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

1. 0:00 – 2:45

   Intro

   1. PAPeter Attia0:01

      [upbeat music] 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 wanna 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 wanna learn more now, head over to peterattiamd.com/subscribe. Now, without further delay, here's today's episode. [upbeat music] 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-CoV-1 and SARS-CoV-2 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 discuss very briefly at the end of this podcast. So most of our contact has actually been through that, but as we got a little bit of breathing room in and around our other projects, inclusive of the one we're, we're working on together, we decided it made sense to, 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

2. 2:45 – 9:00

   His background and early work with coronaviruses

   1. PAPeter Attia2:45

      with Dr. Stanley Perlman. [upbeat music] 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 it-- 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 that, first of all, that you even took the time to respond, and then of course, now we've been able to work together on, 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 wanna understand coronaviruses, you've gotta speak to Stanley Perlman. Everybody is a armchair coronavirus expert now, but y-you actually wanna 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, and immunology per se?

   2. SPStanley Perlman3:39

      Well, I actually started, uh, obtained a PhD many, many years ago in, in the areas actually of cell biology and developmental biology and virology. So I did a whole potpourri of training as, as a PhD student and then again during post-doc, and then I went to medical school. So there was a period there where I learned, oh, I didn't do coronavirus research, but I learned how to do research. And so then when I went to medical school, I became interested in pediatrics and in infectious diseases. And I don't know what my plans were exactly when I started medical school, but became really interested in how baby brains interacted with viruses, which was not good. So when babies are getting infected with viruses, especially in utero, it 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.

   3. PAPeter Attia4:57

      Now, what was the decision point that had you leave sort of a pure academic track, which you would've been on from your PhD and your post-doc, 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?

   4. SPStanley Perlman5:18

      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, of being wanting to really step back a bit and also wanting to find more relevance for human disease.

   5. PAPeter Attia6:04

      You're kind of a Doogie Howser, because how is it you could do med school and re- 'cause today med school's four years, pediatric residency's three, and then pediatric infectious disease would add at least two to that, right?

   6. SPStanley Perlman6:16

      Or three. It's actually three now, yeah.

   7. PAPeter Attia6:19

      You'd be talking about a 10-year training program that you did in six.

   8. SPStanley Perlman6:22

      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, uh, 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 who 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 were really creative and thinking about things. So it was a generally intense, but a very good experience, and you were well-trained at the end.

   9. PAPeter Attia7:15

      So you did your residency at Boston Children's or fellowship or both?

   10. SPStanley Perlman7:18

       Both. Yeah, yeah. Both.

   11. PAPeter Attia7:20

       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, 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.

   12. SPStanley Perlman7:38

       Yeah, yeah, so right. Henry Brazelton. Yeah, yeah.

   13. PAPeter Attia7:40

       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.

   14. SPStanley Perlman7:57

       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 will have hearing problems and visual problems and even cognitive problems. So the babies, just because they're developing, they're incredibly sensitive to anything that disrupts their development. And when I think about it, the direct relationship to what I later did with research was really not so strong, but it was just the whole notion of could you do anything to prevent 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 coronaviruses turned out to have this interesting ability to cause demyelination,

3. 9:00 – 17:45

   Coronavirus family—various types, common traits, and scientific understanding

   1. SPStanley Perlman9:00

      or which was similar to what we see in multiple sclerosis. So it sort of ended up in a long, roundabout way from my studying this multiple sclerosis-like disease for 20 years before SARS came about.

   2. PAPeter Attia9:12

      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?

   3. SPStanley Perlman9:35

      So the coronaviruses are like any other set of viruses. They're... Viruses are put into that category because of what they look like under the microscope, what they look like under the electron microscope, or 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, 'cause that's been made very clear in the COVID-19 outbreak, 'cause that's where this virus undoubtedly started, at least distantly.

   4. PAPeter Attia11:01

      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 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?

   5. SPStanley Perlman11:27

      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 the poliovirus, and yet the virus doesn't seem to do that much more than poliovirus. So a little uncertain exactly why it needs all that genetic information.

   6. PAPeter Attia12:24

      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?

   7. SPStanley Perlman12:30

      Amount of RNA in it. Certainly, the coronavirus is bigger than the poliovirus, but that's because it has all this genetic material stuffed into the middle of it.

   8. PAPeter Attia12:38

      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.

   9. SPStanley Perlman12:53

      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.

   10. PAPeter Attia13:34

       And does it, like human DNA, contain coding and non-coding segments alike that are just as important?

   11. SPStanley Perlman13:42

       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 in 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.

   12. PAPeter Attia14:13

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

   13. SPStanley Perlman14:53

       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 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 are, cause human disease or non-human animal disease, but I think you might get away from others that are actually beneficial.

   14. PAPeter Attia15:39

       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.

   15. SPStanley Perlman15:54

       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 the animal viruses have an important part in maintaining some of the developmental patterns in those insects. I can't tell you. I know that some of them are wasps, but I can't tell you more, remember. But there's definitely viruses that without which there would be problems.

   16. PAPeter Attia16:28

       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 coronavirus? What is the corona referring to?

   17. SPStanley Perlman16:38

       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.

   18. PAPeter Attia16:57

       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?

   19. SPStanley Perlman17:18

       I think we identified the first one in the 1930s and '40s from chicken. That's what I remember, that the infectious bronchitis virus was found in chickens. And then in the 1960s, people identified viruses that caused the common cold that had the same kind of appearance as the infectious bronchitis virus. And I think by then we knew something about some of the pig viruses as well. So the human,

4. 17:45 – 28:30

   The origin of viruses, animal to human transmission, R_0, immunity, and more

   1. SPStanley Perlman17:45

      it was isolated from people with colds that had the same structure as coronaviruses in chickens and pigs. So that's how they knew it was in the Coronavirus family.

   2. PAPeter Attia17:55

      Is it the exception or the rule, Stanley, that a virus that infects humans also has an animal host?

   3. SPStanley Perlman18:03

      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-CoV-2, the cause of COVID-19, can infect animals, so humans can infect these other animals by spreading the virus. SARS-CoV certainly infected other animals. MERS-CoV is 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 gonna play, as I was saying, into the ability to eliminate a virus from the human population.

   4. PAPeter Attia19:22

      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.

   5. SPStanley Perlman19:50

      Maybe. When you think about different viruses, certainly that's true for West Nile virus. If we had the best vaccine in the world, we'd 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.

   6. PAPeter Attia20:21

      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 coronaviruses, the R naught is an order of magnitude lower?

   7. SPStanley Perlman20:36

      Yeah, I think that that certainly contributes to it. With measles, you had five people out of 100 not vaccinated or not resistant to the virus. Those people would get infected if you put them in a room with somebody who was positive for the measles virus. Same thing is true for smallpox too, where it spread without 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 it continues to be in human populations mostly because of poor vaccination and because we use live attenuated vaccine that ended up in the water and either mutates or doesn't mutate, but it's not gone.

   8. PAPeter Attia21:15

      And so where did those viruses come from? If they never had an animal host, where did they evolve?

   9. SPStanley Perlman21:20

      Well, I think they did initially have an animal host. So measles is thought to evolve from rinderpest and, 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 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-CoV-2 that causes COVID-19, we don't really know what it would do if you put it back in bats. No one's gonna try, but I don't know if a bat would be infected by it 'cause it may have changed enough even in the little bit of time it's been out of the bat, so it can't infect the bat very well anymore.

   10. PAPeter Attia21:57

       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.

   11. SPStanley Perlman22:12

       I don't know if, or, but that's making the virus a little more anthropomorphic than it might be needed. If it's in humans, it may never see a bat again. So it's not that it's a more desirable host, but-

   12. PAPeter Attia22:24

       That's a fair point

   13. SPStanley Perlman22:24

       ... 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-"

   14. PAPeter Attia22:35

       Yeah, let me go try that out again and see how it compares to this.

   15. SPStanley Perlman22:37

       Yeah.

   16. PAPeter Attia22:38

       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?

   17. SPStanley Perlman22:53

       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 or 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 non-human primates have an HIV-like virus that's pretty close.

   18. PAPeter Attia23:27

       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?

   19. SPStanley Perlman23:50

       It's actually only two in the mid-'90s, 'cause two of them were discovered after SARS in 2004, so.

   20. PAPeter Attia23:55

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

   21. SPStanley Perlman23:59

       229E and OC43.

   22. PAPeter Attia24:02

       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"?

   23. SPStanley Perlman24:14

       Yeah, it was more the latter. Appropriately so, if you're gonna 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 the thing 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 immune response may be... If you have a mild infection, you may have a more transient immune response.

   24. PAPeter Attia24:47

       Yeah. There are three or four papers that I can't wait to dive into and then we're gonna do it. I just wanna make sure the listener doesn't get too lost in what we're talking about. But actually, if you're listening to this now and you have not listened to the interview with David Watkins, this would be a great time to hit pause, go back, and do that, because in that discussion, we really do the immunology tour de force, and we explain the difference between the innate immune system, the adaptive immune system, and the two branches of the adaptive immune system, the humoral system, which relies on B cells and their antibodies, and the cellular system, which relies on T cells. And I have a very strong suspicion that very soon Stanley and I are going to get into some of the weeds around the B cells versus the T cells. And again, I don't think you can educate yourself enough on this topic if you want to truly understand what's going on with these viruses. Bringing it back to the late '90s, tell me what your interest was at that time. So obviously you're a scholar, you're doing incredible work. Did you think at that point in time, "Gosh, these coronaviruses aren't that interesting. They're not really a threat to humans. They're not really a threat to my patients in the way other viruses are. Even RSV would be more of a threat to children. 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 w- what is it kept you in a field that ultimately turned out to be a very productive decision?

   25. SPStanley Perlman26:11

       At the time, we were interested mostly in this mouse virus and the, uh, 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 sheaths in the brain that cover the axons, and how does the virus, or 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, uh, 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 with multiple sclerosis, is the period when they have remissions after relapsing and remitting 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.

   26. PAPeter Attia27:25

       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 wanna make sure I understand what's happening in trimester one that is potentially injuring a child's brain? Like, those two aren't necessarily mutually exclusive, but were you bent more towards one than the other?

   27. SPStanley Perlman27:54

       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?

   28. PAPeter Attia28:06

       So you're basically now becoming a neurobiologist with a background in immunology, virology, and pediatrics.

   29. SPStanley Perlman28:12

       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, so... By then we were doing some of it, yes. The virus preceded my doing immunology.

5. 28:30 – 35:00

   Insights from the 2002 SARS outbreak

   1. PAPeter Attia28:30

      So tell me what's going on when SARS hits. What is it, the... I can't even remember exactly. Was this '02, '03?

   2. SPStanley Perlman28:37

      The end of '02, became a big deal in 2003, and then it was eliminated in July 2003 for all intents and purposes.

   3. PAPeter Attia28:44

      So tell us this 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 I... If I could drive home without crashing, that was a, 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, and what impact it had on you and how it may have shifted your thinking?

   4. SPStanley Perlman29:13

      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 gonna be a kind of flu virus, 'cause flu viruses, we know, initiate, often start in Southern China, and it's particularly in the city of Guangzhou, which is across the bay from Hong Kong. So we heard about these viruses, and then it became clear that they were a coronavirus. This was isolated by several laboratories. 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, the 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 were 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 were actually had antibodies to SARS-CoV. So we know that this was going back and forth a lot. Then we know that some of the time it spread to, uh, 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 or was brought to the world's attention is that a single, uh, 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 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 anyway is a, is a open question, of course. The main set of events was a single event, and that's why the virus seemed to start from a single point source.

   5. PAPeter Attia31:20

      Now, help me understand something. I think most people listening to this are now familiar with R_0, but we'll explain it again. What was the R_0 of that SARS virus? In retrospect, I guess, what do we believe it was? How transmissible was it?

   6. SPStanley Perlman31:33

      Yeah, so this is a good question because the official numbers are, has an R_0 of about two to three, which means that a single person will infect two to three people. So clearly, as you can see with- without even thinking about it very hard, if, 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.

   7. PAPeter Attia31:59

      And we'll hit pause there for one sec just to put that into context. Earlier, for example, you talked a lot about measles. Measles has an R_0 probably north of 10, correct?

   8. SPStanley Perlman32:09

      Yeah, around 15.

   9. PAPeter Attia32:10

      I mean, that's about as high as they come. I mean, that's an explosive exponential multiplier.

   10. SPStanley Perlman32:16

       Right.

   11. PAPeter Attia32:16

       At the other end of the spectrum, today, HIV's R_0 would be less than one.

   12. SPStanley Perlman32:22

       Yeah, and I think that HIV's a little different because it's not a respiratory spread.

   13. PAPeter Attia32:27

       Yeah, so let's use another respiratory example. What would be a low R_0? Well, let's use the other coronaviruses. If you take those other coronaviruses, they're one to two at most, right?

   14. SPStanley Perlman32:36

       Exactly. So one person infects someone else on the average. This is on the average, of course.

   15. PAPeter Attia32:41

       So going back to now SARS, sorry to interrupt you there, but now you've got a two to three R_0, 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 gonna go back someplace, right?

   16. SPStanley Perlman33:00

       Yeah, so I think that the R_0 of two to three, though, may be misleading because there's no question that, that the R_0 on the average was two to three, 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 R-naught 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.

   17. PAPeter Attia33:58

       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.

   18. SPStanley Perlman34:48

       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

6. 35:00 – 42:00

   Insights from the 2012 MERS outbreak

   1. SPStanley Perlman35:00

      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 in being a deep lung disease. This disease, the mortality is billed as 35%.

   2. PAPeter Attia35:20

      Yeah.

   3. SPStanley Perlman35:20

      So really terrible.

   4. PAPeter Attia35:22

      And it's different, though. So what you just talked about, the 2002 to 2003 virus that started in a market in southern China, who has the same name as the current virus we're talking about, but we refer to them as SARS-1 and SARS-2, they're in the same beta family, which we didn't really get into. 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?

   5. SPStanley Perlman35:46

      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 it's 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.

   6. PAPeter Attia36:38

      And this'll 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?

   7. SPStanley Perlman36:50

      Right. Right.

   8. PAPeter Attia36:52

      Okay. So again, let's now pick it back up. It's what, is it 2009 when MERS came along?

   9. SPStanley Perlman36:57

      Well, MERS in 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?

   10. PAPeter Attia37:13

       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?

   11. SPStanley Perlman37:29

       Nope. This was absolutely not appreciated, 'cause in camels these coronaviruses cause the common cold or they can-

   12. PAPeter Attia37:37

       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?

   13. SPStanley Perlman37:54

       We don't know. The virus had been in camels since the late '80s and probably earlier, though it 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 Peninsula?

   14. PAPeter Attia38:09

       When you look at the MERS virus in the camels, it's still the same in the Arabian Peninsula versus other camels?

   15. SPStanley Perlman38:17

       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.

   16. PAPeter Attia38:33

       And when you say Africa, do you include North Africa? Were there any cases that arose in Egypt or Algeria, Libya, Morocco?

   17. SPStanley Perlman38:41

       Yes.

   18. PAPeter Attia38:42

       They did not occur in those places?

   19. SPStanley Perlman38:44

       Yeah, yeah. Camels are infected there, but people are not.

   20. PAPeter Attia38:47

       Oh, wow. 'Cause 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.

   21. SPStanley Perlman39:09

       Yeah, we don't know. The fact is it not only occurred in 2012, but it's occurring once or twice a week now 'cause people are coming in who actually have no contact with camels, and they're 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.

   22. PAPeter Attia39:30

       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?

   23. SPStanley Perlman39:42

       Yeah. So this is where the R nought factor becomes important again because the official number for MERS is somewhere between zero and four. I think outside of hospitals it's probably nearer to .35, .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.

   24. PAPeter Attia40:10

       And that zero to four, 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 nought. That's the spread from camel to human, and then as you said, human to human transmission is probably gonna 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?

   25. SPStanley Perlman41:00

       Yeah. So this one, like SARS, is mostly transmitted from people who have lung disease already, who have severe lung disease. I don't think the R nought is actually camel to camel. I don't think it takes that into consideration. Rather, what it takes into consideration is the hospital spread. It's like SARS in some of the 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.

   26. PAPeter Attia41:33

       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, an effective portal for the virus to get to you, and then obviously we know how

7. 42:00 – 53:30

   Comparing SARS-CoV-2 to MERS, SARS, and other coronaviruses

   1. PAPeter Attia42:00

      infections like that can spread through intensive care units and such.

   2. SPStanley Perlman42:04

      Yeah, that's exactly right. That's exactly why it's a problem.

   3. PAPeter Attia42:08

      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 a, an epidemic really, let alone a pandemic. Why do you think this just wasn't something that spread despite its potential for devastation at, at the mortality level?

   4. SPStanley Perlman42:32

      'Cause I think that that R nought of .3 really makes it Not possible, not likely. There's plenty of cases with MERS where people went back to relatively poor country after having been a worker in Saudi Arabia, were found to be infected and infected nobody, so that nobody became ill from that patient even though they weren't really looked at. That's as opposed to Korea, where there was that one patient who infected 186 people. So there was a really a confluence of lots of bad luck for that to have occurred.

   5. PAPeter Attia43:02

      And then going back to SARS-CoV-1, what basically accounts for the eradication of that, call it in 2003, 2004?

   6. SPStanley Perlman43:12

      The combination of there being no reservoir, so it's not like camels, which could continue introducing to human populations, and the fact that because you weren't contagious till you were sick, it was easy to look at somebody and say, "Aha, that person has SARS. We're gonna stick him 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 and quarantining that 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.

   7. PAPeter Attia43:46

      I mean, Stanley, to hear you tell the story this way, it's just, it's like a bad movie because you could be lulled into a false sense of confidence by the time MERS blows over. You can say, "Hey, okay, I got it. We've got a few of these coronaviruses. They cause a bunch of colds. You get a runny nose in the summer, but it's really nothing. And yeah, it's true, two really bad actors showed up that on a virus to virus level can really hurt their host, but they're nothing to really be afraid of." In the case of SARS 1, it has two things that make it really friendly to humans. One, it can't bounce back and forth between humans and animals, and two, you don't really spread it. You're very unlikely to spread it if you're not symptomatic. You don't have to shut the world down, but not only that, you get to isolate people when they're sick and treat them before they treat others. So the virus really gave up two big potential superpowers. In the case of MERS, sure, it lives in animals and it's never gonna leave those animals, but it has such a poor ability to spread between humans almost under any circumstance, unless you're probably sticking a breathing tube in them, that it was just so easy to contain. If the story stopped there, you'd say coronaviruses are just not a threat to us.

   8. SPStanley Perlman45:04

      Yeah, so I think some people in the field more than me said, "Well, let's go look at, at coronaviruses in bats." And so what they did is they found other coronaviruses, and, and it was actually for a scientific reason, a different one than just searching for the viruses. We were trying to figure out where did the SARS coronavirus really begin? So people went and looked at bat colonies, um, throughout, uh, uh, China, since that's where SARS began, and asked, "Can we find other bats, other 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 some people who were saying, there were a lot of people, or 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. There may be other viruses that can infect people." And so I think there was a concern that this could happen again, and MERS is 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 gonna be like influenza H5N1. It's gonna have very, very little human to human spread and mostly animal to human spread.

   9. PAPeter Attia46:54

      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-CoV-1 or MERS. If you take the transmissibility of that, which is both, and primarily is a factor of the fact that it can spread before you're symptomatic, coupled with the actual pathology of MERS, which I want 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 five X disaster. Is there anything that tells us that's unlikely because of this feature of the biology of the virus?

   10. SPStanley Perlman47:58

       I don't think there's anything that's unlikely. I don't think there's anything about the feature of the virus. I think about this, uh, uh, SARS-CoV-2 being a mixture of the common cold coronavirus and then a mix of, 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, it was very, very, very transmissible and it killed about a few percent of the people it 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.

   11. PAPeter Attia48:52

       Is there something about the pathology of this virus-- How does it differ? I mean, when you think about SARS 1 and MERS, that let's just say directionally those numbers are right in terms of the denominator wasn't bigger than we think and you're killing basically one in 10 or one in three people infected. What did the virus actually do in the lungs that would render people so helpless?

   12. SPStanley Perlman49:14

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

   13. PAPeter Attia49:50

       Do the other two viruses, SARS 1 and MERS, do they also gain entry through the ACE2 receptor or did they use a different receptor to enter the pneumocyte?

   14. SPStanley Perlman50:00

       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 an appreciable extent, 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.

   15. PAPeter Attia50:20

       And that could also account for the change in transmissibility, because if you are only infecting the lower airway, you're probably less transmissible than SARS-CoV-2, which can infect both.

   16. SPStanley Perlman50:32

       Exactly. Exactly. That's why SARS was not so contagious, because it only re- 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.

   17. PAPeter Attia50:44

       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?

   18. SPStanley Perlman50:59

       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-CoV-2 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-CoV, 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-CoV-2, of those 100 people, maybe 20 of them are going to get the 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, the 6% mortality that we're seeing, the 5% mortality, uh, well, 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 or MERS.

   19. PAPeter Attia51:56

       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-CoV-2 that you're gonna normalize more? Or are you comparing case fatality to case fatality, whereas I'm thinking of it as the IFR as opposed to the CFR for SARS? Because I think the IFR of SARS-CoV-2 is very population dependent, but I think it's much closer to 1 to 2% than the initial numbers that people feared of 5 to 10%, which would put it more in the ballpark of SARS-2.

   20. SPStanley Perlman52:29

       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 nearer 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-CoV-2, if only one out of five people or less actually get pneumonia, then the fraction that die, if you use that same fraction who die over that 20%, you basically are multiplying your number by five. 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

8. 53:30 – 57:00

   COVID-19 survivor potential for long-term damage

   1. SPStanley Perlman53:30

      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.

   2. PAPeter Attia53:40

      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, uh, that I have, comes down to the survivors. I mean, obviously, we think a lot about the mortality of this, but if you take a person who gets infected and they're not asymptomatic, so we know that a lot of people kind of don't even know they've got SARS-CoV-2, and the only reason you figure it out is after the fact, serologic analysis tells us that they did. But there's a, 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.

   3. SPStanley Perlman54:41

      Yeah. When 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 in MERS, particularly MERS, if it's mostly older people, people with diabetes, people whom have comorbidities, it may take them longer to get back to baseline. It's probably not gonna 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, in 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.

   4. PAPeter Attia55:51

      Well, based on your knowledge of coronaviruses and your knowledge, in particular, their impact on the brain, do you think that there are plausible mechanisms by which even for those who recover from SARS, there could be lasting neurologic impact that is not the byproduct of hypoxia or vent head, pump head, any of the other more mechanical or other physiologic accounts? In other words, do you believe that there is a plausible scenario by which the virus could have residual neurologic value?

   5. SPStanley Perlman56:23

      We can't find any evidence of the virus in the brain, and it seems less likely that it's direct virus infection.

   6. PAPeter Attia56:30

      What about an immune response?

   7. SPStanley Perlman56:31

      Yeah, that's what I was gonna 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 in this very, very small subset of children. That certainly leads to consequences in the heart, long-term consequences, or it can. So you can certainly imagine scenarios like that. Well, how often this occurs and what's going on exactly, I

9. 57:00 – 1:07:00

   Using the current pandemic for lessons on future preparedness

   1. SPStanley Perlman57:00

      don't think we know.

   2. PAPeter Attia57:01

      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 gonna 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?

   3. SPStanley Perlman57:27

      I certainly wasn't smart enough to predict that there was gonna be a pandemic. As I said, some of my friends were worried about additional infections in humans. I don't know that anyone would have predicted a pandemic like this one.

   4. PAPeter Attia57:39

      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.

   5. SPStanley Perlman57:46

      I was gonna 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.

   6. PAPeter Attia57:57

      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, 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_0. But okay, fair enough. I'll stop coming down on-- I'm joking, of course, stop coming down on you guys for not thinking this could happen, but so let's fast-forward now to when did you first hear about the outbreak in China? I mean, I'm assuming it was early December, late November.

   7. SPStanley Perlman58:39

      Oh, 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, uh, early January or mid-January, we had eight hundred 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.

   8. PAPeter Attia59:38

      When did it become clear to you personally that this was going to be a much bigger problem than SARS and MERS ever were?

   9. SPStanley Perlman59:48

      Funny you ask 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 gonna be a major problem.

   10. PAPeter Attia1:00:07

       At that time, could you have predicted it would have been this big an issue?

   11. SPStanley Perlman1:00:11

       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 was really a disease in the Arabian Peninsula with that one case in spreading, infecting several people in Korea. But this one, you know, and maybe the dynamics of everything are so different. People spread travel from Wuhan much more frequently because people have more money, so they fly more, they take the train more. So that helped the spread a lot. Then, of course, this is transmissible. The other thing is that we had gone through some of this with H5N1. So in the late 1990s, people were saying, "All we need to do is have this be transmittable, and it'd be a disaster." 'cause we don't really have good immune responses to it, and it never happened.

   12. PAPeter Attia1:00:59

       So yeah, what happened in 2009 with H5N1? 'Cause the skeptics would say, "Hey, we don't need to worry about this SARS-CoV-2. The last time we cried that the sky was falling, it didn't fall."

   13. SPStanley Perlman1:01:11

       Right. So that was H1N1 in 2009, and that started off as a lethal disease. It was identified in Mexico. It seemed to have a high lethality, but as more cases became clear, identified, it was clear that it didn't. It just was lots of cases and very little mortality.

   14. PAPeter Attia1:01:28

       It was basically influenza.

   15. SPStanley Perlman1:01:30

       It was influenza. It was just a variant of influenza. It wasn't H5N1, which causes a severe pneumonia.

   16. PAPeter Attia1:01:37

       H5N1 is the 1918?

   17. SPStanley Perlman1:01:39

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

   18. PAPeter Attia1:01:45

       Ah. Pure swine.

   19. SPStanley Perlman1:01:48

       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 coronaviruses. They hadn't done this so far. We certainly thought they could do it, but this is an interesting question is 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 gonna put developing antivirals, developing 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, uh, 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.

   20. PAPeter Attia1:02:59

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

   21. SPStanley Perlman1:05:24

       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, that they are similar enough so that that would be a reasonable thing to do is to have those on hand. I think that's what Bill Gates was probably talking about more than specific drugs against specific viruses 'cause 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.

   22. PAPeter Attia1:06:11

       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 no- January 11th or 12th, wasn't it?

   23. SPStanley Perlman1:06:18

       Yeah, yeah, earlier than that actually. It's just scaling up the ability to do testing.

   24. PAPeter Attia1:06:23

       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 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

10. 1:07:00 – 1:22:30

    Genetic drift and the potential for long-term immunity to COVID-19

    1. PAPeter Attia1:07:00

       now because nobody wants to hear me rant about that stuff. I, I wanna get back to kinda 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?

    2. SPStanley Perlman1:07:19

       They tend to not be summer viruses, and they tend to be more winter, early spring viruses.

    3. PAPeter Attia1:07:24

       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?

    4. SPStanley Perlman1:07:31

       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.

    5. PAPeter Attia1:07:55

       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 sorta done?

    6. SPStanley Perlman1:08:10

       That's really the question about all common cold viruses, whether they 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 w- why virus immunity wanes. We know there's such huge differences. Smallpox, you could detect in people who 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-CoV-2, impacts the vaccine responses, impacts general herd immunity as we try to get rid of this virus. So really important, but not known.

    7. PAPeter Attia1:09:30

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

    8. SPStanley Perlman1:09:42

       Well, herd immunity is really the other side of what you were talking about, the R naught factor. So if the herd immunity means if you have a virus that's extremely contagious, for people who are susceptible to be protected from the infection, you have to have most of the people around them be resistant to the virus. So to put this in a different context, if somebody who's infected with, whether it be SARS-CoV-2 or measles or anything else, comes into a room and they're spreading virus, the virus is going to land in various places. Some of it will land on the floor. Some of it might land on somebody's hands and could, in theory, infect that person. But if that person is immune to the virus, then it 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 the 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 stayed 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, if 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-CoV-2, which has a lower R naught factor, then of that same 100 people, if there are five are susceptible, the odds are it will not get to the point of infecting the one of those five people. So herd immunity is that ratio, the fraction of people who are immune to a disease. For measles, the number is said to be 95%. If you don't have that 95%, then s- 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, uh, looking at for in terms of immunization or infection with SARS-CoV-2 to protect the general population. It's not the same as being immunized or having the previous infection. You're still susceptible, but it just means that it's much more likely the virus won't spread, and if you get sick, it's unlikely you'll spread it to that 30% of the population that has never seen the virus. So that's why it matters.

    9. PAPeter Attia1:12:00

       Yeah, and there's a very nonlinear but monotonic inverse relationship between R naught 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 y- 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 two to three, 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-CoV-2, or do you think that it could be as low as 20 to 30%?

    10. SPStanley Perlman1:13:02

        Well, I think it's still gonna be 60 to 70%, it's just that there's a higher percentage of people who have immunity already.

    11. PAPeter Attia1:13:11

        So in other words, you're saying, yeah, it's becomes a bit of a, 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.

    12. SPStanley Perlman1:13:21

        Exactly.

    13. PAPeter Attia1:13:21

        But they actually were from an immune... Okay.

    14. SPStanley Perlman1:13:23

        Right.

    15. PAPeter Attia1:13:23

        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?

    16. SPStanley Perlman1:13:47

        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 population, so it changed, but if it had stayed around, I don't know that it would've changed much. MERS is completely a camel virus, so the, any drift you see is what happens in camels, not in people. Again, both for MERS and the human, the other coronaviruses, it's 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 or 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 the virus is changing so far.

    17. PAPeter Attia1:14:45

        That's an important point. I think we wanna kinda 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 its genetic drifting created a different coat on it, a different set of antigens, and y- every year your immune system was caught off guard, that would be very painful. And what you're saying is, hey, we don't have evidence of either of those things happening, that it's genetically becoming more or frankly less harmful. Of equal if not more importance, that it's not becoming a different immune animal as time goes on, at least in the very short window we've studied it. But again, it 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?

    18. SPStanley Perlman1:15:40

        Yeah, exactly. The immunity when you have a mild infection just, you do not develop great immunity.

    19. PAPeter Attia1:15:46

        So n- let's double-click on that. You've said already part of that. I wanna 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?

    20. SPStanley Perlman1:16:33

        Yes.

    21. PAPeter Attia1:16:34

        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?

    22. SPStanley Perlman1:16:45

        Not necessarily. I think the human volunteer studies are our best answers for that for the common cold coronaviruses, and they show that immunity's there as measured by neutralizing antibody, and then it wanes with time, and that a year later s- it's there and may not prevent shedding. It's still... I think it's, sounds remarkably like what I think we're gonna hear about with COVID-19 and immunity when people have mild infections or are asymptomatic.

    23. PAPeter Attia1:17:11

        Now, we've talked about this paper that came out, God, I think it's been maybe three weeks ago. Alex Sette was the senior author on it, 2020 Cell paper that looked at 20 patients who recovered from COVID-19, and I believe about two-thirds of them actually had a CD8 T cell response and a CD4 response that kind of correlated with that. The point being, they looked to have been at least partially aided in their response to SARS-CoV-2 from T cells that looked like they had been sensitized by other coronaviruses. Now, this was a small study, and this was based on in vitro assays. Can you explain that study a little bit or at least the idea behind it, 'cause it's a incredibly interesting idea, and it has clinical relevance if this turns out to be true.

    24. SPStanley Perlman1:18:01

        Yeah. So I think this is one of actually several studies, this is the only published one I think, that shows that people who, who have never seen the virus have some sort of T cell response to SARS-CoV-2. Now, there are some caveats when I read this paper that make me pause 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, like you see after the, the wild type infection, the SARS-CoV-2 infection. And because of this difference, it makes it also a little unclear to me where this response is coming from. So you can say, okay, that doesn't matter, it's still from a common cold coronavirus. But then when people go back and look at the sequence of the common cold 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-CoV-2. 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 that's not completely clear yet.

    25. PAPeter Attia1:19:40

        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?

    26. SPStanley Perlman1:20:04

        I agree with you completely, yes.

    27. PAPeter Attia1:20:06

        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?

    28. SPStanley Perlman1:20:16

        Yeah, and this isn't really signaling. This is a protein-- What was measured were 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.

    29. PAPeter Attia1:20:33

        Yeah. So that's what I was gonna 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. S-so do you know if studies are looking to do that? Because that just seems to be a very obvious thing to want to ask at this point.

    30. SPStanley Perlman1:20:49

        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 nonexistent. 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. Um, 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.
11. 1:22:30 – 1:32:30

    Prevention and treatment strategies for COVID-19 and future diseases

    1. PAPeter Attia1:22:30

       absolutely. This is a totally second layer. Do you think there are other viruses or other vaccines that could provide cross-reactivity?

    2. SPStanley Perlman1:22:38

       I don't think provide cross-reactivity. There's, of course, these ideas that you should immunize everybody with attenuated polio virus 'cause 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, and I think they're in trials even. But in terms of specificity of getting at the coronaviruses, I don't think so.

    3. PAPeter Attia1:23:04

       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.

    4. SPStanley Perlman1:23:47

       I think it's actually contrary to what one might think because those of us who are over 50 had-

    5. PAPeter Attia1:23:52

       You actually got the real virus. [laughs]

    6. SPStanley Perlman1:23:54

       Yeah, the real, all 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 and mumps. Uh, German measles may have been less frequent, but...

    7. PAPeter Attia1:24:08

       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?

    8. SPStanley Perlman1:24:25

       No. I can say that. No one's looked very, very hard, but there's no reason to think that it would. If it was anything like that, we would all have some preexisting immunity to the virus that's way higher than what we're talking about.

    9. PAPeter Attia1:24:39

       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 specificity as it does for the immune system to attack cancer.

    10. SPStanley Perlman1:25:18

        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 turn 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, then 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 with BCG just for fun with the possibility then the next two days I get exposed to the virus.

    11. PAPeter Attia1:26:04

        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 hyper-activated immune sense." So early treatment is antiviral with immune amplifier. Late treatment is immune modulator, antivirals 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, and I think that's probably something that people are starting to think about now, and, 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.

    12. SPStanley Perlman1:27:27

        I agree with you completely because that's exactly the way I think about this disease is just 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 gonna 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 and 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. Well, 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 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, but you treat 100% -

    13. PAPeter Attia1:28:34

        You dilute all the benefit.

    14. SPStanley Perlman1:28:36

        Exactly. Exactly.

    15. PAPeter Attia1:28:38

        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?

    16. SPStanley Perlman1:28:57

        Okay, so there's two parts to 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.

    17. PAPeter Attia1:29:12

        Nope. Yeah. Young, healthy guy in his maybe early 40s and, yeah, never hospitalized, but sick as a dog for two weeks.

    18. SPStanley Perlman1:29:19

        Right. So that's a person you'd like to do a test on and say, "Okay, is he gonna progress or not?" Clearly, in his case, we'd want something to say he's sick, but he's not gonna 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 is 60 in terms of how poorly he felt. And so what you'd want, you'd 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 gonna do better. But when you put them all together, it's not like you have populations that are very high versus very low. You have ones that have a range of X to Y, and the other one would have a range of 0.75X to 1.5X. So you just overlap.

    19. PAPeter Attia1:30:27

        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 preexisting condition, you're gonna weigh that input differently than a 60-year-old with no preexisting conditions or a 40-year-old with type 2 diabetes versus a 60 year-- 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.

    20. SPStanley Perlman1:31:20

        Yeah. So, 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 how, 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 gonna 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 re- the other point you make about the epidemiology on top of that, and maybe you would not even bother testing the 40-year-old because the odds of his getting sicker and meriting all the cost and use of resource 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 use either remdesivir or hopefully an oral form of remdesivir, stop the virus in its

12. 1:32:30 – 1:34:30

    Alternative hypothesis to the origin of SARS-CoV-2

    1. SPStanley Perlman1:32:30

       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.

    2. PAPeter Attia1:32:40

       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 gonna think about this through the lens of vaccination, and we're gonna think about this through the lens of herd immunity, natural or otherwise, we better figure out exactly what's gonna 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, 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 there-- 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?

    3. SPStanley Perlman1:33:33

       I think so. It's the one that says there's a bunch of these, so I'm not sure I have the Ridley one in mind. The one that says it was released accidentally from the Wuhan lab or the one that says it was-

    4. PAPeter Attia1:33:45

       No, the one that said it was basically so genetically stable, it was really, it's mostly a person-to-person transmission. So it, 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?

    5. SPStanley Perlman1:34:13

       No, I don't know that paper then.

    6. PAPeter Attia1:34:14

       Okay. All right. We won't dive into that too much.

    7. SPStanley Perlman1:34:17

       The point is well taken that it is remarkably fit for humans. I don't know about the first part of the conclusion, you know, that it came out earlier, but it is remarkably fit.

    8. PAPeter Attia1:34:27

       Yeah, I mean, I think they basically looked at the amount of genetic

13. 1:34:30 – 1:43:55

    Determining durable immunity to COVID-19 and what a successful vaccine looks like

    1. PAPeter Attia1:34:30

       drift that occurred and said it's-- 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, I think the argument was, look, this has probably been in humans longer than we think. I'll re-forward it to you after just for the purpose of pure interest. So how do we figure out how long people are gonna... Because it might not be that interesting how much immunity people have to regular common cold coronavirus, but it's gonna be pretty darn interesting to know how long people are gonna have immunity to this virus. I mean, we've already at a minimum seen close to ten million people infected worldwide with this virus. Personally, I think that's a gross underestimate of how many people have been affected. I think it's probably closer to a hundred million people have been infected. But regardless, the durability of their immune response has to be one of the most important questions we understand. How would we do that?

    2. SPStanley Perlman1:35:24

       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 for people who had mild disease. That's what we're hearing over and over again, and that's what's been true for other coronavirus infections.

    3. PAPeter Attia1:35:41

       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 need to be an annual vaccine?

    4. SPStanley Perlman1:35:49

       There's two goals. One is to protect the individual who's vaccinated from getting severe pneumonia, and that may actually occur already. You know, 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 and to me is more important. Not important to the individual, but to society.

    5. PAPeter Attia1:36:19

       To me, that's the jugular question that decides what do economies look like when we have subsequent waves of this. Because I did something on Instagram a few weeks ago where I did a kind of Q&A with my son, who's five, and he asked a very honest question, which is, "When is this virus gonna be gone?" And it was an interesting discussion to explain to him, actually, it's never gonna 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 gonna 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 gonna be a risk trade-off, right, and, and we're gonna decide, you might not wanna vaccinate everybody with a SARS-CoV-2 vaccine if the risk is slightly higher than we deem acceptable. So then you have to do a cost benefit analysis. And, 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.

    6. SPStanley Perlman1:37:53

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

    7. PAPeter Attia1:38:18

       But that's the point. It requires a mutation, doesn't it, Stanley?

    8. SPStanley Perlman1:38:21

       Yeah, yeah, yeah.

    9. PAPeter Attia1:38:22

       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-CoV-2, let's just say if we knew that the immune response was gone after a year?

    10. SPStanley Perlman1:38:46

        The question is what is immune response being gone?

    11. PAPeter Attia1:38:49

        Yeah, a sufficient immune response. I mean, it becomes a sliding scale of efficacy, correct?

    12. SPStanley Perlman1:38:53

        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 a s- 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 and you shed 10 to the 8th, and now you shed 10 to the 3rd and it doesn't matter.

    13. PAPeter Attia1:39:31

        Yeah, then it doesn't matter. Yeah. Well, and of course here, so again, I completely agree with you that that's the single most important question. But the other thing is I don't have my fingers crossed that this is perfect because of that upper respiratory part of this. So you said, "Well, what if you don't get the severe pneumonia before?" Well, it turns out the severe pneumonia that came with SARS-1 and MERS isn't really what was the problem. 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-CoV-2 such a problem.

    14. SPStanley Perlman1:40:06

        Yeah, yeah. That's right.

    15. PAPeter Attia1:40:07

        Anyway, Stanley, as you can tell, we could talk about this for days, but I wanna 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?

    16. SPStanley Perlman1:40:30

        No, I think the key thing we talked about is how do you prevent this in the future? We're gonna muddle our way through this one. We're gonna do, we'll get to points, I think, where we'll have antivirals, I hope. Vaccines, uh, with, 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 'cause we have to do it quickly.

    17. PAPeter Attia1:40:58

        Well, that means we're gonna have to talk again.

    18. SPStanley Perlman1:41:00

        Okay. [laughs]

    19. PAPeter Attia1:41:01

        Thanks, Stanley.

    20. SPStanley Perlman1:41:02

        Okay. Thanks, Peter.

    21. PAPeter Attia1:41:05

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Episode duration: 1:43:55