SynBio and mRNA [Jason Kelly]

Jesse: [00:06:03] And if you back up on the DNA, like this notion that it's four letters of code, can you walk us through the history of that? How did that come to be? Who's the father or mother of that? Where did that come to be? And then how did it evolve to today where it sounds like you're able to essentially program your own things in a lab and create them?

Jason: [00:06:19] The first thing to realize is this is just a miracle of biology that it works this way in the first place. Get back four billion years of evolution, here's the magic. When we invented computers, we had to come up with a way to copy things. Do you want to send a file or make... And we realize that instead of like a record player, which is an analog thing, little bumps on the record define the data, but those can move around and change. If you really want to transfer information with high fidelity, make a CD and make it zeros and ones, digital, because every time you copy it perfectly.

Biology figured out the exact same thing. When you have a kid, you want to transmit heritable information, you want your genes to move on to the kid. And the way that biology figured out how to pass information across generations, digital. A, T, Cs, and Gs. It just happens to do it, not with magnetic bits on a computer, but with actual chemicals.

Jesse: [00:07:11] Through our cells.

Jason: [00:07:12] A,T, C, and G, adenine, thymine, they are actual chemicals in a long string, just like a piece of cassette tape back in the day, a long string of molecules. That's just how biology works. There was the discovery of DNA, Rosalind Franklin and Crick and all those folks, Watson, figured out what it looks like, but they just we're discovering it. They didn't invent it, it just was that way. And then we take advantage of it as cell programmers, as synthentic biologists, we take advantage of that fact that it's digital and read and write it to make it do new things across really tons of markets. But Moderna is really the leader.

Jesse: [00:07:46] So when did they discover it? What took it from them discovering it to then maybe The Human Genome Project profiling it to now the point? What are the big milestones and timing between those two things?

Jason: [00:07:56] So one of the technologies that got invented in the late '70s was PCR. And I won't get into much technical detail, but what PCR lets you do is basically pick a certain region of DNA and make a billion copies of it. And you're basically hijacking the fact that cells have ways to copy their DNA because every time XL has a kid, it makes a whole copy of its genome. So there's really great little things called polymerases that read the DNA and pop off a copy. And so PCR, you just do that in the lab. You basically say, "Hey, this little region, make copy, copy, copy." And the advantage of that as you start to get tons of it, it's enough you can work with it in the lab. So that's one technology, PCR. So that's what they did with the insulin. They took a human cell, they found where the insulin gene was, they put these things called primers in which your little markers on either side of the gene, and they use PCR to make billions of copies of it. Now, you get it into the bacteria to make that insulin drug, that built Genentech, now worth hundreds of billions of dollars company. What did they do to do that? A technology called restriction enzymes, which are basically scissors. It's like little molecular scissors that bacteria use to cut DNA out. Why did they do that? Oh, because they're afraid of viruses.

So if a virus infects a bacteria, the bacteria blows up. And so to defend itself, it has the technology that it invented through evolution, which is, "If I see some DNA that isn't mine, chop it into pieces." And in fact, the more modern form of these restriction enzymes is what's called CRISPR. So you might've heard of CRISPR, same shit. Basically, a technology bacteria used to defend themselves from a virus inserting its code into the bacteria, and the bacteria wants to cut that into pieces before it executes. It's wild. And so what Genentech did was it said, okay, I've got this scissor, I know it cuts in a certain place in the bacteria. I got this PCR to make copies of insulin. I'm going to use the scissor to cut the bacterial genome and the PCR products so that they match each other, and then I just paste them together.

Jesse: [00:09:53] And that happened in the late '70s?

Jason: [00:09:56] 1978 was the very first. That was the beginning of humans directly influencing the evolution of biology, life on this planet.

Jesse: [00:10:04] One quick sidebar just occurred to me. Can you even closer? What's actually happening? Is the microscope doing these things? What are the tools that human being is using to do these things? Is it like our biology class where we had a little dropper thing and we dropped from one Petri dish to do that?

Jason: [00:10:17] You're on the right track. Yeah. So I did a PhD at MIT of bioengineering and this is basically 5 years of standing in front of a lab bench with a pipette, which is like a little straw, essentially, sucking up one colorless liquid and squirting it into another colorless liquid and doing these elaborate little lab experiments. Horrible. It was a painful process. You can easily mess it up and you can't see what's going on because everything is microscopic. In modern labs, like at Moderna if you visit them, and here I can go by our works, it's mostly robotics and automation actually doing the work now. That has been part of the reasons, you asked earlier what's different between 1978 and today, one of the other big, big innovations is dramatically more laboratory automation and dramatically more software and data analytics to parse a huge amount of data coming out of that automation. So the way we do lab ...