 of career that has bridged both academic and industrial research. Currently, Dr. Corn is the founding scientific director of Innovative Genomics Institute, which is a unique collaboration between UC Berkeley and UC San Francisco. Additionally, he is an assistant professor of molecular biology and bio-physics, oh, molecular and cell biology at the University of California, Berkeley. Previously to this, he was a group leader at Gen and Tech, noted for incorporating multiple fields in the development of new therapeutics. The current aim of his research is to end genetic disease, such as sickle cell disease, through the development of next generation genome editing technologies. These tools, such as CRISPR-Cas9, have allowed novel discoveries about the fundamental workings of cells and also the mechanisms of diseases. Additionally, Dr. Corn has publicly spoken about potential ethical challenges posed by widespread applications of these technologies. Please welcome Dr. Corn to the stage. Thanks very much for having me here today. Good afternoon. This conference has been really fantastic. I think this is one of the wonderful things about a liberal arts education. I did, my undergraduate at a small liberal arts college, University of Puget Sound in the Northwest, and this is one of the things that I think is so great about these environments, you know, merging both questions about science with questions about how do we think about these things? You know, not just what can we do, but what should we do? I'm gonna start by getting a poll from the audience. I didn't warn anyone in advance I would do this so there's no clicker or anything like that that you can do. But this is an easy poll. How many of you have read a book or seen a movie that incorporates genetic engineering? Right, Jurassic Park or anything like that, Gattaca, right, did it end well? So, typically this is the way we think about genetic engineering, right? In popular culture it's very often this warning sign, scientists go off into a lab, they do something crazy, they make dinosaurs and those dinosaurs end up eating the scientists and it's not great, right? But there's another side to new possibilities in genetic engineering and that's potentially someday to be able to cure genetic diseases. That's one of the things that I'm very passionate about. Genetic diseases are caused by mutations that are in people's DNA. You can treat genetic diseases right now, but it's so-called palliative care. So you treat symptoms, but the underlying cause remains the same and what the hope is for genetic diseases to give people the possibility if they want to be able to treat the mutation in their genome. So that's what I'm gonna talk about, where are we? And not in some sort of science fiction way, but really like where is the technology? What's actually realistic? What can we do today? What might we do in the future? And I promise no dinosaurs. So let's start off by talking about what are we really talking about? We're talking about genes and genes are things inside all organisms that really shape life. So bacteria have genes and in fact the rise of resistance to antibiotics is caused by mutations in genes that are in the bacteria that allow them to process those antibiotics. Whenever you look at your favorite furry friend you can see genes at work. So all dogs are related to each other and just small changes in a couple of genes give the huge diversity between dogs. And of course, if you look at your neighbor you can look left, look right and try to figure out are their ears attached or are they separate? That's a genetic trait, okay? But genes can also go wrong. So mutations in genes can cause genetic disease. This is a picture of the so-called bubble boy. This person was born with severe combined immunodeficiency or SKID. The end result of SKID is that people are born with no functioning immune system. And so they need to be isolated from the environment because they get sick very, very, very easily and very, very badly. The thing about SKID is that there are many, many, many different mutations that can lead to this and all of them result in having no functional immune system. Now there are other types of genetic diseases where there's a single mutation that can cause that disease. An example of that would be sickle cell disease. So everyone with sickle cell disease has the same mutation, okay? And it's in a protein called hemoglobin that normally carries oxygen. And that mutation instead causes the hemoglobin protein to clog up capillaries. So it makes your red blood cells form this weird shape, clogs up capillaries, and it leads to very, very severe pain, okay? That capillary clogging also leads to a greatly decreased lifespan. So in the developing world, people live until maybe they're around 45. In Sub-Saharan Africa, where the trade is most prevalent, people usually die around age five, okay? So this is a genetic disease. Sickle cell disease is very prevalent in tropical or other countries where malaria is quite present. And so in the US, the trade is most often found in individuals of African descent. But it also pops up all throughout the world. So like I said, there are plenty of people in the US that have it, but there are millions of people in Africa. So what we're really talking about here is a huge amount of genetic information in someone's body, okay? So if you think about your body as sort of a, each cell contains a library of genetic information, and that information gets read out. Most of the time when you have mutations, those mutations cause a typo, but you can still figure out what the sentence says. So you can think about maybe you're reading through a book and there's something that changes a word a little bit, you can still figure out what that means, and that would be a neutral mutation. And actually between you and the person sitting next to you, there are thousands of neutral mutations, and they're basically benign. They don't really do anything. But every once in a while, there's a mutation that changes the meaning of a word, and it can change the meaning of the word very, very, very seriously. So simple example might be, if you think about the word dancer, that's one letter away, a C from the word cancer. So you can imagine that in the entire book, if the word dancer gets changed to cancer in just the right way and just the wrong place, that can be really bad. So what do we hope in terms of genetic engineering, the hope is really to be able to take this huge amount of genetic information and to flip things back, to be able to take mutations that have arisen and put them back into a state that does not cause disease. One of the reasons why people are really excited about genetic engineering research right now is because in the last couple of years, we've now understood much more about our own genomes. So when it comes to reading genomes, sequencing genomes, sequencing people, understanding what mutations are out there, there have been huge, huge strides over the last decade. It's now actually possible for individual patients to have their genomes completely sequenced, the procedure is totally non-invasive and it really only costs about $1,000 when you get down to it. So it's actually quite cheap and it gets done on a relatively routine basis. The problem is what you do with all that information because what I told you is that if you take any two individuals and you sequence them, there are going to be thousands of changes and most of them don't really do anything. So there's a big question about how do you know what mutations cause problems, but then of course, once you figure out which one causes the problem, you need to be able to do something about it and that's where genome engineering comes in, gene editing. The problem is we're much better at reading than we are at writing. So we've had tools to be able to change genomes for about 20 years. Things are starting to accelerate. CRISPR-Cas9 is one example of that acceleration, but we're still very new at this. So like I said, gene editing has been around for about 20 years. So that might be a little bit of a surprise to people in the audience, why am I only hearing about this now when it comes to science? Why isn't it that I heard about this 20 years ago? And in part, it's because it was pretty hard to do. So the first gene editing tools were called zinc finger nucleases, and it might surprise you to know that these are actually in the clinic right now. There is a company that is using zinc finger nucleases to try to cure diseases, and in fact, they have pretty promising results to try to cure HIV. So the idea here is that HIV attacks a certain cell in your blood, and it does so by binding onto a certain thing that's on the surface of that cell. And that thing that's on the surface of the cell doesn't seem to do much else. So what do these gene editors do? They delete the thing on the surface of the cell, and now the HIV has nowhere to go, and you can eventually clear it out. So this is actually in phase two clinical trials for HIV and has been shown to cure people of HIV. But again, zinc finger nucleases are hard to use. They're slow to deploy. You really have to be a specialist in the art to use them. So what has really changed gene editing research is the development of so-called CRISPR-Cas9. And the fundamental advance here is not the idea of gene editing in and of itself, but the democratization of gene editing for research and hopefully, eventually, for therapy. So what is Cas9? Let's take a sort of geek out moments, talk about how does this thing actually work. I'm going to present a little blob. In this blob, you have Cas9, which is the protein, and it's recognizing a piece of DNA and opening up that piece of DNA. Cas9 then uses a piece of RNA, which is another piece of so-called nucleic acid in the body to recognize that. So when I talk about DNA and RNA, just think back to ATGC, that kind of thing, which hopefully you've heard about before. One thing you might remember about DNA is that you have pairs of these bases, these nucleic acids. And the way that works is A always goes with T and G always goes with C. That's really the fundamental thing that's transformative about CRISPR-Cas9. If you know that A goes with T, G goes with C, which I just told you, that's it. That's all you need to know to design a genome editing region. So you no longer have to spend decades figuring out how does ink fingers work and what cases do they work and what cases don't they work. If you know that A goes with T and G goes with C, you can design a genome editing region. And that allows people to, instead of focusing on the ins and outs of the tools, they instead can focus on just making the tools, reprogramming those tools and using them. It also means that reprogramming this is simple and easy, and as you'll hear in a bit, that means that you can access many more problems. You can access many more different diseases and ask many different questions that you couldn't get to before. So the way genome editing actually works is you make that program change on the RNA, the ATGC part, and that brings Cas9 to a certain area of the genome. And then Cas9 cuts that part of the genome. And that might sound surprising, right? We're talking about editing. Why are we suddenly doing cutting when we wanna be doing editing? And the reason this works is that all organisms that are out there have evolved great ways to protect their genomes. So if you get a cut inside a genome, your cells will repair that cut. Your cells have defenses against DNA damage. And in your cells, this happens in one of two ways. On the one hand, you have error-prone repair, which leads to deletions and insertions at a region. And on the other hand, you have the opportunity to put in extra information, which the cell will then copy off of and incorporate that information. So what does that mean? When you get the insertions and deletions, that will disrupt whatever's there. So if there was information that was doing something, let's say something said dancer, now it might say DA, XQ, blah, blah, blah, right, all kinds of weird stuff. It breaks whatever was there, okay? That's useful from a research point of view, because the way we do research in biology is taking something that works already, say in a cultured cell or in a model organism, and we try to break it in very precise ways and ask, how does breaking this thing in this precise way change the outcome? That's the way we learn things about the world around us. That's important because the world around us is very complicated. And so instead of trying to say build a car engine just from a whole bunch of parts laying around, we start with already working car engines and take out one piece at a time and ask what does this do? So Cas9 on the one hand is a way to ask fundamental questions about how the engines that are ourselves actually work. From an editing point of view, the sort of more surgical way of doing things, we can swap mutations in and out in a very precise way. So instead of putting in that weird, crazy, ex-QZ in the middle of Dancer, we can take the sequence that says Cancer and change it back into Dancer. So it's very precise and very surgical. So there's uses for fundamental research and there's potential to curing genetic disease. But one of the things is that context really matters. Turns out that not every cell in your body has the same types of repair mechanisms as every other cell. So one of the things that people are trying to figure out right now is when you try to make these fixes in, say, a brain cell versus a blood cell, how do we better control and get the outcomes that we want? So I really wanna stress that we're not at the science fiction future now where we're just able to put these kinds of changes into cells in patients right away. We're still in the, we have new tools, we need to understand how they work and we need to understand how they intersect with our own bodies. So let's zoom in a little bit more from the blob. What I'm showing you here is a 3D model of Cas9. So this is actually what Cas9 looks like. This is based on a so-called crystal structure that was solved relatively recently. So this is actually physically what Cas9 looks like. Cas9 is the protein that's in white. The gene that it's recognizing is in blue and the guide RNA which gets used to pair to the gene, the ATGC pair, that's in orange. We can pop away part of Cas9 and you can see that what happens is the guide RNA wraps around the target gene and when it does so, it leads to these breaks. Once those breaks get put in, that's the signal for the cell to say up, I have a break in the genome and I need to repair it, I need to do something with that. So really Cas9 is a little genome editing machine. I'm not gonna get into the details of how Cas9 and CRISPR systems were discovered other than to take a quick aside to say, CRISPR-Cas9 is one of the really amazing stories of how fundamental research can have huge implications for application and potentially treating therapy. Cas9 and CRISPR are actually bacterial systems, the bacterial machines, they were discovered by people not looking for genome editing machines, there were people who were just trying to ask, how is it that bacterial work? And it turns out they have huge implications for treating disease. So I think one of the lessons that we have is, it's important to, maybe a better way to put it is, fortune favors the prepared mind, you need to go out and ask good questions about the world, but it helps to just be curious and to ask those questions without saying, I wanna find a genome editing machine to just ask generally, how does the world around me work? So let me come back to the idea of democratization. I told you there's this easy way of doing the retargeting, what that does is it really changes the way we think about using these genome editing tools. It used to be that a whole bunch of people would have a whole lot of different questions. And if you wanted to ask those questions using genome editing, you'd have to go to your one genome editing expert, and then everything would bottleneck around there. And so things slowed down a lot. And actually they ended up being quite expensive. And with Cas9 what happens instead is that everybody now can use these tools themselves. And so that's one of the things that I wanna put out there is, using Cas9 and CRISPR systems to cure genetic disease is very, very exciting. But one of the huge possibilities here in general for therapy is the ability to ask and answer questions that are more fundamental, much more rapidly. And that's really I think sort of the snowball effect that will have an effect in our lives. So curing genetic disease is a really important part of CRISPR-Cas9, but now being able to ask the hundreds of questions that people might have and not have all that research bottlenecked in one little area, I think is gonna lead to a huge acceleration in fundamental understanding which will eventually lead to more cures for even non-genetic diseases. To give you an idea of how quickly things are moving, this is a chart showing how many publications mention genome editing. I told you that genome editing was around for about 20 years, so it was in the 90s, but the mentions of genome editing in the literature, in scientific literature were so small before the invention of Cas9 you can't even see them on this graph. So a few people were working in Cas9 right when Cas9 got discovered and CRISPR systems got discovered and deployed, the mentions of genome editing just absolutely exploded. So at this point, there are about 4,000 Cas9 publications in the past four years alone. There are about four papers published every single day. The field is moving at an incredible pace. And I think that just gives you an idea of how exciting people find this. So the use of CRISPR-Cas9 is really transforming biology by letting people ask these kinds of democratized questions. So it's useful in a variety of model organisms. It turns out that it works in non-human primates to ask questions that might be even closer to human health. It works in agricultural species such as wheat, corn, things like that. In my lab, we tend to use it in human cells. So this means, like I said, not only can we use it to ask fundamental questions for research, but we can potentially have hope to apply it towards genetic disease. But as a quick aside, it could even have impacts beyond that. So people have also shown that genome editing using Cas9 works in agricultural species, goats, cows, chickens, et cetera. And people have shown that it works in mosquitoes and the malaria parasite. So people are starting to think about ways of potentially eradicating malaria using genome editing tools. That's a topic for another day because I think we wanna focus on the possibility for, say, genome editing and reproduction. So let's give a concrete example of how genome editing might change the way people treat diseases. Let's focus this on sickle cell disease. Sickle cell disease is a blood disorder. So it's caused by sickling of red blood cells, but that eventually comes all the way back to bone marrow. Your bone marrow is the source of all the blood components that you have. Now, sickle cell disease can be cured permanently through a so-called allogeneic transplant. And allogeneic means you take the bone marrow from a healthy individual and you transplant it into someone with sickle cell disease. And that then renders them healthy, right? They no longer have the bone marrow with the mutation. They have the healthy bone marrow and that cures them. But there are a lot of problems with this. Number one, it can be very hard to find a donor. Number two, the act of doing this bone marrow transplant, you have to ablate the bone marrow and that renders the person who gets the bone marrow transplant infertile. And number three, there is a small chance, about a 1% chance, that people who get this bone marrow transplant will reject the graft. They may have to get another bone marrow transplant to replace their own bone marrow, giving them the disease back again. Or there's a possibility they may never wake up from the operating table. From a gene editing point of view, what we want to do is instead turn this to an autologous transplant. And the easy way of thinking about this is we want to make people their own bone marrow donors. So we want to take someone's bone marrow, which has the sickle cell mutation, take it out, edit the gene to put it back into wild type and then transplant it back into that person. So in this way, rather than taking bone marrow from a healthy person, putting it into someone with a disease, we take someone's own bone marrow where they have the disease and turn it healthy and put it back in. Sickle cell disease is just one example of this. So there are about 100,000 people in the US that have sickle cell disease, which is actually a pretty large number. But worldwide, there are about 350 million people that have some form of genetic disease, at least that have been identified. There are 7,000 different monogenic disorders. That means diseases that are caused by mutations in a single gene, that we know of. And part of the reason people are very excited about CRISPR-Cas9 for genome editing is exactly what I told you previously, which is that it's very easy to make neuroagents. So if it's very hard to make a different genome editing agent, say it takes a year for each one, you can imagine if there are 7,000 different diseases and it takes a long time to make each one, it's gonna take forever to do this, even leaving aside all of the challenges around doing regulation and safety and things like that. Even just finding the first agent to do the editing is gonna take forever. But Cas9 is very fast, it's very easy, and so at least on paper, it could be possible to make a different genome editing agent for each individual mutation, which brings up the idea of personal cures. And the reason I think this is so powerful is something that is actually not private to genetic disease, but it's the idea of something called the long tail. So the long tail may be recognizable to you in the context of something like Amazon or doing Google searches or things like that. And the idea here is that when most people go out, they look for, say, two or three things, two or three products, and that covers a lot of space. Maybe 50% of things are covered by two or three products. So think about this in the context of genetic disease, a bunch of patients have two or three different genetic diseases. And the rest of the 50% is covered up by a huge smattering of a whole bunch of different stuff. That's the long tail, okay? So two or three things capture the first 50%, and the last 50% is covered by thousands. So that's a problem. If you have a tool or reagent to make a cure that is very slow to develop, you'd only be able to do something for the two to three, for 50% of people, for the people who have the two to three diseases. But to really affect the long tail, the other 50%, you need something that's fast and easy. And so the hope that we're not there yet is that Cas9 might be able to address the long tail. Now, there are a lot of challenges here beyond just making these reagents. When you start thinking about personal cures, you have to start thinking about, how do you show that this is safe? How do you run a clinical trial if there are only five people in the world that have this disease? I'm not going to address that because you could probably do an hour-long discussion about just that one issue. I'm gonna focus on just the, I'm gonna say it's potentially there. And so I think one of the things we need to do is start talking about what does the regulation landscape look like now that the possibility is there for the long tail. So I've been talking about gene editing in sort of generic terms. I'm now gonna make a split between so-called somatic gene editing and germline gene editing. Somatic editing means that you make a mutation that has not passed down to different generations. So an example would be this bone marrow transplant that I talked about. You take bone marrow out, you edit it, you put it back in. If the person who got that somatic edit now has a child, their child may still have the mutation passed down to them. The difference in germline editing is that you edit, when you edit the so-called germline, you might be editing the eggs or sperm or even the embryo. And that change would be then passed down through generations. And so that would mean, say, if someone had a genetic disease, you would cure it in them and you would then cure it in their child and cure it in, say, their grandchild. So let's talk first about what issues there might be. I've talked a lot about the promise and how excited people are about this. Some of these concerns came up in the previous discussion and I think were really well covered, but I just wanted to go over them really quickly. The first off being access to treatment. Now, I want to point out this is not a private problem to genetic disease treatment. In fact, the graphic that I'm showing here that shows their problems with stigma, drugs cost too much, there's no confidentiality. All of these things apply to the treatment of genetic disease, but this is a graphic from a WHO handbook, the World Health Organization handbook on treatment for HIV and AIDS. And every single one of these problems, access to clinics that can do gene editing, problems of confidentiality, how do you protect someone did get an edit, did not get an edit, how much is it really gonna cost? All of this applies to a new technology like genome editing. There's another problem which I think has not been covered yet but is no less important, which is part of the challenges of these genetic diseases that they occur in minority populations. And especially when it comes to sickle cell disease, these populations have not been treated well by the medical establishment. And so when I go out and I talk to patients with sickle cell, half of them are excited because they say it's really great that you are focusing on a disease that affects us, who happens to be a minority population. And the other half says, why are you giving us this experimental medicine that you don't actually know is not gonna have some terrible side effect? And I think that's a really important message to take home and one which I don't have a very good answer for. Like we talked about during the discussion, I'm trying to provide options for people but I think that we do have to think hard about where do we test these medicines, how do we show that they're safe and how do we do so in a way that's very responsible to the populations that we're trying to treat. And this especially becomes the case when we start moving into context where these genetic diseases are so rare that say 10 people in the world have the disease and so how do you actually run a trial when running a trial means affecting everyone? The third challenge even with somatic editing is that public acceptance of this is relatively modest. So this is a poll done by Pew Research which I think finished just a couple months ago and they asked people, would you want somatic editing? Not germline editing, but somatic editing. Remember not passed down. Would you want it for your baby if it had a chance of improving that baby's health? And you can see that it's about 50-50 split, okay? So these are people that say my baby is in trouble but I would not want to have editing done and I think it's very telling that in fact there's a split between whether or not people have kids or not and it goes at least to me it went opposite the way that I thought it would. If people have a child, they're actually less likely to think that somatic editing would be a good choice for that child. Now this is in contrast to something that I see a lot when I work with patients who have children with genetic disease. I work with a couple of different patient groups. Some of those patient groups are vehemently for somatic editing. I mean, they want to abolish the FDA and say I don't really want safety trials, I don't want any of that, give me the medicine right now because their children are suffering. And so I think this is another one of those things that would be really interesting to discuss in the future is to what extent do we empower patients to give them access to things when we cannot guarantee that they will be safe. So now let's talk about germline editing. I think people talk a lot about germline editing when it comes to genetic disease but I actually want to start off by talking about the research applications. So this picture is of Kathy Nyakin. She recently had a paper come out in which she asked a very fundamental question using germline editing. And the question she wanted to know is why is it that pregnancies sometimes fail? And you might ask yourself, well, this is surely we must know this by now. The answer is no, we know almost nothing about it. And part of the reason is we have had no tools to be able to ask anything about developing embryos in humans and there's been very little appetite to try to do that research. So Kathy in the UK did a very nice set of experiments trying to ask one part of this fundamental question. And I think that's one of the things that we want to make sure that we do when we talk about germline editing, we don't want to throw the baby out with the bathwater. We want to enable people to answer fundamental questions that will affect a lot of people's lives even in cases that do not impact genetic disease. Now there are cases where germline editing might be useful for therapy. So cases where not just editing the person who's afflicted with the particular disease but making sure that if they don't want to, they don't pass that treat down to their children, there are cases where that might be applicable. And one example of that would be Huntington's disease. Huntington's disease is a so-called repeat expansion disease. You have certain repeats in the gene and for reasons I won't go into, over time over generations they expand out. And what that means is that if the parent is a little bit affected, the child might be more affected, the grandchild will be more affected than that and the great grandchild might be affected most of all. So patients say, look, I'm gonna get a cure for myself but my kid I know is gonna have this disease and they're in fact gonna have it even worse than I do. Why can't I do germline editing to just stop this disease where it starts? And so I think again, this discussion needs to be a little bit more subtle than just like a somatic good germline bad or vice versa. I think we need to talk about these things in terms of specific diseases, specific patients and specific applications. I think we have a little bit of time to do this because it turns out that germline therapy, even if we had all agreed that it would be fine, it's not yet ready for the clinic. So number one, there's a concept of safety. How do you know that you're hitting just what you wanna hit, editing just what you wanna edit and not something else? It turns out that these editing agents can have pleiotropic effects, that means they can hit where you wanna go but they can also hit somewhere else. And until we get very good at only hitting what we wanna hit, you obviously would not wanna chain, you would not wanna pass these off targets on through generations. There's a more subtle problem which is one called mosaicism but actually maybe even more fundamental and harder to get over. Mosaicism is when different cells in the body receive different traits and this can happen in humans. It happens actually, everyone in the audience is familiar with a case of mosaicism which would be a tortoise shell cat. If you see a tortoise shell cat, all those different colors come because those cats are mosaic. Each cell in the coat has a slightly different trait. When you go in and you do germline editing, even in a model organism, such as in these mice which are a real life example, you can see that in these mice, some of the mice are white, some of the mice are black and some of them are modeled. And that's because not all of the cells in that initial mouse, in the initial mouse embryo got the same edit. And this has been the case with germline editing since people started to use it. It's a severe problem and again, we need to understand more about why mosaicism happens to be able to figure out a way around this. A third and possibly the biggest reason to not yet put germline editing in the clinic is really just do we really want to do this? And I think this is actually the biggest barrier. And I think for good reason. When we think about the previous thing, safety mosaicism, these are technical hurdles and those are things that could be overcome probably if we wanted to do it. Public sentiment, that's not something to be overcome, that's something to be discussed, right? That's a question of do we really want to do this? How far do we want to go? What's appropriate, what's not? And I think that it's telling that in this same pure research study, people asked would you be more or less likely to be in favor of gene editing if something was passed on to kids or not passed on to kids? And you can see that if someone made an edit that would be passed on to the whole population, very, very few people find that acceptable. So I think that's something that we need to talk about and I think we need to as societies decide is this something that we want to allow and if it is something we want to allow are there specific cases that we want to allow it in? Why do people even consider this? There's the disease point of view. There's also the question of enhancement. So I want to bring this spectra up in the room because I think this is something that we want to talk about because if we just talk about gene editing for genetic disease, the question becomes relatively easy. Okay, someone has a disease and we want to cure them. There are a lot of subtleties there that we did discuss just a bit ago but it's a little bit easier than saying, well, what about prevention of disease? So for example, there are genes that you can edit in the body that will prevent heart attacks, basically. So there are people that are naturally born that have these mutations and their cholesterol is basically zero. They're incredibly healthy. And the question is, should everybody get this? Rather than taking statins all the time, should everybody get this? There are mutations you can make that can make people more muscular. Like I said previously, there are mutations that can render people HIV resistant. So you might ask yourself, there are questions about enhancement where people talk about hair color and intelligence. Those are not really on the table right now. We don't understand what makes someone more intelligent or taller or anything like that. We do know single genes that could be edited that would render someone HIV resistant. Are those things that should be on the table? So I want to bring that up because I think that's one of those things where if we say yes to one, the question is how do we keep people from doing the other? One of the things that people have actually started to talk about is making edits that will enable people to go to space. So this is something that I think is, this sounds very science fiction, but is one of those things that people are thinking about for the long run. So it turns out humans are not adapted well to space at all. They get osteoporosis. They have, I'm not talking about the breathing in space. No amount of gene editing is going to fix the breathing in space problem. But for example, you develop heart problems, things like that. And so some people have said, look, if we are really, really serious about long-term space travel, sending someone to Mars, we don't want them to arrive on Mars and everybody on the craft has had a heart attack and has brittle bones, right? We need to do something about this. So I think this is one of those things that you would think would only come up in a science fiction book, but people are starting to talk about this and people are starting to say, look, if we're really serious about this as a program, we need to be having these discussions. So I bring this up sort of in the idea of vigorous debate for the further flung future. Finally, why would you consider germline editing? I think the fundamental reason that that is actually the hardest to argue about and comes up the most often with patients is patients say, look, you could do somatic editing and it's gonna affect, but just me. But I want my kids to have a better life than I had. And I think that's something that, personally, I find it very hard to argue with patients about that. How do you tell someone, no, that's not right. You want your kids to have a better life than you did. So I think that's something that we need to really grapple with and I think it's something that we really need to involve patients in. So what is genome editing gonna look like? I've told you a little bit about how the science works and what some of the technical and ethical problems are. Where are we today? Well, right now we can do a lot of research. We can figure out what genes do and we can use that to understand more about how we work and how the world around us works. And that really makes research much faster and much better. In the medium term, I think that we're gonna see really the rise of so-called synthetic biology. People are gonna be able to use genome editing tools to say make better fuels, to make better medicines. And in the medium term, we're actually going to see therapies for these blood disorders. So for example, sickle cell disease. There are several groups, my lab included, but also several companies that are working on cures for sickle cell disease. And several of them have gone on paper to say, we're gonna be in the clinic by 2018 to 2019. Not available for sale, but starting trial. So I think in the medium term, we will start to see somatic therapies for some of these blood disorders. And then in the long term dreams, here I really think the question is, what do we want? I learned a while ago that it's very dangerous to prognosticate about what's gonna happen in 20 years because everything is gonna be different in 20 years. But you might say, well maybe there's a way to do therapies completely in vivo. You don't take bone marrow out and put it back in, you just do an injection and treat sickle cell disease that way. There's this possibility that I brought up of personal cures where say two people in the world have a genetic disease or one individual person has a genetic disease. You could develop something that cures just that one person. So this is really the kind of disruptive science fiction that I think we really need to start talking about. Part of the reason we need to start talking about it is that even though things are early days and everything is kind of chaotic and we're sort of building this car while we're driving, the car really is a race car. Things are moving really, really fast. So we have to consider how are we gonna use this new ability? We're on the brink of these cures for diseases. We could use it for things like designer babies. I get asked questions about designer babies all the time. And there are these bombastic headlines about the end of life as we know it from just editing all the things. Because of these kinds of headlines, the scientific community together with you know, ethicists and sociologists got together and had a meeting in the National Academy of Sciences. You're gonna hear actually from some of the people who are at this meeting. I think to really summarize the outcome of this meeting it was a big yellow light. So what they basically said was germline editing is okay in some restricted sets of things. And I think that is an interesting, it's an interesting distinction to draw. Germline editing is okay, but it's only okay in some situations. When is it not okay? When is it okay? I think our moving targets, at least for me. Things are moving really quickly. I wanna give you an idea of how quickly things are moving, especially on the germline editing front. So just in the last month, three papers came out on editing in human embryos to either correct mutations to reverse potentially pathogenic mutations, or to just learn more about fundamental research. So there was this lull. People were trying to figure out, is this okay? The decision came down that yes, this might be okay in some situations and things are starting to go really fast. Like I said, there are a lot of technical hurdles, but there are also, I think that it's possible those will be overcome. And so the next question for us is just what do we want to do? So I'm gonna leave with just a couple of questions. Really what do you think in the audience? Some things to spark discussion, hopefully in the panel session and in general throughout the day. Just to ask yourself, if you had a genetic disease, would you edit yourself to cure that disease? Somatically, right? Knowing that that would be changing your DNA. Would you edit to prevent a disease? So let's say you didn't have a genetic disease but you had a mutation that predisposed you to something that would happen later in life. Would you edit yourself to prevent that disease? And would you undergo germline editing in either case? If you either had a genetic disease, would you undergo germline editing to prevent from passing it down to your kids? Or if that mutation just gave you a higher chance of getting something, would you get preventative germline editing to avoid passing that down to your children? And finally, how would you balance your own personal family priorities, right? Your own sense of self and your own sense of your own health and control of your own health and your desire to have your kids have a better life versus societal acceptance? I ask this because in several of the patient populations that I've talked to, they've said, look, I know this is not accepted. I frankly don't care. My kids in a wheelchair, they're just getting worse. I really don't care what anyone else thinks. I want this to go forward right now. So I'm not gonna say that I come down on one side or the other. It's a very complicated question but I would encourage everybody in the audience, those particular patients have come down on one side but I've also talked to patients that say, look, even though I have this disease, it's a scary thing. I don't want this type of editing at all. So I encourage you to think for yourself, what would you do if you were in that situation and let's hopefully talk about that over the day. That, I'm gonna finish up. Thanks very much for your attention. And now I think we go to the panel discussion. Oh, no.