The Peter Attia Drive - #117 - Stanley Perlman, M.D., Ph.D.: Insights from a coronavirus expert on COVID-19

Episode Date: June 29, 2020

In this episode, Stanley Perlman shares insights from his impressive career studying coronaviruses—both the common and more deadly ones, like MERS and SARS. In comparing preceding coronaviruses with SARS-CoV-2, Stanley discusses how other coronaviruses can aid our current understanding of, and be used to infer about, COVID-19. He also gives his thoughts on durable immunity, therapeutic strategies, and future outbreak preparedness.   We discuss: His background and early work with coronaviruses [2:45]; The coronavirus family—various types, common traits, and scientific understanding [9:00]; The origin of viruses, animal to human transmission, R_0, immunity, and more [17:45]; Insights from the 2002 SARS outbreak [28:30]; Insights from the 2012 MERS outbreak [35:00]; Comparing SARS-CoV-2 to MERS, SARS, and other coronaviruses [42:00]; COVID-19 survivor potential for long-term damage [53:30]; Using the current pandemic for lessons on future preparedness [57:00]; Genetic drift and the potential for long-term immunity to COVID-19 [1:07:00]; Prevention and treatment strategies for COVID-19 and future diseases [1:22:30]; Alternative hypothesis to the origin of SARS-CoV-2 [1:32:30]; Determining durable immunity to COVID-19 and what a successful vaccine looks like  [1:34:30]; and More. Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/stanleyperlman Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain what those benefits are, or if you want to learn

more now, head over to peteratia MD dot com forward slash subscribe. Now without further delay, here's today's episode. I guess this week is Stanley Proman. Stanley is a professor of microbiology and immunology, along with being a professor of pediatrics and the chair of virology at the University of Iowa. Stanley has researched coronaviruses for nearly four decades, and his lab is currently using mouse models for SARS-CoV-1 and SARS-CoV-2 to better understand the more severe diseases that affect humans. I wanted to talk with Stanley for a few months now. Understandably, he has been incredibly busy. We have been part of a collaboration that is working on a longer study

trying to understand the durability of immune response and the impacts of that, which we discuss very briefly at the end of this podcast. So most of our contact has actually been through that, but as we got a little bit of breathing room in and around our other projects, inclusive of the one we're working on together, we decided it made sense to finally sit down and have this discussion, especially as a beautiful extension of the discussion that I already had with David Watkins. So I do recommend that you would listen to these podcasts in that order. The one with David Watkins, of course, goes over the immunology a little bit. Here we talk specifically about coronaviruses, including the sort of common-called coronaviruses,

and of course, more importantly, the three versions that really have caused incredible damage to humans, none more so than the one we're in today. In this episode, we talk about a whole bunch of things that, again, just, you can probably imagine interest me to no end. When we were talking specifically about SARS-1 and MERS, what did they teach us about this coronavirus? What does our knowledge of this coronavirus today versus what we knew, say, five months ago, tell us about how this story ends?

And what do I mean by ending? All of these are topics that we get into, along with a very interesting discussion around the therapeutic side of things, the vaccination side of things, and ultimately what could happen again. So without further delay, I hope you enjoy my conversation with Dr. Stanley from... I'm going to be doing a little bit of a conversation. I'm going to be doing a little bit of a conversation.

Hey Stanley, thank you so much for making time to talk today. I've wanted to speak with you for a couple of months now, and I know when we first connected, it was just nuts. And you said, hey Peter, thanks for reaching out. Can we talk when things come down a little bit? And I was so gracious. First of all, that you Peter, thanks for reaching out. Can we talk when things come down a little bit? And I was so gracious. The first one that you even took the time to respond. And then, of course, now we've been able to work together on a separate project that

maybe we'll talk about down the line. But I'll tell you, the reason I reached out in the first place was really the result of something that my research team came to me and said, which was, look, Peter, if you want to understand coronaviruses, you've got to speak to Stanley Pearlman. Everybody is an armchair coronavirus expert now, but you actually want to talk to the guy who is studying coronaviruses before they were sexy. And that's Stanley. So, before we get maybe into how you became obsessed with coronaviruses, how did you get

involved in medicine and immunology per se? Well, I actually started at 10 to PhD many, many years ago. In the areas actually of cell biology and developmental biology and virology. So I did a whole potpourri of training at as a PhD student and then again during post-op and then I went to medical school. So there was a period there where I learned though, I didn't do coronavirus research, but I learned how to do research.

And so then when I went to medical school, I became interested in pediatrics, and infectious diseases. And I don't know what my plans were exactly when I started medical school, but became really interested in how baby brains interacted with viruses, which was not good. So when babies are getting infected with viruses, especially in utero, it's often has devastating consequences. And I worked with somebody who was really good at thinking about those babies. And I became just interested in research issues around how viruses interact with the brain. So at that time, point, I became interested. It turned out that coronaviruses

and mice provided a model that could lead to potentially important information. So I went from all the other things that I did and from being a pediatric infectious disease person. Part of my training, I also started working with coronaviruses. Now, what was the decision point that had you leave sort of a pure academic track, which you would have been on from your PhD and your postdoc to sort of take that, I don't like to use the term backwards, but I think you sort of get what I mean. Take that backwards step and go back

to something remedial like medical school. In other words, what really drove you to want to have a clinically active research focus? Well, I think there are two things. One, I was interested in, I felt I was getting compartmentalized in a smaller area of research. I don't think I wanted to be in something that was quite so confined and didn't have too

many relevance for general health issues. And the second thing is that Ironic, I started my PhD at an early age and it was almost like I was looking for a chance to take a little bit of a break. A medical school in residency is more than a little bit of a break, but it was pretty fast. It was a total of starting medical school to finishing fellowship was only six years, which is a long time, but not compared to what most people do to this kind of training. It was a combination of both those things and being wanting to really step back a bit and also wanting to find more relevance for human disease. and also wanted to find more relevance for human disease. You're kind of a doogie-houser because how is it you could do med school and because today

med school's four years pediatric residency is three and then pediatric infectious disease would add at least two to that, right? Oh three, it's actually going to be going out real. You'd be talking about a 10-year training program that you did in six. So I was lucky because when I did went to medical school, there was a shortage of doctors and there was one or two programs that allowed people to truncate their medical school training. I went to one in Miami that if you had a PhD,

you could basically do the whole thing in 22 months. And what you did is you cut the first year down to six months, the second year down to about three months, the entire third year and then you did the fourth year and eight weeks So at the end of it all waited everything and we could do it the people at PhDs though I have to say they took PhDs in whether it be physics or physics the psychology the biology the chemistry So people had different amounts of training the training was good The classes were really full of people who were really creative and thinking about things. So it was generally intense, but very good experience. And you were well trained at the end. So you did your residency at Boston Children's or fellowship still to this day, Boston Children's Hospital remains easily

in the top three in the world, perhaps along with Chop and Sick Kids and maybe a few others. So you're at the sort of premier pediatric hospital in the world. You're training with, I guess you're referring to Brazleton as your mentor there? Yeah, yeah, so right there is your mentor there. Yeah, yeah. So tell me more about childhood development. I mean, I don't know much about it, obviously. And it certainly rings a bell when you say that viruses can really wreak havoc.

One of the few things I remember from OB-GYN is the lengths you would go to to ensure that a mother wasn't infected actively during childbirth. Yeah, so we don't understand everything about this, but certainly these viruses that invade the brain during the first trimester really cause devastating loss of neurological function. And the later you go in the pregnancy, the more likely it is to cause less disease, but even when you're infected during delivery, babies infected with certain viruses, or you have hearing problems, the visual problems, and even cognitive problems. So that babies, just because they're developing, they're incredibly sensitive to anything that disrupts their development. And when I think about it, the direct relationship to what I later did with research was really

not so strong, but it was just the whole notion of could you do anything to prevent the viruses from spreading in the human brain. And then also the way they do spread within the human brain could this be something that would be useful for understanding other functions if you did this in an experimentally infected animal. So that's the kind of the way. And then coronavirus has turned out to have this interesting ability to cause demalination,

or which was similar to what we see in multiple sclerosis. So it's sort of ended up no longer around about way for my we see in multiple sclerosis. So it's sort of ended up going around about way for my studying at this multiple sclerosis like disease for 20 years before SARS came about. Maybe this is probably just as good a time as any Stanley to really give people a bit of the lay of the land on what a coronavirus is because anybody listening to this when they hear coronavirus,

they're thinking of SARS-CoV-2. It might be helpful to put that in a much broader context, which is what is a family of viruses actually mean? When we say the Joneses and the Smiths, we're talking about a family, not Billy Smith necessarily. So what does that look like? So the coronavirus is like any other set of viruses their viruses are put into that category

because of what they look like under the microscope, what they look like under the electron microscope, how they make new viruses, the kind of replication strategy we call it that they use to make more viruses. In the old days, you might have some serological testing that will tell you about relatedness. I say in the old days, we still use that, of course, but we have genetic ways now to really see how close viruses are. So you put all those things together and particularly looking under the microscope, we can say coronaviruses have a certain pattern under the microscope and all viruses that are coronaviruses have those patterns.

Doesn't mean that they all can infect people or they all can infect this animal, this animal, they're really very, very different. And the ones that were known before SARS came about, really were the experimental ones, like the ones we use, which infected mice. And then also these other coronaviruses that infect swine and cows and cats and dogs. And even now, they're finding viruses that are not quite coronaviruses, but are very

closely related that affect insects and snakes. So these viruses infect across lots of species, and that's of course, we know, because that's been very, very clear in the COVID-19 outbreak, because that's where this virus undoubtedly started, at least distantly. So is it safe to say that coronav as a family probably when compared to any other family of viruses, flavy viruses that produce Pepsi that otherwise would have nothing in common? About the only thing that's true of viruses is they need a host to replicate. Is that about where the similarities end across the broadest discrimination of viruses?

Or are there other things that are uniquely, I mean, I guess they all have either DNA or RNA, but typically not both, right? Yeah, they accept maybe HIV seems to have both. But generally, they have one or the other, depending on the amount of genetic information they have, they can do more or less functions than other viruses. These gigantic viruses, or these giant viruses, just they've called that seem to have almost old material, you need to almost be a cell, not a cell, that seem to have almost all the material you need to almost be a cell, not a cell, but they have a lot of their own material for making proteins and RNA.

Most RNA viruses just have the genetic material for programming the functions needed to reproduce the virus and also make the proteins that cause the structure of the virus, the form the structure of the virus. So those are simpler viruses. Coronavirus has the unusual characteristic of being huge. So genetic information of a coronavirus is about four times that of a polio virus, and yet the virus doesn't seem to do that

much more than polio virus. So a little uncertain exactly why it needs all that genetic information. And when you say huge Stanley, do you just mean the amount of RNA in it, or do you mean the actual diameter under an electron microscope as well? The amount of RNA in it, certainly the coronavirus is bigger than the polio virus, but that's because as all this genetic material stuff into the middle of it. Can you put it in context for us, if you take the genetic material contained within a typical

coronavirus, how does it stack up against a human gene? I mean, the listener might not understand what base pairs look like or how many kill adultons we're talking about, but just contextualize it in some way. Well, let me see if how I can do that because it's big for a virus, a gene. If you took genes and laid them side by side, it could be equivalent to 15 human genes laid side by side in terms of length, but human genes have variable length. So if it was a longer human gene, it could be fewer of those for the viral genome. This particular virus codes around probably about 25 or so different proteins varying size. A lot of them are pretty small. So it's a lot of information, but it's not compared to the human genome, which has 20,000 genes. It's a very tiny amount

when you think about 25. And does it like human DNA contain coding and non-coding segments alike that are just as important? No. Human DNA contains both non-coding sequences within genes and non-coding sequences outside and vast majority of the human genome is not for coding. With a virus, the vast majority is for coding. There may be stretches here and there that are spacers as there were between genes, but they're a real and a minority. So the strict answer to your questions, yes, this part that are non-coded, but it's a tiny fraction compared to the amount that actually codes for genes.

Just to go down the path of some speculation, do we have a sense of what the evolutionary pressure was for a coronavirus? I've never really stopped to think about it, but it always struck me as viruses, unlike bacteria, don't really serve a useful purpose. I mean, it's true that maybe most of them don't directly harm us, but if you eradicated this planet of bacteria, we would all die pretty quickly. We live in a very healthy symbiotic relationship, despite a pathologic relationship with a small few of them. But if I could conduct a thought experiment and remove every virus from this universe, wouldn't the world just keep ticking along fine, or is there something I'm missing about their function? Well, I don't think you're right. We have a

lot of great examples. For example, in the ocean, there's resilience of viruses that interact with bacteria. I would bet if you took that interaction away, that there would be a problem. And in the people talk about even in the human gutters, all these viruses that people find, some of them I think interact with those commensal bacteria, and are useful, whether they're absolutely necessary.

I don't think we know as much as we do about commensal bacteria, which are really important for human life and animal life. But I would bet if you took away all the viruses in the world, you should eliminate some of the ones that are cause human disease or non-human animal disease. But I think you might get away from others that are actually beneficial. Yeah, so there might be some knockoff effect where they're helping something that's second order to us. They're helping the bacteria that are helping us or helping some other distant organism that's

way down the plankton subchain that you know, I haven't considered fully. I think that that's a possibility and then bacteria, phage on bacteria are going to be even different than the ones directly at human cells, but there may even be animal viruses that have roles that we don't understand very well that are important. I know there may even be animal viruses that have roles that we don't understand very well that are important. I know there's some animal viruses that interact, insects have a relationship with each other and the animal viruses have an important part in maintaining some of the developmental patterns in those insects.

I can't tell you, I know that some of them are less, I can't tell you more, remember. But there's definitely viruses that, without which, they would be problems. So I'm sure you're tired of telling this, but I think everyone should know this by now, but if not, why does it derive the name corona virus? What is the corona referring to? If you look under the electron microscope, it has these projections from the surface of the virus that look like, either the corona of the sun or the corona of the crown. So I think the first people who saw it under the electron

microscope decided to name it based on that. Yet they have a little imagination, but it's not so far off. And of course, this is relevant when we start to talk about the immune response to it because the immune response is particularly strong when it comes to certain parts of the viral coat and we'll probably come back and talk about spike proteins and things like that. So when did these coronaviruses show up in terms of our understanding of common colds? I think we identified the first one in the 1930s and 40s from chicken. That's what I remember that the infectious bronchitis virus was found in chickens.

And then in the 1960s, people identified viruses that caused the common cold that had the same kind of appearance as the infectious bronchitis virus. And I think by then we knew something about some of the pig viruses as well. So the human, it was isolated from people with colds and had the same structure as coronavirus and chickens and pigs. So that's how the new was in the coronavirus family.

Is it the exception or the rule, Stanley, that a virus that infects humans also has an animal host? I think I would say it can go either way so much that it's hard to make a strong conclusion. Viruses, like measles virus infects only people, smallpox only infects people, that's why we can eliminate them from human populations and theory.

Viruses, or the coronavirus, is mostly seem to be able to infect other animals as well But with virus that I worked with three years in the lab mouse hepatitis virus was a mouse virus And I don't think it affected anything but mice the human viruses even now So we're seeing that SARS-CoV-2 the cause of COVID-19 can infect animals so humans can infect these other animals by spreading the virus. SARS-CoV certainly infected other animals. MERS-CoV is during a camel virus, so by definition it affects other animals. The human common cold coronavirus is at least one of them can infect other animals, and

I don't know, one of them probably came from bats, but I don't know if they can infect bats. So I think coronaviruses usually can go across species, but I don't think a least. And other viruses often can go across species, but not always. And it's really going to play as I was saying, into the ability to eliminate a virus from the human population. So if you're keeping track of all the things that make a virus difficult for us as a species, so if you're trying to build a super virus, having the ability to go into an animal host is an important feature of that, because you can basically quote unquote hide outside of the humans for a while, even while a large population of the humans are either vaccinated

or acquiring natural immunity or even approaching herd immunity and you can effectively lay dormant outside of the humans for a while. Maybe we think about different viruses, certainly that's true for West Nile virus. If we had the best vaccine in the world, we still have West Nile virus floating around the birds and other animals. Of course, West Nile virus really isn't a human virus. It's a virus that ended up in humans at the end but it wasn't really the intent as a word of the virus to infect humans-NOT of measles was just so high that it was like, you just had one little crack in the dam

and it was a disaster, whereas for most things like influenza or even coronavirus as the R-NOT is in order of magnitude lower? Yeah, I think that that certainly contributes to it. With measles, you had five people out of 100, not vaccinated or not resistant to the virus. Those people would get infected if you put them in a room with somebody who was positive for the missing virus.

Same thing is true for smallpox too, where it spread out in animal host. Others, I don't know, for other polio, I don't think of polio as having much of another animal host. I think that it continues to be in human populations mostly because core vaccination and because we use live-eventuated vaccine that ended up in a water and even mutates or doesn't mutate, but it's not gone. And so where did those viruses come from? If they never had an animal host, where did they evolve? Well, I think they did initially have an animal host. So measles is thought to

evolve from interpests in which affects animals in Africa. You see, that's the other thing about the animal host is if you evolve from an animal host, the virus evolved from animal host, but then change so much to, in fact, humans, they may not be able to then cause an infection in the animal host. So these, like the SARS-CoV-2, the causes COVID-19, we don't really know what it would do if you put it back in bats. No, it's going to try it, but I don't know if a bat would be infected by it because it may have changed enough even in the little bit of time it's been out of the bat, so it can't affect the bat very well anymore. Wow, that's really interesting. So it ping-pong's back and forth until it finds a more favorable host.

I mean, this would suggest from an evolutionary fitness standpoint that if it starts in an animal, comes to a human, stays in a human, it must find the human on some level a more desirable host. I don't know, but that's making the virus a little more anthropomorphic than it might be needed. If it's in humans, it may never see a bad again. So it's not that it's more desirable host, but that's a fair point. Yeah,'s not that it's more desirable hosts, but. That's a fair point. Yeah, humans about stone interact that much, even though they interact more than maybe desirable given these viruses.

But it's not like the virus can look around and say, up there's a bad, I think. Yeah, let me go try that out again and see how it compares to this. The last question on this topic. Tell me a little bit about HIV. I'm just not a student of Miami-Nology. Is HIV a virus that is now believed to have evolved?

I mean, I know back, I remember a million years ago, people said, oh, it came from this monkey or that monkey. Do we have a very clear sense of the lineage of HIV? I think it's beyond what I know well. I think that we have a very strong sense that it came from non-human primates. I think we may know more exactly, but what I read periodically is some studies that seem to have the virus within human populations are identified way before it's first obvious entry into people who became HIV infected.

So I think it's clearly from non-human primates, but the exact details I don't know, but I think some people do, and some of these sources, like some of your Hanyu primates have an HIV bike virus that's pretty close. Let's go into the, it's say it's the late 90s, so it's pre-sars. You're working hard on coronaviruses. At that point in time, is it, am I doing the math right that there are basically

sort of four endemic coronaviruses that are not especially severe, but just circulate through humans causing annoying respiratory infections year after year. Is that directionally the lay of the land? It's actually only two in the 90s, because two of them covered after SARS in 2004. Wow. Which were the two that came along and that were there in the 90s? 2,290 and OC 43. Okay. And what did we know about people's immune response to them? I mean,

did anybody ever say, hey, we should vaccinate against these or was it, they're not that interesting, they don't make people that sick. Who cares? Yeah, it was more of a ladder. Properly so if you're going to spend a huge amount of money and we know that huge amounts of money are involved in making a vaccine, why would you spend it on a cold virus? People get colds, it's annoying. The other thing is that really, that maybe relevant, I think that COVID-19 is that people got these cold viruses, they could be reinfected.

So they could be reinfected a year later. And that's what the papers we were talking about earlier, really, to talk about is that immune response may be, do you have a mild infection, you may have a more transient immune response. Yeah, there are three or four papers that I can't wait to dive into and we're gonna do it. I just wanna make sure the listener doesn't get too lost

in what we're talking about. But actually, if you're listening to this now and you have not listened to the interview with David Watkins, this would be a great time to hit pause, go back and do that. Because in that discussion, we really do the immunology tour de force, and we explain the difference between the innate immune system, the adaptive immune system, and the two branches

of the adaptive immune system. The humoral system, which relies on B cells and their antibodies, and the cellular system which relies on T cells. And I have a very strong suspicion that very soon, Stanley and I are going to get into some of the weeds around the B cells versus the T cells. And again, I don't think you can educate yourself enough on this topic if you want to truly understand what's going on with these viruses. Bringing it back to the late 90s, tell me what your interest was at that time. So obviously you're a scholar, you're doing incredible work. Did you think at that point in time, gosh,

these coronaviruses aren't that interesting. They're not really a threat to humans. They're not really a threat to my patients in the way other viruses are. Even RSV would be more of a threat to children. Wootencoff would be more of a threat to children. What is it that kept you in this at the time relatively benign virus? Was it, how do I understand, was that kept you in a field that ultimately turned out to be a very productive decision? At the time, we were interested mostly in this mouse virus and the human disease multiple sclerosis. So, thinking about how does a virus go into the brain end up in the cells that make myelin,

which is the sheets in the brain that make myelin, which is the sheaths in the brain that cover the axons. And how does the virus, so the head of the virus end up there? And then once the host realizes that the virus is there, how does it manage to destroy tissue while it's eliminating the virus? How come the virus, the immune response, can't figure out how to rid the cells of virus without all of destroying the cells themselves and destroying the function of their cells. So that's what I became interested, that's what I was really studying, how does this

occur, what kind of immune responses were delisted by the virus, what mattered the most, what caused demolination, and what caused remolination, which is the process of getting myelin back, which is in people of multiple myelin back, which is, and people have multiple sclerosis, is the period when they have the emissions after relapsing and permissing, or after relapsing have disease, and they get better again for a bit of time, for people who have some form when they get better to a large extent, how does that occur in as well? So we were using the virus to try to study that. But to be clear, was your personal interest at that time more in this is a virus that helps

us understand a disease like MS where we can understand the demyelination, remyelination process, or was it more, I think, from a pediatric and a neurobiological development standpoint, I want to make sure I understand what's happening in trimester one that is potentially injuring a child's brain. Those two aren't necessarily mutually exclusive, but were you bent more towards one than the other? I think that by the mid-90s, I was thinking much more about the first.

How does a virus infecting the brain? How is it cleared? Why does clearance always involve tissue destruction? Why is that happening like that? So you're basically now becoming a neurobiologist with a background in immunology, virology, and pediatrics? Well, at that point, I became a neurobiologist

with a background in virology and cell biology. I didn't really start doing immunology to the early 90s, 1990s. So I then were doing Somerva. Yes, the virus proceeded by doing immunology to the early 90s, 1990s. So I then were doing some of it. Yes, the virus proceeded by doing immunology. So tell me what's going on when SARS hits. What is it? I can't even remember exactly.

Was this O2O3? The end of O2 became a big deal in 2003, and then it was eliminated in July 2003 for all intense and purposes. So tell us the story in some detail. I think for many people, I remember it because there was a component that was in Toronto. I grew up in Toronto. I wasn't living there at the time, but just that sort of perked my ears. But at the same time, I was in residency.

So I was so sleep deprived. I, if I could drive home without crashing, that was an accomplishment. So it's not like I was really paying attention either. But can you give us sort of a really detailed account of where this virus came from, how it emerged and what impact it had on you and how it may have shifted your thinking? Yeah, so the way it emerged, we heard about this virus that was causing a respiratory disease in southern China. And the issue we all thought this was going to be a plan to flu virus, because flu viruses we know initiate often starting southern China. And the issue we all thought this was going to be a plan to flu virus because flu viruses we know initiate often starting southern China. It's particularly in the city of Guangzhou which is across the bay from Hong Kong. So we heard about these viruses and then it became clear that they were a coronavirus. This was isolated by several laboratories but we learned in

retrospect is that they actually came from a live animal market in Guangzhou. And this was a place where animals were all put together for sale for food and other purposes. And so they were bats along with other exotic live animals. And we learned that the coronavirus, the SARS coronavirus, was almost certainly a back virus that spread to these other animals, and the virus rapidly adapted to these other animals and sometimes infected human handlers of that market so people were actually handling the animals to sell them. And many of those became sick, many developed sub-clinical disease, and we know that up to a third of the handlers are actually antibodies to SARS-CoV. So we know that this was going back and forth a lot.

Then we know that some of the time it's spread to a mainland China. How many times that occurred? We don't know whether it was exactly the same virus that we study in the lab. I don't think we really know that well. The reason that this became really, was brought to the world's attention, is that a single animal handler became ill enough to see a position. The physician actually became quite ill, didn't go home, we either went to a Hong Kong hotel, and at that point it was really sick and spread the virus to the other people on the floor, and they all

went through their homes, and that's how the virus ended up spreading around the world, because of this one physician who ended up going to Hong Kong. Whether this would have occurred anyway, as a open question, of course, the main set of events was single event, and that's why the virus seemed to start from a single point source. Now, help me understand something. I think most people listening to this are now familiar with R-NOT, but we'll explain it again. What was the R-NOT of that SARS virus? In retrospect, I guess, what do we believe it was? How transmissible was it? Yeah, so this is a good question because the official numbers are, has an R-NOT of about two to

three, which means that a single person will affect two to three people. So, clearly, as you can see without even thinking about it very hard If a virus starts with one person then it affects two and then each of those infects two more people You don't have four infections, they infect two you get eight so you can quickly get up to high numbers by this Exponential growth. And the will hit pause there for one sec just to put that in the context earlier for example You talked a lot about measles. Measles has an R-NOT, probably north of 10, correct? Yeah, around 15.

I mean, that's about as high as they come. I mean, that's an explosive exponential multiplier. At the other end of the spectrum, today, HIV's R-NOT would be less than one. Yeah, and I think that HIV's a little different because it's not a respiratory spread. Yeah, so let's use another respiratory example. What would be a low R-NOT? Well, let's use the other coronaviruses. If you take those other coronaviruses, they're one to two at most, right?

Exactly. So one person infects someone else on the average. This is all in the average, of course. So going back to Nousar's, sort of to interrupt you there, but now you've got a 2-3 R-NOT. So, this is quite a spreading virus. This physician goes to the hotel. He gets a bunch of people potentially sick, and obviously now that can take the virus

around the world, because presumably people at hotels are going to go back someplace, right? Yeah, so I think that the R-NOT of 2-3 though may be misleading because there's no question that the R-NOT run the average was 2-3, but it consisted of spread within the hospital. Spread occurred much more readily. SARS was a virus that really caused pneumonia not much more. So the virus didn't readily spread from one person to another until that first person was pretty ill. And then if that person went to the hospital and you now started as we're mucking up their lung fluids,

so that virus was now released into the air by procedures either intubation or suctioning or whatever else needed to be done, then we are not fact it would be much more than two or three. And the community, because this is a deep pneumonia, it really isn't that a contagious. So I think that if we split it up, those 8,000 cases would be an average of two to three with quite a range, depending on where the virus was acquired. And I think the other lesson we have to take away from SARS is it gets widely quoted as having a 10% mortality rate.

But again, how could we possibly say that when we don't know the total number of cases? That might be the case fatality rate. I mean, case fatality rate is not that interesting. It's the infection fatality rate that really matters. And it's certainly possible, isn't it, that many more people had it, even, let's say there was five times the number of people who actually had the illness, but didn't come down with a severe enough version

that they warranted hospitalization or testing. You would all of a sudden say, technically the mortality of this is 2%, which is still absolutely devastating virus, but it's not the devastation of, when you hear 10% mortality, I mean, that's literally like playing Russian roulette. That's a way to, I think about it, but it was very hard at the time finding patients who

are asymptomatic and were infected. So the thinking was that anybody who became infected actually became symptomatic. What you say makes perfect sense, but I'll tell you another story. So the next coronavirus that came upon us was the MERS coronavirus, the Middle East respiratory coronavirus. It's a very similar to SARS and being a deep lung disease. This disease, the mortality, is built at 35%. It's really terrible. It's different though So what you just talked about the 2002 to 2003 virus that started in a market in southern China Who has the same name as the current virus we're talking about but we refer to them as SARS-1 and SARS-2

They're in the same beta family which we didn't really get into you want to take a minute to explain that because Merz is a slightly different Subdivision of the family Can you help people understand that nuance? Yeah, so it's all very similar. They're all in the same general group of coronaviruses and within the same subgroup of coronaviruses, but they're slightly different in their genome organization and in some of their coding, so they're put into a separate category. So it's a coronavirus.

Before we knew so much about from sequence, they wouldn't be considered the same type of coronavirus, but it's different enough so we classify it a little differently. What that means is a little more distant from the SARS coronavirus. So it's Lesson thinking that one could actually provide immune protection from the other. Though, in fact, there's some crust reactivity immersed coronavirus is recognized in part by SARS-CoV-1 virus, SIRA, from people who survive.

They're close. It's like your third cousin instead of your first cousin. It's pretty close, but not as close. And this will obviously be interesting when we come back to this discussion of cross-immunity. And basically, that's probably the biggest difference, as opposed to a functional difference about the virulence or the potential for virulence, correct? Right.

Right. Okay, so again, let's not pick it back up. What is it? 2009, when MERS came along? Well, MERS and Camels probably came along at least in 1983, but in people, it was found in 2012, and that's the earliest cases. There's a few mysteries about numerous coronavirus. Why is it only in the Arabian Peninsula?

So tell me about that. Did people, I mean, I say people, I really mean scientists. I'm sure the population wasn't wondering around thinking about this, but did scientists appreciate that there was a coronavirus in camels in the 80s from the early 80s. Was that something appreciated? Nope. This was absolutely not appreciated because in camels these coronavirus is caused to come and cold.

So that's why nobody would care. Camel gets a cold. You don't even know. He goes to camel wall green and you never hear about him again. So what do we think accounts for the virus jumping quite literally from a camel to a human in call it 2012-ish? We don't know. The virus had been in camel since the 80s and probably earlier, and we know it doesn't jump in Africa or other parts of Asia.

So this is real mystery in this virus. Why is it only in the region? When you look at the MERS virus in the camels, it's still the same in the Arabian Peninsula versus other camels. Hard to know. It may be subtly different than parts of Africa where there's no MERS, but we have a lot of trouble saying that those differences account for the fact that there's basically no cases in Africa and you have these cases in Saudi Arabia rising over time now. And when you say Africa, do you include North Africa? Were there any cases that arose in Egypt or Algeria, Libya, Morocco? Yes. They did not occur in those places. Yeah, camels are infected there, but people are not.

Oh, wow. Because a lot of people would sort of say, look, I mean, if something happens in Saudi Arabia, it would be just as likely to happen in Iran or Egypt. I mean, even though they're technically belonging to different continents, they're very similar geographically, but you're saying, no, there was a really hard line distinguishing that. And we don't, to this day, have a sense of what allowed that jump. Yeah, we don't know. The fact is not only occurred in 2012, it's occurring once it's twice a week now.

Because people are coming in who actually have no contact with camels and are coming into the hospital with murs. They often have coma bitties, they're older, or they might have diabetes. But otherwise, they don't even have contact with murs. They often have coma bitties in their older or they might have diabetes, but otherwise they don't even have contact with camel. They have to get it from a camel, but not clear how. So wait a minute, that was my next question. Do we know that it can or cannot spread human to human? Once a person gets it from its most likely source of transmission, which is a camel, can one person infect another? Yeah, so this is where the R-Not factor becomes important again because the

official number for MERS is somewhere between 0 and 4. Think outside of hospitals is probably near to 0.35, 0.5, somewhere in that low range. So it means it's not impossible, but all you need is somebody to be infected and happen to infect someone else who's highly susceptible and that highly susceptible person will then appear in the hospital not having had any contact with a camel. And that zero to four, which is such a broad range, I've read that is the official range, it's so broad as to be unhelpful, that's really the camel are not.

That's the spread from camel to human. And then as you said, human to human transmission is probably going to occur in the hospital. And so, MERS becomes the scariest of them all, just on mortality, because the official numbers are basically it killed a third of the people that were infected. It's about almost 900 deaths out of, call it 2500 confirmed cases. That's about as scary as any virus, maybe outside of Ebola, but again, the absolute numbers are so low, the transmissibility human to human doesn't seem as high, especially when you consider that the scariest viruses are ones that are transmitted from asymptomatic people, right?

Yeah, so this one, like SARS, is mostly transmitted from people who have lung disease already who have severe lung disease I don't think the R-Nort is actually camel to camel. I don't think it takes that into consideration rather It what it takes to the consideration is the hospital spread It's like SARS and some are hospitals but that's been basically not stopped completely Because it's my friends and sorry radio say somebody comes in with this disease, we think about it quickly, but we may not think about it in every case quickly enough so there may be still some spread within the hospital. So nose acomial spread, which you're referring to in hospital spread, is a big problem because you just don't have it on the front of your mind that every person who shows up in respiratory distress could have this, and therefore, a, potentially, the healthcare workers themselves can be infected because it's not just the proximity,

but it's the type of procedures that are being done. When you put a breathing tube in somebody, you're really creating an effective portal for the virus to get to you, and then obviously, we know how infections like that can spread through intensive care units and such. Yeah, that's exactly right. That's exactly why it's a problem. So why did this not turn into even an epidemic within the Arabian Peninsula? I mean, you did mention that we still see a few cases each year, but 2500 confirmed cases directionally makes it not even a sort of an epidemic really let alone a pandemic.

Why do you think this just wasn't something that spread despite its potential for devastation at the mortality level? Because I think that that are not a point three really makes it not possible, not likely. This point in case with murderous people went back to relatively poor country after having been a worker in Saudi Arabia were found to be infected and infected nobody. So that nobody became ill from that patient even though they weren't really looked at. That's as opposed to Korea where there's that one patient who infected 186 people.

So there was a really a confluence of lots of bad luck about to have occurred. And then going back to SARS-CoV-1, what basically accounts for the eradication of that call it in 2003-2004? The combination of there being no reservoir, so it's not like camels which could continue introducing to human populations. And the fact that because you weren't contagious till you were sick, it was easy to look at somebody, say, how that person has SARS, we're gonna stick them in a room by himself,

take care of him, and make sure he infects nobody else. Then you would stop the disease. So, class of kind of quarantining, identification quarantining, we talk about over time with COVID-19, but it's really feasible with SARS when you're talking about a total of 8,000 cases around the world.

I mean, Stanley, to hear you tell the story this way, it's just, it's like a bad movie because you could be lulled into a false sense of confidence. By the time MERS blows over, you can say, hey, okay, I got it. We've got a few of these coronaviruses. They cause a bunch of colds. You get a runny nose in the summer, but it's really nothing. And yeah, it's true. Two really bad actors showed up that on a virus to virus level can really hurt their

host, but they're nothing to really be afraid of. In the case of SARS-1, it has two things that make it really friendly to humans. One, it can't bounce back and forth between humans and animals. And two, you don't really spread it. You're very unlikely to spread it if you're not symptomatic. You don't have to shut the world down, but not only that, you get to isolate people when they're sick and treat them before they treat others. So the virus really gave up two big potential superpowers. In the case of MERS, sure, it lives in animals and it's never going to leave those animals, but it has such a poor ability to spread between humans,

almost under any circumstance, unless you're probably sticking a breathing tube in them, that it was just so easy to contain. If the story stopped there, you'd say, coronaviruses are just not a threat to us. Yeah, so I think some people in the field, more than me, said, let's go look at coronaviruses and bats. And so what they did is they found other coronaviruses. And it was actually for scientific reason, or a different one than just searching for the viruses.

We were trying to figure out where did the SARS coronavirus really begin. So people went and looked at bat colonies throughout a train up since that's where SARS began and asked, can we find other bats, are the bat viruses in a more similar to SARS-CoV than the ones we know about right this minute? Because we could isolate the virus in the wet markets in Orangio, but we didn't know where they came from exactly, which kind of bats. And it was just a trick finding it in bats. But while doing that, people found other viruses that could, in theory, enter a human cell

by using the same kind of mechanism that SARS-CoV-U stands to enter human cells. So there was some people who were saying, there were a lot of people, some people who feel they were saying, well, we potentially have more of a problem because there may be other ways to infect people, but there are other viruses that can infect people. And so I think there was a concern that this could happen again. In merruses, it's the same thing. We haven't identified the exact precursor to merruses and bats, but there's clearly viruses that look like the mer to murs and bats, but it's clearly viruses that look like the murs coronavirus and bats. And so if they were able to use the

human receptor and didn't take too much adaptation to infect humans, then you could imagine the same thing occurring with murs sometimes in the future occurring again with SARS-CoV-V-like viruses. So you write in 2015, we're thinking these viruses really close bad pneumonia, but it's going to be like influenza H5 and one, it's going to have very, very little human to human spread and mostly animal to human spread. Is there a necessary relationship that says the viruses like murs that are incredibly deadly if you get them, just luck is on our side and they

don't have much transmissibility or is that simply luck so far and there's no reason to suggest teleologically that that has to be the case. In other words, you could imagine a scenario where you take something that has the transmissibility of SARS-CoV-2, which we'll get to and explain why it is much more of a headache than SARS-CoV-1 or MERS. If you take the transmissibility of that, which is both, and primarily is a factor of the fact that it can spread before you're symptomatic, coupled with the actual pathology of MERS,

which I want a contrast with these viruses, I mean, that's a double whammy. You can really get into a dangerous situation, not that this hasn't been a disaster, which I want to contrast with these viruses. I mean, that's a double whammy. You can really get into a dangerous situation, not that this hasn't been a disaster, but it could be a 5x disaster. Is there anything that tells us that's unlikely because of this feature of the biology of the virus?

I don't think there's anything that's unlikely. I don't think there's anything about the feature of the virus. I think about this SARS-CoV-2 being a mixture of a common cold coronavirus and then a mix of positive SARS and MERS coronavirus in the lungs. So that's why you have the transmissibility in the severe disease because that's both. But when you think about other bad diseases, I gave them the epidemic flu in 1918. that really did about the same thing. It was very, very, very transmissible and it killed about a few percent of the people

infected, but if you infect everybody, you kill 3 percent or 4 percent, you're killing a lot of people. So that's what this virus is doing also because it's transmissible. So readily because it behaves like a common-c coronavirus, that rate of refalities, not super-high, but the denominator is so huge that you have a lot of people dying from it. Is there something about the pathology of this virus? How does it differ? I mean, when you think about SARS-1 and MERS, that let's just say, directionally, those numbers are right in terms of the denominator wasn't bigger than we think and you're killing basically one in ten or one in three people infected

What did the virus actually do in the lungs that would render people so helpless? Yeah, I think it's the same thing that SARS-CoV-2 does in the lungs in those people who get severe disease I think we don't really understand what's going on We think that there's lots of virus in the lungs, and we think there's a very strong and probably inappropriate immune response that's causing much of the damage that we see in lungs. So it's a combination of those two features.

That's why people are getting with SARS. People are trying to figure out a way to both limit virus replication and also decrease the host immune response so that you don't have this extra result of an exuberant immune response. Do the other two viruses SARS-1 and MERS do they also gain entry through the ACE-2 receptor or did they use a different receptor to enter the pneumocyte? Well SARS uses the same receptor, MERS uses a different receptor. One thing that's really curious is,

SARS doesn't affect the upper airway to a precibox, even though it uses the same receptor. It's also one of the common cold coronaviruss in L63, uses ACE2 only affects the upper airway, and doesn't affect the lungs than the precibox. And that could also account for the change in transmissibility, because if you are only infecting the lower airway, you're probably less transmissible than SARS-CoV-2, which can infect both.

Exactly. Exactly. That's why SARS was not so contagious because it only stayed in the deep lungs until you went to the hospital and had that tube put down for breathing or some other procedure done. So do you think that SARS-1 and MERS were so much more lethal than SARS-2 because they elicited a greater immune response once they infected the lung, or because they caused greater pneumocyte damage when they infected the lung? I think that it's actually because they all caused the same amount of damage or pretty similar, but you have this huge denominator in SARS-CoV-2 if people have mild disease.

So, I think that if one way to look at these numbers, and this is not a perfect calculation, but if you have, with SARS-CoV-A, or MERS-CoV-A, there were 100 people infected, they all get some very ability, some variation in pneumonia, and you have a certain mortality rate ranging from 10% to 30%. Asar as COVID-2, out of 100 people, maybe 20 of them are going to get the lung disease, the other 18 are going to be asymptomatic, sub-clinical, have a cold, have something in the upper respiratory tract. If you now take that 20% as you can your denominator and divide the 6% mortality that we're seeing, the 5% mortality. I don't know what the number is exactly, but let's say 5% by 20%, you have a 25% mortality

which is near to SARS-MIRS. So just to make sure I understand that, are you saying it's more the law of large numbers and we have such a big denominator with SARS-CoV-2 that you're going to normalize more, or are you comparing case fatality to case fatality, whereas I'm thinking of it as the IFR as opposed to the CFR for SARS, because I think the IFR of SARS-CoV-2 is very population dependent, but I think it's much closer to 1 to 2% than the initial numbers that people feared of 5 to 10%, which would put it more in the ballpark of SARS-2.

That's the way I used to think about it when this first started. In January of February, the mortality rate was 2.8%. And now, if you look at anything official, it's near to 5%, 6%. So what you say makes perfect sense is it should be near to 1% to 2%, but it's been hard to prove that by all the official numbers. So what I was saying more is that if the murekaldi rains, SARS and MERS out of everybody who was sick, all had pneumonia and of those people some number died and SARS-CoV-2 if only one out of five people or less, actually getting pneumonia, then

the fraction that die, it used that same fraction that died over that 20%, you basically amultiplying your number by 5. So if your number is 5%, then it goes up to 25%, if 3% goes up to 15%. So where we are exactly, I don't know, but it may be that the upper transmission is the readily transmissibility of the virus is what's really making the numbers so huge and that everything else it's doing is consistent with what SARS-N-MERS did if you can find yourself to just looking at the lower respiratory tract disease. Now, this is something that might be a little bit outside of what you've studied, but

I'll ask anyway. One of the lingering questions, there are so many that I have, comes down to the survivors. I mean, obviously, we think a lot about the mortality of this, but if you take a person who gets infected and they're not asymptomatic, so we know that a lot of people kind of don't even know they've got SARS-CoV-2 and the only reason you figured out is after the fact, serologic analysis tells us that they did. But there's a non-trivial amount of people who get sick as hell, and they get what they would describe as the worst cold of their life. I have at least two friends I can think of in this situation who three months later

can barely run a nine-minute mile again and they're slowly getting back in shape. When I did a quick check on this, looking at the SARS-MIRS patient follow-up data, I didn't find a heck of a lot that told me about long-term lung function. Do you know much about this? I would imagine that there's now more of an interest to go back and assess that than there was three months ago when I tried to look this up. Yeah, even before this all occurred, I asked my friends in Saudi Arabia about follow-up on the murderous patients.

And I could never get information as to what exactly is going on. I suspect that they had problems whether they be forever or a few months is unclear, especially since your friends were younger and fitter. If the murder is particularly murderous, if it's mostly older people, people with diabetes, people who have comorbidities, they may take them longer to get back to base of flying. It's probably not going to be running

miles. I suspect it'll take a while to get back. I don't know how much fibrosis was at the end of it all, how much permanent damage there was. I suspect that there was a better bit, but you always have it. You know, a cancarris people always talk about neurological disease without actually ever finding the virus in the brain, and then it was attributed to being on ventilators and cortical steroids for long periods of time, contributing to a cognitive dysfunction, and occasionally the virus was in the brain. So it's all a mix that's hard to really sort out what the major components are, because there's several things that contribute

to the outcomes. Well, based on your knowledge of coronaviruses and your knowledge in particular, their impact on the brain, do you think that there are plausible mechanisms by which even for those who recover from SARS, there could be lasting neurologic impact that is not the byproduct of hypoxia or vent head, pump head, any of the other more mechanical or other physiologic accounts.

In other words, do you believe that there is a plausible scenario by which the virus could have residual neurologic value? We can't find any evidence of the virus in the brain, and it seems less likely that it's direct virus infection. What about an immune response? Yeah, that's what I was going to say. If you take a disease like Kawasaki's in children, we know that that's a disease that is mediated by some sort of immune response.

We don't know if you won't. Seems here like COVID-19 is somehow provoking this response in this very, very small subset of children. That certainly leads to consequences in the art, long-term consequences, or again. So you can certainly imagine scenarios like that. How often this occurs and what's going on exactly, I don't think, in the mirror. So between the resolution, so to speak, of MERS and where we were called a year ago today, Stanley,

where was your head at with respect to the big one? Were you in the camp that said, yeah, I've carved out a pretty nice niche here. I'm gonna be studying coronavirus as forever, or was there a part of you that said, this is a threat to national security to the world? There's a pandemic brewing here. I mean, how did you think this could unfold? I certainly wasn't smart enough to predict that

there was going to be a pandemic. As I said, some of my friends were worried about additional infections in humans. I don't know that anyone would have predicted a pandemic like this one. I want to pause you there for a second. Why? I mean, not that I did, but I want to push on that for a moment. All the ingredients were there. I was going to say is that Department of Defense in 2010 or 2011 put out a report about possible emerging viruses as being really the major threat. Coronavirus is one of that list. And Bill Gates talked about this. I mean, it's become a very well-known TED Talk that is it's painful to watch now because of how accurate it was. So you have these two examples of viruses that have enormous potential to cause harm, but fortunately for us at the time, they just don't spread well.

A few tweaks, i.e. infection of the upper respiratory tract and a slower onset to symptoms would easily double your R0. But okay, fair enough, I'll stop coming down on, I'm joking, of course, stop coming down on you guys for not thinking this could happen. But so let's fast forward now to, when did you first hear about the outbreak in China? I mean, I'm assuming it was early December, late November?

Oh, no, I don't think it started quite that early. I would say like December. The first case is official cases were in December. We think there may have been some in November, but I think that the people in China, scientists and doctors in China knew something was going on in December. And then it was eventually reported in very early January. So I think we knew a few weeks early. But even then, we didn't really know how much human transmission there was.

Now I have to say that at the time given the number of cases, we should have guessed that something unusual was going on. But to the SARS epidemic, we had these cases and lots of people infected and we didn't really know how the spread was occurring. And at the time, by early January or mid-January, we had 800 cases in the world. So So it didn't seem to be extraordinarily different from these other viruses. Maybe we had had more information about what was going on in Wuhan, we would have realized, aha, this is doing something that's different

than what SARS-N-MIRS did. But we didn't have that information. When did it become clear to you personally that this was going to be a much bigger problem than SARS and MERS ever work. Funny you asked that because I remember in December when we really didn't know anything about human-to-human transmission. I spoke to my friends in China and I got off the phone and told my wife, this is a big

deal. So I'm not sure what I was facing that on because it wasn't so much evidence of human-to-human transmission. It was pretty clear to me that this was going to be a major problem. At that time, could you have predicted it would have been this big an issue? I don't think so. Mostly because all the previous diseases had remained geographically confined. So SARS was really a disease in China with a little spread around the world, merges with really a disease in the Arabian Peninsula

with that one case in spreading, infecting several people in Korea. But this one, you know, maybe the dynamics of everything are so different. People spread travel from Wuhan much more frequently because people have more money. So they fly more, they take the train more. So that helped the spread a lot.

Then of course, this is transmissible. The other thing is that we had gone through some of this with H5N1. So in the late 1990s people were saying what we need to do is have to be transmittable and it would be a disaster because we don't really have good immune responses to it. And it never happened. So yeah what happened in 2009 with H5N1? Because the skeptics would say hey we don't need to worry about this SARS-CoV-2.

The last time we cried that this guy was falling, it didn't fall. Right. So that was H1N1 in 2009, and that started off as a lethal disease, it was identified in Mexico, it seemed to have a high lead validity, but it's more cases became clear, identified as clear that it didn't. It just was lots of cases and very little mortality. It was basically influenza. It was influenza. It was just a variant of influenza. It wasn't H5N1, which causes a severe pneumonia. H5N1 is the 1918?

No, H5N1 is the one that's never made it to human population to an appreciable extent. The problem with the virus is that the virus is not the same as the virus. It is mostly pigs and birds, but it kills birds and most food doesn't kill birds. The concern was that it would change to infect to be transmissible human to human, but it never did. The same thing with thinking about coronaviruses, they hadn't done this so far. We certainly thought they could do it. But this is an interesting question that's, how do you prepare for a pandemic that you don't have? Because it's something I've been asked about and thought about. So you're sitting there in 2005 and SARS goes away.

How do you decide what kind of resources you're going to put developing antivirals, developing vaccines against SARS, the disease that doesn't exist anymore? The way the American system is set up for this, if you have a good idea and you propose to the NIH, you have a good chance of getting funding. But in the other hand, if you're competing against other grants that make more compelling arguments for funding and a deal with diseases that are actually present, they're going to look better to a study section. So you have to figure out a way to identify a disease that could be a problem without going overboard and using lots of resources for diseases that never will be a problem. I mean, it seems that you'd want to structure it in a way that says,

look, there are some no regret moves here for any viral infection. And then there are some things that are going to be very specific. So for example, not that this is an NIH question, but what would a national stockpile of PPE need to look like? What would an electronic infrastructure for contact tracing need to look like. What would a national stash of reagents to develop serologic and PCR testing need to look like? So we don't know what the gene sequence is, but the moment we know the gene sequence, wouldn't it be great if we could hit go and actually deliver a million tests a day and not talk about it for three months and not do it. Those strike me as just a no regret move. You don't need to know a

single thing about what's coming other than it is infectious. It's the little stuff. It's the nasal swabs. It's the reagents. It's all the stuff I just said. And about 20 other things I've been thinking about that kind of I really hope that when this is said and done, this doesn't get forgotten. Because it's not a staggering investment. When you consider what we spend on healthcare and defense, which are disproportionate to any other country by a log order, and oftentimes by two log orders per capita, you put a few billion dollars into this type of resource, and you consider it more vital than you would consider our National surplus of oil or other things for example most people I would assume no this but if not we keep an enormous supply of oil on hand

If the world shut down and we couldn't get a drop of oil from anyone in the world We would at least have I don't know I don't remember these stats but probably a 60 to 90 days supply of complete independence on oil, maybe more than that. And that's just a national defense imperative. So this should easily be in that front. The other thing on the therapeutic side, I would say, is, don't we already have enough evidence to suggest that at least one avenue to treatment is immune-modulating therapy. So maybe not antiviral, because that can be quite specific, but all of these diseases have an enormous component of an overactive immune response, which we'll discuss,

and therefore having a huge stockpile of immune-modulating drugs to be appropriately dozed also strikes me as a no-brainer, right? Yeah, yeah, you could argue that. I'm not sure that these diseases are all the same in terms of the cytokine storm type activity, but they may be close enough so that your point is well taken. They are similar enough so that that would be a reasonable thing to do to have those on hand. I think that's what Bill Gates was probably talking about more than specific drugs against specific viruses, because you don't really know those so well. Think about it. So, the whole stuff with ventilators and all that, that was really, really done. Testing, I think

once we know, you're right about nasopharyngeal swabs and mechanics of being able to do the testing. The actual identification of targets for like R2-2-3-R are not that hard. That probably took four days to figure out. But it took longer to scale up. I think that's the point, right? It's not no, I mean, the virus was sequenced in January 11th or 12th, wasn't it? Yeah, earlier than that, that's just scaling up the ability to do testing. So anybody who says, well, come on, it would be crazy to have $3 billion invested in that

on the off chance that the virus doesn't even make it out of China. To which the answer would be, did you look at what happened to the U.S. economy? It's called a hedge. This is what sophisticated companies do. Sophisticated companies hedge their bets. And if the answer is, every time a really scary virus emerges in China, we have to spend $3 billion to be ready for it to land here. But guess what? We don't have to shut our economy down. As a result, we can instead mitigate 90% of that damage. I mean,

it's the wisest investment that could ever be made. But I'll get off the soapbox now because nobody wants to hear me rant about that stuff. I want to get back to the interesting biology on this stuff. So let's now go back and talk about these four viruses that cause us nothing more than nuisance when we get colds. Do they have any seasonal variability to them, by the way, or they winter viruses, summer viruses, or does it matter? They tend to not be summer viruses, and they tend to be more winter early spring viruses. What determines that, by the way, is that simply a function of being close to each other in the winter and spreading it or is it actually a property of the virus? Yeah, we used to think it was that, but as we know more, I don't know the answer to that.

I know the sum of these respiratory viruses are more active in the late fall, winter, and others in the winter early spring, and I don't know why there's a difference. I don't think anyone else really knows either. We know these viruses are usually happier when it's a little cooler and a little drier. But that wouldn't explain why one virus did well in November and another one did better in March. Interesting.

And then for an immune response, why is it that these viruses haven't basically become irrelevant in the sense that we all eventually get them and we all develop immunity and we're sort of done. That's where the question about all common cold viruses, whether it be corona or otherwise. So why do you actually get re-infected? I don't think we understand it very well. We know that there's an antibody response to these viruses, it seems to weigh in, it goes away. We know that you need a specific kind of antibody, the IgA response that seems to help. We don't have that much information about IgA responses.

They seem to weigh in as well. The T cell response is the other part of the immune system that you mentioned earlier. We don't know that much about the T cell response in common cold coronavirus. Before all this began, we didn't think that was a big deal because common colds usually go away in a few days before you actually have a T cell response. So, we don't know why things will, why virus immunity wanes. We know there's such huge differences. Smallpox, you could detect and people had smallpox in 1918,

you know, 1995, they still had antibody responses that were measurable. Here we have these common gulkerone viruses a year later. They've waned in a couple years later, they're probably almost gone. So, we don't really understand that. That's really a key question. And it both impacts the ability to people to be re-infected by SARS-CoV-2, and packs the vaccine responses responses and packs general herd immunity as we try to get rid of this virus.

It's very important for not known. There probably hasn't been a case of a coronavirus before where we've cared enough about herd immunity to talk about it, but do you mind explaining to folks what you're talking about with herd immunity specifically with respect to SARS-CoV-2 and what it means?

Well, herd immunity is really the other side of what you were talking about, the RNOT factor. So if the herd immunity means, if you have a virus that's extremely contagious for people who are susceptible to be protected from the infection, you have to have most of the people around them be resistant to the virus. So to put this in a different context, if somebody who's infected with whether B.Sar is COVID-2 or measles or anything else comes into a room and they're spreading virus, the virus is going to land in various places. Some of it will land on the floor, some of it might land on somebody's hands, and couldn't theory infect that person. But if that person is

immune to the virus, that you, it doesn't matter. The virus can lend them that person's hands and then that person can touch his face, but he won't get infected or he won't get disease anyway. But if the person is susceptible, then he will. So then if that person is susceptible, he can then spread it to other people in this proverbial, large room if they all stay together for several days. Now if you take a situation where you have an extremely contagious virus so in that room of 100 people are saying report measles, as five of them are susceptible, the virus might spread to 25, 30 people from that one's susceptible person and then of that 5% maybe one or more of those people will become infected.

If you have a virus like SARS-CoV-2 which has a lower R-NAR factor, then at that same hundred people, if they're five or susceptible, the odds are it will not get to the point of infecting the one of those five people. So herd immunity is that ratio, the fraction of people who are immune to a disease. For measles, the numbers said to be 95%. If you don't have that 95%, then measles can infect people who are susceptible. For most common viruses, it's around 60 or 70%. So that's the number that people are really looking at from terms of immunization or infection with SARS-CoV-2 to protect the general population. It's not the same as being immunized or having the previous infection,

you're still susceptible, but it just means that it's much more likely the virus won't spread. And if you get sick, it's unlikely it'll spread into the 30% of the population that has never seen the virus. So that probably matters. Yeah, and there's a very non-linear

but monotonic inverse relationship between R-NOT and herd immunity, which I can't believe I actually just said all that. It's basically math speak for the higher the R-NOT, the higher the need for herd immunity, but the relationship gets there non-linearly. I don't have a non-math way to say that, but the example you gave is a good one, which is, and I said inverse, it's actually not inverse, it's direct. The R-NOT for measles is very high, and the herd immunity threshold is very high, 95 percent, going down to an R-NOT of 2 to 3,

you have a herd immunity threshold of 60 to 70 percent. Now, do you believe that based on everything we know today, and that includes potentially, there being many more asymptomatic people who are infected and who have gotten over the infection than we previously believed? Do you believe that the threshold for herd immunity is still as high as 60 to 70% for SARS-CoV-2, or do you think that it could be as low as 20 to 30%. Well, I think it's still gonna be 60 to 70%. It's just that there's a higher percentage of people

who have immunity already. So in other words, you're saying, yeah, it becomes a bit of an academic or a mood point because it might be that of those 60 to 70% who have to be infected for herd immunity, two thirds of them don't even know they were infected, but they actually were from an immune, okay, fair share point, yeah.

So is there much genetic drift in these viruses the way, like influenza, I think most people know, of them don't even know they were infected, but they actually were from an immune, okay, fair fair point. Yeah. So, is there much genetic drift in these viruses the way, like influenza, I think most people know, hey, I got to get a flu shot every year, but what they might not understand is the reason they're getting the flu shot is probably less because their immune system forgets what influenza looked like and more because influenza looks different every year. How much do these coronaviruses genetically drift to use the lingo? So far, we haven't had evidence that this one drifts.

I think when you look at the other viruses, one of them seems to vary quite a bit. OC43 seems that they're from variants. A lot of the others don't seem to change that much. SARS was adapting to human population, so it changed, but if it had stayed around, I don't know that it would have changed much. Murrors is completely a camel virus, so any drift you see is what happens in camels, not

in people. Again, both for Murrors and the human, the other current viruses is not really well, except for OC43, I don't think this huge effects on immunity. This virus is really, this certainly, lots of talk about changes in the virus and becoming more briland to more weaker, more attenuating, but there's really no evidence so far that says this virus has changed in a way that makes it unlikely a vaccine will work, unlikely that a previous infection won't protect you from a second infection. There may be reasons why it won't, but it won't be because the virus is changing so far.

That's an important point. I think we want to reiterate that, right, which is the Doomsday scenario would be a virus that retains its virulence, but constantly drifts enough genetically that your immune system never recognizes it again, but it retains all of its bad properties. I mean, that's a disaster. If you had a new version of a deadly virus show up every year, it could hurt you just as badly, but somehow it's genetic drifting created a different coat on it, a different set of antigens. And every year, your immune system was caught off guard. That would be very painful. And what you're saying is, hey, we don't have evidence of either of those things happening, that it's genetically becoming more or frankly less harmful, of equal if not more importance, that it's not becoming a different immune animal as time goes on, at least in the very short window we've studied it.

But again, it's helpful to go back and look at these other coronaviruses that you've studied because they've given us a lot of insight, right? Yeah, exactly. The immunity when you have a mild infection just does not develop great immunity. So let's double click on that. You've said already part of that. I want to make sure I understood it. So part of it is the innate system just for whatever reason doesn't seem to do much. You've already talked about how a lot of times with at least the common coronaviruses, they might not even stick around long enough to develop a T cell

response. Can you say a bit more about the adaptive humoral system? What do we know about the IGM and IGG, which again, if you haven't listened to the interview and the discussion with David Watkins, I think this would be a great time to go back and make sure you familiar as yourself with that so that we don't have to go into the details of what those things mean. But six months after a person has a common coronavirus, do you still see evidence of at least the IgG? Yes. And do you know how often it is basically binding, non-binding? Do you have a sense of, what the functionality of that IgG is?

Is it neutralizing fully necessarily? Not necessarily. I think the human volunteer studies are best to answer for that for the common cold coronavirus. And they show that the communities there, as measured by neutralizing antibody, and then it wanes with time, and that a year later, it's there and may not prevent shedding. It's still, I think it sounds remarkably like what I think we're going to hear about with COVID-19 and immunity from people at mild infections or asymptomatic. Now, we've talked about this paper that came out, God think it's been maybe three weeks ago. Alex said he was the senior author on it, 2020 cell paper that looked at 20 patients who recovered from COVID-19. And I believe about two thirds of them actually had a CD8 T cell response and a CD4 response that kind of correlated with that.

The point being, they looked to have been at least partially aided in their response to SARS-CoV-2 from T cells that looked like they had been sensitized by other coronaviruses. Now this was a small study and this was based on in vitro assays. Can you explain that study a little bit or at least the idea behind it because it's an incredibly interesting idea and it has clinical relevance if this turns out to be true? Yeah, so I think this is one of actually several studies. This is the only published one I think that shows that people who have never seen the virus have some sort of T cell response to SARS-CoV-2.

Now there are some caveats when I read this paper that make me pause and join too strong a conclusion. One is that in most of these papers away T cell responses are measured's not by functionality, but rather by being activated in a certain way. And these activations, to my mind, are a surrogate for actual functionality. The functionality was not well demonstrated in any of these studies. You may see a little functionality, but it's not the major point. The second thing is the targets for these viruses, for the T cell responses, not the usual response that you get in terms of targets, you see after them the wild type infection,

the SARS-CoV-2 infection. And because of this difference, it makes it also a little unclear to me where this response is coming from. So you can say, okay, that doesn't matter, it's still from a common cold coronavirus. But then when people go back and look at the sequence of the common cold coronavirus is for the same targets, this is actually very little homology with T cell responses that are recognized in these patients who have never seen SARS-CoV-2. So all together, one hand you could say, well maybe this is something that's important, maybe it contributes to protection,

pathogenicity. In the other hand, it's a little odd because it's mostly measured by activation, not necessarily by function, and that may matter. It's also targets are not totally clear how that's working. It's something that's not completely clear yet. So I'm a bit confused by that, Stanley, because if we were doing this on the B cell side, which is where we normally would, you would do an in vitro assay and demonstrate the presence of neutralizing antibodies,

not just binding, but neutralizing. And that would give us great confidence that the B cell response would translate from the in vitro finding to the in vivo finding. Is that correct? I agree with you, but yes. So we can do comparable T cell assays where we actually look at killing function and not just signaling functions and things like that, right?

Yeah, and this isn't really signaling. This is a protein, what was measured with proteins that come up if a cell has been activated at all. So this is not killing assays, not even making cytokines, which are the my preferred way of doing this because it's easier. Yeah, so that's what I was going to say. Usually when you look at typical studies that are looking at, say, response to flu vaccination, they look at cytokine response on the T cell. So do you know if studies are looking to do that?

Because that just seems to be a very obvious thing to want to ask at this point. Well, for the people who are naive, who've never seen the virus and who have these assays done, T cell responses are done, but they're very, very low levels of activity. So the amount of cytokine producers, extremely low or it's not existing. So you just wonder, part of the issues, we do some of these assays and you can do it very well, but the level of the background as it were is approaching what we're seeing in some of these patients. So I think Jerry's just out on how important it is and what it means.

To me, it's really interesting. It kind of doesn't go with what we've seen in merospatial patients, where we don't really see much of our background, much of evidence of crust reactivity, but we didn't actually do this surrogate assays, these assays for activation. And there may be a temporal component. In other words, it could be that let's assume that on average, a person gets one year of quasi-protection from a given coronavirus until it can infect them again. You now have a hundred people who are in various stages along a continuum of that recovery from

pick your favorite endemic coronavirus. And then they all, at one day, get infected with SARS-CoV-2. Well, presumably there's also a strength and a decline of immune response. So even though they would all have some immune response lingering, some memory of immune response to the benign coronavirus, they could technically mount very different responses to the much more feared SARS-CoV-2 simply as a function of how far they are out from their initial infection, correct? I think that's a different layer because it assumes that there's something there. That's correct. If there's something there, yes, absolutely.

This is a totally second layer. Do you think there are other viruses or other vaccines that could provide cross-reactivity? I don't think provide cross-reactivity is, of course, these ideas that you should immunize everybody with attenuated polio virus because that'll activate the immune system and that'll give you some protection where you should do something like that BCG, which we use for immunization against tuberculosis, whether they have any effect people are suggesting this, and I think they're in trials even. But in terms of specificity of getting at the coronabers, I don't think so. The BCG ones worth probably explaining a little bit to people because it got so much attention.

I think the other one that got quite a bit of attention was MMR. There's a very famous graph that a friend of mine sent me that said, hey, the entire pandemic and the mortality profile, which basically hockey sticks above 50, can be explained by exposure to MMR. People below 50 uniformly had MMR vaccination. People above 50, it's much more spotty, and the further you get from 50, the less likely you were to have an MMR vaccine. And that explains it. Now, I can go on why I don't believe that's the case,

but I'd rather hear your views on whether that is or is not likely. I think it's actually contrary to what one might think because those of us who are over 50 had you actually got the real virus. We're real in three of those infections so I don't consider myself resisting. In fact almost everybody my age had all three of those viruses. Everybody certainly had measles and mumps. Our German measles may have been less frequent. But from an immunologic perspective, Stanley, is there any reason to believe that your memory T cells and B cells to measles, mumps, and or rubella would offer you some protection against this particular coronavirus? Is there any evidence that they offer protection against other coronaviruses? No, I can say that.

No one's hooked very, very hard, but there's no reason to think that it would. If there was anything like that, we would all have some preexisting immunity to the virus that's way higher than what we're talking about. I'll just tell you why I'm also quite skeptical of the BCG claim, which is not to say that in certain cases, maybe there's an anecdote that it works. I mean, obviously, one of the first examples of cancer immunotherapy came out of an understanding of the Kool-East toxins that sort of came out of this idea of BCG, but the reality of

it is, BCG has never shown enough specificity to be a viable immunotherapy against cancer. And it's for that reason, I guess, even if that's overly simplistic, that I really doubt that BCG could have a meaningful impact on a virus because it requires just as much immune specificity as it does for the immune system to attack cancer. Yeah, and there's other agents, so we've worked with agents that turn on and defer. And I think if you give interference at the wrong time in these infections, you may make people worse. So if you're exposed to COVID-19, you have a very good exposure right now.

And I gave you one of these agents that turn on Interferent, that may well help you. Because before you really get an infection, if we jazz up your immune system, that may help you do better with the virus. Once it gets going, that probably isn't true There's all these issues that one could imagine that if he jazzed up the immune system of BCG That it could help you if you got to write the right day and then you were exposed to COVID-19 But I wouldn't want to be an op-cure in a BCG just for fun with the possibility than the next two days I get exposed to the virus

You provided a much more elegant description of how you might possibly benefit from it in a Hail Mary pure luck standpoint, but how mechanistically it just doesn't even make sense. And you're right, by the way, I think the broader point I would take away from your comment is there's a really interesting way to think about this from a targeted therapeutic standpoint. When you think about the sophistication with which we try to treat other diseases with multiple lines of defense, this is a great example of one, going back to everything I said before about when I was on my rant about how would you begin to prepare for the next time a pandemic comes back?

It's all that stuff. On the therapeutic side, I think it's being more thoughtful about what the strategies are. of on the therapeutic side, I think it's being more thoughtful about what the strategies are. The moment we identify those early cases and say, boy, this is a disease that typically, like influenza, is a little bit more of an immune paralysis disease, at least at one point here, you're seeing this hyperactivated immune sense. So early treatment is antiviral with immune amplifier. Late treatment is immune modulator. Antiviral's long-sense gun and respiratory support starts to matter. You can start to really be more sophisticated

in how you think of these things. And I think that's probably something that people are starting to think about now. And I suspect that a lot of the clinical trials now will focus on more partitioning. So we don't just think of it as drug X, good or bad, drug Y, good or bad. We don't have this sort of nonsense binary thinking. I agree with you completely because that's exactly the way I think about this disease. It's just you need antiviral therapy early on and then maybe an immune modulator later. In terms of immune activator, if you just catch it just at the right time, maybe that would help.

I think it's actually going to be the same for severe flu, like the H5N1. I think the same scenario applies. The other thing you point out is that with different patients in different disease courses, one has to be ready to modulate therapy. This is one of the things that I'd love to have that we don't have, which are biomarkers for different stages of disease. I think for so many diseases, we don't have, which are biomarkers for different stages of disease. Well, I think for so many diseases, we know that something works well,

and then we do large studies and we find that, you know, it didn't work as well as we think, but if you go back, you say, within this population, if we could have identified it first, that would be the people who would have responded to this particular therapy. That's one of the reasons that some therapies work, that don't work, that you might think would work,

because if 20% of people go on a category of benefiting from it, would you treat 100%. You dilute all the benefit. Exactly, exactly. That's such an interesting idea. What do you think some of those biomarkers could look like? There's some obvious ones when a patient's inside a kind storm you can measure the cytokines But if you could go deeper than that and you could look at the proteome and you could look at metabolomics or look at the gut or something like

Where do you think the answer could lie? Okay, so there's two parts of the question. First one is what would you sample because the ideal person to be sampled is that person Who comes in like your friend who had trouble running who didn't feel well. And I don't think he progressed to having disease enough to get him in the hospital. Nope. Yeah. Young healthy guy in his maybe early forties and yeah never hospitalized, but sick is a dog for two weeks. Right. So that's a person you'd like to do a test on and say, okay, is he going to progress or not? Clearly in in his case, we'd want something to say, he's sick, but he's not going to progress, because he didn't progress. So that's a person who you might not want to do anything for.

On the other hand, he may look exactly like someone who was diabetes and it's 60 in terms of how poorly he felt. And so what you'd want, you'd need a mark, and not only for severity, but you wanted something that was distinguished between the two of them, and that you could sample easily in the blood because your friend would not have wanted to undergo some sort of longer measurement because it would have been way more invasive than the sickness he felt. So that's why you come back, I think you can come back to things like cytokines and metabolic products.

The problem up to now has been that you can see an increase in platycine X and people are going to be sick and not increasing people who are going to do better. But when you put them all together, it's not like you have populations that are very high versus very low. You have ones that have a range of X to Y and the other one would have a range of 0.75X to 1.5x. So you will be able to do that. It seems to be a problem that is set up perfectly for some type of machine learning because everything you said is correct. And then as you also alluded to, there's another layer here, which is we know quite a bit about the epidemiology. All things equal a 40-year-old

without a single pre-existing condition. You're going to weigh that input differently than a 60-year-old with no pre-existing conditions or a 40-year-old with type 2 diabetes versus a 60 year... They all have a very different physiologic age, even if they're chronologic ages are similar. And so when you start to factor in that, plus some of these signatures, plus the temporal nature of the signature, when am I getting this? I think there is an amazing opportunity for information and data scientists to help prepare us for how we will think about this when it happens the next time. Yeah, so what you need out of this is you need as we've talked about for some of the projects

We've talked about what you'd ideally like to do is you'd like to take people Sample them every couple of days See you have what their numbers look like put them in this machine learning model that you're talking about and then if you Had enough money so you can measure all these different cytokines. You might say okay This person has this block of Markers that say he's going to get saved. Whether it be the 40-year-old, because, you know, the 40-year-old can't get saved, or whether it be an older person, and you put the other point you make about the epidemiology on top

of that, and maybe you would not even bother testing the 40-year-old, because the odds of his getting sicker and meriting all the costs and use of resources is not worth it. We're not there yet in terms of thinking about which markers are best and also how do you actually do this? How do you actually do a study where you can help a person by getting cereal testing and seeing which way he or she is going in terms of disease? But that would be the ideal way because that person, if you saw signs of things from badly, maybe that's the person you use either Remdesivver or hopefully oral form or rendesaver, stop the virus and distracts,

maybe give him unactivator. Again, unclear, I think if you give him unactivated, some people will be deleterious, so it has to be done so carefully. There are two last topics I want to get to. One being how we would study the durability of immune response, which is effectively the most jugular question out there today. I mean, if we're going to think about this through the lens of vaccination and we're going to think about this through the lens of herd immunity, natural or otherwise, we better figure

out exactly what's going to happen to these people who get infected and what superpowers they do or don't have in the future. Before I do that, though, I want to go back to one thing we kind of alluded to very briefly and then skipped ahead, which was that paper that came out kind of recently. Matt Ridley is the journalist who wrote about it. I think in the Wall Street Journal, but he refers to the paper by Zon that came out I think in April that argued basically the virus may not have come from the wet market the way we think it does. I know we've been sending each other so many papers back and forth over the last few weeks. Did you have a

chance to look at that paper? I think so. It's the one that says there's a bunch of these so I'm not sure I have the wriggly one in mind. The one that says it was released accidentally from the Wuhan lab or the one that says it was. No, the one that said it was released accidentally from the Wuhan lab or the one that says it was. No, the one that said it was basically so genetically stable. It was really, it's mostly a person to person transmission. So I think it basically said, look, this is mostly a person to person transmission. And I think it said if it came out of animals, it was so long ago that we don't know about it. Basically argues that the narrative that this came from an animal source to a human source in somewhere between October, November, December of last year is not

correct. Did you see this paper? No, I don't know that paper. Okay. All right. We won't dive into that too much. The point is well taken that it is remarkably fit for humans. I don't know about the first part of the conclusion, you know, that it came out earlier, but it was remarkably fit. Yeah, I mean, I think they basically looked at the amount of genetic drift that occurred and said, I read it, I think four weeks ago, so I'm a little rusty on it, other than a few notes I took that were somewhat cryptic, but I think the argument was, look, this has probably been in humans longer than we think. I'll re-forward it to you after just for the purpose of pure interest. So how do we figure out how long people are going to, because it might not be that interesting, how much immunity people have to regular common-cold coronavirus, but it's going to be pretty darn

interesting to know how long people are going to have immunity to this virus. I mean, we've already at a minimum seen close to 10 million people infected worldwide with this virus. Personally, I think that's a gross underestimate of how many people have been affected. I think it's probably closer to a hundred million people have been infected. But regardless, the durability of their immune response has to be one of the most important questions we understand. How would we do that? Yeah, so just doing the things we're doing, people who are infected measuring their antibody responses

if we can measuring the T cell responses, the odds are that we're going to see weighting immunity for people at mild disease, that's hearing over and over again, and that's what's been true for other coronavirus infections. And what would the implication of that be? Will the implication then be that no matter how successful a vaccine is it's going to need to be an annual vaccine? There's two goals. One is to protect the individual who's vaccinated from getting severe pneumonia and that may actually occur already.

So that may be whether evenly wanes or not that person may never get it severe pneumonia. The other issue which is equally important is how much community need to prevent shedding, to prevent transmissibility to other people. And that's the one that I think is really unknown and to me is more important, not important to the individual but to society. To me that's the jugular question that decides what do economies look like when we have subsequent ways of this because that is something on Instagram a few weeks ago where I did a kind of Q&A with my son, who's five, and he asked a very honest question, which is, when is this virus going to be gone? And it was an interesting discussion to explain to him, actually, it's never going to be gone.

This virus is never going away. There is nothing about this virus that suggests it's ever going away. And so now the question is, how do we coexist with this virus? So even putting aside future pandemics, which could be much worse, for example, an increase in the lethality while preserving the transmissibility of SARS-CoV-2 would be devastating. But just coping with this, if another one never shows up, we have to understand this question, especially if the vaccines are somewhat risky. One thing that doesn't get a lot of discussion is how much risk is going to be posed by vaccines. There's a reason they never come up with RSV vaccines. It's a lot harder from a safe perspective to make an RSV vaccine, unlike an influenza vaccine.

So if everything is going to be a risk trade-off, right, and we're going to decide, you might not want to vaccinate everybody with SRSCO V2 vaccine if the risk is slightly higher than we deem acceptable. So then you have to do a cost-benefit analysis. And then to your point, which I think is even more important is, okay, what does the secondary shedding look like? What do these other factors look like? It's hard for me to imagine a world that's fully functioning without these questions resolved.

Right, that's really the key question. The other hand though, if you get to a point where there's enough herd immunity or that 100 million turns into a six billion people have seen the infection. So nobody gets pneumonia anymore, it turns into a six billion. People have seen the infection. So nobody gets pneumonia anymore. It turns into a common cold. Then there may be enough of a balance between the virus mutating order to become a better common cold and no longer causing the pneumonia.

But that's the point. It requires a mutation, doesn't it, Stanley? We don't have the memory like we do with measles, polio, and smallpox to truly generate herd immunity. In fact, we've never generated herd immunity to influenza commonly. In that case, of course, it's because of the genetic drift. And so, isn't it a bit of a misnomer to suggest that we could ever have herd immunity to SARS-CoV-2?

Let's just say if we knew that the immune response was gone after a year? The question is what does immune response being gone? Yeah, a sufficient immune response. I mean, it becomes a sliding scale of efficacy, correct? Yeah, yeah, yeah. That's right. But if you have enough immune response to protect you from pneumonia, then the question is, how much shedding do you have? So, when we talk about studies, I was thinking about this a little while ago, the simplest study would be to take some human volunteers, give them a common cold coronavirus, and then a year later come back and do the exact experiment that was done in the 80s,

measure, do they get a cold? If you reinfect them in your 80s, they get a cold, and how much shedding do they have? You know they shed, but if you are a naive person of the cold, you get 10th of the week, and now you shed 10 to the third and it doesn't matter. Yeah, then it doesn't matter. Yeah. Well, and of course here, so again, I completely agree with you that that's the single most important question, but the other thing is, I don't have my fingers crossed that this is perfect because of that upper respiratory part of this.

So you said, well, what if you don't get the severe pneumonia before? Well, it turns out the severe pneumonia that came with SARS-1 and MERS isn't really what was the problem. That was the problem for the individual, but that was not the problem for society. The problem for society was the upper respiratory part. That's what we're seeing in SARS, or the lack thereof. And that might be what's making SARS-CoV-2 such a problem. Yeah, that's right.

Anyway, Stanley, as you can tell, we can talk about this for days, but I want to honor our commitment to get you out of here in a certain time. So I look forward to talking with you again very soon as we continue to work on the project. We're working on with David and a group of other really amazing people.

But thank you for your time and your generosity of insight. Anything else, any last thoughts you have on, either this particular pandemic or just coronavirus is in general? No, I think the key thing we talked about is how do you prevent this in the future? We're going to muddle our way through this one. We're going to do, we'll get to points. I think we're going to have antivirals. I hope vaccines, even with the caveats that we talked about,

that should work. How long that work, I don't know. Whether people actually agree to be vaccinated is another issue we didn't really talk about. And then for safety, I mean all these things are going to know very quickly because we have to do it quickly. Well that means we're going to have to talk again. Okay, thanks Stanley. Okay, thanks Peter. Thank you for listening to this week's episode of The Drive.

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