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  • translator: Aaron Shoo, reviewer: Yi-Fan Yu

  • So, has everybody heard of CRISPR?

  • I would be shocked if you hadn't.

  • This is a technology -- it's for genome editing --

  • and it's so versatile and so controversial

  • that it's sparking all sorts of really interesting conversations.

  • Should we bring back the woolly mammoth?

  • Should we edit a human embryo?

  • And my personal favorite:

  • How can we justify wiping out an entire species

  • that we consider harmful to humans

  • off the face of the Earth,

  • using this technology?

  • This type of science is moving much faster

  • than the regulatory mechanisms that govern it.

  • And so, for the past six years,

  • I've made it my personal mission

  • to make sure that as many people as possible understand

  • these types of technologies and their implications.

  • Now, CRISPR has been the subject of a huge media hype,

  • and the words that are used most often are "easy" and "cheap."

  • So what I want to do is drill down a little bit deeper

  • and look into some of the myths and the realities around CRISPR.

  • If you're trying to CRISPR a genome,

  • the first thing that you have to do is damage the DNA.

  • The damage comes in the form of a double-strand break

  • through the double helix.

  • And then the cellular repair processes kick in,

  • and then we convince those repair processes

  • to make the edit that we want,

  • and not a natural edit.

  • That's how it works.

  • It's a two-part system.

  • You've got a Cas9 protein and something called a guide RNA.

  • I like to think of it as a guided missile.

  • So the Cas9 -- I love to anthropomorphize --

  • so the Cas9 is kind of this Pac-Man thing

  • that wants to chew DNA,

  • and the guide RNA is the leash that's keeping it out of the genome

  • until it finds the exact spot where it matches.

  • And the combination of those two is called CRISPR.

  • It's a system that we stole

  • from an ancient, ancient bacterial immune system.

  • The part that's amazing about it is that the guide RNA,

  • only 20 letters of it,

  • are what target the system.

  • This is really easy to design,

  • and it's really cheap to buy.

  • So that's the part that is modular in the system;

  • everything else stays the same.

  • This makes it a remarkably easy and powerful system to use.

  • The guide RNA and the Cas9 protein complex together

  • go bouncing along the genome,

  • and when they find a spot where the guide RNA matches,

  • then it inserts between the two strands of the double helix,

  • it rips them apart,

  • that triggers the Cas9 protein to cut,

  • and all of a sudden,

  • you've got a cell that's in total panic

  • because now it's got a piece of DNA that's broken.

  • What does it do?

  • It calls its first responders.

  • There are two major repair pathways.

  • The first just takes the DNA and shoves the two pieces back together.

  • This isn't a very efficient system,

  • because what happens is sometimes a base drops out

  • or a base is added.

  • It's an OK way to maybe, like, knock out a gene,

  • but it's not the way that we really want to do genome editing.

  • The second repair pathway is a lot more interesting.

  • In this repair pathway,

  • it takes a homologous piece of DNA.

  • And now mind you, in a diploid organism like people,

  • we've got one copy of our genome from our mom and one from our dad,

  • so if one gets damaged,

  • it can use the other chromosome to repair it.

  • So that's where this comes from.

  • The repair is made,

  • and now the genome is safe again.

  • The way that we can hijack this

  • is we can feed it a false piece of DNA,

  • a piece that has homology on both ends

  • but is different in the middle.

  • So now, you can put whatever you want in the center

  • and the cell gets fooled.

  • So you can change a letter,

  • you can take letters out,

  • but most importantly, you can stuff new DNA in,

  • kind of like a Trojan horse.

  • CRISPR is going to be amazing,

  • in terms of the number of different scientific advances

  • that it's going to catalyze.

  • The thing that's special about it is this modular targeting system.

  • I mean, we've been shoving DNA into organisms for years, right?

  • But because of the modular targeting system,

  • we can actually put it exactly where we want it.

  • The thing is that there's a lot of talk about it being cheap

  • and it being easy.

  • And I run a community lab.

  • I'm starting to get emails from people that say stuff like,

  • "Hey, can I come to your open night

  • and, like, maybe use CRISPR and engineer my genome?"

  • (Laugher)

  • Like, seriously.

  • I'm, "No, you can't."

  • (Laughter)

  • "But I've heard it's cheap. I've heard it's easy."

  • We're going to explore that a little bit.

  • So, how cheap is it?

  • Yeah, it is cheap in comparison.

  • It's going to take the cost of the average materials for an experiment

  • from thousands of dollars to hundreds of dollars,

  • and it cuts the time a lot, too.

  • It can cut it from weeks to days.

  • That's great.

  • You still need a professional lab to do the work in;

  • you're not going to do anything meaningful outside of a professional lab.

  • I mean, don't listen to anyone who says

  • you can do this sort of stuff on your kitchen table.

  • It's really not easy to do this kind of work.

  • Not to mention, there's a patent battle going on,

  • so even if you do invent something,

  • the Broad Institute and UC Berkeley are in this incredible patent battle.

  • It's really fascinating to watch it happen,

  • because they're accusing each other of fraudulent claims

  • and then they've got people saying,

  • "Oh, well, I signed my notebook here or there."

  • This isn't going to be settled for years.

  • And when it is,

  • you can bet you're going to pay someone a really hefty licensing fee

  • in order to use this stuff.

  • So, is it really cheap?

  • Well, it's cheap if you're doing basic research and you've got a lab.

  • How about easy? Let's look at that claim.

  • The devil is always in the details.

  • We don't really know that much about cells.

  • They're still kind of black boxes.

  • For example, we don't know why some guide RNAs work really well

  • and some guide RNAs don't.

  • We don't know why some cells want to do one repair pathway

  • and some cells would rather do the other.

  • And besides that,

  • there's the whole problem of getting the system into the cell

  • in the first place.

  • In a petri dish, that's not that hard,

  • but if you're trying to do it on a whole organism,

  • it gets really tricky.

  • It's OK if you use something like blood or bone marrow --

  • those are the targets of a lot of research now.

  • There was a great story of some little girl

  • who they saved from leukemia

  • by taking the blood out, editing it, and putting it back

  • with a precursor of CRISPR.

  • And this is a line of research that people are going to do.

  • But right now, if you want to get into the whole body,

  • you're probably going to have to use a virus.

  • So you take the virus, you put the CRISPR into it,

  • you let the virus infect the cell.

  • But now you've got this virus in there,

  • and we don't know what the long-term effects of that are.

  • Plus, CRISPR has some off-target effects,

  • a very small percentage, but they're still there.

  • What's going to happen over time with that?

  • These are not trivial questions,

  • and there are scientists that are trying to solve them,

  • and they will eventually, hopefully, be solved.

  • But it ain't plug-and-play, not by a long shot.

  • So: Is it really easy?

  • Well, if you spend a few years working it out in your particular system,

  • yes, it is.

  • Now the other thing is,

  • we don't really know that much about how to make a particular thing happen

  • by changing particular spots in the genome.

  • We're a long way away from figuring out

  • how to give a pig wings, for example.

  • Or even an extra leg -- I'd settle for an extra leg.

  • That would be kind of cool, right?

  • But what is happening

  • is that CRISPR is being used by thousands and thousands of scientists

  • to do really, really important work,

  • like making better models of diseases in animals, for example,

  • or for taking pathways that produce valuable chemicals

  • and getting them into industrial production in fermentation vats,

  • or even doing really basic research on what genes do.

  • This is the story of CRISPR we should be telling,

  • and I don't like it that the flashier aspects of it

  • are drowning all of this out.

  • Lots of scientists did a lot of work to make CRISPR happen,

  • and what's interesting to me

  • is that these scientists are being supported by our society.

  • Think about it.

  • We've got an infrastructure that allows a certain percentage of people

  • to spend all their time doing research.

  • That makes us all the inventors of CRISPR,

  • and I would say that makes us all the shepherds of CRISPR.

  • We all have a responsibility.

  • So I would urge you to really learn about these types of technologies,

  • because, really, only in that way

  • are we going to be able to guide the development of these technologies,

  • the use of these technologies

  • and make sure that, in the end, it's a positive outcome --

  • for both the planet and for us.

  • Thanks.

translator: Aaron Shoo, reviewer: Yi-Fan Yu

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