WEBVTT 00:00:00.000 --> 00:00:04.519 Imagine for a second the absolute, the pinnacle 00:00:04.519 --> 00:00:06.639 of professional recognition, the kind of moment 00:00:06.639 --> 00:00:09.960 that just defines a whole lifetime of work. For 00:00:09.960 --> 00:00:11.720 a scientist, I mean, there's really only one 00:00:11.720 --> 00:00:13.339 peak that fits that description, right? It's 00:00:13.339 --> 00:00:15.619 a Nobel Prize. It has to be. That phone call 00:00:15.619 --> 00:00:17.640 from Stockholm, I mean, it changes everything. 00:00:17.820 --> 00:00:19.980 It's the signal to the entire world that you 00:00:19.980 --> 00:00:23.140 haven't just done a good job. You fundamentally 00:00:23.140 --> 00:00:25.379 altered the course of human history. Exactly. 00:00:25.519 --> 00:00:27.500 Fundamentally altered it. So hold that image 00:00:27.500 --> 00:00:30.800 in your mind. The confetti, the press conferences, 00:00:31.120 --> 00:00:33.340 the King of Sweden handing you a medal, just 00:00:33.340 --> 00:00:36.820 the ultimate final validation. The victory lap. 00:00:36.939 --> 00:00:39.200 Yes. Now, I want you to hard cut away from that. 00:00:39.240 --> 00:00:41.380 Yeah. Just wipe the slate completely clean. Okay. 00:00:41.560 --> 00:00:44.259 Where are we going with this? It's 1985. We're 00:00:44.259 --> 00:00:47.799 at a border crossing. Hungary. And it's a gray, 00:00:47.939 --> 00:00:50.640 tense scene. You can picture it. Soviet block 00:00:50.640 --> 00:00:53.159 guards, machine guns, dogs sniffing the wheel 00:00:53.159 --> 00:00:55.420 wells of the cars. Yeah. Not a friendly place. 00:00:55.679 --> 00:00:58.399 And inside this one old Lada, there's a family. 00:00:58.539 --> 00:01:00.259 They're trying to leave the country for good. 00:01:00.340 --> 00:01:03.759 A father, a mother, and a two -year -old girl. 00:01:03.920 --> 00:01:06.099 And the most valuable thing in that car isn't 00:01:06.099 --> 00:01:08.569 the luggage. It's not the passports. It's not 00:01:08.569 --> 00:01:12.150 even the car itself. No. It's a teddy bear. A 00:01:12.150 --> 00:01:14.890 teddy bear. A simple teddy bear sitting right 00:01:14.890 --> 00:01:16.510 there in the lap of that two -year -old girl. 00:01:17.189 --> 00:01:20.230 Because stuff deep inside the batting of that 00:01:20.230 --> 00:01:22.730 bear, right where a kid would squeeze it for 00:01:22.730 --> 00:01:26.269 comfort, is roughly 900 British pounds. Which, 00:01:26.329 --> 00:01:28.370 you know, to us today, that might not sound like 00:01:28.370 --> 00:01:32.530 a fortune. But in 1985 Hungary, behind the Iron 00:01:32.530 --> 00:01:35.439 Curtain. That was an astronomical sum of money. 00:01:35.519 --> 00:01:38.099 Right. It was their entire life savings. They'd 00:01:38.099 --> 00:01:40.239 sold their car, sold off their furniture. They 00:01:40.239 --> 00:01:42.319 scraped together every single forint they had. 00:01:42.500 --> 00:01:44.840 And then exchanged it on the black market, which 00:01:44.840 --> 00:01:47.200 was incredibly risky in itself. The stakes just 00:01:47.200 --> 00:01:49.060 couldn't be higher. I mean, if one of those border 00:01:49.060 --> 00:01:52.019 guards decides to just squeeze that bear a little 00:01:52.019 --> 00:01:54.500 too hard. Yeah. They find that cash. Oh, it's 00:01:54.500 --> 00:01:57.019 not a fine. It's jail time. The career is over. 00:01:57.579 --> 00:02:00.359 The dream is dead. Everything is gone. And that 00:02:00.359 --> 00:02:03.099 money smuggled inside a child's stuffed animal 00:02:03.099 --> 00:02:06.099 was essentially the seed capital for a scientific 00:02:06.099 --> 00:02:09.300 revolution. Today, we are doing a deep dive into 00:02:09.300 --> 00:02:12.520 the story of Catalin Caricarico. And you're right. 00:02:12.580 --> 00:02:14.719 Usually when this story gets told, we start at 00:02:14.719 --> 00:02:17.400 the finish line. We talk about the 2023 Nobel 00:02:17.400 --> 00:02:20.460 Prize in Physiology or Medicine. We talk about 00:02:20.460 --> 00:02:23.360 the COVID -19 vaccines that saved, I mean, literally 00:02:23.360 --> 00:02:25.680 millions of lives. We focus on the victory lap. 00:02:26.199 --> 00:02:29.460 But our mission for this deep dive is it's different. 00:02:29.580 --> 00:02:32.360 We need to look at the 40 years of, frankly, 00:02:32.460 --> 00:02:35.379 darkness that came before all the confetti. This 00:02:35.379 --> 00:02:37.259 isn't just a biography of a scientist. This is 00:02:37.259 --> 00:02:39.800 a case study in resilience. It's a story about 00:02:39.800 --> 00:02:43.159 the blindness of institutional academia and how 00:02:43.159 --> 00:02:46.979 a biological hack. that was ignored, underfunded, 00:02:47.000 --> 00:02:49.860 and even mocked for decades, ended up rewriting 00:02:49.860 --> 00:02:51.919 the source code of modern medicine. It is the 00:02:51.919 --> 00:02:54.599 ultimate survivor story. And to really, truly 00:02:54.599 --> 00:02:56.900 understand the magnitude of what Carrico achieved, 00:02:56.919 --> 00:02:58.960 you have to understand just how close this technology 00:02:58.960 --> 00:03:02.199 came to to never existing at all. It was on a 00:03:02.199 --> 00:03:04.599 knife's edge for decades. So let's rewind the 00:03:04.599 --> 00:03:06.840 tape. We're not starting in some high -tech lab 00:03:06.840 --> 00:03:09.379 at UPenn or BioNTech. We're going way, way back 00:03:09.379 --> 00:03:11.599 to the source. We need to understand the environment 00:03:11.599 --> 00:03:15.240 that forged this person. We are going to Kisushlas, 00:03:15.479 --> 00:03:18.979 Hungary. Kariko was born on January 17, 1955. 00:03:20.120 --> 00:03:22.439 And, you know, when we use that phrase, humble 00:03:22.439 --> 00:03:24.860 beginnings, I think we often gloss over what 00:03:24.860 --> 00:03:27.139 it really means. Yeah, it becomes a cliche. It 00:03:27.139 --> 00:03:29.919 does. But in post -war Hungary, in the countryside, 00:03:30.360 --> 00:03:33.240 this was a life stripped down to the absolute 00:03:33.240 --> 00:03:35.759 essentials. We're talking about a small adobe 00:03:35.759 --> 00:03:39.199 home. Made of mud brick. Exactly. Only one room 00:03:39.199 --> 00:03:42.020 heated in the winter, no television, no refrigerator. 00:03:42.840 --> 00:03:45.960 And the detail that always gets me, no running 00:03:45.960 --> 00:03:48.539 water. Wow. So you're not just turning on a tap. 00:03:48.680 --> 00:03:51.379 You are physically pumping water from a well 00:03:51.379 --> 00:03:53.840 every single day. It's a very physical, very 00:03:53.840 --> 00:03:56.319 direct existence. Her father, Janos, was a butcher. 00:03:56.460 --> 00:03:58.240 Her mother was a bookkeeper. So you have this 00:03:58.240 --> 00:04:01.180 really interesting mix right from the start. 00:04:01.240 --> 00:04:03.719 How so? Well, you've got the practical, visceral 00:04:03.719 --> 00:04:05.560 reality of biology right there in the butcher 00:04:05.560 --> 00:04:07.340 shop, and then you've got the precision of numbers 00:04:07.340 --> 00:04:09.639 and ledgers from her mother. It's the hands -on 00:04:09.639 --> 00:04:12.020 and the analytical all in one household. But 00:04:12.020 --> 00:04:14.000 there's a shadow hanging over this family, isn't 00:04:14.000 --> 00:04:15.979 there? It wasn't just about being poor. There 00:04:15.979 --> 00:04:19.139 was a political weight. A very heavy one. You 00:04:19.139 --> 00:04:22.420 have to remember the context. 1956, the Hungarian 00:04:22.420 --> 00:04:25.180 Revolution. Right, against the Soviets. It was 00:04:25.180 --> 00:04:27.339 a nationwide uprising against the government 00:04:27.339 --> 00:04:29.959 and its Soviet policies, and it was crushed. 00:04:30.480 --> 00:04:34.800 just brutally put down and carco's father janos 00:04:34.800 --> 00:04:39.180 he participated in that revolution and in a soviet 00:04:39.180 --> 00:04:41.540 satellite state in the 50s and 60s you don't 00:04:41.540 --> 00:04:43.480 just move on from participating in a revolution 00:04:43.480 --> 00:04:46.199 no the state remembers the state always remembers 00:04:46.199 --> 00:04:48.540 he was punished for it he lost his job for a 00:04:48.540 --> 00:04:51.439 time so kari grows up in this environment where 00:04:51.439 --> 00:04:55.920 well where authority is dangerous, she sees her 00:04:55.920 --> 00:04:59.040 own father, a strong, hardworking man, having 00:04:59.040 --> 00:05:01.639 to navigate a system that is fundamentally suspicious 00:05:01.639 --> 00:05:04.180 of him. That has to implant a very specific kind 00:05:04.180 --> 00:05:06.920 of worldview in a child. I think so. You learn 00:05:06.920 --> 00:05:09.139 early on that the system isn't always right. 00:05:09.259 --> 00:05:11.399 You learn that institutions can be wrong, and 00:05:11.399 --> 00:05:13.519 that sometimes you have to survive in spite of 00:05:13.519 --> 00:05:15.540 them, not because of them. And yet, despite the 00:05:15.540 --> 00:05:17.459 lack of resources, or maybe, you know, because 00:05:17.459 --> 00:05:19.399 she had to find entertainment in the world right 00:05:19.399 --> 00:05:21.639 around her, she becomes an academic prodigy. 00:05:21.699 --> 00:05:24.990 She was just. Relentless. By primary school, 00:05:25.029 --> 00:05:27.189 she's already placing third in the entire country 00:05:27.189 --> 00:05:31.089 in biology competitions. She had this raw, unfiltered 00:05:31.089 --> 00:05:34.050 curiosity about nature. She wasn't learning biology 00:05:34.050 --> 00:05:36.569 from an iPad or a screen. No, she was learning 00:05:36.569 --> 00:05:38.529 it from the plants in the garden and the animals 00:05:38.529 --> 00:05:41.370 in the yard. Exactly. It was real and tangible 00:05:41.370 --> 00:05:44.189 to her. So she excels. She eventually moves on 00:05:44.189 --> 00:05:46.379 to the University of Saged. She gets her bachelor 00:05:46.379 --> 00:05:50.259 of science in 78, her Ph .D. in 82. She lands 00:05:50.259 --> 00:05:52.259 a good job at the Biological Research Center, 00:05:52.360 --> 00:05:55.240 the BRC. On paper, she's on the perfect path. 00:05:55.420 --> 00:05:58.000 She is. But this brings us to a part of her history 00:05:58.000 --> 00:06:01.779 that is, well, it's really complex and, frankly, 00:06:01.920 --> 00:06:05.579 pretty terrifying. The intel asset. That's the 00:06:05.579 --> 00:06:07.879 one. So decades after the fact, it comes out 00:06:07.879 --> 00:06:11.519 that from 1978 to 1985, her name was listed in 00:06:11.519 --> 00:06:13.439 the files of the communist secret police as an 00:06:13.439 --> 00:06:15.560 intelligence asset. And when that news broke, 00:06:15.839 --> 00:06:17.959 it could have been a career ending scandal. It 00:06:17.959 --> 00:06:19.699 could have been. But we really need to parse 00:06:19.699 --> 00:06:21.920 this with extreme care because the nuance here 00:06:21.920 --> 00:06:25.819 is everything. It is. And Karikora has been incredibly 00:06:25.819 --> 00:06:28.699 transparent about this chapter of her life. She 00:06:28.699 --> 00:06:31.459 wasn't a volunteer spy. She wasn't an informant. 00:06:31.519 --> 00:06:34.220 She was a victim of that very system we just 00:06:34.220 --> 00:06:36.560 described. How did it happen? The authorities 00:06:36.560 --> 00:06:38.860 approached her. They knew her father's history 00:06:38.860 --> 00:06:42.779 as a so -called counter -revolutionary. And they 00:06:42.779 --> 00:06:46.100 essentially, they blackmailed her. The choice 00:06:46.100 --> 00:06:48.860 was laid out in no uncertain terms. So it was 00:06:48.860 --> 00:06:51.839 an ultimatum. A brutal one. Sign this recruitment 00:06:51.839 --> 00:06:54.519 paper or your father will face severe reprisals 00:06:54.519 --> 00:06:56.220 and your own scientific career, which you've 00:06:56.220 --> 00:06:58.439 worked so hard for, will be terminated immediately. 00:06:58.800 --> 00:07:01.329 My God. It's a literal dead end. You sign the 00:07:01.329 --> 00:07:03.810 paper or you lose your entire life's work and 00:07:03.810 --> 00:07:05.730 you endanger your family. There was no choice. 00:07:05.889 --> 00:07:08.569 So she signed. But, and this is the absolute 00:07:08.569 --> 00:07:10.870 crucial part that's been corroborated by the 00:07:10.870 --> 00:07:13.430 historical records, she maintained she never 00:07:13.430 --> 00:07:15.569 acted as an active agent. So she never informed 00:07:15.569 --> 00:07:18.329 on anyone. Never. In intelligence terms, she 00:07:18.329 --> 00:07:20.829 was what you'd call a paper agent. She existed 00:07:20.829 --> 00:07:23.410 in a file to satisfy some bureaucrat's quota, 00:07:23.629 --> 00:07:26.230 but she never reported on her colleagues. She 00:07:26.230 --> 00:07:29.509 never provided operational information. She walked 00:07:29.509 --> 00:07:32.050 this incredible razor's edge of appearing to 00:07:32.050 --> 00:07:35.569 comply while doing absolutely nothing to harm 00:07:35.569 --> 00:07:37.930 anyone. Imagine the psychological weight of that, 00:07:37.970 --> 00:07:40.060 though. You're in your 20s. You're trying to 00:07:40.060 --> 00:07:42.240 decode the fundamental secrets of life in the 00:07:42.240 --> 00:07:44.480 lab. And you have the secret police technically 00:07:44.480 --> 00:07:46.379 breathing down your neck. It's a pressure cooker. 00:07:46.560 --> 00:07:48.579 It has to force you to be self -reliant. You 00:07:48.579 --> 00:07:50.639 learn you cannot trust the institution to protect 00:07:50.639 --> 00:07:53.019 you. Your survival is up to you. And eventually 00:07:53.019 --> 00:07:56.000 that pressure cooker does explode. But what's 00:07:56.000 --> 00:07:57.899 so interesting is that it wasn't the police that 00:07:57.899 --> 00:08:00.360 finally drove her out of Hungary. It was something 00:08:00.360 --> 00:08:03.040 much more mundane, something scientists everywhere 00:08:03.040 --> 00:08:06.000 can relate to. Funding. It almost always comes 00:08:06.000 --> 00:08:08.899 down to funding. In 1985, her lab at the BRC, 00:08:08.959 --> 00:08:11.680 it just, it lost its funding. The money dried 00:08:11.680 --> 00:08:14.860 up. So she had no resources to continue her research. 00:08:15.339 --> 00:08:18.459 Zero. And for a scientist like Carco, I mean, 00:08:18.459 --> 00:08:21.180 not doing research is like not breathing. So 00:08:21.180 --> 00:08:23.899 she starts looking abroad desperately. She gets 00:08:23.899 --> 00:08:26.680 an offer. She gets a job offer from Temple University 00:08:26.680 --> 00:08:30.000 in Philadelphia. It's a lifeline. And that brings 00:08:30.000 --> 00:08:33.240 us right back to that. gray morning at the border 00:08:33.240 --> 00:08:35.759 crossing, the decision to just leave everything 00:08:35.759 --> 00:08:37.960 they know behind. Let's go back to that teddy 00:08:37.960 --> 00:08:40.600 bear for a minute. It's 1985. She's with her 00:08:40.600 --> 00:08:42.960 husband, Bella Francia, and their daughter, Susan, 00:08:43.220 --> 00:08:46.340 who's just a toddler. They sell the car. They 00:08:46.340 --> 00:08:48.259 have to go to the black market to get British 00:08:48.259 --> 00:08:50.860 pounds. Because you couldn't legally just take 00:08:50.860 --> 00:08:52.559 currency out of the country. Right. There were 00:08:52.559 --> 00:08:54.620 strict limits. You were allowed to leave with 00:08:54.620 --> 00:08:57.360 a tiny amount of cash, maybe enough for a taxi 00:08:57.360 --> 00:08:59.559 ride, but certainly not enough to start a new 00:08:59.559 --> 00:09:02.779 life in America. So smuggling was the only option. 00:09:03.039 --> 00:09:05.360 And if that guard had just been having a bad 00:09:05.360 --> 00:09:08.179 day, if he had picked up the bear and felt something 00:09:08.179 --> 00:09:10.539 crinkle? We would not be having this conversation. 00:09:10.879 --> 00:09:13.639 It's terrifying to think about. There would likely 00:09:13.639 --> 00:09:18.059 be no Pfizer or Moderna COVID vaccine in 2020. 00:09:18.590 --> 00:09:20.590 The course of the pandemic would have been completely 00:09:20.590 --> 00:09:24.230 different. So much history hinged on a piece 00:09:24.230 --> 00:09:27.269 of batting and a stuffed toy. But they make it 00:09:27.269 --> 00:09:30.409 through. They land in America, the land of opportunity. 00:09:30.809 --> 00:09:33.750 Or so the brochure says. But the reality for 00:09:33.750 --> 00:09:36.049 an immigrant, even a brilliant PhD scientist, 00:09:36.309 --> 00:09:39.000 is often a lot grittier than that. She starts 00:09:39.000 --> 00:09:41.279 her postdoctoral work at Temple University. And 00:09:41.279 --> 00:09:43.500 to be fair, scientifically, this was actually 00:09:43.500 --> 00:09:45.539 a pretty exciting time for her. She wasn't just, 00:09:45.559 --> 00:09:47.879 you know, washing test tubes in a corner. No, 00:09:47.919 --> 00:09:49.840 she was right in the thick of it. This is the 00:09:49.840 --> 00:09:52.870 mid -80s. She's participating in clinical trials 00:09:52.870 --> 00:09:55.110 using something called double -stranded RNA or 00:09:55.110 --> 00:09:57.210 DSRNA. And they were investigating treatments 00:09:57.210 --> 00:10:00.389 for HIV AIDS and chronic fatigue syndrome. This 00:10:00.389 --> 00:10:02.210 was cutting -edge stuff at the time. So what 00:10:02.210 --> 00:10:03.889 was the mechanism? What were they actually trying 00:10:03.889 --> 00:10:05.929 to do with this RNA? They were studying something 00:10:05.929 --> 00:10:09.250 called interferon induction. Okay, let's break 00:10:09.250 --> 00:10:11.809 that down for the listener. Interferon. What 00:10:11.809 --> 00:10:16.069 is it? Think of interferon as the bodies. It's 00:10:16.069 --> 00:10:19.070 citywide air raid siren. When a cell detects 00:10:19.070 --> 00:10:21.149 a viral invader, it starts pumping out these 00:10:21.149 --> 00:10:23.190 proteins, interferons to tell all the neighboring 00:10:23.190 --> 00:10:25.730 cells shields up. There is an intruder. Stop 00:10:25.730 --> 00:10:27.769 replicating now. OK, so it's an alarm system. 00:10:27.870 --> 00:10:30.769 A very powerful one. And Corico was working on 00:10:30.769 --> 00:10:34.129 using RNA to artificially trigger that siren 00:10:34.129 --> 00:10:37.230 to sort of preemptively boost the immune system's 00:10:37.230 --> 00:10:40.149 defense against viruses. That sounds incredibly 00:10:40.149 --> 00:10:42.649 promising. Groundbreaking even for the 80s. It 00:10:42.649 --> 00:10:45.399 was. The science was fast. Fascinating. But the 00:10:45.399 --> 00:10:48.139 workplace dynamic, that was an absolute disaster. 00:10:48.419 --> 00:10:51.179 She was working for a man named Robert J. Suhodolnik. 00:10:51.360 --> 00:10:53.559 And this relationship turns into a complete nightmare. 00:10:53.720 --> 00:10:56.399 It really does. Look, the mentor -mentee relationship 00:10:56.399 --> 00:10:59.000 in academia is incredibly powerful. Your mentor, 00:10:59.200 --> 00:11:01.919 your PI, they hold the keys to your visa, your 00:11:01.919 --> 00:11:04.120 funding, your reputation, everything. It's a 00:11:04.120 --> 00:11:06.779 huge power imbalance. Huge one. And in 1988, 00:11:07.120 --> 00:11:09.299 Kuriko received a job offer from Johns Hopkins 00:11:09.299 --> 00:11:11.179 University. Which is the big leagues. I mean, 00:11:11.200 --> 00:11:13.080 that's the Ivy League of Medicine. Yeah. Massive 00:11:13.080 --> 00:11:16.159 step up. A huge step up. But she made a tactical 00:11:16.159 --> 00:11:18.940 error. And maybe it was out of excitement or 00:11:18.940 --> 00:11:21.299 maybe just naivety about the cutthroat nature 00:11:21.299 --> 00:11:25.059 of academic politics. She accepted the offer 00:11:25.059 --> 00:11:27.399 from Hopkins before she told Sue Hedelnik she 00:11:27.399 --> 00:11:29.899 was leaving. Oof. And he didn't take it well. 00:11:30.019 --> 00:11:32.759 He took it as a personal betrayal. And his reaction 00:11:32.759 --> 00:11:36.980 was... It was vindictive on a level that is just 00:11:36.980 --> 00:11:40.320 hard to comprehend. What did he do? Because Carrico 00:11:40.320 --> 00:11:43.139 was a foreign national, her visa status was tied 00:11:43.139 --> 00:11:46.539 directly to her employment at Temple. Suedolnik 00:11:46.539 --> 00:11:49.379 knew this. And he threatened her with deportation. 00:11:49.379 --> 00:11:52.529 He actually played the deportation card. on a 00:11:52.529 --> 00:11:54.850 scientist in his own lab. He went even further. 00:11:54.929 --> 00:11:56.990 He contacted the U .S. immigration authorities 00:11:56.990 --> 00:11:59.610 himself and reported her claiming she was in 00:11:59.610 --> 00:12:01.629 the U .S. illegally or that she was violating 00:12:01.629 --> 00:12:03.909 her visa status. That is just astonishing. You 00:12:03.909 --> 00:12:05.610 have a brilliant scientist trying to advance 00:12:05.610 --> 00:12:08.529 her career and her boss calls immigration on 00:12:08.529 --> 00:12:10.470 her because his ego is bruised. And it worked, 00:12:10.509 --> 00:12:12.409 at least in the short term. Johns Hopkins got 00:12:12.409 --> 00:12:14.350 spooked and withdrew the offer. They just... 00:12:14.809 --> 00:12:16.269 They didn't want to deal with the legal mess. 00:12:16.429 --> 00:12:18.809 So she's stuck. She's in legal limbo. She had 00:12:18.809 --> 00:12:21.450 to fight an extradition order. She's facing the 00:12:21.450 --> 00:12:24.049 very real possibility of being sent back to Hungary, 00:12:24.250 --> 00:12:27.230 where she now has no job and has burned bridges 00:12:27.230 --> 00:12:29.909 by leaving in the first place. She did fight 00:12:29.909 --> 00:12:31.950 it, though. She did. She won the legal battle 00:12:31.950 --> 00:12:34.870 eventually. But Suedolnyk didn't stop there. 00:12:35.009 --> 00:12:37.529 He started bad -mouthing her to other institutions. 00:12:38.730 --> 00:12:41.610 In the small, insular world of academic research, 00:12:41.870 --> 00:12:44.090 a bad reference from your principal investigator 00:12:44.090 --> 00:12:47.409 is the kiss of death. She was effectively blacklisted. 00:12:47.649 --> 00:12:50.090 I think most people would have quit. I honestly 00:12:50.090 --> 00:12:51.950 think I would have quit at that point. Okay, 00:12:51.990 --> 00:12:54.129 America doesn't want me. My boss is actively 00:12:54.129 --> 00:12:56.570 sabotaging me. I'm going home. And it really 00:12:56.570 --> 00:12:58.990 speaks to that iron -willed resilience we talked 00:12:58.990 --> 00:13:01.429 about forged back in Hungary. She didn't quit. 00:13:01.570 --> 00:13:04.110 She found a temporary refuge at the Uniformed 00:13:04.110 --> 00:13:06.570 Services University of the Health Sciences in 00:13:06.570 --> 00:13:09.389 Bethesda. A bridge job. Exactly. It kept her 00:13:09.389 --> 00:13:11.309 in the country, kept her working with signal 00:13:11.309 --> 00:13:13.950 protein interferons again. But the real story, 00:13:14.090 --> 00:13:16.549 the one that leads to the Nodal Prize, that begins 00:13:16.549 --> 00:13:18.590 when she finally lands a position at the University 00:13:18.590 --> 00:13:22.750 of Pennsylvania in 1989. UPenn. This is the chapter 00:13:22.750 --> 00:13:26.200 I always think of as the wilderness. That's a 00:13:26.200 --> 00:13:28.220 good way to put it. She gets hired to work with 00:13:28.220 --> 00:13:31.860 a cardiologist named Elliot Barnathan. And this 00:13:31.860 --> 00:13:34.179 is where she decides to bet her entire career, 00:13:34.340 --> 00:13:37.659 everything she has, on messenger RNA. Which to 00:13:37.659 --> 00:13:40.639 us, sitting here today, having had an mRNA vaccine 00:13:40.639 --> 00:13:42.940 shot into our arms, sounds like a great bet, 00:13:43.039 --> 00:13:46.139 a brilliant move. Of course. But we have to contextualize 00:13:46.139 --> 00:13:49.360 this. In 1989, betting your career on mRNA was 00:13:49.360 --> 00:13:51.990 considered scientific suicide. Why? What was 00:13:51.990 --> 00:13:53.850 the reputation of the molecule back then? It 00:13:53.850 --> 00:13:57.419 was a scientific backwater. a dead end. To understand 00:13:57.419 --> 00:14:00.240 why, you have to look at the central dogma of 00:14:00.240 --> 00:14:03.340 biology. DNA makes RNA and RNA makes protein. 00:14:03.580 --> 00:14:06.840 DNA is the hard drive. It's stable. It's permanent. 00:14:07.019 --> 00:14:09.539 It holds the master blueprints. Protein is the 00:14:09.539 --> 00:14:11.700 product. It's the muscle, the enzyme, the thing 00:14:11.700 --> 00:14:13.980 that does the work. And mRNA is just the messenger. 00:14:14.200 --> 00:14:16.580 It's just the memo. It's the sticky note that 00:14:16.580 --> 00:14:18.679 carries the instruction from the hard drive in 00:14:18.679 --> 00:14:21.899 the nucleus to the protein factory in the cytoplasm. 00:14:21.899 --> 00:14:23.740 And sticky notes are fragile. They're temporary. 00:14:24.750 --> 00:14:27.309 Extremely. mRNA is designed to be transient. 00:14:27.509 --> 00:14:29.850 The cell is supposed to read it and then destroy 00:14:29.850 --> 00:14:32.409 it immediately. In the lab, if you even look 00:14:32.409 --> 00:14:34.590 at it wrong, it degrades. It just turns into 00:14:34.590 --> 00:14:38.149 mush. On top of all that, making synthetic mRNA 00:14:38.149 --> 00:14:41.370 was prohibitively expensive. So the scientific 00:14:41.370 --> 00:14:43.970 consensus at the time was, you can't make a drug 00:14:43.970 --> 00:14:46.610 out of this stuff. It's too unstable, too expensive, 00:14:46.710 --> 00:14:48.789 and the body will just chew it up. It's a dead 00:14:48.789 --> 00:14:51.990 end. 100%. All the money, all the excitement 00:14:51.990 --> 00:14:54.409 was around DNA gene therapy, the idea of going 00:14:54.409 --> 00:14:56.889 in and fixing the hard drive permanently. But 00:14:56.889 --> 00:14:59.590 Caruso saw the danger in that. What danger? If 00:14:59.590 --> 00:15:01.389 you edit the DNA, you change the code forever. 00:15:01.549 --> 00:15:03.509 If you make a mistake, it's a permanent mistake. 00:15:03.570 --> 00:15:05.409 It's passed down to every new cell. But with 00:15:05.409 --> 00:15:07.529 mRNA? It's a software patch. It's temporary. 00:15:07.950 --> 00:15:11.820 Her vision was... What if we don't need to permanently 00:15:11.820 --> 00:15:14.279 change a patient's genetics? What if we just 00:15:14.279 --> 00:15:17.240 send in a temporary instruction? Hey, body, make 00:15:17.240 --> 00:15:19.700 this specific protein for a few days to heal 00:15:19.700 --> 00:15:22.039 this wound or fight this virus or replace this 00:15:22.039 --> 00:15:24.399 missing enzyme. You're turning the patient's 00:15:24.399 --> 00:15:27.620 own body into the drug factory. Precisely. It's 00:15:27.620 --> 00:15:31.019 a brilliant, elegant concept. But in the 90s, 00:15:31.019 --> 00:15:33.779 nobody wanted to fund a skyscraper built out 00:15:33.779 --> 00:15:36.700 of wet tissue paper. So she wrote grants. Constantly. 00:15:36.700 --> 00:15:38.620 She submitted grant after grant after grant. 00:15:38.700 --> 00:15:41.700 I want to use mRNA to treat cystic fibrosis. 00:15:42.179 --> 00:15:44.860 Rejected. I want to use mRNA to treat stroke. 00:15:45.580 --> 00:15:48.080 Rejected. And in academia, grants are oxygen. 00:15:48.340 --> 00:15:50.460 They are. If you don't bring in money, you are 00:15:50.460 --> 00:15:52.759 seen as a liability to the university. You're 00:15:52.759 --> 00:15:56.529 taking up space. And this leads us to 1995. The 00:15:56.529 --> 00:15:59.429 year of the demotion. This is a pivotal and I 00:15:59.429 --> 00:16:01.990 think incredibly painful moment in her story. 00:16:02.610 --> 00:16:05.129 Kiriko was on the tenure track. She was working 00:16:05.129 --> 00:16:07.149 toward becoming a full professor. That means 00:16:07.149 --> 00:16:10.120 job security, respect, your own lab. The whole 00:16:10.120 --> 00:16:12.740 thing. To dream. The academic dream. But because 00:16:12.740 --> 00:16:15.139 she could not get funding for her crazy mRNA 00:16:15.139 --> 00:16:17.679 ideas, UPenn gave her an ultimatum. They didn't 00:16:17.679 --> 00:16:19.659 just deny her tenure, they demoted her. They 00:16:19.659 --> 00:16:21.179 knocked her down from the tenure track, they 00:16:21.179 --> 00:16:23.679 cut her salary. They essentially told her, you 00:16:23.679 --> 00:16:25.519 are no longer a professor -in -waiting, you are 00:16:25.519 --> 00:16:28.600 now just a senior research associate. This mRNA 00:16:28.600 --> 00:16:31.559 thing is a hobby, not a career path. That is 00:16:31.559 --> 00:16:34.960 just, it's so humiliating. You're a PhD, you've 00:16:34.960 --> 00:16:38.500 been working for decades, and your employer... 00:16:39.169 --> 00:16:41.629 Basically tells you that you've failed. Professionally 00:16:41.629 --> 00:16:44.009 devastating. And her working conditions reflected 00:16:44.009 --> 00:16:46.769 that status change. She wasn't working in some 00:16:46.769 --> 00:16:49.990 gleaming, well -funded institute. She was often 00:16:49.990 --> 00:16:52.809 relegated to the edges, relying on the kindness 00:16:52.809 --> 00:16:55.129 of other researchers like Barnathan and later 00:16:55.129 --> 00:16:57.250 David Langer to just give her some bench space. 00:16:57.350 --> 00:16:59.750 Can I work in this corner of your lab? So why 00:16:59.750 --> 00:17:02.009 did she stay? I keep coming back to this. Why 00:17:02.009 --> 00:17:04.890 stay at an institution that so clearly didn't 00:17:04.890 --> 00:17:07.609 value her? or her work. Because she believed 00:17:07.609 --> 00:17:09.990 the science was true. It's as simple and as complicated 00:17:09.990 --> 00:17:12.009 as that. She knew that if she could just solve 00:17:12.009 --> 00:17:14.509 the stability and the inflammation problem, the 00:17:14.509 --> 00:17:16.569 potential was limitless. She couldn't walk away 00:17:16.569 --> 00:17:18.650 from the puzzle. And then after all this struggle, 00:17:18.869 --> 00:17:21.769 serendipity strikes. And it strikes in the most 00:17:21.769 --> 00:17:24.609 mundane place imaginable. The photocopier. I 00:17:24.609 --> 00:17:26.970 love this part of the story. It's 1997. She's 00:17:26.970 --> 00:17:28.809 standing at the copy machine at UPenn, probably 00:17:28.809 --> 00:17:30.750 copying yet another rejection letter or some 00:17:30.750 --> 00:17:32.970 journal articles. And she just starts chatting 00:17:32.970 --> 00:17:35.559 with the new guy. Drew Weissman. He had just 00:17:35.559 --> 00:17:37.700 arrived at UPenn from the National Institutes 00:17:37.700 --> 00:17:40.740 of Health, the NIH. He was an immunologist, a 00:17:40.740 --> 00:17:43.579 vaccine guy. And he was frustrated because he 00:17:43.579 --> 00:17:46.099 was looking for a new way to develop an HIV vaccine. 00:17:46.480 --> 00:17:49.599 But all the old methods were too slow and ineffective. 00:17:50.079 --> 00:17:53.200 So you have this collision. Carrico, the obsessive 00:17:53.200 --> 00:17:56.339 biochemist who can make any RNA you want, but 00:17:56.339 --> 00:17:59.150 has zero money. And zero institutional respect. 00:17:59.450 --> 00:18:02.069 And Weissman, the respected immunologist who 00:18:02.069 --> 00:18:04.250 has startup funding from his new position but 00:18:04.250 --> 00:18:07.150 needs a new technology platform. It was the missing 00:18:07.150 --> 00:18:08.990 piece for both of them. A perfect marriage of 00:18:08.990 --> 00:18:11.089 skills. They started talking. Carrico basically 00:18:11.089 --> 00:18:14.130 told them, I can make any RNA you want. Weissman 00:18:14.130 --> 00:18:16.210 was intrigued. He decided to use some of his 00:18:16.210 --> 00:18:18.829 startup money to fund her work. And they formed 00:18:18.829 --> 00:18:20.849 a partnership. Peanut butter and jelly. Exactly. 00:18:21.109 --> 00:18:23.029 But let's be really clear here. Just because 00:18:23.029 --> 00:18:24.690 they teamed up didn't mean it started working 00:18:24.690 --> 00:18:27.039 right away. They immediately ran into... to a 00:18:27.039 --> 00:18:29.700 massive biological brick wall. The inflammation 00:18:29.700 --> 00:18:32.380 problem. This was the hurdle that had stopped 00:18:32.380 --> 00:18:34.400 everyone else in the field dead in their tracks. 00:18:34.680 --> 00:18:37.960 When Caraco made the synthetic mRNA in the test 00:18:37.960 --> 00:18:41.240 tube and they injected it into mice. The mice 00:18:41.240 --> 00:18:43.480 didn't just make the protein. They got really, 00:18:43.559 --> 00:18:45.740 really sick. Sick how? What did it look like? 00:18:45.900 --> 00:18:48.000 They looked like they had a massive viral infection. 00:18:48.180 --> 00:18:50.380 Their fur ruffled up. They became lethargic. 00:18:50.400 --> 00:18:52.559 They stopped eating and moving. Their immune 00:18:52.559 --> 00:18:54.900 systems were launching an all -out attack on 00:18:54.900 --> 00:18:57.140 the mRNA. So the body looked at this synthetic 00:18:57.140 --> 00:19:00.799 message and said, intruder, red alert, kill it. 00:19:00.980 --> 00:19:03.599 Right. Our bodies have these ancient sensors. 00:19:03.720 --> 00:19:05.339 They're called toll -like receptors. They're 00:19:05.339 --> 00:19:08.500 the sentries at the gate. Their entire job is 00:19:08.500 --> 00:19:11.220 to patrol for foreign -looking genetic material 00:19:11.220 --> 00:19:14.680 like the RNA from a virus. When they saw Carrico's 00:19:14.680 --> 00:19:17.339 synthetic mRNA, they pulled the fire alarm. This 00:19:17.339 --> 00:19:19.660 triggered a huge cascade that not only destroyed 00:19:19.660 --> 00:19:22.660 the mRNA, but also caused massive systemic inflammation. 00:19:23.240 --> 00:19:25.559 So it's game over. You can't have a medicine 00:19:25.559 --> 00:19:27.920 that makes the patient sick and on top of that 00:19:27.920 --> 00:19:30.319 gets destroyed before it can even do its job. 00:19:30.650 --> 00:19:32.210 Most scientists would have stopped there. They 00:19:32.210 --> 00:19:33.910 would have said, OK, the critics were right all 00:19:33.910 --> 00:19:36.730 along. It's toxic. It doesn't work. But this 00:19:36.730 --> 00:19:39.309 is where Kuriko's detective brain kicks in. She 00:19:39.309 --> 00:19:41.170 did something brilliant. She looked closely at 00:19:41.170 --> 00:19:43.210 her control group. What was the control? She 00:19:43.210 --> 00:19:46.710 was using transfer RNA or tRNA as a comparison. 00:19:47.230 --> 00:19:49.809 tRNA is a natural form of RNA that's abundant 00:19:49.809 --> 00:19:52.109 in all of our cells. And she noticed something 00:19:52.109 --> 00:19:55.930 crucial. When she injected the natural tRNA, 00:19:56.250 --> 00:20:00.049 the mice didn't get sick. The toll -like receptors 00:20:00.049 --> 00:20:03.329 didn't fire. The alarm stayed silent. So the 00:20:03.329 --> 00:20:05.369 body was totally cool with the natural tRNA, 00:20:05.630 --> 00:20:09.880 but it hated her synthetic mRNA. So why? What 00:20:09.880 --> 00:20:11.319 was the difference? That was a billion -dollar 00:20:11.319 --> 00:20:13.819 question. She looked at the chemistry. RNA is 00:20:13.819 --> 00:20:16.299 built from four letters, four nucleosides. A, 00:20:16.460 --> 00:20:20.400 C, G, and U stands for uridine. Okay, A, C, G, 00:20:20.440 --> 00:20:23.079 U. Got it. Through a series of painstaking experiments, 00:20:23.480 --> 00:20:25.460 she and Weissman figured out that the toll -like 00:20:25.460 --> 00:20:28.000 receptors were specifically reacting to the uridine. 00:20:28.119 --> 00:20:30.299 The U was the red flag that was giving away the 00:20:30.299 --> 00:20:33.160 intruder. Wait, tRNA has uridine in it too, doesn't 00:20:33.160 --> 00:20:37.400 it? It does. But here's the aha moment. In natural 00:20:37.400 --> 00:20:40.170 tRNA... The uridine is often chemically modified. 00:20:40.410 --> 00:20:43.269 It wears a disguise. One of the most common of 00:20:43.269 --> 00:20:46.410 those modifications is called pseudoridine. It's 00:20:46.410 --> 00:20:49.309 basically uridine that's been sort of rotated 00:20:49.309 --> 00:20:51.630 slightly at the molecular level. It's the same 00:20:51.630 --> 00:20:53.589 number of atoms, but it's arranged in a different 00:20:53.589 --> 00:20:57.450 shape. And Carrico's hypothesis was, what if 00:20:57.450 --> 00:20:59.769 the immune system is blind to this specific shape? 00:21:00.160 --> 00:21:02.859 What if I replaced the normal uridine in my synthetic 00:21:02.859 --> 00:21:05.480 mRNA with this modified pseudoridine? It's like 00:21:05.480 --> 00:21:07.740 putting a fake mustache in glasses on the intruder 00:21:07.740 --> 00:21:09.400 so the bouncer lits them right into the club. 00:21:09.759 --> 00:21:12.259 A molecular mustache. That's a perfect analogy. 00:21:12.420 --> 00:21:15.779 Yes. So they went back to the lab. It was tedious, 00:21:15.900 --> 00:21:18.039 painstaking work. They had to synthesize new 00:21:18.039 --> 00:21:20.579 strands of mRNA where every single U was swapped 00:21:20.579 --> 00:21:22.599 out for pseudoridine. What happened? They injected 00:21:22.599 --> 00:21:25.380 it into the mice. They waited. And the mice were 00:21:25.380 --> 00:21:28.319 fine. No sickness? No fur ruffling, no lethargy, 00:21:28.380 --> 00:21:30.559 no sickness at all. And crucially, when they 00:21:30.559 --> 00:21:32.380 checked, the cells were pumping out the desired 00:21:32.380 --> 00:21:35.200 protein in massive quantities. Way more than 00:21:35.200 --> 00:21:38.009 before. They work. It worked. The immune system 00:21:38.009 --> 00:21:40.670 completely ignored the message, but the cell's 00:21:40.670 --> 00:21:42.670 protein -making factories read it perfectly. 00:21:42.990 --> 00:21:45.569 This was the breakthrough. This was it. They 00:21:45.569 --> 00:21:48.549 had turned a toxic, inflammatory molecule into 00:21:48.549 --> 00:21:51.829 a stealthy, potent medicine. That is the eureka 00:21:51.829 --> 00:21:53.569 moment. That is the moment the world changed, 00:21:53.730 --> 00:21:55.630 even if the world didn't have a clue yet. They 00:21:55.630 --> 00:21:58.029 were ecstatic. They wrote up the paper. This 00:21:58.029 --> 00:21:59.809 was going to be huge. They sent it to Nature. 00:22:00.049 --> 00:22:01.970 And Nature immediately cleared the front page 00:22:01.970 --> 00:22:04.329 for them. Nature rejected it within 24 hours. 00:22:04.450 --> 00:22:06.400 Didn't even send it out for... full review. So 00:22:06.400 --> 00:22:08.579 they sent it to science. Science rejected it, 00:22:08.579 --> 00:22:11.019 too. But why? How could they not see the importance 00:22:11.019 --> 00:22:13.720 of this? Because in the grand scheme of science 00:22:13.720 --> 00:22:16.200 at the time, it seemed niche. It was a paper 00:22:16.200 --> 00:22:20.039 on RNA modification. It seemed like a minor biochemical 00:22:20.039 --> 00:22:23.599 curiosity, not a medical revolution. The reviewers, 00:22:23.759 --> 00:22:26.740 the editors, they just didn't grasp the enormous 00:22:26.740 --> 00:22:30.420 implication that this single change solved the 00:22:30.420 --> 00:22:34.220 fundamental barrier to mRNA therapeutics. So 00:22:34.220 --> 00:22:36.240 it did get published eventually, though. Yes. 00:22:36.240 --> 00:22:39.319 It found a home in the journal Immunity in 2005. 00:22:40.589 --> 00:22:43.410 a very respectable journal, but not one of the 00:22:43.410 --> 00:22:47.029 absolute top -tier blockbusters. And even after 00:22:47.029 --> 00:22:50.150 it was published, crickets. Nothing. Curry Co. 00:22:50.349 --> 00:22:52.150 has said she expected her phone to start ringing 00:22:52.150 --> 00:22:54.690 off the hook. It didn't ring once. That is just... 00:22:55.309 --> 00:22:57.390 It's heartbreaking. You solve the puzzle that 00:22:57.390 --> 00:22:59.950 stumped everyone for decades and nobody cares. 00:23:00.130 --> 00:23:01.789 But they kept going. They knew what they had. 00:23:01.970 --> 00:23:04.890 They now had the core technology, the nucleoside 00:23:04.890 --> 00:23:08.890 modified mRNA. They filed for patents. And this 00:23:08.890 --> 00:23:12.210 brings us to the commercialization phase, which 00:23:12.210 --> 00:23:14.230 involves what I honestly think is one of the 00:23:14.230 --> 00:23:16.410 biggest business blunders in the history of university 00:23:16.410 --> 00:23:18.730 tech transfer. The UPenn blunder. Absolutely. 00:23:18.789 --> 00:23:21.349 So Carrico and Weissman had founded a small company, 00:23:21.490 --> 00:23:24.750 RNRX. But under university rules, UPenn owned. 00:23:24.839 --> 00:23:26.480 the intellectual property, the patents. Okay, 00:23:26.480 --> 00:23:29.220 that's standard. It is. And UPenn's tech transfer 00:23:29.220 --> 00:23:31.220 office looked at these patents for this weird 00:23:31.220 --> 00:23:33.640 modified RNA and they said... We don't see much 00:23:33.640 --> 00:23:36.019 value here. Exactly. They shot the license around. 00:23:36.119 --> 00:23:38.799 Nobody from Big Pharma was interested. So UPenn 00:23:38.799 --> 00:23:42.079 decided to just... cut their losses. They sold 00:23:42.079 --> 00:23:44.900 the exclusive license to the patent to a small 00:23:44.900 --> 00:23:47.900 lab supply company in Wisconsin called CellScript. 00:23:48.119 --> 00:23:51.519 A lab supply company, not a biotech firm. No, 00:23:51.660 --> 00:23:54.400 a company that sells reagents to other scientists. 00:23:54.819 --> 00:23:57.359 It was run by a guy named Gary Dahl, who, to 00:23:57.359 --> 00:23:59.420 his credit, saw the value for research tools. 00:24:00.329 --> 00:24:03.130 But UPenn sold the rights for a relatively tiny 00:24:03.130 --> 00:24:06.049 amount. Reports say it was around $300 ,000. 00:24:06.430 --> 00:24:08.430 They sold the Golden Goose for the price of a 00:24:08.430 --> 00:24:11.109 mid -range suburban house. And here's the gut 00:24:11.109 --> 00:24:13.730 -punching twist. A few years later, a venture 00:24:13.730 --> 00:24:16.430 capital firm called Flagship Pioneering, which 00:24:16.430 --> 00:24:19.109 was backing this hot new startup called Moderna, 00:24:19.250 --> 00:24:21.670 they came calling. They contacted Carrico directly. 00:24:21.950 --> 00:24:24.430 They said, we've read your 2005 paper. We think 00:24:24.430 --> 00:24:26.529 this is the future. We want to license this technology. 00:24:26.849 --> 00:24:28.549 And she had to tell them. She had to say, I'm 00:24:28.549 --> 00:24:30.150 sorry, I can't help you. It's not available. 00:24:30.529 --> 00:24:33.170 The university that demoted me also sold the 00:24:33.170 --> 00:24:35.130 rights to my life's work to a guy in Wisconsin. 00:24:35.490 --> 00:24:37.269 Oh, their phone call must have been excruciating. 00:24:37.269 --> 00:24:39.880 Just imagine that. It forced Moderna and later 00:24:39.880 --> 00:24:43.039 a German company called BioNTech to go to sell 00:24:43.039 --> 00:24:45.539 script and pay millions upon millions in sub 00:24:45.539 --> 00:24:48.759 licensing fees. UPenn missed out on what would 00:24:48.759 --> 00:24:52.079 have become a multibillion dollar royalty stream. 00:24:52.220 --> 00:24:54.319 And this had to be the final straw for Carrico 00:24:54.319 --> 00:24:57.259 at UPenn. The writing was on the wall. She realized 00:24:57.259 --> 00:24:59.299 she was never going to get the respect or support 00:24:59.299 --> 00:25:03.460 she deserved there. So in 2013. BioNTech, which 00:25:03.460 --> 00:25:06.140 was a small German startup at the time, but one 00:25:06.140 --> 00:25:09.019 founded on the promise of mRNA, offered her a 00:25:09.019 --> 00:25:11.700 job. And not just any job. No. They offered her 00:25:11.700 --> 00:25:14.299 a vice presidency. They understood the technology. 00:25:14.500 --> 00:25:17.180 They valued her. They saw her as a pioneer. Not 00:25:17.180 --> 00:25:19.400 a problem. So she leaves. She finally moves to 00:25:19.400 --> 00:25:21.400 Germany. She commuted, actually, for a long time, 00:25:21.460 --> 00:25:23.859 living out of a suitcase again. She was finally 00:25:23.859 --> 00:25:25.740 in an environment that got it. They promoted 00:25:25.740 --> 00:25:29.009 her to senior VP by 2019. She was home. Now, 00:25:29.009 --> 00:25:31.009 before we get to the pandemic, there's one last 00:25:31.009 --> 00:25:33.309 crucial piece of the puzzle we need to put on 00:25:33.309 --> 00:25:36.730 the board. We have the mRNA, the message, we 00:25:36.730 --> 00:25:38.509 have the pseudodyne, the molecular disguise, 00:25:38.829 --> 00:25:41.289 but we still need a delivery truck. Correct. 00:25:41.329 --> 00:25:44.490 You can't just inject naked mRNA into the bloodstream. 00:25:44.809 --> 00:25:47.730 There are enzymes in our body called RNAs that 00:25:47.730 --> 00:25:50.730 are designed to do one thing, find and destroy 00:25:50.730 --> 00:25:53.619 free -floating RNA. Your message would be eaten 00:25:53.619 --> 00:25:56.460 up in seconds. It needs armor. And that armor 00:25:56.460 --> 00:25:59.819 is the lipid mannoparticle. The LNP. Basically, 00:25:59.980 --> 00:26:02.920 tiny little balls of fat. Caraco had actually 00:26:02.920 --> 00:26:04.660 collaborated on this problem with a scientist 00:26:04.660 --> 00:26:07.220 named Ian McLaughlin at a company called Techmira 00:26:07.220 --> 00:26:10.599 way back in 2006. So this wasn't a new idea either. 00:26:10.920 --> 00:26:13.079 No. The work on delivery systems was happening 00:26:13.079 --> 00:26:16.279 in parallel. The idea is to encapsulate the fragile 00:26:16.279 --> 00:26:19.420 mRNA inside this lipid shell. The LNP protects 00:26:19.420 --> 00:26:21.400 its precious cargo as it travels through the 00:26:21.400 --> 00:26:24.019 body. Then, when it reaches a cell, its fatty 00:26:24.019 --> 00:26:26.339 outer layer fuses with the fatty cell membrane, 00:26:26.579 --> 00:26:28.779 and it releases the mRNA inside. It's like a 00:26:28.779 --> 00:26:31.160 microscopic Trojan horse made of soap bubbles. 00:26:31.400 --> 00:26:32.940 That's a great way to think about it. So by the 00:26:32.940 --> 00:26:34.940 end of 2019, all the pieces are finally on the 00:26:34.940 --> 00:26:36.900 board. You have the modified non -inflammatory 00:26:36.900 --> 00:26:40.359 RNA. You have the LNP delivery system. of two 00:26:40.359 --> 00:26:42.660 companies, BioNTech and Moderna, that have spent 00:26:42.660 --> 00:26:44.759 years figuring out how to manufacture the stuff 00:26:44.759 --> 00:26:47.720 at scale. It was a loaded gun just waiting for 00:26:47.720 --> 00:26:50.200 a target. And in January of 2020, the target 00:26:50.200 --> 00:26:54.160 appeared, a novel coronavirus emerging out of 00:26:54.160 --> 00:26:57.240 Wuhan, China. The world panicked. I mean, I remember 00:26:57.240 --> 00:26:59.500 it vividly. Governments shut down, economies 00:26:59.500 --> 00:27:02.740 ground to a halt. But inside BioNTech and Moderna, 00:27:02.900 --> 00:27:05.539 there wasn't panic. There was a sprint. Right. 00:27:05.950 --> 00:27:08.349 Because they had this platform technology, they 00:27:08.349 --> 00:27:10.230 didn't have to invent a vaccine from scratch. 00:27:10.759 --> 00:27:12.779 This is the part I think so many people misunderstood 00:27:12.779 --> 00:27:15.779 during the pandemic. I remember hearing it constantly. 00:27:16.019 --> 00:27:18.700 Oh, it was rushed. Vaccines take 10 years to 00:27:18.700 --> 00:27:21.380 develop. How did they do this in 10 months? It's 00:27:21.380 --> 00:27:23.299 the biggest misconception of the whole crisis. 00:27:23.400 --> 00:27:25.220 It didn't take 10 months. It took 10 months, 00:27:25.259 --> 00:27:28.960 plus the 25 years of Carrico and Weissman struggling 00:27:28.960 --> 00:27:31.680 in the dark, being rejected and demoted. They 00:27:31.680 --> 00:27:33.299 just had to plug the new code in. That's it. 00:27:33.380 --> 00:27:35.819 As soon as the genetic sequence of the SARS -CoV 00:27:35.819 --> 00:27:38.539 -2 virus was published online, they just took 00:27:38.539 --> 00:27:41.460 the genetic code for the spike. protein, pasted 00:27:41.460 --> 00:27:43.900 it into their existing mRNA template, and hit 00:27:43.900 --> 00:27:46.900 print. Udur Shaheen at BioNTech designed their 00:27:46.900 --> 00:27:50.180 vaccine in a single weekend. The rest of the 00:27:50.180 --> 00:27:52.460 time was spent on manufacturing scale -up and 00:27:52.460 --> 00:27:54.480 the necessary clinical trials to prove safety 00:27:54.480 --> 00:27:57.359 and efficacy. But the core science, the invention. 00:27:58.119 --> 00:28:00.440 That was ready because of those decades of rejection 00:28:00.440 --> 00:28:02.559 and persistence. And the result was just. Yeah. 00:28:02.619 --> 00:28:06.279 It was spectacular. Over 90 % efficacy against 00:28:06.279 --> 00:28:08.579 the original strain. It saved millions of lives. 00:28:08.660 --> 00:28:11.339 It allowed society to reopen. It is arguably 00:28:11.339 --> 00:28:14.099 the greatest medical and manufacturing feat of 00:28:14.099 --> 00:28:17.559 the 21st century. And finally, finally, the world 00:28:17.559 --> 00:28:20.380 caught up to Kadi Kariko. The avalanche of awards. 00:28:20.559 --> 00:28:22.779 It was surreal to watch it happen in real time. 00:28:23.019 --> 00:28:25.759 She went from being a completely unknown scientist 00:28:25.759 --> 00:28:28.640 to being on the cover of magazines, Time magazine's 00:28:28.640 --> 00:28:30.720 hero of the year. The Lasker Award, which they 00:28:30.720 --> 00:28:33.720 call the American Nobel, the Tang Prize, and 00:28:33.720 --> 00:28:36.680 then the big one. October 2nd, 2023, the Nobel 00:28:36.680 --> 00:28:39.079 Prize in Physiology or Medicine, the summit. 00:28:39.299 --> 00:28:41.380 I love her reaction to it. She didn't give some 00:28:41.380 --> 00:28:43.940 big ego -driven speech. Her quote was something 00:28:43.940 --> 00:28:46.259 like, I dreamt about doing research, not getting 00:28:46.259 --> 00:28:49.009 an award. It's so consistent with her entire 00:28:49.009 --> 00:28:52.369 story. She is a solver of puzzles. She was never 00:28:52.369 --> 00:28:54.769 in it for the fame or the money. She was in it 00:28:54.769 --> 00:28:56.549 because she was obsessed with the question and 00:28:56.549 --> 00:28:58.849 wanted to find the answer. So let's bring the 00:28:58.849 --> 00:29:00.869 story up to the present moment. We're recording 00:29:00.869 --> 00:29:03.930 this in January of 2026, a little over two years 00:29:03.930 --> 00:29:06.230 have passed since the Nobel. What has she been 00:29:06.230 --> 00:29:08.730 up to? Well, she certainly hasn't retired to 00:29:08.730 --> 00:29:12.180 a beach somewhere. In October 2023, just after 00:29:12.180 --> 00:29:14.819 the prize was announced, she published her autobiography, 00:29:15.000 --> 00:29:18.579 Breaking Through My Life in Science. Which is 00:29:18.579 --> 00:29:21.259 a fantastic and very fitting title. It is. It 00:29:21.259 --> 00:29:24.009 became an instant bestseller in Hungary. By 2025, 00:29:24.390 --> 00:29:26.589 it had been translated into nine different languages. 00:29:26.849 --> 00:29:30.250 It won the Libri Literary Prize in 2024 and the 00:29:30.250 --> 00:29:33.970 Asimov Prize in May of 2025. It's really becoming 00:29:33.970 --> 00:29:36.670 a canonical text for young scientists, a story 00:29:36.670 --> 00:29:38.829 of persistence. And she did something really 00:29:38.829 --> 00:29:40.789 special with the prize money, didn't she? She 00:29:40.789 --> 00:29:43.009 did. You know, the Nobel comes with a significant 00:29:43.009 --> 00:29:46.349 cash award, over a million dollars. In April 00:29:46.349 --> 00:29:48.950 of 2024, she donated more than half a million 00:29:48.950 --> 00:29:51.029 dollars of that money right back to her alma 00:29:51.029 --> 00:29:53.480 mater, the University of Sigid. The place where 00:29:53.480 --> 00:29:56.220 it all started. Full circle. Giving back to the 00:29:56.220 --> 00:29:58.759 institution that educated her, making sure the 00:29:58.759 --> 00:30:00.640 next generation has resources and opportunities 00:30:00.640 --> 00:30:03.500 that she didn't have. And speaking of full circles, 00:30:03.660 --> 00:30:06.619 in November of 2024, she returned to Temple University. 00:30:07.059 --> 00:30:09.660 The scene of the crime. Exactly. The scene of 00:30:09.660 --> 00:30:12.099 the deportation threat. She went back to that 00:30:12.099 --> 00:30:15.720 campus, not as a vulnerable immigrant postdoc, 00:30:15.799 --> 00:30:18.819 but as a Nobel laureate to give a lecture. Wow. 00:30:19.299 --> 00:30:21.880 That must have been an incredibly powerful moment. 00:30:22.200 --> 00:30:25.240 A definitive, quiet vindication. And the accolades 00:30:25.240 --> 00:30:28.240 kept coming. In May 2025, she was elected to 00:30:28.240 --> 00:30:30.400 the U .S. National Academy of Sciences, which 00:30:30.400 --> 00:30:32.059 is one of the highest honors for an American 00:30:32.059 --> 00:30:34.460 scientist. So what's her status now? Is she still 00:30:34.460 --> 00:30:37.660 at BioNTech? She left her executive role at BioNTech 00:30:37.660 --> 00:30:40.859 in 2022, even before the Nobel, to devote more 00:30:40.859 --> 00:30:43.900 time to pure research. She's currently a professor 00:30:43.900 --> 00:30:47.500 at Saged. And in the ultimate irony, she's also 00:30:47.500 --> 00:30:49.900 affiliated with UPenn, who now celebrate her 00:30:49.900 --> 00:30:52.099 as one of their greatest luminaries. Funny how 00:30:52.099 --> 00:30:55.039 that works. Once you win the Nobel, the university 00:30:55.039 --> 00:30:57.660 that demoted you and sold your patent for pennies 00:30:57.660 --> 00:30:59.920 suddenly puts your face on the front of the brochure. 00:31:00.079 --> 00:31:03.099 Success has many fathers. Failure is an orphan. 00:31:03.339 --> 00:31:05.920 We have to mention one other person in this story 00:31:05.920 --> 00:31:09.380 before we look to the future. Her daughter, Susan 00:31:09.380 --> 00:31:11.839 Francia. The little girl with the teddy bear 00:31:11.839 --> 00:31:14.240 full of cash. She didn't do too badly for herself 00:31:14.240 --> 00:31:16.579 either. No, not at all. Susan grew up watching 00:31:16.579 --> 00:31:19.000 her mother's relentless seven days a week work 00:31:19.000 --> 00:31:22.579 ethic. She clearly absorbed that intensity. Susan 00:31:22.579 --> 00:31:24.900 Francia went on to become a two -time Olympic 00:31:24.900 --> 00:31:28.380 gold medalist in rowing for Team USA. That is 00:31:28.380 --> 00:31:31.549 just an insane family stat sheet. Mom has a Nobel 00:31:31.549 --> 00:31:33.910 Prize in medicine. Daughter has two Olympic gold 00:31:33.910 --> 00:31:36.289 medals. It really speaks to a certain genetic 00:31:36.289 --> 00:31:39.789 or maybe environmental drive, a capacity for 00:31:39.789 --> 00:31:42.269 enduring pain and discomfort for a distant goal. 00:31:42.509 --> 00:31:45.450 Whether it's rowing a boat until your lungs burn 00:31:45.450 --> 00:31:48.130 or pipetting clear liquids until your eyes blur, 00:31:48.269 --> 00:31:50.549 they simply do not know how to quit. So what 00:31:50.549 --> 00:31:52.450 does all of this mean for us now? We have the 00:31:52.450 --> 00:31:54.789 COVID vaccine. It's part of our lives. But I've 00:31:54.789 --> 00:31:56.650 heard you say before that calling this vaccine 00:31:56.650 --> 00:31:59.230 technology is like calling the Internet email 00:31:59.230 --> 00:32:01.859 technology. It's just it's way too small description. 00:32:02.079 --> 00:32:05.019 It is so much bigger than just vaccines. We need 00:32:05.019 --> 00:32:08.420 to stop thinking of mRNA as just for infectious 00:32:08.420 --> 00:32:11.980 diseases. We need to think of it as a drug platform, 00:32:12.240 --> 00:32:15.279 a new way of making medicine. Explain that shift 00:32:15.279 --> 00:32:17.670 in thinking. Okay, think about most drugs today. 00:32:17.849 --> 00:32:20.630 If you're a diabetic, you inject insulin. Insulin 00:32:20.630 --> 00:32:23.450 is a protein. To get that insulin, we have to 00:32:23.450 --> 00:32:25.809 build these massive billion -dollar factories 00:32:25.809 --> 00:32:28.769 to grow the protein in giant vats of bacteria, 00:32:29.069 --> 00:32:32.390 then purify it, bottle it, and keep it cold all 00:32:32.390 --> 00:32:34.849 the way to the patient. It's a complex, expensive 00:32:34.849 --> 00:32:37.529 industrial process. It is. Carico's technology 00:32:37.529 --> 00:32:40.349 completely flips that model on its head. Instead 00:32:40.349 --> 00:32:42.390 of making the protein in a factory, we just write 00:32:42.390 --> 00:32:44.710 the instruction code in the mRNA for that protein. 00:32:45.450 --> 00:32:48.069 package it in an LNP, we inject the code, and 00:32:48.069 --> 00:32:50.509 the patient's own cells become the factory. So 00:32:50.509 --> 00:32:52.549 you can make the body manufacture its own medicine 00:32:52.549 --> 00:32:55.710 on demand. Exactly. This opens the door to something 00:32:55.710 --> 00:32:58.569 called protein replacement therapy. Think of 00:32:58.569 --> 00:33:01.829 genetic diseases like hemophilia or cystic fibrosis, 00:33:01.849 --> 00:33:04.369 where the body is missing one specific crucial 00:33:04.369 --> 00:33:06.549 protein. We can just send the email with the 00:33:06.549 --> 00:33:08.750 blueprints, and for a short time, the body can 00:33:08.750 --> 00:33:10.890 make what it's missing and fix itself. What about 00:33:10.890 --> 00:33:12.789 cancer? That's the one everyone always asks about. 00:33:13.119 --> 00:33:16.119 That's the holy grail, immuno -oncology. The 00:33:16.119 --> 00:33:18.480 idea is that we can take a biopsy of a patient 00:33:18.480 --> 00:33:22.210 -specific tumor. sequence its DNA, find the unique 00:33:22.210 --> 00:33:24.170 mutations that make it different from healthy 00:33:24.170 --> 00:33:27.190 cells, and then create a custom mRNA vaccine 00:33:27.190 --> 00:33:29.869 that teaches that patient's immune system to 00:33:29.869 --> 00:33:32.390 recognize and hunt down only those cancer cells 00:33:32.390 --> 00:33:35.250 wherever they are in the body. It's truly personalized 00:33:35.250 --> 00:33:37.849 medicine made to order. Heart disease. They're 00:33:37.849 --> 00:33:40.309 already working on it. Injecting mRNA directly 00:33:40.309 --> 00:33:42.569 into the heart muscle after a heart attack, a 00:33:42.569 --> 00:33:44.970 condition called ischemia, to tell the cells 00:33:44.970 --> 00:33:47.170 to grow new blood vessels and heal the damaged 00:33:47.170 --> 00:33:49.819 tissue. It honestly sounds like science. It's 00:33:49.819 --> 00:33:52.759 rapidly becoming science fact. We're also looking 00:33:52.759 --> 00:33:55.559 at using mRNA to temporarily express proteins 00:33:55.559 --> 00:33:58.579 that can reprogram cells to generate pluripotent 00:33:58.579 --> 00:34:01.640 stem cells, basically rebooting older cells to 00:34:01.640 --> 00:34:04.480 a younger, more flexible state. The horizon is 00:34:04.480 --> 00:34:08.000 just. It's limitless. This is a new branch of 00:34:08.000 --> 00:34:10.239 medicine, comparable to the discovery of antibiotics 00:34:10.239 --> 00:34:14.300 or the invention of recombinant DNA. And it all 00:34:14.300 --> 00:34:17.579 goes back to that basement lab, to that demotion. 00:34:17.980 --> 00:34:20.320 To that one scientist who wouldn't give up. It 00:34:20.320 --> 00:34:23.480 does. As we wrap up this deep dive, I want to 00:34:23.480 --> 00:34:26.019 leave our listeners with one final, maybe provocative 00:34:26.019 --> 00:34:30.239 thought. We celebrate Kati Kariko today. We should. 00:34:30.340 --> 00:34:32.619 She's a hero. She has a household name in science. 00:34:32.960 --> 00:34:36.059 But we have to talk about survivor bias. Exactly. 00:34:36.099 --> 00:34:38.960 We know her story because she made it. She survived. 00:34:39.079 --> 00:34:41.960 She survived the secret police in Hungary. She 00:34:41.960 --> 00:34:44.659 survived the deportation threats at Temple. She 00:34:44.659 --> 00:34:47.320 survived the constant grant rejections, the demotion, 00:34:47.380 --> 00:34:49.880 the lack of funding at UPenn. But you have to 00:34:49.880 --> 00:34:52.179 ask yourself, how many other Carcos were there? 00:34:52.280 --> 00:34:54.480 That is a haunting question. How many brilliant 00:34:54.480 --> 00:34:57.039 scientists were there in the 90s or the 2000s 00:34:57.039 --> 00:34:59.460 who had an idea that was just as big, just as 00:34:59.460 --> 00:35:03.139 revolutionary as mRNA, but they got demoted and 00:35:03.139 --> 00:35:04.659 they couldn't take the financial hit and had 00:35:04.659 --> 00:35:07.159 to leave science, or their boss threatened them 00:35:07.159 --> 00:35:09.309 and they just went home? Or they got rejected 00:35:09.309 --> 00:35:11.250 by nature and science three times in a row and 00:35:11.250 --> 00:35:13.630 just decided, well, I guess I'm wrong. And those 00:35:13.630 --> 00:35:16.570 ideas, those potential cures, they just died 00:35:16.570 --> 00:35:19.909 in a trash can. Exactly. We will never know what 00:35:19.909 --> 00:35:22.369 we missed, what cures we don't have today, because 00:35:22.369 --> 00:35:24.769 our academic system is fundamentally designed 00:35:24.769 --> 00:35:27.829 to fund the consensus, not the outliers. The 00:35:27.829 --> 00:35:32.030 system loves the safe bet. It is terrible at 00:35:32.030 --> 00:35:34.670 recognizing the kind of genius that, at first 00:35:34.670 --> 00:35:37.780 glance, looks like a mistake. And for decades, 00:35:38.099 --> 00:35:40.420 Kadi Kariko looked like a mistake to them. For 00:35:40.420 --> 00:35:42.739 40 years, she looked like a failure to the scientific 00:35:42.739 --> 00:35:44.539 establishment. I want to leave you with that 00:35:44.539 --> 00:35:47.579 final image. Not the Nobel ceremony in Stockholm. 00:35:47.800 --> 00:35:49.860 Not all the applause. I want you to picture a 00:35:49.860 --> 00:35:52.920 woman in her 40s. She has just been demoted by 00:35:52.920 --> 00:35:55.500 her university. She is working in a cramped, 00:35:55.539 --> 00:35:57.719 borrowed corner of a lab. She is transferring 00:35:57.719 --> 00:36:00.119 clear, invisible liquid from one plastic tube 00:36:00.119 --> 00:36:02.860 to another. She has no funding. Her bosses think 00:36:02.860 --> 00:36:05.239 she is wasting her time. But she keeps working. 00:36:05.500 --> 00:36:07.800 She holds the key to saving the world in her 00:36:07.800 --> 00:36:09.820 hands. She just doesn't know that the applause 00:36:09.820 --> 00:36:12.000 is still 20 years away. He just keeps working. 00:36:12.280 --> 00:36:14.170 She just keeps working. That's the lesson. That 00:36:14.170 --> 00:36:17.389 is the legacy of Kathleen Carrico. So to all 00:36:17.389 --> 00:36:19.949 our listeners, look for the outliers in your 00:36:19.949 --> 00:36:22.389 own field, the people who are stubbornly, obsessively 00:36:22.389 --> 00:36:24.309 working on something that everyone else thinks 00:36:24.309 --> 00:36:27.150 is weird or a waste of time. They might just 00:36:27.150 --> 00:36:29.110 be on to something big. Thanks for listening 00:36:29.110 --> 00:36:30.510 to The Deep Dive. Thank you.