Plants, Quantum Sensors, and Predicting Cancer Evolution (EP. 25)

Hosted by Lester Nare and Krishna Choudhary, this episode jumps from plant biochemistry to quantum metrology to cancer evolution. We start with a University of York breakthrough that solves a ~50-year mystery in alkaloid biosynthesis—identifying the “missing” enzyme behind a key asymmetric step plants use to build powerful defensive (and pharmaceutically useful) molecules. Then we go deep on quantum sensing with entangled atomic clouds, showing how correlated measurements can beat the standard quantum limit. Finally, we close with ALFA-K, a new tool that maps local fitness landscapes to predict how aneuploid cancers may evolve under pressure from therapy. Summary Plants making medicines — the “phantom enzyme” in alkaloid biosynthesis and why solving this pathway matters for scalable drug production. Quantum measurements with entangled atom clouds — squeezed/entangled states, noise reduction, and why correlations unlock better sensing. Predicting cancer evolution — ALFA-K and measurable fitness landscapes for aneuploidy-driven trajectories under treatment. Show Notes Story 1 — Plant alkaloid biosynthesis (University of York) Paper — New Phytologist Story 2 — Quantum measurements with entangled atomic clouds (University of Basel) Paper — Science Story 3 — Alpha-K (Moffitt Cancer Center) Paper — Nature Communications

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

• 0:00Krishna Choudhary?

  So we've been looking for this gene for like 50 years. And now these guys have finally found it. They literally took a single quantum state. And then they split it into two. But then they maintained entanglement.

• 0:14Lester Nare?

  It looks like it turns out that an extra chromosome isn't always a bad thing.

• 0:19Krishna Choudhary?

  Yeah. If you're a cancer.

• 0:21Lester Nare?

  If you're a cancer.

• 0:22Krishna Choudhary?

  If you're a cancer, extra chromosomes can be really good.

• 0:24Lester Nare?

  But not a Gemini.

• 0:26Krishna Choudhary?

  No.

• 0:26Lester Nare?

  Or a Sagittarius.

• 0:30Lester Nare?

  Hello, Internet. This is your captain speaking, Lester Nare, joined as always by my co-host and our resident PhD, Krishna Choudhary. We are back in studio this week with three great main stories lined up for you along with the rundown. This week, we're going to touch on a story about an overlooked plant and how it could transform medicine production. We're going to get into some quantum entanglement, which is giving us superpowers to measure the impossible. And we're going to end with this new breakthrough tool called Alpha K, which is helping scientists predict how cancer cells will evolve before they actually do. We're going to learn about the science from the ground up because this is from First Principles.

• 1:29Lester Nare?

  For our first story, we have a new research paper out of the University of York in the UK that was published in the New Phytologists with the byline, "Scientists at the University of York have discovered how plants produce chemical compounds that might assist in developing new environmentally friendly medicines." We always like our plant stories.

• 1:55Krishna Choudhary?

  Yes.

• 1:55Lester Nare?

  So let's break down what exactly is going on here in this new study from the University of York, which was published on January 13th.

• 2:03Krishna Choudhary?

  That's right. And you know, plants are not as sexy, let's say, as, you know, animal cells or like bacteria, fungi, but.

• 2:14Krishna Choudhary?

  They're incredibly versatile. They've been around for 450 million years and they've had to deal with a lot over those 450 million years. Right. Because they don't really move around. And because they don't move around, they can't do traditional defenses of just like running away from something that's trying to eat you. Right. They're fixed in place. And so they still need to evolve defenses against herbivores, pathogens, insects that are trying to eat them. And their solution is effectively chemical warfare. Okay. And they're really, really good at chemical warfare. And the core chemicals that we're talking about in this study are something called alkaloids. So they're nitrogen containing secondary metabolites.

• 2:57Krishna Choudhary?

  By secondary metabolites, we mean like, you know, it's not actively involved in photosynthesis and stuff like that. It's a derivative of those compounds. And we're aware of these morphine, nicotine, caffeine, quinine. These are all alkaloids that are made by plants as defense mechanisms that they figured out through their evolution. Right. And this particular study that's out of the York University. It solved a 50 year old mystery about how exactly certain plants make these compounds. Okay. This idea of alkaloid synthesis. They found the gene that does it for a particular pathway. And that could lead to cheaper pharmaceuticals, a lot of really cool things.

• 3:42Krishna Choudhary?

  And I think the chemistry in this particular study is what I found really cool. Because they've, they've figured out the nitty gritty mechanism by which this particular enzyme does what it's supposed to do.

• 3:53Lester Nare?

  So we're going to understand and learn how plants generate and synthesize these alkaloids, which they use as a defense mechanism, but as humans have some potential commercial applications.

• 4:07Krishna Choudhary?

  Exactly. Yeah. Pharmaceutical applications, all of that. So first, let's just try and appreciate the target molecules, right? These alkaloids, they are heterocyclic rings with a nitrogen. By heterocyclic, that means there's a cycle of carbon atoms. But one of the carbon atoms has been replaced by nitrogen. They all come mostly from amino acid. There's a few that come from the nucleic acids, but most of them are derived from amino acids. There's two different types that we can think about. There's the lysine derived, which are from the amino acid lysine. And then there's ornithine derived. Compounds nicotine, probably one that's very ubiquitous. That one comes from ornithine. The idea is you take ornithine, which is this amino acid. It's a linear in chain.

• 4:51Krishna Choudhary?

  And then you remove some stuff, you add some stuff and you put it into a ring. And that ring form becomes then nicotine. Okay. So why are plants even doing this in the first place? Right? Nicotine, for example, very specifically is something that mimics neurotransmitters in animals. Specifically in insects, it paralyzes them. So if there's an insect that's trying to eat this plant, it can't do it anymore. Right? But because of, you know, animal evolution, that particular neurotransmitter in insects is also related to stuff that we use in our brain. Specifically acetylcholine. Here you can see the nicotine molecule and the acetylcholine molecule. Right?

• 5:33Krishna Choudhary?

  The shapes of the two are kind of similar, which means that when nicotine goes inside our brain, the acetylcholine receptors, which are thing are receptors on our neurons that recognize acetylcholine and then open up ion channels to then turn on or turn off a neuron. They could sometimes be triggered by nicotine. This is what leads to the cognitive effects of nicotine. You know, the, the high that you get or the addiction. All of that is just because the Lego block of nicotine is closely mimicking the Lego block that is acetylcholine. Got it. Right? Got it. Yep.

• 6:11Krishna Choudhary?

  And so that's why plants sort of have an advantage when they evolve these types of molecules. Right? And a lot of these types of molecules can be used in pharmaceutical research. Okay. Okay. Now, the question is, how exactly do plants make this happen? Because remember what I said, there's. An amino acid, which is a linear chain, you usually have like an amine group, a carboxyl group, but a carbon in the middle and then some stuff attached to that carbon. It's a linear thing. You gotta now turn this into a ring. Okay, there's several ways to do this at a molecular level, but it's been kind of annoying to figure out how exactly that happens.

• 6:57Lester Nare?

  We understand conceptually how to do so, not naturally in the inside of plant or how plants naturally do so. We can get it conceptually, but we've not yet been able to identify how plants do it in a non-manufactured way.

• 7:14Krishna Choudhary?

  Yes, yeah, yeah, exactly. And so, one of the tools that you can use is something that goes back for at least 50 years. It's something called radioisotope tracing. What you do is you replace the carbon atoms that you grow this plant with, with carbon 13 instead of carbon 14, or sorry, carbon 12. Carbon 12 is six proton, six neutrons in the nucleus. Carbon 13 is the same number of protons, six, but you have an extra neutron. Okay, and when you, you know, let's say we supply the plant pathway with a bunch of glucose that is only carbon 13, right? Now, we can trace, how is that plant gonna break up this glucose and incorporate it into different types of molecules?

• 7:58Krishna Choudhary?

  For example, pyruvate or the citric acid cycle, how much of it is gonna go into fatty acids, right? And we can figure out by weighing the fatty acids and the citric acid and things like that. We can be like, well, the citric acid is only half as heavy as it would be if all of the carbon 13 went in there, right? Because it's got three extra neutrons instead of six extra neutrons, things like that. So that's the logic behind this idea of radioisotope tracing. It's been used to figure out that DNA is the genetic code of life. If we go back to our Watson and Crick episode of last year, right? And so, the question now is, we'd like to apply this technique to how do plants make these alkaloids?

• 8:43Krishna Choudhary?

  Okay, now, let's, let's start with the substrate lysine, which is the amino acid, okay? And this lysine is gonna go on to make like anabecine or a securinine, some alkaloid that we're interested in, okay? The problem is the following: when lysine gets, goes through and becomes this alkaloid, there's an intermediate compound called cadaverine. Okay, here's the idea: lysine is not symmetric because you've got an amino group on one end, that's the H2N, the nitrogen, and then you have an amino group on the other end, but then that's also connected to a carboxyl group, which is the COOH, carbon, oxygen, oxygen, hydrogen. Okay, so it's not symmetric. There's gonna be a process called decarboxylation,

• 9:27Krishna Choudhary?

  where you take that carboxyl group out, and now it becomes a symmetric molecule, right? There's an amino group, H2N on one end, and then there's NH2 on the other end. The switching of the letters is just to show that it's completely symmetric. If I were to look at this molecule, cadaverine, this way, and then I were to switch it around, it would look the same to me. Okay. Okay? Now, if that is an intermediate, then what should happen? Another enzyme would take that intermediate, and then it could grab on one end, or it could grab the other end. Right. Right? Because it doesn't know Right. which way came out of the enzyme, right? Which one, which part, which end of the molecule, the left or right, had this COOH attached?

• 10:11Krishna Choudhary?

  It doesn't know, because it's just freely floating around. So this next step enzyme is gonna grab that, and if I were to do radioisotope tagging Yes. of this molecule, and I were to make a ring out of it, with the nitrogen on one end, and let's say that nitrogen is our index of reference, the radiocarbon could be either on the left or the right. Right? Because the, whatever molecule turned it into a ring, grabbed that cadaverine from either the left end or the right end. Okay? And that's what we see in a lot of our stepwise symmetric pathways. These are called stepwise symmetric. Okay? In the sense that... It doesn't know which one it grabbed.

• 10:51Krishna Choudhary?

  And so that top line, you get nitrogen, you get this heterocarbon ring with the nitrogen. And that tagged carbon is either to the left of the nitrogen or to the right of the nitrogen. Now that happens in some plants, but in other plants, that tagged carbon is always going to be on the left of the nitrogen.

• 11:12Lester Nare?

  Interesting. Okay.

• 11:13Krishna Choudhary?

  Okay.

• 11:13Lester Nare?

  So what is making it move from being a chance of 50/50 to 100% always being on a singular side, which creates consistency?

• 11:22Krishna Choudhary?

  Exactly. And there's actually a lot of these compounds that are like this. Okay. From both lysine and ornithine, you've got plants like nicotiana, plegia. These guys make these asymmetric compounds.

• 11:35Lester Nare?

  Sorry, nicotiana sounds like a Cardi B song.

• 11:39Krishna Choudhary?

  It totally does. And she would be remiss to say that, you know, it is an asymmetric alkaloid, you know? But this is pretty common, is the idea.

• 11:50Lester Nare?

  Yep. Okay. So it's not a unique thing. We see it across a variety of these compounds.

• 11:56Krishna Choudhary?

  Yeah. Yeah. It's across a variety of these compounds. And so there's something very interesting going on. And this might seem kind of just like a boring trick. Okay. So, you know, your carbon is, your tagged carbon is only on one side. But now, who cares? Yeah, who cares? But now let's actually, before we even talk about like applications and stuff, let's actually think about, okay, what could be happening at the chemical level such that my enzyme is always grabbing one end? Right? Of a symmetric molecule. It's a rod that looks exactly the same whether I were to do it this way or turn it around. And yet the enzyme is always grabbing one end.

• 12:40Krishna Choudhary?

  And this is where we come to a hypothesis that was given in 1973 by Lester and Spencer in the Journal of American Chemical Society, 1973. So this is 50 years ago. They said the only way that this can happen. Is if there's a single process that goes from amino acid, strips the COOH, and then makes the ring. If that intermediate cadaverine were to go and freely float around, there's no way that the next enzyme would grab one end. This only happens if like, you know, in some analogy, let's say I'm the enzyme. With my right hand, I grab the amino acid, I strip the COOH,

• 13:24Krishna Choudhary?

  and then I put it to my left hand and I make a ring. Right?

• 13:28Lester Nare?

  Yes.

• 13:28Krishna Choudhary?

  I'm doing it in one smooth process.

• 13:30Lester Nare?

  Yes.

• 13:31Krishna Choudhary?

  There's not, I'm grabbing it, I'm letting it go, and there's some other guy who's grabbing it. Because if the other guy grabs it, it's had time to tumble in the 300 Kelvin environment of the cell. Right? And so it's a very nice kind of hypothesis, right? It's like, when you think about it at the molecular level, this is the only way that it could have happened.

• 13:52Lester Nare?

  There can't be a chain of independent processes.

• 13:57Krishna Choudhary?

  Yeah.

• 13:57Lester Nare?

  Generating this outcome, because it would be the second link in the chain would not have sufficient information to consistently select for the same side.

• 14:08Krishna Choudhary?

  Yeah.

• 14:09Lester Nare?

  So it has to be an end-to-end process.

• 14:11Krishna Choudhary?

  Yes.

• 14:12Lester Nare?

  That is self-contained from start to finish.

• 14:14Krishna Choudhary?

  Yes. And this was in 1973, they had this hypothesis.

• 14:18Lester Nare?

  Okay.

• 14:18Krishna Choudhary?

  And people have been looking for this enzyme ever since.

• 14:21Lester Nare?

  Ah, so we have the hypothesis, which defines this idea that it has to be a singular process. But we've not seen it experimentally.

• 14:29Krishna Choudhary?

  Yeah, we've been trying to look for it.

• 14:30Lester Nare?

  Okay.

• 14:31Krishna Choudhary?

  These guys found it.

• 14:32Lester Nare?

  Okay.

• 14:32Krishna Choudhary?

  That is the paper.

• 14:34Lester Nare?

  Okay.

• 14:34Krishna Choudhary?

  Okay, this phantom enzyme for over 50 years. It's now been found, the study is out in New Phytologist. First author, Wood. Very nice paper.

• 14:45Lester Nare?

  Catherine Wood. And the idea, this is a 50-year-old treasure hunt.

• 14:49Krishna Choudhary?

  Mm-hmm. To try and find this thing. Okay? And there are applications that we'll get to later. But I think it's just incredible that like, there's been the science. Question for 50 years, based on a very simple experiment, which is that this pathway is not symmetric. And the only way it can't be symmetric is, as you said, it's got to be an end to end process.

• 15:09Lester Nare?

  And one thing that's always so interesting in the modern conversations, in the contemporary conversations about science, is this idea that we've already solved all of the problems. And or solving old problems is sufficiently trivial.

• 15:26Krishna Choudhary?

  Yeah.

• 15:27Lester Nare?

  And this is a perfect example. That's obviously not true.

• 15:30Krishna Choudhary?

  It's obviously not true.

• 15:31Lester Nare?

  But this is a perfect example of that.

• 15:32Krishna Choudhary?

  Exactly. And this, this paper is also really nice because it uses very modern techniques to answer this problem. We've got Alpha Fold with AI that we're going to get into later.

• 15:41Lester Nare?

  Okay.

• 15:42Krishna Choudhary?

  New techniques that are only sort of available now in the modern day. Right? So the target organism that they used in the study is Flugia sufruticos. It's actually used in Chinese medicine. Yiyi Q, I believe, is how you pronounce it. I got one of my friends who's Chinese to send me a voice recording. So if that's wrong, that's his fault. Maybe he's setting me up. But it's been used in Chinese medicine. And we know consistently that it forms non symmetric alkaloid securonine.

• 16:18Lester Nare?

  Okay.

• 16:18Krishna Choudhary?

  Okay, so this is now the model organism that we're going to use to try and find what is the enzyme in this plant that is doing this? They do transcriptome analysis. So they extract the RNA from 15 different tissues in the plant. And they do de novo transcriptome analysis of the whole thing to figure out what the mRNA is that is being transcribed from the DNA. From that, they get a bunch of candidates. And they look for what are the enzymes that could be possible that are creating this? They find two enzymes. There's gene 4984, 4984. That's your standard cadaverine. It produces your cadaverine, which is the intermediate product. But then they've got this one gene, 1864.

• 17:03Krishna Choudhary?

  And that produced your one piperidine, which is a precursor of that securonine with the alkaloid. It's producing that end product. In one step, you're not getting any cadaverine. Okay, you're not getting anything in the middle. And that this is that olado enzyme that we're gonna get into later on. But that's the enzyme that they found. And they found that this enzyme could take you from lysine all the way to the end in one go.

• 17:30Lester Nare?

  So the idea is gene four nine eight four was just getting us to in this chart that we're looking at. The middle step where the cadaverine is created. But it did not bring us through the oxidation. And then all the way down into the sort of final product.

• 17:47Krishna Choudhary?

  That's right.

• 17:48Lester Nare?

  But that gene one eight six four, this was the smoking gun because it was that end to end process.

• 17:56Krishna Choudhary?

  Exactly, yeah. And it's the smoking gun, but that's not gonna make your paper.

• 18:02Lester Nare?

  I see, okay.

• 18:03Krishna Choudhary?

  Because if you just submitted a paper being like, hey, we found this enzyme that does the whole thing. Well, it could be doing all sorts of other stuff. Reviewer two is gonna be like, wow, you didn't really show that it's non symmetric and and all this other stuff, right? So reviewer two is gonna get you, you gotta go even deeper. You gotta really convince your reviewers. That this is the thing that is doing that non symmetric grabbing. And how is it doing it?

• 18:32Krishna Choudhary?

  All this other stuff, right? And so that they didn't, they didn't stop there. Next, what they did was they purified that gene, they incubated it. And then they wanted to see how how exactly is it doing this? So they got a lysine and they tagged the nitrogen this time.

• 18:48Lester Nare?

  Okay.

• 18:48Krishna Choudhary?

  Okay, the nitrogen this time is only gonna be on one end. And if it is stepwise, meaning there's an intermediate, then the nitrogen is going to, we're gonna see. We're gonna see a nitrogen getting stripped. And so you'll see the final product not have that radioactivity, that radioactive isotope of nitrogen. Or you're gonna see the radioactivity, right? It's gonna be fifty fifty.

• 19:12Lester Nare?

  Okay.

• 19:13Krishna Choudhary?

  The the nitrogen that you put in that you tagged is either gonna be there or it's not. Because the enzyme is either grabbing the left end or the right end. But. If it is a concerted, single-step reaction, then the nitrogen is always going to be there. The nitrogen that you put in on one end of this lysine is always going to be there. Okay, and that is what they found. They found that this is, again, this radioisotope measurement that they did. The other thing they did was nuclear magnetic resonance, the NMR, which is the stuff when we go to, when we get, you know, our MRIs.

• 19:46Lester Nare?

  Yes.

• 19:47Krishna Choudhary?

  It's the same technology. What they're using is that the nitrogen that they tagged has an odd number of nucleons in it, which means it's going to have a spin. And so you can measure that nuclear spin to figure out if your nitrogen is currently there. Okay, and they found that, yep, that nitrogen is definitely still there in our product, which means that this is the asymmetric reaction. Because your nitrogen in the beginning was only on the left end.

• 20:12Lester Nare?

  Yes.

• 20:12Krishna Choudhary?

  Right? And now the fact that it's 100% there all the time means this enzyme is always grabbing that left end. Right?

• 20:19Lester Nare?

  And so we've used the combination of observational tools and tracing tools to actually watch the evolution of the process to both show the stepwise and concerted versions and what happens. And because we're tagging the nitrogen, which is supposed to always be in the same spot.

• 20:41Krishna Choudhary?

  Yeah.

• 20:42Lester Nare?

  Each time, it's very obvious when you look at the tracing that in one of these pathways, it's always there.

• 20:47Krishna Choudhary?

  Yeah.

• 20:48Lester Nare?

  And so it's a combination of these different levels of tooling that have allowed them to make this observation.

• 20:53Krishna Choudhary?

  Exactly, yeah. And then they want to get into even deeper. This enzyme, how does the enzyme actually work?

• 20:59Lester Nare?

  Still not good enough.

• 21:00Krishna Choudhary?

  Still not good enough. Why is it different from the normal ones?

• 21:03Lester Nare?

  Yes.

• 21:03Krishna Choudhary?

  Okay, so this class of enzymes, they're calling it ornithine lysine arginine decarboxyl oxidases. The decarboxyl oxidases is key because it's both doing the decarboxylation and the oxidation in a single step.

• 21:16Lester Nare?

  These are called olados.

• 21:18Krishna Choudhary?

  Yeah, olados.

• 21:19Lester Nare?

  Olados is the acronym.

• 21:21Krishna Choudhary?

  Yeah, and they're from a class of proteins called PLPs, which use vitamin B6 as a cofactor. So the vitamin B6 is like helping along the enzyme, even though it's not part of the active substrate. It's like in the back, sort of like making sure that the enzyme. Shape is correct. Okay. Next, they used AlphaFold. Okay, this is an AI tool that was developed my Google's Deep Mind to predict the 3D structure. Before, let me just take a step back. But before we had AlphaFold, you had to like do all sorts of protein crystallography, maybe like cryo EM, all this other stuff. Now you can just plug it in to AlphaFold and you'll get a really nice 3D structure.

• 22:06Lester Nare?

  Plug it in, plug it in.

• 22:08Krishna Choudhary?

  Right? And it's like, it's, it's super cheap to do. Once you've got that, now we can figure out what is the difference between the ancestral olado and this particular olado. The difference is a tiny amino acid, difference between tyrosine and phenylalanine. Look at the structures of these two. They're exactly the same.

• 22:29Lester Nare?

  Yes.

• 22:29Krishna Choudhary?

  Except for a hydroxyl group and OH.

• 22:32Lester Nare?

  Yeah.

• 22:32Krishna Choudhary?

  Okay, the phenylalanine just has an OH attached and that OH is the entire difference.

• 22:39Lester Nare?

  That's so funny. Such a miniscule.

• 22:42Krishna Choudhary?

  It's a tiny, yeah. All it is, is one of the carbons is attached to an OH. Otherwise, the entire amino acid is exactly the same. But that one site difference in the active site is what causes this entire change.

• 22:57Lester Nare?

  Downstream, it's what basically changes the down, all of the downstream.

• 23:00Krishna Choudhary?

  All of the downstream, because if you don't have the OH, effectively what that means is if you don't have the OH, the cadaverine comes in or you make the cadaverine and then the OH, if you have the OH, the it, it stops another hydrogen from coming in and sort of freeing this guy.

• 23:19Lester Nare?

  Got it. Got it.

• 23:19Krishna Choudhary?

  Okay, before, there was nothing to stop another H plus ion from coming in and just like freeing this. This thing goes away and then, you know, some other enzyme hooks up with it. Here, because I've got the OH, I'm not messing with this cadaverine. The cadaverine stays inside my enzyme for longer. And then the process of oxidation can actually happen within the same spot.

• 23:38Lester Nare?

  That makes sense. It's sort of like this, because of its presence, it dictates whether it will stay or whether it will go.

• 23:45Krishna Choudhary?

  Yeah, for like the time.

• 23:47Lester Nare?

  Yes.

• 23:47Krishna Choudhary?

  That it stays in. Inside the enzyme is determined by whether that oxygen and hydrogen are there or not. Okay, what's again, very cool about this particular enzyme is also it is very promiscuous. It's not loyal to lysine or ornithine. It does lysine or ornithine, arginine. So it's incredibly versatile if we want to use it for industrial purposes.

• 24:10Lester Nare?

  This goes back to the idea we keep coming up with with some of these things where is it a single point discovery? Or is it in my analogy of it more of a platform?

• 24:19Krishna Choudhary?

  Yeah.

• 24:19Lester Nare?

  That has multiple use case possibilities because it's a fundamental unlock. That has more than a single, a singular point solution.

• 24:28Krishna Choudhary?

  Exactly. Yeah. So it's, it's very cool in that way, right? Because it's, it's very versatile. It can, it can use all sorts of amino acids to create these compounds of many different types. Okay.

• 24:39Lester Nare?

  It's like a little mini factory.

• 24:40Krishna Choudhary?

  Yeah, yeah, yeah. It's very cool. And it's, it's doing both processes at once, you know? It's like a single machine that end to end.

• 24:47Lester Nare?

  Yes. Is it like an efficiency play, less like likelihood for issues, transitioning from a step one to a step two?

• 24:53Krishna Choudhary?

  Exactly.

• 24:54Lester Nare?

  All these kinds of things.

• 24:54Krishna Choudhary?

  All these. Yeah. And you're already getting to sort of what I'm going to talk about at the end, which is the applications. But before we do that, the last bit that they, that they studied was the evolution of this particular enzyme. Okay. How did plants figure out how to make this?

• 25:11Lester Nare?

  Yeah.

• 25:11Krishna Choudhary?

  Okay.

• 25:11Lester Nare?

  Yeah.

• 25:12Krishna Choudhary?

  You would think that the plants, you know, usually you'd naively think the plants have some precursor protein. And then that precursor protein gets mutated in some way. And then I have this new use case. This particular enzyme is actually more related to bacterial enzymes, not plants.

• 25:29Lester Nare?

  Interesting.

• 25:30Krishna Choudhary?

  Okay. That's kind of weird because bacteria are not plants.

• 25:34Lester Nare?

  Right.

• 25:35Krishna Choudhary?

  Unless we remember that the chloroplasts that are inside bacteria were once, I mean, sorry, the chloroplasts that were in, that are inside plants now were once cyanobacteria. They were once bacteria that through endosymbiosis became inter, integrated inside the plant cell. And they've just stuck around for like a billion years because they've had a good, the plant cell has had a good. The plant cell gets glucose and ATP. So energy and food out of the cyanobacteria. The cyanobacteria is in a nice, like all inclusive resort. It doesn't have to worry about like trying to get food for itself because the plant is just supplying it as long as it does the work. Right? So.

• 26:17Krishna Choudhary?

  This particular enzyme is more related to the decarboxylases in bacteria than it is to plants. And if we look through the evolution, there's independent lineages that all of these different plants have. Because remember, we've got different plants, right? We've got rosids, nicotiana, artemisia. All of these are different plants that are finding ways to make this happen. They've independently found this bacteria enzyme, and they've repurposed it. So it's not like one guy did it, and then he let everyone know. All of these different lineages did it at different times, but they found the same use case.

• 27:00Lester Nare?

  That's so fascinating.

• 27:01Krishna Choudhary?

  Which is pretty interesting, right?

• 27:02Lester Nare?

  It's almost like a fundamental thing that's like, each of these lineages were like, this is the most efficient way to do this process.

• 27:10Krishna Choudhary?

  Yeah.

• 27:10Lester Nare?

  And they all sort of ended up centering

• 27:14Krishna Choudhary?

  Yeah, they did.

• 27:15Lester Nare?

  On the same implementation.

• 27:16Krishna Choudhary?

  Yeah, they reinvented the wheel, like four or five times in evolution, you know? It's kind of interesting to think about, because one way you could, one thing you could ask is like, how is this even possible, right? How do you, how do you do this kind of evolution? Well, the cyanobacteria genome gets integrated, the bacterial genome gets integrated into the plant genome. And then what you have is these things called tandem arrays, which is effectively, when you replicate a gene, sometimes you get multiple copies of that gene, okay? And that becomes something called a tandem array. Now, your main copy, you don't want to mess with.

• 27:51Lester Nare?

  Right.

• 27:51Krishna Choudhary?

  Okay? It's kind of like in GitHub, when you like push commits, you have a branch separately for yourself, where you're doing all sorts of heinous crap.

• 28:00Lester Nare?

  Don't push it to main, don't.

• 28:01Krishna Choudhary?

  Yeah, you never push it to main unless you're really sure that it's working, right? And so this tandem array is basically that. It's effectively like multiple GitHub branches. You're messing around here, and your main is still going at it. But with all these copies, you can, you can start doing some mutations, you can figure it out. And if something works, hey, let's keep it, you know, because evolution wants to keep it.

• 28:23Lester Nare?

  Plants invented version control before GitHub.

• 28:26Krishna Choudhary?

  Yeah.

• 28:27Lester Nare?

  So this, you heard it here first.

• 28:29Krishna Choudhary?

  Yeah, yeah.

• 28:30Lester Nare?

  Plant-based version control is the true OG.

• 28:32Krishna Choudhary?

  Yeah, yeah, exactly. And we're just, we're just repurposing it.

• 28:35Lester Nare?

  Repurposing it.

• 28:36Krishna Choudhary?

  So now let's look into applications. What could this be used for? Well, these alkaloids are very important in medicine, right? And what you can do, for example, if you want to make securin, which is this particular compound that we're studying, this is, you know, in cancer, this can be used against leukemia, or leukemia therapy can be used as a kind of neuro-protection type thing. Before, what we used to have to do is grow this plant and get the compound out. You can imagine that's not scalable.

• 29:12Lester Nare?

  No.

• 29:12Krishna Choudhary?

  And it's very expensive.

• 29:14Lester Nare?

  Yeah.

• 29:14Krishna Choudhary?

  Now we know the gene that does it. Furthermore, the gene is a one-step process. So we can just CRISPR this gene into yeast.

• 29:24Lester Nare?

  Mm hmm.

• 29:25Krishna Choudhary?

  And then grow yeast.

• 29:27Lester Nare?

  The, the idea being is we know the, the factory that produces the outcome we're looking for at this molecular level inside of plants. But because we understand the genes, the needed gene expression to replicate

• 29:42Krishna Choudhary?

  Yeah.

• 29:42Lester Nare?

  that factory, we have the blueprints.

• 29:44Krishna Choudhary?

  Yeah, yeah.

• 29:45Lester Nare?

  So we can just take any yeast cell and give it the instructions to build the small factory.

• 29:51Krishna Choudhary?

  Yeah.

• 29:52Lester Nare?

  Which now removes the need to grow the plant.

• 29:54Krishna Choudhary?

  Yeah.

• 29:54Lester Nare?

  Or any of that life cycle process. We literally can just have a single function yeast cell that focuses on producing this outcome. Period.

• 30:03Krishna Choudhary?

  Yeah, exactly.

• 30:04Lester Nare?

  And then we can just scale up the number of yeast cells.

• 30:06Krishna Choudhary?

  Yeah.

• 30:06Lester Nare?

  And we just, it's one step, no life cycle, you can do it in the lab. And this is how you get the industrial grade.

• 30:13Krishna Choudhary?

  Exactly.

• 30:13Lester Nare?

  Industrial volume of production.

• 30:16Krishna Choudhary?

  Exactly. So it's making this very cheap because all you have to do is grow yeast, which we know how to do, that's like bread and beer, right? So this synthetic biology approach can completely revolutionize how we grow these class of compounds, right? And it's a whole class. It's not just that particular one. This is the first enzyme that we found that does this.

• 30:37Lester Nare?

  Right.

• 30:37Krishna Choudhary?

  Now we've got a blueprint on how to even approach this problem.

• 30:40Lester Nare?

  Right.

• 30:40Krishna Choudhary?

  Right? We can scale up. We can do all sorts of really cool stuff.

• 30:45Lester Nare?

  So Securin is the one that's particularly a specific candidate that would help as it relates to leukemia therapy.

• 30:53Krishna Choudhary?

  Yeah.

• 30:54Lester Nare?

  But what you're saying is Securin is one of, only one of the outputs of this mini factory.

• 30:58Krishna Choudhary?

  Yeah, yeah, there's so many alkaloids out there, right? That could be using this one step process. And a one step process is just really good because it's just much more manageable. It's a single factory. You don't need to, you don't need the second one to find the intermediary and da, da, da, da, da, you know?

• 31:16Lester Nare?

  Mm hmm. Very, very, very interesting.

• 31:19Krishna Choudhary?

  So I, I thought, I thought this was a very cool, like, you know, botany doesn't get a lot of love, but this was a very cool, um, cool one.

• 31:26Lester Nare?

  Hey, all the botanists out there, you're always going to get some love on this channel.

• 31:30Krishna Choudhary?

  Yeah.

• 31:31Lester Nare?

  You're always gonna, because that was, and again, it's, there's levels to this, right? It's not only the observation, it's showing how that observation is functionally happening, the, the, the mechanisms by which that process arises. Uh, then getting with that understanding, now it's, let's see how we can apply this to other areas of research.

• 31:50Krishna Choudhary?

  Yeah.

• 31:51Lester Nare?

  Again, it, it feels very much like a platform.

• 31:53Krishna Choudhary?

  Mm hmm.

• 31:54Lester Nare?

  Uh, because you can generate any number of different alkaloids with this factory. Um, it's, it's funny, you know, the old town that I'm from in North Carolina, that area that used to be called like, it's tobacco, used to be the big agriculture. Uh, so like even in Durham, they called it tobacco district. They converted these old.

• 32:14Krishna Choudhary?

  Oh, yeah.

• 32:15Lester Nare?

  Massive tobacco factories into like, you know, coworking spaces and all this and that. I will have everybody know that the collapse of the tobacco industry and the RTP was not due.

• 32:26Krishna Choudhary?

  Yes.

• 32:27Lester Nare?

  To these mini factories. We weren't there yet. However, I mean, I'm, it's, it seems like there is, like if nicotine is one of these alkaloids that could come out of this factory.

• 32:35Krishna Choudhary?

  Yeah.

• 32:36Lester Nare?

  Yeah, that seems like a place that some people who are trying to line their pockets are gonna run to.

• 32:41Krishna Choudhary?

  Yeah.

• 32:41Lester Nare?

  I don't know what the economics are around nicotine production, so that might be totally off base. But there's a million different use cases you can see for this. A great story, number one, starting off with botany, which we don't always cover.

• 32:55Krishna Choudhary?

  No.

• 32:55Lester Nare?

  But we want to give some love. We're gonna jump into one of the most popular parts of the show, the rundown. We are not able to cover every breaking science research story, week to week, because there's just so much science happening globally. So we take the rundown as an opportunity to give you a little taste of what else is happening in the world of science, without going into a deep dive. But before we get into the rundown, just a quick little couple of housekeeping notes, such as, how are you, my friend?

• 33:27Krishna Choudhary?

  Pretty good.

• 33:28Lester Nare?

  We had our Super Bowl festivities yesterday.

• 33:31Krishna Choudhary?

  Yes.

• 33:32Lester Nare?

  One of the most entertaining Super Bowls in recent.

• 33:36Krishna Choudhary?

  I was, I was riveting, dude. It was riveting.

• 33:40Lester Nare?

  As the, as the footballer on the pod, football as in not American football, but the true football, I've only recently learned the rules.

• 33:50Krishna Choudhary?

  Okay, nice.

• 33:51Lester Nare?

  And so I, I, you know, I don't know, it was not great.

• 33:55Krishna Choudhary?

  It was not great, yeah. There was a lot of not running. I think, I think that's the technical term. They did not run.

• 34:04Lester Nare?

  The sports ball term.

• 34:05Krishna Choudhary?

  Yeah.

• 34:05Lester Nare?

  It will be the Super Bowl, if I'm not mistaken, it sounds like it's gonna be in Los Angeles next year.

• 34:10Krishna Choudhary?

  Oh, nice.

• 34:12Lester Nare?

  So if anyone at the NFL wants to do a segment on the science of football.

• 34:17Krishna Choudhary?

  Yeah, yeah, yeah.

• 34:17Lester Nare?

  We are here in local, it's a quick, short drive over SoFi.

• 34:21Krishna Choudhary?

  Yeah, we could do Deflate Gate.

• 34:22Lester Nare?

  We could do, we could do, yeah, we could do a breakdown of Deflate Gate, which is why Belichick apparently didn't get into. The Hall of Fame as a first spell Hall of Famer, which

• 34:30Krishna Choudhary?

  Oh, lol.

• 34:30Lester Nare?

  Is a whole, a whole thing.

• 34:33Krishna Choudhary?

  It's a bit much.

• 34:34Lester Nare?

  It is, I, I'm, I'm

• 34:35Krishna Choudhary?

  Isn't he like the, one of the greatest?

• 34:37Lester Nare?

  I mean, he's, he's, he's

• 34:38Krishna Choudhary?

  Yeah.

• 34:39Lester Nare?

  It's, it's not, you could take away everything after Deflate Gate and he's still top two.

• 34:43Krishna Choudhary?

  Right.

• 34:43Lester Nare?

  So it's like, okay, guys, come on.

• 34:44Krishna Choudhary?

  Yeah.

• 34:45Lester Nare?

  All right. Enough of the sports ball and banter. We will now jump into our rundown. We have four stories. We're starting off with our first story, which was in CBS News, uh, about the delay for the Artemis two launch due to technical challenges. Uh, it faces delays after a critical test revealed that there were hydrogen leaks, pushing the much anticipated launch back. So yeah, what's, what's going on here with this story?

• 35:13Krishna Choudhary?

  Yeah. Um, basically hydrogen is really small, right? The hydrogen atom is the smallest because it's single proton, single neutron. Sorry, single proton, single electron. So it's going to leak through when they're trying to pump up the rocket. Better to catch these things now than later. Um, I always knew there was going to be probably, uh, the first, the first one is always scrapped because the rocket hasn't really been tested, so they really need to make sure. So, you know, Artemis is the SLS, the Space Launch System is still sitting on the launch pad, waiting for its March debut. But they're still going to the moon.

• 35:54Lester Nare?

  I heard that they couldn't get the Hollywood studio prepared for the launch in time. And so, you know, they had to get Netflix ready.

• 36:02Krishna Choudhary?

  There was rain.

• 36:03Lester Nare?

  It was raining and they couldn't mimic the rain. It just wasn't accurate.

• 36:06Krishna Choudhary?

  Yeah, that's what it was.

• 36:07Lester Nare?

  And so for those who are listening and not watching, my face is full of sarcasm. Uh, but we did mention this in our Artemis deep dive, that, you know, it's a launch window, not a launch date. And we explained why this launch in particular, uh, which was our episode 24, has a lot more complications because unlike the Gemini and Apollo missions where we tested different aspects of the workflow across multiple launches, we're basically trying to condense all of that

• 36:38Krishna Choudhary?

  Yeah.

• 36:38Lester Nare?

  into a much smaller amount of launches.

• 36:40Krishna Choudhary?

  Yeah.

• 36:41Lester Nare?

  And so there's a lot of things that can go wrong there. So we will keep an eye out for the actual launch date for Artemis two, which again is built in Lego, not plural, not Legos. Lego, which we got in our comments. Yes, Lego is already plural behind Krishna's left shoulder in all camera views, if you're watching on social or on the pod. Our story number two is about the king of the jungle, which is sometimes debated, but lions having a second roar that scientists have only just discovered, which could potentially help with conservation efforts.

• 37:20Krishna Choudhary?

  Yeah.

• 37:20Lester Nare?

  And so this was a weird story. What's instrumental about this discovery here in animal behavior?

• 37:25Krishna Choudhary?

  Yeah, I mean, so everyone is aware of the lion's roar, right? Lion is the king of the jungle. It has a roar and everyone kind of knows what it sounds like, kind of like that, exactly. And now what they've done is they've taken thousands of hours of recordings of lions and they've ran that through an AI classifier. And what the AI has figured out is there's actually two subtypes of roars that lions make. There's the first one, this loud one that everyone knows. And then there's a second one that is a little bit lower, takes a little bit longer, and is a lot more unique to each lion. So when we say this can be used for population studies, what you could do is you could have

• 38:10Krishna Choudhary?

  a recording of the jungle and you can have an AI then go through and each lion is going to have a different voice profile, right? And so you can identify how many individuals there are in a certain territory. Where are they going? You can identify a lion here and then a month later, if you like went to the neighboring national park, you can say, oh, wow, he like traveled all the way, right? This, um, the recordings were taken from Tanzania and Zimbabwe.

• 38:34Lester Nare?

  Ah.

• 38:35Krishna Choudhary?

  So a lot of these lions have collars that they've been fitted to sort of track and they also have little microphones. And so that's where the data set comes from. I think it could be huge. One thing that I learned when I was reading about this story is that, you know, the MGM roar?

• 38:51Lester Nare?

  Yeah.

• 38:51Krishna Choudhary?

  The Metro Goodwin mayor?

• 38:53Lester Nare?

  Yes.

• 38:54Krishna Choudhary?

  Lion's roar that comes in the beginning of all these different films.

• 38:58Lester Nare?

  Now owned by Amazon.

• 39:00Krishna Choudhary?

  Yes, that's actually now, that's actually a tiger roaring.

• 39:03Lester Nare?

  Yes.

• 39:04Krishna Choudhary?

  It's not even a lion.

• 39:05Lester Nare?

  For those who don't know, the best roar of the big cats, 100%.

• 39:10Krishna Choudhary?

  Is the tiger.

• 39:10Lester Nare?

  100%.

• 39:11Krishna Choudhary?

  Yeah, the lion is not that great. And so they used a tiger, but they put a lion there. It's like, it's like dubbing.

• 39:18Lester Nare?

  It's, it's very low. Lion's roar is a kind of low energy jib. They're a little, they're a little apathetic.

• 39:24Krishna Choudhary?

  Exactly.

• 39:25Lester Nare?

  Tiger, again, the mascot of the greatest university institution on the planet.

• 39:32Krishna Choudhary?

  That's right.

• 39:32Lester Nare?

  It's chosen for a reason.

• 39:33Krishna Choudhary?

  Yeah.

• 39:35Lester Nare?

  Also, a great Zim shout out. Well done.

• 39:37Krishna Choudhary?

  Yeah.

• 39:37Lester Nare?

  Uh, it's not always that we can get to plug, uh, my, my, uh, my motherland.

• 39:43Krishna Choudhary?

  Yeah.

• 39:44Lester Nare?

  In the story. That's a good one.

• 39:45Krishna Choudhary?

  I thought that was a cool one. And the research comes out of the University of Exeter and the University of Oxford. And it's currently out in Ecology and Evolution, the journal.

• 39:53Lester Nare?

  Fantastic. We're going to move to our third breakdown story, uh, related to NASA's Juno mission. Reveals that Jupiter is much smaller than we previously thought. What's going on here?

• 40:07Krishna Choudhary?

  Yeah, this one was weird because I was like, how do you, how do you get the size of a planet wrong?

• 40:12Lester Nare?

  Actually, one that's very.

• 40:13Krishna Choudhary?

  It's like quite big. Like, how do you, how do you do that? Right? And then it's actually an interesting question. How do you measure the size of a planet?

• 40:21Lester Nare?

  Yes.

• 40:21Krishna Choudhary?

  Right? Um, so the way that they measured it before was when Voyager one and two and Pioneer 10 and 11 went to Jupiter. What you can do is you can beam, you know, you're beaming data to JPL at all times, right? The NASA Deep Space Network, which currently is at JPL. I don't know where it was back then. So I shouldn't say that they were beaming to JPL, but now they do. Um, so you're beaming data to JPL. At some point, you're going to go behind the planet. So you're going to get blocked. And then at another point, you're gonna. Get back, you're gonna start beaming. That occlusion tells you how big Jupiter is, the slice of Jupiter at the time, right? Now with Voyager 1 and 2 and Pioneer 10 and 11, you only really have six data points, right?

• 41:06Krishna Choudhary?

  Because it's like, you go behind, you go, so there's but one, two for each, and then there's like, you know, only four, so eight, sorry, eight data points, right? Because you're only going once. They didn't revolve around Jupiter. They just like visited and then they were on their way to the other planets. Yep. Juno has been going around Jupiter for quite a while, right? So we get more measurements, which means that our airbar can get smaller. Now our airbar is less than half a kilometer. Okay. Which is quite good. Quite nice. And since it arrived in 2016, it's collected a lot more data, okay? What these guys did was with that additional data, what you can do is now actually calculate the size of Jupiter,

• 41:47Krishna Choudhary?

  not only, you know, at the equator, but also at the poles, because it's sort of traversing latitude on Jupiter as well as it moves around. What ends up happening is you send radio waves. Now imagine when there's no Jupiter between you, the radio wave just goes through fine. As you start approaching the disk of the gas giant, the radio waves are gonna go through the top parts of the atmosphere, which have a bunch of ions, the ionosphere that we also have on Earth. And those ions are going to start changing the frequency of the radio waves. And it's also gonna start bending the radio waves, right? But just because of refraction. And so you're gonna get that data too. The frequency is gonna change.

• 42:30Krishna Choudhary?

  And then, at some point, it's gonna get completely cut off. Right. Right? And you're doing it at multiple latitudes. What ends up happening is, so we found out that the poles are 12 kilometers smaller than previous measurements. Okay. And the equator is only a little bit smaller by 2.5 miles. So it's flatter and the whole thing is smaller. Okay. And that's what we found. This is important because if we want to make models of Jupiter, like the weather on Jupiter, what kind of... Weather phenomenon, we'd see the climate on Jupiter, things like that. Even a number this small is quite a big deal.

• 43:07Lester Nare?

  Significant for any derivative calculations.

• 43:09Krishna Choudhary?

  Yeah.

• 43:10Lester Nare?

  Or simulation creation.

• 43:12Krishna Choudhary?

  Yeah. Oh, that was cool.

• 43:14Lester Nare?

  Very cool. That one's out of NASA.

• 43:16Krishna Choudhary?

  Yes.

• 43:17Lester Nare?

  Jupiter, smaller, flatter, but still very big.

• 43:21Krishna Choudhary?

  Yes.

• 43:22Lester Nare?

  Very, very big.

• 43:23Krishna Choudhary?

  Yeah, very, very big. And it was in nature astronomy.

• 43:26Lester Nare?

  So our last story is about physicists getting a peek at how matter is born from nothing.

• 43:34Krishna Choudhary?

  Yes.

• 43:36Lester Nare?

  Okay.

• 43:36Krishna Choudhary?

  Out of the vacuum.

• 43:37Lester Nare?

  I'm gonna need an explanation for this one.

• 43:40Krishna Choudhary?

  Out of the quantum vacuum. Right. Okay, so we really want to understand how particles like protons and neutrons get created, especially in the very, very early universe, right after the Big Bang. This mechanism of creation of these particles called hadrons. Hadrons are, you know, this collection of quarks. Quarks are the fundamental atomic particles of the nucleus, not protons, but what's inside the protons.

• 44:10Krishna Choudhary?

  And it's a little unclear how that forms. Okay? There was something called a quark gluon plasma. Quarks are the particles. Gluons are the force carriers of the strong nuclear force. That's the thing that binds a nucleus together. Because if you think about it, the nucleus is a bunch of positive charge, right? Protons on top of protons on top of protons. All that positive charge wants to get away from the other positive charges. Because electromagnetism wants it to leave. But what keeps them together is the strong nuclear force, which overpowers the electromagnetic force. The strong nuclear force is very, very weird. Because if you think about gravity and electromagnetism.

• 44:52Krishna Choudhary?

  The farther you get, the weaker the force. The strong nuclear force up to a certain length scale, the farther you get, the stronger the force. It's very weird. It leads to something called quark confinement, which is this idea that if I have two quarks that are right next to each other, and I start spreading them apart, the force between them is going to get bigger. What does that really mean? That means the energy density in between them is going to get really big. At some point, the energy density is going to be enough where two quarks pop out of existence, out of the, out of just the gluon energy that's there, right? And so you're never going to see quarks on their own. So it's been really hard to study how protons form because you never see the individual constituents on their own.

• 45:38Krishna Choudhary?

  Does that make sense?

• 45:39Lester Nare?

  Yes.

• 45:39Krishna Choudhary?

  Okay. This new paper is about a technique that lets us study that formation process

• 45:45Lester Nare?

  That process.

• 45:46Krishna Choudhary?

  without really relying on trying to see a single quark on its own.

• 45:50Lester Nare?

  Okay.

• 45:50Krishna Choudhary?

  Okay. This is from the start collaboration at the Brookhaven National Lab. They have something called the Relativistic Heavy Ion Collider. This is the largest particle collider that we have in the US, although, you know, people at Fermilab might disagree with that. Depends on what you're trying to talk about.

• 46:06Lester Nare?

  If you're from Fermilab and you want to complain about that factoid, please put in the comments.

• 46:10Krishna Choudhary?

  Yeah, go ahead. And so what, what happens is in this Relativistic Heavy Ion Collider, there's a ton of energy, right? And sometimes what you get is a strange and an anti-strange quark that pops out of the vacuum, just from vacuum fluctuations. Now, vacuum fluctuations, meaning the quantum vacuum is the lowest energy state, but because of the Heisenberg uncertainty principle, that lowest energy state is still going to have a tiny bit of jiggle, right? And that jiggle means there's really particles popping in and out of existence. Sometimes you get a strange and an anti-strange particle that pop in and out of existence. That could borrow energy from this high collision that we're getting inside this collider.

• 46:54Krishna Choudhary?

  And when it borrows energy, it turns into a cousin of the proton called the lambda hyperon. So it's still three quarks. The proton is up, up, down, and the neutron is up, down, down. Those are the three quarks that make up the proton and the neutron. Here, you've got a strange up, down, or a strange up, up. That's this lambda hyperon. So it's like a cousin of the proton. You're going to get The lambda particle and the anti lambda particle because you always have to conserve charge and all this other stuff. But the spins of these guys are going to be correlated because the strange, the strange quarks that came out of the vacuum have correlated spins, right?

• 47:34Krishna Choudhary?

  And what they could do is measure the spin correlations of these particles. Okay? When you do that, that's something I can actually measure, right? I can, I can wait for these lambda particles to decay into different products, measure the angular momentum of all these different products, figure out what the original spin was, and then I could see if these two are correlated because they, you know, formed at the same time and things like that. What's cool is this gives a way to think about how hadrons form without having to worry about trying to observe individual quarks. Now we can actually peer into this process of how does that three constituent particle form from a thing out of the vacuum? How does that spin correlate?

• 48:19Krishna Choudhary?

  If they're closer together, there's higher correlation. If they're farther apart, there's less correlation. And, you know, it's kind of cool because the Relativistic Heavy Ion Collider is retiring now and it's going to become part of something much bigger called the Electron Ion Collider. It's part of the DOE. What they're doing is building with the existing infrastructure at Brookhaven, this larger collider now. So this is one of the last things that it did, but it's, and it's very fundamental. It was, it was in nature out of the star collaboration. It's kind of a, you know, the swan song of that collider. And it's, it's quite fundamental. It's, people are very excited.

• 48:57Lester Nare?

  Just a quick point of order for those who don't know, the DOE is the Department of Energy. They are the federal agency which is in charge of all of our nuclear weapons, for example, and anything that has a nexus to atomic or nuclear energy weapons and fundamental research in those categories. And what's interesting about this, it sort of sounds like we basically have found, it's this whole tracing mechanism, similarly to our past story. It's like, we found a way to look at the derivative products or outcomes and then reverse engineer. With math, what the, where they came from.

• 49:35Krishna Choudhary?

  Yeah.

• 49:35Lester Nare?

  Which allows us to not have to worry about the ability to observe.

• 49:39Krishna Choudhary?

  Yeah.

• 49:39Lester Nare?

  Because we have enough data to get to the original state.

• 49:43Krishna Choudhary?

  Exactly.

• 49:44Lester Nare?

  Derivative observations.

• 49:45Krishna Choudhary?

  Yeah, yeah. And this is a common technique in particle physics. Like when we, when we found the Higgs boson, for example, at CERN, right? Again, it's always these decay products that you wanna catch. And then from that, reconstitute what the Higgs was. What is the mass of the Higgs, so on and so forth. So this is doing it, but now it's actually looking at spin. Looking at the angular momentum of these tiny little objects and trying to make it happen, right? They're trying to trace back what's happening with the quantum vacuum.

• 50:14Lester Nare?

  You know why I love this story?

• 50:16Krishna Choudhary?

  Of course.

• 50:17Lester Nare?

  Because if we're talking about the quantum vacuum or vacuum energy, obviously, we have to talk about zero-point energy.

• 50:25Krishna Choudhary?

  Yeah.

• 50:26Lester Nare?

  And that's how the aliens are getting here, guys.

• 50:27Krishna Choudhary?

  Exactly.

• 50:28Lester Nare?

  It's obviously, they figured out how to manifest and utilize vacuum energy in a very similar way to maybe how we're describing.

• 50:36Krishna Choudhary?

  Yeah, dude.

• 50:37Lester Nare?

  Not proven, I'm sort of just putting it out there, getting it into your minds, letting it ruminate a little bit. Maybe we'll have a future research story that actually points to it.

• 50:48Krishna Choudhary?

  Mm-hmm.

• 50:49Lester Nare?

  But we're not quite there yet. But speaking of the quantum, we're gonna end the rundown here, and we are going to go into our story number two, which is a quantum sensing story. Uh, the question here, or the idea here is we have this new multi-parameter estimation with an array of entangled atomic sensors. This was published in Science in January from the University of Basel, as well as Sorbonne in France, the laboratory Castal-Brocel.

• 51:24Krishna Choudhary?

  Nice.

• 51:25Lester Nare?

  And the, yeah, it was, some, one of us can kind of pronounce French stuff. And the idea here is how can quantum entanglement revolutionize, uh, measurement precision?

• 51:37Krishna Choudhary?

  Yeah.

• 51:37Lester Nare?

  And that appears to be what we have going on here.

• 51:40Krishna Choudhary?

  Yes. Uh, measurement precision is very big in physics. Scientists love to measure things extremely precisely, okay? Now, classical measurement is limited by something called the standard quantum limit. Okay? The idea is... The quantum world is discrete, which means, for example, if I want to measure photons that are coming into my photo detector, there's going to be fluctuating power on that photo detector because photons are going to be arriving one by one. This is the idea of shot noise, okay? And because the quantum world is what it is, it's quantum, there's all this discrete stuff, you're going to get an error based on whatever measurement because of the discreteness

• 52:25Krishna Choudhary?

  of the world that you are measuring, okay? And that error goes like one over the square root of N, where N is the number of particles that you've sort of observed, okay? We want to go even beyond that, right? Because the fundamental limit, when it comes to actually recording something is really the Heisenberg uncertainty limit, right? And what this particular paper is doing is what they've done is successfully split a cloud of atoms that they've made into a Bose-Einstein condensate. They've split it into three, and what they're doing is using the entanglement between those

• 53:04Krishna Choudhary?

  clouds of atoms to then up their game on how sensitive they can measure something. They can do it with multiple parameters, so you can measure something here on the left, you can measure another thing on the right, so on and so forth, and you can do it across space. And they're very clever about how they're able to use this entanglement to then get beyond that standard quantum limit. They're starting to probe the real limit, which is the Heisenberg uncertainty principle, right?

• 53:36Lester Nare?

  I will just note, as someone who comes from the software world, SQL, meaning standard quantum limit, is a little bit, maybe I've done a different naming convention there because SQL is a popular database.

• 53:49Krishna Choudhary?

  Oh, really? Oh, yeah, SQL.

• 53:51Lester Nare?

  So it's, it's...

• 53:52Krishna Choudhary?

  For sure. I don't think physicists care, though.

• 53:55Lester Nare?

  They, 0%.

• 53:56Krishna Choudhary?

  I'm sure they use SQL all the time. I mean, I use it all the time in my work, but yeah. For us, at least for the AMO guys, SQL means standard quantum limit.

• 54:05Lester Nare?

  It's okay. We can always learn multiple algorithms.

• 54:08Krishna Choudhary?

  Yeah. Context switching, right?

• 54:10Lester Nare?

  Exactly.

• 54:11Krishna Choudhary?

  So let's get into uncertainty and information, right? When it comes to the real limit, it is the uncertainty principle that's been guided by Werner Heisenberg in 1927. He came out with the uncertainty principle and people have been chasing this limit ever since. This is the limit of the universe. You can't go beyond this just because of the nature of quantum mechanics and the nature of our reality. Right? The classical limit is the standard quantum limit, one over square root of n. You've got shot noise because there's a uncertainty on how much you can measure based on discrete amount of stuff coming in. Now here's the deal, though. The Heisenberg uncertainty limit is a limit on the product of two observables.

• 54:56Krishna Choudhary?

  The, the product of the noise on two observables. For example, the standard one that you think about is momentum and position. Right? If I know my position really well, then I don't know my momentum that well and so on and so forth. Because the product of these two numbers, if one number is small, the other has to be big such that the product remains about the same. But what you could do is exactly what I said. If I really want to know my position very, very well, I could not care about my momentum. I could squeeze my observation such that my delta on one axis is very big. And my delta on another axis is really small.

• 55:38Krishna Choudhary?

  So instead of a circle where the error in my, let's say X and Y, these are two different observables is the same. My error on X could be really small. That could be my position and my error on the Y axis, which is my momentum could be very big because maybe I don't care. Maybe I don't care to actually measure that. And when I do this with this quantum metrology, I could get a hundred times better than my standard quantum limit and still stay above the Heisenberg uncertainty limit. Okay. Okay. These are called squeezed states. Okay. Because you're squeezing in one direction and you're like. Stretching in the other direction and squeezing in the direction that you care about.

• 56:18Lester Nare?

  Right. We're basically, we want to increase the level of precision in one of these two observed states or dimensions.

• 56:25Krishna Choudhary?

  Yeah.

• 56:26Lester Nare?

  And I'm trying to understand why.

• 56:31Krishna Choudhary?

  Yeah.

• 56:32Lester Nare?

  But we'll get there. But the first idea is, instead of having an even distribution on error across both observed states, we're trying to maximize precision on one while giving up precision on the other.

• 56:44Krishna Choudhary?

  Yes. And to think about like, why would you want to do this? Let's go back to, let's go into like, example like LIGO, the gravitational wave observatory, right? Where we want to measure the position of our spin, of our mirrors really well, right? So I want to measure how far apart one leg is versus another, right? I want to do that. Now, the way I do that is through interferometry, where what I'm really trying to measure is the amplitude of the light that's coming when it goes from on one arm versus the other arm, and it comes back, it interferes. If both the arms are exactly the same length, then the light is going to cancel and I'm going to get zero brightness.

• 57:26Krishna Choudhary?

  But if there's a slight offset, then I'm going to get a tiny amount of brightness in my detector, because the light is not exactly canceling out. The only thing I care about is the amplitude.

• 57:36Lester Nare?

  Right.

• 57:37Krishna Choudhary?

  Right?

• 57:37Lester Nare?

  Yes. Yes.

• 57:39Krishna Choudhary?

  And I couldn't care about, let's say, the frequency of the light, because I know that the laser is my frequency.

• 57:46Lester Nare?

  Right.

• 57:46Krishna Choudhary?

  Right?

• 57:47Lester Nare?

  Right.

• 57:47Krishna Choudhary?

  So this is just like something that I've, I'm sort of doing a back of the envelope here. Obviously, there's other things, but that's the idea.

• 57:54Lester Nare?

  Yes.

• 57:54Krishna Choudhary?

  What if you only care about one thing? In LIGO, the only thing I care about is the amplitude of the light.

• 57:59Lester Nare?

  Yep.

• 57:59Krishna Choudhary?

  Right?

• 57:59Lester Nare?

  Yes.

• 58:00Krishna Choudhary?

  Because then I can make this, this kind of gravitational wave drawing.

• 58:05Lester Nare?

  That makes sense.

• 58:05Krishna Choudhary?

  Okay?

• 58:06Lester Nare?

  Yes.

• 58:06Krishna Choudhary?

  So.

• 58:08Krishna Choudhary?

  The challenge is, there's incompatibility between different observations. For example, what I was saying with the position and momentum. Heisenberg says you can't measure both at the same time. And the other thing is, what if I want to measure at two different spots in space? Okay, that is what, so what ends up happening is, you've got like two different spots in space. What you can do is instead use entanglement. This is your quantum action at a distance, spooky action at a distance, right? This won the Nobel Prize a few years back in, um, in physics. We always use Alice and Bob for these, um, experiments. I don't know why, there's even a quantum company called Alice and Bob.

• 58:51Krishna Choudhary?

  Because that is what we use to show entanglement and teach entanglement. You get a pair of particles, you send one particle to Alice, you send the other particle to Bob. And then you ask one of them to measure their particle. And that's immediately going to affect, in some sense, the measurement that Alice has. Okay, because these two particles, because they're entangled, they're connected to each other across space and time through some weird mechanism. That's like kind of faster than the speed of light, but like not really, but there's nuances. But what ends up happening is if I measure the spin of here, that's going to affect the spin here. At least that's what it looks like. The two are correlated even across these distances, okay?

• 59:34Krishna Choudhary?

  And what these guys figured is, well, actually, what we could do is maybe use this to then up our game in terms of measuring different things at different locations. Okay, they use something, you see what I'm saying? Like, we'll get into it. The first Bose-Einstein condensate, that's what they used. The first Bose-Einstein condensate was in the late 1990s in Boulder, they made it. This is kind of sometimes colloquially called the fifth state of matter. What you end up doing is cooling atoms down to just above absolute zero, such that all of these individual atoms behave like a single entity. They behave like a single quantum wave packet. Yes.

• 1:00:18Krishna Choudhary?

  Okay, they're just riding on top of each other.

• 1:00:22Krishna Choudhary?

  What these guys did, Lee and others, in 2026, in this particular paper, is they created a boson stand condensate. And then they spatially split that macroscopic entangled state and made a bunch of different atomic sensors that were entangled with each other, made an array. And then they could estimate whatever thing they were trying to estimate across these different things while still maintaining entanglement.

• 1:00:51Lester Nare?

  Very cool. You guys, this is... I just... I cannot get over how creative

• 1:01:01Krishna Choudhary?

  Yeah.

• 1:01:02Lester Nare?

  some people are in, at the edges of our understanding and being so clever. Because I can already, I can already see where this is going. But let me, let's continue because I'm curious about a couple of details, but I think you're going to get to them.

• 1:01:16Krishna Choudhary?

  Okay.

• 1:01:17Lester Nare?

  Around how, because ultimately, what we're trying to be able to do is not only, before we talk about increasing precision in one dimension, because of the Heisenberg uncertainty principle, we can't know two observable states with high precision. And this has sort of been the boogeyman that everyone's been trying to work around. And this is, see, appears to be a very clever way to hijack

• 1:01:39Krishna Choudhary?

  Yes.

• 1:01:40Lester Nare?

  the limitations using quantum entanglement.

• 1:01:43Krishna Choudhary?

  And that multiple parameter is what's interesting, right?

• 1:01:46Lester Nare?

  Right.

• 1:01:46Krishna Choudhary?

  Because what you could do is say, hey, what if I just measure the position over here?

• 1:01:50Lester Nare?

  Right.

• 1:01:50Krishna Choudhary?

  With a momentum over here?

• 1:01:51Lester Nare?

  Exactly.

• 1:01:52Krishna Choudhary?

  Because those two, you never said... You didn't, you know what I mean? That's what's happening.

• 1:01:58Lester Nare?

  Yes, okay, got it, okay.

• 1:02:01Krishna Choudhary?

  So, so how did they do it? They've got this thing called the atomic chip. It's microfabricated gold wires that create this, these very steep magnetic field gradients. Okay? And with those very steep magnetic field gradients, you can trap rubidium 87 atoms. And you can use those rubidium atoms as a two-state qubit system. Because the, the outer, the outer electron of that rubidium atom, the spin of that could be either with the nucleus or opposite the nucleus, the same way we talk about the hydrogen hypersplitting. This is the rubidium hyperfine ground state. And that's a two-level system. You can tightly confine that thing. And you can have the atom transfer between, you know, either the electron spinning this way or spinning this way

• 1:02:45Krishna Choudhary?

  by sending in a radio frequency pulse.

• 1:02:47Lester Nare?

  This is our zero or one.

• 1:02:49Krishna Choudhary?

  Yeah, so you've got you've got a kind of qubit here, right? And you can tightly confine this this cloud of atoms near that chip surface. And when you tightly confine it at really low temperatures, you get a Bose Einstein condensate. Okay, great. That's no longer that cutting edge anymore, which is kind of crazy to think about.

• 1:03:05Lester Nare?

  Right.

• 1:03:06Krishna Choudhary?

  Right. In like 20 years, it's like, oh, yeah, okay, fine. You made a beat in Bose Einstein condensate. Great.

• 1:03:11Lester Nare?

  Cool.

• 1:03:12Krishna Choudhary?

  Yeah. Next, what you do is you split them apart. Okay? So now, using your radio frequency, what you can do is toggle that atom and very slowly turn the single potential well, which is where the atoms are sitting. You can start making a little hill in the middle and the atoms are going to split into two.

• 1:03:36Lester Nare?

  Two wells.

• 1:03:37Krishna Choudhary?

  Okay, you got to do this very, very slowly. Okay, you got to do this extremely slowly, adiabatically is what we call it. And when we get there, we're going to create these radio frequency dressed potentials where you have multiple little wave packets of atoms. So a single atom is now being split up into multiple different clouds that are still entangled because we did it slowly enough that the entanglement of that original Bose Einstein condensate is splitting.

• 1:04:07Lester Nare?

  And just as a quick note, just for my recollection about Bose Einstein condensates, the idea there was, you know, when what you are able to do is you create one sort of macro object that maintains all the parameters as one sort of holistic thing.

• 1:04:25Krishna Choudhary?

  Yeah, it's one way function.

• 1:04:27Lester Nare?

  It's one way function.

• 1:04:28Krishna Choudhary?

  Yeah.

• 1:04:28Lester Nare?

  Which has its own inherent value.

• 1:04:30Krishna Choudhary?

  Yeah.

• 1:04:31Lester Nare?

  In and of itself.

• 1:04:32Krishna Choudhary?

  Yes.

• 1:04:32Lester Nare?

  And so now we're building on top of that concept to take that like macro, like this one way function across multiple component parts. And we're now splitting it where they are maintaining entanglement.

• 1:04:47Krishna Choudhary?

  Yeah.

• 1:04:48Lester Nare?

  Um, which is then gonna be our next, but I just want like, I'm correctly understanding the idea behind the bosons.

• 1:04:53Krishna Choudhary?

  Yes, exactly. Yeah. It's one wave function that we're now splitting into, I guess, two wave functions. But the two way functions, because they were derived from the first one and we're doing it slowly enough. The entanglement is still very strong.

• 1:05:05Lester Nare?

  Sustaining. Okay, okay.

• 1:05:06Krishna Choudhary?

  Right? And now what we can do with those multiple clouds of atoms is we can measure one quantity here. We can measure another quantity here, another quantity here, so on and so forth. But because they are entangled, these are not independent variables. And so the noise is not independent. This is what's crucial. Okay? If they were independent, what would happen? If they were independent, let's say I've got atoms, atom cloud A and atom cloud B. Okay? I measure some parameter on atom cloud A. That's gonna be, let's say, you know, A plus or minus some number, because that plus or minus number is an error.

• 1:05:45Lester Nare?

  Yes.

• 1:05:46Krishna Choudhary?

  With B, I'm gonna measure plus or minus some number, right? If I wanted to calculate, let's say, a difference between what is A and what is B and things like that. Those errors would be independent. And when I calculated that sum or that difference, the error would only go down by one over the root two.

• 1:06:01Lester Nare?

  Okay.

• 1:06:02Krishna Choudhary?

  Okay? Because they're independent.

• 1:06:03Lester Nare?

  Yes.

• 1:06:05Krishna Choudhary?

  Now, when I measure A plus or minus something and B plus or minus something. That plus or minus is not independent. They're related. So what I could do is measure something like A plus B and A minus B. Or if I have three things, I can measure A plus B plus C, A minus B plus C, A minus B minus C. I could measure all of these different combinations. And the noise in that total measurement is going to be smaller than if I would have measured the two independently. That is the key.

• 1:06:38Lester Nare?

  Oh, my goodness. Yes. Yes.

• 1:06:41Krishna Choudhary?

  We're doing like. Number magic here.

• 1:06:44Lester Nare?

  Yeah, yeah.

• 1:06:44Krishna Choudhary?

  We're like measuring combinations of states rather than individual states. And whereby we do that, because the noise is correlated, because the stuff is entangled.

• 1:06:53Lester Nare?

  Yes.

• 1:06:53Krishna Choudhary?

  The total noise is smaller.

• 1:06:55Lester Nare?

  It's smaller on the aggregate computation, on the aggregate measurement.

• 1:06:59Krishna Choudhary?

  Yes.

• 1:07:00Lester Nare?

  As opposed to the individual measurement. Fascinating, which goes back to that. Now I'm thinking about that original chart we looked at with the circle and the oval. And the implications on the level of precision.

• 1:07:11Krishna Choudhary?

  Yeah.

• 1:07:11Lester Nare?

  Because the noise is now.

• 1:07:13Krishna Choudhary?

  Yeah.

• 1:07:13Lester Nare?

  Smaller because we're making, we have this aggregate measurement.

• 1:07:16Krishna Choudhary?

  Yeah.

• 1:07:17Lester Nare?

  Allows us to decrease noise.

• 1:07:19Krishna Choudhary?

  This is, it kind of makes sense.

• 1:07:20Lester Nare?

  It, it, it does. And this feels very cool because in theory, let me pause, let me let you continue.

• 1:07:28Krishna Choudhary?

  Yeah, so let's, let's see how they actually did it, right? So they, as I said, they've got, um, they've got a single wave function. With the bosons and condensate. Now let's see what they do with just two clouds. So when they do two clouds, they've got this local microwave that, you know, splits it into two clouds. There you can actually see the sort of two clouds.

• 1:07:46Lester Nare?

  Yes.

• 1:07:46Krishna Choudhary?

  Right next to each other about like a few, um, tens of microns to hundreds of microns apart.

• 1:07:51Lester Nare?

  Yes.

• 1:07:52Krishna Choudhary?

  Right? And what we're going to do is measure some parameter, which effectively means we're measuring like a phase of the wave function. It's like an angle difference between the two things, like we're measuring an angle at all times.

• 1:08:03Lester Nare?

  Okay.

• 1:08:04Krishna Choudhary?

  On something called a block sphere, but we don't have to get into that. We're measuring some parameter. Okay, the two parameters are correlated. And that's why when you look at, you know, if we were to measure phase two versus phase one, the, the clouds are not completely circles. They're spin squeezed. They're these ellipses, right? One direction is the sum theta, um, like phase one plus phase two. The other direction is the difference. Phase one minus phase two. What you can measure is let's say on one end, we measure the sum, which is the axis perpendicular to the ellipse. So that's the squeezed axis, the part that's like shorter.

• 1:08:42Lester Nare?

  Yes.

• 1:08:42Krishna Choudhary?

  On that ellipse.

• 1:08:43Lester Nare?

  Yes.

• 1:08:43Krishna Choudhary?

  We measure that. And then what I can do is rotate the second one. So that now I'm. The squeezed axis is on the difference part. And now I measure the difference. Okay, that's another key thing. They could rotate and manipulate these things such that whatever axis they wanted to do, that's the one that would be squeezed. Okay, so you've got this ellipse and you're like, I want to measure here. Now let's rotate. Now I want to measure here. So they're able to do both. It's not at the same time, so you're still not cheating. Yes, right. Heisenberg is still happy. But at different times, you're getting these measurements. You've measured the sum in one. You've measured the difference in the other. So now with the sum, I can find the average value of this parameter. With the difference, I can find the gradient.

• 1:09:26Krishna Choudhary?

  I can find what is the difference between here and here. Right, and I'm still keeping Heisenberg happy.

• 1:09:31Lester Nare?

  Yes.

• 1:09:31Krishna Choudhary?

  But because of this entanglement and all of the fancy tricks that I've done.

• 1:09:35Lester Nare?

  Yes.

• 1:09:36Krishna Choudhary?

  Each measurement now of the sum and the difference. I've beaten the standard quantum limit.

• 1:09:41Lester Nare?

  Right.

• 1:09:42Krishna Choudhary?

  Right, because I'm not measuring independent.

• 1:09:44Lester Nare?

  Right.

• 1:09:44Krishna Choudhary?

  I'm not measuring phase one and phase two, and then I'm taking the difference. I'm actually just measuring the difference.

• 1:09:49Lester Nare?

  Yes. Right. Through this mechanism of the atomic sensors in the Bose-Einstein condensate. Yeah. Which gives you a level, which gives you this mechanism by which to be able to measure, where now the aggregate measurement has less noise than the independent measurements.

• 1:10:12Krishna Choudhary?

  Yeah.

• 1:10:13Lester Nare?

  And because you can now also rotate in the way that you described it, we can get a level of precision across multiple observable states.

• 1:10:20Krishna Choudhary?

  Yes.

• 1:10:21Lester Nare?

  Instead of having to choose one or the other. So in the LIGO example you talked about earlier, the example is we just care about one.

• 1:10:28Krishna Choudhary?

  Yeah.

• 1:10:28Lester Nare?

  You know, thing which is the mirrors. With this conceptually, you can now expand that to say, well, we care about two things. And we can now get a level of precision above the SQL.

• 1:10:40Krishna Choudhary?

  Yeah.

• 1:10:41Lester Nare?

  Closer to the Heisenberg limit.

• 1:10:43Krishna Choudhary?

  Yeah.

• 1:10:43Lester Nare?

  Which is theoretically the actual limit of observational precision.

• 1:10:46Krishna Choudhary?

  Yeah, we can't get better than that, but we'd like to get as close to that as possible. And here, what we're doing is we're measuring the actual, let's say, difference, right? We're measuring four minus three equals one. Before, we were measuring four, three, and then we'd have to do the math to be like, oh, four minus three is one. Here, we're just measuring one. And the plus or minus on that one is much smaller than we would have done otherwise.

• 1:11:07Lester Nare?

  Because the four and the three would have had their own individual error. So the noise at the, when you get to the. Conclusion is much higher. We're actually observing the conclusion with, okay, very, very, very fascinating.

• 1:11:19Krishna Choudhary?

  And now with three, we can do all three combinations, right? With three, I can do the plus, plus, plus, plus, minus, plus, plus, minus, minus, so on and so forth. And the diagonals that you see is what they're actually doing right? Like, what are, what are you actually measuring? This needs to be a proof of concept, right? It's not like they're measuring some magnetic field that's changing. Because if you were to do that as a first experiment, you'd be like, well, how do you know you even measured it correctly?

• 1:11:45Lester Nare?

  Correct. Yeah, that makes sense.

• 1:11:46Krishna Choudhary?

  So what you do, what do you do? You actually encode the parameter, you engineer in, and you encode the parameter, and then you say, can I measure what I encoded?

• 1:11:54Lester Nare?

  So you ultimately know what the result is prior to measurement, such that it's controlled?

• 1:11:58Krishna Choudhary?

  Yeah, because this is a controlled experiment. This is a proof of concept, right? You need to show that it works on stuff that you already know the ground truth for. And that's what shows in the, in the diagonal. It's like they're trying to, for the off diagonal stuff, it's like you, you encode something, but you're trying to measure in some other state. Like you encoded plus, plus, minus, but then you try to measure plus, plus, plus. You're not able to do that, because that wasn't the point. But that's, and that's kind of the point of that diagonal. Along the diagonal, you get this boost in sensitivity. Okay, that's the negative decibels. The negative decibels is how much more boost do you have over the quantum limit? You're getting like negative five decibels, which is like a three X improvement.

• 1:12:35Lester Nare?

  Improvement, right? Right. And that makes sense. The point is, you know, the, in order to be able to sufficiently prove and convince that this is true, you need to be able to show that it measures something we have a discrete value for.

• 1:12:49Krishna Choudhary?

  Yeah, yeah, yeah. It's like something you've engineered that you know the ground truth for, and then you're like, okay, I was able to do this. Now I can go and use this to measure other stuff, right?

• 1:12:57Lester Nare?

  Yeah, that makes sense.

• 1:12:58Krishna Choudhary?

  And the applications for this are very cool, okay? So for one, you can measure magnetic fields really, really precisely. You can create kind of like a vector camera that images the full magnetic vector field. So you have the X component, the Y component, and the Z component of some material, let's say. You can create this sensor now and measure inside that material, the magnetic fields in each direction. You can do this like- Trick where it's like, okay, now I care about X. Let's measure X. Now I care about Y. Let's measure Y. I mean, again, you're not going to do it simultaneously. But if you do it a thousand times and you have reasonable assumptions about how constant magnetic field is, you can get to pretty nice precision, right? You can just repeat the experiment over and over again.

• 1:13:42Krishna Choudhary?

  Internal, you can have a quantum internet of clocks. Okay, so you know, with by entangling atoms at different sites in a kind of lattice, what you can do is have a distributed clock network where there's a clock here, there's a clock here, extremely precise based on this two level splitting. And and then you can measure gravitational redshifts at the millimeter scale. Meaning I have my boson condensate here. I raise it by one millimeter. If I raise it by one millimeter, it's going to feel the earth a little bit less. By a millimeter, if it feels the earth a little bit less, time is going to be sped up a little bit more.

• 1:14:26Krishna Choudhary?

  And you can actually measure that by having the clock decide where it is on a millimeter scale, right? And finally, if you're like interested in dark matter, there's this one, you know, theory of dark matter and of like, if you want to measure gravitational waves, when a gravitational wave comes through, the each different part of the sensor is going to feel the gravitational wave at different time points. Yep. So you can measure it that way. Yep. If you've got a dark matter particle or a dark matter quantum wave that goes through, you're going to get a jitter. And so the the more sensitive we can get, the better we can measure these really, really tiny things.

• 1:15:02Lester Nare?

  Because the point is that each points of the measurement apparatus, you're going to have up to a three X increase in level of precision, which when we're talking about gravitational wave detection is extremely valuable.

• 1:15:16Krishna Choudhary?

  Yes, it's extremely valuable. And I mean, for the proof of concept, you know, when they, when they went from two at the level of two, I think they got about a three X precision. When they got to three, they didn't have a three X. It was only like maybe, you know, 50, 10% or something like that.

• 1:15:31Lester Nare?

  Which is fair.

• 1:15:31Krishna Choudhary?

  Right, which is fair.

• 1:15:34Krishna Choudhary?

  But it's a proof of concept, right? The, we need a large number of atoms. Right now, they've only got about 5,000 atoms in this bosons condensate. If you had something like, you know, 10 to the 6, a million atoms, then you could start competing with classical sensors, right? And then if you have even more, now you're really going gang muscle.

• 1:15:50Lester Nare?

  Yes, yes.

• 1:15:51Krishna Choudhary?

  With your, with your improvement. You're really hitting that Heisenberg uncertainty limit, right?

• 1:15:55Lester Nare?

  This is quite, this is quite, quite nice.

• 1:15:58Krishna Choudhary?

  So it's, it's a, it's a proof of concept. We're, we're transitioning to this multi parameter quantum metrology, right? And it's going from theory to experimental reality. And I was reading about it. It's like even the theory of this was not really well founded, but they're running with it and they're showing that the experiment kind of works. It's very, very cool.

• 1:16:18Lester Nare?

  This again is out of the physics department at the University of Basel, as well as the laboratory Castel Brusel at the University of Sorbonne in France. The Europeans.

• 1:16:29Krishna Choudhary?

  Doing well.

• 1:16:30Lester Nare?

  Doing well. A quantum.

• 1:16:31Krishna Choudhary?

  The French doing well.

• 1:16:32Lester Nare?

  The French doing well, we have had a lot of French.

• 1:16:34Krishna Choudhary?

  Yeah.

• 1:16:35Lester Nare?

  French stories in the last couple of episodes. Very fascinating, especially because like we talk about all the time, the Heisenberg uncertainty principle is one of those things to me that's still so weird. The analogy I always kind of bring up when we talk about it is like, and this is probably the common analogy in video games. You reach the edge of the level, the map, the edge of where the developers built the map.

• 1:17:00Krishna Choudhary?

  Yeah.

• 1:17:01Lester Nare?

  And you can't, can't go beyond the edge. Like that's the limit.

• 1:17:05Krishna Choudhary?

  Yeah.

• 1:17:05Lester Nare?

  And it's just the limit.

• 1:17:06Krishna Choudhary?

  Yeah.

• 1:17:07Lester Nare?

  And that's it.

• 1:17:07Krishna Choudhary?

  And that's it.

• 1:17:08Lester Nare?

  And you can never know what's outside the limit or, and it's a crude analogy, but.

• 1:17:13Krishna Choudhary?

  It's very weird.

• 1:17:14Lester Nare?

  It's, it's just very weird.

• 1:17:15Krishna Choudhary?

  It's, it's a central tenet of, of quantum mechanics. It's what makes it so different from classical mechanics.

• 1:17:21Lester Nare?

  Right, right, right. Beautiful. We always love a good, solid physics story. We are going to end with our final story of the day, which is about alpha K.

• 1:17:35Krishna Choudhary?

  Yeah.

• 1:17:35Lester Nare?

  Which is this local adaptive mapping that's specific for cancer research. This was in nature communications from the H. Lee Moffitt Cancer Center and Research Institute Integrated Mathematical Oncology. This one, there's a lot of concepts we've talked about that have helped me kind of grok this concept, I think a little bit better because. You know, I didn't understand what gradients and gradient descent was before and things like that. And there seems to be conceptually some overlap here. And so now I have a mental model for us to work with. But what do we have going on here in this sort of new cancer story?

• 1:18:15Krishna Choudhary?

  Yeah, this is a very cool cancer story, I thought. Again, uses a lot of physics, which is my favorite kind of biology. They're introducing this new tool, Alpha K. This is out of the Moffitt Hospital in Tampa, Florida. What they're effectively doing is trying to predict how cancer evolves.

• 1:18:35Lester Nare?

  Okay.

• 1:18:35Krishna Choudhary?

  It's a paradigm shift in the way we think about cancer evolution, because before we used to think there's just no rules.

• 1:18:41Lester Nare?

  Right.

• 1:18:41Krishna Choudhary?

  It's chaotic.

• 1:18:42Lester Nare?

  Right.

• 1:18:42Krishna Choudhary?

  The whole thing is just these, this cancer thing is just trying its hardest to live. These tumors are trying its hardest to beat whatever we throw at it. And the way that it does it is in a very chaotic environment. The genome is is changing very chaotically. And so it's very hard to predict something that is chaotic, right? It's kind of like weather. But at the end of the day, even weather is predictable, right? We have weather models and they're pretty good. Most of the time.

• 1:19:08Lester Nare?

  Yes.

• 1:19:08Krishna Choudhary?

  Right?

• 1:19:08Lester Nare?

  Yes.

• 1:19:09Krishna Choudhary?

  Maybe not like mammoth, because mammoth has mountains and mountains can get in the way of predictions and things like that. But, you know, for Los Angeles, it's like pretty good.

• 1:19:18Lester Nare?

  Quite nice.

• 1:19:19Krishna Choudhary?

  So can we do the same thing with cancer genomes?

• 1:19:23Lester Nare?

  Okay.

• 1:19:23Krishna Choudhary?

  Particularly what they're trying to tackle is something called aneuploidy. Okay, there's a paradox in aneuploidy. We've heard about aneuploidy when it comes to disorders like trisomy 21. That's how you get Down syndrome, right? You get three copies of the chromosome 21, and that leads to Down syndrome.

• 1:19:39Lester Nare?

  Okay.

• 1:19:40Krishna Choudhary?

  We should only have two copies for sort of typical organisms. Two copies of each chromosome. We've got 23 chromosomes, so 48 different chromosomes. If we got two copies, we're good to go. Okay. But aneuploidy is when we have more or less of a specific chromosome.

• 1:20:02Krishna Choudhary?

  It is very bad and catastrophic for normal cells, but cancer cells love it. Okay, 90% of solid tumors are aniploid tumors.

• 1:20:12Lester Nare?

  Okay.

• 1:20:13Krishna Choudhary?

  Okay, here you can look at a cancer cell, there's four of two, there's three of one, three, I guess there's still two, so three is is still chilling. There's four copies of four, three copies of five, three copies of 12, three copies of 11, 10 is still two, you see what I'm saying?

• 1:20:28Lester Nare?

  Yeah, yeah, yeah.

• 1:20:28Krishna Choudhary?

  This, like, if somebody looked at this chromosome, it's like, there's no way this is a normal cell.

• 1:20:32Lester Nare?

  Right.

• 1:20:33Krishna Choudhary?

  Because there's, what is going on?

• 1:20:35Lester Nare?

  Yeah, it's just all over the place.

• 1:20:36Krishna Choudhary?

  It's all over the place. There's three of some, there are some are completely deleted and just not even there.

• 1:20:41Lester Nare?

  Right.

• 1:20:41Krishna Choudhary?

  So what's going on? Cancer loves doing this.

• 1:20:44Lester Nare?

  Okay.

• 1:20:45Krishna Choudhary?

  Okay, and there's a clear evolutionary advantage to doing this for a cancer cell. There's clear disadvantage for a normal cell, but somehow for cancer, those cells love it, right? There's some kind of benefit that you get from that genetic variation. And it kind of makes sense, because the more of a, the more copies of a chromosome that you have, the more you can mess around with mutations, right? It's that same concept of the GitHub main versus your branch. If you're a cancer cell, you've got a bunch of your own branches that you're destroying all sorts of stuff to survive, right? Because whoever the patient is and the doctors that are treating the patient, they're throwing radiation, chemotherapy, everything at you.

• 1:21:27Krishna Choudhary?

  And from a cancer cell's perspective, it's like, I gotta change as fast as I can and evolve out of my current environment to

• 1:21:35Krishna Choudhary?

  get through to the next stage of whatever therapy that they're gonna put in, right? The cancer cell is trying to evolve and survive. And if we wanted to look at the possible number of karyotypes, karyotypes are this set of chromosomes, right? If we were to look at all of the sets of all the different chromosomes that we'd have to model in order to sort of try and figure out some kind of simulation of cancer evolution, it would be something like 10 to the 10 to the 20. So 10 to the 20 zeros.

• 1:22:05Lester Nare?

  That's a

• 1:22:05Krishna Choudhary?

  Which is a billion billion zeros, not a billion billion combinations, a billion billion zeros and a one. Okay, it's a lot. It's never gonna happen.

• 1:22:15Lester Nare?

  You're right.

• 1:22:15Krishna Choudhary?

  Even with quantum computing, it's never gonna happen. Okay, stop trying to make it happen. So instead, these researchers came up with alpha K, which is inferring what's called a local landscape of fitness. And it's, it's trying to figure out how the tumor is going through this local landscape of fitness.

• 1:22:36Lester Nare?

  So the, one of the, the big, the big initial problem is that the scale of trying to just map all the possibilities is so, it's just impossibly large.

• 1:22:48Krishna Choudhary?

  Yeah.

• 1:22:48Lester Nare?

  And so it's not worth trying to like, create the map of everything.

• 1:22:52Krishna Choudhary?

  Yeah, like a brute force strategy.

• 1:22:53Lester Nare?

  Right, right, right. So, so even with, it's just like, the scale is too large. So what they're trying to do is basically say, can we isolate certain aspects of the landscape?

• 1:23:03Krishna Choudhary?

  Yeah.

• 1:23:04Lester Nare?

  That are meaningful to, to basically deal with the scale problem.

• 1:23:09Krishna Choudhary?

  Yes, exactly, exactly. Specifically, when it comes to this aneuploidy. And before we move off aneuploidy, I just wanted to talk about Ohalo by David Freyberg.

• 1:23:18Lester Nare?

  David Freyberg.

• 1:23:19Krishna Choudhary?

  Of the other podcast fame.

• 1:23:22Lester Nare?

  Yes.

• 1:23:23Krishna Choudhary?

  And he has, he's CEO of this company called Ohalo. They are doing aneuploidy effectively. They have, they have something called boosted, what is it called? Boosted reproduction or boosted genetics. Effectively, you know, when we were born, we get half of our genes from our mom, half of our genes from our dad. And so you get one set of chromosomes from your mom, one set of chromosomes from your dad, and that makes you. What he figured was in plants, what if we just got, what if we just kept the, kept the entire set? So we had tetraploids, meaning two chromosomes from dad, two chromosomes from mom, right, in the nucleus. And I was

• 1:24:03Krishna Choudhary?

  really surprised that it works. Like that it doesn't just, the, the, the plant doesn't just die.

• 1:24:10Lester Nare?

  Right.

• 1:24:10Krishna Choudhary?

  To me trivially, it's like, you should just die. But these plants are, they're making bigger potatoes. The potatoes are like lasting longer on the shelf, all sorts of stuff. It's like incredible genetic technology and they must have done some crazy.

• 1:24:28Krishna Choudhary?

  Engineering to make sure that these, you know, these cells are like actually lasting as long as they do.

• 1:24:33Lester Nare?

  The, the, I think the main idea behind Ohalo is, you know, if we look at our agricultural supply chains globally.

• 1:24:40Krishna Choudhary?

  Yeah.

• 1:24:41Lester Nare?

  Which are very susceptible to any number of both environmental as well as geopolitical crises. If folks remember back to the beginning of the Russia, Ukraine conflict, one of the things that was brought up is, oh, the Ukraine is one of the bread baskets of Europe. And if the agriculture goes down, there's going to have these cascading supply chain issues across not only Europe, but other countries as well. And, you know, we obviously have anthropogenic climate change issues and all of this stuff. And so finding ways to make the yield on agriculture and crops higher for the same amount of used space.

• 1:25:22Lester Nare?

  We don't need to expand to larger amounts of area being used for crops, but can we just actually genetically modify the or just be better?

• 1:25:33Krishna Choudhary?

  Yeah.

• 1:25:33Lester Nare?

  More rice, bigger potatoes, bigger tomatoes.

• 1:25:35Krishna Choudhary?

  Yeah.

• 1:25:36Lester Nare?

  So that, that's like the fundamental concept.

• 1:25:37Krishna Choudhary?

  And, and it's incredible. I mean, apparently it's working, but the way that they went about with that genetics, I just thought it would, it would never work.

• 1:25:44Lester Nare?

  And it's fascinating.

• 1:25:46Krishna Choudhary?

  Yeah.

• 1:25:46Lester Nare?

  It's a good thing, you know?

• 1:25:47Krishna Choudhary?

  Yeah, it is a good thing. And I'd love to know, I'd love to like, one day when we get big enough, I'd love to, I'd love to have the chief scientist of Ohalo on and just ask him like, how is this even possible?

• 1:25:58Lester Nare?

  If you are connected to the chief scientist at Ohalo and you are a fan of the pod and would like to send them a DM, we would love to dig into this because it's, I think, a really impactful concept.

• 1:26:10Krishna Choudhary?

  Yeah, I think it's very cool.

• 1:26:11Lester Nare?

  And it's very cool technically.

• 1:26:13Krishna Choudhary?

  Yeah.

• 1:26:13Lester Nare?

  Uh, so we, we'd love to connect. However, for this story, that is not the focus.

• 1:26:17Krishna Choudhary?

  That is not the focus. I just wanted to, because the aneuploid, it reminded me of,

• 1:26:21Lester Nare?

  Totally.

• 1:26:21Krishna Choudhary?

  Of, you know, this multiple copies.

• 1:26:23Lester Nare?

  Totally.

• 1:26:23Krishna Choudhary?

  So now let's get back into the genealogy of cancer. Let's talk about something called the fitness landscape. This is something that we've been alluding to. You alluded to the gradient descent and things like that. In 1932, there's this guy Seawell Wright. He came up with this analogy of how evolution happens. Okay, what you can think about is a 2D landscape that has hills and valleys. Okay, the axes in 2D, so the direction north, south could be how much of gene A do I have? East, west could be how much of gene B do I have? Okay, so every point is a location in genetic space where it's like I have this much of gene A, this much of gene B. There would be hills, which is where you're more fit.

• 1:27:07Krishna Choudhary?

  So it's an advantage to be here. And there's valleys where there's less fit, right? And so you don't want to be in the valley. You want to be towards the hill. This is the fitness landscape analogy of evolution. And physicists love this because everything is a potential energy landscape. And we're just looking at trying to get to the highest point.

• 1:27:27Lester Nare?

  Makes sense, and I just want to make sure I'm understanding this graphic. So we're looking at basically sort of a XYZ.

• 1:27:32Krishna Choudhary?

  Yeah.

• 1:27:33Lester Nare?

  Uh, like plane. And we see gene A and gene B in the way that you just described.

• 1:27:40Krishna Choudhary?

  Yeah.

• 1:27:40Lester Nare?

  And then the, I guess the.

• 1:27:42Krishna Choudhary?

  Height?

• 1:27:43Lester Nare?

  Yeah, the height is this population fitness.

• 1:27:45Krishna Choudhary?

  Yeah.

• 1:27:46Lester Nare?

  And so the idea is the taller, like the hills are where it's highly fit. And then the valleys are where it's lowly fit. So it looks like if you've ever played like create a level in Fortnite or any video game, and you want to put like you can generate hills or mountains. It kind of looks like that, that sort of imagery in terms of just what we're visualizing.

• 1:28:06Krishna Choudhary?

  Yeah, if you, if you want to be a sniper, you want to get to the.

• 1:28:09Lester Nare?

  Highest elevation.

• 1:28:09Krishna Choudhary?

  Highest elevation, right?

• 1:28:10Lester Nare?

  Right.

• 1:28:11Krishna Choudhary?

  So here, if you're an organism, you want to get to the highest elevation on this fitness landscape.

• 1:28:15Lester Nare?

  Okay.

• 1:28:15Krishna Choudhary?

  Now, this is a nice metaphor, and for the longest time, it was just a metaphor. Okay, what these guys have done with the alpha K concept is operationalize that metaphor into something that's quantifiable.

• 1:28:28Lester Nare?

  Okay.

• 1:28:28Krishna Choudhary?

  Okay, because what you can do is now make empirical fitness estimates based on data. That is what this paper is doing.

• 1:28:37Lester Nare?

  Okay.

• 1:28:37Krishna Choudhary?

  It's taking that metaphor and it's saying, actually, this is a real thing that we can at least apply very quantitatively to the problem of aneuploidy. Because in aneuploidy, your axes. Don't have to be genes, they can be number of a certain chromosome. You can have this axis be, I have one of chromosome one, I have two of chromosome one, three, four, five copies, six copies, right? That'll be one axis. The other axis will be, how many of chromosome two do I have? How many of chromosome three do I have? The fourth axis. And so you have twenty two dimensions, each chromosome. And the point where you are is how many copies of each chromosome you have, right?

• 1:29:20Krishna Choudhary?

  So if you only had three chromosomes, let's say you were some organism, and you had three copies of one, two copies of of number two, and four copies of number three, then my point on this axis would be, three this way, two this way, four up. That's where I am. That's where this particular cell is.

• 1:29:36Lester Nare?

  Yes.

• 1:29:36Krishna Choudhary?

  Right? So now we can create an actual quantitative landscape. And we can measure at each point, what is the slope of this landscape? Because we can track that cell at that particular point and ask, which way did it go? Right? And we can reconstruct the fitness landscape that way. That's what they're doing. Very quantitatively, they're like reconstructing this in a very real sense. It's no longer a metaphor.

• 1:30:03Lester Nare?

  Initially, this concept was strictly meant as a mental model.

• 1:30:08Krishna Choudhary?

  Yeah.

• 1:30:08Lester Nare?

  As a way to grok or to kind of imagine how this happens.

• 1:30:13Krishna Choudhary?

  Yeah.

• 1:30:13Lester Nare?

  What we're saying is now scientists are actually taking real world data and creating a literal fitness landscape. Particularly in oncological studies.

• 1:30:23Krishna Choudhary?

  Yes, yes. And that's why it's called adaptive local fitness landscapes or aneuploid karyotypes. They're literally making that fitness landscape. And then from that construction, now we can tell which way is it gonna go? Is it gonna go down the valley? Is it gonna go up this way to this peak? Or is there another peak that's nearby? These are the questions that they can answer. This is not a trivial problem to do, right? Because, and it really comes from technology. So before, we used to have the standard single cell sequencing, where what we'd do, something called MDA. What we would do is Effectively have these polymerases, these DNA replicators, they would exponentially amplify certain parts of DNA. So if we wanted to sequence the DNA of a single gene, single cell,

• 1:31:08Krishna Choudhary?

  there's not a lot of DNA, right? So in order to sequence, you need to amplify the amount of DNA so that then we can sequence it. When you amplify things, you could get exponential speed up on certain chromosomes. And then, you know, the, the protein that's doing the DNA replication maybe got to another protein, got to another chromosome a little bit later. So there's not a lot of five because it started on five later. But on one, it started right away. And so one, there's like a thousand copies of one, but there's two copies of two. That's not going to help for us, especially for aneuploidy, right? If we've got like a thousand copies of gene one, which is on chromosome one. Well, I don't know if that's because there's actually a thousand copies. Or if you just started there.

• 1:31:51Krishna Choudhary?

  Or if, or if the guy just like started there first, right? Instead, these guys used the DLP plus solution. There was already a paper that was out that had a direct library preparation of single cells. What you're doing with DLP plus is you don't care about the sequences of the chromosomes. You only care about the number, right? Because that's what you want for this particular study. Yes. And so what you do here is you dilute your tissue. So you've got the tissue with a bunch of cells. You dilute it so that each drop that comes out of your pipette has a single cell in it. You put each drop into a microfluidics like array.

• 1:32:34Krishna Choudhary?

  It's like a chip and you can now weigh each droplet to figure out how much of this chromosome is there? How much of this? Because each combination is going to get you a unique weight, right? If I have like four one kilogram weights and two five kilogram weights, so on and so forth, I can like figure out and back construct how much of each is there, right? And that's what they used. Okay. That's the data set that they used. It was already there and they're actually using this data set to now create this.

• 1:33:04Krishna Choudhary?

  22 dimensional space.

• 1:33:06Lester Nare?

  Because what they're doing there is it removes the distinguishing, the distinguishing, the problem of how to distinguish.

• 1:33:13Krishna Choudhary?

  Mm hmm.

• 1:33:14Lester Nare?

  Uh, because everything is sort of universe, like it's, it's, it's like a clean base.

• 1:33:19Krishna Choudhary?

  Yeah, it's a clean place. It's like flat. There's uniform coverage. It's not like, oh, from someone got lucky.

• 1:33:25Lester Nare?

  Yeah.

• 1:33:25Krishna Choudhary?

  It's kind of like, you know, when you want to just figure out how many pages there are in a book.

• 1:33:29Lester Nare?

  Mm hmm.

• 1:33:30Krishna Choudhary?

  Right? The MDA analogy would be you, you have a noisy photocopier that sometimes it'll copy for a thousand copies of page one, two copies of page two, 5,000 copies of page three. Fine, you'll get to read the book.

• 1:33:45Lester Nare?

  Yeah, but it's.

• 1:33:46Krishna Choudhary?

  But I don't know if the original book had a thousand, I don't know, you know, maybe the author was crazy.

• 1:33:51Lester Nare?

  Right.

• 1:33:51Krishna Choudhary?

  But with DLP plus, all you're doing is weighing the book.

• 1:33:55Lester Nare?

  Mm hmm.

• 1:33:55Krishna Choudhary?

  And from that inferring how many pages it has, because the only thing you care about is the pages.

• 1:33:59Lester Nare?

  Yes.

• 1:33:59Krishna Choudhary?

  You don't want to read the book.

• 1:34:00Lester Nare?

  Right.

• 1:34:00Krishna Choudhary?

  Right? For this particular use case.

• 1:34:02Lester Nare?

  Understood. Yep.

• 1:34:03Krishna Choudhary?

  You only care about the number of chromosomes that you've got.

• 1:34:06Lester Nare?

  Yes.

• 1:34:07Krishna Choudhary?

  And so from that, from that discrete data point, now we've constructed this 22 dimensional space. This is the original paper from 2021 in nature that actually put out that data library.

• 1:34:19Lester Nare?

  Yes.

• 1:34:20Krishna Choudhary?

  And this is the data library that they're using.

• 1:34:22Lester Nare?

  So that again, this goes back to what I always like to talk about is this science has this compounding effect.

• 1:34:27Krishna Choudhary?

  Yes. Yeah.

• 1:34:28Lester Nare?

  And, you know, new discoveries can enable others. So basically what we, what we're saying is there's a, a library that this DLP plus library.

• 1:34:36Krishna Choudhary?

  Yeah.

• 1:34:36Lester Nare?

  That the Alpha Key team was able to use to deal with this, uh, problem of number of different, uh, expressing the note, the volume of expression.

• 1:34:50Krishna Choudhary?

  Yeah.

• 1:34:50Lester Nare?

  That was not what they were measuring for. They just needed a clean base in order to be able to look at, um, this specific issue as it relates to how cancer, like how.

• 1:35:02Lester Nare?

  Cancer is making these selections about number of chromosome types as a means to traverse this fitness landscape.

• 1:35:08Krishna Choudhary?

  Exactly. And now we can finally get into reconstructing the fitness landscape.

• 1:35:13Lester Nare?

  Right.

• 1:35:14Krishna Choudhary?

  Because now we can follow single cells.

• 1:35:16Lester Nare?

  Right.

• 1:35:16Krishna Choudhary?

  And we can ask, what are they doing?

• 1:35:18Lester Nare?

  Right.

• 1:35:19Krishna Choudhary?

  Right?

• 1:35:19Lester Nare?

  Right.

• 1:35:20Krishna Choudhary?

  How are they going about in this fitness landscape? You can ask for a frequency change based on, you know, individual fitness. And you can look at what is the slope of a particular cell at a certain point. Right? And from that infer, okay, this is actually a really steep slope because the cell is is reproducing way faster. That means that it's going up in fitness. Right? And so on and so forth. So it's, it's, it's actually very, very cool to think about. The other really cool technique that they used was something called crigging. Have you heard of crigging?

• 1:35:50Lester Nare?

  No.

• 1:35:50Krishna Choudhary?

  Yeah, I hadn't heard of it either. It's, it's called Gaussian process regeneration. Effectively, you've got a bunch of points and you ask, okay, how do I smoothly fit a bunch of Gaussian processes such that you can interpolate between these different points? Okay. So it's not just like standard interpolation where you just like add lines between points. You want there to be some kind of flow. This was originally found because they were looking for how to infer where the gold was in a South African mine.

• 1:36:21Lester Nare?

  Of course.

• 1:36:22Krishna Choudhary?

  Okay. Like they were, they, they drilled bore holes everywhere and they, they found the amount of gold in each bore hole. And then they figured, okay, a gold line is going to be kind of a Gaussian sort of smooth thing. So if I have data here, how do I infer where the gold is in between? Right? And that's what it was originally used for, but now people are using it on all sorts of stuff. It's used in finance a lot too, but in this case for cancer research, which I thought was very cool.

• 1:36:49Lester Nare?

  That is interesting.

• 1:36:51Krishna Choudhary?

  So.

• 1:36:53Krishna Choudhary?

  Now we got to prove that this map is real, right? We've constructed this map.

• 1:36:56Lester Nare?

  Right. We understand how you were able to generate this fitness landscape. And now, okay, great. That's cool. Nice diagram.

• 1:37:04Krishna Choudhary?

  Yeah, nice diagram, nice like 22 dimensional space. Can you actually predict stuff?

• 1:37:09Lester Nare?

  Yes.

• 1:37:09Krishna Choudhary?

  Okay, they did in silicone validation, so they made agent based models where they simulate sort of cancer. And they saw that the cancer was great, but again, that's simulation.

• 1:37:19Lester Nare?

  Yeah.

• 1:37:19Krishna Choudhary?

  So I'm gonna get you a paper in nature communications.

• 1:37:22Lester Nare?

  Okay.

• 1:37:22Krishna Choudhary?

  Okay, you've got to have some experimental data.

• 1:37:24Lester Nare?

  Yes.

• 1:37:25Krishna Choudhary?

  To back it up. So what they did was something called sister passages. What you do is you've got a cancer tissue. You split that up into two. You sequence one of them. And you train your model or you parameterize your model that way. And then you ask the model, okay, now try and predict where the cancer is going to go. And you follow that second sister cells to see how it would move.

• 1:37:50Krishna Choudhary?

  And it's tracking.

• 1:37:51Lester Nare?

  I'm so mad.

• 1:37:52Krishna Choudhary?

  Right? That's kind of nice.

• 1:37:54Lester Nare?

  This is, this is, this is really good. This is, this is really good. The, the point is, we created a map, a 22 dimensional space map.

• 1:38:01Krishna Choudhary?

  Yeah.

• 1:38:01Lester Nare?

  Of a fitness landscape using that library that was created in that previous nature paper. And I think it was 2021.

• 1:38:07Krishna Choudhary?

  Yeah.

• 1:38:08Lester Nare?

  And the idea was, this was used to be this theoretical concept that's actually like literal.

• 1:38:14Krishna Choudhary?

  Yeah.

• 1:38:14Lester Nare?

  Like it translates literally. We created our Google Maps of, of cancer. And we took

• 1:38:22Lester Nare?

  one cancer cell, we split into two. We create, generated the map based off one. And then the real world other one traversed what the map said it would traverse.

• 1:38:32Krishna Choudhary?

  Yep.

• 1:38:32Lester Nare?

  Meaning that that fitness landscape is literal.

• 1:38:35Krishna Choudhary?

  Yeah. And it's like literal.

• 1:38:37Lester Nare?

  Yeah, yeah, yeah.

• 1:38:38Krishna Choudhary?

  Yeah, like there is a fitness landscape and these guys are following it, right? In chemotherapy, this, this works out really well. So cisplatin, which is a type of chemotherapy. One could ask, well, you've made a fitness landscape now. Suppose I introduce a stress like cisplatin. That's going to completely change the fitness landscape.

• 1:38:59Lester Nare?

  Right.

• 1:38:59Krishna Choudhary?

  Right? It's going to be now dynamic because certain hills are going to become valleys.

• 1:39:03Lester Nare?

  Yes.

• 1:39:03Krishna Choudhary?

  And so on and so forth.

• 1:39:04Lester Nare?

  Yes.

• 1:39:04Krishna Choudhary?

  Can you, um, can you predict there?

• 1:39:09Lester Nare?

  Yes.

• 1:39:09Krishna Choudhary?

  And they could, they could show that there was an increased variance. And this actually is in support of something called punctuated equilibrium.

• 1:39:16Lester Nare?

  Okay.

• 1:39:16Krishna Choudhary?

  Which is a model of evolution that is not gradualism. In gradualism, you get changes very gradually over time.

• 1:39:23Lester Nare?

  Right.

• 1:39:23Krishna Choudhary?

  Punctuated equilibrium is there is a stress. That stress leads to bifurcations in your tree of life. And so there's a certain stress and then all of a sudden you get different types of species and cell lines and so forth.

• 1:39:36Lester Nare?

  Basically, almost not instantaneously in a literal sense.

• 1:39:40Krishna Choudhary?

  Yeah, but.

• 1:39:40Lester Nare?

  Short time.

• 1:39:41Krishna Choudhary?

  In a short time scale. Short time scale. And this actually shows that cancer is very much a punctuated equilibrium process. Right? The therapy actually sharpens the selection gradients. So certain, certain fitness hills could become even more steep.

• 1:39:54Lester Nare?

  Hmm.

• 1:39:54Krishna Choudhary?

  Some, some totally get.

• 1:39:56Lester Nare?

  Hmm.

• 1:39:57Krishna Choudhary?

  Squashed and so on and so forth.

• 1:39:59Lester Nare?

  Which tracks like conceptually, like if you were to think about like, why is cancer so hard to defeat? Like it moves so fast. It would make sense that this punctuated equilibrium is, is what's happening. And it's cool to see that you can actually measure, get measurements that, uh, you know, that point to that being the case.

• 1:40:16Krishna Choudhary?

  Exactly. And one thing that one can think about is like, so why, why would cancer cells do this? Where this, you have this whole genome doubling sometimes where, you know, kind of like in a hollow. All of your chromosomes have now four copies instead of two. Okay. Why would you do this? Well, what this does is create a flat fitness landscape. And so you have something called survival of the flattest. Where imagine, right? Before, if there's a really.

• 1:40:46Krishna Choudhary?

  Thin peak, your organisms will want to stay near that really thin peak. Because that thin peak is really, really tall. But with cancer, because you're throwing so much at them, you kind of want to be in a flat hill rather than a thin peak. Because in a thin peak, if you go off by a little bit, it's like El Cap, right? In Yosemite, you're just gonna fall. But if you've got a sort of nice Kilimanjaro-like hill, then even if you stray a lot in your landscape, you're still gonna be able to be doing just fine in terms of fitness. And you can literally see that with this kind of trade-off, the tumor shifts from this sharp peak,

• 1:41:29Krishna Choudhary?

  high fitness, low tolerance, to flat peaks, right? And the clinical relevance is if you've got instability and that instability pushes you past some kind of error threshold, then your population is going to collapse onto flatter peaks and not stay on that thinner peak. So then you're gonna have a harder time, maybe. Because at the flatter peak, there's a lot of different stuff that cancer can explore and still be just fine.

• 1:41:56Lester Nare?

  The point being, you know, you don't want to basically give an evolutionary advantage unnecessarily by how you're targeting your therapies and stuff like that. And so like if you can say like, hey, we know if we sort of attack this in a particular way, it's actually going to spread the evolutionary optionality that the cancer cells have across a wider surface area, which is then gonna actually make it substantially more difficult to deal with. Which is like, it's kind of like, it's an interesting way to think about it. Is that like how you try to treat does have an impact on how it evolves? And there's actually like right and wrong choices to minimize the surface area of risk in how you treat.

• 1:42:41Krishna Choudhary?

  Exactly. And the other thing you can do is with that kind of rugged landscape, right? Suppose you've got a single peak and now there's a neighboring peak that's nearby. Traditional theory says that I can't get to the neighboring peak because I'd have to go through the valley. But now- Now with this alpha K, we can actually, it's kind of like providing a navigational chart to steer and predict how it goes from one to the next. How it could go from one peak to the other without going through the valley, right?

• 1:43:08Lester Nare?

  Right, because it's basically this map.

• 1:43:09Krishna Choudhary?

  Yeah, yeah.

• 1:43:10Lester Nare?

  And so we know all the routes between two different points on said map. And so we, ah, that's so good.

• 1:43:16Krishna Choudhary?

  And it's really cool. I mean, it just shows this very quantitative physics-based approach.

• 1:43:21Lester Nare?

  Yes.

• 1:43:22Krishna Choudhary?

  So now I'm like going up on a fitness landscape.

• 1:43:24Lester Nare?

  Yes.

• 1:43:25Krishna Choudhary?

  I can sequence, not sequence, but I can tell how much of a particular chromosome I have in certain cells. And from that, create this map of karyotypes, right? And create, okay, how much of cell one do I need? It can depend on my past. It can depend on all the other contexts that I have because this model can build that in. It's very cool and the computational cost is, you know, it's, right now it's 22 dimensions. So it is pretty expensive, but it's better than doing the sister chromosome, the sister cell treatment, which is what we used to do, where you take a little bit of the cancer cell and you see how it evolves in the test tube. I mean, here you can just plug it into a computer.

• 1:44:07Lester Nare?

  Right, right, right, which, which, you know, one, while it may be expensive now, it's the first formulation of the concept. You can in theory create other flavors.

• 1:44:18Krishna Choudhary?

  Yeah.

• 1:44:19Lester Nare?

  That choose for different levels of dimensional precision as one key aspect. But two, it's, it's all simulation. So you don't have the physical lab-related costs associated with it. This is very, very good stuff.

• 1:44:32Krishna Choudhary?

  Yeah, I thought it was very cool and you know, this one is doing it for aniploidy, which is number of chromosomes, but now you can think about creating, you know, you can think about creating landscapes for actual within a chromosome.

• 1:44:46Lester Nare?

  Yes.

• 1:44:47Krishna Choudhary?

  How much of gene one do I have? How much of gene two do I have?

• 1:44:49Lester Nare?

  Right.

• 1:44:49Krishna Choudhary?

  In a transcriptome, how much of mRNA for this particular gene do I have? You know, it's like really taking that fitness landscape and being like, no, we can actually just treat it as real.

• 1:44:59Lester Nare?

  Right. And then you can apply that to more than just the aniploidy for cancer. I mean, it's, it can be applied in across the board.

• 1:45:06Krishna Choudhary?

  Right. And I can now forecast what the cancer would do if I give it this treatment.

• 1:45:11Lester Nare?

  This is very, very good. I mean, you know, obviously cancer treatment, we've talked about a lot of different type of cancer-related research stories. And you know, one of the, there's so many challenges that are involved in it. Like there's, it's like, um, Multi combinatorial massive stuff. Yeah. But one of the things that's been so interesting is our tools to look, measure and or understand what is literally happening have have been accelerating. Yeah. Because we kind of right now have like more of a shotgun approach for therapeutics. Yeah. The sniper approach. Obviously, there's some cases that are getting more close to a sniper approach. But like chemo is obviously very destructive to all the cell, like all the cells, which we actually discussed in a previous episode. Yeah. Why that's the case. Yep.

• 1:45:57Lester Nare?

  So stuff like this is really, really impactful for oncology generally. Which is fascinating. I mean, my my mom works in clinical trials and they've, you know, historically, they've looked at a whole variety of things. Obviously, a lot of big pharmaceuticals are trying to go to big ticket things. Yeah. That have huge market value. And obviously oncology is a huge one. Huge one.

• 1:46:19Lester Nare?

  And so really great stories, a nice spectrum. Yeah. That we covered. We started with

• 1:46:27Lester Nare?

  Botany, one of our first plant stories about alkaloid biosynthesis. And that small factory, we're now able to replicate in yeast. And the new phytologist that was from York, University of York in the UK. We had a great rundown with a bunch of different, a variety of different pieces. The quantum entanglement story was fantastic. That one out of the University of Basel and Sorbo. Very, very interesting. Again, measurement precision, talking about my favorite, the Heisenberg uncertainty principle. We now can sort of not break the concept. No. We're not, we're not, we're not, we're not doing anything when it's not magic. Yeah.

• 1:47:11Lester Nare?

  But it's clever creativity for how to work around those limitations. And we ended with this alpha K local adaptive mapping, which again, I now have a way to grok this concept because we've talked about. Concepts like gradient descent in the past, like with a lot of the foundation and frontier models, that's how these things work, is they're traversing.

• 1:47:32Krishna Choudhary?

  Yep.

• 1:47:34Lester Nare?

  You know, these high, multi-dimensional spaces. And so, all very, very good stuff. I just, the only thing that I think we forgot this episode was what people should comment.

• 1:47:46Krishna Choudhary?

  Oh, yeah.

• 1:47:47Lester Nare?

  We didn't come up with a good one yet. So, we're gonna do this on the fly.

• 1:47:51Krishna Choudhary?

  How about, how about AlphaK, alternative?

• 1:47:54Lester Nare?

  Alternative.

• 1:47:56Krishna Choudhary?

  Alternative full forms of the acronym AlphaK, which is not Alpha, like the Alpha particle or Alpha Greek, it's A-L-F-A-K.

• 1:48:04Lester Nare?

  Yes. Yes. That's a good one. So.

• 1:48:07Krishna Choudhary?

  Yeah, let's, let's see what people come up with, because we do have some comedians.

• 1:48:10Lester Nare?

  We did see a lot of good responses to LBF from last episode.

• 1:48:14Krishna Choudhary?

  The freedom one was the best.

• 1:48:16Lester Nare?

  Pound force.

• 1:48:17Krishna Choudhary?

  Yeah. Pound force is the correct one, but pounds per freedom, I think, we're good.

• 1:48:22Lester Nare?

  And, yes, the, the imperial system versus metric system is, has, has its.

• 1:48:29Krishna Choudhary?

  Yeah.

• 1:48:30Lester Nare?

  Issues. My name is Lester Nare, joined as always by my co-host and our resident PhD and all-around science genius, Krishna Choudhary. This is From First Principles.