[RADIOLAB INTRO]

KEVIN ESVELT: Let me tell you, there is nothing like the sheer elation of discovery. And I was thinking, you know, this is the end of malaria. This is the end of everything else mosquitoes spread. Wait a minute, ticks spread Lyme disease. We can probably get rid of that too.

SOREN WHEELER: So in the morning, you're like woo-hoo!

MOLLY WEBSTER: You're singing to the turtles in the park and ...

KEVIN ESVELT: Pretty much. And I gave myself a full day of being "woo-hoo," and then I started thinking but—but—but—but what if something goes wrong?

JAD ABUMRAD: I'm Jad Abumrad.

ROBERT KRULWICH: I'm Robert Krulwich.

JAD: This is Radiolab. And the guy that you just heard is Kevin Esvelt. He is a scientist. He was talking to our producers Soren Wheeler and Molly Webster ...

ROBERT: About CRISPR, which is a technology. Actually it's a new—it's a gene-editing technology that can reshape life, actually.

JAD: Yeah. And we ended up doing an entire show about this.

SOREN: Yeah. And we called it "Antibodies, Part One."

JAD: I remember that.

SOREN: As if there was gonna be a part two.

MOLLY: It's like telling someone you got them a birthday present, but you haven't yet.

SOREN: Yeah.

JAD: Yeah, that's true.

SOREN: Maybe we should just own up. Radiolab listeners? We did not get you a birthday present.

JAD: Let's just—that seems mean. No, we meant to.

ROBERT: Yes, we did.

JAD: We meant to have a part two. But, you know, we were doing a story, it fell apart.

ROBERT: Life doesn't always work out.

JAD: The tape sucked, frankly. And we thought it was gonna be a story, but it just didn't turned out to be a story.

ROBERT: But now we have—what we're going to do is we're going to pay you what you're due.

JAD: This is the part two.

ROBERT: Yeah, this is the part two.

JAD: Finally part two, because CRISPR in the time that we did the thing 'til now has gone banana crazy.

ROBERT: Yeah, so much has happened really.

JAD: Yeah, like, every day in the science section—which I know we all read religiously—there is a CRISPR thing.

ROBERT: Yeah.

JAD: So just to get us started, we're gonna play you the original piece for those of you who never heard it, just to sort of set the baseline. And then we're gonna come back and tell you all the stuff that has happened since.

ROBERT: Yeah. Yes.

JAD: All right, so let me explain to you how I got started with this.

ROBERT: You were at some kind of an affair?

JAD: Yeah. So I'll tell you how—I was at a party.

ROBERT: Party.

JAD: It was a conference where they had a lot of different people of different disciplines come together. You know, one of those. There were panel discussions of various things. So we were at one of the functions, and it was a situation where, like, dinner hadn't yet been served, and there was a lot of booze being served. So everybody was drunk on an empty stomach. So I was standing there with some biologists.

ROBERT: Oh, they're the fun ones, the drunk biologists, yes.

JAD: That's 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 and 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 can do it with CRISPR." And I was like, "What the hell is this thing?"

CARL ZIMMER: You want me to sit here as usual?

JAD: 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 gotta talk to Carl. So I basically asked him, like, why all the fuss? Maybe it was just the alcohol, or—but maybe there's something really happening here?

CARL ZIMMER: Oh, there's something totally happening here. I mean, it's big.

JAD: He started at the beginning.

CARL ZIMMER: 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."

JAD: E. coli are a bacteria inside humans. And like all living things, E. coli is made up of DNA—As and Ts and Cs and Gs. And what happened was that these scientists were reading a chunk of that genetic code when ...

CARL ZIMMER: They found this really strange stretch of DNA.

JAD: Strange how?

CARL ZIMMER: 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.

JAD: These little blurps. So it'd be like ...

[Beep, beep, beep. Honk! Beep, beep, beep. Honk! Beep, beep, beep. Honk! Beep, beep, beep. Honk! Beep, beep, beep. Honk!]

CARL ZIMMER: And they looked at this and they were like, "What? This is nothing like we've seen before."

JENNIFER DOUDNA: Repeated sequences in bacterial genomes are kind of unusual.

CARL ZIMMER: Seems very strange.

JENNIFER DOUDNA: Some biologists felt that, you know, there must be a purpose for these.

JAD: Among those purpose seekers?

JENNIFER DOUDNA: Jennifer Doudna, University of California-Berkeley.

JAD: She's a cell biologist.

JENNIFER DOUDNA: Yeah.

JAD: So it's Doudna, not Dudna?

JENNIFER DOUDNA: It's Doudna. I used to be called "The Dude," sometimes in school. [laughs]

ROBERT: In the movie, she will be played by Jeff Bridges.

JAD: Right. Anyhow, as time goes on, scientists start seeing these little repeat-blurp-repeats everywhere.

CARL ZIMMER: Yes.

JAD: Or at least in bacteria.

CARL ZIMMER: Lots and lots and lots of species of bacteria. They say ...

JENNIFER DOUDNA: "Hmm."

CARL ZIMMER: "Okay, wait a minute."

JENNIFER DOUDNA: "That's kind of cool."

CARL ZIMMER: They're finding it so often that they decided they had to give it a name.

JAD: And is this where the name CRISPR comes from?

CARL ZIMMER: Yes. The full official name is Clustered, Regularly Interspaced, Short Palindromic Repeats.

JENNIFER DOUDNA: Clustered, Regularly Interspaced, Short Palindromic Repeats.

JAD: Oh, my God.

ROBERT: Oh!

CARL ZIMMER: I don't know why they called it CRISPR. It's kind of a ...

JAD: CRISPR. It's like a furniture manufacturer or something.

CARL ZIMMER: It sounds like an app.

JAD: Yeah.

ROBERT: Yeah. CRISPR.

CARL ZIMMER: CRISPR.

JAD: But now scientists had this puzzle.

ROBERT: If nature, at this level, preserves something intact here and here and here and here and here and here, and some of these heres are creatures that have been around for hundreds of millions of years, you figure, well, whatever this is ...

JAD: It's doing something.

ROBERT: ... it's doing something.

JAD: But what?

CARL ZIMMER: It doesn't take very long before the first big clue comes up.

JAD: 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."

CARL ZIMMER: 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 ...

JAD: That those bits of DNA between the repeats, the stuff in the middle, those blurps ...

CARL ZIMMER: These are matching virus DNA. Like, you can find viruses with genes where these little ...

JAD: So the bacteria had virus inside of them?

CARL ZIMMER: Yep.

ROBERT: Does that mean that a virus brought it into these cells? Does it tell you anything about the origin of it?

CARL ZIMMER: Well, 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.

JAD: 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.

ROBERT: How do we interpret this?

CARL ZIMMER: Well actually, there was one scientist, who's named Eugene Koonin, who looked at these results and just said, "Okay, I get it. It's a defense system."

JAD: [laughs] What?

ROBERT: Why would he think that?

CARL ZIMMER: Because he's a brilliant man!

ROBERT: 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.

CARL ZIMMER: 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 gonna just let virus DNA get into their genes willy nilly, okay? Remember, viruses are the big enemy.

ROBERT: Right.

CARL ZIMMER: If you're bacteria, viruses make your life a nightmare. Think about in the ocean, okay? The ocean is full of viruses, and viruses kill up to 40 percent of all of those bacteria every day.

JAD: Really?

CARL ZIMMER: Every day.

ROBERT: Oh!

CARL ZIMMER: Yeah. And we know that they have defenses. What Eugene Koonin said was, "Okay. I'm gonna 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."

JAD: Oh!

ROBERT: It's like little Polaroid shots of the enemy.

CARL ZIMMER: Right.

ROBERT: Know thy enemy.

CARL ZIMMER: Yeah, like a "Most Wanted" poster.

EUGENE KOONIN: What you call the mugshot.

JAD: This is Eugene Koonin.

EUGENE KOONIN: Leader of the evolutionary genomics group at the National Center for Biotechnology Information.

JAD: 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 itself.

EUGENE KOONIN: 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.

JAD: So can you walk us through how the mechanism is likely to work?

EUGENE KOONIN: All right. What happens is ...

CARL ZIMMER: You know, when a virus comes into a cell, it just kind of explodes and kind of releases naked genes, basically.

JAD: If you're this bacteria, these things might take over your cells, so you've gotta respond.

EUGENE KOONIN: Most of the time, you have multiple weapons of defense.

JAD: If you've never seen this virus before, usually the first thing you do, says Eugene, is you send out these enzymes that attack the viruses. They're sort of like the ground troops, and they fight really hard.

EUGENE KOONIN: But much of the time they fail, and then no one will hear about you again.

JAD: They're not terribly sophisticated fighters, so very often the virus takes over, the bacteria dies.

EUGENE KOONIN: But there is some non-zero probability that you actually survive the attack.

JAD: 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.

EUGENE KOONIN: And then cut the enemy DNA into suitable small pieces.

JAD: And here, he says, is 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.

EUGENE KOONIN: Right there and nowhere else.

ROBERT: So I use those spaces in my own DNA as a storage facility?

EUGENE KOONIN: Yes, if you will. You use it as a memory device.

JAD: Because here's what happens: next time that virus shows up, it 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 gonna 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 it will 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."

ROBERT: Kill. And these attackers, do we know what one of them looks like?

JENNIFER DOUDNA: Yep. So we know what the protein looks like. It actually looks—I would describe it a little bit like a clamshell.

JAD: Sort of imagine Pac-Man, but kind of misshapen and rough. And each one of these guys ...

CARL ZIMMER: What it has is a copy of that virus DNA.

JAD: It's got the mugshot.

CARL ZIMMER: That it's kind of waving around. What then happens is that ...

JAD: Whenever the Pac-Man bumps into some virus DNA ...

CARL ZIMMER: It pulls apart the DNA, unzips it ...

JAD: Reads it. If it's not the right one, it goes on. Nope. Uh-uh.

CARL ZIMMER: And if that RNA has the same sequence, then click-click, it just locks in.

JENNIFER DOUDNA: And if that happens, then the DNA is trapped, and molecular blades come out.

CARL ZIMMER: And chop.

EUGENE KOONIN: Cutting its head with a mighty blow.

CARL ZIMMER: Yeah.

ROBERT: So this is smart scissors.

JAD: 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."

ROBERT: Snip!

JAD: Snip.

CARL ZIMMER: Right, now we're gonna kill.

JAD: Oh, I see.

CARL ZIMMER: Yeah, and it has to be an exact match.

JAD: When scientists first discovered this whole system, they were fascinated.

CARL ZIMMER: They were working it out. They were like, "Oh, okay, then this happens, and this happens, and this happens. Cool."

JAD: But then, in walks ...

JENNIFER DOUDNA: The Dude.

JAD: ... Jennifer Doudna with a crazy idea. Well, I don't know if it's crazy, but radical.

JENNIFER DOUDNA: This could be an amazing technology.

CARL ZIMMER: This is a tool.

JAD: This is a tool?

CARL ZIMMER: Yeah.

JENNIFER DOUDNA: Right.

CARL ZIMMER: This is a tool that we can use to cut DNA where we want to cut DNA.

JAD: 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 had a mouse with something like hemophilia.

ROBERT: Okay.

JAD: 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 ...

CARL ZIMMER: Then you set it loose.

JAD: And just like it's programmed to, it will find that gene ...

CARL ZIMMER: And click click chop. The scissors will end up cutting exactly the gene you want ot to cut.

JAD: So the bad gene's gone. Now the question is: how do you put in the good gene?

ROBERT: Right.

JAD: It turns out actually, according to Jennifer Doudna, that that's actually not as hard as you would think.

ROBERT: Really?

JAD: 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.

JENNIFER DOUDNA: You don't have to get super precise. I mean, it turns out that there are repair enzymes that are probably continually surveying and checking for breaks.

JAD: She says what will happen is it inside the cell, these repair crews that 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."

ROBERT: Put the pretty guy in this space.

JAD: Exactly.

JENNIFER DOUDNA: So we take advantage of a natural repair pathway that cells have.

JAD: They trick both the cutters and the fixers.

CARL ZIMMER: Yeah. Now we're not assassinating anymore. Now we're actually engineering. We've gone from killing to refashioning.

ROBERT: Well, but haven't we been designing genes, doing genetic—a form of genetic engineering for, I don't know, like 30 years?

JAD: Yes, but not like this.

BETH SHAPIRO: Genome editing technologies have been around for a long time, but none of them have been as powerful as CRISPR is.

JAD: That's Beth Shapiro from UC-Santa Cruz. She was actually one of the biologists that I drunkenly talked to at that thing.

BETH SHAPIRO: Was it a modern art museum? I can't even really remember.

JAD: I don't remember either.

ROBERT: Must have been quite an evening to have the setting be so vague.

JAD: 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 ...

BETH SHAPIRO: 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.

JAD: [laughs] So it's like, "You just take a right at Staten Island." But it takes a left.

BETH SHAPIRO: And not only would it take a 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 it's really easy.

JAD: You just give it that mugshot.

BETH SHAPIRO: And it goes. "I'm gonna find that guy exactly."

JAD: 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.

CARL ZIMMER: You can use the same CRISPR system on anything.

ROBERT: Can you, like, do it if corn is vulnerable ...

CARL ZIMMER: Do it in corn.

ROBERT: ... to a certain pest? You can do it in corn?

CARL ZIMMER: Do it in corn, do it in anything. I am waiting for someone to say "CRISPR doesn't work in species X." And I have not heard of that.

JAD: 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 Doudna says the moment the full impact of that landed on her ...

JENNIFER DOUDNA: I really—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. [laughs]

ROBERT: 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.

JAD: [laughs] Do you see those clouds on the horizon?

ROBERT: I see it's getting sort of dark over there. But we'll be right back.

[LISTENER: Hi, This is Lauren from Atlanta, Georgia. Radiolab 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.]

JAD: This is Radiolab. I'm Jad Abumrad.

ROBERT: I'm Robert Krulwich.

JAD: Okay, so clearly the possibilities are there to use CRISPR to treat disease, right?

ROBERT: Right.

JAD: 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.

BETH SHAPIRO: 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.

JAD: Or what if you could take an elephant, and snip snip snip, gradually turn it into its long-lost relative, the wooly mammoth?

ROBERT: No.

JAD: Because they're related. But the genes are similar.

ROBERT: But the wooly mammoth is over.

JAD: Well, right. But if you know the wooly mammoth genome—which they do, because they apparently got it off some bone or some hair ...

ROBERT: Yeah.

JAD: ... then you could compare the number of differences, use CRISPR to CRISPR out the different parts of the elephant and put in wooly mammoth instead.

ROBERT: 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 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.

JAD: We sort of got into all of this with Carl Zimmer, the science writer.

ROBERT: 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.

CARL ZIMMER: Well, there's no winged pig lab. You know, the best you can hope for right now is a wooly mammoth lab. And that's down the hall from where the real action is at.

ROBERT: But now there's a hall. And at the end of the hall is a winged pig lab.

CARL ZIMMER: No.

ROBERT: It hasn't been built yet. It may be 20 years from now, but that's what you're looking at.

CARL ZIMMER: Well, I think—but the thing is that then you're ...

ROBERT: Well, what's wrong with this thought? Why shouldn't anyone realize that that's really what we're talking about?

CARL ZIMMER: Well, because you can't make winged pigs, just because of sort of evolutionary barriers, okay?

ROBERT: Well, there's no real reason for pigs to fly except for the joke.

CARL ZIMMER: No. No. Gentlemen, calm down. Calm down! Okay, I don't think that we need a Federal Department of Homeland Pig with Wings Security. I think we're okay there, all right? What we do need is, like, we do need to figure out what are we gonna do about CRISPR in humans? I mean, they're gonna be using CRISPR for cancer, okay? They're gonna take people's immune cells out of their body, and they're gonna use CRISPR to basically allow them to make proteins that are gonna be able to grab on to cancer cells and attack their own cancer.

ROBERT: Really? Wow!

CARL ZIMMER: Yeah.

ROBERT: Well, you have to be for that. I mean, you have to be.

JAD: Well, I don't know. I mean, are you for it?

CARL ZIMMER: Well, you are tinkering with someone's own body. You are altering their own cells, you know?

JAD: Dude!

ROBERT: Where do I—it's just I can't even—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 scientist human beings—all human beings, that 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.

CARL ZIMMER: I don't think it is new, because if you go back to the start of the scientific revolution, someone 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 gonna say, like, "Okay, now we're gonna outlaw this."

ROBERT: I'm not suggesting that.

CARL ZIMMER: Well, what are you suggesting then?

ROBERT: I think we should cringe a little, as opposed to just have a big party.

CARL ZIMMER: Okay. All right. Let's all cringe. Ready? One, two, three.

ROBERT: Don't make fun of me! No, no! That's not fair!

CARL ZIMMER: Now what? We've cringed, and now what? What do we do now?

ROBERT: I don't know.

JAD: Well, we all cringed. If that's what you're arguing for, we cringed too.

ROBERT: No, you cringed meanly, and you cringed with attitude. I am cringing with ...

JAD: I would like to know ...

CARL ZIMMER: Because you're afraid of, like, dragons.

ROBERT: [laughs]

CARL ZIMMER: You're saying, "Oh my God!"

ROBERT: Yes. I'm afraid of dragons now that ...

JAD: Okay. 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 begin and end? Well, one of the lines that had been drawn by Jennifer Doudna and others 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 ...

JENNIFER DOUDNA: That is a permanent change, right? That is a change to the DNA that will be passed on to their children.

JAD: And their children's children, and their children's, children's children.

JENNIFER DOUDNA: And you can't ask the person if that's okay, because you're doing it before they're born.

JAD: Consent becomes a real issue. And if you imagine making these changes, and they cascade through generation after generation ...

JENNIFER DOUDNA: You could affect the evolution of organisms. And it's, I don't want to say trivial, but it's fairly easy to do it.

JAD: Wow.

JENNIFER DOUDNA: It's kind of profound. I feel it's really profound.

JAD: Profound, but it was just an idea. That is, until ...

[NEWS CLIP: For the first time in history, researchers in China have successfully edited the human genome in an embryo.]

JAD: ... just two months ago, it was announced that a Chinese team ...

[NEWS CLIP: ... from Sun Yat-sen University used a technique called CRISPR ...]

[NEWS CLIP: ... to edit DNA in human embryos.]

[NEWS CLIP: It's a way of hacking evolution itself.]

[NEWS CLIP: Well, this is hugely controversial.]

JAD: Now these embryos the Chinese team had edited, they were created through IVF and they were not viable.

[NEWS CLIP: So these are embryos that are not going to actually develop into a person, so they're going to be discarded anyway.]

JAD: But still, if they could figure it out with those embryos, what's to stop any of us from going further?

[NEWS CLIP: Biologists and bioethicists are sounding an alarm.]

[NEWS CLIP: The scientists face accusations that they crossed an ethical line.]

[NEWS CLIP: That this sort of thing could be sort of a slippery slope towards ...]

[NEWS CLIP: ... towards designer babies.]

[NEWS CLIP: Essentially, genetically engineering the human race.]

JAD: Now that the cringe party had spread and Robert didn't seem like such a loon, we called up Carl again.

ROBERT: Well, we have to revisit because in our Armageddon conversation, in which I believe I was extremely alarmist and you were extremely down-putting, I feel that I should do a small little parade called the—it's not 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.

JAD: [laughs]

CARL ZIMMER: I'm sorry. So are we actually surrounded by an army of clones with superpowers?

ROBERT: Not yet. Not yet, but I think the dike has been opened. I believe I'm gonna quote somebody who said, maybe a few weeks ago, maybe it was last week even, writing for National Geographic. 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.

CARL ZIMMER: I think I actually said it was a historical moment.

ROBERT: That's right. Yes, that's right.

CARL ZIMMER: Yes. And I still stand by that.

JAD: Do you feel differently now than the first time we talked?

ROBERT: Yeah, that's really the question.

CARL ZIMMER: I don't feel different, actually, because there's really no scientific surprise here.

JAD: He says people who have been doing all these CRISPR experiments on all these different mammals ...

CARL ZIMMER: We're mammals.

JAD: ... this was bound to happen. And in fact, it may be happening more than we think. One account in the journal Nature 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.

CARL ZIMMER: It worked kind of. I mean, in only a few of the cases did they really get exactly what they wanted.

JAD: They tried using CRISPR in about 86 embryos, and they only got it to work right in maybe 28. And in a lot of them, CRISPRs made the wrong cuts and screwed up the cells.

BETH SHAPIRO: 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.

ROBERT: Huh.

CARL ZIMMER: 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 gonna be able to sort of find refuge there in, like, 10 or 20 years. In 10 or 20 years, 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?

JAD: In fact, Jennifer Doudna told us that this experiment—or similar experiments—had been repeated in mice with more advanced CRISPR systems, because apparently there are many different kinds. And there it was done with almost no errors.

CARL ZIMMER: Sometimes I feel like we're sort of displacing all our ethical concerns onto something that hadn't happened yet. If we really are concerned about what we're doing to the human gene pool, you know, it's already here.

JAD: 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.

CARL ZIMMER: 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.

JAD: Yeah.

CARL ZIMMER: You know, now I'm gonna sound like I'm on Robert's side of this. I mean, okay. So ...

ROBERT: It won't hurt. It won't hurt.

CARL ZIMMER: Okay. All right. Here we go.

JAD: Deep breath.

CARL ZIMMER: So you guys know about all this stuff going on in Iceland, where they're looking at people's DNA, and 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, "You know, 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-protecting variant. Would you like that? Do you want to add that to your procedure?"

JAD: Sure, yeah.

CARL ZIMMER: Or would you like your child to face a future of Alzheimer's? Your choice.

JAD: See, here's my thing. Here's my thing with this whole thing. 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 a question that's open anymore, because if we're already doing this kind of stuff—and who's gonna say no to that? Who's gonna say no to that?

ROBERT: Exactly. That's what he just was demonstrating. Yeah.

CARL ZIMMER: Yeah.

JAD: We've already answered the question.

CARL ZIMMER: Yeah, we may have.

ROBERT: So that's how we ended our piece, which is now two years old.

JAD: Roughly.

ROBERT: Roughly. And the drunk biologists at Jad's cocktail party couldn't have been more prescient when you think about it.

JAD: You know, this is one of those strange cases where you do a story, usually we just kind of leave it behind, we move on to other things, but in the last almost two years, so much has happened ...

ROBERT: Unbelievable.

JAD: ... that we figured we need to update this thing.

ROBERT: Yeah.

JAD: And so what we did is we asked our producer/editor Soren Wheeler and our producer Molly Webster to sort of just go out, ask around, make some calls, and tell us, you know, what's been going on.

SOREN: Well, for one, Molly, do you want to give them the big news?

MOLLY: That Jennifer Lopez is gonna do a television show based on CRISPR.

JAD: No!

ROBERT: You mean, a fiction?

MOLLY: It takes an active role in the fictional narrative of the show.

ROBERT: Oh, okay!

JAD: Oh, like she's a cop or something?

MOLLY: Yes. She's like some sort of—I don't know, medical something. and CRISPR is involved.

JAD: Really?

MOLLY: Yeah. That got big headlines.

ROBERT: Let me show you these scissors.

JAD: Wow. It's crossed over to that extent?

MOLLY: That's the thing is it's—I was like, "Jennifer Lopez knows about CRISPR?" And she was like, "This is such a hot button issue. We're doing a show."

JAD: That's amazing!

MOLLY: Yeah.

JAD: Okay, moving—putting J-Lo aside ...

ROBERT: Yeah, let's do some science developments. There have got to have been quite a few of them. We know there have been a few of those, right?

JAD: Yeah, what are those? Run us through those.

MOLLY: I mean, I guess I would just say that it's being used everywhere now. So it's being used in crops, it's being used in medicine, it's being used in basic research. It's being used ...

SOREN: Humans.

MOLLY: ... in humans.

SOREN: In cows.

JAD: Really?

MOLLY: It's being used in eyeballs.

JAD: In eyeballs?

MOLLY: Yeah, they want to start a clinical trial where they're actually injecting a syringe full of CRISPR-carrying viruses into your eyeball to overcome a genetic condition that leads to blindness.

JAD: This would be like the virus is injecting the CRISPR that then goes and cuts out the bad genes?

MOLLY: Yeah, exactly.

CARL ZIMMER: Just take a big syringe full of viruses and just stick it in people's eyes. Yeah.

MOLLY: So of course, when we did the update, Soren and I called Carl Zimmer.

CARL ZIMMER: Yeah, it's—things are moving very fast.

SOREN: And what kinds of things?

CARL ZIMMER: So they are doing things that look like curing diseases.

MOLLY: Carl told us about one study where it seems like they cured a certain type of muscular dystrophy in mice.

ROBERT: Cured muscular dystrophy?

JAD: They cured muscular dystrophy in mice? Wow!

SOREN: Well, the mice don't become normal mice, but they get much, much stronger than they would have been.

MOLLY: Yeah. So in your body, you have a gene that makes a protein that gives your muscle strength, but with muscular dystrophy, there's like a typo in that genome mutation, and so that protein's not made.

CARL ZIMMER: And the result is that your muscles start to turn into sort of a fat-like substance. That's how it's been described.

MOLLY: Oh, so you have, like, no power.

CARL ZIMMER: Yeah.

MOLLY: Okay.

CARL ZIMMER: So your diaphragm gets weaker and weaker, your heart gets weaker.

MOLLY: So in this case, they use CRISPR to fix that gene, so you get the protein in these mice. And they actually saw, like, the heart gets stronger, or the mouse was able to push with more force on a button. And so they said over weeks, they just saw, like, strength building up.

ROBERT: Really?

JAD: Wow. Are they gonna do that in humans?

SOREN: Pretty first step-py at this point, but ...

CARL ZIMMER: Yeah, this is literally like one of the first experiments to show that this approach could work in muscular dystrophy.

JAD: But I mean, that's not a disease with a cure, is it?

SOREN: Not until potentially in mice now.

MOLLY: Yeah. Yeah.

JAD: Wow!

CARL ZIMMER: And there are some human trials that have either started or are probably gonna start soon treating cancer.

MOLLY: For example, people are talking about one in lung cancer.

ROBERT: They think they can what, cure lung cancer?

MOLLY: Well, no. What they want to do though, is they want to use CRISPR to go into immune cells where it would cut out the part of the DNA that kind of puts the brake on the immune cell.

CARL ZIMMER: And so you're taking your immune cell off the leash, and it can attack tumors more aggressively.

ROBERT: I see. So the folks who invented this then must stand to earn a fortune, I think?

MOLLY: Oh, billions. There's actually a big patent dispute that's happening right now.

ROBERT: Right now?

JAD: Yeah. This is the one thing that I have heard about a lot.

MOLLY: If you had been checking your CRISPR inbox, you might have seen last week there were two teams, Jennifer Doudna's team out at UC-Berkeley.

ROBERT: Oh, our—the one we just heard from?

JAD: Yeah.

MOLLY: Sort of the West Coast team. And then on the other side is this group of researchers at the Broad Institute, which is on the East Coast. And so basically, they both filed for a CRISPR patent.

JAD: Okay.

MOLLY: So there was sort of this, like, East Coast, West Coast for the last year showdown. And just last week, the US Patent Office decided that it would indeed go to Broad.

JAD: This is the not-Doudna team?

MOLLY: The not-Doudna team. But there are more patents to be awarded, and there will probably be appeals. So I don't think anyone thinks it's settled yet.

JAD: So in the Civil War of—over CRISPR patents, there has been a Gettysburg, but the war is not won.

MOLLY: There's been a battle. But there are many more battles I think that will happen.

JAD: Okay. Gotcha.

MOLLY: Yeah.

JAD: Is there anything else on the list of what's happening now? Exciting stuff happening now?

SOREN: Oh, yeah.

MOLLY: Can we do favorites, Soren? Can I do my favorite?

SOREN: You can do your favorite.

MOLLY: And then you can do your favorite?

SOREN: Yeah, sure.

MOLLY: So my favorite came from Carl.

CARL ZIMMER: Yeah, yeah. They're actually trying to use it as an alternative to antibiotics.

MOLLY: Wait, how? I don't even understand what that means.

CARL ZIMMER: [laughs] What are you saying?

MOLLY: I was like, an antibiotic to me is a pill that I take. So what would CRISPR—how would CRISPR replace that?

CARL ZIMMER: Well, your pill would have CRISPR in it.

ROBERT: How would it work?

MOLLY: You know, in the same way you would take your amoxicillin or your antibiotic pill, you would actually take a pill that was filled with CRISPR, and then it would go out and it would fight bacteria that is attacking your body.

CARL ZIMMER: So you could pick out some super-essential gene that it has and chop it, and that will kill the bacteria.

JAD: Oh, you would turn the assassins on the bacteria?

MOLLY: Exactly.

CARL ZIMMER: So there you go.

ROBERT: Wow!

MOLLY: Yeah, the antibiotic thing seems huge, right?

JAD: That's pretty amazing.

MOLLY: Because everyone's at this moment where they're like, "What happens with the next superbug?" If you could actually just go in there and kamikaze the DNA of, like, staph or whatever, you'd be solving a lot of illnesses.

JAD: Yeah. Well, what's ...

MOLLY: Okay, Soren. Your favorite.

JAD: Yeah, Soren. What's your fave?

SOREN: Well, so the coolest thing, I guess for me ...

KEVIN ESVELT: Hello!

SOREN: ... Maybe the scariest too.

SOREN: Hi, Kevin.

KEVIN ESVELT: Hey, Soren.

MOLLY: How are you?

KEVIN ESVELT: I'm doing great. How are you?

SOREN: Came from a conversation that we had with this guy Kevin.

KEVIN ESVELT: I'm Kevin Esvelt.

MOLLY: Esvelt.

SOREN: He's very svelte.

KEVIN ESVELT: I'm at the MIT Media Lab.

SOREN: He was sort of on the early edge of thinking about CRISPR.

KEVIN ESVELT: I think of myself as an evolutionary engineer before anything else.

SOREN: Got into biology because when he was a kid, he went to the Galapagos.

KEVIN ESVELT: Yeah, my parents took me there when I was 10 or so, and I was just captivated just looking at all of the creatures. And I thought, "I want to make organisms that are as beautiful as that."

MOLLY: You actually thought, "I want to make organisms as beautiful as that?"

KEVIN ESVELT: Yeah.

MOLLY: What?

KEVIN ESVELT: But then that's like the childhood vision. And then it's so hard, right? It was impossible. And so you sort of forget it. But now with CRISPR, like, almost all things become possible.

SOREN: So anyway, to get to the crazy part, Kevin, a couple years back, he's working at the Harvard Medical School, and one day he's walking to work through this park.

KEVIN ESVELT: This park called the Emerald Necklace in Boston. It's beautiful, and there's a small river flowing through it, and you have these ponds.

SOREN: And there's turtles and whatever.

KEVIN ESVELT: Geese.

SOREN: And, you know, he's thinking about CRISPR and what it can do, and all these different animals that are around him. And he has this thought.

KEVIN ESVELT: What if we could encode CRISPR in the genome? What if we program the genome to do genome editing on its own?

JAD: Wait, what? I'm not sure I follow that. What is he—what is he saying?

KEVIN ESVELT: Well, the first gene drive system ...

SOREN: Here, maybe this is a way to think about it. Let's say that you want to tweak a mosquito and make it so that the little parasite that carries malaria—terrible, awful malaria—either can't get into the mosquito or can't live in it, and so that mosquito will no longer carry malaria.

ROBERT: That would be great.

SOREN: That would be a great thing because malaria is a bad thing.

JAD: Uh-huh.

SOREN: So you could now take CRISPR, send it into the mosquito and change a gene inside the mosquito so now that mosquito either doesn't let malaria parasite in or kills it or whatever, but basically doesn't carry it. And that's great. But then I put it out into the wild, and it's gotta fend for itself amongst all the other mosquitoes. So my mosquito has a special gene, but it's gonna mate with some mom mosquito, and that mom mosquito is gonna have the normal old gene, and the baby's gonna get my special gene, but it's also gonna get the normal gene. And that means that your baby has, like, a 50 percent chance of having your special trait.

JAD: Oh, because only one of those two genes gets expressed.

SOREN: Right, in the baby. And then in the next generation, the grandbaby, there's only a 25 percent chance and, you know, on and on and on.

JAD: So you're exponentially losing CRISPR powers.

SOREN: Your chances just each generation get less and less that this gene is gonna stick around.

KEVIN ESVELT: That's right, because regardless of what we do, natural selection wins in the end.

SOREN: Until Kevin is walking to work through the park and has his idea, which is to use CRISPR to create something called a ...

KEVIN ESVELT: Gene drive.

SOREN: Gene drive.

JAD: Gene drive.

SOREN: Yeah.

KEVIN ESVELT: Instead of just snip the DNA and insert the gene that we want, we also insert the genes that encode the CRISPR system and tell it to make that particular change.

SOREN: Here's how it works: you go into the mosquito and give it the new gene that makes it resistant to malaria, and then right next to that you put the genes for the CRISPR system you just used to make that change.

JAD: Like you're putting a spare scissors or something?

SOREN: Yeah. And here's how that plays out: your first mosquito has this gene with the new change, and it also has the scissors.

JAD: Yeah.

SOREN: And then it meets a normal mosquito, which has the normal gene. The two end up side by side in the baby, and now the new mosquito gene makes the little scissors which go over to the normal gene, snip it and turn it into itself. So now there's two copies of the new gene.

KEVIN ESVELT: In the offspring without any human assistance, CRISPR will cut the original version and copy over the change.

SOREN: That gene does the work that I used to do in the lab, on its own inside the baby.

JAD: Oh, interesting. So okay, so ...

SOREN: It's like I set it on autopilot.

JAD: So you're basically allowing then the mosquito parent to pass the scissors to the baby?

SOREN: Yup.

JAD: Which then snip, snip, snip. And then that baby passes the scissors to the next baby. Snip, snip, snip.

SOREN: Yup. Yup.

JAD: And it is literally like a chain reaction?

SOREN: Yeah. And so, you know, from baby to grandbaby to great grandbaby, now instead of letting that gene disappear, you're driving it into the next generation.

JAD: And then that just keeps going down the line, down the line, down the line.

MOLLY: Yes.

KEVIN ESVELT: This is something that spreads indefinitely.

SOREN: This gene is gonna spread like wildfire through the entire wild population. So you don't change just one mosquito ...

KEVIN ESVELT: You change all of those insects probably everywhere in the world.

SOREN: According to Kevin, this is the kind of change that could, given enough time, spread across an entire species.

JAD: Huh. So this idea of the mosquitoes and watching it rampage through a population, have they done this?

KEVIN ESVELT: After we first published the idea, we tried it in yeast. Worked on the first try, you know?

SOREN: They just plopped a little yeast loaded with the gene drive into a population to see if it would take over, and ...

KEVIN ESVELT: One week later? Yup.

SOREN: Kevin told us there are probably now, I think it's 10 different groups who are working on gene drive systems?

MOLLY: Yes, they are doing it in mosquitoes and in parasitic worms and in rodents. It's all happening in the lab.

SOREN: But still, they are trying out, you know, this method for spreading genes through a population.

KEVIN ESVELT: Yeah.

MOLLY: I just think that sounds terrifying. Like, honestly, I just keep thinking of it's like, oh, we've just hit over a domino and then walked away and aren't watching where the rest of them are falling.

KEVIN ESVELT: I'm very glad you think that way. It took me one full day to reach that point. Initially, I was elated. Let me tell you, there is nothing like the sheer elation of discovery. And I was thinking, you know, this is the end of malaria, this is the end of everything else mosquitoes spread. Wait a minute, ticks spread Lyme disease, we can probably get rid of that too, I thought.

SOREN: So in the morning, you were like, "Woo-hoo!"

MOLLY: You're singing to the turtles in the park.

KEVIN ESVELT: Pretty much. I gave myself a full day of being, "Woo-hoo," and then I started thinking, "But—but—but—but what if something goes wrong?" And suppose—let's go back to your malaria case, making the mosquitoes malaria resistant, well, that seems pretty safe. I mean, malaria is a human pathogen, doesn't really affect other animals. But what if, say, the change you make to the mosquito makes it slightly more toxic to something that eats those mosquitoes? So then you have to consider, okay, what eats those mosquitoes, and what eats those things?

SOREN: You know, it could be that all the frogs or the fish or whatever start to die off, and then that makes something else die off and something else die off.

KEVIN ESVELT: And that's an incredibly complex system, and you just don't know.

SOREN: Or it could be that making a mosquito malaria resistant, also somehow makes it do better in some environment, and then the mosquito population blows up. And then it turns out that it somehow makes it easier to carry some other disease.

KEVIN ESVELT: So is it even likely to go wrong? No, but how do you know?

MOLLY: We should say at this point that Kevin is really thinking about all this stuff. He brought together a group of scientists to come up with some safeguards for this type of research so it doesn't escape out of the lab.

SOREN: And his team is only working with this version of gene drive that they sort of rigged it so that it only lasts for a certain number of generations, and it sort of runs out of steam.

MOLLY: Mm-hmm.

KEVIN ESVELT: But scientists can perfectly well start playing around with something in the lab that could affect a whole lot of other people if it happened to escape. I think what this technology forces us to reckon with is that now it's at least theoretically—and again, we don't know for sure, but it's theoretically possible for one person to decide to change the local or possibly the global environment. And that's ethically problematic, right?

MOLLY: [laughs] Yeah.

CARL ZIMMER: I mean, if and when somebody uses CRISPR on an embryo, and that embryo grows up into a person, that will be a momentous thing. But if you were to gene drive somebody, think about that. You know, gene drive, like, say a few people and not tell them, and they have kids and so on. You would be driving whatever gene it is that you were engineering into more and more people. And that's—that's different.

JAD: God, you know, and I'm thinking about the thing that Jennifer Doudna said—I think it was her—in our first piece about, like, if you make a change in, say, an embryo, like, "Okay, let me give this—let me snip, snip, snip, give this future child, make it taller."

MOLLY: Right.

JAD: Whatever. Like, you're doing that without the consent of that unborn thing.

MOLLY: Yes.

JAD: But if you now do what you guys are talking about using this gene drive thing, well now you're doing it without the consent of that unborn thing and all future generations of that unborn thing. And so the consent issues just become unfathomable.

ROBERT: Exactly. You know, I guess we're all for taller, but we're not all for taller. So in the end it has something to do with democracy itself. Like, you sit there with a tool of change in your hand and you choose it, but in the act—with this gene drive, in the act of choosing it for yourself this way, you choose it for an uncountable number of others who do not have the choice.

JAD: Thank you to Soren Wheeler and Molly Webster for the update. And to, I guess, all the people we thanked the first time, because those thanks still stand.

ROBERT: Those still stand.

JAD: Many thanks to science writer Carl Zimmer who has 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 Erik Kowalski, otherwise known as Casino Versus Japan.

ROBERT: Special thanks to Anna Rascouët-Paz.

JAD: Lee McGuire.

ROBERT: Dr. Blake Wiedenheft.

JAD: Dr. Luciano Marraffini.

ROBERT: Dr. Sean Burgess.

JAD: And Dr. Jin Wei-Shi. I'm Jad Abumrad.

ROBERT: I'm Robert Krulwich.

JAD: Thanks for listening.

ROBERT: One quick note of business: some of you may remember we did a show about meat allergies a little while back with the inimitable Amy Pearl. We did that together with the Sporkful podcast produced here WNYC. It turns out they've just done a little follow up with Amy. She went back to get tested for her allergy one more time, and the results were not at all what she'd expected. So you might want to check that out at TheSporkful.com.

[ANSWERING MACHINE: To hear the message again press two. To delete it—start of message.]

[CARL ZIMMER: Hello, this is Carl Zimmer.]

[BETH SHAPIRO: Hi, this is Beth Shapiro.]

[JENNIFER DOUDNA: Hello this is Jennifer Doudna.]

[BETH SHAPIRO: Radiolab is produced by Jad Abumrad.]

[CARL ZIMMER: Our staff includes Brenna Farrell, Ellen Horne, Dylan Keefe.]

[BETH SHAPIRO: Matt Kielty, Lynn Levy.]

[CARL ZIMMER: Andy Mills.]

[BETH SHAPIRO: Latif Nasser, Malissa O'Donnell, Kelsey Padgett.]

[JENNIFER DOUDNA: Arianne Wack, Molly Webster.]

[CARL ZIMMER: Soren Wheeler and Jamie York. I think I said "Wabster." Let me try it again.]

[JENNIFER DOUDNA: With help from Danny Luis, Kelly Prime and Damiano Marchetti.]

[BETH SHAPIRO: Our fact-checkers are Eva Dasher and Michelle Harris.]

[JENNIFER DOUDNA: Awesome.]

[BETH SHAPIRO: Thank you much!]

[CARL ZIMMER: Later!]

[ANSWERING MACHINE: End of message.]

-30-

 

Copyright © 2023 New York Public Radio. All rights reserved. Visit our website terms of use at www.wnyc.org for further information.

 

New York Public Radio transcripts are created on a rush deadline, often by contractors. This text may not be in its final form and may be updated or revised in the future. Accuracy and availability may vary. The authoritative record of programming is the audio record.