WEBVTT - Breakthrough, Part Six: Unlikely Heroes 0:00:00.880 --> 0:00:05.600 On a warm September day in Berlin, Hungarian biochemist Catalan 0:00:05.720 --> 0:00:10.440 Cattico walks into the nearly century old auditorium at Berlin's 0:00:10.480 --> 0:00:14.080 chetty Tay Hospital. She takes her seat in the front 0:00:14.200 --> 0:00:18.400 row of a World Health Organization event. She surrounded by 0:00:18.440 --> 0:00:24.080 politicians and public health leaders. Just a year earlier, there 0:00:24.079 --> 0:00:26.800 would have been little reason for Catalan to be there 0:00:26.800 --> 0:00:29.520 at all. A few of the other guests would have 0:00:29.560 --> 0:00:33.440 even known her name, But now she's a guest of honor. 0:00:34.600 --> 0:00:40.040 Catalan spent her life researching messenger RNA, the tiny postal 0:00:40.120 --> 0:00:45.800 workers that carry genetic instructions inside cells. For decades, few 0:00:45.880 --> 0:00:52.040 paid attention to what she found that has now changed. Yes. 0:00:54.800 --> 0:00:59.920 Even at the event in September, German Chancellor Angelo Meeric 0:01:00.040 --> 0:01:05.679 called praises Catalan for not giving up. The German Chancellor 0:01:05.840 --> 0:01:09.800 tells the audience that Catalan's thirty years of effort laid 0:01:09.840 --> 0:01:14.880 the groundwork for our current fight against COVID nineteen. In 0:01:14.959 --> 0:01:20.119 her own remarks, Catalan says her collaborators deserve credit too. 0:01:21.040 --> 0:01:23.840 First of all, I would like to correct you because 0:01:23.880 --> 0:01:27.040 there are many, many people contributed to it, and I 0:01:27.160 --> 0:01:29.040 was just one of them. And I am glad that 0:01:29.080 --> 0:01:31.800 I go also goold have I am just representing all 0:01:31.840 --> 0:01:35.680 of those fellow scientists. Then she makes a plea, but 0:01:35.760 --> 0:01:38.920 the dignitaries in the audience to give people with ideas 0:01:38.959 --> 0:01:43.240 that seem crazy a chance. Those who who might have 0:01:43.280 --> 0:01:47.240 an idea which is too weird to support, maybe they 0:01:47.280 --> 0:01:51.440 get more support and sort of problems we were facing 0:01:51.480 --> 0:01:57.560 the future. Catalan doesn't stick around long for drinks. Afterward, 0:01:58.280 --> 0:02:00.320 She's at the co check In less than an hour, 0:02:01.040 --> 0:02:04.480 She's going to Budapest. They're painting her picture onto the 0:02:04.520 --> 0:02:08.920 side of a building there. She's only awards circuit, but 0:02:09.040 --> 0:02:11.600 she says she'd rather be back in her lab as 0:02:11.680 --> 0:02:15.680 soon as possible. Catalan helped lay the groundwork for a 0:02:15.760 --> 0:02:18.600 most important weapon against the deadly virus that has so 0:02:18.720 --> 0:02:21.680 far killed more than five million people around the globe. 0:02:22.520 --> 0:02:26.160 She never expected that, but she also showed the world 0:02:26.200 --> 0:02:31.120 the potential for a new technology, messenger RNA, And this 0:02:31.360 --> 0:02:36.959 is what Catalan had hoped for all along. This is 0:02:37.000 --> 0:02:40.200 a story about what most people would agree is the 0:02:40.240 --> 0:02:44.959 biggest success of the pandemic. Messenger RNA vaccines could never 0:02:45.040 --> 0:02:48.600 have proven themselves so quickly outside the crucible of that 0:02:48.680 --> 0:02:54.279 first pandemic year. The technology may well win some researchers 0:02:54.320 --> 0:02:58.760 and Nobel Prize. It will almost certainly have big implications 0:02:58.800 --> 0:03:02.400 for the future of medicine. Odds are you've taken one 0:03:02.440 --> 0:03:06.280 of these mr Anda vaccines yourself, and you might think 0:03:06.320 --> 0:03:08.800 you know the story of how they swooped onto the 0:03:08.800 --> 0:03:12.960 world stage so quickly, But odds are you don't know 0:03:13.000 --> 0:03:16.400 the half of it. This is also the story of 0:03:16.440 --> 0:03:19.680 as unlikely a bunch of world saving heroes as you'll 0:03:19.720 --> 0:03:24.440 ever encounter. My name is Naomi Kraski, and I'm a 0:03:24.480 --> 0:03:27.840 health journalist for Bloomberg News. In the first half of 0:03:27.880 --> 0:03:31.480 the season, you've heard about the lingering consequences of COVID 0:03:31.760 --> 0:03:36.200 for many patients and hospitals. Now we'll tell you about 0:03:36.240 --> 0:03:40.960 the consequences for science. They're a lot more hopeful. From 0:03:40.960 --> 0:03:59.080 the Prognosis podcast, this is Breakthrough. I first heard of 0:03:59.200 --> 0:04:04.080 messenger are A vaccines more than a year before the 0:04:04.200 --> 0:04:09.160 mysterious new virus emerged in Wuhan. The biggest buzz in 0:04:09.200 --> 0:04:12.120 the drug industry at that time was the idea of 0:04:12.240 --> 0:04:15.480 using the immune system to attack tumors and help cancer 0:04:15.480 --> 0:04:19.920 patients live longer. Scientists were trying a bunch of different 0:04:19.920 --> 0:04:22.599 ways to do this, and a source told me I 0:04:22.600 --> 0:04:26.080 should talk to the people at a German startup called BioNTech. 0:04:27.240 --> 0:04:32.560 Inside European biotech, everybody knew them, but outside that insular 0:04:32.600 --> 0:04:36.520 world a few people had ever heard of them. They 0:04:36.520 --> 0:04:40.000 were trying to make something that had failed many times before, 0:04:40.440 --> 0:04:43.440 a cancer vaccine, but they were trying to do it 0:04:43.640 --> 0:04:50.240 using messenger RNA. Here's BioNTech CEO Uger Shahin speaking at 0:04:50.240 --> 0:04:54.719 a tech conference called codex in. I think you have 0:04:54.800 --> 0:04:59.120 to dare to start without having all solutions in the hand, 0:04:59.279 --> 0:05:03.839 hoping that something would come up. It was fascinating stuff, 0:05:04.000 --> 0:05:07.520 full of hope and cutting edge science, but as is 0:05:07.600 --> 0:05:11.040 often the case in the risky business of biotech, it 0:05:11.120 --> 0:05:13.680 wasn't at all clear that the MR and A vaccines 0:05:13.720 --> 0:05:16.839 would actually work. I wrote a feature story for the 0:05:16.880 --> 0:05:19.800 news wire, then moved on to other topics and went 0:05:19.880 --> 0:05:25.040 on maternity leave. Then in January my boss called. He 0:05:25.120 --> 0:05:28.039 said a new story was keeping him busy, strange new 0:05:28.040 --> 0:05:31.599 coronavirus that had emerged in China and was spreading around 0:05:31.600 --> 0:05:34.799 the world. It's too bad you're not here now, he said. 0:05:35.680 --> 0:05:37.880 It'll probably be all over by the time you're back. 0:05:38.960 --> 0:05:41.640 Of course, when I came back to the office the 0:05:41.680 --> 0:05:46.120 next month, it wasn't over. It was spreading. I live 0:05:46.160 --> 0:05:49.600 in Germany. A few weeks later we went into our 0:05:49.640 --> 0:05:54.400 first lockdown, and it's still not over. The world has changed. 0:05:54.960 --> 0:06:06.000 We're still finding out just how much our story starts. 0:06:06.040 --> 0:06:10.840 In nine the modern study of human genetics was just 0:06:11.040 --> 0:06:15.680 getting going. Only eight years prior, scientists had discovered the 0:06:15.680 --> 0:06:19.919 double helix structure of DNA. Now they were trying to 0:06:19.920 --> 0:06:23.720 figure out how cells act on the instructions encoded in 0:06:23.760 --> 0:06:27.800 the genes. A team from the Pastor Institute in Paris 0:06:27.839 --> 0:06:32.040 identified an elusive molecule that copies pieces of genetic code 0:06:32.520 --> 0:06:35.839 and delivers its instructions into the machinery of the cell. 0:06:36.920 --> 0:06:43.000 They named it messenger RNA. RNA stands for ribonucleic acid, 0:06:44.600 --> 0:06:49.040 where DNA is a double strand RNA is a single strand. 0:06:50.000 --> 0:06:53.120 There are a few types of RNA that play important 0:06:53.240 --> 0:06:58.599 roles in sending DNA's instructions to cells, and messenger RNA 0:06:59.480 --> 0:07:03.159 is essentially leave the errand boy. One of the best 0:07:03.200 --> 0:07:07.960 explanations I've heard of how the biology works comes from 0:07:08.000 --> 0:07:13.440 Derek Rossy Harvard University stem cell biologists. M RNA is 0:07:13.480 --> 0:07:19.920 actually a necessary and obligate intermediate between genes, which are 0:07:20.480 --> 0:07:24.320 encoded in DNA and live in the nucleus, and proteins, 0:07:24.680 --> 0:07:27.480 which do all the busy work of the cell. But 0:07:27.560 --> 0:07:31.880 they're made in another part of the cell called the cytoplasm, 0:07:31.920 --> 0:07:35.480 so the two don't meet the nason the nucleus, protein 0:07:35.520 --> 0:07:38.080 synthesis is and the cytoplasm. So there had to be 0:07:38.120 --> 0:07:41.400 an intermediate molecule, which was discovered to be messenger RNA 0:07:41.360 --> 0:07:46.120 an appropriate an appropriate name. It carries the message encoded 0:07:46.120 --> 0:07:50.440 by the gene out to allow that sort of code 0:07:50.480 --> 0:07:54.280 to be turned into something that has utility, something that 0:07:54.360 --> 0:08:00.400 has function proteins, So DNA makes mRNA makes protein, makes 0:08:00.600 --> 0:08:05.320 all of life. Three French scientists shared a Nobel Prize 0:08:05.320 --> 0:08:08.400 in nineteen sixty five for the discovery of m r 0:08:08.480 --> 0:08:13.000 and A, but for decades after that, m RNA wasn't 0:08:13.000 --> 0:08:16.560 a very high profile area for research. Part of the 0:08:16.680 --> 0:08:20.160 reason was that the molecules fragile and hard to work with. 0:08:20.840 --> 0:08:23.360 Scientists didn't figure out how to synthesize it in the 0:08:23.480 --> 0:08:29.520 lab until in the nineteen nineties. The field Superstars focused 0:08:29.520 --> 0:08:33.840 on DNA instead. DNA was easier than RNA to work 0:08:33.880 --> 0:08:37.080 with and more stable. It was also in the limelight 0:08:37.400 --> 0:08:39.440 thanks to the mapping of the genome and the Human 0:08:39.480 --> 0:08:46.240 Genome Project that lasted from two thousand three. Scientists focused 0:08:46.240 --> 0:08:49.720 on the idea of curing illnesses by fixing errors in 0:08:49.760 --> 0:08:54.120 the genome, but there were a few exceptions researchers who 0:08:54.120 --> 0:08:58.680 stuck with m RNA despite the challenges both scientific and personal. 0:08:59.480 --> 0:09:02.240 One of them came from Hungary. By the time the 0:09:02.280 --> 0:09:05.200 pandemic was a year old, her name would be known 0:09:05.320 --> 0:09:08.199 around the world as the woman who pioneered mr and 0:09:08.280 --> 0:09:12.720 A vaccines. She would be covered endlessly in newspaper articles 0:09:12.760 --> 0:09:16.360 and TV shows. But each time I think I've learned 0:09:16.400 --> 0:09:20.000 everything about her story, something new turns up to surprise me. 0:09:29.760 --> 0:09:35.480 Catalan Cadko was born in Hungary. In she's in grade 0:09:35.520 --> 0:09:39.040 school when the first MR and A discoveries are being lauded. 0:09:40.120 --> 0:09:43.920 The Poster Institute and Nobel Prizes would have seemed very 0:09:43.960 --> 0:09:47.800 far away to her. She grows up under communism in 0:09:47.880 --> 0:09:52.440 gishuis Sarash, a small town in the countryside of eastern Hungary. 0:09:53.400 --> 0:09:57.640 Her father is a butcher, but she knows even as 0:09:57.640 --> 0:10:01.640 a teenager that she wants to be assigned best. Catalan 0:10:01.800 --> 0:10:05.199 declined to be interviewed for this podcast. I and others 0:10:05.280 --> 0:10:08.960 that Bloomberg had already spoken to her many times, and 0:10:09.040 --> 0:10:11.480 she said she wants to focus again on her work 0:10:11.600 --> 0:10:14.600 after being on the interview circuit. I get where she's 0:10:14.640 --> 0:10:17.560 coming from, so we decided to draw from what I 0:10:17.600 --> 0:10:21.400 think is her most unusual interview. She's spoken May with 0:10:21.480 --> 0:10:26.079 Clube Radio, an independent broadcaster based in Budapest. We've dubbed 0:10:26.120 --> 0:10:32.280 her voice from her native Hungarian Madam, I'm not a 0:10:32.320 --> 0:10:35.760 special person at all. I saw that my parents were called, 0:10:35.840 --> 0:10:38.240 and I also tried to help them. Along with my siblings. 0:10:39.200 --> 0:10:46.440 We studied odd that was our job as Catalan earned 0:10:46.480 --> 0:10:50.680 her PhD in Hungary at the University of second just 0:10:50.840 --> 0:10:54.240 a two hour drive from where she grew up. She 0:10:54.320 --> 0:10:57.800 started her postdoctoral research in the same city at the 0:10:57.840 --> 0:11:03.400 Biological Research Center of the Hungarian Academy of Sciences. In 0:11:04.400 --> 0:11:08.000 eight As a PhD student in Hungary, she worked with 0:11:08.160 --> 0:11:11.720 RNA for the first time. It was the start of 0:11:11.760 --> 0:11:17.480 a lifelong obsession. In she got the opportunity to move 0:11:17.520 --> 0:11:21.720 to the US for a job at Temple University in Philadelphia. 0:11:22.440 --> 0:11:25.800 She took it, moving with her husband and toddler daughter. 0:11:26.840 --> 0:11:29.920 The Hungarian government only allowed them to bring a hundred 0:11:30.000 --> 0:11:34.160 dollars with them. Legally, they sold another nine hundred pounds 0:11:34.200 --> 0:11:38.160 about one thousand, two hundred dollars into her daughter's teddy 0:11:38.160 --> 0:11:45.560 bear alment. We flew off. We didn't have any foreign renatives. 0:11:46.080 --> 0:11:51.240 We couldn't count on anyone to send us money. What 0:11:51.400 --> 0:11:55.280 she found wasn't what she had expected either. She says 0:11:55.320 --> 0:11:57.959 the lab wasn't as well equipped as the one back home, 0:11:58.559 --> 0:12:02.480 and one of the co workers doors and yelled. After 0:12:02.520 --> 0:12:06.040 a week she wanted to leave. She stayed out of 0:12:06.120 --> 0:12:13.720 necessity and out of hope. Were in survival mode, and 0:12:13.800 --> 0:12:16.439 I thought I would learn something interesting and we would survive. 0:12:17.120 --> 0:12:19.960 And this is what changes people, that they become so 0:12:20.080 --> 0:12:23.120 defenseless and they must rely on their talent and make 0:12:23.200 --> 0:12:28.559 do with the best they can. By nine, things were 0:12:28.559 --> 0:12:33.040 looking slightly better. Catalan got a research assistant professor position 0:12:33.160 --> 0:12:36.439 at the University of Pennsylvania. This was a chance to 0:12:36.480 --> 0:12:40.560 make a name for herself maybe eventually get tenure. Because 0:12:40.559 --> 0:12:42.960 of the way these jobs work, she was expected to 0:12:43.000 --> 0:12:46.520 win her own grant funding to support her research, but 0:12:46.640 --> 0:12:49.880 she ran into a big roadblock. She was still obsessed 0:12:49.880 --> 0:12:52.920 with m R and A. Well she had seen so 0:12:53.000 --> 0:12:55.800 far in her experiments convinced her that it would make 0:12:55.840 --> 0:12:59.839 a better medicine than d n A. But no, but 0:13:00.040 --> 0:13:05.839 the else agreed. She wrote a lot of grand proposals, 0:13:06.120 --> 0:13:10.040 at one point one every month, she told us, but 0:13:10.120 --> 0:13:13.960 nobody wanted to fund the experiments she wanted to do. 0:13:14.679 --> 0:13:17.400 Nobody wanted to fund work on m R and A. 0:13:18.480 --> 0:13:22.360 She didn't exactly make it easier on herself. One thing 0:13:22.400 --> 0:13:25.920 I learned from her Hungarian interview was that she wasn't 0:13:26.040 --> 0:13:30.120 a networker. Instead, she wanted to spend her time at 0:13:30.160 --> 0:13:38.679 the lab bench doing science. Should I always keep those 0:13:38.720 --> 0:13:42.000 meetings filled with small talk, which could have held my career? 0:13:42.559 --> 0:13:46.080 Those really drove me crazy. Even in stores if they 0:13:46.120 --> 0:13:50.280 were long lines, I thought, you're stealing my time, would you? 0:13:53.520 --> 0:13:56.800 Elliott barn Nathan was her boss at the time. He's 0:13:56.840 --> 0:14:00.640 a cardiologist who was then an associate professor of medicine 0:14:00.800 --> 0:14:04.480 at Penn. Elliott was later to leave academia for a 0:14:04.559 --> 0:14:08.200 drug industry career. He's an executive at Johnson and Johnson now, 0:14:09.080 --> 0:14:13.600 but he remembers Catalan. Well, so the first thing is 0:14:14.040 --> 0:14:18.000 she's incredibly hard working and and brilliant, I mean, really 0:14:18.080 --> 0:14:22.880 truly brilliant. And the thing that's interesting is that she's 0:14:22.920 --> 0:14:27.720 a voracious reader, and and so she would always read 0:14:27.840 --> 0:14:30.920 science and Nature and come into the lab this morning 0:14:30.960 --> 0:14:34.520 with the latest, you know, issue of science that you 0:14:34.760 --> 0:14:37.440 hadn't even come across my desk yet, and she had 0:14:37.480 --> 0:14:42.880 already read it and figured out somebody researching something completely 0:14:43.000 --> 0:14:47.520 different in a different content and a different disease entity. 0:14:47.560 --> 0:14:51.800 But there was a kernel here that was going to 0:14:51.960 --> 0:14:54.200 help us do the next step of what we needed 0:14:54.200 --> 0:14:58.760 to do. And she was always connecting the dots. Messenger 0:14:58.960 --> 0:15:02.280 r n a degree quickly in the body. There are 0:15:02.400 --> 0:15:06.440 enzymes that break loose mrn a down outside of cells, 0:15:07.240 --> 0:15:10.080 but it also goes away quite quickly once it's delivered 0:15:10.080 --> 0:15:14.400 its message inside the cell. Catalan thought that would actually 0:15:14.400 --> 0:15:17.760 be a good thing. She reasoned that you could use 0:15:17.960 --> 0:15:20.120 m RNA to flip a switch in the self for 0:15:20.200 --> 0:15:23.960 a limited period of time. Elliott told me the idea 0:15:24.040 --> 0:15:27.200 would be for it to have the desired effect then 0:15:27.280 --> 0:15:32.360 go away. But convincing the scientific establishment to give her 0:15:32.400 --> 0:15:37.480 experiments a chance proved very, very difficult. They could only 0:15:37.520 --> 0:15:42.400 see the challenge, not the potential benefit for them. mRNA 0:15:42.600 --> 0:15:47.000 was too fragile, too fleeting a dead end, so it 0:15:47.080 --> 0:15:49.400 was very It was very heretical back in those days. 0:15:49.720 --> 0:15:53.000 People said, oh, you're crazy, you know, m RNA will 0:15:53.040 --> 0:15:58.800 never work, it's too unstable. But she really firmly belowd 0:15:59.120 --> 0:16:02.360 She had a vision that it was doable. It was 0:16:02.480 --> 0:16:04.880 just we needed to figure out how to do it. 0:16:05.240 --> 0:16:09.520 Elliott used his own research funding to subsidize Catalan's experiments. 0:16:10.120 --> 0:16:13.800 They had some successes, but time and time again she 0:16:13.920 --> 0:16:18.880 failed to get grant funding. In she was stripped of 0:16:18.960 --> 0:16:23.080 her assistant professor title and demoted to essentially a glorified 0:16:23.160 --> 0:16:27.800 lab researcher. It seemed unlikely that she would ever get 0:16:27.840 --> 0:16:32.040 her own lab. People just couldn't see the see the 0:16:32.080 --> 0:16:37.600 truth of it. Unfortunately, it was a bitter blow. After 0:16:37.720 --> 0:16:41.280 making it all the way from Ural Hungary depend one 0:16:41.280 --> 0:16:45.040 of the top research institutions in the world, Catalan faced 0:16:45.080 --> 0:16:48.160 the very real possibility that she might have to stop 0:16:48.240 --> 0:16:52.120 doing the work that she loved. At the same time, 0:16:52.440 --> 0:16:56.080 she was dealing with a cancer scare and her husband 0:16:56.080 --> 0:16:58.600 was stuck back in Hungary for more than four months 0:16:58.760 --> 0:17:01.080 due to a processing to life for his green card. 0:17:02.120 --> 0:17:06.359 In the Hungarian radio show, she's interviewed alongside a singer 0:17:06.560 --> 0:17:11.160 named Zoran Stephan of It. The show has a unique format. 0:17:11.640 --> 0:17:14.840 It tries to put two people from totally different walks 0:17:14.880 --> 0:17:18.800 of life on the air together. In this case, Oron 0:17:18.960 --> 0:17:23.040 wrote Catalan's favorite song, a ballot called Diamond and Gold. 0:17:23.720 --> 0:17:26.320 She chokes up when she talks about listening to him 0:17:26.320 --> 0:17:34.320 sing when things got tough, that did That's offen. Oran 0:17:34.440 --> 0:17:38.480 released the song in the same year. Catalan moved to 0:17:38.520 --> 0:17:42.280 the US and was the frontman for two Hungarian rock 0:17:42.320 --> 0:17:46.159 bands in the nineteen sixties and nineteen seventies. Under a 0:17:46.160 --> 0:17:49.600 communist regime that opposed rock music, he knew a singer 0:17:49.640 --> 0:17:54.480 or two about persevering during tough times. Zorn's song is 0:17:54.520 --> 0:17:56.760 about how you need to work hard and stay the 0:17:56.800 --> 0:18:00.119 course to achieve your goals. Diamond and Gold of a 0:18:00.240 --> 0:18:03.400 nice shine, he says, but you need to dig deep 0:18:03.440 --> 0:18:07.639 to get it. This resonates with Catalan. She digs a 0:18:07.680 --> 0:18:10.960 long time before she hits pe dirt, and even when 0:18:10.960 --> 0:18:13.960 she does, she's one of only a few who recognizes 0:18:14.320 --> 0:18:26.800 what she's found. The first time I interviewed Catalan was 0:18:26.840 --> 0:18:31.959 in summer. Each time she speaks, I'm struck by how 0:18:32.040 --> 0:18:35.080 little bitterness she expresses about getting shut out by the 0:18:35.160 --> 0:18:40.800 academic establishment for so long. She sounds disappointed, yes, and 0:18:40.880 --> 0:18:45.160 sometimes frustrated. She also talks about how she really got 0:18:45.160 --> 0:18:48.600 a raise. She was hired at forty dollars, and two 0:18:48.600 --> 0:18:52.200 decades later she was making sixty dollars, which she says 0:18:52.320 --> 0:18:55.000 is less than what a laptech would make. But I 0:18:55.040 --> 0:18:57.800 got the impression that because she managed to keep on 0:18:57.880 --> 0:19:01.200 doing science, the lack of our cognition and low pay, 0:19:02.000 --> 0:19:06.080 these were secondary concerns. Here. She is earlier this year, 0:19:06.359 --> 0:19:09.520 speaking for a Bloomberg project about the one year anniversary 0:19:09.560 --> 0:19:13.800 of the pandemic. This is previously unaired audio. As long 0:19:13.880 --> 0:19:15.879 as I was in the lab and focus what I 0:19:15.920 --> 0:19:19.760 can do, I was very happy. I mean, at the weekends, 0:19:20.040 --> 0:19:23.000 long days. And my husband once said that, you know, 0:19:24.040 --> 0:19:27.919 probably my earning is first than in a McDonald's, because 0:19:27.960 --> 0:19:33.720 he collplated probably won all right, So as a biochemist 0:19:33.760 --> 0:19:37.280 in the nineteen nineties, she was probably making less per 0:19:37.320 --> 0:19:40.400 hour than I did at the time. Babysitting the kids 0:19:40.480 --> 0:19:46.200 on my street in Elliott barn Nathan, who was subsidizing 0:19:46.200 --> 0:19:49.560 Catalan's work at Penn, left the university to take a 0:19:49.680 --> 0:19:53.679 job at a biotech. She managed to find a spot 0:19:53.800 --> 0:19:58.399 in another lab, but she needed a close collaborator, someone 0:19:58.520 --> 0:20:02.359 enthusiastic about the science with the cloud, to ensure she 0:20:02.400 --> 0:20:06.159 could fund her projects. How she found this person is 0:20:06.240 --> 0:20:09.680 one of those great water cooler moments that will probably 0:20:09.720 --> 0:20:15.359 go down in science textbooks. In early Catalan started seeing 0:20:15.359 --> 0:20:18.639 a new face at the Xerox machine where she'd copy 0:20:18.720 --> 0:20:22.919 the academic journal articles that she read so eagerly. He 0:20:23.080 --> 0:20:27.280 was an immunologist named Drew Wiseman, fresh off a fellowship 0:20:27.320 --> 0:20:30.399 at Tony Fauci's lab at the National Institute's of Health. 0:20:31.359 --> 0:20:35.960 Drew was also a voracious suiteader of journal articles. Back 0:20:36.000 --> 0:20:37.800 in those days, you'd have to hunt them up in 0:20:37.800 --> 0:20:41.720 the library or somebody else's lab, then copy them and 0:20:41.760 --> 0:20:45.960 take them home. They weren't online. Drew says. They copied 0:20:46.080 --> 0:20:51.320 hundreds of articles before I ran into Katie Carrico over 0:20:51.400 --> 0:20:56.359 a Xerox machine and we would both sort of fight 0:20:56.480 --> 0:21:00.000 over it, but really just wait for each other to finish, 0:21:00.280 --> 0:21:05.160 and we started talking. Drew was interested in dendridic cells, 0:21:05.760 --> 0:21:09.480 which helped the immune system adapt to fight new intruders. 0:21:10.280 --> 0:21:16.080 They migrate throughout the body and collect foreign things, so 0:21:16.240 --> 0:21:22.920 that includes viruses, bacteria, parasites, tumor cells, and they bring 0:21:23.040 --> 0:21:28.520 those two lymph nodes where they start immune reaction. And 0:21:28.520 --> 0:21:32.320 why that's important for a vaccine is that they're the 0:21:32.440 --> 0:21:37.440 critical cell that picks up a vaccine and turns on 0:21:37.920 --> 0:21:42.520 the immune reactions. Drew wanted to work on an HIV vaccine. 0:21:43.160 --> 0:21:47.919 Catalan thought m RNA could help. We started talking and 0:21:47.960 --> 0:21:51.439 I told her about my interest in dendrodic cells and HIV, 0:21:52.280 --> 0:21:55.040 and she told me about her interest in m RNA. 0:21:55.880 --> 0:21:59.640 So we started working together and we started doing experiments 0:21:59.680 --> 0:22:04.600 together other and and that's where our collaboration started. It's 0:22:04.600 --> 0:22:08.480 important to note that up until then, Catalan wasn't really 0:22:08.560 --> 0:22:12.200 thinking about RNA as something you'd used to make a vaccine. 0:22:13.000 --> 0:22:17.480 She wanted to make treatments to use mRNA to spur 0:22:17.640 --> 0:22:20.520 the cells machinery to make a protein that the body 0:22:20.600 --> 0:22:25.920 needs to heal itself. In that sense, Wiseman's involvement broadened 0:22:25.920 --> 0:22:30.040 her perspective. I should also note that some experiments at 0:22:30.080 --> 0:22:33.040 that point had already shown the promise of using genetic 0:22:33.119 --> 0:22:39.840 material to spur the body's cells to produce vaccine. Researchers 0:22:39.840 --> 0:22:42.400 at Merk and Co. Were able to spurn immune response 0:22:42.480 --> 0:22:46.680 in mice by injecting them with DNA that contained instructions 0:22:46.720 --> 0:22:52.439 for influenza proteins. But seeing something working animals and having 0:22:52.480 --> 0:22:56.159 it work in humans, those are two very different things. 0:22:57.640 --> 0:23:02.520 The old line in this mice lie and and macacs exaggerate, 0:23:02.840 --> 0:23:07.040 So if it happens in a mouse, that's never a 0:23:07.080 --> 0:23:11.080 guarantee it'll happen in the human. The body has multiple 0:23:11.160 --> 0:23:14.320 lines of defense against any m RNA that looks like 0:23:14.520 --> 0:23:18.800 it might not belong. These guards are enzymes that will 0:23:18.840 --> 0:23:24.080 break down loose m RNA found outside a cell. If 0:23:24.200 --> 0:23:27.440 m RNA conduct those attacks and try to get inside 0:23:27.440 --> 0:23:32.720 a cell, its troubles aren't over. Derrick Rossi, Harvard stem 0:23:32.720 --> 0:23:36.000 cell scientists we heard from earlier, says the cell's first 0:23:36.040 --> 0:23:38.680 response is to do the exact opposite of what you'd 0:23:38.720 --> 0:23:42.359 want if you're going to use m RNA for a therapy. 0:23:42.520 --> 0:23:46.479 It's to stop making any proteins at all that doesn't 0:23:46.520 --> 0:23:49.640 want viral proteins being made in the cell. And then 0:23:49.680 --> 0:23:54.000 if the response is robust enough, it triggers these ultruastic 0:23:54.040 --> 0:23:57.600 self kill pathways uh and they die because it's better 0:23:57.640 --> 0:24:01.399 for the cell to die than it is to serve 0:24:01.440 --> 0:24:06.959 as a manufacturing facility for a hundred thousand viral particles. Essentially, 0:24:07.080 --> 0:24:11.159 the sell flips a self destruct swich. This makes a 0:24:11.160 --> 0:24:15.320 lot of sense from a biological standpoint. It ensures cells 0:24:15.400 --> 0:24:18.840 stay on track, make the right amount of the right protein, 0:24:19.040 --> 0:24:22.800 and don't get duped into producing a pathogen. But to 0:24:22.960 --> 0:24:26.480 use mr and A as a drug, Catalan and Drew 0:24:26.760 --> 0:24:28.959 had to figure out how to get it into the 0:24:29.000 --> 0:24:33.480 cell without flipping that self destruct switch. That was a 0:24:33.560 --> 0:24:36.560 lot of years of research. It's about seven years of 0:24:36.720 --> 0:24:40.600 work together. And what we did is we first had 0:24:40.600 --> 0:24:45.679 to figure out why it was inflammatory, So what receptors 0:24:46.200 --> 0:24:50.200 was it activating, How was it being recognized. So we 0:24:50.640 --> 0:24:56.600 found some receptors, other people found receptors. In total, there 0:24:56.600 --> 0:25:01.840 are seventeen of them, and we started to look at 0:25:01.280 --> 0:25:06.520 how RNA interacted with those receptors. They did years of 0:25:06.600 --> 0:25:11.600 painstaking experiments trying to disable the self destruct switch. Finally 0:25:11.840 --> 0:25:16.680 the breakthrough came in an unexpected place. You could say 0:25:16.720 --> 0:25:20.520 Look played a role. Look made possible by years of 0:25:20.600 --> 0:25:25.320 hard work. Catalan's old boss, Elliott Barnathan, explained it to me. 0:25:26.040 --> 0:25:30.000 She's a brilliant scientist, and you know, sometimes it's the 0:25:30.040 --> 0:25:35.240 controls that you use that really help you to make 0:25:35.600 --> 0:25:38.119 the advance. Is not necessarily what the experiment is, but 0:25:38.400 --> 0:25:41.600 how well controlled it was. The control group is the 0:25:41.640 --> 0:25:45.200 part of the experiment where you usually don't change anything, 0:25:45.800 --> 0:25:48.480 the part that's supposed to serve as a comparison to 0:25:48.560 --> 0:25:54.320 show whether the hypothesis you're testing is true. Catalan was 0:25:54.400 --> 0:25:57.760 using a special type of RNA called transfer rna as 0:25:57.800 --> 0:26:02.080 a control in one of her experiments. This t RNA 0:26:02.600 --> 0:26:07.119 has an important difference compared to mRNA. There's a different 0:26:07.200 --> 0:26:13.000 arrangement of a structural piece called uridine. So Catalan uses 0:26:13.040 --> 0:26:16.240 this t RNA in the control group and she notices 0:26:16.359 --> 0:26:22.840 something unusual. The immune response inflammation didn't happen in those cells. 0:26:23.720 --> 0:26:25.560 That was sort of the light bulb that went off 0:26:25.560 --> 0:26:29.000 in her head. She decides to make a slight modification 0:26:29.080 --> 0:26:32.520 to the RNA molecule to mimic what naturally occurs in 0:26:32.600 --> 0:26:37.800 transfer rna bingo. The cells don't try to fight off 0:26:37.840 --> 0:26:41.600 the foreign RNA, and even better, they make ten times 0:26:41.600 --> 0:26:45.359 as much protein, and so it was a double whammy. 0:26:45.440 --> 0:26:50.240 And that was really the fundamental patent that both Maderna 0:26:50.440 --> 0:26:55.680 and the fisor bio in tech vaccines use in terms 0:26:55.760 --> 0:27:04.320 of m RNA therapy. In two thousand five, Catalan Currico 0:27:04.600 --> 0:27:08.080 and Drew Wiseman published a paper laying out their method 0:27:08.200 --> 0:27:11.000 for modifying r n A. I asked Drew what he 0:27:11.040 --> 0:27:14.239 thought would happen next. So that was one of my 0:27:14.359 --> 0:27:19.119 more embarrassing moments, because what I said to Katie after 0:27:19.200 --> 0:27:22.159 the paper was published was that our phones are going 0:27:22.240 --> 0:27:24.919 to start ringing off the hook, and people are going 0:27:24.960 --> 0:27:27.000 to call us up and want to work with RNA, 0:27:27.720 --> 0:27:31.199 and drug companies are gonna want to use RNA, and 0:27:32.119 --> 0:27:35.880 our phones never ran. We would sit there looking at 0:27:35.880 --> 0:27:39.159 the phone, and nothing happened. In days and weeks and 0:27:39.240 --> 0:27:43.840 months and years went by and nothing happened. Nobody was interested. 0:27:43.960 --> 0:27:47.119 Even though we published how to make it work well 0:27:47.800 --> 0:27:51.160 and how to use it as a drug, nobody was interested. 0:27:52.400 --> 0:27:55.920 I find that astonishing. I asked him what he thought 0:27:56.000 --> 0:27:59.840 that was. You know, I think that even though we 0:28:00.080 --> 0:28:03.680 published that paper, they still said RNA is too difficult 0:28:03.720 --> 0:28:06.359 to work with and they just didn't want to work 0:28:06.359 --> 0:28:11.480 with RNA. Catalan said she felt like Cassandra, the mythological 0:28:11.600 --> 0:28:15.600 trojan priestess who finds that her gift of prophecy is 0:28:15.640 --> 0:28:19.520 really a curse. I mean, I knew that it can 0:28:19.640 --> 0:28:21.800 be used for everything, and you know, kind of a 0:28:21.880 --> 0:28:25.640 Cassandra feeling that I can see the future and nobody 0:28:25.720 --> 0:28:30.480 believes me. Catalan and Drew filed for a patent to 0:28:30.640 --> 0:28:34.119 keep on doing experiments, but it would take someone with 0:28:34.240 --> 0:28:37.840 more salesman skills to bring the technology to the limelight. 0:28:41.480 --> 0:28:44.440