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

Hey everyone. Welcome to the Drive Podcast. I'm your host, Peter Attia. 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 peterattiamd.com subscribe Now without further delay. Here's today's episode. My guest this week is Stanley Perlman. 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 COV1 and SARS COV2 to better understand the more severe diseases that affect humans. I've 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 discussed 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 cold 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 Perlman. 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 calm down a little bit? And I was so gracious, first of all, 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 Perelman. Everybody is an armchair coronavirus expert now, but you actually want to talk to the guy who was 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, obtained a Ph.D. many, many years ago in the areas actually of cell biology and developmental biology and virology. So I did a whole potpourri of training as a PhD student, and then again during postdoctoral, 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, men 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 get infected with viruses, especially in utero, it 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 in 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 backward 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 small 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 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 and 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 for 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.

You're kind of a Doogie Howser, 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?

Or three. It's actually three now.

Yeah, 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, did the entire third year, and then you did the fourth year in eight weeks. So at the end of it all, we did everything and we could do it. The people had PhDs, though I have to say they took PhDs in whether it be physics or physics to psychology to biology to chemistry. So people had different amounts of training. The training was good. The classes were really full of people who are 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 or both?

Both. Yeah, both.

So at the time, and probably still to this day, Boston Children's Hospital remains easily in the top three in the world, perhaps, along with Chop and Sickkids 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 Brazelton as your mentor there.

Yeah, yeah. So. Right.

Yeah, 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 OBGYN 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 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 have hearing problems, visual problems, and even cognitive problems. So the babies, just because they're developing, they're incredibly sensitive to. 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 these 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 demyelination, which was similar to what we see in multiple sclerosis. So it sort of ended up in a long, roundabout way for my studying 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 does 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 coronaviruses are like any other set of viruses. Viruses are put into that category because of what they look like under the microscope. What they look like under the electron microscope? Well, how they make new viruses, the kind of replication strategy we call it that they use to make new Viruses, in the old days, you might have some serological testing that would 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 or that 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 used, 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 bats, of course. We know, because that's been made 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 coronaviruses as a family, probably, when compared to any other family of viruses, flaviviruses that produce hep C that otherwise would have nothing in it 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. Except 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. There's these gigantic viruses, or these giant viruses, as they're called, that seem to have almost all the material you need to almost be a cell. They're 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, that form the structure of the virus. So those are simpler viruses. Coronaviruses have the unusual characteristic of being huge. So the 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 it has all this genetic material stuffed 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 kilodaltons we're talking about, but just contextualize it in some way.

Well, let me see 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 it were, between genes, but they're really a minority. So the strict answer to your question is yes, there's parts 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 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 lots of great examples. For example, in the ocean, there's zillions 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 gut, there's all these viruses that people about talk 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 bacterias which are really important for human life and animal life. But I would bet if you took away all the viruses in the world, sure you'd eliminate some of the ones that cause human disease or non human animal disease. But I think you'd 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 sub chain that I haven't considered fully.

I think that that's a possibility. And then bacteriophage on bacteria are going to be even different than the ones directly on 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's some animal viruses that interact, insects have relationship with each other. And 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 wasps, but I can't tell you more, remember. But there's definitely viruses that without which there 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 a crown. So I think the first people who saw it under the electron microscope decided to name it based on that. You have to 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. When men 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. It had the same structure as coronaviruses in chickens and pigs. So that's how they knew it 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. In theory, viruses, or the coronaviruses mostly seem to be able to infect other animals as well. But the virus that I worked with for 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 COV2, the cause of COVID19, can infect animals. So humans can infect these other animals by spreading the virus. SARS COV certainly infect us other animals. MERS COV is really a camel virus, so by definition infects other animals. The human common cold coronaviruses, 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 it can infect bats. So I think coronaviruses usually can go across species, but I don't think always. 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 have the best vaccine in the world, we still have West Nile Virus floating around in 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 it were, of the virus to infect humans. Others, like measles, did just fine with having infecting everybody and having huge amounts of herd immunity and still every three years or less coming out and infecting human populations again.

Is that because the r naught 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 AR naught is an order of magnitude lower.

Yeah, I think that that certainly contributes to it. With measles you had five people out of a hundred 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 measles virus. Same thing is true for smallpox too, where it spread out an 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 continues to be in human populations mostly because of poor vaccination and because we use live attenuated vaccine that ended up in water and either 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 rinderpest, which affects animals in Africa. You see, that's the other thing about the animal host is if you evolve from an animal host, if the virus evolved from an animal host but then change so much to infect humans, it may not be able to then cause an infection in the animal host. So these like the SARS COV2 that causes COVID19, we don't really know what it would do if you put it back in bats. No one's going to try, but I don't know if a bat would be infected by it because it may have changed enough even in a little bit of time. It's been out of the bat, so it can infect the bag that very well anymore.

Wow, that's really interesting. So it ping pongs 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 inhumans, it may never see a bat again. So it's not that it's more desirable.

Host, but that's a fair point.

Yeah, humans and bats don't interact that much, even though they interact more than may be desirable given these viruses. But it's not like the virus can look around and say, oh, there's a bat. I think I'll.

Yeah, let me go try that out again and see how it compares to this last question on this topic. Tell me a little bit about hiv. I'm just not a student of my immunology. 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 from what I read periodically is some studies, it seems like the virus was in human populations are identified way before its 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 human primates, have an HIV like virus. That's pretty close.

Let's go into the. Let'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 mid-90s because two of them discovered after SARS in 2004. So.

Wow. Which were the two that came along and that were there in the 90s?

229E and OC43.

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 the latter, appropriately. So if you're going to spend huge amounts 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 may be relevant to think about. COVID 19 is that people who 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 talk about, is that the immune response may be. If 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 going to do it. I just want to 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. Then 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 virus, 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. Whooping cough would be more of a threat to children. What is it that kept you in this? At the time, relatively benign virus. Was it. Help me 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 are the sheets in the brain that cover the axons, and how does the virus. So how does 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 also 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 elicited by the virus? What mattered the most? What caused demyelination and what caused remyelination, which is the process of getting myelin back and which is in. People have multiple sclerosis is the period when they have remissions after relapsing and remissing, or after relapsing have disease and they get better again for a bit of time, or people who have some form where they get better to a large extent, how is that occurring 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 till the early 90s, 1990s, and then we were doing some of it. Yes, the virus preceded my doing immunology.

So tell me what's going on when SARS hits, What is it?

The.

I can't even remember exactly was this O2?

O3, the end of O2 became a big deal in 2003 and then was eliminated in July 2003 for all intents and purposes.

So tell us the story in some detail. I think for many people it's. I mean, 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, 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 initially we all thought this was going to be a kind of flu virus. Because flu viruses we know initiate often start in southern China, 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. What 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 there were bats along with other exotic live animals. And we learned that the coronavirus and SARS coronavirus was almost certainly a bat 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 who are actually handling the animals to sell them and many of those became sick, many developed subclinical disease. And we know that up to a third of the handlers are actually had antibodies to SARS CoV. So we know this was going back and forth lot. Then we know that some of the time it 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 physician. The physician actually became quite ill, didn't go home, rather 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 to 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 anyways is an 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 Naught, but we'll explain it again. What was the R naught 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 has an R naught of about two to three, which means that a single person will infect 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 infects two, and then each of those infects two more people, you now have four infections, they infect two, you get eight. So you can quickly get up to high numbers by this exponential growth.

And we'll 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 naught 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, HIVs r naught would be less than 1.

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 naught? 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 on the average, of course.

So going back to now, sars, sorry to interrupt you there, but now you've got a 2 to 3r naught. 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 R0 of 2 to 3, though, may be misleading because there's no question that the R0 on the average is 2 to 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 in the hospital and you now started as it were, 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 the R0 factor would be much more than two or three. And the community, because this is a deep pneumonia, it really isn't that 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 were 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. And this is a disease that's exactly the same. Not exactly, but very similar to SARS and being a deep lung disease, this disease, the mortality is billed as 35%.

Yeah.

So really terrible.

And it's different, though. So what you just Talked about, the 2002-2003 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. Do you want to take a minute to explain that? Because MERS 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 would have been 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 there's less thinking that one could actually provide immune protection from the other. Though in fact, there's some cross reactivity. MERS coronavirus is recognized in part by SARS coronavirus sera 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 now pick it back up. It's. 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 MERS coronavirus. Why is it only in the Arabian Peninsula?

So tell me about that. Did people. And when I say people, I really mean scientists. I'm sure the population wasn't wandering 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 coronaviruses cause the common cold.

So. And that's why nobody would care. Camel gets a cold, you don't even know, he goes to camel Walgreen 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 camels since the 80s and probably earlier looked earlier. And we know it doesn't jump in Africa or other parts of Asia. So this is a real mystery in this virus. Why is it only in the Arabian miniature?

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 in 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 all the 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, but it's occurring once or twice a week now because people are coming in who actually have no contact with camels and are coming into the hospital with mers. They often have comorbidities, they're older or they might have diabetes, but otherwise they don't even have contact with camels. And 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 naught factor becomes important again because the official number for MERS is somewhere between 0 and 4. I 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 at the hospital not having had any contact with a camel.

And that 0 to 4, which is such a broad range, I've read that as the official range, it's so broad as to be unhelpful. That's really the camel r naught, 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 2,500 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 R0 is actually camel to camel. I don't think it takes that into consideration. Rather, what it takes to consideration is the hospital spread. It's like SARS is so much hospital spread and that's been basically not stopped completely because as my friends in Saudi Arabia 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 nosocomial spread, what 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 2,500 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 R0 of 0.3 really makes it not possible or not likely. There's plenty of cases with MERS where people went back to a 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 was that one patient who infected 186 people. So those are really a confluence. Lots of bad luck for that to have occurred.

And then going back to SARS, COV1 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 continually introduce into human populations and the fact that because you weren't contagious until you were sick, it was easy to look at somebody say, aha, that person has sars. We're going to stick them in a room by himself, take care of him and make sure he Infects nobody else, then you would stop the disease. It's a classic kind of quarantining, identification, quarantining we talk about all the time with COVID 19. But it was 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, one, 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 breez 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 in bats. And so what they did is they found other coronaviruses and it was actually for scientific reason, a different one than just searching for the viruses. We were trying to figure out where did the SARS coronavirus virus really begin? So people went and looked at bat colonies throughout China, since that's where SARS began, and asked, can we find other bats? Are the bat viruses that are 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 Guangzhou, but we didn't know where they came from exactly which kind of bats. And it was just a trick finding it in bats. And so 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 used to enter human cells. So there was people who were saying, there were a lot of people, some people in the field who were saying, well, we potentially have more of a problem because there may be other ways to infect people, maybe other viruses that can affect people. People. And so I think there was a concern that this could happen again in mers. It's the same thing. We haven't identified the exact precursor to MERS in bats, but there's clearly viruses that look like the MERS coronavirus in 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 MERS sometimes in the future occurring again with SARS CoV like viruses. So you're right. In 2015, we were thinking these viruses really cause bad pneumonia, but it's going to be like influenza H5N1. 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 MERS 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 COV1 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 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 future of the virus. I think about this as SARS cov2 being a mixture of the common cold coronavirus and then a mix, plus either SARS or MERS coronavirus in the lungs. So that's why you have the transmissibility and the severe disease, because it does both. But when you think about other bad diseases, like even 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 and you kill 3% or 4%, 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 cold coronavirus, that rate of lethality is 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 1 in 10 or 1 in 3 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. 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, from the beginning 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, SARS1 and MERS, do they also gain entry through the ACE2 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 appreciable express, even though it uses the same receptor. There's also one of the common cold coronaviruses NL63 uses ACE2, only affects the upper airway and doesn't affect the lungs to any appreciable extent.

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 CoV2, which can infect both.

Exactly, exactly. That's why SARS was not so contagious because it only it 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 cause the same amount of damage or pretty similar. But you have this huge denominator in SARS cov2 of people who 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 or MERS COVIA, there were 100 people infected, they all get some variability, some variation in pneumonia and you have a certain mortality rate ranging from 10% to 30% SARS CoV2. Of those 100 people, maybe 20 of them are going to get lung disease. The other 18 are going to be asymptomatic, subclinical, have a cold, have something in the upper respiratory tract. If you now take that 20% as 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 emerge.

So just let me 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 COV2 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 COV2 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 and February, the mortality rate was 2.8%. And now if you look at anything official, it's near to 5 to 6%. So what you say makes perfect sense. 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 mortality Rate in SARS and MERS out of everybody who was sick all had pneumonia and of those people some number died in SARS cov2 if only 1 out of 5 people or less actually get pneumonia then the fraction that die use that same fraction who died over that 20%. You basically are multiplying your number by so if your number is 5% then it goes up to 25%, if it's 3% it 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 and MERS did. If you confine 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 COV2 and the only reason you figure it 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 MERS 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? And 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 MERS patients and I could never get information as to what exactly was 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 MERs, particularly MERs, if it's mostly older people, people with diabetes, people whom have comorbidities, they may take them longer to get back to basal line, 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 or how much permanent damage there was. I suspect that there was a fair bit, but you always have it, you know, can SARS 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 corticosteroids for long periods of time, contributing to 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 values?

We can't find any evidence of the virus in the brain. Then 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 to what seems here like COVID 19 is somehow provoking this response response in this very, very small subset of children. That certainly leads to consequences in the heart, 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 we know.

So between the resolution, so to speak, of mers and where we were, call it 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 going to be studying coronaviruses 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 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 the Department of defense in 2010 or 11 put out a report about possible emerging viruses as being really the major threat. Coronaviruses were on 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 r naught. 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. 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.

No, I don't think it started quite that early. I would say late December. The first cases, 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 to 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 were 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 it didn't seem to be extraordinarily different from these other viruses. Maybe if 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 and MERS 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 were?

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 basing that on because there wasn't so much evidence of human to human transmission. It was pretty clear to me then 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. MERS is 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. And 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 all we need to do is have this be transmittable and it'd 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 cov2 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. Was identified in Mexico. It seemed to have a high lethality, but it's more cases became clear identified. It's 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 influenza. It wasn't H5N1, which causes a severe pneumonia.

H5N1 is the 1919.

No, H5N1 is the one that's never made it to human populations to an appreciable extent.

Ah, pure swine.

Yeah, it's mostly pigs and birds, but it kills birds and most flu doesn't kill birds. So the concern was that it would change to infect to be transmissible human to human, but it never did. So same thing with thinking about coronavirus is they hadn't done this so far. We certainly thought they could do it. But this is an interesting question as 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, vaccines against sars, a 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 on the other hand, if you're competing against other grants that make more compelling arguments for funding and 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 NE 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 the no regret moves. 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, know 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 day 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 dosed also strikes me as a no brainer. Right?

Yeah, yeah. No, 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 poorly 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 RT PCR are not that hard. I mean that probably took four days.

To figure out, but it took longer to scale up. I mean, I think that's the point, right? It's not. No. I mean the virus was sequenced January 11th or 12th, wasn't it?

Yeah, yeah, earlier than that actually. It'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 US 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 inst. 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 kind of 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? Are 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 that some 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, another one did better in March.

Interesting. And then from 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 really the question about all common cold viruses, whether it be corona or otherwise. So why do you actually get reinfected? I don't think we understand it very well. We know that there's an antibody response to these viruses. It seems to wane, 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 wane 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 coronaviruses. 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, 1995, they still had antibody responses that were measurable. Here we have these common cold coronaviruses. A year later they've waned, and 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 reinfected by SARS CoV2 impacts the vaccine responses, impacts general herd immunity as we try to get rid of this virus. So really important for matno, 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 CoV2 and what it means?

Well, herd immunity is really the other side of what you were talking about, the R0 factor. So if the herd immunity means if you have a virus that's extremely contagious for people who are susceptible to beeperty 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 it be SARS CoV2 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 could in theory infect that person. But if that person is immune to the virus that you doesn't matter. The virus can land on 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 person is susceptible, then he will. So then if that person is susceptible, he could 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 I was saying before with measles is five of them are susceptible, the virus might spread to 25, 30 people from that one susceptible person. And then of that 5%, maybe one or more of those people will become infected. If you have a virus like SARS CoV2, which has a lower r naught factor than at that same hundred people, if their five are susceptible, the odds are it will not get to the point of infecting one of those five people. So herd immunity is that ratio the fraction of people who are immune to a disease. For measles, the number is 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 in terms of immunization or infection with SARS CoV2 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 you'll spread it to that 30% of the population that has never seen the virus. So that's why it matters.

Yeah. And there's a very non linear but monotonic inverse relationship between R noxication and herd immunity, which I can't believe I actually just said all that. It's basically math speak for the higher the R naught, the higher the need for herd immunity. But the relationship gets there nonlinearly. 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 naught for measles is very high and the herd immunity threshold is very high, 95%. Going down to an R naught of 2 to 3. You have a herd immunity threshold of 60 to 70%. 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 COV2, or do you think that it could be as low as 20 to 30%?

Well, I think it's still going to 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 moot 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, fair point. Yeah. So is there much genetic drift in these viruses? The way like influenza, I think most people know, hey, I gotta 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 to have different variants. A lot of the others don't seem to change that much. SARS was adapting to human populations, so it changed, but if it had stayed around, I don't know that it would have changed much. MERS is completely a camel virus. So any drift you see is what happens in camels, not in people. Again, both for MERs and the human, the other coronaviruses is not really. Well, except for OC43, I don't think there's huge effects on immunity. This virus is really. There's certainly lots of talk about changes in the virus and becoming more virulent and more weaker and more attenuated. 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. Because the virus is changing.

So far, that's an important point. I think we want to kind of 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, that 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, is 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 do 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 familiarize 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 answers for that, for the common cold coronaviruses. And they show that immunity is there, that's 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 when people have mild infections or asymptomatic.

Now, we've talked about this paper that came out, God, I think it's been maybe three weeks ago, Alex Seti 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 CD8T 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 COV2 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 a 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 CoV2. Now, there's some caveats when I read this paper that make me pause in drawing too strong a conclusion. One is that in most of these papers, the way T cell responses are measured is not by functionality, but rather by being activated in a certain way. And these activations, to my mind, are a surrogate for actual functionality. And the functionality was not well demonstrated in any of these studies. You may see a little functionality, but it's not the major point. Second thing is the targets for these virus for the T cell response is not the usual response that you get in terms of targets as you see after the wild type infection, the SARS CoV2 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 coronaviruses for the same targets, there's actually very little homology with T cell responses that are recognized in these patients who have never seen SARS cov2. So altogether on one hand you could say, well maybe this is something that's important, maybe it contributes to protection pathogenicity. On the other hand, it's a little odd because it's mostly measured by activation, not necessarily by function. And that may matter. And it's also targets are not totally clear how that's working. So to me it's something it'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 completely. 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 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, they're very, very low levels of activity. So the amount of cytokine produced are extremely low or non existent. So you just wonder. Part of the issue is 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 jury'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 used to see, what we've seen in MERS patients where we don't really see much of a background, much evidence of cross reactivity. But we didn't actually do these 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 100 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 COV2. Well, presumably there's also a strength and a decline of immune response. So even though they would all have some immune response response, lingering some memory of immune response to the benign coronavirus, they could technically mount very different responses to the much more feared SARS CoV2 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 were other viruses or other vaccines that could provide cross reactivity?

I don't think provide cross reactivity. There's 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. Or you should do something like that bcg, which we use for immunization against tuberculosis, Whether they have any effect. People are suggesting this. I think they're in trials even. But in terms of specificity of getting at the coronaviruses, I don't think so.

The BCG one's 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, the real infection.

Three of those infections. So I don't consider myself resistant. In fact, almost everybody my age had all three of those viruses. Everybody certainly had measles in mumps. German measles may have been less frequent, but.

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 looked very, very hard. But there's no reason to think that it would. If there was anything like that, we would all have some pre existing 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 Cooley's 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 system specificity as it does for the immune system to attack cancer.

Yeah. And you know, there's other agents. So we've worked with agents that turn on interferon. And I think if you give interferon at the wrong time in these infections, you may make people worse. So if you were exposed to COVID 19 and you had a very good exposure right now, and I gave you one of these agents that turned on interferon, 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 you jazzed up the immune system with bcg, that it could help you if you got it right the right day and then you were exposed to COVID 19. But I wouldn't want to be inoculated BCG just for fun, with the possibility that in 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. 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 high hyperactivated immune sense. So early treatment is antiviral with immune amplifier. Late treatment is immune modulator. Antiviral's long since gone 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 is you need antiviral therapy early on and then maybe an immune modulator later. And 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. And 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 know that something works well, and then we do large studies and we find out, you know, it didn't work as well as we think. But if you go back, you say within this population, if you. 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 fall in a category of benefiting from it, if you treat 100%.

You dilute all the benefit.

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 in cytokine 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 40s, and yeah, never hospitalized, but sick as 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 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 has diabetes and 60 in terms of how poorly he felt. And so what you'd want, you need a marker not only for severity, but you wanted something that would distinguish 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 lung 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 till now has been that you can see an increase in cytokine X in people who are going to be sick and not increased in 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 will have a range of 0.75x to 1.5x. So you.

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 old. Like they all have a very different physiologic age, even if their 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, and 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 what their numbers look like, put them in the 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 sick, whether it be the 40 year old, because you know the 40 year old can get sick, or whether it be an older person. And you put the other, the other point you make about the epidemiology on top of that, maybe you would not even bother testing the 40 year old because the odds of his getting sicker and meriting all the cost 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 serial 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 going badly, maybe that's the person you'd use either remdesivir or hopefully an oral form of remdesivir, stop the virus in its tracks. Maybe give immune activator. Again, unclear. I think if you give immune activator to some people, it'll 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 Zahn 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 Wrigley 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 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. 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. Had you seen 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 that it came out earlier, but it is 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 ref 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, how long people are gonna 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 100 million people have been infected. But regardless, the durability of their immune response has to be one of the most important, 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 their T cell responses, the odds are that we're going to see waning immunity with people at mild disease. That's what we're hearing over and over again. And that's what's been true for other coronavirus infections.

And what will the implication of that be? Will the implication then be that no matter how successful a vaccine is, it's going to 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 immunity wanes or not. That person may never get a severe pneumonia. The other issue, which is equally important, is how much immunity do you need to prevent shedding, to prevent transmissibility to other people? And that's the one that I think is really unknown 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 waves of this? Because there is something on Instagram a few weeks ago where I did a kind of Q and A with my son, who's 5, 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 a vaccine, vaccinate Everybody with a SARS CoV2 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 6 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 a little 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?

Yeah, yeah, yeah.

We don't have the memory like we do with measles and 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 COV2? Let's just say if we knew that the immune response was gone after a year.

The question is, what is immune response being gone?

Yeah, A sufficient immune response. I mean, it becomes a sliding scale of efficacy. Correct? 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? See, that would be. Actually, 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 a year later, do they get a cold? And how much Shedding do they have. We know they shed, but if you are a naive person with a cold, you shed 10 to the eighth 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'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, 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. I mean, 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 cov2 such a problem.

Yeah, yeah, that's right.

Anyway, Stanley, as you can tell, we could 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 coronaviruses 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, where will have antivirals, I hope vaccines, even with the caveats that we talked about, that should work, how long they'll 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. We're 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.

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