What's the Deal with mRNA Vaccines?

Perry: [00:00:00] Emily, one of the things that is really interesting about the mRNA vaccines, at least, is that people have really different responses to them. So I want to know if you're one of the lucky ones who gets an mRNA vaccine for Covid or whatever, and like goes about their day, or if you're the type like me whose body seems to think they are under assault from some kind of alien chemical.

Emily: [00:00:27] Yeah. I was in bed for a day after my early Covid vaccines, and I am not a person who spends time in bed. So I had a pretty extreme reaction, I think like, yeah, but my husband had like nothing.

Perry: [00:00:43] Yeah, yeah. I'm so jealous. You know, I don't track things very much. Like I have a fitness watch or whatever that I never look at. But I definitely noticed my sleep score went from like, you know, 90 to 20 or something. Like it was insane. [00:01:00] Um, the night after I got one of these shots.

Emily: [00:01:03] So the other person who has no I know who had no reaction to this is my father. My father has gotten a Covid booster every year. He must have gotten 50 Covid vaccines by now, and he has never had any reaction to them. And I wonder if, like, people who have a better immune system have more of a reaction. That's how I'm explaining the difference between me and my husband.

Perry: [00:01:22] Yeah.

Emily: [00:01:23] Validate me.

Perry: [00:01:24] Please. I had thought the same thing because I wanted to be like, oh, I'm, I'm so sweaty. I this must, this must be good. And I actually did dig into the data a little bit. And honestly, like, there's not that much correlation between your symptoms post-vaccine and your antibody levels or anything like that.

Emily: [00:01:41] So okay, well, that's too.

Perry: [00:01:44] Bad, but that is just scratching the surface of this amazing molecule called RNA, which I'm so excited to talk to you about today.

Emily: [00:01:53] I can't wait. I'm Emily Oster, I'm an economist and a data expert. [00:02:00]

Perry: [00:02:00] And I'm Perry Wilson. I'm a medical doctor.

Emily: [00:02:02] It's Thursday, July 2nd, 2026. And this is Wellness, Actually.

Perry: [00:02:08] Because you're getting a staggering amount of health and wellness information nowadays from every source imaginable. And some of it is awesome.

Emily: [00:02:16] And some of it is, well, actually bullshit. Fortunately, we're both people who know how to read studies, how to parse the data, and can tell you what's worth thinking about and what you can safely ignore.

Perry: [00:02:29] But before we dig in a note that this podcast is for educational purposes and should not be construed as medical advice. We don't know your unique situation, so talk to your doctor for personal health decisions.

Emily: [00:02:40] This week we're asking what's the deal with RNA? Perry and I will give the official smash or pass, and then we'll get to your question of the week. But first let's do the health news roundup after the break. And [00:03:00] now for the health news of the week. First up, Perry, the FDA has dropped their enforcement action against whoop for its blood pressure feature. Uh, I have a whoop. I have never used it to record my blood pressure, but I'm curious what is going on here and how do you feel about it as a real doctor?

Perry: [00:03:24] Uh, so, uh, always good to talk about. Whoop. I know that you're a fan. And as I've disclosed before, whoop actually funded a study from our lab a while ago. So a bit of a conflict of interest to disclose that said, blood pressure measurement using things that don't squeeze your arm or your wrist is sort of fraught. Like there are a lot of devices on the market that promise to do this, like non squeezy things. And watches are clearly one of them. The data on their accuracy is generally not great, but that's not what got him in trouble. What got him in trouble is that you cannot [00:04:00] diagnose a disease if the if you haven't gotten FDA clearance. And because they said your blood pressure was in the red zone, if it was greater than systolic, greater than 140 or whatever the FDA was like, that's hypertension. You're diagnosing a disease that's a no no. What I love is how we got around this, which is that they I don't know if you saw this on your hoop, if your hoop was like equipped with the blood pressure thing or not, but, um, the graphic had like originally it was like green, yellow, red. So there were three zones, right? And the red zone was hypertension. That's a no go. So what they did is they changed it to like a gradient. So it changes from green to yellow to red, but without a defined cut point. So now they're not diagnosing a disease anymore. It's just like a wellness. Like how could you like qualitative action thing? And, uh, and so the FDA has dropped its, um, concerns.

Emily: [00:04:52] What I find so interesting about that is in general, these cutoffs are always very stupid. Like we should always.

Perry: [00:04:59] They are arbitrary. [00:05:00]

Emily: [00:05:00] Yeah. We should always be thinking about things as a continuum. So as a reporting mechanism that's great. Of course as a way to find your blood pressure things, as you point out, things that live on your wrist are not as good as things that squeeze your arm, which is actually how we measure that.

Perry: [00:05:15] Can I like, make Emily Oster mad for a second because, um, I was reviewing some of the literature on these cuffless blood pressure machines. And the ones that really do are, are measured blood pressure, like pass through FDA clearance, the whole deal. And one of the studies I saw that got FDA clearance. This is the design. Emily, tell me what the problem is here. You come to the mall, you sit down, they measure your blood pressure, you sit down, they measure your blood pressure with a cuff. Okay, that's the gold standard. Okay. Then they put on their little device on your wrist and they calibrate it. Okay. To the measured blood pressure. Okay. So they're like, okay, your blood pressure's 135 or 75. We're calibrating this thing to your wrist. Okay, now you go and walk around the mall for a while. Come back an hour later. They measure [00:06:00] your blood pressure with the cuff thing again, and they see what the watch reports and they say, oh, look, they're very similar. Like the watch is very similar to the blood pressure cuff, which like. Emily. Yeah. What's the problem here?

Emily: [00:06:16] There are a lot of problems. There's a lot of problems. What's the problem you most want to identify?

Perry: [00:06:22] I want to say that if my watch did nothing more than just report out whatever the original value you calibrated it to was, it would do great, because most people's blood pressure doesn't change that much over an hour when they're sitting down, right? Like, this is not a test. You could just have an algorithm that's like, I always just say 135 or 75 or whatever you calibrated me to originally. Totally.

Emily: [00:06:46] It would be just as it's just as good basically as an algorithm that's like we took the blood pressure measurement and then we just said, that was your blood pressure. Yes. And then it's about right. On average, it's going to be right. It's going to be right on average.

Perry: [00:06:57] Most of the time. So anyway, I'm suspicious of [00:07:00] these cuffless blood pressure cuffs. Moving on. Emily, there is some concerning news about baby formula. When isn't there concerning news about baby formula? But this time it's botulism, I guess. What's going on?

Emily: [00:07:12] Yeah. So in the past year, there have been two outbreaks of botulism in baby formula. There was one last fall in like October in a formula called by heart, a bunch of babies got sick like over 50 babies. None of them died. Thank goodness. Botulism is treatable, but it can be quite serious. And some of these babies have had long term consequences. This was the first time there was ever a botulism outbreak in baby formula. Botulism gets in because of bacteria gets in and it produces these botulism spores. It is not something we have traditionally tested for in formula because we haven't seen it. And so You know, this was a surprise. And then a few weeks ago, there was another botulism case in a different formula, another [00:08:00] three cases identified. And I think it really caused a lot of people to say, oh my God, is there just botulism in all formulas? Is this an issue with baby formula that it just gets botulism more than we thought, and we should be sort of worried about all of this. The thing that came out towards the end of last week and over the weekend is that, in fact, this is basically the same outbreak. So both of these companies were using the same provider of the organic whole milk that they were using the same milk provider, the same drying plant. That was not obvious from earlier reporting. Let's put aside why. But it does seem like actually there is like one thing that happened in one plant in Nevada where some botulism got into this powdered organic milk, and both companies used it. So on the one hand, I don't know how reassuring it is, but I think it's a little bit reassuring to suggest that, in fact, this is like one specific thing that happened. We still need more regulatory oversight. But. [00:09:00]

Perry: [00:09:00] Um, yeah, that's super concerning. Botulism causes like a flaccid paralysis in kids. You know, it's Botox, right? Like this is the toxin that botulism secretes is Botox. And that's fine if you're injecting into in tiny amounts into small muscles in your face and you're an adult, it's not great if it's getting systemic in your body.

Emily: [00:09:19] So that's that. Okay. Let's turn to something a little weirder, which is that STAT news has been reporting that there was a request by the white House for compassionate use of Eli Lilly's new weight loss drug, which is called.

Perry: [00:09:40] Retatrutide. Retatrutide.

Emily: [00:09:43] Which is a very it's a GLP one, but, uh, reportedly in the trials, like enormously effective.

Perry: [00:09:49] Super potent.

Emily: [00:09:50] Yeah, it has not yet been approved, but things that are not yet approved can be requested for compassionate use in some circumstances. This would be an unusual circumstance, [00:10:00] but the STAT news is speculating that the patient was Trump. Yeah, WTF Perry? I don't, so I can't even understand what's going on here.

Perry: [00:10:09] Okay. Yeah. For people not in this space. Like let me first of all say that STAT news is no rag. Like this is a really excellent.

Emily: [00:10:20] Not Bob's Bob's speculative blog. I mean, it's like a real reporting.

Perry: [00:10:23] Real news organization with real reporters. Um, so, so the facts of the case that we have is that there's been one approval for compassionate use for retatrutide. And the reason that there's only one is because like, why would a GLP one be used for compassionate use? Like that's not, you know, usually these are drugs, like for end of life, like late stage cancers, you know, like last ditch Hail Mary types of things. Okay, fine. We know it was done in April for a 79 year old patient. We know that. I'm not sure it was the white House, but there were top health officials involved, including a senior clinician at the NIH [00:11:00] whose name is Ranganath Muniyappa, who requested the drug to treat whoever this patient was for refractory obesity with obstructive sleep apnea and pulmonary hypertension, which is a complication of severe obesity, and that the patient had previously tried tirzepatide, which is mounjaro. So it was and and it had been ineffective. So okay, fine. There are lots of 79 year olds in April in Washington, D.C.. I like what I'm just. Could it be Trump? Sure. But like what? It strikes me, and I don't want to get conspiratorial that they must have some other sourcing here than just like, oh, a 79 year old man. And like, Trump seems like he's overweight, like, right.

Emily: [00:11:46] I agree, there's something going on behind this that we don't understand. And I, I don't know how much we will learn, although I will say that there are people in the Senate. Maggie Hassan in particular is like trying to get RFK Jr to like reveal [00:12:00] who this person is that got this special access. Yeah, I don't know, like everything in this space, there are so many like messed up incentives and, and distrust and anger on all sides. It's very difficult to understand what is actually going on.

Perry: [00:12:15] I, and honestly.

Emily: [00:12:16] I couldn't even parse this. I know.

Perry: [00:12:18] Right? Like, I guess if Trump wants to take a GLP one grave for Trump, if it if it were Trump, the the only scandal kind of would be. I mean, sure, I guess it's like pulling the levers of power to, you know, get something special for yourself. But what else?

Emily: [00:12:33] A lot of people are getting this stuff from like compounding pharmacies in China already anyway. So.

Perry: [00:12:37] Exactly. Um, I think more it would be that they made such a big show of releasing his quote unquote, health records and was like the healthiest person in the world. So if it turns out that he has severe obstructive sleep apnea that's led to pulmonary hypertension, you sort of want to know why that wasn't reported. But anyway.

Emily: [00:12:56] We'll keep you updated on this really, really weird story [00:13:00] as we go. And that is it for the health news of the week after the break. What's the deal with RNA? All right, we're back and we're going to talk about what is the deal with RNA. And before we get into it, before we start talking about vaccines and controversies and Jeffrey Epstein and other important topics in this space, I think it's important to return to high school biology. I'm very up to date on this because I have a person who just finished high school biology, so I basically know everything, but I think the we want to set the stage here for people and explain what is RNA. And when I say mRNA in particular, which is what a lot of this conversation is going to focus on. What are we talking about? So although I have recently finished a course in ninth grade biology, Perry, I'm going to turn this over to you as a person who is a scientist.

Perry: [00:13:59] Sure, sure. [00:14:00]

Perry: [00:14:00] So there are three elements that we need to know here DNA, RNA, and protein. Dna gets transcribed into RNA. Rna gets translated into protein. Let me explain what those words mean. So DNA lives in the nucleus of the cell. And think of DNA as like a big cookbook. Like it's got a recipe in there for every single thing that any cell could make, like a really good cookbook. Okay. And it's all there and it's bound really nicely, you know, leather bindings, it smells of rich mahogany and it's very protected. The nucleus is like the holiest of holies of the cells. It's very difficult to get things in and out of the nucleus. They need special signaling and all kinds of stuff. So that's DNA. You don't want to mess with that, right? We know if you mess with DNA too much, you get cancer or other problems. So that's kept very sacred. But then you've got to get the recipes out to the cell to tell the factories of the cell, like what to build today. Right. I'm a, you know, if you're a white blood cell and you need to make antibodies or whatever it is, your job is to make [00:15:00] so that DNA gets transcribed into RNA. So DNA, you'll remember, has four bases, like four letters, essentially, that is the genetic code. And so it's just like a G, C, T, like whatever, and different combinations of those letters.

Perry: [00:15:16] That's what makes you human. And it's billions and billions and billions of base pairs. Long. And mRNA also has four letters, although one of them is different than the DNA letters. Doesn't even matter. But RNA now, which is a single helix as opposed to DNA's double helix, is allowed to exit the nucleus. It special permission. It leaves the nucleus and goes into the cytoplasm of the cell in the cytoplasm of the cell. Rna docks with these factories, which are called ribosomes, which reads that code and every three letters of code corresponds to one amino acid. If you go back to our protein episode, you will remember that proteins are just long chains [00:16:00] of amino acids. And there's something like 22 amino acids. So we've got to change these four letters in various combinations into 22 amino acids plus codes that say stop, you know, stop working and you're done and things like that. And this is like, like, we know what all this is. It's kind of amazing. Like, we know that if you have, you know, a, a, a like that corresponds to this specific amino acid. And if you have a C a and it responds to this specific amino acid, and so that code gets translated into a chain of amino acids and those amino acid chains grow and then fold and become a big sticky glob. That's what we call a protein. And that's how cells work.

Emily: [00:16:42] I just want to pause here because I think when we talk about this biology, like it is easy to just listen and be like, okay, you're right. Like they come out and they turn it and it turns all the amino acids and insurance into protein. But I would like us to retain in this conversation a sense of wonder. Yeah. Which is like, how fucking [00:17:00] amazing is that? That like, we have these things and then the RNA comes out and it like just clicks along and it makes all the little Legos and it puts them together like, holy shit. And then it becomes all the things you need and it turns into these protein and makes your body like that is really, really, really incredibly cool. It's just really, really cool. It's just cool.

Perry: [00:17:23] It's, it's super cool. And what's I think additionally fascinating to me is that proteins are so complicated, right? Like there's a million proteins, like proteins that make your hair and proteins that make lungs, you know, mucus and like all these different kinds of proteins And, you know, in millions fascinating combinations. And all of it can be represented by just like a single chain of these four letters in a very specific order. That is very important. It's it's amazing.

Emily: [00:17:53] It's really cool. Okay. So when we talk about mRNA, in what way is that different from [00:18:00] the RNA or that is the RNA.

Perry: [00:18:02] So mRNA is a subtype of RNA. So RNA is any of these single helix molecules that have these four unique base pairs in a chain. And mRNA is certainly the one that you're learning about in high school biology. It stands for messenger RNA. It is the message coming from the DNA in the nucleus out into the cytoplasm in like, here's what you need to do. Cell like please produce this protein for me.

Emily: [00:18:26] I think in your, in your like beautiful cookbook example. Yeah. This is a recipe. So it's as if we took, we opened up the cookbook. We copied like Xerox one of the pages and sent that recipe out in the cell and said, okay, now you know, you make like peas and tomatoes, sheet pan meal. And then the thing puts together the thing into the chickpea and tomato sheet pan meal protein and folds it up and sends it to make your hair or whatever. But, and then, and I think importantly, after that recipe is made and the, the chickpea protein leaves, the [00:19:00] page just goes away. It just gets trashed.

Perry: [00:19:05] Your cells are absolutely lousy with substances that break down RNA when I did, I'm a clinical researcher now, so I work with humans, which is, which is much more fun than being in a wet lab. But when I did work in a wet lab way back in college and stuff and was working with RNA, it was like DNA. I'll just say it's super hearty, right? You can like.

Emily: [00:19:27] So stable.

Perry: [00:19:28] You can extract it from amber and clone dinosaurs like you can do, right?

Emily: [00:19:33] Actually, okay. Just people. That doesn't actually work. Don't try it. Don't try it.

Perry: [00:19:37] I mean.

Emily: [00:19:38] It goes poorly.

Perry: [00:19:39] It does go poorly. But no DNA, you know, can last for centuries. Whatever. It's super easy. Doesn't matter. Rna. When we were working with RNA, it was like, okay, clean everything off the off the benchtop and like, wipe it down with all these special things and like, don't breathe on it. Wear a mask because you have rnases in your breath and your sweat and everything you touch. It's just like so ephemeral. [00:20:00] And that's really important actually, because, you know, to stick with our recipe analogy, it's like you photocopy, you know, something from your cookbook for a plate of brownies and like, you want that to be done, right. You don't want the dumb factory to just be like brownies, brownies, brownies, brownies, brownies, brownies, brownies forever. It has to degrade and it does. Not to mention, there are a bunch of pathogens, viruses where RNA is their nuclear material. It's the same RNA that we have. Like we're all Earthlings. We all have the same code, which is kind of weird and cool in and of itself. Of. But we've evolved to fight those things off. And RNA your body sees in general as a hostile force, which means when you inject RNA into someone, your body responds generally quite robustly.

Emily: [00:20:51] Okay, this is great background. Now I want to talk about why this is such an interesting path for potentially [00:21:00] doing various health related things in your body. And I think in some sense it's quite simple, which is the proteins that you make are doing like everything that's all the like a huge share of what your body is doing is being driven.

Perry: [00:21:13] You are your proteins, right?

Emily: [00:21:14] You are your proteins. And so let's say I wanted to do something different. I wanted to make a more of something or less of something or something new that I wanted to introduce the idea in principle that I could give me something, inject it like in some way, treat a person and tell their body, make this protein you weren't making before feels incredibly powerful. Or we'll get to this maybe at the end, like, don't make this protein anymore, right? So, so there's a sort of control of your protein idea here, which feels like conceptually in some ways very straightforward. And most of the issues that people encountered, the reason that mRNA is a relatively new technology is your body [00:22:00] does not want you to do that. Like it is a very, very poor idea for your body to just be like, give me some RNA, I'll make whatever, like your body's like, no, no, no. I came up with a plan. I had these things. I was going to make these proteins. I'm not going to make the other protein. You know, I'm not going to make other proteins that, you know.

Perry: [00:22:17] I mean, that's like viruses whole deal is they're like, hey, man, here's some, here's some RNA. Like, can you make more of me, please? And in general, your body doesn't want to do that. And the successful viruses obviously have figured out ways to get around that. And now and now, so have we.

Emily: [00:22:32] But evolving. Yeah, but evolving in a world full of viruses, we are like, we have developed a lot of ways to not allow our external RNA forces to control our cells. Yeah. And so most of the research that allowed the creation of the mRNA vaccines and many of the other things that are now potential are things that allow us to better control how our body deals with proteins.

Perry: [00:22:56] Yeah. Um, yeah. And we don't have to go into too much detail about like [00:23:00] how we fixed the RNA, the central RNA problem. But there are two Nobel Prizes here, which I always feel like if there's some Nobel prizes, we should at least give a hat tip for two technologies.

Emily: [00:23:09] I don't have any. So yeah, neither of us have any. So let's talk about them.

Perry: [00:23:14] Not yet. Emily. Not yet. Not yet. So the one that I think most people will have heard of because it is directly relevant to the Covid vaccine, was Katalin Kariko and her colleague Drew Weissman, who got the Nobel Prize in 2023. They figured out that swapping one of these letters uridine in RNA for a very slightly modified chemical called Pseudouridine. It looks almost the same. Eliminates a large proportion of that intense immune response to RNA. So without that, like any RNA that comes in your body, unless it's packaged in a virus or something that's like has its own techniques to avoid detection is just getting chewed up like before it hits the floor. Um, so [00:24:00] major advance there. That was by the way, they got the prize in 2023, but they developed that in 2005, which is really the start of human mRNA technology. There's another Nobel Prize in this area that will go, uh, that attaches to inhibitory RNAs, which you had alluded to the idea of like telling your cells not to do something, which is even more mind blowing to some extent, which we'll get to later on.

Emily: [00:24:22] The second innovation that has been incredibly important here is how you get the mRNA into the cell. The cell does not want you to be Putting mRNA into, uh, into it. And they basically figured out how to like surround it with a lipid, uh, that allows it to be coming into the cell. And then the lipid goes away and the, they delivered the mRNA to, to the cell.

Perry: [00:24:48] So yeah. So it was a long time coming. It was an idea. Like this wasn't a crazy idea. People have talked about this for decades and decades and decades. It just took some technology to make it feasible.

Emily: [00:24:58] But once it was feasible, this [00:25:00] is incredibly cool. And I think.

Perry: [00:25:03] Game changer.

Emily: [00:25:03] Game changing. And I think it's worth like talking about it in the context of the the Covid vaccine. So just the Covid vaccine, the mRNA Covid vaccines, these are the Moderna and Pfizer vaccines work in a very specific way. They introduce mRNA, which codes for a spike protein on the Covid virus. And that is a particular protein on the outside of of the virus. And what this does is it tells your body to make this protein. And then because this protein is not a protein that you've identified, your body makes antibodies to that protein. And then if you are have the actual Covid virus arrives, you already have antibodies to this. And this is actually very different than traditional vaccines because a traditional vaccine would introduce either a killed form of the virus, in which you would then create [00:26:00] antibodies to that virus structure overall. Or there are some protein based vaccines which would actually introduce the protein completely. But this is harnessing your body's own cells to make the effectively make the the vaccine. So it's like incredibly cool and it is incredibly fast. So a typical traditional vaccine development takes what Perry like 10 or 15 years? Yeah, yeah. On January 10th of 2020, they published the first SARS-CoV-2 genome online. Like somebody had sequenced the genome of this virus, which is the thing we can do. And they put it up online.

Perry: [00:26:44] Remember?

Emily: [00:26:45] Yes.

Perry: [00:26:45] Cast your mind back to January 10th, 2020.

Emily: [00:26:48] You didn't know about Covid.

Perry: [00:26:49] You didn't know about Covid.

Emily: [00:26:50] We're not thinking about it.

Perry: [00:26:50] It was like a China thing. It's March where we get locked down. Right. So okay, January. We've got.

Emily: [00:26:56] January 10th. Published online on January [00:27:00] 13th of 2020. They had the sequence locked in to produce the vaccine. They could effectively print the vaccine three days after they had this. That is.

Perry: [00:27:13] Absolutely insane.

Emily: [00:27:15] Bananas. The first human phase one injections of this were March 16th, 2020, which is, uh, basically the day that we locked down. So it was like the first day we had lockdowns. We already had. We were already not only do we have the vaccine, we were putting it in people. Yeah. And then it was December when there was an emergency use authorization issued at the end of, you know, so almost all of that time, the vast, vast majority of the time was just doing trials, which of course is you can't really make any faster because that's how trials work. They involve.

Perry: [00:27:52] Yeah. You got to recruit people. You get some placebo, some get the vaccine. Yeah.

Emily: [00:27:56] It's just like, it's just absolutely. Like [00:28:00] it's astonishing.

Perry: [00:28:02] Yeah. It is. You know, I think one of you alluded to the fact that, okay, the code that was being used, that they had three days to take the entire genome of SARS-CoV-2 and decide which component of that they wanted to put in the vaccine. And they chose the spike protein, which is appropriate because that is in SARS viruses. That's the thing your body generates antibodies to. We already know that's like the thing it likes to fight against. So great spike protein, you could ask, okay, why not just produce a bunch of spike protein and inject people with that instead of mRNA? And the reason is that proteins are sticky, gross, complicated things that have to fold in a very particular way to work and require these incredibly sensitive conditions, and are chains of 22 amino acids. And all of those are difficult to work with. And mRNA is just four letters. And you said, you know, could be printed. And yeah, I mean, that's it's it's literally like writing a computer program. [00:29:00] Let me give you a way to put this in context. So like, if you think of the flu vaccine, which is a vaccine we produce every year, obviously the flu vaccine, the way that works is you infect fertilized chicken eggs so that you give the poor embryonic chickens the flu, and they get a bunch of flu virus in the chicken eggs, and then you crack the chicken eggs and blend them up. And then you inactivate the flu virus. So you kill the flu virus in all those chicken eggs. And that's what you get injected into you. And so you need. Yeah. 500 million eggs a year to do that for for an mRNA vaccine. Um, if you have a ten liter bioreactor, so ten liters is so five of those Coke bottles. Okay. A ten liter bioreactor can make a few million doses a day of mRNA vaccine. There is absolutely no contest. I mean, [00:30:00] we can talk about efficacy and all that stuff, but like, in terms of sheer scalability and rapidity, that is what makes mRNA really, really special.

Emily: [00:30:09] Yeah, it is really, really cool. Um, and I think printing is the analogy that these guys, when you talk to these guys about making the printing, the analogy is the analogy, sort of tell the thing, okay, make this one. And then like this one in the bioreactor, and then you have and then you have it.

Perry: [00:30:24] And then you have it. And what's weirder is it actually worked like, like I, you know, those initial randomized trials that came out for the initial version of the vaccine, the vaccine efficacy against infection was above 90%, which was, was, was nuts. Now, did that persist over time? It definitely did not. The virus mutates. We have to keep up with various strains. The spike protein changes. There's a lot of issues with that as there are with all vaccines. And Covid is one that has been tricky to keep up with. But I will say even [00:31:00] the most the latest studies, including that, that our friend Doctor Jay Bhattacharya suppressed from CDC, still demonstrates moderate efficacy against hospitalization and severe illness.

Emily: [00:31:13] And in the first I mean, again, I think it's like to to return to both the the wonder and also the moments early in Covid, like the, the protective like this saved literally millions of people. And having the vaccine in December rather than in, you know, December of 2030 or whenever, like it's just that that is millions and millions and millions of people who did not die. And that is just really important. Um, it's really important.

Perry: [00:31:42] Also to point out the difference between an mRNA vaccine, which is causing your cells to generate one protein. And most vaccines like the flu vaccine and even some of the mRNA based Covid vaccines, which use the whole virus. You know, Covid has 27, 29 proteins [00:32:00] in it. So COVID's RNA codes for 29 different proteins. And the way it works when you get an infection is it latches onto your cell and it injects all its RNA into your cell, and your cell starts making those 29 proteins. And those 29 proteins come together and create a new Covid virus, and your cell gets filled up with those Covid viruses until it bursts and spreads it throughout the rest of your body until your immune system can get Ahold of it. And so, you know, when we think about vaccination, there's a real argument that mRNA is kind of the cleanest form of vaccination. Like you're exposing your body to more or less the minimal amount of substance that you need to generate an immune response, as opposed to like the entire virus, for what it's worth.

Emily: [00:32:42] So I will say again, I think this is like, there is so much wonder here. And I think that when people were first encountering this, that wonder was much more dominant than it has become over time. And we're going to talk about like some of the conspiracy theories and some of [00:33:00] the stuff that sort of came out of all of this crazy discussion. But it is also worth, before we get into that, talking about whether there are well documented non conspiratorial risks that are associated with this particular approach to vaccines as opposed to these other approaches. I think the one that is a real risk that is worth discussing is the risk of myocarditis, particularly in young men.

Perry: [00:33:30] Yeah. Yeah. That's real.

Emily: [00:33:32] So let's talk about that before we let's start with that because I do think people should hear that piece of it. And then we'll talk about the the rest of the stuff, which is much less, much less well supported.

Perry: [00:33:42] Yes. Okay. So myocarditis is inflammation of heart muscle cells. And it can obviously be caused by a wide variety of things. There are autoimmune forms of myocarditis. There is infectious forms of myocarditis. Covid itself can cause myocarditis. But there is vaccine associated myocarditis [00:34:00] associated with the mRNA vaccines. The cause is a little bit unclear. Um, the thought, the sort of leading hypothesis is that the spike protein bears some similarity to a protein that lives on heart cells. It's like a potassium channel on heart cells. You know, they sort of they're like, they just happen to kind of have similar shapes. And so in some people, if you're generating antibodies against spike protein, you those antibodies might cross-react with some of the heart cells. It's quite clear that estrogen is protective against this. And that testosterone is makes this worse, which is one of the reasons I think we see a higher risk in young men than in other populations. So there's clearly a risk, right? So the question, as you know, will always come up with every medical decision that anyone ever makes is, is the benefit worth the risk? [00:35:00]

Emily: [00:35:00] Yeah. And I think, you know, here, if we kind of look at the numbers, you know, in a million, these estimates suggest in a million vaccines, you'd expect something like 40 myocarditis cases. But, you know, the number of hospitalizations and, potential serious illness that might be prevented by that is actually quite significantly in excess of that. And that's particularly was particularly true early on in the early on in the pandemic. You know, we we have arrived at a place where Covid boosters have become a much less common thing for healthy adults and for kids. And so at this point, most people with teenage boys are not getting them an additional Covid booster. And the groups that are having the most significantly should be engaging with the boosters. I think at this point, in my view, are older adults for whom myocarditis is actually not a significant, not a significant risk, perhaps because their testosterone is not so good anymore.

Perry: [00:35:56] Yeah, it'll be really interesting to see if the people, now that testosterone supplementation [00:36:00] is having its moment, like what's going to happen.

Emily: [00:36:02] You have.

Perry: [00:36:03] More, there's going to be an interaction. Yeah. I mean, it's not I don't want to say that there's a recommendation for teenage boys not to get the Covid vaccine. It is. It is worth having a discussion with a healthcare provider about the risks and benefits, because it's going to differ a bit based on your own susceptibilities. You know, the thing we don't know, I think, is that in the initial phase of the pandemic, many of us had never been exposed to spike protein at all. Right. It was brand new. It was the novel Coronavirus nCoV, if you remember when it just got started. Now we're in an era where basically everyone has been infected at least once. Many people have, you know, been vaccinated, if not once, multiple times. And so there is obviously we haven't reached a state of herd immunity because people are still getting infected, but the severity of infections have decreased even among people who weren't vaccinated. Um, you know, back in the original days, the infections [00:37:00] I remember. So I was on service, uh, in April of 2020. And I, instead of being a kidney doctor, I got plucked out to be a Covid doctor because that's what was happening to everyone. And I remember this like 35 year old guy, totally healthy coming in with Covid was on cardiopulmonary bypass because that's how bad it was. And these things do still happen with Covid, but it's not the same. And in part, it's not the same because we do. We have been exposed before. And, you know, there's just a fundamental difference between being exposed to a virus, even a mutated form that you've been exposed to previously and one that your immune system is completely unprepared for. So there's some really interesting questions about how to proceed with vaccination. I certainly agree that the the benefits outweigh the risks for the vast majority of people. My only sort of question is in this young male group, who tend to do pretty well with the virus if they get it.

Emily: [00:37:57] Yeah. So I think one really [00:38:00] important point is, regardless of how you feel about the Covid vaccine at this point, you know, I think there are people here are going to be like, look, I've had Covid six times. I'm not getting any more boosters. I'm not boostering my kids. It's like, just if I look out at the world. That is where a large share of people are. But this conversation about mRNA is still incredibly important, because there are many other things, other vaccines that we might want to use mRNA for, other things like cancer treatments, which we'll talk about in a second. And so, yeah, I actually, I want to make sure that we're, we're sort of stepped out of the particular Covid Covid thing and keep thinking about the mRNA, the potential of this technology. So in leading into that, it is probably worth debunking some of the conspiracy theories that I think really arose around Covid. So look, let me just the way I would like to do this is I'm just going to give you the theory and you're going to tell me yes or no. [00:39:00] Science survives on this theory. Okay, okay. True or false? Perry mRNA changes your DNA.

Perry: [00:39:10] False. I think this is okay. Wait. I'm sorry. You said one thing. I think this is the Uber conspiracy theory. I think part of the reasons, aside from the fact that Covid was just like we all had free time on our hand to bake conspiracy theories. And that's where Emma and I got started, I think because it sounds like DNA and that sounds like gene editing and like it just it fosters this. And I just want to reiterate that your the nucleus of the cell where the DNA lives is this highly, highly protected inner sanctum. It is very difficult for RNA to get into the nucleus. It requires special codes, special transporters, and even then it's extraordinarily hard for RNA to get reverse transcribed to DNA and get put into DNA. Remember, there's a whole set of viruses [00:40:00] that. Their trick is that they bring with them reverse transcriptase to make RNA go into DNA instead of vice versa. Hiv being the best example of this. Retroviruses like that, like this is their trick is like, oh, we're going to get the RNA into your DNA. They had to evolve an entire system to do that. Rna itself is like deliberately excluded from the nucleus and the DNA.

Emily: [00:40:27] Okay, great. We also have a couple of clips. So that's like the Uber thing. Then there are some more specific things. So we're going to play these. We're going to play these clips.

Influencer: [00:40:35] So whoever's walking around with a jab they got a little bit of Epstein in them.

Influencer: [00:40:38] No way.

Influencer: [00:40:39] Epstein is the main funder of the mRNA and Bill gates Fauci. And what he did was he put a little bit of his own genetic code in each one of the jabs. What? Yeah.

Influencer: [00:40:48] How did he pull that off?

Influencer: [00:40:49] It's all in the files, man. He was doing experiments and funding that Crispr and that mRNA technology back in the day. And he said in the same document that he wanted to have his code in all of it. So anytime [00:41:00] anybody injects, they got a piece of him inside of him.

Influencer: [00:41:02] Is that his consciousness being transferred or what exactly?

Influencer: [00:41:04] Just a little code. It's a little ego thing. You know, how much of an effect is it going to have on a person who knows. But for him, consciously, it's like, I'm in everybody, right? Like every single person's out here. I'm inside of it.

Influencer: [00:41:14] You know, half the population.

Influencer: [00:41:15] Right? Sick.

Emily: [00:41:16] Okay. Perry. Uh, what about that one?

Perry: [00:41:20] Epstein. Epstein's DNA in the RNA vaccines. You know, Epstein's DNA is in a lot of places, but not there.

Emily: [00:41:31] Not there. Um, yeah, we're going to leave that one. Uh, and then we have this, uh. De-population. Well, I'm just going to play it for you.

Influencer: [00:41:44] The mRNA de-population technology that was in the Covid vaccines is now in our food supply. And who has this been sponsored by? This is sponsored by yours only, Bill gates. Bill gates funded. Tirana Biosciences is now moving to reprogram plant [00:42:00] life itself. They are planning to spray synthetic mRNA pesticides on your crops, on your vegetables, on your fruits, on your meat, on everything in the food chain, as revealed by doctor Mike Eden, who has been vice president of Pfizer for 16 years, that this mRNA technology is de-population technology, and they have been doing this for a long time now. They have been trying to sneak it into our food supply. And finally, he warns that this mRNA technology is intentionally manufactured to cause infertility and to kill human beings. Now, this is not something new if you look at it. De-population.

Emily: [00:42:32] Oh my God. Okay, it's in our food supply. What?

Perry: [00:42:37] What dude, what? I want to ask some of the conspiracy. Do you remember early on, they were like, everyone was getting one of these shots is going to be dead within 30 days. And like, why, why does it? No one is there no to them and be like.

Emily: [00:42:51] Do we know? Check. Hey.

Perry: [00:42:54] Everyone's still here. Yeah.

Emily: [00:42:55] So look, I mean, I think the, the best this is not [00:43:00] the universe of conspiracy theories about mRNA. There are a million crazy things. I think the best defense about them from an individual standpoint, is just understanding the basic biology of what this is and what it does, which demystifies the whole situation. So if you are still the next time you hear one of these crazy conspiracy things, just go back and listen to like the first six minutes of this deep dive and make yourself feel better. And that is very important because there are some incredibly cool, possible things that may come down the line with mRNA. The most interesting? Well, the one we are furthest along on, I would say right now is the idea that this may actually be a cancer vaccine. So that is incredibly cool. And I think the basic idea, and then maybe you can tell us how far we have gotten along with this, is that if I have a tumor and I biopsy the tumor, that tumor may have specific antigens, [00:44:00] sort of specific characteristics that I could in principle have antibodies to fight. And if I could make a vaccine that would effectively create antibodies to your particular tumor, that may actually be a path to treatment. And because mRNA is.

Perry: [00:44:20] Great, but it takes 10 to 15 years to make a vaccine. Emily, you don't have that kind of time.

Emily: [00:44:25] And because mRNA is programmable and we can do it in a short period of time, it may actually be feasible at an individual level in this kind of personalized medicine way that that really hasn't been possible with our existing technology.

Perry: [00:44:39] Yeah. I mean, this, this is where we get to the future and why RNA is so much more than Covid vaccines or flu vaccines and things that are getting developed. So yeah, this is real. I'll give you a study that appeared in The Lancet in 2024. So this was a trial of 157 patients. They had, uh, relatively high [00:45:00] stage stage three B to four cutaneous melanoma. So skin cancer melanoma Skin cancer. Pretty serious. They were randomized to get pembrolizumab, which is that immune therapy that's really transformed melanoma over the past decade. That's what Jimmy Carter got which kept him alive for so long. Great drug. That was the standard. Or they got pembrolizumab plus an mRNA vaccine. And this was like a custom printed mRNA vaccine for their specific tumor. So they took the biopsy. They figured out what proteins were different than their normal cells, and they made an mRNA for them. And again, you can do this in like a matter of weeks, which is just insane. So they gave the patients their. The primary outcome was recurrence of melanoma or death. 40% of people in the pembrolizumab alone group. That's the Jimmy Carter standard of care. 40% had recurrence of melanoma or death. That's actually a good outcome for this stage of [00:46:00] melanoma. It's obviously advanced. Melanoma is very serious. 40% versus 22% in the combo group. So it essentially cut in half the new melanoma and death rate in this disease. And it's totally personalized medicine. This is the real promise of RNA technology.

Emily: [00:46:21] Yeah. And I mean, it feels like there are many kinds of cancers for which this would be potentially would be every.

Perry: [00:46:27] Every kind of cancer. I mean, like, I challenge every cancer has mutations compared to your ordinary cells or otherwise or otherwise. It would be your ordinary cells. So there's always something, you know, whether it's targetable with antibodies is just about revving up your immune system. That's why pembrolizumab works. But now we can say like not only just rev up the immune system, on the whole, we can be like, and specifically for cells that, you know, look like this. So cool.

Emily: [00:46:53] Yeah. And I think, you know, part of what makes this kind of treatment so exciting is that many of our [00:47:00] existing a huge share of our existing cancer treatments. Basically, most of chemotherapy works by killing. You know, all of your fast. Yes. Like targeting cells based on, you know, how fast they produce and so on. And that's why you lose your hair, you lose your fingernails. People have gut issues, all kinds of other other stuff. If you can find a way to target only the cancer things, that's obviously a path to a much lower side effect, much more effective treatment. Were there significant either side effects or downsides in that Lancet trial?

Perry: [00:47:28] Not really. I mean, the side effects were associated primarily with pembrolizumab. You get like autoimmune types of conditions in other organ systems. But the vaccine related side effects were what we've come to expect from RNA vaccines, which is like, you don't feel great for a day or so, but you're probably willing to accept that in this scenario for sure.

Emily: [00:47:47] Okay, so before we go, let's talk about one other like promise thing, which is C RNA.

Perry: [00:47:54] This is so sci fi.

Emily: [00:47:56] It's very sci fi. So we've been talking a lot about about [00:48:00] RNA treatments that tell your body, okay, make more of this protein. Um, but the idea here is to make less of a protein.

Perry: [00:48:09] It's sort of so cool. Yeah. So I guess what you need to know about siRNA is that your body has a built in mechanism, multiple built in mechanisms to degrade mRNA. Remember, we don't want to keep making the brownies over and over and over again. So you've got all sorts of proteins and enzymes and things that are out there being like degrade mRNA, like don't let it be used too many times, which is important and good. And we want that. One of the mechanisms and the Andrew Fire and Craig Mello got the Nobel Prize in 2006 for discovering this mechanism is there's a protein in your cell that targets mRNAs and choose them up. That's its job. It's a garbage, garbage eating protein. But the protein itself has a binding pocket for RNA, and that RNA tells the protein what RNA to look for and [00:49:00] digest. So it like it's a programmable it like the protein is programmable to look and target for specific mRNAs, which like why we have something like, I mean, evolution, it's amazing. It's unbelievable. But we can exploit that. And that's what siRNAs are. There are these custom designed RNAs that bind to this special protein and say, look for this mRNA and chew it up. And what that means is that if there's a protein you don't like, you can tell cells, hey, chew up any, any copy of that recipe, any brownie recipes you see, chew them up. I don't even want to see it get made right. I don't want a single brownie coming out of this cell. And what this lets you do.

Emily: [00:49:39] Insane. Totally, totally bananas.

Perry: [00:49:41] Is totally bananas is give someone an injection that treats them for months at a time, six months at a time. For example, there's a drug called Inclisiran, which targets a protein called Pcsk9. [00:50:00] So you inject this drug. It's an RNA drug. It makes your liver cell not produce this Pcsk9 protein. That's a major component of the cholesterol synthesis cascade. There are other drugs that you take once a day that target Pcsk9. But this drug, you get injected once and for six months. In this trial, the LDL level was 50% lower in the treatment group than the placebo group, one injection six months long, and everyone was on max dose statins. Every single person in the trial was on max dose statins. And then you get one drug. There's another. There's another drug called ZIL basaran. This was in the New England Journal 2023, which is a twice yearly blood pressure medication. So it targets a protein called Angiotensinogen, which raises your blood pressure, basically suppresses that protein for six months at a time. And on average, compared to placebo, people had a 15 to 20mm of mercury drop in systolic [00:51:00] blood pressure. That's the number on top. One injection, six months of blood pressure control. Now, as a doctor, I'm like, that makes me a little nervous because like, what if you get sick and have diarrhea and stuff? Like maybe you want a little blood pressure, I don't know, cholesterol I feel better about, but like, from a technological standpoint, there's a future out there where instead of every morning you wake up and brush your teeth and take your six pills you like, go twice a year and you get a couple of injections and you're good to go. Absolutely nuts.

Emily: [00:51:28] That is totally, just completely insane. So you talked about blood pressure. This is potentially like an incredibly rich technology. So early in my career, I worked a lot on Huntington's disease. I was doing a lot of work with people. Huntington's is a degenerative neurological disorder. It's genetically caused is totally, totally devastating. Uh, runs through families. And there within the last year or two, there has been probably the most significant [00:52:00] step forward in treatment of this disease, which relies on this kind of technology effectively limiting production of this protein. This is a disease where you produce too much of this protein and that leads to degeneration. And so again, turning off the potential for producing that protein has, uh, you know, slowed disease progression like 75% over several years in, in dosing. So it's just a, it's just a technology with unbelievable amounts of potential going forward.

Perry: [00:52:27] Yeah. It's so exciting. It's good that people are starting to learn about it and hopefully learning about it in a broader way than what you might see on social media.

Emily: [00:52:36] Totally. Okay. Um, my goal in this episode, I will be just totally up front was to deliver a sense of wonder. I mean, I think these technologies are incredibly exciting and I really hope we do not stop researching them because people did not like the Covid vaccine, which feels like really throwing away what is potentially one of the most significant [00:53:00] innovations of the past many decades. Because you didn't like one specific, you know, kind of lockdown or whatever. So more mRNA research would be great. I think we could smash or pass.

Perry: [00:53:14] Let's do.

Emily: [00:53:14] It. Let me guess, Perry, are you a smash or pass on RNA technologies?

Perry: [00:53:19] I, I am a huge smash on RNA technologies. Um, these will transform medicine. Mark my words. It's a major paradigm shift. Emily. Smash or pass.

Emily: [00:53:31] I'm also smash on these. I am incredibly excited about them and I just, uh, I just really hope we keep pushing this stuff forward. All right, that's it for RNA. Your mailbag. Question of the week after the break.

Mailbag: [00:53:49] Hi, Emily and Perry, this is Melissa from the Seattle area, and I'm listening to your sleep episode, and I have a couple questions that maybe you can diagnose me and figure out if I'm okay. The [00:54:00] first is that I believe that since I was in middle school or high school, maybe a few times a year, I'll have a really bad dream where I am being either chased or someone is hurting me, and I'm aware that it's a dream. But in my dream or in real life, I guess I can't breathe. And the only way that I wake up is from screaming and I'm a side sleeper. And if I fall back asleep in the same side, the dream immediately comes back. Or if I flip my body, it goes away. But again, I can't breathe in my sleep. And the only way for me to wake up from this dream that I know is a dream, but it's really scary, is from screaming. And I think my twin sister sometimes has the same thing. Uh, any idea what that is? Another thing that has happened a few times is that I, um, have bit my husband on the arm in the middle of my sleep, because I'm having a dream that I need to bite into something harder. And I also do the same thing with my three year old [00:55:00] son. When we were sharing a bed on vacation, I bit his finger and, uh, luckily woke up before anything bad happened. But, um. Yeah. Can you diagnose me? What's going on? Thanks, guys.

Emily: [00:55:12] Oh, man. Okay, Perry, what do you think?

Perry: [00:55:17] Yeah. Okay, so, first of all, really sorry you're going through this. This sounds both scary, you know, and if not outright traumatizing. I mean, I do need to say, because I'm a medical doctor that, like, I can't despite being asked. I can't diagnose you from afar. I don't know your medical history or anything like that. But I appreciate that you heard some things on the sleep episode that seem to be resonating. I agree that, you know, there's some stuff that you mentioned that sound like it's worth discussing with a sleep medicine doctor. Um, in particular, the like acting out of dreams that we talked about in the episode can be associated [00:56:00] with a condition called REM behavioral disorder, REM behavioral disorder that the like real terrors that are happening could sound a little bit like night terrors. There is a really clear test for this. Uh, so there's a special kind of sleep study called video polysomnography. So it's not only your conventional sleep study that would detect things like sleep apnea. Um, you mentioned something about position being important. So that also leads the question of sleep apnea. But a video polysomnography records you during sleep. And this is critical for REM sleep disturbances because the EEG on your brain knows you're in REM. And if you listen to our sleep episode, remember, you're supposed to be paralyzed when you're in REM sleep, so you don't act out your dreams. And so the video can then be correlated with that to see if paralysis is working as intended. So this is definitely something to check out, especially if you've, you know, hurt or come close to hurting a loved one who shares the bed with you.

Emily: [00:56:57] Yeah. And I will just let me just say one [00:57:00] thing about this and all of these sleep questions, which is like, if there is an issue in your sleep that is affecting, that is affecting your life, you should try to get help with it. I think actually sleep is a place where people under, under invest in trying to figure out what the help would be, in part because it's not so clear, like, well, what are you going to do? And I think the answer and that answer made it very clear is like, here's the thing, you probably didn't know about this, but here is a thing that you would do in this situation. If you go to someone and say, I'm having this problem with my sleep, here is the issue. It is really affecting my life. There is probably something that can at least help you figure out more about what could be done or what's going on. So don't suffer. Don't suffer in silence.

Perry: [00:57:40] Yeah, don't mess with sleep. Well, that's it for us today. Stick with us next week when we'll ask what's the deal with cortisol?

Emily: [00:57:51] Well, this actually is produced in association with iHeartMedia. Our senior producer is Tamar Avishai. Our executive producer at iHeart is Jennifer [00:58:00] Bassett. Our theme music is by Eric Deutsch, and our content is for educational purposes only.

Perry: [00:58:06] If you like the show, help other people find us. Leave a rating and review on Apple Podcasts or your podcatcher of choice and help us spread the word about the show. You can follow us on Instagram at Wellness Pod. And don't forget, we want to hear from you. Head over to wellness.fm and leave us a question for our mailbag or suggest a topic for a future show.

Emily: [00:58:27] We'll let the influencers have the last word.

Paul Simon: [00:58:32] These are the days of miracle and wonder. This is the long distance call. The way the camera follows us in slow mo. The way we look to a song. The way we look to a distant constellation.