 1:20:53Lester Nare?

  But if you're moving.

• 1:20:54Krishna Choudhary?

  But in a boat, even a moving boat creates, this is, this is a big.

• 1:20:58Lester Nare?

  Okay.

• 1:20:58Krishna Choudhary?

  Uh, this is, this is a fine detail. A boat that's moving at constant velocity is still gonna create waves.

• 1:21:05Lester Nare?

  Yes, that's fair, that's fair.

• 1:21:07Krishna Choudhary?

  A, a charged particle that moves at a constant velocity will not create a light wave.

• 1:21:11Lester Nare?

  Interesting.

• 1:21:12Krishna Choudhary?

  Light is only created from accelerating particles. So, something that's moving in a circle means that it's changing velocity. That is gonna create a radiating effect. Something that's speeding up or slowing down is gonna create a rating, radiating effect. But something that is moving at a constant velocity is not. There's actually a very simple argument.

• 1:21:32Lester Nare?

  Okay.

• 1:21:32Krishna Choudhary?

  For why this is the case. It's one of my fundamental, it's one of my favorite arguments about, um, from Einstein's special relativity, okay? So. Suppose. Not, right? We're gonna do this by a proof of contradiction. Suppose not. Suppose that. A charged particle that moves at a constant speed does create light. What if I were to boost myself into a reference frame that I'm moving with the charged particle at a constant speed? In my reference frame, that charged particle is stationary.

• 1:22:03Lester Nare?

  Yes.

• 1:22:04Krishna Choudhary?

  So I'm not gonna see any light.

• 1:22:06Lester Nare?

  Hmm.

• 1:22:06Krishna Choudhary?

  But now there's a contradiction.

• 1:22:08Lester Nare?

  Yeah, right, immediately, got it.

• 1:22:09Krishna Choudhary?

  Immediately, there's a contradiction, because a stationary observer observed light, but me moving with this particle does not observe light. It would be something if the stationary observer observed a a a particle with some light and I observed it at a different energy, right? Maybe it was like boosted in ultraviolet or down in infrared or something like that, but the fact that I observed no light.

• 1:22:31Lester Nare?

  Yes.

• 1:22:32Krishna Choudhary?

  Is unphysical.

• 1:22:33Lester Nare?

  Yes.

• 1:22:33Krishna Choudhary?

  Because both me and the stationary observer should observe the same physics.

• 1:22:38Lester Nare?

  Yes.

• 1:22:39Krishna Choudhary?

  Right?

• 1:22:39Lester Nare?

  Yes.

• 1:22:39Krishna Choudhary?

  So.

• 1:22:41Lester Nare?

  Yes.

• 1:22:41Krishna Choudhary?

  It's a consequence of relativity, the constant velocity motion does not radiate.

• 1:22:45Lester Nare?

  Okay.

• 1:22:46Krishna Choudhary?

  The same thing happens with gravity, right? Suppose there's a gravitational object that's moving at a constant velocity. If I boost myself into that reference frame, that object is now stationary and I shouldn't observe any gravitational waves. Well, if I don't observe any gravitational waves in my in my frame of reference with the body, then a stationary observer should also not observe gravitational waves. On the other hand, if it's accelerating, if it's moving.

• 1:23:12Lester Nare?

  Yes.

• 1:23:12Krishna Choudhary?

  If it's accelerating and it's speeding up or it's slowing down, then no matter what inertial frame I choose.

• 1:23:17Lester Nare?

  Yes.

• 1:23:17Krishna Choudhary?

  It's also gonna be either speeding up or slowing down, so I am gonna observe some form of gravitational radiation.

• 1:23:24Lester Nare?

  Yes.

• 1:23:24Krishna Choudhary?

  Or, in the case of charged particles, some form of electrical radiation, light.

• 1:23:28Lester Nare?

  Yes.

• 1:23:29Krishna Choudhary?

  You know, that's kinda.

• 1:23:29Lester Nare?

  No, that's a great.

• 1:23:31Krishna Choudhary?

  Such a great, like, simple argument you can make, using just the symmetries of physics.

• 1:23:35Lester Nare?

  Yes.

• 1:23:35Krishna Choudhary?

  Um, so anyways, we need some, something that's accelerating, okay? So for the longest time gravitational radiation was just this thing that, you know, it's hypothesized, but even Einstein said you're never gonna find it.

• 1:23:49Lester Nare?

  Yeah, yeah.

• 1:23:50Krishna Choudhary?

  Never, because you you can do a back of the envelope calculation about how how how much stuff would would stretch and squeeze by.

• 1:23:59Lester Nare?

  Right.

• 1:24:00Krishna Choudhary?

  And it's on the factor of like ten to the minus twenty.

• 1:24:03Lester Nare?

  Meaning like the actual fabric that would be measurable by us would be so.

• 1:24:07Krishna Choudhary?

  Any length would be corrected by ten to the minus twenty. Right, like if you take a meter stick, an atom is ten to the minus ten of that meter stick. Right, so it's an atom of an atom. Even Einstein's like, yeah, okay, like this is, this is a cool, like, you know, theoretical exercise, but.

• 1:24:26Lester Nare?

  So the point being that i- i- his view was like, we, we won't be able to get to a level of experimental verification because of the. The, the scope is just so outside, like it was an engineering problem for detection and that we weren't.

• 1:24:41Krishna Choudhary?

  But the engineering problem required physics that was like stupid.

• 1:24:45Lester Nare?

  Yeah, yeah, yeah, yeah.

• 1:24:46Krishna Choudhary?

  Right?

• 1:24:46Lester Nare?

  Yeah.

• 1:24:46Krishna Choudhary?

  You know what I mean? And he was just like, it's, it's like a cool thing.

• 1:24:49Lester Nare?

  Yeah.

• 1:24:49Krishna Choudhary?

  But it's a cool thing.

• 1:24:50Lester Nare?

  Yes.

• 1:24:51Krishna Choudhary?

  Okay, um, nineteen seventies actually is when we first got a confirmation that gravitational waves exist.

• 1:24:58Lester Nare?

  Okay.

• 1:24:58Krishna Choudhary?

  It was by Taylor and Holtz. Um, actually, one of their, one of their, um, plaxes on the Princeton University Physics.

• 1:25:06Lester Nare?

  Yeah.

• 1:25:07Krishna Choudhary?

  Uh, thing because he won the Nobel Prize for it. I think he was a postdoc at the time at Princeton and, um, or maybe a PhD student. So they use the Aracibo. Radio telescope.

• 1:25:21Lester Nare?

  Yep.

• 1:25:21Krishna Choudhary?

  Have you seen this thing in Puerto Rico? It's, it's a giant radio telescope that's like.

• 1:25:26Lester Nare?

  In the.

• 1:25:27Krishna Choudhary?

  In, in a bowl created by the geography of the mountain.

• 1:25:30Lester Nare?

  Wasn't it recently kind of had like a hurricane came through or something, had a little damage to it and then they had to.

• 1:25:35Krishna Choudhary?

  Yeah, and they had to, and they had to fix it and everything, but it's, it's, it's, it's a bowl created by the earth.

• 1:25:41Lester Nare?

  Right.

• 1:25:41Krishna Choudhary?

  That we then put concrete over and then it basically just scans the sky with the earth.

• 1:25:46Lester Nare?

  Yes.

• 1:25:46Krishna Choudhary?

  Um, and tries to find radio sources. So they were trying to look for pulsars at the time with that radio source and what they found was a pulsar.

• 1:25:57Krishna Choudhary?

  And they were very happy because at back in the day, like pulsars were very new, so they found a new pulsar. But this was a very weird pulsar, okay, it was a pulsar that had a cycle of sixty, um, sixty milliseconds. So seventeen times a second it would, I mean seventeen times a second it would like go go down. And a pulsar is basically a neutron star that kind of acts like a lighthouse. It's got these strong magnetic fields, so it's got these jets of radio light that are coming out. And it's a lighthouse in the sense that as it rotates, right?

• 1:26:28Lester Nare?

  Yes.

• 1:26:28Krishna Choudhary?

  The the the part of the beam, the radio beam is gonna just like go through the earth.

• 1:26:33Lester Nare?

  Yes.

• 1:26:34Krishna Choudhary?

  Every sixty milliseconds, right?

• 1:26:36Lester Nare?

  Which is quite fast.

• 1:26:37Krishna Choudhary?

  It's quite fast and it's a really precise clock. Okay, it's one of the, these pulsars are some of the most precise clocks ever made in the universe. Right? Because it's really hard to slow down a neutron star that's the size of several suns. That just because of the conservation of angular momentum is just gonna keep going, okay? So most pulsars, they're very reliable. They'll just be like clockwork. This pulsar was different.

• 1:27:04Lester Nare?

  Okay.

• 1:27:04Krishna Choudhary?

  Okay, because this pulsar, every once in a while, it would, the the pulses would arrive

• 1:27:13Krishna Choudhary?

  three seconds too late or three seconds too early. Remember, it's going at sixty milliseconds. But you can you can plot the trajectory of how their delay is.

• 1:27:23Lester Nare?

  Yes.

• 1:27:24Krishna Choudhary?

  And that delay was happening three seconds too late or three seconds too early. And what they figured was this pulsar is actually rotating with another neutron star. That other second neutron star is also a pulsar, but we're not seeing it because the lighthouse isn't crossing our line of sight.

• 1:27:46Lester Nare?

  Yes.

• 1:27:46Krishna Choudhary?

  So it's probably maybe doing one of these and we're missing that.

• 1:27:48Lester Nare?

  It's going up down instead of.

• 1:27:49Krishna Choudhary?

  But this one is coming right at us and it's revolving in this binary pulsar system.

• 1:27:54Lester Nare?

  Got it.

• 1:27:55Krishna Choudhary?

  Okay, this became a really nice test bed for general relativity. Because now all of a sudden you had rotating objects that were massive that were accelerating. Right?

• 1:28:07Lester Nare?

  Yes.

• 1:28:07Krishna Choudhary?

  Because they're they're revolving around each other, which means they're constantly correcting their motion because of the gravity between them. Which means. If they're close to each other, right, three seconds in light distance, like the moon is about one and a half seconds away. So this is, imagine like it's the earth and like another two moons away.

• 1:28:26Lester Nare?

  Yes.

• 1:28:26Krishna Choudhary?

  Two stars that are like the size of the sun and more.

• 1:28:30Lester Nare?

  Yes.

• 1:28:31Krishna Choudhary?

  That are revolving around each other, right?

• 1:28:32Lester Nare?

  So the point is they're very quite, they're quite close.

• 1:28:34Krishna Choudhary?

  Quite close.

• 1:28:35Lester Nare?

  So their gravitational impact, the gravity independently is gonna have a high impact on each other because of proximity.

• 1:28:41Krishna Choudhary?

  Exactly.

• 1:28:42Lester Nare?

  Yeah.

• 1:28:42Krishna Choudhary?

  Which means that according to Einstein's GR, these should be radiating gravitational waves. If they're radiating gravitational waves, then they should be losing energy because it takes energy to deform space and time.

• 1:28:57Lester Nare?

  Yes.

• 1:28:57Krishna Choudhary?

  And if they're losing energy, they should be falling into each other and they should be rotating faster. So you can do all of the math.

• 1:29:04Lester Nare?

  I was gonna say you can do the math.

• 1:29:05Krishna Choudhary?

  You can do the math and you can figure out, according to GR, how fast should that decay be? Right, of their, of their total energy.

• 1:29:13Lester Nare?

  Yes.

• 1:29:14Krishna Choudhary?

  And it's a beautiful plot that they have in their paper, where it shows a line that shows the theoretical prediction, and then it shows dots.

• 1:29:23Krishna Choudhary?

  And the dots are lining up exactly to Einstein's GR.

• 1:29:27Lester Nare?

  Which means the, the math in the GR paper is now, which was theoretical at the time, there's now an experimental observation that was verifiable

• 1:29:36Krishna Choudhary?

  Yeah.

• 1:29:36Lester Nare?

  to what the underlying sort of statement of work is

• 1:29:40Krishna Choudhary?

  Yeah.

• 1:29:40Lester Nare?

  around GR.

• 1:29:41Krishna Choudhary?

  Yeah, exactly. And it's like, it's like, where could this energy be going? It has to be going in the general, in the gravitational waves, which is what's predicted by this equation, and the equation also predicts exactly the decay, and that's exactly what we see. And now we've been watching this pulsar for the past forty years now.

• 1:29:57Lester Nare?

  Which makes sense.

• 1:29:57Krishna Choudhary?

  And it's just, it just continues down.

• 1:29:59Lester Nare?

  It's like the perfect experiment in the sky.

• 1:30:01Krishna Choudhary?

  Yeah.

• 1:30:01Lester Nare?

  For any number of different types of observational, you know, research, this being just one.

• 1:30:06Krishna Choudhary?

  Yeah, and they won the Nobel Prize in nineteen ninety-three in physics for this discovery. It was a very big one, right? It established the reality, the experimental reality of gravitational waves. Okay.

• 1:30:17Lester Nare?

  Now, I, I just wanna make a note that that's, what's interesting is it required no specialized measurement equipment

• 1:30:24Krishna Choudhary?

  No.

• 1:30:24Lester Nare?

  at the time. It was just What we already had, radio telescope?

• 1:30:29Krishna Choudhary?

  Yeah, it was just a radio telescope.

• 1:30:30Lester Nare?

  Radio telescope and math.

• 1:30:30Krishna Choudhary?

  Yeah, aerosibo and math, right? And so this established at least the existence

• 1:30:36Lester Nare?

  Yes.

• 1:30:36Krishna Choudhary?

  of gravitational waves, of the fact that space and time undulate in this wave-like manner and it carries energy. The same exact amount of energy that Einstein's equations predict. Okay, now it's something to go from these things exist to let's actively try and sense them.

• 1:30:55Lester Nare?

  Right, right, right.

• 1:30:57Krishna Choudhary?

  Cause that's what Einstein was going at. He was like, this is gonna be impossible to sense these.

• 1:31:01Lester Nare?

  This was an indirect confirmation.

• 1:31:04Krishna Choudhary?

  Yeah, it's an indirect observation.

• 1:31:05Lester Nare?

  But it was not a direct observation.

• 1:31:07Krishna Choudhary?

  It's not like, oh, that I just saw one.

• 1:31:10Lester Nare?

  Yeah.

• 1:31:10Krishna Choudhary?

  Right? It's just like, oh, this thing is just putting it out into the sky. And we're seeing it because it's losing energy.

• 1:31:18Lester Nare?

  Right.

• 1:31:18Krishna Choudhary?

  Right? So that's the indirect observation. By the conservation of energy, that energy has to go somewhere. Where does it go? Into these gravitational waves.

• 1:31:25Lester Nare?

  Yep.

• 1:31:25Krishna Choudhary?

  Okay, so now we're getting to the, so this is the 1970s, they find this thing. Also in the 1970s, people start thinking about how do we actually make a direct detection of gravitational waves. So that's where we start getting into people like Feynman, actually. Feynman starts, he, he, he gave this talk about

• 1:31:49Krishna Choudhary?

  sort of a, a thought experiment of how to actually detect gravitational waves. And he showed that, you know, if you had like a sort of rod attached to springs and stuff, and if a gravitational wave of in, in insanely high capacity went through, then the rod would actually

• 1:32:05Lester Nare?

  Um, undulate.

• 1:32:06Krishna Choudhary?

  Undulate because the, the springs would be attached to that space and time. So this thing would like move and then part of the energy of the gravitational wave would actually go into the spring. And then if you measured the spring, you could actually measure the gravitational wave. So he showed that that mathematics of like something like this.

• 1:32:23Lester Nare?

  Like a system that could do the direct observation.

• 1:32:26Krishna Choudhary?

  Yeah, yeah, yeah.

• 1:32:27Lester Nare?

  What the structure of that system would be and why it can work.

• 1:32:29Krishna Choudhary?

  Exactly. And so given, given that sort of theoretical work of showing that a system like that would work. Um, this guy Joseph Weber from the University of Maryland in the 1960s and 70s. He created a gravitational wave detector, which was sort of something that he could fit inside a laboratory. Um, and he said that he found some. Now we know that he probably didn't because people couldn't replicate it as his experiment and science is all about replication, right? And probably he didn't find any. And it sort of marred the field because you know, you've got this guy who's saying, I found him, but. Uh, he didn't and he was an honest scientist, but you know, even honest scientists can get sort of hung up and um, and not. See the sources of their errors, right?

• 1:33:14Krishna Choudhary?

  So it was kind of lacking, let's say, the field. Okay, so this is where the two heroes of our story come in, Kip Thorne and Rayner Wise. Okay? And to really understand where they come in in the nineteen seventies and eighties, we gotta go back to their roots. Okay, um. Kip Thorne gets his PhD at Princeton. Under John Wheeler, okay, John Wheeler is. A.

• 1:33:50Krishna Choudhary?

  Seminal figure in the field of physics, okay? He's kind of like, I would say, the American Arnold Sommerfeld. Remember Sommerfeld that we talked about? Yes. Sommerfeld being this guy who tutored. Amazing physicists in their own right, but never won the Nobel Prize himself. John Wheeler is one of those guys, okay? He tutored Kip Thorne, won the Nobel Prize. He tutored Richard Feynman, also got his PhD under John Wheeler. Um, he tutored Hugh Everett. Who is the guy behind the many worlds interpretation of quantum mechanics, this idea of multiverses and all the, you know, Marvel stuff. Um, he also tutored um, Jacob Beckenstein, which is a guy who did.

• 1:34:30Krishna Choudhary?

  Seminal contributions to black hole thermodynamics, the idea of like entropy in black holes and information in black holes. He sort of revamped. He made general relativity cool again. Uh, after the war. Yeah, okay. Yeah, because. General relativity was sort of this field that was not cool, okay? It wasn't something that you could do direct detection on. Einstein had sort of closed the book.

• 1:34:57Lester Nare?

  Yeah, right.

• 1:34:58Krishna Choudhary?

  By finding the Einstein field equations and then people thought it was sort of just, oh, like, you know, it's just bookwork at that point of like trying to find new directions with GR.

• 1:35:08Lester Nare?

  Is it similar to how when people say string theory is cool on paper, but we can't do anything experimentally to really see the things that are being argued?

• 1:35:17Krishna Choudhary?

  Yeah.

• 1:35:17Lester Nare?

  Like, like, like, like a parallel?

• 1:35:19Krishna Choudhary?

  It's kind of parallel. GR, I wouldn't compare to string theory, obviously, because GR actually has insane experimental, um, even back then.

• 1:35:27Lester Nare?

  Okay, fair.

• 1:35:28Krishna Choudhary?

  Right, even like Mercury's orbit was explained by GR.

• 1:35:31Lester Nare?

  Fair.

• 1:35:31Krishna Choudhary?

  One had done, um, uh, the detection of bending of light around a solar eclipse. That was Arthur Eddington. So, uh, GR had its confirmation.

• 1:35:40Lester Nare?

  So you're saying string theory is trash?

• 1:35:41Krishna Choudhary?

  Yeah.

• 1:35:41Lester Nare?

  I'm kidding, I'm kidding.

• 1:35:42Krishna Choudhary?

  Well, okay, actually, in a, um, you know, speaking of string theory, string theory actually started with John Wheeler. John Wheeler, um, came up with this idea of the S-matrix, which was, I don't, I don't understand much about it, but it's some way of like defining a new way of dealing with quantum mechanics that, that had to do with combining gravity and quantum mechanics. Um, S-matrix was then taken by Werner Heisenberg and developed into a theory. And then that sort of formed into string theory later on. So John Wheeler is even, in fact, responsible for the-

• 1:36:17Lester Nare?

  For that whole wing.

• 1:36:18Krishna Choudhary?

  The, the, the genesis, the very, very embryonic genesis of string theory. Um, he did a lot of really crazy stuff, dude. He did S-matrix theory. He coined the term wormhole.

• 1:36:29Lester Nare?

  Mm-hmm.

• 1:36:30Krishna Choudhary?

  Um, he did the one electron universe. I don't know if you've heard about that, where it's like every electron is just one electron in many different, like, people love trying to go into like the science fiction of this, of this kind of stuff. Um, he popularized the term black hole.

• 1:36:46Lester Nare?

  Mm-hmm.

• 1:36:46Krishna Choudhary?

  Um, he also actually was one of the first people to foray into quantum gravity, of trying to combine quantum mechanics with gravity.

• 1:36:53Lester Nare?

  Yes.

• 1:36:54Krishna Choudhary?

  So this incredible, incredible physicist, um, sort of became the, you know,

• 1:37:01Krishna Choudhary?

  This godhead status at Princeton physics. Um, but attracted attracted the talent. Created talent with Kip Thorne and with Feynman, but he never himself won the Nobel.

• 1:37:12Lester Nare?

  He was the prince who never became king.

• 1:37:14Krishna Choudhary?

  Yeah, but I mean, to to those who know physics, like John Wheeler is is a very big deal. Right? Um. Yeah, he was one of the few people who if he defended Freeman Dyson when Freeman Dyson was going up against Oppenheimer. Um, and yeah, it was like, you know, he's he's one of the few guys that can let go against the big wigs. Even go up against Einstein and be like, nah, that doesn't make sense. And Einstein would actually listen. Instead of being like, I'm never gonna publish here ever again, you know, like so. Um, and we Kip Thorne was um Wheeler's PhD student.

• 1:37:49Lester Nare?

  Yep.

• 1:37:49Krishna Choudhary?

  And Wheeler sort of started this idea of revamping general relativity. Okay, Kip Thorne grew into that. He they wrote textbooks together. And Wheeler was the sort of theoretical part of the wing. And then there was this experimental part that was Robert Dickey. Okay, Robert Dickey is another one of these guys, great princes and greats. He's um, he's responsible for the invention of the lock-in amplifier. Which is um, an electrical way of finding small electrical signals that are of some characteristic frequency in a bastion of noise. He also was the discoverer of the cosmic microwave background.

• 1:38:32Krishna Choudhary?

  Okay, the, you know, the CMB, the radiation from the Big Bang.

• 1:38:36Lester Nare?

  Yes.

• 1:38:36Krishna Choudhary?

  He was one of these first sort of applying general relativity to cosmology problems. And um, him and his student Wilkinson and Peebles published the paper right after the experimental discovery. They were actually planning to make a dish to observe the cosmic microwave background. And then meanwhile, unmined unmined to them. Penzias and Wilson were neighboring in Bell Labs, which is right down the street from Princeton. They they were stuck with a microwave antenna. They're trying to do research with microwave antenna and they keep getting this. Noise.

• 1:39:11Lester Nare?

  Yep, yep.

• 1:39:12Krishna Choudhary?

  And they're like, what the hell is this noise? And they're trying to find where the noise is coming from. One of them actually like crawled in and started like scraping the pigeon poop. That was in the antenna cuz they're like, I don't know, maybe it's the pigeon poop and they're like scraping. They got rid of the pigeon poop, the pigeon, the, the noise was still there. And they're like, dude, what is this noise that we're getting? And they called up Robert Dickey. And they're like, we're getting this noise, like you guys are, you guys are physicist at Princeton. And Dicky's like, he hangs up the phone and he tells his collaborators, boys, I think we got scoop.

• 1:39:48Krishna Choudhary?

  Because they're trying to make a, a thing and these guys have done it. Penzison Wilson immediately recognized what it is. They immediately publish. Um, Dicky Peebles and Wilkinson published their paper on the CMB, the theoretical background. Right after theirs. So you can see when they published, actually, it's like back to back in the same issue of the journal they're publishing, right?

• 1:40:12Krishna Choudhary?

  And Penzison Wilson go on to win the Nobel Prize for the discovery. It really should have been a three person with Dicky. Um, but actually, you know, years later, I think in the last two or three years, Jim Peebles, who was the, the guy who published the theoretical paper, he actually won the Nobel Prize. And it was kind of a validation. It was kind of a posthumous. Nobel Prize for, for Robert Dickey who had already died. Um, but it was kind of, it was kind of cool that like, you know, that collaboration finally won the Nobel.

• 1:40:46Lester Nare?

  It got recognition.

• 1:40:47Krishna Choudhary?

  It got recognition. Peebles won it for all the other stuff that he did with cosmology later on. He actually showed that, you know, the CMB should look like this with this bumpy, wavy nature. When you, when you look at the power spectrum and then when people did the power spectrum, they found the bumpy, wavy nature. Wilkinson, who was the other guy who did the, um, paper with them. Um, the WMAP, um, satellite, which is the Wilkinson Anisotropy Probe. That's, that was sent into space to actually capture the cosmic microwave background in excruciating detail. That was named after Wilkinson. So, you know, they got their credit in their own right, but, um, it's unfortunate that Dicky didn't get his. Recognition with a Nobel Prize, but one of Dickey's postdocs was Rayner Weiss.

• 1:41:29Krishna Choudhary?

  And Rayner Weiss still to this day says that, you know, one of his biggest influences in terms of physical thinking was Robert Dickey at Princeton. There's a beautiful photo of Kip Thorne and Robert Dickey standing right next to a plaque that commemorate, sorry. There's a beautiful photo of Kip Thorne and Rayner Weiss, the two Nobel Prizes that were awarded for LIGO. They're standing next to the plaque that commemorates Robert Dickey at Frisk Campus Center, right? There was a big um celebration of his work and both of them were in attendance, along with Wilkinson, who was in attendance. Um, so you know, it's it's this big tradition that sort of started at Princeton of like, let's take GR seriously.

• 1:42:14Lester Nare?

  Yeah, yeah.

• 1:42:15Krishna Choudhary?

  Okay, um, they move on to their different things. Kip Thorne goes to Caltech, Rayner Weiss goes to MIT, and they start thinking more earnestly about gravitational research in the experimental domain. Okay, and they're like, can we actually do this? Can we actually?

• 1:42:32Lester Nare?

  The thing that Einstein said.

• 1:42:34Krishna Choudhary?

  Like, say that Einstein couldn't do, can we actually do this? Okay. Rayner Weiss starts thinking about it. He's he's more on the experimentalist side, so he's from Dickey's group, right? So he's trying to actually think about the experiment, and he comes up with this idea of the interferometer.

• 1:42:50Lester Nare?

  Okay.

• 1:42:50Krishna Choudhary?

  Okay, which is really what LIGO's um design is today. The idea is you've got an, you've got an L-shaped instrument where I have light moving in this direction and light moving perpendicular. It's the same setup that Michelson-Morley used back in the late 1800s to show that light was moving in the same speed in both directions, regardless of an ether and all this other stuff. That same thing, what if we just made it big?

• 1:43:18Lester Nare?

  Mm hmm.

• 1:43:19Krishna Choudhary?

  Okay. What his main contribution, what Rayner Weiss's main contribution was with that paper in the 1970s and 80s was to figure out what are the types of noise that I'm gonna run into? When I make an instrument of this scale? And I wanna measure something this precisely. Okay. And he came up with a list of all of the noise sources that they're gonna have to deal with. There's gonna be seismic noise.

• 1:43:47Lester Nare?

  Right.

• 1:43:48Krishna Choudhary?

  Earthquakes. Even an earthquake that's on the other side of the world is gonna create low frequency vibrations on the earth.

• 1:43:54Lester Nare?

  At the level that we're trying to measure.

• 1:43:56Krishna Choudhary?

  And that's gonna create stuff. The waves from the ocean.

• 1:44:02Krishna Choudhary?

  That's gonna create noise. Cars and trucks, people walking by, that's gonna create noise.

• 1:44:08Lester Nare?

  Elephants in the Sahara.

• 1:44:09Krishna Choudhary?

  Yeah, like, like all the stuff that you could think of, he created a list of all the stuff that that we would have to. Come up with, and at the end, he had something called quantum noise.

• 1:44:19Lester Nare?

  Okay.

• 1:44:19Krishna Choudhary?

  Which is literally the Heisenberg uncertainty principle.

• 1:44:22Lester Nare?

  Yes.

• 1:44:22Krishna Choudhary?

  Okay.

• 1:44:23Lester Nare?

  Yes.

• 1:44:23Krishna Choudhary?

  It's like, there's noise that we're not gonna get rid of, ever.

• 1:44:27Lester Nare?

  Yes.

• 1:44:28Krishna Choudhary?

  Because that's just how it is.

• 1:44:29Lester Nare?

  Yes.

• 1:44:30Krishna Choudhary?

  And we'll, we'll get back to that later because the AI story actually ties into that. So. He made a list of all of these, all of these noise sources, and he came up with. Sort of the, the ways in which we can, we can make this happen. Kip Thorne, on the other hand, he, he starts doing theoretical calculations of what are the sources in astronomy that could create. These gravitational waves, right, that we would be able to see.

• 1:44:54Lester Nare?

  Right.

• 1:44:54Krishna Choudhary?

  How often would these go off?

• 1:44:56Lester Nare?

  Right.

• 1:44:57Krishna Choudhary?

  Given our assumptions about the universe.

• 1:44:59Lester Nare?

  Right.

• 1:44:59Krishna Choudhary?

  And theoretically, is it possible, like that Heisenberg uncertainty limit, what is that limit? Right? Are we hopeless? Or is the Heisenberg uncertainty limit just below?

• 1:45:12Lester Nare?

  Right.

• 1:45:13Krishna Choudhary?

  The sensitivity that we need. To actually find these things, okay? So you've got these two, the Rayner Weis is spearheading the. Approach from the experimental side and Kip Thorne is spearheading the approach from the theoretical side.

• 1:45:26Lester Nare?

  Yes.

• 1:45:27Krishna Choudhary?

  Okay. They think that, you know, maybe, maybe this could actually work. Okay?

• 1:45:33Lester Nare?

  They're like, just so crazy.

• 1:45:34Krishna Choudhary?

  They, they're like, maybe this could actually.

• 1:45:36Lester Nare?

  The audacity.

• 1:45:36Krishna Choudhary?

  Yeah, dude, and. In the seventies, they, they, they decide to pitch it. To the NSF. Okay?

• 1:45:47Lester Nare?

  National Science Foundation.

• 1:45:49Krishna Choudhary?

  That's the National Science Foundation. They pitch it to the NSF and the NSF is like. This is this.

• 1:45:55Lester Nare?

  We have this amount of money.

• 1:45:57Krishna Choudhary?

  Yeah, we have this amount of money and what you're saying is something that Einstein said wouldn't work. So they're like, all right, we're gonna give you a little bit of funding. Why don't you try to get down to these sources of error? We're gonna give you enough funding where you're not gonna find gravitational waves. But you can at least start making a prototype to figure out if you can mitigate these sources of error.

• 1:46:20Lester Nare?

  Yeah, right, right, right, right.

• 1:46:22Krishna Choudhary?

  Before we even get down to that ten to the minus twenty, let's get down to ten to the minus ten. All right, where it's like, can you even theoretically like and experimentally make such a? Instrument.

• 1:46:33Lester Nare?

  Yes.

• 1:46:34Krishna Choudhary?

  Okay, so they start going into it, um. Caltech gets um a telescope that's about like ninety meters, which is pretty big.

• 1:46:43Lester Nare?

  Yeah.

• 1:46:44Krishna Choudhary?

  Even then, you know, um. MIT also gets an instrument and and they start experimenting with with this kind of stuff. And it seems promising. It seems like they're actually working. So then Kip Thorne um recruits Ron Draver. Who's from Scotland, who had also worked on the early parts of this gravitational wave research. And um he gets them together and he's like, all right, we're gonna pitch this thing. This is gonna be big. It's gonna be a big deal. All right, boys, we ready? So they start doing it. Upper management has turmoil. Personal reasons, Ron Draver doesn't get along with um this guy Voight. Who's also part of the experimental collaboration. They.

• 1:47:26Krishna Choudhary?

  They just really don't get along.

• 1:47:27Lester Nare?

  Hate to see it.

• 1:47:28Krishna Choudhary?

  You hate to see it, but the two of them are like, I'm out, I'm out. So now Kip Thorne and Rayner Wise are just like, okay.

• 1:47:34Lester Nare?

  Okay, it's just us again.

• 1:47:35Krishna Choudhary?

  So it's just us again. Um NSF halts funding. Cause they're like, you you guys are like headless chickens. You have no idea what's going on. Um. We're gonna halt funding and we're gonna i- if you guys come up with a a strategy.

• 1:47:50Lester Nare?

  Right.

• 1:47:50Krishna Choudhary?

  That actually makes sense and that that isn't like petty, then maybe we can talk. So that's when Kip Thorne invites Barry Bearish. Who was at Caltech. Okay, Barry Bearish is um in nineteen ninety four, he's brought on as the new director.

• 1:48:08Lester Nare?

  Okay.

• 1:48:09Krishna Choudhary?

  Of the project. And Barry Barish is the reason why producers get the best picture award.

• 1:48:19Lester Nare?

  How do you mean?

• 1:48:20Krishna Choudhary?

  The Oscars, okay, the Oscars give the best picture award to not to the directors or the writers. It goes to the producer. It's the guy who's like putting it all together.

• 1:48:30Lester Nare?

  Yeah.

• 1:48:31Krishna Choudhary?

  Barry Barish is that guy.

• 1:48:33Lester Nare?

  This is so random.

• 1:48:35Krishna Choudhary?

  It's so random, but he he's he's really a he's an experimental physicist. Who does particle physics research. He was involved with the um super superconducting super collider. Which had failed in Texas. So he had already learned his lessons there. Okay? He knew how to deal with people. He knew. How to figure out what he wanted. He knew how to talk to people to get what he wanted. And he knew how to get people on board.

• 1:49:01Lester Nare?

  He was the politician of the group.

• 1:49:02Krishna Choudhary?

  He was the guy. Yeah, he was the guy who saw the big picture.

• 1:49:06Lester Nare?

  Yes.

• 1:49:06Krishna Choudhary?

  And he's the guy who, when he was when he was brought on. He transformed LIGO from a forty man operation to this thousands of people. That is what is required to make that detection.

• 1:49:17Lester Nare?

  He became the wartime CEO.

• 1:49:19Krishna Choudhary?

  You dude, and actually you say that, but somebody actually said to him, like when they were advertising like who Barry Barish is. At the time, you know, the the war in Iraq wasn't very popular.

• 1:49:29Lester Nare?

  Yes.

• 1:49:30Krishna Choudhary?

  And they said, you know, if Barry Barish was in charge of the war in Iraq, it would have been over by now. That's how they advertise it. He really was the wartime CEO.

• 1:49:39Lester Nare?

  Yeah.

• 1:49:40Krishna Choudhary?

  He was the guy who was like, okay, we're gonna build this. We're gonna build this thing.

• 1:49:43Lester Nare?

  Yes.

• 1:49:44Krishna Choudhary?

  We're gonna require two detectors.

• 1:49:46Lester Nare?

  Right.

• 1:49:46Krishna Choudhary?

  We're gonna have one in Hanford in Washington State.

• 1:49:49Lester Nare?

  Yes.

• 1:49:49Krishna Choudhary?

  This is actually the original site where we enriched plutonium for the Manhattan Project. Now it's being used for this. There's gonna be another another one in Livingston, Louisiana.

• 1:49:59Lester Nare?

  Yes.

• 1:50:00Krishna Choudhary?

  Okay, we're gonna build them two. Um, and he really started this collaboration and it started taking a life of its own.

• 1:50:07Lester Nare?

  Yes.

• 1:50:07Krishna Choudhary?

  And even Kip Thorne and Rayner Weis were like, thank God.

• 1:50:11Lester Nare?

  Got it.

• 1:50:11Krishna Choudhary?

  For Barry Barish, you know, because he just, he, he just full steam ahead.

• 1:50:17Lester Nare?

  Yep.

• 1:50:17Krishna Choudhary?

  Like, we're gonna build this thing. I'm not gonna have another failure.

• 1:50:21Lester Nare?

  Yes.

• 1:50:21Krishna Choudhary?

  Like the SSC on my hands.

• 1:50:22Lester Nare?

  Yes.

• 1:50:22Krishna Choudhary?

  You know, and he, he, all credit to him, you know, he created that collaboration.

• 1:50:28Lester Nare?

  Every, every project always needs the operations guy.

• 1:50:31Krishna Choudhary?

  Yeah.

• 1:50:32Lester Nare?

  It's funny, my, you know, my dad works in stage one drug discovery, you know, and.

• 1:50:36Krishna Choudhary?

  Yeah.

• 1:50:36Lester Nare?

  He was over in Scotland and there was a researcher at one of the Scotland universities that had a really interesting fundamental discovery. He went to go to VCs to say, hey, give me million dollars to make this a thing. And they were like, okay, great. And he wanted to be CEO and they were like, we need a Barry Barish. We don't need a you. And my dad came in as that operations person who like understands the fundamentals.

• 1:50:59Krishna Choudhary?

  Yes.

• 1:50:59Lester Nare?

  But understands the way in which the business world and all these things that are not about the science necessarily.

• 1:51:05Krishna Choudhary?

  Yeah.

• 1:51:06Lester Nare?

  Do matter a lot.

• 1:51:07Krishna Choudhary?

  Exactly.

• 1:51:08Lester Nare?

  Talking about these huge, large scale projects.

• 1:51:10Krishna Choudhary?

  Yeah, yeah. When you're talking about that, this is something that requires something beyond like knowing how the Einstein field equations work.

• 1:51:16Lester Nare?

  Right.

• 1:51:17Krishna Choudhary?

  Which ob- obviously Barry Barish does. He's a trained physicist.

• 1:51:20Lester Nare?

  Right.

• 1:51:20Krishna Choudhary?

  But his real expertise is in this ability to manage.

• 1:51:25Lester Nare?

  Yes.

• 1:51:26Krishna Choudhary?

  A thousand people towards one goal.

• 1:51:28Lester Nare?

  Which is, which is not trivial.

• 1:51:30Krishna Choudhary?

  It's not trivial, no. And this is the guy who did it, right?

• 1:51:34Lester Nare?

  So fascinating.

• 1:51:34Krishna Choudhary?

  And he, and he, you know, so he started construction.

• 1:51:37Lester Nare?

  Yes.

• 1:51:38Krishna Choudhary?

  He got the money from NSF.

• 1:51:39Lester Nare?

  Yes.

• 1:51:40Krishna Choudhary?

  Convinced NSF, this is gonna work, guys. He got the money from NSF. It took five years to build the buildings. In Livingston and Hanford in Washington in Louisiana where, you know, you've got these three kilometer long tunnels. Right? And the tunnels are so long, they have to be kept completely straight that they're accounting for the curvature of this, of the earth.

• 1:52:01Lester Nare?

  Right.

• 1:52:01Krishna Choudhary?

  Where they have to actually go under a little bit and, and then get over, right?

• 1:52:05Lester Nare?

  Yes.

• 1:52:05Krishna Choudhary?

  Um. In the entire tunnel, you've got to create a vacuum that's better than outer space. In the entire three kilometer tunnel. And it's like the stupid stuff was actually hard, like creating a tunnel that's better than anything we've ever had.

• 1:52:19Lester Nare?

  Yes.

• 1:52:19Krishna Choudhary?

  Right? All of the stuff was completely brand new.

• 1:52:22Lester Nare?

  Right.

• 1:52:22Krishna Choudhary?

  You had to create the best mirror of all time. To have these laser interferometers where the laser is going down both and then bouncing back. That mirror needs to be near perfect. And it is near perfect. It's near perfect glass. It's the best mirror that we've ever made. This mirror, if you left it ringing, right? Not that you would want to do this, but like if you like rang it and had it like vibrate. That thing would vibrate for a hundred million times. Before actually stopping. Because the, the, there's nowhere for the energy to go.

• 1:52:50Lester Nare?

  Go.

• 1:52:51Krishna Choudhary?

  In this vacuum.

• 1:52:52Lester Nare?

  Self-propagating.

• 1:52:52Krishna Choudhary?

  Yeah, so it just stays within itself and becomes this like perfect spring pendulum thing that just vibrates, right? So you've got to create all of these new technologies, right?

• 1:53:03Lester Nare?

  Just to create the environment.

• 1:53:04Krishna Choudhary?

  Just to create the environment. And finally, in like two thousand one, you had LIGO in its first iteration. Um. This is when the technology is there to find, if you're lucky. Gravitational waves. And this was just a proof of concept. To say that, okay, we've reached this far where we've reached the sensitivity level. Where if we get really lucky and there's like some massive merger that's like right next to us in the galactic neighborhood, we're gonna find it. They didn't find anything, but that's, that's science, right?

• 1:53:34Lester Nare?

  They, they solved a lot.

• 1:53:35Krishna Choudhary?

  The probability was very low.

• 1:53:36Lester Nare?

  They solved a lot of the engineering problems and this was the crawl, walk, run approach. And we're like in between the crawl, crawl and walk stage.

• 1:53:42Krishna Choudhary?

  Yeah, they were in the walk stage at this point.

• 1:53:44Lester Nare?

  Got it.

• 1:53:44Krishna Choudhary?

  Okay, and then they upgraded LIGO. To this LIGO two point O. To this higher sensitivity. And this is right around um the twenty teens.

• 1:53:55Lester Nare?

  Okay.

• 1:53:55Krishna Choudhary?

  Okay, they're upgrading.

• 1:53:58Krishna Choudhary?

  And this is now the run. Now we're getting to a point where it is likely. That we will catch gravitational waves.

• 1:54:06Lester Nare?

  If it were to pass the earth. You know. We are now able to detect at a sufficiently small level. That it will detect it if it is there.

• 1:54:16Krishna Choudhary?

  That's right, yeah. And so then comes the detection. Okay, this is September fourteenth, twenty fifteen. It's at four, yeah, it's at four fifty AM.

• 1:54:28Lester Nare?

  Mm hmm.

• 1:54:29Krishna Choudhary?

  Um Louisiana time, the LIGO computers at both Louisiana and Hanford detect something. Okay, they detect something and they've got an automated email system that sends it out to like a core group of people.

• 1:54:45Lester Nare?

  It's like that scene in movies when they detect aliens for the first time. Go off, everyone gets an email, everyone's like, wait, wait, wait, wait, is it?

• 1:54:52Krishna Choudhary?

  Is it? Yeah, but in this case, so this was still, they were still in the middle of their run phase, where they were still testing stuff. They were like ramping up. But so the the P A system in the actual control room had not been like configured yet.

• 1:55:06Lester Nare?

  So funny.

• 1:55:07Krishna Choudhary?

  So it just, the email went out, okay, and the people in the control room had no idea, okay, so. There, LIGO had just had this two hundred million dollar upgrade, right? It's it was called Advanced LIGO at the time. But they were still getting the bells and whistles of this upgrade together. And there was, there was a likelihood, but people weren't thinking it was gonna happen so soon, right? And so the alert goes out and it's only a handful of data analysts. They see this thing, there's a guy in Germany, there's a guy in University of Florida, there's obviously guys at Caltech and MIT. They look at this, they're like, huh, yeah, right.

• 1:55:46Lester Nare?

  Yeah, right, right, right, yeah.

• 1:55:48Krishna Choudhary?

  Yeah, right, because it's so beautiful. The the the signal is like, is like something, you know, like you do simulations and you're like, this is what it should look like. And then out comes an email saying, hey, this is what I found. It's like, okay.

• 1:56:02Lester Nare?

  It's exactly like.

• 1:56:03Krishna Choudhary?

  It's like exactly like what you're saying. So it's like, no, right? And all of the big scientists are like, no, this is too good to be true. The the guy at Caltech actually was was just like, I don't have time for this. He he looked at the email, he's like, and then he just went on about, because he's got other stuff to do, he's it's Advanced LIGO, he's got. And you know, his grad students and postdocs are like, did you see the? He's just like, dude, it's you young people. This is not how it works, okay?

• 1:56:29Lester Nare?

  The world is not idealistic.

• 1:56:31Krishna Choudhary?

  This is not how it works and it just wouldn't go away. Because usually, you know, they they used to have these things called, um.

• 1:56:41Krishna Choudhary?

  They would inject noise, blind injections to see if the system works.

• 1:56:45Lester Nare?

  Yes.

• 1:56:46Krishna Choudhary?

  So maybe there's a guy who's injecting the the fake data in there to see if the email alert works.

• 1:56:52Lester Nare?

  Right.

• 1:56:52Krishna Choudhary?

  So they call everybody who's in charge of that and he's like, no dude, I didn't do that. Um, they go back into the nitty gritty of the data.

• 1:56:59Lester Nare?

  Yeah.

• 1:56:59Krishna Choudhary?

  Of the raw data and they're like, it's it's in the raw data.

• 1:57:02Lester Nare?

  Yeah, yeah, yeah.

• 1:57:03Krishna Choudhary?

  And they're like, okay, so so now they just start getting real paranoid.

• 1:57:07Lester Nare?

  Yeah, yeah, yeah.

• 1:57:08Krishna Choudhary?

  They're like, who is doing this?

• 1:57:09Lester Nare?

  Yeah, right, right, right.

• 1:57:10Krishna Choudhary?

  Okay, who is the evil genius?

• 1:57:11Lester Nare?

  Right, right.

• 1:57:12Krishna Choudhary?

  That like went into the rod and it turns out there's only a handful of people that know the instrument.

• 1:57:16Lester Nare?

  Right.

• 1:57:17Krishna Choudhary?

  At such a level where they can, they've covered all their tracks.

• 1:57:21Lester Nare?

  Right, right, right, right, right.

• 1:57:22Krishna Choudhary?

  Right? And pretty soon they start thinking like, actually, it can't be a single person.

• 1:57:26Lester Nare?

  Yeah.

• 1:57:27Krishna Choudhary?

  Because it happened at both Washington and Louisiana. So it has to be. So it must be a bunch of people. So now it's like there's a giant conspiracy and everyone's looking at each other like, okay. What is what's going on? Then it turns out, it turns out, so this happened at four fifty AM, right? Um, that night on September fourteenth, there were two postdocs outside of the Livingston facility that were trying to test the system. With local noise and what they were doing was they they got in their car. And they were just driving down the arms.

• 1:57:59Lester Nare?

  Yeah, yeah, yeah.

• 1:57:59Krishna Choudhary?

  And just like accelerating and then braking and accelerating and then braking. They were trying to see if. This would inject noise into the into the Livingston facility.

• 1:58:08Lester Nare?

  Yes.

• 1:58:09Krishna Choudhary?

  But they had stopped at four o'clock because the guy had to catch a flight at six AM. He's like, I need to get to the airport.

• 1:58:15Lester Nare?

  Yes.

• 1:58:15Krishna Choudhary?

  Um, so, so uh uh they call up these postdocs and they're like, what were you doing? It's like four fifty, actually, no, I know for a fact that I was driving to the airport.

• 1:58:25Lester Nare?

  Yes.

• 1:58:25Krishna Choudhary?

  So it definitely wasn't me. I was nowhere near. And also like, why would it, why would that happen at the Washington? But at this point, everyone's like, like, real paranoid, right? So they're they're trying to be. Their own worst enemy, trying to see who faked the signal because this signal is just too good.

• 1:58:41Lester Nare?

  Yes.

• 1:58:41Krishna Choudhary?

  Right? Like, God isn't this kind.

• 1:58:43Lester Nare?

  Yes.

• 1:58:43Krishna Choudhary?

  Um.

• 1:58:45Krishna Choudhary?

  And at the end of the day, it's like, okay, is this a prank? All of the, all of the dudes that could have done this, get in a room. And there's like, all right.

• 1:58:53Lester Nare?

  Do you do it?

• 1:58:54Krishna Choudhary?

  Did you do it?

• 1:58:55Lester Nare?

  What about you?

• 1:58:55Krishna Choudhary?

  What about, did you do it? And everyone's like, no, we didn't do it. And it's like.

• 1:59:00Lester Nare?

  Silence descends.

• 1:59:02Krishna Choudhary?

  Dude, what? Okay, so then. You say, okay, so nobody did this. And it's kind of like that Sherlock Holmes quote, right? Where it's like, when you eliminate the impossible, what remains, however improbable is, is the truth, right? Is the reality. They're like, dude, this is crazy. So now they start having, um, they have, they have a blind.

• 1:59:28Krishna Choudhary?

  Data. Augmentation technique where they have a blind team that tries to decipher. How likely is this to be chance? That the detectors just like randomly, that maybe there was an earthquake that was right in the middle. That like arrived at the same time or something, you know? Um, or like the detectors themselves, like did this like fluctuation randomly? How likely is that? So they start going down this rabbit hole of like, okay, what if, how much of this is a fluke? Cause you gotta figure out a confidence, right? Remember the confidence is five sigma. So these guys are in charge of that. And they go through and there's this, there's this big unblinding party.

• 2:00:13Krishna Choudhary?

  Where they open the box. It's like a gender reveal. So what happened, yeah, what happens is they do all of their analysis without actually looking at the real data.

• 2:00:22Lester Nare?

  Got it.

• 2:00:22Krishna Choudhary?

  And then they open the box and that now they take the real data and say, okay, given our analysis, where does the real? Given our distribution, where is the real data?

• 2:00:30Lester Nare?

  Mm hmm.

• 2:00:31Krishna Choudhary?

  Okay, they don't even know. That the real data is, right, okay? They've been doing this blind. So they have this unblinding party where they open the box and everyone knows when this is gonna happen, um. And the, the, the party happens, you know, their Zoom meetings are only set up for like fifty people. But like everybody in the collaboration shows up. So, so it crashes.

• 2:00:56Lester Nare?

  Right, right.

• 2:00:57Krishna Choudhary?

  And so then they're scrambling, they're like, okay, we gotta get the Zoom meeting up. Finally get it up. They unblind and this is well above five sigma.

• 2:01:04Lester Nare?

  Oh my god.

• 2:01:05Krishna Choudhary?

  And everyone is like, that's when the champagne comes up.

• 2:01:08Lester Nare?

  Right, yeah, yeah, yeah.

• 2:01:09Krishna Choudhary?

  That's when they're like, wow, we got him.

• 2:01:10Lester Nare?

  We got, we got him.

• 2:01:11Krishna Choudhary?

  We got him. Like, we got a single gravitational wave that was like so ridiculous, right? Because had those, had those two postdocs been going on their thing.

• 2:01:24Lester Nare?

  Through five, four fifty.

• 2:01:25Krishna Choudhary?

  For like through four fifty, we wouldn't have, we wouldn't have caught this thing that happened. It's such a, it's, it's now become like part of like Lego lore.

• 2:01:33Lester Nare?

  Yeah, yeah, yeah.

• 2:01:33Krishna Choudhary?

  Of like, and those two postdocs are now like famous. Like, they decided to like call it early at like four o'clock in the morning, you know? It's so cool to think about that, like, yeah, like we, we were listening to, you know, gravitational radiation from billions of light years away from two black holes that merged. And to think about the incredible, like, sensitivity of this instrument. We really haven't gotten into just how incredible this is. I, I threw around a number like ten to the minus twenty.

• 2:02:05Lester Nare?

  Yes.

• 2:02:06Krishna Choudhary?

  Right? To give you a sense of how small that is, that's like measuring the distance from the earth to the sun. And then you add an extra atom.

• 2:02:19Lester Nare?

  Ah, yeah, yeah, yeah.

• 2:02:20Krishna Choudhary?

  To that distance.

• 2:02:20Lester Nare?

  To that distance, yeah, yeah, yeah.

• 2:02:22Krishna Choudhary?

  That's stupid.

• 2:02:23Lester Nare?

  Yeah, no, I don't, this is where.

• 2:02:24Krishna Choudhary?

  This is why Einstein was like, no.

• 2:02:26Lester Nare?

  No, because it's so outrageously arrogant for us to think.

• 2:02:33Krishna Choudhary?

  To think that we could measure that.

• 2:02:34Lester Nare?

  We can measure a disturbance at a degree that is so small.

• 2:02:42Lester Nare?

  And be able and make it verifiable.

• 2:02:45Krishna Choudhary?

  Yeah, yeah, ten to the minus nineteen meters is what we actually did. Which um ten to the minus fifteen is a proton. So this is ten thousandth the distance of a the the the diameter of a proton, the size of.

• 2:02:58Lester Nare?

  So we have these two, three kilometer tunnels on different sides of the country.

• 2:03:01Krishna Choudhary?

  And we're measuring a diff difference.

• 2:03:03Lester Nare?

  Of a tenth of a proton.

• 2:03:05Krishna Choudhary?

  A tenth, no, ten thousandth.

• 2:03:06Lester Nare?

  A ten thousandth.

• 2:03:08Krishna Choudhary?

  Of a proton, right? Like the the detectors themselves are made out of atoms that are made out of protons and the protons are like a ten thousandth the size of the atom and now you've got. So it it's an incredible achievement, right? And it took a thousand people.

• 2:03:24Lester Nare?

  Right.

• 2:03:24Krishna Choudhary?

  Experimentalists, theorists, um NSF bet big on this. The National Science Foundation really like bet the farm on this thing working and it worked, right?

• 2:03:36Lester Nare?

  Took decades and yeah, and we got them.

• 2:03:38Krishna Choudhary?

  And we got them and uh it's it's a new way to look at the universe, right? Before we were limited to electromagnetic radiation. We had pulled all the stops when it comes to electromagnetic radiation. We'd gone all the way from radio, which is long wavelength, all the way from radio to infrared, microwave, infrared, visible, the optical spectrum, ultraviolet, X-ray, gamma ray. We've got gamma ray telescopes that are looking at gamma ray bursts.

• 2:04:09Krishna Choudhary?

  We've we've done particle detectors, right? We've had neutrino detectors, cosmic ray detectors and now.

• 2:04:15Lester Nare?

  Many of which we've talked about previously on this podcast.

• 2:04:17Krishna Choudhary?

  Podcast and now we were listening to the universe, not just looking at it, right? We were listening to the spacetime ripples. And what what's crazy is like the the ripples that come in, especially for for this first discovery was in the human audible range. And so you could actually just hook up an amplifier and like hear it and hear these black holes coming in. It would it would be a chirp because the frequency would increase with time. So it'd go yip like that, like yip. Because the black holes are coming together and as they get together conservation of angular momentum. They're gonna speed up.

• 2:04:53Lester Nare?

  Yep.

• 2:04:53Krishna Choudhary?

  And as they speed up, they're gonna release higher frequency gravitational waves. And so the. The the signal that we were seeing and that that's why these guys were like, there's no way this is real.

• 2:05:03Lester Nare?

  Right.

• 2:05:04Krishna Choudhary?

  Cause the, you know, if you look at the spectrogram, the frequency versus time, you see this characteristic thing.

• 2:05:11Lester Nare?

  Yeah.

• 2:05:11Krishna Choudhary?

  It's like exactly like in the simulations, you're just going.

• 2:05:14Lester Nare?

  There's no.

• 2:05:15Krishna Choudhary?

  There's no way this is real. Right? And so it took it took them five months from detection.

• 2:05:22Lester Nare?

  Yeah.

• 2:05:23Krishna Choudhary?

  To like being confident enough where they were like, all right, let's announce it.

• 2:05:26Lester Nare?

  Because as we've talked about, you you you don't wanna put something out. That you know, is not prepared for, cause everyone's gonna come at you with knives out.

• 2:05:34Krishna Choudhary?

  Yes, yeah, and especially because in the past, like with Weber and his gravitational wave detector, right? Those were fake. But like this, at this point, it's like they had done all of the, they had done all of the work and the international corral collaboration had done all the work. They really weren't very confident until they saw the second one.

• 2:05:50Lester Nare?

  Oh, okay.

• 2:05:51Krishna Choudhary?

  They saw a second one and they're like, oh, okay, this is real. We're like literally listening to the universe.

• 2:05:55Lester Nare?

  Yeah, yeah.

• 2:05:56Krishna Choudhary?

  Then um, the Italian crab collaboration Virgo.

• 2:05:59Lester Nare?

  Yes.

• 2:05:59Krishna Choudhary?

  Came online. Virgo is a detector very similar to LIGO. Um, it came online and the three of them, so the two Ligos and Virgo detected a neutron star merger.

• 2:06:10Lester Nare?

  Mm hmm.

• 2:06:10Krishna Choudhary?

  And that was a big deal because now that you've got three.

• 2:06:13Lester Nare?

  Yes.

• 2:06:13Krishna Choudhary?

  You can actually do triangulation.

• 2:06:15Lester Nare?

  Right.

• 2:06:15Krishna Choudhary?

  Okay, with only two detectors, the only signal you really have is the. Time difference between the arrival here and the arrival here. Now gravitational waves propagate at the speed of light. So for example, if they both arrived at the same time, then you know that it's on this plane.

• 2:06:33Lester Nare?

  Yes.

• 2:06:33Krishna Choudhary?

  Right? And it came from this angle.

• 2:06:35Lester Nare?

  Yes.

• 2:06:36Krishna Choudhary?

  But if it arrived here before and then here later, then it came from this angle.

• 2:06:40Lester Nare?

  Yes.

• 2:06:41Krishna Choudhary?

  Right? And you get this sort of arc.

• 2:06:43Lester Nare?

  Yes.

• 2:06:43Krishna Choudhary?

  In the sky of where it could have come from.

• 2:06:46Lester Nare?

  Right.

• 2:06:46Krishna Choudhary?

  But that's a giant arc.

• 2:06:48Lester Nare?

  Right.

• 2:06:48Krishna Choudhary?

  Okay, if you've got three, then you've got. Three arcs, you've got an arc here, an arc here, and an arc here. Wherever those three arcs intersect has gotta be the spot.

• 2:06:59Lester Nare?

  Yes.

• 2:06:59Krishna Choudhary?

  That it came from. So then, once we had the signal from all three, we could point our telescopes to it and actually see.

• 2:07:06Lester Nare?

  What is generating.

• 2:07:07Krishna Choudhary?

  What is generating it. And that was crazy because what would what would end up happening is the gravitational wave comes in first. Because there's nothing that's impeding gravitational waves. It's just going. Neutrinos actually came in. Right after because neutrinos also they're very they don't interact with anything. So they're just coming through.

• 2:07:25Lester Nare?

  Yes.

• 2:07:25Krishna Choudhary?

  Light was actually later because light it was interacting with all the stuff. And then there was a tiny delay.

• 2:07:32Lester Nare?

  Yes.

• 2:07:33Krishna Choudhary?

  And so we had just enough time to point our telescopes to this thing and see the neutron stars colliding. And that's where we got our first sense of where these heavy elements, the precious metals like platinum, gold. These guys, they actually come from these neutron star mergers. More than like supernovae and things like that. It's from these neutron star mergers where we get. The gold that's in my wedding ring and things like that, right?

• 2:07:58Lester Nare?

  You know what's so this.

• 2:08:00Krishna Choudhary?

  And so it it opened up a it's just so cool.

• 2:08:02Lester Nare?

  A great uh story to look back and listen to is our our story covering Ice Cube, the neutrino detector in in Antarctica. Because it kind of explains this neutrino travel time and light travel time and why there's a difference between those two. Which the implications of which dovetail with this gravitational wave detection first.

• 2:08:24Lester Nare?

  Light then shortly after. Why is that happening? Go back and listen to our Ice Cube story because we kind of touch on the mechanics.

• 2:08:31Krishna Choudhary?

  Exactly.

• 2:08:31Lester Nare?

  Light traveling and neutrinos traveling.

• 2:08:33Krishna Choudhary?

  Yeah.

• 2:08:33Lester Nare?

  I just it's funny because all these things, again, these are just. They're all connected.

• 2:08:38Krishna Choudhary?

  Yeah, they're all connected. And now we've got a fourth one, Kagura in Japan.

• 2:08:42Lester Nare?

  Yes.

• 2:08:42Krishna Choudhary?

  We um we did a story on how all four found the largest black hole merger.

• 2:08:47Lester Nare?

  Yes.

• 2:08:47Krishna Choudhary?

  Um, that was another story on the podcast. So now we've got four, so we can triangulate even better.

• 2:08:53Lester Nare?

  Yes.

• 2:08:53Krishna Choudhary?

  Um, I think India and Australia are in plans to make their own gravitational wave detectors. So now we're gonna we're gonna have this entire collaboration, right? And now. The trick is, so we've discovered gravitational waves. We can now listen in on gravitational waves. We're getting signals at about the rate of like tops like five a year.

• 2:09:14Lester Nare?

  Yes.

• 2:09:15Krishna Choudhary?

  In the in the volume of the universe that we can listen to.

• 2:09:18Lester Nare?

  Yes.

• 2:09:18Krishna Choudhary?

  Right before it gets like so small that we can't listen to it.

• 2:09:21Lester Nare?

  Yes.

• 2:09:21Krishna Choudhary?

  Um.

• 2:09:22Lester Nare?

  So they're they're proximally at some proximally close location.

• 2:09:26Krishna Choudhary?

  Yeah, yeah, yeah. They're like close enough where the gravitational wave hasn't dissipated so so much that we're not sensitive. Now, if we make it more sensitive, then we can expand that volume, right? We can actually expand the radius and the volume goes up by R cube.

• 2:09:42Lester Nare?

  Yes.

• 2:09:43Krishna Choudhary?

  So just even ten to fifteen percent difference in the radius amounts to twice the volume.

• 2:09:49Lester Nare?

  Mm hmm.

• 2:09:50Krishna Choudhary?

  Right? Because you're gonna cube that.

• 2:09:51Lester Nare?

  Yes.

• 2:09:52Krishna Choudhary?

  So now the challenge is, how do we make LIGO better? Where we're not only seeing a larger volume, but the stuff that we're seeing. We're starting to notice all of the overtones and all of the stuff that makes a musical note great, right? If you've if you've heard like, you know, the uh the the note that comes out of your phone when you're trying to tune your guitar. That's a pure note. It's a C or an A, not very interesting, right? But a piano, why is a piano note interesting? It's because there's all of these overtones and nice characteristics from the piano itself that give it that beauty.

• 2:10:34Lester Nare?

  Would would would a way to phrase like the texture that the physical piano adds to the tone itself.

• 2:10:41Krishna Choudhary?

  Exactly.

• 2:10:42Lester Nare?

  Which is a manifestation of its physical construct, like how it physically exists and on all of that.

• 2:10:48Krishna Choudhary?

  Yes, yeah, exactly. Like a a guitar string playing the C is different from a piano string playing the C is different from a violin resonating at C. And it's all because of that texture of the note. And the texture is actually in the form of all of these higher characteristics of that musical note.

• 2:11:05Lester Nare?

  Mm hmm.

• 2:11:06Krishna Choudhary?

  The overarching note, if you were to do a, you know, a physics. Breakdown of it, the overarching note is still gonna be that base C.

• 2:11:15Lester Nare?

  Yes.

• 2:11:15Krishna Choudhary?

  But all that stuff on top is what gives it the beauty. So the question is, how do we make LIGO see that beauty?

• 2:11:22Lester Nare?

  That that pure.

• 2:11:23Krishna Choudhary?

  In the gravitational wave.

• 2:11:25Lester Nare?

  Without any of that.

• 2:11:26Krishna Choudhary?

  Instead of seeing just the C.

• 2:11:28Lester Nare?

  Oh, oh, seeing it in its, I got it.

• 2:11:30Krishna Choudhary?

  You know what I'm saying?

• 2:11:30Lester Nare?

  I understand what you're saying.

• 2:11:31Krishna Choudhary?

  Instead of seeing just the note, which is what it's good for right now, we're seeing I did a rip. But now there could be stuff on top.

• 2:11:38Lester Nare?

  Yes.

• 2:11:39Krishna Choudhary?

  That would give us characteristics about the environment that the

• 2:11:43Lester Nare?

  Yes.

• 2:11:43Krishna Choudhary?

  black holes were in, where the neutron stars were in, right?

• 2:11:46Lester Nare?

  Yes.

• 2:11:46Krishna Choudhary?

  How long they've been going at it?

• 2:11:48Lester Nare?

  Mm hmm.

• 2:11:48Krishna Choudhary?

  All of this other stuff, all all of the other characteristics.

• 2:11:51Lester Nare?

  Mm hmm.

• 2:11:51Krishna Choudhary?

  And that's where the recent paper that's out of Caltech and DeepMind comes in.

• 2:11:57Lester Nare?

  Got it.

• 2:11:57Krishna Choudhary?

  Okay, what they're trying to do is push the sensitivity of LIGO to levels that were unimaginable before. I mean, LIGO itself is unimaginable.

• 2:12:08Lester Nare?

  Imaginable.

• 2:12:09Krishna Choudhary?

  Right? Um, but now they're they're taking it a step further with the use of AI.

• 2:12:13Lester Nare?

  Okay.

• 2:12:13Krishna Choudhary?

  Okay?

• 2:12:14Lester Nare?

  Okay.

• 2:12:14Krishna Choudhary?

  So why, why do we need, why do we need AI, right? Um, LIGO has this problem that's called a wall of noise. Okay, there's a wall of noise right at ten to thirty hertz. Okay, above thirty hertz, they're pretty good. Okay? But below thirty hertz at these low frequencies, they're having a real issue.

• 2:12:37Lester Nare?

  There's too much noise?

• 2:12:38Krishna Choudhary?

  There's too much noise, okay? The noise is coming from seismic effects, like whenever you have a giant earthquake, the earth rings in these low frequencies and it rings for a while. Okay, on the other, also, um, the moon tugging on the oceans creates these tides. And the wave action itself

• 2:13:01Lester Nare?

  Mm hmm.

• 2:13:01Krishna Choudhary?

  is ringing around the earth, creating, so we're pushing that level.

• 2:13:05Lester Nare?

  Got it.

• 2:13:06Krishna Choudhary?

  And we're trying to get rid of that. Now,

• 2:13:10Krishna Choudhary?

  what they've tried so far is something called feedback control. Um, and you've actually used feedback control in your own life. You have AirPods, right? The new AirPods, they've got noise cancelling. You've probably used noise cancelling headphones. The way noise cancelling headphones work is they've got a feedback loop. That senses low frequency noise and then that sensor then. Counteracts that noise and destructively interferes with it to cancel it out.

• 2:13:42Lester Nare?

  Okay, is this creating, it's creating an interference pattern, so it cancels it out?

• 2:13:46Krishna Choudhary?

  Yes, exactly. It's creating an interference pattern so that it cancels it out. This works really well on the airplane because the airplane is a low frequency hum, right?

• 2:13:54Lester Nare?

  Yep.

• 2:13:55Krishna Choudhary?

  That that's the ambient noise.

• 2:13:56Lester Nare?

  That makes, I was like, that makes sense, because I just was on a flight and I'm like, these, I was like, these.

• 2:14:00Krishna Choudhary?

  These are really good. Yeah, the reason why is because the airplane is low frequency and you can do that with low frequency. Because with low frequency, you have enough time to respond with your control system.

• 2:14:10Lester Nare?

  Right.

• 2:14:10Krishna Choudhary?

  Right? The time scale of that vibration is slow enough where you can actually like counteract.

• 2:14:15Lester Nare?

  Yep.

• 2:14:15Krishna Choudhary?

  But now comes a trade off, right? There's a trade off because aggressive control at these low frequencies means you're going to introduce. Noise from the control system itself.

• 2:14:27Lester Nare?

  Yes.

• 2:14:28Krishna Choudhary?

  At higher frequencies.

• 2:14:29Lester Nare?

  That makes sense.

• 2:14:30Krishna Choudhary?

  Right? Now for noise cancelling headphones, it's fine. You might, you might sometimes if you're really careful, you'll hear a really high pitched tone. In your noise cancelling, if you're like really trying to.

• 2:14:41Lester Nare?

  Yeah, here.

• 2:14:42Krishna Choudhary?

  Find it, right?

• 2:14:42Lester Nare?

  Right.

• 2:14:43Krishna Choudhary?

  Um, but what you're really worried about is the loud low frequency.

• 2:14:47Lester Nare?

  Right.

• 2:14:47Krishna Choudhary?

  And so you're getting rid of that, you're happy on an airplane.

• 2:14:49Lester Nare?

  The level of precision we need at headphones is a very different scale than what we're trying to do when we talk about detection at this level.

• 2:14:56Krishna Choudhary?

  At this level, at a LIGO's level.

• 2:14:58Lester Nare?

  Right, right. That, that, that.

• 2:14:59Krishna Choudhary?

  Now, it's, that's even that is annoying.

• 2:15:01Lester Nare?

  Yeah.

• 2:15:02Krishna Choudhary?

  Right?

• 2:15:02Lester Nare?

  Yeah, yeah.

• 2:15:03Krishna Choudhary?

  It was not annoying because that's what allowed us. The feedback control on the mirrors themselves, you've got these actuators on the mirrors, because the mirrors themselves have noise, right?

• 2:15:12Lester Nare?

  Yes.

• 2:15:12Krishna Choudhary?

  They can be tilted in a certain way, they can be like up and down if the, if there's like some seismic effect, then the, the mirrors can wobble. And then the wobble is going to be greater than the, you know, uh, ten to the minus nineteen meters that you're trying to do. It's incredibly ridiculous, right? How still you're trying to make these mirrors.

• 2:15:31Lester Nare?

  Yes.

• 2:15:31Krishna Choudhary?

  Okay, so in order to actually get that.

• 2:15:36Krishna Choudhary?

  We use these feedback control mechanisms, right? But the feedback control mechanisms inject high frequency noise. The target would be to get rid of that high frequency noise and be limited by only quantum noise.

• 2:15:49Lester Nare?

  Mm hmm.

• 2:15:50Krishna Choudhary?

  By the Heisenberg uncertainty principle.

• 2:15:51Lester Nare?

  From that list that we talked about earlier.

• 2:15:53Krishna Choudhary?

  Mm hmm.

• 2:15:54Lester Nare?

  Yes.

• 2:15:54Krishna Choudhary?

  We want to be limited by the universe itself, right? And the laws of quantum mechanics.

• 2:15:58Lester Nare?

  Yes.

• 2:15:59Krishna Choudhary?

  The quantum mechanics noise comes in two forms. There's shot noise, which is, you know, the laser itself. I mean, at this rate, we're talking about photons hitting the mirror. And the photons are going to hit the mirror at random arrival times.

• 2:16:14Lester Nare?

  Yeah.

• 2:16:14Krishna Choudhary?

  So that's called shot noise.

• 2:16:15Lester Nare?

  Because, because the difference of arrival time is.

• 2:16:18Krishna Choudhary?

  The difference in arrival time in the photon is enough to cause the shot noise.

• 2:16:22Lester Nare?

  Oh, my God.

• 2:16:23Krishna Choudhary?

  Okay, that's the level that we're working at with these mirrors.

• 2:16:26Lester Nare?

  Yeah.

• 2:16:26Krishna Choudhary?

  These mirrors are like kilograms big and they're worried about like tiny photons hitting it at random times. It's like, that's what we're complaining about. The other um limit is quantum back action, which is not only is the photon coming at random times, but when it hits and goes back, it's going to transfer momentum.

• 2:16:45Lester Nare?

  Yeah, to the mirror.

• 2:16:45Krishna Choudhary?

  And the mirror is going to wobble because the photon has a reaction force.

• 2:16:50Lester Nare?

  Right, and because there's multiple points, the reaction force is happening everywhere.

• 2:16:54Krishna Choudhary?

  Yeah, and it's like, it's like, it's like, so, so that we can't control because the universe is like, you're, you're doing too much.

• 2:16:59Lester Nare?

  Yeah, yeah, you know, this, this is a admin privileges only.

• 2:17:03Krishna Choudhary?

  Yeah, yeah, exactly. All right, the fact that you're getting this far already, I'm like, wow. Uh, but yeah, let's, let's slow down. But that's, that's where we're trying to get to, okay?

• 2:17:14Lester Nare?

  To having that being the only remaining noise in the data set.

• 2:17:17Krishna Choudhary?

  It's like Zen, it's like, okay. And, and so that's where um this scientific AI comes in.

• 2:17:22Lester Nare?

  Okay.

• 2:17:23Krishna Choudhary?

  Okay, what we're, what, what these guys are trying to do at DeepMind and at Caltech is they're trying to quiet LIGO's control systems using a radically new AI approach.

• 2:17:34Lester Nare?

  Okay.

• 2:17:34Krishna Choudhary?

  Okay, and this isn't the first time that AI has been sort of used to um, you know, help scientific collaboration. But most of the time, AI has sort of played the role of a data analyst.

• 2:17:45Lester Nare?

  Right.

• 2:17:45Krishna Choudhary?

  Right after the data has been collected like um we've talked about the Vera Rubin telescope, right? Once the Vera Rubin takes all of these pictures, AI can go through and sift through and find asteroids that move around. Or new transient effects from supernovas and things like that. AI can also be used in cosmology for running simulations faster for the universe's evolution and things like that. But this idea of using AI actively in the data acquisition.

• 2:18:11Lester Nare?

  Right, right.

• 2:18:11Krishna Choudhary?

  And in the experiment itself is kind of new. It's it's not without precedent. Um CERN uses it at the Large Hadron Collider. Um they actually use AI algorithms and machine learning systems to actually um trigger whether to keep a certain particle scatter data or whether to discard it. So there there's a machine learning algorithm that basically makes this split second decision on whether a particle collision and the shower that came afterwards is interesting.

• 2:18:41Lester Nare?

  Yeah.

• 2:18:41Krishna Choudhary?

  Or whether it's something that you don't want to save because the the amount of the particle collisions that are happening are astronomical. I mean, even though CERN's data storage capabilities are insane, it's not going to be able to save everything, right? So you need some way to sift through that and machine learning is doing that. It's also accelerating simulations on these particle systems. But this approach from LIGO is another thing in that vein of using AI actively in the experiment itself.

• 2:19:09Lester Nare?

  Yep.

• 2:19:10Krishna Choudhary?

  So what they figured was, okay, we're trying to keep the mirror as still as possible.

• 2:19:13Lester Nare?

  Yes.

• 2:19:14Krishna Choudhary?

  Okay. Why don't we use a reinforcement learning agent to train and devise its own strategy on how to keep the mirror stationary.

• 2:19:24Lester Nare?

  And it's great that we just did an episode on reinforcement learning because it goes very deep into the structure of why this was in our DeepSeek uh coverage.

• 2:19:33Krishna Choudhary?

  Yeah.

• 2:19:33Lester Nare?

  They just did these two papers on how they went from uh human feedback.

• 2:19:38Krishna Choudhary?

  Yeah, to just pure reinforcement learning.

• 2:19:40Lester Nare?

  And so the point about pure reinforcement learning here is that you as a human who is designing the AI system are not giving it feedback about whether the answer that it's going down is correct.

• 2:19:51Krishna Choudhary?

  Yeah.

• 2:19:52Lester Nare?

  Incorrect, which enables, I think the point here is like now. Ideas about how to solve the problem. That's not limited by our perspective.

• 2:20:00Krishna Choudhary?

  Exactly.

• 2:20:00Lester Nare?

  Or our perception.

• 2:20:01Krishna Choudhary?

  Yeah, exactly. In this case, the reinforcement learning agent is gonna just try all these different strategies.

• 2:20:07Lester Nare?

  Right.

• 2:20:07Krishna Choudhary?

  See what worked.

• 2:20:08Lester Nare?

  Right.

• 2:20:09Krishna Choudhary?

  And then go down that path and make that strategy better.

• 2:20:11Lester Nare?

  Yes.

• 2:20:12Krishna Choudhary?

  And that's exactly what they did. They created a reinforcement learning agent. They gave it an environment, which is this um highly accurate computer simulation of LIGO.

• 2:20:20Lester Nare?

  Yes.

• 2:20:21Krishna Choudhary?

  I mean, they can't give it LIGO.

• 2:20:22Lester Nare?

  Right.

• 2:20:22Krishna Choudhary?

  Right? LIGO is busy trying to listen.

• 2:20:24Lester Nare?

  Yes.

• 2:20:24Krishna Choudhary?

  Right? So so they made a computer simulation of LIGO, and that's the environment that this agent is now playing around with.

• 2:20:31Lester Nare?

  Yes.

• 2:20:31Krishna Choudhary?

  Um, the current mirror was the state, like whatever the mirror was, and then the action it could take was, you know, moving it with all the actuators.

• 2:20:39Lester Nare?

  Yes.

• 2:20:40Krishna Choudhary?

  And it could play around and figure out how to keep this mirror as still as pro possible.

• 2:20:44Lester Nare?

  Yes.

• 2:20:44Krishna Choudhary?

  And you can inject noise into it and see how it would do.

• 2:20:46Lester Nare?

  And you can do it hundreds and thousands, millions of times and different parameters.

• 2:20:51Krishna Choudhary?

  Different parameters and and you can see and you can give it a reward every time it does a good job and and you can penalize it every time it does a bad job. Um, in this case, the the process of actually rewarding it was actually kind of cool, because you can't just be like, keep it still.

• 2:21:06Lester Nare?

  Yeah.

• 2:21:07Krishna Choudhary?

  That's that's a little too much freedom. So what they did was they they they created three distinct bands in the frequency space. They call this approach the DLS approach, which is deep loop shaping.

• 2:21:20Lester Nare?

  Mm hmm.

• 2:21:21Krishna Choudhary?

  Loop shaping, meaning this kind of control paradigm where you're um worrying about the frequency response of your system and deep from deep learning.

• 2:21:28Lester Nare?

  Yes.

• 2:21:29Krishna Choudhary?

  Okay, so deep loop shaping. What they did was they got that frequency band of all of the noise and they split it up into three different categories. So there's a low pass filter for stuff that's below three hertz, three hertz, meaning three cycles per second. And um that's where all of the seismic disturbances, your sort of.

• 2:21:51Krishna Choudhary?

  Um, the, the, the tides and all of this stuff.

• 2:21:55Lester Nare?

  This is like, this is like, for people who play like, who work in music, this is like all the bass.

• 2:22:00Krishna Choudhary?

  All the bass, yes. So we're trying. The bass.

• 2:22:02Lester Nare?

  Right, okay.

• 2:22:03Krishna Choudhary?

  Yeah, and um, with that bass stuff, it basically said, you're gonna, you're gonna get aggressive stabilization. We want to teach you aggressive stabilization. You get a high reward if you eliminate the bass noise. Okay, great. Then there's the bandpass filter of eight to thirty hertz. That's the part that we're trying to really optimize. Okay, that's where the control noise comes in from these guys. And so what they gave was a penalty, a negative reward. If it got any noise.

• 2:22:36Lester Nare?

  In that eight to.

• 2:22:37Krishna Choudhary?

  In that eight to thirty hertz, okay? The low, low part was just reward positive. This has a negative reward. Okay, it's like penalizing heavily and the, the high pass filter also penalizing, okay? But different weights.

• 2:22:51Lester Nare?

  Yes.

• 2:22:51Krishna Choudhary?

  And then the, the crucial thing what they did was they multiplied the rewards at the end. To give a final reward instead of adding. A lot of reinforcement learning techniques have added with additive reward. Nowadays, people are, are slowly foraying into this idea of multiplicative. The, the, the problem with multiplication of reward is it can easily blow up.

• 2:23:13Lester Nare?

  Right.

• 2:23:14Krishna Choudhary?

  And like be very dangerous, but there's, there's now, there's come mitigation strategies against that. And so now with multiplicative reward, you force the rate, you force the agent to perform well on all three tasks.

• 2:23:27Lester Nare?

  Right, because you could have one in the summation model, you can have one that's super, super high, that kind of drowns out.

• 2:23:34Krishna Choudhary?

  Yeah, and it's just like zero noise in the base, but then you're just like completely wrecked in the other one.

• 2:23:39Lester Nare?

  That's actually interesting. It through the math, it sort of forces equal distribution of optimization.

• 2:23:45Krishna Choudhary?

  Exactly, yeah, yeah, that's exactly right.

• 2:23:47Lester Nare?

  Interesting.

• 2:23:47Krishna Choudhary?

  And so they, they, they tested it on this digital twin that they had made of LIGO and it worked really well. And they're like, okay, this is pretty cool. They, they injected noise and it was still able to, it was still able to do it. And then for one hour. They were given time.

• 2:24:04Lester Nare?

  You know, Ligo's real busy. You gotta check the schedule. I think we can get you one hour.

• 2:24:09Krishna Choudhary?

  Yeah, you they got so they got one hour on Ligo. And they installed this this device on Ligo and it was a great success. The AI controller stably managed these mirrors for an hour and the amount of noise on the actual thing.

• 2:24:27Lester Nare?

  The physical.

• 2:24:28Krishna Choudhary?

  The physical Livingston Observatory, they they they got the controls for the actuators.

• 2:24:32Lester Nare?

  Yes.

• 2:24:33Krishna Choudhary?

  They attached it to this agent. They're like.

• 2:24:35Lester Nare?

  That was the driver of the bus.

• 2:24:37Krishna Choudhary?

  And now now you you you take the wheel. Let's see what you do. And for over an hour in real world conditions.

• 2:24:43Lester Nare?

  Yes.

• 2:24:43Krishna Choudhary?

  And the noise was like shot.

• 2:24:46Lester Nare?

  Like it.

• 2:24:47Krishna Choudhary?

  It like.

• 2:24:47Lester Nare?

  Insane.

• 2:24:49Krishna Choudhary?

  Like an insane amount.

• 2:24:52Krishna Choudhary?

  Right? And it's like, oh.

• 2:24:54Lester Nare?

  Yeah, like.

• 2:24:55Krishna Choudhary?

  This is the future.

• 2:24:55Lester Nare?

  This is the future.

• 2:24:56Krishna Choudhary?

  Yeah.

• 2:24:57Lester Nare?

  There's so many. I I could talk about this.

• 2:24:59Krishna Choudhary?

  They were they were they were getting down to quantum level, dude. They got down to that quantum limit. They were saying the noise level was well below the design goal, being ten times quieter than the quantum back.

• 2:25:12Lester Nare?

  Holy.

• 2:25:13Krishna Choudhary?

  And so now, now that they did it on Livingston, now they're gonna make it even better. Put it on both Ligos. They're gonna give it to Virgo, put it on theirs, give it to Kagura, put it on theirs. And then now we're gonna have four gravitational observatories. That are limited by quantum noise.

• 2:25:31Lester Nare?

  It's so, it's so, it's so incredible. Like, I think. The the efficacy and impact. I mean, there's so many levels to this. One is our ability to create a digital twin to such levels of fidelity.

• 2:25:44Krishna Choudhary?

  Yeah.

• 2:25:45Lester Nare?

  That it translates from the simulated environment to the real world environment.

• 2:25:48Krishna Choudhary?

  So well.

• 2:25:49Lester Nare?

  So well, like that in and of itself.

• 2:25:51Krishna Choudhary?

  Yeah, that itself is great.

• 2:25:53Lester Nare?

  The the com- thinking about the reward model and using reinforcement learning and finding a way to get that reinforcement learning really tight, um, such that the optimization that it ended up with again gets to that degree. And it's basically, we're just gonna do a software patch, not, I know that's not literally the translation, but like like it's the existing hardware. Hardware does not change.

• 2:26:16Krishna Choudhary?

  Yeah.

• 2:26:17Lester Nare?

  At all.

• 2:26:17Krishna Choudhary?

  At all.

• 2:26:18Lester Nare?

  And every one of these four detectors globally is just gonna get this ten X noise reduction optimization benefit. Just.

• 2:26:26Lester Nare?

  A relatively snap of a finger, given the time it's gonna took to build Lego.

• 2:26:30Krishna Choudhary?

  To be fair, the noise reduction is more than 10x.

• 2:26:33Lester Nare?

  It's okay. Wow.

• 2:26:34Krishna Choudhary?

  Right? It's like from before to now, the noise reduction is like 10 to the 3. It's just that now we're below the quantum noise by 10x.

• 2:26:42Lester Nare?

  Got it.

• 2:26:42Krishna Choudhary?

  So now the limiting is the quantum noise. And that, we just, I don't know what to do with that, right?

• 2:26:49Lester Nare?

  This is so insane.

• 2:26:50Krishna Choudhary?

  It's insane. And, and you know, this has actionable consequences on what Lego can see. For one, it's more sensitive, so it's got a larger volume of the universe. But the other, it's now sensitive to a new frequency band. This 10 to 30 hertz, right? Which was not accessible to us before. And this is exactly where you have intermediate black holes. Intermediate mass black holes. And this is, this is gonna help us solve a huge...

• 2:27:15Lester Nare?

  Below supermassive? So it's like, yes, smaller in size?

• 2:27:18Krishna Choudhary?

  Exactly. Smaller in size from supermassive, but larger in size from stellar mass.

• 2:27:22Lester Nare?

  Ah, got it.

• 2:27:23Krishna Choudhary?

  There's been this contention in the black hole physics community about where the hell are the rest of the black holes? We see a bunch of stellar mass black holes, right, with Lego and things like that. We obviously see supermassive black holes at the center of galaxies. But the black hole mass gap is what it's called. This gap between supermassive and stellar mass, this intermediate mass black holes, where are they? Well, now Lego is gonna be sensitive to those intermediate mass black hole mergers. Because those would happen slower than the stellar mass. The stellar mass, they can get closer together. And if you get closer together, you speed up, right? Neutron stars as well. The closer you get, the more you speed up.

• 2:28:07Krishna Choudhary?

  So with the neutron stars, you can actually start observing them earlier in their decay cycle, right? Where before, you had to sort of wait till they got really close to create these big, fast gravitational waves. Now you can spy on them from the very beginning and see them speed up and get closer and closer together.

• 2:28:27Lester Nare?

  The idea, and just to make sure I'm kind of understanding, the idea is part of the spinning and the closeness is what dictates the size of the gravitational wave that's being sent. And this is where we talked about, they have to be really, really big when we started for us to see them because we couldn't detect at this range. By having this range now accessible to us, we can detect fainter...

• 2:28:50Lester Nare?

  gravitational waves which one of the sources being these intermediate black hole

• 2:28:54Krishna Choudhary?

  yeah and the other one being the neutron star mergers early

• 2:28:57Lester Nare?

  earlier in its

• 2:28:58Krishna Choudhary?

  yeah so now like you can imagine you can have a you can have a early warning system

• 2:29:02Lester Nare?

  right

• 2:29:03Krishna Choudhary?

  that something's gonna happen and then minutes in advance not like fraction of a second

• 2:29:07Lester Nare?

  right

• 2:29:07Krishna Choudhary?

  because the the the gravitational wave itself lasts the ones that we've seen last like fractions of a second

• 2:29:13Lester Nare?

  right

• 2:29:14Krishna Choudhary?

  because that's when they get close enough to actually get big enough the the waves get big enough for us to see

• 2:29:18Lester Nare?

  yes

• 2:29:19Krishna Choudhary?

  but like now we can have a minutes long

• 2:29:22Lester Nare?

  yes

• 2:29:22Krishna Choudhary?

  advance

• 2:29:23Lester Nare?

  yes

• 2:29:23Krishna Choudhary?

  where now

• 2:29:24Lester Nare?

  yes

• 2:29:25Krishna Choudhary?

  even the James Webb

• 2:29:26Lester Nare?

  yes

• 2:29:26Krishna Choudhary?

  with minutes

• 2:29:27Lester Nare?

  right

• 2:29:27Krishna Choudhary?

  James Webb could drop what it's doing and

• 2:29:29Lester Nare?

  like

• 2:29:30Krishna Choudhary?

  you know and point and we could we could see it at the moment

• 2:29:33Lester Nare?

  and so this is a combination of being able to hear the universe and see the universe and this sort of new level of accessibility allows us to combine both of these toolsets

• 2:29:44Krishna Choudhary?

  mm hmm

• 2:29:44Lester Nare?

  in combination to be able to now not only hear it have a window of time of long enough that any number of different uh earth based

• 2:29:53Krishna Choudhary?

  yeah

• 2:29:54Lester Nare?

  or space based detection platforms that are looking at infrared or optical could look in the direction of the source because we have four locations

• 2:30:02Krishna Choudhary?

  yeah

• 2:30:02Lester Nare?

  so we can triangulate a smaller region of space in the sky to point and now we can get this multi spectral

• 2:30:09Krishna Choudhary?

  yeah

• 2:30:09Lester Nare?

  view of these like crazy events

• 2:30:13Krishna Choudhary?

  events

• 2:30:14Lester Nare?

  that are oh my goodness

• 2:30:16Krishna Choudhary?

  it's like well yeah we're we're we're we really are living in a golden age of

• 2:30:22Krishna Choudhary?

  time domain astronomy

• 2:30:23Lester Nare?

  mm hmm

• 2:30:24Krishna Choudhary?

  right

• 2:30:24Lester Nare?

  mm hmm

• 2:30:25Krishna Choudhary?

  we had a golden age of astronomy in general but it's like we were looking at still pictures

• 2:30:29Lester Nare?

  right right

• 2:30:30Krishna Choudhary?

  right and now and now the universe is dynamic and we have access to that extra dimension

• 2:30:36Lester Nare?

  mm hmm which is time passing and us then seeing the transition of

• 2:30:39Krishna Choudhary?

  yeah

• 2:30:40Lester Nare?

  these objects over time with really really high fidelity

• 2:30:43Krishna Choudhary?

  yeah we have early warning systems now we got the Vera Rubin that's gonna find random stuff

• 2:30:48Lester Nare?

  yes

• 2:30:48Krishna Choudhary?

  yeah and this is another now that we have this um ten to thirty hertz band that we're sensitive to we got that unknown unknowns coming back again right

• 2:30:57Lester Nare?

  this is I I think what's so interesting this Time domain astronomy point is it's like returning on the light. For the first time, we've sort of been like having candlelight.

• 2:31:08Krishna Choudhary?

  We've been doing flash photography.

• 2:31:09Lester Nare?

  Flashing, right, right. In this like small window. And so not only do we have a larger window, we also now have this ability to see. Things in time, which again means our ability to understand what's actually happening in the universe around us is. Is like right now, today, like not twenty years ago, not fifty years into the future. We talk about our room. It's gonna be putting out data every three days. Globally in real time, that's gonna see things we've literally never seen before and lots of it, like lots of it. This is, I love these retrospectives because it, you know, science is a story. It's a human story. It transcends generations.

• 2:31:49Lester Nare?

  We're building on the, the work, the blood, sweat and tears of those before us. And we are expanding the aperture by which we again can just understand so many pieces. And people always talk about AI in this like, oh, in this purely generative LLM chat GPT universe of like. Oh, these LLMs aren't that great. It's just a stochastic parrot that repeats back what it's already heard before.

• 2:32:16Krishna Choudhary?

  No, no, no, no.

• 2:32:17Lester Nare?

  That like this, like one of the reasons like this.

• 2:32:20Krishna Choudhary?

  It's doing things that, that we really wanted it to do and is doing it way better than we could do it.

• 2:32:25Lester Nare?

  Right. Or that we necessarily even thought it could do at this stage in its development cycle. And I think it's why it's so important to talk about these AI stories in the context. Of the experimental design, of the, the, the historical storyline of these like instruments. Right? Cause at the end of the day, science is so much about instruments. And when we talk about experimental uh stuff, and this is why we spend hundreds of millions of dollars on this stuff. I just, this was so, so fast. We started off first with our CRISPR story. How we understand what CRISPR is, what is CAS nine?

• 2:33:02Krishna Choudhary?

  The twenty twenty Nobel.

• 2:33:03Lester Nare?

  The twenty twenty Nobel Prize, the legal battle between two of our elite research institutions around who owns the human. Domain aspect of this. And how AI is making that gene editing process better. And the same kind of ideas, different implementations, different details. But using AI as a system to augment and make our existing tools more advanced with LIGO for gravitational wave detection. And what we're going to be able to see with that is so crazy.

• 2:33:33Krishna Choudhary?

  Yeah.

• 2:33:34Lester Nare?

  And how good it worked. And also, the time scales of iteration with this AI stuff is much smaller than the hardware time scales.

• 2:33:42Krishna Choudhary?

  Yeah.

• 2:33:42Lester Nare?

  And so like, we have these long arcs of time where to get these new hardware instruments online. And then we have these much shorter time scales of where we can now use these new AI models to continue to polish the diamond.

• 2:33:57Krishna Choudhary?

  Yeah.

• 2:33:58Lester Nare?

  Um, another great American exceptionalism story with LIGO too. Uh, we need to fund our elite research universities and institutions.

• 2:34:05Krishna Choudhary?

  And we need to do basic science research because, you know, the, the technologies that are coming out of LIGO, like these control systems, this is going to be useful in all sorts of technology.

• 2:34:14Lester Nare?

  Right, right, right.

• 2:34:15Krishna Choudhary?

  But like, it was, it was pushed to its very limit on LIGO, right? Cause things like LIGO are what, like, make us go all the way to the very end. I mean, think about it, we're sensing to the quantum limit.

• 2:34:32Lester Nare?

  Yes, yes.

• 2:34:33Krishna Choudhary?

  There's gonna be insane amounts of quantum sensing technology that comes out of this.

• 2:34:38Lester Nare?

  Yes.

• 2:34:39Krishna Choudhary?

  Um, control system technology that comes out of this, the mirrors, the vacuum technology that's gonna come out of this.

• 2:34:46Lester Nare?

  Yes.

• 2:34:46Krishna Choudhary?

  You know, it's.

• 2:34:47Lester Nare?

  All of these, all of those had to be new fundamentally, new fundamental engineering solutions that have applications well beyond gravitational wave detection.

• 2:34:58Krishna Choudhary?

  Yeah.

• 2:34:58Lester Nare?

  Your new iPhone is gonna have, you know, these AG, these AI driven, you know, optimization models for capturing your 32x zoom.

• 2:35:08Krishna Choudhary?

  Yeah, exactly.

• 2:35:09Lester Nare?

  Selfie.

• 2:35:10Krishna Choudhary?

  It's gonna be crazy.

• 2:35:11Lester Nare?

  Unbelievable. This is a great lead up to our Nobel Prize week. Again, tune in. We're gonna be doing, there's no channel where you're gonna get better coverage of what's happening this, in this year's Nobel Prizes, understanding the scientists, understanding the history behind their discoveries, how that human story turns, what does it mean moving forward? I'm so excited to have you on that. It's, it's, it's really good. Again, we're gonna be doing all three days.

• 2:35:37Krishna Choudhary?

  Monday, Tuesday, and Wednesday. Monday is when the Medicine Prize comes out, Tuesday the Physics, and Wednesday the Chemistry.

• 2:35:45Lester Nare?

  And Princeton is almost certainly going to be on the podium for one of those, at least we hope.

• 2:35:50Krishna Choudhary?

  At least we hope, yeah.

• 2:35:51Lester Nare?

  At least we hope. My name again, Lester Nare, your host, joined as always by my co-host and our resident PhD, and one of the greatest science communicators of a generation, Krishna Choudhary.

• 2:36:03Krishna Choudhary?

  Thanks, sir.

• 2:36:04Lester Nare?

  This is from First Principles. We'll see you guys for Nobel Prize week.