WEBVTT - Spike 0:00:08.245 --> 0:00:13.405 School of Humans. In nineteen sixty six, an outbreak of 0:00:13.485 --> 0:00:19.125 respiratories and sicial virus spread through Washington DC. RSV is 0:00:19.125 --> 0:00:21.685 a highly contagious virus that usually pops up in the 0:00:21.725 --> 0:00:24.685 colder months. It can block the airways of infants and 0:00:24.765 --> 0:00:28.285 cause pneumonia in older adults. Tens of millions of people 0:00:28.325 --> 0:00:32.805 get sick from it every year, and thousands die. To 0:00:32.805 --> 0:00:35.765 stop those deaths, a team at the National Institutes of 0:00:35.805 --> 0:00:39.085 Health created some RSV vaccines and tested them in babies, 0:00:39.525 --> 0:00:44.565 mostly babies from poor black families. The trial went badly, 0:00:45.365 --> 0:00:49.605 really badly. Dozens of infants got a new RSV vaccine, 0:00:49.925 --> 0:00:52.165 and not only did the vaccine not protect them from 0:00:52.205 --> 0:00:55.725 the virus, it actually seemed to expose them to graver sickness. 0:00:56.365 --> 0:00:59.565 So the vaccinated babies who caught RSV fared worse than 0:00:59.605 --> 0:01:02.765 those who got no vaccine at all. Eighteen of those 0:01:02.845 --> 0:01:05.725 kids ended up in the hospital and two of them die. 0:01:07.245 --> 0:01:10.765 As far as vaccine trials go, it was a total disaster. 0:01:12.925 --> 0:01:15.805 It's a cruel irony of vaccine development that those two 0:01:15.885 --> 0:01:19.125 kids deaths fifty years ago indirectly led to one of 0:01:19.125 --> 0:01:22.005 the greatest successes in the history of modern drugs. The 0:01:22.125 --> 0:01:27.285 COVID nineteen vaccines, the single biggest breakthrough in coronavirus vaccine research, 0:01:27.765 --> 0:01:30.925 was inspired by scientists who wanted to protect kids from RSV, 0:01:31.965 --> 0:01:34.285 and because of that work, they figured out how to 0:01:34.325 --> 0:01:37.525 make a vaccine for coronavirus two years before the first 0:01:37.525 --> 0:01:40.645 case of COVID nineteen. In this episode, we're going to 0:01:40.725 --> 0:01:43.085 get a little technical on you, but it's necessary in 0:01:43.165 --> 0:01:45.365 order to get to the heart of how these vaccines work. 0:01:47.165 --> 0:01:50.165 From iHeartRadio and School of Humans, I'm Sean Revive and 0:01:50.245 --> 0:02:00.525 this is long shot. Yeah, people want, you know, they 0:02:00.565 --> 0:02:04.845 want to see smoking vessels of like Purvalla, but you know, 0:02:05.165 --> 0:02:09.205 by all just for not chemists. That's Jason McClellan. He 0:02:09.245 --> 0:02:12.045 works at the University of Texas in Austin, and he's 0:02:12.045 --> 0:02:14.845 telling us that his office isn't as exciting as visitors 0:02:14.925 --> 0:02:17.645 might think. I mean, when people come to visit, we 0:02:17.645 --> 0:02:20.005 add food, gallering and things because they want to see yellow. 0:02:20.085 --> 0:02:22.605 But like everything the work of his water, it's like biological. 0:02:23.965 --> 0:02:27.285 I'm in Austin, Texas, at the University of Texas. I'm 0:02:27.325 --> 0:02:30.925 in one of the departments called a Molecular Biosciences department. 0:02:32.045 --> 0:02:36.405 I'm a structural biologist. Structural biologists zoom a way in 0:02:36.565 --> 0:02:40.245 on large molecules or groups of molecules and figure out 0:02:40.285 --> 0:02:42.605 how their parts are put together and why they work 0:02:42.685 --> 0:02:45.885 the way they do. They spend a lot of time 0:02:45.925 --> 0:02:48.485 looking at proteins, which play a ton of roles in 0:02:48.525 --> 0:02:51.925 the body of humans and other living things. Proteins help 0:02:51.925 --> 0:02:56.325 you grow, digest food, fight disease, stay energized. They also 0:02:56.445 --> 0:03:01.365 help bind cells together and transport nutrients. Some hormones like insulin, 0:03:01.405 --> 0:03:07.125 are proteins. Antibodies are proteins, Enzymes are proteins. Hemoglobin, which 0:03:07.165 --> 0:03:09.645 is the dominant component of our blood, is a protein. 0:03:10.765 --> 0:03:14.485 Structural biologists like Jason want to know exactly what proteins 0:03:14.525 --> 0:03:17.125 look like. Without the structures, we don't really know what 0:03:17.165 --> 0:03:20.485 these proteins look like. We draw them as ovals or squares. 0:03:20.525 --> 0:03:23.045 But once we determine their structures, we're able to like 0:03:23.125 --> 0:03:26.885 three D print the actual molecule essentially and know where 0:03:26.885 --> 0:03:29.765 every amino acids is located on the protein, how the 0:03:29.805 --> 0:03:34.565 proteins fold The structure leads to function. So by understanding 0:03:34.565 --> 0:03:37.005 the structure, we know something about how the protein works. 0:03:37.645 --> 0:03:39.925 And if you know how proteins work and how they look. 0:03:40.485 --> 0:03:43.885 You can figure out ways to alter them, change amino acids, 0:03:44.325 --> 0:03:47.765 maybe make the protein more stable, or chop off some parts. 0:03:47.805 --> 0:03:50.005 We don't want to try to make them the best 0:03:50.085 --> 0:03:56.365 possible vaccine antigens. Understanding what specific proteins do is the 0:03:56.445 --> 0:03:59.405 key to the COVID vaccines. But it's not like Jason 0:03:59.445 --> 0:04:02.805 went to college and majored in proteins. Oh, it was 0:04:03.605 --> 0:04:06.405 a kind of winding path, I guess. I went to 0:04:06.965 --> 0:04:11.765 college Wayne State University in Detroit, Michigan. I wanted to 0:04:11.765 --> 0:04:14.725 do pre med and be a doctor. Most I was 0:04:15.045 --> 0:04:16.325 just trying to think of things I could do to 0:04:16.765 --> 0:04:21.085 help people. But early on I realized I really liked chemistry. 0:04:21.205 --> 0:04:24.245 Was quick good at chemistry, so I went to graduate school. 0:04:24.605 --> 0:04:28.005 I've learned a technique called X ray crystallography, and that's 0:04:28.085 --> 0:04:32.605 one of the methods for determining structures of proteins. But 0:04:32.765 --> 0:04:34.445 ultimately I wanted to do a bit more than just 0:04:34.525 --> 0:04:38.525 determine destructures. I wanted to try to have some applied 0:04:38.885 --> 0:04:42.325 research to create things that could end up going into 0:04:42.405 --> 0:04:46.405 humans and improve human health. Around two thousand and eight, 0:04:46.605 --> 0:04:48.845 Jason heard about a guy at the NIH doing a 0:04:48.845 --> 0:04:51.405 lot of cool stuff with HIV, looking closely at the 0:04:51.445 --> 0:04:54.845 virus's structure and trying to design a vaccine. He joined 0:04:54.885 --> 0:04:57.245 the lab there, and while at the NAH he ended 0:04:57.285 --> 0:05:00.085 up working with a doctor and virologist named Barney Graham, 0:05:00.125 --> 0:05:05.205 a world expert on RSV. The RSV vaccine that failed 0:05:05.205 --> 0:05:07.565 back the sixties was made by weakening a strain of 0:05:07.565 --> 0:05:10.485 the virus by passing it through animal tissue or human cells. 0:05:11.045 --> 0:05:13.085 That's the way the great vaccine creators of the past, 0:05:13.285 --> 0:05:17.365 like Maurice Hilleman made their vaccines. Jason and doctor Graham 0:05:17.405 --> 0:05:19.725 wanted to create a vaccine in a totally different way. 0:05:20.525 --> 0:05:24.045 They wanted to manipulate a specific protein of the RSV virus, 0:05:24.605 --> 0:05:28.525 the one the virus uses to infect human cells. It's 0:05:28.565 --> 0:05:32.245 called the f protein f as in fudge, and it 0:05:32.245 --> 0:05:36.485 comes in two forms or a scientists say two confirmations, 0:05:36.925 --> 0:05:42.525 prefusion and post fusion. Here's Jason to explain more. Proteins 0:05:42.525 --> 0:05:45.405 exist in some initial confirmation on the surface of the virus. 0:05:45.525 --> 0:05:49.765 That's what we call the prefusion confirmation. Then there's an 0:05:49.765 --> 0:05:53.645 event that causes the protein to begin refolding and rearranging, 0:05:53.845 --> 0:05:57.125 much like a transformer, going from a car to a robot. 0:05:57.565 --> 0:05:59.725 Parts of it, parts of the protein, just start moving 0:05:59.765 --> 0:06:04.445 and refolding, and it ends up forming an intermediate confirmation 0:06:04.645 --> 0:06:08.165 where it's part of the protein into our host cell membrane. 0:06:09.005 --> 0:06:13.885 That's pretty confusing, so let's try and visualize it. There's 0:06:13.885 --> 0:06:16.805 a virus cell and a human cell. We'll picture them 0:06:16.805 --> 0:06:21.045 as tennis balls. The virus tennis ball has its protein 0:06:21.125 --> 0:06:23.245 on its surface, sort of shape like a cone or 0:06:23.285 --> 0:06:28.965 a stubby mushroom stalk. That's its f protein. So the 0:06:29.045 --> 0:06:32.085 virus tennis ball looks for human tennis balls in the body, 0:06:32.405 --> 0:06:35.965 and when it finds one, here's what happens. The mushroom 0:06:36.005 --> 0:06:39.485 stalk stretches and elongates and attaches itself to the human 0:06:39.525 --> 0:06:42.205 tennis ball. So it's like a bridge between the two 0:06:42.245 --> 0:06:46.285 tennis balls, human and virus. So it's stock between the 0:06:46.325 --> 0:06:49.765 host cell membrane and the viral membrane. The membrane of 0:06:49.765 --> 0:06:52.685 a cell is like its skin. It separates the inside 0:06:52.685 --> 0:06:54.925 of the cell from whatever is on the outside, and 0:06:54.965 --> 0:06:58.205 then it bends back around like a hairpin to bring 0:06:58.245 --> 0:07:01.485 the two membranes together, and then it adopts this final 0:07:01.565 --> 0:07:05.325 state called the postfusion state. So after the stock on 0:07:05.365 --> 0:07:08.605 the virus tennis ball has elongated and attached itself to 0:07:08.645 --> 0:07:11.285 the human tennis ball, it folds itself in half in 0:07:11.365 --> 0:07:15.365 order to bring the two tennis balls together. That's the fusion. 0:07:17.405 --> 0:07:20.285 And so when the f protein has already elongated and 0:07:20.365 --> 0:07:25.805 then folded, it's in its postfusion form. By then it's 0:07:25.845 --> 0:07:27.885 too late. You want to teach your body to fight 0:07:27.925 --> 0:07:31.285 the prefusion form before the mushroom stock has folded and 0:07:31.325 --> 0:07:34.005 attached to the human cell. And so, if you think 0:07:34.005 --> 0:07:36.565 of your immune system as a security guard, you want 0:07:36.565 --> 0:07:39.165 to train your immune system to recognize the form that 0:07:39.245 --> 0:07:41.685 might impact you, like the dangerous form, and that's the 0:07:41.685 --> 0:07:45.885 prefusion form. If you train it to recognize the postfusion form, 0:07:45.925 --> 0:07:49.685 the prefusion form can still sneak by you. So in 0:07:49.765 --> 0:07:52.725 order to train the immune system to recognize the prefusion 0:07:52.765 --> 0:07:56.125 form of rsv F proteins, Jason needed to keep the 0:07:56.165 --> 0:08:00.845 proteins in their prefusion unfolded form. But that isn't easy. 0:08:02.085 --> 0:08:05.245 First of all, rsv F proteins really want to go 0:08:05.285 --> 0:08:10.365 into their post fusion form. Second, proteins are tiny. It's 0:08:10.365 --> 0:08:12.165 not like they could go in with tweezers and hold 0:08:12.205 --> 0:08:14.845 the F protein in place. The F protein has a 0:08:14.845 --> 0:08:18.445 molecular mass of fifty seven point four kilo daltons, which 0:08:18.485 --> 0:08:21.165 means it's weight in Grahams has twenty one zeros. After 0:08:21.205 --> 0:08:24.045 the decimal point, it's really difficult to see what they 0:08:24.045 --> 0:08:27.725 look like, much less alter their behavior. And nobody could 0:08:27.725 --> 0:08:30.005 figure out how do we create a form of the 0:08:30.005 --> 0:08:33.525 prefusion molecule that will stay in the prefusion shape and 0:08:33.525 --> 0:08:36.125 allow us to purify it and inject it into evil. 0:08:36.805 --> 0:08:41.165 But in twenty thirteen they had a breakthrough. They were 0:08:41.205 --> 0:08:44.165 finally able to determine the exact structure of the prefusion 0:08:44.245 --> 0:08:47.765 form of the rsv F protein. Plus they figured out 0:08:47.765 --> 0:08:49.805 how to keep it in that form, how to keep 0:08:49.805 --> 0:08:52.845 it from elongating, and we could start making changes like 0:08:53.125 --> 0:08:56.725 adding in little molecular staples to link two regions together 0:08:56.805 --> 0:08:58.725 so that we the one part couldn't pull away from 0:08:58.765 --> 0:09:01.285 the other. And that work. We were eventually able to 0:09:01.325 --> 0:09:05.245 make four different changes to the protein that really locked 0:09:05.285 --> 0:09:08.565 it in the prefusion confirmation and allowed its use as 0:09:08.565 --> 0:09:12.165 a vaccine antigen. Basically, they discovered how a sort of 0:09:12.325 --> 0:09:16.125 staple the mushroom stock in place, and when Barney immunized 0:09:16.165 --> 0:09:21.365 mice and compared postfusion versus prefusion, the mice receiving the 0:09:21.405 --> 0:09:26.005 prefusion form of the F protein elicited neutralizing antibodies about 0:09:26.005 --> 0:09:31.245 ten times higher than those that received the postfusion This 0:09:31.325 --> 0:09:35.285 is huge. This was the first time structural biology had 0:09:35.325 --> 0:09:38.685 helped discover a new way to stop a virus. Science 0:09:38.725 --> 0:09:40.765 magazine called it one of the top ten breakthroughs of 0:09:40.805 --> 0:09:44.045 twenty thirteen, and their success in stabilizing the F protein 0:09:44.485 --> 0:09:46.645 made them want to try the same process with other 0:09:47.005 --> 0:09:51.445 similar viruses. What else could we take this new approach, 0:09:51.485 --> 0:09:54.605 the structure based approach, and apply to what other pathogens 0:09:54.645 --> 0:09:57.925 are important? And that was around the time that the 0:09:58.325 --> 0:10:01.965 MIRS coronavirus had emerged in the Saudi Arabia and the 0:10:02.005 --> 0:10:06.765 Middle East. That's Middle East respiratory syndrome, which is caused 0:10:06.765 --> 0:10:11.325 by a coronavirus called MRS Covey. The disease was first 0:10:11.365 --> 0:10:14.725 reported in Saudi Arabia in twenty twelve. It causes bad 0:10:14.805 --> 0:10:23.645 respiratory illness, fever, cough, shortness of breath, and it can 0:10:23.685 --> 0:10:27.405 eventually kill you with pneumonia and kidney failure. Even today, 0:10:27.445 --> 0:10:30.085 there are still cases that pop up on occasion. Thirty 0:10:30.085 --> 0:10:32.285 five percent of people infected with it were dying. It's 0:10:32.285 --> 0:10:35.965 a real lethal virus, and we thought that this would 0:10:36.005 --> 0:10:38.045 be a good target to try to take everything we 0:10:38.085 --> 0:10:41.405 had just learned about RSV and apply it to not 0:10:41.525 --> 0:10:45.485 just mers, but coronaviruses in general, because we knew Stars 0:10:45.565 --> 0:10:49.005 coronavirus had emerged in China in two thousand and two 0:10:49.325 --> 0:10:53.245 and it caused an epidemic. Remember Eddie Holmes spoke about 0:10:53.285 --> 0:10:55.565 the First Stars in episode one. I realized is that 0:10:55.645 --> 0:10:59.445 raccoon dogs. They were implicated in the First Stars I 0:10:59.565 --> 0:11:01.805 break of two thousand and two two thousand and three 0:11:01.805 --> 0:11:04.765 because they were positive. First came Stars one, then came 0:11:04.805 --> 0:11:07.845 Mrs Here's Jason again, and then ten years later we 0:11:07.885 --> 0:11:10.325 saw Mirrors emerge. We felt like maybe we were on 0:11:10.485 --> 0:11:14.205 a ten year cycle or something where we keep having 0:11:14.525 --> 0:11:18.165 coronaviruses emerge into the human population, and so we wanted 0:11:18.205 --> 0:11:20.765 to figure out how can we do structure based vaccine 0:11:20.765 --> 0:11:24.845 design or coronaviruses to make the best possible vaccine antigens. 0:11:25.925 --> 0:11:28.245 Jason and Barney Graham wanted to use their ability to 0:11:28.325 --> 0:11:31.205 zoom in on viruses and their ability to play around 0:11:31.245 --> 0:11:36.005 with them to make better vaccines. Since Mrs Covey was 0:11:36.005 --> 0:11:39.645 on their radar, they focus on that virus MERS has 0:11:39.645 --> 0:11:42.405 a protein very similar to the F protein of RSV. 0:11:42.885 --> 0:11:48.005 It's called the spike protein. The spike protein acts pretty 0:11:48.045 --> 0:11:51.845 similarly to the F protein, it just has this additional part. 0:11:52.805 --> 0:11:55.205 If you're thinking about the F protein as a mushroom stock, 0:11:55.725 --> 0:11:57.845 the spike protein is kind of like a full mushroom 0:11:57.885 --> 0:12:01.445 with a cap. When attacking a human cell, the cap 0:12:01.525 --> 0:12:04.325 of the spike protein binds to a certain enzyme on 0:12:04.365 --> 0:12:07.445 the surface of the human cell. The enzyme is called 0:12:07.485 --> 0:12:11.365 the ACE two receptor. The ACE two receptor sort of 0:12:11.565 --> 0:12:14.365 pops off the spike protein's cap, and then the spike 0:12:14.365 --> 0:12:17.125 protein stalk does all the things the F protein does. 0:12:17.645 --> 0:12:21.125 Based on decades of literature, for many researchers, it was 0:12:21.125 --> 0:12:24.805 clear that the spike protein is a key component of 0:12:25.085 --> 0:12:29.325 any vaccine because when humans are infected with coronaviruses, they 0:12:29.365 --> 0:12:33.165 make a large antibody response to the spike protein because 0:12:33.485 --> 0:12:36.205 it's really that that's the major protein on the surface 0:12:36.285 --> 0:12:38.365 of the of the virus. So we know we needed 0:12:38.365 --> 0:12:41.205 to use spike protein as the vaccine but we also 0:12:41.245 --> 0:12:43.605 know that the spike protein can change shapes and isn't 0:12:43.605 --> 0:12:46.405 so stable, so then you know what form do you 0:12:46.445 --> 0:12:48.845 want to use. Our previous work, it's shown that what 0:12:48.965 --> 0:12:54.205 you really want to immunize with is a prefusion stabilized 0:12:54.285 --> 0:12:57.205 form that that can't change shape. So that way we 0:12:57.285 --> 0:13:00.205 train our immune system to recognize the shape of the 0:13:00.245 --> 0:13:03.725 spike protein as it exists on the surface of the virus. 0:13:04.685 --> 0:13:08.205 So with coronavirus, they knew they wanted to stabilize the 0:13:08.245 --> 0:13:10.965 spike protein, the key protein on its surface. They wanted 0:13:11.005 --> 0:13:14.565 to make sure it did not elongate. The spike protein 0:13:14.645 --> 0:13:18.205 was pretty unstable. Its stock was liable to elongate and 0:13:18.325 --> 0:13:20.565 go to post fusion form on the drop of a dime, 0:13:21.365 --> 0:13:24.325 and they had trouble even seeing its structure. To make 0:13:24.365 --> 0:13:27.965 it easier, they switched to another virus, one that we've 0:13:27.965 --> 0:13:32.645 all gotten, HKU one. That's one of the four coronaviruses 0:13:32.765 --> 0:13:35.125 that we've probably all been infected with. It's one of 0:13:35.125 --> 0:13:38.965 the many causes of the common cold. And for whatever reason, 0:13:39.725 --> 0:13:42.605 the spike protein from HK one was actually pretty stable 0:13:42.965 --> 0:13:47.645 and it was amenable to the structured determination efforts, and 0:13:48.045 --> 0:13:50.725 we brought in another group, doctor Andrew Ward's group at 0:13:50.765 --> 0:13:55.125 the Script's Research Institute. He's an expert in cryoelectron microscopy, 0:13:55.445 --> 0:13:57.565 and working together they were able to get that first 0:13:57.605 --> 0:14:02.405 structure of a human coronavirus spike protein in the prefusion shapes. 0:14:02.485 --> 0:14:05.125 Now we had our first blueprint to start making changes 0:14:05.485 --> 0:14:11.285 tweaks to stabilize spike proteins of coronaviruses. Using this blueprint, 0:14:11.805 --> 0:14:14.645 Jason's post duc Nian Chung Wang look closely at the 0:14:14.685 --> 0:14:20.685 mirror structure here, he is, it's actually pretty boy, but 0:14:20.765 --> 0:14:24.485 it's also increasing. Why is it boring and why is 0:14:24.485 --> 0:14:30.125 it interesting? Is that we got to try okay and 0:14:30.325 --> 0:14:34.045 again most of the time it's got to feel yeah, 0:14:34.085 --> 0:14:37.245 it's not that too easy. Nianshuang tested more than one 0:14:37.285 --> 0:14:40.685 hundred different mutations to the spike protein until finally coming 0:14:40.725 --> 0:14:44.205 across two changes that stabilized it, that kept the spike 0:14:44.245 --> 0:14:47.365 in its pre fusion form, and it was really stable. 0:14:47.685 --> 0:14:50.685 It stayed all in the pre fusion shape. What was 0:14:50.725 --> 0:14:53.405 exciting is that the region where we made these changes 0:14:53.605 --> 0:14:57.685 is very similar between different coronavirus spikes, So the same 0:14:57.765 --> 0:15:02.645 changes we could also introduce them into stars. Kobe from 0:15:02.685 --> 0:15:05.645 two thousand and two, and that led to stabilization. So 0:15:05.725 --> 0:15:08.845 my twenty seventeen we really had this method, kind of 0:15:08.845 --> 0:15:13.205 a universal method for stabilizing data coronavirus spikes in their 0:15:13.245 --> 0:15:17.045 prefusion confirmation. But there was one problem with their success 0:15:17.085 --> 0:15:23.085 stabilizing the MERS spike protein. Nobody really cared. It flew 0:15:23.085 --> 0:15:25.765 away under the radar because by then it was evident 0:15:25.805 --> 0:15:29.765 that MERS, as dangerous as it was, didn't spread very easily. 0:15:30.645 --> 0:15:33.365 A few people were getting MERS a vaccine for it 0:15:33.405 --> 0:15:38.205 didn't seem super important. Yeah, it's kind of painful. At 0:15:38.205 --> 0:15:42.845 that time, most coronavirus at that time was not considered 0:15:42.765 --> 0:15:47.125 a big issue because there are few our cases, so 0:15:47.245 --> 0:15:52.125 people didn't pay matt attention on that kind of coronavirus. 0:15:53.045 --> 0:15:55.725 Although their work didn't get much attention, they knew they 0:15:55.765 --> 0:15:58.565 had a vaccine technology ready to be put into action. 0:15:59.485 --> 0:16:02.765 By twenty seventeen, they were prepared to test their stabilizing 0:16:02.805 --> 0:16:07.205 spike protein method on another coronavirus. They just needed an outbreak. 0:16:08.885 --> 0:16:12.525 And then two years later we found out in the 0:16:12.565 --> 0:16:15.765 beginning of twenty twenty that this new virus that was 0:16:15.805 --> 0:16:20.165 causing pneumonia outbreaks in Wuhan China was a coronavirus and 0:16:20.365 --> 0:16:23.765 very similar to Stars Kobe Ie. They'd finally have a 0:16:23.845 --> 0:16:26.045 chance to test out the spike protein in real life, 0:16:26.725 --> 0:16:30.885 but a big question remained, would it work in people. 0:16:35.245 --> 0:16:37.885 Jason and his team spent years figuring out how to 0:16:37.965 --> 0:16:40.445 keep a spike protein stable and use that to make 0:16:40.445 --> 0:16:43.445 a new kind of vaccine, but they needed an outbreak 0:16:43.645 --> 0:16:46.525 to test it on real people infected by a coronavirus. 0:16:47.805 --> 0:16:50.245 Then all of a sudden, they have a real time 0:16:50.245 --> 0:16:53.685 pandemic crashing down on the world. The reports were coming 0:16:53.685 --> 0:16:57.205 out of these pneumonia clusters in Wuhan. We could just 0:16:57.245 --> 0:16:59.765 see it following along on science, Twitter and on the news, 0:16:59.845 --> 0:17:02.765 and so people were already kind of nervous, especially in 0:17:02.765 --> 0:17:05.245 the coronavirus feel that we could be looking at the 0:17:05.485 --> 0:17:09.445 beginnings of a coronavirus outbreak. And then it was early 0:17:09.525 --> 0:17:12.925 in January when it was learned that in fact, it 0:17:12.965 --> 0:17:16.485 is a coronavirus, a beta coronavirus that's similar to the 0:17:16.805 --> 0:17:20.525 first Stars Kobe from two thousand and two. At this point, 0:17:20.605 --> 0:17:23.005 Jason's working at the University of Texas and he's on 0:17:23.125 --> 0:17:26.365 vacation with his family. Barney Graham called me. He said 0:17:26.525 --> 0:17:29.405 he was in contact with the US CDC Chinese CDC. 0:17:30.205 --> 0:17:33.365 They were going to try and work quickly work with Maderna. 0:17:33.525 --> 0:17:37.005 Maderna was then an upstart company based in Cambridge, Massachusetts 0:17:37.085 --> 0:17:39.405 that had never brought a vaccine to market, but they 0:17:39.485 --> 0:17:42.965 tested several vaccines for other viruses, and Barney Graham had 0:17:42.965 --> 0:17:44.605 a plan to work with them on a bat born 0:17:44.685 --> 0:17:48.485 virus called NIPA, but when the novel coronavirus came along, 0:17:49.125 --> 0:17:52.005 doctor Graham told Maderna they should focus on that instead, 0:17:52.485 --> 0:17:55.685 and he wanted to know if we were interested in 0:17:55.685 --> 0:17:59.285 continuing our collaboration to determine the structure of the stars 0:17:59.325 --> 0:18:03.045 Kobe to spike protein and use that information to create 0:18:03.565 --> 0:18:08.005 the vaccine antigens. Jason texted his graduate student Daniel Rapp 0:18:08.445 --> 0:18:10.045 and told him they were going to be busy the 0:18:10.085 --> 0:18:12.885 next few days. Based on this information, we were sort 0:18:12.885 --> 0:18:15.405 of ready to go. That's Daniel, because we've been studying 0:18:15.445 --> 0:18:17.485 these spike proteins for such a long time. We knew 0:18:17.485 --> 0:18:20.525 how to effectively stabilize spike in the pre fusion confirmation 0:18:20.645 --> 0:18:23.885 and that acts as a really good vaccine candidate, and 0:18:24.125 --> 0:18:25.725 so during that time we were kind of just like 0:18:25.725 --> 0:18:28.605 sitting on our hands, like really anxiously waiting for that 0:18:28.645 --> 0:18:31.325 information to become available to everybody, because that was the 0:18:31.325 --> 0:18:33.725 thing that was holding us back from getting started back 0:18:33.725 --> 0:18:35.245 to Jason, and then we just kind of had to 0:18:35.245 --> 0:18:36.965 wait a couple of these because nothing we could really 0:18:37.005 --> 0:18:39.925 do until the genome sequence became available so we could 0:18:39.925 --> 0:18:42.845 see what the sequence of this spike protein was. On 0:18:42.965 --> 0:18:46.485 January eleventh, a scientist in China made it available for all. 0:18:46.765 --> 0:18:49.325 That was John jen Jang who sent the sequence to 0:18:49.405 --> 0:18:52.765 Eddie Holmes in Australia, who then posted it online. Jason 0:18:52.805 --> 0:18:54.965 got the sequence and started working on a vaccine with 0:18:55.005 --> 0:18:57.965 his team the next day. So what does it actually 0:18:57.965 --> 0:19:01.485 mean to get a virus's genetic sequence. The sequence is 0:19:01.565 --> 0:19:04.085 kind of like it's barcode. You're scanning the letters in 0:19:04.165 --> 0:19:06.405 its genome to figure out actually what it is and 0:19:06.485 --> 0:19:09.005 how it works. It's essentially a file like somebody can 0:19:09.005 --> 0:19:11.605 just you know, it's an attachment, the text file that 0:19:11.685 --> 0:19:14.925 somebody can send us containing the sequence, just a bunch 0:19:14.925 --> 0:19:17.605 of letters, so like computer code. And then we have 0:19:17.605 --> 0:19:19.725 to figure out what changes we want to make very 0:19:19.805 --> 0:19:23.205 quickly just by taking that sequence and aligning it to 0:19:23.325 --> 0:19:26.405 the other spike sequences. We knew right where to put 0:19:26.445 --> 0:19:30.765 the two changes that we had identified earlier, so that 0:19:30.885 --> 0:19:33.125 was probably done within a couple of hours. Just the 0:19:33.165 --> 0:19:37.045 design of these constructs. Remember, Jason's team is looking for 0:19:37.045 --> 0:19:39.045 a way to alter the proteins on the surface of 0:19:39.045 --> 0:19:42.485 the virus so they won't go into that post fusion confirmation. 0:19:43.285 --> 0:19:45.845 The change that Niche Wong and the team had discovered 0:19:45.885 --> 0:19:49.765 working with mers is called the two P mutation. The 0:19:49.885 --> 0:19:53.445 P stands for prolene, one of twenty amino acids that 0:19:53.485 --> 0:19:57.565 are the building blocks of all living things. Proleins are 0:19:57.605 --> 0:20:01.765 special because they're the most rigid amino acid and because 0:20:01.805 --> 0:20:05.325 they are rigid. Swapping out two other amino acids for 0:20:05.605 --> 0:20:08.845 two proteins at a certain joint of the spike protein 0:20:09.645 --> 0:20:13.405 keeps the mushroom stock in place, meaning it keeps it 0:20:13.405 --> 0:20:17.405 in pre fusion form. But Jason and his team couldn't 0:20:17.445 --> 0:20:20.325 just do the two P mutation on the laptop. They 0:20:20.325 --> 0:20:23.965 had to do it in real life. There are companies 0:20:23.965 --> 0:20:26.525 out there that can take a modified genetic sequence like 0:20:26.565 --> 0:20:29.565 the one they designed at UT and turn it into 0:20:29.605 --> 0:20:33.325 something physical. And you need to turn it into a 0:20:33.365 --> 0:20:36.885 biological substance. Like actual DNA. And so that's where we 0:20:36.925 --> 0:20:38.885 need to work with the companies, where we send them 0:20:38.885 --> 0:20:41.765 the file and they're able to synthesize DNA and send 0:20:41.805 --> 0:20:43.285 it send it back to us, and then we have 0:20:43.325 --> 0:20:45.565 to stitch some of it together and do some other things. 0:20:45.685 --> 0:20:47.885 And so in the lab we were working with the DNA. 0:20:48.005 --> 0:20:51.525 When Jason says he's working with DNA, he essentially means 0:20:51.565 --> 0:20:54.765 that they're making changes to genes in order to program 0:20:54.885 --> 0:20:59.405 human cells to produce the stable spike proteins. Remember this 0:20:59.485 --> 0:21:02.405 is the key to the whole vaccine. Our own cells 0:21:02.445 --> 0:21:05.365 will be the factories that produce the stable spike proteins, 0:21:05.845 --> 0:21:09.245 and the DNA is the thing sending those instructions via 0:21:09.325 --> 0:21:14.165 messenger RNA. So that way the cells realized the instructions 0:21:14.165 --> 0:21:17.205 have changed, the recipe has changed, if you will, and 0:21:17.245 --> 0:21:20.525 they just make a protein containing proteins at those positions 0:21:20.605 --> 0:21:24.485 instead of the original amino acids at those positions. I 0:21:24.485 --> 0:21:28.085 think within ten days, maybe a bit more, Nianchwang had 0:21:28.085 --> 0:21:31.885 had cloned like ten different plasmids. Plasmids are like small 0:21:32.005 --> 0:21:36.125 snippets of DNA molecules, ending Chwang was working around the 0:21:36.165 --> 0:21:39.285 clock to stitch them together. Into a full DNA strand 0:21:39.485 --> 0:21:43.885 that could encode for the spike proteins. Meanwhile, Barney Graham's 0:21:43.965 --> 0:21:47.005 lab was talking to MODERNA telling them how to stabilize 0:21:47.005 --> 0:21:50.045 the spike protein with a two P mutations, like what 0:21:50.325 --> 0:21:53.085 spike protein to encode in the mRNA, where to put 0:21:53.125 --> 0:21:58.085 the stabilizing prolein mutations. Then came January thirtieth, twenty twenty. 0:21:58.405 --> 0:22:01.885 It was an exciting day. We Daniel was harvesting. He's 0:22:01.925 --> 0:22:05.165 talking about his grad student, Daniel Repp, the purified spike 0:22:05.205 --> 0:22:08.005 proteins that were produced by the cells we had growing 0:22:08.005 --> 0:22:11.125 in the lab. So we was able to harvest the spike, 0:22:11.365 --> 0:22:18.045 purify it and start freezing cryoEM grids. cryoEM stands for 0:22:18.085 --> 0:22:23.965 cryoelectron microscopy, a method for seeing proteins at atomic resolution. First, 0:22:24.245 --> 0:22:26.925 Daniel would flash freeze the proteins in ice on a 0:22:27.005 --> 0:22:31.485 tiny mesh disc. Then he'd use an electron microscope to 0:22:31.485 --> 0:22:34.965 take thousands of two dimensional images of the proteins. A 0:22:35.005 --> 0:22:38.005 computer program then use those pictures to create a three 0:22:38.085 --> 0:22:41.445 D image showing the structure of the proteins. That allowed 0:22:41.525 --> 0:22:44.565 us to start the data collection that night, and we 0:22:44.565 --> 0:22:47.445 could see the individual spike proteins for the first time, 0:22:48.005 --> 0:22:50.525 and within twenty four hours we had collected a complete 0:22:50.565 --> 0:22:53.045 data set and we got the first looks at the 0:22:53.125 --> 0:22:58.925 molecular shape of the coronavirus spike protein. Within about thirty 0:22:59.005 --> 0:23:02.525 days we had determined in a manuscript submitted that paper 0:23:02.565 --> 0:23:05.325 has been sighted close to four thousand times now we have. 0:23:05.525 --> 0:23:09.525 We were sharing the coordinates of the structure, the blueprint 0:23:09.565 --> 0:23:11.365 of the structure to people all over the world. We 0:23:11.405 --> 0:23:14.245 were shipping the plasmids that we had made two hundred 0:23:14.245 --> 0:23:16.245 groups or so. Is that way they could make the 0:23:16.285 --> 0:23:21.525 spike protein in their labs for diagnostics, for antibody isolation 0:23:21.725 --> 0:23:25.045 or additional structural studies. So it is a really crazy 0:23:25.045 --> 0:23:28.485 time early last year. Now they knew exactly how to 0:23:28.525 --> 0:23:31.845 stabilize the spike protein the mushroom shape on the surface 0:23:31.845 --> 0:23:36.365 of the coronavirus. They'd actually created stabilized spikes in the lab, 0:23:36.765 --> 0:23:40.285 and the pharmaceutical company Baderna would use these stabilize spikes 0:23:40.405 --> 0:23:43.245 as building blocks for the vaccine. They are just directly 0:23:43.245 --> 0:23:49.005 synthesizing the mRNA, but it's still at the instructions level, 0:23:49.165 --> 0:23:51.605