WEBVTT - Immature Cells 0:00:08.245 --> 0:00:14.485 School of humans. Growing up in Japan, Shinya Yamanaka broke 0:00:14.525 --> 0:00:18.645 bones all over his body. He cracked them practicing judo 0:00:19.085 --> 0:00:23.365 and snapped them playing rugby. So when he became a 0:00:23.405 --> 0:00:26.845 doctor in nineteen eighty seven, he chose orthopedic surgery to 0:00:26.845 --> 0:00:29.365 fix the broken bones of other athletes like himself, who 0:00:29.405 --> 0:00:33.285 treated their bodies like crash test dummies. He was obviously 0:00:33.365 --> 0:00:36.245 no dummy, but Yamanaka wasn't a very good surgeon either, 0:00:37.045 --> 0:00:38.845 and he saw a lot of patients that he couldn't 0:00:38.845 --> 0:00:42.285 help with the scalpel, Like his own father, who had 0:00:42.325 --> 0:00:46.885 died of liver cirrhosis. Only research and new discoveries could 0:00:47.005 --> 0:00:51.645 lead to their cures. Yamanaka changed paths, moving from the 0:00:51.645 --> 0:00:57.485 operating table to the laboratory. Twenty years later, after many failures, 0:00:57.925 --> 0:01:00.805 Yamanaka made one of the biggest discoveries in the history 0:01:00.885 --> 0:01:05.765 of science. When we first start to form, you're just 0:01:05.805 --> 0:01:09.965 a bunch of identical immature cells. As we grow, those 0:01:09.965 --> 0:01:15.005 cells divide and multiply into different specialized cells like skin cells, 0:01:15.045 --> 0:01:19.045 nerve cells, muscle cells, and brain cells. In two thousand 0:01:19.045 --> 0:01:21.885 and six, Yamanaka discovered that these mature cells could be 0:01:21.925 --> 0:01:25.845 reprogrammed to an immature state, and once the cells were 0:01:25.885 --> 0:01:28.485 in an immature state, they could then be grown into 0:01:28.525 --> 0:01:32.445 whatever types of cells were needed. He called these cells 0:01:32.845 --> 0:01:40.005 induced pluripotent stem cells or IPS cells. Pluripotent basically means 0:01:40.005 --> 0:01:42.325 that their cells that can become any other type of cell. 0:01:43.245 --> 0:01:46.045 By adding just four genes into the skin cells of mice, 0:01:46.605 --> 0:01:49.885 Yamanaka could reprogram them into immature cells that were just 0:01:49.965 --> 0:01:54.085 like embryonic stem cells, cells that resemble those from an embryo. 0:01:56.365 --> 0:02:00.325 As one article put it, it was like biological time travel. 0:02:01.325 --> 0:02:03.405 Want to turn a skin cell into a muscle cell, 0:02:03.445 --> 0:02:06.445 to help regrow a lost limb, Want to replace a 0:02:06.485 --> 0:02:11.885 failing kidney. Now scientists had a place to start, and 0:02:12.005 --> 0:02:13.885 that was only one of a million things that could 0:02:13.885 --> 0:02:18.445 be done for human health with Yamanaka's reprogrammed cells. On 0:02:18.565 --> 0:02:20.765 this episode of a Long Shot, we'll talk to one 0:02:20.805 --> 0:02:24.565 scientist so inspired by Yamanaka's discovery that it changed the 0:02:24.725 --> 0:02:27.685 entire course of his life. He'd go on to start 0:02:27.765 --> 0:02:32.925 a little company called Maderna. We'll also talk about lipid nanoparticles, 0:02:33.365 --> 0:02:37.245 the protective shell of the mRNA vaccines, and last we'll 0:02:37.285 --> 0:02:39.845 hear about the role that Jennifer Andison's hair played in 0:02:39.925 --> 0:02:44.925 this whole story from My Heart Radio and School of Humans. 0:02:45.045 --> 0:03:05.005 I'm sean revive and this is long shot. The world 0:03:05.005 --> 0:03:08.445 found out about Shinya Yamanaka's discovery on June thirtieth, two 0:03:08.485 --> 0:03:11.285 thousand and six, when he gave a talk in Toronto 0:03:11.365 --> 0:03:14.245 at an annual meeting of the International Society for Stem 0:03:14.285 --> 0:03:17.605 Cell Research. The researchers in the room knew this was 0:03:17.645 --> 0:03:21.685 a huge announcement. If Yamanaka could create embryonic like cells 0:03:21.725 --> 0:03:23.805 in a mouse, then he can also do it in 0:03:23.845 --> 0:03:28.005 a person. That could lead to nearly unlimited enhancements in 0:03:28.125 --> 0:03:31.285 human health. I remember being in the audience and just 0:03:31.405 --> 0:03:37.325 being blown away by his presentation. That's Canadian scientist Derek ROSSI. 0:03:37.925 --> 0:03:41.085 The study is one that I returned to. I've read 0:03:41.125 --> 0:03:46.525 it many times. I mean, it's really fantastic. We're talking 0:03:46.565 --> 0:03:50.805 over zoom. He's wearing red rounded Andy warholesque glasses and 0:03:50.885 --> 0:03:53.645 a black David Bowie T shirt. It's not the picture, 0:03:53.685 --> 0:03:56.645 but it's a picture from the cover of Ziggy Stardust. 0:03:57.485 --> 0:04:00.045 Derek is fifty five years old, but looks a bit younger, 0:04:00.245 --> 0:04:04.325 with slick back fashionably graying dark hair. He's the CEO 0:04:04.405 --> 0:04:08.165 of Convelo Therapy X, a company based in Cleveland. They 0:04:08.165 --> 0:04:12.605 do work on multiple sclerosis. His parents were first generation Canadians. 0:04:12.805 --> 0:04:16.485 They immigrated from Malta right after World War Two. His 0:04:16.565 --> 0:04:18.605 dad worked at autobody shops and his mom ran a 0:04:18.685 --> 0:04:22.405 daycare center. It was not a science family, but he 0:04:22.445 --> 0:04:25.725 had a brother with an absolutely crazy love for wild animals, 0:04:26.245 --> 0:04:29.525 and the house was filled with them. We literally had, 0:04:29.565 --> 0:04:33.125 you know, an endless parade of really exotic animals marched 0:04:33.125 --> 0:04:36.165 through our house, you know, from a great horned owl 0:04:36.445 --> 0:04:38.445 we had, you know, as a pet in the home, 0:04:38.845 --> 0:04:43.845 a raccoon, squirrel, you name the snake species, we had it. 0:04:44.245 --> 0:04:49.285 We had a cayman brought he brought home an and eater. So, 0:04:49.325 --> 0:04:53.245 of course Derek wanted to be a veterinarian until I 0:04:53.365 --> 0:04:56.365 took a molecular biology course. Well it's a greade eleven 0:04:56.405 --> 0:05:00.445 biology in high school. My teacher started to teach us 0:05:00.485 --> 0:05:03.045 about molecular biology. He had just come out of college 0:05:03.045 --> 0:05:05.605 and it was the early days of molecular biology, and 0:05:05.645 --> 0:05:09.485 he started telling us about DNA replication and mRNA and 0:05:09.565 --> 0:05:14.725 protein synthesis. Derek was hooked. He trained as a molecular 0:05:14.725 --> 0:05:18.445 biologist at the University of Toronto, then moved to Helsinki, 0:05:18.525 --> 0:05:21.325 Finland to get a PhD. He did a fellowship at 0:05:21.365 --> 0:05:24.445 Stanford on stem cell biology, and then soon after he 0:05:24.445 --> 0:05:27.445 heard that lecture about Shinya Yamanaka, he moved to Harvard 0:05:27.485 --> 0:05:30.725 to teach. So if you took a skin cell, which 0:05:30.885 --> 0:05:33.445 normally would live its whole hyphasis skin cell and wouldn't 0:05:33.485 --> 0:05:36.645 turn into anything else, now Yamanaka could turn it into 0:05:36.765 --> 0:05:39.845 something that cell type. Now that could become a hard cell, 0:05:40.005 --> 0:05:44.565 or a brain cell, or a liver cell. So Yamanaka 0:05:44.605 --> 0:05:46.445 publishes his paper and then the whole world is all 0:05:46.485 --> 0:05:49.165 of a sudden using this technology to make pluripotent stem 0:05:49.205 --> 0:05:53.005 cells to study disease and drug mechanisms and tissue engineering. 0:05:53.605 --> 0:05:57.205 It's an enormous leap in medicine. It was that pervasive 0:05:57.285 --> 0:06:02.325 and that applicable to so many different aspects of the 0:06:02.485 --> 0:06:06.205 work that many different biologists were doing, from you know, 0:06:06.525 --> 0:06:10.765 studying cell identity, to modeling disease in a dish, to 0:06:12.125 --> 0:06:17.805 screening for therapeutics to move the needle on a particular disease. 0:06:19.485 --> 0:06:21.645 When Derek started his own lab in two thousand and seven, 0:06:21.685 --> 0:06:24.365 at Harvard, he and his colleagues took up a project 0:06:24.445 --> 0:06:29.445 inspired almost entirely by Yamanaka's work, But there was one 0:06:29.485 --> 0:06:33.365 major drawback to Yamanaka's method. To get cells to regress 0:06:33.445 --> 0:06:36.245 to their embryonic like state, you had to use a 0:06:36.325 --> 0:06:40.045 retrovirus that's a virus that inserts its RNA into your cells, 0:06:40.605 --> 0:06:45.765 like coronavirus. To make the regress happen, Yamanaka added four 0:06:45.845 --> 0:06:48.925 genes into a cell. They came to be known as 0:06:49.005 --> 0:06:52.685 the four Yamanaka factors. But adding those genes means you 0:06:52.845 --> 0:06:57.565 risked creating cancerous cells that would obviously not fly for 0:06:57.725 --> 0:07:01.805 human patients. As we mentioned last episode, the saying amongst 0:07:01.805 --> 0:07:06.485 scientists is that DNA makes RNA, makes protein, makes life. 0:07:06.965 --> 0:07:10.525 I call it the trifect of life. DNA makes mRNA, 0:07:10.885 --> 0:07:15.205 makes protein, makes life. What Yamanaka was doing was inserting 0:07:15.285 --> 0:07:18.405 strands of DNA into cells in order to change them. 0:07:19.885 --> 0:07:22.725 But in between inserting the DNA and the cell's changing, 0:07:23.245 --> 0:07:28.005 there's a fundamental intermediary step. The cell has to interpret 0:07:28.045 --> 0:07:30.445 what the DNA is saying, and it does this by 0:07:30.525 --> 0:07:36.085 turning DNA into messenger RNA or mRNA, so that messenger 0:07:36.205 --> 0:07:39.885 rna is basically a readable copy of the DNA. It's 0:07:39.885 --> 0:07:42.445 the mRNA that instructs the cell to revert to its 0:07:42.525 --> 0:07:47.445 immature state. But remember, inserting DNA was too dangerous, so 0:07:47.645 --> 0:07:51.565 Derek's big change to Yamanaka's process was to just skip 0:07:51.685 --> 0:07:55.845 that step. Post hocrofello. In my lab, doctor Luigi Warren 0:07:56.325 --> 0:07:59.125 had the idea, very simple idea, just saying, hey, you 0:07:59.205 --> 0:08:02.605 know we need to make these transcription factors. Let's just 0:08:02.725 --> 0:08:06.165 skip the whole DNA part. Let's just use mRNA bypass 0:08:06.245 --> 0:08:10.205 the DNA and get the mRNA into the cell. I'm 0:08:10.245 --> 0:08:12.485 going to get a bit technical here, but I think 0:08:12.525 --> 0:08:17.045 it'll be worth it. Most DNA, which stores our genetic information, 0:08:17.805 --> 0:08:21.205 lives in the nucleus of cells. When DNA converts into 0:08:21.285 --> 0:08:25.205 messenger RNA, that also happens in the nucleus, but then 0:08:25.245 --> 0:08:28.325 it migrates to the cytoplasm. That's a thick fluid that 0:08:28.365 --> 0:08:32.525 fills the cell. It's where proteins are made. When Derek 0:08:32.565 --> 0:08:35.285 and his team wanted to send instructions to cells, they 0:08:35.365 --> 0:08:38.085 needed to get mRNA straight into the cytoplasm of the 0:08:38.125 --> 0:08:40.885 cells they were using in the lab. The problem, though, 0:08:40.885 --> 0:08:45.485 arose when we introduced the RNA into cells in the dish. 0:08:46.165 --> 0:08:49.445 What we were doing now was bringing it from outside 0:08:49.485 --> 0:08:52.765 the cell to the inside of the cell. And the 0:08:52.925 --> 0:08:56.565 challenge that we face though, was that the cells didn't 0:08:56.645 --> 0:09:00.045 like that at all. When Derek tried to put mRNA 0:09:00.605 --> 0:09:05.325 messenger ribonucleic acid right into some cells, the cells thought 0:09:05.325 --> 0:09:08.525 they are being attacked. To the cell, it looks like 0:09:08.605 --> 0:09:12.605 an invading virus, quite frankly, which caused the cell to 0:09:12.765 --> 0:09:15.685 respond by saying, Oh, looks like a virus is coming in. 0:09:15.925 --> 0:09:19.205 Let's kill our celves, you know, an altruistic suicide and 0:09:19.885 --> 0:09:22.165 cell death, which is a good thing for the cell 0:09:22.245 --> 0:09:25.445 to do, you know, rather than let it be hijacked 0:09:25.485 --> 0:09:28.045 by a virus and have it made hundreds of thousands 0:09:28.085 --> 0:09:32.165 of viral protocols. Again, Derek and his team weren't putting 0:09:32.245 --> 0:09:36.205 viruses into cells, just some snippets of RNA, but the 0:09:36.285 --> 0:09:39.245 cells thought it was a virus, so they needed to 0:09:39.285 --> 0:09:42.045 work around a better way to get RNA into cells. 0:09:43.325 --> 0:09:46.205 It turned out that a workaround already existed and have 0:09:46.285 --> 0:09:54.365 been sitting around waiting for someone to use it. Catalan Corrico, 0:09:55.045 --> 0:09:58.405 Hungarian immigrant and daughter of a butcher, was a floundering 0:09:58.525 --> 0:10:02.645 scientist obsessed with RNA. She'd been working with RNA since 0:10:02.685 --> 0:10:05.965 the nineteen eighties, floating from lab to lab, unable to 0:10:06.045 --> 0:10:08.445 get one of her own. Instead, she had to work 0:10:08.525 --> 0:10:12.965 under other seemingly more successful scientists. Many times now they 0:10:13.085 --> 0:10:18.125 describe my life story, it sounds like, you know, struggle 0:10:18.285 --> 0:10:21.645 and very difficult. Doctor Kurka was on break with her 0:10:21.685 --> 0:10:24.165 new grandchild when we reached out. But here she is 0:10:24.205 --> 0:10:27.565 in an online Q and A. But let me say 0:10:27.685 --> 0:10:32.365 in advance, even if you know things didn't work out 0:10:32.485 --> 0:10:36.365 how I expected, I was always happy, happy in the lab. 0:10:38.045 --> 0:10:40.565 RNA was not exactly a hot topic during much of 0:10:40.605 --> 0:10:44.125 her early career. It was unstable and very difficult to 0:10:44.165 --> 0:10:48.485 work with, as Derek Rossi discovered, but Karko was obsessed 0:10:48.525 --> 0:10:50.925 with it and believed RNA could be used to instruct 0:10:50.965 --> 0:10:54.405 the body to make its own medicines. One day after 0:10:54.525 --> 0:10:58.325 losing it another lab position, she met Drew Wiseman, a 0:10:58.485 --> 0:11:00.845 researcher looking to make a vaccine for HIV at the 0:11:00.925 --> 0:11:04.605 University of Pennsylvania. Kariko told Wiseman that she could make 0:11:04.645 --> 0:11:08.365 anything with m RNA. They teamed up, but they ran 0:11:08.445 --> 0:11:12.205 into the same issues that Derek Rossi would later when 0:11:12.245 --> 0:11:16.045 Corico and Weissmann injected mRNA into mice, their cells saw 0:11:16.125 --> 0:11:21.165 invaders and their immune systems attacked it. But they knew 0:11:21.325 --> 0:11:25.085 that cells didn't treat all RNA as invaders. They had 0:11:25.125 --> 0:11:28.485 to figure out why. It turns out that a component 0:11:28.565 --> 0:11:33.045 of some types of RNA, a molecule called pseudouridine, can 0:11:33.125 --> 0:11:38.565 help evade an immune system reaction. In other words, if 0:11:38.605 --> 0:11:41.245 they added pseudouridine to the mr anda they were trying 0:11:41.285 --> 0:11:44.325 to get into mouse cells, the cells would stop thinking 0:11:44.365 --> 0:11:47.845 of it as an invader. Pseudouridine acted as a cloak. 0:11:48.725 --> 0:11:52.125 And so we published the paper into CELS and five 0:11:52.285 --> 0:11:55.085 and the drew said that, no, no, we can prepare. 0:11:55.445 --> 0:11:59.525 People are inviting us everywhere. Oh waited. I mean we 0:11:59.645 --> 0:12:01.765 did a lot of experts not sitting and waiting. But 0:12:01.965 --> 0:12:05.525 you know, a couple of years best nobody cared, but 0:12:05.605 --> 0:12:08.845 Derek Rossi cared. He read about Carrico and Weisman's cloaking 0:12:08.885 --> 0:12:11.925 method and integrated it into his own work. And so 0:12:12.205 --> 0:12:14.285 when we read that study, we thought, well, maybe we 0:12:14.325 --> 0:12:19.285 could use these modified nucleosides to get mr ANDA into cells, 0:12:19.805 --> 0:12:24.725 to get past these ancient sort of sensing mechanism rather 0:12:24.845 --> 0:12:28.045 than killing the cells, because quite frankly, prior to doing that, 0:12:28.165 --> 0:12:30.645 we killed a lot of cells in the dish as 0:12:30.685 --> 0:12:33.085 a way of seeing if their MR and A modifications 0:12:33.205 --> 0:12:37.405 worked in mice cells. Derek and Luigi Warren, his post doc, 0:12:37.965 --> 0:12:42.925 would test it to create green fluorescent protein, literally coming 0:12:43.005 --> 0:12:46.885 from jellyfish. Green fluorescent protein is sort of a standard 0:12:46.925 --> 0:12:50.045 way of seeing if a protein creating method works in 0:12:50.125 --> 0:12:53.525 a lab. If you shine some uvy light on them, 0:12:53.885 --> 0:12:56.485 they'll glow green under the microscope and you can see 0:12:56.565 --> 0:13:00.485 if your experiment works. Before they found Carrico and Weisman's 0:13:00.525 --> 0:13:04.205 work on pseudourdine, they only got a little green, But 0:13:04.325 --> 0:13:08.965 once they modified the RNA to include pseudouridine, things changed. 0:13:09.205 --> 0:13:11.325 We could now get a lot of green cells in 0:13:11.405 --> 0:13:15.445 the dish and very happily surviving and not dying anymore. 0:13:16.565 --> 0:13:19.565 That was the technological breakthrough that led to the development 0:13:19.765 --> 0:13:25.005 of modified RNA in the lab. They called it mod RNA. 0:13:26.245 --> 0:13:28.445 So now Derek had a working method for putting the 0:13:28.525 --> 0:13:32.365 four Yama naka factors into human skin cells and turning 0:13:32.405 --> 0:13:36.725 them into immature embryonic like cells. Those cells could then 0:13:36.805 --> 0:13:39.725 theoretically be turned into whatever types of cells they wanted. 0:13:41.565 --> 0:13:44.605 For his work modifying RNA, Derek was named one of 0:13:44.645 --> 0:13:47.245 the hundred most influential people in the World by Time 0:13:47.325 --> 0:13:50.565 magazine in twenty eleven. The potential to do great things 0:13:50.725 --> 0:13:53.325 was there, but first he wanted to turn his modified 0:13:53.445 --> 0:13:56.565 RNA methods into a business, so he got a meeting 0:13:56.645 --> 0:13:59.685 with one of the biggest serial entrepreneurs of our time. 0:14:04.725 --> 0:14:08.325 An article in Harvard Business Review calls Bob Langer the 0:14:08.565 --> 0:14:12.685 Edison of medicine. He's taught at MIT for decades and 0:14:12.805 --> 0:14:16.165 as head of the eponymous Langer Lab, which churns out 0:14:16.245 --> 0:14:21.885 new biotechnologies like a revd up vending machine. You know, 0:14:21.965 --> 0:14:25.645 it's very interdisciplinary, and the kinds of problems we try 0:14:25.685 --> 0:14:27.885 to do is it's still i would say, very basic 0:14:28.365 --> 0:14:32.245 science and engineering, but basically to try to make discoveries 0:14:32.405 --> 0:14:35.165 or create technologies that we feel can have a big 0:14:35.205 --> 0:14:38.485 impact on the world. That's a little bit about the lab. 0:14:39.285 --> 0:14:42.525 Bob has more than fourteen hundred pending or granted patents 0:14:42.805 --> 0:14:46.005 and is the most cited engineer in history. His lab 0:14:46.045 --> 0:14:48.245 has had a thousand or so students come through it 0:14:48.325 --> 0:14:51.445 over the years, and together with Bob, the lab has 0:14:51.485 --> 0:14:55.125 produced more than forty companies worth many billions of dollars. 0:14:55.605 --> 0:14:58.045 That's been wonderful. I mean, I think those companies can 0:14:58.125 --> 0:15:00.685 take some of the discoveries we make in academia and 0:15:01.005 --> 0:15:03.085 get them out to the world. And there's nothing I 0:15:03.205 --> 0:15:06.085 think more satisfying to the students who've worked these projects 0:15:06.125 --> 0:15:08.885 and to see that happen and me too. In other words, 0:15:09.485 --> 0:15:12.405 Bob is a super producer or a super supporter of 0:15:12.485 --> 0:15:16.085 both technologies and businesses, mostly to do with medicines and 0:15:16.165 --> 0:15:18.685 tissue engineering, but he's also worked in the hosts of 0:15:18.725 --> 0:15:21.725 other fields, like a couple of years ago he helped 0:15:21.765 --> 0:15:24.725 develop a technique for giving people invisible tattoos that contain 0:15:24.765 --> 0:15:27.285 their medical history. And then there's that time he started 0:15:27.285 --> 0:15:30.645 a company with Jennifer Aniston. We actually even got into 0:15:30.765 --> 0:15:34.165 cosmetics once. We started a company with Jennifer Aniston, and 0:15:34.245 --> 0:15:38.325 that's so called Living Proof, and so it's, you know, 0:15:38.885 --> 0:15:42.085 to help people have less fisty hair and better hair 0:15:42.245 --> 0:15:45.245 and stuff like that. It started when one of Bob's 0:15:45.285 --> 0:15:47.605 former students came to see him one day and was like, 0:15:48.325 --> 0:15:50.365 let's do some stuff with hair. So we took a 0:15:50.445 --> 0:15:55.165 more fundamental look about why what causes FRIZ and basically 0:15:55.285 --> 0:15:58.765 came up with some materials that are much more hydrophobic, 0:15:59.085 --> 0:16:01.485 you know what, are repellent than what anybody ever did 0:16:01.565 --> 0:16:07.965 before their solution scanning for approved compounds that were hydrophobic 0:16:08.325 --> 0:16:13.045 and approved for human use, and found ones that were, 0:16:13.445 --> 0:16:16.805 you know, super super hydrophobic, almost like as hydrophobic as 0:16:16.845 --> 0:16:19.445 a teflon frying pan. And we tried it and it 0:16:19.525 --> 0:16:21.765 worked really well. We got patents for it, and it 0:16:22.045 --> 0:16:24.325 became very popular. It's actually used all over the world. 0:16:25.285 --> 0:16:27.125 They also came up with a product to give hair 0:16:27.245 --> 0:16:29.885 more body, and then they just needed a famous backer. 0:16:30.525 --> 0:16:32.845 Some of the business people and the company, I guess 0:16:32.885 --> 0:16:36.965 talked to some of Jennifer Anderson's agents, and he got 0:16:37.085 --> 0:16:39.045 very excited about it. She actually came to my office 0:16:39.085 --> 0:16:43.725 several times and actually asked really good questions. In twenty ten, 0:16:43.965 --> 0:16:47.885 Bob Langer started yet another company. Derek Rossi, who was 0:16:47.965 --> 0:16:52.445 a young professor at Harvard and came to see me 0:16:52.845 --> 0:16:56.085 because he'd made a discovery that he could put certain 0:16:56.165 --> 0:17:01.925 types of modified Messenger RNA in cells and make them 0:17:03.045 --> 0:17:08.405 more like a stem cell. Here's Derek I was showing 0:17:08.485 --> 0:17:13.485 the science to a colleague Kim Springer, who had experience 0:17:13.525 --> 0:17:16.045 in biotech. He put me in touch with Bob Langer Earthly. 0:17:16.085 --> 0:17:18.285 He said, oh, let's go get Bob's opinion on this. 0:17:18.965 --> 0:17:22.405 So he emailed Bob, and then Tim and I traveled 0:17:22.445 --> 0:17:25.725 over to Bob's office. Bob and Derek met, and Derek 0:17:25.765 --> 0:17:29.925 explained the science, and Bob's reaction was, this is terrific. 0:17:30.045 --> 0:17:31.925 What can I do to help? I just thought, what 0:17:32.325 --> 0:17:33.965 can Bob do to help? And then I thought, well, 0:17:33.965 --> 0:17:35.765 why don't I ask him to co found this company 0:17:35.845 --> 0:17:41.965 with me? Because you know he's a delivery expert. When 0:17:42.005 --> 0:17:45.405 Derek calls Bob Langer a delivery expert, he doesn't mean 0:17:45.485 --> 0:17:48.965 he works for ups. Since the mid nineteen seventies, Bob 0:17:49.045 --> 0:17:51.605 has been a pioneer in several methods of drug delivery. 0:17:52.525 --> 0:17:55.405 Drug delivery means getting a medicine to its intended target 0:17:55.445 --> 0:17:57.685 in the body, whether it's a certain part of the 0:17:57.725 --> 0:18:00.685 brain or the liver, or to attack cancrous cells in 0:18:00.725 --> 0:18:04.485 the skin. Drug delivery can also mean delivering the drug 0:18:04.605 --> 0:18:10.605 consistently for time. That's called controlled release drug delivery. Bob 0:18:10.765 --> 0:18:13.925 is sort of the founder of controlled delivery, a technology 0:18:14.005 --> 0:18:17.005 that allows the large molecules of a drug to disperse 0:18:17.125 --> 0:18:21.285 slowly into the body. Drug delivery can also mean protecting 0:18:21.325 --> 0:18:24.005 the actual substance of a drug so that it can 0:18:24.085 --> 0:18:26.365 get to its target in the body without degrading or 0:18:26.445 --> 0:18:31.325 falling completely apart. Bob has used most of these delivery 0:18:31.365 --> 0:18:33.845 methods in his work, and here's some of the super 0:18:33.885 --> 0:18:37.925 cool technologies. He's helped develop. An implanted wafer that can 0:18:38.005 --> 0:18:42.005 deliver chemotherapy directly to a brain tumor, contact lenses that 0:18:42.125 --> 0:18:46.005 can deliver drugs through the eyes, controlled release systems that 0:18:46.165 --> 0:18:49.365 use magnetism to increase the release of drugs in your body. 0:18:51.325 --> 0:18:53.845 A huge part of Bob's work in drug delivery has 0:18:53.885 --> 0:18:59.925 been with LNPs lipid nanoparticles. They're fatty spheres that carry 0:19:00.045 --> 0:19:03.485 drugs into the body and that work really well carrying 0:19:03.645 --> 0:19:09.045 DNA or RNA. Researchers, not just Bob, have been looking 0:19:09.045 --> 0:19:13.365 at LMP's for drug delivery for decades. They play an 0:19:13.405 --> 0:19:17.765 indispensable role in the mr anda COVID nineteen vaccines, allowing 0:19:17.845 --> 0:19:21.765 the RNA to deliver its spike building instructions into our cells. 0:19:23.325 --> 0:19:25.685 And to learn a bit more about them, I spoke 0:19:25.725 --> 0:19:32.805 with another expert on LMPs. The much larger challenge was 0:19:32.925 --> 0:19:39.285 to identify carriers systems that could deliver biological molecules inside cells, 0:19:39.765 --> 0:19:44.525 and being able to do that efficiently has taken decades 0:19:44.725 --> 0:19:50.205 to accomplish. That's doctor Thomas Madden. Thomas is a biochemist 0:19:50.285 --> 0:19:53.165 and he's worked in the biotechnology field for like thirty years. 0:19:54.005 --> 0:19:59.365 He's president and CEO of Acutous Therapeutics in Vancouver. Acutus 0:19:59.485 --> 0:20:03.605 provides the lipid nanoparticle technology used in the mRNA based 0:20:03.725 --> 0:20:07.525 Fiser vaccine. The vaccine itself was actually developed by a 0:20:07.565 --> 0:20:12.645 German company called Bioentech. Thomas was introduced to Biointech by 0:20:12.725 --> 0:20:16.325 Catlin Corrico. I asked Thomas to break down what a 0:20:16.365 --> 0:20:21.285 lipid nanoparticle is. The nano refers to the fact that 0:20:21.445 --> 0:20:26.605 the size range of these particles is in the nanomesa range, 0:20:27.045 --> 0:20:30.805 So typically these particles are less than one hundred nanometers 0:20:30.885 --> 0:20:34.765 and so that's why we were referred to it as nanoparticles. 0:20:36.845 --> 0:20:40.765 A nanometer is a billionth of a meter. Lipids are 0:20:40.925 --> 0:20:44.805 organic compounds that are insoluble in water but soluble in 0:20:44.925 --> 0:20:49.045 other solutions. A lot of natural oils like olive oil 0:20:49.205 --> 0:20:53.405 and canola oil and waxes like carnabo wax or bees wax. 0:20:54.005 --> 0:21:00.005 Those are all lipids. They're tiny lipid spheres, you know, 0:21:00.125 --> 0:21:02.405 they're less than a thousandth of the width of a hair, 0:21:02.885 --> 0:21:06.445 and they have four different composed us that are all 0:21:06.565 --> 0:21:10.685 required in order for them to work effectively. So they 0:21:11.045 --> 0:21:15.205 have two lipids that are actually naturally occurring lipids. One 0:21:15.285 --> 0:21:20.805 is cholesterol and another is caught diasterol phosphatyl choline. It's 0:21:20.805 --> 0:21:24.725 a lipid that's found in our membranes, are biological membranes naturally. 0:21:26.125 --> 0:21:30.245 LMPs also of two proprietary lipids, basically the secret formula 0:21:30.285 --> 0:21:33.965 lipids that each maker of lipid natal particles uses lipids 0:21:34.045 --> 0:21:37.885 that allow it to have the functionality that it needs. 0:21:38.765 --> 0:21:42.085 Thomas couldn't talk specifics about this, but he did describe 0:21:42.125 --> 0:21:46.125 these ingredients of LMPs in broader terms. The most important 0:21:46.165 --> 0:21:50.005 one of these is caught an ionizable lipid, and it's 0:21:50.085 --> 0:21:54.325 the lipid that really determines how effectively it looks like 0:21:54.525 --> 0:21:58.085 a protein, how effectively it's taken up into cells, and 0:21:58.285 --> 0:22:02.205 also how effectively it can allow the payload the drug 0:22:02.645 --> 0:22:05.525 to be released into the interior of the cell. The 0:22:05.645 --> 0:22:09.485 fourth component is called a peg lipid, and it's really 0:22:09.965 --> 0:22:13.445 it coats the outside of the particle and it's intended 0:22:13.525 --> 0:22:17.245 primarily to stabilize the particle when it's formed, and when 0:22:17.285 --> 0:22:22.365 the drug is loaded inside, and during storage of the 0:22:22.525 --> 0:22:28.285 vaccine or the therapeutic. So what he's saying is you 0:22:28.405 --> 0:22:31.325 need to protect the mr anda from falling apart before 0:22:31.405 --> 0:22:35.085 it reaches the cell. That's one job of lnp's The 0:22:35.205 --> 0:22:38.405 second job is getting the mRNA into our cells. The 0:22:38.605 --> 0:22:41.925 LNPs needs to be recognized by human cells, or else 0:22:42.005 --> 0:22:44.245 the cells will just ignore them and not get any 0:22:44.285 --> 0:22:47.885 instructions from the mr anda encapsulated within them. The way 0:22:47.965 --> 0:22:50.645 they do this is to make the LMP spheares resemble 0:22:50.765 --> 0:22:54.965 something called lipoproteins, which cells recognize and use to get 0:22:55.045 --> 0:22:57.965 nutrients they need. So Acutus makes the surface of an 0:22:58.085 --> 0:23:02.245 LMP look like the surface of a natural lipoprotein. And 0:23:02.685 --> 0:23:05.925 when it has that surface characteristic, then there's just a 0:23:06.005 --> 0:23:11.285 particular protein in the blood called apoe which will bind 0:23:11.365 --> 0:23:15.205 to it, and that apoe is then recognized by cells. 0:23:15.245 --> 0:23:18.405 There are receptors for it on the external surface of 0:23:18.485 --> 0:23:21.405 the cells, so it'll bind to the cells and basically 0:23:21.445 --> 0:23:24.125 tell the cells, you know, take me up. I've got 0:23:24.205 --> 0:23:29.725 a a parcel containing lipids for you that you need 0:23:30.285 --> 0:23:33.845 for metabolism. So we take advantage of that natural uptake 0:23:34.485 --> 0:23:39.125 mechanism in order to you know, get these particles into 0:23:39.205 --> 0:23:42.685 a cell. In case all of that was a little 0:23:42.725 --> 0:23:45.365 too in the weeds, Thomas Madden sums it up with 0:23:45.445 --> 0:23:50.365 a nice metaphor, you know, a really a good analogy 0:23:50.565 --> 0:23:53.685 for for what our technology does. That's like a real 0:23:53.805 --> 0:23:58.525 world example is if if you wanted to order a 0:23:58.645 --> 0:24:02.805 really fragile glass ornament online and you wanted it delivered 0:24:02.845 --> 0:24:06.445 to your to your home. If you use the equivalent 0:24:06.525 --> 0:24:10.605 of our delivery technology, then the ornament would be would 0:24:10.605 --> 0:24:14.005 be wrapped and packaged to protect it, and about how 0:24:14.125 --> 0:24:18.365 rough the journey was to your to your house. The 0:24:18.605 --> 0:24:23.205 package would would find your house, it would open the 0:24:23.285 --> 0:24:26.285 front door by itself and let itself in, and then 0:24:26.325 --> 0:24:29.725 it would unwrap itself. So the ornament is waiting for 0:24:29.765 --> 0:24:32.325 you to come along and pick up in your hallway. 0:24:33.605 --> 0:24:49.525 Lipid nanoparticles the FedEx of vaccines. When Derek Rossi went 0:24:49.565 --> 0:24:51.965 to Bob Langer's office to present his idea for a 0:24:52.045 --> 0:24:55.925 company that uses modified RNA to create new drugs. He 0:24:56.085 --> 0:24:58.805 knew that Bob was a pioneer in delivering drugs into 0:24:58.845 --> 0:25:02.245 the body. The Languor Lab had developed the first nanoparticles 0:25:02.285 --> 0:25:05.765 that could deliver nucleic acids like RNA and many of 0:25:05.845 --> 0:25:08.725 the principles and components behind the LMPs that are now 0:25:08.925 --> 0:25:12.565 used in the mr anda COVID vaccines. And so in 0:25:12.645 --> 0:25:16.005 the summer of twenty ten, Bob and Derek and another 0:25:16.045 --> 0:25:18.925 scientist they brought in named Kenneth Chen got some funding 0:25:18.965 --> 0:25:23.005 from a venture capital firm then called Flagship Ventures, and 0:25:23.165 --> 0:25:26.805 together they started a company. But it wasn't much of 0:25:26.885 --> 0:25:30.165 a company at first. There were no full time employees, 0:25:30.605 --> 0:25:34.045 There was no office. And how many people worked at 0:25:34.085 --> 0:25:36.125 the company when it was first founded. Was it literally 0:25:36.165 --> 0:25:38.205 just the four of you or was there a whole 0:25:38.205 --> 0:25:40.925 staff at the first No, it was nobody other I mean, 0:25:41.045 --> 0:25:42.805 and we weren't none of us were full time. I 0:25:42.845 --> 0:25:46.605 mean basically we would meet in Flagship's offices or my 0:25:46.805 --> 0:25:50.925 office and you know, and just brainstorm, and you know, 0:25:51.005 --> 0:25:53.845 that was probably the first six months. And back to Derek, 0:25:54.605 --> 0:25:57.285 I kept my day job in academia, so I was 0:25:57.325 --> 0:26:00.685 always you know, had my professorship at the med school. 0:26:01.885 --> 0:26:06.125 Eventually the company did have a name. Maderna comes from 0:26:06.165 --> 0:26:09.045