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Ep #18 Transcript | Alina Chan: Virus Biology and the Origins of SARS-CoV-2 & COVID-19

Full episode transcript (beware of typos!) below:

Nick Jikomes

Alina Chan, thank you for joining me.

Alina Chan 2:36

Hi, thanks for having me.

Nick Jikomes 2:39

Can you tell everyone a little bit about your background and what you do what you've been working on the past few years as a scientist,

Alina Chan 2:46

I'm a postdoc researcher at the Broad Institute of MIT and Harvard. I currently work in gene therapy. I used to work in genetic engineering, not not in humans, of course, but in human cells in the lab. Yet it's a it's a whole field I've been really excited about and it's, it's really about delivering genes for medical purposes to do your, you know, life changing diseases in humans.

Nick Jikomes 3:12

Where, what is the Broad Institute?

Alina Chan 3:16

Oh, the Bruins did is I think the best, the best human genetics Genomics Institute in the world. Of course, some other entities might try to battle for that title, but I think it's very well known. It's kind of its own standalone Institute. But its professors are all drawn in from the neighboring universities. So from MIT and Harvard, especially. And so they have their labs at the brode. And, and now it's over the years, it's expanded to just cover a whole plethora of topics. So used to be very human genomics focus, but now you've got everything like infectious diseases, you've got CRISPR, of course, you've got just everything, just drug screening, cancer, just everything is covered almost anything that's really top like life sciences research, like human health research.

Nick Jikomes 4:04

Okay, so what about just to give people a little bit of sense for what you're working on? What exactly is gene therapy? And how do we generally approach that in the lab?

Alina Chan 4:15

So gene therapy is a booming field now that there are so many labs working on this, 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 it could be anything I think, one of the more famous, famous applications of sickle cell. So the labs trying to do cure it using base additives to do so what this means is that there's this CRISPR or caste nine based therapy that goes into human cells, and it fixes the gene. So fix this the gene that causes the disease. And that's what a whole bunch of labs do. They do this for every disease that they think can be cured using a genetic edit and the human genome, but 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 expressed in a controlled mental and that manner and that the patients have as little adverse side effects as possible?

Nick Jikomes 5:20

So would the idea be that for a 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 would you do that?

Alina Chan 5:43

Yeah, so this is, this is the fun part. So the current way that a lot of gene therapies are delivered, or will be delivered in the future, it's an active very large fuel. So the right now is true, these viruses called abs, adeno associated viruses, and these are non pathogenic, so they don't make us like sick normally. So they would they were chosen because they do not cause severe disease in humans, but not effective at delivering genes. And so you put your genetic therapy, the gene that you're trying to fix, or the enzyme that should be able to fix your gene inside these viruses, and you inject them into patients.

Nick Jikomes 6:23

I see. So fundamentally, it's it's using viruses, it's like co opting a virus, to, to do something that normally does, but in a beneficial way. So viruses, essentially a little, a little 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.

Alina Chan 6:49

Yeah, I think this is actually the unfortunate part about the public narrative mode viruses is like, every time you hear about a virus, it's killing somebody. People don't normally hear about viruses, they're doing good things. And they're, and they're only such a small percentage of viruses, other 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 they don't cause severe disease in humans. So the virus that we're using 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 a lab, it, even if you spilled it on yourself, it's not like you're gonna give it to someone else. Because it cannot transmit after that it cannot infect you, and then transmit to another human.

Nick Jikomes 7:45

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?

Alina Chan 8:10

Yeah, so where is this 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. 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 of which is almost like a planet to them. They get inside, they use the genetic blueprint to make more copies of themselves using the host machinery. So they have to use the host biology the cell to make more copies of themselves.

Nick Jikomes 8:49

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.

Alina Chan 9:00

Yeah, exactly. And surprisingly, this has led to a very strange group of people who believe that either the virus doesn't exist or doesn't cause disease, because it doesn't mean it doesn't meet Koch's postulates. Because viruses just don't meet Koch's postulates, you can isolate them and culture them alone in a solution without a whole cell. So

Nick Jikomes 9:28

So these these postulates, you're referring to who who came up with those and what exactly are those?

Alina Chan 9:34

No, I come up with a first name, but it's definitely the last name coke. KFC and so this these, these partial lists were first developed for bacteria, so they will not develop for viruses, although the first virus was found around the same time in the late 1800s. So the Koch's postulates were meant for bacteria, which had been discovered like two centuries before that. And they were essentially a way of determining does this bacteria cause this disease in this human more than us? Then looking at right now?

Nick Jikomes 10:16

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.

Alina Chan 10:33

Yeah, exactly. And actually, some viruses, some bacteria don't even meet those postulates to some bacteria, we just have not found ways to culture them. So you can isolate no culture of bacteria.

Nick Jikomes 10:44

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 COVID stuff. A couple more questions about viruses. I hear about DNA viruses and RNA viruses. So what's the difference there?

Alina Chan 11:02

So the difference is the genetics. So the building blocks of the blueprint and the genetic blueprint. So DNA is a more stable version than RNA, RNA. So example of RNA viruses is the Coronavirus is the source Corfu virus that we're all having this pandemic for now. So RNA is much less stable than DNA.

Nick Jikomes 11:23

I see. And then just in terms of normal biology, what what role does RNA play in terms of, you know, you've got DNA or RNA, you got protein? Can you just link connect the dots between those three things for people that are unfamiliar?

Alina Chan 11:36

Yeah. So there's this central dogma in biology. If you've taken like an undergrad, or even High School nowadays, to teach it, you, you still have DNA, which is like the most stable form of the blueprints. 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 this closely guarded library called the nucleus, and all your DNA is in your genome is in there. So I'm talking about human cell right now. In order to use that library of blueprints to make another cell or to maintain yourself, 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 visual the RNA, so RNA don't last forever, they tend to get degraded quite quickly. But they are good way to read the blueprints without destroying the blueprint. So imagine if you had to keep reading the blueprint every hour, and you kept checking the book in and out of the library, the books gonna get tattered real quick. One way of making sure your DNA safe is by making photocopies of it that are seen.

Nick Jikomes 12:46

So the book you can check the books out a library that helps them stay pristine, what you're allowed to make as many photocopies as you want to go and share with your friends.

Alina Chan 12:55

And that's the irony. Yeah. And yeah, so you take that photocopy out of the library and into the rest of yourself. And you can use that to create proteins. So proteins are sort of the last step. They are the product that you're looking for that the thing that has function. So I think over over the years, there's been a blurring of the lines between what has function and not a lot of RNA has functions. But proteins in the central dogma that the last step.

Nick Jikomes 13:23

So there's DNA viruses, there's RNA viruses, the differences are DNA viruses injecting DNA into the host in RNA viruses injecting RNA, the RNA is less stable than the DNA and SARS COVID to 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. 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 this particular virus actually infect cells. What are some of the major steps and some of the key molecular players that allowed this virus to actually get inside of ourselves?

Alina Chan 14:07

So this Saskatoon is a Coronavirus. The story behind the name Coronavirus, 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 of these little balls surrounding the virus. And she thought it looked like a Corona like a solar corona like the sun's corona. So that's how the name came about. She called it the Coronavirus. And so now we know that those those little balls that surround the outside of the wires, those are spikes. They're now called spike proteins. So they stick out of the virus of its membrane envelope. And they Their job is to latch on to a wholesale so on to in this case a human wholesale although it can be any animal or wholesale burden. You DSL, and it latches on to 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, undergoes cleavage, and it fuses the proof that the virus fuses with your cell. And its genome, the RNA genome in this case is released the yourself. And then from there, the cell can read that blueprints of the virus, and it gets hijacked, it does making 1000s and millions of copies of the virus.

Nick Jikomes 15:32

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 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 set, correct.

Alina Chan 15:55

Yes, and most of the vaccines in play right now are spike vaccines. So they don't encode the entire virus, there's no need to, because a good portion of the antibodies that are raised in each person, when you get naturally infected with SARS virus is against a spike. So there's no need to give everyone like flu virus, you just need to take the pad that elicits the most antibodies and you you inoculate people then.

Nick Jikomes 16:25

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?

Alina Chan 16:49

Yes, so much that they can also detect cells that have been infected. So cells have been infected, sometimes display these spike proteins on the surface. And if your immune system recognizes these infected cells, or even all the other viruses, that free floating in your system, then they can take them down.

Nick Jikomes 17:08

Interesting. So it's an RNA virus, the spike protein is how it gets into ourselves. Thankfully, we have vaccines developed that that seemed 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 that 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.

Alina Chan 17:55

I'll answer that in reverse order. So why is it important 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 podcast. So why should we care where this came from? It's already here. Or what? The reason is that, it's only by knowing how this came about that we can prevent another pandemic or happening, 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 what life then you have to think about shutting down some of these wildlife traits, or environmental destruction or habitat invasion, if it came from a research laboratory or from fieldwork, then you have to attempt down on those activities or recent more regulations in place. If it came through the frozen food, like cold chain, supply, some experts on the LinkedIn consider, then then here to think about what to do, but the frozen foods trade. I think that that last one is, is a little bit out there. Yeah.

Nick Jikomes 19:05

So so it sounded like you basically laid out some of the major hypotheses for where these can come from, but could you just reiterate what those are? Yes.

Alina Chan 19:13

So, in terms of a complete 100% natural spill over with nothing to do with research activities or lab laboratories, that are that two ways to split unless 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, bats, so in this case, we'll be talking about the direct transmission of the virus from bats to humans. And bats are well known they've been characterized over the last decade and more to carry almost two decades actually do carry these Coronavirus is also one but many other types of viruses too, like Ebola. Yeah, and so they all depending on the location, but carry Different types of these wires. And they know that the bats down in South China and extending down into Southeast Asia have these saws to like viruses. So this is like 1000 kilometers away from one city, which is all the way up in central China. The second scenario from natural spillover is when you have an intermediate host. So it doesn't go from bad directly to humans, it goes through something like a civet cat like was one or two pangolins as Miss suggested for this, or make which we've seen that coming from outbreaks of COVID-19. And then it jumps into humans, the reason why the intermediate host is important is because there has been almost no documented instance of a software is coming 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 pasture in its immediate post something that's more similar to humans,

Nick Jikomes 21:02

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. And then hypothesis number three,

Alina Chan 21:30

that's the lab leak hypothesis. But I think this, this hypothesis also has several different pathways by which it could be true. So unfortunately, the most popular version of the lab beat hypothesis is one that involves lab engineering, with genetic engineering of the virus. So a lot of people when they hear 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 the lab. And it's like it could be a natural virus that was collected in nature, brought back to the lab in the city, and just growing up in cells and leaked out. Another way is also that you've got these dozens and dozens of scientists around the world going on to these very remote places and sampling 10s and 10s of 1000s 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 all that related meat,

Nick Jikomes 22:25

because it's coming from laboratory personnel doing their work.

Alina Chan 22:30

Yeah, so if if you didn't have these research activities ongoing, then it wouldn't have happened.

Nick Jikomes 22:36

So let's take these one at a time. So when we talk about the zoonotic 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 source code to.

Alina Chan 23:19

So it's happening all the time, so spillover from speed across different species is happening all the time, like pathogens are opportunistic, right? So they don't, they don't show any fidelity to a particular host. If they have the chance to jump, they will try it. But whether they're successful is an entirely different story. So a lot of people somehow have the impression that, you know, they could go into Batcave and immediately get infected and then cause an outbreak. That's not very common. Even as recently as two months before, at least two or three months before COVID actually broke out in one city, the scientists who are studying this in Ohio and published a paper saying that this type of spillover of SARS viruses, from bats into into humans, no matter directly or indirectly, was rare. So let's talk about the areas directly in proximity to these caves, where sours versus fun, they still say that that type of spill over 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.

Nick Jikomes 24:30

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.

Alina Chan 24:43

Yes, so the many steps that the virus has to get over in order to become a fully fledged like pandemic pathogen. So it has to figure out how to infect different cells in your body to cause like a spreadable transmissible disease. It has to figure out How to get from you to another human. So, you know whether it's by surfaces, which is apparently very rare for COVID-19 that someone estimated like only one in 10,000 COVID patients get it by touching a commonly used surface. Or it has to learn how to turn that diffuse through the air or or through like spit or like sneezing and coughing.

Nick Jikomes 25:23

Okay, so zoonotic 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.

Alina Chan 25:39

Yes, and the efficiency like high enough to cause a pandemic?

Nick Jikomes 25:44

And in general, it sounds like that, it's certainly seems to the 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 our 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 species to be a bad as maybe one would think from listening to the media?

Alina Chan 26:08

No, they are very common reservoir for different viruses. And I have to say that I'm not an expert in this field. So it's something that 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 love reading all these papers, especially about the researchers who study bats. There's even one professor, the brothers who studies this. And so surprisingly, they are not that closely related to rodents, which is another thing that's surprising. We're the first day I think that's like flying rats. But they're not that they're way further diverged from from humans and then read

Nick Jikomes 26:56

Yeah, many, many millions of years ago. So 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 human.

Alina Chan 27:07

Yes, yes. And that's the 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. And their immune systems have also evolved in the center kind of temperature. And so for some reason or other, this setup in basic biology allows them to carry many different types of viruses without dying. So a lot of 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 essence, they're like this reservoir, what is marshes can recombine with each other, still apart from each other.

Nick Jikomes 27:50

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 penguins? You mentioned pangolins. A lot of people don't even know what a penguin is. So what is a penguin? And why were penguins in the new so much this past year?

Alina Chan 28:13

Yeah, so penguins are these scaly creatures that the auto shell is made of these nail like substances, so it's like your nails, but they cover the entire body of the pangolin almost. And so they uses a defense mechanism if they're attacked by like a larger animal like a lion in Africa or something like they curl up into this ball, and they become this the shell. So imagine if you're covered by huge pieces of nails, and so they they're very highly sought after for traditional medicine in Asia, unfortunately, and the illegal trade of pangolins bringing them up from Southeast Asia from Malaysia, for example, or from Africa into China or Vietnam is very high. So it's it's like worth like, I think millions of dollars every year. And so the reason why it became a suspect for being an intermediate host of Saskatoon is because a string of papers came out around the same time in February 2020, all claiming that they found the pangolin Coronavirus in smuggled pangolins that they caught that they intercepted in China. This Coronavirus shed a very similar part of the spike to Sasquatch to the COVID-19 virus.

Nick Jikomes 29:31

Okay, so that there are some papers that came out last year. They found a virus a Coronavirus inside of these smuggled penguins and it looked apparently a lot like the source code to virus So that's some evidence potentially, that maybe this was our candidate for the species from which stars Cove to hopped from. Was there anything? What is your interpretation of the data that was behind that

Alina Chan 29:59

it wasn't listening. Have the despite similarity that surprised me so much as the fact that I later discovered and confirmed with my coworker, Shane Hagen, who just goes PhD in evolutionary biology at the University of British Columbia. We found that these papers, were all describing the same batch of confiscated pangolins in Guangdong province in China. So it's only that a pengelola pangolin Coronavirus, then has that highly identical part of the spike This is called to. And so that finding was surprising 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 smuggled batch of pangolins. So that was, I think, at least mind blowing for us.

Nick Jikomes 30:49

Why? Why exactly? I mean, if I mean, they're just working from the same pool of data, why would that be unusual?

Alina Chan 30:57

They, they didn't cross like each other. So see, to a delay reader, if you saw these four or five papers that came out all at the same time. So actually, four of them were pre printed within three days of 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 bars. I see. They found four different batches or

Nick Jikomes 31:21

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, if they were if they weren't on the same batch, and they were communicating with each other, they would have cited each other but they did not do that.

Alina Chan 31:36

Yes. And you know, that someone could say that. Maybe they didn't know about each other? Yes, they did. They didn't know about each other. And these are, the two published in Nature knew about each other. But the name one of the nature papers knew but the one in PLOS pathogens, nobody, you know that. So it's my tracing the authorship of the papers. So some of them share co authors, they were pre printed on the same day, they drew from the same data set, which some of the authors the shine artist had published before in October 2019. And later, when this organization called us, right to know, so the intervening in this matter, they managed to fire some of these emails, and published on these emails. And they showed that these authors knew about each other.

Nick Jikomes 32:25

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, it'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 peer review mechanisms to take weeks and months and months, for this new information to come out. Was there anything? So that's and that's reasonable, like we need this knowledge? Quickly, was there anything else unusual about about these studies in terms of how quickly they came out? Or what the underlying data actually looked like?

Alina Chan 33:08

Yes, certainly, 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 your work, you can create the genome that they claim to have published, they claim to have assembled a genome. And these genomes, the sequences along the to the sequences were being used by dozens of scientists around the world immediately, because we're also excited to analyze these virus genomes. Very few people actually tried to independently reproduce the work. So the moment you tried to independently reproduce the work, that's when you notice that there are some discrepancies here, there's some very severe scientific issues with the two babies that that put out the pangolin genome. Today, the plus pathogens paper, the authors have not been able to produce the gene or the data underlying the genome that they claimed to have assembled. 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 sale at our XAO, at our nature paper on pangolins, you see that editors have put up a note saying that they've been alerted to issues and are investigating.

Nick Jikomes 34:31

So this would be 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.

Alina Chan 34:46

Sometimes scientists are a bit sloppy, so they can be late 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 a

Nick Jikomes 35:02

it's weird. It's at the very least it's very weird.

Alina Chan 35:07

Very weird. And I think unacceptable.

Nick Jikomes 35:10

I mean, especially for something this important in high profile. Yeah. 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 publish the stuff, right?

Alina Chan 35:27

Yeah, for sure. You can do it in like five minutes or like, less than an hour, you can assemble the whole like virus genome, if you give him the raw data, it's more difficult for me, because that's not my specialty. The so what you said earlier about peer review happening very fast, because these are pandemic papers, I'm on board with that. In fact, I think peer review can happen a lot faster than is currently. Normally it takes months or sometimes years at some journals. But if you're going to do that, if you're gonna speed through peer review, make the peer review open the 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? So this paper and was fixed? And more than that, if you know that this problem paper corrected 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 errors. Yeah, those corrections have to be fast, too. Because Yeah, it's getting propagated. Yeah, yeah,

Nick Jikomes 36:43

yeah, it's getting propagated, and people just take it as truth because it's in nature. Yeah. 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.

Alina Chan 37:14

Yes, so I've done quite a bit of peer reviewing, too, sometimes not under my own name. Lots of fun, my current lab my scores is really good. But the that goes peer reviewers. So sometimes the P eyes are too busy, which is natural, and they they pass it down to a trainee, like even a grad student, or postdoc, and they are the ghost peer reviewer. So these guys, they get their reviews in under the PIs name. 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, let's say just just fix this single grammatical error, and you're good to go. And that provided them like a whole, like, multiple points of constructive advice. It did change the paper. Yeah.

Nick Jikomes 37:58

Interesting. So through some weird things that you and others noticed about some of these early papers. And these early papers had to do with the potential zoonotic origin of SARS Cove to one, how would you describe, so the last few months, like, in terms of, you know, was 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.

Alina Chan 38:37

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.

Nick Jikomes 38:58

You have a preprint out right now called SARS, cov. Two as well adapted for humans. So I, you know, it's I understand that 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?

Alina Chan 39:30

Yeah, the preprint is a collaboration between mainly me and Xing Patreon. And my sponsor, Ben also joined the paper because he called 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 source to the sauce one. The reason why we picked out one is because it has a very similar emergent story deserves to the both the most highly related pandemic pathogens and outbreak pathogens. sextiles one in Saskatoon, Saskatoon was named SOS two because it's highly related SAS one, they both broke up in the Chinese city in the winter. At a market like a market was involved in the in the origin story. They both by the same receptor as two in humans, they both are risk of respiratory disease, they both spread well, indoors and through the air. They, the customer 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 south one is the closest to SAS two, we had looked at some other viruses, and we looked at most, but most of them were complicated sample history and very different origin story. So involves like people living in rural areas, not in the city, that doesn't involve any markets. It's involved camels instead of civet cats, for example, or market animals. It was sporadic, there have been multiple spillovers of MERS. And, again, it's very difficult to compare those two because they don't even use the same receptor. And the setting is totally different. So we considered some of the viruses too, but it was clear that SAS one was the standard that compares us to two.

Nick Jikomes 41:11

And how can you give us a brief summary of the SARS one story like when did that happen? And what do we know about where that virus came from?

Alina Chan 41:20

Yeah, so the first cases of SARS two were detected in January of 2003. So that's one. That's one. Yeah. And then the, the clinics at the time noticed that it was a strange new pneumonia going around. At the time, there wasn't this kind of technology to quickly sequence the genome of a virus or pathogen. So what they did was he saw the contact tracing in January, and they found cases going back to November that they were from outside of that city. In fact, when they did, where they had those January cases, by March, it had become a pandemic, like pedogenic had a super spreader event. And so that's when things got really real. That's when they started to track the index cases, they found that the index cases were most likely to be food handlers. So they found the investigators the Chinese scientists, at the time thought we should go to the markets where they're selling these life animals and see whether it's the weather the viruses that they had isolated in March 2003. So they went to these markets in May 2003, and they collected animal samples, and the majority of them were salzmann positive animals, so they had like civet, cats, raccoon, dog, and a badger. And they, from comparing the size one genomes in those from those animals versus the human cells, one genomes, they saw already dozens of differences. So they saw functional differences. So changes in the protein, not just the RNA, changes in the protein even doesn't within the spike alone within the spike gene alone. So and from that they at the time, we weren't even sure whether this was an intermediate host, but they didn't realize this was spreading out of markets. And then they in May of 2003, they started collecting samples from hundreds of market animal sellers. They collected blood samples also from healthcare workers, within expos and South patients and things that they will control. And To their surprise, they found that a whopping 20 to 40% of the animal traders have really had antibodies despite not being SARS patients. So these these people who are selling the live animals at the markets, they already had antibodies and a large number of them had antibodies to SARS viruses. So then they realize that this this is spilling over from animals into humans quite a bit in in a province in Guangdong and so they the whole pandemic of SARS, one was able to be tamped down by summer so by August by July August it was it was under control, like the pneumonia cases. But then it spill over a few times from from labs actually, so labs started studying South one. And it's it's built elite on the Latin into the human community one time in Singapore, one time in Taiwan and at least two times in Beijing. And then a spill over again naturally. So in the winter of 2003 spill over again from animals into humans in Guangdong again. So this time, the index patient was a waitress, and upon diagnosing her, the Chinese authorities were really unhighlight so when they when they diagnosis positive or sad, they went straight to her workplace. The waitress actually said, No, I don't have animals at my restaurant. They didn't believe her. They just went straight to her workplace. The truth they expected there was civet cats in the restaurant. They sample those they sample everyone in the restaurant. Another next case was a person that dine in the restaurant and they found antibodies in the in the restaurant workers and also viruses from the from the civet cats and again they looked more like animal SARS virus than humans as well. So this was caught quite early. Before virus had the chance to mutate and become more customizable.

Nick Jikomes 45:03

So there's a, there's a bunch of people that were infected, and they made antibody. 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?

Alina Chan 45:29

Yeah, one of those features is the ability to bind well, to the human receptor, which, which I mentioned earlier, it's called h2. So h2 also exists in bats and intermediate hosts. So you can think of how this virus has to go from best to intermediate host to humans, it has to change its spike, so that it can change from binding h2 embeds to bind the h2 in the intermediate host, which is closer to humans. And then from that change to bind the human race to it has to take multiple steps to become like a human optimized version.

Nick Jikomes 46:05

And so what does it mean, in your paper? When you say that source code to is well adapted for humans? What's the importance of that statement? And how do you know that?

Alina Chan 46:14

Yeah, so let's say mean, for lay person, it means that by the time we detected this virus in December 2019, it was already good to go. So it didn't, it didn't mean 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, it isn't obvious. Just from the the our lot, you can tell that it's a really highly transmissible wires, like yes, but you need to kind of show the working, like show the data. And so when we come back to the south one, in the first two to three months of it, you had seen the sounds one versus picking on like dozens, like 10s of mutations in that in that first two months. Before SAS two does like barely anything, and it was more similar to the late phase, the late stage SAS one, but timing really picked up all these mutations that made it better and binding human h2.

Nick Jikomes 47:08

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 we go from the early to the late stage of that first epidemic. And 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 human host. And so it's more genetically homogenous.

Alina Chan 47:47

Yeah, I also want to press this point is that the viruses are always mutating, but it's not like they stopped mutating the moment they're great like, it's, you can measure like millions and 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 repeating itself, you get these variants of the virus that accumulated that build up different mutations that useful. 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 do you still see mutation, you still see different variants emerging, but you don't see that rapid accumulation of dozens of mutations.

Nick Jikomes 48:31

I see. So So you're saying that for SARS Cove to at the early parts of this current pandemic, it looked like it had already sort of accumulated all the mutations that it needed to be very good at transmitting.

Alina Chan 48:44

Yeah, and this is, this is not like some out there or like, 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 W IV The Institute of Neurology is paper that came out in January 2020 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 a sequence of you are the index patients that you haven't seen, like what what makes you think is getting more human transmissible.

Nick Jikomes 49:21

Interesting. Interesting. Let's come back to that. So okay, anyways, so source code 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.

Alina Chan 49:56

Yeah, one other possibility is that it was no intermediate. animal does very similar to humans, right? So actually, a lot of scientists were trying to see monkeys or primates were being sold at the market. There are no records of that they know like 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 post and had these good mutations for binding to the human h2 receptor.

Nick Jikomes 50:24

So we're what would you say is the current state of, you know, when we're thinking about these, what markets in China and elsewhere that have so many of these different animal species, 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?

Alina Chan 50:59

So at the beginning of the pandemic, in January, the Chinese government announced that most likely it came from that one and seafood market. And so they announced it. So then everyone just thought it was a rehash of sauce one. So, you know, two sides versus the same thing happened. And then there was this wave of racism that went around of people showing my videos of Chinese people eating bats, which turned out to not even be in one city. And so, people bought the idea, they bought it really quickly. It wasn't to me 2020 that the Chinese CDC director reversed, and he told the Chinese state media, he said, look like it wasn't the market, the market was just a victim, the virus had existed long before the market.

Nick Jikomes 51:44

How do we know that? Oh, yeah, the genetic

Alina Chan 51:47

data doesn't point to it. So they tested hundreds of animals at the market tested hundreds of environmental samples of surfaces. And they found that the genetic, the only samples that were positive for genetic material of the virus would environmental samples, and they came from the parts that weren't even selling like life and life mammals or holes, they're susceptible to source to transmission. And those sequences were identical, 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 phenotypes. So especially the spike so they, it showed that this virus had spilled over from animal and was accumulating mutations to get better infecting humans. But in SAS to the sequences were the same. So it was more indicative of a human super sporadic event. So somebody come in and coughed on the surface or something. And there was a class of cases that we know about the financial market. So most likely, it was a later cluster of people a super spread that event.

Nick Jikomes 52:50

Okay. And then let's talk about the Wuhan Institute of virology. So for those that are unfamiliar, Hey, where is Wuhan in China? geographically? Let's just remind people of that, because it's easy to forget. And what is it 100 student virology? 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?

Alina Chan 53:14

Yeah, so one is in central China, it's 1000 kilometers away from this I spill ozone and where people are found sauce to like, viruses that hold the nature versus is low when you want to these also 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. So it's not a place where the bats flying over and people are getting software's sprinkle on them. That w IV The Institute of Neurology in ohon is a top class like virus Institute. So it's the first BSL four that was built in China. Although they weren't doing class work in the BSL four, they hadn't received approval yet. So all the tasks what they were doing wasn't done at BSL two and three, what is

Nick Jikomes 54:00

what is that nomenclature? BSL two and four? Oh,

Alina Chan 54:02

yeah, so these are biosafety levels. They refer to increasing increases with number increasing levels of safety restrictions and regulations required to work with the pathogens, and in each level, so like, BSL two is actually quite relaxed. So if you if it seems on BSL two labs, like something, people don't wear gloves, not to mention lab coats and goggles. BSL three is a bit more is bigger step up. So you have to wear protective, much more PBE. Yep.

Nick Jikomes 54:36

So what's the highest is that is it for?

Alina Chan 54:39

Yes, the highest is full.

Nick Jikomes 54:40

And so what in a normal BSL four lab, what types of things would they be worth 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.

Alina Chan 54:57

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 leads of SARS one came from a BSL four lab. And it was a human error because the person tried to clean up the waste fluids without gloves on. I know a lot of people like, oh, why would he do that? Sometimes when you're cleaning waste from these, like they've really gone through bleaching and things like that. So you kind of don't have don't have don't have as high of a level of danger off here. But that's why means that even at a very high BSL four 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 this is a reporter journalists, amazing journalist in the US, Alison young, and she's been covering so many of these BSL four accidents. There are many, but they don't get reported in the news. A lot of entities that have these accidents on the on the download on the advertise that oops, we had like five leaks this year. And it can be anything like a door not working, or like a suit being punctured and not being detected that there's so there's too many ways for accidents to happen.

Nick Jikomes 56:17

I see. So BSL four is mostly work with biological agents that are or could plausibly become infectious is that basically the rule

Alina Chan 56:29

those are also as BSL three but the levels are also subject to human judgment right so so now after after COVID, then SARS was upgraded to BSL four. So now you're not allowed to just play around at BSL two like they used to in the past years before COVID. But yeah, generally BSL four are the top most scariest viruses that can highly transmissible and highly deadly.

Nick Jikomes 56:56

So what what kind of research was going on or is going on there around Coronavirus biology stuff?

Alina Chan 57:02

Yeah, so arguably the the most prolific size research lab in China was at the W IV. So this was led by a professor called Xu Jian Li. 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 South one. So Batman's was one of the elite they they kind of knew that those intermediate holes, right, so they thought, yeah, the Civic cat they're giving to us. But whether the Civic cats get it from the check all the farms that were supplying these markets, and there was nothing, so none of these firms had sick civet cats with us. So they thought, where are the server cats getting the virus from? They convened the team of scientists, which include includes a srijan lien, and also Peter de Shaq, who is the president of the equal Health Alliance out here based in New York, and other international parties as well. And they all went out looking for the reservoir and one of them linphone Wang, who is based in Singapore, now he he said, Let's check the beds. And so they found they went to check the bat, and they found very similar relative size, whereas in bats in Union, which is another Southern Chinese province,

Nick Jikomes 58:09

I see. And people have been talking about gain of function research. What What is gain of function research?

Alina Chan 58:18

Yeah, so game of Fortune research is a very broad term. And, and there's a lot of controversy swirling around it, because it was some people describe as a ban, but it was just a pause on funding during the Obama era. 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 Nah, not gonna voluntary pause my research. So this pause on funding only affected future funding decisions like future federal funding decisions didn't mean that private parties had to stop funding this or research either. And more importantly, this, this gain of function umbrella didn't apply to natural lifan viruses. So the type of work that was done at the web where they were going out into nature over the past decade, plus and sampling 10s of 1000s of bats and mold animals and also humans, these will all come to this natural pathogens, so they didn't fall under this gain of function research of concern, paws on funding. And they were really funded before the pause on funding. So the it's not like they were recklessly doing dangerous work on sourcing it from us to China.

Nick Jikomes 59:34

But what exactly does it mean for research? What does gain of function mean?

Alina Chan 59:38

Yeah, gamma function means just getting a new function in your organism. But the problem is that almost every life sciences experiment is a gain or loss or put servation of function you move one gene from organism to organism beads gain of function. So the the wording in this pause and funding and the downstream review process was that this game 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 relevant, then it didn't fall under this umbrella. Pause on funding. Yeah. So again,

Nick Jikomes 1:00:23

every gain of function researches is quite a vague term if you're changing a biological agent, so that it has a property that had before that's the gain of function. But that could be quite innocuous, 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.

Alina Chan 1:00:42

Yes. And the wording in the in the pause on funding was also very flexible. So they said that if if you talk to your funder, the person who's managing your funds, and you say, I don't think this is going to make it more transmissible, there was sufficient, you can 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.

Nick Jikomes 1:01:06

So what would be who I mean? At least half of this question might sound obvious, but let's just say it anyway. So when you're doing gene 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 how common is it would you say,

Alina Chan 1:01:27

so I'm a complete newcomer to this, because I don't work with pathogens, I don't work with things that cause severe disease. But from what I've read on this game of function debate, which was quite fierce, and spending several years, 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 a pandemic pathogen is like, so that we can come up with ways to mitigate a future pandemic. But the people who were against this kind of functional research always wanted more regulations and more review processes in place. They said that you're just creating a novel risk, by ramping up to start with research around the world, you're creating all these pandemic pathogens around the world, they can lead from labs, and then a real pandemic will happen.

Nick Jikomes 1:02:14

I see. 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 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 likely areas are for some highly virulent 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 virulent version. And that is actually a risk in case it does somehow get out.

Alina Chan 1:02:51

Yes, and 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 see like, did the promises hold true? So did we actually learn a lot from from Dino function research that helped us define this pandemic? I don't think it's zero. But was it worth the risk and then follow that calculation has to factor in this pandemic come from a lab.

Nick Jikomes 1:03:19

So one thing I want to summarize for people is, you use your 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 zoonotic transmission, versus if it was a lab, like in terms of how we conduct ourselves at the societal level moving forward.

Alina Chan 1:03:57

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 innovation research, because they think that we need to start preparing against more of these pandemic pathogens, or in bed threatening spill or anything. This is actually counterproductive if the pandemic came from a lab, right? Because you're ramping up the activities that led to it emerging. If it came from a lab, then we have to really sit down and be quite serious about this and say, like, you know, all this work, this virus hunting work, even if it's not Dino function, they were extremely well intentioned, but it looks like it, 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 change that in the future so that this sort of pandemic doesn't happen again.

Nick Jikomes 1:04:52

So it really is a trade off. It's not merely an academic kind of disagreement among intellectuals. It 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 in do the types of research that are going to make it more likely to happen again,

Alina Chan 1:05:18

we are investing in the NIH and NIH, we have been investing more millions since the pandemic started in this virus surveillance and hunting programs. I'm not saying is 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 do you bring the virus to a densely populated city like one and have an expo it's true the wildlife trade or something, right. So similarly, if this is from nature, by pasture lab, the lab work is bringing back into densely populated cities where these VSR threes and fours are. So humans are somehow bringing it from these remote, extremely remote caves into places where it can ignite a wildfire pandemic. Yeah, and

Nick Jikomes 1:06:03

it's presumably fairly difficult to build a Research Institute like this out in the countryside, just because nobody wants to work. No one wants to work there.

Alina Chan 1:06:16

Wow, yeah, I think this is a point that somehow had to communicate to the public that scientists are humans to us, like, we have families. So you do have kids, like you don't want your kid to just not go to school, and like the top universities and things like that. So there are many human factors. And this is not just a scientific, cold blooded calculation.

Nick Jikomes 1:06:38

Interesting. So what can you talk a little bit about some of the new variants that have been emerging? 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?

Alina Chan 1:06:56

So I'm gonna actually do a shout out to our browser COVID Cg COVID and then CG dot o RG. It's, the name is COVID cogent genetics, and using that you can track all these different variants and mutations around the world that have been the data has been deposited in the GSA database. So using that you can see like where the UK version has appeared in which countries and when exactly, so these new variants, as I 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 new emerging variants. And then part of the reason was that this virus was so genetically stable in the first half a year, even like we weren't really seeing any changes. So people thought that we could just fight them 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 will have to keep updating all vaccines and therapies to fit new emerging variants, and very few people thought there'd be 100 million cases 130 million cases today. So far total. So this new variants, some people have speculated that a top top experts have speculated and been doing experiments to check whether they emerged in immunocompromised patients, they've been trying to see whether these variants evolved, not not the transmitted better amongst humans, so to say, but to get around our immune response. So the cause of these variants, immune escape variants, and some of the hints have pointed that are that they, they evade antibodies against the original version of the virus. So sad to but the original version before these variants emerged. This is really fantastic nature paper where they they looked at an immunocompromised patient who was given convalescent plasma for a long period of time, and they tracked the evolution of the virus inside that patient using sequencing. And they showed that yes, it was picking up like variant mutations of concern. So other other studies have been done, but they haven't seen something that's similar. So 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, my guess, my informed guess, and then the hypothesis by some experts, other these these variants emerged so that this viruses could reinfect people who already had sauce to before.

Nick Jikomes 1:09:48

Interesting, do we know where those mutations are like are they in in components of the spike protein?

Alina Chan 1:09:54

Definitely all over. So in this case, it's difficult to tell which mutations are the important Then once functionally whizzes which ones are just passengers, so like people mutations you pick up on the way, but they doesn't matter if they're there or not. And but we do know that some of them are functional, so they allow the new variants to get around antibodies.

Nick Jikomes 1:10:19

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, longer period of time that it tends to become less virulent 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 what do we what do we expect to see that with with this virus?

Alina Chan 1:10:46

Yes, that's a that's a common speculation. And I think there's some circumstantial evidence, in some cases, some specific viruses, but sauce to a really was quite an attenuated virus. And it's really sneaky. A lot of scientists have described it as like the trickiest, like wires to deal with because it can spread pre symptomatically on 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 a pub, or like, you know, just all essential workers like they have no choice but to go to work. If they're not on their deathbed, they will go to work. So then it just spreads like it's a really great like it's, it doesn't need to become less than this spread well. But it could be different for something that kills like half of the people it needs right? For most maybe if there had been a larger MERS pandemic, then we would see that happening. And for SARS to in the case of a virus like this, the reason why some experts have said that, that we would see less and less of your cases it's not, it's not because the viruses mutating, but because the human population is building a 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 that, that leanness over time the mortality decrease, it's not because the virus has mutated become less deadly is because we have built up like herd immunity.

Nick Jikomes 1:12:08

Yeah, herd immunity. 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 herd immunity and how it works?

Alina Chan 1:12:24

Yeah, and I think it's really ties in with vaccines, and how to think about it to 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, I'll get sick. But that's not true. So the, the vaccine works differently in different people. 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 doesn't mean that you can be infected again, or that you won't pass it to other people. So if it's just you, who has gotten vaccinated, but you go to a place where like, COVID is rampant, you will still get sick. So the idea of herd immunity is that there are enough individuals in your community. So something numbers have been quoted, like 70%, but now they want 90%. If you mentioned 90% of the people around you have all been vaccinated. So the chances of a virus jumping in the community between people is much, much really reduced compared to a place where only you are vaccinated. That's jumping everywhere. And you will also probably get in if you hang around for too long.

Nick Jikomes 1:13:41

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?

Alina Chan 1:13:59

Some of the scientists have come out really strongly saying that this almost definitely was a natural spillover origin. They they also have said that we are entering an era of pandemics. So this includes Dr. Fauci as well. He says that just because human activities that invade natural habitats and you know, disrespect animals, is on the rise, that we shouldn't expect to see more spillover and more pandemics. For me, I think it's true too. And also because 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 four in every province. And some of these provinces like Guangdong they, they even want to have like dozens of VSL trees across that province alone on top of the BSL four. So when you think of that much human activity that disrupts nature and also damaged 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.

Nick Jikomes 1:15:08

How you know how common is a BSL four 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 common these things are?

Alina Chan 1:15:19

there two biosecurity experts, Dr. Filippo lentils, and Gregory Copeland's. I think I'm saying that name a bit wrong. They are trying to map all the BSL fours right now. There are many. They're not that rare nowadays. There's one in Boston, so that there are several across the US. I don't know how many exactly there are. There. There are two in China right now that I know are operational. But other countries like once, once they want to become a world leader in this sort of research, they will want to build a VSO for Singapore, for example, wants to build one India, India Island, like right, like 20 minutes drive away from the airport. So I think like, it's not a rare situation is not going to be a rare situation anymore.

Nick Jikomes 1:16:07

I see. So it's not there aren't dozens and dozens and every country now there's probably a couple or a few, but they're becoming more common.

Alina Chan 1:16:13

Yes. And rapidly. So it's not like 10 years later, it's like in the next five years. Yeah.

Nick Jikomes 1:16:18

I mean, your your description earlier of the tension here, in terms of, you know, the importance of knowing whether the importance of knowing whether or not this is a zoonotic origin, or a lab leak, I mean, there really his attention, 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, it'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 ra Tg 13. Can you describe what that is, and give people give people a sense for what that is in comparison to some of the other candidate viruses for where source code to come from.

Alina Chan 1:17:12

So RTG that then has its own very interesting backstory. And I'm gonna tell it so it relates to these very tragic cases of my days back in 2012. So almost a decade ago, these were the Chinese miners. Yes, this was in Union China, in South China, in the spillover zone, also SARS viruses. And so these six men got admitted to this specialized Hospital in Kunming University. And they all had this mysterious pneumonia. At the time, they didn't know what was giving them this pneumonia and the doctors just check them on. They had fevers, headaches, like chills, like low blood, oxygen, that kind of thing. So something quite similar to the COVID. The older patients suffered a lot and passed away quicker than the two so the two to be discharged professors were the youngest and the attorneys from the hospital. But throughout this time period of the patients, one of them was even discharged in September, so like more than 100 days after they've been first admitted in April or May of the year 2012. And so during this time, they consulted the so called Dr. falchi of China, whose name is Dr. Joe Manchin. And so he was a hero from SARS one he had helped to develop a treatment for SOS one and when he was called in look at these miners after antifungal that film, so as much as it was cave disease, like when you go into the cave, you get infected by this fungus that's in bed poop. They thought it was that they tried all sorts of antifungals and didn't work. So then john and john came in and he said, Go to that cave and get those beds and check them facades, check these patients will size. And by the end of this whole episode, the doctor in charge of overseeing these cases wrote a medical thesis, saying that these minor is most likely had been sickened with a SARS like viruses from bats. But because Joe Manchin was only caught in more than two months of these patients were admitted, by this time the virus was gone. So when you get COVID, the virus sticks around for a short while and 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 still positive for like SARS. After two months. Wi Fi was calling so web got patient samples and they said they were positive for virus for antibodies RGM against wires, but they didn't say which virus but the thesis concluded was SAS viruses. So after these cases, top lamps in China all went to that mine that same mine were the six men and worked to sample the bat and read them for viruses. One of them even published in Science Magazine and the most prestigious journal saying that they found a different virus there but unlikely it was what affected this mess because it couldn't culture they couldn't make more copies of it in human cells. But In 2013, the Wi Fi, on their fourth trip trip to this mine, they found the first SARS virus. And they published a small fragment of this in 2016 paper. It was the only SARS virus known in the literature that time from this mind where the minus had died from the sounds like Jonas. And that fragment was under a different name is called for 991. So, first of all the way up to 2019 December 2019, January 2020, who is looking at these sequences from COVID patients the virus sequence, they check the database and they find the closest match is already budgeted in. So they didn't make the connection that 4991 was already budgeted in some internet sleuths had to make that connection. They didn't find the 2016 paper, they didn't tell anyone about those monies from that cave where this sample had been collected from. So internet sleuths had to connect all those dots. And by the end of it in November 2020, the web wrote an addendum to the nature paper confirming that yes, 491 is the same sample as RTG didn't. And yes, these were collected from a cave where the miners had second oven pneumonia likely or virus induced pneumonia. 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 sauce to you. But in the end, they contradicted the thesis. And actually another thesis describing it's minus those two pieces had said that those miners were positive and one of them said they were positive for size idg antibodies. But in that this nature done them by the web, they said that they checked the samples and there was no size in them.

Nick Jikomes 1:21:49

Wow. So what do you think? I mean, what 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 research on the origins of this virus?

Alina Chan 1:22:03

So I think that Internet's loose, and then outside is like, may have carried a lot of this research in the past year on our backs, and been properly ridiculed for it. And 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 COVID what do they call it? Maybe check it, it's called COVID CPG. And I tweeted about it today, it's actually being led by, by top scientists so that the person was leading this commission was the 911, commission like executive. And they have like all these top biologists and experts across different fields. They, they hope that this work, this new commission that they're doing is going to feed into a national commission on COVID. Let's see, it is called the COVID Commission planning group.

Nick Jikomes 1:23:03

I see. So this is a US effort, some kind of task force that's going to try and understand more about the origins of this.

Alina Chan 1:23:10

Yes. And they, they know, it's important to bring in international partners. So they're working with some international bodies, but they're also working with a team from john hopkins. And they are going to look into the origins amongst a total of nine task groups. So they have these nine working groups on different topics, but the first one is, is on the origins.

Nick Jikomes 1:23:31

How has how has this affected you personally, your investigation of this area

Alina Chan 1:23:40

Um, I think is burning me out quite a bit. Like a sometimes I feel extremely overwhelmed because I I didn't quit my day job, I still have my day job. But in fact, we're recording the middle afternoon now, after this I need to do my day job. But um, 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 done as much as I can, and now it's up to the the real experts to step in. And do I conduct a credible investigation into the origins

Nick Jikomes 1:24:17

interesting so so the work you've done is basically been stuff that you could do from your laptop at home with access that data to access online?

Alina Chan 1:24:24

Yes, and a lot of information has been turned up by internet spoofs. I really cannot say enough about that and that of all these discrepancies and curiosities have been turned up by by anonymous people on the internet, some some not anonymous. And 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 by automatically.

Nick Jikomes 1:24:49

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.

Alina Chan 1:25:15

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 is a negative outcome 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. But for other other more, more settled less controversial parts where you know, like, the biology is clear, like vaccines and things. There's so many resources, not just on scientific websites, but even like New York Times, or, 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.

Nick Jikomes 1:26:04

And you know, before we end up I am curious about some of your I'm 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?

Alina Chan 1:26:20

Yeah, so I fully intend, I never wanted to make COVID and I didn't my lifelong like research thing, like a lot of people have been telling me why don't just switch tracks completely and become like a COVID fighter, I didn't want to and I really enjoyed my my original work, which is like genetic engineering and gene therapy is that that's what like, makes me really excited, like tinkering around with ways to engineer the human genome or not in the Frankenstein kind of way, but in a, in a medically appropriate way. And so I'm currently working on those AAV gene therapies is really exciting. And we're finding ways to make these gene therapy safer for people, regardless of your background, your medical history, and things like that. Finding ways to deliver these gene therapies more efficiently so that you don't have to shoot someone up with like, you know, insane amount of virus. So even though these are non pathogenic, if you give someone enough of anything, it becomes a poison. Right? So this work is is life saving?

Nick Jikomes 1:27:27

Are you working on like general purpose tools for gene therapy? Or is there specificity for certain diseases?

Alina Chan 1:27:35

Yeah, the lab I'm looking at right now, the focus is on gene therapies that are delivered pass the blood brain barrier. And so this is really exciting, too. But it's, it's not the only application that I'll work with, and the plane is flying over. It's not the only application that that our technologies with wouldn't benefit.

Nick Jikomes 1:27:58

Interesting. Um, do you have any final thoughts that you want to leave people with? Before we wrap up here?

Alina Chan 1:28:07

Though, 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 asked me, will we ever find the answer is always say, Yes, I think we are going to find the answer. For some reason, a lot of people think that the time is over that we missed our chance, and they will 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, more 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 gonna find that trail leading to the origin. So whether it's a lab, whether it's a wildlife market somewhere or farm somewhere that we're shipping, Frozen, whoever. I think we will, we'll find that true.

Nick Jikomes 1:28:49

Interesting. Well, Lina Chan, thank you for your time. I really appreciate it and have a good rest of your

Unknown Speaker 1:28:54



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