JAD ABUMRAD: (Singing) Webster, are you there? Are you...

MOLLY WEBSTER: Yeah.

JAD: Hey.

MOLLY: That was amazing. You started coming - I still don't see you.

JAD: I'm Jad Abumrad. This is Radiolab dispatch number whatever number we're at. I'm going to say 14. I'm not sure. This dispatch is a little bit more lo-fi than even our others because - I don't know. I just wanted to play you a conversation I had with senior correspondent Molly Webster. She and I check in every Friday morning where she usually just kind of updates me on new research she's following, things she's been interested in. And in this case, her research update to me last Friday was just so interesting...

JAD: I'm recording. You are here.

MOLLY: You are recording.

JAD: ...That we decided to record.

MOLLY: OK, we'll talk. And then you just tell me to stop whenever.

JAD: I will tell you to stop. But why would I tell you that?

MOLLY: You know, Jad, you'd be the rare person in my life who doesn't.

JAD: She told me about a few new studies that she had just read. These are articles about different individual COVID patients from different spots around the world. And each paper looked at how the virus behaves inside a single human body. One, a case study from the U.K., starts with a man in his 70s coming into a hospital with an immune system that was already pretty low.

MOLLY: Yeah, his immune system was low because he had lymphoma and then was on a drug to try and keep the cancer in check. And that lowers your...

JAD: Got it.

MOLLY: ...Immune system.

JAD: So this man in his 70s...

MOLLY: He had a suppressed immune system. And he shows up in a hospital because of cancer stuff. And while he's there, they test him, and he's positive for SARS-CoV-2.

JAD: OK.

MOLLY: But he seems relatively fine, and he just has, like, a small cough or something. And so they send him home. And then 35 - or 34 days later, on Day 35, he walks back into the hospital. And what had been a cough for the last month had, like, turned into a shortness of breath. And they test him again. And he has coronavirus.

JAD: Which most likely meant that he had coronavirus for the whole month and couldn't get rid of it.

MOLLY: So he tests positive for coronavirus. And he has, like, the COVID-19 pneumonia kind of that settles into your lungs.

JAD: The crackly cough thing.

MOLLY: Yeah. You know, the gray spots on the lungs that they, like, identify in CT scans and stuff.

JAD: Yeah.

MOLLY: And so they check him into the hospital. And then what basically starts is just a series of trying to treat this man. At the same time, the U.K. is actually really good about taking samples and genetically sequencing them, as we all know, in a way that America is not doing right now.

JAD: Yeah.

MOLLY: And so over the course of his time in the hospital - and he does eventually end up dying on what they say is day 102.

JAD: Oh, wow.

MOLLY: Over the course of that time, they sequenced his virus 23 times.

JAD: So basically, over the last 3 1/2 months of this man's life, the doctors take snapshots of the virus inside him. You can think of these as a series of stills that capture what the virus is doing, how it is moving. You can think of them as mugshots, a series of mugshots. Now at this point, this - going back a year, there was really only one main version of SARS-CoV-2 that was out there or at least in our consciousness. There weren't all of these variants from South Africa or Brazil...

MOLLY: Or the New York City variant.

JAD: That - there's a new one?

MOLLY: Yeah [laughs]

JAD: I didn't know.

MOLLY: The New York City one is new. And now there's a new Oregon variant.

JAD: Oh, snap. None of that was on our radar yet. We were just focused on the original.

MOLLY: The original, like what I call, like, OG SARS-CoV-2...

JAD: That was the perp that the doctors expected to see on all those mugshots, and they did see it on Day 1. But then when he went away and came back 34-ish days later and proceeded to get sicker and sicker in the hospital, they sequenced again. And this time, they saw something different. Instead of just one COVID virus inside him...

MOLLY: They saw pop up, like, little subpopulations...

JAD: They saw a whole bunch of different kinds.

MOLLY: ...With enough variation that they look different. What they noticed is like, oh, there's still the dominant, like, OG SARS-CoV-2 genetic sequence all over this body.

JAD: OK.

MOLLY: But there's, like, really small, quiet, like, subpopulations that are hanging around. And at the time, they were like, whoa, whoa, whoa. There's all these, like, variations. Whoa, has this person been infected by, like, six different types of this virus and they all happened to get into this...

JAD: Oh.

MOLLY: ...Person at the same time?

JAD: Oh, like, he somehow managed to have six different encounters with six different coronaviruses?

MOLLY: Or, like, Day 1, he had a case, and then it cleared.

JAD: Yeah.

MOLLY: And then maybe he got it again.

JAD: And then again and again and again. So the doctors, at that point, have a new thought. Maybe this isn't the same infection that he's had the whole time. Maybe these are separate viruses, entirely separate.

MOLLY: But then they realized, no, this is one strain that got in and just keeps changing, changing, changing...

JAD: Wow.

MOLLY: ...Changing, changing.

JAD: In other words, what the researchers came to understand - and they weren't trying to study this, they were simply trying to save the man's life - is that these subpopulations were one virus rapidly mutating, trying out new forms inside a human body. That when you have a human body that has a compromised immune system, the COVID virus will just rapidly experiment.

MOLLY: That the immune-suppressed body is like a playground of sorts because, like, nothing actually shuts the virus down, and it can replicate uninhibited. This one researcher said that at any point in time when you're, like, infected with coronavirus, you can have, like, at least a billion copies of the virus inside of you.

JAD: One billion?

MOLLY: And so - 1 billion.

JAD: Oh, my God.

MOLLY: And so that means that every time it replicates, it has a chance to, like, mutate, substitute, delete one little nucleotide.

JAD: But I thought the whole deal with the coronavirus - I mean, you and I...

MOLLY: Yeah.

JAD: ...Did a story about this - is that unlike the other RNA viruses, which are super sloppy, the coronavirus actually catches its own mistakes pretty well and doesn't mutate that much.

MOLLY: So it doesn't actually mutate that fast, but it still does just mutate. And every time it replicates, there is a chance that a mutation can set in and hence, evolution can happen, right? Because if you change part of your genetic code, you have a chance to, like, have new characteristics that let you survive in the world in a different way. And so if it's in the body and it's allowed to replicate a billion times with really nothing to stop it, every time it replicates, you throw the dice and something can happen.

JAD: So getting back to this guy. The researchers notice that he's got all of these different subpopulations of SARS-CoV-2 viruses, different kinds inside of him. But most of the new variants?

MOLLY: They're not really doing much. They don't have much dominance. Like, if you actually look at the numbers, I think it's something like - I may be making this up, but I don't think I am - but it's something like the original genetic virus is almost at 100% dominance, and every other little subpopulation is, like, less than 2%.

JAD: But then, she says, the doctors start to give this guy treatments.

MOLLY: So he gets to hospital Day 35. Day 41, they do a round of Remdesivir.

JAD: That's one of the few drug treatments available against the virus.

MOLLY: Day 54, they do another round of Remdesivir. And then on Day 63, they give him convalescent plasma from a donor. And this is, like, the, you know, blood you take from the body of a person who has successfully fought off CoV-2. And you put it in a person who's struggling to mount an antibody defense system to, like, take the virus down.

JAD: The thought is - and this is also a story we've done - the antibodies in the survivor's blood will help you fight off the virus. So Day 63, guy gets infusion of plasma.

MOLLY: And then on Day 65, they give him another batch of convalescent plasma. So they're, like, giving treatments, and then as they're giving treatments, they're taking samples and genetically sequencing them. And what they see is that by the time they check his samples in, like, the 80's - like, Day 82 or Day 81 - the different subtypes have, like, exploded.

JAD: Really?

MOLLY: And there are, like, very noticeable changes in the coronavirus inside his body.

JAD: More on that after the break.

JAD: This is Radiolab. I'm Jad Abumrad. Today, we are in Molly Webster territory. Actually, we are in the middle of a recording of her and I's weekly meeting, where she was telling me about some papers that have just come out that show how the SARS-CoV-2 virus behaves inside a single human body. I also just want to say before we rejoin that conversation, God bless the man in the U.K., the human beings who are at the center of these case studies. Papers kept their identities secret. Of course, we will obviously do the same. But in a few of these cases - not all - these people passed away. And they allowed doctors to study them in the final months of their life so that we could all learn something about the nature of this enemy. So endless gratitude to those people.

JAD: So before the break, Molly was explaining that in this man in the U.K. with a compromised immune system, the doctors first noticed that there were all of these variants of the coronavirus popping up, like all these different subpopulations, which were basically kept in check for a while. But then as soon as the doctors started trying to treat the patient with drugs and convalescent plasma, those subpopulations just explode.

MOLLY: And there are, like, very noticeable changes in the coronavirus inside his body. They see, like, these deletions that they call, you know, Deletions 69 and 70. And then, there's this other mutation at something called 796. It's very wonky, like all based on, like, amino acid positioning.

JAD: OK.

MOLLY: And suddenly, that virus variant is, like, dominant. And the OG SARS-CoV-2 virus variant has, like, become a quiet subpopulation.

JAD: Weird. So, OK, help me unpack what that...

MOLLY: Yeah.

JAD: I don't quite know how to hear that.

MOLLY: [laughs]

JAD: Does that mean that whatever it was in the plasma or whatever antibody army came in from the donor obliterated OG SARS, but it somehow allowed for this little subpopulation to just bloom?

MOLLY: Essentially. So what they say is like, oh, my gosh, we added in all of these antibodies, and we've just witnessed how SARS-CoV-2 might try and get around those antibodies.

JAD: So they basically witnessed evolution happening right in front of them.

MOLLY: Yes, that's right.

JAD: Is that the way to say it?

MOLLY: That is right.

JAD: And in the example you just gave, where there was a mutation in 69 or 70 or whatever it was, what does that actually do for the virus?

MOLLY: So the 69/70 deletion on its own makes the virus twice as efficient at infecting cells.

JAD: Really?

MOLLY: And they think that's because it can clamp on more tightly to your cells. And so if you have that variation, you bind more tightly, which means, like, when you inject your genetic material, it all gets inside.

JAD: Oh.

MOLLY: And, like, the cell can't shake you.

JAD: OK, so we're only at stage one here. So they see this scary mutation bloom in this one patient, this poor man. And then Molly says, as they kept trying to treat the man and then test him to measure the effect of those treatments, they saw this kind of real-time evolution just continue and escalate. They'd see all of these different populations come and go, rise, fall.

MOLLY: There might be two different types, and they rise and fall together. And then, there's some where, like, if virus Variant A is in there, D won't survive. I have this, like, little part of the paper cut out. I'm just going to read it to you.

JAD: Yeah, yeah.

MOLLY: It says, patterns in the variant frequency suggests competition between virus populations carrying different mutations. Viruses with the mutation deletion pair spike letters 796, 69/70 rose to high frequency during convalescent plasma therapy, but were then outcompeted by another population in the absence of therapy. Specifically, these data are consistent with a lineage of viruses with the NSP2I513T and RDP - no, RDRPV157L variant, which was dominant on day 66 but was outcompeted during therapy by the mutation deletion variant - that's 796 and 69/70. With the lapse in therapy, the original strain - which had acquired NSP15(N1773S) and the spike Y200H, T240I - regained dominance followed by the emergence of a separate population with the spike W64G, P330S variant. [laughs] That's, like, one paragraph from the paper.

JAD: So those are all different, like, subpopulations of coronaviruses that are kind of duking it out in this one guy?

MOLLY: This all happened in that one body...

JAD: Wow.

MOLLY: ...In that one patient in the U.K. This is just from that paper.

JAD: Dang. How many different corona tribes are we talking about?

MOLLY: Let's see. Wait, let's just see if we can do a quick count. So it's 501Y, 796, 69/70, 240I, 200H, 330S, W64G, I513T, V157L, N1773S - so something like at least 10 different populations rose and fell.

JAD: Whoa.

MOLLY: Viruses have stayed - like, these virus variants have existed in different parts of the body. Some of them exist all over globally. Some exist in different parts of the body. And they're all having different types of battles...

JAD: Whoa.

MOLLY: ... with the things that you're putting inside. And then, they're all having different types of battles with each other.

JAD: And they're seeing this in a single human?

MOLLY: Yes, a single person.

JAD: Wow. I don't know why, but this is completely blowing my mind.

MOLLY: Well, because one of the scientists described it as like, you can see a single body, a single patient as, like, a battleground or a training ground...

JAD: Oh, wow.

MOLLY: ...Where if you can look...

JAD: That's scary. Yeah.

MOLLY: (Laughter) Yeah, I know. It's like, if you can look in and follow the action, it's almost like "The Truman Show." But rather than us being in "The Truman Show," you're looking into "The Truman Show," like, watching the world...

JAD: Wow.

MOLLY: ... change and be manipulated. And you're like, now, I want to make it rain [laughs] Now...

JAD: Whoa.

MOLLY: Now, I will cause a tornado, and I'm going to see, like, how this world reacts to that. It's just like a whole microcosm inside one person.

JAD: And in that passage you read, it said that the different populations of coronavirus are competing. Are they fighting? How are they fighting?

MOLLY: It's not fighting. It's all about real estate, really. It's like, can you get in a cell?

JAD: Oh.

MOLLY: How fast can you get in a cell and how quickly can you replicate in that cell? If you think about the body, there is a limited number of cells for the virus to infect. And so if it wants to make lots of different types of itself - and I'm saying wants like it has, like, a wish - if it wants to make different types of itself, all of those different variants are fighting for the same real estate.

JAD: Huh.

MOLLY: Like, there's one paper about a patient who had corona - who was immune suppressed, had coronavirus for at least 70 days...

JAD: Whoa.

MOLLY: ...Asymptomatic. Eventually, it cleared their system, but they saw the virus, like, mutating inside this one person. There's something that medicine can witness - I think it's not even, like, learn, it's, like, actually like what we can witness is, in a sense, everything that is happening out in the wild, but, like, in one place...

JAD: Whoa, whoa, whoa.

MOLLY: ...Which happens to be - oh, yeah. I just did a big jump. Yeah.

JAD: You just made a jump, yet - which is where my mind was going, which was...

MOLLY: Yeah.

JAD: OK. So if we zoom out just a bit...

MOLLY: Yeah.

JAD: ...And we look at this one body...

MOLLY: Yeah.

JAD: ...And we see that these variations - these different populations that are rising and falling and competing for real estate - is there anything that they are seeing in these single human cases, inside of these single immunosuppressed people, that is mirroring what we're seeing out in the world in terms of all the different variants that are floating around in South Africa and Brazil and all that?

MOLLY: So that's where it gets really spinny. That's where it gets really trippy is that these patients end up being, like, a blueprint. Like, with them, you could see what the virus might do in the future. And to break that down, what they saw happen inside those bodies were the formation and creation of mutations that then appeared out in the wild six months later in, like, the U.K. variant, the South African variant and the Brazil variant...

JAD: Whoa.

MOLLY: ...That we're all, like, running scared from.

JAD: Whoa.

MOLLY: Five months before a scary virus variant showed up in the wild, they saw it inside a person.

JAD: OK, ok, ok. If they're seeing these mutations dominate in immunocompromised bodies before they dominate in the wild, does that tell them that they started in immunocompromised bodies and then got out into the wild?

MOLLY: Well, so that's an interesting question. So with these specific case studies that were written up, whatever happened inside the body never left the body because the patient was in a hospital the whole time and closed down.

JAD: Oh, OK.

MOLLY: But the thought now is - based on two of these case studies and a few others that have come out - is that probably at least the U.K. variant, that B.1.1.7, came out of an immunocompromised body because they said that variant has, like, eight significant mutations in it. And in order to get that in the wild, it would take many, many months. And if you were genetically sequencing like they do very frequently in the U.K., you would see the tracings of that change start to happen.

JAD: Oh, interesting.

MOLLY: You'd be like, oh, there's a change here. That's change one. There's a change here. That's change two. There's a change here. That's change three. But everyone said one day they woke up and there was a new virus with, like, eight significant changes...

JAD: Oh, wow.

MOLLY: ...Which makes them think that, like, that all happened in one hidden place and then, like, burst onto the scene.

JAD: That's so funny because that was the experience of consuming the news was like, oh, you know, CoV-2. And then, like, I remember hearing that, like, it doesn't mutate that much. OK, great. Whew.

MOLLY: (Laughter) Yeah.

JAD: Glad to hear that. And we've got these vaccines coming in - yay. And then suddenly - like, literally on a Tuesday - everyone was like, oh, snap. There's a variant.

MOLLY: We've got a new variant. (Laughter) Yeah.

JAD: We've got a new variant. And I'm like, wait, what? Where did that come from?

MOLLY: Yeah, where did that come from? Well, scientists had the same reaction. And what they're saying is, in these, like, immune-suppressed patients where you can witness the virus trying to adapt and where you can, like, step by step, see how it interacts with each treatment you give it, you can actually have a clue to, like, how the virus might change in the future because if...

JAD: That's bananas. That's so weird. It's like seeing the future.

MOLLY: It is. It is. Like, this one guy called it a crystal ball. Another guy called it a harbinger of, like, what's to come in the virus. And so, like, the...

JAD: That is so wild.

MOLLY: Yeah. The idea is, at some level, the virus can change a lot of ways, but at another level, it can only change so many ways. And so if you watch it mutate, like, a million, 2 million, 3 million, 4 million, 5 million times inside a person's body, and you see which variants dominate, there's, like, a pretty good chance that, like, OK, if the virus ever rolled the dice out in the wild and it landed on this mutation, this mutation would take hold and thrive.

JAD: So it's very possible it's going to hit the same mutations in different places independently, and we might be able to see that in advance inside one person.

MOLLY: Yes.

JAD: Yeah. You know, it's - what I'm struck by?

MOLLY: Yeah?

JAD: It's really - it's interesting to hear this story right now, you know? Because it's like from one moment to the next, it's really hard to know whether to feel optimistic or pessimistic, right?

MOLLY: [laughs] Right.

JAD: You know, it's like - and kind of the story you're telling - and it's weird to, like, look outside and see like, oh, it's sunny. Like, spring is coming. Like, the vaccines are rolling out. We might actually get to go have dinner with friends again. And everybody's, like, in this kind of like, ah, normal. Normal life is returning. The story you're telling me is like, is it? The virus is crafty. But then, maybe so are we. I don't know. It's weird to juxtapose what you're saying against that sense of, like, optimism that's out in the world because what I'm hearing is that simultaneously, this virus is figuring us out, and we're figuring it out.

MOLLY: Yeah.

JAD: And maybe we're turning the corner or maybe we're just in the first chapter of a very long story, you know?

MOLLY: Yeah. Like, I think I keep having a lot of visuals. Like, myself and I would say my community are probably at the lowest ebb I've seen them at in the last year, but also with a whole bunch of, like, hope just starting to, like, glimmer. I keep thinking of that "Midnight In The Garden Of Good And Evil" statue. Do you know what that is? It's, like, the little girl, and she has her hands up by her shoulders with her palms, like, up to the sky. And it's, like, good and evil are, like, weighted on each side. (Laughter) I feel like that feels like this moment in COVID to me...

JAD: Yeah.

MOLLY: ...Where you're holding, like, optimism and pessimism. You're holding, like, hope and just, like, utter exhaustion. [laughs]

JAD: Yeah.

MOLLY: ...Like, on both shoulders.

JAD: Yeah. Wow, yeah. That's exactly it. Senior correspondent Molly Webster.

MOLLY: This episode would not be possible without the counsel and interviews with Ravi Gupta and Jonathon Li. Thank you both so, so much.

JAD: Huge thanks to them. And thanks again to Molly and to you for listening. I'm Jad Abumrad. We'll be back with you again next week.

[LISTENER: Hi. My name's Lucienta. I'm calling from Bonn, Germany. Radiolab was created by Jad Abumrad and is edited by Soren Wheeler. Lulu Miller and Latif Nasser are our co-hosts. Suzie Lechtenberg is our executive producer. Dylan Keefe is our director of sound design. Our staff includes: Simon Adler, Jeremy Bloom, Becca Bressler, Rachael Cusick, David Gebel, Matt Kielty, Annie McEwen, Sarah Qari, Arianne Wack, Pat Walters and Molly Webster, with help from Shima Oliaee, Sarah Sandbach, Jonny Moens and Karen Young. Our fact-checkers are Diane Kelly and Emily Krieger.]

 

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