Radiolab - Antibodies Part 1: CRISPR

Episode Date: June 6, 2015

Hidden inside some of the world’s smallest organisms is one of the most powerful tools scientists have ever stumbled across. It's a defense system that has existed in bacteria for millions of years and it may some day let us change the course of human evolution.  Out drinking with a few biologists, Jad finds out about something called CRISPR. No, it’s not a robot or the latest dating app, it’s a method for genetic manipulation that is rewriting the way we change DNA. Scientists say they’ll someday be able to use CRISPR to fight cancer and maybe even bring animals back from the dead. Or, pretty much do whatever you want. Jad and Robert delve into how CRISPR does what it does, and consider whether we should be worried about a future full of flying pigs, or the simple fact that scientists have now used CRISPR to tweak the genes of human embryos. As of February 24th, 2017 we've updated this story.

Wait, you're listening. Okay. All right. You're listening to Radio Lab. Radio Lab. From W. N. Y. C. See?

Yeah. And NPR. This is Radio Lab. I'm Jad Abumrod. I'm Robert Krollowich. All right, so let me explain to you how I got started with this. You were some kind of an affair? Yeah, so I'll tell you how I was at a party. Party.

It was a conference where they had a lot of different people. of different disciplines come together. You know one of those. There are panel discussions of various things. We were at one of the functions and it was a situation where dinner hadn't yet been served and there was a lot of booze being served.

Everybody was drunk on an empty stomach. So I was standing there with some biologists. Oh, they're the fun ones. The drunk biologists, yes. My people, apparently. And they started to lose their shit,

like genuinely lose their shit. about this thing called CRISPR. And like, I have never seen scientists this excited about anything. So I was like, what is this thing? What is CRISPR? And they were trying to explain it to me, but they couldn't slow down enough

for me to get it. I gathered it had something to do with genetics. And then at one point, one of the biologists turned to me. He was like, I'll tell you what it is. I can use CRISPR to take a little dog and poof, make it into a big dog. Give me a chihuahua.

I could turn it into the size of a Great Dane. And I was like, no, you can't. He's like, yes, I can. I could do it with CRISPR. I was like, what the hell is this thing? You want me to sit here as usual? Yeah, if you sit here, I will get out. I mean to imply in any way that we'd be sitting here together.

So what happened was I came back and I immediately called science writer Carl Zimmer because I just figured for this kind of thing, this is a Carl thing. I got to talk to Carl. So I basically asked him, like, why all the fuss? Maybe it was just the alcohol, but maybe there's something really happening here. Oh, there's something totally happening here. I mean, it's big. He started at the beginning.

So you can actually find, like, the first reference to CRISPR in a 1987 paper from some Japanese scientists. They basically described something weird in E. coli, and they said, we don't know what this is. E. coli are bacteria inside humans. And like all living things, ecoli is made up of DNA, A's and T's and Cs and Gs. And what happened was that these scientists

were reading a chunk of that genetic code when... They found this really super... strange stretch of DNA. Strange how? Well, so basically what it was was five identical sequences in a row. And then they were separated by very short sequences in between them that were all different from each other. These little blurbs would be like, and they looked at this and they're like, what?

This is nothing like we've seen before. Repeated sequences in bacterial genomes are kind of unusual. Seems very strange. Some biologists felt that, you know, there must be a purpose for these. Among those purpose seekers? Jennifer Dowdna, University of California, Berkeley. She's a cell biologist. Yeah.

So it's Dowdna, not Dudna. It's Dowdna. I used to be called the dude sometimes in school. In the movie, she will be played by Jeff Bridges. Right. Anyhow. As time goes on, scientists start seeing these little repeat, blurp repeats everywhere. Yes.

Or at least in bacteria. Lots and lots of species of bacteria they say, hmm, okay, wait a minute. That's kind of cool. They're finding it so often that they decided

they had to give it a name. Is this where the name CRISPR comes from? Yes. The full official name is Clustered, regularly interspaced, short palindromic repeats.

Oh my God. I don't know why they called it CRISPR. It's kind of a... Crispur. It's like a furniture manufacturer or something. It sounds like an app.

Yeah. CRISPR. CRISPR. But now, scientists had this puzzle. If nature at this level preserve something intact here and here and here

and here and here and here and here and some of these here's are creatures that have been around for hundreds of millions of years, you figure, well, whatever this is, it's doing something. It's doing something. But what? It doesn't take very long before the first big clue comes up.

All right, fast forward. 2005, now scientists have these big, searchable databases of DNA sequences. So some scientists think, well, let's do a search. Let's see if these repeating patterns we keep finding match anything else that's out there in the world.

And these scientists are using computers to just line up these stretches of DNA with thousands upon thousands of different species and then click. All of a sudden, they discover that those bits of DNA between the repeats, the stuff in the middle, those blur, These are matching virus DNA.

Like, you can find viruses with genes where these little, you know, these little... So the bacteria had virus inside of them? Yep. Does that mean that a virus brought it into these cells? Does this tell you anything about the origin of it? The first recognition was, this is virus DNA. Somehow, all these bacteria have little snippets of virus DNA wedged in these particular places in their genome.

which is a little weird if you think about it. I mean, these are totally different creatures. It would be like inside a human finding a little bit of mosquito DNA. How do we interpret this? Well, actually, there was one scientist, his name is Eugene Coonin, who looked at these results and just said, okay, I get it. It's a defense system. What?

Why would he think that? Because he's a brilliant man. What do you mean? If I went to a large sanitation dump and I found a teeny bit of human hair, Why would I think, oh, I get it, it's a defense mechanism? I wouldn't know. It's just like a bit of human. Right.

Well, you see, that metaphor might sort of betray your lack of skill in microbiology. I'm just saying, like, this is not a dump, all right? This is bacteria are not going to just let virus DNA get into their genes willy-nilly. Okay, remember, viruses are the big enemy. Right. If you're bacteria, viruses make your life a nightmare. Think about it in the ocean, okay? The ocean is full of viruses,

and viruses kill up to 40% of all of those bacteria every day. Really? Every day, yeah. And we know that they have defenses. What Eugene Kuhn said was, okay, I'm going to bet that these bacteria are somehow grabbing pieces of DNA from viruses, and then they're storing it, and now they have a way of recognizing those viruses if they come in later.

Ah. It's like little Polaroid shots of the enemy. Right. Know thy enemy. Yeah, like a most wanted poster. What you call the mugshot. This is Eugene Coonan. Leader of the evolutionary genomics group at the National Center for Biotechnology Information.

He's the guy that Carl referenced who thunk up the whole idea that maybe these bits of virus DNA inside the bacteria, is the bacteria trying to defend it? But really, if I would credit myself with anything here, it was not so much guessing this, because, you know, when you see these identical sequences, that gets pretty obvious. It is figuring out how the mechanism was likely to work. So can you walk us through how the mechanism is likely to work? Oh, right. What happens is, you know, when a virus comes in to... a cell, it just kind of explodes and just kind of releases naked genes, basically.

If you're this bacteria, these things might take over your cells, so you've got to respond. Most of the time, you have multiple weapons of defense. If you've never seen this virus before, usually the first thing you do, says Eugene, is you send out these enzymes. To attack the viruses, they're sort of like the ground troops, and they fight really hard. But much of the time, they fail, and then no one will hear. hear about you again. They're not terribly sophisticated fighters so very often,

the virus takes over. The bacteria dies. But there is some non-zero probability that you actually survive the attack. If you do, then what the bacteria will do is send in some new enzymes to basically clean up, to go out, find any stray

viruses. And then cut the enemy DNA into suitable small pieces. In here, he says, where you get to the storage part, those enzymes will then take those little bits of virus and shove them into the bacteria's own DNA, right in those little spaces between the repeats. Right there and nowhere else. So I use those spaces in my own DNA as a storage facility?

Yes, if you do, you use it as a memory device. Because here's what happens. Next time that virus shows up, sprays its genes everywhere. and now you are prepared. And this is where the CRISPR story really gets going. Because instead of sending out the ground troops, who are probably going to get their asses beat, now you can actually send out the big guns.

And in fact, what the cell does is it will manufacture these special molecular assassins. And they'll give those assassins a copy of that little bit of virus DNA it has in storage, basically saying, here, take this mugshot, If you see anything that matches this pattern, kill it. Ew. And these attackers, do we know what one of them looks like?

Yep, so we know what the protein looks like. It actually looks, I would describe it a little bit like a clamshell. Sort of imagine Pac-Man, but kind of misshapen and rough. And each one of these guys... What it has is a copy of that virus DNA. It's got the mugshot. That it's kind of waving around. What then happens is that...

Whenever the Pac-Man bumps into some virus DNA, It pulls apart the DNA and zips it. Reads it. If it's not the right one, it goes on. Nope. Mm-mm. And if that RNA has the same sequence, then click-click, it just locks in.

And if that happens, then the DNA is trapped, and molecular blades come out. And chop. Cutting its head, the mighty blow. Yeah. Wow. So this is smart scissors. So it's like, are you like the thing I got?

Are you like the thing I got? You're like the thing I got. Snip! All right, now we're going to kill. Oh, I see. And it has to be an exact match. When scientists first discovered this whole system, they were fascinated. They were like, they were working it out.

They were like, oh, okay, then this happens, and this happens. This happens. Cool. But then, in walks. The dude. Jennifer Dowdna with a crazy idea. I don't know if it's crazy, but radical. This could be an amazing technology.

This is a tool. This is a tool. Yeah. Right. This is a tool that we can use to cut DNA where we want to cut DNA. Her basic thought was, why don't we turn this defense into offense? Because these things, they seem to be really good at cutting, and yet they only seem to cut the things that are on their mugshot.

So maybe I could just replace what's on their mugshot. So instead of them going after viruses, maybe they could go after a gene that causes Huntington's disease or hemophilia. For example, and this is actually something that's been done, say you got a mouse with something like hemophilia. Okay. This is a disease that's caused by one bad gene. So what you do is you take these little surgeons, you give them the mugshot for the bad gene. Then you stick the surgeon with the new mugshot in a mouse. Then you set it loose.

And just like it's programmed too, it will find that gene. And click, click. chop. The scissors will end up cutting exactly the gene you wanted to cut. So the bad gene's gone. Now the question is

how do you put in the good gene? Right. It turns out, actually, according to Jennifer Dow, now that that's actually not as hard as you would think. Really? Yeah, apparently what you do is just throw this new good gene

kind of in the neighborhood of where the old gene used to be, just in the general vicinity. You don't have to get super precise. I mean, it turns out that You know, there are repair enzymes that are probably continually surveying and checking for breaks. She says what will happen is it inside the cell? These repair crews, they'll come along, they'll see the break.

They'll see the good gene just sitting there next to the break. They'll be like, all right, I'll just stick it in. Put the pretty guy in this space. Exactly. So we take advantage of a natural repair pathway that cells have. They trick both the cutters and the fixers. Yeah, now we're not assassinating anymore. Now we're actually engineering.

We've gone from killing to refashioning. Although, haven't we been designing genes, doing a form of genetic engineering for, I don't know, like 30 years? Yes, but not like this. Genome editing technologies have been around for a long time, but none of them have been as powerful as CRISPR is. That's Beth Shapiro from UC Santa Cruz. She was actually one of the biologists that I drunkenly talked to at that thing. Was it a modern art museum? I can't even really remember.

I don't remember either. It must have been quite an evening to have the setting be so vague. Anyhow, here's how she put it to us. Back in the day, this was just like two years ago, you would have these gene editor things. You would take one, put it in a cell. And what happened before was you would give it some instructions about where to go. And it might go there, but it might go to somewhere that's kind of related to where that was.

So it's like, you just take it right at Staten Island, but it takes a left. And not only would it take left at Staten Island and not find there, but it would have cost you a fortune and taken up six months of your time to get that thing. And now, you know, it's really easy. You just give it that mugshot. And it goes, I'm going to find that guy, exactly. So it seems to be pretty precise. And it's cheap. Like the old tools would set you back about five grand just to use them once.

CRISPR, about 75 bucks. And here's the kicker, says Carl, it seems at the moment that you can take these things out of bacteria, stick them into almost any other creature. And it still works. You can use the same CRISPR system on anything. Can you like do it if corn is vulnerable to a certain pest, you can do it in corn? Do it in corn. Do it in corn. Do it in corn. I am waiting for someone to say, CRISPR doesn't work in species X, and I have not heard of that. So basically what you have for the first time in science is this gene editing technology

that is cheap, precise, and possibly universal. And Jennifer Dowdena says the moment the full impact of that, landed on her? I literally had, you know, the hairs on the back of my neck were standing up. Just processing the fact that this thing exists, you know, and that you could actually program it to cut DNA. And just like this molecular scissors, and I can just program it and it cuts DNA wherever I want.

It is amazing unless you think about it further, which we will do in just a moment. I feel a cloud coming in over the horizon. Just over there. Do you see? I see it's getting sort of dark over there, but we'll be right back. Hi, this is Lauren from Atlanta, Georgia. Radio Lab is supported in part by the Alfred P. Sloan Foundation,

enhancing public understanding of science and technology in the modern world. More information about Sloan at www.sloan.org. This is Radio Lab. I'm Chad. I'm Ron. I'm Robert Crulwich. Okay, so clearly, though, the possibilities are there to use CRISPR to treat disease, right? But what if you could get a little more fanciful, right? Like, what if you could actually go back in time and resurrect long-lost creatures?

I mean, this is something that Beth Shapiro has talked about a lot. We could reconstruct using a computer what the genome sequence of the ancestor of all birds was, and that would have been a kind of dinosaur, and then we could use CRISPRs to turn a chicken into that thing. Or what if you could take an elephant and snip, snip, snip, snip, Snip gradually turn it into its long-lost relative the woolly mammoth. No. Because they're related, but if you, their genes are similar.

Well, right. But if you know the woolly mammoth genome, which they do because they apparently got it off some bone or some hair, then you could compare the number of differences, use CRISPR to crisper out the different parts of the elephant and put in woolly mammoth instead. If you can, in effect, go backwards in time and make changes, then obviously I think you can go the other way too, right? I mean, humans are good at design. We're designing animals. So if it doesn't seem to me to be a crazy notion to imagine parents all over the world wanting, I don't know, taller children, so silencing the short genes and favoring the taller genes,

getting rid of weak muscles and going for stronger ones and on and on and on. And I don't know where the designing stops. We sort of got into all this with Carl Zimmer, science writer. If you can be very, very gene-specific and you learn more and more about genes over time, why couldn't you invent a creature? Why couldn't you make a pig with wings? You might one day get sophisticated enough to do that. There's no winged pig lab. The best you're going to hope for right now is a Willie Mammoth Lab,

and that's down the hall from where the real action is at. But now there's a hall, and at the end of the hall is a winged pig lab. It hasn't been built yet. It may be 20 years from now, but that's what you're looking at. Well, I think, but the thing is that then you're... Well, what's wrong with this, though? Why shouldn't anyone realize that that's really what we're talking about here? Well, because you can't make winged pigs, just because of sort of evolutionary barriers, okay?

Well, there's no real reason for pigs to fly, except for the joke. Calm down. Calm down. I'm just soaking. I mean, okay, I don't think that we need a federal department of homeland pig with wing security. I think we're okay there, all right? What we do need is, like, we do need to, like, figure out what are we going to do about CRISPR in humans? I mean, they're going to be using CRISPR for cancer, okay?

They're going to take people's immune cells out of their body, and they're going to use CRISPR to basically allow them to make proteins. They're going to be able to grab onto cancer cells and attack their own cancer. Yeah. But you have to be for that. I mean, you have to be. Well, I don't know. I mean, are you for, that is... Well, you're, you are tinkering with someone's own body.

You are altering their own cells, you know? Dude. Where do I... It's just, I tell you, this is me. I don't know if it's a religious thought or just the thought of a conservative person. But, I mean, I grew up in the test tube baby era. I now know many wonderful adult formerly test tube babies. and I remember being astonished that, no, so I can't, I don't know where the sacred begins and ends anymore on that particular turf.

I guess what I'm instead on is I'm on a Hobbesian view of human beings, that there is something about human beings, including scientists, human beings, all human beings, that is there's a darkness and a light. There's an angelic side to being human, and there's a very, very difficult side. And as the human beings get more and more power to create and design and essentially create a future, that future will include the imaginations, both light and dark of humans. And that will be new in the world. I don't think it is new because if you go back to the start of the scientific revolution, something like Francis Bacon would say explicitly, like science is going to be both about learning about how the world works

and using that knowledge to control it. You know, this has been discovered. This has been published. Everybody knows it exists. If you're going to say, like, okay, now we're going to all, we're going to outlaw this. I'm not suggesting that. Well, what are you suggesting that? I think we should cringe a little as opposed to just kind of a big part.

All right. That's all cringe. Ready? One, two, three. Don't make fun of it. No, no. Now what? We've cringed.

And now what? What do we do now? I don't know. We all cringed. I'm not saying. If that's what you're arguing for, we, we cringed. We cringed. You cringed.

You cringed me. And you cringe with attitude. I'm cringing with... I would like to know. Because you're afraid of like dragons. You're saying, oh my God. Yes, I'm afraid of dragons. Okay, so that conversation with Carl was four months ago.

And a lot has happened in that time. Because to the question that you asked, like, where does the sacred being and end? Well, one of the lines that had been drawn by Jennifer Doudna and, was that we should not use this technology on humans who haven't been born yet, meaning not on sperm cells or egg cells, because if you CRISPR, say, an embryo. That is a permanent change, right? That is a change to the DNA that will be passed on to their children. And their children's children's children's children. And you can't ask the person if that's okay, because you're doing it before they're born. Consent becomes a real issue.

And if you imagine making these changes and they cascade through generation after generation, you could affect the evolution of organisms. And it's, I don't want to say trivial, but it's, you know, it's fairly easy to do it. Wow. It's kind of profound. I feel it's really profound. Profound, but it was just an idea. That is, until...

For the first time in history, researchers in China have successfully edited the human genome in an embryo. Just two months ago, it was announced that a Chinese team... from Sunyatsun-Yotsin University, use a technique called CRISPR. To edit DNA in human embryos, it's a way of hacking evolution itself. Well, this is hugely controversial. Now, these embryos, the Chinese team had edited, they were created through IVF, and they were not viable. These are embryos that are not going to actually develop into a person, so they're going to be discarded anyway. But still, if they could figure it out with those embryos, what's to stop any of us from going further?

Biologists and bioethicists are sounding an alarm. The scientists face accusations that they cross. lost an ethical line. That this sort of thing could be sort of a slippery slope towards... Toward designer babies. Essentially genetically engineering the human race. I'm going to use it to the chips to kind of test your levels. Okay.

Now that the cringe party had spread and Robert didn't seem like such a loon, we called up Carl again. Well, we have to revisit. We have to revisit because in our Armageddon conversation in which I believe I was extremely alarmist and you were extremely downputting, I feel that I should do a small little parade called the Don't remember the alamo It's like remember China

And you have to So you should just begin Anytime you want Like getting on your knees And saying how sorry you are And we can start from there I'm sorry So are we actually surrounded

By an army of clones With superpowers? Not yet Not yet But I think the dyke has been open I believe I'm going to quote Somebody who said Maybe a few weeks ago

Oh, I think he was, maybe it was last week even writing for National Diagraph. I think it was. Maybe it was somebody named Carl who said that the news from China and that news was probably the beginning of an entire new era. I think I actually said it was a historical moment. That's right, yes. Yes. And I still stand by that. Do you feel differently now than the first time we talked?

Yeah, that's really the question. I don't feel different, actually, because there's really no scientific surprise here. He says, people have been doing all these CRISPR experiments on all these different mammals. We're mammals. This is bound to happen. And in fact, it may be happening more than we think. One account in the journal Nature has said that four other Chinese labs are doing this kind of work as we speak. But Carl also told us, which he said was unsurprising too, but I actually find it kind of surprising,

that the CRISPR work this Chinese team did didn't work very well. It worked kind of. I mean, in only a few of the cases, did they really get. exactly what they wanted. They tried using CRISPR in about 86 embryos, and they only got out to work right in maybe 28. And in a lot of them, CRISPR's made the wrong cuts and screwed up the cells.

And that led them to conclude that this is a technology that's not ready right now for application in the human germ line. And I agree. Oh. We still are in this kind of fortunate position where we can say, oh, well, it's dangerous, so we shouldn't use.

it on human embryos. I just don't think that we're going to be able to sort of find refuge there in like 10 or 20 years. In 10 or 20 years, you know, CRISPR will be so sophisticated that people will be able to say, I can get you the change you want, and I can do it safely. I can guarantee you that you will have human embryos that have the alteration in the particular gene you want. So then what? In fact, Jennifer Dowdna told us that this experiment, or similar experiments, repeated in mice with more advanced CRISPR systems, because apparently there are many different kinds, and there it was done with almost no errors. Sometimes I feel like we're sort of displacing all our ethical concerns onto something that hasn't happened yet. If we really are concerned

about what we're doing to the human gene pool, you know, it's already here. Take, as an example, in vitro fertilization. About 60,000 kids are born a year through IVF, and it's probable that some of those parents chose whether they wanted a boy or a girl and and when people started doing IVF there was a huge controversy people said this was dangerous this was unnatural I don't see people who are unable to sleep at night because of the existence of IVF yeah you know now I'm going to sound like I'm on Robert's side of this I mean okay so so it won't hurt it won't it won't it won't okay okay so okay so deep breath so you guys know about uh all the stuff going on in Iceland where they're they're looking at people's DNA and, you know, they're looking for disease genes and so on.

And when they were looking at these Icelandic people, they found that some people had a gene that protects them against Alzheimer's. It reduces their odds of getting Alzheimer's. Let's imagine your doctor said, now, if you'd like, for an extra thousand dollars, we will take these IVF embryos and we will use CRISPR to give them the Alzheimer's, VARient would you like that do you want to add that to your to your procedure sure yeah or would you like your child to To face a future of of Alzheimer's your choice see here's my here's my thing here's my thing with this whole with this whole thing I'm I'm a little bit haunted by the thing you said which is that when it's not dangerous anymore What will we do and I'm afraid we've already answered that question that it's not it's not a

question that's open and anymore. Because if we're already doing this kind of stuff, and who's going to say no to that? Who's going to say no to that? That's what he just was demonstrating. Yeah. We've already answered the question. Yeah, we may have. Many thanks to science writer Carl Zimmer. He's written many books. You can check them out at Carlzimmer.com or at RadioLab.org. This piece was produced by Molly Webster.

We had original music this hour by Eric Kowalski, otherwise known as Casino v. Japan. Special thanks to Anna Rusk Wet Paz Lee McGuire Dr. Blake Weedenhaft Dr. Luciano Marfini Dr. Sean Burgess And Dr. Junway Shi I'm Chad Abumrad

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