1,421 words · auto-generated from the episode video
59:11It's like a bunch of tiny little magnets. 78 of them come together and make this barrel shape. Beautiful structure, >> right? This very beautiful symmetric barrel-like structure. They're all just coming together. There's these two subunits that come together, one on each side, 39 on each of them. >> And the Young's modulus of this thing, like the stress and strain, like how hard it is, it's about as hard as like some plastics or like viral capsids, which is very good because >> it's, you know, it's quite sturdy. >> Yeah. And the other thing is unlike viral capsids when you like poke them the viral capsids are kind of you're going to go all the all over the place and they're not really going to be able
59:51to recover. With these major vault proteins there's interactions with that protein. the way it sort of just magnetically locks into place with all of the others that ensures that if I were to like poke it with let's say a little um tip like an AFM tip or something like that with atomic force microscopy tip the vault protein will break and then when I remove the stress it'll just form back up just naturally. Biology has figured out this exact design to make this beautiful barrel-like structure that is >> resistant to stress. >> It's incredible. And we still don't know what it does. Like 40 years later,
1:00:33>> 1986, 40 years later, we still quite don't know what it does. >> But it is clearly uh fantastically engineered through evolutionary biology. >> Yeah, it's it's it's absolutely amazing. Right. So, how do how do we get from vaults to now time vaults? >> Yes. >> This is a really funny story. Okay, so one of these students at the Harvard Lab found Leonard Rome's YouTube channel. >> Mhm. >> He's called the Vault Guy. >> The Vault Guy >> on YouTube and he makes a bunch of YouTube videos about vault proteins and just like molecular biology in general. >> Shout out to the Vault Guy. >> And yeah, I guess one of these like grad students in the Harvard lab found the YouTube channel and was like, "Yo, this Vault guy is making some pretty cool stuff. Maybe we could use him for our
1:01:15purposes, right?" And that's where they got the idea of time vaults. And then this paper has come out in science, a genetically encoded device for transcriptto storage in mamalian cells. The idea is we're going to use these vaults as our Mac time machine. >> Yes. >> Right. >> Yes. >> Very cool. So how do we do that? How do how exactly mechanistically does it work? Because you know on this podcast we like to focus on just the Lego blocks >> Yes. of biology and how you put together a bunch of Lego blocks that actually work the way that they're supposed to >> because because the the concept of what what they're trying to accomplish and the reason why makes total sense.
1:01:56>> Yeah. >> Uh and then the entry point of, >> you know, these vaults being a possible conduit >> Yeah. >> to an engineered kind of functionality >> is interesting, but there's a big gap between those two things. >> Yeah. How am I going to get the mRNA inside and then how does it stay inside and all this other kind of stuff, right? This is again at the molecular level. >> Okay. Well, at the molecular level, everything is Lego blocks. So, let's talk about mRNA. One of the properties of mRNA is when it comes out, it has something called a poly A tail, which means at the end of the mRNA after it gets transcribed from the DNA, there's a bunch of aa the addinine, there's just
1:02:37repetition of adinine. And that poly a tail is kind of like a handle. >> Mhm. >> For figuring out where to take this mRNA and things like that. You you need to be able to grab it without messing with the genetic information that's later. Right. So you need some kind of handle for the sword. >> It's it's Yeah. It's Yeah. I was going to say it's it's like on a knife. You don't want the end to be a blade that you're grabbing. >> Yeah. Yeah. Because then you'll mess with the blade or you'll like kill yourself, you know. So, so the polyatail is there and the stuff that interacts with the polyatail is something called the polya binding protein pab. And what these guys figured is we could have a container and a bait. Okay, the
1:03:20container is my vault protein shell and my bait would be this protein that interacts with the poly tail and also has a little domain on the protein that interacts with the vault. Mhm. >> Okay. So, the PABP, that binding protein, is going to grab the poly A tail >> and then part of it is going to get stuck to the vault. >> Yes. >> Okay. And all of this we can put in a single piece of DNA >> such that when it gets transcribed, the vault protein gets transcribed to make the vault and also the poly A >> binding protein gets transcribed. >> Goodness. >> You see, >> that is so good. >> And so when I turn this thing on, it it makes the whole package. It makes my
1:04:01vault and it makes the thing that grabs the mRNA and puts it inside the vault. >> We've created a vertically integrated stack at this molecular level to effectively go through the creation of the individual component parts necessary. We don't have to hijack something existing. We're literally able to say, "No, we want the time vault. We want the grab pro the transporter." Yeah. >> Uh and so it's fully self-contained as a process. >> Yeah. Fully self-contained. >> Fascinating. Amazing, right? And then what you can do is this entire genetic circuit you can turn on and off based on this TET on TET off mechanism which is effectively what you do is you introduce an antibiotic called doxycyc and then
1:04:42when you introduce it on this genetic pathway gets triggered. So it makes the vault protein and it makes the interaction protein right and then and then there's another called docs off where I can introduce docs off and then it's going to stock stop the vault protein. And so now I have a controlled time window where I can make this time machine. I can trigger it. It can turn on. It can make all this stuff and it'll just grab a bunch of mRNA, stick it inside the vault protein, and then I'll I can make it stop. >> For some listeners may have heard of doxy cycling before because it's like a it's an antibiotic you'll get for like a variety of use cases. So I'm like it's
1:05:24simply just doxy triggers the initialization of the storage. That's again it's it's you're not inventing like we're taking things that are already there >> but [clears throat] just putting these Lego blocks together in a really clever way right? >> And then now you can see if this time vault stuff works, right? >> So you can you can show that there's no new capture. This time vault the halflife of the mRNA and the time vault is now 132 hours which is 5 days instead of the 5 hours that we had before. So the mRNA is sticking around because it's been captured. And if I now lice the cells, it's still in there. >> Mhm. Mhm. >> Right. >> Yes. This is good. >> So you you can now you can now basically
1:06:05tell a cell >> Yes. >> I want you to save all your memory right now. >> Yes. Yes. Simply by introducing. >> Yeah. Yeah. It'll save all the memory and then you can just have the cell go on its merry way because all of the stuff is inside the vault protein. It's not interacting with the stuff outside. And we know that the vault protein is not toxic to the cells themselves because it was already there in the first place. >> So it can just hang around doing the function we want it to because it's non-toxic and it's self-contained meaning like the mRNA inside cannot