WEBVTT - The Coronavirus is Mutating 0:00:15.396 --> 0:00:21.916 Pushkin from Pushkin Industries. This is Deep Background, the show 0:00:21.956 --> 0:00:25.076 where we explore the stories behind the stories in the news. 0:00:25.476 --> 0:00:29.036 I'm Noah Feldman. Today we're going to talk about the 0:00:29.116 --> 0:00:36.036 novel coronavirus and evolution. All viruses mutate and evolve, and 0:00:36.156 --> 0:00:40.876 that includes SARS cove two, the virus that produces COVID nineteen. 0:00:41.436 --> 0:00:44.116 The version of the virus that we saw when the 0:00:44.156 --> 0:00:49.196 pandemic first started this winter is slightly different from the 0:00:49.316 --> 0:00:52.676 version of the virus that has emerged today in ninety 0:00:52.716 --> 0:00:56.516 five percent of the cases that we're seeing. But what 0:00:56.716 --> 0:01:01.756 does that tiny, little single point difference mean one amino acid? 0:01:02.636 --> 0:01:05.076 Is it something we should be concerned about? That is 0:01:05.116 --> 0:01:08.036 something that scientists are in the process of figuring out 0:01:08.876 --> 0:01:12.396 to day. We're joined by one of those scientists, Nevill. 0:01:12.476 --> 0:01:15.516 Sanjana is a geneticist at the New York Genome Center 0:01:15.636 --> 0:01:19.436 and New York University. He has been researching and publishing 0:01:19.716 --> 0:01:25.396 about how the coronavirus is mutating. Nevill, thank you so 0:01:25.476 --> 0:01:29.356 much for joining me. Let's start with the call it 0:01:29.436 --> 0:01:32.916 the medium picture. Let's talk about the changes that we 0:01:33.036 --> 0:01:36.316 know have happened through mutation in the stars. CoV two 0:01:36.396 --> 0:01:41.396 virus since the original version surfaced in Wuhan over the 0:01:41.396 --> 0:01:44.876 course of the spring. Sure, so I think there's several 0:01:44.916 --> 0:01:48.156 different changes that have been found in different patient populations. 0:01:48.756 --> 0:01:51.356 Like many RNA viruses, I think one thing that is 0:01:51.396 --> 0:01:54.076 important to know about stars CoV two is it doesn't 0:01:54.076 --> 0:01:57.516 say the same it does mutate. There's elements of how 0:01:57.556 --> 0:02:03.116 the virus replicates where errors can be made during RNA transcription, 0:02:03.756 --> 0:02:06.596 and those errors can get packaged into new viruses and 0:02:06.636 --> 0:02:09.676 then propagated. Most of the time, most of those errors 0:02:09.916 --> 0:02:13.356 changes or variants or mutations probably have very little effect. 0:02:13.516 --> 0:02:16.716 But occasionally you have changes that really do have some 0:02:16.916 --> 0:02:21.356 functional impact on the virus. So one of the mutations, 0:02:21.356 --> 0:02:24.636 a single point mutation that you've been working on and 0:02:24.676 --> 0:02:26.796 that's gotten a fair amount of coverage, not as much, 0:02:26.836 --> 0:02:31.036 perhaps as it ought, is a mutation at the six 0:02:31.156 --> 0:02:36.316 hundred and fourteenth place in the genome of the starscoby 0:02:36.356 --> 0:02:39.156 two virus. Tell us about that one and tell us 0:02:39.156 --> 0:02:42.516 how it's moved through the population, right, Yeah, So the 0:02:42.636 --> 0:02:46.356 mutation that's in the spike protein. So Spike is really 0:02:46.516 --> 0:02:50.316 amongst the coronavirus proteins, probably the most famous proteins. So 0:02:50.396 --> 0:02:54.036 Corona just means crown. And the reason that coronavirus has 0:02:54.076 --> 0:02:57.276 this name with crown in it is because the individual 0:02:57.356 --> 0:03:01.436 viral particles, the varions are decorated with the spike protein 0:03:01.476 --> 0:03:03.676 that kind of sticks out and gives it this crown 0:03:03.756 --> 0:03:06.156 like appearance. So, just out of curiosity, because I've been 0:03:06.156 --> 0:03:08.436 wondering about this, It's called the spike protein because it 0:03:08.556 --> 0:03:11.556 literally spikes up and a number of spikes make the crown. 0:03:11.756 --> 0:03:13.916 It looks yeah, it looks like a spike. Yeah, it's 0:03:13.956 --> 0:03:17.556 by far the most distinguishable feature of any pictures we've 0:03:17.596 --> 0:03:20.956 seen at the virus. So the spike protein, the RNA 0:03:21.036 --> 0:03:25.076 port encodes a protein and that protein has thousands of 0:03:25.076 --> 0:03:28.916 amino acids in the six fourteenth position. Is this mutation 0:03:28.956 --> 0:03:32.156 that we've started to focus on, and the reason that 0:03:32.356 --> 0:03:36.636 we've started to think about this is totally accidental. My 0:03:36.716 --> 0:03:39.876 lab works on crisper and gene editing. We are very 0:03:39.916 --> 0:03:44.516 interested in using those tools to understand what are the 0:03:44.556 --> 0:03:47.476 host genes, what are the human genes that are essential 0:03:47.516 --> 0:03:50.116 for viral entry? And by figuring out which are the 0:03:50.196 --> 0:03:53.196 essential genes for viral entry, we were hoping that we 0:03:53.236 --> 0:03:55.676 could find ways to maybe block some of those genes 0:03:55.836 --> 0:03:58.556 or suppress the activity of some of those genes, and 0:03:58.836 --> 0:04:01.956 by doing that protect people from the virus entering. And 0:04:02.076 --> 0:04:04.276 this was just one of these accidents and science. You 0:04:04.356 --> 0:04:07.116 often hear about science that when you tell the story 0:04:07.116 --> 0:04:09.596 of science that it's like super linear, but when you're 0:04:09.596 --> 0:04:12.596 actually doing science, it actually is not so linear. There's 0:04:12.916 --> 0:04:16.676 twists and turns and different paths, sometimes dead ends. And 0:04:16.716 --> 0:04:19.236 so with the what we were trying to do in 0:04:19.276 --> 0:04:22.036 the lab to understand what are the host proteins that 0:04:22.076 --> 0:04:26.276 are required from viral entry, we started using a very 0:04:26.356 --> 0:04:28.356 safe virus that we use in the lab, and all 0:04:28.396 --> 0:04:30.996 we did was we attached to it the spike protein 0:04:31.076 --> 0:04:33.956 on the outside of that virus from stars Kobe two, 0:04:34.316 --> 0:04:36.716 because we know that the spike protein, because it spikes out, 0:04:36.996 --> 0:04:39.956 is the first point of contact between human cells and 0:04:40.036 --> 0:04:44.396 the coronavirus. And what we found actually was something pretty sad, 0:04:44.476 --> 0:04:47.316 which was that we were really barely able to get 0:04:47.356 --> 0:04:50.396 any cells infected with this virus that we had put 0:04:50.396 --> 0:04:54.156 the spike protein on. And so at that time in April, 0:04:54.596 --> 0:04:57.316 we had started to hear about this mutation that was 0:04:57.356 --> 0:05:00.276 circulating the population and looked like it was increasing it 0:05:00.316 --> 0:05:04.916 had come about sometime maybe in early February, likely in Europe, 0:05:05.236 --> 0:05:09.796 based on the best viral population genomics work with sequences viruses, 0:05:10.236 --> 0:05:13.516 and it looked very rapidly after it's kind of emerged 0:05:13.596 --> 0:05:16.756 in early February that it started to take over kind 0:05:16.756 --> 0:05:19.236 of the world populations. And that's true up to today 0:05:19.516 --> 0:05:22.276 where it's greater than ninety five percent of the circulating 0:05:22.316 --> 0:05:27.516 coronavirus today seems to be carrying the spike mutation, so 0:05:27.676 --> 0:05:30.476 new in February, but now here in July, it really 0:05:30.476 --> 0:05:33.356 seems to be quite dominant. So we thought, okay, let's 0:05:33.756 --> 0:05:35.876 modify the spike protein that we have in the lab. 0:05:36.116 --> 0:05:39.916 Let's just insert this little mutation that seems to be dominating. 0:05:39.916 --> 0:05:42.636 This is back in April. We did this and let's 0:05:42.636 --> 0:05:44.236 give it a try in the lab. And what we 0:05:44.356 --> 0:05:47.716 found was indeed it solved our problem. Our problem is 0:05:47.756 --> 0:05:50.316 we couldn't get the virus are kind of safe virus, 0:05:50.356 --> 0:05:52.956 the pseudovirus that we have decorated with the spike protein, 0:05:52.956 --> 0:05:55.076 we couldn't get it to enter our human cells. But 0:05:55.156 --> 0:05:58.516 when we changed it to have this mutation, we were 0:05:58.556 --> 0:06:00.956 able to see it enter much much better, five to 0:06:01.036 --> 0:06:04.196 ten times better, and we thought, great, we've solved our 0:06:04.236 --> 0:06:06.476 technical problem we had here in the lab. And then 0:06:06.516 --> 0:06:08.156 a day or two later we started to think about 0:06:08.196 --> 0:06:11.516 this and we said, wait a minute, this is pretty important. 0:06:11.556 --> 0:06:14.476 Maybe instead of just running on from this technical problem, 0:06:14.516 --> 0:06:16.836 we should maybe we should report this. Maybe we should 0:06:16.876 --> 0:06:19.756 tell people like, look, this is a functional change in 0:06:19.796 --> 0:06:24.476 how the virus infects humanselves. There are many fascinating things 0:06:24.476 --> 0:06:25.956 in the story you just told, and I want to 0:06:25.956 --> 0:06:27.956 just break them down a bit at a time. So 0:06:28.036 --> 0:06:32.436 let's start with the kind of astonishing fact that in January, 0:06:32.516 --> 0:06:37.076 when the first sequencing of the stars COVID two genome began, 0:06:38.316 --> 0:06:42.516 almost none and maybe none of the viruses that were 0:06:42.796 --> 0:06:49.956 sequenced had this mutation at place six fourteen. By March 0:06:50.076 --> 0:06:54.236 the number was noticeable. By April, it was sufficiently noticeable 0:06:54.276 --> 0:06:57.076 that your lab was thinking, let's try it out. By 0:06:57.116 --> 0:07:01.556 May it was in seventy percent of reported cases, and 0:07:01.676 --> 0:07:04.676 now it's at ninety five percent. So the first question 0:07:04.676 --> 0:07:08.116 I want to ask is does this count as strong 0:07:08.236 --> 0:07:12.196 evidence to you, as among other things such geneticist, that 0:07:12.276 --> 0:07:15.996 there must be some adaptive feature of this change, or 0:07:16.076 --> 0:07:19.436 is there some way that this could have happened without 0:07:19.476 --> 0:07:25.916 this particular mutation helping the virus to replicate more successfully. Yeah, 0:07:25.916 --> 0:07:28.316 so I think scientists are naturally very careful. So when 0:07:28.356 --> 0:07:31.836 we got this first functional data in late April early May, 0:07:32.396 --> 0:07:34.676 we weren't sure whether to believe it. And one of 0:07:34.716 --> 0:07:38.116 the great things about science during the COVID era is 0:07:38.156 --> 0:07:40.316 that there's been a lot of sharing and very rapid 0:07:40.316 --> 0:07:43.756 sharing new results. And in May what we saw were 0:07:43.796 --> 0:07:47.476 lots of different groups steadying the viral genomics and the 0:07:47.716 --> 0:07:51.796 evolution of viral sampling through the world, and there was 0:07:51.876 --> 0:07:55.636 really quite a dichotomy of views. There were folks who 0:07:55.636 --> 0:07:59.596 thought this is clear evidence of selection going on for 0:07:59.636 --> 0:08:02.916 the spike mutation, and then there was completely opposing views, 0:08:02.996 --> 0:08:05.916 which is less so today, but was more then where 0:08:05.956 --> 0:08:08.196 people thought, maybe it's something about a founder effect. You know, 0:08:08.596 --> 0:08:12.836 if hasn't seen coronavirus before, but just the first introduction 0:08:12.836 --> 0:08:15.476 of coronavirus into that country happens to be the one 0:08:15.476 --> 0:08:18.716 that carries this variant, and then maybe the next introduction 0:08:18.756 --> 0:08:21.436 into that country happens a week later. Well, you know, 0:08:21.516 --> 0:08:24.036 exponential growth, So if you have a week of lead time, 0:08:24.396 --> 0:08:27.676 that can really result in a lot more infections, especially 0:08:27.676 --> 0:08:30.916 because we know asymptomatic people can infect others, you know, 0:08:30.996 --> 0:08:33.676 I think sitting where we are right now, especially with 0:08:33.756 --> 0:08:36.116 all the functional data that's come out, there's about five 0:08:36.236 --> 0:08:39.356 or six different groups that have shown functional data is 0:08:39.356 --> 0:08:42.316 similar to what we did here in the lab, I 0:08:42.356 --> 0:08:45.156 think it's pretty clear that this version of the virus 0:08:45.196 --> 0:08:48.756 is more transmissible. And it's not just laboratory experiments, but 0:08:49.156 --> 0:08:51.396 something that we do in our preprint is we look 0:08:51.396 --> 0:08:55.076 at data from Sheffield University in the UK and also 0:08:55.116 --> 0:08:58.116 the University of Washington in Seattle. So these are two 0:08:58.196 --> 0:09:02.636 totally different groups sampling different populations UK population and US population, 0:09:03.316 --> 0:09:07.876 and they're basically looking at data from the qPCR test, 0:09:08.196 --> 0:09:10.996 which is the test that involves the nasal swab and 0:09:11.196 --> 0:09:15.596 qPCR just stands for quantitative polymerate chain reaction. It's actually 0:09:15.636 --> 0:09:19.236 quite a standard lab technique and because it's got that 0:09:19.356 --> 0:09:22.436 q and it quantitative, it can actually detect how many 0:09:22.516 --> 0:09:26.196 viral copies they are in a particular nasal swab. And 0:09:26.476 --> 0:09:30.516 what's super consistent over the two sites is the difference 0:09:30.676 --> 0:09:33.916 between the people who have the D variant or the 0:09:33.956 --> 0:09:36.596 G variant. These are the two different spike variants. The 0:09:36.676 --> 0:09:38.476 D is the original one, the G is the new one. 0:09:38.756 --> 0:09:41.876 And what both the sites find is that there's about 0:09:41.876 --> 0:09:46.876 a threefold increase in viral RNA detected in the nasal 0:09:46.916 --> 0:09:50.916 swabs of people with this new G variant, and that's 0:09:51.076 --> 0:09:55.756 consistent between Sheffield and the group in Seattle. And so 0:09:56.116 --> 0:09:58.276 to me that that suggests, I mean, we can't say 0:09:58.316 --> 0:10:01.036 something about person to person transmission, but something that we 0:10:01.076 --> 0:10:03.956 can definitely say with that data is that perhaps within 0:10:03.996 --> 0:10:06.276 the body, and remember the body is kind of a 0:10:06.356 --> 0:10:09.596 collection of cells, independent cells, where you know, you can 0:10:09.636 --> 0:10:11.396 have cells that are infected in cells that are not 0:10:11.436 --> 0:10:14.476 that are just fine. So perhaps within the body there's 0:10:14.596 --> 0:10:19.316 greater infection, greater distribution of the virus amongst cells when 0:10:19.396 --> 0:10:22.676 they are carrying the SPIKE variant. That sounds like it's 0:10:22.716 --> 0:10:25.636 a very powerful reason to think that the spike variant 0:10:26.196 --> 0:10:29.396 is superior with respect from the virus perspective, inferior from 0:10:29.396 --> 0:10:33.996 our perspective, and that it is adaptive. Let's talk about 0:10:34.036 --> 0:10:38.196 the question of why it seems to be better at 0:10:38.476 --> 0:10:43.076 effectuating transmission. What is it about the crown that works 0:10:43.116 --> 0:10:46.516 better from the virus's perspective at latching on to your 0:10:46.556 --> 0:10:50.276 cells in the G variant compared to the D variant 0:10:50.316 --> 0:10:53.196 with which the virus began. That's a great question. Yet, 0:10:53.276 --> 0:10:55.756 so if it is more infectious, like we show in 0:10:55.796 --> 0:10:58.436 a few different cell types, why is it what's you know, 0:10:58.476 --> 0:11:02.276 how does this one amino acid change create such a 0:11:02.276 --> 0:11:05.836 big difference in infectivity. That's a great question. We have 0:11:05.916 --> 0:11:08.356 the exact same question. And so when you look at 0:11:08.396 --> 0:11:12.476 the structure of the protein, there's different functional domains across 0:11:12.556 --> 0:11:16.316 the length of the protein. Something that we noticed is 0:11:16.356 --> 0:11:19.596 that kind of the closest functional domain to where this 0:11:19.756 --> 0:11:24.036 mutation is the receptor binding domain. That's the thing that 0:11:24.196 --> 0:11:28.956 actually makes contact with the human receptor for coronavirus, which 0:11:28.996 --> 0:11:32.076 we think is in a receptor called ACE two. So 0:11:32.116 --> 0:11:34.636 we said, okay, it's it's not in the receptor binding domain, 0:11:34.676 --> 0:11:36.636 but it's very close to. It's the closest kind of 0:11:36.916 --> 0:11:39.356 domain of the protein that has this well defined function. 0:11:39.596 --> 0:11:41.996 So it must be that, right, It must be. You know, 0:11:42.036 --> 0:11:44.956 something that this mutation is doing. It's increasing its affinity 0:11:45.356 --> 0:11:47.876 for ACE two. It's just like you know, if you're 0:11:47.916 --> 0:11:51.356 able to have kind of a tighter handshake, then that's 0:11:51.396 --> 0:11:53.916 a going to increase infection versus somebody that just kind 0:11:53.956 --> 0:11:57.156 of waves from a distance. Right, So we set about 0:11:57.196 --> 0:11:59.756 actually with some collaborators here at NYU to really to 0:11:59.836 --> 0:12:02.516 test this. And you know, as is often the case 0:12:02.516 --> 0:12:05.396 in science, you know, you have some very strong hypothesis 0:12:05.396 --> 0:12:08.356 about here's what the data should look like, and you know, 0:12:08.476 --> 0:12:12.836 reality and tells you, hey, you're wrong, And that's exactly 0:12:12.836 --> 0:12:15.836 what happened here. You know, our hypausis going into this 0:12:15.956 --> 0:12:20.156 was it was likely stronger binding to the receptor ACE two. 0:12:20.396 --> 0:12:22.676 We found that there was basically no difference between the 0:12:22.756 --> 0:12:26.636 purified spike or the spike variant with ACE two binding. 0:12:26.996 --> 0:12:30.156 So this was definitely not the right answer. It's fascinating 0:12:30.196 --> 0:12:32.796 to hear about a hypothesis that doesn't pan out, and 0:12:32.836 --> 0:12:34.836 it helps the rest of the world to trust science, 0:12:34.876 --> 0:12:36.556 to realize that it's not that the scientists start with 0:12:36.556 --> 0:12:38.516 the hypothesis then claim to prove it. Some things work, 0:12:38.596 --> 0:12:41.316 some things don't. That's part of the process. So what 0:12:41.356 --> 0:12:42.996 did you do next when you realize that the ACE 0:12:43.036 --> 0:12:45.836 two wasn't the answer? You know, there are other aspects 0:12:45.956 --> 0:12:48.276 of what spike you know, which, after all, is just 0:12:48.316 --> 0:12:53.156 this little micromachine that helps the virus. It is not 0:12:53.236 --> 0:12:56.596 there just to have the handshake with the ACE two receptor, 0:12:56.916 --> 0:12:59.276 it performs a lot of other functions that are very 0:12:59.316 --> 0:13:02.236 important for the virus to actually enter an inject it's 0:13:02.236 --> 0:13:05.836 genetic material into the human cell. The handshake is really 0:13:05.876 --> 0:13:09.516 just the first part. After that, the spike protein actually 0:13:09.516 --> 0:13:13.436 sheds kind of a piece of it and unveils this 0:13:13.636 --> 0:13:16.996 very hydrophobic piece, which is a way to say it's fatty. 0:13:17.076 --> 0:13:20.436 It's made of lipids, and why is that important. Lipids 0:13:20.516 --> 0:13:23.956 like to stick to other lipids, and the membranes of 0:13:23.956 --> 0:13:27.156 our cells are all fats, and so basically by unveiling 0:13:27.156 --> 0:13:31.116 this hydrophobic piece, it can stick into the plasma membrane, 0:13:31.116 --> 0:13:34.396 the fatty lipid by layer of our cells, and that 0:13:34.476 --> 0:13:37.716 way fuse basically make kind of this fusion between the 0:13:37.796 --> 0:13:41.676 viral membrane, which is also a lipid and the cell membranye. 0:13:41.956 --> 0:13:46.116 But this little dance, you know, is well orchestrated, and 0:13:46.156 --> 0:13:49.516 so what we eventually did find is that one difference 0:13:49.556 --> 0:13:52.476 we could see between the variant, the mutant form of 0:13:52.516 --> 0:13:55.436 spike and the original form of spike is that this 0:13:55.556 --> 0:13:58.076 kind of processing that enables the protein to go through 0:13:58.116 --> 0:14:01.876 this dance that in the end unveils. This piece that 0:14:01.996 --> 0:14:05.596 sticks into the host cell seems to be different between 0:14:06.036 --> 0:14:09.236 the wild type spike and the variant spike that it 0:14:09.276 --> 0:14:14.716 seems to be more resistant to certain kinds of premature unveiling, 0:14:14.836 --> 0:14:18.156 let's say, of this fatty region, and that actually might 0:14:18.236 --> 0:14:20.876 help it, because if you think about it, these viral proteins, 0:14:21.036 --> 0:14:23.876 they don't just come out and start to infect cells. 0:14:23.916 --> 0:14:27.956 They're produced inside a cell that's already infected. And if 0:14:27.996 --> 0:14:29.756 the spike protein has to go through this kind of 0:14:29.796 --> 0:14:33.236 complicated dance where it changes its confirmation a little bit, 0:14:33.636 --> 0:14:37.356 if that happens too early, it might be an irreversible change. 0:14:37.356 --> 0:14:40.196 It might not be able to become functional again. And 0:14:40.236 --> 0:14:42.956 so if that happens, say in the cell that produces 0:14:42.996 --> 0:14:46.556 the spike, then maybe that's too early. It really has 0:14:46.556 --> 0:14:50.036 to happen after it sees ACE two, it does the 0:14:50.076 --> 0:14:52.476 handshake with ACE two, and then it can kind of 0:14:52.556 --> 0:14:55.476 undergo this conformational change to stick itself into the membrane. 0:14:55.716 --> 0:14:58.516 And if that's happening too early, which is something that 0:14:58.516 --> 0:15:03.996 our data suggests, that might actually lead to varians that 0:15:04.116 --> 0:15:06.836 have spike on them. But the spike is not really functional, 0:15:07.276 --> 0:15:09.556 and perhaps what the mutant spike does is it just 0:15:09.636 --> 0:15:14.076 leads to more functional spike on the surface of the viruses. Now, well, 0:15:14.156 --> 0:15:18.956 let's turn now to the bigger picture consequences of these 0:15:18.996 --> 0:15:21.836 really remarkable findings that you and your co authors have 0:15:21.956 --> 0:15:27.516 contributed to making. When the ordinary person hears that possibly 0:15:27.596 --> 0:15:30.996 the new version of stars covy two is five to 0:15:31.076 --> 0:15:35.116 ten times better at transmitting itself than the old version, 0:15:35.596 --> 0:15:40.356 the natural thought is, oh boy, that's scary. So first question, 0:15:40.836 --> 0:15:43.076 is there any reason to think that an initial mutation 0:15:43.116 --> 0:15:46.196 of that sort would be an indicator that there could 0:15:46.236 --> 0:15:51.276 be future mutations that might similarly improve the transmission rate, 0:15:51.356 --> 0:15:53.956 that is, make it worse for us better for the virus. 0:15:54.636 --> 0:15:56.796 Or is it the case that just because this was 0:15:56.836 --> 0:16:00.076 a random point mutation, there's just no reason to think 0:16:00.196 --> 0:16:02.676 that there would be some other random mutation that would 0:16:02.716 --> 0:16:05.276 make this an even better virus at transmitting itself. Yeah, 0:16:05.316 --> 0:16:07.636 that's a fantastic question. I mean the real answer is, 0:16:07.676 --> 0:16:10.876 of course, like many things COVID related, we really don't know. 0:16:11.716 --> 0:16:14.796 I think based on this rapid evolution that we've seen 0:16:14.916 --> 0:16:18.076 just you know, with months of this virus circulating, I 0:16:18.116 --> 0:16:21.236 think it certainly is not beyond a shadow of a 0:16:21.276 --> 0:16:24.276 doubt kind of possibility that there might be another mutation, 0:16:24.356 --> 0:16:26.436 maybe in the spike protein, maybe in some of the 0:16:26.476 --> 0:16:29.996 other twenty five odd proteins that are in this virus 0:16:30.036 --> 0:16:35.276 that either leads to increased transmissibility or you could lead 0:16:35.316 --> 0:16:39.076 to hopefully not but some sort of increased lethality of 0:16:39.076 --> 0:16:42.596 the virus. And that sounds very scary. I don't think 0:16:42.636 --> 0:16:44.396 it has to be scary. I mean, one thing that 0:16:44.516 --> 0:16:47.596 is very great to see right now, which we certainly 0:16:47.596 --> 0:16:50.836 didn't have during the nineteen eighteen you know, flu pandemic, 0:16:51.316 --> 0:16:54.796 is the use of rapidly deployable genomics thing. It's like 0:16:54.796 --> 0:16:57.036 the work that I'm talking to you about today, where 0:16:57.076 --> 0:17:00.476 we've been able to very quickly functionally characterize the impact 0:17:00.476 --> 0:17:03.876 of some of these mutations. There's a large scientific community 0:17:03.876 --> 0:17:06.636 of people working on this right now, and I do 0:17:06.716 --> 0:17:09.636 think we can either react in real time to a 0:17:09.676 --> 0:17:12.236 lot of these mutations at least understand what their functional 0:17:12.236 --> 0:17:15.356 impact is, or but the kinds of cool DNA synthesis 0:17:15.356 --> 0:17:19.516 technologies and RNA synthesis technologies that exist, we can actually 0:17:20.196 --> 0:17:23.436 make mutations and test them in a massively parallel way 0:17:23.636 --> 0:17:25.916 to kind of figure out, hey, what does this mutation do, 0:17:25.956 --> 0:17:29.236 what does that mutation do, and really fully characterize what's 0:17:29.316 --> 0:17:31.876 kind of a broad spectrum of what these proteins are 0:17:32.076 --> 0:17:33.956 capable of. And that way maybe we can start to 0:17:33.996 --> 0:17:36.796 predict and already think about, well, how do we improve 0:17:36.796 --> 0:17:40.116 our vaccines, how do we improve our therapeutics. And this 0:17:40.156 --> 0:17:42.516 has been done before with highly mutating viruses, so this 0:17:42.596 --> 0:17:44.996 is not a crazy idea to suggest. Perhaps the most 0:17:45.116 --> 0:17:49.476 mutagenic RNA virus that everyone knows well is HIV, the 0:17:49.556 --> 0:17:54.276 virus that causes aids. That virus is tremendously mutagenic, and 0:17:54.476 --> 0:17:56.996 what was found in the in the early and mid 0:17:57.116 --> 0:18:01.516 nineties was that drugs that were seemingly effective against HIV 0:18:02.316 --> 0:18:04.436 didn't really work in the long term, meaning that the 0:18:04.476 --> 0:18:08.396 virus was able to evolve ways around the drugs. You know. 0:18:08.436 --> 0:18:10.356 The real break through was in the late nineties the 0:18:10.356 --> 0:18:12.996 development of what we now referred to as the cocktail, 0:18:13.356 --> 0:18:16.316 which was a few different attacks on the virus, three 0:18:16.356 --> 0:18:19.556 different drugs brought together, and it turns out that even 0:18:19.556 --> 0:18:22.636 though the virus is very good at mutating that RNA virus, 0:18:23.396 --> 0:18:25.636 the three drugs together proved to be kind of a 0:18:25.716 --> 0:18:29.076 knockout punch and still to this date, twenty years twus 0:18:29.156 --> 0:18:32.516 after the development of the HIV cocktail, it is still effective. 0:18:32.876 --> 0:18:35.436 And so I think that provides a really nice roadmap, 0:18:35.716 --> 0:18:38.076 you know, I think it should inspire us that we've 0:18:38.116 --> 0:18:41.236 been able to lead with science. Let's talk then about 0:18:41.396 --> 0:18:45.596 vaccines and reinfection and what the practical consequences will be 0:18:45.676 --> 0:18:50.076 for those of this observed mutation. Let's start with reinfection. 0:18:50.196 --> 0:18:51.996 If you're in China, this may matter much more if 0:18:51.996 --> 0:18:53.596 you're in China than if you're in Europe or the 0:18:53.636 --> 0:18:57.276 United States. But you got the early version and now 0:18:57.396 --> 0:19:00.556 here comes the mutated version back around it comes back 0:19:00.676 --> 0:19:03.596 via Europe or the United States. I know there was 0:19:03.636 --> 0:19:06.636 concern initially in China that it might be that whatever 0:19:06.676 --> 0:19:08.796 immunity people have, and I realize we don't fully know 0:19:08.796 --> 0:19:10.836 how much community people have when they have been infected, 0:19:10.996 --> 0:19:14.076 but whatever immunity people did have might no longer be 0:19:14.076 --> 0:19:16.836 sufficient to hold off this new mutation of the virus. 0:19:17.516 --> 0:19:19.076 Is there data on that yet or do you have 0:19:19.116 --> 0:19:22.156 an intuitive sense absent the data, what is likely to 0:19:22.156 --> 0:19:24.036 be the case with respect your reinfection of people who 0:19:24.116 --> 0:19:27.796 got it the first time. Yeah, there's not data from US, 0:19:27.796 --> 0:19:30.196 But there's data from several other groups that have now 0:19:30.196 --> 0:19:33.756 started to look either at therapeutic antibodies that are being 0:19:33.756 --> 0:19:37.436 tested or antibodies isolated from patients who have had a 0:19:37.476 --> 0:19:41.516 COVID nineteen disease. Course, what they found is that many 0:19:41.556 --> 0:19:44.556 of these antibodies targets, say, for instance, that ACE two 0:19:44.556 --> 0:19:47.276 binding domain, which is the part of spike that's kind 0:19:47.276 --> 0:19:49.556 of on the farthest away from the virus. It's on 0:19:49.596 --> 0:19:53.636 the surface really of the virus. And so the good 0:19:53.636 --> 0:19:56.276 news is again because the mutation doesn't really seem to 0:19:56.316 --> 0:20:00.316 alter that receptor binding domain so much that most of 0:20:00.356 --> 0:20:03.836 those antibodies still are very effective against the mutant spike. 0:20:03.916 --> 0:20:06.516 So that'll suggests that this one mutation probably doesn't wipe 0:20:06.556 --> 0:20:08.876 out that kind of immunity. And just so I understand, 0:20:08.916 --> 0:20:11.236 is that because you did a great job of describing 0:20:11.716 --> 0:20:14.476 the two part process of how the virus gets you. 0:20:15.036 --> 0:20:17.476 First it shakes hands and then it's in the door, 0:20:17.516 --> 0:20:19.556 and then it takes off its hat or something like 0:20:19.596 --> 0:20:23.596 that or its mask and reveals the fatty lipid bind 0:20:23.596 --> 0:20:25.556 to you and then you're stuck. Are you saying that 0:20:25.596 --> 0:20:29.076 the reason that the antibodies are likely to work. Nevertheless, 0:20:29.756 --> 0:20:33.276 is that they primarily target the initial handshake, and as 0:20:33.316 --> 0:20:37.476 you showed in your initial lab efforts, there's not actually 0:20:37.476 --> 0:20:39.756 a major change in the nature of the handshake derived 0:20:39.756 --> 0:20:41.916 from this mutation. It's the later part. It's the taking 0:20:41.916 --> 0:20:44.716 off the mask. Yeah, I think that's that's exactly the case. 0:20:45.196 --> 0:20:48.956 Let's talk about vaccines in that case. Sure. So. Obviously, 0:20:49.516 --> 0:20:53.356 some of the vaccines seek to replicate precisely the antibodies 0:20:53.596 --> 0:20:55.996 that occur naturally, but there are also different kinds of 0:20:56.076 --> 0:20:59.036 vaccines that are being experimented with. Now. There are these 0:20:59.156 --> 0:21:02.956 so called trojan horse vaccines like the Oxford approach, there's 0:21:02.996 --> 0:21:06.756 the RNA vaccine like the Maderna approach. What does the 0:21:06.956 --> 0:21:11.476 evolution in the virus suggest with respect to those vaccines 0:21:11.476 --> 0:21:14.036 that would those also be just as effective on the 0:21:14.036 --> 0:21:16.276 earlier version as the late version or is it trickier 0:21:16.276 --> 0:21:19.316 than that? Yeah, I think the implication for vaccines is 0:21:19.356 --> 0:21:23.076 something that definitely merits some research. So there's about one 0:21:23.156 --> 0:21:26.956 hundred and thirty or so vaccines under in various stages 0:21:26.956 --> 0:21:29.916 of clinical development right now. In terms of how we 0:21:29.956 --> 0:21:33.036 think about virus manufacturing, one thing that I think was 0:21:33.036 --> 0:21:36.356 really impressive was how quickly some of these, especially the 0:21:36.436 --> 0:21:39.676 new clique acid based vaccines, the DNA and the RNA vaccines. 0:21:39.836 --> 0:21:42.676 How quickly we can go from sequencing the virus, you know, 0:21:42.716 --> 0:21:47.156 the first coronavirus sequence that was released in January, to 0:21:47.316 --> 0:21:50.796 having a vaccine ready to go, which was also in January, 0:21:50.796 --> 0:21:53.996 as you mentioned with maderna. And so what might be 0:21:54.076 --> 0:21:57.876 more important than being too worried about is this vaccine 0:21:57.876 --> 0:21:59.396 out of date? Has it kept up with all the 0:21:59.396 --> 0:22:02.396 newest spike mutations? Is to think, how can we develop 0:22:02.436 --> 0:22:05.876 a process or a pipeline where we can quickly capture 0:22:06.076 --> 0:22:10.876 population genomic data and I mean circulating virus data, sequence 0:22:10.916 --> 0:22:14.356 the genomes quickly, and then quickly update the vaccines to 0:22:14.396 --> 0:22:17.476 take into account new restraints and this kind of whatever 0:22:17.516 --> 0:22:19.596 you want to call it, like tightly closed loop sort 0:22:19.636 --> 0:22:22.196 of system or something like that. You know, that's really 0:22:22.196 --> 0:22:24.356 that could be a powerful process that doesn't just protect 0:22:24.396 --> 0:22:28.196 against this spike variant, but perhaps any future spike variants 0:22:28.196 --> 0:22:32.556 we might be worried about. Are there any general lessons 0:22:32.636 --> 0:22:36.516 from other viruses and the course of their mutations that 0:22:36.596 --> 0:22:39.516