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

(upbeat music) - Hello, I am Suresh Subramani, professor of the section of molecular

biology

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

biology

and

evolution

of COVID-19. So we are gathered here today to discuss the coronavirus pandemic that has affected the entire world in just three months since it was first brought to the attention of the World Health Organization on New Year's Eve 2019. There are three main reasons why the world is very concerned about this new virus, against which, as far as we know, no one has natural immunity.

First is the rapid spread of the virus. In just three months it has spread to more than 200 countries. The second is that it poses significant morbidity and mortality that threatens to overwhelm global health systems. So since the first report of this virus in Wuhan, China, until March 30 there were more than 750,000 cases and 36,000 deaths worldwide, which is a mortality of about four and a half percent, which is higher than that of the flu virus and even as By broadcasting this particular program, the United States leads the world as a COVID-19 hotspot. The third reason is the huge pool of carriers for this particular disease.

It is estimated that there may be ten times as many asymptomatic carriers without symptoms of the disease, meaning there could be more than seven and a half billion carriers worldwide. So, in summary, this is a disease that is spreading very rapidly around the world, with the number of cases doubling every three or four days, and which has spread fear and unpredictability around the world, which requires the implementation of social distancing and confinement. policies. Stressing our medical capabilities to the extreme and causing serious economic consequences that are still unfolding. How long all of this will last is completely unknown, but no one knows.

So today we have brought together here a panel of biologists who work and teach widely on infectious diseases, how they emerge, evolve, and spread to infect humans around the world by evading our otherwise robust immune systems. Therefore, these teachers are committed to sharing their knowledge about 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 more broadly on our lives. They are here specifically to talk about the biology of viruses, but not to provide medical advice or policy issues related to this particular virus.

Let me introduce you to our three-speaker panel, consisting of three professors 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, after which each will give a brief presentation and then at the end of the presentations we will have a roundtable discussion on topics of interest. So let's start with our first panelist, Dr. Emily Troemel, a professor in the Cell and Developmental Biology section. Her laboratory studies interactions between pathogens and hosts and, in particular, 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 consisting of ribonucleic acid as opposed to deoxyribonucleic acid that most organisms have. And coronaviruses, by the way, have these ribonucleic acid or RNA genomes. So she is going to address the issues as follows. The basic biology of cornonaviruses, how we test if someone is infected with this virus called SARS, COVID-2 and how scientists predict and model the spread of this particular virus in the population. So Emily, I'll leave it to you to give us your introduction first. - Very good Suresh, thank you very much for that presentation.

And thank you for the opportunity to share with you some of the basic biology of the coronavirus and how it relates to the COVID-19 disease. So I'm going to talk to you about three different aspects of COVID-19. The first of them is simply to define how COVID-19 diseases are related to this virus called SARS-CoV-2. Below I will tell you how we test for the presence of SARS-CoV-2 infection. And then I'll share with you what we've learned about the SARS-Co-V2 genome. Suresh mentioned that it is an RNA genome and we can observe changes in the sequence of this genome and that allows us to track the spread of this virus around the world and it is really part of an incredible open scientific effort with a kind of unprecedented level acquisition and exchange of information between researchers.

First, I just want to clarify how COVID-19 is related to SARS-Co-V2. So, COVID-19 is the disease that is part of this pandemic and is caused by a virus that has recently been named SARS-Co-V2. And here is a connection that can be imagined in terms of the disease AIDS being caused by the HIV virus. Similarly, in 2002 and 2003 there was a severe acute respiratory disease called SARS, which was caused by a virus called SARS-Co-V, now called CoV-1. And since the virus of this current pandemic is related and sequenced, it has been called SARS-Co-V2. And so, SARS-Co-V1 and two are part of this group of viruses called coronaviruses, which get their name because of the appearance of the viral particle, as you can see in an electron micrograph here, where these red spots are the proteins with spikes on the outside of the viral particle that form a kind of halo around the crown, a corona.

And that is the source of the name, coronavirus, and it is abbreviated CoV. So, as many of you know, viruses are completely dependent on their hosts to replicate. So unlike many disease-causing agents, such as most bacterial pathogens or pathogenic fungi, which can replicate on their own, viruses absolutely need a host present. And it is for this reason that the social distancing measures we have heard about and have been implementing can be so effective. Because while the virus can survive, in the case of SARS-Co-V2, perhaps two or three days outside of a host, it cannot make more of itself without entering a host cell.

So the process of entering a host cell and producing more of itself is diagrammed here with this rectangle representing a host cell, for example, a cell in a human lung where outside the cell is a virus, like this green hexagon here. If it is able to find a suitable receptor on the cell surface, it combines with that receptor and is taken up by the cell. The virus will then release its genome to allow gene expression to occur. Replication of its genome and late expression to allow the formation of new viral particles. And here we have one virus coming in, and then three new viruses are created and released to 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 created from one cell. And also, as Suresh mentioned, the coronavirus genome is actually different from the genome of most living things. So for most living bacteria in humans, the blueprint for making more of ourselves, the genome, is the molecule called DNA. And some viruses use DNA, so this generalized life cycle here shows some sort of DNA turning into RNA, which turns into protein. But many viruses use RNA for their genome, and coronaviruses in particular are positive-sense single-stranded RNA viruses, meaning they can quickly hijack the host's protein synthesis machinery, start making proteins, and thus hijack and very quickly take over a host cell.

So knowing that the coronavirus has RNA in its genome helps us understand how we test for the presence of the coronavirus. You may have heard about the need for more testing, we've had an extreme shortage of testing and there were some issues with the original tests that were available and it's really critical that we get more testing and I just want to explain how these tests work. The most common is the RT-PCR test, which stands for reverse transcription polymerase chain reaction, and is sometimes also called a real-time test. So the way this test works is that you isolate a sample from a patient, extract the RNA, and then reverse transcribe it into DNA.

This DNA is then amplified with this polymerase chain reaction to allow the detection of a segment of the viral RNA genome. So this RNA detection allows us to determine who is currently infected with the virus. However, this type of RT-PCR test will not detect 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 type of test is a serological test that measures the antibodies that were generated against the presence of that virus. And the antibodies that are generated against the virus can be detected if someone is currently infected and is generating an immune response or if someone 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 not yet It has developed. for some reason, an antibody response, perhaps because the infection is still very early, people who have the infection and have developed an immune response and people who no longer have the infection but had it in the past and developed an immune response immune and potentially those antibodies eliminated the infection. So this RT-PCR test detects RNA from a single gene in the viral genome, but the virus has several different genes that are converted into proteins, which are part of its entire genome and that is represented here with this line of different colors . which represents different genes converted into different proteins.

And because the technology has improved so much, we are acquiring sequence information very quickly and at low cost, we can sequence the entire genome of this virus, from many, many different samples. And it really has been an amazing and unprecedented pace at which we acquire this information, share it, and analyze it. And a lot of this information is basically obtained from samples from patients around the world who submit information to a website called GISAID, run by the German government, originally organized to acquire information about influenza. Now in adaptation for the coronavirus. That information is quickly moved to a website called Nextstrain.org that has these really wonderful visualization tools so we can

look

at how the genome sequence is changing.

And this, as I mentioned, is that there is more and more information about the genome every time you

look

at this website. This morning, more than 2,000 genomes from 2,000 different infected patients were analyzed and compared. And the way they compare is in a kind of family tree shown here, on the X axis is time, and the colors represent where the virus was isolated from. For example, purple represents viruses isolated from China, red represents viruses isolated from the Americas, and then the links on the branches of these trees tell us how closely related these different viruses are, so you can see that viruses from China are closely related to some viruses that were isolated from people in the Americas.

From this information we can learn that someone in China transmitted the virus to someone in America. And not only can we now track how this virus has spread using these kinds of fingerprints of mutations and changes in the viral genome, but also, because of what we know about the biology of this virus, we can learn how it spreads. the virus. The biology of the virus is changing, how it may be altering the way it interacts with host cells and also potentially different ways we could treat it. And I think it's a real success story in terms of the power of open science and the power of sharing information between researchers so that we can better understand how this virus is spreading around the world, how its biology is changing, and hopefully, also how we can treat it.

So with that information, I think this should provide a basis for Matt to talk next about the

evolution

of this virus and Justin more about the spread. I will be very grateful for your attention and will return it to Suresh. - Thank you very much Emily. Our next speaker is Matt Daugherty. He is an assistant professor in the molecular biology section. He studies the evolutionary arms race in the adaptations of the host's immune system, on the one hand, and the surface proteins of its pathogens, on the other. He will discuss how viruses evolve to become human pathogens, how they jump from theirnatural animal hosts to humans and why human immune systems cannot cope with the new strain of viruses that the immune system has never seen before. - Thanks Suresh for the introduction and thanks to Emily for the great introduction to coronaviruses.

So what I want to talk about in the next few minutes is how this SARS-Co-V2 virus, which is causing the COVID-19 pandemic, fits into the context of other viruses that are circulating in the human population or that have caused epidemics. previous. . Because we, as a species, are always exposed to viruses, as illustrated very well in this image of Alice from the famous Lewis Carroll books being chased by all kinds of viruses and pathogens. So, using this perspective, I would like to address three questions about SARS-Co-V2: first, how viruses like SARS-Co-V2 enter the human population and become pandemics; secondly, how this virus is actually related to current circulation. as past and present human epidemic viruses, and third, based on all this information, what does this tell us about what we might expect from our future existence with this virus in terms of potential long-term immunity or coexistence with its virus ?

First, it is important to note that every human pandemic virus that we know of in recent times comes from another species, what we call zoonotic transmission or zoonosis. And I'm showing you here a case in which we say it comes from a bat, which we call the reservoir species. For SARS-Co-V2, bats were probably the original reservoir, but of course many different animals serve as reservoir species for zoonotic viruses, as we will discuss in a moment. But zoonotic transmission to a single human is only the first step. There is also a second very important step, which is that the virus must be able to have sustained transmission from person to person.

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 that there are many circulating human coronaviruses that cause mild systems that we often refer to as common colds, and until about 20 years ago people didn't pay much attention to them. These viruses because, again, they were just one of the many types of viruses that cause a common cold. What we have also learned in the last 20 years is that, in fact, within animal populations, especially among bats, there are many, many coronaviruses circulating.

And again, we assume that because these resonate in these animal populations, they have fairly low case fatality rates. So the danger arises when infected bats or some intermediate host come into contact with humans and we have what is called a spillover event. These infections result in zoonotic viruses in the human population, but fortunately they often have limited or no real capacity to be transmitted from person to person. And within the coronavirus family we have an example of this, where starting around 2012 we began to see cases of a virus known as Middle East respiratory syndrome coronavirus or MERS-CoV.

We have seen about 2,500 cases of this virus and, as is common with these types of zoonotic viruses, the case fatality rate is quite high, which is quite alarming. But again, human-to-human transmission appears to be low. But for other viruses, once that contagion event occurs, whether because the virus initially adapted to do it or quickly adapted to do it, it is now capable of having sustained person-to-person transmission. These are the viruses that have enormous pandemic potential and this is where we find ourselves with SARS-Co-V2. In this case, the first cases appear to have been detected in November or December 2019, and as of March 30, we are rapidly approaching one million cases worldwide.

What we also see is that the case fatality rate is much lower than what is seen with MERS, which again is quite common with viruses that have been transmitted from person to person, although it is certainly much higher than we are. seeing with circulating coronaviruses. And as Emily also mentioned, there was a previous case where this happened with coronaviruses, where in 2002 there was an outbreak of a virus known as SARS-Co-V. And luckily it was stopped before it spread globally, but it 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 the molecular level. So what leads to the emergence of pandemics? That's why it's important to not only think about species but also about the viruses within those species. And as Emily has already presented very well, viruses mutate, so we know that the virus circulating in humans is only about five percent different compared to known circulating bat viruses. And if we want to know how these differences changed the virus, we need to remember what Emily presented about the viral life cycle.

All of these points of contact shown here in the schematic that Emily used, between the virus and the host throughout the life cycle, may be barriers that the virus must overcome to enter the new population. What I will focus on now is the step by which the virus enters the cell and binds to the cell receptor mediated by an interaction between this viral protein called Spike and the host cell protein called ACE2. And we often schematize these interactions as basically a key that has to fit into a lock, but of course the real interactions look a lot more like this, with a three-dimensional structural interaction of the Spike protein that then interacts with this ACE receptor.

So 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 can't necessarily interact with Human ACE2. Which I would have to be able to do to jump between species. And I've drawn that ACE2 looks different because we know that host proteins that interact with viruses tend to evolve very rapidly between host species, presumably because of these high-risk host-virus conflicts. And again, because Emily introduced viruses mutate a lot, we imagine that within the bat population a variant of this virus emerged that could use human ACE2 and if that right virus found a human virus that could transmit it to humans.

So the last thing to say on this is to simply reiterate that Spike and ACE2 were just 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 example, we already know that there are many coronaviruses circulating in bats, which can already use human ACE2, but presumably they haven't made the jump to humans because there is some other molecular barrier to replication. So, having talked about how coronaviruses like 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 genomic viruses.

As I mentioned in my previous slide, there are coronaviruses that span this entire range of steps in the emergence of human viruses, from animal viruses to zoonotic viruses to circulating human viruses. But of course we know many human viruses and we have had many human pandemics. For example, one of the most common things we hear now is how they are related to influenza viruses. Partly this is because the influenza virus causes respiratory symptoms like coronaviruses, but partly there is also a very clear analogy in terms of the various influenza viruses in the categories shown here. So, at the pandemic level, we've all heard about these big pandemic flus, going back to 1928, the so-called Spanish flu in 1968 and even as recently as 2009.

But of course we know that in addition to these pandemic flu strains there are several strains of seasonal flu that we have to deal with every year, as well as virus strains that are transmitted through birds and have very high fatality rates, but so far have limited transmission from person to person. And just like with MERS, one of the big concerns is that if any of these viruses, like H7N9, are transmitted from person to person, we really need to worry about that. And we also know that the true reservoir of this virus is the many strains of avian and swine influenza that circulate among animal populations.

And at the same time, there are many other pandemic viral strains besides influenza, many of which come from some animal reservoir at some point. Thus, for example, smallpox, HIV and Ebola have caused epidemics in humans, and we know, for example, that HIV was transmitted to the human population several times independently of primate reservoirs, only a little over 100 years ago. years. Of course, we also have many human viruses in circulation, such as measles and polio, that probably had some zoonotic transmission in their ancestry but were not as recent as either of these, as well as viruses in this category of zoonotic transmission with high lethality . .

Among them is the rabies virus, which is essentially 100% fatal if untreated, but is not transmitted from person to person, and also the Nipah virus, which has a very high case fatality rate and is also famous for being the virus that people use as viruses. Model for the movie "Contagion". And finally, and this is where some basic virological surveillance has been carried out, we know that there are many, many viruses circulating in reservoir species that are an unknown number of evolutionary steps away from being zoonotically transmissible. So one thing that comforts me about all these other viruses is that we are not constantly dealing with pandemics of influenza, smallpox and other pandemic viruses and that is due to the largely effective role of our immune system that Suresh once mentioned when dealing with these viruses. the immune system has really been primed.

And with that, we'll start talking about this last question of what we might expect from SARS-Co-V2 in the long term. I'll start by saying that we don't really know much about long-term immunity to SARS-Co-V2, because all of this information is only recently emerging. So, for example, we don't know whether people who have been infected are now resistant to secondary infection, which is a kind of hallmark of long-term protective adaptive immunity. But we can get a clue from some of these other viruses we talked about. So the good news is that we have long-term protective immunity against many viruses and you will see that all of these are vaccine targets, some of them are pandemic viruses like smallpox, some of them have limited transmission in humans and some of them are circulating human viruses. .

So we have very good ways of producing effective vaccines and the hope is that this will also apply to SARS-Co-V2. Although vaccine development will of course take some time. We also know that in the case of something like Ebola, where we don't know yet that we have a good vaccine, but we know that we can take blood from people who have been infected and then cleared the infection and use antibodies from that infected person to give to people who are currently infected. And this can actually be quite protective, so with SARS-Co-V2 we hope that it can be a limited but effective way to treat current infections.

Of course, there are also several viruses where we have limited or unknown levels of short-term protective immunity; Unfortunately, for example, there's something we don't know now because circulating coronaviruses aren't incredibly well studied: We don't actually know if people have long-term effects. immunity to these common cold coronaviruses. In fact, some work suggests that there may be short-term immunity, perhaps for a year or two, but that eventually people can be reinfected with essentially the same strain of coronavirus. So this could have implications for what we might expect from SARS-Co-V2. We also know that we need a new vaccine every year against the flu virus.

This has less to do with the effectiveness of the vaccine and more to do with the enormous rate of evolution of the flu. The advantage here is that even with limited immunity, but due to viral evolution, we know that pandemic flu strains with a high case fatality rate do not last, right? Basically, they become seasonal flus in future years. So I think overall this is encouraging because the precedent of other viruses suggests that once we can deal with this virus at a public health level, we could expect effective productive immunity, protective immunity against SARS-Co-V2. . And while we still don't know what the long-term future holds, many of these other viruses can be contained through effective vaccines or protective human immunity.

So I'll just summarize before talking about Suresh and Justin again, sayingfirst that SARS-Co-V2 is just one of many viruses that we know have entered the human population and will continue to enter the human population. And for all of these reasons, our best defenses right now are vigilance, the ability to quickly mount an effective public health response, and of course, as Emily pointed out, these collaborative scientific efforts like the ones we're seeing now with this pandemic are It will really push us to develop effective vaccines and treatments. And finally, it comforts me to know that these types of pandemics pass and we will overcome it; no doubt many people will get sick, but still the hope and expectation is that perfective immunity will arise and we will see this disease become less severe or disappear completely.

That said, I'll hand it back to Suresh and look for more discussions in a moment. - Thank you very much Matt. Our final speaker is Dr. Justin Meyer, assistant professor in the Ecology, Behavior and Evolution section. He studies the evolution of viral host recognition systems and the strategies they both use, and also observes in the laboratory how viruses evolve and studies their adaptations at various scales. Emily talked about mutations in the genome of viruses; This actually results in changes in the properties of viral surface proteins, such as the encoded protein, which the host immune system finds and attacks.

Therefore, he will analyze the variables that contribute to the infectivity of pathogens in humans. Whether such epidemics and pandemics are more likely with increasing environmental invasions and climate change and, finally, where else in the world such tipping points are likely to occur. In this case he saw that it came from China, but he will probably tell you that it can happen anywhere in the world. So, Justin, I'll turn it over to you, please. - Thanks Suresh and thanks Emily and Matt for the great introduction to viruses. So in my section I want to talk about three topics related 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 think about how the world is changing, we actually find that we predict that there will be a higher probability of pandemics in the future. So while that's a little daunting, we can also use those variables, as well as other science, to predict where in the world we can expect the next pandemic. And if we can predict where it might happen, we might be able to stop it before it happens. So rather than just giving you a long list of variables that improve or decrease viral spread, I'd like to give you a broader framework for understanding how those factors work, so that as you encounter different factors in the news, etc. , you can have that framework to include that factor and understand how it really works.

So I want to go over this concept in epidemiology: it's a variable called R zero. R zero is the reproductive potential of a pathogen and what that variable is, it is a number that epidemiologists calculate and it is the number of susceptible individuals to whom an infected individual is likely to transmit the disease. So in this diagram, that disease is spreading to 2.5 people. So the way R zero works is that when you have an R zero value greater than one, that is a case where a pathogen can spread exponentially through a population. However, if that R zero is less than one, that is the case where the pathogen will eventually infect fewer and fewer people until it eventually becomes extinct from the population.

So what is the R nothing 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 can see, around the world it is expanding exponentially in many, many countries. So what exactly does calculating R zero entail? R zero, the actual math to calculate this variable is quite complex, but the concept in mathematics really boils down to R zero being a function of two terms. The first term is infectivity, which is basically the probability that one person will transmit the disease to another during the period of infection.

So the longer a person is infected with this virus, the greater the chance of the virus spreading from one person to another. These are broader concepts of infectivity and infection period, where many different variables affect the infectivity of the virus or the infection period. So two of the main factors that improve the infectivity of a virus are how contagious the virus is. This means that if a virus can be transmitted through aerosols rather than water droplets in the air, that makes the virus very contagious. While if it is transmitted through bodily fluids it is less contagious.

Furthermore, what influences infectivity is the number of contacts that an infected person has with susceptible people. The infection period is the time during which the virus can be transmitted from one person to another. In theory, if humans contract a virus, that virus could stay with a human for the rest of their lives. But two main factors can intervene to limit that period of time, and one is that the human being can gain immunity to the virus, making it cure itself and then making it immune to any future infection. So when this happens, the virus can no longer be transmitted from that person.

Additionally, if the virus is deadly enough, it can cause mortality. And when mortality occurs, when the person dies, the virus can no longer spread from that person and that actually limits the period of infection. People often associate viruses with mortality and that association makes people think that host mortality is good for the virus, but in reality host mortality is really bad. Basically, by sinking the ship, the virus goes down with the ship. So viruses like Ebola have really high mortality rates and that's why they tend to have a much lower R 0 than SARS-Co-V2, because they basically just burn out their entire population and there are no more people who can spread it. further away.

So this is the concept of R zero, and R zero is an intrinsic property of the virus. However, there is another concept that is effective R. This is the reproductive potential after the intervention. So we know that we can change our behaviors, we can change the way society works to influence whether the virus can spread or not. So, ideally, while R zero might be 2.5 for SARS-Co-V2, hopefully we can change our behaviors in ways that reduce that R below one so that the virus can eventually become extinct from our populations. So, there are a number of measures that we will look at.

The first is that we can affect how contagious someone infected with the disease is simply by having them wear masks. This actually creates a real barrier for viral particles to become trapped and unable to be transmitted to other people. We can practice social distancing and quarantine and this obviously influences the number of contacts the infected patient has with other susceptible people. And finally, with good health care we can speed up recovery so that the patient does not have as many opportunities to spread the disease. These are the measures we can take against this disease right now.

However, hopefully in the future we will have technology that we can apply, such as vaccines or medicines. So we all think that vaccines are very good for us because they make our cells immune, but they also have broader population effects, so when you give a vaccine to multiple individuals, they become immune, they are no longer immune. susceptible, so you're basically changing this variable, the number of contacts, and you're lowering R and hopefully helping to push the virus out of the population. When administering drugs, you actually have dual effects on a population scale. The speed at which patients recover is being increased so that they no longer spread the disease, and also, if the drug stops viral replication, an individual who has the pathogen, who is infected, will not survive as long. many viral particles and therefore those individuals will be less contagious.

So, these measures that help preserve our own lives also have effects on the entire population that will help expel the disease. So, as I said, given everything we know from these conferences and some other sciences, it is predicted that there will be a higher probability of pandemics in the future. This is due to a series of factors that I want to analyze. First, we have increased exposure to non-human pathogens. As Matt pointed out, viruses that are new to humans aren't really new, they just come from another species, so there are a number of ways we've increased our behaviors around the world to increase our interactions with other animals and then, obviously, their viruses too, increasing the possibility of that host change.

And so we have increased meat consumption, which means we have larger chicken and pig farms and these are giant reservoirs of potential pathogens. We have increased the invasion of natural areas and, obviously, as we go into these forests to deforest them, we are exposed to an enormous diversity of mammals, an enormous diversity of animals that have viruses that could potentially jump into our population and, of course , if we have an increase in the exotic animal trade, which is a very close and direct interaction with animals and a diversity of animals that could encourage the emergence of a new virus.

Another problem is urbanization. So as we grow as human populations grow around the world and since our Earth has limited resources, we have to be very conservative and therefore it is better for us to live in cities to preserve resources; However, urbanization also leads to the average person having more contacts with other people and therefore thinking in terms of R nothing and those calculations that increase the potential for virus spread. Globalization is also a problem, so so much global travel means that a local epidemic can become a pandemic relatively quickly, as we have seen with COVID-19.

The fourth factor is climate change. We are increasing the temperature of the Earth and the environment in a way that makes us more susceptible to disease. For example, when we warm the Earth, we create more habitats for mosquitoes that carry bacteria like malaria, and by increasing their range, they can spread to new human populations that are not affected by malaria. As temperatures rise, we increase flooding and there are many pathogens that are born from water, such as cholera, to which we will expose more and more people. So while this is all pretty bleak, we can take these factors and we can actually predict where in the world these new emerging diseases are likely to occur and then hopefully start to intervene.

So now I would like to ask where will the next disease arise? This is obviously a map of the world. This was produced by EcoHealth-Alliance. It was published in 2017 in Nature Communications and shows us where there are hotspots from where we anticipate future pandemics to begin. So where does the onset of diseases occur? You can see that the origin of this new SARS virus is actually a hotspot, but you can also see that also in North America, in Southern California and in the New York areas, those are also other hotspots. . I must say that these are just statistical predictions, we do not know exactly where a disease will arise.

The reason these regions are hotspots is that they take into account all those things I talked about. These are regions where there are many people, there are people exposed to biodiversity and there are also people who are more sensitive to global climate change. So while this is kind of a warning sign and certainly what we're going through right now is horrible, we don't want to go through that again. I think having these kinds of efforts to predict and, as Matt was talking about, monitor virus populations and, as Emily said, with sequencing efforts we can bring all that information together to be able to predict where the emergence will occur and hopefully intervene. , change behaviors, change society in a way that reduces the possibility of having a new pandemic.

So, thank you Suresh and thank you all. - Thank you very much Justin. Now let's move on to the panel discussion section. I'm going to ask some questions and our speakers can chime in and give us their wisdom on these particular topics. So let me start with you all pointing out that coronavirus is actually a very common virus that often causes common colds and I think about 30% of common colds are caused by coronaviruses so they are relatively harmless for the most part. So what makes this virus, SARS-Co-V2, especially reach the lungs, makes it much more dangerous? - I think probably, again, I think we're all still trying to figure all this out, if we take examples of other seasonal viruses and pandemic viruses, for examplethe 1918 flu versus the seasonal flu, a big part of it, or a A big part of that was the amount of inflammation that was being caused and, in particular, where in the lung it was replicating.

So in the case of seasonal influenza, it is usually in the upper part of the lung, in the case of pandemic influenza, it was able to easily access the lower part of the lung. I think the early reports on this coronavirus are similar and I think there is also an increased amount of inflammation that is a result of an infection in the lung. With this virus instead of the seasonal coronaviruses. Again, we have much less information about seasonal coronaviruses than we do about the seasonal influenza virus and obviously we have much less information about SARS-Co-V2, but I think in many cases what we see with these viruses that are not adapted to the human population is simply that the inflammatory response is very, very, very strong and as a result of that we have things like fluid leaks that result in things like pneumonia that emerge in the lungs much more likely than with these viruses. that perhaps they are a little better adapted to the host population. - Yeah, that's very interesting Matt, you mentioned this inflammatory response and I just want someone to comment on the fact that at some point the body, our immune system, turns on these cells by trying to protect this immune response until it's unleashed.

Hell. releases right at that point, so it 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 following what Matt says, what we're trying to understand about SARS-Co-V2 is largely based on SARS-Co-V1, where, as Matt said, it causes this aggravated inflammation and what It's called a cytokine. storm where all these signals are sent in the body to recruit immune cells and what is an overly exuberant response that causes tissue damage and I also understand that I guess SARS-Co-V1 is capable of inhibiting some antiviral responses and SARS is predicted -Co-V2 could do that too.

So this inflammation occurs, but it is not necessarily a productive immune response, but rather a harmful one. And this is where the immune system comes in as a kind of double-edged sword that is often described as something that can help us and harm us. - Yes very good. We talked a little bit about the potential for developing a vaccine or drugs, so can we talk a little bit about what the appropriate vaccine target is in this case? And how soon is the vaccine likely to arrive? Could someone walk us through the steps to get started from a goal of how long it takes to manufacture the vaccine, test and validate it, and approve it by the FDA;

I think this will be very useful for the audience. - Yes, again, I think one of the reasons I mentioned the Spike protein is that I think it will be one of the main targets of the vaccination. And I think in terms of the steps that need to be taken, I think a big part of this is finding out in people who have already been infected, what are their antibodies targeting, right? So we can really use the diversity of immune responses that people generate in these several hundred thousand people who have overcome the infection. In fact, we can observe where their antibodies are going and then we can use that as a clue to generate good targets for vaccination.

As for time, Tony Fauci said between a year and 18 months and I think that's probably pretty reasonable. I mean, a big problem with vaccines is that they have to be incredibly safe, right? You can't vaccinate people, you can't put something in healthy people that has any chance of being potentially risky. And I think that's a big problem with vaccination, is that there needs to be a lot of testing on a lot of people before we really determine that it's safe to distribute the vaccine widely in areas where there's still at least as big a chance. Currently the chances of getting sick or even dying from this infection are quite low.

So you don't want to cause more harm with a vaccine than with the disease itself. - Yes, that is a very good point. There have been, there have been arguments in the press about if we have a vaccine candidate that is ready, why can't we skip all the intermediate steps and go directly to people? And this point you made about that sometimes some of the vaccines can actually make things worse for the individual if they're not tested properly, so we need to have most of the models before we get to the final vaccine distribution. . Now Emily, both you and Matt talked a little bit about the various steps in virus entry and replication and how it gets packaged back into virus particles and then exits the cell and of course each of those steps is a potential for a drug target, that if you could interfere with that step then you would potentially have a target and also noted that there are many other viruses, including other coronaviruses, that although they can bind to different receptors, following the same mechanism, they replicate in general, By the same mechanism, can you start looking for drug targets where things have been developed for other related viruses and try to use them and are they likely to do it again in the same time period or is it more likely that we can reach a agreement? medication in less than a year, for example? - Yes, I guess I would comment in terms of what Suresh says about the use of drugs against related viruses, there is another Ebola RNA virus where there is a drug called Remdesivir and that will basically interfere with the replication of the virus and my understanding is that Gilead is trying to test that and there is only one patient who was treated and recovered, but of course one still doesn't mean much so you know we really have to do extensive testing just to make sure that we're not going to cause more. the damages that the benefits we generate.

There has also been a lot of publicity about chloroquine, which is an anti-malarial drug, it is also used to relieve rheumatoid arthritis and it is still in the early stages of determining with very carefully controlled studies if it will be a good treatment. Yes, I can hand it over to Justin if there are other drugs you want to comment on. - Yes, I don't know of any other drugs that are in development at the moment. I think we need to consider not only whether they have negative side effects, but also the likelihood of the virus mutating around the drug.

So if we give everyone a drug to which a single mutation in the virus can confer resistance, given the size of the virus population within a single patient and its high mutation rates, it is not as high as that of some viruses, but it has a fairly high effect. mutation rates we will develop resistance almost immediately and our drugs will not be useful. So I think it is important to study not only whether or not it is effective today, but also whether it will be effective tomorrow. And then I think coming up with strategies like drug cocktails where we have a couple of different drugs to target a couple of different steps in the replication process can be really helpful.

Getting back to the vaccine discussion, I know they are starting to test vaccines so we are on the way, it will be a long road but I am pretty sure something will make its way here. We have a lot of attention, a lot of very bright scientists working on it. - That is fantastic. And Justin, you mentioned the idea that if you have a drug, the virus continually mutates at its own natural rate, so I just want to contrast a little bit when DNA replicates, the machinery that's involved in replication also has a function of correction, so it corrects the errors that are made, but the enzymes that replicate RNA do not have this correction function, so they end up producing mutations that are more frequent than in DNA genomes.

So is there any evidence that SARS-Co-V2 has an extraordinarily high mutation rate? Does anyone comment on that particular point? - It seems that its mutation rate is high as an RNA virus usually is, but not as high as other RNA viruses. Therefore, it is not an atypical case in the world of viruses. And it seems that while the machinery that replicates RNA is very error-prone, meaning it causes a lot of mutations, this virus has some ability to correct itself, although I don't know much about the mechanism myself. - Matt, do you have any comments? - Yes, so there is an additional component to the preliminaries in this family of viruses, which is different than any other RNA virus where they have proofreading capabilities, so part of that is that these viruses are two or three times larger than most other RNA viruses and without that correction ability, if they were making errors at the same rate as the polio virus or HIV, they would presumably run into this kind 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 larger, they actually have a lower error rate than most RNA viruses and that's because of this extra prefix activity.

It's still much, much more error-prone than what we see with our polymerases or, you know, a bacterial polymerase or something, the error rate is still quite high. - So I deduce from what Emily said that this virus is evolving in real time, that is, Emily, have we seen evidence of this from what you presented of mutations that are happening in real time in the genomes of these viruses from different parts of the world? ? - Yes, so we can, as Matt and Justin said, see that the mutation rate of this virus, while, according to RNA viruses in general, it is higher than that of DNA viruses, it does not seem to be as high as, for example, influenza, and I think we return to this topic about how this can connect to vaccine development, influenza, which is an incredibly neglected virus and in terms of replication errors, there have been efforts to address to create a vaccine against what is common among the different influenzas. strains, so that is something that I also think that in the future with the manufacture of a vaccine against SARS-Co-V2 we want to be attentive to try to dedicate efforts to manufacture a vaccine against, I mean first any vaccine, but then again to a vaccine against something that is common. against different strains of the virus.

And in terms of the speed, the places that SARS-Co-V2 is mutating, I can give it to Matt or Justin. - So before we talk about that again, I want to connect something that Emily just said and something that Matt said earlier. Matt suggested that we may want to 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 strains of SARS or different strains of coronavirus. So, Matt is that just because they're outside, and then they just... - Yeah. - A brilliant target... - Yeah. - For the immune system? - And presumably that's also why the Spike protein is evolving so quickly, it's just that, you know, it's the main epitope that the immune system, or the main type of surface antigen that the immune system can see, and so we see it with many others. virus, that those surface proteins because that's what antibodies respond to, which is what we're generally talking about, when we talk about creating a vaccine response, those proteins are being driven to evolve rapidly by that selection of the immune system. system.

Now, we don't have many other targets on the outside of the virus that we can use, at a minimum, to stimulate the antibody response. So. - And yet, in this sense, yes, I understand that with this universal flu vaccine there is an effort to try to address things that are not changing as much. So I guess it must be some part of a viral protein that is simply limited because it can't change without losing its basic function. - Yes Yes Yes Yes. It's the same thing we see with HIV. When people who develop these, what are called broadly neutralizing antibodies to HIV, they still target these rapidly evolving surface proteins, but they target regions of those rapidly evolving surface proteins that most antibodies don't.

They can achieve it, but you are here for whatever it takes. reason can, and they are, they are highly preserved. Presumably, that's the approach we would use for the flu and potentially here for coronavirus as well. - Matt, I also have a follow-up question. I think you're presenting an evolutionary dilemma, where our immune systems are driving the evolution of these host recognition proteins, and then we know that genetic variation of those host recognition proteins is what helps. Pathogens jump from one species to another, so do you think there's some kind of interesting dilemma or feedback between these things?

That the balanced immune system is essentially what drives the evolution that leads to the emergence of the pathogen? - Yes, it's an interesting question. I mean,I think that's driving the evolution of the recognition aspect of the Spike protein, so in many of these cases the recognition parts of the protein are not necessarily the same, so the part of Spike that recognizes ACE2 is not . necessarily what antibodies recognize, right? So I think they're actually probably separate surfaces. I don't know enough about what the antibody response is to coronaviruses to know in that particular case, but in many of these other cases you know that you have this type of surface protein of a virus that targets some receptor here and the Antibodies are actually attaching to other parts, not necessarily at that direct interface. - Well. - While we're on the topic, because I think so, Justin Matt and I really like this topic of the interaction between the surface protein of the virus and the host receptor.

Matt, you mentioned the bat ACE2 receptor, which the coronavirus uses in bats. Since it is much more difficult to do research with bats and genetic manipulation, etc., it is possible that there are other receptors... - Yes. - And I am curious to know what is known about what other receptors there may be in bats that can tell us what other recipients may be accomplishing. - Yes, as far as I know, we don't know of any other receptor for a certain coronavirus, we don't know of any other receptor, in other species, so that always seems to be the case with these, things like SARS1 and SARS2. appears to be ACE2 and all related bat viruses.

There are other coronaviruses that use other surface receptors, right? So you would imagine that there would be the possibility of that particular jump and of course that's something that Justin pays a lot of attention to as well, right? This is how to use a new receiver. But I think in the case of this, what's happening is not these big jumps in terms of which receptor is used, but actually a kind of small, fine tuning of when a given species of bat has a couple of amino acid changes. on its surface. Basically, the Spike protein needs to adapt to that in order to replicate in the new species of bat, and of course the same goes for humans.

But again, I think this point, and there was a study that came out a couple of years ago, that actually sampled a lot of these bat coronaviruses and a lot of them could use human ACE2. So I think that jump in many ways has already been made, and a lot of these other things, like immune response modulation and things like that, will probably no longer 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 talk a little bit about this, let's talk a little bit about the expectations of natural human variation that might be resistant to this particular virus, what we know about this from studies with other viruses and how that might relate to SARS? -CoV-2? - Yeah, maybe I'll start and then Justin and Matt can chime in in more detail. You know, the lesson of 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 who had two mutant copies of that.

The recipients were quite resistant, I think so, correct me if I'm wrong, like the sex workers in Africa who remained exposed and did not get infected. So the question is, yes, what is the natural human variation of this ACE2 receptor, among other factors that will regulate coronavirus infection? And you know, I think the short answer is that the jury is still out, but maybe it will. Let's let Matt and Justin expand on how much we know at this point. - Yes, I think this is a really interesting topic that we understand almost nothing about, in terms of infectious diseases.

So Emily mentioned this case of HIV, there have been a couple of other cases where we can map human genetic variation to differences in disease susceptibility, but it's really, really rare. Very different from the way that, for example, we can say that someone has a high risk of susceptibility to breast cancer or Alzheimer's disease or things like that, and then I think we don't know, as Emily mentioned and you know, I do too. I mentioned, all of these points where the virus interacts with the host could be points where variation in human proteins could actually have an effect.

I think one of the potential things that can come from this is that we could really start to map the genomic types of the virus to the genotypes of the person and the actual outcome of the infection. And really, maybe you start to get into that level of detail. But so far, I think ACE2 is not particularly polymorphic in the population, but many of the other proteins that these viruses interact with are quite polymorphic in the human population and some of them could determine susceptibility to disease. Excuse me. And some of them could just be random, right? - And I guess in that sense a phenomenon related to the study of HIV infection was that there are things called restricting factors, and this is what Matt was also referring to, different steps along the path in which you can block the virus and a particular restriction factor called a ubiquitin ligase, called TRIM5, that is present, is able to basically degrade parts of HIV in certain primate species that humans lack or have a different version of.

And then it can be things, not just like the receptor that changes, but also whether or not there is something that recognizes the virus as something that is not its own, something foreign that needs to be defeated. And it will also be interesting to see how that varies in the human population. - I think it was Matt who talked about normal immunity and vaccines, etc., at some point depending on the particular virus and the vaccine, you get something called herd immunity where even those who are not immunized have protection because the virus cannot . find as 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 physically impracticable for a variety of reasons, whether there will be a combination of herd immunity and social distancing that It will end up creating a final balance. So at what point can we expect herd immunity? Can we talk a little more about that? - I can do a follow-up based on that concept of R nothing. So, that R zero concept comes from this epidemiological model called the SIR model and those models predict herd immunity.

I think we will rely on herd immunity when we have a vaccine, but hopefully not before. So for herd immunity to work, you have to have a large fraction of your population being immune to the pathogen and that basically means that there are all these people around that it can't spread to, so it makes it harder for it to spread. and then your R zero will differ from R, drop below one, and leave the population. But that fraction of people that have to be immune so it doesn't spread is really high and that would mean that if we had that effect before we had a vaccine, it would mean that this pandemic has completely gotten out of control, kind of like you.

We know that between 30 and 60% of the world's population has experienced it and is now immune, but due to the high mortality rate of this virus, not as high as Ebola but higher than influenza, that would mean that millions and millions of people would die. So I think in the end we will have to distance ourselves, isolate ourselves. And then take advantage of the time so that eventually, when we have the vaccine, we can start to be immune to this on a really large scale and then herd immunity suppresses COVID-19. - I want to just chime in on this topic of immunity in terms of a sort of cautionary tale, I think that my understanding of the efforts to develop a vaccine against one strain of dengue actually led to people being more susceptible to other strains, and I think that perhaps there were some preliminary results that suggested that SARS-Co-V could have a similar effect.

So, again, I think there's an incredible amount of hope for the vaccine, while also really requiring us to do careful testing and make sure we're not creating more problems than we're solving. - Yes, so, you know, this brings me to this: the active debate about how long we should practice social distancing and the government has considered in some circles whether we should return to work for Easter and of course now that has been extended . So Justin, you talk wonderfully about the factors that go into it and why social distancing works in terms of R nothing and what it does, so can you say how long you think social distancing is necessary at least with the US. in context? ? - Yes, I guess I want to respond with the caveat that I am an evolutionary biologist and I teach epidemiology, but I am not an epidemiologist.

What do I say to my family and friends who are freaking out? I think that's the best way to answer this. I tell them to take each day at a time, that we have to continue social distancing. I tell them I hope we have a break around June, there are some ideas that maybe in the summer this won't extend as much, but also for June what that does is it gives us the opportunity to socially distance, especially in the The United States, within each of the individual states peaked and then declined in the number of patients with illnesses and then we calmed down.

But in June, what does that mean? Does that mean we all immediately go back to work, immediately go back to the bars, and immediately go back to normal life? That's not what we should do. Then we will have to evaluate in June, okay, we had this very strict measure that helped us stop the exponential spread of this virus, but now how do we move forward to not reignite that exponential spread again? So I think it will have to be carefully considered, but it will be a while before life returns to normal. I know it's terrible news.

And I think to deal with it, just live each day and be as careful as possible to avoid getting this disease and spreading it. - 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 it in different parts of the world with different start and end dates etc. then they could be this, running the risk of a rebound 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 again.

So there have been cases even in China where, after seeing cases drop, there are now cases coming in from abroad. So how is this managed at a global level? - Again, I'll give the same caveat that Justin did, which is that I studied the evolution of hosts and viruses, so I'm not an epidemiologist, but in some of the reading I've done I think there are a couple of things to talk about here. One, we see it, in fact, even in, recently there was a nice article in "National Geographic" about this rebound effect that you were talking about during the 1918 pandemic in different cities in the US.

And a really important message is that even When there was a rebound or this type of recovery, the cities that were doing the strongest social distancing generally had the lowest mortality rate. So the idea is that by flattening this curve we can allow things to catch up, right? We can allow the healthcare system to catch up, we can allow, I mean, a big thing about how we can move forward from this lockdown of everyone 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 respond much more quickly to these kinds of possible localized recovery effects of reintroduction or something like that.

So I think a lot of it is just allowing the system and science and society to really catch up so that we can implement public health measures that make sense in terms of containing the disease but are also less detrimental to the society and the economy and the mental health of everyone. So. - I want to follow exactly what Matt was saying, I agree that we really need better testing. And I also want to continue. I guess I just learned of a study, also of the 1918 influenza pandemic, that addresses this issue. I think people have proposed that we choose to save lives or save the economy.

And they did this type of study comparing which cities applied earlier, stronger and more intense social distancing that saved lives; Those were also the cities to whichIt was better economically. And so by saving lives, you're actually helping the economy and I think that's a very important message to drive home and make sure people know that. - Yes, very good point. - So, Emily, you started your presentation by talking about open science and how every government in the world is now turning to scientists, technologists and medical professionals to find the fastest, cheapest and most scalable testing tools and cures for this disease in particular. good?

So let's talk a little about the concept of open science and creating platforms to share study results in real time instead of waiting for the slow process of peer-reviewed publications and publishing manuscripts, etc. This is a crisis of unprecedented proportions and we simply need, everyone needs to come together to solve this problem as quickly as possible, so let's leave this for discussion. - Yes. - Actually, if we could start with you Emily. - Yes, wonderful topic. It's very inspiring, over the last two months, to learn about these resources where full genome information is available. That GSAID, I'm not sure how they pronounce it, that website that within an hour the information is moved to NextStream.

All that information is freely available. People can download it, they can analyze it, they can do their particular form of evaluation and that is a form of open sharing and then there is also this open sharing that has really been transforming the world of publishing 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 publish that information there as well. And then anyone can see it, they can comment on it, and the information spreads much more quickly than if we were waiting.

And of course we still want to wait for peer review, I think everyone has different opinions, I still think that's absolutely critical, we need experts to evaluate the data so that we only have really well vetted results that are published. But yeah, if you look at bioRxiv and medRxiv, I think there are now almost a thousand articles between the two of them that are related to the coronavirus just in the last few months and several journals are also making information and coverage about the coronavirus available for free, so I think that's, That's really going to change science.

The more people can share information, the more progress we will make. - Yeah, and I'll just add one thing to that, which is all of these social media tools that have been developed over the last, I don't know, 10 years, right, of Twitter and Slack and Zoom, right? ? And the ability to have these conversations in real time has been really transformative. I mean, even within the San Diego community, there's a huge group of people that have created all these resources that are just messaging each other saying, "Hey, I need this or do you have a, do you have access to this equipment or something like that?" , right?

And that's really been, I mean, it's been a little overwhelming to be a part of, but it's also been really, I mean, it's just that everything is moving so much faster. - This is really a ray of hope. for this dark cloud flowing over us. - Yes. - Justin, do you have any comments on this open science? - Yes, I mean, of course, all of this inspires me too. I'm going to have to say that I'm about to give a course on the evolution of infectious diseases and that 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 just can be a big part of the course because of these resources , these databases and where people do real-time analysis of the most recent and up-to-date data and because of the open source publishing or, sorry, the preprint publications where we can see what the latest science is and I can present it in my class. So the diffusion is not only among scientists but also among students and the public very quickly and, in general, we are much more informed. This is how I do it, I find it... - Yes, and I must add that this goes far beyond science, because with everyone sitting at home with all kinds of thoughts, and the thousands of jobs and professionals who need to do their work, Therefore, people are being exceptionally creative in finding ways to communicate, help each other through medical help, and therefore social connections.

And I know I've personally called more people in the last two weeks than I have in the last two years, so at least the world is coming together. So before I finish, let me talk about some of the lessons that each of you have learned from this particular pandemic that will prepare us for the next one, which will hopefully be some distance away, but you never know what is. just around the corner. . - Yeah, I guess I would, you know, kind of reiterate it. What we said before about open science, open sharing, but being able to track where that virus has spread, where it comes from, where it's going, how it's changing, It's been very inspiring and I think it really will be.

It will be crucial for the next time this happens, because it will continue to happen. This is like what Matt said in his presentation about the Red Queen, it's just that we are continually running, keeping up with the pathogens and they are trying to keep up with us. And I guess I would also say that I really hope that our government takes this seriously, that a pandemic response team had been established and disbanded and that we need those kinds of resources and support to prepare better. Go ahead, because as soon as we have effective testing we will be able to contain, track and learn how to treat these types of diseases quickly. - I guess similar to what Emily was saying, I think one thing we've learned from this is that we're a hundred years advanced from where we were with the 1918 flu and yet this still brings us to our knees. virus and I think one thing is that public health is really, very, very critical to this kind of rapid deployment of intelligently designed and well-executed systems; public health is really critical to this.

I mean, we can say that we will develop a vaccine in 12 to 18 months or that we will develop drugs in that period of time, but actually these ideas of social distancing and containment and testing and all of that are really the key to this rapid emergence of these viruses. , because Emily's image of the virus going in and a hundred coming out is similar to Justin's image of one virus going into one person and taking three out and that's what gives us this exponential curve and no matter how smart science is that many Sometimes the way to contain the viral infection seems to be these types of measures and that has been very effective in some cases that, fortunately, we have not heard of, became pandemics.

After the 2009 swine flu, there have been some cases of bird flu that worried people a lot. Even SARS1, I think the measures were effective in containing those viruses even with all those flaws, so I think one thing we really need to learn is what can we do to make sure they're always there, even when science is trying to detect them. above. -Justin? - Yes, what I have learned personally is that people should take these things seriously. We've known this was a possibility for a long time. I begin the first and last part of my evolution of the course of the disease by pointing out that the same slide, or a slide similar to the one I showed you during my presentation, says that the world is changing in a way that this is much more likely to happen. and again. again.

So we can't ignore them and we see that there is a new disease spreading somewhere in the world, even if we think it is very far away from us, so we have to take it seriously, and I think the other thing we could really gain a lot is better disease surveillance in bat populations. In other mammal populations, we know what's out there, maybe even what has the potential to carry over to humans, and I think there's a lot of fundamental knowledge we need to learn as well. We don't know exactly what genetic mutations could have helped this virus appear in humans, so it would be good to know more about basic biology and evolution to be able to predict what types of genetic variants could be most problematic.

I mean, to be honest, in our lab we've seen evolution very similar to this, it's in a very different virus, but there are a lot of common themes. Of course, that could just be the human brain making these connections, but there could actually be something there. And so, the strain that emerged in humans, this SARS-Co-V2, 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 changes in host range. . And so if we start gathering more and more information from more and more viruses and doing controlled experiments and looking at natural variation, maybe we can better predict what the potential bad diseases are and intervene at an earlier step before they emerge in our population.

Of course, I agree with what Matt is saying, that once they emerge there are fast-acting containment strategies, that's really critical and of course in the end having a way to create vaccines quickly is another preventative measure or way of address these things, but I also think we can even stop at an earlier step. - Well, I must thank you all for a really fascinating conversation. We began eager to spread some of our teaching skills and information to our students and teachers and to anyone who would listen, but I myself have learned a lot from this conversation, many fascinating questions in biology that have not yet been answered. and if the audience loves this and wants us to talk about other related things, let us know through the comments and we will be happy to do more of this.

So thank you all for being a part of this conversation and stay safe. (upbeat music)