# Medical Research is Going SciFi **Creator:** Hank Green **Platform:** youtube **Duration:** 29m **Source:** https://www.youtube.com/watch?v=G0xl0oIjKB4 ## Summary Recent advancements in gene editing therapies, particularly targeting PCSK9, have raised both excitement and ethical concerns in biomedical research. A small trial demonstrated promising results in lowering LDL cholesterol levels in patients with familial hypercholesterolemia, but the long-term implications of such genetic modifications remain uncertain. - Gene editing therapy aims to permanently alter the PCSK9 gene to reduce LDL cholesterol, potentially preventing heart disease. - The trial involved 35 adults with high LDL levels, showing significant reductions in both PCSK9 and LDL cholesterol after a single infusion. - Safety data from the trial appear positive, with no serious adverse events reported, though long-term effects are still unknown. - Ethical questions arise regarding the permanence of gene editing and its implications for healthy individuals versus those with genetic predispositions. - The potential for gene therapy to become a preventative measure rather than just a treatment raises concerns about accessibility and societal implications. - The discussion highlights the need for caution in advancing gene editing technologies, particularly regarding unintended consequences and long-term safety. - The evolution of medicine towards preventative measures, including gene therapy, could fundamentally change patient care and health management. ## Transcript [[0:00]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=0s) Things are getting pretty weird in biomedical research. Now, they've always been a little bit weird, but our tools are getting more powerful and the results are starting to feel promising, but also scary and they're raising questions that are harder to answer both scientifically and ethically. Questions like, for example, if you change the human body so that it creates its own medicine, what happens if the patient wants or needs to stop taking the medicine? And also questions like if a human body is functioning basically the way it evolved to function, how chill is it exactly to permanently change it? [[0:32]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=32s) Anyway, the reason I'm thinking about this is because of a very exciting but also tiny trial of a gene editing therapy that was published recently. There's a chance, though probably not a huge chance, that we'll look back on this moment that we're in right now as like a really big deal pharmacologically in terms of like how we are good at affecting the body. Probably not, though. and we're going to get into the probably nots of it. But heart disease remains a really big problem. It's still killing a lot of people and also there's like annoyance and disability that come with our current ways of treating heart disease which often involve cutting open a body and doing a bunch of work in there. And so it would be great if we just had to do that a whole lot less. [[1:10]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=70s) And there is this weird idea that has turned out to be a thing that definitely works in so far as it has a like a measurable outcome. And does it work in such a way that like someday everybody will get this treatment? Probably not. But like this is a moment where this weird idea that would totally have sounded fake to me 10 years ago became a thing that was published in a journal that was done in real humans that has had a real benefit for those humans. But in order to explain it, let's start here. Some people are born with genes that make them carry much less LDL cholesterol in their blood. And those people are dramatically protected from coronary heart disease. They are also somewhat protected maybe from other things including strokes. And then there are other people who are born with genes that make them carry much more LDL cholesterol in their blood. And those people get heart disease very early. [[1:57]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=117s) Sometimes they die dramatically prematurely because they have so much of this bad cholesterol. A thing that cardiologists will say is that it's like not where your cholesterol is now. It's the time under the curve. So if your cholesterol is super high right now, but it's been low, then that's not that big of a deal. If it's super high and has been high for a very long time, then that's really bad. And that is often what happens with these people who have these genetic predispositions to high LDL cholesterol. Now, we end up talking a lot about how much LDL cholesterol the body is producing. That's not what we're going to be talking about today. So certainly the body does produce this stuff, but also it clears it and there's a rate at which it clears it. So there's an amount that's produced, an amount that's removed, and the difference between those is the amount that you have in your body. The big genetic difference between people is how well the liver clears LDL particles out of the blood. So there's like little receptors, like little catchers on the surface of liver cells, and LDL particles will dock there and they'll get pulled out of circulation. They'll stop wandering around the bloodstream where they can eventually cause trouble if there's too many of them. In people with familial hyperc cholesterolimeia or FH, that's I think that I said that right, that clearance system is often broken or not functioning optimally. So you've basically, and I'm going to be very basicallying here, you have LDL receptors that grab and pull stuff out. [[3:13]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=193s) And those might not be work working right in these people. And then also you have this thing that kind of regulates how many of those receptors are on the surface of the cell. So like one is somebody gets produced. And there's also like a thing that cleans them up and removes them. And that's called PCSK9, which we're going to be talking a lot about PCSK9 in this video. So let's get used to saying PCSK9. So people with FH that have too much LDL, they might have too much PCSK9. But however it happens, the result is that LDL stays high from childhood, which is bad. Like it's not a bad month, it's bad forever. And so these people often die prematurely. Even with current pharmarmacology, like just taking statins, you might not be able to get these people's LDL low enough. But there are also people who have the opposite situation. They have PCSK9 that's kind of broken. So it can't remove the LDL receptors as well. And when that happens, when the PCSK9 works less well, more LDL receptors survive and the liver clears more LDL and blood LDL goes down. And those people are not usually suffering from anything in particular. It seems like their cells still make cholesterol. Their brains seem to work just fine. They just have fewer LDL particles circulating in their blood year after year after year. And these people are healthier than average people. They have less heart disease. [[4:26]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=266s) they seem to otherwise have no difference from an average person. And so you look at that and you're like, "All right, well PCSK9 is definitely a drug target." And first we did that with antibbody drugs that sort of just like globed onto them and and blocked them from doing stuff. And then we had RNA based drugs that reduce PCSK9 production. And now we have this new trial that just came out that is wild and asks the question, can we use gene editing to make the liver cells of a person who has maybe like overactive PCSK9 to have instead broken varants of PCSK9? Basically, can we turn them from people with familiar hyper cholesterol cholesterolimeia to people with familial hypoc cholesterolimeia where they don't have as much cholesterol? make them into the version of people that has less LDL. [[5:16]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=316s) So at this this came out of Eli Liy. They designed a trial called Verve 102. It is an invivo base editing gene therapy. And when I say invivo, I mean invivo in the body in the vivo. The patient gets an IV infusion. Inside that infusion, there are lipid nanop particles that carry two pieces of molecular machinery that work together. There is an mRNA that tells cells like it guides the cell to make a base editor like a thing that edits the DNA and then a guide RNA that points the editor to a specific place in the PCSK9 gene and then it makes like one single change. So this is different from crisper which is might might you might have that in your head where you have like molecular scissors that cut the DNA and pull out a chunk and then swap it with a new chunk. [[6:02]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=362s) This is like a one letter change. It goes to like one of the base pairs in the DNA and it swaps it for another one. And the goal is to do that in such a way that creates this broken version which is a one base pair letter change and you disrupt PCSK9 and liver so much that the cells make less of the protein or they make a broken version of the protein. I'm actually not entirely sure which one of those it is but the effect is the same. Now, the liver, important to say, the best place to start this work. It's just like where the blood goes, it goes and it filters through all of the tissues of the liver. And so, if you're doing an infusion into the bloodstream, it's going to be way easier to edit cells of the liver than edit cells anywhere else in the body. There's kind of like a sliding scale like the brain would be the hardest place to do this. [[6:47]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=407s) So, this is a convenient target because it is a liver produced protein and probably it's not really a protein that's produced much else in the rest of the body. So you can get it to the liver, edit in the liver, you know that you're doing liver stuff. The trial was an open label phase 1B trial. What does that means? It means everybody knows that you're getting the drug. There's no placebo group. And the main thing that they're trying to figure out is safety and dosing and whether the biology actually changed at all. And it was 35 adults. So this is a very small group, especially because they're being divvied up into different dose groups. And all of them either had hyper cholesterolmia or they had premature coronary artery disease. and they could not control their LDL. They had tried other ways of lowering LDL and they hadn't worked. So they took these people. So in these people they have kind of basically a disease and they're treating them for this disease. That's how we're starting this. We will discuss the fact that this is pointing us in a direction beyond that. But for now these are people with the disease and we're treating it. It's a very easy procedure. They got every one of them got a single infusion for 4 hours and they got different doses. So from.3 milligs per kilogram to 1 milligram per kilogram. And the results were the kind of results that make people start typing in all caps on Twitter. They're also the kind of results where you have to keep saying small trial, we don't have safety data yet over and over and over again. So small trial, we don't have safety data yet. So PCSK9 proteins in these people fell by an average of 51% at the lowest dose and 88% at the highest dose. And LDL cholesterol, as you might expect, also fell. The reductions were by dose 9%, this is going to sound weird, 9%, 44%, 45%, 33%, 51%, and 62%. That kind of bumpiness probably is just like a small trial effect. So, you definitely see like some version of dose response going on in there, but there's bumpiness in the middle, which is just there's not very many people in the trial. That would probably smooth out if there were more people, but overall, you got a clear picture here. One infusion changed PCSK9 LDL dropped hard in a dose dependent way and also this effect maintained itself. So as long as 18 months out the median follow-up was about 9 months. Participants are expected to be followed for up to 15 years because that is the only way this kind of thing can work. Like if you want to know the safety effects and how well the effect lasts over 10 years, you have to wait 10 years. As much as we would like for there to be a science time machine and that would make everything much easier, we do not have science time machines. Now, so far the safety data look good. Uh the Lily that Eli Lily did this, they report no treatment related serious adverse events. Again, tiny tiny trial um no dose limiting toxicities and the adverse events that they saw was like lowgrade infusion reactions, sometimes fatigue. So that's all great. [[9:33]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=573s) Uh, now there was no placebo here, so we can't even do that comparison, but it seems like, you know, if you're getting an infusion, you're going to experience some stuff sometimes. And if you're getting your jeans edited, you might experience some stuff sometimes. But important here, like, we don't really know how to do long-term safety with a drug that you can't stop taking. Like, this is really editing the genes of the liver to behave differently. So, this is something that we're not sure how to handle. It makes sense to me that we would not like immediately start giving this to a lot of people because we don't know. And importantly, an earlier therapy that worked similarly had enrollment pause after a serious drugrelated adverse event involving liver enzyme elevation and low platelets. That does not mean that it's going to have the same problem. Delivery system is different here, but uh you got to keep your eyes open as biology. [[10:18]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=618s) Biology is messy. Now, also importantly, all these people have had high LDL for a long time. So, it's not like they're going to have no heart disease in the future. They It's the area under the curve again. So these people still have LDL in their arteries. It doesn't just go away like the plaques that have built up have built up. But if you have had high LDL for a long time, it's very important to have it be as low as possible for as long as possible after that. But let's talk about why LDL is bad. So LDL and HDL are often called the bad cholesterol and the good cholesterol. And that's useful because we used to have it just be like all cholesterol is bad, but we've now we've broken it up into these two. But actually it's more complicated than that. Cholesterol is not cholesterol. [[10:57]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=657s) But these are both lipoproteins. They're little transport particles made of fats and proteins. And LDL particles carry cholesterol through the blood to tissues. The problem with LDL particles is that they can get into a wall of an artery. And I'm simplifying things a lot here, but like because of the immune response and inflammation and stuff, the smooth muscle cells will change and the artery wall becomes inflamed and it gets hard and that's a plaque. A heart attack is often the sudden ending to that very slow story. So the plaque will rupture and then the blood in the artery will touch this ruptured plaque and it is not supposed to touch that and then it forms a clot because clotting is supposed to be a fast process. It clots very quickly but it clots inside of the artery and if that clot blocks blood flow to the heart muscle the heart muscle starts dying. [[11:44]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=704s) This is the thing that we call a heart attack. There are other heart disease problems that are not this but this is a big one and it's called a heart attack. The plaque might have been building for 30 years, but then like the emergency becomes very sudden in that moment where the plaque breaks. And that is why LDL is so cleanly connected to coronary heart disease. If you lower your LDL, if you take your statins, major vascular events fall a lot. If you're born with genetics that keep LDL lower from the beginning of your life, the effect appears even larger because the arteries are exposed to less LDL for decades. [[12:13]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=733s) Some numbers here, you know, are are kind of hard to get, but one study estimated roughly 50 to 60% lower risk of coronary heart disease per 39 mg per deciliter lower lifetime LDL. But PCSK9 numbers sort of like dwarf all of this. So the 2006 study, the big 2006 study, PCSK9 variants in black participants, so black Americans were associated with 28% lower LDL and 88% lower risk of coronary heart disease. In white participants, a different PCSK9 variant was associated with 15% lower LDL and a 47% lower risk of heart disease. Now, these are specifically for coronary heart disease, not dying of a heart attack. Those things are certainly correlated, but it's a big signal like it's obvious that this is medically important. This is not a fake thing. And that is why they started working on this line of therapies. Now, stroke here is also important, but more complicated. LDL lowering helps prevent some kinds of strokes. Essic strokes are connected to atheroscleros a freick me atherosclerosis god. But stroke is not one thing. [[13:17]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=797s) There's a lot of kinds of strokes. So it will lower risk of stroke but only because it lowers risk of some strokes. Probably doesn't lower risks of all strokes. So LDL is definitely a heart attack story. Like big heart attack story. Um statins reduce stroke risk in trials. So we know that there is some effect on stroke. But the PCSK9 loss of function genetics point much more toward this is a coronary heart disease fix than this is something for stroke. But it wouldn't like make it worse if anything's going to get a little better at least. Now you might be thinking okay why not just do statins? With people with familiar hyper cholesterolmia they often cannot be helped enough just with statins. For the average person though there's another problem with statins which is not that they do not work. They work. The problem is that they ask us to do a thing that apparently is difficult for humans, which is take a medicine every day for decades in exchange for something that never happens. People who have had a heart attack have are better adherence to statins than people who have not yet but are having their heart attack prevented by it. But even those people, even people who have had a heart attack, often go off their statins just because like when you take a statin, you don't feel anything. Your smartwatch doesn't like go off and say, "Good job. [[14:30]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=870s) you prevented a heart attack today. This is the day you would have had the heart attack. You never get that. So, it's just like a thing that people are bad at. And so, people go off their statins. It's like the adherence to statins is something like 50% over a year. It's less than that over two years. We are mammals. Our brains are bad at this. Prevention is hard. Um and and so a lot of heart attacks, like one of the leading causes of heart attack today is people being bad at taking their statins. You know, you could put it that way. So, this new gene editing thing, like, you can't go off it. It It's almost to solve for a behavior problem, which feels a little dumb, right? Like, you'd think that maybe we could just get people to take their freaking statins. [[15:09]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=909s) And there are ways to do it. Like, I I know there This is a crazy thing, but um some people have chronically low vitamin D, but are just so bad at taking vitamin D that they never do it. And so, they're prescribed a monthly vitamin D shot instead of just taking the cheap pills. But like if you have this problem, you can't do it. Like you can't you got to deal with the brain you got. And so like maybe we could have something like that where like some kind of thing inside of you, an implant that releases your statins every day. I don't know. I I don't know what's possible. But this is like a way around it. And also for these people who even with statins, they can't control it effectively. That's a a legitimate advance. And that's what this therapy is targeted at right now. But I keep kind of half talking about the other thing which is would this be a therapy that a healthy person would get who has like normal genes and and we're so let's talk about that I guess first of all uh huge uh benefit of a statin is that you can stop it if you have adverse effects and there's also PCSK9 antibodies that block PCSK9 from working that also wears off RNA drugs wear off gene edits don't leave like they're not they don't wear off. I mean, maybe. [[16:23]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=983s) We're not actually sure in the long term if there's like a slow tail off, but over 18 months, it doesn't look like there is. So, that's crazy. But if you were to do this to a person who is healthy, you're going to have a bunch of risks that we don't know about with 35 people. So, first, you could edit somewhere you did not intend to edit. Uh, and that could be in genes elsewhere in the body, different genes. It could be in the same gene elsewhere in the body that is doing a different thing somewhere else in the body. That doesn't seem to be a thing with PC CSK9, but you know, certainly with other gene therapies, you have to worry about that. [[16:55]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=1015s) And maybe with this, I'm not sure. I'm not an expert on this. God damn. You could also edit in the right place, exactly the way that you wanted to, and then learn that the biology had some job that you didn't appreciate. You could have immune reactions to the delivery system. So, like you've got these two little pieces of machinery. The immune system might react to them. That might be why some people got fatigued. Rare events are not going to show up when you do 35 people. They're going to show up when you do 35,000. And those rare events might be so impactful that you do not want to do it for the other 34,995. [[17:26]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=1046s) You know, it looks safe so far, but permanent editing of an adult's genes is not going to be in the same category as a drug that will go away the month after you stop taking it. But also, like I I don't know where I feel on the ethics of this. I think I I don't know. I'm not going to say like I have I don't know enough to have a strong opinion on this. When the body is making its own medicine kind of permanently, if you if you take a medication and you hate it, you can't stop. Like in general, if you take a medication and you hate it, stopping is a thing that you could do. With a permanent edit, that changes and that just part of your body now. Like the therapy becomes a part of the patient's biology and that's like might be initi like what the patient wants at the beginning. It might be what saves them, but also, you know, you need to make sure that everybody like gets this cuz it's a different kind of thing. I think that people will get it, but like I sometimes I'm surprised by what people don't get. People with a disease that causes their LDL to be very high, I think this is pretty straightforward. [[18:26]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=1106s) But people who are like born with normal bodies and like the everything is just functioning correctly and then you go and you break a gene and it means that they have a longer healthier life on average, that's crazy. I don't know. That's weird, right? like we're headed there. And it's not just this one thing. Like eventually you get pressure toward taking that step, not just in this way, but maybe in a lot of different ways. If this works for people with a very high genetic risk, then people are going to start to ask whether it should be for people with moderate risk. And then you ask if it's what about people with average risk? And then what about people who just have enough money and they don't like the probability curve that they were born with? And also, if it's all about the area under the curve, do we just do this when somebody's 18 or 19 years old so that they live their whole life this way? I don't know. I don't like I'm not trying to sell this. I'm not trying to say that we shouldn't do it, but like we are headed down a road where you like at some point maybe you're 20 years old and you get a bunch of gene edits and and some of them aren't going to be specific to you. Some of them are like are just things that maybe everybody will be on average healthier and happier if they get them. [[19:35]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=1175s) I don't know, man. That's weird. Medicine has always treated disease, but more and more of medicine now is about increasing the number of healthy years a person gets. And of course, we already accept this with behavior, like don't smoke, wear sunscreen, exercise, eat fiber, sleep. Those are the main ones. And this is also already a thing with medicines. Now, we're weirder about it with medicines. You know, vaccines are preventative medicine. Blood pressure drugs are preventative medicine. [[20:01]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=1201s) Statins, prep. And we're starting to talk about vaccines that can lower your risk of certain cancers, especially for people at high risk. All of this is headed off in a direction that like medicine not just being about treating disease, but medicine being about people having longer, healthier lifespans with lots of sort of like little preventative changes. But gene therapy for prevention, I don't know. It feels like a little weirder to me. I'm just I'm curious how people think about this because like I don't I don't know. I'm fine with it of course for people who have, you know, lifelong super high cholesterol. That's great, but like what about for everybody? I mean, obviously we're not going to do that right now. [[20:39]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=1239s) It's a trial with 35 people. So, I'm jumping way ahead here, but I don't know. I spent a lot of time watching science fiction about this kind of stuff. And you start out with trying to have people have fewer heart attacks. And what do you end up with? You know what? Like where do we go from there? Hopefully it'll be boring. I feel like it might be boring, but at the same time at the same time, people are crazy about this stuff. So there's like I I am like letting fantasy run ahead of the science. And that's normal. You might think, okay, well, if we can edit PCSK9 to prevent heart attacks, why not edit like a thing so you never get colon cancer? And like maybe you could edit something to lower your risk of colon cancer. It seems like there's like a really good target here, which there isn't for lots of diseases. This is a thing that we see over and over again in medicine. We're like, "Oh my god, we found this amazing new therapy. It's going to be able to apply to all kinds of things." And then it turns out that it applies to basically the thing that you applied it to initially and kind of nothing else. And there's reasons why PCSK9 is like really a good candidate here. Colon cancer is a great example of something that wouldn't be a good candidate. So, you've got a bunch of different failures all in a row and and like they happen in different orders and sometimes they like it happens without any of these. So you've got like a bunch of different genes in involved and you've got also things that are not genetic. You've got microbiome and inflammation and you've got the architecture of the tissue. You've got stem cells tucked down in the crypts and editing that is going to be a lot harder. We didn't just do a thing that means like okay we can edit these so that we can solve every problem. That's definitely not what happened here. [[22:04]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=1324s) There's like a a bunch of reasons why PCSK9 like checks a bunch of boxes unusually well. So the target tissue is reachable. The edited cells are longlasting. The disease has one big genetic thing that can be affected and also the desired change is seen in people who are already healthy and seem normal and happy and we can see that they have normal lives that are better. We're not going to get that for everything. Now, I will say it's fantastic that we get that for this because coronary heart disease is a big problem. It's a big killer. It's a big cause of disability. Like absolutely a win. And I just want to note that like with Heart Attack, the wins have been coming for a long time. We have done a huge amount here. I like I just recently watched Contact. This is a weird segue, but the movie Contact based on the Carl Seagan book. The main character, Ellie Arowway, her father dies of a heart attack. And watching it now, I'm like, well, that's convenient for the plot. [[23:00]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=1380s) This young father uh dies of a heart attack. But like actually, when the movie came out and like this takes place in the past as well, like it's it's not in the present of the book. So, this is like a flashback kind of thing. Actually, a lot of middle-aged men died of heart attacks. A lot. A man in his 50s dropping dead of a heart attack in the 1970s was like an ordinary nightmare. This is like the thing that it just happened all the time. And we changed that. Like, this stat is wild. [[23:26]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=1406s) From 1970 to 2022, age adjusted death rate from acute heart attack in the US fell by almost 90% already. Like, that already happened. That almost doesn't feel real to me. So, like it's wild to like watch that scene now and be like, "Oh, that's kind of like so convenient for the plot." But no, like it's it it's changed. Like I feel that way now because the world changed and I don't remember what it was like. I mean, I wasn't alive in the ' 70s, so that's part of why, but like a bunch of stuff happened. cholesterol testing happen, understanding of how cholesterol works, statin, aspirin protocols, but also like the functionality of the medical system, ambulances, like whole wings of the hospital that didn't exist. You've got drugs that are good at breaking up clots. You got a bunch of treatments that we didn't have back then. You like stances. We didn't have stances then. I don't know if we had bypass surgery. [[24:19]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=1459s) When did we get that? I remember my grandmother having bypass surgery in the 80s or ' 90s. And also we just like understand the progression of coronary heart disease better and we understand the progression of an individual heart attack better. Like what do you have to do? How much time do you have to do it? How do you get people to care fast enough? etc. So like all this stuff changed and it wasn't like one big thing. It was a bunch of things. So we already have made so much progress on this and that's part of why cancer deaths are going up because people aren't dying of heart attacks which is great. Now we have to take on cancer which is not the subject of this video though maybe you know you could see you could see potential applications here. I I'm just kind of surprised by how I'm feeling right now. And this is not just a conversation about this trial, which is, you know, probably 10 years out from being a regular medicine. Maybe not. I hope not. You know, if it can really help people with chronically high LDL, then that would be great. And if it happened sooner, but like it's tricky. [[25:12]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=1512s) It's Anyway, I am surprised by the way I'm feeling, which is with this and with other things just very much in the middle of history. Like I think the normal thing is to kind of feel like you're at the end of history because of course you in one way are you know history happened and now we're in the present. But I just I feel so in the middle of history right now. Like the tools that we have developed are so advanced and so powerful. But there are things happening right now where I'm like so you're delivering little RNA machines into cells to rewrite people's the DNA of people's genomes in their livers specifically in their liver. [[25:47]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=1547s) That's wild. That feels so much more powerful than than a lot of the way that I imagine medicine to work. Like that really feels like sci-fi. It feels like I'm reading a Michael Kiteon book. So, I get that the tools are powerful. These new ones feel so sci-fi. And at the same time, I don't know. I've lost like friends this year and it like just way too early. I have another friend who is, you know, at the end of her life in in her 50s and it's just unacceptable. It is so frustrating and I just like we've seen so much progress and sometimes that like invisible progress like it's background noise but like it's so real but also we have so much more progress to make and I'm like a little like ready you know it's just making me antsy you know and and but it's also making me feel like hopeful of course like of course I have lots of people for whom this has been too late for but like we're getting better at stuff it's kind of amazing and now at the same time like it's going to be a part of this terrible system that we have. And I worry about that. But like there's nothing like a human for seeing a problem and thinking, okay, well, maybe it doesn't need to be that way. And death, I don't know. Like I'm not going to say we're like close to like I'm going to die. I'm aware. Uh but but like it's a problem. like it's natural but it's I should make a video about this but like I'm not a person who's like I don't know death is a part of it and it but like no it's a I as a person who saw that who like you know had a window into it like no that's bad I don't want to do it natural things aren't necessarily good like you know cancer is natural I'm not a fan I've seen too many of my friends die now I do feel some belief that this will happen relatively slowly like understanding the long-term impacts of gene therapy is just going to take a long time you can't like there's no science science. Time to shame. [[27:34]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=1654s) >> But I can't help but get the sense that like some subop is going to figure out how to do weird stuff to themselves because they're already doing it. The peptide thing is very like let's get weird vials of stuff from China and inject it into our bodies. That's already weird. Um and people are taking active pharmaceuticals like retatrite is a great example that are not through clinical trials. there's good evidence that they're good therapies, but like often times taking them when they there's other available treatments that would probably be just as good and are much well more well understood. And I I don't understand this the psychology behind this, but it obviously exists. [[28:10]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=1690s) And if someday we see it with gene therapy, that would be wild. Like if people are ordering gene therapy kits from from some other country and getting them in the mail and like giving themselves an infusion, which is not impossible to imagine doing, right? This is all imaginable stuff. That's a goddamn mess. That would be a goddamn mess. And and like I don't know like watching a bunch of people in Silicon Valley give themselves offmarket Red Trudeide makes me feel or like other weird ones that I've never heard of and they're like yeah you know sometimes it it like gives you a bunch of new moles and I'm like oh god don't do that. Like if like if it's doing that what else is it doing? Don't don't I don't know what that I don't know what that one is but I saw this on TikTok where it was like yeah there's a peptide I'm taking. It gives me new moles. Ah. Ah, that's no. [[28:55]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=1735s) And so if people are doing that, like I could totally imagine someday ordering a little kid on Amazon, giving yourself an infusion. It's not that hard. You know, I know how to hit a vein. That sounds like that sounded weird. I do, though. You know, I've had a lot of blood draws. It's It's a It's a thing you could learn how to do. I don't know. I'm letting the sci-fi get ahead of itself. So, what I think I should do is maybe talk to an expert. So, I'm going to do that. It is so weird to feel as if I am in the middle of history in a way that I have not for most of my life. I just feel very in the middle of history right now. [[29:29]](https://www.youtube.com/watch?v=G0xl0oIjKB4&t=1769s) But so far, you know, everybody's been in the middle of history, so I should get used to it. And so apparently should