Pod Insights Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas 357 | Jeff Coller on mRNA, Vaccines, and Bespoke Therapeutics About this episode Messenger RNA (mRNA) plays a literally central role in the functioning of life as we know it, shuttling information back and forth between the DNA where it is stored to the ribosome where it is used to produce proteins. RNA may even have been the first molecule to kick-start the origin of life. Today, scientists are learning how to manipulate mRNA to cure and prevent diseases, whether through vaccination or literally editing one's DNA. Jeff Coller explains how it all works and how mRNA is revolutionizing medicine as we know it.
Blog post with transcript: https://www.preposterousuniverse.com/podcast/2026/06/15/357-jeff-coller-on-mrna-vaccines-and-bespoke-therapeutics/
Support Mindscape on Patreon https://www.patreon.com/seanmcarroll.
Jeff Coller received his Ph. D. in cell and molecular biology from the University of Wisconsin-Madison. He is currently Bloomberg Distinguished Professor of Biomedical Engineering and Director of the RNA Innovation Center at Johns Hopkins University. He is co-founder of Tevard Biosciences and the Alliance for mRNA Medicines, and leads the REPAIRx consortium. He is a fellow of the American Association for the Advancement of Science.
Web site http://collerlab.org/ Johns Hopkins web page https://www.bme.jhu.edu/people/faculty/jeff-coller/ Google Scholar publications https://scholar.google.com/citations?user=wSJc28sAAAAJ&hl=en "This May Be the Most Important Medical Story of the Decade," New York Times, April 9, 2026 https://www.nytimes.com/2026/04/09/opinion/genetic-editing-diseases-health-care.html
Transcript 13,386 words · 6 speakers
Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.
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0:59 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
1:42 Sean Carroll? and truly astonishing how rapidly those vaccines were developed. 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.
2:10 Sean Carroll? 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
2:51 Sean Carroll? 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. 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.
3:33 Sean Carroll? 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
4:20 Sean Carroll? 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 Koller, 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. And he will explain, you know, 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
5:03 Sean Carroll? 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 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,
5:44 Sean Carroll? we can go and 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. 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
6:30 Sean Carroll? 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.
7:06 Sean Carroll? Jeff Koller, welcome to Mindscape Podcast.
7:08 Speaker 03 Great, thank you for the invitation, Sean.
7:10 Sean Carroll? 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. Like, what is the whole cast of characters here?
7:39 Speaker 03 Yeah, sure. So, you know, 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
8:21 Speaker 03 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.
8:52 Sean Carroll? So, so sorry, just very quickly, the DNA is very long, but the mRNA, mRNA are little short things, one per gene, you said?
9:02 Speaker 03 The one per gene, that's exactly right. So we have about 25,000, 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.
9:14 Sean Carroll? And how does, this is just, 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 like a summons from somewhere else in the cell?
9:33 Speaker 03 Yeah, I mean, there's lots of inputs that decide when you're going to turn a gene on or off. You know, 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.
10:16 Speaker 03 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, as this messenger that then gets read by the cook.
10:45 Sean Carroll? And so you turn on the gene and mRNA is assembled from things floating around?
10:51 Speaker 03 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.
11:16 Sean Carroll? Tell us what the differences are.
11:18 Speaker 03 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's 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.
12:01 Sean Carroll? But there's still four of them. They still pair up with the base pairs in the
12:05 Speaker 03 Pretty much the exact same.
12:06 Sean Carroll? Nucleotides of the DNA. Good.
12:08 Speaker 03 That's right.
12:08 Sean Carroll? And my, again, I did a little bit of, I have a little bit of knowledge from just talking to people about the 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 and the proteins or the DNA?
12:32 Speaker 03 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 Chek and Sidney Allman back in the 80s,
13:15 Speaker 03 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.
13:36 Sean Carroll? 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.
13:43 Speaker 03 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.
13:51 Sean Carroll? Sorry, I thought it has an extra oxygen.
13:53 Speaker 03 No, DNA has less oxygen.
13:55 Sean Carroll? Deoxy, unoxify, not dioxin, yes.
14:00 Speaker 03 No, no, deoxy. So it has one less oxygen.
14:03 Sean Carroll? 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.
14:19 Speaker 03 Yeah. And the other thing that, part of this in terms of like 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 where, you know, 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.
14:57 Sean Carroll? And then we have various forms of RNA.
15:01 Speaker 03 That's right.
15:02 Sean Carroll? M and T and so forth. Are these literally different chemistries, or are they just doing different purposes?
15:08 Speaker 03 Doing different purposes, and it goes back to what I said about being able to form different structures. So the largest
15:17 Speaker 03 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.
15:30 Sean Carroll? Okay.
15:30 Speaker 03 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, you know, is the is the machine that reads the genetic code. And then there are bunches of a bunch of other RNAs around the cell that do different different work. But mRNA in and of itself is a direct copy of a gene within the DNA.
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17:01 Sean Carroll? You know, every time I talk to molecular biologists or other people about these things, like even though I know better, I'm slightly tempted by intelligent design because it's there's so much going on here that is so delicate.
17:15 Speaker 03 I mean, it's fascinating to see it all because the it all works in such beautiful harmony with itself. And you can see that, like, 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, our RNA that we talked about, that 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, and in some of the most primordial life forms on Earth.
17:53 Speaker 03 And so it can be, and in fact, this was, study of ribosomes was one of the reasons that led a guy named Carl Rosa 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.
18:17 Sean Carroll? And it seems like, you know, 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?
18:33 Speaker 03 You know, 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 genetic material, but they discovered the structure. And but about the same time, it was hypothesized that there had to be a intermediary between DNA and proteins. And so we knew that DNA was a genetic material in the 1950s. We knew protein was a very important part of biology. And a guy named Sidney Brenner was one of the first people to propose that there must be this theoretical intermediary between them,
19:19 Speaker 03 which then later, not, you know, about 1964 or so, was shown to be Messenger RNA. And so the the discovery of messenger RNA dates back to forty, fifty years ago.
19:32 Sean Carroll? Okay.
19:33 Speaker 03 Probably more than that, seventy years ago, to the sixties. And and and as, you know, molecular biology has developed in the last, you know, seventy years, we've just learned more and more about the complexity of RNA within the cell. And and like I said, there's there's dozens of different types.
19:50 Sean Carroll? 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?
20:01 Speaker 03 Yeah. So in fact, your your cell, your your nucleus, which contains your nuclear DNA, that 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 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.
20:37 Sean Carroll? Yeah.
20:38 Speaker 03 So that we have to live with it. And that is what your mitochondria is.
20:41 Sean Carroll? Right.
20:42 Speaker 03 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 not human looking, I should say.
21:02 Sean Carroll? 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 those billions of years of evolutionary history.
21:13 Speaker 03 That's right. It's it is. It is kind of a mess because, you know, 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 and to the point where you just can't can't reconstruct it to make it something much more elegant and simplistic.
21:30 Sean Carroll? 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?
21:42 Speaker 03 No, there's thousands. So there's about, you know, 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.
21:51 Sean Carroll? A lot of manufacturing facilities for all the proteins.
21:54 Speaker 03 Yeah, within, within one cell. So half a million ribosomes within one cell.
21:58 Sean Carroll? 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 like the, all I know about it is that there's like three little nucleotides making up part of the genetic code.
22:15 Speaker 03 Yeah, so the, this was really, you know, going back to the 50s and the 60s, we knew that DNA contained the genetic information and deciphering that genetic information was, 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 there
22:59 Speaker 03 are, what DNA does is it makes mRNA, and that mRNA makes a protein. All right. 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 what that, 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.
23:33 Speaker 03 You need 64 words to you, and if you're going to use four letters, you need 64 words to have 20 meetings. That's the only way you can do it mathematically.
23:42 Sean Carroll? I mean, sorry, just because-
23:43 Speaker 03 Everybody just sit that down with a piece of paper, you'll figure it out, essentially.
23:48 Sean Carroll? Just because if you only had two nucleotides, it'd be four times four is 16. You can't cover all the 20.
23:55 Speaker 03 You can't cover. And then, then what happens by having three letters per word, you get 64, which is too many.
24:02 Sean Carroll? Yeah.
24:03 Speaker 03 But there, but there's nowhere in between.
24:04 Sean Carroll? Right.
24:05 Speaker 03 And so you have a three letter, you have four letters that get arranged in these three, you know, three at a time. And then that leads to 20 amino acids. So it's 64 words, basically. Does that make sense?
24:16 Sean Carroll? It absolutely makes sense. And it raises, I mean, I presume, I know the answer to this one, but I'll ask it anyway. It, 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. Like some of the, some of the 64 patterns give you the same amino acid at the end of the day.
24:45 Speaker 03 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.
25:05 Sean Carroll? Okay, wow.
25:06 Speaker 03 And so that, that, that just of these 64 words, there's some repetition.
25:12 Sean Carroll? Yeah.
25:13 Speaker 03 And that's the way Mother Nature did it.
25:15 Sean Carroll? Is there some rhyme or reason about it? Do like, are some amino acids special and I get more words that talk to them?
25:23 Speaker 03 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, it's the nucleotide ATG.
25:46 Sean Carroll? Okay.
25:47 Speaker 03 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.
26:01 Sean Carroll? Right.
26:01 Speaker 03 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 some point in evolution. And now all organisms use the exact same, for the most part, genetic code.
26:41 Sean Carroll? My impression is that even though only 20 amino acids are used in biology, there are more amino acids chemically, is that right?
26:49 Speaker 03 Yeah, there are, but for the most part, life uses those 20.
26:54 Sean Carroll? But we had room to use like 60 some.
26:57 Speaker 03 We had room to use, well, we had room to use 61. We still needed those three periods.
27:02 Sean Carroll? Punctuation.
27:03 Speaker 03 Punctuation marks, but 61 was theoretically possible, but we don't use it.
27:07 Sean Carroll? Do, are there any biologists who get grants to study how life could be different if we chose to use more of the amino acids?
27:16 Speaker 03 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.
27:39 Speaker 03 There are people that look at that, so synthetic biologists. But there are, you know, there are amino acids out there that are not used routinely in biology.
27:51 Speaker 03 You know, could you stitch them into a protein and what consequence would that have? Who knows?
27:55 Sean Carroll? Yeah. I guess I'm just wondering, is, are there like reasons of chemical stability or affinity that we have these 20 that are useful? Or is that one of these frozen accidents?
28:05 Speaker 03 I think it has more to do with their natural abundance in the environment.
28:09 Sean Carroll? That makes perfect sense.
28:11 Speaker 03 But there's a lot of that we don't understand, right? Why these 20, you know, why are they here on Earth? And, and why are they abundant on Earth? And, and, um, you know, we have, I mean, this isn't my area of expertise, but some of these amino acids have been seen in, you know, outer space. Like you can see them in nebulae and other places where, so they might actually have a common origin, sort of natural origin within the universe that makes them a good, uh, you know, a good property to be using them because they're enriched.
28:44 Sean Carroll? Again, my impression is that back from the classic Miller-Yuri experiment, we decided that it's actually not that hard to make amino acids. It's making the RNA and DNA that is hard.
28:54 Speaker 03 It's getting it all organized. It's the actual building blocks of all of this, of DNA and RNA and protein, they, they tend to form naturally with the ingredients that are out there in the universe and, and with some heat and radiation, they come together. But the stitching it all together in a way that gives life, meaning you, where life is really a, a chemical reaction that perpetuates itself, that's what's, you know, that's something we don't understand how that happened yet.
29:23 Sean Carroll? Right. I mean, throwing a bunch of transistors in a bag is not going to make a computer.
29:28 Speaker 03 That's right. That's right. That's exactly right.
29:31 Sean Carroll? And are there any like secret messages hidden in why some codons, some list of three nucleotides is, is used rather than other ones? Or are they, are they purely redundant when they give you the same amino acid?
29:45 Speaker 03 They don't seem to be so, and that's something my lab has studied where, as I said, these codons will, there's degeneracy, meaning that, uh, you can encode the same amino acid with multiple codons or multiple words. But the way the ribosome reads those words, I've 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, you know, he's reading this recipe.
30:27 Speaker 03 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 like if you had a bucket of, you know, bingo balls and all of them were colored blue and one of them's red. You have, you know, one would be very, the red one would be very hard to find if you were just sampling randomly. And that's the same thing here with the ribosome.
31:07 Speaker 03 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, 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 had 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.
31:45 Sean Carroll? Okay.
31:46 Speaker 03 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.
32:01 Sean Carroll? So the destruction process is active or does it just fall apart?
32:04 Speaker 03 It's active, very active.
32:08 Sean Carroll? Okay, so yeah, we so we read it and then we burn the message, just like in Mission Impossible.
32:12 Speaker 03 That's exactly right. Destroy upon reading.
32:15 Sean Carroll? 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. I mean, maybe just first talk a little bit about the crowd pleaser, which is the mRNA vaccines.
32:36 Speaker 03 Sure, yeah. So this is a very old history with mRNA being used in medicine despite what probably popular press has as an idea. I mean, the fact that mRNA exists, we know that this is the cook, or sorry, 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 mRNA's in the 60s, of course, this was exciting, because it means that if we can design mRNA's, we can get
33:15 Speaker 03 the cell to make any protein we want, regardless of whether it naturally exists or not. And so this is, this is a natural system. mRNA 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 mRNA's that can stick into a cell and then have the cell make that protein, right, in anything of anything we want. And that's what, you know, really electrified scientists in the late 90s and early 2000s to start thinking, could we design mRNA's to be used in medicine? And, you know, and there's lots of places where this could be
33:59 Speaker 03 very powerful. One, and the place where people really got excited was in cancer. And I imagine we'll talk more about that in a little while.
34:07 Sean Carroll? Yeah.
34:07 Speaker 03 But the other was with vaccines. Because with vaccines, vaccines are always usually are usually a protein, a protein that is a
34:18 Speaker 03 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 and knows every protein in you.
34:33 Sean Carroll? Yeah.
34:34 Speaker 03 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.
35:02 Sean Carroll? Yeah.
35:03 Speaker 03 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 for more. You know, so it's just that speed of being able to manufacture these is what has really electrified the community.
35:36 Sean Carroll? 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. Like, how big is the space of proteins?
35:50 Speaker 03 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.
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36:44 Speaker 01 ChatGPT for Teens is designed to help teens learn, think critically, and grow their skills. ChatGPT for Teens supports active learning by breaking concepts down. Rather than giving teens the answer, study mode helps teens work through problems, and interactive quizzes test their knowledge and provide immediate feedback. Safety protections are on by default, and parental controls offer families additional options, like setting study hours and quiet hours. Visit chatgpt.com/parents to learn more.
37:11 Sean Carroll? Is there any chance that mRNA technologies are going to cure my allergies?
37:17 Speaker 03 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.
37:29 Sean Carroll? Yeah.
37:29 Speaker 03 And one of the places where people are looking into this is in immune reactions. So, or autoimmunity is another, autoimmunity is a big issue where you, you have the ability to this, 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, you know, people would probably recognize like arthritis is a good example of that. And if you can learn to down-regulate the immune system through mRNA technology, which people are investigating, then it's one way to, to protect, you know, protect from autoimmunity
38:11 Speaker 03 or an overstimulation of the immune system as you get with allergy reactions.
38:16 Sean Carroll? All right, I'm going to support this then. I was on, I was wavering, I was on the, I was on the fence, but now you, now you've sold me.
38:23 Sean Carroll? Good. We've heard probably of mRNA vaccines in the context of COVID, right? Were they around before then?
38:32 Speaker 03 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.
38:59 Sean Carroll? Okay.
38:59 Speaker 03 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, well, everyone in 2019, this was a new technology to them. It wasn't to the scientists. We had over 20 years of the inhuman testing that had already been conducted with mRNA technologies.
39:29 Sean Carroll? And the word inhuman there does not mean non-human. It means inside human beings.
39:33 Speaker 03 Inside a human being. That's exactly right.
39:35 Sean Carroll? Yeah, okay. And just to like, 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.
39:52 Speaker 03 That's exactly right, yeah. And that's the beauty of the mRNA technology too, because you're, 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 going to mount an immune reaction. And, and then the, 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 which that's what gives you the immune reaction that you've carried forward for months, hopefully years.
40:32 Sean Carroll? And what exactly would the difference be between an mRNA vaccine and a non mRNA vaccine?
40:38 Speaker 03 Well, I mean, the main difference is what they are, which is most vaccines are protein.
40:43 Sean Carroll? Okay.
40:44 Speaker 03 Where the mRNA is the mRNA that then makes the protein. So yeah, from from just a product standpoint, that's, that's the major difference is you have, you know, 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
41:26 Speaker 03 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. So it because it requires, you know, 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 or a DNA or an mRNA to make that protein and then grow it up. And you'd have millions of eggs to do this and then purify that protein from those eggs. And that's a costly project.
42:11 Sean Carroll? Sounds rather slow. Yeah.
42:12 Speaker 03 Yeah, it's slow. And it takes, you know, 20, 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 you can develop it in silico in the computer, you know, 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.
42:42 Sean Carroll? 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?
42:54 Speaker 03 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 the when the COVID hit in 2019 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
43:36 Speaker 03 at Moderna, he downloaded and he put it into his program and had designed the vaccine that went into, you know, millions and millions of human beings within just a matter of hours.
43:49 Sean Carroll? Pretty good.
43:49 Speaker 03 It's not that complicated.
43:51 Sean Carroll? Well, what's the name of your grad student, your former grad student?
43:54 Speaker 03 His name was Vlad Presnyak.
43:56 Sean Carroll? Okay, cool. Yeah, he chose a wise place to go.
44:01 Sean Carroll? He couldn't have known how important it would have been.
44:03 Speaker 03 No, in fact, when he got the information, because we were all still not really completely aware what was going to hit us.
44:10 Sean Carroll? Right.
44:11 Speaker 03 He didn't really know the implications of what he had just done.
44:15 Sean Carroll? Yeah. And so it seems to me, you know, you've been talking about the recipe and the cook, et cetera. But in biology, it's just, there's a long road from knowing the recipe to knowing what the dish is going to taste like, right? Like, how easy is it for your grad student or anyone or whoever to say, okay, I'm going to put together a little sequence of RNA that will lead to the protein I want?
44:43 Speaker 03 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 they, it's a large protein in SARS-CoV-2. They clone, 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.
45:27 Speaker 03 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, the S protein that's naturally occurring in, in SARS-CoV-2 with a few little changes.
45:39 Sean Carroll? Those S proteins, those like, the little protuberances we see on the cartoons of all the COVID.
45:44 Speaker 03 That's right. S protein is short for spike.
45:47 Sean Carroll? Spike proteins, yes.
45:48 Speaker 03 The spike protein.
45:49 Sean Carroll? They look very cute.
45:50 Speaker 03 Which makes, you know, reason why it's called a coronavirus, because it looks like a crown.
45:54 Sean Carroll? Oh, okay, good. So I did learn something in this, in this podcast. But, okay, I mean, if I know, so 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?
46:11 Speaker 03 Yeah, that's pretty much what we do. So if you identify a new, you know, everybody's talking now about, you know, this heptavirus that people are worried about. It wouldn't be that hard to develop a vaccine, put it in a vaccine for heptavirus. 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, and then you'd have to do testing.
46:40 Sean Carroll? All right. And then you don't need chicken eggs. I mean, how do you actually make all of this vaccine for, from the mRNA?
46:47 Speaker 03 Yeah, so it's all done in a test tube. So it's done using what we call in vitro procedures. So the meaning in vitro being in a test tube. So you have a, you make a DNA template.
47:04 Speaker 03 And from that DNA template, you can use a couple of enzymes and amplify up mRNA in like huge volumes.
47:12 Sean Carroll? Okay.
47:12 Speaker 03 So in fact, like 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, you know, this is basically a vat, you know, like a giant pot that you're cooking it in. A bioreactor for a traditional vaccine would be on the order of like the size of a small, you know, it could fill like half of a aircraft carrier, aircraft hangar, you know, you would put like thousands and thousands of liters of these vats into a room that you would make your vaccine.
47:54 Speaker 03 With an mRNA, your bioreactor can be about as big as your body for the entire population on Earth.
48:02 Sean Carroll? Okay, that's, it seems like a cost-saving measure.
48:05 Speaker 03 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 like a two-liter of soda that would hold enough mRNA to inoculate the entire planet.
48:20 Sean Carroll? But then we got to get it into the body somehow, right? Like that seems to be a tricky thing, as far as I can tell.
48:26 Speaker 03 Yeah, so your body doesn't like to take up strange, you know, nucleic acids, as it shouldn't, right? Because that viruses are in fact nucleic acids, like RNA and DNA. And so the way we, and to be honest, you eat RNA, mRNA, and DNA every single day.
48:47 Sean Carroll? Yeah.
48:48 Speaker 03 Every single, 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, you know, cow DNA in it, and cow mRNA is in it. So you, you can't just readily take those things up because they would work just like any mRNA in your body. Um, 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 a, you know, your cells are made out of lipids.
49:26 Sean Carroll? Hmm.
49:27 Speaker 03 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, you know, 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.
49:49 Sean Carroll? Hmm.
49:50 Speaker 03 And that's what a lipid nanoparticle is a lip, your cells are lipids. We put a, 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.
50:04 Sean Carroll? Does it need to go all the way to the nucleus or do we not care?
50:07 Speaker 03 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 um, is, is read by the cook, the ribosome in the cytoplasm.
50:22 Sean Carroll? Is that the same ribosome that translates the mitochondrial DNA?
50:27 Speaker 03 No, no, the mitochondrial ribosomes within the mitochondria.
50:30 Sean Carroll? Okay, all right. There's just a lot of ribosomes floating around doing all this work. Okay.
50:34 Speaker 03 Well, you sell, you sell when it really comes down to it, it's just a big bag of ribosomes.
50:38 Sean Carroll? All right. Now, now I know. Okay, that's good. Okay. So you, 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.
50:52 Speaker 03 That's exactly right. All through these natural processes.
50:55 Sean Carroll? Are there, um, 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, is that like something we're trying to do even better? Or do we, the little fatty blobs going to be the state of the art?
51:10 Speaker 03 It's really, it's, it is the way we have now. Um, but there are lots of people out there working on improving delivery in different ways. Because these lipid nanoparticles, they, 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 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
51:53 Speaker 03 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, even it doesn't matter whether it's Tylenol, aspirin, or whatever, everything goes to your liver. So, right now, we can target MRNAs to these immune cells in your basically, you know, in 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
52:33 Speaker 03 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.
52:44 Sean Carroll? 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 that, is all the work being done by the mRNA in my arm? Or does the mRNA spread through my body first?
53:02 Speaker 03 mRNA doesn't really spread far. It's basically at the injection site because that's where the cells are being taken up, the the LNP and the mRNA, and then those cells are the ones that are learning, expressing the the foreign protein, and then the immune system's learning from that and that's spreading. The MRNAs themselves are very unstable, meaning they they have half-lives, that's on the order of hours. So, you know, even by the time you drive home from the pharmacist, most of it's gone. So, it doesn't stick around very long.
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54:06 Speaker 01 ChatGPT for Teens is designed to help teens learn, think critically, and grow their skills. ChatGPT for Teens supports active learning by breaking concepts down. Rather than giving teens the answer, study mode helps teens work through problems, and interactive quizzes test their knowledge and provide immediate feedback. Safety protections are on by default, and parental controls offer families additional options, like setting study hours and quiet hours. Visit chatgpt.com/parents to learn more.
54:34 Sean Carroll? 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?
54:53 Speaker 03 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, 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.
55:39 Sean Carroll? Yeah, okay.
55:40 Speaker 03 So that you can go right through the brain barrier.
55:44 Sean Carroll? And again, you say, 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?
55:58 Speaker 03 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 better, best word to call it is immune system. It's like a way that it knows whether it's been infected by viruses.
56:34 Speaker 03 And so CRISPR is, 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? And 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.
57:15 Sean Carroll? Right.
57:16 Speaker 03 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, a guy named David Liu, had taken CRISPR and hooked it up with another set of proteins that could make changes to the DNA. All right. So you can now with CRISPR, you can hone, you can localize it to a very specific region, you know, GPS target. 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.
57:57 Speaker 03 All right. And that's what's a 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, you know, wander around the DNA, then it might make a change somewhere else.
58:39 Sean Carroll? That could be bad.
58:40 Speaker 03 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, you take that CRISPR base editor protein and make it as an mRNA. And so the beauty, so basically think about it this way, 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 going to deliver it? You're going to deliver it with that recipe card, the mRNA. And the reason why you want to do this is because of the key that I've been saying during the entire podcast, mRNA is destroyed after reading.
59:25 Sean Carroll? Yeah.
59:26 Speaker 03 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.
59:47 Sean Carroll? And what kind of therapeutic uses would this be? This is not a vaccine.
59:52 Speaker 03 No, this is not a vaccine. These are, these, 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.
1:00:34 Speaker 03 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.
1:00:44 Sean Carroll? Okay.
1:00:45 Speaker 03 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.
1:01:22 Speaker 03 And if you don't have it, you build up toxic ammonia in your body.
1:01:29 Sean Carroll? Okay.
1:01:29 Speaker 03 And it causes severe neurological damage because ammonia is poisonous to us. And when KJ Muldoon was born with this CPS one 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 like really significant surgery.
1:02:09 Sean Carroll? Yeah.
1:02:09 Speaker 03 And, and it does build on the tragedy of someone else and, and the guarantee, you can't always guarantee that a liver is going to 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, 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 CPS one gene back to normal.
1:02:53 Speaker 03 And they, you know, moved heaven and earth to do this. And like an unprecedented
1:03:02 Speaker 03 set of exercises were able to secure FDA approval within a matter of weeks, a week, 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.
1:03:21 Speaker 03 You know, thriving, he's no longer in danger. He's metabolizing proteins appropriately. He's walking, he's talking. He still has to be monitored. You know, 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 a 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. You know, because his liver is going to grow. It's going to expand. He still has some cells in there that have the mutant copy of the DNA.
1:04:06 Speaker 03 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. All right? 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.
1:04:47 Sean Carroll? I'm not sure I have a question here, but I just want to say, wow.
1:04:51 Speaker 03 Yeah, wow.
1:04:52 Sean Carroll? They went in and fixed someone's DNA.
1:04:54 Speaker 03 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, I mean, we, there are over 7,000 genetic diseases that humans suffer from. And we often call these, you know, rare genetic disorders. But one in 13 people suffer from some form of genetic disease. And so it's not that rare. Rare, they're just rare as an individual indication, meaning some of them will have cystic fibrosis, some might have two chains muscular dystrophy, some may have, you know, Alzheimer's or dementia or sickle cell.
1:05:38 Speaker 03 All of these are the result of a 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?
1:05:55 Sean Carroll? It does strike me that, you know, 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?
1:06:07 Speaker 03 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.
1:06:29 Sean Carroll? Yeah.
1:06:30 Speaker 03 And 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, you know, because we're not going to go in and do a biopsy on him. But with other diseases, you know, with gene therapy, sometimes you may only need maybe 10, 15% improvement over the baseline that they're already at.
1:06:59 Sean Carroll? Yeah.
1:07:00 Speaker 03 To get some sort of benefit. And, you know, and it's, it's, 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, their medical needs reduced, you know, all of that is a good outcome for any therapeutic. So it's hard to say how much, you know, correction we would need for any particular indication. But in some cases, it may only be, you know, 10, 15% above what they already have to give a meaningful change to their lives.
1:07:35 Sean Carroll? So I guess the dream is that we master the idea of bespoke genetic therapies. And, you know, whenever someone has a disease, you're just like, oh, let's just sequence it, figure out how to fix it, and you'll be back on your feet the week later.
1:07:50 Speaker 03 You know, if that, there's a whole group of, you know, researchers, I mean, there's thousands of researchers and thousands of small biotech companies that have tried to make gene therapies for every disease under the sun.
1:08:06 Speaker 03 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.
1:08:13 Sean Carroll? Right.
1:08:14 Speaker 03 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, you know, and humans are really good at when there's, you know, what is the need is the mother of necessity, or whatever that saying is, you know?
1:08:44 Sean Carroll? Necessity is mother of invention.
1:08:45 Speaker 03 Mother of invention, that's right. Necessity is the mother of invention. And that's where we're at, where, you know, if we have a technology that we know could reach the brain, or it could make significant changes to patients with ultra-arrhenic disorders of the central nervous system, we're going to figure it out. We will, in time.
1:09:02 Sean Carroll? And you, you went down a list of diseases, cystic fibrosis, Alzheimer's, dementia. These are not unimportant diseases to try to tackle. So, so you're, I'm going to, I mean, I presumably know the answer to this one, but just to be sure, you're, these are realistic chances that we have in a reasonable time scale of making important progress.
1:09:26 Speaker 03 Absolutely. Absolutely. You know, the, the technology, and I would have to say, the technology that keeps us back right now is really the delivery component.
1:09:35 Sean Carroll? Right.
1:09:36 Speaker 03 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 like, a couple hundred bucks now. You know, the Human Genome Project cost over a billion dollars. We can sequence a human's DNA in a day now for a couple hundred dollars. I mean, that's incredible technology in 30 years. So we can do that. And so we and we can identify the genetic basis of most diseases. And now we have these CRISPR mRNA base editors. We can make changes. Those are improving.
1:10:19 Speaker 03 You know, those are going to continue to iterate and get much, much better. But delivery is going to be the challenge and every organ has a unique challenge. Yeah, cystic fibrosis is a great example of that. It's the lung. Your lung is coated with mucus.
1:10:35 Sean Carroll? Yeah.
1:10:36 Speaker 03 And because that's how it functions. That's what, you know, it needs to have that thick mucosal layer. Well, that and that mucosal layer, partially what it does is help trap foreign things. So you breathe in like a virus, 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 doesn't, it can't get through that thick mucosa. So there's a challenge there.
1:11:01 Sean Carroll? You could inhale it, but the lungs would prevent it from being absorbed.
1:11:04 Speaker 03 Yeah, it would just stick to the
1:11:05 Sean Carroll? Yeah.
1:11:05 Speaker 03 The mucus and never really penetrate in. But yeah, but well, 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, you know, a tool, a tool book, a toolbox of all these delivery mechanisms to get CRISPR base editors to different cell types into different tissues. And it will be the standard of care for genetic medicine.
1:11:41 Sean Carroll? And you mentioned cancers also. Do they count as genetic diseases?
1:11:45 Speaker 03 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, not the CRISPR base editor, but the mRNA tech 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 you could, when cancer cells develop, cancer basically is like an, it's your cell that goes crazy.
1:12:25 Sean Carroll? Yeah.
1:12:25 Speaker 03 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
1:13:07 Speaker 03 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 which 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, you know, pancreatic cancer is scary, right?
1:13:38 Sean Carroll? Yeah.
1:13:39 Speaker 03 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.
1:13:57 Sean Carroll? Wow.
1:13:58 Speaker 03 And so it's 50%, that's, that's not 100%, but
1:14:02 Sean Carroll? Still.
1:14:02 Speaker 03 much better than 95% chance of death within a year.
1:14:06 Sean Carroll? Yeah.
1:14:06 Speaker 03 And, you know, 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, we're making headways there.
1:14:27 Sean Carroll? We actually had James Allison on the podcast.
1:14:30 Speaker 03 Did you?
1:14:30 Sean Carroll? You just reminded me. And so, yeah, the, the. Immunotherapy aspect was there, but the mRNA aspect is new to me. So that's a good combination.
1:14:39 Speaker 03 Well, his, and again, it's one of those things where, you know, 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.
1:14:55 Sean Carroll? 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 course, for the force of bad rather than good?
1:15:19 Speaker 03 Well, everything can be used for the force of bad, I suppose. But I would actually say that the, the force of good is, is more, more prevalent than bad. Cause the one thing I would say is what, 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, you know, people that want to demonize it because it's a way to get, you know, people scared and blah, blah, blah.
1:15:55 Speaker 03 You know, there was a study that came out a few months ago that was using artificial intelligence to design viruses.
1:16:05 Speaker 03 And these were viruses that would infect bacteria. So they're not human pathogens. But using, 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.
1:16:30 Sean Carroll? What does better mean?
1:16:31 Speaker 03 Meaning they were able to kill the bacteria more.
1:16:33 Sean Carroll? Okay, good. That's what I thought of that. Right.
1:16:35 Speaker 03 More readily, I suppose. So these are, you know, 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, you know, 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.
1:17:19 Speaker 03 It's the only thing we could ever leverage in and deploy to our troops or to a population at a speed that would be a natural deterrent to those, to that, to that threat. And so that is something that I think, you know, bothers me because it, 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, the, the other party to develop a technology because you've got the countermeasure that can, that can match it with equal speed and, and performance. So we've got to protect this technology rather than throw it away.
1:18:03 Speaker 03 And it is an American invention and it should be.
1:18:05 Sean Carroll? But it sounds like there will be an mRNA arms race.
1:18:08 Speaker 03 There already is. I mean, China is developing about, about 46% of all mRNA-based vaccines are now being developed in China, not in the United States.
1:18:19 Sean Carroll? But it's been 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.
1:18:31 Speaker 03 That's right.
1:18:33 Sean Carroll? So, you know, there could be, I guess, bioweapons and also bio protections, you know, improving in their efficacy simultaneously.
1:18:42 Speaker 03 And this is not, you know, this is not far-fetched science fiction because, you know, it used to be, there was a time back in, you know, the, the Middle Ages where they used to launch infected people over the walls of the castle. It's like if you, they would have anthrax, they would actually launch their bodies into the castle in order to spread anthrax within the castle walls. I mean, this is something we know how to do. And the other side of that is the, the incapacitation of troops with pathogens is much more effective than kinetic weapons. And we saw this in, during COVID with USS Cole. USS Cole, coronavirus
1:19:24 Speaker 03 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 USS, an entire destroyer.
1:19:40 Sean Carroll? And you, 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?
1:20:04 Speaker 03 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... Then this very concerted miss and disinformation campaign, which is based on falsehoods and not science.
1:20:44 Sean Carroll? And also, I presume there are regulatory issues, right? Like, we don't want to have to go through a month-long process every time a baby has a rare disease.
1:20:54 Speaker 03 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, you know, when you have a drug like a GLP-1 inhibitor that costs hundreds of million 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 cross, that cost among all those patients. That's not true when you deal with ultra rare genetic disorders. It still costs a hundred million dollars to develop it. But now you have five patients worldwide. So how do you, the economic model just doesn't work.
1:21:34 Speaker 03 So the FDA is really designed on that blockbuster drug mentality. You know, 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 could not, would be, you know, 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. And the same thing's true with a bespoke gene therapy for a baby like KJ.
1:22:19 Speaker 03 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 can't, 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.
1:22:48 Sean Carroll? So just for my entirely selfish reasons, I hope you get that allergy thing straightened out right away and then move on to, you know, cancer and Alzheimer's disease. These are all very, very good things to be solving.
1:22:59 Speaker 03 Absolutely. Hopefully. And it's not unrealistic that that might happen the next five years.
1:23:04 Sean Carroll? Yeah, I like to think maybe I was born at the right time in some ways. So that this is incredibly useful, incredibly full of things to think about. So Jeff Coller, thanks very much for being on the Mindscape Podcast.
1:23:15 Speaker 03 Yeah, thank you. Thank you for your time.
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