Nobel-Winner Jennifer Doudna on How CRISPR Will Combat Climate Change, Disease & Hunger

Well, I'll start by saying it's a real pleasure to be here. I think back on my time in Hawaii with real fondness. It was an amazing place to grow up. It was a natural environment that was completely foreign to me at the time. My family moved to Hawaii when I was seven. So, we moved from Michigan. So you might imagine that's a bit of a culture shift.

Very different. But I just remember being inspired by the natural world and the evolution of plants and animals in that environment that were entirely unique. I didn't think about it that way at the time, but I just found it incredibly interesting. And as I went forward in my education, I started to think about the possibility of studying why those evolutionary changes happened, and in particular the chemistry of the biology. And that was really the beginning of my interest in science and biochemistry.

Well, I have to start by shouting out to my father because, you know, he really did appreciate my fascination in science. He was not a scientist. He was a literature professor, but he loved books and he loved to throw interesting books my way, including the one you mentioned, The Story of the Double Helix and the discovery of the DNA structure. And then beyond that, I had several very influential teachers in both middle school and high school. I've mentioned them in the past, but Mrs. Hapai was my biology teacher in high school. Miss Wong was my chemistry teacher. Bob Hillier was my English teacher in high school. All three of them gave me an appreciation for knowledge and really the process of discovery that I found so exciting. To be honest, in school I often felt bored when I was asked to memorize a bunch of things. It was much more exciting when there was a question, a mystery, a puzzle to be solved. And that's what I found compelling about science when I first started to think about working in that area.

Oh, 100%. Yeah.

The process of discovery.

The whodunit. Yeah. Right.

That's fantastic.

Well, I'm a bit of a contrarian at times. You know, I like to be working in areas where I feel like there aren't a lot of people investigating. And of course, that world has changed for me quite a lot with CRISPR. But for me in the beginning, I think it was really thinking back on when I got started in science, which really was frankly graduate school, when I really started to dig into what area of science I might want to focus and what was fascinating. And when I think about it, my advisor in graduate school was very interested in the question of the origin of life. Where did life come from? How did it evolve? It seemed like one of the biggest questions you could pose. And his genius, Jack Szostak was his name, he's a very active researcher currently at the University of Chicago but at that time he was at Harvard, and he was interested in this question of the origin of life. And there was a hypothesis called the RNA world hypothesis.

Some scientists speculated that RNA, which is a chemical cousin of DNA, might have in fact been responsible for the very early forms of life that first evolved on our planet or even potentially elsewhere in the universe. What an interesting idea. And I couldn't imagine how you could actually study something like that. But my advisor Jack Szostak had some very specific questions that he proposed addressing by studying the behavior, in particular the chemical properties of RNA that might allow it to do two very important things for life. One is encode genetic information, and we know RNA does that because it can form the genetic material of viruses like the famous COVID-19 virus but many others. But the other thing that had been newly discovered in the 1980s by one of my former advisors, Tom Cech, is that RNA can also work as a chemical catalyst. It can catalyze reactions, make them go faster. And so there was the idea that wouldn't it be interesting if originally on our planet there was an RNA molecule that could both encode genetic information for making more copies of itself and be the actual catalyst to synthesize those copies. And so that was really the subject of my early work in graduate school was to investigate that possibility.

Correct.

It does not. No. And so it's only with RNA that that process actually...

Okay.

Yeah.

So they're the engine that's actually copying the genetic code. RNA is the intermediary. It's a kind of, you could think of it as a temporary copy of little snippets of DNA. It forms the little messages that tell cells what to do and which proteins to make and things like that. So in that regard, it's a little bit mysterious how it's working. It's a little bit fleeting. It's not around for as long. It's less stable, but it also has more chemical capabilities. And that's what I found intriguing.

I think yes. I think RNA is a little bit mysterious. It's transient and that made it harder to maybe get a handle on initially, really to figure out why it might be important in cells, what it was really doing biologically. And by the way, that's still a question that scientists are unpacking. There's still so many functions of RNA that I think haven't yet been discovered or certainly not fully analyzed. So that's why the search continues.

Well, I met her in the spring of 2011 and it was at a meeting that isn't the typical type of science conference that I go to. It was a meeting of the American Society of Microbiology. I'm not a microbiologist, but Emmanuelle is. And so, I went to this meeting feeling a little bit guilty. I was leaving my husband home with our young son and there I was going off to a lovely place and enjoying some exciting science for a few days. And while I was there I met Emmanuelle and I remember the meeting very vividly. I was walking into a cafe and she was sitting at a table in a corner and a colleague of ours said, 'Oh, I'd really like to introduce the two of you.' And it's one of those moments when you meet someone and you immediately feel a spark of interest. She seemed interesting. She was a petite Parisian woman. She was clearly very excited about ideas. She wanted to talk about science. She wanted to talk about areas of science that we were both starting to work on, namely how bacteria fight viral infection using an adaptive immune system called CRISPR. Her lab had done some work on CRISPR that they had published a prominent paper the year before that our lab and my colleagues had read with great interest. And in our case, we were also investigating aspects of CRISPR from a different perspective. We're biochemists, we study molecules and look at molecular function. And so when we got together we started talking about mutual interests, but the fact that we were both scientists coming to this question about how CRISPR works from different perspectives was interesting. And later in the meeting, she and I went for a walk around Old San Juan, Puerto Rico, wonderful, beautiful cobblestone streets. And I remember that conversation very well. We were talking about a mysterious protein that her lab had been studying and only a few other labs had paid any attention to, that is now known as a protein called Cas9, part of the CRISPR adaptive immune system in bacteria. There was evidence that it was somehow responsible for protecting cells from foreign DNA, such as the DNA coming in from a virus, but how that worked was unknown. And so this is what we decided to work on together was to figure out and really try to unpack the molecular basis for Cas9 working as a protector of bacteria in adaptive immunity.

Possibly. But I think it happened faster because the two of us got together. And importantly, I can't not mention that the work that was done as a result of that conversation was performed by two wonderful scientists who are working in our labs. In my lab, Martin Jinek, and in Emmanuelle's lab, Krzysztof Chylinski. These two young scientists, I think, immediately understood how exciting it would be to figure out the molecular basis of an adaptive immune system. And by the way, we weren't thinking about a technology at the time. We were really driven by this fundamental question at the time. Nobody knew that bacteria would have the ability to adapt to viruses in real time. It's sort of an extraordinary idea. I was intrigued by that. I was fascinated by how such a pathway would evolve. And because Emmanuelle had a lot of experience working with a particular type of bacteria that we ended up focusing on in terms of studying Cas9, that expertise was very helpful in terms of setting up the kinds of experimental systems that we could use to test our findings.

It's kind of a lightning strike in the sense that as soon as Emmanuelle said, 'You know, we've been working on this protein and we're not biochemists so we haven't been able to purify it. We don't really know how it's functioning, but genetically it's clearly at the heart of this system of defense against viruses. Would you like to work together to figure out how it works?' And I just felt this little chill go down my neck. It's just like this little sparkle of almost like lightning striking. It's like, oh, I think this is going to be really fun.

Well both. So Cas9 is a protein, a specific protein. So we refer to it in the field as CRISPR-Cas9 to indicate that it's part of a CRISPR system. But when we use the term CRISPR, we're really talking about the whole suite of pathways that are related but involve defense against viruses that is programmable. And we'll talk about that probably here shortly, but it's really a whole set of molecules, not just Cas9, that work together or sometimes work in parallel in bacteria to provide viral defense.

Well, it's clusters of regularly interspaced short palindromic repeats is the... don't ask me to say that.

And it's a memorable acronym because it reflects what's so interesting about the biology. It's a system that allows bacteria to acquire in real time defense against viruses that they're getting infected with. And the way it works is that it allows bacteria to make a little genetic recording of a viral infection in the form of taking a small piece of viral DNA and integrating it into a place in their own bacterial genome called the CRISPR locus that has inserted sequences from many viruses over time. So try to imagine a little two-dimensional checkerboard where these little pieces of viral DNA are slowly getting integrated into the bacterial genome. They're keeping a record of past infection and they use that as the template to synthesize molecules of RNA. So when those RNA molecules get made, as we discussed earlier, they're little transient copies of DNA that in this case provide the genetic information to find those same viruses should they show up again because they have a sequence that matches the viral sequence. And importantly, those CRISPR RNAs combine with proteins like Cas9 that provide the genetic engine. They're a little machine that is able to cut DNA once it's targeted by the little RNA copy, the CRISPR RNA. So together the Cas9 and its guide or CRISPR RNA are able to find foreign molecules of DNA and cut them in bacteria. It's a great way that bacteria can cut up foreign DNA and ultimately trigger its destruction. But what's magical about CRISPR as a technology is that it provides scientists with a way to literally program these molecular scissors like Cas9 to identify any DNA sequence, a DNA sequence that we designed by designing the right RNA guide molecule that can recognize that sequence. And so in that way it was possible to take this fundamental discovery of how bacterial immunity works and turn it into a way to target DNA sequences in any kind of cell or organism for really targeted precision changes in the genetic material.

No. No, you're correct. Yeah. Well, here's the interesting thing. It's different at a molecular level. So we don't have, to our knowledge, CRISPR systems in our own cells. However, the principle of adaptive acquired immunity is probably very familiar to people, right? We know that when you get... this is how vaccines work. It's how it works when you get an infection and then you develop antibodies against that infection. And in a way, you could say, well, CRISPR is that type of a system, but for bacteria and it works in a different molecular mode, but the outcome is the same. Bacteria can acquire immunity to viruses using CRISPR.

Well, let me just unpack a little bit how, connecting the dots between that original fundamental discovery about CRISPR and how it works and then how we got to where we are today with CRISPR now being increasingly deployed to correct disease-causing mutations or figure out ways to mitigate disease-causing mutations using genetic changes in DNA. So with the discovery that CRISPR-Cas9 is an RNA-guided molecular DNA cleaver, that triggered connections to other areas of science that initially weren't thought to have anything to do with CRISPR. And that's because scientists had been investigating how DNA gets repaired in human and plant and animal cells. It's different than what happens in bacteria partly because the animal and plant cells are growing much more slowly than bacterial cells. So there's actually time to detect DNA damage or DNA breakage and fix it. And so with CRISPR, we had in our hands a tool that could be used to make DNA breaks or other kinds of chemical marks in DNA in a targeted way that could be controlled by the scientist. And that allowed the development of a whole suite now of tools that allow precise manipulation of genetic sequences. And you can imagine that when this first started to happen, and it happened really very quickly after the initial publication of the work that we did with Emmanuelle back in the summer of 2012.

Oh, very quickly. I mean, by later that year, there were already scientists who were emailing me and there was kind of buzz in the field about this is really looking very interesting.

Well, not really. Because I remember when we submitted that article for publication, so Emmanuelle and I were working with our lab members working on that during the spring and summer of 2012 and we knew it was going to be a big deal. And so when we submitted that article, we said to each other, you know, there's going to be a tidal wave. We just don't know how big it is, right? We knew a lot of people would be interested in this, and it wasn't clear yet at the time how effective it would be as a genome editing tool, but it seemed certainly easy to test that. So, we knew that a lot of people would get to work, you know, testing it, and they did.

So it was really exciting when those papers early in 2013 started to be published showing that CRISPR could be used to make targeted changes in human cells, in various kinds of insect cells, in fish, in whole fish. I mean it was just amazing. It was kind of mind-blowing. And so immediately many people started thinking about the opportunities to not only understand fundamentals of human genetics in a new way using this kind of technology but frankly to also rewrite the genetic code in a precise way. Imagine, we already started to think about what if you could correct a disease-causing mutation, something like the mutation that causes sickle cell disease. It had been known for a long time how the disease works, but there wasn't a way to mitigate it. You couldn't really do anything. You couldn't do anything at the source of the disease, namely the mutation, to help patients. And with CRISPR, it seemed like at last we might have a way to do that. It was a very exciting moment in the field.

Oh gosh, there have been so many that have really amazed me and I guess that many of them have been more on the research side, fundamental research side. So for example, scientists started using CRISPR to understand the genetics of butterfly wing pattern development. I mean, so interesting. And it was fascinating because butterflies have been studied for a long time but mostly just by observers, by observing them and looking at natural changes that happen in butterflies in nature. But with CRISPR you could actually go in and make targeted changes in their DNA and look at what the effect was. And so it was super interesting to see that kind of application. Another was figuring out why seashells have their shells curling around in one direction and not the other and the genetics of that and a lab was able to actually use CRISPR to reverse it and make the shell curl in the other way. So they could really get at the details of the genetics of a process like that in a way that had never previously been possible. So those kinds of applications were certainly very interesting and continuing. I still see frequently new uses of CRISPR for fundamental research. But I think what's really been exciting is especially over the last few years is to start to see CRISPR coming to the fore in terms of treating disease. And you brought this up earlier. There's the FDA-approved therapy now using CRISPR for sickle cell patients, which is amazing. And there was a recent case of a baby who had a very rare genetic disease, a metabolic disease in which CRISPR could be used to treat him and was developed in real time to create a form of CRISPR that would be targeted to his particular disease-causing mutation. And that was used and he has been treated effectively. This is a baby known in the media as baby KJ. So I think these are examples that illustrate to all of us what is possible and to me now it's not a question of if this can be done with CRISPR. It's really a question of how to scale it and make it much more widely available to people that can benefit.

Well, let's start with how it's delivered because this is one of the really big challenges of CRISPR currently. So in the case of both sickle cell disease and the baby KJ story, those were both diseases that could be treated using essentially off-the-shelf capabilities, technologies for putting molecules into cells. In the case of sickle cell disease, the way the CRISPR molecules are introduced into the patient are through targeted editing of blood stem cells. So these are cells that are taken out of the bone marrow of a patient, right? And they're put into a dish in the lab. They're treated with CRISPR. They're edited in the lab. And then after the edits are tested and it's clear that the correct edits have been made to those cells, then the cells are transplanted back into the person using a bone marrow transplant type procedure. Very expensive, very arduous for the patient requiring weeks of hospitalization. And so clearly that type of delivery is not conducive to a scalable system, right? It's just never going to be possible for probably many patients or maybe even most to go through that kind of a procedure for various reasons. And with baby KJ, similarly, in his case the disease was a metabolic disease. So the editing that was done was done in his liver using what's called a lipid nanoparticle which is a big fancy word but it just basically means a little oil droplet that carries the CRISPR molecules into cells of the liver by an injection into his system. And so that again is a technology that's been very well-developed for other purposes and could be quickly repurposed for delivery of CRISPR, but it's only going to be effective for people that suffer from a disease that involves the liver. If they have a muscular disease or a problem in their lungs or their brain, right now, those lipid nanoparticle approaches are not going to work or not going to work very well. So we know that for CRISPR to really be deployed on a much wider basis, we're going to have to have ways of delivering CRISPR molecules into cells in the body where they can be effective. And that's really at the forefront of the field currently.

Well, in the case of sickle, it actually can be deployed in most patients that have the same mutation. Yes. Because the way that treatment works is that it actually overrides the effect of the sickle mutation. It doesn't make a direct correction, but it turns on a different gene called fetal hemoglobin that makes a developmental form of the blood protein hemoglobin that carries oxygen and that can actually provide sufficient oxygen carrying function that it renders the cells of the patient effectively normal. So that can be done in basically all patients that have sickle cell disease which is great. So that does promise scalability.

It does. I think it does. And so I think as soon as a technology is available for directly delivering CRISPR into these blood stem cells in the patient, maybe through an injection, maybe someday it's a pill, then you could start to see a path to a much broader scalability of the technology. And it's going to happen, it's a question of when, but it will happen in my view.

Well, we haven't talked about agriculture yet. And we should because I think when we founded the Innovative Genomics Institute, which is an institute that currently involves three campuses of the University of California, it's Berkeley, San Francisco, and Davis. We founded that institute in 2015 with the idea that we're a public university. We should be accelerating the rate at which discoveries like CRISPR can have real world impact. I wanted that institute from the very beginning to focus not only on healthcare where clearly there were going to be some very interesting opportunities but also on agriculture because everybody's got to eat and agriculture plays such an important role in economies around the world. There are so many interesting opportunities even with fundamental research on plants and the microorganisms that support agriculture that CRISPR could play a role in. But at the time and even I would say today there still are many unrealized opportunities. So I really wanted our institute to be catalyzing that area of science. And frankly, when we think about the global impact of CRISPR, I still think that we're going to see a bigger global impact sooner with agricultural applications of CRISPR because it's easier in a way to do the kinds of manipulations in plants that might have really beneficial impacts going forward, especially as we deal with challenges of a growing population, climate change happening. It's a lot easier for me to see the scalability of that type of an approach than when we talk about treating rare diseases or even other kinds of human disease where there's still frankly a lot of work to be done and necessarily a lot of work on safety to ensure that the procedures are working as intended.

Well, we try to do both frankly. The word innovative in the title of the institute is about that fundamental discovery. I think where there's an appreciation that what academic labs do well is that process of early discovery, ideas that scientists might have that they're curious about something, just the way CRISPR was discovered. It's a curiosity about the world that is driving scientific investigation. These are the kinds of projects that companies aren't going to do typically. They don't have an immediate impact. They don't have an obvious commercial profit path, right? So investors are maybe rightfully not going to put money behind those ideas in the beginning. This is where, frankly, government funding plays an essential role. And in the United States, ever since World War II, our government has funded scientific research with the goal of stimulating these kinds of discoveries that get made often simply by scientists who are curious about things and who start investigating an idea or figuring something out and only later realize, oh, that actually could be very important for solving a real world problem. I wanted the Innovative Genomics Institute to do both. I wanted it to continue to catalyze fundamental discoveries, but I also wanted to connect that in a more direct way to opportunities for real world impact. And it's a fun challenge, but it is a challenge to do that because what we try to do is encourage our scientists to be working on the questions and problems that they are curious about, but always with an eye towards, is there a problem that could be solved with this discovery? Is there a way that I could take this research along a path that would end up having real impact? And we give them the tools to do that and the resources to do that. And it's been really exciting so far to see what's been happening over the last decade at the institute.

Well, we've always been interested in partnering with companies and we've been doing that really from the beginning. For companies, it's often a question of do they see an opportunity for the research that they might be supporting to have impact in the not too distant future on products or product pipelines that they're invested in. And so we look for those opportunities and frankly with CRISPR they're often quite clear. There's ways that we can absolutely leverage some of the fundamental work going on with figuring out how CRISPR works and discovering new kinds of CRISPR molecules and related pathways that tie into goals that we identify with companies as being really practical and important for future product development. That being said, to fund the really innovative work that maybe is going to lead to tomorrow's breakthroughs, we know that we must be able to finance scientists to do that really high risk but potentially high payoff kinds of projects. And those are in some cases there are companies willing to fund that type of work, but in my experience, it's more often philanthropic efforts that support that. And so we do a lot of work with philanthropists at the institute as well. So we invite people to come in, learn about who we are, what we're doing, see how incredibly exciting the science is and how motivated our scientists are to have their work have real world impact and that gets a lot of people very excited. So, it's been really fun to start hiring in the next generation of breakthrough scientists who are working on tomorrow's discoveries and trying to figure out where science is going in the future and then give them the kinds of opportunities they need and the funding they need to make those investigations and then when they do come up with something extraordinary, connecting them with teams that can help them figure out, is it time to start a company? Is it time to partner with a company? Or is it time to just maybe hunker down and really dig in academically to understand better a system that they're working on before taking it into the commercial realm?

Well, you know what's really scary to me is actually the broader impact of what's happening. I think we're seeing across the board a lot of universities have cut back on graduate enrollment, meaning that in the United States, at least right now, we're going to be training many fewer professional scientists. What does that mean for the whole pharmaceutical industry, for the tech sector at large? We're just going to have many fewer trainees in the STEM fields here in the US and that's happening at a time when there's also reluctance to bring in people from other countries in those fields. So I'm worried frankly, I think that's really a dangerous thing to be doing because I think the investments in STEM by the federal government for the last several decades have truly driven extraordinary economic development. A number you often see quoted is the fact that NIH, National Institutes of Health, which is a taxpayer-funded national institute that funds a lot of fundamental research across the healthcare-related fields. Every dollar of NIH funding that gets invested returns at least two and a half dollars in economic benefit. So if we start cutting back on those funds, then there's no way that we're going to be able to maintain the kind of economic benefits that we've all had access to over the last few decades. And that's happening also at a time when other countries, namely China, but others too, are investing more in science. So I think it's really putting the US at a real risk of losing our leadership across the science sector.

I think it was late 2014 and I was sitting in my office in Berkeley. I opened up my scientific journal summary for the day and there was an article that had just been published in the journal Cell that was about making CRISPR edits in monkey embryos that were then transplanted into the mother monkey that led to the birth of CRISPR-edited baby monkeys.

Well, you know, Planet of the Apes. It was quite profound as a moment for me because up until that point I had sort of thought, gosh, I don't see any reason technically why you couldn't edit embryo DNA, but no one had done it at the time. And I thought, well, are people really going to go there? And the answer was yes, they are. So we organized fairly in short order after that article was published. We organized, and this 'we' is the Innovative Genomics Institute, our colleagues and I organized a meeting that we held up in the Napa Valley with just about 20 scientists who were brought in because of their expertise, not so much in CRISPR at the time, but really in other types of technologies that could intersect with CRISPR, namely in vitro fertilization, experts in human development, experts in human genetics and human genetic disease and some bioethicists who think deeply about the kinds of ways that technologies can intersect with human societies and the kinds of challenges that raises. It was a fascinating meeting. It was a little bit scary to me because at the meeting, a couple of the scientists there were circulating copies of manuscripts that were not published at the time but were in review at scientific journals that were editing human embryos. And so we all thought, okay, lines have been crossed already, basically. And I think that for me it was really kind of the beginning of what has become one trajectory in my journey since that very early work we did with Emmanuelle in terms of thinking about the impact of scientific discovery on society. How does a scientist who is working on potentially very fundamental research as we were doing, when you realize that the science is going in directions that have real and potentially profound ethical implications for human societies. How do you manage that? How do you deal with that? Do you say anything or not? And in conversations again in those early days with a number of scientists in the field, many were quite reluctant to speak out or say anything publicly. I understand that. A lot of us felt we're not experts in bioethical questions. We're not bioethicists ourselves. We don't have training in that field. Maybe it would be better to leave discussions about ethical considerations to the experts, whoever they might be. But I came to feel that that wouldn't work because in the end for a technology like CRISPR in those early days there really were just a handful of people working in the field like myself and Emmanuelle who were deeply knowledgeable about the science and what was possible, what was maybe potential but not happening quite yet and what was frankly science fiction. And so if we didn't speak up and get involved and start explaining the risks of the technology and trying to figure out a path forward in terms of ensuring the safe and responsible use of CRISPR, that didn't sit well with me. I couldn't do that myself. And so that led to not only this early Napa meeting but then a series of meetings that were held later and sponsored by the National Academies of Science in the US and in other countries that got together to say, let's really do a deep dive into the technology. Let's invite in experts not just in science but in other fields, stakeholders, people representing patient groups, people representing farmers, anybody who could in the future either benefit or be harmed by the technology and get a conversation going. And I think that was incredibly important and it's also led to a really global sense among scientists that we need to work together to ensure responsible use of CRISPR. And there's no obvious way to do that. We have to encourage transparency, we have to encourage journals to be holding articles that are going to be published up to a certain standards, all of those things that come into play when you have powerful technologies that are developing in a way faster than regulators can keep up.

Well here's the thing. It turned out that back in the 1970s there was a meeting known as the Asilomar conference that was held here in California at Asilomar that was put together by scientists who were at the time working on something called molecular cloning.

that could be produced very quickly in bacteria and used to make things like drugs. So in those early days, for example, people were cloning the gene that makes insulin, encodes the insulin protein, and being able to make a lot of insulin for patients in bacteria, which seems like a great thing to do and has been incredibly useful. On the other hand, scientists back in the early days of that technology recognized that there could be risks there. Could you imagine engineering bacteria to make a dangerous protein? And if it was a bacterium that naturally populates the human gut, like the human microbiome, could that cause risk in humans? Nobody really knew the answer to that at the time. So the outcome of that Asilomar conference was that there were a series of guidelines that were put in place nationally in the United States through the National Institutes of Health that created a framework for conducting molecular cloning and other related types of research in a safe fashion. And with CRISPR, we found that many of those guidelines were very applicable to CRISPR as well. So we were kind of lucky in a way that those scientists in the 70s had done some important work that ended up creating a framework for CRISPR later that was very enabling and valuable. At the same time, as we've been discussing, CRISPR also opened the door to other things that were going beyond what was happening with molecular cloning, namely germline editing, or there also are applications in organisms in the environment where there could be risks of spreading a genetically altered insect, for example, or making an insect population vulnerable to certain drugs or to sterilization that could be seen as beneficial, but it also could have unintended environmental impacts. So I think there was an appreciation that we really need to be quite thoughtful about the ways that CRISPR might be deployed and really try to create an international community of people that would be paying attention to this and creating, if not exactly legal requirements, at least a framework that scientists would respect and would create a culture of responsible use of CRISPR.

Well, I think it does. Yeah, I think it really does. I mean, I think that we saw that in the 70s with the molecular cloning example and we've seen that subsequently. I think that there is really a kind of an international feeling that we're all part of a community, that science doesn't really have boundaries in a sense, and that we need to be working together to ensure that scientific research is having positive benefit on our societies and on the planet. Does everyone share that view? Of course not. But I think the majority do, and because of that, there's been a lot of momentum in the CRISPR field since those early days about 10 years ago of scientists saying, you know, we really need to pay attention to this. This isn't something to just leave to somebody else to deal with. I remember when that Chinese scientist came out and had done this genetic modification to these twins, seemingly good intentions to make them immune to HIV, right? So that's what it was.

I was surprised initially, but the more I thought about it and talked to my colleagues, including friends and colleagues in China, it made sense because I think there is a real desire in China for international respect. I think that especially 10 years ago, or I guess that announcement about the edited babies was in 2018, so not quite 10 years ago, but I think there was a really very strong feeling that the science being announced out of China, being published out of China, the scientists being celebrated for their work needed to be scientists and discoveries that would be internationally respected. And when it was clear that this was not the case for editing human embryos and using them clinically to create a pregnancy, I think that led to a very rapid response on the part of the Chinese government to shut down the scientist's lab, to cancel his funding, to put him in jail, which is what happened, and to really make it clear that this was not acceptable and that others shouldn't proceed in his footsteps.

I think the baby KJ story, just to come back to that for a moment, our institute was a participant in that. We were able to work with the clinical team at the Children's Hospital of Philadelphia where that boy was being treated to help create a version of CRISPR that would work in that particular mutation to treat that disease, and then to test it for safety and help them then take the next steps in terms of preclinical testing and ultimately getting approval from the FDA to proceed and use it in the child. And so that whole team effort, and it was many people and groups coming together, including a company that was willing to make the CRISPR molecule in real time and make it at a grade that could be delivered to the patient, showed us all that this is doable. It's very possible. And so we're excited now to figure out how to scale that process, how to reduce the cost, how to ultimately come up with a better delivery method that's going to open the door for many other patients to get access. And it's very exciting to think about what's coming.

Well, lots of people talk about how AI is going to transform biology, and I think it will, too. It's just that I think that at the moment, what I'm seeing in our own work and also work being done elsewhere is that it's mostly being utilized right now to accelerate things that we're already doing. It's not so much that it's generating brand new ideas nobody ever thought of before. It's more that it's helping us to quickly collate data, quickly go through the scientific literature and pull out trends or things that, yeah, you could do it manually but it would take a lot of time, and you can use AI-based methods to much more quickly do that sort of analysis. So that's very helpful. I think that increasingly we're going to see AI being used to accelerate research. I always tell my students, we should be looking for ways to use AI to help us predict which experiments to do and frankly which ones not to bother with because they're not very likely to work. And so I think that over time, experimental biologists like me will increasingly be able to do that. We'll be able to vet ideas using AI and figure out how to focus our attention in areas that are more likely to be fruitful. But I don't currently see AI being the generator of innovation. I don't really see that. I think that it's trained on existing information and data, and so it's able to very nicely help collate that and make sense of it. But I think we're going to need humans for the foreseeable future certainly to come up with new ideas and innovations.

Right. Well, the institute was started in 2015, and when the pandemic started, or when it was just on the horizon, maybe you could say, in very early 2020, we were not quite five years old at the time as an institute. And I, like everybody else, started wondering what is it that we as scientists can do in this moment to be useful and to be helpful. And our labs were being closed, our universities were being closed, we were being told that we couldn't really proceed with our work. And so there was an afternoon, it probably was sometime in March of 2020, when it was becoming clear that there was a real crisis emerging, that we held a meeting at the Innovative Genomics Institute that was mostly virtual, people joining by Zoom. And I was astounded that we called this meeting the day before we held it, and yet there were dozens of people that joined the meeting from all over our campus. So it was clear there were a lot of people asking themselves the same question: What can we be doing to be helpful and useful in this moment? And the outcome of that meeting was, well, the most urgent thing that's needed right now is we need to be able to diagnose the virus and people that are ill with this virus. And there's a very well-known technology called PCR for doing that, where you can amplify genetic sequences and detect them very quickly using very well-established PCR technology. It was just that we didn't have a lab set up to do that at the time. And if you want to do that in a clinical sense, meaning that you want to be able to take patient samples and diagnose them for disease and then be able to report the results to the people donating the samples or to their doctors, you have to have certification. You have to be a clinical testing lab, and that requires all kinds of regulatory guidelines. UC Berkeley is not a medical school, right? So we didn't have a pre-existing clinic that did that type of diagnosis that we could pivot for that purpose. So it was fascinating to see what happened because there was such a determination on the part of all of us that we must figure out how to do this. It is essential that we get this done. So we ended up working with our student health center at Berkeley, who did have a diagnostic lab there. It was very small, but they already had the framework in place for diagnostic testing. We actually went all the way up to the governor of California to get an approval quickly for establishing a larger version of that testing lab at the IGI. And then we worked with companies to get equipment in place, again, robotic equipment, so that we could do very high-throughput, scalable testing quickly. And then hiring in some people that were trained in clinical testing that could help manage the lab. We trained a lot of our students with how to safely collect samples and feed them into this process for testing. We all had to be HIPAA certified so that we could report clinical data in an ethical fashion. All of those things had to happen very fast, and it really took about three weeks. It's amazing. I mean, if you tried to do that in the absence of a crisis, it would probably take three years at least, right? But it went very fast because I think many people appreciated that it was an emergency. And as a result, we ended up with this wonderful testing lab that until very recently was operating as a real clinical testing lab. We've now pivoted to use it for other things. But it was a lab that allowed us to quickly provide testing to not only our campus, but to members of our community. We had firefighters, we had the police giving us samples to test because they really couldn't get rapid testing done anywhere else. We had a lot of donors that stepped up to fund the process and make it possible to very quickly ramp up those procedures. And it taught me something very important, and that is that when you have an organization like ours, you have the ability to harness the incredibly exciting potential of people with different types of expertise to do things that are really big, really hard, really impactful, and that none of us could have done independently. And so it really underscored the value of the institute, and I think it showed everybody in our institute and beyond what would be possible.

Yes, in the sense that I do feel an urgency around applications of CRISPR that, again, it's the sense that this is entirely possible technically, like treating rare diseases of the type that this young boy KJ suffered from. That's entirely possible. There's no technical reason we can't do it. It's just that you don't have the infrastructure today to scale it and make it available and affordable. So I'm really motivated by this. I feel the sense of urgency from patients. I mean, I interact now fairly frequently with families that are suffering from these types of diseases, whether they contact us directly or whether, recently I was at a conference in Boston on Rett syndrome, for example, which affects girls. It's a rare disease, and yet, what is it? Well, it's a disease that is very sad in a way because girls that are born with this are born normal. They appear normal, but when they are a few months to a couple of years old, they begin to suffer from neurodegeneration. And so they develop to a certain point and then they start to regress. And so it's very painful, and animal models suggest that it should be entirely reversible. So people have been able to show using CRISPR and other technologies that if you can actually make a corrective change to the gene that is causing this disease, then you can reverse the effects, which is tantalizing, right? You can see that, oh my gosh, you could really give these girls and their families back a normal life. And so that's incredibly motivating because again, you can see that technically it's possible. It's just that we don't have the delivery capabilities currently, and there's a, you're sort of all, so close but so far. So close but so far. And so this is very, very motivating to me personally.

Right. Well, many people, when we first started saying we're going to work on climate change at the IGI, I got the same question that you just posed. What does CRISPR have to do with climate change? And what's fascinating is that when you think about what's causing climate change, well, it's increased carbon in the atmosphere, and that's coming from a number of sources, but a big one is agriculture. And I didn't realize this when we first started looking into it, but it turns out that about a third of the global methane that's released around the world that comes from human activity is from agriculture, which is an incredibly destructive way, more than CO2. Methane is really destructive. It's really destructive. That's right. So being able to mitigate that would have an enormous impact. And yet it has to be global. It has to be scalable. Again, it's the same kinds of challenges that we have in healthcare. When we think about agricultural and climate applications, we have to be able to scale it. We have to make it economically viable for farmers, let's say. And so when we started thinking about this, we realized that just up the road from us at Berkeley is one of the world's best agricultural universities, namely UC Davis, with experts there working on cattle and methane emissions from cattle, ways to mitigate that. They had shown some very compelling evidence that you could alter the microbiome in cattle, in the cow rumen. These microbes are the ones actually producing the methane, and they could show by dietary changes in cattle that you could absolutely change the makeup of the microbes in these cattle cow rumen to reduce methane emissions. So that was very exciting. However, not scalable, not cost-effective, not something that you could really do on a widespread basis. And so this is where CRISPR comes in because we said, well, you know, CRISPR is a technology that could actually be used to fine-tune the metabolism of these bugs. And we could do it in situ, namely we could do it by applying CRISPR directly in cattle, maybe through a pill or something that you could feed to them in their diet, maybe do it once in a way that would alter the microbiome over their entire lifetime. And we currently have 24 cows right now that are up at Davis that are being tested with this type of an approach. So we're very excited because we think that again, it's just like in the case of treating rare disease. We can see that all of the pieces are coming together technically to be able to do this kind of mitigation of methane release. And increasingly the questions are about scalability. They're about helping farmers understand this technology and decide to test it. It's about working with regulators, working with governments. So it's a really interesting moment in the field where we've been fortunate to attract significant philanthropic support of the effort through the TED Audacious program. So we've got a whole cohort of young scientists at the IGI that are all in different ways contributing to the project working on that.

Oh, so much. It's very, very exciting what's happening in plants. I'll just give you a couple of quick examples. So, one of the early applications of CRISPR in a crop was in rice. And so this is work of Pam Ronald, who's a scientist at UC Davis, who has had a long-standing interest in the pathways in rice that are involved in drought resistance. And so way before CRISPR, she was actually using more traditional plant breeding approaches to test the genetics of drought resistance and then to actually introduce genetic changes in rice that would make them drought resistant and then testing them in the field. So she did a lot of that pre-CRISPR. And the exciting answer is yes, you can absolutely generate drought-resistant rice that are still very productive in terms of their crop yields. It's just that again it wasn't easy to do it and it wasn't very scalable and if you did it in a plant that you were testing in the laboratory that might not be the same species that a farmer would want to be growing in Asia or South America, for example. And so with CRISPR it then became possible to start making those same kinds of changes but in different species of rice. You could do it much faster. You could test different combinations of genes that might contribute to a trait like drought resistance. And so as a result, we've been able to really help Pam accelerate her work using CRISPR. And this is now leading to field testing that we're currently doing. We have a partnership in South America to work with farmers, help them understand the technology, learn about how it could help in the way that they're raising their crops and protect yields while also protecting them from climate impacts. It's really exciting. So that's one area where we have a big effort. We're also quite interested in opportunities in other plants like, you know, I'll just say cacao, you know, if you like chocolate, cacao.

You know, so these are all crops that are being impacted by changes in the climate in different ways. And so we're working closely with groups in other, mostly in other countries, you know, but with bananas it's in Ecuador, right? Helping farmers there to figure out how they could use CRISPR to help protect bananas from disease that otherwise is a really big threat.

I guess, you know, something that I had worried about a lot in the beginning and I still worry about at some level is that with all the companies that are now developing CRISPR for different kinds of applications, I worried that there might be a rush to do something or deploy something with CRISPR that would end up having harmful impacts in some way, whether it would be harmful impacts in patients or harmful impacts on the environment or on animals or something like that. And I think for various reasons that hasn't happened, and I've been happy about that. And I'll just point out that when I think back on the field of gene therapy, which is what it used to be called, this started a few decades ago where people were exploring the idea of using viruses in those days to deliver genes into cells and doing this in patients where the patient might be missing a critical gene and trying to deliver it with a virus. And that did sort of precede, one could argue, perhaps too quickly from a safety perspective, and it led to a patient death. You know, Jesse Gelsinger, who died from a gene therapy trial very early on in that field. And unfortunately, that event really put a damper on the entire field for at least a decade where it kind of almost became toxic to work on it or to even talk about gene therapy as a real opportunity. And so I didn't want that to happen with CRISPR. And I think we're lucky that for the most part, I think that people have proceeded with appropriate caution and where safety has really been number one for companies and researchers working on it. This is why the outlier was the germline editing in the twins that we talked about, right? Was really kind of an outlier, an example of somebody who wasn't putting the safety of families and patients first.

Well, partly because of my experience very early in the CRISPR field with reticence on the part of scientists to really engage in these kinds of more public conversations, when we started the IGI, we started it with a public impact team. So from the very beginning, we said, look, we've got to weave that into our work. We need to have, it doesn't need to be, it can't be an afterthought. It has to be something that we discuss from the very beginning of a project. And as a result, we've got a very actively engaged group of leaders at the IGI who work closely with regulators, with government representatives, with stakeholders in other areas like whether they're patient advocacy groups or whether they're farming or agricultural groups to help them, number one, understand the technology and get facts and data that they can trust from us. And secondly, to help them make decisions that they might be making about deploying CRISPR, even just theoretically thinking about how could it be useful or not in work that they might be doing. And so that's been, I think, very important. And I always wanted the IGI to be a trusted resource. We don't lobby, we're not advocating anything, right? We're just scientists who say, look, we work with data. We want to make data accessible. We want to make it understandable to people that are not experts. We want to answer questions. We want to give them resources so that they can make responsible decisions. Now, obviously, we live in a time when, you know, it can be hard to know who to trust, you know, there's lots of data, or quote data, right? I mean, pick your facts. Yeah. Unfortunately. But I really wanted to make sure that people who are willing to look into it know that if they come to us or come to our website, they can trust that we're going to be showing real data that come from real experiments and that we're going to explain our thinking and our decisions based on actual data.

I think it has to, I don't know, I'm sort of thinking out loud here, but I think it has to happen at a very grassroots level. I think it's going to be hard to have a dictum coming down from on high about how we should all operate. Americans hate that for one thing, right? Americans love that. Kind of doesn't work in our country. We've seen examples of that over and over. But I think what can work is for individuals who have been affected by situations where CRISPR has an impact on them to be speaking out and telling their stories, you know, not proselytizing, just saying here's my story. You know, I think Victoria Gray is a great example, right? She's the first US patient to receive the CRISPR therapy for sickle cell disease in a clinical trial, and she's now several years out from that one-and-done therapy, and she hasn't had a sickle cell crisis since.

I mean it's extraordinary. It's amazing. And not only that, but she's a very compelling person. She's willing to tell her personal story and she's not trying to convince anybody of anything. She's just saying this is what happened with me. And it's really interesting to see her in action, which I now have had the pleasure of doing on a few occasions. And I think that kind of engagement is really effective because what she has told me is that when she goes to, say, some kind of a conference and tells her story, all the folks that hear that who then go back and tell their families and friends, and then they tell their families and friends, and there's sort of this ripple effect going out of people sharing a story that they found compelling, and it causes them, at least some of them, to think about it, to want to learn more about it, to want to find out, you know, could this benefit me or somebody I know. It's really been good. And another example I'll give you quickly is now quite a number of years ago when I was at a meeting with several House members and we were having a dinner together, and I was told that I was going to be seated across from one of the rookie House members from a very conservative district who was absolutely opposed to any kind of genetic manipulations in humans. And so I was kind of wondering how this conversation would go over dinner. Well, it turned out that this person ended up telling me a story about herself. She said that she had been through a pregnancy the previous year when they discovered while she was pregnant that her child had a genetic disease of the kidney that was very difficult to manage. And they had to go through extraordinary procedures during her pregnancy to protect the child. And then when the child was born, it had to have surgery. And she said, she leaned across the table and she said to me, 'If CRISPR had been available for me and I could have cured my child of this disease, I wouldn't have hesitated.' It was so interesting and it taught me that when people, you know, it's one thing to have sort of a view that's kind of out there, you know, other people are affected but not me. But when something is personal, your views can change. And so I do think that it's important, that's why I think it's so important for personal stories to be told, for people to share their experience. I think that's a very human thing that we respond to that's different than when you hear a demagogue speaking about something in a very general way. It's much different than when you feel it personally.

Yeah.

Well, yes. And probably the biggest thing is knowledge. We don't know which genes to tweak, you know, and for any kind of trait that you just mentioned, it's not going to be one gene. It's going to be pretty complicated. It'll be complicated, right? And it may even be a different cohort of genes for each one of us depending on our specific genetic background. So I think that's something that will maybe come over time, but it's going to take time and effort to figure out enough about human genetics that we could make those kinds of tweaks. But in the future, could such a thing happen? Sure. I think it could. And so again, I've been an advocate for discussing this kind of thing openly and transparently. I think we have to get ready for the time when such potential enhancements are possible. And this kind of intersects with the whole area of germline editing, which we haven't really talked about too much, but it's sort of the idea that you could make heritable changes. Because by the way, just to be clear, all of the applications that we talked about in humans earlier in this conversation are being done in individuals, but they're not making heritable changes that are passed on to future generations.

Yes it was.

Right. Well, it's an important one because to me it's pretty different. I mean, if you have a somatic mutation or a somatic application of CRISPR, then it means that you are affecting an individual but you're not affecting anything about their germline. You're not changing the genetics of their children in the future. And so it means that a use of CRISPR like that is in a way not different from any other kind of therapeutic that you might use in an individual, and it comes with risk, but it's risk to that person. It's not a risk to future generations. Germline editing is different though, right? Germline editing means making changes in eggs or sperm or embryos that are then inheritable by future generations. So it's a much more fundamental kind of an application of CRISPR. And this is really what happened with the children in China, the twins in China who were edited back in 2018. That was a heritable change.

Exactly. Exactly.

Right. Well, so this is an interesting question. I mean, people debate this and discuss it, and some people feel that, yeah, if I have a genetic disease in my family and every generation is going to have to deal with this, and maybe I could go through IVF every time and do embryo selection, etc., but what if I could just make a one-time correction to that gene and never have to worry about it in the future? Wouldn't that be better? And I think, to me, there could be an argument for that, but the safety of the technology would have to be there, right? And I think today for embryo editing, it isn't, you know, we don't really understand how it works in embryos very well, and I don't think that we could guarantee the safety at a level that would justify the risk. And so I think that it's an area that a lot of people are, of course, interested in, germline editing. It's gotten a lot of media attention, but I think the reality is that it's not likely, I don't think, to be a real opportunity for most people in the near future at any time. Now, does that mean we shouldn't talk about it? No, I think we should because I think it's, technically it's certainly possible to use CRISPR that way. So I think we have to be considering it as a future potential application that must be carefully controlled, right.

Well, possibly, but I would say that there's so many challenges that I don't think we're going to run out of, far from the deadline, I don't think we're going to run out of challenges anytime soon. But I do agree that we have to be thoughtful, don't we, about how we use technology. I mean, I think, to me, one of the interesting dilemmas that I think about a lot right now is vaccine skepticism. And the fact that in a way you could argue that because vaccines have been so successful at protecting human health, especially in developed countries like in the US, that for many people, they just don't have any real experience with communicable diseases that are virally caused. And so they don't really appreciate what we really have, the benefit of widespread vaccinations. And so they maybe think, we don't really need vaccines because none of us are really getting sick. So why would we take the risk of a vaccine without appreciating that, well, yeah, it's because of vaccines that we don't have these kinds of huge pandemics that are happening every year, every other year, thankfully. And so it is a strange irony that in a way we were almost too successful with vaccine technology that now has made us forget collectively the value that they really have.

Which is way below herd immunity. It's terrible. It's terrible.

Yeah, human nature. What was it, was it Einstein said the difference between intelligence and humility, I don't even know if he said this, but they give him credit for everything, the difference between intelligence and stupidity is there's no limit to human stupidity. I think that's what it was. So, we'll keep learning. We'll keep falling down and falling on our face.

I think we're wrong to think we understand a lot about biology, because what I've learned, if I've learned anything as a biologist over the decades, I've learned that the more we learn, the more we realize there is to know. And it's so true in genetics. I think when the human genome was first reported, the sequence of the genome back around the year 2000, there was a feeling across the field that we were sort of on the downhill slope now of really being able to control biology, to understand the contents of the genome and manipulate it, etc. And here we are 25 plus years later, and I think we realize just how not true that is, you know, how deep the rabbit hole goes, right.

Oh, certainly. And will it, you know, is CRISPR the end of the story? No, it's the beginning really because I think that, you know, we're just now starting to understand the way not only the technology works but also the ways that it's going to have really important impact broadly. And so my guess is that certainly over the next decade and probably beyond, we're going to see increasing applications of genome editing at large, across different sectors of biology where it's going to have increasing impacts. And the challenge for scientists is just to make sure that that happens safely.

That it happens equitably for people and that we continue to motivate the next generation of scientists to make the next set of breakthroughs.

Thank you for inviting me. Thank you.