Virus Biology, SARS-CoV-2, & Origins of COVID-19 | Alina Chan | 18

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Nick talks to genetic engineer Alina Chan, PhD. She is working on engineering new forms of gene therapy using viral vectors to target diverse patient populations. In addition to her core scientific focus, Alina has recently investigated genomic data related to SARS-CoV-2, the virus responsible for the COVID19 pandemic.

They discuss the basics of virus biology, including what kind of virus SARS-CoV-2 is and how it infects human cells. They also talked about the published research on this virus that has come out in the past year, Alina’s recent investigations into the origins of this virus and why it’s crucial for humanity to understand exactly how this virus originated, as well as new variants that have emerged, and where this virus might be going.

*This content is never meant to serve as medical advice.

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[Music] [Music] Welcome to the good chemistry podcast. I’m your host, Nick Jaccomus, and today I’m speaking with Dr. Alina Chan. Alina is a genetic engineer and a scientist at the Broad Institute of Harvard and MIT. She is working on engineering new forms of gene therapy using viral vectors to target diverse human populations. In addition to her core scientific focus, Alina has recently investigated genomic data related to SARS Kovv2, the virus responsible for the CO 19 pandemic. That research has suggested that the virus has been well adapted for human transmission from the start of the pandemic and that in terms of how the virus originated, we cannot yet rule out the possibility that it may have leaked from a research lab. Alina and I went over some of the basics of virus biology, including what kind of virus SARS KV2 is and how it infects human cells. We also talked about the published research on the virus that has come out in the past year. Her recent investigations into the origins of this virus and why it’s actually crucial for us to understand exactly how the virus originated as well as the new variants that have emerged and where this virus may be going. Unfortunately, because the topic has become politicized and toxic in many ways, Alina has suffered from various safety and privacy concerns. For this reason, the video version of the podcast on YouTube will simply show a static episode graphic for this episode. As always, if you enjoyed the podcast and you find the information here valuable, please do consider supporting us. The two ways that you can support us today besides liking, sharing, and subscribing are to one, just subscribe on YouTube. It’s free and easy to do, and it really helps boost our presence on that channel. And two, you can look up Good Chemistry or Nick Jaccomus on Patreon and become a monthly supporting patron for as little as $5 per month. And with that, here’s my conversation with Dr. Alina Chan. [Music] Alina Chan, thank you for joining me. Hi, thanks for having me. Uh, can you tell everyone a little bit about your background and and what you do, what you’ve been working on the past few years as a scientist? I’m a postto researcher at the Broad Institute of MIT in Harvard. I currently work in gene therapy. Uh, I used to work in genetic engineering, not not in humans of course, but in uh human cells in the lab. Um yeah, it’s a it’s a whole field that I’ve been really excited about and it’s uh it’s really about delivering genes for uh medical purposes to to cure uh you know life-changing diseases in humans. Where what is the Broad Institute? The Broad Institute is I think the best the best human genetics genomics institute in the world. uh of course some other institutes might try to battle for that title but I think it’s very well known um it it’s kind of its own standalone institute but its professors are all drawn in from the uh neighboring universities so from MIT and Harvard especially and so they have their labs at the broad and and now it’s over the years it’s expanded to just cover a whole plethora of uh topics so it used to be very human genomics focused but now you’ve got everything like infectious diseases you’ve got crisper of course You’ve got um just everything just drug screening, cancer, just everything is covered almost and anything that’s really top like life sciences research like human health research. Okay. So what about um just to give people a little bit of sense for for what you’re working on? What exactly is gene therapy and how do we generally approach that in the lab? So gene therapy is a booming field now that there are so many labs working on this. uh there are people working on the actual therapy so the actual gene that is delivered into humans into patients so this this is specific to each disease so and it could be anything I think one of the more uh famous uh famous applications are cle cell so there are labs trying to to cure it using base editors to to uh so what this means is that there’s this crisper or castine based um therapy that goes into human cells and it fixes the gene. So it fixes the gene that causes the disease. Uh and that’s what a whole bunch of labs do. They they do this for every uh disease that they think can be cured using a genetic edit in the human genome. Uh but there also labs like the one I’m working in where you work on the vector. So the delivery mechanism. So how do you get these genes into humans in the first place and make sure that it’s uh expressed in a controlled manner in manner and and that the patients have as little adverse side effects as possible. Mhm. So would the idea be that for certain disease states that have a genetic clear genetic basis you essentially have a gene that is broken let’s say and your research would be working on ways to deliver a functioning version of that gene into the person’s cells. Yep. How do you actually get it into human cells ultimately? How how would you do that? Yeah. So, this is this is the fun part. So, uh the current way that a lot of gene therapies are delivered uh or or will be delivered in the future. It’s an active very large field of study right now is through these viruses uh called AEVs adeno associated viruses and these uh are non-pedogenic. So, they don’t make you like sick normally. So they would they were chosen because they do not cause severe disease in humans but are effective at delivering genes. And so you put your genetic therapy the gene that you’re trying to fix or or the enzyme that should be able to fix your gene inside these viruses and you inject them into patients. I see. So fundamentally it’s it’s using viruses. It’s like co-opting a virus to to do something it normally does but in a beneficial way. Okay, so a virus is essentially a little a little uh entity that injects genetic material into a cell. And when we think of viruses, we normally think about getting sick, but in this case, you’ve you’re choosing to use a virus that allows you to get a new version of a gene that’s actually good into a cell. Yeah, I I think this is actually the unfortunate part about the public narrative about viruses. It’s like every time you hear about a virus, it’s killing somebody. They people don’t normally hear about viruses that doing good things and and there and there only such a small percentage of viruses are are the severe disease killing kind of viruses. Actually the vast majority of viruses either don’t infect humans or those that were found a lot of them are not severe diseases. So um they don’t cause severe disease in humans. Um so the virus that we’re using uh in the lab to deliver gene therapies these these have been gutted. So they can no longer make more copies of themselves. So what you what you get what you work with in the lab it even if you spilled it on yourself it’s not like you’re going to give it to someone else because it cannot transmit after that. It cannot infect you and then transmit to another human. I see. So you literally engineer the viruses so they can’t do things they normally do and instead they’re doing things that you want them to do. Yeah. Interesting. So, so your background is in genetics, genomics, and in virus biology. Can we talk a little bit about just basic virus biology for the people that aren’t familiar? Like what what exactly are viruses and how are they different in how they replicate compared to a cellular organism? Yeah. So, viruses, they are still infectious agents, but there is debate on whether they meet all the seven rules of whether something is a living organism or not. uh they in order to make more copies of themselves they have to have a host. So they can only replicate make more copies of themselves using a host. You can almost think of them as like these space alien invaders. They have to hijack a host which is almost like a planet to them. They get inside they use their uh genetic blueprint to make more copies of themselves using the host machinery. So they have to use the host biology the cell to to make more copies of themselves. Interesting. So they’re not necessarily alive. It’s kind of on the fence, but they have certain properties of life. So they replicate, but they can’t do it on their own. They require another organism. Yeah. Exactly. And surprisingly, this has led to a very strange group of people who believe that either the virus doesn’t exist or it doesn’t cause disease because it doesn’t meet it doesn’t meet Coke’s postulates. So uh because viruses just don’t meet coax postulates. You can’t isolate them and culture them alone in a in a solution without a whole cell. So I see. So these these postulates you’re referring to uh who who came up with those and what exactly are those? No, I can’t remember the first name, but it’s definitely the last name Coke. K O C H. Um and so uh this uh these these partials were first developed for bacteria. So they were not developed for viruses. Although the first virus was found around the same time in in the late 1800s. So the uh coke portulates uh were were meant for bacteria uh which had been discovered like two centuries before that. uh and and they were essentially a way of determining does this bacteria cause this disease in this uh human or animal that I’ve that I’m looking at right now. I see. So, so the idea would be that you identify something as a pathogen in the bacterial world. One of the criteria for doing that is you’re able to isolate and independently culture that in a petri dish, say, but you can’t do that for a virus because if it’s all on its own, it actually can’t reproduce and survive. Yeah. Exactly. And actually some viruses sorry some bacteria don’t even need those postulates too. So some bacteria we just have not found ways to culture them. So you you can’t isolate or culture those bacteria. Okay. So so viruses are interesting. They require a host to replicate. They are different from bacteria and cellular life in some important ways. Before we get into co stuff a couple more questions about viruses. I hear about DNA viruses and RNA viruses. So what’s the difference there? So the difference is the genetics so the the building blocks of the blueprint the genetic blueprint. So DNA is a more stable version than RNA. RNA uh so example of RNA virus is is the corona virus is the SARS cof 2 virus that we all having this pandemic for now. So RNA is much less stable than DNA. I see. And then just in in terms of normal biology, what what role does RNA play in terms of, you know, you’ve got DNA, you’ve got RNA, you got protein. Can you just link connect the dots between those three things for people that are unfamiliar? Yeah. So, uh there’s this central dogma in biology. Uh if you’ve taken like an undergrad or I think even high school nowadays, they teach it. uh you you start with DNA which is like the most stable form of the blueprint and people liken it to a book in a library and then you so imagine that your cell has this library that’s in the center of it this closely guarded library called the nucleus and all your DNA is in there your genome is in there so I’m talking about a human cell right now um in order to use that library of blueprints to make another cell or to maintain your cell you need to turn that information into RNA So people have compared this to making photocopies of the book. So it’s like taking your DNA and making photocopies of it which are like which are the RNA. So RNA don’t last forever. They tend to get degraded quite quickly. Uh but they are good way to uh read the blueprint without destroying the blueprint. So imagine if you had to keep reading that blueprint every hour and you kept checking the book in and out of the library. That book’s going to get tattered real quick. So, uh, one way of making sure your DNA is safe is by making photo copies of it that RNA. So, the book, you can’t check the books out of the library. That helps them stay pristine, but you’re allowed to make as many photocopies as you want to go and share with your friends. Yes. And that’s the RNA. Yeah. And Yeah. So, you take that photocopy out of the library and into the rest of your cell and you can use that to create proteins. So, proteins are sort of the last step. they are the the product that you’re looking for the thing that has function. So I think o over over the years there’s been a lot of blurring of the lines between what has function or not. So a lot of RNA has function too. Uh but uh proteins are in this central dogma the last step. So there’s DNA viruses there’s RNA viruses. The difference is a DNA virus is injecting DNA into the host and RNA virus is injecting RNA. The RNA is less stable than the DNA. And SARS cove 2, the virus responsible for the pandemic that we’re all familiar with or at least have heard about at this point, is an RNA virus. Mhm. So, what else do we know about the basic biology of this virus? Let’s maybe walk people through before we get into the origins and where it’s going. Let’s walk people through how the how this particular virus actually infects cells. what are some of the major steps and some of the key molecular players that allowed this virus to actually get inside of our cells? So, this SARS COV 2 is a corona virus. Uh the the story behind the name corona virus comes from the first time it was visualized under electron microscope. So the first time a scientist looked at it, she saw this ring, this halo like shape with these little balls surrounding the the virus and she thought it looked like a a corona, like a a solar corona, like the sun’s corona. So um that’s how the name came about. She called it the corona virus. And so now we know that those those little balls that surround the outside of the virus, those are spikes. They’re now called spike proteins. So they they stick out of the virus of its uh membrane envelope and um they their job is to latch onto a whole cell. So onto in in this case a human host cell although it can be any animal or host or bird even uh their cell and it latches onto a specific protein that sticks out of your cell and that way the virus knows this is the host cell that can make more copies of me. And once that happens, it under goes cleavage and it fuses the the pro the virus fuses with your cell and its genome the RNA genome in this case is released into your cell and then from there the cell can read that blueprints of the virus and and it gets hijacked and it starts making thousands and millions of copies of of the virus. I see. So these new vaccines that people have been hearing about, they are at least some of them, the mRNA vaccines, it’s sort of like it has to do with that spike protein that’s on the outside of the viral particle. It it makes your body make that spike protein and that’s what’s actually being recognized by your immune system in order for you to learn how to combat the disease. Is that correct? Yes. And and most of the vaccines in play right now are spike vaccines. So they don’t encode the entire uh virus. There’s no need to because uh a good portion of the antibodies that are raised in each person when you get naturally infected with SARS virus is against the spike. Uh so there’s no need to give everyone like full virus. You just need to take the part that elicits the most antibodies and and then you and you inoculate people with that. So this virus is spherical. It’s basically like a ball and on the outside of the ball you’ve got these spike proteins and the spike proteins are like the key key thing for how this virus actually gets into our cells. And so when we train our immune systems either through a natural infection or through vaccination, we’re creating antibodies that are sticking to the spike protein and basically preventing it from recognizing our own cells. Is that accurate? Yes. So not just that, they can also detect cells that have been infected. M so cells that have been infected sometimes display these spike proteins on the surface uh and and if your immune system recognizes these infected cells or even all the all the viruses they’re free floating in your system then they can take them down. Interesting. So it’s an RNA virus. The spike protein is how it gets into our cells. Thankfully we have vaccines developed that that seem to be quite effective. And one of the things that people have been talking about for a while is where this virus actually came from. Where in the world did it originate? And how exactly did it evolve? And so I want you to lay out for everyone a couple of things to start out with. One, what are the major hypotheses that are out there that could explain how this virus originated? And is it even important for us to worry about where it came from in the first place? Couldn’t someone say, “Well, it’s already here. it’s already a problem. Maybe we should just keep focused on the new variants and we don’t have to worry about exactly where it came from. I’ll I’ll answer that in reverse order. So, why is it important to to find out where this came from? And it’s very surprising how many people are not interested in where it came from. They’re like, “It’s here to stay.” Even scientists, even a lot of scientists I’ve talked to or heard on podcasts, they say, “Why should we care where where this came from? It’s already here.” Well, the the reason is that it’s only by knowing how this came about that we can prevent another pandemic from happening or another outbreak of a similar type of virus. So, the way that you prevent against different emergence scenarios are different. So, if it came from wildlife, then you have to think about shutting down some of these uh wildlife traits or uh environmental destruction or habitat invasion. uh if it came from a research laboratory or from field work then you have to temp down on those activities or at least set more regulations in place. Uh if it came through the frozen food like cold chain supply as as as some experts are willing to consider then then you have to think about what to do about the frozen foods uh trade. I think that that last one is is a little bit out there. Yeah. So, so it sounded like you basically laid out some of the major hypotheses for for where these can come from, but could you just reiterate what those are? Yes. So, in terms of uh a complete 100% natural spillover with nothing to do with research activities or or laboratories, uh there are there two ways to split at least at least one of them is is direct from the reservoir. So from from the reservoir to humans. So the reservoir in the case of SARS viruses are bats. So in this case we’ll be talking about the direct transmission of the virus from bats to humans. Uh and bats are well known. They’ve been characterized over the last decade and more to carry almost two decades actually to to carry these uh corona viruses amongst one but many other types of viruses too like Ebola. Uh yeah and and so they they all uh depending on the location bats carry different uh types of these virus and and they know that the bats down in South China and extending down into Southeast Asia have these uh SARS 2 like viruses. So this is like a thousand kilometers away from Wuhan city which is all the way up in central China. Um the second scenario for for natural spillover is when you have an intermediate host. So it doesn’t go from bats directly to humans. It goes through something like a civid cat like for SARS one or through uh pengalins as been suggested for this or or mink which we’ve seen uh there have been mink farm outbreaks of of covid-19 um and then it jumps into humans. The reason why the intermediate host is important is because uh there has been almost no documented instance of assass jumping from bats to humans because bats are really different from humans in terms of the receptors on our cells that are the things that are bound by the spike also in terms of our biology. So, so a lot of scientists think that it has to pass through an intermediate host something that’s more similar to humans. I see. So hypothesis one is the virus comes directly to humans from another animal. Hypothesis two is it comes to humans from an animal that got it from another animal. And the idea there is it needs to go from something like a bat to something that’s more biologically similar to a human before the virus is in a position to then evolve the ability to infect a human. Mhm. And then hypothesis number three. Uh that’s the the lab leak hypothesis. But I think this this hypothesis also has several different uh pathways by which it could be true. So unfortunately the most popular version of the lab leak hypothesis is one that involves lab engineering. So genetic engineering of the virus. So a lot of people when they hear lab leak they immediately think it was genetically engineered. But this is not true. So you don’t have to genetically engineer a pathogen that leaks from a lab. In fact, it could be a natural virus that was collected in nature, brought back to the lab in a city and just grown up in cells and leaked out. Um, another way is also that you’ve got these dozens and dozens of scientists around the world going out into these very remote places and sampling tens and th tens of thousands of animals. So there’s a chance that during this process they get infected and they bring that back into the city. And I consider that also a lab leak, a lab related leak because it’s coming from laboratory personnel doing their work. Yes. So if if you didn’t have these research activities ongoing, then it wouldn’t have happened. Mhm. So let’s take these one at a time. So when we talk about the zunotic origin of a virus, that means that we’re getting a virus that comes into humans either directly or indirectly from some reservoir species that was the source of it. So maybe it goes directly from species one to humans. That was your first hypothesis you laid out or a hypothesis that you laid out. The second version of that is it goes from one species to another species which is more similar to human and then to humans. Can you just unpack a little bit how common is is it for viruses to go from one species to another? Is this relatively rare? Is it relatively common? And what are some of the key species people have been talking about with respect to SARS cove 2? So it’s happening all the time. So spill over from spe across different species is happening all the time. Like pathogens are opportunistic, right? So they they don’t they don’t show any uh fidelity to a particular host. If they have the chance to jump, they they will try it. But whether they’re successful is is a entirely different story. So a lot of people somehow have the impression that, you know, they could go into a bad cave and immediately get infected and then cause an outbreak. That’s not very common. So, uh, even as recently as two months before, at least two or three months before CO actually broke out in Wuhan city, the scientists who were studying this in Wuhan published a paper saying that this type of spill over of SARS viruses from bats into into humans, no matter directly or indirectly was rare. So, let’s talk about the areas directly in in proximity to these caves where SARS virus is found. they still said that that type of spillover was rare. So there’s some reasons for this. So even if a bad virus somehow makes it into humans and gets you sick, it doesn’t mean that it’s suddenly very good at transmitting between you and your friends and family. So it still has a huge hurdle to get over. Mhm. So is that simply because the virus is adapted to being inside of a bat body? It’s not really adapted very well to a human body. So it’s unlikely to be able to do all of those things. Yes. So there are many steps that the virus has to get over in order to become a fullyfledged like pandemic pathogen. So uh it has to figure out how to infect different cells in your body to cause like a spreadable transmissible disease. Uh it has to figure out how to get from you to another human. So uh you know whether it’s by surfaces which is apparently very rare for COVID 19. Someone estimated like only one in 10,000 CO patients get it by touching a commonly used surface. Uh or it has to learn how to to to diffuse through the air or or through like spit or like sneezing and coughing. Mhm. Okay. So, zunotic diseases, the the hopping of a virus from one host species to another is actually very common, but there’s several steps that need to happen that the virus needs to accomplish before it becomes successful at spreading through a second type of species. Yes. And at a at a efficiency like high enough to cause a pandemic. Mhm. And in general, it sounds like bad. It certainly seems to the uh person who’s not educated in this that whenever you you talk about this type of thing, bats seem to come up a lot. Like are bats a particular a particularly good reservoir for different types of viruses or is that just is it actually not as common for the reservoir of species to be a bat as as maybe one would think from listening to the media? No, they they are very common reservoir for different viruses. Um and I have to say that I’m not an expert in this field. So it’s something that I I started studying and reading about very extensively about a year ago because again my specialty is in genetic engineering and gene therapy. So but the literature on this is just immense and it’s incredibly interesting like I I love reading all these papers especially about the researchers who study bats. There’s even one professor at the broad who who studies this and and so uh surprisingly they are not that closely related to rodents which was another thing that surprised me because at first I think of bats as like flying rats but they they’re not they’re they’re way further diverg from from humans than than uh rat. Yeah. Yeah. Many many millions of years ago. So they’re they’re very different from us in terms of their biology. different enough that that’s that’s the reason you were saying earlier that it’s uncommon for viruses to go directly from a bat to a human. Yes. Yes. Um and and uh bats their biology is really different. So some scientists have speculated that it’s because of their ability to fly. Their bodies generate such high temperatures that they’ve evolved to be able to withstand that kind of temperature. Um and their immune systems have also evolved to stand that kind of temperature. And so for some reason or other, this setup in bats’s biology allows them to carry many different types of viruses without dying. So a lot of the viruses that somehow become quite lethal in humans, bats can carry them, no big deal. And they can carry multiple ones of them. So in a sense, they’re like this reservoir where these viruses can recombine with each other and steal parts from each other. Okay? Okay, so for whatever reason, they are able to tolerate not only many different viruses one at a time, but actually multiple viruses at the same time. And those viruses can like recombine and mix with each other to create new types of viruses. What about penglins? You mentioned penglins a lot of people don’t even know what a penglin is. So what is a penglin and why were penglins in the news so much this past year? Yeah, so penglins are these scaly creatures. uh the their outer shell is made of these nail- like substances. So it’s like your nails but uh they cover the entire body of the pengalin almost and so they use it as a defense mechanism if if they’re attacked by like a a larger animal like a lion in Africa or something like they curl up into this ball and they become this this shell. So it’s imagine if you’re covered by huge pieces of nails. And so they they are very highly sought after for traditional medicine in in Asia unfortunately. And the illegal trade of penglins uh bringing them up from Southeast Asia, from Malaysia for example, or from Africa into China or Vietnam is is very high. So it’s it’s like worth like I think millions of dollars every year. Um and and so the reason why it uh became a suspect for being the intermediate host of SARS 2 is because a string of papers came out around the same time in February 2020 all claiming that they had found a penglin corona virus in smuggled penglins that they caught that they intercepted in China that this corona virus shed a very similar part of the spike to SARS 2 the CO 19 virus. Okay, so there were some papers that came out last year. They found a virus, a corona virus inside of these smuggled penguins and it looked apparently a lot like the SARS CO 2 virus. So that’s some evidence potentially that maybe this was our candidate for the species from which SARS cove 2 hopped from. Was there anything what is your interpretation of the data that was behind that? It wasn’t the finding of the the spike similarity that that surprised me so much as the fact that I later discovered and and confirmed with my c-orker uh Shing Hi Jan who who just got his PhD in evolutionary biology at the University of British Columbia. Uh we found that these papers were all describing the same batch of confiscated pengalins in Guangong province in China. So it’s only that a pangala cor panggalin corona virus that has that highly identical part of the spike to saskov 2. And so that finding was surprising to to us because some of these groups of authors knew about each other. In fact they all drew from the same well of data and and the smuggled batch of pengalins. So that was I think at least mind-blowing for for us. Why why exactly? I mean, if if I mean, they’re just working from the same pool of data, why would that be unusual? They they didn’t cross-sight each other. So, I see to to lay reader, if you saw these four or five papers that came out all at the same time. So, actually, four of them were preprinted within 3 days, February 18 to February 20. So, if you read all these individually, you wouldn’t have connected the dots and been like, “Oh, they’re all actually describing the same virus.” I see. You would have thought they found four different batches of I see. So it’s four separate studies that come out at the same time and you would have assumed that they’re working from four different batches because otherwise uh if they were if they were working from the same batch and they were communicating with each other they would have cited each other but they did not do that. Yes. And you know someone could say that maybe they didn’t know about each other but actually they did they did know about each other. At least uh the two published in nature knew about each other. Uh the n one of the nature papers knew about the one in plus pathogens know about how do you know that? So uh it’s by tracing the authorship of the papers. So some of them share co-authors. They were preprinted on the same day. Uh they uh drew from the same data set which some of the authors the shared authors had published before in October 2019. Um and later when this uh organization called US right to know started intervening in this matter they managed to uh foyer some of these emails and published some of these emails and they showed that these authors knew about each other. So okay so so there’s there’s actually a paper trail where they were communicating. Yes. So, so I imagine you know one of the things that was happening that’s still happening just because of the nature of the pandemic is everything has been sort of accelerated and that includes science right so like there’s many many studies going on we have to get the information as fast as possible so we can’t necessarily wait for all of the normal peerre mechanisms to take weeks and months and months um for this new information to come out was there anything so that’s and that’s reasonable like we we need this knowledge quickly Was there anything else unusual about about these studies in terms of how quickly they came out or or what the underlying data actually looked like? Yes. So actually many of these studies didn’t publish the data. So they published the paper without releasing the data. You had to chase down the authors for the data. So without that data you couldn’t reproduce their work. You couldn’t create the genome that they claimed to have published. They they claim to have assembled the genome. uh and these genomes the sequences along the 2D sequences were being used by dozens of scientists around the world immediately because we were also excited to analyze these virus genomes. Uh very few people actually try to independently reproduce the work. So the moment you try to independently reproduce the work that’s when you notice that there’s some discrepancies here. There are some very severe scientific issues with the two papers that that pulled out the penglin genome. Um till today the plus pathogens paper the authors have not been able to produce the gene uh the data underlying the genome that they claim to have assembled. Uh the editor knows about it. Plus pathogen knows about it. They’ve known about it since May 2020. Until now there’s been no change on that paper. There’s been no correction, no notice of concern for the Nature paper. They did eventually put up an editor’s note. So if you go to check out this uh sea and al x i ao at nature paper on penglins, you see that the editors have put up a note saying that they’ve been alerted to issues and are investigating. Mhm. So this would be it, correct me if I’m wrong, it would be very unusual for someone doing this type of research to not include the underlying genome sequences of the organism in question. Sometimes scientists are a bit sloppy. So they can be late in in publishing or releasing it. But if you cannot produce it for months and months and months or you can’t explain why your data looks a lot like the data in another paper without attributing it, then it’s uh it’s a problem. At the very least, it’s very weird. Is that fair? Very weird and I think unacceptable. Yeah. Yeah. I mean, especially for something this important and high-profile, you think. Yeah. And it’s not like, right, it’s not like a virus genome is a gigantic thing that we have no idea how to deal with. Like this is people know how to assemble these genomes and and publish this stuff, right? Yeah. For Shing, he can do it in like five minutes or like less than an hour. He can assemble a whole like virus genome if you give him the raw data. It’s more difficult for me because that’s not my specialty. Uh the So what you said earlier about peer review happening very fast because these are pandemic papers. I’m I’m on board with that. In fact, I think peer review can happen a lot faster than it is currently on normally it takes months or sometimes years at some journals. But if you’re going to do that, if you’re going to speed through peer review, make the peer review open. So publish the contents of the review, you don’t have to publish who reviewed it so that people can judge for themselves like was this paper properly peer reviewed and what did the peer reviewers say? Did they find any problems of this paper and were those fixed? And more than that, if you know that this problem of paper correct it immediately, why has it been left to sit for almost a year now? So both nature and plus pathogens knew were alerted to these issues and it took them a while to investigate. But they have known for months now that the data cannot be found or that they cannot explain some of these to me unacceptable scientific uh errors. So okay yeah those corrections have to be fast too because it’s getting propagated. Yeah. Yeah. Yeah. It’s getting propagated and and people just take it as truth because it’s in nature after all. Exactly. Interesting. Yeah. I had a whole other discussion about publishing recently. And I don’t want to get too deep into that but you know one of the things that you cited here was that we don’t normally publish the actual content of the peer review that happens for papers. And so there’s actually no way to judge how rigorous or how sloppy the peer review process itself was for any given paper. Yes. So I’ve done quite a bit of peer reviewing too. Sometimes not under my own name. I’d say not not so far in my current lab. My school wise is really good. Uh but the they’re ghost peer reviewers. So sometimes the PIs are too busy which is natural and they they pass it down to a traininee like even a grad student or postto and and they they are the ghost peer reviewer. So, these guys, they get their reviews in under the PI’s name. Uh, and I’ve seen during peer reviewing that some peer reviews can be quite sloppy. Like, I literally saw one this in the past year that say just just fix this single grammatical error and you’re good to go. And I had provided them like a whole like multiple points of of constructive advice to change the paper. Yeah. Interesting. So there were some weird things that you and others noticed about some of these early papers and these early papers had to do with the potential zooonautic origin of SARS cove 2. What how would you describe so the last few months like in terms of you know was was it described as like this virus this virus jumped to us from a penguin or a bat either directly or indirectly and that’s the way it almost certainly happened. Has it has it been described like that or has it been have there been multiple competing hypotheses the whole time? There have been multiple hypotheses the whole time, but the lab origins hypothesis has been cast as a conspiracy since early 2020, right? And it’s only recently started to become seen as something we should consider scientifically as a plausible hypothesis of how this virus originated. You have a pre-print out right now called SARS Cove 2 is well adapted for humans. So I, you know, as I understand it, what you did is you looked at certain aspects of the genetics of this virus and you noticed some patterns that were there or some patterns that were not there and you you were able to compare this to other viruses that we know got to humans from animals and there were some differences there. So can you kind of explain the point of that preprint and what your basic finding was? Yeah, the preprint was a collaboration between mainly me and and Shing. Hey John. Um, and and my supervisor Ben also joined the paper because he con like contributed a lot and helped us look over the paper and go through the analysis and and so what we did there was to compare SARS 2 to SARS one. The reason why we picked SARS one is because it has a very similar emergence story to SARS 2. They’re both the most highly related pandemic pathogens like outbreak pathogens like SARS one and SARS 2. SAS 2 was named SARS 2 because it’s highly related SARS one. Uh they both broke up in a Chinese city in the winter uh at a market like a market was involved in the in the origin story. Um they both bind the same receptor A2 in in humans. Uh they both are resp respiratory disease. They they both uh spread well uh indoors and through the air. Uh they they cause similar symptoms not not the same. Of course there are many distinctions between the two. But in terms of the rest of the viruses we know about that have infected humans so far SARS one is the closest to SARS 2. We had looked at some other viruses too. We looked at M. But M has a very complicated sample history and very different origin story. So it involves like people living in rural areas not in a city that doesn’t involve any markets. It’s involves camels instead of uh civic cats for example or market animals. Uh it was sporadic. There have been multiple spillovers of M. Um and again it’s very difficult to compare those two because they don’t even use the same receptor. uh and the setting is totally different. So we considered some other viruses too but it was clear that SARS one was the standard to compare SARS 2 and how can can you give a a brief summary of the SARS one story like when did that happen and what do we know about where that virus came from? Yeah. So the first cases of SARS 2 were detected in January of 2003. So of SARS one sorry SARS one. Yeah. Yeah, that’s one. Yeah. And then uh the the clinics at the time noticed that there was a strange pneumonia going around. Uh at the time there wasn’t this kind of technology to quickly sequence the genome of a of a virus or a pathogen. So what they did was they started contact tracing in January and they found cases going back to November that that were from outside of that city. In fact where they did where they had those January cases uh by March it had become a pandemic like pathogen. it had had a super spreader event. Uh and so uh that’s when things got really real. So that’s when uh they started to track the index cases. They found that the index cases were most likely to be food handlers. Uh so they uh the investigators, the Chinese scientists at the time thought we should go to the markets where they’re selling these live animals and see whether it’s there, whether the virus is there. They had uh isolated it in March 2003. So they went to these markets uh in May 2003 and they collected animal samples and the majority of them were SARS one positive in animals. So they had like civid cats, a raccoon dog and a badger. Uh and they u from comparing the SARS one genomes in those from those animals versus the human SARS one genomes they saw already dozens of differences. So they saw uh functional differences. So changes in the protein not just the RNA changes in the protein even dozens within the spike alone within the spike gene alone. So uh and from that they at at the time they weren’t even sure whether these were intermediate host but they they realized this was spreading out of markets and then they uh in May of 2003 they started collecting samples from hundreds of market animal sellers. They collected uh blood samples also from healthcare workers who’ve been exposed to SAS patients and things they didn’t control. And to their surprise, they found that like a whopping 20 to 40% of the animal traders already had antibodies despite not being SARS patients. So these these uh people who were selling the live animals at the markets, they already had antibodies and a large number of them had antibodies to to SARS viruses. So then they realized that this this is spilling over from animals into humans quite a bit in in in in that province uh in Guangong. And so um they they the whole pandemic of SARS one was able to be tempted down by the summer. So by August by July August it was it was under control like no no more cases. Uh but then it spilled over a few times from from labs actually. So the labs started studying SAS one and it’s it spilled it leaked out the lab into the human community. One time in Singapore, one time in Taiwan and at least two times in Beijing um and then it spilled over again naturally. So in the winter of 2003 it spilled over again from animals into humans uh in GuangDong again. So uh this time the index patient was a waitress and upon diagnosing her the Chinese authorities were already on high alert. So when they when they diagnosed her as positive for SARS they went straight to her workplace. The waitress actually said no I don’t have animals at my restaurant but they didn’t believe her. They just went straight to her workplace. And true to what they expected there were civic cats in the restaurant. They sampled those. They sampled everyone in the restaurant. For example, another index case was a person that dying in the restaurant and they found antibodies in in the in the restaurant workers and also viruses from the from the civet cats and again they they looked more like animal SARS virus than human SARS virus. So this was caught quite early before the virus had a chance to to mutate and and become more transmissible. So there’s a there’s a bunch of people that were infected and they made antibodies, so their immune system detected the infection and responded to it, but they weren’t necessarily symptomatic or necessarily spreading it around much. Is that related to what you were saying earlier? Does that mean like because it came from an animal, the virus can infect a human, but it’s not like optimized for making the human sick and then transmitting to other humans or how do you think about that? Yeah, one of those features is the ability to bind uh well to the human receptor which I which I mentioned earlier is called A2. So A2 also exists in bats and intermediate host. So you can think of how this virus has to go from bats to intermediate host to humans. It has to change its spike so that it can change from binding A2 in bats to bind the A2 in the intermediate host which is closer to humans and then from that change to bind the human A2. So it it has to take multiple steps to become like a human optimized version. And so what does it mean in your paper when you say that SARS cove 2 is well adapted for humans? What’s the importance of that statement and how do you know that? Yeah. So that statement for lay person, it means that by the time we detected this virus in December 2019, it was already good to go. So it it did not it didn’t need any more dramatic changes in its genome or in its spike to become better at transmitting between humans. And some people even scientists have said like duh isn’t it obvious just from the the arot you can tell that it’s a really highly transmissible virus. I’m like, yes, but you need to kind of show the working like show show the data. And so when we compare to the SARS one in the first two to three months of it, you can see that the SARS one virus was picking up like dozens like tens of mutations in in that in that first two months. Uh but for SARS 2, there’s like barely anything and it was more similar to the late phase, the late stage SARS one by time it already picked up all these mutations that made it better at binding human A2. I see. So So let me make sure I’m getting this. So with SARS one, the idea is the virus starts infecting human beings, but it’s not optimized to transmit from human to human. So it has to do some evolution. So it’s accumulating different mutations in its genome that are allowing it to more effectively infect a human host. And so when you go from the early to the late stage of that first epidemic, you see that you go from like more genetic diversity in the virus as it’s adapting and trying to get the right mutations and then by the end it’s sort of found the right mutations to be optimized for a human host and so it’s more genetically homogeneous. Yeah. I also want to press this point is that the viruses are always mutating. So it’s not like they stop mutating the moment they’re great. It’s you can imagine like millions to trillions of them like inside inside your body like fighting to be the fittest and the best the best transmissible one gets into the next person. So and if that if that process keeps uh repeating itself you you get these uh varants of the virus that accumulated they build up different mutations that are useful. U but when when there isn’t that when you’ve hit a ceiling in terms of how many more steps you can take to get better at transmitting then you don’t see this accumulation. You you do You still see mutation. You still see different variants emerging, but you don’t see that rapid accumulation of dozens of mutations. I see. So, so you’re saying that for SARS Cove 2 at the early parts of this current pandemic, it looked like it was had already sort of accumulated all the mutations it it needed to be very good at transmitting. Yeah. And and this is this is not like some out there or like uh I think naive point of view. Even top like biologists and evolutionary biologists, this is a principle that they’ve been publishing papers on for years before this. In the WIV, the Wuhan Institute of Biologies paper that came out in January 2020 in in nature, they also said that in their paper they they said it looks like this virus is getting more human transmissible. And when I read that, I was like, wait, how did you know that you’ve only sequenced a few of the index patients? Like you haven’t seen like what makes you think it’s getting more human transmissible? Interesting. Uh interesting. Let’s come back to that. Um so okay. Anyways, so SARS CO 2 is well adapted for humans. The interpretation of that that that we’ve been discussing is essentially this virus looked like it was ready to go on day one. So either either it somehow already explored the mutational landscape that it needed to because it was maybe circulating undetected for longer than we think or it was already adapted to humans for some other reason. Yeah. One other possibility is that it was in a intermediate animal that was very similar to humans. Right. So actually a lot of scientists were trying to see if monkeys or primates were being sold at the market. There are no records of that. There no live monkeys as far as we can tell like being recently in in 2019 being sold at the market. But that’s also a possibility that it was already in a very human-like host and had these good mutations for binding to a human A2 receptor. So, where what what would you say is the current state of, you know, when we’re thinking about these wet markets in China and elsewhere that have so many of these different animal species? Um, these are often described, at least in the news, as I’ve read it, as, you know, these are really good petri dishes because you’ve got so many species that are potentially harboring so many different viruses and they’re all in close contact with humans and and each other, so there’s lots of opportunities for things to hop. what’s the current state of evidence for the likelihood that this particular virus got to us that way? So at the beginning of of the pandemic in January, the Chinese government announced that most likely it came from that Juan Seafood Market in Wuhan city. So they announced it. So then everyone just thought it was a rehash of SARS one. So, you know, two SARS viruses, the same thing happened. And then there was this wave of uh racism that went around of people showing like videos of Chinese people eating bats, which turned out to not even be in Wuhan City. Um and and so people bought the idea. They bought it really quickly. It wasn’t until May 2020 that the Chinese CDC director reversed stance. He he he told the Chinese state media, he said, “Looks like it wasn’t the market. The market was just a victim. The virus had existed long before the market. How do we know that? Oh, uh, yeah, the genetic data doesn’t point to it. So, they tested hundreds of animals at the market, tested hundreds of environmental samples, or surfaces, and they found that the genetic the only samples that were positive for genetic material of the virus were the environmental samples. And they came from the parts that weren’t even selling like live like life mammals or or host that susceptible to uh SARS 2 transmission. Um and those sequences were identical to the human version. So thinking back to SARS one, when you looked at those animals that were positive for the virus, they had very different uh genotypes. So especially in the spike, so they uh it showed that this virus had spilled over from an animal and was accumulating mutations to get better at infecting humans. But in SARS 2, the sequences were the same. So it was more indicative of a human super spreader event. So someone had come in and coughed on the surface or something and and there was a cluster of cases that we know about at the Han seafood market. So most likely it was a later cluster of people a super spreader event. Okay. And then let’s talk about the Wuhan Institute of Viology. So for those that are unfamiliar, a where is Wuhan in China geographically? Let’s just remind people of that because it’s easy to forget. And what is the Wuhan Institute of Urology? What type of research is done there? And is this something that’s unique to that area or is this type of research going on in many different places? Yeah. Uh so Wuhan is in central China. It’s a thousand kilometers away from the silo or zone and where people have found SARS to like viruses. That whole lineage of viruses is nowhere near is also a very modern city. If you Google pictures of it, you can tell right away. It’s much more modern than actually a lot of US cities. Uh so it’s not a place where the bats flying over and people are getting sir sprinkle on them. Uh the WIV the Institute of Biology in Wuhan is a top class like uh virus institute. So it’s uh the first BSL 4 that was built in China. Um although they were doing SARS work in the BSL 4, they hadn’t received approval yet. So all the SARS work they were doing was done at BSL 2 and three. What is what is that nomenclature? BSL 2 and four. Oh uh yeah. So these are biosafety levels. They uh refer to increasing it increases with the number increasing levels of safety restrictions and regulations required to work with the pathogens in in in each level. So like uh BSL 2 is actually quite relaxed. So if you if you if you seen some BSL2 labs like sometimes people don’t even wear gloves although they’re supposed to. Not to mention lab coats and goggles. BSL3 is a bit more is a bigger step up. So you have to wear protective much more PPE. Yeah. So what’s the highest? Is it is it four? Yes, the highest is four. And so what if in a normal BSL4 lab, what types of things would they be work? What types of biological agents would they be working with? And just give people a sense for like the level of security that would be expected for that work. So the level of security for that is a lot higher but it’s not impenetrable. So just for context like the one of the lab leaks of SARS one came from a BSL4 lab and it was a human error because the person tried to clean up the waste uh fluids without gloves on. I know a lot of people like why would he do that? Sometimes when you’re cleaning waste from these like they’ve already gone through bleaching and things like that. you you kind of don’t have don’t don’t have as high a level of uh danger of or fear. Um but that’s what I mean is that even at a very high BS4 level where you have this inflatable suits with like air pressure and everything like sometimes you it doesn’t mean that it’s not prone to human and technical error. So uh there’s this uh reporter journalist like amazing journalist in the US Allison Young and she’s been covering so many of these BSL4 uh accidents uh that there are many but they don’t get reported in the news. A lot of the institutes that have these accidents want to keep it on the down low. They want to advertise that oops we had like five leaks this year. Um, and it can be anything like a door not working or like a suit being punctured and not being detected that there’s a puncture in them. So, there’s still many ways for accidents to happen. I see. So, BSL4 is mostly work with biological agents that are or could plausibly become infectious. Is that basically the rule? uh those are also as BSR3 but the levels are also subject to human judgment right so so now after after co then SARS work got upgraded to BSL4 so now you’re not allowed to just play around at BSL2 like they used to uh in the past years before CO um but yeah generally BSL4 are the top most scariest uh viruses that can are highly transmissible and highly deadly um so what what kind of research was going on or is going on there around coronavirus biology stuff. Yeah. So, arguably the the most prolific SARS research lab uh in China was at the WIV. So, this was led by a professor called Xi Jungli and she the reason why she’s so famous and why she’s in charge of all this work is because she was one of the scientific heroes who traced the origins of SARS one. So, back when SARS one had leaked they they kind of knew that there was an intermediate host, right? So they thought yeah the civic cats they’re giving it to us but where did the civic cats get it from? They checked all the farms that were supplying these markets and there was nothing. So none of these farms had sick civic cats with SARS. So they thought where are these civic cats getting the virus from? uh they convened a team of scientists which include uh uh it includes uh Xi Jang Lee and also Peter Dashak who is the president of the Eco Health Alliance out here based in New York uh and other international parties as well and they all went out looking for the reservoir and one of them Linfa Wang who is based in Singapore now he he said let’s check the bats and so they they found they went to check the bats and they found very similar relatives to Saras in bats in Yunan which is another southern Chinese uh province I see. And people have been talking about gain of function research. What what is gain of function research? Yeah. So gain of function research is a very broad um um and and there’s a lot of controversy swirling around it because it was uh some people describe it as a ban, but it was just a pause on funding uh during the Obama uh era. uh this was in 2014 that the pause on funding was announced. So they said any previously funded research is fine but they asked the scientists to voluntarily pause their research. You can imagine how a lot of scientists would be like no I’m not going to voluntarily pause my research. So this pause on funding only affected future funding decisions like future federal funding decisions. It didn’t mean that private parties had to stop funding this sort of research either. And more importantly, this this gain of function umbrella didn’t apply to naturally found viruses. So the type of work that was done at the WIV where they were going out into nature over the past decade plus and sampling tens of thousands of bats and wild animals and also humans, these were all counted as natural pathogens. So they didn’t fall under this gain of function research of concern pause on funding and they were already funded before the pause on funding. So the it’s it’s not like they were recklessly doing dangerous work or outsourcing it from US to China. Mhm. But what exactly does it mean for research to be g what does gain of function mean? Yeah. Uh gain of function means just getting a new function in your in your organism. But the problem is that almost every life sciences experiment is a gain or loss or perturbation of function. You you move one gene from organism A to organism B, it’s a gain of function. Uh so the the wording in this pause on funding and the the downstream review process was that this gain of function had to result in increased transmissibility of the pathogen or increased deadliness. So unless you could unless you could reason like demonstrate that this work will create a virus that was more transmissible or more rural then it didn’t fall under this umbrella pause on funding. Yeah. So gain of re gain of function research is is quite a vague term. If you’re changing a biological agent so that it has a property it didn’t have before. That’s gain of function. But that could be quite innocuous um or it could be quite serious and it only counts in this more serious sense if you are giving it a function that’s clearly increasing things like transmissibility. Yes. And and the wording in the in the pause on funding was also very flexible. So they said that if if you talk to your funer, the person who’s managing your funds, and you say, “I don’t think this is going to make it more transmissible.” That was sufficient. You could get around the review requirement because they would say, “Yeah, I talked to the scientists and they said it wasn’t going to be more transmissible.” So what would be I mean, at least half of this question might sound obvious, but let’s just say it anyway. So when you’re doing gain of function research and you’re giving viruses, you’re potentially increasing their transmissibility or their severity, what are the risks and benefits of doing that type of research and and how common is it would you say? So I’m a complete newcomer to this because I I don’t don’t work with pathogens. I don’t work with things that cause severe disease. Uh but from what I’ve read on this gain of function debate which was quite fierce and spanning several years um the people who were pro- gain of function research said this is the only way we can predict like we can simulate it in the lab to see what the pandemic pathogen is like so that we can come up with ways to to mitigate a future pandemic. M but the people who were against this gain of function research or at least wanted more regulations and more review processes in place they said that you’re just creating a novel risk by ramping up this type of research around the world you you’re creating all these pandemic pathogens around the world they could leak from labs and then a real pandemic will happen. I see. So, so the basic idea is, oh well, if we do, if we do this gain of function research that gives a virus or some other bug a new property, we’re sort of uh preemptively able to help protect ourselves against that new version before it actually evolves out in the real world. We can identify like where where the most um likely areas are for some highly virilent version of a virus or something to evolve and preemptively try and take care of that. And then the flip side as you said would be that well in doing that you’re actually creating that more virilent version and that is actually a risk in case it does somehow get out. Yes. And I I think it’s worthwhile now to have a scientific forum looking back at this type of research over the past decade for example and and see like did the promises hold true. So did we actually learn a lot from from gain of function research that helped us to fight this pandemic? I don’t think it’s zero, but was it worth the risk? And and part of that calculation has to factor in did this pandemic come from a lab. So, one thing I want to summarize for people is you you s you aren’t you aren’t saying this was a lab leak. You’re just saying this is a possibility. Transmission from an animal is also a possibility and we need to understand which was true. So what would be like the implications for how like let’s let’s just say like we learn it’s one or the other. We come up with definitive evidence and everyone agrees. What would be the implications if it’s a zunotic transmission versus if it was a lab leak in terms of how we conduct ourselves at the societal level moving forward? So a lot of scientists and the public have already decided or perceived that this is from nature. So then a lot of scientists have advocated for increased virus sampling, increased virus hunting and collection in the wild and more gain of function research because they think that we need to start preparing against more of these pandemic pathogens and bad threatening spill over anytime. Uh this is actually counterproductive if the pandemic came from a lab, right? Because you’re ramping up the exact activities that led to it emerging. Um if it came from a lab then we have to really sit down and be quite serious about this and and say like you know all this work this virus hunting work even if it’s not gain of function they were extremely well intentioned but it looks like we need to be safer we need to think about the amount of work we’re doing and where we’re doing it and how we’re doing it and and change that in the future so that this sort of pandemic doesn’t happen again. H so so it really is a trade-off. It’s not merely an academic kind of uh disagreement among intellectuals. I like the policy consequences could be quite large because if I heard you correctly, you know, if it was let’s just say it was a lab leak and it did not come from nature. You’re saying that, you know, if we if we act as if it did come from nature, we would actually we would invest and do the types of research that are going to make it more likely to happen again. We are investing in those research. So the NIH and NID have been investing more millions since the pandemic started in in this virus surveillance and hunting programs. I’m not saying it’s wrong at all. I think it’s good. I think it’s good to do it. But we just have to rethink how we’re doing it like because when you think about this nature things like how how do you bring the virus to a densely populated city like Wuhan and have it explode? It’s through the wildlife trade or something, right? So similarly if this is from nature by pasture lab the lab workers are bringing it back into densely populated cities where these BSL trees and falls are uh so humans are somehow bringing it from these remote extremely remote caves into places where it can ignite a wildfire pandemic. Yeah. And it’s presumably um fairly difficult to build a research institute like this out in the countryside just because nobody wants to work there. No one wants to work there. Wow. Yeah. Yeah. I think this is a point that’s somehow hard to communicate to the public that scientists are humans too. Yeah. It’s like we have families so they have kids like you don’t want your kid to just not go to school in like the top universities and things like that. So it’s there are many human factors in this. It’s not just a scientific cold bloodooded calculation. Interesting. So what can you talk a little bit about some of the new variants that have been emerging? Right. Right. So, people have been talking about new variants in the UK and South Africa. What What is a new variant exactly? And what do we know about these new variants in terms of what distinguishes them from their predecessors? So, I’m going to actually do a shout out to our browser cog. So, it’s CO and then CG.org. Uh it’s it’s the name is COVID genetics. uh and and using that you can track all these different variants and mutations around the world uh that have been the data has been deposited in the Jade uh database. So um using that you can see like where the UK variant has appeared in which countries and when exactly. So um these new variants I had to say that a lot of scientists already knew they were coming but it was difficult to persuade the public which was still reeling from the first and second waves of the pandemic like people didn’t want to believe that we had to watch out for these uh new emerging varants and and part of the reason was that this virus was so genetically stable in the first uh half a year even like we weren’t really seeing any changes so people thought that we could just fight it the same vaccines and same antibodies and then we’ll be done with it by by the end of 2021. Very few people wanted to think that we would have to keep updating our vaccines and therapies to fit new emerging variants and very few people thought there’d be 100 million cases 130 million cases today uh so far in total. Um so these new variants some people have speculated that top top experts have speculated and and been doing experiments to just to check whether they emerged in imunompromised patients. They’ve been trying to see whether these variants evolved not not to transmit better amongst humans so to say but to uh get around our immune response. So they call some of these variants uh immune escape variants. uh and some of the hints that pointed to that are that they they evade antibodies against the original version of the virus. So SARS 2 but the original version before these variants emerged. uh there’s this really fantastic uh nature paper where they they looked at an imuno compromised patient who was given a convolescent plasma over a long period of time and they tracked the evolution of the virus inside that patient uh using sequencing and and they showed that yes it was picking up like variant mutations of concern. So uh other other studies have been uh done but they haven’t seen something that similar. So uh these variants they they also appear in places where there’s a really very high case count. So lots of people have been infected. So the hypothesis is that it could be trying to reinfect people and we know that some of them like the South African variant can reinfect people who already had COVID before. So in this case uh my guess my informed guess and then the uh hypothesis by some experts are that these these variants emerged so that this viruses could reinfect people who already had SARS 2 before. Interesting. Do we know where those mutations are? Like are they in in components of the spike protein? They’re actually all over. So in this case, it’s difficult to tell which mutations are the important ones functionally versus which ones are just uh passengers. So like PE mutations you pick up on the way, but they it doesn’t matter if they’re there or not. Um and but we do know that some of them are functional. So they they allow the new variant to get around antibodies. Interesting. And you know, I’ve heard I have no idea if this is true, but I’ve heard it described that as you know, as the virus as a virus interacts with any given population over a longer and longer period of time that it tends to become less virilent over time because it’s actually counterproductive for a virus to be too deadly because it kills its own host. Is there any truth to that? And would we would we expect to see that with with this virus? Yes, that’s a that’s a common speculation and and I think there’s some circumstantial evidence in in some cases some specific viruses, but SARS 2 already was quite an attenuated virus and it it’s really sneaky. A lot of scientists have described it as like the trickiest like virus to deal with because it can spread pre-ymptomatically or asymptomatically. Lots of people have no severe symptoms. So, they’re still ready to go outside and party in a rave or like go to pub or like you know just or essential workers like they have no choice but to go to work. If if they’re not on their death beds, they will go to work. So then it just spreads like it’s already great like it’s it doesn’t need to become less deadly to to spread well. Um but it could be different for something that kills like half of the people it needs, right? Or M. Maybe if if there had been a larger M pandemic then we would see that happening. Uh and for SARS too in in the case of a virus like this uh the reason why some experts have said that that we would see less and less severe cases is not it’s not because the virus is mutating but because the human population is building up pre-existing immunity. So at some point like all of us almost all of us are going to have been exposed or vaccinated. So even if we see the deadliness over time the mortality decrease it’s not because the virus has mutated to become less deadly. It’s because we have built up like her immunity. Yeah. Her immunity. Um I think for some people that’s an intuitive concept but I’ve I’ve heard different things articulated about this in the media. For the sake of completeness, can you just describe the phenomenon of her immunity and how it works? Yeah. Yeah. And I think this really ties in with vaccines and how to think about it too. So some people they think that as long as I get the vaccine then I’m a superman or superwoman and I can go anywhere and do anything I want and I’ll never get infected or get sick. But that’s not true. So the the vaccine works differently in different people. It depending on your health status and your own unique biology, you elicit a different level of immunity. So most likely the vaccine makes the actual infection if you actually get infected it will make it less severe but it doesn’t mean that you can’t be infected again or that you won’t pass it to other people. So if if it’s just you who has gotten vaccinated but you go to a place where like co is rampant you you will still get sick. Uh so the idea of her immunity is that there are enough individuals in your community. So something numbers have been quoted like 70% but now they want 90%. Uh if like imagine 90% of the people around you have all been vaccinated. So the chances of a virus jumping in that community between people is much much really reduced compared to a place where only you are vaccinated that’s just jumping everywhere and and you will also probably get it if you hang around for too long. Are you surprised that we’ve gone as long as we have before this pandemic without seeing something happen at a global scale like this? Do you think it’s going to like in our lifetimes? How likely do you think it is that we’re going to see pandemics like this? Some of the scientists who have come up really strongly saying that this almost definitely was a natural uh spillover origin. They they also have said that we are entering a an era of pandemics. So this includes Dr. Fouchi as well. He says that just because human activities that invade natural habitats and and uh you know disrespect animals is on the rise that we should expect to see more spillover and more pandemics. Uh for me I think it’s true too and also because uh we are ramping up the amount of pathogen research being done worldwide. So China has announced that within four years from now they want to have a BSL 4 in every province and some of these provinces like Guangong they they even want to have like dozens of BSL trees across that province alone on top of the BSL4. So when you think of that much uh human activity that disrupts nature and also that much human activity creating pandemic pathogens in the lab and studying them or collecting them just just collecting them not even doing anything to them then the risk is rising on both sides. Mhm. How you know how common is a BSL4 lab? Are there just a few of these throughout the world or are they like at every major research university? Can you give people a sense for how how common these things are? So there are two biocurity experts uh Dr. Philippenos and and Gregory Cobblants. I think I’m saying that name a bit wrong. They are trying to map all the BSL4s right now. Uh there are many. They’re not that rare nowadays. Uh there’s one in Boston. So uh there several across the US too. I don’t know how many exactly there are. Um there are there are two in China right now that I know are operational. Um but other countries like once once they want to become a world leader in the sort of research they will want to build a BSL 4. So Singapore for example wants to build one in their in their island like right like 20 minutes drive away from the airport. So I think like it it’s not a rare situation. It’s not going to be a rare situation anymore. I see. So it’s not there aren’t dozens and dozens in every country now. There’s probably only a couple or a few but they’re becoming more common. Yes. And rapidly. So it’s not like 10 years later, it’s like in the next five years. Yeah. I mean your your description earlier of the tension here in terms of you know the importance of knowing whether you know the importance of knowing whether or not this is of zooonautic origin or a lab leak. I mean there really is a tension because I mean as you mentioned you know if it’s one versus the other it has almost opposite implications for what you might want to do to prevent more of this from happening. Yeah. It’s uh that’s an interesting conundrum to think about. Um one of the things that I came across that we didn’t talk about explicitly while I was reading about this is this virus called RATG-13. Mhm. Can you describe what that is and give people a give people a sense for what that is in comparison to some of the other candidate viruses for where SARS CO2 may have come from? So, RTG13 has its own very interesting backstory and I’m going to tell it. So, it relates to these very tragic cases of miners back in 2012. So, almost a decade ago. These were the Chinese miners. Yes. This was in Eunan, China uh in South China in the spillover zone of SARS viruses. Uh and so these six men got admitted to this uh specialized hospital in Kuning University. Uh and they all had this mysterious pneumonia. Um at the time they didn’t know what was giving them this pneumonia. The doctors just checked them all. They they had fevers, headaches, like chills like um low blood oxygen and that kind of thing. So something’s quite similar to to CO. The the older patients suffered a lot and passed away quicker. that the two so uh the two to be discharged the fastest were the youngest in their 30s from the hospital. Um but uh throughout this time period of the patients one of them was even discharged in September. So like more than 100 days after they had been first admitted in April or May of the year 2012. And so during this time they consulted the uh so-called Dr. Fouchi of China whose name is Dr. Chong Nanchan. And so he was a a hero from SARS one. He had helped to develop a treatment for SAS one and when he was called in to look at these miners after antifungals had failed. So at first they thought it was a cave disease like when you go into a cave you get infected by this fungus that’s in bat poop. Uh they thought it was that they tried all sorts of antifungals. It didn’t work. So then Chong Nanchan came in and he said go to that cave and get those bats and check them for SARS. Check these patients for SARS. And by the end of this whole episode, the doctor in charge who had overseen these cases wrote a medical thesis saying that these miners most likely had been sickened with a SARS like viruses from bats. But because Jungan Chan was only called in more than 2 months after these patients were admitted by this time the virus was gone. So when you get CO the virus sticks around for a short while it ravages your body and then it leaves you up to like any other infection that’s in your body. It doesn’t doesn’t stick around. you’re not too positive for like SARS after 2 months. Uh WIV was called in. So WIV got patient samples and they said they were positive for virus for antibodies IGM against virus but they didn’t say which virus but the thesis concluded it was SARS viruses. So after these cases top labs in China all went to that mine that same mine where the six men had worked to sample the bats and rats there for viruses. One of them even published in in Science magazine another prestigious uh journal saying that they found a different virus there but unlikely it was what affected those meds because they couldn’t culture they couldn’t uh make more copies of it in in human cells. Uh but in 2013 the WIV on on their fourth trip to this mine they found the first SARS virus and they published a small fragment of this in a 2016 paper. It was the only SARS virus known in the literature at that time from this mine where the miners had died from a SARS like illness. Uh and that fragment uh was under a different name. It was called 4991. So fast forward all the way out to 2019, December 2019, January 2020. W is looking at these sequences from CO patients the virus sequence. They check their database and they find the closest match is RATG13. So they didn’t make the connection that 4991 was RG13. Some internet sloops had to make that connection. They didn’t site their 2016 paper. They didn’t tell anyone about those miners from that cave where this sample had been collected from. So internet sloops had to connect all those dots. And by the end of it in November 2020, the WIV wrote an addendum to their nature paper confirming that yes, 4991 is the same sample as RTG13 and yes, these were collected from a cave where this minus had sickening with a pneumonia likely a virus induced pneumonia. Uh, and not just that, but they found eight other SARS viruses in this mine. They didn’t provide information on that on those eight other SARS viruses that were very closely related SARS 2. uh but in the addendum they contradicted the thesis and actually another thesis describing it miners. Those two thesis had said that those minors were positive and one of them said they were positive for SARS IGG antibodies but in this nature tended by the WIV they said that they checked these samples and there was no SARS in them. Wow. So what do you think um I mean what do are are you continuing to do any research related to this virus right now or what do you think what are people focused on in terms of of research on the origins of this virus? So I think that internet sl and and outsiders like me have have carried a lot of this research in the past year on our backs uh and and been properly ridiculed for it uh and and uh you know caught conspiracy theories and stuff. I think now it’s time to hand it off to the actual experts. I was very encouraged today to see that there’s a new uh CO uh what do they call it? I need to check it. It’s called CO CPG. Uh and I tweeted about it today. It’s it’s actually being led by by top scientists. So the the person who’s leading this commission was the 911 commission like exe executive and they have like all these top biologists and experts across different fields. Um they they hope that this work this new commission that they’re doing uh is going to feed into a national commission on co uh let’s see it is called the co commission planning group. I see. So so this is a US effort some kind of task force that’s going to try and understand more about the origins of this. Yes. And they they they know it’s important to bring in international partners. So they’re they’re working with some international partners. Uh they’re also working with a team from John Hopkins and they are going to look into the origins amongst uh a total of nine uh task groups. So they they have these nine working groups on different topics but the first one is is on the origins. How has how has this affected you personally your investigation of this area? Um, I think it’s burning me out quite a bit. Like I sometimes I feel extremely overwhelmed because I I I didn’t quit my day job. I still have my day job. In fact, we’re recording in the middle of afternoon now. So after this, I need to do my day job. But umh yeah, I’d like to I’d like to stop doing it and pass the torch. I think it’s important to recognize when when I’ve I’ve done as much as I can and and now it’s up to the the real experts to to step in and and do a conduct a credible investigation into the origins. Interesting. So So the work you’ve done has basically been stuff that you could do from your laptop at home with access the data you’ve been able to access online. Yes. And a lot of information has been turned up by internet sloo. really cannot say enough about that that a lot of these discrepancies and curiosities have been turned up by by anonymous people on the internet some some not anonymous uh and there’s this whole group now they call themselves drastic on Twitter and they’re constantly looking at this data there are some scientists amongst them that are looking at the data biohmatically okay interesting do you have any advice for people in terms of you know what they should you know if you’re interested in learning more about the virus generally or you’re interested in trying to understand how the story around its origins evolves. Do you have any advice for you know sources that people should be looking at or not looking at if they want to think about this in a dispassionate way? It depends on which aspect of the virus they’re interested in. So something like the origins is still really unsettled and very controversial and high stakes. So there are disincentives for scientists to raise this issue. Not for all scientists, but certainly for some scientists there’s a negative outcome if if this if this virus came from a lab. So in that case I can’t just say go to nature news and get all your news from there. Um but for other other more more settled less controversial parts where you know like the biology is clear like vaccines and things like that there are so many resources not just on scientific websites but even like New York Times or like like there’s so many sites now that have their own resource page to explain like what to do if you get COVID or what the vaccines and you know before we end up I am curious about some of your I’m I am curious about your day job. So, can you tell us a little bit? What can you tell us about what you’re working on and excited about for your your real research focus? Yeah. So, I fully intend I I never wanted to make COVID 19 my my lifelong like research thing. Like a lot of people have been telling me why don’t you just switch tracks completely and become like a COVID fighter. I didn’t want to. And I really enjoy my my original work which is like genetic engineering and gene therapy because that that’s what like makes me really excited like tinkering around um with uh ways to engineer the human genome or not in the Frankenstein kind of way but in a in a medically appropriate way. Uh and and so I’m currently working on those uh AEV uh gene therapies. Uh it’s really exciting and um we’re finding ways to make these gene therapies safer for people regardless of your background, your medical history and things like that. Uh finding ways to deliver these gene therapies more efficiently so that you don’t have to shoot someone up with like you know an insane amount of virus. Uh so even though these are nonpoggenic, if you give someone enough of anything, it becomes a poison, right? So uh this work is uh is life-saving. So are you working on like general purpose tools for gene therapy or is there specificity for certain diseases? Yeah, at uh the lab I’m working in right now, the the focus is on uh gene therapies that are delivered past the blood brain barrier and um so this is really exciting too, but it’s it’s not the only application that our work would and and a plane is flying or it’s not it’s not the only application that that our uh technologies would would benefit. Interesting. Um, do you have any final thoughts that you want to leave people with before we wrap up here? No, I I think I’m I’m very positive about this whole origins thing. I think one thing that has surprised a lot of people when they ask me, will we ever find the answer is I always say yes. I think we’re going to find the answer. For some reason, a lot of people think that the time is over, that we missed our chance, and that we’ll never find where this came from. There’s so much information out here outside of China that people experts should be looking at. And I believe that even if not now, not in the next few years, at least in the next decades when the technology gets better, when more information is revealed, I think we’re going to find that trail leading to the origin. So whether it’s a lab, whether it’s a wildlife market somewhere or a farm somewhere that was shipping frozen, whatever, like I I think we will we will find that trail. Interesting. Well, Alina Chan, thank you for your time. I really appreciate it and have a good rest of your day. You too. [Music]