Jeffery DelViscio: [00:00:00] This is a Science Talk podcast from Scientific American I'm Jeff DelViscio. Today's guest is Britt Glaunsinger, a virologist at the university of California, Berkeley, and the Howard Hughes Medical Institute. She's a specialist in infectious viruses, and she's been studying them with a focus on the herpesvirus in particular for the last 25 years. Welcome to science talk, Brit. Great to have you.
[00:00:26] Britt Glaunsinger: [00:00:26] Thank you, Jeff. It's great to be here.
[00:00:29] Jeffery DelViscio: [00:00:29] It's a really important moment to look back at our very different reality just 12 months ago. In December 2019, the first infections were just emerging inside of China. SARS-CoV-2, didn't have a name yet, and no one could imagine the global effects that the virus would have on us all. But it was also clear that this novel coronavirus lit a fire underneath the seat of science. So my question is how far has our scientific understanding about the biology and the behavior of the virus come since then?
[00:00:58] Britt Glaunsinger: [00:00:58] Yeah, we have learned some really critical things about how the virus works and also importantly about how our immune system responds to it and how this virus SARS-CoV-2, essentially causes our immune system to misfire in cases of severe COVID-19 and misfiring really centers on the very early immune responses that our body mounts, these are called innate immune responses. This innate immunity is a part of our body that really uses sensors that detect pieces of pathogens, like the CoV-2 virus that are not from our own body. And once these factors or sensors detect these viral bids they sound out an immediate alarm system that operates through molecules called cytokines and interferons. And these are important for activating those later immune responses like T-cells and antibodies that we hear about. And what we think is that it's likely that people who sound this innate immune alarm early upon exposure to the virus and induce early and high levels of that interferon alarm system go on to pretty rapidly and effectively clear the virus. So these might be the individuals with asymptomatic or moderate or mild disease.
[00:02:25] However, what scientists have learned is that people who go on to develop severe COVID do so probably because in them, the virus causes a misfiring of that immune response. So like the wrong sets of immune cells may be brought in and they might not induce that early interferon alarm system quickly or strongly. And then they can't control the viral load. The virus amplifies to really high levels in their body. So their body responds to this continued presence of the virus, basically by increasing production of factors that are involved in inflammation.
[00:03:02] This is an overexuberant inflammation or inflammatory response. And that's what leads to the lung tissue damage, which is really a hallmark of COVID pathology. So what we've discovered scientists over the past year is that there are biomarkers that can give clues about who ultimately goes on to get severe disease.
[00:03:24] Scientists have also discovered genetic differences or mutations that some people have in those innate immune genes that can contribute to poor initial control of the virus. I think that this understanding that there are essentially two phases of COVID-19 disease, that initial phase that's dominated by viral amplification. And a second phase that in severe cases is dominated by a misfiring of the immune response is really important. It's important because it illustrates that there are two types of therapies that are probably needed depending on the phase of the disease. So drugs that target the virus directly to stop its replication.
[00:04:07] These would be things like Remdesivir that we've heard a lot about in the news, or maybe treating with things like recombinant interferon. This is something that is used to treat other chronic viral infections. Those types of therapies are probably only going to be effective at stopping that first phase of the disease, um, but are not going to be very effective if they're given during that second phase, because, uh, it's then it's not the virus, but the immune system that's driving illness. And so conversely drugs that dampen that overexuberant inflammatory response, and dexamethazone is one of those these, might be dangerous of given during that first phase, when you really want a rapid and robust immune response, but could be helpful at dampening the damage that's caused by the immune system at later stages.
[00:04:59] Jeffery DelViscio: [00:04:59] One of the key parts of understanding the virus itself and how we fight it is scientifically really about timing, right?
[00:05:05] Britt Glaunsinger: [00:05:05] Exactly, timing is really key. A timing of figure out how your body responds very early and later. And you know, the timing and the dose of the virus that you might receive, understanding how sort of, you know, that timing or the kinetics of infection and response are essential. And we've made a lot of progress on that over the last year.
[00:05:27] Jeffery DelViscio: [00:05:27] So let's talk about some of that specific progress inside your own lab and within UC Berkeley. What kind of work have you been doing over the last year? And what kind of work is being done across the university itself?
[00:05:39] Britt Glaunsinger: [00:05:39] Yeah. So what my lab has been working on, uh, during this past year related to Coronavirus is understanding the viral side of things. So we know that this virus has a lot of strategies to try and dampen those early innate immune sensors. It is evolved to try and shut down that component of the immune response because that part of the immune response is so essential in essentially dampening down the ability of the virus to replicate very early on.
[00:06:12] And so what my lab and others at UC Berkeley have been doing is trying to figure out the strategies that the virus is using to fight that innate immune response--how it is lowering the levels of these innate immune sensor, proteins and genes that could be used by your body to counteract the virus. And so we study this at the molecular level, at the level of the individual RNAs that the virus is targeting and blocking from being expressed.
[00:06:45] But there's a wide variety of other research that's going on across campus. That sort of spans the scales of, uh, trying to solve the atomic structures of various viral components. Because with these, you can use that information to design specific inhibitors against viral enzymes, and also at the scale of designing diagnostic tests and setting up testing centers to, to do community-based surveillance and campus testing and things like that. So really, uh, you know, Spanning the understanding the fine molecular details of how the virus works and interacts with its host cell up through community-based surveillance work.
[00:07:27] Jeffery DelViscio: [00:07:27] So, can we step back a little bit, and just talk about the innate immune response. Maybe we can go from when the body first encounters it to post-infection. And could you talk a little bit about what we know about immunity post-infection and how long that might last given what you understand about the innate immune response? How can it be useful and effective or not, and helping them body to, to fight the virus?
[00:07:48] Britt Glaunsinger: [00:07:48] Yeah, well, it is known of course that the innate immune response plays really important roles in activating the adaptive immune response, those T cells and B cells that will either produce antibody in the case of B cells or T cells are components of the adaptive immune response that will come in and kill already infected cells and be able to recognize them.
[00:08:11] So there, these are two arms of the immunity the immune system, the innate and the adaptive, but there are clear links and crosstalk between them. We know that. A very important question, which you bring up is to what extent does our body have the capacity to remember this particular virus? If you encounter the virus naturally through an infection and mount long lasting. adaptive immunity to the virus. And this is a really important question, right? Because it will tell us, for example, if you've already been infected with SARS-CoV-2, are you protected against reinfection? And it's possible that you are, but it's also possible that you're not. We know from work that's been done with the cold causing Corona viruses.
[00:09:02] There are circulating Corona viruses. Of course, that caused about 30% of the common cold. Um, we know that individuals who are infected with these cold causing Corona viruses. Can get reinfected, um, as early as a year later, uh, with that same virus, which suggests that they don't have what we would call sterilizing immunity, meaning that your immunity is so good that your immune system blocks the virus from setting up any kind of infection.
[00:09:30] But the good news is is that these individuals, even if they get reinfected are generally protected against disease. And so that says that there is, uh, an immune response that can protect at least against disease and that's hopeful. And so we don't know yet what the situation is going to look like for SARS-CoV-2, because we're still barely a year into this pandemic. Um, although there are rare cases that have been reported already of reinfection with CoV-2 in individuals, um, from various parts of the world, including Hong Kong and the US and in Europe, et cetera, these are pretty rare examples, but they could be emblematic of the fact that natural infection with this virus, um, may not completely protect against re-infection, uh, within a short, relatively short period of time. Although it's possible that natural re-infection could protect against, um, severe disease. So the idea is that what we want to do is generate vaccines that could, um, in fact, improve that level of protection.
[00:10:36] So you could get a better, more long lasting immune response from a vaccine than you could from the virus in part, because we know that the virus itself has a lot of mechanisms built into dampen that innate immune response, and it may hide itself in ways that makes it difficult for our bodies to generate a robust, adaptive immune response.
[00:11:00] And by delivering pieces of virus, uh, through vaccines, we may actually get a better response. And I think that's the hope, but it is still too early for us to know whether that is going to bear out because you simply just have to wait the length of time and see, you know, one year out how many people are protected or from infection at all versus protected from disease two years out, five years out, uh, what happens there that unfortunately is just a long waiting game. There's no way to speed up getting an answer to that question.
[00:11:34] Jeffery DelViscio: [00:11:34] I'm glad you bring up vaccines because obviously there's a lot of focus on that right now. And that's because there are a few vaccine candidates who've done phase three trials by now, which is the last step before some kind of approval by the Food and Drug Administration. And that emergency approval may even come in the time between when we're recording this and when it goes live, that's how fast this process is moving.
[00:11:55] So two companies are reporting better than 90% efficacy. Those are Pfizer and Moderna. It should also somebody noted that there's another vaccine candidate from the University of Oxford and the drug company, AstraZeneca that's showing promise.
[00:12:08] But to go back to the Pfizer and maternal vaccines, they're both mRNA vaccines. Could you talk a little bit about what an mRNA vaccine actually is and how it works?
[00:12:18] Britt Glaunsinger: [00:12:18] Certainly, yeah, these two vaccines are... the data, first of all, are incredibly exciting to, to most, all of us in that the efficacy appears from these initial results that have been released to be very high. And, um, that's exceptionally great news. There are many unanswered questions, uh, related to these vaccines that we can certainly touch on. So it's not that that we have all of the information yet, but I think that's great news in part, because these messenger RNA vaccines. We don't have any track record with them.
[00:12:52] This is the first rollout or testing phase three testing of any mRNA vaccine. So we didn't know if this was going to work at all. Um, and the fact that they appear to be working so well is extremely exciting. So what is a messenger RNA vaccine compared to a traditional vaccine? Uh, to understand this, I need to just take a second to explain the concept of what an antigen is.
[00:13:15] An antigen is a bit of virus that you are, or a pathogen in general, but for our purposes, we're, we're talking about Cove too. So it's, it's a bit of virus that you're going to show to the immune system and tell the immune system essentially make. Antibodies against this, make an adaptive immune response against this and, you know, vaccine context, you are showing it an exact bit of virus that we know that if an antibody is made to that bit, that antibody can block or neutralize the virus.
[00:13:48] This is important because in the context of a natural infection, your immune system, doesn't a priori know which bit of the virus, if it makes an antibody to it is going to stop that virus. So it makes lots of antibodies to everything it sees and can. And many of those may bind the virus, but not bind it in a way that's actually gonna block it.
[00:14:10] And so the benefit of a vaccine for, um, developing immunity is that you're basically telling your immune system exactly what are the right kind of antibodies, hopefully for it to make. And so that's the benefit of that over a natural infection for acquiring immunity. And there are a couple of ways to give that antigen or that bit of the virus to an individual. The more traditional way would be to, uh, inject a person with a vaccine that, that has that protein already made.
[00:14:40] And so that the antigen of course, that all of the vaccines are targeting is the spike protein of the virus. That's that surface protein that is essential for allowing the viruses to bind cells and enter cells. And so if you can block spike protein binding, and the function, you essentially have stopped the virus in its tracks because it can't get into the cell.
[00:15:03] And a virus that can't get into a cell is for all practical purposes inert, and non-pathogenic. So traditional vaccines would deliver that protein directly. Either you grow up the protein, uh, you know, in a, in a big bio-reactor and injected itself, these are called subunit vaccines, or the protein is already present on the surface of an inactivated virus in some way.
[00:15:30] The thing that's different about the messenger RNA vaccines, and this is similar for DNA vaccines, similar for the, um, the, the adenovirus, the vector based vaccines, which is the weakened non-infectious, uh, vectors, all of the basic, you know, the front runners that we're going to hear about early on for the phase three trials is that they don't deliver the protein directly. They deliver the sequence, the gene coding sequence for that spike protein, uh, into your cells and use your own cells to then, uh, make the protein from that set of genetic instructions for spikes. So the messenger RNA is basically delivering the gene sequence for the spike protein, or maybe just the RNA, the receptor binding domain of the spike protein, uh, which is then, uh, used by your cells to produce protein in your own cells to then show the immune system.
[00:16:28] Do you think Mr. And a vaccines would have come so far so fast without the virus around? Is it a chicken, egg virus, vaccine situation?
[00:16:39] It certainly wouldn't have happened as quickly. And in fact, you know what we have here as a platform, unlike we've ever had before, where all of the possible types of vaccines are basically being generated and tested simultaneously. Both the sort of more classic tried and true, uh, strategies for vaccine making that have been used for other FDA approved vaccines and these newer platforms like the DNA based vaccines and the MRNs vaccines that have shown promise, but have never, um, been tested in these large scale clinical trials for vaccines before. So we'll be able to cross compare them. Uh, and of course the speed with which we're getting data for these is accelerated dramatically. We've never had a phase three trial results within less than. a year after a virus has emerged. The fastest and of course, with a four to five years, which was lightning fast compared to how long it takes to develop most vaccines.
[00:17:42] Jeffery DelViscio: [00:17:42] So it seems that SARS, cov two has remodeled the way science works.
[00:17:47] Britt Glaunsinger: [00:17:47] It is definitely remodeled the way that science works. Uh, I can't think of a time, um, in recent history or even maybe an older history where the entire scientific community and medical community has turned their expertise with laser-like focus onto one thing, in particular. We have a lot of big diseases, right? We've got cancer, we've got TB, we've got AIDS, we've got heart disease, all of which have a lot of effort dedicated towards them. But this virus has really brought the world to its knees in such a dramatic way that, um, that everybody is working, uh, together, uh, to use their expertise, whatever it may be to try and find ways to learn about and combat this virus and other viruses. And so the hope of course, is that, um, the, what comes out of, of this, uh, parallel approaches from many, many, many different angles and scientists and expertise can be extrapolated to other diseases as well, other viral diseases, other pathogens.
[00:18:54] So for example, the mRNA platform or the DNA platform for a vaccines, the benefit there is that you can do this plug and play of inserting the gene sequence, very easily, they can be very rapidly designed. And if they worked here that provides, uh, you know, a proof of principle, well, the next emerging pathogen that comes. We can use these as a starting point and have a good sense that, that, uh, they're going to be effective.
[00:19:23] Jeffery DelViscio: [00:19:23] As much damage as this virus has done to people's lives to the economy in a strange way, it sort of seems like a bit of a catalyst.
[00:19:30] Britt Glaunsinger: [00:19:30] Yeah, you could see it as a catalyst, a catalyst based on need.
[00:19:37] Jeffery DelViscio: [00:19:37] That's desperation in some ways, right?
[00:19:39] Britt Glaunsinger: [00:19:39] That's right. That's right.
[00:19:41] Jeffery DelViscio: [00:19:41] Let's talk about the future. Let's not try to project a year ahead. That seems unknowable. Given how much changed in the last year. So let's talk about the next few months. And maybe we can start in the White House. There's a change in the administration coming. How do you think the federal response to the virus might change in the coming month?
[00:19:59] Britt Glaunsinger: [00:19:59] I would say I don't have any insider information, but I can give you what is just my opinion from what I've read in the news and whatnot. Uh, and that's what, what I'm coming to expect is that there's going to be more of a coordinated federal response instead of, um, relying on sort of state to state. Uh, uh, responses, uh, you know, sort of figuring it out on their own and, and doing their own thing. My, my expectation is that there's going to be more coordination and more of a unified response that is led by the federal government, which I think will be very important, particularly for issues related to vaccine distribution and prioritization of course, of who gets the vaccine first and which factors do they get et cetera. And also in thinking about, you know, policy of should the federal government be the one, uh, eliciting perhaps mandates about, uh, distancing or mask wearing or shut downs instead of relying on States. And we may be seeing a more heavy hand there is, is my guess.
[00:21:06] Jeffery DelViscio: [00:21:06] And in terms of what happens with the virus, it's not waiting for anything, obviously. Can you talk to me about mutation? How important is it for the future of the virus? How might that change our approach to fighting it?
[00:21:17] Britt Glaunsinger: [00:21:17] Yeah. Mutation is something that we always think about in the context of pathogens and viruses in particular, because they randomly incorporate errors into their sequence every time they make a copy of themselves. Uh, and that's because for, for most viruses, they don't have the capacity of copying their genome sequence in a way that is error free. Our own cells have lots of ways of copying our own genome, um, and, and proofreading and checking and double checking it to make sure that errors are not made when we amplify, you know, our own genome and ourselves as cells, divide viruses by and larger many viruses, particularly viruses with them RNA genomes do not have that capacity.
[00:22:04] And this leads usually to, uh, for RNA viruses, very rapid mutation. And that mutation, uh, is something that can be really challenging in the context of developing antiviral drugs and in developing vaccines, because the concern is always that a very interim mutant version, a changed version of the virus will emerge that is resistant to, uh, an antibody or to a, um, an antiviral drug.
[00:22:38] Now there's good news on that front for the coronavirus, which is that yes, it mutates all viruses mutate, but that it is not mutating at the hyper speed rate that some other RNA viruses, mutate like influenza and HIV. Those are really tricky problems because of the rates that they, they, um, are undergoing mutation.
[00:23:04] Coronavirus has a special sort of feature that is very unusual for RNA viruses, um, in which it can actually correct errors that occur as it is copying its genome. It can proofread its own genome copying mechanism. And what that means is that the virus accumulates fewer errors than many other RNA viruses. Doesn't mean no errors. So of course people are constantly looking at how this virus is changing and they are identifying mutants that can arise. And in some cases, mutants that may help the virus bind to cells better or enter cells better. So called increase its uh, transmissibility or an infectability.
[00:23:55] And so those mutations, um, do exist and, but they are not arising at a super rapid clip. It's not like we're, we're seeing tons of escape mutations, particularly in the spike protein for where the receptor binding domain might be. It's relatively speaking stable, which I think is good news for the vaccine front, but it's definitely something that people are continuing to actively monitor. There are hundreds of thousands of coronavirus sequences that have been deposited into the database that, um, evolutionary biologists and genomic scientists are looking at exactly how these mutants are arising and what they mean for antibody escape and things like that.
[00:24:40] Jeffery DelViscio: [00:24:40] Well, in a seemingly unrelentingly bad year, that seems like a hint of at least a little good news. Am I being too hasty?
[00:24:48] Britt Glaunsinger: [00:24:48] I mean, that's it. What one might consider good news in this things. But I also think that it's important to keep in mind that as you mentioned, the virus is raging right now. Um, we're undergoing the third wave of infection here in the United States, the first being in April or may, and then we had a second wave in the summer and we're now encountering the third wave. We're seeing exponential growth of the virus pretty much across the nation. Um, and so there's a lot of concern that our darkest days may be ahead of us. We've got great news on the vaccine front potentially, but that's not going to materialize even in a best case scenario for several more months to come. And those several months, I think we're going to see a large number of deaths and severe infections and transmissions. And it's partly because we're entering the traditional respiratory illness season, right? This cold and flu season and coronavirus is one of those viruses that is a respiratory virus and tends to have seasonality to it.
[00:26:04] So I think that, you know, there's a real concern that, you know, part of it is exponential growth that is linked to people being indoors more and much of our lives are spent in doors and that's a, of course, much more so during the cold winter months.
[00:26:18] The problem with indoors and coldness is this tends to be environments where there's decreased humidity, uh, so low relative humidity, maybe, uh, 20 to 40%, uh, cold dry air. These are conditions where viruses tend to be more stable and easier to transmit through the airborne route. Um, dry air can also, uh, clear out some of the antiviral sort of mucus based clearing mechanisms that are in our airways that can impair that early innate immune response.
[00:26:53] And so, um, there are reasons to think that the, you know, the cold fall and winter air can exacerbate this problem, uh, of infection and that, uh, you know, so we've just got to be extra vigilant, even though we've got these great pieces of news from the vaccine that does not mean we can let down our guard, people need to be extremely careful during the wintertime about distancing and mask wearing and hand-washing and things like that. It's going to be up to all of us to, to prevent the spread as much as we can, as we wait for the vaccine distribution to happen and, you know, antiviral drugs to be discovered, et cetera. We all have pandemic fatigue, but you know, it's you get a time when boy, if we let our guard down, it's going to be a disaster over the next couple months.
[00:27:40] Jeffery DelViscio: [00:27:40] Well, it seems that science is not going to stop pushing on this. Finally, could you talk just a little bit about what it means to be you right now? Someone who's really been engaged with this kind of research for 25 years. What is it like to be working on this particular subject so closely given how important it is to really the whole world?
[00:27:59] Britt Glaunsinger: [00:27:59] It's a humbling experience on the one hand, because I, my perspective having worked on viruses so long helps me realize the magnitude of the problem and the magnitude of the challenge that, that faces us in a pandemic like this. And, and so, um, that's a very humbling, uh, experience, but also it's one that, that makes all of us who work on viruses and scientists in general, feel a sense of, of duty that we have something to contribute. We have a knowledge base. We have a skillset that can help us learn how this virus works and fight it. And, and that's a really motivating and invigorating feeling to, to know that that we have something to contribute and that my knowledge, you know, hopefully is useful in this context and as we go on in the future as well. And so, um, you know, if it continues to fuel my passion for virology, which has always been strong.
[00:29:00] Britt Glaunsinger is a virologist at the University of California, Berkeley, and the Howard Hughes Medical Institute. Thank you so much for joining us on Science Talk, Britt.
[00:29:08] Thank you so much for having me, Jeff.
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What Science Has Learned about the Coronavirus One Year On - Scientific American