Editing Your DNA with Nobel Prize Winner Dr Jennifer Doudna

There is a microscopic technology that now gives us the power to edit our own genes while we're alive, to cure certain diseases, possibly prevent others, maybe boost what our bodies can do, or even one day give our kids abilities that nobody has ever had before, effectively putting evolution into our hands. And this is not some sci-fi future. We are already using this technology in real medicines, in plants to grow new crops, in animals to create new species. It's called CRISPR-Cas9. And Jennifer Doudna won the Nobel Prize for discovering it. It's incredible. It's extraordinary. So deciding how we should use this new superpower will be one of the greatest challenges we have ever faced and one of the biggest opportunities to reduce human suffering. So, in this video, we're going to use specific examples to help you see how gene editing is already affecting your life and help you decide how should we use it, when is it wrong, and when is it wrong not to. This is Huge Conversations. Genetics. The secret of life. DNA. DNA. What does it mean that we have this new power? To eliminate diseases like hemophilia. Sickle cell. Alzheimer's. Huntingtons. It would almost be unethical not to use it. It's great to be here. Thank you so much for doing this. I'm really looking forward to it. My goal for this conversation is to work together to explain how this new power to edit DNA might really impact this audience's lives. What's possible? And how can we help this gene editing future go right? The audience that you're talking to is great. They are smart and optimistic. And also, because we cover so many different things, this might be the first time they're ever hearing about CRISPR. For myself, I have now done months worth of research for this conversation, but I'm no expert. Our bigger goal for this show, Huge If True, is to explore better futures, because we believe that when people are able to see them, they help build them. What's your goal in this conversation? Why do this interview? I share your goals. I think CRISPR is such an exciting technology. And it's the beginning of what will be possible in the future with genome editing and how we can manipulate our environment and our bodies to maximize our health and maximize our experience in life and to really understand our role in the world. So I'd love to share that with everybody in the audience. And I imagine incredible insights and science coming from all of them in the future. That's Huge If True. To explain why this is a huge moment in human history, we need to explain why CRISPR-Cas9 was such a big leap. My understanding is that we've known for over a century that there are specific molecules inside our cells that carry information in a four-part code. And then our cells use groups of that code as a blueprint for how to make the proteins that govern so much about us, from how we look to how we think to how we get or fight disease. But for most of that century, we could only read this genetic code. We couldn't change it. Could you help me understand how what you pioneered with Emmanuel Charpentier was different from the gene therapies and other gene editing systems that came before? What was the big insight and why is it so important? CRISPR is a technology that came out of fundamental science. The very first tool that was used for gene manipulation really was coming from the natural world and that was viruses. Some viruses naturally insert into the human DNA in our cells. HIV is one example of a virus that does that. By studying how viruses manipulate DNA and how they get into DNA, there were a lot insights about how we could potentially, as scientists, change DNA sequences. But we didn't have the tools to do it. So what happened next was that there were a series of tools developed to find a particular set of letters in the DNA of, say, a human cell and alter them using tools that were generated for that specific purpose. For the wonkier folks in the audience, these include zinc finger nucleases and talon proteins. These showed that DNA manipulation was possible and also could be very powerful. But what was challenging with those tools is that they were bespoke, meaning you had to make one of them for every single change that you might want to produce in a cell, for example. And that meant that they were expensive, they took a long time to produce and then to deploy. And this is where CRISPR comes in, because what viruses and bacteria over eons interacting in nature had figured out is that they could use proteins that were directed by molecules of RNA, which are chemical cousins of DNA. They interact with DNA, so they look at the DNA sequence on a letter-by-letter basis, but they allow easy recoding. And so scientists, once we understood how that recoding works with RNA, we could easily manipulate and change the sequences in DNA that CRISPR can recognize. And that's really the crux of the technology. It becomes a programmable tool that can be directed to essentially any DNA sequence where it can make a change in a targeted way and in a way that is easily controlled in the lab. So the big change is that within the last few decades, we've gone from observing our genes to trying to change them, but slowly and with one-off tools, to now with CRISPR, we have quick, precise editing, like a text editor for the instruction manual of life. What does it mean for us that we have this new power? What are the stakes here? Well, it's kind of profound, I think, because if you start imagining what you can do when you have that kind of capability to manipulate DNA sequences, it's everything from changing the ability of crops to resist drought or to produce more tomatoes, to changing sequences in a human embryo that alter heritable traits that get passed on for future generations. And so especially the latter application has truly profound implications. It means that if you think about it now as human beings, we have in our hands the technology to change chemically, fundamentally, who and what we are. It's quite extraordinary. Huge if true. Yes, thank you. You talk in your book about, you say, the question is not whether we can change our genes anymore, it's how should we? My understanding is that within that debate, there's a big divide between whether we're editing cells that are not involved in reproduction, so the change would end with us, versus cells that are, in which case they would get passed down to our kids and our kids' kids and maybe even a whole population, depending on the gene. Why is that distinction so important? It goes back to concepts like eugenics and thinking about even the Mary Shelley's Frankenstein, thinking about what we can do when we have the power to alter who we are fundamentally. And to me, and I think in general, it's a very different set of concerns when you're thinking about changing DNA in an individual, which of course has safety and ethical considerations, but nothing like if we're changing DNA in a heritable way, in embryos. The embryos can't make that decision, for one thing, and once that change is made, it's permanent, and it gets passed on to all future generations. And so you can imagine starting to change the whole genetic makeup of human populations if this were to go far enough. If I'm imagining this as two columns, one is somatic and one is germline, then there's also the type of change itself, sort of with a spectrum between treating diseases that we would all agree are diseases, to prevention of future diseases, to what some people might call enhancements, moving someone or their descendants into a new part of what is possible for humans. And I've even, because this is a show called Huge If True, heard people talk about changes that might move people out of what is now normal for others, so super enhancements. And in fact, in order to keep us grounded, I have prepared some specific examples. I'd love to use each of these examples and get your help to understand where do they fit into this debate, how real or not real are they scientifically, how could they actually impact the audience's lives or not, and what gets you most excited in these different categories. Okay, so my first example is curing sickle cell in one individual. Could you tell me the story of Victoria Gray and what's happening with CRISPR right now in sickle cell disease? Well, this is a big success of the CRISPR field. In the, I think, late fall, it was November and December of 2023, the Food and Drug Administration in the U.S. and their counterpart in the U.K. approved a CRISPR-based therapy for sickle cell disease patients. So these are people that have a single genetic mutation that gives them a very severe blood disease that results in frequent, you know, requirements for frequent blood transfusions, and if they don't have those, they have organ failure over time, they have very severe crises that happen frequently that are very painful for them, so you can imagine extremely disruptive to their lives. And with this CRISPR-based treatment, it's a one-and-done therapy that doesn't exactly cure the disease at the genetic level, but what it does is suppress the effect of the disease-causing mutation. And it does that by turning on the production of a protein normally only made when we're developing in the womb, which is a protein called fetal hemoglobin, that when turned back on using CRISPR can suppress the effect of the disease-causing mutation in adult hemoglobin. And as a result, people like Victoria Gray, and she was the first U.S. patient to receive this therapeutic, have not had another sickle cell crisis since receiving this one-and-done therapy. So it's incredible. It's extraordinary. And having talked to her and a couple of other folks that participated in that very first clinical trial, I've heard their stories about being just, you know, their lives being completely transformed by this, and their ability to then function in a way that they never imagined to be possible given their previous disease experience. So it's amazing. I would put this in the category of, I'd call it a treatment, and I'd call it a treatment for an individual right now. We're not using it in the human germ line, but it's clearly a very exciting advance for the field, with some caveats. Right now, this therapy is very expensive, meaning that most people who could benefit from it globally can't get access to it. It also requires hospitalization because they have to go through a bone marrow transplant, and that's something we're working very hard on here in our institute to overcome. We'd love to have this therapy ultimately deliverable in an easy format that doesn't require hospitalization. How should I think about the fact that this treatment for sickle cell is based on the fact that sickle cell is related to one gene? Well, you put your finger on a really good point, Cleo. That's exactly right. So this is a disease that results from one gene that's gone awry, and right now, CRISPR is well suited to treat that type of disorder. It's a lot harder to think about how you would treat a disease like, let's say, schizophrenia, which almost certainly results from maybe hundreds of mutations in the human genome. So those are going to be a lot harder to treat. And as I understand it, CASGEV requires removing blood from the patient, making those changes in a lab, and then putting blood back in. If we wanted to use CRISPR for a single gene or maybe a very small number of gene changes for treatments in individuals, but those treatments needed to be in our lungs or our liver or our brain, how would that work? Yeah, that's a lot harder. It would work with difficulty. We don't have a good strategy in general for getting the CRISPR molecules into particular cells in the body, although again, that's something that's changing quickly. It's an area to really keep an eye on over the next few years, because many, many scientists appreciate that this is an important challenge, not only for CRISPR, by the way, but also for any kind of human therapy, is how do you do the therapy in the right cell type or the right tissue in the body? How do you get it there in a safe and effective way? And that's clearly a challenge with CRISPR. I think that over time, what we're going to see is increasingly sophisticated technologies for doing exactly that. We're already at a point where for a disease like sickle cell, I think we're, you know, maybe within a few years of having that capability to deliver in the body and safely, and I think at a cost that would make this therapy much more widely available, and I can't tell you how excited I am about that. Me too. Just to be even more nerd out on this point a little bit more, because I know that delivery is a big interest area for a lot of people that are working on this. What are the actual challenges with the delivery? Is it that our immune system attacks it? Well, let's think about how the body is put together. We have a lot of different kinds of cells that make up our bodies, and even within one particular organ, like let's say our brain, many different kinds of cells are required to form the human brain. But when we have a disease that affects our brain, like let's say Alzheimer's disease, that disease is primarily affecting only some of the cells, we think, not all of them. And so ideally, what one would like to be able to do is you'd like to get the genome editor into just those cells where a change to the DNA sequence could have a positive effect on the patient and not bother any of the other cells in the body. But doing that, as you can imagine, is very tricky, and that's partly because the cells are all growing together. So you have to have sort of a chemical mechanism of distinguishing one cell type from another. Fortunately, cells often have little zip code molecules on the surface that mark them as different cell types. But so far, science is still trying to figure out what they are and figure out which zip codes go with which cell type. So that's something that's very much work in progress. And even once we know that, then the challenge is how do we recognize one particular set of molecules on certain cells and ignore all the others? That's something that viruses are actually very good at doing. So one of the motivators and sort of inspirations in the delivery field right now is looking at how viruses do that kind of recognition and delivery, and then taking advantage of it for delivering other molecules. Rather than delivering a virus, can we deliver our CRISPR cargo? I know you've used the analogy of we now have the ability to cut and paste DNA like a text editor. And so I'm imagining if I play this analogy out a little bit, it's like we now have the ability to cut and paste and create new letters, but we are still inventing the postal system. We're still trying to figure out how to send the letters. Exactly. Yeah, that's right. Got it. Yep. My second example is curing Huntingtons or removing Huntingtons from all your future descendants. What do I need to know about this example and this general category? Well, Huntington's disease is an interesting example because it often does run in families. And as some folks in the audience may know, it's a neurodegenerative disease, so it causes severe degeneration of the brain over time. It often doesn't begin until somebody is in their midlife somewhere, so 20s, 30s, 40s, depending on the exact detail of the mutation they have. It's an interesting target for CRISPR because like sickle cell disease, it's a single gene that causes the disorder that's very well defined. And furthermore, we know of families in the world where this disease gene is inherited by kids from their parents. And so it's terrible in the sense that they can see what's coming and know that they have this genetic predisposition, but they can't do anything to prevent it. So it's, you know, it's really a sort of a horrible thing to contemplate. And with CRISPR, one could imagine at some point being able to remove that disease-causing mutation from an embryo such that not only does the individual, once they're born, not bear the Huntington trait, but they also don't pass that trait on to their kids. It would be amazing. It could change a lot of people's lives. It could change a lot of people's lives. And I certainly think that if and when that capability is in our hands, that it would almost be unethical not to use it for that purpose. But we're not there yet. And the reason is that it's very tricky to control the way that DNA repair, which is really part of the whole editing process, the way that that is conducted, especially in embryos, is still very much under, you know, investigation. And so I think until we have a good handle on how it works and then how to do it safely, it will remain a, you know, future aspiration, but not something that I think should be done today. That brings us to my third example, which is preventing something like HIV in your future descendants. There was a scientist in 2018 that edited human embryos, and those embryos were born into babies who, as far as I can tell, are still alive. And many scientists, including yourself, opposed that decision. My understanding from your book is that you opposed it because you felt the risks to those kids were greater than the rewards. Could you explain why that was the case in that example, but also more generally, what are the other options besides CRISPR for many of these diseases? And how should we think about when a use of CRISPR is actually necessary and therefore potentially has a much greater incentive to use it? I think with any therapy, you have to ask yourself, do the risks outweigh the benefits or not? And with CRISPR, and especially if we're using it in embryos or the germline, the risks are quite significant in the sense that any change that gets made is permanent and it gets passed on to future generations. So you want to be very confident that those changes are going to have a positive impact and have the desired outcome. And so in the example that you cited, yeah, it was a very kind of alarming case because it was a situation where a scientist informed parents that they were going to receive a treatment for their unborn children that would prevent HIV transmission to those kids during birth and later in their lives, and furthermore, that that trait would then be transmissible to their kids. But I don't think, from what I understand, that those parents in the trial really understood the risks of the technology and that, for example, it had never even been tested in animals prior to putting into people, which is one really big ethical concern. Furthermore, with the example of HIV, there already are well-known treatments that can prevent transmission in kids, even if they have an HIV-positive parent, as was the case in that situation. So given that there was already a very well-tested and safe way to prevent transmission, arguably it's pretty unethical to then apply an untested, untried new technology to do this in people. And then the third issue kind of gets in a little bit more in the weeds of what actually happened, but when it was revealed how the genome editing was done in those embryos, it was clear that it wasn't a clean edit. In other words, it wasn't a way of making a very precise manipulation to the DNA, that instead what probably happened was that multiple different kinds of edits happened in the cells of those embryos so that those kids were actually born chimeras, meaning they had a mixture of different kinds of genetic makeup in their cells. Would that be harmful or not? The answer is we don't know because it had never been tested before. So these are all things that I think are really important to understand when people evaluate whether a new technology, especially something to be used in embryos, would be allowed to go forward. It seems like a really hard challenge, especially as someone who's a pioneer in the field, because we talk a lot on the show about how the status quo, the world that we live in right now, sucks in all kinds of ways. It is just as bad to allow the existence of a huge amount of suffering when you could change it as it is to cause that suffering by changing it. This is a classic human problem that we deal with in so many different ways. One of the things that I found incredibly powerful in your book, there's this quote, this is Charles Sabine, a victim of Huntington's. He says, anyone who has had to actually face the reality of one of these diseases is not going to have a remote compunction about thinking there's any moral issue at all. The reason why that has really stuck with me is because I think it's one thing to talk about these weights and counterweights in theory. Then you talk to someone whose life could actually be changed and you come away feeling like, holy cow, how can we help as quickly as we can in the way that keeps them safe and keeps the rest of us safe? What's that actually like for you when you hear from people who are experiencing diseases that you feel CRISPR could be really good candidates to help solve? It's really getting to the heart of what it means to suffer from a disease like that and then to have the opportunity to have a cure for it, something that might have been unimaginable even a few years ago. You're right, I hear from people pretty much now it's probably at least once a week that write to me about diseases in their families that are of genetic origin. Often it's a disease affecting kids and asking when and how will CRISPR be able to make a change. It's a really big challenge. I feel I'm humbled by it. I'm honored that people share their personal stories with me. I have to admit, I sometimes feel a little bit helpless because I realize the challenges still that lie ahead scientifically and technically to make it possible. At the same time, I feel an incredible sense of motivation and passion because you can see how, especially with the sickle cell story, how it can be so positive and so beneficial. It's a real motivator getting out of bed every day. Yeah, I bet. Speaking of good health, I want to show you something. I'm wearing the Whoop MG. It just came out and I've been testing it over the last month, so let me show you what I find most interesting. My goal is to just feel great. I want to wake up and I want to have energy and I don't want to feel tired and I want to be able to make this show and learn and I want to feel strong and I want to feel that way for as many days as I can for the rest of my life. So I use Whoop to set a goal to feel better and to keep track of my daily habits. It uses these sensors to measure, among other things, nine biometrics that have a long-term impact on my health outcomes and it combines them into what Whoop calls my health span. And that helps me understand how my habits right now affect my long-term ability to have as many healthy days as possible. One thing I found helpful is the Whoop AI coach. Today, for example, I was feeling tired, so I just asked it, I'm feeling tired, why? Then it analyzed my real data from the last month and helped me understand a couple things that I could do, especially around hydration and workouts. And it also has sensors that measure electrical activity from my heart through my skin, so I can do an ECG. All of this just helps me feel better day-to-day and hopefully long-term too. So if you want to try it, go to this link right here or click the link in the description. Now back to gene editing. As someone who is lucky enough not to be currently struggling with disease, when I think about how CRISPR might most directly impact my life, I think about the genes that correlate to future disease and how we might prevent future disease. I think about reducing Alzheimer's risk, which I understand relates to ApoE4, or heart disease and PCSK9, or cancer and BRCA. That would completely change my life. And I'm curious, what are the most interesting, relevant examples in this category that you think about? I think those are three great ones. In fact, it's probably worth pointing out that there's already a clinical trial running for people who have the gene that makes them susceptible to high cholesterol buildup and hence to cardiovascular disease. Yes, many of us do have this. And the idea in that clinical trial is to use CRISPR as a preventative. So can you make edits in the DNA of the liver that would prevent cholesterol accumulation in people that are otherwise susceptible to this? If it works, it would be incredible because again, it's a one-time therapy that avoids the need to take drugs daily or weekly or monthly to control cholesterol levels and would give people freedom from worrying about heart attacks at a young age, if that would be otherwise something they might experience. So I think that's really exciting. It also raises the bar, I think, for what we would demand in terms of safety, because probably none of us would want to, if we're not currently ill, we don't want to take something that might make us ill. And we want to take something only if it can really improve our health. Does that study that you just mentioned relate to what we talked about with the challenge of delivery? Because if they're delivering it to the liver, that implies that they, are they editing it in a lab in the liver? Are they also trying to find a delivery mechanism that works? They are. Amazing, right? Now, here's the thing. So the liver is an organ that naturally filters toxins in our body. So a lot of molecules will end up in the liver quite naturally. So it's a bit of a unique organ in that regard. And so it means that for a lot of the interest in CRISPR, at least in the very early days before there were many strategies for delivery, it was, you know, people kind of recognized that the liver would be a great organ to target because it very naturally accumulates molecules, including CRISPR. So that's been the basis for this ongoing trial. And they're actually using little greasy blobs that are known as lipid nanoparticles. These are known to any of us that have had the COVID vaccine because that's the basis for delivering the COVID vaccine is using these little lipid nanoparticles. And those particles will naturally traffic to the liver in the body and they'll carry along other molecules like CRISPR. So that's been the basis for that trial. Cool. Yeah. Okay. So now we're getting into the category that I think people would call enhancements. Here, people talk a lot about eye color and height and things like that, but there are also, and these are the ones I find most interesting, genes that might relate to enhancements for health that are not related to disease. So genes, for example, like the MSTN gene associated with building larger muscles, or, and this one I get very excited about, DEC2, which I understand is associated with needing less sleep. What examples do you think about in this category that are most genuinely interesting and what should people know about what's realistic here? Well, I think those two you brought up are interesting. There's also a gene that was identified by a colleague of ours at UC San Francisco. In fact, he won the Nobel prize for that work that is involved in pain perception. And so you could imagine, you know, in fact, there are natural variations of that gene in the human population and people that have a certain type, a certain format of that gene are naturally pain tolerant. And so you could imagine ways that you might use that type of genetic manipulation to remove experience of pain in, you know, say cancer patients or, you know, people that have a chronic pain causing disease. And so I think those are all extremely interesting. And yeah, do we, you know, it's a little bit, this starts to get into, to me, a bit of a gray area. Are those enhancements? Like if we're talking about pain perception, that's, you know, it's really a health related thing, but it's an important aspect of thinking about genetic manipulation because it forces us to, you know, to really ask ourselves, where do we draw that line? And I argue that it's very hard to do that. I think it's, you know, there's a kind of a continuum and there's certain modifications that some of us might call enhancements and the rest of us might call health related. So who decides? And I think those are some of the real issues that we're grappling with. This is the area, if I'm honest, I started to struggle with. A concern that came up a lot, and I'm sure is coming up right now for the audience as they're watching this, is that we move into a world more like the movie Gattaca. That there is a divide between what people can and can't get, maybe based on wealth, maybe based on other factors, that that harms society because there is a gene gap, as you call it. At the same time, I've, and I think everyone has witnessed over and over again, an expensive technology becoming less expensive over time as it's used by more people. A sort of subsidy maybe of that technology early on that then ends up benefiting the rest of us because it gets time to develop and exist and just sort of comes into the world. And I have a hard time with the argument that we shouldn't use something because only a people could use it in the short term when the hope, right, is that everyone can use it. I wonder, you know, why do we care about this when it is a huge opportunity to reduce human suffering, but not when it's our iPhones? How do you think about something like that? I think I'm with you, Cleo. I really, it doesn't sit right with me to argue that we shouldn't develop a technology because today it's only available to a few. And as you said, that's often true when new technologies come along. They're not easily distributed early on, typically, and they often are expensive in the early days. I mean, think of even personal computers kind of went through that transition. And so I think that we have to be very forward thinking and we have to be imagining what could be possible in the future. I'm highly motivated, for example, by the idea that CRISPR, although today as a therapy, it's only available to a few, that's not going to be true forever. It's clearly not. And also, I'm a big believer in you have to imagine the future to create it. You have to think about where you want to go and then work to get there. Me too. My understanding is that one of the ways that people can get some of these, all the above, prevention enhancements, treatments, is through selection of the embryos that they actually end up using in the first place, PGD. Could you explain how that works and how the existence of that option influences how we might or might not find it appropriate to use CRISPR? So one thing that's important to point out with CRISPR when we think about using it in embryos is that it would be done in the context of in vitro fertilization. Maybe that's obvious, but in vitro fertilization or IVF technology has come a long way from where it started. And today, it's possible for people that are having a child using in vitro fertilization to actually conduct embryo selection if they want to. They can identify embryos that have certain traits or avoid certain traits that they otherwise might inherit. And so that's been a great way for families to screen out disease-causing mutations, for example. I think that with CRISPR, you could imagine using it similarly, where you could use it to remove a trait and then screen embryos for the ones that have, you know, where you've successfully done that. And also, the key difference would be that CRISPR can actually make changes that might be present in all embryos for that specific couple. CRISPR could edit, whereas PGD merely selects. Correct. Yeah. I also think an important thing to talk about with respect to PGD is none of this is easy. I did the egg freezing process, and I can tell you that getting that number of eggs out is hard. That's the first step in IVF. It's difficult and time-consuming and expensive no matter what. And so, you know, we're dealing with a lot of different weights and counterweights about what might be easy or difficult for people in different ways. Yeah, absolutely. You know, I think there are going to be some interesting changes over time. Again, I don't think they're happening, you know, immediately, but I do think that there's a lot of work being done on human reproduction about gametes, you know, eggs and sperm that are, you know, going to probably change the landscape of what's possible in the future. And I'm talking about over the coming decades, right? So, you know, for folks that are, you know, very young kids right now, you know, this might be something that would become possible in their lifetime or something they would want to consider doing. So that's an area definitely to keep an eye on, because I do think there's a lot of activity. Before we move into plants and animals, which I really want to get to, because I think it's one of the biggest ways CRISPR might impact people's lives, there is one additional category here within humans. The final category, and this is a show called Huge If True, is as we understand more about our genes, there could potentially be ways to move people beyond what is possible for anyone right now. Helping you heal faster, extending your life beyond what's normal, giving your kids abilities that seem like superpowers. I don't know what's possible. How do you think about this? I had a call years ago now from a reporter at Sports Illustrated. They wanted to do a story on enhancements, or maybe even you could call them super enhancements, that would create super athletes. You know, imagine basketball players that were eight feet tall or, you know, could jump unreasonably high, or people that had, and I guess this is already one thing that is theoretically possible, having, you know, very, very well-developed muscles and muscle structure. I think these are fascinating. I think for the most part, they're not really realistic at the moment, mostly because we don't understand the genetics well enough to understand how manipulating those genes would affect our health in other ways. And we know for sure that, you know, our genes are interconnected. So when you tweak one thing, you're probably not just changing one effect, you're changing lots of other things. So I think that for any of those kinds of manipulations, clearly a lot of research would need to be done. But I'll just mention that since I know we're going to get to plants and animals in the plant world, we're already seeing just incredible advances using CRISPR to create the type of plants that, you know, certainly breeders have never had success in creating, and that if you tried to do it with traditional breeding would take inordinate amounts of time, probably decades, that increase the yields of crops, that increase the nutritional value of crops in ways that could be incredibly valuable and exciting for probably all of us and probably not in the distant future. So I think that's an example of the kinds of super enhancements in organisms that we're going to see with CRISPR. So play that out for me. What happens next in the world of plants and animals using CRISPR? I've thought for a long time that the extraordinary global impact of CRISPR will probably happen first with plant and animal manipulations. And the reason is when we're talking about making changes in human beings, that obviously requires a lot of testing to make sure that it's safe. We have to do a lot of research so we understand how a genetic manipulation will affect our health. Whereas if we're making changes in, let's say, a plant, you know, we can conduct that as an experiment, and many of those can be performed at the same time. And with CRISPR, we now have a tool that allows the kind of precise manipulation that plant breeders could only dream of in the past. So maybe just to explain how traditional plant breeding works for people. Traditionally, plant breeders would introduce random changes into the DNA of plants, and they would do it by using chemicals that would change DNA sequences randomly, or even exposing seeds to radiation that would also lead to random genetic changes. Then planting the seeds and allowing them to grow up and looking for plants that had changes to their traits that were desirable, and then picking those and breeding them. And so you can start to think about that. There's a few issues there, right? First of all, it takes a long time. Secondly, the changes are really random. So if you wonder, why is it that we have roses that are thornless, which might be a desirable trait, but they've lost their nice smell? Well, it's because, you know, traits are coupled, right? And so you tweak one thing and you get something that comes along with it that maybe you didn't want, but you now can't get rid of. And we see that over and over again. So with CRISPR, we truly now have an opportunity to make targeted, precise changes that only alter one trait and don't affect other things. So I think that's really exciting. And another aspect of CRISPR in plants that is just truly mind-blowing for me is that you can use CRISPR in multiple genes at one time. Now, you could do that in humans too, and I'm sure that will come, but today in plants, it's already possible to change 5, 10, 15 genes at a time. And that means that we can make really quite sophisticated alterations to plant traits in one shot and do it safely and do it precisely. And the more that we learn about the genetics of plants, and that's a whole separate area of research for sure, but, you know, they kind of go hand in hand. We learn which genes we can tweak, and then we have the tool to tweak them. Is that happening right now in a way that I might not notice when I'm at the grocery store? Am I eating plants that have been edited with CRISPR or not yet? Only if you're in Japan. Interesting. Well, in Japan, there's a tomato that's been approved that has a CRISPR change that makes it, they argue, have higher nutritional value. Will that happen in the U.S.? Oh, yeah. I mean, it's certainly coming. And already there are changes in plants like, well, fungi like mushrooms where there are non-browning mushrooms that were created using CRISPR. And a colleague of ours has created tomatoes here in his lab in the U.S. that are much higher yielding than normal, unedited tomato plants. But they don't have any other differences in the taste or the look or the, you know, the sort of properties of the tomato. So again, something potentially very exciting and very desirable. Right now, there's an ongoing sort of debate in different countries around the world about how those types of crops will be regulated. And here in the United States, the U.S. Department of Agriculture has ruled that when changes are made to the DNA of plants that could be done by traditional breeding, if you took the decades to do it, but are sped up by using CRISPR, those are not considered genetically modified and they're not regulated, which is so interesting, right? So I think absolutely in that regard, at some point in the not distant future, we could see these types of crops in the grocery store. Fascinating. I also know the two other categories that I want to talk about here are related to climate change and related to human health by virtue of editing other animals. So on climate change, the example that I have is making cows fart less methane. Did you tell me about that one? Yeah, that's a good one. That's a good one. So the, yeah, this is a project that, you know, a lot of scientists have come to recognize that one of the most significant contributors to global carbon emissions in the form of methane, which is a powerful greenhouse gas, is the farming of animals, and in particular is cattle. And they produce a lot of methane and they produce it primarily from bugs in their gut that are methane makers and that, you know, produce this gas instead of using food that the cattle are eating to make more milk or more meat. So wouldn't it be great if there were a way to alter the metabolism of those organisms, those bacteria, we call it the microbiome, in these cattle that are producing methane, dial that down and turn up the ability of their, of the these metabolic pathways to generate nutrients that are actually valuable to the animal and valuable to the farmer and to the consumers of these products. That's exactly what we're doing now with CRISPR because, again, CRISPR is a great tool for this. It's a tool that has the ability to go into the DNA of just one type of bacterium to one gene in that type of bacterium and make the kinds of changes that will alter their metabolism permanently. We've got some of the best cattle biologists in the world who are working at Davis and they had already shown that if you change the cow microbiome by altering their diet that you could have a very profound effect on methane production. So that's very exciting. We know this is an approach that can work. The challenge there is that altering the cow diet is not an approach that's inexpensive and it's not easily deployed to farmers around the world. Whereas if we had a very easy, let's say it was a pill that you could give once to cows when they're born that would edit their microbiome in a way that was sustainable over their lifetime, you could imagine that type of change being incredibly profound and also easy to deploy. And that's exactly what we're working on. And again, you're editing the microorganisms inside the cow, not the cow itself. That's right. It's a different category of assistance for the animal. That's right, yeah. How can we do that in humans and how might that help us? Without editing us, editing the microorganisms in us. This is such an interesting area of medicine. I think it's early days, but I think there's a lot of evidence pointing to our own microbiome, the human microbiome, having a profound impact on our health in ways that we're only starting to appreciate. And we have a colleague at University of California, San Francisco, who has shown that in people, especially in kids that are susceptible to asthma, they tend to have molecule produced in their own microbiome that's not present in people that don't have asthma. And she's shown a correlation between the concentration of that microbiome produced molecule and disease susceptibility. So again, we see a really exciting opportunity to use CRISPR to turn down the production of that molecule and potentially prevent asthma in kids. So that's something that we're currently testing with her laboratory in animals. And if it works, then we hope to test it in humans. What are the other examples that you think about often that I haven't asked you about? There are areas of sort of understanding microbial human health biology, where I think there's a lot of exciting potential. And one is really understanding the connection between our microbiome and our brain. And another is thinking about the connection between our microbiome and our immune system. So imagine that when we're born, we have our immune system is developing, we're also becoming hosts to lots of different kinds of microbes. So there has to be an interplay there. And we know that there's a relationship between inflammation in the brain, which often involves microbial activity and activity of our immune system, and later susceptibility to diseases like Alzheimer's. So I think as the genetics of those interactions become better understood over time, and by the way, that's something that CRISPR can help with is really dissecting the genes that are involved in those interactions. We now have the ability to change those genes, whether it's changing them in the microbiome of an affected person, or as we talked about with prevention, potentially doing it before we're susceptible to disease. If someone is coming to the end of a story about CRISPR, what do you want them to know? Well, we've talked about a lot of great applications of CRISPR. I guess I want to circle back to maybe where we started in the conversation, because I find that a lot of students today will ask me questions about, you know, how did I get interested in this area of science? Or how did I, how did I, you know, how did I start working on CRISPR in the first place? Did I know that it was going to be, you know, a really exciting technology when we got started in the first place? And the answer is no. And I think it's important to emphasize a couple of things here that are, I feel, and especially in this moment that we're in, in our country and in the world, that I think has been perhaps missed by a lot of people. And that is that, you know, science is really a, it's a process. And it's a process that's very much a human endeavor. Now, maybe AI will change that at some point. I'm sure it will assist us. But fundamentally, my experience is that it's very much driven by human curiosity. It's a person or a few people wondering, I wonder how something works, and then digging in to figure it out. And if you look at the fundamental breakthroughs that have happened over time in the biological sciences, certainly, the vast majority of those have come about from that type of question and answer. And CRISPR is very much in that category. So I think it's great for people to appreciate that that's kind of how science works. And so I always encourage students to think about what they're curious about, what they're interested in. What do they find fascinating? What's something that they've experienced in their lives where they have no idea how it works, and they wonder, what the heck, right? And they want to figure it out. Because that's always how I've directed my research. And there's real value to that. And that's really how fundamental breakthroughs are made. So I think we have to, first of all, appreciate that. And secondly, I hope, agree that we're going to continue to support that kind of curiosity-driven science for the next generation, hopefully, who are listening to this. I hope so, too. What are some of the, what the heck, curiosities for you right now? Feel free to get as nerdy and specific and maybe don't explain. Like, just, what are some of the things that are, that feel what the heck to you? Well, I mean, I'm curious about all kinds of crazy things. Like, I heard about a great project to investigate how bipedalism emerged, how it evolved. You know, why are we bipedal, whereas our ancestral apes were originally not bipedal? And so there's actually a scientist that I know who's using CRISPR to try to figure this out in rodents, because there are related rodents, some of which are bipedal, naturally, and some of which are not. So she's trying to figure out the genetics of that. So there's a, that's a kind of a cool one. What the heck? What the heck? In our own research, I'm, you know, very interested in, well, as we discussed, this connection between microbiomes and our health. So there's a number of things that we're investigating there by tweaking the genes of microbes and then asking, how does that affect the behavior of human cells? So I think that's a, you know, that's an area that there continues to be lots of kind of curiosities to explore. And then the third thing is more applied, but a big area that we're focused on in my own laboratory and here at our institute is this question of how we deliver molecules specifically into cells, because that that's really going to be transformative when we have that, that capability more broadly. And so I'm curious about how this happens in nature. And of course, viruses do it, but it turns out so do bacteria, you know, certain bacteria have the capability to get into particular cell types. So we continue to investigate those fundamental processes, hoping that we can, you know, learn from them and learn how to do it ourselves. What the heck? Can I ask you, what does it feel like to have been such an important part of bringing this new power into the world? Humbling, I guess, is the first word that comes to mind. I feel grateful too. I feel so excited to be part of it. You know, I feel, you know, when I was a kid growing up, I just could dream of doing science in the future and imagine myself as a scientist, but I had no idea really what I would work on or where I would end up. I could have never in a million years and, you know, imagined all of this coming to pass, but it's been such an incredibly interesting journey. And I also feel that I'm always learning, you know, so it's given me great opportunities to learn new things. My last question for you is, could you read this? You wrote it, that last paragraph. Few technologies are inherently good or bad. What matters is how we use them. And when it comes to CRISPR, the possibilities of this new technology, good and bad, are limited only by our imaginations. I firmly believe we can use it for the former and not the latter, but I'm also cognizant that this will require determination from us individually and collectively. As a species, we have never done anything like this before, but then again, we've never had the tools to do it. The power to control our species' genetic future is awesome and terrifying. Deciding how to handle it may be the biggest challenge we have ever faced. I hope, I believe, that we're up to the task. Thank you so much for your time. I really appreciate it. Awesome. Thank you. Boy, I'm really impressed. You clearly did a lot of homework and you had great questions. Thank you. We got more deeply into this than is usually possible in this type of a conversation. Yes, that really means a lot to me. Thank you for saying that.