What's the deal with mRNA vaccines?

21:48I 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. They come out and they turn all the amino acids and it turns into protein. but I would like us to retain in this conversation a sense of wonder, which is like how 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 and then it becomes all the things you need and it turns into these protein and it makes your body like that is really, really, really incredibly cool.

22:26It's just really, really cool. It's just cool.

22:29Emily Oster: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, you know, 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 amazing. It's really cool. Okay. So when we talk about mRNA, in what way is that different from the RNA or that is the RNA? So mRNA is a subtype of RNA.

23:11Emily Oster: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 and like, here's what you need to do, cell. Like, please produce this protein for me. I think in your beautiful cookbook example, this is a recipe. So it is if we opened up the cookbook, we copied Xerox one of the pages and sent that recipe out in the cell and said, okay, now you make chickpeas and tomatoes sheet pan meal.

23:51And 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 chickpea protein leaves, the page just goes away. It just gets trashed.

24:11Emily Oster: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 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 hardy, right? You can like - So stable. You can extract it from amber and clone dinosaurs. Like you can do - Doesn't actually, okay, just people that doesn't actually work. Don't try it. Don't try it. I mean - It goes poorly. It does go poorly. But no, DNA can last for centuries, whatever.

24:48Emily Oster:It's super easy. It doesn't matter. RNA, when we were working with RNA, it was like, okay, clean everything off the benchtop and wipe it down with all these special things. And don't breathe on it. Wear a mask because you have RNAs in your breath and your sweat and everything you touch. It's just so ephemeral. And that's really important actually because to stick with our recipe analogy, it's like you photocopy something from your cookbook for a plate of brownies. And 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.

25:23Emily Oster: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. We're all earthlings. We all have the same code, which is kind of weird and cool in and of itself. 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. Okay. This is great background. Now I want to talk about why this is such an interesting path for potentially doing various health-related things in your body.

26:09And 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 by -

26:19Emily Oster:Yeah, you are your proteins, right? You are your proteins. And so let's say I wanted to do something different. I wanted to make 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.

26:59And most of the issues that people encounter, the reason that mRNA is a relatively new technology is your body like 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 don't want to.

27:23Emily Oster:Yeah, I mean, that's like viruses' whole deal is they're like, hey, man, 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 so have we. 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.

28:02Yeah.

28:03Emily Oster:Yeah. And we don't have to go into too much detail about like 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. I don't have any. So yeah. Neither of us have any, so let's talk about them. 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 Catalin Carrico 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.

28:53Emily Oster:So without that, any RNA that comes in your body, unless it's packaged in a virus or something that has its own techniques to avoid detection, is just getting chewed up before it hits the floor. So major advance there. 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 attaches to inhibitory RNAs, which you had alluded to the idea of telling your cells not to do something, which is even more mind-blowing to some extent, which we'll get to later on. The second innovation that has been incredibly important here is how you get the mRNA into the cell.

29:34The cell does not want you to be putting mRNA into it. And they basically figured out how to surround it with a lipid that allows it to be coming into the cell. And then the lipid goes away and they've delivered the mRNA to the cell. So, yeah.

29:54Emily Oster:So it was a long time coming. It was an idea. 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. But once it was feasible, this is incredibly cool. Game changer. Game changing. And I think it's worth talking about it in the context of 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 the virus.

30:39And 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 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 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 effectively make the vaccine.

31:25It's like incredibly cool. And it is incredibly fast. So a typical traditional vaccine development takes, what Perry, like 10 or 15 years. 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.

31:50Emily Oster:Remember, cast your mind back to January 10th, 2020. You didn't know about COVID at that time. You didn't know about COVID. We're not thinking about it. It was like a China thing. It's March where we get lockdown, right? So, okay. January, we've got the code published online. On January 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 absolutely insane. Bananas. The first human phase one injections of this were March 16th, 2020, which is basically the day that we locked down. So it was like the first day we had lockdowns, we were already not only did we have the vaccine, we were putting it in people.

32:39And then it was December when there was an emergency use authorization issued at the end of a, 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 people and all kinds of other stuff.

32:59Emily Oster:Some placebo, some get the vaccine. Yep. It's just like, it's just absolutely, like, it's astonishing. 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?

33:41Emily Oster: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. 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.

34:33Emily Oster: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 an mRNA vaccine, if you have a 10 liter bioreactor, So 10 liters is, so five of those Coke bottles, okay? A 10 liter bioreactor can make a few million doses a day of mRNA vaccine. There is absolutely no contest. I mean, 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. Yeah, it is really, really cool. and I think printing is the analogy that these guys, when you talk to these guys about making, printing is the analogy.

35:24They sort of tell the thing, okay, make this one. And then it makes this one in the bioreactor and then you have it.

35:30Emily Oster:And then you have it. And what's weirder is it actually worked. 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 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 the latest studies, including that that our friend Dr. J. Bhattacharya suppressed from CDC, still demonstrates moderate efficacy against hospitalization and severe illness.

36:19And in the first, I mean, again, I think it's like to to return to both 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.

36:47Emily Oster:It's really important. 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 non-mRNA-based COVID vaccines, which use the whole virus, you know, COVID has 27, nope, 29 proteins 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.

37:29Emily Oster: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. 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 the stuff that sort of came out of all of this crazy discussion.

38:12But 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 But one that is a real risk that is worth discussing is the risk of myocarditis, particularly in young men. Yeah.

38:37Emily Oster:Yeah, that's real. 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 rest of the stuff, which is much less well-supported. 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 associated with the mRNA vaccines. The cause is a little bit unclear. here. The sort of leading hypothesis is that the spike protein bears some similarity to a protein that lives on heart cells.

39:26Emily Oster:It's like a potassium channel on heart cells. They just happen to kind of have similar shapes. And so in some people, if you're generating antibodies against spike protein, those antibodies might cross-react with some of the heart cells. It's quite clear that estrogen is protective against this and that testosterone 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 the benefit worth the risk?

40:06Yeah. And I think, you know, here, if we kind of look at the numbers, you know, in a million, some of these estimates suggest in a million vaccines, you'd expect something like 40 myocarditis cases. But, you know, the number of hospitalizations and, and, you know, 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.

40:46And 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 risk, perhaps because their testosterone is not so good anymore.

41:02Emily Oster:Yeah, it'll be really interesting to see if the people, now that testosterone supplementation is having its moment. What's going to happen? Are we going to have more? There's going to be an interaction. Yeah. I don't want to say that there's a recommendation for teenage boys not to get the COVID vaccine. 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. 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?

41:35Emily Oster:It was brand new. It was the novel coronavirus end cove, 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 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. Back in the original days, the infections, I remember, so I was on service 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.

42:19And I remember this like 35-year-old guy, totally healthy, coming in with COVID, was

42:24Emily Oster: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 have been exposed before. And 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 benefits outweigh the risk 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.

43:03Yeah. So I think one really important point is regardless of how you feel about the COVID vaccine at this point, I think there are people here going to be like, look, I've had COVID six times. I'm not getting any more boosters. I'm not boosering 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 I actually, I want to make sure that we're sort of stepped out of the particular COVID COVID thing and keep thinking about the mRNA, the potential of this technology.

43:50So 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. Science or vibes on this theory. Okay. Okay. True or false, Perry? mRNA changes your DNA.

44:16Emily Oster:False. I think this is - False. 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 mRNA got started. I think because it sounds like DNA, and that sounds like gene editing, and it just fosters this. And I just want to reiterate that 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.

44:54Emily Oster: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 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, this is their trick. It's like, ooh, we're going to get the RNA into your DNA. They had to evolve an entire system to do that. RNA itself is deliberately excluded from the nucleus and the DNA. Okay, great. We also have a couple of clips. So that's like the Uber thing. Then there are some more specific things.

45:39So we're going to play these clips. So whoever's walking around with a jab, they got a little bit of Epstein in them. No way. Epstein is main funder of the mRNA, him, 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.

45:54Emily Oster:How did he pull that off? 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 anybody injects, they've got a piece of him inside of them. Is that his consciousness being transferred or what exactly? 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. Every single person's out here. I'm inside of it. Half the population.

46:21Emily Oster:Right. Sick. Okay, Perry. What about that one? Epstein's DNA. No? Epstein's DNA in the RNA vaccines. You know, Epstein's DNA is in a lot of places, but not there. Not there. Yeah, we're going to leave that one. And then we have this depopulation. Well, I'm just going to play it for you. The mRNA depopulation 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 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.

47:16As revealed by Dr. Mike Yeadon who has been vice president of Pfizer for 16 years that this mRNA technology is depopulation 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 wants 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, depopulation technology. Oh, my God. Okay, it's in our food supply. What?

47:46Emily Oster:Dude, what I want to ask some of the conspiracy. Do you remember early on, they were like, everyone who's getting one of these shots is going to be dead within 30 days. And like, why does it? No one ever go back to them and be like – Do we know of – check? Hey. Everyone's still here. Yeah. So look, I mean I think the best – this is not the universe of conspiracy theories about mRNA. There are a million crazy things. 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. situation.

48:20So 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 or specific characteristics that I could in principle have antibodies to fight.

49:13And 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 program.

49:27Emily Oster:Right, but it takes 10 to 15 years to make a vaccine, Emily. You don't have that kind of time. 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 really hasn't been possible with our existing technology. Yeah. I mean, 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 relatively high stage, stage 3b to 4 cutaneous melanoma.

50:09Emily Oster: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 like Jimmy Carter got, which kept him alive for so long. Great drug. That was the standard. or they got prembrolizumab 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.

50:48So they gave the patients there.

50:51Emily Oster: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 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. Yeah. And I mean, it feels like there are many kinds of cancers for which this would be potentially...

51:32Every kind of cancer?

51:33Emily Oster:Every cancer has mutations compared to your ordinary cells 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. Yeah, and I think part of what makes this kind of treatment so exciting is that many of our existing, a huge share of our existing cancer treatments, basically most of chemotherapy, works by killing all of your fast, like targeting cells based on how fast they produce and so on.

52:17And that's why you lose your hair, you lose your fingernails, people have gut issues, all kinds of 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?

52:34Emily Oster: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. Okay. So before we go, let's talk about one other like promise thing, which is siRNA. This is so sci-fi. Very sci-fi. So we've been talking a lot about RNA treatments that tell your body, okay, make more of this protein. But the idea here is to make less of a protein.

53:15Emily Oster:It's 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. Don't let it be used too many times, which is important and good, and we want that. One of the mechanisms, and 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 chews them up.

53:52Emily Oster:That's its job. It's a 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 digest. So it's a programmable, 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. They're 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 copy of that recipe, any brownie recipes you see, chew them up.

54:39Emily Oster:I don't even want to see it get made. I don't want a single brownie coming out of this cell. And what this lets you do - Totally, totally bananas. 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 incliceran, which targets a protein called PCSK9. So you inject this drug, it's an sRNA 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 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.

55:34Emily Oster:One injection, six months long, and everyone was on maxedostatins. Every single person in the trial was on maxedostatins. And then you get one drug. There's another drug called Zilbeceran. 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 20 millimeter of mercury drop in systolic blood pressure. That's the number on top. One injection, six months of blood pressure control.

56:10Emily Oster: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 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 go twice a year and you get a couple of injections and you're good to go. Absolutely nuts. 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 like genetically causes totally totally devastating uh runs through families and there within the last year or two there has been probably the most significant step forward in treatment of this disease, which relies on this kind of technology effectively limiting production of this protein.

57:13This 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 slowed disease progression like 75 % over several years in dosing. So it's just a technology with unbelievable amounts of potential going forward.

57:33Emily Oster: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. Totally. Okay. 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 innovations of the past many decades because you didn't like one specific kind of lockdown or whatever.

58:14So more mRNA research would be great. I think we could smash or pass.

58:19Emily Oster:Let's do it. Let me guess. Perry, are you a smash or pass on RNA technologies? I am a huge smash on RNA technologies. These will transform medicine. Mark my words. It's a major paradigm shift. Emily, smash your pass. I'm also a smash on these. I am incredibly excited about them. And 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.

58:53Oh, I have had no luck lately. Wait, lady luck? Breski, I got you. I've had so much luck. on spinquest.com. They have all of my favorite games, slot games, live blackjack craps, and bubble craps. You can even get a$30 coin pack for just$10.

59:10Emily Oster:$10 for$30? I'm adding it over to spinquest.com right now. SpinQuest is a free-to-play social casino. Avoid where prohibited. Visit spinquest.com for more details. Apple Vacations, where your story starts. The July Savings Event from Apple Vacations is here. Book by July 23rd and save up to$400 off your flight and hotel package to Mexico, the Caribbean, Central America, Hawaii, or Europe. From all-inclusive escapes to bucket list adventures, Apple Vacations makes it easy to create memories with the people who matter most. Start today at AppleVacations.com or contact your trusted travel advisor.

59:47Apple Vacations, where your story starts. This is Ashley I from the Almost Famous Podcast. Can I be honest for a second? Some mornings I look in the mirror and I think, why do I look this tired? Puffiness around the eyes, dullness, because sometimes stress starts showing up on your face before you even realize it. And that's why I've been loving this holistic goddess organic castor oil roll-on with frankincense. No crazy chemicals, no expensive treatments. It's just organic castor oil, frankincense, and this rose quartz roller that feels so good on tired, stressed skin. I look for anything that can de-puff me and this really did my under eyes look brighter.

1:00:30My face looked way more refreshed. It's almost like my face just exhaled. So try the Holistic Goddess Organic Castor Oil Roll-On with frankincense yourself. Use my promo code Ashley at tryhg.com slash Ashley for 15 % off. Promo code Ashley at tryhg.com slash Ashley. hi i'm liam 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 first is that um 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

1:01:37Emily Oster: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 did the same thing with my three-year-old son when we were sharing a bed on vacation i bit his finger and uh luckily woke up before anything bad happened But yeah, can you diagnose me? What's going on?

1:02:18Thanks, guys. Oh, man. Okay, Perry, what do you think?

1:02:24Emily Oster: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 there's some stuff that you mentioned that sounds like it's worth discussing with a sleep medicine doctor. In particular, the acting out of dreams that we talked about in the episode can be associated 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.

1:03:16Emily Oster:There is a really clear test for this. 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. You mentioned something about position being important. So that also leads to the question of sleep apnea, but a video So 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.

1:03:50Emily Oster: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 hurt or come close to hurting a loved one who shares the bed with you. Yeah. And I will just, let me just say one thing about this and all 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.

1:04:22Like, 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, you know, 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. Yeah.

1:04:47Emily Oster: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? all. Wellness Actually is produced in association with iHeart Media. Our senior producer is Tamar Avishai. Our executive producer at iHeart is Jennifer Bassett. Our theme music is by Eric Deutsch. And our content is for educational purposes only. 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 wellnessactuallypod. And don't forget, we want to hear from you.

1:05:27Emily Oster:Head over to wellnessactually.fm and leave us a question for our mailbag or suggest a topic for a future show. We'll let the influencers have the last word.

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