Future Risks and Regulatory Challenges

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Get ten percent off your first eligible purchase Hurry to wayayfair. com or download the app now Hello everyone and welcome to the Mindscape podcast. I'm your host, Sean Carll. Many of you are old enough to remember the COVID nineteen pandemic. slightly joking there, it wasn't that long ago, and of course COVID nineteen is still with us. It hasn't gone away But Things are very different now than they were in the year twenty twenty. In twenty twenty, there were a lot of lockdowns, a lot of prophylactic measures to try to make sure infection rates stayed low 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 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 there' 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 then 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 twenty twenty. 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 lararger 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 CISPR technologies we 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 Coaller, 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? thingsings like this. How do MRNA techniques change how we to Therapies of various sorts, how do we get them into the bodies? whereere 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 becausecause for exactly the same reasons that we could make design and produce the MRNA vaccines quickly for COVID nineteen 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 decades to produce and many, many millions of dollars to develop You wouldn't do that for a disease that only twelve 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 If nothing else, this podcast episode with Jeff should convince you that we should get our axing 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. Jeff Coller, welcome to Mindescape podcast. Great, thank you for the invitation Sewn. So I think that this is one of those where the audience has probably heard of well, they've certainly heard of RNA. 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 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 and every cell in your body, you have DNA and DNA is basically the blueprint of life. It's basically like a giant recipe book tells your body how to be you And within that recipe book are hundredundreds 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 MRNA's Tmit 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 Aribosome. That is the cook ically makes the individual recipe p makes the u the dish that's going to be made that 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 so sorry, just very quickly. the DNA is very long, but the MSRA MRNA are little short things, one per gene, you said The one per gene, that's exactly right. So we have about twenty five thousand Approximately twenty five thousand genes in the human body, so there will be twenty five thousand.'s a little bit more than that, but about twenty five thousand. MRNA's 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 genes to copy at any one moment. know, does it get like a summons from somewhere else in the cell Yeah, I mean, there's lots of inputs that decide when you're going to turn a gene on or off. know 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. and vice versa. And so that's just a rough example of this. But so that means you would turn on genes into 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. 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 jean basically making an MRNA, You're making a copy of that gene as this messenger that then gets read by the cook And so you turn on the gene and the MRNA is assembled from things floating around Yeah, esssentially, 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. Tell us what the differences are. 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. DNA is D oxy ribonucleic acid and RNA is riboonucleic acid. It doesn't have D oxy 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 RNA, it doesn't have the T Okay so in RNes A U C and G. And so those are really the major differences. But there's still four of them. they still pair up with the base pairs in the pretty much the exact nucleotypes that DNA That'. And again, I did a little bit 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, um ribosone and the proteins for the DNA Yeah. so it's often believed by most scientists now, at least m the 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 talk about, that oxygen that's present within R andA, that's the key that has led scientists to think that be capable of being the first precursor to life because it gives it the ability to do unique chemistry DNA cannot do And scientists like Tom Cck and Sydney Ellman back in the eighties were able to show that RNA in fact do enzymatic catalysis. it had the ability to stimulate a chemical reaction where DNA cannot do that. DNA cannot do that And that's a that's a necessity of life. You have to be able to catalyze reactions and RNA can do that 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 That's right. So DNA tends to be more stable again for the same reason. It doesn't have that little oxygen tends to last a lot longer Sorry, I thought it had an extra oxygen DNA has less oxygen, less unoxen Doxy. Not dioxy, yes. No, no, Doxy. So it has one less oxygen Okay, I see. good. Yeah. So so the reason the story would be that RNA is sort of more flexible and can do more things, but it's a little bit less permanent. so it might be good first try, but using both in concert is a more sophisticated system Yeah. and the other thing that part of this in terms of like the RNA world hypothesis, which is what you're talking about, 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 how you find it as a double helix, where RNA can get into all sorts of toorted 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. the four. a DNA world And then we have various forms of RNA. That's cor M and T and so forth. Are these literally different chemistries or are they just doing different purposes 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 ribosomome. 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. But the part that actually reads the genetic code is in fact RNA. so it's called the ribosomal RNA and it forms this really large very complicated three dimensional structure that's consistent through all of life And u, you know, is is these is the machine that reads the genetic code And then there are bunch a bunch of other RNA's around the cell that do different different work. But MRNA in and of itself is a direct copy of a gene within the DNA Hey everyone, it's Cal Penn. I'm the host of EarsSaid. Audible and IHart Audiobobook Cub. This week on the podcast, I am sitting down with Ray Porter, the narrator of Andy Weir's audiobobook project Hail Mary, Massive sci fi adventure about survival and science. And what happens when you wake up alone very far from Earth And I really had to make a decision because I caught myself getting that frog in my throat and starting to get teary as I'm narrating some of these sections. and it's like, okay, yo, yeo, yo is this indulgent? And I really thought about it. I was like, No, at this point, it would kind of be betraying the trust the author and the listener have and telling this story if I don't go through it. There's places in this book deeply emotionally affected me And I left it on the mic. That's great, 'cause it served the story. People will say like, oh my Godd, I cried at the end. It's like, yeah, dude me too. Listen to EarsSay, the Audible and I heart audiobook Cub O the Ir Heart Radio app or wherever you get your podcasts Beach Bum's June Jackpot is dealing out winners all week long. sccore seven dollarars Sn or sppray tans, seven dollars Red lightight or sauna, seven dollar lotions and more. Feeling lucky? G buy one, get one seventy percent off packages. No gamble, just glow. The odds are in your favor, and these seven dollarars deals are your ticket to a golden summer. Beachbum's June Jackpot sale is live through june seventh. Don't miss it at Beachbum Tanning. Your glow up starts now. Head to beachbum dot com and stay tan and tasty all summer long You know, every time I talk to molecular biologists or about these things. like even though I know better, I'm slightly tempted by intelligent design because there's so much going on here that is so delicate I mean, its it's fascinating to see it all because the the it all works in such, you know, beautiful harmony with itself. and you can see that For example, what you realize when you when you dive deeper into 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 rribosomes that are within the human body are not much different from hribosomes you will find in fungus you'll find in bacteria and some of the most primordial life forms on Eth. And so can be and in fact This was study of variosomes was one of the reasons that led a guy named Carl Rosa suppose that RNA was in fact the precursor to all life So it's as if as though there was a primordial life form that evolved eventually evolved into a ribosome and then that And it seems like, you know I don't know. what was discovered first? I know the DNA was discovered before we understood its role. When did we get to an understanding of the RNA? aspect of the story U You know, a lot of this happened in the early nineteen sixties when investigators were looking at, I mean, you had famously you had the double helix, which was in the fifties with you know Watson and Crick discovering that DNA was Um N 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 nineteen fifties, we knew protein was a very important part of biology And and a guy named Sidney Brenner was one of the first people to propose that there must be this theoretical intermediary between them which then later not about nineteen sixty four. so was shown to be messenger RNA And so the discovery of Messenger RNA dates back forty fifty years ago. Okay, probably more than that seventy years ago to the sixties and And as molecular biology has developed in the last, know seventy years, we've just learned more and more about the complexity of RNA within the cell and like I said, there's there's dozens of different types I know that there's DNA in our nucleus of the cells, but there's also mitochondrial DNA. Are there separate RNAs and ribosomes for all the different kinds of DNA floating around Yes, of in fact, your're uh, your cell, your your nucleus, which contains your nuclear DNA There's a ribosome that is used in the cytoplasm to code those MRNA's, the MRN's 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 and best specifically made to decode the MRNAs from your mitochondria. material looking not human looking, I should say 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 this billions of years of evolutionary history 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 you com within the cell. It just gets built on top of each other and to the point where you just can't reconstruct it to make it something much more elegant and simplistic. 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 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 A lot of manufacturing facilities for all the proams. withithin one cell. So half a million ribosomes within one cell 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 all I know about it is that there's like three little nucleotides making up part of the genetic code Yeah. so the this was really going back to the fifties and the sixties, Um We knew that DNA contained the genetic information and Dciphering that genetic information was important. 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' are DNA does is it makes MRNA and that MRNA makes a protein There are twenty building blocks to a protein. And theseese are called amino acids I take you four letters that have to encode twenty words And then that's really the simplicity of the genetic code. Four letters, twenty works. And so what that so twenty meanings, I should say, not words. there are twenty meanings And so what evolution has done is if you do the mathematics of this It's sixty four words you need sixty four words to use and if you're going to use four letters, you need sixty four words to have twenty meetings. That's the only way you can do it mathematically. I sorry everybody just sit that down with a piece of paper, you'll figure it out. it's actually Just because if you only had two nucleotides itd be four times four sixteen, you can't cover all the twenty You can't cover. And then then what happens by having three letters per word. You get sixty four, which is too many. Yeah. but there's nowhere in between And say you have a three letter, you have four letters They get arranged in these three, you know, three at a time. And then that leads to twenty amino acid, so it's sixty four words, basically. Does that make sense? It absolutely makes sense. And it raises, I mean, I presume I know the answer to this one, but ask it anyway One way of doing it would be that there's sixty four possibilities But in real world DNA, you only get twenty actual examples But that's not what actually happens. In the real world, you get all sixty four, but they're redundant. L some the some of the sixty four patterns give you the same amino acid at the end of the day That's exactly right. So we call that the degeneracy of the genetic code. 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 argining. Okay. Wow. And so that that just of these sixty four words, there's some repetition And that's the way Mother nature did it Is there some rhyme or reason about it? Do like are some amino acids special and I get more words that talk to them? 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 nucleotides ATG And that word means methione And so every protein always starts with methionine. and it has to be that way because then The riosome knows that the first time it sees the word methione, It's the start of a sentence, right 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 Rhbism 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. 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 in genetic code. My impression is that even though only twenty amino acids are used in biology, there are more amino acids Chemically, is that right Yeah, there are, but for the most part, life uses those twenty But we had room to use like sixty some We had room to use well we had room to use sixty one. We still needed those three periods. Punctuation Punctuation marks, but sixty one was theoretically possible, but we don't use it arere there any biologists who get grants to study how life could be different if we chose to use more of amino acids U There are people that work on unique you know, chemistries U with bothoth the adapter molecules that read the genetic code These are Um 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 U There are people that look at that sort of synthetic biologist But there are, you know, there are amino acids out there that are not used routinely in biology Um you know, could you stitch them into a protein and what consequence would that have? Who knows? Yeah. I guess I'm just wondering is are there like Reasons of chemical stability or affinity that we have these twenty that are useful or is that one of these frozen accidents I think it has more just to do with their natural abundance environments That makes perfect sense. But there's a lot of that we don't understand, right? Why these twenty, you know, why are they here on eararth? And why are they abundant on Earth? 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 nebulai 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 property to be using them enrich. 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 RNA and DNA that is hard. It's getting it all organized. the actual building blocks of all this 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. U stitching it all together in a way that gives life, meaning where life is really chemical reaction that perpetuates itself That's what's, you know, That's something we don't understand how that happened yet. R I mean, throwing a bunch of transistors in a bag is not going to make a computer. That's right, That's right. That's exactly right And are there any like 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 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 You can encode the same amino acid with multiple codons for 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 dictate how fast you read the word And so a real simple way to think about this is The hibbosm is the cook that's reading the message You know, he is reading this recipe and it has to interpret sixixty four 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 I could have 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 ribosm. It's randomly sampling these transfer RNA's in order to decode the genetic code And so it hesitates or it can go fast over some of these words and that speed 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 MRNA's 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 Okay. And so if it's read really well, if it's something that you can read very easily that message around a lot longer then if it's a message that's really hard to read, and you're just having trouble reading it then you destroy it So the destruction process is active or does it just Fall apart It's active. Okay. veryy active Okay, so yeah, so we read it and then we burn the message just like in mid.'s impossible. Thatlysly right. Destroy upon reading 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 a little bit about the crowd pleaser, which is the MRNA vaccines. Sure yeah. So this is Very old history with MRNA being used in medicine despite what probably popular trust has as an idea. I mean, the fact that MRNA exists, we know that this is the No, 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 yourself What to make at any given time. And when we discovered MRNAs in the sixties, 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 this is a natural system. MA 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 We can stick into a cell and then have the cell make that protein in anything anything we want And that's were were, you know, really electrified scientists in the late nineties and early two thousands to start thinking, could we design MRNAs to be used in medicine you know, and there's lots of places where this could be very powerful. One 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 always usually are usually a protein Protein that is a 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. 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 MRNA's and 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 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 develop it very quickly where The classic way of making vaccines takes ten years for more Yeah, so it's just that speed of being able to manufacture these is what has really electrified the community 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? Oh, I mean, it's infinite. There's an infinite number of possible protein signatures out there And 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 You know, you're picking up pollen and there are tree or plant proteins that you're breathing in and it's irritating your immune system Hey everyone, It's K Cal Penn. I'm the host of EarsSaay. Audible and IHart Audiobook Cub. This week on the podcast. I am sitting down with Ray Porter, the narrator of Andy Weir's audiobook project Hail Mary Massive sci fi adventure about survival and science. and what happens when you wake up alone very far from Eth? I really had to make the decision because I caught myself getting that frog in my throat and starting to get teary as I'm narrating some of these sections and it's like, okay, yo, yeo, yo is this indulgent? And I really thought about it and I was like, No, at this point it would kind of be betraying trust the author and the listener have and telling this story if I don't goo through it. There's places in this book that deeply emotionally affected me And I left it on the mic. That's great because it served the story People will say like, Oh my God, I cried at the end. It's like, yeah dude me too. Listen to EarsSay, the Audible and I heart audioobook Cub the Ir Heart Radio app or wherever you get your podcasts Beachbum's June Jackpot is dealing out winners all week long. score seven dollars Sun or sppray tans, seven dollarars Red light or sauna, seven dollars lotions, and more. Feeling lucky? G buy one, get one seventy percent off packages. No gamble, just glow. The odds are in your favor, and these seven dollar deals are your ticket to a golden summer. Beachbum's June Jackpot sale is live through june seventh. Don't miss it at Beachbum Tanning. Your glow up starts now. Head to beachbum dot com and stay tan and tasty all summer long Is there any chance that MRNA technologies are going to cure my allergies? 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 Yeah. And one of the places where people are looking into this is in immune reactions So or auto immunity is another auto immunity is a big issue where you you have the ability to say 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 u if you can learn to Um down regulate the immune system through MRNA technology, which people are investigating then it's one way to pretend you know from autoimmunity or overstimulation the immune system as you get with allergy reactions. All right, I'm going to support this then. I was on I was wavering. I was on I was on the fence, but now now you've sold me Um we've heard probably of MRNA vaccines in the context of COVID, right U Were they around before then Yeahes, so before COVID hit in twenty nineteen There were probably about, I think it was over at least a hundred FDA trials currently inhuman. for different MRNA technologies. Most of these were around cancer and vaccination. So at the time when COVID should Moderna, for example, was testing a vaccine for influenza. Okay 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 Well, everyone in twenty nineteen This was a new technology to them. It wasn't to the scientists. We had over twenty years of the inhuman testing that had already been conducted with MRNA technologies And the word inhuman there does not mean nonhan. It means inside human beings. Inside a human being. That's exactly right. Yeah, okay And just to like refresh us, you've already said a little bit about this or alluded to it, 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 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' recognizing that and going, this protein doesn't belong, so I'm going to mount an immune reaction And and then the 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 that's what gives you the immune reaction that you carried forward for you know months hope full years And what exactly would the difference be between an MRNA vaccine and a non MRNA vaccine Well, I mean, the main difference is what they are, which is most vaccines or proteins Okay, where the MRNA is the MRNA that then makes the protein So yeah, from just a product standpoint,s that's the major difference is you have . 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 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 twenty twenty six. 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 even if we weren't doing it in the body The second thing is costs. because to make a protein is very costly. So 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 somethingomething like a chicken egg with a virus or or of DNA or an MRNA to make that protein and then grow it up. you'd to have millions of eggs to do this and then purify that protein from those eggs And that's a costly product. It sounds rather slow. Yeah. Yeah, it's slow. and it takes, you know, twenty, you know, it could take fifteen years to develop whereere MRNA you can develop in just a matter of weeks in terms of manufacturing And 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 ono the public So rapid response at low cost and high efficacy and safety Well, let's think about that Design on the computer. I use the word design there. Yeah Can I just download an app and design myself some vaccines or like what is going on It wouldn't be that hard. to be honest, of the way I mean, I have a lot of inside baseball in this one because the u when the COVID hit in twenty twenty nineteen and December of twenty nineteen the Chinese researchers had sequenced and identified You know, SRS COVD too as the virus that was responsible for COVID nineteen. They sequenced its genome. and then release 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 at the COVID vaccine. A 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 Are. That's not that complicated But what What's the name of your grad student? Your former gradent is Vlad. Hs name is Vlad Presny Okay, cool. Yeah, he chose a wise place to go He couldn't have known how important it would have been. fact in fact when he got the information because we were all still not really completelyare what was going to hit us.. He didn't really know the implications of what he had just done. Yeah And uh So it seems to me, 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? 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 Well, in this case, what was done for the COVID vaccines is they took a particular protein from SARS COVI twoI, 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 COVD two 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? it 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 COVIDI with a few little changes. Those S proteins, those like The little protuberances we see it on the cartoons of all the COVID. That's right. S protein is short for spike Spike proteins. Yeah. the spike protein. They look very whichich makes which makes, you know, reason why it's called a coronavirus because it looks like a crown 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 U is it more or less Straightforward then to say, here's a protein. here is the sequence of RNA that would code for it Yeah, that's pretty much what we do. So if you identify new you know, everybody's talking now about, you know, as heptavirus that people are worried about. it wouldn't be that hard to develop a vaccine, putative vaccine for heEptav virus. You just If you know the genetic sequence of that virus, you identify a protein that Um 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 All right, and then you don't need chicken eggs. I mean, how do you actually make all of this vaccine from the MRNA 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. And from that DNA template, you can use couple of enzymes and amplify up MRNA in like huge volumes Okay, so in fact, like if you think about this from a manufacturing standpoint traditional vaccines that are based on proteins You need what are called bioreactors. And those bioreact you know, this is basically a vAT You know, think of like a giant pot that you're cooking it in bore reactor for a traditional vaccine be on the order of like the size of a small I could seill like half of it. aircraft carrier aircraft hanger. You know, you would put like thousands and thousands of leaders of these vats into a room that you would make your vaccine withith an MRNA your bioreactor can be about as big as your body. for the entire population on Earth Okay, it seems like a cost saving measure. 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 inaugulate the entire planet But then we got to get it into the body somehow. likeike I said that seems to be a tricky thing as far as I can tell Yeah, so your body doesn't like to take up strange, you know, nucleic acids as it shouldn't, right? Because 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. Yeah E every single bite of organic food, whether it's a steak, or a salad. Bean, whatever. it's got bean RNA in it. It's got, you know, cow DNA in it and cow MRNAs in it. So you can't just readily take those things up because They would work just like an MRN in ear bud 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, yourself are made out of lipids And we make these littleow fat bubbles out of lipids that we keep the M R and A 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 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. li Y cells are lipids. We put the MNA in a lipid. And so when they touch each other just fuses. and joins together and that MRNA will enter into the cell Does it need to go all the way to the nucleus or do we not care 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 is read by the cook, the ribosome in the cytoplasm Is that the same ribosome that translates the mitochondrial DNA? No. No, the mitochondria ribosomes within the mitochondria. Okay, All right. there's just like floating around, doing all this work. Okay. Well, you sell your sell when it really comes down to it is just a big bag of ribazomes. All right 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 them RNA in, right? And then you're getting the body to do your work for you That's exactly right all through these natural processes Are there Okay, so that's what we do as a matter of empirical fact, are there O ways to get the MRNA in there? 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 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 they lack what we call tropism. and what I mean by tropism is that 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 commommunicate 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 deliver And that's because everything goes to the liver in your body. It doesn't matter what it is. your liver is detoxifying Oregon And so if you inject anything into your body, even it doesn't matter whether it's Tylenar or aspirin, or whatever, everything goes to your liver So Right now, we can target MRNAs to these immune cells in your basically 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 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 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 Uh is that Are all the work being done by the MRNA in my arm or does the MRNA spread through my body first MRA 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 the foreign protein And then the immune system's learning from that and that's spreading The MRNAs themselves are very unstable. mean they have half lives. that's on the order of hs So, you, even by the time you drive home from the pharmacist, most of it's gone So it doesn't stick around very long Hey everyone, it's Cal Penn. I'm the host of EarsSaay. Audible and IHart Audioobook Club. This week on the podcast. I'm sitting down with Ray Porter, the narrator of Andy Weir's audiobook project Hail Mary, Massive sci fi adventure about survival and science. And what happens when you wake up alone very far from Earth? I really had to make the decision because I caught myself getting that frog in my throat and starting to get teary as I'm narrating some of these sections and it's like, okay, yo, yeo, yo is this indulgent? And I really thought about it. I was like, No, at this point, it would kind of be betraying the trust, the author and the listener have and telling this story if I don't go through it. There's places in this book deeply emotionally affected me And I left it on the mic. That's great. ' it served the story eople will say like, Ohh my god, I cried at the end. It's like, yeah, dude me too. Listen to EarsSay, the Audible and I heart audio book club On the Arhartt Radio apppp or wherever you're getting your podcasts Beachbum's June Jackpot is dealing out winners all week long. sccore seven dollarars Sn or sppray tans, seven dollars Red lightight or sauna, seven dollars lotions, and more. Feeling lucky? G buy one, get one seventy percent off packages. No gamble, just glow. The odds are in your favor, and these seven dollar deals are your ticket to a golden summer. Beachbum's June Jackpot sale is live through june seventh. Don't miss it at Beachbum Tanning. Your glow up starts now. Head to beachbum dot com and stay tan and tasty all summer long And And like you said, we're trying to learn ways to target other organs. I mean brain I don't want to necessarily get a shot into my brain, but maybe is that the kind of thing being contemplated or there clever ways the MRNA so that it will eventually get to the brain 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 of material between the bloodstream and the brain 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 Okay so that you can go right through the brain barrier And again, you say You said design before and we talked about the computer program and whatever H' been these wonderful advances in gene editing and CISPRcasts and stuff like that? A they useful for this project? Yeah, so that's what, u 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 CrISPper is a It's basically a Uh system that was discovered from bacteria So bacteria have this primordial 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 is was harnessed by researchers u to basically target specific areas within your DNA and then make And that's what CRISPR does. can 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. if you want to spepecifically change or work on one tiny, tiny little region of that DNA You need a GPS locator. Let's find it And that's what CISPR 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 Lu had how taken CIisSper and cooked it up with another set of proteins that could make changes to the DNA All right, so you can now with CRISPR, you can h, you can localize it to a very specific region. 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. And that's what's ob base editing So CISperR fused with base editing is this sort of surgical way 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 CISPper to kind of you know, wander around the DNA that it might make a change somewhere else. That could be. You don't want that machine always present in your body And that's where this has been now married to MRNA technology. So take you take that crISPper Base editor protein and make it as an MRA And so the beauty, so basically think about it this way CrisSper 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. Yeah. So you introduce it do what it needs to do to 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 is now gone back to a normal P and D and that So it's just like a surgical instrument And what kind of therapeutic uses would this be? This is not a vaccine 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 need to be changed for something like sickle cell anemia So you do the change ex vivo. So you do this the change outside of the body And then you put those corrected cells back in the body And that has worked by In that case, it always had to be done outside of a body By combining the three technologies, the base edit than 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, okay, which is this young baby, this baby that was born last year um or twenty twenty four in in Pennsylvania named KJ Maldoon So KJ was born with an ultra rare genetic condition. that affects about one in one point three million children born And it's a deficiency in an enzyme in his liver. And so that enzyme is a protein called CPS one And what that protein has to do is help metabolize protins And if you don't have it Build up Toxic ammonia in your body and it causes severe neurological damage ammonia is poisonous to us and When KJ Maldon was born. with, um 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 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, really significant Sgery Yeah And and it does build on the tragedy of someone else. and the gu you can't always guarantee that a liver is going to be compatible with person that you're putting in for the same reason, the immune system, right So what researchers at theren'sospal the Children's Hospital of Philadelphia decided to do. was to create this Never before and 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 to normal. and They, you know, moved heaven and earth to do this. in like an unprecedented set of exercises we're able to secure FD eight apppproval 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 you know, suribing He's no longer in danger. He's metabolizing proteins appropriately. He's walking, he's talking U, he still has to be monitored. You know, he's not cured. We can't say that he's cured Hm doesn't need a liver transplant And The incredible thing about this is that 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 Maybe he'll need another round of correction to build up more normal selves. And we can do it with that approach So that has everybody super excited because ultra rare genetic disorder Ultraarogenight 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 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 Nmot sure I have a question here, but I just want to say Wow Yeah Wow. They went in and fixed someone's DNA. 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 any kind of therapeutic I mean, we There are over seven thousand genetic diseases that humans suffer from and we often call these you rare genetic disorders. But one in thirteen peopleople suffer from some form of genetic disease And so it's not that rare. They're just rare as an individual indication. meaning some of them will have cystic fibrosis, some might have two changeed muscular dystrophy. someome may have, you know Alzheimer's or uh, you know, dementia or um or sickle cell 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. It does strike me that, you know, my body has a lot of cells in it. is this There be literally trying to fix all or most of the DNA in my cells 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 them a little bit Yeah. Th they gave them a little bit more weighted, gave them 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 Um with other diseases No. withith gene therapy, sometimes you may only need maybe ten per, fifteen percent improvement over baseline that they're already at to get some sort of benefit And you know, and some it's it's It would be a miss 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 know correction we would need for any particular indication. But in some cases, it may only be you know, ten percent, fifteen percent above what they already have to give a meaningful change to their lives 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 Squence it, figure out how to fix it, and you'll be back in your feet the week later You know, if that there's a whole group of You know, 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. If we could make the correction in our DNA, that's the solution. 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 Ne is the mother of necessity or whatever that saying is, you know, neecessity is mother of invention. 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 could make significant changes to patients with ulterra aogenetic disorders of the central nervous system We're going to figure it out. We will in time So And you went down a list of diseases, cystric fibrosis, Alzheimer's, dementia, These are not unimportant diseases to try people. So going I mean, I presume I know the answer to this one, but just to be sure Uh, you're These are realistic chances that we have in a reasonable timcale of making important progress Absolutely Absolutely You know, the technology And I would have to say the technology that keeps us back right now is really the delivery component.ight How do you get it to the right cell types Um, 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 couple hundred bucks You know, the human genome project cost over a billion dollars We can sequence a human's DNA Day now. for a couple hundred dollars. I mean, that's incredible technology in thirty years We can do that And u So and we can identify the genetic basis of most diseases And now we have these crISper MRNA based editors. We can make changes. Those are improving You know, those are going to continue to iterate and get much and much better But delivery is going to be the challenge and every organ has a unique challenge Y cystic fibrosis is a great example of that It's the lung Your lung is coated with mucus And because that's how it functions. That's what it needs to have that thick mucosal layer Well, and that mucuusalayia partially. what it does is help trap foreign things. So you breathe in like a virus, or you breathe in the bacteria gets trapped there so it doesn't get into your body Well, the same would be true of a a gene therapy. It doesn't it can't get through that thick mucosa So there' a challenge there. but you could inale it, but the lungs would prevent it from being absorbed. Yeah It would just stick to the mucus and never really penetrate in. But ye, but there are people that in fact are working on that to try and get it past that mucosal weare. 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 twenty years, maybe less. will' have you know, a Tools, a toolbook, a toolbox of all these delivery mechanisms to get CISPR based seditors to different cell types into different tissues. and it will be the standard of care for genetic medicine And you mentioned cancers also. do they count as genetic diseases? Yeah, I mean, they in different ways. So cancer is Oh complex disorder where people are really getting excited by the same not the CRISPper 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 you could When cancer cells develop Cancer basically is like it's your cell that goes crazy And when it goes crazy, it tends to rearrange your genome And when it does that It's making unique protins 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, body can work for it attack your cancer cells and then lead to a remission of that cancer and what investigators are doing with the MRNA technology. 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 Tumor. And a great example that came out of sllam Cuttering in twenty twenty two was this paper in the magazine Nature and that would showed in a small clinical trial They developed personalized cancer. therapy, what's called a new antigen therapy using an MRNA patients with pancreatic cancer. So this is, you know, pancreatic cancer is scary, right? yeah, eighty five percent mortality within a year and They injected these personalized ne anigen therapies into these patients and fifty percent of them responded and are alive today six years later U Well, the study was started in twenty twenty, so it's been like six years. so they're pretty much cancer free And so it's fifty percent. that's not one hundred percent But still much better than ninety five percent chance of death within a year And 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 We actually had James Tallson on the podcast. just reminded me. And so yeah, the Immunotherapy aspect was there, but the MRNA aspect is new to me. So that's a good combination. Well, 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 noobel prize winning idea. The MR andA is a Nobel prize winning idea. You put peanut butter and chocolate together and it makes a great candy bar 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 Well, everything could be used for the force of bad, I suppose But I would actually say that the force of good is more more prevalent than bad because the one thing I would say is would 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 U demonized by Um, you know people that want to demonize it because it's a way to get scared and yable. Um You know, 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. Okay. usings 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 sixteen of those performed better. than the viruses that had been seen. what does better mean Meaning they were able to kill the bacteria more That's what I thought more readily, I suppose So these are You know, these are viruses that affect bacteria. So okay, well right but And these researchers werere American researchers, so they're bound by ethics regulations and couldn't program their AI algorithms with human viruses 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 humans 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 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 bothers me because it we can't throw away a technology that really is We call this in national defense, this is called deterrence by denial. And so you don't allow the u