How Gene Editing Works

you Stuff you Should Know friendhouse Stuff Works dot com. Hey, welcome to the podcast. I'm Josh Clark with Charles W. Chuck Bryant, and there's Jerry. Did you see that squirreled W Chuck Bryant picture. Yeah, it's pretty great. Big thanks to Sally Ridge, illustrator Drawer of Things, who made this one of We used to get a lot of fan ar't have you noticed we don't get that much anymore. Everybody take this for grana. Uh maybe no, we get

jingles now. Yeah, we get all kinds of cool stuff, But we just used to get a ton of fan art, and this is like one of the more delightful pieces of pan art we've ever gotten. We posted it on our Instagram actually yeah, and Facebook, So thank you Sally for that and go to Sally rich dot net to see her work. Uh and I'm a little squirrel, I'm a weasel, which I don't know what to make of. Ye,

I'm just going with it. It's cute. I first saw that too, and I was like, h r. It was like if it was a weasel in the skunk could be like, I really have to think it, think it through. But you as a squirrel, you have a little beard even too, it's pretty cute. It is very cute. Um, so Chuck. We say all that to say, have you ever seen a gene a grown gene naked? Can you? Can you keep up with jeans and DNA and all that nuclear tides? Do you remember this stuff? A little bit?

I had to go back and brush up on a little. If you have a primer, feel free, because I have a bit of a primer. I'll probably screwed up royally. Well. I was gonna say, an alternate title for this show could be called, um, how the crisper gene editing works? Uh A, k A, what's gonna mess up? Yeah, it's it's kind of I mean, it's sort of simple, but it also is a little minded thing. It's simple. If you are a geneticist, it's it's almost like laughably scarily simple.

But um, two people like us, it's it's like sure, um, all right, well let's go back. Let's talk a little bit about genes first, right to a little weasel in a squirrel. So if you if you go into one of those squirrels cells and you go into the nucleus of the cell, you're gonna find a pair of chromosomes, right, And these chromosomes are made up of DNA, and the DNA itself is made up of nucleotide pairs. What is it? G A t TC Is that right? Um? Add nine goes to oh who is it? Yeah? Add nine goes

to thymine and guanine goes to cytoscene. Right, Okay, so you got attica. Yes, And when you put these these amino acids together, you have what are called nucleotide based pairs and they make up d N A. Now, if you take a strand of DNA, this thing from um it's like a Stanford site for dummies. So it really spoke to me. But it said it said that if you could stretch out your d NA, it would be like six ft long. Did you know that in the

nucleus of a cell. I thought you were about to say it would be the exact exact height that you are. That would be pretty neatly in my mind would have been blown. Yeah, that would be something else. Wow, maybe it is because I'm about six ft Because supposedly your wingspan is a fingertip to fingertip is the same as your height. I've heard that before. That's not true, though, because some people have larger wingspans than others than their height,

like proportionately. I got you anyway, go ahead. So it's just a dirty lie, I think. So. Huh. Well, if you take this DNA right and you look at it, you can see that there's different sequences and along this these this very long six ft strand of d N A, these sequences are broken down into what are called genes, right, And so a gene is really just a string of nucleotide base pairs that create or lead to the production of a specific protein. And you say, okay, well, great protein,

we eat that it's steak done. No. Proteins do way more than that. They're involved in just about every part of your body, from like the building box of cells to chewing to blinking, the thinking like, proteins are very very important, and your proteins are expressed through your genes. Okay,

I think I got that fairly right. Every once in a while, this code, especially when a cell divides and the d n A that was in the original cell is copied for to the new cell, that translation can go a little bit wrong, and so all of a sudden, along these billions of base hairs, there's a there's a there's a mistranslation, and what you have then is a mutation.

For the most part, mutations are not problems. As a matter of fact, Um, any one of us has something like an estimated five to ten mutations deadly mutations in our genes right now. But we only have one copy. And there are very few diseases that you only need one copy of a genetic defect for, right, So we're basically fine. If you get two pairs of mutated problematic genes, then you can have a disease. And there's a lot

of diseases that are genetic in origin. Everything from um cystic fibrosis to cancer is the result of a gene that's mutated and gone Haywire. The whole point of everything I just said is that we from the dawn of humanity, even before then, ever since we were little amiba, have been subject to the ms and the vagaries of genetic mutations. Sometimes they help us, sometimes they do nothing, sometimes they

create disease. But as of two thousand twelve, we are technically leaving the thumb of genetic mutations tyranny potentially, yeah, through Crisper Jean editing. Yeah. It's it's pretty remarkable, it really is. It's very tough. I know, I say this a lot. I think I said it's tough to underestimate the craze of super balls or something stupid like that. It's really tough to overstate how much the Crisper gene

editing um technique could change humanity in the world. If everything goes well, hopefully within the next decade we'll see real human trials for some of these applications. That's the hope. Yeah. Uh, and it may happen because this is one of the most heavily funded arms of scientific health medicinal research out

there right now. It's also one of the newest too, and it's already one of the most heavily funded because it's it's showing that much promise, Like everybody keeps looking into it more and more and more, and they're like every every time they look at it where they're like, it's like we just unlocked a secret of life. Yeah, we just figured it out, and we can make so much money on it. So let's start a company and

invest a lot of money in its research. Alright. So crisper c R I s p R all capitalized stands for clustered regularly interspaced short palindromic repeats, which is why they called it crisper, because that is a mouthful. And unless you're a geneticist, like you said that, probably those string of words together probably just make your head spin, right, but if you if you take them in separate. And I watched this video. I can't remember who did it,

but I'll post it on the podcast page, this Ted Talk. No, it wasn't a Ted Talk. It was by a dude. Oh um, oh, what's Bozeman Science? It was a Bozeman science video. It was really good Bozeman Montana. It was just Bozeman science. So now there's a Bozeman Montana and a Bozeman Science But anyway, the guy on the video said, just kind of take it separately, and it's actually to

two parts. You've got the short palindromic repeats are the thing, and the clustered regularly inner space then kind of describes what that thing is. Right, So the short palindromic repeats is what you need to focus on the start. But let's back up a little bit. Let's talk a little bit about genetically modifying things. Uh, we've been doing this for a while. Everyone knows about Dolly the sheep and

cloning and genetically modified fruits and vegetables. Um, even selective breeding is a is a type of genetic model application. Sure you know. So it's nothing new, it's been going on for a while. But um, in the early two thousand's, there was a discovery of an enzyme. We'll not discovery the enzyme, but a discovery of how to use an enzyme called zinc finger nucleaise And what that would do is replace, it would delete and replace very specific bad

genes that would make you get a disease, let's say. Right. So it was a huge finding but really expensive. Yeah, they were about five thousand dollars a piece, and they didn't work every time for sure, and um, they were just difficult to manufacture, difficult to understand, difficult to implement. But they did do something pretty amazing, which was they went in removed a gene from a strip of DNA and could replace it with another gene that you wanted.

The thing is, it was just tough to use, basically, So there was a big breakthrough, but it wasn't a sweeping breakthrough because it was it was fragile and difficult and expensive. That's right. Uh, fast forward to well, I guess let's go back in time rather seven. Uh, sophomore in high school. George Brett was the man. Yeah, sure he was. Uh. John Cusack started say anything in seven maybe something around there. I think that was eighty nine ish.

No singles was like no singles is definitely in the nineties, because I was I think it's like ninety I'm gonna go with one, all right, while you look that up. So nine eight seven is when the word crisper first appears in a journal article because the scientists said, you know what, we found this thing in E. Coal i these short repeats. What year was it? Uh? These short repeats and the E. Coli bacteria UM of d n A and that's weird. There should not be repeats of

DNA and this bacteria. So it was noteworthy. Yeah, it's like what is that, right, it's a little weird. So they took note, and I guess just say anything came out and they decided to watch Cameron Crow movies for the next decade. As they got bad, they started watching singles and UM. In twelve is when Crisper and this is just a few short years ago, is when Crisper really came on the scene. Uh. And that's when all this money started pouring into the research. And it's like

advanced light years in the last four years, right. And the big, the big difference between what happened in seven what happened in two dozen twelve is that they figured out what these um short palindromic repeats were. Right, you have these little strips of d n A in E. Coli And then they found out later on you can find it in most bacteria, if not at all. These short little strips seemed to be separating out these these what seemed to be like random strings of DNA, but

they separated them out in a red alert interspersed manner. Right, So they looked at the little bits of random DNA and they realized that it matched viral DNA, and they totally weird, Yeah, because they're like, well, wait, this is a bacteria. What is viral DNA doing in here? And someone I'm not exactly sure who's just Eugene Conan was a paradigm changing giant is the unsung hero in this. Coonan said, you know what I think is going on.

I think what we're seeing here is essentially a database that a bacteria houses in its own DNA where when it's invaded by a virus, it captures that viruses DNA or RNA, snips up some of it and stores it in. It's the in this um genetic database, so that when it sees that again, it will recognize the virus and

can attack it. Yeah, it's a it's a genetic adaptation present and is not all bacteria, but in any bacteria cells to help it survive, because the bacteria has like a few minutes once it starts to get attacked by a virus to live, right, Okay, so it's part of its immune system, right, this database of what's called crisper. Yeah, then there's another thing that they figured out about bacteria

that's associated with the Crisper database. In any given bacteria and a bacteria that has it, it's called CAST nine. It's Crisper associated um enzymes. I think C A S nine. It's a it's a protein. It's an RNA guided enzyme in protein, right, and it has this really neat function. It goes to a virus or viral DNA or viral RNA, and it captures it. It unzips it, which is not everything can do that now, and then it also precisely snips it and then delivers that snip to the bacteria's

Crisper database for storage. Yeah, so what you have is a it's an it's an edit as a p posed to like we've been working with working with genetic addition and transfer for years, like treating people with transferring into like bone marrow. Let's say, but this is an actual edit, like they like in it in this article, even though our own article never mentioned CAST nine, which is like, I can't even believe you can't really have one with

the other. It was weird, but uh, this CAST nine is literally they liken it to an assassin like that comes in very surgically with a pair of scissors, very specifically removes ideally just that part. Yeah, the bad part. So we'll talk a little more about this. We get to take a break though, everybody. We're getting a little work though, So Chuck, you you're calling the cast the Crisper cast nine system, which is basically what it is, a an assassin for bacteria, right, it goes after the

viruses cuts him up. Somebody figured out along the line that you can take this natural bacterial immune response and sick it on not just viruses, but other stuff, not just somebody. Cal Berkeley scientist Jennifer Doodna. Yeah, she's gonna win a she's gonna win a Nobel Prize one day. She's totally up for it. She will and and I would advise if anyone is into Ted Talks to watch her Ted Talk on this. Yeah. It's really good. Yeah. So, um, she is a Juda Dowdna. Uh well, I said Dudna,

but we'll go with down okay, one of those. Um. She she was the first to suggest that you can use this natural system to edit jeans and other things things. And I think they started out in very simple organisms, but what they found over time. Is that this seems to be universal that as long as something has DNA you can use the Crisper cast nine system on it to edit genes. Yeah to uh. She likened it to fixing a typo or she said it was like a

genetic vaccination card that yourself can have. Yeah, So it goes in, it snips out the bad part, and sometimes it just joins from there and just repairs it. But other times it sticks uh, something else in it joins it. Right, So depends Yeah, it depends on the system that you're using.

Like you can you can just stick a Crisper cast nine thing, So you you give it a You basically give this bacterial immune response a little piece of the gene that you want edited, and it says, exam is it just like it would if if it were in a bacteria and it were being invaded by a virus. So it examines this gene and says, Okay, this is what I need to go find, And it goes and finds it on a strand of DNA. And this thing

doesn't care what DNA it's looking at. It's just doing its thing right, So if you stick it on any DNA, it's going to go find that sequence, that genetic sequence on whatever DNA it's exposed to, and then it's going to un zip it. It's going to cut it out, and then one thing you can do is just say done and done, and then the DNA is going to

repair itself. But what you've just done is removed that whole sequence of nucleotide base pairs that makes up a gene, and so when it's fuses back together, it's going to be missing that gene. So you can delete a gene is what that's called, or you can add a third component to and say, here's what you're looking for, here's the here's the guide RNA that you want to go find. Um use the cast nine system to go cut it out, un zip and cut it out, and then replace it

with this. Here's some blueprints for what you should install in the in the place of the gene you just edited out, so you can delete and then now add whatever gene you want. And what they found, this incredibly mind bobbling, chuck, is that you can take a gene from a different organism and put it into another organism. You can basically just copy and paste and cut and paste DNA and that's what this system is allowing people

to do. So what does all this mean. It means you could potentially remove a gene for blindness, You could remove a gene for cystic fibrosis and repair. Uh. Well, we'll talk about HIV a little bit more in a minute. Um, you could create more disease resistant crops. Uh. You could create a bioweapon that could wipe out a species. I mean there are bad applications as well. Well. The people

have talked about that. And remember was zekea virus? Like people are saying, well, let's just get mosquitoes to to stop reproducing and then that'll stop the spread of zecra virus. What they're talking about is using gene editing. Yeah, and if you watch that uh ted talk from Jennifer down she says, slow we need to slow it down. And um, she and her I don't know she was partnered. She said she co invented. I don't know if it was Coonan or not, but whoever her partner and crime here

is I was a French, a French um researcher. So it wasn't Emmanuel something I can't remember last name. So she said they basically called for a moratorium for now and said everyone just stopped for a minute. Yeah, and everybody's like, well, how much money is There's a lot of money at stakes, so we'll see where that goes. But she she did call for a pause, is what she called it. UM, so they could kind of set up some guidelines on how to use and not misuse

this technology. Yeah. And the reason why UM, I mean, I salute her for that. That's a big deal. But that's a big problem that we're facing in this world is that our technology is starting to outpace our understanding of all of the things that can do. And then in addition to that, it's becoming much more democratized to where people can get their hands on incredibly advanced technology

UM in the comforts of their own home. And this is a really good example of that because the Crisper system you can send off for on the internet for anywhere from like thirty bucks to seventy five bucks, and you will have a bacteria that you can introduce your guide RNA too or your host RNA too, and and basically airstolize it and expose it to a mouse, and that bacteria will go in and edit that mouse's Janes, and you can do this if you know what you're

doing with a relatively clunky setup at your in your home and in the So like the idea that we need to stop in and talk about what direction we should go with this or what restrictions we should place on it. I think that's a fantastic idea. Well, yeah, because we all we did a show on Designer Children. Uh jeez, was it before two thousand twelve? I don't know. I would guess it came out of this because I

don't remember. I don't remember talking about the crisper jine in that episode, but that's potentially one of the applications is I don't want my child to have Huntington's disease, and it's in there, so let's take it out. Oh I also want my kid to be tall and have blue eyes. Yeah, it gets a little dicey, it does. Um Designer Humans, Well, just go back and listen of that episode. It's fun fraught with complications. You start to

run into the idea of like genetic or eugenics. Well, yeah, they have and they have nuts because obviously not everyone could afford to do something like that, So then you have you know, the wealthy uber races even taller and blonder than ever, right exactly. But then they've also decided that tall and blond is the ideal, So then they start like editing people's jeans who aren't tall and blond, and then all of a sudden, you have nothing but tall and blonde people. Right, Like you said, I've never

even seen that movie. What's a good one? Is it? Really? Yeah? Man, they're like a you know, a thinking person's reindeer game sci fi. You bring that movie up way too much. Um, just a thinking person's sci fi future movie. Have you seen Equilibrium with Christian Bale? No? I haven't either. It's got like three stars on Netflix, and that's not enough for me to pull the trigger on I've never heard of that, which is a bad sign. It seems like it's from about the same time as Gadica make me

a little earlier. But it's Christian Bale. He's good. Yeah, it's a little crazy, he's still good. We're done, you and me. He's never gonna live that. What a great tirade. He did it right before we shot our TV show too, so like we walked around on set like say and that all that was a running joke that was fun. Uh, you want to take another break. Let's take a break and we'll talk about kind of where we are right now and and what some people think about his future.

All right, Chuck. So obviously we're on the verge of UM great designer children like probably next week, right. I don't think it's that quick, No, But I did read this article because this sounded too good to be true when I was reading it. It's like, Man, the Christopher gene. That's it's going to solve everything from food shortage to every disease known demand like cancer. Right. Cancer, Cancer is basically the result of UM something called the P fifty

three protein not being expressed by a gene. And the P fifty three protein goes in and says, hey, I think you're a tumor. You stop multiplying. And if that, if that protein is not there to tell the cell to stop multiplying, it keeps multiplying, and all of a sudden, you got a tumor, a k A cancer. Right, So you could go in and and just edit that gene to make sure the P fifty three UM protein is expressed. Bam, you just cured cancer on the genetic level. So yes,

it could just improve the world. Correct sir, So I read this article, I was all excited, um, and you should still be excited. This isn't a complete poopoo, but this was just like this week. Uh, the gene editor Cristoper won't fully fix sick people anytime soon. And here's why. Um. So this lady, Jocelyn Kaiser sort of throws a bit of a wet blanket on it, um, but not completely there. She's just sort of like, there's still a ways to go.

So here's one of the things, um, most diseases apparently, uh like cystic fibrosis, muscular dystrophy um, where gene correction is already kind of a thing, like where they require gene correction. Um. Basically, what she's saying is it has to be done in a living person. Like you can't extract the cells and do it and then put the cells back in like they currently do with gene transfer, because uh, not enough of the cells will survive apparently.

So that's one of the roadblocks right now. You need to treat the cells inside the body. Well, one thing I have challenge, one thing I wondered maybe this this um lady talks about it. But how do you how do you direct the the Crisper CAST nine system to the right cell? She just said it's I mean, in her ted talk, she doesn't get super specific. She says, it's an RNA guided protein. Um, that's what I ran across too. I didn't run acress anybody said, oh well this is how did that look for that too? I

think it will just call it the magic of science. Um. Yeah, but I mean it's it's very precise though. You know, it's not like they just throw it in there and see what happens. So there there's something guiding it. Um. It's a safety risk right now because when this this Crisper cleaves it off with the scissors. Uh, it is in a very specific location. But they don't know yet if it could potentially, because once you've created these things,

you deliver it through a viral vector. It's in there and this cast nine is going to keep replicating itself for forever. So they don't know if fifteen years down the line, if the thing starts cleaving causing cancer basically. But what they think now is they haven't seen that yet. So it's just like, let's keep an eye out for this so it's not like the worst news ever, but so far these mice are doing well and that's not happening. Well.

This is like a very hot topic in bioethics as well, and one of the things that people I'm sure like um Dubner are um pressing for is figuring out how to reverse engineer the stuff or reverse the effects of it, to engineer it so it stops after a while, so that if it it like if you did introduce it into a wild population, it wouldn't just wipe that population off the face of the earth. It would eventually slow.

Well that's exactly what they're hoping to do, is that CAST nine will eventually stop doing it thing there's you can hope in one hand and then figure it out scientifically. And they're trying to figure it out. Okay, yeah, I thought you were saying, like yeah, they just oh no, no, no, that that they know that's an issue, and that's one

of the like roadblocks are trying to overcome. One of the other things is the CAST nine um it's a process that it can only be active when the cells are like dividing actively dividing, and apparently that's just not you know, the liver, you're stem cells, your eyes, your blood. It's not always actively dividing. So they're trying to work around that. Basically every limitation they found so far, they're saying, it's not a it's not a deal Breaker's not a

deal breaker. Yeah, we think we can figure something out to work around it. I'm sure they will. So that's the good news. It's just too it seems to be working too well, and it's just too easy to do. There's this there's not just gonna like leave it on the table. Well, no way. I couldn't get around the liver cells not replicating. Uh. And then you know, we mentioned HIV earlier. This article needs updating in our on our site because it said that it kind of overcame HIV. Uh,

but that's not true. Now apparently HIV defeated the efforts Christoper right now, but again they said that this isn't this doesn't mean it's over. Um, we think we can overcome this as well, and that eventually could be a cure for HIV. So right now, and they said they weren't too surprised because HIV. To go back and listen to our episode on that it is a tough tough cookie cookie and UM has a knack for mutating and

replicating in the face of all kinds of drugs. But they think if they use those drugs along with this, maybe that could be an alternative. UM. Yeah, I mean the future is bright. I think they just it's so early in the game, is the deal. But that's why I think a pause is a good idea. I don't know if I've gotten that across that. I feel like, Yeah, there's one other thing I ran across and researching, something

called a DNA drive. You can take this Crisper gene UM Crisper cast nine system, and UM you can add this other component called a DNA drive. Right, And so

this DNA drive is basically like UM. It has the ability to during reproduction two not only take the edited gene, or not only to edit a gene in say a miss guito, but when that mosquito reproduces the chromosomes that are contributed with the edited gene, basically, UM break the corresponding spot on the other parents chromosomes, and then when it repairs itself inserts the blueprints so that the edited

gene is copied. So then the offspring has both two pair or one pair of the edited gene, which means when they reproduce and they reproduce to somebody else that has both pairs of the same gene, um their offspring has a chance of inheriting that gene and so it can spread through a population of mosquitoes and fix it for your family, fixes it or keeps you from reproducing

or whatever. The gene is. Yes, and in a large population, say like a big mosquito population, that means you can spread the edited gene and like a single growing reason. But that's one reason why people are like, we need to figure out how to be able to turn this off because maybe we need mosquitoes. That turns out we shouldn't just wipe them off the face of the earth, although we remember we did a show on that, and some scientists think, no, we don't need them. Yeah, I

remember that. Are you got anything else? I got nothing else. I'm sure we can do a follow up on this if we want. If you want to know more about the Crisper gene editing, sweet, you can type that word into the search part house to works dot com and insisted search parts time for listener mail. I'm gonna call this l s D. We've got a lot of great emails from well, I just read this from people who use it and like it. Hey, guys, love the show, but UH, it's been great to learn so much about

a variety of topics to and from work. I recently listened to LSD. I got to share my story. Three years ago, my father died unexpectedly a stroke, and it took my whole family by surprise. And became very depressed for MutS and felt like I was diving into on autopilot and wasn't finding any enjoyment in my day to day life. One night, I was hanging out with my friends and was offered some LSD. I had taken some years ago and had a wonderful experience with it, so

I thought maybe this could be helpful. Turned out to be the best decision I ever made. I had several powerful revelations about life and developed a deeper appreciation for my friends and family and for the love that binds us all together. Also gained a fresh perspective on how much beauty there is in the world and how I am a part of it. This experience really helped UH set me back on the right path and is a moment in my life that can point to as life changing.

I believe the drug has a lot of potential for psychiatric use, can be immensely beneficial with helping people work through serious psychological and emotional issues. I truly hope that it is reclassified from Schedule one so it can be further studied and seen as a medicinal aid and not a harmful chemical. Uh. And that I'm gonna just say is from anonymous because I didn't hear back whether or not this dude wanted his name right on the air.

Thanks a lot, anonymous, anonymous man, and thanks to everybody who sending emails like that. We heard from a lot of people who are like, yeah, I really love acid, you know, and you know they weren't stories from people that hurt, like you're going to hear this man. Yeah, it was like, hey, I enjoy taking LSD sometimes and I'm a responsible, growing up adult and nothing that helps

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