Editing Genes with CRISPR

the listeners in on a little secret. So the first time we recorded this episode, there was an audio glitch where we lost the first half of it. Yep. Um, So what we're going to be doing now is re recording part of this episode. I say that in case you're wondering why we might have like a callback joke at the end that calls back to nothing. It's like we're stuck in a time loop, like we went through

that nebula with con and then what happens. We're definitely not trying to have like some sort of inside joke that you're not privy to. You would have been privy to it had the technical glitch not happened. That being said, what are we talking about today, Joe, Well, we're talking about Mr DNA. Someone someone's been watching the Jurassic World

trailer and just what did you come from? You know, I always love that moment in Jurassic Parker, Mr DNA comes out and they explain to you about the wondrous of DNA. But everybody's heard about DNA by now. It's it's no longer a big surprise that we've that we've got these coding segments and the cells in our body that tell us what kind of body plans to produce.

They make the proteins that make our bodies, and so we get our traits are sort of inherited physical traits from our d N A. And this is long led people to wonder like, Wow, could I make myself better if I could just change my DNA? Could I head off any disorders or diseases? More importantly, I mean, and this is the thing that we definitely said the first time, if we were going to change something about you, Jonathan, it would absolutely be the color of your beard. That's right.

That is something we did. Purple beard it would need to be purple. I'm so I'm so pleased that you remember that. I was listening back to the garbled audio that we had and we got to the point about my purple beard, and I thought, I don't worry about that being talked about again because it's not in our notes. But sucka darn it. Yeah. I mean, the technology that we have to change something like the color of someone's

beard right now is like bleach and die. Yeah. It's not something about, you know, changing the innate properties of me so that I'm growing purple beard here right. But if we want to change other traits, like, for example, diseases like like cancer, something that is heritable, you can't just drink bleach and die, or I mean you could, but I don't recommend that. That's not a medical treatment.

Please don't do that. Don't do that. No, No, We're talking about a more serious scenario where imagine that, um, we've reached the level of genetic sophistication where you can produce an embryo that's going to be your child, and you can look at the d n A of that embryo and analyze it, run it through the computer and say, oh, No, it looks like this child is going to have a genetic condition which makes him or her prone to any number of you know, diseases, something that that we wouldn't

want for this child that the embryo is going to grow to be. So could we make a little edit and fix the d n A so that the child doesn't have to suffer from this disease? If you could do such a thing, Obviously, lots of people would want that opportunity, right, And we've talked about this very subject a couple of times in previous episodes, including one about

gene therapy. But the reason why we're bringing it up again now is that we wanted to really focus on a system that makes the potentially could make editing genes far simpler and more efficient, less expensive than previous methods, and therefore has the potential to revolutionize the way we

work with genes. And because of this revolutionary quality, this new system is being heralded with caution, right, we should say, lots of scientists have recently spoken up saying, hey, we need to we need to take stock of where we are in gene editing technology right now and and make sure that we're taking all the proper precautions and sort of treading carefully on this ground because we get into some pretty weird territory when you talk about editing genes.

But let's let's talk about the new system itself. Well, here's the crazy thing. The system, if you think of it as the actual process, is not new. The new part is that we're employing it or can employ or that we know that it exists at all. Yeah. The cool thing about this, the super cool thing about this, is that it's a natural process that was observed many years ago but not understood until relatively recently. Yeah. And so this process is known as the Crisper cast nine system.

And the Crisper cast nine system is based on a naturally occurring system found in bacteria. In it's an immune process in bacterial cells, right, And crisper is not referring to some kind of refrigeration system within bacteria. It's an acronym. Right, It's an acronym for clustered, regularly interspaced short palindromic repeats, and that refers to sections of DNA code in these bacteria and how they use this system to protect themselves

from viruses. So, the blocks of repeated gene sequences were first observed in bacterial cells and mentioned to paper by Japanese researchers in the Journal of Bacteriology in nineteen seven, and at the time scientists didn't know what they did. They're like, no, we saw these things, we don't know what the purpose is, right, It wouldn't be until several years later that more observations would give us insight into

what was actually happening. A couple of decades. Really, yeah, so we now know that these are used to create a system within the bacteria that protects the bacteria from viruses. And it's actually what's known as an adaptive immune system. Now what is that so? Adaptive means that you are building up like you're you're you're constantly evolving and tweaking your your immune system so that you can fight off

a broader array of potential pathogens. All right. That's why vaccines work, because they give your body just a little bit of a inactive virus to look at, to observe, to take a little bit of the protein from the virus shell from and to incorporate that inter into your immune system so that in the future, your immune system can recognize that type of virus and say like no, thank you, sir, exactly. Yeah, And and so this is sort of bacteria's approach. Actually it's not sort of. It

is bacterious approach to fighting off viruses. If a bacteria survives, uh, and encounter with a new type of virus, it adds that information to its quote unquote like database of viral info. Yeah. Yeah, and that's that's what these little crisper strands are there. There these strands of of little bits of repeating DNA that have little bits of viral codes smushed in representing all of the viruses that that bacteria or that bacteria's

ancestors has run across. Right, because it's inheritable. So this is really interesting for lots of different reasons. Okay, so to get into how we could use this bacterial immune system or a version of it to edit jeans, let's look at how it actually works in the field in real life. Right, what happens when a bacterium that has this defense mechanism encounters of virus. Okay, here's how it

goes down. You got your virus. Now your virus. Imagine that you've got a little it looks like a little spacecraft, especially if you played Yards Revenge, watched an Atari documentary recently. Anyway, so you've got this little virus inside this shell is viral DNA, and the way of virus replicates is it ends up infecting a host cell. So some viruses target very specific cells and ignore anything else. It's all through

protein markers. Anyway, the virus lands on a host cell and it injects its own DNA into the host cell. That DNA essentially hijacks all the assets inside the host cell to start replicating more viral DNA and virus shells. So it's essentially telling the host, uh, sell, hey, I know what you're doing is tot's important, but you gotta drop it and make some of this stuff asap. And

that's what the host cell does. It's it's getting new instructions and it just starts churning out more and more viruses until you know, more instances of the same virus I guess I should say, until you get to a point where the little virus shells all break free from the host cell, killing it in the process, and then they go on their merry way to do the same thing to other host cells. And that's how the virus spreads So that's how a virus typically would attack a bacterium.

But let's say that the bacterium actually has this adaptive immune system we just mentioned what's going on there. Well, assuming that the bacterium or one of its ancestors had encountered that particular type of virus before, it's gonna have a strand in its DNA that matches part of the viral DNA. And when it detects the the intrusion of viral DNA that the bacteriums DNA will end up creating a strand of RNA, actually two strands one strand of

that RNA. We'll have pairs well half of a pair, uh, that you would find in the double helix that match up to the viral DNA. Yeah. Sort of think about the way that a key is made to fit the pins in a certain lock. The key has these particular series of bumps and grooves that will fit into that lock. This immune system device has RNA that's like a key that fits the virus. Yeah. So if you think of h d NA, like, you know, you've got this double helix.

If you imagine you straighten it out so it looks like it's a ladder, and each run of the ladder is actually a pair that joined together. The RNA is one half of that ladder that can match up to

half of the virus DNA. Now it creates an enzyme um it's actually it's a protein that the casting line protein and creates a few things, but the castline protein is the one that's important for this discussion, known as an indo nuclea, and it ends up unwinding separating the viral DNA so that the RNA created by the bacterium will join up to the viral DNA, and it also will snip the viral DNA at a very specific point and this essentially deactivates the viral DNA, killing it so

that the viral attack fails. It is not able to hijack the cells operations and create more viruses, uh, which

is you know, pretty awesome. And also, like we were mentioning before, if it happens to be the case where the bacterium or its ancestors has never encountered that particular virus but it survives the attack, then for that information gets added to the bacteriums DNA so that future encounters with that virus will be handled with extreme prejudice for that bacterium and all its descendants, right, and in a word about these these these casts proteins and specifically CAST nine,

which is the important one DAYA that stands for Crisper associated proteins and number nine a number nine like a like love potion number nine, yes, and are probably not. This is like death potion number nine. And the Crisper arrays make a bunch of these different cast proteins that all have different jobs, like like integrating those new bits of those like wanted wanted poster sequences into the Crisper strand.

And CAST nine's job, which it is really good at, is uh, both to unzip the DNA and to snip the ends at that specific location along the helixes hees. So this indo nuclease, this CAST nine is it's kind of like a little pair of scissors. A lot of people have computed molecular scissors, and people say can go in and make little snips and cuts to DNA, which, obviously, once you see something like that in action in UH in the microbial world, you start to think, huh, I

wonder if we could take advantage of that. Yeah, because it's able to cut it at a precise location and cut at the same location across both of the helices, as we were saying, so that you have an extreme level of control, which is really important if you want to do something like target a very specific strand of DNA or section of a strand of DNA, I should say right. And this is especially interesting because research has shown that this crisper cast nine SmackDown of genes may

also occur within a bacterial cell itself. It's not just in application to viruses. In research that was published in Nature in from a team out of Emery University, a particular bacteria was shown to to use crisper Cast nine to shut down one of its own lipoproteins. And okay. In bacteria, lipoproteins help the bacteria attached to a host cell, but they also trigger inflammatory responses in a host, which triggers the host summune system, which sucks for the bacteria.

Um By shutting off this lipoprotein, it lets the bacteria kind of fly under the radar, multiplying without interference and biding its time until it goes pathogenic. Interesting. Yeah, another cool thing. This is almost a tangent, but a cool side effect of This is that you can look at UH back you know, the the DNA of a bacteria and or or of bacteria I guess I should say UH, and be able to tell a lot about it, including you know, which viruses it has encountered in the past.

And this kind of ends up being a fingerprinting approach. So let's say that there is a bacterial outbreak somewhere some some sort of illness that is due to bacteria. For example, let's call you know, food poisoning. We hear at how stuff works, are familiar or with that particular idea. Um, So let's say that you have an outbreak of food poisoning.

You could end up analyzing the bacteria and by looking at the this information which viruses encountered in the past, you could possibly use that information to trace it back to wherever the source of the food poisoning was. So

it's actually got some interesting forensic identification processes. It's being used like that by the cultured dairy industry to check whether the strains of helpful bacteria that they use in order to make cheese, at yogurt and delicious stuff like that that requires bacteria for the process to check whether their bacteria are immune against common viruses. They can then select bacteria colonies of bacteria that are stronger and more

likely to remain effective at driving these processes. So it's it's like a more technical bacterial version of breeding really healthy animals to make sure that their offspring are healthy. I'm just imagining, like the Saruman of cheese over his factory, breeding the uricai of bacteria to make delicious cheese. I don't get the reference. Tom kidding, kidding, says the guy with the Lord of the rings. Tonight we dine on cheese,

all right. So where does the gene editing come in? Well, in a group led by Jennifer DOWDNA and Emmanuel Charpentier and apologies if I mispronounced that, I did my best, but they published findings in Science that the Crisper system could be used to edit any kind of DNA you want through quote RNA programmable genome editing. And that was in a paper called a programmable dual RNA guided DNA

into nuclease Inadaptive Bacterial immunity. Yeah. So subsequent studies have shown that it works not only in bacteria with Crisper based immune systems, but in all kinds of organisms and

potentially in humans. So with crisper based gene editing, it's a very similar process to what we just described with the bacteria fighting off of virus, except instead of trying to identify a virus and kill the d n A so that you don't have to worry about viruses replicating inside the cell, what it's looking for is a specific strand that relates back to a gene that you want to target. So, in other words, we make we can manufacture RNA that matches up to a specific gene and

use the same sort of process. This this dual, these dual strands of RNA, one of which is matched to the gene to go. Uh, the same sort of thing happens. It'll it'll end up using creating the castinine protein that will end up unraveling the helix and uh, the RNA will bind to with chever gene you specifically want to target, and it can snip the ends of the helix exactly where you want it, and thus you can isolate a specific gene. And it's really not hard to do, yeah,

especially compared to previous methods. So we we have a couple of capabilities here. One of them is the simplest, which is just to knockout genes you don't want, right, just to see what happens. Yeah, you can like deactivate

a gene isn't right. So I know we've used an analogy to explain genes before, and I'm going to go ahead and rely on that again because I think it's helpful if you imagine your genes like a giant switchboard, and the switches have on and off, So whether a gene is on or off determines whether that gene will

ultimately be expressed. However, it gets a lot more complicated from that point forward, right, because it's not always true that one gene directly correlates to one trade maybe in some cases, but in a lot of cases, you have complexes of gene that work together to create complexes of effects, and not all of them really go together in a

logical way. Like I mean, this is a pure imaginative example, but it's the equivalent of like how fast your toenails grow being connected to your eye color being connected to whether or not you get cancer, and and these things are really complicated because, uh, nature, because stuff is messy and Uh, you know, nothing was really created in our gene sequences anticipating that we were going to want to go in and just flick switches on and off. So

nature doesn't owe us an explanation. Yeah. And so in other words, isolating these genes and being able to turn them off can tell us more about what what is the the role of that gene and how does it affect the rest of the system. Right, So that that's really important information for us to have. Sure, But in addition to being able to just knock out and turn off specific gene, we could also make changes to genes. Yeah,

more accurately, I should maybe say changes to the genome. Well, and this is important in case you identify a gene that's undergone some form of mutation and is not, uh the way you would have expected it to be, and that it could potentially cause harm, you may wish to be able to go in snip that part out and replace it with a healthy gene. Right. Okay, Well, we now have this system, this Crisper cast nine system for editing genes. But this is not the only method there

has ever been for editing genes. So what makes this one an especially big deal? The biggest deal is that

it's way easier, like like way like way easier. It's incredibly precise, efficient, apparently really cost effective and simpler than the previous methods that have been employed to do essentially the same thing, because it goes about it in a very different way, right right, So the two leading types of gene editing right now, other than crisper are zinc finger nucleases z f ns and transcription activator like effect or nucleases or talents talent talents sounds much better than

ziffens ziffens um. Both both of these depend upon creating a thing, a protein, which is what a nuclease is, that will bind to the sequence of DNA that you're interested in deactivating. So your z fns and your talents are only as good as your binding agent. If it's not specific enough or not strongly attracted enough to the sequence that you're targeting, it won't be very effective and could even have dangerous consequences. Like think think of your

word processors search and replace function. It's really hard to create a protein that will bind to the DNA equivalent of a whole word like like tomatoes. Okay, if you're protein only binds to say tom or toe or toes. Then that binding agent could latch onto a lot of unintended bits of DNA by accident, which is potentially really

bad times. Yeah, so very different from those approaches obviously, right, So by making this type of gene editing and research much faster, easier, more efficient, and in a lot of cases,

more precise. The positive side is a lot of researchers have pointed out that this could speed up research on genetic disorders, you know, any inherited genetic condition that we want to cure, like cystic fibrosis or muscular dystrophy, you know, heritability for a propensity to develop certain cancers, anything like that, like like dramatically to a point that's that's almost hard to imagine compared to what the progress had been before. Sure,

the downside is that it's really easy. So it might be so easy that we are getting a little bit ahead of ourselves and finally could also be the method that we use to you know, hack ourselves, like to

to change things about people. This is the one that's raising some alarms, the idea of where we to decide we would go down this road right where we Yeah, it could potentially go beyond like let's make sure no one has cancer and go into like let's make sure everyone has the specific visual traits that we want or whatever.

It is essentially non therapeutic uses for the technology, and that's something that could be a future possibility, but it's one of those things that raises a lot of ethical questions. And now we have to actually start looking at those ethical questions because something again that was hypothetical a few years ago is now something that could be a reality maybe a few years from now. Ah. Yeah. And it's not just you know, lay people who are disinterested in

science as a whole who are freaked out about this. No, there are actual scientists who are legitimately concerned about this. Yeah. There have been at least two high profile calls from scientists in the past month or so, well, in the past month from the time we're recording this, which one which is April. Yeah, so in uh March March twelve between a group of scientists published a comment in Nature basically calling for a moratorium on editing the human germ line.

And this is a specific, uh specific portion of the application of crisper. They're they're they're not saying like like hall Doll, Crisper forever um. The human germ line is specifically human reproductive cells that can pass on heritable traits. It can it can lead to changes in generations down the line. Yeah, yeah, So what what is the fuss? Like?

What are they concerned about? The big one that we don't know enough to know what consequences will from those sort of actions if we were to alter the germ line, we don't know which ones might be safe, which ones could be dangerous, which could harm harm future generations, and without knowing that, it is irresponsible to to to experiment

in that field now. And that's the real concern is that, you know, in our efforts to do things like head off potential disease in children, which obviously is something that is an honorable pursuit, the trying to eradicate disorders and diseases that could affect the unborn is a big honorable pursuit. But if in doing that we end up creating more problems down the line, then obviously that was not necessarily the best choice, And that was really where their their

objections came in. Um So, I think it's completely understandable. I I agree that there there needs to be caution. And again, like you were saying, Lauren, they're not suggesting that we completely abandoned using this methodology. I think it's

more like, we'll hold up for a minute. We need to figure out what we're doing before we do it, right, Yeah, Yeah, especially when you're dealing with new human life, and especially especially when you're dealing with the types of cells in new humans that they can pass on to their new

humans down the line. Right, And they even mentioned scenarios like, imagine that you were going to target uh, particular type of DNA that's going to be found within an embryo, and let's say the cells divide between when you have

started your treatment and when it's actually over. It may be that some cells have been affected and the offending DNA has been clipped out, but in other cells it hasn't, and then you've got a genetic mosaic and it could potentially cause really severe issues done the LT we just don't know. In fact, we don't even know what it might do, and that is in itself unethical and problematic when you're talking about human life. So that's where the

real concerns come in. And they you know, I think they raised some good points, and they weren't the only ones. So there was another group as well. Right, Yeah, there was another comment in Science in March of from a group that included the Nobel Prize winning David Baltimore of Caltech, but also Jennifer DOWDNA, one of the creators of the

Crisper technique. From that paper, and there's an actual quote that I would like to read from that where it says the group wishes to initiate an informed discussion of the uses of genome engineering technology and to identify proactively those areas where current action is essential to prepare for future developments. We recommend taking immediate steps towards ensuring that the application of genome engineering technology is performed safely and ethically.

So again they're crying out for a responsible approach to research and saying, look, this tool is amazing and has the potential to make amazing advances in medicine and to truly help out human beings, but we need to make certain that we pursue that in a way that is going to be ethical and responsible and not put people in danger just because we now have the access to this amazing tool. Sure, and and governments are kind of

already on this. There was a review that was done in by bioethicist Tetsi I. E. Of Hakkaido University UM and it found that of the thirty nine countries investigated already do have laws or guidelines that ban germline gene

editing in humans. So so so, so that's pretty covered. Um. But even considering that, there's just a general concern within the scientific community that even if most researchers are responsible and ethical and follow these sorts of guidelines, that any breach into less responsible or non therapeutic modifications could cause a public outcry that would lead to a huge crackdown on on the funding and regulation of these genetic technologies,

which would obviously not be of benefit to anybody. Right. So, so part of it is saying we shouldn't do this because it's wrong, and even if you don't think it's wrong, other people do think it's wrong, and it's gonna mess everything up for everybody if you do it, so just don't do it. I can get behind that, we get to a point now where we can talk about how we feel about this. I'm pretty much in line with

the concerns that the scientists have have have raised. I think that this is definitely an amazing technology that could end up helping us in ways we can't even comprehend right now. But I also think that obviously we need to use some uh some logic, some uh you know, compassion, some rationality when we approach this, and and not go crazy with it just because it opens up lots of opportunities. Yeah, as with UM, as with any new potential therapy, I

think they're you know, they're competing interests. I mean you could look at it from the other point of view and say, well, what if you're somebody who is who has a heritable you know, trait that causes genetic defects that can I don't know, like kill a child or something, and you want to reproduce. I mean, you might be one of the people who's saying, like, no, I you know, I want these therapies sooner. I want them available so that I could feel that my you know, the child

I have with my partner would be safe. And so I can see how somebody would could take that point of view as well, like you know, they want haste in a way, because this really does matter in a lot of cases, but at the same time, the concerns voiced by these scientists or yes, I obviously quite valid ones. I mean I don't think we're in any position to

disagree with that whatsoever. Oh sure, No, I mean, I mean, once you get that full picture of like, well, we could stop this one thing from happening, but it could have all of these unintended consequences that we don't even know about, that we're not even aware of. Um. And so I would say that, you know, this is really cool, this is just unimaginably terrific. Uh. But also yeah, let's let's let's proceed with caution. Let's let's co develop more

knowledge about the human genome. Let's figure out how all of these things are interacting with each other, and not dive into anything before we know what we're doing. Well, let me ask you guys another question. Let's let's assume let's let's put ourselves into the far off distant future where we have a full understanding and appreciation for UH genetics. Let's let's assume that that eventually happens and we now know how to proceed without causing unintended consequence. Is obviously

we're in an idealized world at this point. So so we're sort of imagining at this point the human genome is open source, and we understand it as well as we understand the lines of code and a computer proof and that, and that we can be we can be reasonably confident that any changes we make, we will be making in such a way as to not cause harm to unborn generations. At that stage where we have that confidence,

do you think that the designer babies issue? Do you do you see that as being a bad thing where parents could make decisions upon how their babies may you know, the traits those babies might exhibit in the future. I think that's a really interesting question. I think you're sort of saying, like, if we we rule out the possibility of unintended effects, we just set that aside from it. Is it inherently wrong to mess with nature? Yeah, that's the question I'm getting at. What what what is your

personal opinion on that? I don't know. I mean that that's a that's a tough decision. I feel like I would personally feel very iffy about doing that myself, But then again, I don't know if I would feel comfortable telling somebody else they couldn't do that. See, it's kind of a mood question for me. I've decided not to have kids, but assuming that I were to have kids, I almost feel like, um, that the idea of being able to choose things is no more sinister than leaving

it up to chance. So you know, like saying like, well this is this, you know, whether you can determine ahead of time. Now, granted, you know you're not giving the kid any say in the matter, but the kid

doesn't have any saying the matter either way. It's just is it wrong for the parent to have that input or is it you know, yeah, yeah, Well there's there's a lot of questions wrapped up in that, and and you know, depending on different people's ideologies of what makes a better baby, like like what traits they would want to instill in their future generations. I mean, you know, it gets into really weird sticky territory like, are are the things that I think might be good for my

potential kids actually good? Uh? You know, would we want would we want Kim Kardashian being able to choose how her babies come out? I mean, you know, this is sorry to be able to program like I want hyper obedient children don't question anything. Well, there's also the question about social pressures that could come in about you. Of course, there's science fiction that obviously has has tread all of this. Yeah, I mean, and also you get dangerously close to weird

stuff like eugenics. Like there's some definite, like huge ethical questions here. When you look at it from an individual basis, it seems simple, but then you've got to remember we're not all we don't all exist in a vacuum unto ourselves. We all work together in various cultures and societies, and there are other factors that will apply to these kind of decisions. They're never going to be something that is completely made by a person, I think, at least not

if it's if it's a technology that's widely available. I mean, obviously there would be other questions too, Like let's say that the technology becomes widely available. I'm sure it would be one that would become widely available for specific segments of the population and not so right, and then you've got a disparity between you know, you talk about haves and have nots. I mean, this is why we have so many amazing science fiction stories that are based around this.

Those are really kind of like their explorations of human behavior, human psyche, human society, and culture, and they ultimately are important because assuming that technology and our scientific knowledge continues to improve, we could potentially arrive at a day where it's truly relevant. It's not just speculative. So that's why I want to ask the question of you guys. Like, again, from an individual basis, I'm like, oh, I'm totally okay

with it. It's when I start expanding that to everybody and what that might mean for the future where I think maybe I'm not that okay with it, And ultimately, for me, it's mood, so it's kind of a mean thing. Yeah, ask anyway, I don't know. I don't know. I'm just imagining a world in which, even like, even like in a D and D game, if everyone could tweak their dice rolls to to roll their perfect character, how obnoxious

would that be? He'd be like, I'm just gonna roll these seventeen sixcited die and pick the three topics, you know, really leaving things up to chance. Uh, this is kind of a you know, obviously one of those ongoing conversations, but is one that we need to have seriously, because we're again approaching an era when this is some of these things are are potentially possibilities, So I'm curious what our listeners think too. I would love to hear your

thoughts on this. Uh do you do you automatically think like, well, I'm perfectly cool with addressing things like disorders and diseases, but I don't ever want to think of this in a non therapeutic sense. Do you think the hacking the body is something that needs to be on the table as long as it's got certain qualifiers. Maybe you think there need to be no qualifiers at all. I want to hear what they think, so send us email. Let

us know what your thoughts are on this subject. Our email addresses FW Thinking at how Stuff Works dot com. Also remember you can suggest future topics. You can uh leave any other comments or questions you have. You can also get in touch with us on Facebook, Twitter, or Google Plus. At Twitter and Google Plus, we are FW thinking on Facebook. Just search FW thinking in the search bar. We will pop right up. Leave us a message there.

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