From First Principles - From Cells to Circuits to Crystals — 2025 Nobel Prizes Unpacked (EP. 11)

Episode Date: October 9, 2025

Hosted by Lester Nare and Krishna Choudhary, this one-episode special brings all three 2025 Nobel Prizes in the sciences into a single listen: Medicine (immune tolerance and FOXP3), Physics (macroscopic quantum tunneling in superconducting circuits), and Chemistry (metal–organic frameworks and “new rooms for chemistry”).SummaryMedicine: Regulatory T cells and the FOXP3 gene that prevent autoimmune disease.Physics: Macroscopic quantum tunneling and energy quantization in electrical circuits — the bridge to today’s qubits.Chemistry: Metal–Organic Frameworks (MOFs) — modular porous crystals enabling CO₂ capture, water harvesting, and hydrogen storage.Show Notes Nobel Prize Press Release (2025 Medicine) Nature Genetics (2001) — FOXP3 mutation and IPEX link Nature Genetics (2001) — FOXP3 Mutation Causes Dysregulation Nature Genetics (2001) — FOXP3 Gene Cause IPEX Syndrome Science (2003) — FOXP3 function in regulatory T cells German Journal of Immunology (1995) — Sakaguchi’s first Treg paper Nobel Prize Press Release (2025 Physics) Physical Review Letters (1980s) — Macroscopic Quantum Tunneling Experiments (UC Berkeley) BCS Theory (1972 Nobel) — Bardeen, Cooper & Schrieffer, University of Illinois Josephson Effect (1973 Nobel) — Brian D. Josephson Google Quantum AI Lab — Quantum Supremacy Paper (Nature, 2019) Nobel Prize Press Release (2025 Chemistry) Nature (1999) — MOF-5 Discovery (Omar Yaghi et al.) Science (2003) — Reticular Chemistry Foundations Journal of the American Chemical Society (1989, 1990) — Richard Robson’s Early Frameworks Lawrence Berkeley National Laboratory — ChatMOF and AI-Assisted Materials Discovery

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Fit for your ambition for Citizens Bank. Ladies and gentlemen, good morning. Okay, we are here live for Nobel Prize Week, Day 1, which is medicine. Looks like the presentation is starting. My name is Thomas Harald. 2.30 a.m. I'm the Secretary General of the Nobel Assembly. I will first read the announcement in Swedish followed by English.

We will then, as usual, present some background to the prize and open up for questions. Okay, here we go. Nobel Fershamning at the Carolinian Institute has today that Nobel Prize in Physiology or Medicine, year 2025 shall be able between

Mary Brunkel Fred Ramstad and Shimon Sakaguchi for their objectives that peripier

So the predictions are wrong The Nobel Assembly at Karolinski Institute that has today decided

to award the 2025 Nobel Prize in Physiology or Medicine jointly to Mary Brank

Fred Ramstell and Shimon Sakaguchi for their discoveries concerning peripheral immune tolerance okay okay here are the three laureates Mary Branco was born in 1961 in and received a PhD from Princeton University in the United States the work for what she's awarded was performed at a biotech company Celtic kiro science in Bothel, Washington. She is currently a senior program manager at the Institute for Systems Biology. Oh, wow. So it's not even an academic institution.

Oh, interesting. Fred Ramsdale was born in 1960 and received a PhD in 1987 at the University of California in Los Angeles. The year for which he's awarded was performed at the same biotech company, Celltech Chiro Science. He's currently a scientific advisor at the company he himself founded, Sonoma.

Can't believe you got the double. Biotroupics in San Francisco and in Seattle. Shimon Sakaguchi was born in 1951, earned an MD in 1976, and a PhD degree in 1983 from Kyoto University in Japan. The work for which he is awarded was initially. at ICH Cancer Center Research Institute in Nagoya. He's currently a distinguished professor at the Immunology Frontier Research Center at Osaka University. Okay, at Osaka University. Okay, so we got two private people and Osaka University.

I think we need a wardrobe change. Yeah, no, I mean, what? Yeah, that's crazy. Okay, okay. I'm going to do some research. And we'll dive in. Yeah, and then we'll be right back. We'll be right back.

Hello, Internet. This is your camera. Captain speaking, Lester Nare, joined as always by my co-host and our resident PhD, Krishna Chowdary. We are now doing a deep dive on day one of the Nobel Prizes. We had the Medicine Award for Peripheral Immune Tolerance, just go out. As you can see, we have a little bit of Princeton representation. Yeah. We are back on the board with one of the Nobel winners who just won being a PhD at Princeton.

Yeah. But let's dive right in. Peripheral immune tolerance. just won in medicine. Let's start with why this prize matters. Yeah. This prize matters because it's effectively, if you go to slide two,

it's the military police for our body. Okay. The military you can think of as the immune system. They're the ones that are fighting the invaders, right? But every once in a while, some people might act up, okay? And then what ends up happening is you need to control parts of the immune system

that might be attacking the self. And that's where these regulatory T cells come in. Okay. And that's why I think it's kind of like the military police. And these three Nobel laureates in slide one, Shimon Sakaguchi, Mary Bruncow and Fred Ramsdell, they are responsible for doing a lot of the research that elucidated this system of regulation of our immune system.

Basically answering the question like, why doesn't everyone have an autoimmune disorder? Okay. And that sounds like kind of crazy, but it'll become a non-trivial problem once I get into some of the details about exactly how our immune system works. Okay? So with the immune system, there's two different kinds of basic immunity that we have. So we've got the innate immunity, which is what you see on the left over there. That's stuff that doesn't require learning. That's in our genetics. We're wired to recognize viruses. We're wired. We're wired. to recognize bacteria or wired to recognize outside pathogens that are coming in. Okay. Then there's something called adaptive immunity. These are our T cells and our B cells. Okay.

They're specialized to have a kind of memory of stuff. They're specialized to really recognize things at a molecular level. And these things are slower and it involves a lot of different molecular mechanisms that we're going to try and get into. What we're really going to focus on are something called T cells. Okay. Okay. T cells, they're a type of white blood cell.

You know, our blood has basically three types of cells. We've got the red blood cells, which carry oxygen. We've got platelets, which do a lot of the clotting and, like, tissue repair. And then finally, we've got white blood cells, which are our immune system, right? And the ones that we're going to focus on today are called T cells. They develop in the thymus, which is an organ of our body. hence the name T-cell. T-cell.

There's two types of T-cells. There's the helper T-cell, which coordinates an immune response. It doesn't actually do the killing. But it like tags stuff and then makes other help, other like B cells come in or macrophages come in. Macrophages, like big eaters that like come in and like actually, actually like eat things and digest it, like within the cell.

Yes. And then they're like scouts. Yes. The helper T-cells are exactly like scouts. Yep. Okay. And then you've got your killer. T cells, right? And the killer T cells, like the one you're seeing over there, that's attacking,

the smaller one is the killer T cell. And it's taking on this giant cancer tumor cell, right? And it's attacking it. So killer T cells can kill infected cells. They can kill cancerous cells directly. And the mechanism by which they understand whether something requires killing or not is the focus of this problem. Got it. Does that make sense? Yes. Because imagine, right, you're, again, you're a cell.

The senses that you have are just lock and key. That's like at the cellular level, you're worried about concentrations of certain molecules. Like how many of this molecule do I see around here? Is that a red flag? Or on the other hand, like, you know, you go to another cell. How do you know if that cell is healthy or it's been taken over by something? Right. Right.

And to get into that, we're going to have to go into exactly how these T cells actually find, you know, which one is wrong, which one is right. How does our first line of defense? No. No. Yeah. What to go after. Yeah. And effectively, like, you know, in a normal society, the police come over and they check your ID.

These guys are doing kind of the same thing. Okay. So in slide five, you'll see this is from the Nobel Prize Committee. They release these like, you know, things for the press to sort of explain and understand. It's a really good cartoon. So on the left-hand side, you've got a healthy body cell that's been infected by a pathogen, right? That's the stuff that's coming in. And what these cells do is they've got these receptors on the outside of their surface

that actually take whatever is inside the cell. and display it. Got it. It's like an ID card for everything that's inside your cell. Okay? Every little protein that's been degraded or like broken down, they're going to take little parts of that protein and they're going to put it out.

Got it. And then what the T cell does is they've got receptors that actually come in and bind. And if one of the receptors matches like it does over there, then it's like, oh, that's bad. That's sort of center screen. Yeah. That's sort of attached.

to that receptor, that T-cell has recognized something that is quite bad. And so it's going to elicit an immune response. That's that lock and key model that I was talking about. Yes. Right? Yes. I think there's a literal scene in the movie Osmosis Jones that that walks through T-cells going and checking ID as the metaphor.

Dude, that's literally what this is. Yeah, yeah. And so the way that the ID check happens is if you go to photo six, this is a picture of the human leukocyte antigen. And this is the protein that is responsible for taking whatever is inside the cell and displaying it. So that red part that you see at the very top, like right over here, that red thing is maybe it's a viral fragment. Or maybe it's a part of our own DNA, our own, sorry, protein complexes inside. What they've done is they've broken down the proteins and they display them in little tiny segments outside.

Okay. And the T-cell's job is to come in and try to figure out if that little fragment is self or not. Yep. Understood? Yes. Okay. Yes. So this human leukocyte antigen, it's part of the MHC major histocompatibility complex.

It's basically, it's found in like, you know, animals and so on and so forth. This is the thing that's actually involved in like mate selection. So like, you know, have you heard about that research where it's like people with different immune systems smell better? Yeah, yeah, yeah. And that's why you're, like, more attracted to them. That's this stuff. That's interesting. Okay, that's the human leucoside antigen.

Okay. Like, everyone has different versions of this, of this antigen. And really, only, like, your identical twin has the same one. Okay? And the more different you are, the better, you know, it is for the kid. Because the, the idea is you had, there's less of these potential threats, vectors that you are going to be susceptible to because you're so different. Yeah, yeah, exactly.

And so, like, you have, like, a broader. Broaders, yeah, immunity. And the other reason, like, you know, organ transplant rejection, a lot of times that happens because your HLA, this antigen complex, is different. And so the organ is like, that's not me. Right. Right? Like, and I don't want that as part of this body.

And so people who are actually studying this organ transplant problem, they won the Nobel Prize in 1980, Jean de Saut and George Snell, for discovering this, human leukocyte antigen, this idea of like these proteins that actually take what's inside the cell and display it out. And the fact that they're different is what causes all of these rejections. So that was our first clue as to like how this stuff works. Understood.

So now we've figured out how cells in our body displayed their ID. Right. In order for the T cells to be able to identify whether or not it's something that they need to deal with or not. Or not. Yeah. Now, the next part of the clue is how did the T cells, which are the police, or the military in this case, how do they decide whether that ID is okay or not? Okay? And so this is one thing is the display of the ID. Yeah. The second thing is like running it through the, like, yeah. It's like actually scanning it to be like, are you in the database? Are you in the database or not? And that's where T cell receptors come in. Okay. So T cell receptors are, they look like that. Okay. They're the ones on the outside. And you can think of this as the case. key. Got it.

If the HLA things that we were talking about earlier where the cells are displaying it, that's the lock. Okay. And these keys have to match the lock. And if they match the lock in a bad way, then that means you're a bad person. If they sort of match it in a good way, then you're fine. Right? The idea is these T cell receptors are sort of protruding, looking to be able to fit into the lock

of a matching, you know, person on the bad list. Yeah. And if that then happens, then they know we need to now have our approach. appropriate immune response. Exactly. Yeah. And it's actually kind of an insane thing to think about, right? Because as a T-cell, you're going to have to come up with a bunch of different keys. Right. Right. Right. For all the stuff. For all of the stuff that's out there. And if you want to have a bunch of different keys, you want to have diversity. This is in the protein. You want, you want different shapes in your protein. That means you need different sequences of amino acids.

You want different sequences of amino acids, that means you need a different sequence of DNA creating that amino acid. And for the longest time, it was like a really big challenge to figure out because we have like something like 10 to the 15 different receptors. Okay. To code for 10 to the 15 different receptors, you would need like 10 to the 13 amino acids at least or 10 to the 14, right? Because it's three for one. I'm doing some really crude math here. 10 to the 14 different sequences of DNA, that's a lot of DNA. That's larger than our genome.

Right. Okay. So how does that happen? How are we actually storing the memory and facilitating the creation of the T-cell receptors in this wide, this massive scale that is necessary for us to survive in the way we start? Exactly. And if you go to photo, photo eight, that's a pretty good depiction of it. Like, on the right-hand side, you've got all.

these different shapes, right, that the T-cell receptor can be. Okay. Right? And it's trying to generate all of these different shapes. And the challenge is, how do you generate so many different protein sequences without blowing up on the genetic side of things? Right. Correct.

Right. And that was made possible by something called VDJ, variable diversity and joining locuses. They're different gene segments. And what ends up happening is the cell mixes and matches. So it's like you have like 10 different pairs of socks, you know, 20 different shirts, 20 different pants. And now you can come up with a commentatorially much larger outfit. Yes. Right.

That's exactly what these T cells are doing. Got it. Okay. And this process was discovered by Susumu Tonegawa and he won the Nobel Prize in 1987. He's now at MIT. He's doing actually optogenetic stuff. Ah, which is what I had slated. He's actually chasing his second Nobel, I'm pretty sure.

He does like optogenetics on the hippocampus, which is the Center for Learning and Memory in our brain. So good luck to him on that. And then the last part of it was, so this is, so Tonegawa figured out how to make all of these different proteins. Right, right? All of these different shapes without blowing up the genetic face. The final key was in 1996, they won the Nobel Prize,

Peter Deherty and Rolf Zinkernagel. And they were the ones who showed that actually that human leucosite antigen, the part that was displaying the ID, that's crucial for the T-cell lock and key model. The T-cell isn't just locking in on everything. It's doing it specifically on the stuff that this thing is putting out and displaying.

Instead of doing no-knock warrants at every door, they check the ID at the door and only do the bust when there's a match there, which then decreases the volume of the activity itself. Exactly. Yeah. Now you can be a lot more specific. You can manage, like, you know, the whole.

You actually scale to a complex. To a complex organism like us with like billions of cells, right? So that's the background behind how T cells do their job if they're doing it correctly. Right. Okay. Okay. Now, some T cells are inevitably going to recognize your own body. Because these guys are making, as I said, 10 to the 15 possible receptors, right?

Some of these receptors are going to match to, like, the stuff that we have, right? How do we make sure that those guys don't just, like, go off? Right, right, right, right. Because each T cell is expressing a specific shape. Yes. Okay? Each individual T cell is expressing a specific shape. So what we basically want to do is the ones that are recognizing our body, we should just get rid of them.

We should tell them to commit cell death. And then we don't have to deal with that anymore. So that first line is called central tolerance. That's the first filter. It happens in the thymus. Okay. So these T cells, what they do is they can bind, this photo 10, they can bind strongly to self-proteins. And whenever they do that, the process that happens in the thymus, when we're very, very young,

is those T cells go off and they don't, they don't proliferate to the rest of the body. Okay. Okay. Okay. The filter is not perfect, though. And there's some that get through. Okay. That second line of defense, that is what this Nobel Prize is about. After that first sort of purge, there's still some remaining leftover T cells that recognize our own bodies as as invaders. Yeah. Incorrectly. Incorrectly. Yeah. And so now there's a second, after the first. After the first filter, which you just talked through, there's a second line of defense.

Yes. Yeah. And that's photo 11. If you go there, these are called regulatory T cells. So on the left-hand side, what you're seeing is, you know, are this rogue T-cell that's misbehaving that's recognized our own body and a protein fragment in our own body as something that needs to be taken care of. Now, comes a regulatory T-cell. And what that does is going to suppress the immune response. of that incorrect T-cell.

Okay? And this regulatory T-cell is what stops the autoimmune response from happening. Autoimmune meaning it's an immune response on yourself. It's almost like internal affairs and those cop movies when the cops do something bad and they come in and they investigate their own people to make sure that it gets taken care of and you remove the people from the force that are problematic. That are problematic. If only that actually happened, but you know, that's exactly what's going on.

It's like you've got, you've got like the ones who regulate the cops. The cops, right? And if they do a good job, like in most of us, we don't have those, right? And so mostly it works. And where it doesn't, we need to figure out how, what's going on with the regulatory T cells and if there's ways to prevent that from happening. So we have our first filter. And then, you know, once we get past the first filter, there's still some remaining

T cells that are attacking our own body. So then regulatory T cells come in to suppress that. immune response, but that doesn't happen 100% of the time still, even at that second later. And so now there's ongoing, ongoing work even today. Like I was looking today when I was like researching this stuff. Even today, there's papers coming out about how do we make this system better. But the first step is always understanding how the system works. And that's what our three Nobel Prize winners did, okay, was just figuring out that the system

existed in the first place. Discovering the fact that there are such things as regulatory T-cells. that are uniquely different from the rest of the T cells, from helper T cells, from killer T cells. This is a totally different class of immune cells that come out of the thalamus, right? So you have the ID system, you have the T cells that are the ID system,

you have the T cells that are going out and actually doing the work. And then now there's this third bucket, which is the police of the police. Police of the police, exactly. Yeah, and these guys are the ones who, like, solved it. Okay? So now we're going to get into actually

what these three researchers did. We're going to start with Shimon, Sakaguchi. He got his PhD at Kyoto University. And then he started getting really into these autoimmune disorders. So the first thing he did was figure out that actually if I lesion the thymus of an animal in the lab, then the animal develops an autoimmune disorder. Okay. So the thymus is key. I mean, this was already known. But now you've got sort of test bed. Yep. Okay. And the key thing that he did was he injected a fraction of immune cells like over there.

On the top row you see just you lesion the thymus, the guy's sick. But if you take a fraction of immune cells from a healthy mouse and you inject that into this guy who doesn't have a thymus, he's going to be fine. So what you've done is there's something in the mature immune cells of a healthy individual that when you transfer to someone who does have this no thymus defect,

he's going to be fine. Right. So what you've done is transfer this tolerance. Yes. Right? You've transferred this mechanism. Yes. Okay. Yes.

And this was back when like they didn't have like monoclonal antibodies. They didn't have any of this stuff. So they used to use like blood serum to basically classify like what was in the thing that I injected, which is like very coarse grain. Right. Now nobody uses it. But back then that was cutting edge. And so you just knew that in whatever cock. that I injected it, there was something magic.

Then came the introduction of monoclonal antibodies, right? And with monoclonal antibodies, now what I could do is I could start identifying a subpopulation of T cells that have a specific thing, like a specific surface marker. Because monoclonal antibodies will then go and attach to that surface marker. And then you can say, oh, this thing has the CD4 plus or the CD425. CD is just like a naming convention for like the proteins that are on the outside. And the number is just like the number in which that it was discovered. So you can now start saying that this specific T cell that mattered actually had this very specific type of protein.

And so it's different from all the rest that we've been looking at. And he started calling these regulatory T cells or Tregs. And without these cells, the mice developed autoimmunity. But with them, they were fine, right? And he finally published his paper. in the journal of immunology, this was the first sort of seminal paper in 1995. Okay.

Okay. The first one with the serum was published in the 1980s. Everyone was like, yeah, probably. But at the time, you know, that's the best you can do. Now we've gotten to, like, this resolution of like, now we've got cells. Right. All right. So there was a level of higher fidelity to get to the answer.

Exactly. Exactly. And so, fine. Now you've got these cells. We still need a little bit more convincing. right? You got to get to the genetic level to really see if there's something that is changing at the gene level that is expressing a difference between these regulatory T cells and the normal T cells. Because even normal T cells, like the conventional activator effector T cells, they also have CD25, which is this marker that he identified. Sure, fine, it's like a little bit lower density, but it's still there, right?

So it's not as convincing. Right, right, right. And so what is the actual mechanism? Yes. That allows the differentiation in when these T cells are, you know, when they get created. Like what makes it know I'm a helper versus a killer versus a wrangletor. Yeah, yeah. Exactly.

Exactly. Like the courses that they took in the training academy. Yeah, yeah. But what exactly did they read? Right. Yeah. How did they get to? Yeah.

Exactly. You know what I mean? Yes. So that was Shimon Sakaguchi. Yes. He had sort of come into the foray. Now we're going to get to our next two Nobel Prize winners, Mary Bruncow and Fred Ramsdale. Their story is pretty interesting.

So actually, to get to their science, we first need to talk about 1940s Oak Ridge National Lab. I think you've got a photo of that there. Yeah, that's where we enrich uranium for the atomic bombs. And, you know, there's a lot of radiation there. And in the 1940s, researchers found a mutant mouse strain in Oakridge that had scaly skin, swollen lymph nodes, early death. And, you know, as scientists do, they're like, oh, let's study this thing. Right, right, right. Okay.

They called it the scurphy mouse strain. Okay? They called it the scurphy mouse strain. And what they noticed was only male mice developed this disease. Okay. of like having this like sort of autoimmune type of disorder, right? And so if you look at photo 17, if only male mice display this disease, but females are fine. Yes.

That means that it has to be an X-linked disorder. X-linked meaning that whatever genetic thing is making this thing happen is happening on the X chromosome, right? Because females have two copies of the X chromosome. So if one of them is defective, the other one is still going to print the correct protein and you're going to be. fine. But if you're an XY and this thing is defective, then you're just totally screwed. Yeah. That makes sense. So they figured out that it's got to be on the X chromosome. They did a lot of different tests to figure out and they narrowed it down to 500 base pairs. Okay. And their job, what Bruncoe and Ramsdale did, they were these basically gene hunters at

cell tech chiro science. Mary Bruncoe had finished her Ph.D. at Princeton. We got We got another one, baby. We got it. We're on the board. And then Fred Ramsdale at UCLA, which is where I went for PhD. So that's kind of cool that today, both my institutions were. I was going to say, but both undergrad and plus one, baby. Yeah.

So after they're done with that and they're done with their postdocs, they joined cell tech chiro science, which is, I think it's kind of like a bioscience startup in Seattle at the time. And what they want to do is if you go to number 18, they want to identify this mutative. that's on the X chromosome. Right. Okay. Now, back then, we don't have the kind of high throughput DNA technology, like 23 and me. Right.

Like, mail a sample and then... Just so crazy. And then, like, just get back all my DNA results, right? Back then, this is in the 90s. So this is before Human Genome Project. Yeah, right. Like, this is when, in the heyday of that. So we've got these, like, really, really old technologies.

One of them is called BAC cloning, bacterial artificial chromosomes. What you do is you take. a segment of whatever part of DNA that you're trying to sequence, you stick that into the bacterial chromosome and then have the bacterial replicate it. And then, you know, you can then start testing each little part.

There's also called shotgun sequencing where you break up the DNA into different parts. You sequence each part and then you play a jigsaw puzzle where you're trying to see how they overlap. And it's like an intensive process requires like, you know, two or three years from like two or three researchers. Nowadays, it's like a day, a hundred bucks, and a laptop. But back then, this is like several PhDs. It's just like figuring out, what are these 500 kilobase stretch of DNA doing? And so

if you go to photo 19, we've got a photo from their, from their paper. On the top there, that's the 500 kilobase stretch of DNA, okay, from the X chromosome. And they figured out that they've got 20 candidate genes that they need to sequence. So, One by one, they're sequencing the 20 candidate genes. And it was their 20th gene. Of course it is. They could have given up, but they didn't. They're like, let's just do all 20.

Finally, on their 20th gene, they found the mutation that was responsible for this scurphy mouth strain. It was a two-base insertion. And if there's an insertion of two bases, remember, it's three base pairs to a single amino acid. Yes. Right. So if I put in two, not only have I made a mutation right there, I've also done what's called a frame shift. Yeah, yeah, yeah. Yeah. Yeah. Like if you're reading music, like I've just made each measure. Right. Like now half of this guy is in the other measure. And so my reading for all of the rest is going to be completely nuts. It's not a point mutation. Right. Right. Right. And so and so this two base insertion created like a made the gene effectively.

shorter because later on there was part of that frame shift was like oh this is a stop code on which means i'm going to stop making my protein well the protein is supposed to be so long so like now it's just completely wrecked right it's it's completely wrecked and so they named this um gene the forkhead box protein p3 or fox p3 okay and it turned out that it was a transcription factor and they published this in nature genetics 2001 that was their first big paper with the two of them together. Again, this is Bruncow and Ramsdale. Yes.

They also published another one in nature genetics, where they linked this mutation, the scurphyumice mutation, to diabetes and other autoimmune disorders, specifically IPEX, IPEX, which is immune dysregulation, polyendocrinapathy, enteropathy, and it's also X-linked. Which is crazy, right? Because on the mouse chromosome, it was also on the X-Rom And in humans, it's also on the X.

This sort of also shows why it's, why we do animal studies in the first place. Right. You know, we'd like to think that we're very different. But like, you know, at a real molecular biology level, we're very similar. Especially for, for old systems like the immune system. That makes sense. Right. The immune system is, is a very old system for mammals.

So a lot of the same mechanisms are happening across the mammalian species. Yes. So the final paper that they published was also in nature genetics. I guess the editor there really liked that or something. But all in 2001, all in 2001, three papers and paper in nature genetics. And this was the nail in the coffin. What they did was cross-breeding of scurphy mice with people that had the wild type and they could show a recovery of function.

And so it's really like, it's like definitely, that's the location that's causing all of this. And so now we've got a mechanism in the DNA that is perhaps where we've got a location in our DNA where perhaps this regulation is happening. Yes. Okay. And this is when Sakaguchi gets back. Yes. So in 2003, he publishes this work, which basically combines those two papers. He combines the Sakaguchi paper from earlier, which showed that these T-cell regulators were we're functioning in this way to suppress this autoimmune response. And then it's combining this Fox P3 gene thing that's happened in 2001 to show that actually if you add the FoxP3 gene to normal T cells, they'll turn into regulatory T cells.

It's like a retraining. It's like you send them back to the training academy to relearned what it may have been missed. Yeah, so you can insert this FoxP3 genome and it'll actually like turn them into regulatory. That's very, okay. Okay. So that's, it's so cool, like the mechanistic way in which we can, we can manipulate these things to really be convinced that this is how it works. Yes. You know?

Yes. No, 100%. Yeah. It's really cool. So he published this in 2003 in science. I think that's 24 you can see. And this is sort of the last, last of the papers. that we're going to review.

Okay. Okay. And so 2003, and then now it's been, what, about 20 years, 20 plus years, and they get the Nobel Prize for it. Right.

But Sakaguchi's been at it since the 1980s. Right, right. He's been at it like for a while. Right. That's crazy. Yeah. And so that's effectively what this Nobel Prize is about. It's completely characterizing this military police kind of narrative.

Yes. Police of the police. Yes. And in Photo 25, I have like the, they always make a cartoon of, um, of like what the Nobel Prize is about. So here you've got like the, you've got, um, the Treg. Yeah, the regulatory T cell. Which, which is like the spaceship, I guess. Yes.

And it's got this, this, this, this receptor, the T cell receptor. Yeah. That's trying to identify if there's been an incorrect immune response. Yes. And then the alien or whatever is inside. Yes. That has a Fox P3 cap on. You know, so that's the DNA that is, I don't know how they come up with this.

That's cloud. But that's actually having walked through, because I saw this image at the beginning, it meant nothing. Yeah. And now having walked through, I actually can point to each of the things. Exactly. Yeah, yeah. And I identify what's going on and why it matters. Yeah.

So the T-Ragg outside, that's Sakaguchi. And then the Fox P3 gene that is responsible for that, that is Brun-Cal and Ramsdale, you know? And so congrats to the the three laureates. Yes, yes. You know, they did amazing work. And now there's, in current frontiers, there's a lot of stuff going on. So you're actually going to ask, like, so now, now knowing that we have that

understanding, because this was like a, rather than like the implementation of a tool necessarily like CRISPR, this was more of an understanding of a functional, functional processes in a way that unlocks a whole variety of implications. Yes, yeah. Now we can start getting into how do we understand when T-Regs themselves don't do their job, right? Because that's when we get these autoimmune disorders like IPEX and diabetes. Wishing you could be there live for the big game, soaking up the atmosphere in the crowd. But too often, life gets busy. Or the price holds you back. Price line is here to help you make it happen.

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Ralph's fresh for everyone. The reason it's among other things, the reason at some point is because it's so directly related to this autoimmune disorder problem. Exactly. Yeah, this is one of the ways in which an autoimmune disorder manifests. Which is very pernicious. Yes, exactly. And it's something that we need to solve.

And at the end of the day, it is a Nobel Prize for medicine, right? And so now there's been so much research about it, dude. Like now there's subsets of T-Regs. There's something called the natural T-Regs. And then there's induced T-Regs that are induced in peripheral tissues after antigen exposure. So there's like normal T-cells that like get induced to become T-Regs because of their environment. They decide to go back to their own because the gene is already in there, right, in their DNA. It's just been repressed.

They can take out that repressor. And then you can also induce them in vivo and use them in cell therapy. You know, right now we've got work. In 2025, I was just reading some of the work that's come out now. There needs to be, people have found that in inflamed tissues, where there is an immune response, you'll find that the T-Rags actually need strong, FoxP3 expression. So they need more expression of that magic gene in order to actually remain stable.

They've identified repressors, transcriptional repressors, which are literally like little proteins that come in and sit on your DNA and prevent that stretch of DNA from getting transcribed, right? And so they've discovered repressors that can inhibit Fox P3. Right? And then if you block the repressor, then this thing is no longer inhibited. And you can actually get regulation. So that's one way that you can actually do therapy.

Yes. You know, they've discovered enhancers, which go in and actually do the volume control on that FoxP3 gene that we talked about another episode. Yes. There's like 200 plus clinical trials that are happening right now. Related to RELATRIC. Related to TREG as a general. Yeah.

Yeah. So, you know, it's a ubiquitous now, like, method. by which the people are trying to tune the immune system and then fight disease in this way. And it wouldn't be possible without like fundamentally understanding all of these mechanisms down to the molecular level of like how this stuff works. Yes. You know? Yes.

100%. Yeah. This is a, I mean, obviously, you know, the immune system and all of the medicine in particular, I think it's been post-COVID there is. been a very interesting discussion about how the body works that is not necessarily informed from first principles. Yeah. Right?

Because there's a lot of these fundamental processes. Yeah. That just are what they are. Yeah. And there is a benefit to having an understanding of what those are. Yeah. I mean, I love thinking about the body as just a bunch of Lego blocks. Lego blocks.

Right? That are just trying to find each other. And like all of the complicated decision making is happening at that Lego block level, right? at the molecular level. It's kind of insane. It's such a complicated set of things. Right. Where tiny things go wrong and it just totally wrecks you.

Right. And now we're getting to understanding things at such a level when those tiny things go wrong, we can go in and fix it. And even just one very, very tiny, small aspect of this combinatorial process that has so many implications. So it seems like this has solved sort of this,

100 year mystery of like how the immune system restrains itself. Yeah, exactly. Yeah, pretty cool. This is, this is very cool. This is day one. So this is the medicine. Yep. We did, I said in our predictions, Princeton was going to get on the board. Yeah, I didn't know it was going to be the first day. We're on the board. Yeah, I mean, at least my predictions were wrong, but we got on the board. We got on the board. We'll take that. Do we're actually accurate but tactically wrong? Yeah. So tomorrow we're going to be doing physics.

Same time. Yep. Same place. Congratulations to the winners. And we're going to, again, make sure we put all these out across all the socials, etc. So be sure to tune in, but we will be back tomorrow for day two of Nobel Prize Week. My name is Lester Nare, as always joined by my co-s and our resident PhD Krishna Chowdary. This is from First Principles.

We'll see you guys tomorrow. Okay, here we go. Yep. This year's prize is about encountering quantum mechanics on a new scale. Okay, so not atomic force microscopy or topological physics. Kungley-wetonskedomin has a day decided to out-dial 25-year Nobel Prize in physics to John Clark, University of California at Berkeley, USA. Michelle DeVosier, Yale University, and University of California at Santa Barbara,

USA. John Martinez, University of California, Santa Barbara, USA. That's also UCSB. Okay. For uptects of macroscopic quantum, mechanistic,

and energy quantization in an electric crats. The Royal Swedish Academy of Sciences has today decided to award the 2025 Nobel Prize in Physics to John Clark, University of California at Berkeley, USA.

Michel DeVore, Yale University and University of California at Santa Barbara, USA. And John Martinez, University of California at Santa Barbara, USA. I wonder where they got their PhDs and stuff.

For the discovery of macroscopic quantum mechanical tunneling and energy quantization in an electric circuit. Macroscopic quantum tunneling. Hello, Internet. This is your captain. speaking, Lester Nare, joined as always by my co-host and our resident PhD, Krishna Chowdary. We are on day two of Nobel Prize Week for the physics prize. We just watched the live press

conference. Macroscopic quantum tunneling was the winner. We're going to dive in and understand what exactly this all means. So interestingly, not AFM, not topological physics. Yep, yep. Very much still important. So what matters about this macroscopy quantum tunneling winning the Nobel for physics this year. You might have heard of quantum computers. Yes. Right? Actually, I just looked it up.

John Martinez, who's one of the winners of the Nobel Prize today, he's actually the head of the Google quantum AI law. Oh, interesting. Okay. In UCSB. Yes. So it's kind of a win for large devices that have these quantum mechanical properties that can then go on to do all sorts of stuff.

It's a bit surprising to me that something like as adjacent to quantum computing as this got the Nobel Prize. But I think it's it, I mean, it's four experiments that were done in the 1980s. And that has sort of started a whole new field of quantum devices, quantum experiments, things like that. So it's not just for, you know, quantum computing, but it's sort of a foundational prize. So it was given to three people. It was given to John Clark, Michelle DeVore and Jean Martinez for the discovery of macroscopic quantum mechanical tunneling and energy quantization.

And I think it's a bit of a nod to what happened 100 years ago. We did an episode on the fact that 2025 is the year of quantum, right? According to the UN. Yes. And that's because 100 years ago is when the first seminal paper. and quantum mechanics by Werner Heisenberg were published. We did a whole episode on that paper itself. And in photo two, you can see that's a, it's a, oh, okay, never mind.

Photo two is actually just about the quantum tunneling itself. This is the Nobel Prize cartoon. They always have a Nobel Prize cartoon, right? About, about what's actually happening. So this is a cartoon of on the left-hand side, you see like electrons. And it's turning into this giant current. Yes. It's because it's one giant quantum state.

Okay. Okay. And we're going to sort of get into like what this thing means as we go on in the story. Photo three is a nod to the 2025 year of quantum physics. That's a photo of three of some of my favorite scientists. We've got Werner Heisenberg in the middle. On the left is Paul Lee. And on the right is Enrico Fermi.

Yes. Three seminal figures in quantum mechanics. And on the left, is a letter from Werner Heisenberg to Wolfgang Pauley talking about his 1925 paper and how everyone else is wrong. Pauley was also of the opinion of Werner Heisenberg where we needed a new paradigm to do everything quantum related. And so I really think that this year's Nobel Prize

goes to quantum because of the fact that it's the year of quantum. I think that was definitely part of the back chatter. That makes sense. Okay. Okay. So to get into like what exactly is going on in the physics, we need to understand something called quantum tunneling. Okay. So if we have like a classical particle and you've got like, let's say a wall, like a brick wall and I like throw stuff at it, it's going to bounce right back. In no world is a ball that's the size of my hand ever going to go through. Right. In quantum, in the quantum world, that's no longer the case. Right. You can have a barrier and then have a single particle go through. And this is something that you can solve in a. undergraduate physics, just using the Schrodinger equation, you'll have a probability that that

particle goes through the barrier. And if you look at this description here, that's the Schrodinger equation getting solved for this potential landscape. The potential landscape is zero everywhere, and then you've got this high potential region, that's basically the barrier. And then you've got some particle with initial energy going from left to right. Okay. Notice, that on the right-hand side, you've got the wave function is highly diminished. So what that means is that the probability of finding the particle on that side

is way smaller than finding the particle on the left side, which makes sense, right? I'm going from the left side, so the probability of tunneling is low. But crucially, notice that the waviness of the wave function on the right is the same as on the left, meaning the wavelength hasn't changed.

And what that means is the energy hasn't gone down. So if I were to find a particle with low probability, fine. But if I were to find that low probability outcome of a particle on the right hand side, the energy has not gone down. It's almost as if the particle just teleported through this energy barrier. Yes. That's very not classical. Right.

Right. Yes. That is very much like not a classical thing. Yes. Right. In a classical thing, even if it like somehow went through, it would be slowed down by the barrier. But here, it's a probabilistic outcome.

But if it happens that the particle goes through, it's going to be moving with the same energy. That's so interesting. That's the magic of quantum mechanics there. Right. Right. Okay. So historically, it's actually been seen in all sorts of different phenomenon. Like, for example, with radioactive decay,

this is the idea where nuclei, like large nuclei, like the uranium atom, can decay and they spit out an alpha particle, right? And it happens with a certain probability. That can actually be modeled using this quantum tunneling landscape. What you can imagine is you've got the nucleus of the atom, and the nucleus of the atom has a bunch of particles that are kind of moving around, right? Each of these nucleons are moving around either the protons or the neutrons. And if the proton or neutron tunnels itself outside of that little well, right,

then it's going to find itself on the other side of that barrier, and it's going to be going with pretty high energy. Yes. Right? And the probability with which that tunneling happens tells you the half-life of your material. If it's a high probability, then the half-life is lower. If it's a really low probability, that means it's a very stable nucleus, and the half-life is much larger, right? And that is why half-lifes, and the fact that half of your nuclei are going to decay with a certain amount of time.

that's a very probabilistic thing to say. And it's rooted in this quantum mechanical probability stuff. Okay. Does that make sense? 100%. So, like, we know that quantum tunneling happens. Right. Also in the core of like the reason why we're all alive on Earth and Earth has been going

for four billion years with life on Earth is because the Sun has been doing quantum tunneling in its nucleus, right? You would imagine that the Sun's nucleus is like, I think it's something like a million Kelvin, a million degrees Celsius. And, you know, at that speed, I mean, at that temperature, the nuclei inside the sun are moving extremely fast, right? And the idea is two hydrogen nuclei, just protons, are moving so fast that they bump into each other.

But what's preventing them from bumping into each other is the fact that they're both positive charges. And so the Kulam barrier, which is basically repulsion, positive, positive don't like to be next to each other, is going to make them not bump into each other, right? And they're actually not moving fast enough to get over that energy barrier. Okay?

The reason why sometimes they get stuck right next to each other and the strong nuclear force takes over and fuses them into a single nucleus is because sometimes these guys tunnel past that energy barrier that's created by the Kulam potential. And so all of a sudden sometimes you'll have the proton tunnel through that barrier bind itself right next to the other proton, and then you'll have the fusion happen that creates

the light that we see. Right? So quantum tunneling is, we can thank quantum tunneling for the light from the sun. Literally the light that powers everything that entire ecosystem. Yeah. And so quantum tunneling has always been something that is well known, but it's been well known for small numbers of particles, right? even with nucleons and alpha decay, that's like four protons, right?

Four sort of, it's a pretty small mass. Yes. Right. With the stuff in the sun, again, few nucleons. What this year's Nobel Prize winners did was experimentally confirm quantum tunneling and quantum behavior for like on the order of a billion individual particles, all acting together and quantum tunneling together. Interesting.

Okay. So it's several orders of magnitude. above that sort of undergraduate level like problem sets that we used to do. Right, right. Right. It's very cool, I think. So in order to really understand the experimental setup,

right, we got to talk about superconductivity. Okay. This was made very famous with the whole LK99 scam that happened from the Korean scientists. It was not real. It was not a room temperature. It was not a room temperature superconductor. Yeah, this is an example of an actual superconductor that's been cooled down.

That's why it's like condensing all the stuff around it, right? And with superconductivity, you have this amazing phenomenon where at low temperatures, you have zero resistance to electrical current. Okay? And by zero, I don't mean near zero. You mean more. Or like a little bit. I mean literally zero.

Literally zero. Literally zero. There are superconducting currents that have been kept alive just by the fact that they've been kept cold for like decades now. Interesting. Okay. In experimental physics labs. Because like it's, because there's no resistance, you can keep this state for decades and it'll be the same exact current value. Because no current is leaving.

No current is entering. It's the same amount of energy that's locked into this apparatus that you have. Yeah. Yeah. So for 20 years, you can experiment on the same exact thing, right? And make your, make everything else bigger and bigger. But like the thing that you're, you're messing with is exactly the same. Yeah. It's been decades. Yeah. All you have to do is keep it cold. Right. Okay. So it's not a perpetual motion machine. Okay. Do not get me wrong. Right. It takes a lot of electricity to keep this thing that cold. Okay. But if you can keep it cold, then this little state

is just going to stay forever, right? That's the magic of superconductivity. And the physics behind superconductivity is quite interesting. It was discovered by three people, Bardeen, Cooper, and Schiefer at the University of Illinois in Urbana-Champaign. And it comes from the fact that electrons can interact with the lattice of atoms in a superconductor in a very specific way. So I think we've got a picture here that we can show.

here's what's going on, okay? So you've got two electrons, okay? They're the little tiny blue dots. And then you've got a lattice of atoms, which are these positive charges, right? Well, they're really neutral, but they've got positive nuclei, and then electron clouds around them.

Right? So the positive is the teal color. Okay? What happens is when there's an electron in that lattice, what it's going to do is deform the lateral, in a way that the positive nuclei are going to kind of get smudged towards the electron. Okay? Now, what is that going to create?

That's going to create a localized positive charge where the electron is. Because usually that electron and all the positive charges would perfectly cancel out. Right. But because all the positive charges are now sort of scrunched up and localized, there's a higher density of positive charge there, then the electron is able to cancel out. So there's a slight positive charge there. This is in that sort of slightly pink area.

Yes, exactly. There's a slight positiveness to it. Yes. Okay. And that is going to couple with the negative electron. That's in the lattice. Right. Yes.

Exactly. And these two, these two particles, they obey the Pali exclusion principle, meaning that you can't have the quantum states right on top of each other. they don't want to sort of like talk to each other all that much. Okay. But because they're two different electrons, you can have them obey the Pauly Exclusion principle within themselves and create something called a boson. Okay.

Like these two are fermions, meaning that they obey the Pauley Exclusion principle. But together, they use their disagreement to sort of cancel each other out and create a boson, okay? And this boson is something that can have quantum states that are right on top of each other. Interesting. And so you have very different physics. You can have something, I mean,

you might have heard of something called a Bose Einstein condensate. I was literally going to just ask that, yes. Exactly. So the bosonson condensate is this idea that all, like when you get something really, really cold, they start behaving like bosons. Yes. And then they start going on top of each other

and they obey like one giant quantum function. Okay. That's what these Cooper Pets. can now do. These are called Cooper pairs. Yes. And the pairs can act like quasi-particles that can stack on top of each other. And you can have this kind of Bose-Einstein condensate in your superconductor, right?

The mathematics is about the same. Interesting. Okay. Yeah, yeah. And what that means is these condensate can now move around like a single quantum state. It almost has a shared state across these independent electrons. Yes. that act at that act in unison as an as an emergent effect of this these parameters that you just described.

Yeah, exactly, exactly. And so they can, it's like multiple pairs. They occupy the same quantum state. And because they're occupying the same quantum state, they can move as one. And so the electrical resistance, which is what you usually get when all these electrons are bumping into each other is no longer there. Right. Does that make sense? Yeah, 100%.

So the Cooper pairs are talking. nice to each other. Yes. And they're moving. Yes. And without any, without any bumping. And that lack of resistance creates, like, there's opportunity that gets created from that low resistance environment.

Yes. Zero resistance. Zero resistance environment. Zero resistance environment. And once you have zero resistance, then you have stuff like the Meissner effect, which is where you get the levitation over a magnetic field. Yes. And you get Maglev trains in Japan.

That's how Maglev works. Yeah. Yeah. So that's how superconductors work. Okay. Fundamentally, the physics is, you. You've got these Cooper pairs that are pairing up. The two fermions are pairing up to create a boson.

And then those bosons become like one giant thingy that like moves in the in the superconductor. And it was, they won the Nobel Prize for it in 1972. This is Bardeen, Cooper, and Schiffer. And it was at the University of Illinois, Urbana Champaign. Bardeen actually alumni of Princeton University. And he's the only person to have won the physics prize twice. Oh, okay. Yeah, once for inventing the transistor at Bell Labs.

No big deal. And no big deal. And then he came over here and, like, did the seminal work for superconductivity. What a life. Yeah, what a life, dude. BCS theory. So now we understand how superconductors work, right? Now, there's this guy, Brian Josephson.

He predicted that what superconductors can do is they can actually tunnel across a, insulating barrier together. Before we used to talk about how particles individually tunneled, right, across barriers. What Josephson figured out is actually these Cooper pairs that are acting like particles, they can tunnel across a barrier as well. As one. As one. As one.

Right. So on the top there, this is again a cartoon from the Nobel Prize Committee. On the top there, that's a normal current, right? All the electrons are pissed off and they're like fighting each other. And being disagreeable. Yeah, they're being disagreeable. And then in the middle, that's your superconductor. So all of the electrons are paired up.

They've got little smiles. I don't know if you can see that from here. But they've got little smiles and they're paired up. And they're moving across that barrier. That's called a Josephson junction. Okay. So that was a Brian Josephson. The bottom rung is what the Nobel Prize is now we're doing.

Which is we're going from Cooper pairs to now a giant current. That is one thing. That is one thing. Okay? Yes. That is tunneling across the barrier. Right. Okay.

So we're going from like two particles to now 10 to the nine. Right. Okay. Right. Yes. And Josephson, he won the Nobel Prize in 1973 for that. And this is a depiction of a Josephson junction, which is the sort of theoretical thing that he was trying to look at. Okay.

So on the left-hand side, you've got two. superconducting regions, okay, that is separated by an insulator. Yes. Okay? And the idea is that even when there's zero voltage across this barrier, you can have Cooper pairs go through. Go through. And there's going to be some max amount of critical current that you can get

out of that from those Cooper pairs pairing up and moving through. Yes. Okay? And you can imagine the Josephson Junction as like a schematic on the right where you've got a capacitor, you've got a resistor that holds all of the resistance of the entire circuit somehow. And then you've got a current in the middle, and that's your critical current, and that's the maximum amount of current you can do with zero voltage. If you apply more voltage, then it's just going to become a classical system, right?

Okay. So that's how Josephson junctions work. Now, in 1978, Anthony Leggett, who is another Nobel Prize winner, he started asking, well, can I make a macroscopic tunneling experiment happen where instead of doing Cooper pairs that are tunneling, and like each little thing is treated like a quantum mechanical state, what if the entire circuit is a quantum machine? Right. It's like a, it's like a, the entire circuit is an atom. Yes. In some sense.

Yes. That's doing this quantum mechanics, okay? And what he considered was a current biased Joseph's injunction. And that's what we're going to see over here. So what we're looking at is that Joseph's injunction that we had earlier, right? And he's asking, now, what is the energy landscape of the current in that Joseph's injunction? Okay. You can ask, the Joseph's injunction.

can be parameterized by something called the phase, which is like if you have an alternating current, the phase difference between the two sides is like a parameter that describes the position of this circuit. You can imagine the circuit is like a particle and the position of that circuit is the phase. And in physics, when you do that and you go to the equations, then it like starts obeying kind of like Newton's laws

kinds of stuff, right? Where you've got like a potential landscape and you've got the energy minima. and like it wants to move towards the energy minima, right? So when you start putting the language of the Joseph's injunction into this sort of mathematics, you get these potential landscapes. And the idea is on the top, you've got on the left, if you don't apply a current, remember, this is a current bias Joseph's injunction.

So I'm applying an external current, right? And if I apply very little current, then the energy states look like on the top left, where I've got these energy minima, right? And the particle is sort of going to get stuck in one of those. Right? The circuit is going to get stuck in one of those states. If I apply too much current, then you're going to get this effect where the energy landscape gets completely tilted. Yes.

Right? And then you have no energy minima. Okay. So the question was, the experimental question was, is there a macroscopic? degree of freedom, such that the entire circuit behaves like this multi-energy minima thing, right? Where on the bottom, if there's no such macroscopic degree of freedom where stuff can get quantum at a big level, then you're going to have the stuff in C, which is a very continuous energy landscape.

And it's just like a particle on a hill, okay? ball rolling down a hill, it can be in any of those positions on the hill, right? If it's quantum, on the other hand, then in that potential barrier, right, in that little well, where the particle is sitting, where this current particle is sitting, there's going to be discrete energy levels. Within that well. Within that well. Right. And there's going to be discrete quantum states. So that is the experimental question, right? Right. And Leggett says that there should be, but this is going to be notoriously hard to actually make. You can imagine this is in the 1980s.

So again, we don't have the technology that we have today. Today we have all of the upgrades from this to create like giant super, like superconductors and giant quantum computers. This is so fascinating. With that with that set up, the fact that you, like the question is, I've got a, I've got a circuit now. that's made that's it's a fancy josephson um this junction biased yeah it yeah it's got this like biased um it it's got this biased current that goes in um can i make the entire circuit a quantum object right that's the idea right and the entire circuit is made up of like 10 to the nine things right and can all of those 10 to the nine things move as a single quantum object

object, right, that tunnels and does all of the stuff that I wanted to do. As a result of this sort of concept, we just walk through around how quantum tumbling fundamentally works. The thing is, can we scale it up from a single, like there's a particle, which is a single Lego block? And we talked about Cooper pairs, which is like, imagine components of a whole Lego structure, but it's like larger than a block. And now we're saying, can we make it the whole, the whole building, like the completed

Lego structure behind you? Yeah. And have that entire system operate as this single. A single quantum object. A quantum object. Right? Like that has well-defined quantum states. Okay.

So that is where we get to UC Berkeley. Okay? One of my favorite universities in California. So we're in the physics building. This is photo 12. That's the physics building of UC Berkeley, legendary building right in the center of campus, right next to the giant tower that UC Berkeley campus is well known for.

That's the building where, where Oppenheimer's been in. That's the building where plutonium was discovered. Several Nobel Prizes. And actually, now they got a plus three on a single day. That's unbelievable. Unbelievable. Because we were excited yesterday.

Yeah, we were excited with plus one. But yeah, in a single day, UC Berkeley has a plus three. Because John Clark at the time after his PhD at Cambridge, he became a professor at UC Berkeley. He was joined by Michelle Deverey, who was a postdoc in his life. lab and Jean Martinez, who was a PhD student. All three of them were in the same lab and the same building together. And they start asking if they can create a superconducting electrical circuit with a Joseph's injunction that has this property where billions of these Cooper pairs, 10 to the

nine particles, are acting like a single quantum particle. Right? Yes. Can we do this? Okay. So, We get to, we get there. And now this is their setup. Okay, this is actually a photo that's adapted from John Martinez's thesis. Oh, okay. Okay. Imagine writing a PhD thesis. Yeah.

And then like a figure is like in the Nobel committees cartoon. You know, it's so legendary. It's so legend, dude. Like this is literally in his thesis. That's unbelievable. Yeah. Yeah. And his PhD thesis.

So this is the. the current that they came up with, the circuit that they came up with. On the left-hand side, you've got the power that's coming in, okay? And on the right-hand side, all the way over here,

I guess, from my left, all the way over there, that's the Joseph's injunction part. In the middle, you've got, like, copper in the middle. And this is the part I actually still don't understand, is how they're saying the copper is, like, shielding.

But, like, I thought, copper was electrically conductive. They don't really go into it, and I didn't really have time to, like, figure out how. So if somebody in the comments who knows how this works, like, I don't know how copper is shielding. Okay. Anyways. But somehow they're saying it's shielding. All right.

So, so, but, but the idea is, you know, you want to get this thing really cold. And, and so, and you want to shield it from all sorts of electrical noise, all sorts of every type of noise. Okay. All these external factors. all of these external factors. And what you want to do is also measure the resistance and the capacitance of this entire circuit independently at that temperature

so that then you can fit everything to the, you can plug everything into the equation and then see if the properties are making sense, right? So before this group, before this group was doing all that, what people would do is they would like do these kinds of experiments, but they'd fit parameters. Right.

And be like, see, it's kind of where, That's not convincing, right? What you want to do is say this is the equation. This is this number. This is this number. This should be this number. This is what I measured. We're good.

We're good. It's not like if these numbers are this, then it makes sense. Right. That's not, I mean, it's still like fundamentally good science. It's just not sort of closing the book. It's not a complete, it's not like a sort of the complete circle, complete loop. You're arbitrarily creating.

It's not closed logic, right? It's like, there's too many free parameters. Yes. Okay. So they make this thing. They put it inside of cryostat. And on the top, you see that little antenna there? That's a little microwave antenna.

That's going to get really important later on. But this is effectively the setup. You've got a power source. You've got the Josephson Junction. And then you've got a microwave antenna that kind of talks to it. With some copper in the middle for shielding. Yes, with the copper in the middle for shielding, which I still don't quite understand how that were. I thought they were trolling when I read it.

And I was like, okay, whatever. I guess, yeah, there's always some weird physics, you know, that I just didn't have time to figure out. So they make this thing. And what they do is they want to see if the current, if they feed a weak current, am I going to get the system? Can the system tunnel out of this state with a sudden voltage that comes up in that? in that power thing that I put in. Okay? And that's what they actually find.

What they find is if they repeat this experiment thousands of times, on the right-hand side, what you can see is a photo from their paper, which was in the physical review. And this is the one that, like, you know, finally won the Nobel Prize. So you've got this macroscopic tunneling happening because the diagonal is what the classical circuit should do.

And you see this nice uptick as you decrease the temperature. what we're seeing is the current is stabilizing. Right? There's some minimum amount of current that's happening. Yes. Right? Yes. At that.

And the amount of current on the on the on the on the on the on the on the. On the on the theory. Oh, tells you. And and the and the little the the the, the, the, the plateau is happening right. Right. Right at that tick.

On the X axis, it's also telling you where the plateau should start according to theory. And that's also lining up. with the experiment. We love to see it. Right? And you love to see that experiment

theory confirmation happening. And so on the left-hand side, I don't really like this cartoon. It's like a switch that is like turning on and off. And that's it. So I don't know how that's like quantum.

Anyways, that was the Nobel Committee's best attempt. They were like, this quantum stuff is tough. Let's just put a switch on there. Yeah, let's put a switch on there. Yeah, let's put a switch. Make it two states. We're good to go.

Okay. So now we've shown that there's like this current. Right. The killer is that this thing is quantized. This state is quantized. Okay. And the way they did that was remember that microwave antenna? They used microwaves to excite the system and they observed energy levels that were quantized. So if you go to the next slide, on the left, this is the cartoon of quantized energy. levels, right, that are like discrete.

It's not continuous like it would be in classical, classical physics. And on the right, what you're seeing is that the tunneling would occur faster if you were in the higher energy state, which makes sense, right? According to, that's like Eisenberg's uncertainty principle, actually. Like energy and time are both related by that quantity where the product has to be less than something. So if you increase the energy, you're going to have to decrease the amount of time that it stays within that state.

So it's consistent with quantum mechanics. and on the on the on the on the on the on the upper panel you can see this quantized energy landscape right so so this was kind of the nail in the coffin of like this of like this entire thing of 10 to the 9 billion of cooper pairs are behaving as a single quantum thing that is like going between one state or another in unison in unison that's exactly right right pretty it's pretty it's pretty cool And this was in the 1980s. So they waited, I guess, 40 years to give it to them. To give it to them.

Yeah. But in those 40 years, a lot of advancement has happened. I mean, I can imagine. Yeah. Yeah. A lot of stuff has happened. So the way it's made me think, just like the implications of understanding. Because obviously with quantum, everything quantum related, it's always, it's a little

hand wavy. It's a little like, don't look in the corner over here. You know, we haven't figured that part out yet. Yeah. Yeah. But this feels like a really solid root that has a lot of branches that can come from having experimental confirmation. Yeah, yeah. And it's like, dude, 10 to the 9 particles that are behaving in a quantum way is like pretty insane.

Yeah. Yeah. It's pretty insane. It's an entire circuit that is like an atom, right? I mean, sure, it's like cold. It's like near zero Kelvin. Right. But like we're not talking about room temperature.

Yeah, yeah, because there's too much noise and. room texture. But even down there, like, the fact that the noise is so low and the quantum connections are so robust that it's able to like maintain coherence and maintain this single state, right? Across these transitions from one state to another. It's not like losing stuff. Pretty crazy. And, you know, it started a whole field of quantum devices. Superconducting circuits are now used as quantum qubits. And that's one of the applications that we can focus on. So this is a photo of IBM's quantum computer. The cubit, so the photo, what you're seeing is like the chandelier type design. That's because this whole thing is inside a dilution refrigerator that like gets you

down to that temperature. Right. Right. So you got to get really cold. These quantum systems have to look so bizarre. Yeah. It's because it's the the cooling apparatus is like half of it, right? In terms of In terms of the actual mass of the stuff, it's like a lot of it's just like the refrigerator. But the cubit itself is the next photo that I have. And that is the transmom quantum cubit. The arrow that you're seeing, that little square in the middle, that's the Josephson Junction. Okay. And the little like radiator type things on the right hand side of that, that's like a microwave cavity.

that's being used to talk to the Joseph's injunction. So they basically miniaturized this work. This work, right? And John Martinez is actually now, he's, in 2014, Google poached him from UC Santa Barbara. And they, I think it was a multi-million dollar deal. Of course it was. And like now Google's quantum AI lab is headed by John Martinez. And I don't know if you remember a few years ago, there was that quantum supremacy paper, maybe like two years ago.

I think I texted you about it because I was like, hey, is this it? Yeah, yeah. And it's like, you know, in the in the quantum community, it's like, yeah, maybe. I mean, it's certainly very impressive that they have so many qubits that are running. John Martinez is that team, right? So I bet Google's, like, press is going to like have a field day. They're going to have a field day. They're having a field day.

They're having a field day. We told you. Yeah. We're on the board. Yeah. Yeah. Now Google has a... Google's on those...

Because we're going to start a scoreboard for the institutions with the most Nobel's. Yeah. And so now Google's... Yeah. Google's getting up there with the private institutions, right? I don't think anyone's ever going to beat Bell Labs. Bell Labs has like eight, which is insane. That's pretty...

That's pretty crazy. But, yeah, like, it's a pretty profound contribution. And now, you know, the Nobel... celebrates that this collective behavior of many particles is doing it, right? We've got John Clark. He got his PhD at Cambridge, and then he was a professor at Berkeley. Michelle Devereate, he got his PhD in Paris, and then came to the States, now at UC Santa Barbara in Yale, and then finally, John Martinez, who's at Google and UC Santa Barbara. Unbelievable. What a fantastic. That's actually a really helpful.

explanation. I think one of the people in our comments on our predictions video talked about how they thought that the quantum tunneling was going to be the one that won. And it's one of those words that I hear all the time tossed around, especially with some of the UAP stuff. People always like to throw the word without the actual first principle of understanding. Quantum tunneling, for sure. That's how they're doing all the crazy flight movement.

But this is super fascinating. And I think it's interesting because your view is somewhat unexpected. I thought it was somewhat unexpected because usually like Nobel Prizes go for things that have actually worked. I wouldn't say that quantum computing has really worked. It's fair. Okay. But it has worked in the sense that I like, you know, I am creating giant. things that are entangled in a quantum way, right?

So in that sense, it's definitely worked. And so maybe given that, this thing makes sense. Because, like, this is the first sort of experiment that showed that in principle I could create billions of particles that are behaving together in a quantum way. Would you say that in part some of the understanding related to understanding quantum tunneling and energy quantization. Like it helps to elucidate this like the unification

problem with classical and quantum mechanics. Or is this? Certainly does. I mean, I think personally I think that the more the larger we push quantum systems. Right. That's kind of the thought. The the weirder it gets.

Right. But fundamentally actually, I don't think like doing these kinds of experiments will really solve the measurement problem. You're just making the measurement problem bigger in terms of like, you know, now it's no longer I'm observing a photon. It's like, okay, now I'm observing 10 to the nine particles. But philosophically, the problem is still the same, right?

Which is like, how does the Joseph's injunction know whether to, you know, be in one state or the other? Right? Which we talked about this last quantum. So it's an interesting problem. I mean, I also saw there was a paper, I think, two years ago that used these Josephson Junction-type superconducting circuits to get at Bell's inequality. And Bell's experiment is the one where you take two entangled particles, you put it on either side, and then you measure one, and that sort of affects the measurement of the other, right? There's like correlations that wouldn't be possible unless these two were actually entangled across that distance.

So there have been, there have been experiments that use these cubists to do that. And I think they did it over 30 meters, right? Which is a pretty big, a pretty big distance when it comes to like particles, right? Yeah, yeah. So there's going to be like fundamental physics experiments that you can do with these things too. But I think, yeah, fundamentally, this is just showing that the world is really weird. Yeah. Right?

And the world gets weird even when you get really big. Day two's conclusion, the world is really weird. Yeah. And we are awarding those who help us see that. It is indeed quite curious. Yeah. Really weird. So this was day two for the Nobel Prizes.

We have macroscopic quantum tunneling. John Clark, Michelle DeVorei, John Martinez. We'll be back tomorrow for day three. Yep. The last of the sciences, chemistry. Yeah. Bright and early again. Be sure to tune in.

I'm your host, Lester Nare, joined as always by my co-host and our resident PhD, Krishna Chowdary. This is from First Principles. See you guys tomorrow. This year's prize is about creating new rooms for chemistry. What does that mean? New rooms? New rooms for chemistry. Kungley Wetskedom

has today have today has made to add up 2025 year's Nobel Prize in Chemie

to Somo Kitagava Kyoto University Japan Richard Robson University of Melbourne

Australia Omar Yaki I knew it That's amazing I told you yep yep yes

I called it on Sunday called it on from first principal's podcast baby that's so funny Hello, internet. This is your captain speaking, Lester Nare, joined as always by my co-host and our resident PhD, Krishna Chowdary. We are day three of Nobel Prize Week. Chemistry. We just watched the live stream. And the winner is metal organic frameworks, which was part of our prediction on Sunday, a branch of reticular chemistry. And so we're going to dive right into understanding what are metal organic frameworks and why this is so important. Yeah, I mean, so the chair of the Nobel Committee said new rooms for chemistry. What are you talking about? Well, it's a pretty good way of talking about metal organic frameworks. Okay, what we're doing is we're making new rooms for chemistry that have custom sizes, custom doors, and they're made out of custom walls. So they've got a cartoon, as they always do. On the left there, that's the cartoon from the Nobel Committee. Yes. And on the right is the actual, what?

One of the examples of a chemical compound that exhibits this metal organic framework. Okay. And the idea is these things are exceptionally useful, mainly because they got a bunch of holes. Okay. They have a bunch of like vacancies that you can use to do really cool things. For example, suppose you want to filter out carbon dioxide from exhaust, right? This porous material can now do that. Yeah.

Right? suppose you want to like get water from thin air. The porous material can now do that, right? Because you're making holes that are the size of the chemical compounds. Or like that are going to interact with the chemical compounds that you're trying to extract or you're trying to catalyze things like that. So it's it's like you can tune the building material. Right. Using using these metal organic frameworks.

It's like I built a resort and each room is custom built for each guest that I have at the resort. Yeah. And you can now build each thing. Yeah. Right. Because it's effectively like really, really complicated Lego blocks. Okay. Okay.

If the Lego blocks individually are like atoms and small molecules, now we're creating like structures that you can then just like attach. That makes sense. And make like buildings. Yes. That can fit whatever molecule that you want. Okay. Right.

Okay. It's really cool. So the award was given to these three individuals for basically starting this field, okay, and like bringing it to its heyday. So the first one is Richard Robson. He's the one in the middle from the University of Melbourne. He's the guy who sort of founded this back in the 1980s. And then there's Susumu Kitagawa from Kyoto University and Omar Yagi.

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Hilton for the stay. Brought the field forward to where now it's like so many industrial applications, right? I think it's very cool. I've been doing a lot of research. I was a little bit better prepared this time because I did have the prediction. But it was still like getting into the weeds. It was really cool to see how the history progressed.

Right. Okay. So chemistry has been really good for a very long time with something called zero dimensional chemistry. Okay. Zero dimensional chemistry is like something that is localized. Okay. Like even the Bucky Ball or like small molecules, right?

Those things are in some sense zero dimensional because they're point like. Okay. And that's a zero dimension. Right. Then we started getting really good at 1D, right? Polymers, that's a carbon nanotube. And we wanted to get to 2D and 3D, okay? But that was known as kind of a synthetic wasteland

because it was really hard to figure out how to create stable 2D and 3D structures. 1D you can imagine, right? You just like add in a chain of like nerd like, you know, those nerd ropes. It's like that. It's like relatively easy. Okay? compared to the 2D and 3D stuff that this Nobel Prize is going for. But there was a precedent to try and find these things, okay?

There are these minerals that are found naturally. They're called zeolites. It was discovered by the Swedish mineralogist Alex Tronstet in 1756. And what he did was he observed that like if you take this material, right, which in this case it's still bite. Zeolite is the class of materials. What he discovered was this particular one. this thing could absorb water, okay?

And then when he heated it up, steam would come out. Okay, very simple observation. But what does that mean? That means inside the chemistry, it's trapping water molecules, right? And then as you heat it up, those water molecules are going away in the form of steam. So what that means is there's like some, there's some ability of this thing to absorb chemical compounds and then put them out. Right, right? And there's like holes inside where this water molecule is going.

right? And that's why he coined it Zeolite because Zio is Greek for boil and lithos for stone. It's like a boiling stone. And these zeolites became like a big passion of chemists because they're found naturally and you want to try to characterize them. The next thing that kind of gets into this is the Berlin Blue, which is this pigment that was discovered in the 18th century. It's got a relatively complex structure. Like on the right hand side, you're seeing the structure, which is basically a bunch of iron, which is iron ions. So iron two and iron three, that means it's either two electrons are gone or three electrons are gone.

And then inside, they're linked by these carbon nitrogen bonds. Okay. Okay. And now we're starting to get into metal organics, right? Metal, the iron organics, anything that has carbon. This is the like day zero. Okay. And on the left, that's the famous great wave off Kanagawa.

Yes. The print by Hokusai in the 1800s. Yes. Right. That blue pigment is the Berlin blue. Berlin blue. Right? The Japanese printmakers would like import this from Europe because making blue was incredibly

difficult. Like the Egyptians used to make blue and then we forgot how to do it. Because like the Egyptians. That's such a crazy like, I mean, knowledge is forgettable. Yeah. Knowledge is very fragile, dude. If you're not, if you're not careful. Right.

actively keeping it up. It's funny, that same blue wave. My wife has a Snoopy bag. She got from the Snoopy store in Japan with that blue wave on it. So I'll tell her that fun fact. Yeah. Yeah. It's pretty cool. And that is like the, you know, day zero metal organic framework that sort of led to all of the developments and then created the Nobel Prize today. So we know that these things are possible. Right. Right. Because they occur in nature. Yeah. They occur in nature. The idea is we want to, we want to be able to engineer and very specifically put stuff together, okay? In order to basically get the emer, like the emergent property, so we're looking for. Yeah, yeah. And in order to figure out exactly how we're going to do

this engineering, we need to do a little bit of basic chemistry. Always, you got to start from first principles. So we go to 1913. Alfred Werner wins the Nobel Prize in 1913. He basically starts this field of coordination chemistry. Okay, he starts, he starts thinking about metal ions and how metals can bond covalently with other atoms. And he characterizes these tetrahedral complexes, tetrahedral meaning the like four, you know, tetra meaning four. So four bonds that are in this like sort of nice crystalline pyramidal structure. And these bonds between the metal atom and the other atom is what's called a coordinate bond. Okay. And this is different from a covalent bond. So if you go to the next slide, I'll show you what the difference is.

So in a normal covalent bond, you've got shared electrons, right? In 2002, for example, oxygen and oxygen, each oxygen is sort of donating an electron to the bond to create the O2 molecule. Same thing with CO2, H2O. With a coordinate covalent bond, there's only one donor. Okay, the other guy's kind of leaching. Okay. Okay. So over here, you've got, you know, on the left-hand side, you've got the yellow atom.

that's got a full shell with eight electrons. Yes. And then on the pink atom has two holes. Right. So the yellow atom goes in and donates. Now everyone has full electron shells and everyone's happy. This is called a coordinate covalent bond. Okay.

And this is going to be the sort of building block of the chemistry that we're about to talk about, the one the Nobel Prize. Okay. Because metals, metals make ions, right? And what ions, usually with metals, the outer electrons, which are in the D shells, that are like far away from the nucleus, they're just going to go away. So you're going to get like a copper ion, which is C plus. That means one electron left. Or the ones we were talking about iron two, iron three, that means two or three electrons left.

So they got these holes. But now other atoms can come in and fill that gap. And you get a coordinate covalent bond, right? And that's going to be the building block for the chemistry that we're about to talk about. Yes. Okay? So with that in mind, let's go into. to our Nobel laureates. So first we got Richard Robson. He is in the University of Melbourne. He's

teaching classes in 1974. And this is a great example of how teaching actually leads to discovery. Okay. So he's teaching and he needs, you've probably seen these in like high school chemistry classes, right? The balls that have like holes and then he put sticks in it to make molecules. So he's trying to get those made in the wood shop. Okay. Okay. So he's sending over instructions on where to put the holes. Because each atom is going to have specific geometry on where the holes go and where the atoms are being made. And as he's doing that, he needs to mark out where the holes are.

He gets inspired by this. And he's like, wait, if the holes in the atoms tell me the geometry of the bond, right? But these holes can be on the outside of bigger molecules. And those holes will still preserve the geometry, right? on the outside. And he was inspired by the diamond, which is we've talked about. In the next slide,

we can look at the crystal structure of the diamond. That's a tetrahedron. It's carbon. With the carbon, you've got four holes that you make, which is one on the top and then three sort of pyramidal ones on the bottom. And then you can connect all of these together

to create a tetrahedral crystal of carbon, and that's what a diamond is. So he was inspired by this. And he's like, okay, if I want to create a diamond-like thing, but I want to do it with bigger building blocks. Right, right? Can I do that?

Right. Okay? So he decided to try the copper ion, which is CU Plus. And with the copper ion, he attached copper ions, so four copper ions, he attached that to a molecule that already had this tetrahedral geometry, right? The molecule is called 4444-Tetrophenolmethane. Okay. This is one of the reasons why I never really got into chemistry in high school.

The names were just ridiculous. But the main idea behind this molecule is it's pretty rigid. Right. Okay. It's a rigid molecule. And on the ends of that pyramid, the top and the three ends, there's something called a nitral group, which is this CN, carbon and nitrogen. Yes.

And those things really like bonding with copper. Okay? So what you can do is put four copper ions at the points of this pyramid. And then those four copper ions can then bind to the next pyramid and the next pyramid. And what you get is this very nice crystalline framework. This is the first metal organic. It's not really organic, but it's the first sort of idea behind like creating a metal crystalline structure using metal. ions and other stuff in between.

Yes. And it had a bunch of holes. Right. Remember? Right. It had a bunch of holes. And he published this in the American Society, the American Chemical Society in 1989 and 1990.

And this was very unexpected at the time. Right. Okay. Right. This was like, this was like very, very cool because people used to think like, oh, like, if I just put together, if I just put together metals with this other kind of stuff, I'm going to get a molecular bird's nest. Right.

You know, birds' nest is like very kind of disorganized. It like maintains its shape. Right. But it's not this kind of regular sort of thing, right? Yes. Yes. So this was, this was very cool when it first came out. And at the same time, he also started talking about the predictive framework in how to design these 3D molecules, right?

Like, what are the rules that are sort of needed to put these Lego blocks together? and have them be sort of stable. Okay? He also, at the time, he started talking about the future of applications. He's like, this could be used into the absorption of gases, catalytic reactions. He was very forward thinking, right? And it sort of started a lot of people along this track. Along this trail.

Right? Yeah, and two of those people are the other. He opened the door for other people to think in this direction. As like, oh, there's a there there. Yes. That's worth study and exploration. Exactly. Yeah.

It was still, the stuff that he made was still kind of rickety and it tended to fall apart, right? And this is where Kitagawa and Yagi come in. All right. Yes. So now we're going to go to our second Nobel Prize winner, Susumu Kitagawa. And he makes this. Okay. So this is in about, in I think, 1995, he publishes this.

And it's a tongue and groove where he's using cobalt, nickel, and zinc ions in a 3D framework. and this is really stable. Okay. Okay. This is the first sort of like nice stable thing. You make this in water, okay, in a soluble sort of chemistry. That's how I saw this thing is manufactured. You've got like these grooves that are like crossing, cross linking to each other.

And the trick is if you dry it up, it's still stable. And it can also be used and reused to absorb gases and then let them out and then absorb more. So it's a stable complex. It's not like, it's a true catalyst in that sense, right? It's not getting used up. It's not a single use or like a limited end number of use. It is structurally going to repeat the same process every time. Yeah, and it's sturdy, that kind of thing, right?

So this is the first demonstration of a reversible gas absorption. Okay. Adorption, meaning like at the surface you're taking in the gas. As opposed to absorption with a B, which is just, just like a volume absorbing. Absorption means like a 2D kind of thing. Yep. Yep.

And so he gets really big on that. At this point, it's still, he's, he actually had a lot of trouble trying to get funding to do this kind of stuff. Because people were like, oh, zeolites already exist. They weren't really convinced that the stuff that Robson was doing was going to work because it was so rickety. Yes. Right?

It was just this kind of like fringe thing. But he was at Kyoto University at the time, got his Ph.D. And then he got a lab there. And he finally started making these things work. Okay. And the thing that really convinced people was the porous crystal that he made. That's the next one. The porous crystal that he made, and that's Kitagawa on the right,

the porous crystal that he made was soft in the sense that it deformed and changed its shape based on whether it had stuff inside in those cavities. Okay? So now this is something that zeolites can't do. Right. Right. The natural occurring mineral are extremely rigid. Right.

But you've got this thing where like it can like the bonds are flexible. So if there's nothing inside, now you can imagine right, like creating these the, you know those, those toys where you got a magnet magnetic ball and like the stick. Yeah, yes. Yes. Yes. Yeah. It's like those things can like move around.

Right. And this is doing the same thing. So this was very big, right? It was expanding and contracting like a lung. And again, the dynamic structural behavior is the key difference here to the naturally occurring. To the naturally occurring. Zeolites. Yeah.

Yeah. And so this was the first clue that it was like new chemistry. Right. There was a more fundamental understanding that could be gleaned from continuing to go down this thought. Yes. Yeah. And creating like way new materials that you definitely can't find natural. So the material science implication became more obvious.

Mm-hmm. Yeah. Fascinating. Pretty cool. And in parallel, we've got Omar Yagi. Yes. Omar Yagi has an incredible life story. Which we talked about a bit on Sunday.

Yeah. He was a Palestinian refugee in Jordan with his family. Like, very poor. The entire family lived in a single room. But he got really into chemistry at the age of 10. He came to the states for higher studies, got his PhD at University of Illinois or Banna-Champaign, and then he started really getting into these metal organic frameworks. He was like, this could be something, right? You got really interested in that. And at Arizona

State University, that was his first faculty appointment, that's when he publishes this 2D molecule that can hold stuff, and it can remain stable up to 350 degrees Celsius. Oh, wow. It is. this thing up and it can still hold its stuff and and not get completely degraded. He published that in nature. Yes. So this was the first sort of big, big thing, right? He starts making a name for himself. And in 1999, he publishes the big one.

Okay. The big one. This is the, this is the sort of classic example of metal organic frameworks. Okay. And there's posters of this in every chemistry department. Okay. Okay. This is called MOF5, Metal Organic Framework 5.

It's got a zinc at its center. Then oxygen molecules in a pyramid. Okay. That creates a little pyramid. You attach four of those pyramids together with carbons on the end, right? And you get the middle thing, which is, four pyramids together to create one giant sort of diamond type thing with carbons at the end.

And that carbon is key because now we're getting into the organic. With those carbons at the end, you can now start attaching linkages to other diamonds, other blue diamonds, and start creating cavities. This was the MOF5 molecule. Okay? And this thing was insane. This thing was like 3,000 meters squared of surface area. per gram. That's the thing I was,

when we were talking about it on our predictions. Right, right. It's a single gram of this substance is going to have enough surface area. Right. Of like a football field or like several football fields. So crazy.

It can absorb a lot more than zeolite can because of that. Because of that thing. Yes. And also it's again, stable until 300 degrees Celsius. Right. So it's resilient. Yes.

It's pretty simple to make. Yes. And. it's hugely functional hugely functional yeah exactly the possibilities are endless

right and this is the field that introduced sort of reticular chemistry this is the beginnings of it this is yeah it's like using modular components to make these crystalline lattices right it was yagi and kittagawa

together that sort of figured this this whole thing out and yagi went even further so in in photo 16 you'll see he takes the MOF which is the one on the left and he figures those linkages, right, between the carbon molecules, between those carbon atoms. That are on the edges.

That are on the edges that are creating this cubic cavity. Those linkages, I can just make those linkages bigger. Okay. Right? And then I'm going to have more space. Oh, on the, uh, yes. Yes. It's so simple.

Yes. The linkages are organic molecules that are made out of carbon rings, attached to carbon rings, attached to carbon rings. Well, I can just start adding more and more carbon rings. And now you're actually increasing the, that surface area of available space. Yes. And what you can do is you can have customizable size of the pore.

Oh, yes. By saying, okay, I have three carbon rings. Yes. The pore is going to be this size. I add six, then it's going to be a little bit bigger. So whatever chemistry you want to do, do you see now? You can build for exactly the size and like exactly the parameters that you need. And so this is really the like the dial that you can turn.

Yeah. in order to get to the, again, the outcome that you're looking for. Yes, exactly. Fascinating. Right? And now, now this is when things got really big. He published those two papers in nature and science, and those are basically the papers that won the Nobel Prize. Got it.

Okay? It's the papers from Robson, Kitagawa, and finally the Nature and Science papers. That's, and I totally get your point about the implications of the linkages. being malleable in terms of their size and how that creates more available potential space. Yeah. That's usable. Yeah. Yeah.

It becomes totally customizable now, right? Now you literally have... It's programmable. Yeah. Link, like, things. You can engineer properly. You can engineer completely properly, okay? And so he started out at University of Arizona.

Yes. And then he moved actually to UCLA in 2012. Yes. Because by this point, I think everyone knew he was going to win. Yeah. Right, right, right. The Nobel. Okay.

So now institutions are like... Berkeley. No, no, no. First he moved to UCLA. First he moved to UCLA. Okay. Actually, no, you're right. So I got the year wrong.

I think it was 2005 or six when he moved to UCLA. Okay? That's how he got to California. Yeah. And then that's how we got to California. And then he was in the chemistry department at UCLA. Yes. And then in 2012,

Berkeley was like offered him a, you know, an offering camp of fees. Of course. Because Berkeley was like, was like, okay, he's definitely winning by now. Right. And we want that plus one. 100%. So he moved to Berkeley in 2012. He became the director of the molecular foundry at the Lawrence Berkeley National Lab, co-director of the Covley Energy, Nanoscience Institute.

And just in 2025, earlier this year, he became a university professor, which is the top honor in the University of California, reserved for, like, the highest distinction. So he was working his way up to, like, everyone's, sort of, that's why it was like kind of easy to predict that. It was going to be him because the signals were there. The signals were all there. And, but, you know, UCLA first poached him and then Berkeley poached it from UCLA. No, that's ours. Yeah. Like, you said the little brother of Berkeley in this context. Yeah, exactly. Yeah. So it's like, okay, now I'm going to keep that one. And yeah, now he's won the Nobel Prize. Yes. And so these three people won the Nobel Prize. Right now, there's so many different applications to this,

metal organic frameworks. We're just going to go through a couple, a few of them. So this first one, these are three molecules. The one on the left, that's used to capture water vapor. Okay. Okay. The one in the middle, that's, that can be used to catalyze the decomposition of crude oil. Oh, very interesting.

Right? Which is very nice for like environmental people. 100%. On the right, that's something that can absorb PFAS, which is perifloro-alcohol. It's one of these like forever chemicals. Yes. The EPA always talks about. it like they never degrade, get into our bodies, get into the environment.

That's something that can absorb those forever chemicals from water. And so one of the ideas here is that we can begin to create these chemical compounds that we can then use for things like, you know, controlling emissions, issues. Yeah, that's actually the next one. Oh, beautiful. Yes. Yeah. You're exactly right. The one on the left, that's for mining rare earth metals from wastewater. Oh, okay.

Yeah. Because like waste, industrial waste is going to have a bunch of metals. Yes. And you don't want it to go into the... That's a huge application. Yeah. That's an unbelievable application. Right.

And then in the middle, that's to absorb CO2. There you go. There you go. That's what you were talking about. Yep. And then on the right, that one's actually my favorite. That one can store and release hydrogen at normal pressure. Oh, really?

Okay. So you don't need a tank of compressed hydrogen. That's really crazy. And that's huge. Yeah. Because compressed hydrogen. Hydrogen is how you get the Hindenberg in your car. Right?

Right? And like everything explodes. So nobody wants hydrogen fuel cells. Well, now with this kind of stuff, you can get hydrogen fuel cells. I can understand why this won the Nobel. Right. Yeah. And what you saw there is like all of these things have like pretty similar, you know, the, you can see that they're the same chemistry.

Yes. You know what I mean? Yeah. They share sort of a similar substrate of structure. Yeah. Yeah. Yeah. It's repetitive.

It's crystalline. but each of the little tiny crystals instead of being a single atom, now they're these giant building blocks, right? And the holes can be giant. In the world of atoms, these things are giant, right? You can do nanometers, tens of nanometers. This is interesting because it's kind of similar

conceptually to yesterday's prize in physics around this idea of scaling up to larger sizes with the quantum tunneling, but in this case with metal organic frameworks. Yeah. It's an incredible, incredible field. And I just wanted to see what was happening nowadays. So they got AI going to know this too.

Of course. They have a chat. They have a chat MOF. Really? Yeah. A chat metal organic framework. Kind of like chat with it. And then it'll like generate like it's like I want a, you know, chemical compound that does this.

And then it'll like spit out like, oh, you should try these things. Chat. M. Yeah. They have a generative framework there for like, you know, generative AI can make photos. Right. Well, it can also, if you train it on the chemistry, it can start making these metal organic frameworks.

And on the right, that's a news article from Berkeley. Omar Yagi in his lab, he's actively using AI. And one of his students, I think, came up with like 15 molecules in six months. Again, just accelerating this process, right? Yes, yes, yes, yes, yes, yes. It's pretty cool. This is what we talk about a lot, which is, again, a lot of generative AI conversation, et cetera,

revolves around consumer use cases, understandably, because that's where most people are actually using it currently. But there's not as much chat. I mean, just we've talked about this. There's, you know, Genive AI for CRISPR. We have it for MOF. There's also things like AlphaFold.

LIGO. Oh, that wasn't generative, but still AI. Still AI sort of assisting and accelerating the process of research and discovery. And it has like real world implications. Yeah. In terms of us getting to these things quickly with fewer human capital resources, with less financial capital resources. Yeah, it's also like a democratization process.

Yep. Because people who maybe, you know, chemistry labs who want to do something, right, but don't have the expertise of the metal organic framework, can go to this chat thing and be like, hey, like, this is the thing that I want to accomplish. Yes. Can I do it with MOFs? And the chat will be like, yeah, actually, just make this, this and this and then put it in this way. It's so crazy.

I think there's this conversation happening, a CEO of OpenA. Sam Altman, yesterday or the day before, did an interview where he was asked about AGI. Okay. Because this whole AGI is near conversation. Yeah. And there's usually two sides of where people are like,

we're nowhere close. Other people are like, we're very close. And the signal that's being alleged as like why we're getting close is, in these kind of research use cases, there is, you know, AGI for some people's defined as like being able to have novel insight. And there are a couple now cases.

in these, again, research contexts where the models are actually having novel insights that are working and not just working, like working really well. It's not AGI in the way I think people imagine it from the movies. But, you know, there's a glimmer. If these models can truly generate novel insights,

even at small scales, that's hugely important. Yeah, that's going to be crazy. Fascinating. Yeah. Well, and that was the chemistry of Pell Prize. So, so, and I think there's, there's so many implications for this more broadly moving forward. Yeah, dude. It's, it's going to be, yeah, it's going to be very cool.

I want to take a moment. So we've talked about, this is our day three of the last day. So many of you, thousands of you have sort of joined us for this journey. It's been an incredible week. Yeah. So thanks to everyone for tuning in. We did medicine on Monday, physics on Tuesday, and then chemistry today. I wanted to do a quick tally about the winners.

All right. Right. We're going to break this down in sort of two, two categories, institutions and countries. This is like our ESPN top 10. Yeah, yeah. So on the institution side, we had some unsurprising number one winner. So at the top with four nobles is Berkeley. Yep.

Three for physics, one for chemistry. Kyoto at two. UCSB, unexpectedly, for me, two. UCLA one. Princeton got on the board. We got on the board with one. Yale with one. Princeton, we're printing before Yale because we came first.

Yeah. And then we have a University of Illinois, Urbana-Chirpain with one. Oxford, Melbourne, Cambridge, and Parasude University, all with a single Nobel. Yeah. And if we look at it by country, number one, big old America. USA, baby. Six universities in the U.S., two from the U.K., one from Japan, one from France. and one from Australia.

Yeah. So great representation. Yep. The UC system ran the board. Ran the board, dude. California, baby. California continues to lead in sort of fundamental research. Yeah.

And this was the public institutions in California. Right, right. Not the point. I guess Stanford and Caltech didn't show up this year. Maybe next year, guess. Maybe next year, yes. Neither did MIT or Harvard. But Princeton's there.

Princeton's there. Oh, goodness. Again, another just great episode. We talked about metal organic frameworks, a branch of particular chemistry. We did talk a little bit more about this also in our Sunday preview. So if you're interested, go back and take a listen to that. But just an unbelievable. We'll definitely do this next year again.

Oh, yeah. We'll probably have a little bit more going. We'll maybe get the Nobel Society to help us get some inside access. I'm Lester Nare, your host, joined as always, by my co-host and our resident PhD, Krishna Chowd. Thank you all again for joining us for Nobel Prize Week. It's been an incredible week. We will see you all next week. Nice.

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