SynBio and mRNA [Jason Kelly]

The CEO of Gingko Bioworks explains the last 40 years in synthetic biology.


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 work now, night and day from what it was in 1978. So that means where they could do one gene, we can do 10 or 20,000. It's a really big change in capacity.


Jesse:
[00:11:17] Oh wow. So in the late '70s, it was like to build this insulin example, a bunch of human beings doing this boring exercise of guess and test effectively of PCR. I can copy this and I can splice it with the scissors, insert it and then test it. And I did that probably hundreds of times before it actually worked?


Jason:
[00:11:34] Yes. And you really didn't get many shots because it was so laborious. If you didn't get it to work in the first 10 or 50, you were never going to get it to work because you just couldn't try that many designs.


Jesse:
[00:11:45] And now many parts of our life, its software and hardware are somewhat automated to the point where this can happen at a scale, what you used to be able to do at a year is like a day?


Jason:
[00:11:54] Yeah. To give you a sense of scale, in grad school, I probably did 50,000 letters of DNA in 5 years at MIT, a big month at Ginkgo today will be like 50 million letters. So like we're doing in a month many thousands of times the amount of designs I was able to try at 5 years. And that was back in grad school in the early 2000s.


Jesse:
[00:12:15] So basically, from the late '70s, is it fair to say that computing power over time basically the real delta in what's allowed it to become-


Jason:
[00:12:22] Computing and laboratory robotics and then continued innovation in the tools at the bench, what you're actually doing there, that has been improving as well. CRISPR is a better version, for example, of those restriction enzymes. CRISPR was around, but no one had discovered it in the late '70s and understood how it worked and now we do, and so that gives you a much better tool.


Jesse:
[00:12:42] When you say printing, you mean mixing together chemicals that replicate those letters, is that the right way to think about it?


Jason:
[00:12:48] Historically, the way you made DNA was like you're thinking, chemistry. I remember like a chemistry class, you'd see these weird columns full of stuff. You just put the letters in, A and then T, and then C, and they would stitch into a piece of DNA.


Jesse:
[00:13:03] And A, T, and C are just chemicals.


Jason:
[00:13:04] Adenine, thymine, cytosine, guanine, yeah. They're called nucleotides. They're a type of chemical. And they're a special chemical that snaps with each other so that they can make a string. And then there's the double helix, remember, A binds the T, and C binds the G? That's a little trick so that you can split it apart and then make a copy of each side, and that's how DNA replicates. But the new way you make DNA actually came out of Hewlett Packard, so it's literally printing. As a division of Hewlett-Packard is a company called Agilent. And they took inkjet printing technology instead of ink in there, they put the A, T, Cs, and Gs and they spotted on a little slide and you get the little A, T, Cs, and Gs, you get them, they're about 100+ letters long in little teeny bits. And then we do some fancy stuff in the lab to stitch those pieces into 1,000 or 10,000 letters, which is what you need for a whole gene. But the actual beginnings, the DNA, when it's done it's printed with something that looks like inkjet.


Jesse:
[00:13:57] Because literally, printing is the right word. It's the same thing, they're just taking the chemicals and putting them on a thing that...


Jason:
[00:14:02] Yeah. Yeah.


Jesse:
[00:14:02] Wow. That's unbelievable. Can you just draw the analogies to tech, everyone understands it. What's the parallels in our bodies are in this whole DNA world?


Jason:
[00:14:12] Let's take Moderna's mRNA vaccine, as an example to talk through this. What they want to have happen is they want cells in your body to express little pieces of the virus. In other words, to produce small amounts of the virus so that your immune system will recognize it, and fire up. That way, if the whole virus shows up later, the immune system takes it out. There's lots of ways you can do that. Historically, we have to just put pieces of the virus in, you could do dead virus and all kinds of stuff. Moderna had a different idea, which is, they want to say, well, we know the cell can read code and make things. And the way it does that, is it has DNA, which is what the whole genome is made of, it's like the hard drive of the cell, kind of. And then that DNA, there's little things that come along called ribosomes. They read the DNA, they make a piece of what's called messenger RNA, Which is like a temporary piece of code, and a ribosome shows up, reads the messenger RNA, and makes protein. So there's like DNA, which gets read to make a little temporary piece of code. Think of it like RAM and your computer or something temporary, and then along comes the ribosome and makes the protein.


Jesse:
[00:15:22] And that's like the RAM in your computer memory, it runs it real time? Is that the way to think about it?


Jason:
[00:15:26] It is a way for you to decide what parts of the genome you want to turn on at a given time. To simply think about it is, in your cells, the same genome makes your eyes cells as your nose, and it's just, what genes are getting turned on, allows you to run different programs from that same underlying genome that is you. What Moderna said is, okay, great. I'm going to come in at that level. I'm going to basically install some mRNA in your cell that is not in your DNA, it's going to be a little piece of the COVID-19 virus, and your cell is going to read that mRNA because that's what it does. The ribosome is going to read it, and they're going to make a little piece of the virus. And then your cell is going to essentially express that and show it to the immune system.


That hack is how their vaccine works. And so if you look at what it is, it's basically, just let's call it a lipid nanoparticles, basically like a little fatty ball with that mRNA sitting inside of it. And when it gets to one of your cells, the mRNA squirts in, which is basically how it works.


Jesse:
[00:16:27] And so the computer analogy there would be, it's like there's some program in my DNA, memory in my DNA, and this mRNA is essentially activating the software. It's like a temporary software patch that's going to create-


Jason:
[00:16:39] What I would say is the mRNA is the software your cell is currently executing. That's a good way to think about it. There's a lot of different options in your genome of what code you want to run and depending on what's going on with your cell at a given time, it turns on different parts of the DNA and converts them to RNA, and then it executes them. RNA is like the code you're actively executing. What Moderna does is they pop in and they say, "Here's some RNA, run it." And your cell dutifully runs it because that's what it does when it sees RNA. And so the idea behind Moderna is in this moment, you want to put in RNA for COVID, but tomorrow it could be RNA for cancer treatment, or heart disease, or whatever. Your cells can do pretty powerful stuff if you just gave them the right code, then you could deal with disease X, Y, or Z. That's theory of Moderna.


Jesse:
[00:17:24] Is the COVID vaccine the first version of this with human beings and curing something or whatever the word you'd use is protecting against the virus?


Jason:
[00:17:32] It is the first ever RNA vaccine.


Jesse:
[00:17:36] This is the beginning of, you were just talking about cancer and all these other ailments, it's the first time this technology has ever been used really in human beings to solve a large spread disease effectively.


Jason:
[00:17:46] Certainly for a vaccine, yeah. There's been trials. There's an area called gene therapy where you're basically trying to deliver code for the treatment of disease. There are a few diseases where there are drugs like that. This is by far the biggest rollout of an RNA, any kind of nucleic acid, DNA, or RNA drug in history, and the first ever vaccine. It is a huge turning point. From my standpoint, it's basically like being in 1978 with insulin, is what both Moderna and BioNTech, which is the other company, the Pfizer one, those RNA vaccines being as successful as they were with 95% efficacy and the whole thing. To me, that is Genentech and insulin all over again, but for a whole new category of drugs.

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