Science
The Viral Universe Inside Us
In this episode of 'Incubation,' host Jacob Goldstein explores the mysterious world of viruses, including those we don't yet understand—dubbed 'viral dark matter.' With insi...
The Viral Universe Inside Us
Science •
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Interactive Transcript
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Viruses are in the air we breathe, in the water we drink.
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They're in the ground we walk on, they're on our skin, they're in our bellies, they have
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us surrounded.
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And the wild thing is, we've only identified a fraction of them.
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In other words, not only are we surrounded and permeated by viruses, we're surrounded
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and permeated by viral dark matter, by viruses that we don't even know exist.
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We have lots of viruses in us and we have no idea what they're doing.
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And potentially in that dark matter, there are some answers to the questions on what
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are they doing there.
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I'm Jacob Goldstein and this is Incubation.
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Today on our final episode of season two, we're going out to the scientific frontier to
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talk about all the viruses we don't know about in the world and in our bodies.
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In the second half of the show today, I'll be speaking with a researcher who has recently
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discovered hundreds of families of viruses that live inside the human gut.
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And he's found a link that suggests some of those viruses could actually help kids stay
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healthy.
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But first, I'm going to talk with Ken Stedman.
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He's a professor of biology at Portland State University.
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He studies viral dark matter, which basically means he goes looking for viruses in wild
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places.
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To start, I asked him, how do you look for a virus that nobody knows exists?
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Couple of different ways, all viruses we know of by definition have to have a host that
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they infect.
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What we do is we'll go and collect samples in the craziest places we can find, usually
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volcanic hot springs, and then we bring back to lab and see if they infect our favorite
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microbes that also happen to grow in these hot springs.
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I've read a little bit about your work at Lassen Volcanic National Park in Northern California.
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So tell me about what's going on there.
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Tell me about boiling springs lake.
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So boiling springs lake, I like to describe as the biggest hot spring in the world that
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nobody has ever heard of.
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It's a slight exaggeration.
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The low temperature in the lake is about 130, 140 degrees Fahrenheit.
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And so what does that mean for finding weird viruses?
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Well, hang on, just a second.
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That's the temperature.
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I haven't told you about the pH yet, have I?
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Wait a minute.
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If you like the temperature, you're going to love the pH.
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Exactly.
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So the pH is about two.
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pH of two means it's acidic.
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It's highly acidic.
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So not great for soaking is what you're telling me.
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We've seen people walking up there and they're swimming gear and we tell them not a real
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good idea.
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So you go to this hot acidic lake and what do you do there?
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We just took about 200 liters worth of water from the lake and then purified all of the
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virus size particles in it, then determined what their genetic sequences were.
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What we call a metagenome.
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But basically all the viruses, what genes do they have in them?
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So you're basically just pouring this acid into a machine and saying, tell me all the
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genes that are in here?
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Or less?
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Yeah.
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So one of the things about viruses, which makes viruses incredibly unique, is they have
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what we like to call it a Varian.
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It's the virus structure.
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So the lunar land or module kind of thing.
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Right.
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Your classic virus looks like a little lunar land or like a pod and then little legs coming
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out.
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Absolutely.
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And it's relatively small.
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So what you do is.
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A cage, right?
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That's the classic phase.
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That's the classic phase.
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That's the classic phase.
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That's the classic phase.
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That's the classic phase.
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The LAY is on the bacteria and then inserts its genetic material.
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Injects it exactly.
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But even if you think about, you know, SARS-CoV-2, virus that causes COVID-19, also is a little
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no bag, which has genes on the inside of it.
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Sure.
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So you break up in the bag and you throw it into the machine.
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And then it gives you back hundreds of thousands of sequences in our case.
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Now millions of sequences with the newest technology.
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So millions of genes, hundreds of thousands of genes, but they're not genes, they're
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gene fragments, they're little pieces.
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Now at first, you just want to look at what those little pieces are relative to known
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sequences.
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Uh-huh.
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The dark matter is going to be, you know, those little pieces that don't match anything
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and the light matter is going to be stuff that does.
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90 plus percent of the sequences that we got back of our hundreds of thousands of sequences
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didn't match anything.
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And what did you think when you saw that?
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Oh, it's like other environments.
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Other people would see very similar things.
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So you do this with seawater, you do this with things you find in soil, 90 odd percent
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plus or minus don't match anything.
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Does that mean that we don't know about 90% of the viruses that are out in the world?
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Is that broadly what that implies?
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That is exactly what it implies.
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And it's not just, you know, weirdo boiling acid lake.
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How about just in the dirt if I just went into my yard and dug up some dirt and send it
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to somebody who could put in one of your machines?
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What percentage of the viruses in my backyard are known to science?
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Roughly.
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20%?
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Wow.
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80% are dark matter or unknown.
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I love that.
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It keeps us employed.
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Yeah.
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Right.
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So, okay.
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So you get this result back.
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It's 90% is unknown.
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And so what you just have is like a genetic mess that you don't know what to do with because
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it's not like each little fragment is like, oh, that's a new virus.
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It's just these are weird fragments that we don't understand.
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Yeah.
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Exactly.
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Weird fragments that we don't understand.
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But one of the other things that we found is some of the fragments that we could actually
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identify didn't look like sequences that we should have found.
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Meaning not only are they different than anything that's been found before they they're like
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too weird.
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They're like, wait, that doesn't make any sense.
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How could that even be?
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Exactly.
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Did you think you had made a mistake of some sort?
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Absolutely.
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The machine was broken.
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We thought that we had absolutely screwed up in this case.
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So we've got genetic material for viruses.
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You got RNA viruses.
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You got DNA viruses.
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Right.
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So basically, a virus is just like a bag with genetic material in it.
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And there's some viruses have DNA and some viruses have RNA.
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And even though these are like two types of viruses, sort of historically, evolutionarily,
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they're like really different from each other, right?
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DNA viruses and RNA viruses.
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We always thought we're completely different relative to each other.
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And if you think about the evolutionary relationship between RNA viruses and DNA viruses, there basically
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seems to be almost none.
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Like how big is the gap sort of whatever evolutionarily?
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How different are DNA and RNA viruses?
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So the difference between DNA and RNA viruses is probably billions of years, evolutionarily speaking.
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Okay.
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Okay.
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I was going to say like, it's like as big as the difference between mammals and reptiles,
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but it's way bigger than that.
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It's probably more like the difference between bacteria and people.
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Bacterian people, exactly.
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Much more like that in terms of evolutionary difference.
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Wow.
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Okay.
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So there are these profoundly different things.
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So we sequenced a bunch of DNA, put it into our machine, and said, hey, get some DNA sequences.
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And then some of those, approximately a couple of thousand sequences that actually match
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something in those sequences were things that looked like RNA viruses in terms of their
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sequence.
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But it's DNA that you're seeing.
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But we'd sequence DNA.
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Yeah.
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But we, and when I say we, mostly a graduate student working in our group, Jeff Deemer,
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he then started to try and put some of these pieces together.
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What he found was those pieces that looked like RNA viruses were connected genetically
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to sequences that looked like DNA viruses.
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Okay.
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And connected like physically, like they were physically on the same piece, a chain
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of genetic material.
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Exactly.
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And then what we did is we went back to the samples that we collected from boiling
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springs lake.
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And instead of pouring them into the machine to get the sequences, we then made many, many
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copies of whatever this piece was and this piece was to show that we're actually connected
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to each other.
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So there are these, what we're now calling cruciviruses that appear to have evolved by
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DNA viruses and RNA viruses coming together.
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It's okay.
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So we thought these were like totally different kinds of viruses.
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But now you have discovered this new kind of virus that's kind of like a cross between
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the two of them, right?
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What does that mean?
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What does it mean for how we think about RNA viruses and DNA viruses?
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It means that there's communication between them and there's this combination.
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So it's not billions of years of evolutionary difference, which is what we thought.
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Now it looks as if they can be exchanging genetic information with each other, which is
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really kind of revolutionary in terms of thinking about virus evolution.
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And what it means is we always thought DNA viruses evolved like this and RNA viruses evolved
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like this.
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But if they can exchange genes with each other, that kind of throws a lot of what we think
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about virus evolution kind of out the window.
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Turns out that these viruses in and of themselves are just so different from any other virus
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anybody's ever seen before in terms of their shape, in terms of their genes, what is in
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them.
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So you and your colleagues found this crucivirus in the boiling acid lake.
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I know that since then a number of other of these cruciviruses have been found.
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So just give me the landscape, give me what we know so far of like where are they, what
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are they doing, etc.
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We do not know what they're doing.
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Crucivirus has been found in boiling springs lake and dark dick lakes in deep sea sediments
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off the coast of Greenland in Korean air samples.
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Isopods off the coast of Oregon, monkey feces and dragonfly guts, soil just outside the
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lab at Portland State University.
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Basically anywhere that we have looked, we found these cruciviruses, very low amounts
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of them, but seem to be very ubiquitous.
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So where are they everywhere?
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Love it.
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What are they doing?
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We don't know.
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Are they in my body right now?
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Probably in your body right now.
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So these things are all around us all over the world, possibly in our guts and nobody
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knows what they're doing.
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That is exactly correct.
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I love it.
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Me too.
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So what do we know about like what they're doing?
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We're trying to figure out what they infect.
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We think they're infecting microbial eukaryotes, so things like fungi or produce these paramecia
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things, you know, swimming around in lakes.
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Are those things also, are there also organisms like that in our bodies?
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They definitely are.
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Is that part of the microflora?
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Yeah.
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We have a eukaryotic microflora.
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Mostly these are going to be fungi, some kinds of yeast, etc.
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But there are many other of these.
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And again, this is something which has been not very well studied.
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So you kind of put your environmental viruses have not been well studied.
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These microbial eukaryotes have not been very well studied.
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So you put those two together extremely poorly studied.
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Very dark.
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It's a very dark matter.
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Very dark matter, but at the same time, really exciting, because there's so much to discover.
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Like, why does microbial dark matter matter besides being cool?
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I think it's an area where we can make discoveries.
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There's so much we don't know.
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We have lots of viruses in us, and we have no idea what they're doing.
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And potentially, in that dark matter, there are some answers to the questions on what are they doing there?
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So I think that that's a very important thing to think about.
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Not just how are they making us sick, but how are they keeping us healthy?
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How might they get out of balance at times and contribute in indirect ways to sickness?
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Certainly seems plausible.
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We know that happens with the bacteria in our gut.
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Yeah.
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I think that that's a very reasonable thing to think about.
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And then just in a larger ecological sense, you know, understanding the ecology,
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there's still so much that we don't know.
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I think understanding the virus's role in not just us, but also in life on our planet.
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I think understanding that dark matter will really help us understand what's going on with all of these different viruses.
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I appreciate your time. It was a fun conversation.
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Yeah, it was fun conversation for me too.
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I learned things, so thank you for that.
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Good.
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Ken Steadman is a biology professor and extreme virologist at Portland State University.
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His work and his team's work are expanding our idea of what a virus can be.
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In a minute, discovering hundreds of kinds of new viruses that live in the human gut.
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I'm going to go out on a limb and say, the most underrated viruses are phages.
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Phages are the viruses that infect bacteria.
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They're the most abundant biological entity on Earth and they're killers.
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Every other bacterium on Earth gets killed by a virus every day, actually.
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That's wild to think about.
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Yeah, it really sucks for them.
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Shiraz Ali Shah studies the phages that live inside people.
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He's a senior researcher on a project called Capsack.
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The Copenhagen perspective studies for asthma in childhood.
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The project is following hundreds of kids from birth into childhood to try to understand the causes
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of asthma. Shiraz focuses on the human virus.
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The universe of viruses that live in the human gut.
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And he told me that studying the virus from birth is really important.
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In the first year of life, the baby has an immune system that has not yet matured.
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So it does not know how to distinguish friend from foe.
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What happens in the first year of life is that the immune system is still trying to get to know
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what is it supposed to attack and what is it not supposed to attack.
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And it seems that so there's more and more evidence showing that if you are not
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exposed to a diverse array of good bacteria in the body and on the body within the first
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year of life, then the immune system is not properly trained and then you're way more prone
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to chronic inflammatory or immune diseases in the future.
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Like asthma.
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Like asthma, like allergy, like asthma.
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Even stuff like depression, anxiety, inflammation,
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inflammation, linked heart disease, most definitely cancer, most definitely diabetes,
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most definitely yes.
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So okay, so now you're getting into some of what you study, right?
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Tell me about your work on this.
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So this is a place called Copsack, Copenhagen perspective studies for asthma in childhood.
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It's a place where they're trying to understand how asthma works in kids.
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Exactly.
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And so the way that they do this is basically they have a bunch of kids that were born in 2010
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and they've been following them since the mom's got pregnant and today they're like 15 years old,
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right?
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What they're doing is they're recording as much data on these children as possible,
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as humanely possible.
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Like where do they go to to date here?
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How many siblings do they have?
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But also blood tests, which chemicals do they have in their bodies, in their pee,
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what bacteria do they have in their poop, in their lungs, etc.
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So we have like jigger bites upon jigger, but also their own genes,
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their own genomes we also have.
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And so just to be clear is the idea of doing all this and starting
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before the child is even born, is the question they're trying to answer,
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why do some people get asthma and others don't?
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Exactly.
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Because even though asthma is such a common childhood kind of disease,
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it's very poorly understood.
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And this is not only the case for asthma, it's also the case for all the other chronic disease,
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basically that killed adults like cancer, heart disease, diabetes,
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you know, chronic respiratory disease, multiple sclerosis, you know,
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all of these.
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And so maybe by collecting all of this data on the children,
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we can start predicting based on the data who's going to get which disease.
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And based on that, maybe we can figure out, okay,
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if we do this, this and this, maybe we can avoid that and that and that,
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and that chronic disease.
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Every time the kids visit us and they do so once a year,
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we take as many samples as we possibly can.
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Right. So you have this whole poop library going over the kids whole lifetime that you can sort of
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examine over time.
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Yes.
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And how many kids are in this cohort?
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So we have two cohorts.
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What I'm going to talk about today, the data is from the Cops Act 2010 cohort.
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So they were born in 2010.
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They're like 14 years old now, right?
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And the 2010 cohort is 700 kids.
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So the cohort you're following is 700 kids who are born in 2010.
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You're coming into this as a person who has been studying
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viruses that attack bacteria.
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Exactly.
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For our purposes here.
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Yes.
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And so when you get there, what do you do?
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I get there.
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And then my boss, he basically explains me some of the studies that they've been doing on the
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bacteria in the gut so far.
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And one of the major studies that they did just like one year before I came
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was that they found that in one year olds when you're basically still a baby,
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the bacteria that you have in your gut when you're a baby end up determining whether or not you
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get asthma as a five year old.
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And I was like, what?
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I mean, how is that even possible?
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And so what the general picture is that if you have only a few different bacteria in your gut
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when you're one year old, then you have a much higher risk of getting asthma as a five year old,
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right?
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But if you have like loads and loads of different bacteria in your gut when you're one year old,
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then you're much more protected from asthma as a five year old.
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And so basically that got me thinking, wow, that means that most bacteria are actually good for
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us. I mean, there are a few bacteria, maybe a hundred species in total that can cause infections.
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Sure.
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But the total number of bacteria in nature is like a hundred million species at least.
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So those other hundred million are not causing.
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It's just one out of a million bacteria that is bad and the other one...
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One in a million gives them a bad name and a fact that they're keeping us healthy.
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So go on.
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So I was thinking, okay, if that's the case for bacteria, then what about viruses?
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What if it's the same for viruses?
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What if the only viruses that we know about are the ones that cause disease?
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And there are loads of other viruses that are actually good for us.
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That's what I was thinking back then.
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But the funny thing is that this other guy called Dennis Nielsen, who is a professor at
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Copenhagen University because he's an expert at figuring out which viruses are in a sample.
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He basically said, okay, you guys found this thing with bacteria.
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Why don't we look at the viruses in the gut and maybe we can find something similar or even
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cooler?
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And so when I started Copsack, this data set is already in the process of being generated.
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Dennis has taken 700 fecal samples, extracted viral particles, and then he has basically
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put them through a sequencer and we're getting in sequences from each child.
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Sequences, meaning genetic sequences that allows you to determine what viruses.
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Yeah, exactly.
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So you get there in 2017 and another researcher is already just starting to look for
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what viruses are in the fecal samples of these kids in the study.
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How do you get involved to what do you do?
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What happens?
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Back then, what people used to do when they got gut viral data is that they would then take all
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the DNA sequences that came out of that and they would then blast it.
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It's what it's called against a public database of viruses.
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Viruses that scientists have already discovered and know about so that you can figure out which
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viruses are in those samples.
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The problem is that most of the viruses in the human gut at that time were unknown to science.
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So by doing that exercise, you're only going to get a list of contents of maybe 10
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viruses, whereas the actual diversity in these samples is going to be like maybe 10,000 or maybe
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a thousand or something.
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Right, but the problem is you don't know what you're looking for.
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Right?
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You just have this random strings of genetic material and if you're trying to find newly discovered
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viruses, well, how do you even do that?
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In fact, how do you do it?
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So what we first do is we assemble all the sequences like a piece of a puzzle
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and get extended so that you get larger and larger fragments of DNA that must have come from
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the same virus.
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You have this weird set of little chains and you need to put together like, ah, here is a virus
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and here is a different virus.
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Yeah, exactly.
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And so that's then what happens.
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Now we got a bunch of DNA sequences for me's child.
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So that then what I do is I annotate all the protein coding genes on these strands of DNA.
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So that I know which proteins are encoded on each DNA fragment.
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And by looking at those proteins, what they encode, what kind of functions those
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proteins to encode, I can start making qualified guesses and terms of, okay,
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this one must be a virus and this one must not.
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Are you like actually looking at sequences and like looking like like one looks at jigsaw
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puzzle pieces on a table?
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Yeah, I guess you could say that I mean, I can look at the protein coding genes that are encoded
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on each cluster and I manually look through 10,000 clusters of sequences and out of those 10,000
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around 300 of them were the ones that I could constantly didn't say were viruses and they correspond
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to viral families.
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So when you're saying you're manually looking through 10,000, is that like years of work?
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Yeah, it took five years actually, four years.
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Yeah.
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And so you do this work, you spend four or five years going through this data,
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how many viruses do you find that live commonly in the human gut?
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In the children who we looked at and that's all we can really say anything about.
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There are 10,000 species of viruses distributed in around 250 viral families.
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So you discover all these new viruses?
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Does that mean you get to name them?
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Super good question.
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So this is, this was actually a huge issue for us.
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So now we're finding 250 new viral families.
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How are we going to present this in a paper?
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Right, it can't just be like A, B, C. You're going to write out a letter.
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Exactly.
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And so a lot of different suggestions were on the table.
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Pokemon was one of them.
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Did you have a Pikachu in mind?
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That's the first question.
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Who gets to be Pikachu?
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Yeah, exactly.
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Pikachu, Verde, you know, Charmander Verde, etc.
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And then a colleague of mine, Jonathan, who's the third author of this paper,
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he suggested why not just name them after the kids?
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Are the kids in the study?
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The kids whose poop had the viruses in it?
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Exactly.
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So we shuffled all the names and then we just distributed them over the 250 viral families.
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So what are some of the names?
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Christian Verde, Lucas Verde, Josephine Verde.
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Yeah.
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So you do this work.
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You identify all of these previously undiscovered viruses that live in the guts of these kids.
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Do you then start to try and understand the health implications of different
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viral homes, etc?
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That was the entire purpose of this exercise, right?
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So those bacterial phages, which were also by far most of all the families.
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The viruses that infect bacteria.
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Exactly.
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Those bacterial phage families can be divided into like two broad categories.
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They're the virulent bacterial phages and the temperate bacterial phages, right?
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The virulent bacterial phages, they just kill the bacteria.
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Okay.
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Whereas the temperate bacterial phages, they integrate themselves as pro-phages on the bacterial DNA.
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So first you look at the viruses that infect bacteria and then you divide those into two categories.
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And you say there's the viruses that just destroy the bacteria and there's the viruses
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that infect the bacteria but don't destroy it.
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Exactly.
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Does that tell you anything clinically?
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Yeah.
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So Christina, who was the first author of that paper that came out in Nature Medicine earlier this year,
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she found that it was the temperate bacterial phages that were predictive of later asthma.
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For some reason, the children that end up developing asthma by age five,
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they had way more temperate phages, bacterial phages, and their gut at age one.
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And so the key data set is you're looking at the viral of the kids at age one
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and trying to understand, is it predictive of asthma by age five?
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And what answer do you and your colleagues find to that question?
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What we find is that there are more temperate phages in the kids who end up developing asthma
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later. Then we look at the temperate phages specifically and look, we look at which families
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of temperate phages are predictive of disease.
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And then what we find, which is kind of surprising and funny, is that 19 of the 250 families we
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had in total, 230 of them were temperate, 19 of them, if you look at the amounts of those 19
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families in the children, you can actually distinguish between kids that end up developing asthma
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as five year olds or not. And what's interesting is that the kids that develop asthma as five
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year olds have less of these 19 families than the healthy ones.
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Aha. So is it right that these 19 families of viruses seem to maybe be protective against asthma,
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like having more of these particular viruses is correlated with a lower risk of asthma?
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Exactly. That's very interesting. Now I get nervous that even though it passes some set of
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statistical tests, this is going to be a fluke finding. You know, it's going to be due to random
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chance. And so what I really want you to do is go run this test on some other kids at age one,
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make your prediction and have it come true by age five. Is that a reasonable thought?
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That is super reasonable. I have to say Jacob. And this is also something that nature medicine
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asked us to do. And we said, well, nobody else has viral data for so many children. Unfortunately,
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such a cohort does not exist. You know, Copsack 2010 is one of the most deeply phenotype cohorts in
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the world. So we were not able to replicate it in another cohort. Yeah. Yeah. So you have this
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finding that a certain family of virus seems to be protective against asthma.
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Are you able to understand anything about what causes a kid to have or not have this
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apparently protective of family of viruses in their gut? Super good question. I don't know. I think
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it has a lot to do with different environmental factors that end up determining for random reasons,
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which viruses end up in the guts of these children. I mean, when you say you don't know,
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does that mean there's no way in your data set to investigate the question?
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There definitely is. And this is what we're doing. It's ongoing.
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So what we do see is that there's a huge correlation in, for example, where the kids live,
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whether they live in a rural environment or like a city environment. The ones that really live in
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a rural environment have a much more diverse, you know, ecosystem in the gut in terms of the bacteria.
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We haven't looked at the viruses directly yet, but we have an intuition that it is same might
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apply for viruses as well. Also, there's there are huge, you know, kind of links to the diet,
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the kind of food that you eat, whether it's very processed food or whether it's like whole foods,
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whole foods are generally associated with a way, way higher diversity. So if you want to increase
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your chances of having the good viruses in your gut, then it's a good idea to live, you know,
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early or at least spend some time in nature. It's a good idea to eat whole foods instead of
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processed foods, etc. Okay. So that's based on like what we know about bacteria and what you suspect
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is true also for viruses. Let me let me ask you this. When you think about the future,
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what do you hope we know about the viral in five, 10, 20 years that we don't know now?
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I'm hoping in the future that we have a much better overview in terms of what kinds of chronic
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diseases are caused by deficits in which viruses, but also in bacteria, so that we can prevent maybe
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10, 20, 30 years from now, we can prevent a lot of chronic diseases that cause a lot of problems
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today, that those can just be prevented by giving babies viruses or bacteria or even adults.
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Thank you so much for your time. It was great to talk with you. Good to talk to you too.
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Shira's Shah is a senior researcher at the Copenhagen University Hospital Gimphofdom.
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Thanks to both of my guests today, Shira's Shah and Ken Stedman.
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Incubation is a co-production of Pushkin Industries and Ruby Studio at I Heart Media.
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It's produced by Kate Furby and Brittany Cronin. The show is edited by Lacey Roberts.
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It's mastered by Sarah Brugher, fact checking by Joseph Friedman.
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Our executive producers are Lacey Roberts and Matt Romano. I'm Jacob Goldstein.
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Thanks very much for listening to this season of Incubation. I hope we'll be back next year with season three.