357 | Jeff Coller on mRNA, Vaccines, and Bespoke Therapeutics

0:00:01.6 Sean Carroll: Hello, everyone, and welcome to the Mindscape Podcast. I'm your host, Sean Carroll. Many of you are old enough to remember the COVID-19 pandemic. Slightly joking there. It wasn't that long ago. And of course, COVID-19 is still with us. It hasn't gone away, but things are very different now than they were in the year 2020. In 2020, there were a lot of lockdowns, a lot of prophylactic measures to try to make sure infection rates stayed low. It was a real global disruption in many ways, and the world is very different. It's mostly back to pre-pandemic behaviors. And that's in large part because we have vaccines for the virus. And I think that it's kind of underappreciated and truly astonishing how rapidly those vaccines were developed.

0:00:49.7 SC: Of course, by now, it's become politicized and there are tribal markers and stuff like that. But put all that aside. Let's be reality-based right now. COVID was bad. The vaccines are wonderful and they came about very, very quickly. And you may have heard that it's because they're a special kind of vaccine, mRNA vaccines. RNA is, of course, the part of our genetic material that transfers, the messenger RNA in particular, the mRNA, is how you get information from the DNA in our cells, where the genetic information is stored, to the ribosome, where you turn that genetic information into proteins. It's the RNA, the mRNA in particular, the shuttling back and forth. And the idea of an mRNA vaccine, I don't know why I really struggle to say mRNA very quickly, but the idea of it is that rather than injecting the body with a protein like a conventional vaccine, and then letting the body react against that protein and build up its immunity, you inject a little bit of genetic material, a little bit of RNA, messenger RNA, which then the cells in your body turn into the proteins, which then generate this immunization response. And we can control and design and also produce mRNA enormously faster than we can the proteins that you would need.

0:02:20.2 SC: So that particular technology turned out to be incredibly successful and incredibly fast and efficient for the particular challenge that we had back in 2020 and just in time. It's a very, very new kind of technology. It's sufficiently new that we are still very much in the process of finding new applications for mRNA technology. Vaccines, broadly speaking, are, of course, one big application, but there's much larger potential applications. I mean, think about it. You're injecting into your body a little bit of genetic code, which then your cells will use to make some kind of protein. Right? That's an enormously big arena to play in if you're trying to come up with therapies for various kinds of diseases. And even more, even more recently and even more exciting, we can join this mRNA technology to gene editing technologies like the CRISPR technologies we've talked about on the podcast before, to do not just vaccines, but genetic repair. We can fix mistakes in your DNA while it is still in your body. At least that is the vista that is going to be laid out in the podcast today. We're talking with Jeff Coller, who is here at Johns Hopkins. He has a wonderful title. He is Professor of RNA Biology and Therapeutics. So very much the person to talk to about exactly the topic of today's podcast.

0:03:54.3 SC: And he will explain... We're going to start very simply with what is an RNA, how does genetics work, things like this, how do mRNA techniques change how we do therapies of various sorts? How do we get them into the bodies? Where do they go? What are the challenges? Because there's lots of challenges. It's a very, very new technology. But also what are the prospects? And I think you'll be convinced. I don't want to give anything away. You're supposed to listen to the podcast, but by the end, you should get the idea that in principle, these ideas are absolutely going to revolutionize how we treat a whole bunch of diseases, both very, very common diseases, but also even more kind of provocatively, rare diseases. Because for exactly the same reasons that we could make, design, and produce the mRNA vaccines quickly for COVID-19, we can relatively inexpensively create new therapies for diseases that not too many people have. And that's important, because back in the day when these kinds of therapies took decades to produce and many, many millions of dollars to develop, you wouldn't do that for a disease that only 12 people had in the world. Now, maybe you can.

0:06:08.3 SC: We're not in the perfect environment for that, politically, financially, scientific research-wise, international cooperation-wise, and a whole bunch of things. But if nothing else, this podcast episode with Jeff should convince you that we should get our acts in gear and we should very much take advantage of this enormous possibility that biological science has given to us to make huge advances in fixing some diseases that cause a lot of people enormous misery in the world today. If you can get rid of that misery, it's a good thing. We should at least, given the opportunity, do everything we can to make it happen. So let's go.

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0:06:09.0 SC: Jeff Coller, welcome to the Mindscape Podcast.

0:06:10.7 Jefr Coller: Great. Thank you for the invitation, Sean.

0:06:12.9 SC: So I think that this is one of those where the audience has probably heard, well, they've certainly heard of RNA. They probably have heard the phrase mRNA vaccine, but maybe they don't know what all the implications of the letters and words there are. So let's just back up and set the stage. We have RNA, we have DNA, we have mRNA, proteins. What is the whole cast of characters here?

0:06:41.5 JC: Yeah, sure. So just to get everybody on the same page about what we are talking about when we use the word mRNA. So in your body, in every cell in your body, you have DNA. And DNA is basically the blueprint of life. It's basically like a giant recipe book that tells your body how to be you. And within that recipe book are hundreds and hundreds of different recipes. And what an mRNA is, is an individual recipe. And so for each gene in the human body, there will be made mRNAs that transmit information. So these are messages. These are recipes that have to go from the kitchen, which is where the... Or I should say from like a library, if you will, which is where the DNA is. And that recipe has to go to the kitchen, which is a ribosome. That is the cook that basically makes the individual recipe, that makes the dish that's going to be made that day. And so these mRNAs then tell the cell what to make. And what's really important is that after that mRNA is read, it's destroyed. And that way the cook doesn't keep making the exact same recipe over and over again.

0:07:55.4 SC: So, sorry, just very quickly, the DNA is very long, but the mRNA are little short things, one per gene, you said?

0:08:05.0 JC: One per gene. That's exactly right. So we have about approximately 25,000 genes in the human body. So there will be 25,000, it's a little bit more than that, but about 25,000 mRNAs.

0:08:18.3 SC: And how does... This is just a great opportunity for me because I'm just a poor, humble physicist who doesn't understand any of these things. How does the DNA and the RNA, et cetera, know what genes to copy at any one moment? Does it get a summons from somewhere else in the cell?

0:08:36.3 JC: Yeah, I mean, there's lots of inputs that decide when you're going to turn a gene on or off. A good example of that is you don't need... When we eat, for example, if you eat something that's very sugary versus very fatty, you don't necessarily need the proteins that would digest sugar if you're eating a bunch of fat, for example, and vice versa. And so that's just a rough example of this. But so that means you would turn on genes in response to certain stimulus. And so you could have a stimulus that might be a food source, but a stimulus could also be something like a growth hormone or a signal from a particular part of the body that says, "Hey, it's time to make this." Like, for example, if you have a bunch of sugar in your bloodstream, it would be time to make more insulin so that you can take that into your cells. So a lot of times these stimuli are external signals that say it's time to turn that gene on or this gene off. And so you're turning on... When you turn on a gene, you're basically making an mRNA. You're making a copy of that gene as this messenger that then gets read by the cook.

0:09:47.2 SC: And so you turn on the gene and the mRNA is assembled from things floating around?

0:09:53.7 JC: Yeah, essentially there are these components, these building blocks that are within your cells. They really are kind of sugars in and of themselves that are stitched together to make an mRNA. They're very similar to DNA. MRNA is almost identical to DNA with one tiny, tiny little difference. But other than that, it's pretty much a direct copy.

0:10:18.8 SC: Tell us what the differences are.

0:10:21.1 JC: Well, the one difference... There's really only two differences, but the one major difference is that it has a single oxygen on it that DNA doesn't have. So DNA is deoxyribonucleic acid and RNA is ribonucleic acid. It doesn't have the deoxy part. So it's pretty much the same. There are some more nuanced differences, like it has a unique letter. So you've probably heard in DNA that there are these four letters that make up DNA. So they are A, T, C, and G. In RNA, it doesn't have the T. And so in RNA, it's A, U, C, and G. And so those are really the major differences.

0:11:03.8 SC: But there's still four of them. They still pair up with the base pairs in the nucleotides in the DNA. Good.

0:11:07.5 JC: Pretty much the exact same. That's right. That's right.

0:11:12.5 SC: And again, I have a little bit of knowledge from just talking to people about theories of the origin of life and things like that. RNA plays a big role in some of those stories. I know that's not exactly your bag, but does it make sense to you that RNA would have been there before either the ribosome or the proteins or the DNA?

0:11:34.8 JC: Yeah, so it's often believed by most scientists now, at least molecular biologists, that RNA was the predecessor to DNA, that life evolved on Earth first using RNA as a genetic material rather than DNA. And it's really that little difference that I talked about, that oxygen that's present within RNA, that's the key that has led scientists to think that it could be capable of being the first precursor to life because it gives it the ability to do unique chemistry that DNA cannot do. And scientists like Tom Cech and Sidney Altman back in the '80s were able to show that RNA, in fact, could do enzymatic catalysis. So it had the ability to stimulate a chemical reaction, where DNA cannot do that. DNA cannot do that. And that's a necessity of life. You have to be able to catalyze reactions, and RNA can do that.

0:12:38.5 SC: And my impression is that, on the other hand, DNA is more stable, so it's a good place to keep your information for long periods of time.

0:12:45.6 JC: That's right. So DNA tends to be more stable, again, for the same reason it doesn't have that little oxygen, so it tends to last a lot longer.

0:12:53.4 SC: Sorry, I thought it has an extra oxygen.

0:12:55.9 JC: No, DNA has less oxygen.

0:12:57.1 SC: Deoxy. Unoxygenated. Not dioxy. Yes.

0:13:02.1 JC: No, no, deoxy. So it has one less oxygen.

0:13:06.0 SC: Okay, I see. Good. Yeah. So the reason, the story would be that RNA is sort of more flexible and can do more things but is a little bit less permanent, so it might be the good first try, but using both in concert is a more sophisticated system.

0:13:22.0 JC: Yeah, and the other thing, part of this in terms of the RNA world hypothesis, which is what you're talking about, is RNA can do chemistry but also can adopt very unique, complex shapes, where DNA really only exists famously as the double helix. And that's how you find it, as a double helix, where RNA can get into all sorts of contorted shapes and sizes and have this ability to do chemistry. So it really does become an ideal molecule to see how life could have evolved on Earth before a DNA world.

0:13:59.5 SC: And then we have various forms of RNA...

0:14:04.5 JC: That's right.

0:14:05.1 SC: M and T and so forth. Are these literally different chemistries or are they just doing different purposes?

0:14:11.2 JC: Doing different purposes, and it goes back to what I said about being able to form different structures. So the largest set of RNAs in your cell are your ribosomes. So the ribosome, that cook that I talked about at the beginning, that cook that reads the mRNA, is actually RNA in and of itself. It's half protein, half RNA.

0:14:32.9 SC: Okay.

0:14:33.4 JC: But the part that actually reads the genetic code is, in fact, RNA. So it's called a ribosomal RNA, and it forms this really large, very complicated three-dimensional structure that's consistent through all of life and is the machine that reads the genetic code. And then there are a bunch of other RNAs around the cell that do different work. But mRNA in and of itself is a direct copy of a gene within the DNA.

0:15:06.0 SC: Every time I talk to molecular biologists or other people about these things, even though I know better, I'm slightly tempted by intelligent design because there's so much going on here that is so delicate.

0:15:20.2 JC: I mean, it's fascinating to see it all because it all works in such beautiful harmony with itself. And you can see that, for example, what you realize when you dive deeper into the structure of these complexes is that it evolved very early on and has diversified from there. So, for example, that ribosome, that RNA, rRNA that we talked about, the ribosomes that are within the human body are not much different from ribosomes you will find in fungus, that you'll find in bacteria, in some of the most primordial life forms on Earth. And so it can be... And in fact, this study of ribosomes was one of the reasons that led a guy named Carl Woese to propose that RNA was in fact the precursor to all life. So it's as if though there was a primordial life form that evolved, eventually evolved into a ribosome, and then that evolved from there.

0:15:58.9 SC: And it seems like, I don't know, what was discovered first? I know that DNA was discovered before we understood its role. When did we get to an understanding of the RNA aspect of this story?

0:16:37.7 JC: A lot of this happened in the early 1960s when investigators were looking at... I mean, you had famously, you had the double helix, which was in the '50s with Watson and Crick discovering that DNA was... They didn't really discover that it was the genetic material, but they discovered the structure. But about the same time, it was hypothesized that there had to be an intermediary between DNA and proteins. And so we knew that DNA was the genetic material in the 1950s. We knew protein was a very important part of biology. And a guy named Sydney Brenner was one of the first people to propose that there must be this theoretical intermediary between them, which then later, about 1964 or so, was shown to be messenger RNA. And so the discovery of messenger RNA dates back to 40, 50 years ago, probably more than that, 70 years ago to the '60s. And as molecular biology has developed in the last 70 years, we've just learned more and more about the complexity of RNA within the cell. And like I said, there's dozens of different types.

0:17:54.8 SC: I know that there's DNA in our nucleus of the cell, but there's also mitochondrial DNA. Are there separate RNAs and ribosomes for all the different kinds of DNA floating around?

0:18:06.8 JC: Yeah. So in fact, your cell, your nucleus, which contains your nuclear DNA, there's a ribosome that is used in the cytoplasm to decode those mRNAs, the mRNAs that come from your nucleus. There's a separate ribosome that's present within the mitochondria. And so just for your listeners, it's often thought that the way evolution proceeded is that there was a bacterial invasion of a cell. So at some point, a cell went inside a cell and became permanently fixed so that we have to live with it. And that is what your mitochondria is. And if you look at your mitochondria, it actually looks very bacteria-like, including those ribosomes. Those ribosomes that are specifically made to decode the mRNAs from your mitochondria are bacterial-looking, not human-looking, I should say.

0:19:06.8 SC: This is the point of the podcast where traditionally I say it is so much simpler to be a physicist than to be a biologist. There's just so much mess going on with all these billions of years of evolutionary history.

0:19:18.1 JC: That's right. It is kind of a mess because the thing about evolution is that there's really no selection for simplicity when it comes within the cell. It just gets built on top of each other to the point where you just can't reconstruct it to make it something much more elegant and simplistic.

0:19:35.1 SC: And so I guess the final of these elementary questions, is there just one ribosome for the nucleus and one for all the mitochondria, or is it more complicated than that?

0:19:47.5 JC: No, there's thousands. So there's about... In a given human cell, it's between probably about a half a million ribosomes that would be there. So it's quite a bit.

0:19:55.9 SC: A lot of manufacturing facilities for all the proteins.

0:19:58.4 JC: Yeah, within one cell. So half a million ribosomes within one cell.

0:20:02.7 SC: Okay, cool. So moving on a little bit to your specific work, I know the word codon appears a lot in your research statements. The codon is... All I know about it is that there's three little nucleotides making up part of the genetic code.

0:20:21.1 JC: Yeah. So this was really going back to the '50s and the '60s. We knew that DNA contained the genetic information, and deciphering that genetic information was important and learning what the code was. And so I think I had mentioned a few minutes ago that DNA contains these four letters, A, T, G, and C. And they're written... If you look at billions of base pairs of DNA, it has a billion different combinations of those four letters. And those letters make up what we now call the genetic code. And so there are four bases, these four letters within DNA. And what DNA does is it makes mRNA, and that mRNA makes a protein. There are 20 building blocks to a protein, and these are called amino acids. So you have four letters that have to encode 20 words. And that's really the simplicity of the genetic code. Four letters, 20 words. And so 20 meanings, I should say, not words. There are 20 meanings. And so what evolution has done is, if you do the mathematics of this, it's 64 words. So you need 64 words if you're gonna use four letters, you need 64 words to have 20 meanings.

0:20:56.8 JC: That's the only way you can do it mathematically.

0:21:47.0 SC: I mean, sorry, just because...

0:21:48.5 JC: Everybody just sit down with a piece of paper, you'll figure it out. It's actually...

0:21:53.4 SC: Just because if you only had two nucleotides, it'd be four times four is 16. You can't cover all the 20.

0:22:00.1 JC: You can't cover. And then what happens by having three letters per word, you get 64, which is too many. But there's nowhere in between.

0:22:05.0 SC: Right.

0:22:10.1 JC: And so you have four letters that get arranged three at a time, and then that leads to 20 amino acids. So it's 64 words, basically. Does that make sense?

0:22:21.2 SC: It absolutely makes sense. And it raises... I mean, I presume I know the answer to this one, but I'll ask it anyway. One way of doing it would be that there's 64 possibilities, but in real-world DNA, you only get 20 actual examples. But that's not what actually happens. In the real world, you get all 64, but they're redundant. Some of the 64 patterns give you the same amino acid at the end of the day.

0:22:50.0 JC: That's exactly right. So we call that the degeneracy of the genetic code. So some of the words... So if we use a very specific example, there's an amino acid that makes up proteins called arginine. So arginine, in fact, has five words in the genetic code that mean arginine.

0:23:01.0 SC: Okay. Wow.

0:23:12.0 JC: And so of these 64 words, there's some repetition.

0:23:14.8 SC: Yeah.

0:23:17.6 JC: And that's the way Mother Nature did it.

0:23:19.3 SC: Is there some rhyme or reason about it? Are some amino acids special and they get more words that talk to them?

0:23:27.9 JC: Not really. I mean, you can look at it in a lot of different ways. One is that there's two amino acids that only have a single word. And that is very important for one of them because every single protein always starts with that first word. And that word is the nucleotides A, T, G.

0:23:39.6 SC: Okay.

0:23:51.3 JC: And that word means methionine. And so every protein always starts with methionine. And it has to be that way because then the ribosome knows that the first time it sees the word methionine, it's the start of a sentence. Okay, so it's just like the capital letter of a sentence. And then there are words, there's three of them, that are a punctuation mark, a period. And so that's the ending of the sentence. And so those two parts are very important for the ribosome because it knows how to read that genetic code, knows when to start and knows when to end. But for the rest of the amino acids, it's relatively random. In fact, Francis Crick called it a frozen accident, where basically this is just what happened, it got frozen at some point in evolution, and now all organisms use the exact same, for the most part, genetic code.

0:24:45.6 SC: My impression is that even though only 20 amino acids are used in biology, there are more amino acids chemically. Is that right?

0:24:54.2 JC: Yeah, there are. But for the most part, life uses those 20.

0:24:58.6 SC: But we had room to use 60-some.

0:25:02.3 JC: Well, we had room to use 61. We still needed those three periods...

0:25:07.3 SC: Yeah. The punctuation...

0:25:07.9 JC: Punctuation marks. But 61 was theoretically possible, but we don't use it.

0:25:12.8 SC: Are there any biologists who get grants to study how life could be different if we chose to use more of the amino acids?

0:25:20.2 JC: There are people that work on unique chemistries with both the adapter molecules that read the genetic code. These are RNAs called transfer RNAs. They actually are little tiny RNAs that read each of those words, and then bound to them is one of these amino acids. There are people that look at that, sort of synthetic biologists, but there are amino acids out there that are not used routinely in biology. Could you stitch them into a protein, and what consequence would that have? Who knows?

0:25:59.7 SC: Yeah, I guess I'm just wondering, are there reasons of chemical stability or affinity that we have these 20 that are useful, or is that one of these frozen accidents?

0:26:10.0 JC: I think it has more just to do with their natural abundance in the environment.

0:26:14.0 SC: Okay. That makes perfect sense.

0:26:15.5 JC: But there's a lot that we don't understand, right? Why these 20? Why are they here on Earth, and why are they abundant on Earth? And we have... I mean, this isn't my area of expertise, but some of these amino acids have been seen in outer space. You can see them in nebulae and other places, so they might actually have a common origin, sort of natural origin within the universe that makes them a good property to be using them because they're enriched.

0:26:48.6 SC: Again, my impression is that back from the classic Miller Urey experiment, we decided that it's actually not that hard to make amino acids.

0:26:56.6 JC: It's really hard.

0:26:57.2 SC: It's making the RNA and DNA that is hard.

0:26:58.3 JC: It's getting it all organized. The actual building blocks of all of this, of DNA and RNA and protein, they tend to form naturally with the ingredients that are out there in the universe, and with some heat and radiation, they come together. But the stitching it all together in a way that gives life, meaning where life is really a chemical reaction that perpetuates itself, that's something we don't understand how that happened yet.

0:27:28.8 SC: Right. I mean, throwing a bunch of transistors in a bag is not going to make a computer.

0:27:33.0 JC: That's right. That's right. That's exactly right.

0:27:36.4 SC: And are there any secret messages hidden in why some codon, some list of three nucleotides, is used rather than other ones? Or are they purely redundant when they give you the same amino acid?

0:27:50.0 JC: They don't seem to be. And that's something my lab has studied where, as I said, these codons will, there's degeneracy, meaning that you can encode the same amino acid with multiple codons or multiple words. But the way the ribosome reads those words, I mentioned, is using this other little RNA that's called the transfer RNA. And it turns out that the abundance of that transfer RNA will dictate how fast you read the word. And so a real simple way to think about this is the ribosome is the cook that's reading the message, he's reading this recipe, and it has to interpret 64 of these words. And some of these words it will stumble upon because it doesn't necessarily find, so every time, there's these transfer RNAs that are sort of floating around in a cloud around the ribosome, and how concentrated that tRNA is dictates how fast the ribosome can read it. It's no different than if you had a bucket of bingo balls and all of them were colored blue and one of them's red. The red one would be very hard to find if you were just sampling randomly.

0:29:10.3 JC: And that's the same thing here with the ribosome. It's randomly sampling these transfer RNAs in order to decode the genetic code. And so it hesitates or it can go fast over some of these words, and that speed is dictated by the genetic code. And that's what my lab has studied, is how fast the genetic code gets read, because it has serious implications into the stability of the mRNA. So I mentioned that mRNAs are these recipes that get read, and as soon as they're read, they're destroyed. And how fast they're destroyed is a consequence of how well they're read.

0:29:30.4 SC: Okay.

0:29:50.4 JC: And so if it's read really well, if it's something that you can read very easily, you keep that message around a lot longer than if it's a message that's really hard to read and you're just having trouble reading it, then you destroy it.

0:30:05.3 SC: So the destruction process is active, or does it just fall apart?

0:30:09.1 JC: It's active. It's very active.

0:30:13.0 SC: Okay. So yeah, we read it and then we burn the message. Just like in Mission Impossible.

0:30:16.5 JC: That's exactly right. Destroy upon reading.

0:30:20.9 SC: And, of course, the excitement... We're being good, we're laying the groundwork and helping us understand, but there's a lot of excitement with therapeutic uses of RNA in general and I guess mRNA in particular. Maybe just first talk a little bit about the crowd-pleaser, which is the mRNA vaccines.

0:30:40.8 JC: Sure, yeah. So this is a very old history with mRNA being used in medicine, despite what probably the popular press has as an idea. I mean, the fact that mRNA exists, we know that this is the recipe that sends the information to the cook. And so there's an mRNA for every one of your genes because it is basically telling your cell what to make at any given time. And when we discovered mRNAs in the '60s, of course, this was exciting because it means that if we can design mRNAs, we can get the cell to make any protein we want, regardless of whether it naturally exists or not. And so this is a natural system. MRNA are natural products of your body. We understand the genetic code, we understand a lot about how proteins work, and so we can design mRNAs that we can stick into a cell and then have the cell make that protein, right, of anything we want. And that's what really electrified scientists in the late '90s and early 2000s to start thinking, could we design mRNAs to be used in medicine? And there's lots of places where this could be very powerful.

0:32:05.1 JC: One in the place where people really got excited was in cancer, and I imagine we'll talk more about that in a little while. But the other was with vaccines, because with vaccines, vaccines are usually a protein, a protein that is a non-native protein, meaning something that comes from a virus or a bacteria, something that is a foreign invader to your cell. So your body has the ability to tell who you are. It knows every protein in you.

0:32:21.8 SC: Yeah.

0:32:38.6 JC: And if there's a foreign protein, it attacks it. And so could we use mRNA now to make those foreign proteins so that the body could recognize that foreign protein and then launch an immune reaction? And that's really the genius of using mRNAs in vaccines, because there's really kind of three things about this. One is it's natural, it's a natural product, and the body destroys it quickly.

0:32:53.3 SC: Yeah.

0:33:08.0 JC: So it destroys it within a matter of hours. But the other side of it is that you can deploy these really fast. We can make an mRNA and design an mRNA in just a matter of hours. So when it comes to preparedness for a pandemic or an emergent infection, you can develop it very quickly, where the classic way of making vaccines takes 10 years or more. So it's just that speed of being able to manufacture these is what has really electrified the community.

0:33:41.2 SC: So when you say that our bodies know all the proteins that we already are equipped with, there must be a lot more proteins out there than are in any one body, I guess. How big is the space proteins?

0:33:54.5 JC: Oh, I mean, it's infinite. There's an infinite number of possible protein signatures out there. And we all know this from if you have allergies, seasonal allergies, that's basically an immune reaction against a foreign protein, usually a protein that you're picking up pollen, and there are tree or plant proteins that you're breathing in and it's irritating your immune system.

0:34:19.2 SC: Is there any chance that mRNA technologies are going to cure my allergies?

0:34:25.4 JC: Well, that's actually not far-fetched because people are, again, the fact that mRNA is this emissary of the genetic code, we can use it to do all sorts of biology.

0:34:31.2 SC: Yeah.

0:34:37.0 JC: And one of the places where people are looking into this is in immune reactions. So autoimmunity is another... Autoimmunity is a big issue where you have the ability to say what proteins in your body are yours and what are not, but sometimes your immune system goes haywire and starts attacking your own body. This is often, people would probably recognize like arthritis as a good example of that. And if you can learn to downregulate the immune system through mRNA technology, which people are investigating, then it's one way to protect from autoimmunity or overstimulation of the immune system as you get with allergy reactions.

0:35:23.6 SC: All right, I'm going to support this then. I was wavering, I was on the fence, but now you've sold me. Good. We've heard probably of mRNA vaccines in the context of COVID, right? Were they around before then?

0:35:40.1 JC: Yeah. So before COVID hit in 2019, there were probably about, I think it was over at least 100 FDA trials currently in human for different mRNA technologies. Most of these were around cancer and vaccination. So at the time when COVID hit, Moderna, for example, was testing a vaccine for influenza.

0:35:53.8 SC: Okay.

0:36:07.4 JC: And that allowed them, because they had that program already built, that allowed them to quickly change the influenza sequence out for the COVID sequence, and then had all that infrastructure already in play. So I think it's important for the public to realize that because this, while everyone in 2019, this was a new technology to them, it wasn't to the scientists. We had over 20 years of in-human testing that had already been conducted with mRNA technologies.

0:36:36.6 SC: And the word in-human there does not mean non-human. It means inside human beings.

0:36:41.4 JC: Inside a human being. That's exactly right.

0:36:44.5 SC: Yeah. Okay. And just to refresh us, you've already said a little bit about this or alluded to it, but the way that vaccines work in general, because I find it fascinating, you're basically tricking the body into thinking that it's undergoing an attack and it's the body that is doing the work.

0:37:00.5 JC: That's exactly right. Yeah. And that's the beauty of the mRNA technology too, because you're basically letting the body make a protein that is foreign and the body's recognizing that and going, "This protein doesn't belong, so I'm gonna mount an immune reaction." And then the amazing thing about that is the mRNA then disappears, it goes away. And so the only thing that remains is the memory, the immune system's memory of that so-called foreign invader, and that's what gives you the immune reaction that you carry forward for months, hopefully years.

0:37:39.5 SC: And what exactly would the difference be between an mRNA vaccine and a non-mRNA vaccine?

0:37:46.3 JC: Well, I mean, the main difference is what they are, which is most vaccines are protein...

0:37:49.0 SC: Okay.

0:37:51.7 JC: Where the mRNA is... The mRNA that then makes the protein. So yeah, from just a product standpoint, that's the major difference is you have the MMR vaccine or the yearly flu vaccine that you might get. These are proteins that are eliciting the immune reaction. In the mRNA, we're just giving the instructions to make the protein. But that has a serious implication in two manners. One is the speed at which you can develop it, because it's actually very difficult even in 2026 for us to make proteins at scale, meaning large amounts of proteins. It's difficult. And to be honest with you, we would still use an mRNA even if we weren't doing it in the body. The second thing is costs, because to make a protein is very costly because it requires a large amount of material to do that. Usually what you have to do to make a protein vaccine is you have to program something like a chicken egg with a virus or DNA or an mRNA to make that protein and then grow it up, and you'd have to have millions of eggs to do this and then purify that protein from those eggs.

0:39:17.1 JC: And that's a costly process.

0:39:18.6 SC: It sounds rather slow. Yeah.

0:39:21.9 JC: Yeah, it's slow. It could take 15 years to develop. Where mRNA you can develop in just a matter of weeks in terms of manufacturing, and you can develop it in silico in the computer within a matter of hours and then scale it in a matter of weeks. And so the cost is significantly lower to be passed on to the public. So rapid response at low cost and high efficacy and safety.

0:39:50.2 SC: Well, let's think about that design on the computer. I mean, you use the word design there. Can I just download an app and design myself some vaccines or what is going on?

0:40:01.5 JC: It wouldn't be that hard, to be honest. So the way, I mean, I have a lot of inside baseball on this one because when COVID hit in December of 2019, the Chinese researchers had sequenced and identified SARS-CoV-2 as the virus that was responsible for COVID-19. They sequenced its genome and then released that genome publicly around the world. And the day that came out was in early January. And the very next day, the sequence had been downloaded. So my graduate student, who was the lead designer of the COVID vaccine at Moderna, he downloaded it and he put it into his program and had designed the vaccine that went into millions and millions of human beings within just a matter of hours.

0:40:29.5 SC: Pretty good.

0:40:57.5 JC: It's not that complicated.

0:41:00.7 SC: Well, what's the name of your grad student, your former grad student?

0:41:02.4 JC: His name was Vlad Presnyak.

0:41:04.0 SC: Okay, cool. Yeah, he chose a wise place to go. He couldn't have known how important it would have been.

0:41:11.8 JC: In fact, when he got the information, because we were all still not really completely aware what was gonna hit us.

0:41:15.3 SC: Right.

0:41:18.8 JC: He didn't really know the implications of what he had just done.

0:41:23.2 SC: Yeah. And so it seems to me, you've been talking about the recipe and the cook, et cetera., but in biology, there's just a long road from knowing the recipe to knowing what the dish is gonna taste like, right? How easy is it for your grad student or anyone or whoever to say, "Okay, I'm gonna put together a little sequence of RNA that will lead to the protein I want?"

0:41:50.9 JC: Well, in this case, what was done for the COVID vaccines is they took a particular protein from SARS-CoV-2, which is called the S protein. And the S protein is a protein that's used by that virus to help it stick to the cell, to a human cell, and get inside. And what's key here is we don't make an S protein. Humans don't have an S protein. So it's a large protein in SARS-CoV-2. They put that entire sequence for the S protein into the vaccine. And so there wasn't really much in terms of how do you design it. There wasn't really too much trickery to how you designed it. It was just, "We'll take the S protein and we'll stick it into an mRNA." Now, there's a little bit more nuances to that, meaning there's some optimization of the sequences, but for the most part, it is the S protein that's naturally occurring in SARS-CoV-2 with a few little changes.

0:42:46.0 SC: Those S proteins, those are like the little protuberances we see on the cartoons of all the COVID virus?

0:42:51.8 JC: That's right. S protein is short for spike.

0:42:53.7 SC: Spike proteins. Yeah.

0:42:55.7 JC: The spike proteins. They look very cute, which makes the reason why it's called a coronavirus, because it looks like a crown.

0:43:01.8 SC: Oh, okay, good. So I did learn something in this podcast. But okay, if we know the protein because we know the disease we're trying to cure, is it more or less straightforward then to say, "Here's a protein, here is the sequence of RNA that would code for it?"

0:43:19.3 JC: Yeah, that's pretty much what we do. So if you identify a new, everybody's talking now about [0:43:26.6] ____ hantavirus that people are worried about. It wouldn't be that hard to develop a vaccine, putative vaccine for [0:43:33.6] ____ hantavirus. You just, if you know the genetic sequence of that virus, you identify a protein that might be a good candidate for a vaccine, and you would clone it, you'd put it into an mRNA, and then you'd have to do testing.

0:43:48.2 SC: All right. And then you don't need chicken eggs. How do you actually make all of this vaccine from the mRNA?

0:43:55.7 JC: Yeah, so it's all done in a test tube. So it's done using what we call in-vitro procedures, meaning in-vitro being in a test tube. So you make a DNA template, and from that DNA template, you can use a couple of enzymes and amplify up mRNA in huge volumes.

0:44:08.2 SC: Okay.

0:44:20.7 JC: So in fact, if you think about this from a manufacturing standpoint, for traditional vaccines that are based on proteins, you need what are called bioreactors. And those bioreactors, this is basically a vat, think of a giant pot that you're cooking it in. A bioreactor for a traditional vaccine would be on the order of the size of a small, well, they could fill half of an aircraft hangar. You would put thousands and thousands of liters of these vats into a room that you would make your vaccine. With an mRNA, your bioreactor can be about as big as your body for the entire population on Earth.

0:45:10.6 SC: Okay. It seems like a cost-saving measure.

0:45:13.3 JC: And in fact, some of the newer technologies that I've seen, I've talked to investigators where they have bioreactors that are no bigger than a 2-liter of soda that would hold enough mRNA to inoculate the entire planet.

0:45:27.8 SC: But then we gotta get it into the body somehow.

0:45:30.4 JC: You got to get it into the body.

0:45:32.0 SC: That seems to be a tricky thing, as far as I can tell.

0:45:34.3 JC: Yeah. So your body doesn't like to take up strange nucleic acids, as it shouldn't, right? Because viruses are, in fact, nucleic acids like RNA and DNA. And to be honest, you eat RNA, mRNA, and DNA every single day.

0:45:55.3 SC: Yeah.

0:45:55.9 JC: Every single bite of organic food, whether it's a steak or a salad, a bean, whatever, it's got bean RNA in it. It's got cow DNA and cow mRNAs in it. So you can't just readily take those things up because they would work just like any mRNA in your body. So the way we get the body to take these up is that we encapsulate them in these little fat bubbles, and that's called a lipid nanoparticle. And it's basically, your cells are made out of lipids, and we make these little fat bubbles out of lipids that we keep the mRNA in. And there's this old saying in chemistry that like dissolves like. And so water and fat don't go well together. Everybody who cooks knows this, right? If you put oil in a pot of water, you'll see it separate. But if you put oil on top of oil, it'll mix. And that's what a lipid nanoparticle is. Your cells are lipids. We put the mRNA in a lipid, and so when they touch each other, it just fuses and joins together, and that mRNA will enter into the cell.

0:47:12.5 SC: Does it need to go all the way to the nucleus, or do we not care?

0:47:15.2 JC: No, it doesn't. In fact, it's a feature that it doesn't go to the nucleus. MRNA works in the cytoplasm, so it never goes near the DNA and is read by the cook, the ribosome, in the cytoplasm.

0:47:30.1 SC: Is that the same ribosome that translates the mitochondrial DNA?

0:47:34.5 JC: No. No, the mitochondrial ribosome's within the mitochondria.

0:47:38.2 SC: Okay. All right. There's just lots of ribosomes floating around doing all this work.

0:47:42.5 JC: Well, your cell, when it really comes down to it, is just a big bag of ribosomes.

0:47:46.4 SC: All right. Now I know. Okay, that's good. Okay, so it's all a matter of just tricking the body. You're tricking the body into thinking that it has an invader. You're tricking the cells into letting mRNA in, right? And then you're getting the body to do your work for you.

0:47:59.5 JC: That's exactly right. All through these natural processes.

0:48:05.6 SC: Okay, so that's what we do as a matter of empirical fact. Are there other ways to get the mRNA in there? Is that something we're trying to do even better, or are the little fatty blobs gonna be the state of the art?

0:48:17.7 JC: It's really, it is the way we have now, but there are lots of people out there working on improving delivery in different ways because these lipid nanoparticles, they lack what we call tropism. And what I mean by tropism is that they, so they work really well if you stick it into your arm because you have cells from your immune system that are kind of there and they'll take it up. They'll read it, and then they'll communicate that information to your other immune cells, and that will spread naturally through your body, the information that those cells had. But the only other place that we really have good ability to deliver to right now is the liver. And that's because everything goes to the liver in your body. It doesn't matter what it is. Your liver is your detoxifying organ. And so if you inject anything into your body, it doesn't matter whether it's Tylenol or aspirin or whatever, everything goes to your liver. So right now, we can target mRNAs to these immune cells and basically the area around your skin, the injection site, and then your liver. But investigators are working quite seriously on trying to develop delivery mechanisms to other cell types, like the pancreas, like the brain, like the heart, kidneys, whatever, so that we can tap into the potential of delivering these medicines to the places that they really need to be.

0:49:53.2 SC: Do I gather that when I get a shot in my arm, so there's the mRNA in there telling some cells to start making the antibodies. Is all the work being done by the mRNA in my arm, or does the mRNA spread through my body first?

0:50:10.3 JC: MRNA doesn't really spread far. It's basically at the injection site because that's where the cells are being taken up, the LNP and the mRNA, and then those cells are the ones that are learning, expressing the foreign protein, and then the immune system's learning from that and that's spreading. The mRNAs themselves are very unstable, meaning they have half-lives that's on the order of hours. So even by the time you drive home from the pharmacist, most of it's gone.

0:50:40.7 SC: Wow.

0:50:41.6 JC: So it doesn't stick around very long.

0:50:44.7 SC: And like you said, we're trying to learn ways to target other organs. I mean, the brain... I don't want to necessarily get a shot into my brain, but maybe is that the kind of thing being contemplated, or are there clever ways to wrap the mRNA so that it will eventually get to the brain?

0:51:02.8 JC: The brain's tough because of what's called the brain barrier, the blood-brain barrier. So your listeners may or may not know this, but there's very little exchange of material between the bloodstream and the brain. So the brain is a very protected space with which is called the blood-brain barrier, the BBB. So getting things across the blood-brain barrier is difficult, and there's no real good way to do that through an injection in your arm, for example. In the type of gene therapies that have been developed, and I'm not talking about mRNA, I'm talking about other gene therapies that have been developed for devastating brain disorders, those usually are injected directly into the brain so that you can go right through the brain barrier.

0:51:54.6 SC: And again, you said design before and we talked about the computer program and whatever. There's been these wonderful advances in gene editing and CRISPR-cas and stuff like that. Are they useful for this project?

0:52:08.3 JC: Yeah, so that's what the world is very excited about right now. So it's kind of the amalgamation of several really incredible technologies, two of which are Nobel Prize-winning technologies. So CRISPR is a, it's basically a system that was discovered from bacteria. And so bacteria have this primordial, the best word to call it is immune system. It's like a way that it knows whether it's been infected by viruses. And so CRISPR was harnessed by researchers to basically target specific areas within your DNA and then make cuts. And that's what CRISPR does. It's like a GPS signal, find this piece of DNA and then make a cut. So why is that important? It's important because you have billions and billions of base pairs of DNA. And if you want to specifically change or work on one tiny, tiny little region of that DNA, you need a GPS locator to find it. And that's what CRISPR does. It's a discovery coming out of bacteria. Okay, so there's that piece. And then on top of that, researchers at the Broad, guy named David Liu, had taken CRISPR and hooked it up with another set of proteins that could make changes to the DNA.

0:53:48.2 JC: All right, so you can now, with CRISPR, you can hone, you can localize it to a very specific region, GPS target it. And if you can target to a piece of DNA and a region of DNA, and if there's an error there, you could make a correction now. All right, and that's what's called base editing. So CRISPR fused with base editing is this sort of surgical way to go in where there's a mutation, where there's a change in the genetic code, and find that region and then correct it so that it's normal again. All right, so those are the two big pieces of technology. But the problem with that is that it's not perfect, meaning you can make a change there, but if there's any opportunity for that CRISPR to kind of wander around the DNA, then it might make a change somewhere else that could be bad. You don't want that machine always present in your body. And that's where this has been now married to mRNA technology. So you take that CRISPR base editor protein and make it as an mRNA. And so the beauty, so basically think about it this way.

0:55:09.0 JC: The CRISPR base editing, this thing that is a surgical instrument to change the DNA, think of that as the recipe, the new recipe that your body needs to make. And so how are you gonna deliver it? You're gonna deliver it with that recipe card, the mRNA. And the reason why you wanna do this is because of the key that I've been saying during the entire podcast, mRNA is destroyed after reading.

0:55:22.5 SC: Yeah.

0:55:36.0 JC: So you introduce it, you help it do what it needs to do, make the little correction, and then you destroy it so that it's no longer there. And so the only thing left is the change that was made, the correction, which has now gone back to a normal piece of DNA. So it's just like a surgical instrument.

0:55:57.9 SC: And what kind of therapeutic uses would this be? This is not a vaccine.

0:56:02.3 JC: No, this is not a vaccine. These are, so there's been a handful of these done in vivo, meaning in the human body. The first example of this wasn't using an mRNA. They were done on blood cells. So they would take blood out of the cell, or cells that needed to be changed for something like sickle cell anemia. So you do the change ex vivo, so you do the change outside of the body, and then you put those corrected cells back in the body. And that has worked. But in that case, it always had to be done outside of the body. By combining the three technologies, the CRISPR, the base editor, the mRNA, it allows it to do it in the body, to do this correction in the body. And we only have one example of this, which is this young baby, this baby that was born last year or 2024 in Pennsylvania named KJ Muldoon. So KJ was born with an ultra-rare genetic condition that affects about 1 in 1.3 million children born. And it's a deficiency in an enzyme in his liver. And so that enzyme is a protein called CPS1. And what that protein has to do is help metabolize proteins. And if you don't have it, you build up toxic ammonia in your body.

0:57:33.9 SC: Okay.

0:57:38.9 JC: And it causes severe neurological damage because ammonia is poisonous to us. And when KJ Muldoon was born with this CPS1 deficiency, and like I said, it's one in a million babies, so it's very rare, but it was clear something was going wrong. And the only option for him was a liver transplant. He had to have a liver transplant, but he was way too young and way too delicate to survive a liver transplant. And a liver transplant is not a great option anyway. I mean, it's a really significant surgery.

0:58:09.0 SC: Yeah.

0:58:19.5 JC: And it does build on the tragedy of someone else. And you can't always guarantee that a liver is gonna be compatible with the person that you're putting in for the same reason, the immune system, right? So what researchers at the Children's Hospital of Philadelphia decided to do was to create this never-before-done technique of taking CRISPR base editors with an mRNA and going into his body because it was liver, and we can get things to go to the liver, to see if they could make a correction in his DNA that then would restore his CPS1 gene back to normal. And they moved heaven and Earth to do this in an unprecedented set of exercises, were able to secure FDA approval within a matter of weeks, a week, and treat him within a few months of his birth, I think it was about six months of his birth. And essentially, it corrected his mutation. And now he's thriving. He's no longer in danger. He's metabolizing proteins appropriately. He's walking, he's talking.

0:59:38.4 JC: He still has to be monitored. He's not cured. We can't say that he's cured, but he doesn't need a liver transplant. And the incredible thing about this is that the fact that he has an mRNA-based technology that was used on him, and again, that mRNA goes away over time. It's no longer in his body. He could be redosed again in five years if we figured that he needed a little bit more correction because his liver's gonna grow, it's gonna expand. He still has some cells in there that have the mutant copy of the DNA. Maybe he'll need another round of correction to build up more normal cells. And we can do it with that approach. So that has everybody super excited because it's an ultra-rare genetic disorder. An ultra-rare genetic disorder, one in a million. And he has a personalized therapy that basically is going in like a surgical instrument, changing his DNA back to normal, and he's thriving.

1:00:43.6 SC: Right.

1:00:44.1 JC: If we can do it for him, we can do it for one of any ultra-rare genetic disorders or more common genetic disorders in the future if we invest and we have the right technologies in play.

1:00:56.7 SC: I'm not sure I have a question here, but I just want to say wow.

1:01:01.6 JC: Yeah, wow.

1:01:01.8 SC: They went in and fixed someone's DNA.

1:01:03.9 JC: Absolute science fiction stuff, right? I mean, it's really cool. They fixed his DNA, which is ultimately where we've always wanted to be in any kind of therapeutic. There are over 7,000 genetic diseases that humans suffer from. And we often call these rare genetic disorders. But one in 13 people suffer from some form of genetic disease. And so it's not...

1:01:30.9 SC: Not that rare.

1:01:31.7 JC: Rare. They're just rare as an individual indication, meaning some of them will have cystic fibrosis, some might have Duchenne's muscular dystrophy, some may have Alzheimer's or dementia or sickle cell. All of these are the result of an abnormality in their DNA. And if we have the power to go in and correct these, then it's a potential path toward improved lives for these individuals, right?

1:02:06.0 SC: It does strike me that my body has a lot of cells in it. Is this therapy literally trying to fix all or most of the DNA in my cells?

1:02:17.4 JC: Yeah, I mean, that's always a challenge for any particular disease is how much do you have to correct? And for the most part, we don't know for a lot of diseases. In the case of baby KJ, he was dosed three times with this corrector. And so they did it in sort of stages. They gave him a little bit.

1:02:28.7 SC: Yeah.

1:02:40.0 JC: Then they gave him a little bit more, waited, gave him a little bit more. And then he started to show signs that he was improving. And to this day, we don't really know how much correction he got because we can't tell that because we're not gonna go in and do a biopsy on him. But with other diseases, with gene therapy, sometimes you may only need maybe 10%, 15% improvement over the baseline that they're already at to get some sort of benefit. And it would be amiss to say that we're curing people. We're not. We're not there yet. But if we're improving their lives, making their lives more tolerable, having them live longer, having their medical needs reduced, all of that is a good outcome for any therapeutic. So it's hard to say how much correction we would need for any particular indication, but in some cases, it may only be 10%, 15% above what they already have to give a meaningful change to their lives.

1:03:44.8 SC: So I guess the dream is that we master the idea of bespoke genetic therapies. And whenever someone has a disease, you just like, "Oh, let's just sequence it, figure out how to fix it, and you'll be back on your feet a week later."

1:03:57.8 JC: If that... There's a whole group of researchers, I mean, thousands of researchers and thousands of small biotech companies that have tried to make gene therapies for every disease under the sun. For all the ones that have a genetic origin, which is the vast majority of them, if we could make the correction in their DNA, that's the solution.

1:04:11.0 SC: Right. Yeah.

1:04:24.3 JC: And so you need to do a few things. You need to be able to get to those cells. And that is a limitation. We have to be very honest about that. Right now, we can reach the liver. That's where we can go. We don't have the ability to go to a lot of other places. But there also hasn't been a lot of incentive to do that because we haven't had technologies that are so powerful. And humans are really good at when there's... What is the... Need is the mother of necessity or whatever that saying is.

1:04:56.1 SC: Necessity is the mother of invention.

1:05:05.1 JC: Mother of invention. That's right. Necessity is the mother of invention. And that's where we're at, where if we have a technology that we know could reach the brain or could make significant changes to patients with ultra-rare genetic disorders of the central nervous system, we're gonna figure it out. We will, in time.

1:05:14.1 SC: And you went down a list of diseases: Cystic fibrosis, Alzheimer's, dementia. These are not unimportant diseases to try to tackle. So I presume I know the answer to this one, but just to be sure, these are realistic chances that we have in a reasonable time scale of making important progress.

1:05:38.3 JC: Absolutely. Absolutely. The technology... And I have to say, the technology that keeps us back right now is really the delivery component. How do you get it to the right cell types? But the ability to go in, find... So the ability to identify a mutation in a patient, that's there, right? We have had that for many years now. We can sequence a person's genome for a matter of a couple of hundred bucks now. The Human Genome Project cost over a billion dollars. We can sequence a human's DNA in a day now for a couple of hundred dollars. I mean, that's incredible technology in 30 years. So we can do that. And we can identify the genetic basis of most diseases. And now we have these CRISPR mRNA-based editors. We can make changes. Those are improving. Those are gonna continue to iterate and get much and much better. But delivery is gonna be the challenge. And every organ has a unique challenge. Cystic fibrosis is a great example of that. It's the lung. Your lung is coated with mucus.

1:06:12.4 SC: Yeah.

1:06:46.4 JC: Because that's how it functions. That's what it needs to have, that thick mucosal layer. Well, that mucosal layer, partially what it does is help trap foreign things. So you breathe in a virus or you breathe in a bacteria, it gets trapped there so that it doesn't get into your body. Well, the same would be true of a gene therapy. It can't get through that thick mucosa. So there's a challenge there.

1:07:11.3 SC: You could inhale it, but the lungs would prevent it from being absorbed.

1:07:13.9 JC: It would just stick to the mucus and never really penetrate in. But there are people that in fact are working on that to try and get it past that mucosal layer. And if we can do that, then we can go after diseases of the lung. The point is every organ has a unique challenge. And my gut feeling is in 20 years, maybe less, we'll have a toolbox of all these delivery mechanisms to get CRISPR-based editors to different cell types and into different tissues. And it will be the standard of care for genetic medicine.

1:07:51.2 SC: And you mentioned cancers also. Do they count as genetic diseases?

1:07:55.3 JC: Yeah, I mean, they... In different ways. So cancer is a complex disorder. But where people are really getting excited by the same... Not the CRISPR-based editor, but the mRNA technology. Again, mRNA is this natural product, this thing that delivers information to your body. And we tap into that. And what was identified a number of years ago by James Allison, that when cancer cells develop, cancer basically is your cell that goes crazy.

1:08:15.2 SC: Yeah.

1:08:35.2 JC: And when it goes crazy, it tends to rearrange your genome. And when it does that, it's making unique proteins. And when you make a unique protein that your body doesn't normally see, that's a target for your immune system. And so if you can train your immune system to attack your cancer cells, your body can work for it and attack your cancer cells and then lead to a remission of that cancer. And what investigators are doing with the mRNA technology is to try and identify those unique protein signatures within a cancer and then stitch them together into an mRNA that then you would inject into the tumor and then train the immune system to attack that tumor. And a great example that came out of Sloan Kettering in 2022 was this paper in the magazine Nature that showed in a small clinical trial, they developed a personalized cancer therapy, what's called a neoantigen therapy, using an mRNA for patients with pancreatic cancer. So this is, pancreatic cancer is scary, right? It's like 95% mortality within a year. And they injected these personalized neoantigen therapies into these patients, and 50% of them responded and are alive today, six years later. Well, the study was started in 2020, so it's been like six years. So they're pretty much cancer-free.

1:09:45.9 SC: Wow.

1:10:08.2 JC: And so it's 50%. That's not 100%, but...

1:10:12.7 SC: Still.

1:10:13.0 JC: Much better than 95% chance of death within a year.

1:10:14.1 SC: Yeah.

1:10:15.9 JC: And so that's just out of the box. So as we get better and better of using mRNAs to go after cancer, we're learning the rules that really can revolutionize our treatment of some of the worst cancers that we've ever had to deal with, like melanoma and glioblastoma and pancreatic cancer. And we're making headway there.

1:10:37.4 SC: We actually had James Allison on the podcast.

1:10:40.2 JC: Did you?

1:10:40.3 SC: You just reminded me. And so the immunotherapy aspect was there, but the mRNA aspect is new to me. So that's a good combination.

1:10:49.0 JC: Well, and again, it's one of those things where a lot of these incredible technologies are being put together. I mean, he had a Nobel Prize-winning idea. The mRNA is a Nobel Prize-winning idea. You put peanut butter and chocolate together, and it makes a great candy bar.

1:11:05.2 SC: Okay, since we're past the hour mark now, this is traditionally where we get to let our hair down in the podcast and ask the slightly crazier questions. You've given us a lot to be hopeful and optimistic about with these therapeutic uses. Are there worse uses out there? Can people use these for the force of bad rather than good?

1:11:29.3 JC: Well, everything can be used for the force of bad, I suppose, but I would actually say that the force of good is more prevalent than bad. Because the one thing I would say is what sort of keeps me up at night with what some of the policy decisions that have been made in the last few years around a technology that's been sort of demonized by people that want to demonize it because it's a way to get people scared and blah, blah, blah. There was a study that came out a few months ago that was using artificial intelligence to design viruses. And these were viruses that would infect bacteria, so they're not human pathogens. But using AI programmed with millions of viral sequences for bacteria, the researchers were able to develop novel viruses that had never been seen before by Mother Nature. And 16 of those performed better than the viruses that had been seen.

1:12:39.9 SC: What does better mean?

1:12:41.3 JC: Meaning they were able to kill the bacteria more.

1:12:43.4 SC: Okay, good. That's what I thought it meant. Right.

1:12:45.5 JC: More readily, I suppose. So these are viruses that affect bacteria. So, okay, well, who cares, right? But and then these researchers were American researchers, so they're bound by ethics regulations and couldn't program their AI algorithms with human viruses. But as AI gets more and more powerful and a bad actor anywhere in the world who has access to a simple AI algorithm could do the same thing programmed with human viruses. So you potentially could create a human pathogen using artificial intelligence that could be quite deadly. The only countermeasure we have to that threat is really mRNA-based vaccines. It's the only thing we could ever leverage and deploy to our troops or to a population at a speed that would be a natural deterrent to that threat. And so that is something that I think bothers me because we can't throw away a technology that really is, we call this in national defense, it's called deterrence by denial. So you don't allow the other party to develop a technology because you've got the countermeasure that can match it with equal speed and performance. So we've got to protect this technology rather than throw it away. And it is an American invention and it should be.

1:14:15.4 SC: But it sounds like there will be an mRNA arms race.

1:14:19.2 JC: There already is. I mean, China is developing about 46% of all mRNA-based vaccines are now being developed in China, not in the United States.

1:14:29.4 SC: But I just meant an arms race in terms of... It doesn't sound like you need the resources of a country to do something bad in the virus designing game, but we need countermeasures against that also.

1:14:36.1 JC: That's right.

1:14:42.8 SC: So there could be, I guess, bioweapons and also bioprotections improving in their efficacy simultaneously.

1:15:16.2 JC: And this is not far-fetched science fiction because there was a time back in the Middle Ages where they used to launch infected people over the walls of the castle. If they would have anthrax, they would actually launch their bodies into the castle in order to spread anthrax within the castle walls. This is something we know how to do. And the other side of that is the incapacitation of troops with pathogens is much more effective than kinetic weapons. We saw this during COVID with the USS Cole. USS Cole, coronavirus went rampant through it, and it was taken completely out of commission within a few days because of this infection. Something that a kinetic weapon was incapable of doing, a virus took down an entire destroyer.

1:15:49.6 SC: And you've touched on this a couple of times, but maybe as a final thing to think about, I presume we don't live in the best environment for governmental support of these kinds of things. What would be the right kinds of things that we need? What should the government be doing to improve the rate at which we develop these therapies and so on?

1:16:13.9 JC: I mean, we should invest into education about what they actually are, right? And into the infrastructure that we created in the United States. There's been a demonization, an unnecessary demonization of the technology that was very much an American invention that really did help end the pandemic and saved millions of Americans' lives. And we need to keep building that infrastructure rather than this very concerted mis- and disinformation campaign, which is based on falsehoods and not science.

1:16:54.3 SC: And also, I presume there are regulatory issues, right? We don't want to have to go through a months-long process every time a baby has a rare disease.

1:17:03.8 JC: Oh yeah. I mean, the regulatory issues are huge because the FDA and the regulatory agencies are set up to deal with blockbuster drugs. So when you have a drug like a GLP-1 inhibitor that cost hundreds of millions of dollars to create, but it's a drug that is needed by hundreds of millions of people around the world, and so you can distribute that cost among all those patients. That's not true when you deal with ultra-rare genetic disorders. It still costs $100 million to develop it, but now you have five patients worldwide. So how do you... The economic model just doesn't work. So the FDA is really designed on that blockbuster drug mentality, a drug that is going to be used in millions of patients, not dozens. And we need to change that regulatory framework now because we have technologies that are personalized. Whether that's a cancer approach that I talked about with pancreatic cancer, because that is personalized. That cancer therapy would be a $10 million therapy if we had to go through the current FDA for pancreatic cancer because each one of those drugs would be an individualized product.

1:18:23.8 JC: And the same thing's true with a bespoke gene therapy for a baby like KJ. This is an individualized, personalized medicine for him, and it's not useful for any other person. It's useful for him and cost $8 million. So we have to change our regulatory and our commercial enterprise to meet this moment, which is we now have the capacity with the technology to treat individuals one by one to their unique genetic signature.

1:18:58.2 SC: So just for my entirely selfish reasons, I hope you get that allergy thing straightened out right away and then move on to cancer and Alzheimer's disease. These are all very, very good things to be solving.

1:19:08.8 JC: Yeah, absolutely. Hopefully. It's not unrealistic that that might happen in the next five years.

1:19:14.8 SC: I'd like to think maybe I was born at the right time in some ways. So this was incredibly useful, incredibly full of things to think about. Jeff Koller, thanks very much for being on the Mindscape podcast.

1:19:25.4 JC: Yeah, thank you. Thank you for your time.

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