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Ep #32 Transcript | Sarah Otto: SARS-CoV-2 Variants, mRNA Vaccines, Virus Evolution & the Future of

Full episode transcript (beware of typos!) below:

Nick Jikomes

Sarah Otto, thank you for joining me.

Sarah Otto 3:13


Nick Jikomes 3:14

Can you start off by just giving everyone a brief overview of who you are and what you do?

Sarah Otto 3:20

I'm an evolutionary biologist, I mainly use math modeling to predict and understand how evolution proceeds, it actually is very complicated. With all sorts of things happening at the same time. As we can see, with a pandemic, there's mutations going on and selection going on and movement over space. And to combine all of those forces together, math can really help us kind of see what will work and what won't, just like an economist would want maybe use models to predict how an economy will change. That's kind of what I do with math, and understanding evolution.

Nick Jikomes 3:55

So a lot of what we're going to talk about today is the evolution of SARS, cov. Two, but I want to spend a little bit of time, just getting listeners up to speed on some very, very basic stuff about viruses generally in this virus, as well as some basic stuff about mutation and selection and some of these terms that you deal with a lot. So let's just start with SARS. cov. Two, what is a virus or what kind of virus is this one?

Sarah Otto 4:21

Yeah, so viruses, there are many forms of it. And one of the basic divisions is whether it stores its genetic information in RNA or in DNA. And this particular one is an RNA virus. And so it uses bases but not ACTG AC ug, and those viruses that RNA gets inserted and used in your body, just like our bodies use RNA to turn our DNA into proteins are kind of short changing that process and going straight from RNA to protein. So first, a virus has to get into our cells, of course, and we can talk more about how that that happens that with SARS, code two and this is important evolutionarily, this spike protein, that thing you see on the outside, attaches to ourselves to an ace two receptor. And that allows entry of the virus into our cells, the RNA that goes in and uses our regular machinery to copy and turn that RNA, either into other RNA copies, or to translate it and turn it into proteins. So there's other types of viruses that are DNA based, but the art the art, this one is known as an RNA base. And what does it matter if it's RNA or DNA base? Well, it turns out RNA is a little bit more unstable, it's a lot easier to make mistakes when you copy RNA viruses. So a lot of RNA viruses have a really high mistake or error rate. And that leads to mutations, which are changes to that information that RNA information from virus virus virus.

Nick Jikomes 5:58

What about something like the common cold or the flu? How did those viruses compare to this one?

Sarah Otto 6:03

Yeah, so the flu, the common cold, that actually a mixture of a whole bunch of different viruses, the flu is also an RNA virus and the flu, some both then are RNA and kind of a little unstable. What is unusual about this type of Coronavirus, that causes COVID is that it actually has one part of inside its RNA code, it has one part that proofreads and double checks and make sure that when it's replicated, that it's doing a good job. And so because of that it actually turns over and mutates at a slightly lower rate. I think it's about six times lower rate than the flu virus, which evolves faster. And the fast evolution of the flu virus, that fast turnover, is why we have to get flu shots every couple of years, and why we get the flu over and over again in our lifetimes unless we get a shot.

Nick Jikomes 6:58

I see. So the flu virus is just changing very rapidly. It goes through mutations a lot. Yeah. What about the size of these viral genomes? How many base pairs are there? How many genes do they have? And is that going to be important for anything we discuss?

Sarah Otto 7:14

Yeah, so the partly because it's an RNA virus with an ability to check, it's actually got a bigger genome, it's 29,000 or so base pairs? And, you know, I think we there's still a lot that we don't know, because sometimes there'll be a part of the RNA is like, Is this doing something or not doing something? There's so I, we I can't tell you exactly how many genes precisely, or how many aspects of the RNA are coding for something that's important to the virus. But we know the big ones, we know what helps it get into the cell, we know what the, the nucleo capsid gene is really important to kind of form the virus what we see, and then those spike proteins as well. So those are some of the very important genes, whether particularly important, those outside ones are important to what our immune system see. That's, that's the, they're the outward face of this virus, and other genes are involved in that replication within ourselves. And honestly, we know still very little about what genes are important and how they're important and kind of subverting the normal cellular machinery and turning it into a virus making factory.

Nick Jikomes 8:28

So when we talk about mutations, we mean that somehow the sequence of RNA in this case changes. Can you talk a little bit about genetic mutations in the context of evolution? And in particular, I'm hoping you can describe for people the difference between adaptive neutral and deleterious mutations, what are those? And how common are they relative to each other.

Sarah Otto 8:52

Let's start by an analogy, you've got a vacuum cleaner, and you kick it. Now, most of the time, if you kick it, it's either not gonna break your vacuum cleaner, or it's probably going to make it worse. So if it doesn't do anything, then that's a neutral mutation, it's a change that doesn't do anything. If you just broke your vacuum cleaner, then that's a deleterious mutation, something bad for it. Maybe your vacuum cleaner wasn't perfect before, and maybe by some remote chance, you kick it and make some vacuum cleaner, better. Those would be beneficial mutations, but just like a vacuum cleaner, most organisms that have evolved, are functioning pretty well. So it's pretty rare to change them and make them a more a better functioning organism. And that's true for this virus as well. It's evolved for millions of years. And so most mutations either hurt it, and by hurting it means make it that means it makes it less likely to be able to transmit from person to person and persist over evolutionary time. Neutral means it has no effect on that and beneficial from the viruses point of view is just about that transmission and persisting over time.

Nick Jikomes 10:06

And so when we think about the different types of mutations and what the virus wants, if we anthropomorphize the virus, what's the difference between natural selection and adaptation? Versus genetic drift? I've heard that term come up.

Sarah Otto 10:21

Yeah, so selection is about what about for a virus, that transmission and persistence, anything, any change that allows that virus to better transmit and better make viral babies that transmit and persist over time, those will be favored by natural selection. On the other hand, something that makes it not able to get inside a cell would be disfavored by natural selection. So natural selection is the process about the kind of differential success and failure of any of the variants any of the mutations that arise in any organism. So natural selection is that process of the ones that are better able to survive and reproduce, do so the ones that can't are eliminated. Now, you mentioned another term, which is pretty specialized Evelyn evolutionary term, and that is genetic drift, or random genetic drift. And that's an important process too, because not all changes that we see our evolution by natural selection, we also see, evolution just means change. So a change in population that you're following. So change can happen piece of natural selection, but can also happen because of drift. And by that, imagine you had a bowl of m&ms and you only picked one that out, you need to have a lot of variation in your original bowl, lots of colors, you picked one out and it's read. So now that is genetic drift, there's been a change in frequency from a mixture to 100%, right. And that process happens a lot. And it happens a lot with viruses, because you can have a large population of viruses within our body. But only one virus is lucky enough to transmit to the next individual. So there's a big element of chance that happens there. And even if you have if you're talking about different people, and lots of different viruses within different people, there's also a lot of chance in which of those people happen to board an airplane and fly to another country and bring service code to wisdom to this other country. So that those chance events play have played an enormous role in the unfolding of the pandemic, particularly we saw who first took the virus from Asia to Europe, that was just a random kind of a draw of the people that were there in China. And that caused the frequency to shift in Europe, relative to what we saw in China. So that's evolution, but it's not evolution by natural selection. It's evolution by chance.

Nick Jikomes 13:01

And so when we think about mutations happening, to create new variants, which we'll come to what part of this virus's lifecycle? Is all that mutation happening?

Sarah Otto 13:13

Yeah, so those mutations are, as far as we know, all happening during replication. So that would be all within our bodies. And, you know, so goes into our cell, the RNA is replicated to more RNA strands. It's not perfect. So that's the where the majority of mutations if not all of them are occurring.

Nick Jikomes 13:36

So when Yeah, it's when the viruses inside of us it's not like the viruses floating around and picking up mutations?

Sarah Otto 13:43

No, I mean, it's possible, but I would expect that that would be more damage, which would be then probably make the virus unable to infect like, for example, we know ultraviolet rays are mutagen, they can cause us our DNA to mutate. That's why we're advised to wear sunscreen. Well, more likely for a virus, it damages it, and then it's done.

Nick Jikomes 14:11

So the virus can infect someone, it's inside their body that starts to replicate. And during that replication process errors happen, mutations happen. And now we get sort of different variations on the original virus that are inside of that host body. Can you unpack some different terms for people variant, lineage, strain and species? And I guess the overarching question is, you know, how much difference has to arise before we talk about two viruses being variants of each other versus different strains, etc?

Sarah Otto 14:41

Yeah. Lots of terms. So strains are is a term referred to for very distantly related viruses. So we'll talk about one different Coronavirus strains SARS code to is one string. So we're not none of the various ability that we see in the pandemic is creating different strains. Variants is a loose term. And so one mutation can create a new variant. And but not all of as I mentioned, not all variants matter, some could be neutral, some could be deleterious. And so that's why the World Health Organization introduced this new terminology, which is variant of concern, a variant of concern is one of these types of virus, but that actually has an impact on disease, it either transmits better, it causes more severe disease, or it gets around our immune reaction, either an immune reaction Ps were vaccinated or an immune reaction, because we've already had COVID. So there's variants of concern, there's variants of interest, which are, oh, there's something suspicious about this variant, that the mutation that's happened in this particular virus, something suspicious, we're going to keep an eye on it. Maybe it has changes in that spike protein that'll make it more likely to get into our cell, or, you know, maybe those are the main ones that cause it. Or maybe it's just risen in really in high frequency. For example, when we saw that lambda Rosen really high frequency in Peru, or Chile, that might be because of some genetic change in that variant, or it might have been those evolution by chance events, but the that the people that happen to kind of first come and cause COVID, to spread in those countries happen to carry lambda. So that's what that is, what is a variant of, of interest. And then there's variants under investigation, which are kind of similar to that. But anyway, let's step back variant of concern is something we know to be harmful, more harmful to us as humans, it's a very human oriented perspective. But a variant is any variation caused by mutation, lineage and clade. Those are more technologic technical terms, lineage. So evolution is unfolding, it's creating what's called technically a phylogenetic tree of life. But you can think of it as a family tree. And so a lineage is a branch on that family tree of these viruses. So if I pass the virus on to you, and then you pass it on to somebody else, that creates a lineage of descent where the virus has passed from person to person, those close those lineages tend to be very similar to one another until enough time has passed. And so the there's a kind of correspondence to how close you are on the family tree of viruses, and how similar your RNA seek the RNA sequences will be. I

Nick Jikomes 17:41

see. So variants are different versions of the same strain within the same lineage. They're very closely related. And sometimes they're of concern to us because it increases the transmissibility or something of the virus, and sometimes they're not. Yeah, before we get into some of the new SARS, cov, two variants that people have maybe heard about in the news, I want to talk a little bit about different types of people in terms of how viruses mutate. So I was reading one of your review papers, and you talked a lot about the importance when thinking about viral evolution of immunocompromised individuals. So why why is that population of people important here?

Sarah Otto 18:23

Yeah, so mutations happen just by chance. But there, it ends up being on average, like a block, you know, you see, every month or so there's a couple a change in this virus. And so we can watch and as changes accumulate, we expect it to tick at a certain rate. And but sometimes, and then some people we see a lot more mutations than others, and immunocompromised individuals, some of them have been suffering from COVID for six months. And this isn't like long COVID. Most people with long COVID don't have persistent virus, but immunocompromised individuals are have COVID replicated the virus replicating within their body for months, over six months in some cases. And then though in those patients that are less able to suppress the virus, the virus is able to replicate more times reach a higher population size and replicate and replicate and replicate miss that fast and large series of replications that cause it higher mutation rate and a higher accumulation of mutations within those individuals.

Nick Jikomes 19:37

I see. So they have an immune system that's compromised in some way. They simply can't get rid of the virus. So there's, there's just many more chances for the virus to continue to replicate and accumulate more mutations. Is this quite a diverse group of individuals? Do they tend to be people that have pre existing diseases that make them immunocompromised?

Sarah Otto 19:55

Yeah, there's a few reasons I think some people are born immunocompromised, others are On immunosuppressant drugs in order to tackle a cancer or the thing that they are dealing with. So there are a number of reasons why people can be immunocompromised, and even. And I think that term can encompass an array from really no immune system to a weakened immune system. And so somebody with a weakened immune system can still fight source code to off. So we're really talking about just a handful of people that have been followed tracked over months, so that we know in those people at least, we have this fast turnover virus, and a higher than expected mutation rate. Now, why that matters, is it turns out that that, that the variants of concern that have emerged, particularly alpha, it was puzzling, because we have this kind of molecular clock ticking note long, the viruses changing at this kind of predictable rate, blah, blah, blah, blah, blah. And then also, there's a strain alpha that appeared B 117. It was first called in the UK. And it had, like 20 more mutations than we'd expect for a virus that has been circulating in humans for that amount of time. And so you know, that my first thought was, well, maybe it was passage through make or another animal, because we've known that there's been human to animal back to human transmission of SARS cope to. But there was no, there was no sign of that no sign of any buddy in the history of that virus being near mink, Farmer anything like that. So the most likely explanation, and it had a kind of the same sorts of changes that we see in immunocompromised individuals, lots of changes in the spike protein. So the working hypothesis is that somewhere along the lineage leading to alpha, a person that happened to get it was immunocompromised, and had a higher than average rate of replication, leading to this boost in mutations.

Nick Jikomes 22:06

So alpha was that first variant of concern from the UK is the convention for something like this to go alpha, beta, and so on and so forth.

Sarah Otto 22:14

No, the B 117. terminology is really more like on this family tree or phylogeny of the virus, it's labeling the different branches and numbering them that way. And, you know, the who was recognizing it was hard for everybody to keep track B 161 7.2. That's stilted, it's hard to keep track of it. So they came up with this convention of giving it a Greek letter alpha, for the one in the UK, beta for the one in South Africa, gamma, for the one in Brazil, delta for the one that first rose and frequency in India. But the problem with that, is that static, right, you can't give an evolving thing, a static name. So we've got delta, but actually, already, there's tons of variants within delta. And we don't know which of them matter if any, so giving it a name, your there's going to be a delta point one or Adelphi another, we're going to have to go. We're gonna run out of Greek letters.

Nick Jikomes 23:18

So one thing that strikes me is, and this could just be my ignorance. We're, you know, we've already got these, you know, handful of variants for this virus. But earlier, you were talking about how the flu actually mutates faster. So are we seeing like the typical amount of variants come up for this virus that you would expect based on its mutation rate? And its basic biology or are more popping up in than you would expect?

Sarah Otto 23:46

Yeah, I think, well, our expectation is based on that first year of trends, where it was really the number of mutations over time was was a nice linear trend fit it well. And then we're seeing these boosts so, so yes, and no, we're seeing that the virus is making kind of leap froggy jumps in mutation rates. And really, why why that probably is and why we know it is just there are so many cases worldwide, something happens and this is kind of an accident of evolution goes through an individual that in which the virus is better able to replicate and does so more often introducing more mutations.

Nick Jikomes 24:33

With these variants, have there been any patterns? Like do they have similar mutations causing similar phenotypic changes and and what have those been what parts of the virus are changing?

Sarah Otto 24:43

Yeah, so they're the same mutation is appeared over and over and over again. So all of those 29,000 base pairs pretty much the we've had so many cases globally now that the evolution has kind of explored all possible changes, but that's what One change at a time. And it's combinations of these changes that really lead the virus into kind of evolutionarily unexplored space. And we're still, you know, you said about the phenotype of the virus, the phenotype of the virus is something that we can't directly measure, we can't directly measure whether it transmits better, we can't directly measure whether it leads people into the hospital more often. And then it can be very difficult to make the kind of statistical association between the which genetic changes underlie higher hospitalization rates are faster transmission. But it is interesting that the, during the first year of the virus, we really didn't see one strain taking over the world. And if you looked at that evolutionary tree of life, you could tell that that was true, because it was kind of like everything was doing pretty well. And all lineages were persisting, almost equally. And then alpha rose, and we saw something different all of a sudden, now, this strain, this second, not strain, right, this variant, with the mutations that it held, was spreading faster and faster. And so that part of the evolutionary tree of the virus grew to be much more predominant. And country after country after country in which alpha was found it was displacing the previous variants of SARS code two. And now of course, we're seeing that same thing play out, but with Delta replacing alpha.

Nick Jikomes 26:35

And this is this has primarily been through increased transmissibility so far.

Sarah Otto 26:40

Yeah. So that that's, that's a statistical thing. And this that the statistical assessments have been like doing the following, looking at households of a known case, to see how often the household members get infected. And with Delta, more of the household members get infected, then with alpha, and for alpha more of the household members get infected than with the wild, wild type strain that originated in humans?

Nick Jikomes 27:11

And is that what we would expect at this stage? Would we expect a lot more higher transmissibility to be favored, say, as opposed to a deadly or virus? And if so, like, why, why is that the expectation? Yeah.

Sarah Otto 27:23

So before, for the for the virus, its evolutionary fate just depends on persisting and transmitting. And anything it does to us really is kind of a side consequence. Now in some for some diseases, that if if the virus kills you, then it's unable to transmit. But with SARS Cove two, it's a bit unusual, in that most deaths are long after the virus has come and gone and rapid viral load has risen and fallen. And then the deaths happen in the month after that. And that's because most it seems like most of the severe cases are immune reactions and kind of spiraling out of control. And it's not actually the virus replicating within our body. And so because of that, those severe side, those severe outcomes of, of COVID are not important to the viruses transmission, because they happen long after the virus transmits. So can't really see that part selection can't see it. So that doesn't mean the virus can't evolve and affect our hospitalization and death rates. It means it's evolving to transmit effectively. And as a side consequence, it could increase or decrease mortality rate.

Nick Jikomes 28:49

I see. So well had a next question. But I'm already thinking a little bit ahead. Now, I have heard. And I don't know if this is true at all. But I have heard many times from many different people that in general, viruses tend to become less virulent over time. First of all, is that true? And then what do we expect that for this virus? It almost sounded like what you were saying, though, is, we wouldn't necessarily expect that because you have that dissociation between when it replicates and when it becomes

Sarah Otto 29:19

exactly, exactly. And and you really have to get your mind into the perspective of the virus, you have to really think okay, um, that's fire sound, my evolving over time, some diseases, it's through the death that the virus is actually transmitted, or the pathogen into the environment. In that case, higher death rates can evolve, because that makes it easier for that pathogen to get transmitted. In other cases, and this is where that classic classic thought comes from deaths takes the personnel out of circulation. And so if that and then the virus can transmit so we it's really a pathogen by pathogen question. And for SARS Cove to as we were talking about the virus is as far as the viruses evolution is concerned, our deaths are immaterial.

Nick Jikomes 30:11

I see. So there's there's not necessarily any direct selection for the virus to become deadly or however if it does become deadly, or there's nothing sort of pushing that topic. Yeah, yeah, that's right. Well, that's unfortunate.

Sarah Otto 30:26

That's unfortunate. Yeah. But you know, that does mean. So the two major variants alpha and delta are both deadlier, unfortunately, leading to more severe disease. But that doesn't mean that the next variant will necessarily be one that causes more severe. And so that's maybe good, Matt, we we may in the future be dealing with a variant that drives down hospitalization rates?

Nick Jikomes 30:50

Yeah, that makes sense. The other thing I wanted to ask you about was on the transmission side. So you have this one concept in this paper, that was pretty much the 8020 rule that you hear about in lots of different contexts. But the term that that was in the paper was over dispersion. So what is that? And how, why is that important for thinking about transmission?

Sarah Otto 31:09

Yeah, so I'm, not everybody that gets infected is equally likely to transmit the virus to others. And we still really don't know why that is. And it could be something as simple as which cells inside our body get infected. And is it easier for us to cough them out or breathe them out. And so is it in our nasal passages it is it are deep in our lungs. And that can in fact, affect the transmission probability from a single infected individual. And so people I think, are more this overdispersion has to do with this kind of concept of super spreaders, individuals that that may be more likely to spread the virus from person to person. They're super spreader people, which is how they are infected, and how they interact with the world means the virus can get out of them better. And then they're super spreader events, whether it's nothing unusual about that particular patient, but more that the environment allowed the virus to remain airborne and affect more people because it was a crowded indoor environment without good ventilation.

Nick Jikomes 32:18

I see. One of the things I want to discuss too, is vaccination. So actually, before we get there, you know, it sounds so far, if I sort of, sort of piece some things together, viruses accumulate mutations predominantly inside our bodies after we've been infected. So the new variants are going to come from having arisen inside someone that got an infection, and then they they start transmitting to others. So the more people that are getting infected and holding on to the especially if they're holding on to the virus for a long period of time, such as if they're immuno compromised, that just more and more chances for new mutations, and so more and more chances for new variants is part of the reason that we're seeing now several variants arise so far for SARS, cov. Two, because so many people have yet to get vaccinated, or, or just get natural immunity. And so I guess my question is, would you expect us to see several new variants from now?

Sarah Otto 33:15

Yeah, so the number of variants and the variety that we see across the world really depends on the case count when so we, when we have globally high case counts around the world, then that's just more evolutionary tickets that this virus is buying in its jackpot. So, but so far, with maybe the exception of beta and gamma, most of the selection for alpha and I think for delta as well had nothing to do with vaccines or with people that had had previous exposure to the virus because, you know, beginning of 2019, none of us had exposure to SARS cope to and so that was it's the virus has been mainly evolving in a fairly naive population. But they're, you know, the gamma from Brazil there was there was evidence that a lot of people had been infected there previously that a lot of people had and you natural immunity to SARS Cove to and yet this took off like wildfire. So we're still unsure if that was because that variant was better able to reinfect somebody that it had previous but kind of to evade the immune reaction better able to get in, or if it just was spreading in that remaining population. They haven't gotten it the first time. So that there's still a little unclear whether and to what extent these viruses are getting a fitness boost by not just transmitting better between everybody but transmitting to people that other viruses can't get into.

Nick Jikomes 34:54

Is there a good chance? I mean, people are already talking about booster shots and things Is there a good chance that this is going to be something This particular virus and its variants, this will be something where people will be asked to get vaccines every year sort of like a flu shot.

Sarah Otto 35:08

No, I don't think so because of this lower mutation rate, we may get, we may need a booster in the next year, simply because there's so many global cases that we are evolving these kind of unusual events happen, where there's a higher number of mutations, and we're just getting more and more variation across the across the world. So I expect maybe in the next couple of years, a booster will be necessary, but then not so often as the flu.

Nick Jikomes 35:36

after that. I see. Is there any risk? So I don't know what the precise numbers are. I think we have a majority of the adult population, at least in the US vaccinated or in somewhere in the the one to two dose range for vaccination. But there's a sizable chunk that have not and, you know, for better or worse, it looks like a lot of people will not elect to get a vaccine for whatever reason. Is there any danger in having that sort of like, sizable chunk of the population that never gets the vaccine? And that sort of creates a window for sort of a perpetual evolution of new virus new new variants?

Sarah Otto 36:14

Yeah, yes, absolutely. So and having that population constantly in contact with vaccinated individuals means that there's a lot of opportunities for transmission that happen and opportunities for mutations to arise that can then get into vaccinated individuals. And so if the if we could gate we should be aiming for 100% vaccination, the number one reason is if you have 20% of your population on vaccinated you have 20% of the population that can land in the hospital and die from COVID 19. So get vaccinated, to protect your own health, but also get vaccinated, because you don't want to be the one that transmits it to your neighbor, your friend or your parents and, and then lands them in hospital. So get vaccinated, because you don't want to be the cause of somebody else's COVID-19 severe reaction. And then finally, and this is low down on that list, but it's still in there, get vaccinated so that you make it a little bit harder for this virus to persist and spread within the human population and you thwart its evolution.

Nick Jikomes 37:25

So which vaccine did you get you get one of the mRNA vaccines? And can you explain for people what those mRNA mRNA vaccines are as compared to a traditional vaccine.

Sarah Otto 37:37

So Maderna, and finer, Pfizer are giving the little instruction manual, the mRNA, but just for one protein, the spike protein, and the reason why the companies developed it for that is that's also on the outside, that's what our immune systems see. And so it's one of the safest vaccines ever produced in that it's, it's not an inactivated virus, it doesn't have all of the genetic coding, it would need to actually make a virus, it's just this teeny piece of the genome that just makes one protein. And, you know, honestly, I think they it works better than anybody ever expected it to that that we just be inserting the the RNA in our bodies would take hold and recognize it and amount such an immune reaction. So it's really quite impressive how much protection you get, even after one dose and especially at two doses.

Nick Jikomes 38:38

And now, did you choose to get that one? Or is that just the one that you happen to get?

Sarah Otto 38:42

Um, it is the one I happen to get. A lot of people here of my age group were had AstraZeneca, but it was all out when I was looking. So anyway, yes, I could have gotten AstraZeneca. But it was Maderna that I did.

Nick Jikomes 38:58

Now, if given the choice, is there any evidence that these are clearly more effective than the traditional style vaccines? Or is it comparable?

Sarah Otto 39:08

mRNA versus AstraZeneca? Yeah, yeah. Yeah. You know, it depends on what exactly you look at. So AstraZeneca does have a very, very, very small side effect. risk of clotting. And so, you know, given equal availability thing, go for the one with the lowest risk. If you look at protection against symptomatic disease, oftentimes mRNA virus vaccines have higher protection, but if you look at protection against hospitalization and death, and AstraZeneca is often at the top of the list. So it's a you know, it's a little bit hard to know and of course, the other question is, what about with variants and which of these vaccines is going to give confer a stronger reaction and you know why? It could depend on the variant with Delta, we're seeing that the mRNA vaccines are doing really well.

Nick Jikomes 40:05

Now, the mRNA vaccines are interesting, because not only have they performed so well, but as you mentioned, the mRNA they contain encodes the spike protein only. Now, naively, I might think that that would, that would lead to an immune reaction that was very specific for the spike protein, and perhaps not so good at recognizing other parts of the virus. And so it's sort of like a less just sort of a less robust overall immune response, are we seeing any indication of that so far?

Sarah Otto 40:35

Not yet, you know, when people were looking at what our antibodies were reacting against, it turned out it was like a lot of the different parts of the virus, but mainly the nucleo, capsid, and even more, so the spike protein, so you're basically they've designed the vaccine for exactly the target that is normally recognized by our immune system, let's say about 50% of the time, if our antibodies are made against spike,

Nick Jikomes 41:00

are you saying, in response to an mRNA vaccine we're making

Sarah Otto 41:03

in a natural infection, then the most antibodies are I can't remember exactly the numbers, but let's say 50%, spike, 40%, nucleocapsid, everything else a little bit. And so there's this kind of correspondence between a natural reaction and the reaction to only this one little piece, this spike. The other thing about spike is it has to get the virus has to get inside ourselves. So it's constrained. And evolutionary constraint is an important concept of something that can't change too much, or function. And so the spike can't change too much, or it won't attach to the AC to receptors and get inside ourselves. So that constraint is also a good thing, because that means the virus can't mute. Some mutations are prevented from happening.

Nick Jikomes 41:53

I see so so we can have some of these new variants with Spike protein mutations that are that variant to transmit better, but there really is a sort of limit to how many of those could could happen.

Sarah Otto 42:04

That's right, there is a limit, because that would be deleterious if they prevent it from getting inside ourselves. But the other thing that's kind of interesting is there's a lot of unknowns. And so here are a few unknowns, the viruses mutating, it's accumulating changes, and so eventually, our immune reactions that are primed by our RNA virus won't recognize something that's very, very, very distant. And so as the mutations accumulate mutations, that will happen. But so, what will have boosters, but the fact that we didn't use nucleo, capsid, in our first viral RNA vaccines meme, it's kind of in it's a, it's a, it's another tool we could use in future vaccine development, targeting a different part of the virus. And so I think, we may see that that turns out to have been a really strong element, strong benefit of having a one protein vaccine. Let me tell you a little bit more about why I think that might turn out to be important is that if you get a boost, so there was a if you get a booster with a vaccine that's been targeted to a different variant, that may not actually cause you to recognize the variant very well, because it's mainly going to boost your memory, immune cells that are already targeting the first vaccine that you had. So that's called the hypothesis is of original sin in terms of immunology, what you for that disease, that you the variant that you first got exposed to is the one that you're best able to fight for the rest of your life. And we don't know if that's going to play out with source code to, but it does mean that boosters may not you might not just be able to go oh, now I'm going to get the Delta, the Delta booster and now I'm going to get the omega and booster and in your immune system may not track that those changes, as well, because they're primed for in my case, they were primed for the Wuhan stream, the original stream.

Nick Jikomes 44:20

Interesting. What do you make of it? Can you just explain for people the programmability of these new mRNA vaccines? What exactly does that mean? And how? How do you look? I mean, how do you look at that in terms of our ability to adapt to new viruses in the future? Not necessarily this virus either. But what does mRNA vaccines allow us to meaning

Sarah Otto 44:39

they're, they're game changers because, well, I'm not in the lab actually making them I should be careful. But they basically allow a DNA sequence and RNA sequence to be converted into a vaccine that can design it and convert it within a matter of weeks, which is As you know, so amazingly quick, it's harder to the hard part is getting it approved and getting it manufactured. But the design of it is no longer a major challenge. Just amazing.

Nick Jikomes 45:13

And do you imagine that we'll be seeing more of these mRNA vaccines for other things in the near future? Yeah, absolutely.

Sarah Otto 45:19

And the other the other thing, that trick that a lot of vaccine producers are aiming for, are what are those evolutionarily constrained parts of a virus that are just so like, I can't change at all or I'm not going to work? Because if you target your vaccine there, then the virus can't evolve and escape your immune reaction.

Nick Jikomes 45:41

That makes sense. Yeah. What about the length of immunity? Obviously, only, you know, so many months have gone by so far for us to have even done some of these measurements. But how is there any data out there right now, that shows us that people are having a persistent immune reaction, either from a natural infection or from these mRNA vaccine so far?

Sarah Otto 46:02

Yeah, and so we're accumulating more data, including from vaccinated individuals, because it's now been months since. And so first of all, your listeners should know, the immune system is incredibly complicated. And we don't understand how it all works. And we don't understand how it all works in general, let alone for this particular virus. So there's some really fundamental things that we don't know like, let me toss some terms around neutralizing antibodies are antibodies. And then there's T cell and B cells, and they do different things. So it's still unclear how important the neutralizing component is those neutralizing antibodies are the T cells. And so these are like different armaments, different ways of fighting a disease that our bodies have evolved to do. And our bodies have evolved these incredibly complex armories of different tools to attack a virus. Okay, so now let's, let's dig into that.

Nick Jikomes 47:07

Can you actually explain those neutralizing antibodies? Yeah, T cells?

Sarah Otto 47:10

Yeah, exactly. Well, you should get a guess that's an immunologist, because this is going to be a cartoon version. But that's what I'll give you. So neutralizing antibodies, they are called neutralizing, because they prevent the vaccine, that virus from actually getting inside our body. So they and that's because they attached to the part of spike that needs to attach to our AC too. So if the antibody attaches there, the virus can't get in. And that's what it neutralizes the virus preventing it from even entering in our into our cells in the first place. So that neutralizing antibody is great news. And that's, that's what we like to see the a lot of the rapid antigen tests can assess those antibodies, we'd like to see him because it means that virus can't even infect an individual. But those wane over time. And then normally, when we don't have neutralizing antibodies, that these are sky high levels for the rest of our lives, it's typical that it rises and then falls in about a six month period. And that's what we're seeing with COVID 19, as well. So we have that kind of you can't get inside protection, but only for a little while, then the antibody levels plateau at some lower level. Now a T cell and B cells do other things, they recognize cells that are infected, and then they get them out of the system, the B cells do things like say to amplify and produce those antibodies kind of over the long term. So these these B cell and T cell over the long term, are kind of your long term memory of past viruses. And, and so they can when they kick in, they recognize oh, these cells are infected, get rid of them, they also recognize, oh, I need to make those antibodies, those neutralizing antibodies again, and so they start kicking up a storm. So those so those all play a role I've heard, I've read that T cells play a more important role in actually protecting people from severe disease. So the neutralizing antibodies are really important in keeping you from getting infected but keeping you out of the hospital, given that you didn't get infected, it's those T cells that play a really important role. Okay, so that's my, my cartoon understanding of what's going on inside our bodies. And those T cells and B cells are long term there. They are triggered by these memory cells that have long term persistence. So what that leads me to predict is that arch our chances of getting infected after vaccination is probably really, really low in the first six months. But then after that, we may be more likely to get infected but then immune systems recognize this virus and kick it out. That's consistent with Sorry,

Nick Jikomes 50:07

I'm just gonna say so that pattern that you're just describing there that we've seen in the response to SARS, cov. Two, it's actually pretty typical.

Sarah Otto 50:14

Yeah, yeah, super typical and predicted by some of the best immunologist in the world, and they were like, do not that it's not, that's not a typical, and this is what we'd expect. And many of our vaccines last for decades, in their efficacy, because of these long term memory reactions, not because of those kind of short term, neutralizing antibody reactions. And so you know, that right now we're seeing more cases of vaccinated individuals getting infected, there was this recent event in Providence, Rhode Island, where I think 300, vaccinated individuals were infected. And that sounds like a, you know, a large number. But first of all, there were a lot of people there. So 300, out of 10s, of 1000s is not a very large number. But the second, again, infection is not something that we should be that surprised by that that happens. And it's really, were those individuals then clear to the virus and healthy the next week,

Nick Jikomes 51:26

I see. So let's say you get you get just to summarize my understanding, you get vaccinated, you know, first six months, you've got these really high levels of neutralizing antibodies that are pretty much probably going to prevent that virus from getting back into at all, maybe another six months go by the levels of those antibodies go down. So now it might be possible that virus or new variant gets back into you. But also, it's likely that some of your other immune cells will be able to take care of it before it really does a lot of damage.

Sarah Otto 51:54

Yeah. Okay. Yeah. And so that's why we're seeing things like 25 times lower hospitalization rates among vaccinated individuals. Yeah. And I should say also, that the neutralizing antibodies ramp up, you know, like, you get your vaccine in the first two weeks, you have no protection, and so they ramp up before they come

Nick Jikomes 52:14

back. So that's why it's super important to be cautious in those first two weeks or so after

Sarah Otto 52:19

at least two weeks. Yeah. And even after that, it takes a while from its maturing. So it takes a while to really ramp up.

Nick Jikomes 52:27

So what's the difference between a vaccine and antiviral medication? I've been hearing some talk about antiviral medications. Typically, this is in a disc in discussions around, you know, prophylactics things you might take to prevent the infection before it even happens. Are there good antivirals for this virus? Is that something that would be ideal in combination with vaccines? What what do we think about that?

Sarah Otto 52:52

You know, that's something that's outside of my area of expertise, antivirals, and the nice thing about vaccines is it it feeds into our evolved immune system that so that provides this kind of really robust and multifaceted response, that it's not just recognizing this part of Spike, but it's recognizing lots of different parts of Spike. Sometimes when we give drugs, and I'm just going to speak generally, when we give a drug to then then bacteria, viruses, fungi just evolved to avoid that drug in some way to do things and in slightly different ways. So it's a little bit easier to outwit our drugs, and you see that with antibiotic resistance, we introduce a new antibiotic, within six years, we've got antibiotic resistance. And that's because it's normally one thing, it's killing the bacteria in one way, or the fungus in one way. And the the microbe just does does something else, and avoids our, our attempts to kill it. But that's different than a vaccine, because a vaccine goes into us. And then and then the hammers are all of these many, many different kinds of hammers that our immune system kicks in, not just one type.

Nick Jikomes 54:13

I see. So it sounds like overall, you're actually relatively optimistic. But I do want to ask just the overarching question of where do you see this virus and new variants going in the next six to 12 months?

Sarah Otto 54:25

Oh, you know, and I oscillate between optimism and pessimism. Delta is now such a more transmissible variant and it causes hospitalization at such a high rate that, you know, the old the last year, thought that vaccines if we got to 80% vaccinated, it would be all over. Now, we're kind of at the point where it's like, you know what, we may still see circulating SARS code to even if we got to 100% vaccination, people might not end up in hospital At that point, but it's still able to transmit and in fact, even among vaccinated individuals. So that if that, that just means that what we're dealing with is keeping people out of the hospital, keeping them from dying, but that there is not a chance of ending COVID-19

Nick Jikomes 55:26

as an evolutionary biologist, generally speaking, are you because this is the first pandemic like this of my lifetime? And I think it's been, you know, beyond my lifetime, before we've seen something quite quite this big in this global. Is that what you would expect? Or are you actually, would you expect that, you know, within my lifetime, within your lifetime, that we're gonna see more pandemics like this from other types of bugs?

Sarah Otto 55:52

I don't know. Well, we Yeah. So I think we were learning, we've learned a lot of lessons about pandemic response, I think there's this this pandemic, but many of the other ones, it's with the main messages, you got to act fast, and you got to act early travel shutdowns a lot earlier than we had, for example. So we may be learning those. But the other thing is, we've changed the world so much, we've got so many people around the world, our interactions with wildlife are so modified, in contact with wildlife much more often caging wildlife, which is allows diseases to spread in those high density caged environments. So we are seeing evidence that viruses hop into humans more often. In recent times, and so that just leads me to expect that we'll see more. And to some extent, other people more pessimistic than me, or like, well, this is the easy pandemic, which is a horrible thing, you know, given the number of people that have died. But

Nick Jikomes 57:05

yeah, yeah, but it is. I mean, it is we've seen humanity has seen more, more deadly bugs in the past. So it's entirely possible. This. One thing I did want to ask you about, is that human to animal transmission, and in the other direction, is this happening more with this virus than with other coronaviruses? are related viruses, and what does that mean for new variants and things

Sarah Otto 57:27

like that? Yeah, so I don't know about other coronaviruses. But what it does seem to be a fairly generalist virus. And that's because it uses ace, two, which is conserved and similar among a lot of mammalian hosts. And so because it's, it's the the lock that it's unlocking to get into our cells, that protein is conserved, it can get into us, it could get into cats, it can get into gorillas, it can get into tigers. And so that we're seeing and minx and other we're seeing this virus jump from species to species to species. Now, a lot of times that's not true. And what the kind of Achilles heel that the virus uses to get into ourselves is very, very different from what a chimpanzee or a gorilla or other species uses. And that's most of most of the time, we're talking very host specific kinds of viruses that can't jump as easily. But that has this other this consequence that we don't know. We don't know which other we know a lot of other animals have AC two that are similar enough to our receptors. We also know that a lot of other animals have gotten infected by us, what we don't know is whether or not and which other species are going to actually have a pandemic on their own. And, and some of those pandemics may turn out not to kill those other species, like they could be just not not lethal to some species. And then those would just be a read maybe a reservoir of this virus long term. But for others, it could potentially drive them extinct. And when I just don't know which of our which wildlife species are at risk, it doesn't get into fish doesn't get into birds, but of the mammals that it can get into, it was at risk.

Nick Jikomes 59:26

So this pandemic has really brought to light. And it's unfortunate that it takes something like this the importance of evolutionary biology as a field of expertise that we want people to be knowledgeable of, because evolutionary biology is often sort of seen as Ivory Tower, a purely academic part of biology. Do you have any general thoughts on on that, you know, and the importance of having people at least have a basic understanding of evolutionary dynamics?

Sarah Otto 59:51

Absolutely. I mean, evolution, we understand life on this planet, through evolution, and it's incredibly rich. field in a way of thinking about organisms and how they've evolved and come to be the way they are. But you know, when I started, I guess it was human evolution was a bad word. And I would often say I was a population geneticists, which is another word for what I do, just to kind of avoid that seeming like an alien beast when I was on an airplane by somebody. But then, you know, 2030 years ago, I was like, you know, I'm gonna take this on. I'm an evolutionary biologist. And it's important that people have a face to an evolutionary biologist, I'm not an alien, I'm not a monster, I'm, I'm a nice person. And in that, and I think that the, that this pandemic, but even before that, we've really understood we can't, we can't find antibiotics, we can't fight cancer without understanding evolution, we, with global climate change species around the world are facing a completely different selection pressures. And we have to understand how they evolve in order to better protect wildlife and the world around us. So I think I think people come to accept that evolution is a kind of fundamental cornerstone of biology and of understanding life. But that said, you know, still it's kind of funny is every once in a while the radio, I'll be on the radio or the news, and I'll say, how should I introduce you? And I'll say, I'm an evolutionary biologist. And it's funny how often that evolution gets dropped out. And I don't know if that's because people don't want to Ailey's still are thinking of it is this bad word? Or what's going on? But let's normalize it. I'm an evolutionary biologist.

Nick Jikomes 1:01:57

So my correct me if I'm wrong, but you don't focus a lot on viral evolution. So what? What is your general research interest? And what are you working on right now?

Sarah Otto 1:02:06

Yeah, so I'm a generalist to I use, I've studied things like, what are the features that cause populations to go extinct? What are the features that make them more likely to persist? What's the math behind that extinction versus persistence? I'm also interested in in the evolution of how we reproduce, why are we sexual, there's a lot of organisms on this planet that can reproduce asexually, it makes a lot more sense. You know, you don't, you don't have to find a mate, you don't have to risk disease transmission when you make, and you and you don't have to do this really weird thing of mixing your genome that you know, that works, because you're alive and able to reproduce and mix it with that genome of another individual to make this mixed up thing that who knows that offspring will be able to survive to reproduce. So I've been doing a lot of mathematical modeling to figure out and a lot of the older theories didn't hold up very well. And so I've been really trying to, to figure out what the main reasons for the evolution of sex. And you know, that you know, you might be that's weird, but it turns out, almost all eukaryotes reproduce sexually. So this is something that we really have to understand. Why did that? Why is that pattern so come?

Nick Jikomes 1:03:28

Well, the standard textbook explanation that I can remember is sexual reproduction allows for more genetic diversity, and that's automatically good. So it almost sounded like you said, that doesn't quite cut it.

Sarah Otto 1:03:40

Quite hold water. Yeah. And, you know, through, there's a few reasons, like, if you have selection, actually generating variation, then what sex can do is bring everything back to the mean and reduce variation. So depends on what selection is doing. But something but sex can actually collapse and reduce variation rather than promote it. That's one thing. And then the other thing is a lot of variation is bad. So you know, if you have popular individuals that have survived to reproduce, variability is basically saying, take the tried and true and make something else that's more likely to be deleterious. And we do see that a lot of times, if you compare an organism that reproduces sexually to one that's asexual, you find that the asexual offspring are fitter because they come from parents that were fit. And then the it's called a recombination load. All of these offspring that were kind of mixing and matching of genes, various genes are less than So those that's basically the backdrop just say you have to account for all of that. How, what is selection do how much variation was there in the population, and what happens to sexually produced offspring versus a sexually produced offspring? And but it's funny because in the end, after all of the mathematical crunching, it is that basic understanding of about variation that sex provides. But the twist to it is why that variation is needed is that that the the number of genomes, the number of individuals in a population is finite. And we really rapidly natural selection really rapidly evolves the best of what's available, and then runs out of steam. And so it's that finite nature of every population on this planet, and a very large number of gene genes in our genome. And you can just think about the combinatorics of we have a 3 billion base pair genome, there are so many combinations of the AC T G's at those 3 billion sites, that if we were asexual, then it would just be the best of that those genomes available on Earth. But if we combine them all through sex, then evolution can continue to move forward. And so that's, that's the type of math that is needed to be able to say, oh, it's got something to do with the finiteness of every population, and the lack of combinations that will happen. And and that's why sex has evolved and continues to be maintained and somebody is racist, which is crazy. But Sure.

Nick Jikomes 1:06:23

Any final thoughts you want to leave people with on the general topic of evolution, or SARS, cov. Two,

Sarah Otto 1:06:30

it really is a fascinating area, I feel very privileged to have worked on it for my career at night, you know, and my feel very privileged to have had the students to that, that have not only taken this kind of questions further, but done in new ways. In the next generation, we're seeing young people really taking leadership roles with the source code to pandemic and that's because a lot of them have kind of the latest computational bioinformatics skills there. There used to open data processing, GitHub and those types of things. So it's really just this incredible time to be an evolutionary biologist.

Nick Jikomes 1:07:19

Alright, Sally auto, thank you for your time. You're welcome.


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