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A Deep Look into the Biology and Evolution of COVID-19

A Deep Look into the Biology and Evolution of COVID-19
(upbeat music) - Hello I am Suresh Subramani a Professor in the section of molecular

biology

and the Director of the Tata Institute for Genetics in Society at U.C. San Diego. Thank you to all of the viewers for tuning in to this program, on the

biology

and

evolution

of COVID-19. So we are gathered here today to discuss the coronavirus pandemic that has engulfed the entire globe in just three months since it was first brought to the attention of the World Health Organization on New Year's Eve of 2019. There are three primary reasons why the world is so concerned about this new virus, to which no one to our knowledge has natural immunity. So first is the rapid spread of the virus. In just three months it has spread to over 200 countries. The second is that it poses significant morbidity and mortality that threatens to overwhelm the global healthcare systems. So since the first report of this virus in Wuhan, China, as of March 30th there were over 750,000 cases and 36,000 deaths worldwide, which is a mortality of about four and half percent, which is higher than that of flu virus and even as we air this particular program, the USA leads the world as the hotspot for COVID-19. The third reason is a huge reservoir of carriers of this particular disease. It is estimated that there may be tenfold more asymptomatic carriers without symptoms of the disease which means then that could be over seven and a half billion carriers worldwide. So, in summary then, this is a disease that is...
a deep look into the biology and evolution of covid 19
spreading very rapidly across the globe, with the number of cases doubling every three to four days, and it has sewn fear and unpredictability across the globe, requiring the implementation of social distancing and lockdown policies. Stressing our medical capabilities to the extreme and causing severe economic fallout that is still unfolding. How long all of this will last is completely unknown, is anybody's guess. So we've gathered here today, a panel of biologists who work and teach broadly about infectious diseases, how they arise, evolve and spread to infect human beings around the globe by evading our otherwise robust immune systems. So, these faculty are incurred to share their knowledge regarding the

biology

of the virus. Why this pandemic has brought the world to its knees and they will also discuss the implications of infectious diseases broadly in our lives. They're here specifically to talk about a

biology

of the viruses but not to provide medical advice or policy matters relating to this particular virus. So let me introduce our panel of three speakers, which consists of three faculty from the Division of Biological Sciences at U.C. San Diego. They are doctors Emily Troemel, Matt Dougherty and Justin Meyer. I will introduce them one at a time, following which they will each give a short presentation and then at the end of the presentations we will have a round table discussion on topics of interest. So let's begin with our first panelist, Dr. Emily...
a deep look into the biology and evolution of covid 19
Troemel is a professor in section of cell and developmental

biology

. Her lab studies host pathogen interactions and in particular she focuses on intracellular pathogens that are completely dependent on the host for their replication. These include fungal parasites, called microsporidia, as well as viruses that have genomes that consist of ribonucleic acid as opposed to the deoxyribonucleic acid that most organisms have. And coronaviruses by the way have of these ribonucleic acid or RNA genomes. So she is going to address the topics as follows. The basic

biology

of cornonaviruses, how we test whether someone is infected with this virus that is called SARS, COVID-2 and how scientists predict and model the spread of this particular virus in the population. So Emily, I'm going to turn it over to you to do, to give us your presentation first. - All right Suresh, thanks so much for that introduction. And thanks for the opportunity to share with you some of the basic

biology

of coronavirus and how that relates to COVID-19 disease. So I'm gonna tell you about three different aspects of COVID-19. The first of which is just defining how the COVID-19 diseases relates to this virus called SARS-CoV-2. Next I'm gonna tell you how we test for the presence of the SARS-CoV-2 infection. And then I'm gonna share with you what we've learned about SARS-Co-V2 genome. Suresh mentioned it's an RNA genome and how we're able to

look

at changes in the sequence in this genome...
a deep look into the biology and evolution of covid 19
and that's enabling us to track the spread of this virus around the globe and it's really part of an amazing open science effort with sort of an unprecedented level of information acquisition and information sharing among researchers. So first off I just want to clarify how COVID-19 relates to SARS-Co-V2. So COVID-19 is the disease that's part of this pandemic and it's caused by a virus that's recently been named SARS-Co-V2. And there's a connection here you can think of in terms of the disease of AIDS being caused by the virus HIV. Similarly back in 2002 and 2003 there was this severe acute respiratory called SARS, the disease, that was caused by a virus that's called SARS-Co-V now called CoV-1. And since the virus of this current pandemic is related and sequenced it's been named SARS-Co-V2. And so SARS-Co-V1 and two are part of this group of viruses called coronaviruses, which are named because of the appearance of the viral particle, as you can see in an electron micrograph here, where these red blobs are the spiked proteins on the outside of the viral particle that form kind of a halo around corona, a crown. And so that's the source of the name, coronavirus, and it's abbreviated CoV. So, as many of you know viruses are completely dependent on their hosts for replication. So, unlike many disease causing agents like most bacterial pathogens or the fungal pathogens that are able to replicate on their own, viruses absolutely need a host...
present. And it's for this reason that the social distancing measures that we've been hearing about and been implementing can be so effective. Because while the virus can survive in the case of SARS-Co-V2 maybe two to three days outside of a host, it cannot make more of itself without getting inside of a host cell. So that process of getting inside of a host cell and making more of itself is diagrammed here with this rectangle representing a host cell, for example a cell in a human lung where outside of the cell a virus, such as this green hexagon here. If it is able to find a proper receptor on the surface of the cell combined to that receptor and be taken up into the cell. The virus will then release its genome to enable gene expression to happen. Replication of its genome and late expression to enable the formation of new viral particles. And here we've got one virus coming in, and then three new viruses being made that are released to go and infect new hosts. And in fact, you can have a much larger replication number than this, for example some viruses can have tens to thousands of new viral particles made from a cell. And also as Suresh mentioned, the genome for the coronavirus is actually different from the genome of most life. So most life like bacteria in humans the blueprints to make more of ourselves, the genome, is the molecule called DNA. And some viruses do use DNA, so this generalized life cycle here is showing sort of a DNA being made into RNA which...
is made into protein. But many viruses use RNA for their genome and in particular coronaviruses are single stranded RNA viruses that are positive sense, which means that they can rapidly hijack the host protein synthesis machinery, to start making proteins and in this way really rapidly hijack and take over a host cell. So knowing that the coronavirus has RNA in it genome helps us understand how we test for the presence of the coronavirus. So you may have heard about the need for more testing, we've had an extreme shortage of tests and there were some problems with the original tests that were availible and its really critical that we get more of these tests and I just want to explain how these tests work. The most common of which is a RT-PCR test, which stands for Reverse Transcription-Polymerase Chain Reaction, also sometimes called a real time test. So the way this test works is that a sample from a patient is isolated, the RNA is extracted, and then it's reverse transcribed into DNA. This DNA is then amplified with this polymerase chain reaction to enable detection of one segment of the viral RNA genome. So, this RNA detection then enables us to determine who is currently infected with the virus. This kind of a RT-PCR test however, will miss infections that have already been cleared. And so a related test will be able to detect those infections that occurred in the past. And this kind of test is a serology test that measures antibodies that were generated against...
the presence of that virus. And the antibodies that are generated against the virus can be detected if somebody is currently infected and is mounting an immune response or somebody who was infected in the past and has cleared the virus but still has those antibodies, because they can last for years and even decades. And so with the combination of these two tests where the RT-PCR test is able to detect the presence of viral RNA in current infections together with the serology test that measures the immune response we can determine who has the infection but hasn't yet mounted for some reason an antibody response, maybe because the infection is still so early, people who have both the infection and have mounted an immune response and people who no longer have the infection but had it in the past and mounted an immune response and potentially those antibodies cleared the infection. So this RT-PCR test is detecting RNA from just one gene in the viral genome, but the virus has a number of different genes that are made into proteins, that are part of its entire genome and that's represented here with this line the different colors representing different gene made into different proteins. And because the technology has gotten so much better, we're really rapidly acquiring and cheaply acquiring sequence information, we're able to sequence the entire genome of this virus, from many, many different samples. And it's really been an amazing, kind of unprecedented rate...
at which we're acquiring this information, sharing this information and analyzing this information. And a lot of this information so it's basically getting samples from patients around the globe that are sending information to a website called GISAID, that's run by the German government, originally organized to acquire influenza information. Now being adapted for coronavirus. That information is rapidly ported to a website call Nextstrain.org that has these really wonderful visualization tools so we can

look

at how the sequence of the genome is changing. And this, a I mentioned, this is increasingly there's more and more genome information every time you

look

at this website. So this morning there was over 2,000 genomes from 2,000 different infected patients that were analyzed and compared. And the way they're compared is in sort of the family tree shown here, with on the X axis here is time, and the colors are representing where the virus was isolated from. For example, purple represents isolated from China, red represented virus isolated from the Americas, and then the branch links of these trees are telling us how closely related this different viruses are, so you can see that viruses from China are very closely related to some viruses that were isolated from people in the Americas. From this information we can learn that somebody in China transmitted the virus to somebody in the Americas. And not only are we now able to track how this virus has spread...
by this kind of fingerprint of the mutations and the changes in the viral genome, but we also, because of what we know from the

biology

of this virus can learn about how the

biology

of the virus is changing, how it may be altering the way it interacts with host cells and also potentially different ways that we could treat it. And it's I think, a real success story in terms of the power of open science and the power of sharing information among researchers so that we can better able understand how this virus is spread around the globe, how its

biology

is changing and also hopefully how we can treat it. So with that information I think this should provide some foundation for Matt to next talk about

evolution

of this virus and Justin more about spread and I'll thank you very much for your attention and hand it back to Suresh. - So thank you so much Emily. Our next speaker is Matt Daugherty. He is an assistant professor in the section of molecular

biology

. He studies

evolution

ary arms race in adaptations of the host's immune systems on the one hand and the surface proteins of their pathogens on the other. He will discuss how viruses evolve to become human pathogens, how they jump from their natural animal hosts to humans and why human immune systems cannot cope with the new strain of virus that has never been seen before by the immune system. - Thank you Suresh for the introduction and thanks to Emily for the great introduction to coronaviruses. So what I wanna talk...
about in the next few minutes is how this virus SARS-Co-V2, which is causing the COVID-19 pandemic, fits into the context of other viruses that are circulating within the human population, or have caused previous epidemics. Because we as a species are always being exposed to viruses as is illustrated very nicely in this image of Alice from Lewis Carroll's famous books chased by all sorts of viruses and pathogens. So using this perspective, I'd like address three questions about SARS-Co-V2, first, how do viruses such as SARS-Co-V2 enter the human population become pandemics, second how does this virus actually relate to currently circulating as well as past and present epidemic human viruses, and third, based on all this information, what does this tell us about what we could expect for our future existence with this virus in terms of potential long-term immunity or coexistence with his virus. So first, it's important to point out that every human pandemic virus that we know of in recent times has originated from another species, which is something we called zoonotic transmission or zoonosis. And I'm showing you here a case where we're saying it's coming from a bat, which we call a reservoir species. For SARS-Co-V2 bats were likely the original reservoir, but of course many different animals serve as reservoir species for zoonotic viruses as we'll discuss as in a moment. But the zoonotic transmission into a single human is only the first step....
There's also a very important second step, which is the virus then needs to be able to have sustained human to human transmission. So these two steps together really result in a virus that has pandemic potential. Now if we

look

at this in the context of coronaviruses we know there are plenty of circulating human coronaviruses that cause mild systems that we often refer to as common colds, and up to about 20 years ago people didn't really pay too much attention to these viruses because again, they were just one of many types of viruses that cause a common cold. What we've also learned in the last say 20 years is that in fact within animal populations, again, especially among bats, there are many, many circulating coronaviruses. And again, we assume that because these are resonate in these animal populations these have pretty low case fatality rates. So where the danger comes is when infected bats or some intermediate host comes in contact with humans and we have what's called a spillover event. These spillovers result in zoonotic viruses in the human population, but fortunately many times these have limited or no real ability to transmit human to human. And within the coronavirus family we have an example of this, where starting in about 2012 we started seeing cases of a virus known as Middle Eastern Respiratory Syndrome Coronavirus or MERS-CoV. We've seen about 2,500 cases of this virus and as is common with these type of zoonotic viruses the case fatality...
rate is really quite high which is pretty alarming. But again, human to human transmission appears to be low. But for other viruses, once that spillover event occurs, either because the virus was initially adapted to do it or rapidly adapted to do it, it's now able to have sustained human-to-human transmission. So these are the viruses that have massive pandemic potential and this is where we are with SARS-Co-V2. In this case, the very first cases appear to have been detected in November or December of 2019 and as of March 30th we're rapidly approaching one million cases globally. What we also see is that the case fatality rate is much lower than you see with MERS, which again is pretty common with viruses that have sustained human-to-human transmission, although it's certainly much higher than we're seeing with circulating coronaviruses. And as Emily also mentioned, there was previous case of this occurring in coronaviruses where in 2002 there was an outbreak of a virus that was known as SARS-Co-V. And fortunately it was stopped before it spread globally but was also quite deadly. So we already knew that there was pandemic potential in this family of viruses, but of course SARS-Co-V2 has really emerged on a much larger scale. So if we want to understand how this happens we really need to understand the

evolution

of viruses and hosts at a molecular level. So what leads to the emergence of pandemics? So it's important to not just think about the species but...
actually the viruses within those species. And as Emily has already nicely introduced, viruses mutate and so that we know that the virus that's circulating in humans is only about five percent different compared to known circulating bat viruses. And if we wanna know how these differences changed the virus, we need to think back to what Emily introduced about the viral life cycle. All these points of contact shown here in the schematic Emily used, between the virus and host along the life cycle can be barriers that the virus needs to jump to get into the new population. The one I'm gonna focus on now is the step by which the virus enter the cell which is binding to the cellular receptor which is mediated by an interaction between this viral protein that's called Spike and the host cell protein called ACE2. And we often schematize these interactions as basically a key that needs to fit into a lock, but of course the real interactions

look

much more like this, with a three dimensional structural interaction of the Spike protein that then interacts with this ACE receptor. So now if we go back to our bats, we know that the bat virus must have had a spike protein that could interact with Bat ACE2 but a circulating bat virus may not necessarily be able to interact with Human ACE2. Which it would need to be able to do to jump species. And I've drawn ACE2 as

look

ing different because we know that host proteins that interface with viruses tend to themselves evolve very...
quickly across host species, presumably because of these high stakes host virus conflicts. And again, as Emily introduced viruses mutate a lot, so we imagine that within the bat population a variant of this virus arose that could utilize human ACE2 and if that right virus encountered a human virus that could transmit it to humans. So the final thing to say about this is to just reiterate that Spike and ACE2 were only one piece of this puzzle, and for a virus to be successful, it needs to adapt to many of the genetic differences between humans and the reservoir species. So for instance we already know that there are many coronaviruses circulating in bats, that can already utilize human ACE2, but presumably haven't made the jump into humans because there's some other molecular barrier to replication. So having talked about coronaviruses such as SARS-Co-V2 can and have entered the human population, I want to return to this question of how SARS-Co-V2 relates to other circulating epidemic genome viruses. As I mentioned in my earlier slide there are coronaviruses that span this whole range of steps in human viral emergence from animal viruses to zoonotic viruses to circulating human viruses. But of course, we know many human viruses, and have had many human pandemics. For instance, of one of the common things we're hearing about now is how these relate to influenza viruses. Partly that's because the influenza virus causes respiratory symptoms like coronaviruses, but...
partly there's also just a very clear analogy here in terms of the various influenza viruses in the categories shown here. So at the pandemic level, we've all heard of these major pandemic flus, from 1928 the so called Spanish Influenza in 1968 and even as recently as 2009. But of course we know that in addition to these pandemic strains of flu there are several seasonal flu strains of influenza that we have to deal with every year as well as strains of viruses that transmit from birds and have very high case fatality rates but so far have limited human-to-human transmission. And as with MERS, one of the big concerns is that if any of these viruses, like H7N9, gain human-to-human transmission we really need to worry about that. And we also know that the real reservoir of this virus is the many, many strains of avian and swine influenza that circulate within animal populations. And at the same time there are many other pandemic viral strains outside of influenza, many which come from some animal reservoir at some point. So for instance, Smallpox and HIV and Ebola have all caused epidemics in humans, and we know for instance that HIV transmitted into the human population several independent times from primate reservoirs, only a little over a 100 years ago. Of course we also have plenty of circulating human viruses like measles and polio that probably had some zoonotic transmission

deep

in their ancestry but wasn't quite as recent as any of these, as well as viruses...
in this category of zoonotic transmission with high case fatality. Among these is rabies virus, which is essentially 100% fatal if left untreated, but doesn't transmit person-to-person and also Nipah virus which has a very high case fatality rate and is also famous for being the virus people used as the model for the movie "Contagion". And finally, and this is where some basic virology surveillance has taken place, we know that there are many, many viruses circulating in reservoir species that have an unknown number of

evolution

ary steps away from being zoonotic transmissible. So one thing I take comfort in about all these other viruses is that we aren't constantly dealing with influenza pandemics and Smallpox and other pandemic viruses and that's because of the largely effective role of our immune system that Suresh mentioned in dealing with these viruses once the immune system has actually been prepared. And so with that, we'll start talking about this last question of what we might expect for SARS-Co-V2 in the long term. I'll start off by saying we don't actually really know much about the long term immunity to SARS-Co-V2, because of all this information is only recently emerging. So for instance, we don't know whether people that have been infected are now resistant to secondary infection, which is sort of the hallmark to long term protective adaptive immunity. But we can get a hint from some of these other viruses that we talked...
about. So the good news is is that we have long term protective immunity against many viruses and you'll see that all of these are vaccine targets, some of these are pandemic viruses like Smallpox, some have limited transmission in humans and some are circulating human viruses. So we have really good ways of making effective vaccines and the hope is that this will hope for SARS-Co-V2 as well. Although the development of vaccines of course take some time. We also know in the case of something like Ebola where we don't know yet know we have a good vaccine, but we know we can take blood from people that have been infected and then cleared the infection and use antibodies from that infected person to administer to people that are currently infected. And this can actually be quite protective, so with SARS-Co-V2 we expect this might be a limited but effective way to treat current infections. Of course there's also several viruses where we have limited short-term or unknown levels of protective immunity, unfortunately for instance one thing we don't now because circulating coronaviruses are not incredibly well studied, we don't actually know whether people have long term immunity to these common cold coronaviruses. Some work actually suggests that there can be short-term immunity, maybe for a year or two, but people can eventually be reinfected with essentially the same strain of coronavirus. So this could have implications for what we could expect from...
SARS-Co-V2. Also we know that we need a new vaccine every year against influenza virus. This has less to do with how effective the vaccine is and more to do with the vast rate of influenza

evolution

. The upside here is that even with limited immunity, but because of viral

evolution

we know that pandemic strains of flu with high case fatality rate don't endure, right? They essentially turn into seasonal flus in future years. And so I think overall this is encouraging in the precedent with other viruses suggest that once we can get in front of this virus on the public health level, we might expect effective productive immunity, protective immunity against SARS-Co-V2. And while we don't yet know what the long term future holds, many of these other viruses can be contained by either effective vaccines or protective human immunity. So I'll just summarize before I turn things back to Suresh and Justin, by saying first that SARS-Co-V2 is just one of many viruses that we know has entered the human population and will continue to enter the human population. And for all of these reasons our best defenses at this point are surveillance, the ability to rapidly mount an effective public health response and of course as Emily pointed out, you know these collaborative scientific efforts like we're seeing now with this pandemic that are really gonna push us toward developing effective vaccines and treatments. And finally I take some comfort in knowing that these types of...
pandemics do pass and we will get through this, many people will no doubt become sick, but still the hope and expectation is that perfective immunity will emerge and we'll see that this disease becomes less severe or goes away altogether. So with that, I will turn it back to Suresh and

look

to more discussions in a bit. - Thank you so much Matt. Our final speaker is Dr. Justin Meyer who is an assistant professor in the section of Ecology, Behavior and

Evolution

. He studies the

evolution

of viral host recognition systems and the strategies that are used by the two, and he also observes in the laboratory how viruses evolve and he studies their adaptations at various scales. So you heard from Emily about the mutations in the genome of the viruses, this actually translates to changes in the properties of the viral surface proteins like code protein that are encountered by and targeted by the host immune system. So he's going to discuss the variables that contribute to the infectivity of the pathogens in humans. Whether such epidemics and pandemics are more likely with increasingly environmental encroachments and climate change, and finally where else in the world such hot spots are likely to occur. In this case you saw that it came from China, but he will probably tell you that it can happen anywhere in the world. So, Justin I'm going to turn this over to you please. - Thank you Suresh, and thank you Emily and Matt for the great introduction to viruses. So for my...
section I want to talk about three subjects that relate to our ability to predict the next pandemic. The first are the variables that contribute to the spread of pathogens, and when we learn about these variables and we think about how the world is changing, we actually find out that we predict that there's an increased likelihood of pandemics in the future. So while that's kind of grim, we can also use those variables as well as other science to actually predict where in the world we can expect the next pandemic. And so if we can predict where it might happen, we might be able to stop it before it does happen. So rather than just giving you a long list of variables that either enhance viral spread or diminish viral spread, I'd like to give you a larger framework to understand how those factors work so that as you encounter different factors in the news or so forth, you can have that framework to put that factor in and understand how it actually works. So, I wanna go over this concept in epidemiology it's a variable called R naught. R naught is a reproductive potential of a pathogen and what that variable is, it's a number, that epidemiologists calculate and it's the number of susceptible individuals that one infected individual is likely to spread the disease to. So in this diagram here, that disease is being spread to 2.5 people. So the way that R naught works is that when you have an R naught value that's greater than one, that is a case where a...
pathogen can spread exponentially through a population. However, if that R naught is less than one, that's the case where the pathogen will over time infect fewer and fewer people until eventually it goes extinct in the population. So what is the R naught of SARS-Co-V2? So it's actually estimated to be 2.5. This means that this virus can spread rapidly through populations and as you see around the globe it's expanding exponentially in many, many countries. So what exactly goes into calculating R naught? R naught, the actual math to calculate this variable is pretty complex, but the concept in the math really boils down to R naught being a function of two terms. The first term is infectivity, this is basically the probability that a person will spread the disease to another person times the infection period. So the longer that a person is infected with this virus, the more potential the virus has to spread from one person to the next person. So these are sort of these larger concepts infectivity and infection period where a lot of different variables affect the infectivity of the virus or the infection period. And so two of the main drivers of what enhance the infectivity of a virus is how contagious the virus is. So this says if a virus can be transmitted through aerosol instead of droplets of water in the air then that makes the virus very contagious. Whereas if it's spread through bodily fluids it's less contagious. Also what goes into infectivity is the...
number of contacts an infected person has with susceptible people. Infection period is the length of time in which the virus can be transmitted from one person to another person. Theoretically, if humans get a virus, that virus could stay with a human for the rest of their lives. But two main factors can intervene to limit that time period, and one is that the human can gain immunity to the virus, making them curing themselves, and then making them immune from any future infections. So when this happens then the virus can no longer be spread from that person. Also, if the virus is deadly enough it can cause mortality. And when mortality happens, when the person dies, the virus can no longer spread from that person and so that actually limits the infection period. Often, people associate viruses with mortality and that association makes people think mortality of the host is good for the virus, but in fact the mortality of the host is really bad. So basically by sinking the ship, the virus goes down with the ship. So, viruses such as Ebola have these really high mortality rates and that's actually why they tend to have a much lower R naught than SARS-Co-V2, because basically they just burn through all of their population, and no more people can spread it any further. So, this is the concept of R naught, and R naught is an intrinsic property of the virus. However, there's another concept which is effective R. This is the reproductive potential after intervention. So we...
know that we can change our behaviors, we can change the way the society functions in ways to influence whether or not the virus can spread. So ideally while R naught might be 2.5 for SARS-Co-V2, we can hopefully change our behaviors in ways that would reduce that R below one so that the virus could eventually go extinct from our populations. And so, there's a number of measures that we'll walk through, first is we can affect how contagious somebody who's infected by the disease is by simply having them wear masks. This actually creates an actual barrier so that viral particles get caught and can't be transmitted to other people. We can practice social distancing and quarantining and this obviously influences the number of contacts the infected patient has with other susceptible people. And lastly, with good healthcare we can actually speed up recovery so that the patient doesn't have as much opportunity to spread the disease. So these are the measures that we can take against this disease right now. However, hopefully in the future, we have technology that we can apply such as vaccines or medications. And so vaccines we all think that vaccines are very good for us because they make our cells immune, but they also have these larger population effects such that when you apply a vaccine to a number of individuals, they become immune, they're no longer susceptible, so basically you're changing this variable, the number of contacts and you're...
diminishing R and hopefully helping drive the virus out of the population. By administering drugs you actually kind of have dual effects at the population scale. You're increasing the rate at which patients recover so they don't spread the disease anymore, and then you are also if the drug is stopping the viral replication then an individual who has the pathogen, who is infected, won't make as many viral particles and so those individuals will be less contagious. So these measures that help preserve our own lives, also have these population wide effects that will help drive out the disease. So, next like I said, given everything that we know from these lectures and some other science is predicted that there's an increased likelihood of pandemics in the future. So this is due to a number of factors that I wanna walk through. First, we have increased exposure to non-human pathogens. Like Matt pointed out, viruses that are new to humans are not really new they're just coming from another species and so there's a number of ways that we have augmented our behaviors around the world to actually heighten our interactions with other animals and then obviously their viruses as well, increasing the chance of that host shift. And so we have increased meat consumption, this means that we have larger farms of chickens and pigs and these are giant reservoirs for possible pathogens. We have increased encroachment on natural areas and obviously as we move into these...
forests to deforest them we are being exposed to a huge diversity of mammals, a huge diversity of animals that have viruses that potentially could jump into our population and of course if we have increased exotic animal trade that's a very close, direct interaction with animal and a diversity of animals that could foster emergence of a new virus. Another problem is urbanization. So as we grow as human populations grow around the world and since our Earth is limited in resources we have to be very conservative and so it's best for us to live in cities to preserve resources, however, urbanization also leads to the average person having more contacts with other people and so thinking about in terms of R naught and those calculations that increases the potential for viruses to spread. Globalization is also a problem, so much global travel means that a local epidemic can turn into a pandemic relatively quickly as we've seen with COVID-19. The fourth factor is climate change. We are augmenting the temperature of the Earth and environments in a way that we're making ourselves more susceptible to diseases. For example, when we warm the Earth we create more habitats for mosquitoes that carry bacterias like Malaria and by increasing their range they can spread to new human populations that are not impacted by Malaria. By increasing temperatures we're increasing flooding, and there's many pathogens that are water born, such as cholera which we will be exposing...
more and more people to. So while this all is pretty grim, we can take these factors and we can actually predict where in the world are these new emerging diseases likely to occur and then hopefully begin to intervene. So, now next I'd like to ask where will the next disease emerge? This is a map of the globe obviously. This was produced by EcoHealth-Alliance. It was published in 2017 in Nature Communications and it shows us where there are hotspots where we anticipate future pandemics to start from. So where disease emergence happens. You can see that where this new SARS virus came from, is actually a hotspot, but you can see that also in North America in southern California, and in New York areas those are also other hot spots. I should say that these are just statistical predictions, we don't know exactly where a disease is going to emerge. Why these regions are hotspots is they factored in all those things that I talked about. These are regions where you have lots of people, you have people being exposed to biodiversity, and also you have people that are more sensitive to global climate change. So, while this is something of a warning sign and certainly what we're going through right now is horrible, and we don't wanna go through that again. I think that having these kinds of efforts to predict and like Matt was talking about to surveil populations of viruses and as Emily has said with sequencing efforts we can bring all of that information together to be...
able to predict where emergence is gonna happen and hopefully intervene, change behaviors, change society in ways that diminishes the chance of having a new pandemic. So, thank you Suresh and thank you guys. - So thank you so much Justin. So now we are going to turn over to the discussion section of the panel. I'm gonna throw out some questions and our speakers can just chime in and give us their wisdom on these particular topics. So, let me just start with the, all of you pointed out that coronavirus is actually a very common virus which often causes common colds and I think about 30% of the common colds are caused by coronaviruses, so they're relatively harmless most of the time, so what is it that this virus, the SARS-Co-V2, particularly to the lungs that makes it so much more dangerous? - I think it's probably, again, I think we're all still trying to figure all of this out, if we take examples of other seasonal viruses and pandemic viruses for instance the 1918 flu versus seasonal influenza one big piece of this, or one big piece of that one was the amount of inflammation that was being caused, and in particular where in the lung it was replicating. So, for seasonal influenza it's usually in the upper lung, for the pandemic influenza it was able to easily access the lower lung. I think the early reports on this coronavirus

look

similar and I think there's also a greater amount of inflammation that is the result of infection in the lung. With this...
virus rather than the seasonal coronaviruses. Again, we have much less information about the seasonal coronaviruses than we do about seasonal influenza virus and we obviously have much less information about SARS-Co-V2, but I think in a lot of cases what we see with these viruses that aren't adapted to the human population is just that the inflammatory response is just very, very, very strong and as a result of that we get things like fluid leakage which results in things like pneumonia emerging in the lungs much more likely than we do in these viruses that are maybe a little bit more well adapted to the host population. - Yeah, that's very interesting Matt, you pointed to this inflammatory response and I just want to have someone comment on the fact that at some point the body, our immune system turns against these cells in trying to protect this immune response till all hell breaks loose just at that point, so aggravates the whole situation to the point where there is severe lung damage and breathing difficulties, right? So, does anyone else want to comment on that particular point? - Yeah, I guess just following on what Matt says, what we're trying to understand about SARS-Co-V2 is based a lot on SARS-Co-V1, where like Matt said it causes this aggravated inflammation and what's called a cytokine storm where there's all these signals in the body being sent to recruit immune cells and what's an over exuberant response that causes tissue damage and my...
understanding is also that I guess SARS-Co-V1 is able to inhibit some antiviral responses and it's predicted that SARS-Co-V2 could do that as well. So you're getting this inflammation, but it's not necessarily a productive immune response, but rather is damaging. And it's where that immune system comes in as being kind of this double edged sword that is oftentimes described as something that can both help us and harm us. - Yes. Very good. So we talked a little bit about potential possibility of developing a vaccine or drugs, so can we talk a little bit about what is the appropriate vaccine target in this case? And in what time frame is the vaccine likely? Someone could walk us through the steps of starting from a target how long it takes to make the vaccine, test it and get it validated and approved by FDA, this will be very useful for the audience I think. - Yeah, so again, I think one of the reasons I brought up the Spike protein is that I think this is gonna be one of the main targets for vaccination. And I think in terms of the steps that need to happen, I think a big part of it is actually figuring out in people that have been infected already, what are their antibodies targeting, right? So, we can really use the diversity of immune responses that people mount in these several hundred thousand people that been, have cleared the infection. We can actually

look

to see where their antibodies are targeting and we can use that then as a lead to generate kind...
of good targets for vaccination. Timing wise, Tony Fauci said a year to 18 months and I think that's probably pretty reasonable. I mean, a big issue about vaccines is they need to be insanely safe, right? You can't vaccinate people, you can't put something into healthy people that even has any chance of being potentially risky. And I think that is a big issue with vaccination, is that at there needs to be a lot of testing in a lot of people before we really determine that that vaccine is safe to distribute widely in areas that, where still the probability at least as it currently stands the probability of getting sick or certainly of dying of this infection are quite low. So you don't wanna do more damage with a vaccine than you do with the disease itself. - Yes, that's a very good point. There has been, there have been arguments in the press as to if we have a vaccine candidate that's ready, why can't we skip all the steps in between and go directly to people? And this point that you've made about sometimes some of the vaccines can actually make it worse for the individual if they're not tested properly so we need to have most models and before we get to the final dissemination of the vaccine. Now Emily, both you and Matt talked a little bit about the various steps in the entry of the virus and the replication and how it packages itself back into virus particles and then leaves the cell, and of course each one of those steps is a potential...
for a drug target, that if you could interfere with that step then potentially have a target and you also pointed out that there are many other viruses, including other coronaviruses that although they might bind different receptors, going by the same mechanism, they replicate in general by the same mechanism so can one begin to

look

at drug targets where things have been developed for other related viruses and try to use those and are those likely again in the same time frame or is that more likely that we could come up on a drug in less time than a year for example? - Yeah, I guess I would comment in terms of what Suresh is saying about using drugs against related viruses, there's, Ebola's another RNA virus where there's a drug it's called Remdesivir and that's basically gonna interfere with replication of the virus and my understanding is that Gilead is trying to test that and there's a single patient that was treated and recovered, but of course an equals one doesn't mean very much and so you know we really have to do thorough testing just to make sure we're not gonna cause more harm than benefits that we generate. There's also been a lot of hype about Chloroquine which is an anti-malarial drug, it's also used for, to relieve rheumatoid arthritis and that's still in sort of the early stages of determining with really carefully controlled studies is that gonna be a good treatment. Yeah I can hand it over to Justin if there's...
other drugs you want to comment on. - Yeah, so, I don't know of any other drugs that are under development right now. I do think that we have to consider not just if they have bad side effects but how likely the virus is to mutate around the drug. So if we give everybody a drug that a single mutation in the virus can confer resistance to it, given the size of the population of viruses within a single patient and its high mutation rates, it's not as high as some viruses but it has pretty high mutation rates we're gonna develop resistance almost immediately and our drugs aren't gonna be useful. So I think that studying sort of not just whether or not it's effective today but whether or not it'll be effective tomorrow is important. And then I think coming up with strategies like drug cocktails where we have a couple different drugs to target a couple different steps in the replication process that may be really helpful. To go back to the discussion of vaccines, I do know that they're beginning to test vaccines, so we are along the ways, it will be a long ways but I am pretty confident that something will break through here. We have a lot of attention, a lot of very bright scientists working on that. - That's terrific. And Justin, you brought up this idea that if you have a drug, the virus is continuously mutating at it's own natural rate and so I just want to contrast a little bit when DNA replicates there is the machinery that is involved in...
replication also has a proofreading function, so it corrects mistakes that are made, but the enzymes that replicate RNA don't have this proofreading function so they end up making mutations that are more prevalent than in DNA genomes. So is there any evidence that SARS-Co-V2 has a mutation rate that is extraordinarily high, anyone comment on that particular point? - It appears that its mutation rate it's high like an RNA virus typically is, but not as high as other RNA viruses. So it's not an outlier in the world of viruses. And it does appear that while the machinery that replicates RNA is very error prone, that means that it causes lots of mutations, there is some proofreading capacity in this virus, although I don't know too much about the mechanism myself. - Matt, do you have a comment? - Yeah, so there's an additional component to the preliminaries in this family of viruses, that's unlike any other RNA virus where they do have proofreading capabilities, so part of that is that these viruses are two to three times bigger than most other RNA viruses and without that proofreading capability if they were making mistakes at the same rate as polio virus or HIV they would presumably run into this sort of error catastrophe, where the virus would basically have too many mutations to survive so what we see in coronaviruses is that because they're a little bit bigger, they actually have a lower error rate than most RNA viruses and that's due to this...
added preliminary proofreading activity. It's still way, way, way more error prone than we see for our polymerases or you now know, a bacterial polymerase or something like that, the error rate is still quite high. - So I gather from what Emily said that this virus is evolving in real time, meaning that, Emily have we seen evidence of this from what you presented of mutations that are happening in realtime in the genomes of these viruses from different parts of the world? - Yeah, so we're able to like Matt and Justin said, see that the mutation rate for this virus while as in keeping with RNA viruses in general is higher than DNA viruses it doesn't seem like it's as high as for example as influenza, and I think kind of touching back on this topic about how this may connect with vaccine development, influenza which is an incredibly sloppy virus that in terms of replication errors there's been efforts to try to make a vaccine against what's common among the different influenza strains so that's something I think also that going forward with making a vaccine against SARS-Co-V2 we wanna keep an eye to try to dedicate efforts toward making a vaccine against, I mean first any vaccine but then again a vaccine against something that's common against different strains of the virus. And in terms of the rate it which, the places in which SARS-Co-V2 is mutating, I can hand that either to Matt or Justin. - So I actually wanna, before we get into that again,...
sort of connect something you just said Emily and something that Matt said earlier. Matt suggested that we might wanna create a vaccine that targets the Spike proteins, but we also know that these Spike proteins evolve the fastest and have the most variation between different SARS strains or different coronavirus strains. So, Matt is that just because they're on the outside, and so they're just-- - Yep. - A bright target-- - Yep. - For immune system? - And that's presumably also why the Spike protein is evolving so fast is just that it's you know, it is the main epitope that the immune, or the sort of main surface antigen that the immune system can see and so we see this with many other viruses, that those surface proteins because that's the thing that antibodies respond to, which is generally what we're talking about, when we're talking about creating a vaccine response that those proteins are being driven to evolve fast by that selection from the immune system. You now, we don't have many other targets on the outside of the virus that we can use for stimulation of the antibody response at the very least. So. - And yet, along the lines, yeah my understanding for this universal influenza vaccine that there's this effort to try to target things that aren't changing as much. So I guess that must be some part of a virus protein that just constrain because it cannot change without losing its basic function. - Yep. Yeah, yeah, yeah. It's...
the same thing as we see with HIV. Where people that develop these, what are called broadly neutralizing antibodies against HIV, they're still targeting these rapidly evolving surface proteins but they're targeting regions of those rapidly evolving surface proteins that most antibodies can't reach, but these ones for whatever reason can, and they are, they're very highly conserved. So presumably that's the approach that we would use for flu, and potentially also here for coronavirus. - So Matt, I have a follow-up question too, I think you kind of presenting an

evolution

ary dilemma, where our immune systems are driving the

evolution

of these host recognition proteins, and then we know genetic variation those host recognition proteins is what helps pathogens jump from one species to the other species, so you know, do you think there's some kind of interesting dilemma or feedback between these things? That the balanced immune system's essentially are driving the

evolution

that leads to the emergence of the pathogen? - Yeah, it's an interesting question. I mean, I think that what's driving

evolution

of the recognition aspect of the Spike protein, so in many of these cases the recognition parts of the protein aren't necessarily the same, so the part of Spike that is recognizing ACE2, isn't necessarily the thing that the antibodies are recognizing, right? And so, I think it's actually probably separate surfaces. I don't know...
enough about what the antibody response is to coronaviruses to know that in that particular case, but in many of these other cases you know you have this sort of surface protein of a virus that is targeting some receptor here and antibodies are actually sticking to other parts, not necessarily at that direct interface. - Okay. - While we're on the topic, because I think yeah, Justin Matt and I all really like this topic of the interaction between the surface protein of the virus and the host receptor. Matt, you had mentioned the bat ACE2 receptor, that's used by coronavirus in bats. Given that it's so much harder to do research with bats and genetic manipulation et cetera, it's possible there's other receptors-- - Yeah. - And I'm curious what's known about what there may be other receptors in bats which may tell us about what other receptors may be achieving. - Yeah, so, to my knowledge we don't know of any other receptors for a given coronavirus we don't know of any other receptors, in other species, so it always seems to be with these, things like SARS1 and SARS2, it seems to be ACE2, and all the related bat viruses. There are other coronaviruses that use other surface receptors right, and so you could imagine that there would be, there would be the possibility of sort of that particular jump and of course that's stuff that Justin pays a lot of attention too, right? It's how you utilize a new receptor. But I think in the case of...
this, what is happening is not these big jumps in terms of what receptor's being used, but actually sort of small, fine tuning of when a given bat species has a couple of amino acid changes on its surface, the Spike protein just basically needs to adapt to that in order to replicate in the new species of bat and the same holds of course for humans. But again, I think this point, and there was a study that came out a couple of years ago, that really was sampling a lot of these coronaviruses from bats and many of them could actually utilize human ACE2. So I think that jump in many respects has already been made, and so it's gonna be a lot of these other things like modulation of the immune response and things like that that are probably gone be responsible for that kind of fine tuning. - So, as this disease spreads around the world, we want to separate fact from fiction. And there are people in some parts of the world who believe that they are not as susceptible to this virus, either because they have intrinsic immunity or because the climate there is warmer or whatever. So I wanted to just talk a little bit about this, let's talk a little bit about expectations for natural human variance that might be resistant to this particular virus, what do we know about this from studies with other viruses and how can one relate that to SARS-Co-V2? - Yeah, maybe I'll start and then Justin and Matt can chime in in more detail. You know the lesson from HIV was that there...
were natural variants in the human population that had a change in the receptor, in that case it was this receptor called CCR5, used by HIV to enter the cell and people that had two mutant copies of that receptor were quite resistant, I think there was, correct me if I'm wrong, like sex workers in Africa that kept getting exposed and weren't infected. And so the question then is, yeah what is the natural human variation for this ACE2 receptor, among other factors that are gonna regulate infection by coronavirus and you know, I think the short answer is that the jury is still out but maybe I'll leave it to Matt and Justin to expand how much we know at this point. - Yeah, so I actually think this is a really cool topic that we understand almost nothing about, in terms of infectious diseases. So Emily brought up this case of HIV, there was a couple of other cases where we can map human genetic variance to differences in disease susceptibility, but it's really, really rare. Very different than the way that for instance we can say someone has a high risk of breast cancer susceptibility or Alzheimer's disease or things like that, and so you know I think we don't know as Emily mentioned and you know I also mentioned, all of these points where the virus is interacting with the host could be points where variation in human proteins could really have an effect. I think it's one of the potential things that may, good things that may come out of this, that we...
could really start to map the genome types of the virus to the genotypes of the person to the actual outcome of the infection. And really, you know maybe start to get into some of that level of detail. But, I think so far, I think actually ACE2 is not particularly polymorphic in the population but a lot of the other proteins that these viruses interact with are quite polymorphic in the human population and some of those could be actually determining susceptibility to disease. Excuse me. And some of them could just be random, right? - And I guess along those lines a related phenomenon from studying HIV infection was that there are these things called restriction factors, and this is what Matt was referring too, different steps along the way that viruses can be blocked and a particular restriction factor it's called a ubiquitin ligase the name was TRIM5 that present, is able to basically degrade parts of HIV in certain primate species that humans lack, or have a different version of. And so it can be things, that not just like the receptor that changes, but also whether or not there is something that will recognize the virus as something that's non-self, something that's foreign that needs to defeated. And that will also be interesting to see how that varies in the human population. - I think it was Matt who talk about normal immunity and vaccines and so on so at some point then depending on the particular virus and the vaccine you get this thing called herd...
immunity where even those who are not immunized have the protection because the virus cannot find so many hosts to transmit the disease to. So, is that likely, so I often wonder in very, very densely populated regions around the world in India, Africa being examples where social distancing is just physically impractical for a variety of reasons, whether there will be a combination of herd immunity and a social distancing that will end up creating a final balance. So at what point can one expect herd immunity? Can we talk a little bit more about that? - I can follow up based on that concept of R naught. So that concept of R naught comes from this epidemiological model called an SIR model and those models do predict herd immunity. I think that we will rely on herd immunity when we have a vaccine, but hopefully not before that. So, for herd immunity to work you have to have a large fraction of your population being immune to the pathogen and so basically that just means that there's just all these people around that it can't spread to so it just has a harder time spreading and then its R naught will defer to R, it will drop below one and it will leave the population. But that fraction of people that have to be immune for it to not spread is really high and that would mean that if we had that effect happening before we had a vaccine it would mean that this pandemic has gotten completely out of control, something like you know 30 to 60% of the population of the world has...
experienced it and are now immune, but because of the high mortality rate of this virus so not as high as Ebola but higher than influenza that would mean millions and millions of people dying. So I think in the end, I think we are going to have to distance ourselves, isolate ourselves. And then ride out the clock so that eventually when we have the vaccine we can begin to become immune to this at a really large scale and then herd immunity will suppress the COVID-19. - I do want to just chime in on this topic of immunity in terms of kind of a cautionary tale, it think my understanding with efforts to develop a vaccine against one strain of Dengue Fever actually led people to be more susceptible to other strains, and I think there was maybe some preliminary results that suggested the SARS-Co-V may have similarly effect. So just again, I think there's an amazing amount of hope for vaccine, at the same time it really does require that we do careful testing and make sure that we're not creating more problems than we're solving. - Yes, so, you know this brings me to this, the active debate going on about how long we should practice social distancing and the government has considered in some circles whether we should get back to work by Easter and of course now that has been extended. So, you want, Justin you talk beautifully about the factors that go into and why social distancing works in terms of R naught and what it does, so can you say how long you think the social...
distancing is necessary at least with the USA in context? - Yeah, so I guess I wanna respond with the caveat that I'm an

evolution

ary biologist, and I teach about epidemiology, but I'm not an epidemiologist. What do I tell my family and friends that are freaking out? I think that's sort of the best way to go about answering this. I tell them to take each day at at time, that we have to continue social distancing. I tell them that hopefully we do have a break around June, there are some ideas that maybe in the summertime this thing won't spread as much, but also by June what that does is it gives us an opportunity to all socially distance, for the, especially in the United States for within each of the individual states they hit their peak and then to be dropping down in the number of patients with disease and then for us to sort of mellow out. But at June, what does that mean? Does that mean that we all immediately go back to work and immediately go back to the bars and immediately go back to normal life? That's not what we should do. We will have to then asses at June sort of okay, we had this very strict measure that helped us stop the exponential spread of this virus, but now how do we go forward so that we don't reignite that exponential spread again? So I think it's gonna have to take careful consideration, but it's gonna be awhile till life gets back to normal. I know that that's terrible news. And I think to cope with it, just live...
each day and be as careful as you can at preventing catching this disease and spreading this disease. - So this, Justin you brought up an interesting point that was implicit in your statements, and that is that for this to work the entire world has to practice social distancing so that we stop the virus cold, right? But, if you don't and you do this in different parts of the world with different start dates and stop dates and so on then they could be this, running on the risk of a ricochet effect. So you think you've flattened the curve in one area and then the neighboring country or state or whatever is still transmitting the virus and then you can get it back again. So, and there have been cases even in China where after they saw the cases drop, now there are cases coming in from outside. So, how does one manage this at a global level? - So again, I'll give the same caveat that Justin did, which is I studied

evolution

of hosts and viruses, so I am not an epidemiologist, but in some of the reading I've done I think there's a couple of things to talk about here. One, we do see, in fact even in, there was a nice "National Geographic" article just recently about this ricochet effect that you were talking about during the 1918 pandemic in different US cities. And one really take home message from that is even when there was ricochet or this sort of bounce back, the cities that were doing the strongest social distancing overall had the lowest...
mortality rate. And so, the idea is that by flattening this curve we can allow things to catch up, right? We can allow the health system to catch up, we can allow, I mean one big thing about how we can move forward from this lock down of everybody is if we actually knew who was infected, right? If we had effective testing or effective serology like Emily was talking about then we could actually much faster respond to these sort of localized potential bounce back effects from reintroduction or something like that. So I think a lot of it is just allowing the system, allowing the science, allowing society to really catch up to being able to deploy the public health measures that makes sense of terms of containing the disease but are also less disruptive to society and the economy and everybody's sort of mental health. So. - I wanna follow on that exactly what Matt was saying, I agree that we really need better testing. And I also wanna follow on I guess I just learned about a study, also from the 1918 influenza pandemic where, that addresses this issue I think that people have proposed that we're either choosing to save lives or save the economy. And they did this sort of study comparing which cities did the earlier, stronger, more intense social distancing that saved lives, those were also the cities that did better economically. And so by saving lives, you're actually helping the economy and I think that's such an important message to drive home and make sure...
that people know. - Yeah, very good point. - So Emily you began your presentation by talking about the open science and how all the governments in the world now are

look

ing to scientists, technologists and medical professionals to find the fastest, cheapest and the scalable testing tools as well as cures for this particular disease right? So let's talk a bit about the concept of open science and the creation of platforms for sharing results of studies in realtime rather than waiting for the slow process of peer reviewed publications and getting manuscripts out and so on. This is a crisis of unprecedented proportions and we just need, the whole world needs to get together to solve this problem as fast as possible, so let's throw this out for discussion. - Yeah. - Actually if we could start with you Emily. - Yeah, wonderful topic. It's so inspiring to, just over the last month or two to learn about yeah, these resources where the entire genome's information is available. That GSAID, I'm not sure how they pronounce it, that website that within an hour the information gets ported to NextStream. All of that information is freely available. People can download it, they can analyze it, they can do their particular form of assessment and that is one form of this open sharing and then also there's this open sharing that's really been transforming the publication world and one aspect of that is preprint servers and there's a preprint server called...
bioRxiv, there's one called medRxiv so when people submit their paper to a journal, they can post that information there as well. And so anybody can

look

at it, they can comment on it and the information gets out much more rapidly than it would if we were waiting. And we still of course want to wait for peer review, I think everybody has different opinions, I still think that's absolutely critical, we need to have experts asses the data and so that we only have really well well scrutinized results that are being published. But yeah, if you

look

at bioRxiv and medRxiv I think there's now almost a thousand papers between the two that are related to coronavirus just from the last few months and several journals are also providing coronavirus information and coverage freely available, so I think that's, that's really gonna change science. The more people can share information the more progress we're gonna make. - Yeah, and I'll just add one thing to that, which is just all of these social networking tools that have been developed in the last, I don't know, 10 years, right, of Twitter and Slack and Zoom, right? And the ability to actually have these conversations in real time has really been transformative. I mean, even within the San Diego community right, there's this huge group of people that have set up all these resources that are just firing messages back and forth to each other saying hey I need this thing or do you have an, do you have...
access to this piece of equipment or something like that, right? And that has really been, I mean it's been kind of overwhelming to be part of, but it's also been really, I mean it's just everything is moving so much faster. - This is truly a silver lining to this otherwise dark cloud that is flowing over us. - Yeah. - Justin, do you have comments about this open science? - Yeah, I mean, so of course I'm also inspired by all of this. I'm gonna have to say that I'm about to teach a course on

evolution

of infectious disease and COVID-19 will be a big part of the course, because that's what students are most interested in right now. And it can, it can only be such a big part of the course because of these resources, these databases and where people are doing real time analysis on the most recent up to date data and because of the open source publication or the sorry, the preprint publications where we can

look

at what is the most modern science and I can present it in my class. And so, then the dissemination is not just among scientists but it is to students and to the public really quickly and so as a whole we're much more informed. So I do, I find it-- - Yeah, and I should add that this goes way beyond just the science, because with everyone sitting at home all kinds of thought, and the thousands of jobs and professionals need to get their work done, so people are just being exceptionally creative about finding ways to communicate, reach out to...
help each other from medical help and so one social connections. And I know I personally have called more people in the last two weeks than I've done in the last two years so you know at least world's coming together. So let me just before we finish throw out, just talk about some of the lessons, that each of you has learned from this particular pandemic that will prepare us for the next one that hopefully is some distance away but you never know what's around the corner. - Yeah, I guess I would just you know, kind of reiterating what we said before about open science, open sharing, but being able to track where that virus has spread, where it came from, where it's going, how it's changing, like that's, that has just been so inspiring and I think it really will be crucial to the next time this happens, because it's gonna continue to happen. This is like what Matt had in his presentation about that the Red Queen, it's just we're continually running, keeping up with the pathogens and they're trying to keep up with us. And I guess I would also say that you know I really hope that our government takes this seriously that there was a pandemic response team that had been established and that was disbanded and that we need those kind of resources and support in order to better prepare going forward, because as soon as we have effective testing we can so much rapidly contain, track and learn how to treat these kinds of diseases. - Similar I...
guess to what Emily was saying, I think one thing we've learned from this is that we are a hundred years advanced from where we were with the 1918 flu, and yet we're still being brought to our knees by this virus and I think one thing is that public health is really, really, really critical for these sorts of rapid deployment of intelligently designed, well executed, public health is really critical to this. It's, you know we can say we're gonna develop a vaccine in 12 to 18 months or we're gonna develop drugs in that amount of time, but really these ideas of social distancing, containing and testing and all of that is really the key to this rapid emergence of these viruses, because Emily's picture of the virus going in and a hundred going out is similar to Justin's picture of a virus going into one person and getting three out and that's what gives us this exponential curve and no matter how smart science is, the way a lot of times to contain viral infection seems to be these sorts of measures and that has been very effective in some cases that fortunately we haven't heard, became pandemics so. The 2009 Swine Flu, there have been some cases of the Avian Influenza that people were really worried about. Even SARS1, I think that the measures were effective at containing those viruses even with all those flaws and so I think one thing to really learn is what can we do to make sure that those are always there, even as the science is trying to...
catch up. - Justin? - Yeah, so, what I've learned personally is, people need to take these things seriously. We knew that this was a possibility for a very long time. I start the first last of my

evolution

of disease course by pointing out that the same slide, or a similar slide as I showed you during my presentation that the world is changing in a way that these are much more likely to happen again and again and again. And so, we can't brush them off, and we do see that there's a new disease spreading somewhere in the globe, even if we think that it's very far away from us, and so we have to take it seriously, and I think that the other thing that we could really gain a lot from is better surveillance of diseases in bat populations. In other mammal populations knowing what's out there, maybe even what has the potential to move into humans, and I think there's also just a lot of fundamental knowledge that we need to learn as well. We don't know what precisely the genetic mutations are that might have aided this virus's emergence into humans and so it'd be nice to actually know more about the basic

biology

and the

evolution

so we will be able to predict what kinds of genetic variants might be more problematic. I mean to be honest, in our lab we have seen

evolution

that's very similar to this happening, it's in a very different virus, but there's a lot of common themes. Now of course that might just be the human brain making these...
connections, but there might actually be something there. And so the strain that emerged in humans, this SARS-Co-V2, it has deletions in a key protein that we have shown the same, the analogous protein in our virus when there are these deletions in this region tends to drive host range changes. And so, if we start putting together more and more information from more and more viruses and having controlled experiments and

look

ing at natural variation perhaps we could better predict what the bad potential diseases are and intervene at an earlier step before the emerge into our population. Of course I agree what Matt is saying, that once they emerge you have fast acting containment strategies, that's really critical and of course in the end having a way to create vaccines quickly is another preventive measure or way dealing with these things, but I also think we can even stop at an earlier step. - Well, I must thank all of you for a truly fascinating conversation. We started off just eager to disseminate some of our teaching skills and information for our students and faculty and anyone who wants to listen, but I've learned a great deal from this conversation myself, lots of fascinating questions in

biology

that remain to be answered and if the audience loves this and wants us to talk about other related things, please let us know through the feedback and we'd be happy to do more of this. So thank you all for being a part of this conversation and stay safe all of you....
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