WEBVTT - The Super Episode 0:00:08.245 --> 0:00:14.805 School of Humans. This is the tenth and final episode 0:00:14.845 --> 0:00:17.765 of Long Shot, and this time around, I want to 0:00:17.765 --> 0:00:21.005 do something different. We've covered a lot of vaccine ground 0:00:21.045 --> 0:00:24.405 in this series, starting thousands, even millions of years ago 0:00:24.765 --> 0:00:27.045 and bringing it forward to the pandemic days we're still 0:00:27.085 --> 0:00:31.405 living in. In this super episode of Long Shot, we'll 0:00:31.405 --> 0:00:33.725 go over all the coolest things from the series and 0:00:33.845 --> 0:00:36.565 fill in a few gaps along the way. It's gonna 0:00:36.605 --> 0:00:38.965 move pretty fast, but if you're listening to this series, 0:00:39.045 --> 0:00:42.445 your brain probably moves pretty fast too. From School of 0:00:42.485 --> 0:00:46.325 Humans and iHeartRadio, I'm Sean Revive and this is Long Shot. 0:00:51.965 --> 0:00:56.005 Let's get this party started two ninety three million years ago. 0:00:56.725 --> 0:00:59.645 That's when Joel Wertheim, an associate professor of Medicine at 0:00:59.685 --> 0:01:04.605 UC San Diego, estimates coronavirus has first appeared. Our estimates 0:01:04.845 --> 0:01:08.325 put the incestor of all coronaviruses at hundreds of millions 0:01:08.325 --> 0:01:11.205 of years old, which actually would line up with the 0:01:11.245 --> 0:01:16.045 split between bats and birds or their divergence. Now, as 0:01:16.125 --> 0:01:18.365 much as I'd like to think, in all of that 0:01:18.525 --> 0:01:21.485 noise and all of that uncertainty, we managed to hit 0:01:21.525 --> 0:01:24.085 the nail on the head going back hundreds of millions 0:01:24.085 --> 0:01:28.045 of years and identifying the split between bats and birds. 0:01:28.245 --> 0:01:32.685 I just think that that's a lucky happenstance, and nobody 0:01:32.725 --> 0:01:35.725 knows how old they are. Okay, so he's not really 0:01:35.765 --> 0:01:38.245 sure about that number, but it's probably safe to say 0:01:38.285 --> 0:01:41.805 that coronavirus has first appeared millions of years ago. But 0:01:41.925 --> 0:01:45.285 the practice of innoculation, the prevention of disease through contraction 0:01:45.325 --> 0:01:50.565 of that disease, doesn't start with coronaviruses. It starts with smallpox. Yep. 0:01:50.805 --> 0:01:55.005 Smallpox one of the deadliest diseases in human history, killer 0:01:55.045 --> 0:02:01.005 of hundreds of millions of people. Smallpox probably predates written history, 0:02:01.605 --> 0:02:04.565 but some Egyptian mummies were found with signs of smallpox. 0:02:05.485 --> 0:02:08.325 There are written descriptions of smallpox from seventh century India, 0:02:09.205 --> 0:02:11.365 so we know it goes back many hundreds of years 0:02:11.405 --> 0:02:16.685 at least. But what about smallpox inoculation. There's a legend 0:02:16.685 --> 0:02:20.885 about smallpox inoculators living unmountain in China about the millennium ago. 0:02:22.485 --> 0:02:27.005 The son of a local governor got very sick from smallpox, 0:02:27.805 --> 0:02:31.045 which by len had to plague the China for at 0:02:31.205 --> 0:02:35.805 least a thousand the years. The governor offered the piles 0:02:35.845 --> 0:02:39.325 of gold to anyone who could help. He's his son. 0:02:41.365 --> 0:02:44.725 Real documentation of inoculation comes about five hundred years later 0:02:44.925 --> 0:02:47.645 in a fifteen forty nine medical text by a Ming 0:02:47.725 --> 0:02:51.965 dynasty physician. Things start getting less hazy in the sixteen hundreds. 0:02:52.605 --> 0:02:55.685 In sixteen eighty, in an ooculator named fushang Lin is 0:02:55.765 --> 0:02:58.525 chosen by an emperor in China to protect his children. 0:02:59.285 --> 0:03:03.645 Lo the Conci emperor, survived the smallpox, he did not 0:03:04.005 --> 0:03:08.085 escape it to trauma. Every time there was an outbreak 0:03:08.085 --> 0:03:12.125 of small pox, he was haunted both by his fallest 0:03:12.205 --> 0:03:16.845 death and by the isolation, and so when he grew 0:03:16.885 --> 0:03:21.485 into an adult, the county emperor searched far and wide 0:03:21.765 --> 0:03:27.405 for the umpire's best inoculators. Thirty five years later, in 0:03:27.485 --> 0:03:32.765 seventeen fifteen, Lady Mary Wortley Montague, a talented British poet 0:03:32.765 --> 0:03:36.845 and young aristocrat, gets smallpox, which is probably the single 0:03:36.885 --> 0:03:40.525 deadliest disease in England at the time. Her symptoms are horrible, 0:03:41.045 --> 0:03:44.725 a wicked fever, a rapid pulse, trouble breathing due to 0:03:44.725 --> 0:03:48.125 the swelling of her nose and throat, liquid filled pustules 0:03:48.125 --> 0:03:52.125 that eventually cover her entire body and face. Lady Mary 0:03:52.165 --> 0:03:55.565 survives the pox, but her face is scarred for life. 0:03:57.365 --> 0:04:00.085 The next year, she moves from London to Constantinople with 0:04:00.125 --> 0:04:04.325 her ambassador husband. There she hears the Turkish have a 0:04:04.365 --> 0:04:08.205 way of protecting against pox. What they do is purposefully 0:04:08.245 --> 0:04:11.725 inject a patient with a little smallpox matter, and that 0:04:11.805 --> 0:04:16.765 gives the patient lifelong protection from full blown smallpox. Two 0:04:16.845 --> 0:04:20.245 years later, in seventeen eighteen, Mary has her five year 0:04:20.245 --> 0:04:23.925 old son inoculated. He may be the first english person 0:04:23.965 --> 0:04:27.405 ever to be inoculated. And when she returns to London, 0:04:27.765 --> 0:04:31.085 she has her daughter inoculated by a surgeon named Charles Maitland. 0:04:32.245 --> 0:04:35.245 He'd go on to perform an innoculation experiment on prisoners 0:04:35.245 --> 0:04:40.645 in seventeen twenty two. Here's historian Arthur Boylson. So six 0:04:40.685 --> 0:04:45.005 of them, all of them quite young, late teens, early twenties, 0:04:45.725 --> 0:04:49.125 and they were all inoculated with a big public spectacle. 0:04:49.205 --> 0:04:52.285 They had all been sentenced to hang from various crimes. 0:04:52.765 --> 0:04:58.605 And the King agreed that he would allow Maitland to 0:04:59.285 --> 0:05:03.605 inoculate some prisoners. And at one point somebody complained to 0:05:03.645 --> 0:05:06.485 the King and said, even that's a fairly nasty thing. 0:05:06.525 --> 0:05:09.725 To do. McKey said, well, it's better than they preferred 0:05:09.765 --> 0:05:14.765 it to hang. Regardless of the ethics of this experiment, 0:05:15.085 --> 0:05:21.085 all six prisoners live and are pardoned. Meanwhile, around this time, 0:05:21.365 --> 0:05:25.645 an enslaved African brings anoculation to the United States. His 0:05:25.725 --> 0:05:28.365 name is One Samous and he's owned by a Puritan 0:05:28.405 --> 0:05:32.845 minister in Boston named Cotton Mather. And One Samous changes 0:05:32.885 --> 0:05:36.925 the course of inoculation history in the US. When Mather 0:05:37.045 --> 0:05:40.365 asks One Samius if he's ever had smallpox, on Samius 0:05:40.365 --> 0:05:44.005 replies both yes and no. He shows Mather a scar 0:05:44.125 --> 0:05:45.925 and says it's from an operation where he got a 0:05:45.965 --> 0:05:48.845 small mountain of smallpox in order to protect him from 0:05:48.845 --> 0:05:54.325 the disease. Years later, when a smallpox outbreak comes to Boston, 0:05:55.045 --> 0:05:58.845 Mather becomes the strongest voice in favor of anoculation, and 0:05:58.965 --> 0:06:02.525 by the time of the American Revolution, General George Washington 0:06:02.565 --> 0:06:06.765 makes an oculation standard practice for soldiers, so he inoculates 0:06:06.805 --> 0:06:10.805 the entire continent alarmy over a period of weeks. Within 0:06:10.845 --> 0:06:16.965 the army, it prevented smallpox, and thereafter inoculation became part 0:06:17.005 --> 0:06:21.525 of the enrollment ritual for new soldiers. They were given 0:06:21.565 --> 0:06:26.365 a shirt and gun shoes and inoculated. It's the reason 0:06:26.485 --> 0:06:31.605 the United States exists. A few decades after Lady Mary 0:06:31.685 --> 0:06:34.725 in the UK and once Amiss in the US, a 0:06:34.805 --> 0:06:37.725 family by the name of Sutton starts at innoculation business 0:06:37.765 --> 0:06:42.845 in rural England, traveling around and inoculating entire towns. They're 0:06:42.885 --> 0:06:48.285 the first inoculation entrepreneurs. It was explosive. There were villages 0:06:48.365 --> 0:06:52.605 all over the country that adopted the Suttonian system. They 0:06:52.685 --> 0:06:55.525 hire a preacher to speak of God's support for the practice. 0:06:56.285 --> 0:07:00.405 This is the way for our escape. Reason directs us 0:07:00.405 --> 0:07:06.965 to it. Experience proves the utility and safety. This sickness, 0:07:07.405 --> 0:07:13.485 as caused by innoculation, is not unto death. The Sutton's 0:07:13.485 --> 0:07:16.685 helped make anoculation to mainstream practice, and by the time 0:07:16.725 --> 0:07:19.765 their work is finished, a new type of smallpox prevention 0:07:19.845 --> 0:07:23.405 is discovered by Edward Jenner. The legend goes that he 0:07:23.485 --> 0:07:26.645 meets a milkmaid with perfect skin and she tells him 0:07:26.645 --> 0:07:29.925 about being exposed to cow pox, which gives her protection 0:07:30.005 --> 0:07:34.245 from smallpox. We all know and believe that beautiful story 0:07:34.285 --> 0:07:37.085 of the milk Maide and how she was gorgeous, but 0:07:37.125 --> 0:07:40.365 it's not true. It's made up. Even if the story 0:07:40.445 --> 0:07:43.925 isn't true, Jenner does pretty much invent vaccination with his 0:07:44.085 --> 0:07:49.405 use of cowpox to fight smallpox. In seventeen ninety six, 0:07:49.725 --> 0:07:53.245 Dinner makes history by testing his vaccine on his Gardner's son, 0:07:53.565 --> 0:08:00.005 eight year old James Phipps, and the boy lives. In 0:08:00.045 --> 0:08:03.965 the eighteen eighties, Louis Pasteur creates vaccines for anthrax and 0:08:04.005 --> 0:08:08.445 then rabies, using the practice of attenuation, weakening the virus 0:08:08.485 --> 0:08:14.285 before injecting it into the body. In nineteen eighteen, the 0:08:14.325 --> 0:08:17.005 Spanish flu arrives and sort of takes over the entire 0:08:17.085 --> 0:08:20.325 world for a couple of years, killing somewhere around fifty 0:08:20.365 --> 0:08:25.805 million people. The next year, Maurice Hilleman is born. Well, 0:08:25.845 --> 0:08:31.645 I'm Marie's Haliman. I had a long career in science, 0:08:31.685 --> 0:08:36.365 about sixty years. Hilleman is the goat of vaccine invention. 0:08:37.445 --> 0:08:41.845 He helps develop most of the vaccines that we get today, measles, rubella, 0:08:41.885 --> 0:08:47.245 hepatitis A, hepatitis B, Beninjacoccus, hib streptococcus, chicken pox. That's 0:08:47.285 --> 0:08:51.965 all him. He also accidentally helps discover ad no viruses 0:08:52.325 --> 0:08:55.805 while culturing the cells of a dead man's trachea. And 0:08:55.885 --> 0:08:58.045 I said, well, I'd like to have his trachia. So 0:08:58.125 --> 0:09:00.645 I went over to the morgue and waited for him 0:09:00.685 --> 0:09:03.925 to carve out the trachea, wrapped it up newspaper and 0:09:04.005 --> 0:09:07.445 brown back the lab, cut dope and start chopping on tissue. 0:09:08.565 --> 0:09:13.565 Some days, you know, everything just goes right. Ad No 0:09:13.725 --> 0:09:16.285 viruses are used today as a delivery system for some 0:09:16.365 --> 0:09:20.445 of the COVID vaccines, like Astra's ENCAS and Johnson and Johnson's. 0:09:21.365 --> 0:09:24.525 Hillman even creates a vaccine from his own daughter's cells 0:09:24.645 --> 0:09:27.805 in nineteen sixty three. The name of the vaccine is 0:09:27.805 --> 0:09:30.205 the Journal and Strain. It's on all of the boxes 0:09:30.205 --> 0:09:33.565 and package inserts that come out. I have had the 0:09:33.565 --> 0:09:36.325 pleasure throughout my life of also being called Miss Mumps, 0:09:36.525 --> 0:09:42.765 and usually by pediatricians. And while Maurice Hillman is doing 0:09:42.805 --> 0:09:45.605 his thing, some other cool things are happening with vaccines. 0:09:47.365 --> 0:09:51.045 By the nineteen forties, we've got new vaccines for diphtheria, tetanus, 0:09:51.085 --> 0:09:54.885 and pertussis. In nineteen fifty five, Jonah Saut comes out 0:09:54.885 --> 0:09:58.605 with his vaccine for polio. There's also some not so 0:09:58.645 --> 0:10:02.725 cool stuff happening when the polio vaccine comes out. One 0:10:02.725 --> 0:10:06.405 of the company's mass producing it cut her laboratory messes 0:10:06.485 --> 0:10:10.765 up and creates tens of thousands of doses containing live poliovirus. 0:10:12.245 --> 0:10:15.365 Fifty one people are paralyzed and five die after getting 0:10:15.405 --> 0:10:19.245 the vaccine meant to prevent polio. And in nineteen sixty six, 0:10:19.325 --> 0:10:22.285 a vaccine trial for respiratories and scial virus and DC 0:10:22.725 --> 0:10:27.285 goes bad. Eighteen babies, mostly from poor black families, end 0:10:27.325 --> 0:10:30.805 up in the hospital and two of them die. RSV 0:10:31.205 --> 0:10:33.605 can be deadly in children, and there is still no 0:10:33.765 --> 0:10:37.285 FDA proof vaccine today. We'll get back to RSP in 0:10:37.285 --> 0:10:42.245 a sec In nineteen eighty, smallpox returns to the news 0:10:42.365 --> 0:10:48.005 when the World Health Assembly officially declares the virus eradicated. Yes, 0:10:48.245 --> 0:10:51.205 after thousands of years, vaccines have ridded the world of 0:10:51.205 --> 0:10:55.645 one of humanity's greatest killers. But HIV and AIDS appear 0:10:55.685 --> 0:10:59.325 around that time. They spread throughout the eighties, at first 0:10:59.325 --> 0:11:02.445 primarily in gay men, but also in intravenous drug users 0:11:02.485 --> 0:11:07.005 and later in countries in Africa. Virologist named Eddie Holmes 0:11:07.125 --> 0:11:10.285 goes to Edinburgh, Scotland to study HIV spread in the 0:11:10.285 --> 0:11:13.645 early nineties. What we were trying to do was trying 0:11:13.645 --> 0:11:16.845 to work out how the virus was spreading through that population, 0:11:16.965 --> 0:11:19.365 how it diffused, and how it got into city, and 0:11:19.445 --> 0:11:22.525 how it spreading. In the nineties, a team at the 0:11:22.645 --> 0:11:26.125 US National Institutes of Health creates a vaccine called rhoda 0:11:26.165 --> 0:11:30.685 Shield to fight a deadly childhood disease called rhodavirus. Rhoda 0:11:30.725 --> 0:11:34.005 Shield gets the nod from the CDC, but within months 0:11:34.365 --> 0:11:37.485 some cases of a rare intestinal disorder pop up and 0:11:37.565 --> 0:11:42.285 the CDC withdraws its recommendation. But all throughout the eighties 0:11:42.285 --> 0:11:44.845 and nineties, another team of researchers is working on a 0:11:44.925 --> 0:11:49.565 rival vaccine for rhodavirus called Rhodotech. That one gets low 0:11:49.605 --> 0:11:52.005 from the FDA and CDC in two thousand and six, 0:11:52.805 --> 0:11:55.365 but not before the biggest clinical trial in the history 0:11:55.405 --> 0:12:01.565 of medicine eleven countries and nearly seventy thousand infants. Here's 0:12:01.605 --> 0:12:04.885 Paul Offitt, one of the developers of Rhodotech, and it 0:12:05.045 --> 0:12:07.525 ended in so called Phase three trial, a prospect the 0:12:07.645 --> 0:12:11.085 placebo control, the eleven country four year, three hundred and 0:12:11.125 --> 0:12:13.885 fifty million dollars trial to prove that the vaccine worked. 0:12:14.365 --> 0:12:17.205 The size of that enormous trial leads to the similarly 0:12:17.285 --> 0:12:20.485 giant trials we have in twenty twenty for the COVID vaccines. 0:12:21.645 --> 0:12:25.565 Johnson and Johnson, Astra, Zeneca, Fizer, Maderna, and others around 0:12:25.605 --> 0:12:28.285 the world are all amongst the largest clinical trials ever. 0:12:29.645 --> 0:12:31.565 In two thousand and two, we get an outbreak of 0:12:31.645 --> 0:12:36.165 severe acute respiratory syndrome the first stars. More than eight 0:12:36.165 --> 0:12:39.085 thousand people in twenty nine countries get it, but by 0:12:39.085 --> 0:12:43.285 two thousand and four it mostly dies out thanks to 0:12:43.325 --> 0:12:46.445 people like Maurice Hilleman. We've got tons of vaccines at 0:12:46.445 --> 0:12:50.005 this point. But in two thousand and six, a new 0:12:50.005 --> 0:12:53.285 discovery leads to all sorts of advances in medicine, including 0:12:53.285 --> 0:12:58.205 the way we make vaccines. That year, Shinya Yamanaka, a 0:12:58.285 --> 0:13:02.605 Japanese researcher, discovers a way to reprogram mature mouse cells 0:13:02.925 --> 0:13:05.925 into immature cells. They can then be turned to whatever 0:13:05.965 --> 0:13:09.845 type of cells he wants. Here's Derek Rossi who's in 0:13:09.885 --> 0:13:14.005 the audience when Yamanaka announces his discovery. So what he 0:13:14.285 --> 0:13:17.805 demonstrated was that he could take any cell type, any 0:13:17.845 --> 0:13:21.525 differentiated cell which would normally we had thought been sort 0:13:21.565 --> 0:13:24.765 of fixed in its identity, but he discovered a way 0:13:24.805 --> 0:13:30.685 by introducing four genes to turn back the developmental time 0:13:30.965 --> 0:13:35.165 on what was differentiated cell type and reverted back to 0:13:35.285 --> 0:13:39.525 an embryonic stem cell like state. Derek is at Harvard 0:13:39.525 --> 0:13:41.685 in two thousand and seven and he wants to build 0:13:41.725 --> 0:13:46.245 upon Yamanaka's work changing mature cells to immature cells. Yamanaka 0:13:46.325 --> 0:13:49.125 is inserting strands of DNA into cells in order to 0:13:49.205 --> 0:13:53.165 change them, but this is dangerous for humans. It could 0:13:53.285 --> 0:13:57.245 give you cancer. So Derek decides to use mRNA instead, 0:13:57.885 --> 0:13:59.525 which is kind of like skipping a step in the 0:13:59.565 --> 0:14:02.525 way that life is made. I call it the trifect 0:14:02.565 --> 0:14:08.485 of life. DNA makes mRNA, protein makes life. Postdoctor Othello. 0:14:08.565 --> 0:14:12.245 In my lab, doctor Luigi Warren had the idea, very 0:14:12.285 --> 0:14:15.045 simple idea, just saying, hey, you know, we need to 0:14:15.085 --> 0:14:19.245 make these transcription factors. Let's just skip the whole DNA part. 0:14:19.365 --> 0:14:22.405 Let's just use m rna. That turns out to be 0:14:22.445 --> 0:14:27.005 a genius move, but he runs into another problem When 0:14:27.045 --> 0:14:30.125 he puts RNA into cells, the cells think they're being 0:14:30.165 --> 0:14:34.405 attacked by a virus, which caused the cell to respond 0:14:34.445 --> 0:14:37.325 by saying, looks like a virus is coming in. Let's 0:14:37.325 --> 0:14:40.765 shut down the protein production. And it really looks like 0:14:40.805 --> 0:14:43.565 a virus is coming in, so let's kill ourselves, you know, 0:14:43.725 --> 0:14:47.725 an altruistic suicide and cell death, which is a good 0:14:47.725 --> 0:14:50.445 thing for the cell to do, you know, rather than 0:14:50.525 --> 0:14:53.045 let it be hijacked by a virus and have it 0:14:53.165 --> 0:14:57.085 make hundreds of thousands of viral particles. He finds a 0:14:57.125 --> 0:15:00.925 workaround from a couple of researchers at the University of Pennsylvania. 0:15:01.325 --> 0:15:05.085 The researchers are Catlin Corrico and Drew Weissman, and they 0:15:05.125 --> 0:15:07.925 figured about a cloaking method for tricking cells into not 0:15:08.005 --> 0:15:11.605 thinking they're being invaded. Derek integrates it into his own 0:15:11.645 --> 0:15:14.605 work and lo and behold, now we can change human 0:15:14.605 --> 0:15:18.645 cells without killing them or causing cancerous mutations. That was 0:15:18.725 --> 0:15:23.165 the sort of technological breakthrough that led to the development 0:15:23.165 --> 0:15:26.645 of modified mRNA. We called it in the lab mod RNA. 0:15:26.725 --> 0:15:29.085 He takes this work down the street to Bob Langer, 0:15:29.725 --> 0:15:33.045 a serial entrepreneur based at MT, and they start a 0:15:33.045 --> 0:15:36.765 company that they eventually name Maderna. By the way, just 0:15:36.925 --> 0:15:40.645 as a a fun fact, you know, Maderna. It comes 0:15:40.685 --> 0:15:43.085 from the term that we used in the lab describing 0:15:43.125 --> 0:15:46.565 the technology. We called it mad RNA. So mod RNA 0:15:46.605 --> 0:15:48.485 if you put any in there, you get Maderna. That's 0:15:48.525 --> 0:15:52.445 where the name came from. At its formation, Maderna has 0:15:52.485 --> 0:15:57.045 exactly zero full time employees and no products. They won't 0:15:57.125 --> 0:16:01.325 have one for ten more years. In two thousand and eight, 0:16:01.605 --> 0:16:05.845 structural biologist Jason McClellan takes a job at the NIH 0:16:06.045 --> 0:16:09.525 where he meets Barney Graham. Graham wants to create a 0:16:09.605 --> 0:16:13.085 vaccine for RSV, which is that virus I mentioned earlier 0:16:13.125 --> 0:16:16.965 that can kill infants. The RSV vaccine that failed back 0:16:16.965 --> 0:16:19.725 in the sixties was made by weakening a strain of 0:16:19.725 --> 0:16:22.765 the virus by passing it through animal tissue or human cells. 0:16:23.245 --> 0:16:25.525 That's how Maurice Hilleman made a lot of his vaccines. 0:16:26.405 --> 0:16:29.005 But Jason and doctor Graham have a new method in mind. 0:16:29.685 --> 0:16:31.885 They want to mess with the F protein of RSV. 0:16:32.805 --> 0:16:35.365 That's the one the virus uses to infect human cells. 0:16:36.445 --> 0:16:39.285 Before the F protein attaches itself to a human cell, 0:16:39.685 --> 0:16:43.045 it is in its prefusion state. If you think of 0:16:43.045 --> 0:16:45.645 your immune system as a security guard, you want to 0:16:45.645 --> 0:16:48.405 train your immune system to recognize the form that might 0:16:48.445 --> 0:16:51.885 infect you, like the dangerous form, and that's the prefusion form. 0:16:51.925 --> 0:16:54.965 If you train it to recognize the postfusion form, the 0:16:55.005 --> 0:16:58.445 prefusion form can still sneak by you. Barney, Graham, and 0:16:58.525 --> 0:17:00.485 Jason want to figure out how to keep the F 0:17:00.645 --> 0:17:04.965 protein in this state, and in twenty thirteen they do. 0:17:06.325 --> 0:17:08.365 They figure out a way to sort of staypule the 0:17:08.365 --> 0:17:12.125 protein so it stays in that form. And when Barney 0:17:12.125 --> 0:17:17.765 immunized mice and compared postfusion versus prefusion, the mice receiving 0:17:17.805 --> 0:17:22.245 the prefusion form of the F protein elicited neutralizing antibodies 0:17:22.245 --> 0:17:26.565 about ten times higher than those that received the postfusion. 0:17:28.125 --> 0:17:31.445 This is the first time that structural biology, looking super 0:17:31.445 --> 0:17:34.165 closely at the structure of a virus helps discover a 0:17:34.165 --> 0:17:36.765 new way to stop it. But now they want to 0:17:36.765 --> 0:17:39.045 see what other viruses they can work on using this 0:17:39.245 --> 0:17:43.085 prefusion protein state. This is right around the time that 0:17:43.165 --> 0:17:47.205 Middle East Respiratory Syndrome is first reported in Saudi Arabia. 0:17:47.485 --> 0:17:51.805 MERS is a really bad coronavirus. Thirty five percent of 0:17:51.845 --> 0:17:55.005 people infected with it we're dying. It's a real lethal virus, 0:17:55.565 --> 0:17:57.965 and we thought that this would be a good target 0:17:58.005 --> 0:18:00.005 to try to take everything we had just learned about 0:18:00.125 --> 0:18:04.285 RSP and apply it to not just MERS, but coronaviruses 0:18:04.365 --> 0:18:07.885 in general, because we knew the Stars coronavirus had emerged 0:18:07.965 --> 0:18:10.805 in China in two thousand and two and it caused 0:18:10.965 --> 0:18:14.805 an epidemic. It turns out that MERS has a protein 0:18:14.885 --> 0:18:17.965 that works kind of like the rsv F protein. It's 0:18:17.965 --> 0:18:21.325 called the spike protein, and when the merge virus attacks 0:18:21.405 --> 0:18:25.005 human cells, the spike injects itself into them in order 0:18:25.045 --> 0:18:28.445 to spread throughout the body. But it's not easy to 0:18:28.525 --> 0:18:32.285 staple the spike protein. It takes tons of trial and error. 0:18:33.405 --> 0:18:37.085 Here's Nanchan Wang Jason's post doc to explain how hard 0:18:37.125 --> 0:18:40.685 it is to figure this out. We got to try 0:18:41.485 --> 0:18:45.005 again and again most of the time. It's got to feel. Yeah, 0:18:45.045 --> 0:18:48.485 it's not so too easy actually to find their mutation 0:18:48.565 --> 0:18:55.325 that to stabilize as product, it's pretty italented. By twenty seventeen, 0:18:55.645 --> 0:18:57.885 they figure out how to staple the spike protein in 0:18:57.965 --> 0:19:00.765 place and use that to teach the immune system to 0:19:00.805 --> 0:19:03.805 fight off a MERGS infection, but they don't have any 0:19:03.805 --> 0:19:06.925 people to test it on. Turns out MERS doesn't spread 0:19:07.005 --> 0:19:09.485 very easily and the outbreak is mostly over by then. 0:19:10.885 --> 0:19:14.645 No outbreak means no human trials, no human trials, means 0:19:14.645 --> 0:19:17.645 they can't be sure that stabilizing the spike protein really 0:19:17.685 --> 0:19:22.365 works as a vaccine candidate. Then in December twenty nineteen, 0:19:22.925 --> 0:19:27.565 a new coronavirus appears. Here's Derek Rossing. You could see that. 0:19:27.965 --> 0:19:30.685 You know, it was really snowballing. I mean it had 0:19:30.725 --> 0:19:34.925 everything that a good pathogen would want. It was a respiratory. 0:19:35.405 --> 0:19:39.125 When it was first being reported, the fatality rates and 0:19:39.205 --> 0:19:42.005 the illness rates were very very high. We didn't, you know, 0:19:42.045 --> 0:19:43.565 it was a new virus. We didn't know how to 0:19:43.565 --> 0:19:46.365 respond to it. So the fatality rate was around two percent. 0:19:46.725 --> 0:20:00.045 That's pretty darn serious. In mid December twenty nineteen, a 0:20:00.085 --> 0:20:03.405 worker at the Huanan seafood wholesale market gets sick with 0:20:03.445 --> 0:20:07.805 theemmonia like symptoms. He's admitted to Central Hospital of Wuha 0:20:08.165 --> 0:20:10.805 and he's one of the first novel coronavirus patients in 0:20:10.845 --> 0:20:15.085 the world. Central hospital happens to be where British phiologist 0:20:15.245 --> 0:20:18.325 Eddie Holmes and it's Chinese colleague Jan Jang Jang are 0:20:18.365 --> 0:20:22.445 studying patients with acute respiratory symptoms around that time. But 0:20:22.685 --> 0:20:25.685 what that meant was we were kind of like on site, 0:20:25.845 --> 0:20:29.645 almost looking at the same Z syndrome in the right 0:20:29.845 --> 0:20:34.165 tissue samples with the right technology, and so we happen 0:20:34.245 --> 0:20:36.765 to be in the wrong place the wrong time. I 0:20:36.765 --> 0:20:39.285 feel like when it all kind of started, and that's 0:20:39.805 --> 0:20:41.725 gave us an open door to really to try and 0:20:41.845 --> 0:20:44.725 look at some of the early first cases to see 0:20:44.725 --> 0:20:47.365 what was going on. Late at night and January fifth, 0:20:47.485 --> 0:20:52.445 twenty twenty, Jang finishes sequencing the virus, but Chinese authorities 0:20:52.445 --> 0:20:54.725 are trying to keep anything related to the virus from 0:20:54.765 --> 0:20:58.245 being made public. The Ministry of Health were controlling everything, 0:20:58.525 --> 0:21:00.965 and they wanted They wanted to control the message, they 0:21:01.005 --> 0:21:03.965 wanted to damp down on rumors, they wanted to be 0:21:04.045 --> 0:21:08.245 in control of the situation. On January eleventh, Jang gets 0:21:08.245 --> 0:21:10.765 on a plane in Shanghai and is about to take 0:21:10.805 --> 0:21:14.925 off when his phone buzzes. It's Eddie. I cooled jan 0:21:15.125 --> 0:21:17.205 very early, and I said we need to release he 0:21:17.325 --> 0:21:20.925 stay tonight. Jang agrees, has a post duct send the 0:21:20.965 --> 0:21:26.045 sequence to Eddie. Eddie tweets out a link. That moment 0:21:26.125 --> 0:21:29.965 kicks off development for the COVID nineteen vaccines, and that's 0:21:30.005 --> 0:21:33.885 exactly what Jason McClellan starts working on the reports were 0:21:33.925 --> 0:21:37.605 coming out of these pneumonia clusters in Wuhan. We could 0:21:37.605 --> 0:21:39.765 just see it following along on science Twitter and on 0:21:39.845 --> 0:21:43.765 the news. And then it was early in January when 0:21:43.925 --> 0:21:46.365 it was learned that, in fact, it is a coronavirus 0:21:46.965 --> 0:21:50.565 beta coronavirus that's similar to the first stars Kobe from 0:21:50.565 --> 0:21:54.045 two thousand and two. Jason's at the University of Texas. Now, 0:21:54.765 --> 0:21:57.485 I was a snowboarding with my family in Park City, Utah, 0:21:57.525 --> 0:22:00.445 and Barney Graham called me. He said he was in 0:22:00.485 --> 0:22:04.765 contact with the US CDC Chinese CDC and they were 0:22:04.765 --> 0:22:08.085 going to try and work quickly work with Maderna try 0:22:08.085 --> 0:22:11.245 and create a vaccine. Maderna is still considered an upstart 0:22:11.285 --> 0:22:14.325 company at best, and it's never brought a vaccine to market. 0:22:14.765 --> 0:22:18.285 Anyone to know if if we were interested in continuing 0:22:18.325 --> 0:22:21.845 our collaboration to determine the structure of the stars cope 0:22:21.845 --> 0:22:26.205 to spike protein and use that information to create the 0:22:26.285 --> 0:22:31.365 vaccine antigens, Jason texts has graduate student Daniel Rep. We 0:22:31.365 --> 0:22:34.725 were sort of ready to go, that's Daniel, because we've 0:22:34.765 --> 0:22:36.845 been studying these spike proteins for such a long time. 0:22:36.885 --> 0:22:39.725 We knew how to effectively stabilize spike in the prefusion 0:22:39.725 --> 0:22:42.925 confirmation and that acts as a really good vaccine candidate. 0:22:45.125 --> 0:22:47.445 Within a few weeks, they figure out how to stabilize 0:22:47.445 --> 0:22:50.925 the spike protein of the novel coronavirus. But to make 0:22:50.965 --> 0:22:53.485 a vaccine work, they need to make sure the mRNA 0:22:53.565 --> 0:22:55.805 gets where it needs to go to instruct the body 0:22:55.845 --> 0:22:59.885 to make stabilize spike proteins. What MADERNA does is encapsulate 0:22:59.925 --> 0:23:03.405 the mRNA in a lipid nanoparticle shell to protect the 0:23:03.485 --> 0:23:07.325 mRNA on its way to doing its things. Here's biochemist 0:23:07.405 --> 0:23:11.205 Thomas Madden of Acuteous Therapeutics in Vancouver to remind us 0:23:11.285 --> 0:23:13.965 what an l enp is and does. If you wanted 0:23:14.045 --> 0:23:18.405 to order a really fragile glass ornament online and you 0:23:18.445 --> 0:23:21.405 wanted it delivered to your to your home, if you 0:23:21.645 --> 0:23:25.725 used the equivalent of our delivery technology, then the ornament 0:23:25.765 --> 0:23:29.605 would be would be wrapped and packaged to protect it 0:23:29.645 --> 0:23:32.885 and noboutter how rough the journey was to your to 0:23:32.965 --> 0:23:37.445 your house. The package would would find your house, it 0:23:37.445 --> 0:23:40.325 would open the front deck door by itself and let 0:23:40.365 --> 0:23:43.725 itself in, and then it would unwrap itself. So the 0:23:43.845 --> 0:23:46.605 ornament is waiting for you to come along and pick 0:23:46.685 --> 0:23:52.045 up in your hallway, so the lipidano particle delivers the vaccine, 0:23:52.565 --> 0:23:56.965 kind of like how FedEx delivers a package. Around the 0:23:57.005 --> 0:23:59.565 same time that the Phase one trials from Aderna begin, 0:24:00.445 --> 0:24:03.605 the US starts shutting down. Rush to the grocery store 0:24:03.685 --> 0:24:07.405 like every single other person, and you know, the meat 0:24:07.485 --> 0:24:10.685 sections were empty, and that just kind of that was 0:24:10.725 --> 0:24:14.205 a little eerie to see. This is Nicola Pescarilli, and 0:24:14.205 --> 0:24:15.925 all of a sudden, I just felt like everything was 0:24:15.965 --> 0:24:19.605 closed off, and I didn't like that feeling. And so 0:24:19.645 --> 0:24:21.885 it's like, what can I do to get everything to 0:24:21.965 --> 0:24:25.245 return back to normal as soon as possible? What can 0:24:25.325 --> 0:24:27.285 I do? What can I do to make things better? 0:24:27.325 --> 0:24:30.845 Because I felt just so hopeless. Tom Hanks has COVID, 0:24:31.285 --> 0:24:35.005 the NBA has shut down, entire cities and countries around 0:24:35.005 --> 0:24:38.405 the world shut down, and Nicola volunteers for the Phase 0:24:38.485 --> 0:24:42.245 one trial at the Hope Clinic in Atlanta. I'm in 0:24:42.325 --> 0:24:45.685 Phase one, like, I am one of fifteen people getting 0:24:45.765 --> 0:24:49.245 the highest dosage that no one else in this country, 0:24:49.445 --> 0:24:52.245 in this world has ever gotten. And I think for 0:24:52.285 --> 0:24:55.405 a moment, I thought, oh God, it might crazy, Like 0:24:55.685 --> 0:24:57.965 could I die? And then I was like, no, it's fine. 0:24:58.125 --> 0:25:01.965 Modern medicine is great, and it is great. The phase 0:25:02.045 --> 0:25:06.725 one trial is a success. It was a very small process, 0:25:07.125 --> 0:25:10.685 and I remember afterwards they wanted me to stay to 0:25:10.725 --> 0:25:14.205 observe me for a while after the vaccine, and it 0:25:14.285 --> 0:25:16.485 was still just like getting used to the whole new 0:25:16.645 --> 0:25:21.285 change in the world. Meanwhile, more than a hundred other 0:25:21.365 --> 0:25:24.725 vaccines are in the works around the world, all sorts 0:25:24.725 --> 0:25:28.005 of them spot Nick in Russia, Sino farm and Sino 0:25:28.085 --> 0:25:32.485 vac in China, Astra Zenica in the UK, Covaccine in India, 0:25:32.645 --> 0:25:36.765