 Good evening and welcome to the 2019 Arrow Lecture Series on Ethics and Leadership. My name is Rob Riesch. I'm a professor in the Political Science Department and I'm the Faculty Director of the Center for Ethics in Society, which is the sponsor of the Arrow Lecture Series and this evening's event. Tonight's presentation by Professor Jennifer Doudna is also co-sponsored by the Center for Biomedical Ethics at the Stanford Medical School and the Center for Law and Biosciences at the Law School. I want to begin just by saying a few words about the lecture series. The Arrow Lectures were created in 2005 and they have become amongst the most prestigious lectures at Stanford University. Previous Arrow Lectures include a roster of exceptionally distinguished social scientists and philosophers including Esther Duflo, Paul Collier, my namesake Robert Riesch, Thomas Piketty, and Nobel Prize winner Amartya Sen. Speaking of Nobel Prize winners, the Arrow Lectures are named in honor of our colleague and Stanford emeritus professor, Kenneth Arrow. Arrow was one of the most renowned scholars ever to have taught at Stanford. He was one of the most influential economists of the 20th century and he died just a little less than two years ago, leaving behind an incredible legacy of research and teaching. Ken was the youngest recipient ever of the Nobel Prize in Economics. He was 51 years old when he won it and perhaps more remarkable than that lofty achievement is this, no fewer than five of Ken Arrow's students have gone on to win the Nobel Prize in Economics. We honor him tonight with the lecture from Dr. Jennifer Doudna, whom many consider to be a shoe in herself for a future Nobel Prize. Albeit not in economics. Our topic tonight with Jennifer Doudna is the promise and peril of genetic editing. And yes, for any of the name freaks in the audience, Professor Doudna is aware that her last name spells out do you DNA. The CRISPR technique for editing the human genome that Professor Doudna has identified is revolutionary. It permits in principle nothing less than the ability of human beings to take control of evolution. The Israeli historian Yuval Harari in his most recent book has said that the twin revolutions in information technology and biotechnology will determine the fate of the human species in the 21st century. And that unless these revolutions are harnessed to the interests of human beings and supporting the agency of humans, it may cause the complete rewriting and reformulation of what it means to be human. He was thinking, Yuval Harari was, of CRISPR and the possibility that genetic editing will be used not just for therapeutic purposes, but to selectively enhance future generations of human beings. And of course, our discussion tonight couldn't be more timely. If you've been following the news, you know that late last year, a Chinese scientist, Dr. He, announced the birth of the first CRISPR edited human baby. We'll be discussing this tonight with Jennifer Doudna. The format for the evening. Dr. Doudna will offer a presentation followed by a 30 minute conversation with me, a philosopher and Professor Kelly Ormond, a geneticist here at the Stanford School of Medicine, followed by questions from the audience. Professor Doudna and Professor Ormond will be introduced by an amazing Stanford undergraduate named Jiwu Li. Hold on to your seats as I tell you a bit about Jiwu. She's a sophomore here at Stanford, majoring in computational biology. She's been working on CRISPR since her high school days at the Academy for medical science technology in Hackensack, New Jersey. And as a high school junior, she's set to work on a novel approach to cell specific cancer therapeutics with CRISPR genome editing in human cell lines. Her resume lists dozens of prizes in local, state, national and international science competitions, including first place in the biggest competition of all, the Intel International Science and Engineering Fair. She's continued this research here at Stanford University, working in Stanford Labs, as well as at the Broad Institute at MIT and Harvard. Her work caught the attention more than a year ago of Jennifer Doudna. And Doudna then nominated Jiwu Li for the Wired Magazine 25 prize, where the 25 most important leaders of today select the 25 people who will shape the next 25 years. Jiwu has also presented at the White House. And in whatever little free time she has, she's also a sorority member on a dance team and a health educator at the Cardinal Free Clinics. Ladies and gentlemen, remember this name, and please welcome Stanford sophomore Jiwu Li. Thank you so much for the introduction, Professor Oish. So I'm particularly honored to have been asked to introduce Professor Doudna tonight because of how important her work has been for my own research. So my journey with CRISPR began in 2014 when I was a sophomore in high school. And I was a 14 year old biology enthusiast who had noticed the recent explosion of CRISPR publications and who was also fortunate enough to go to a high school that had its very own research program and in-house laboratories. And excited by the promise of this new genome editing technology, I quickly joined the cell biology lab. And with the help of my research mentor, I began to develop a new approach to cancer therapeutics. So because current cancer treatments have a lot of side effects, I wanted to create a CRISPR system that would kill cancer cells without harming normal cells in the hopes that this would eliminate these side effects. And when I began this research in 2014, the CRISPR revolution was still in its infancy. So much of my early research involved combing through scientific literature. And during several of these searches, I came across publications by Professor Doudna. And Professor Doudna is one of the leading figures in the discovery that CRISPR, which is originally discovered in bacteria, could be hardest for genome editing. And many of our publications were crucial in helping me develop my own project. As I continued to work with CRISPR for the next three years, running experiments and sharing my science with others, my excitement for CRISPR only grew. After I graduated high school in 2017, I was excited to continue CRISPR research in college and have since joined an amazing CRISPR lab at Stanford. By stroke of fortune, within a few weeks of starting my freshman year at Stanford, I had heard that Dr. Jennifer Doudna was coming to speak at Stanford about her current work with CRISPR. And I was able to attend her talk and finally see the person whose work I had poured over during all those years. And I was inspired to hear her speak of a role in discovering today's hottest genome editing technology, as well as her vision for its future. Just this past summer, I received an email saying that Professor Doudna had noticed my work with CRISPR and had nominated me for Wire 25. And I was able to meet with her just this past summer and talk with her one-on-one about the future applications of CRISPR, as well as what kind of ethical implications they will bear. And she shared some of her concerns about the unethical uses of CRISPR. And as a member of the generation in which human genome editing will become extremely relevant, I share many of her concerns. And with the recent reports of the first ever CRISPR edited babies, the topics that we discussed over the summer have become all the more relevant, and we are very lucky to have her speak with us today. Professor Doudna is a professor in the Department of Chemistry and the Department of Molecular and Cell Biology at the University of California, Berkeley. She's also the lead cushing chancellor's professor in biomedical and health sciences. And she has been an investigator at the Howard Hughes Medical Institute since 1997, as well as a senior investigator at the Gladstone Institute since 2018. She's also the executive director of the new Innovative Genomics Institute. And Professor Doudna has received many prestigious honors, including the 2015 Breakthrough Prize in Life Sciences, as well as membership in the National Academy of Science, National Academy of Medicine, National Academy of Inventors, and the American Academy for Arts and Sciences. I also want to introduce Professor Kelly Ormond, who we will hear from later tonight with Professor Reich. So Professor Ormond is a professor in the Department of Genetics at Stanford, as well as a faculty member in the Stanford Center for Biomedical Ethics. She received her bachelor's degree in biology and psychology from Bucknell University, as well as her master's degree in genetic counseling from Northwestern University. She also has a post-doctoral fellowship certificate in clinical medical ethics at the McLean Center at the University of Chicago, and has also been certified by the American Board of Genetic Counseling. With that, please join me in welcoming Professor Jennifer Doudna. Good evening, everyone. It's a great pleasure to be back at Stanford. I would like to start by thanking Rob Riesch and, of course, Ji Wu for that fabulous introduction and for the invitation to come and speak with you. And to share a very interesting evening, I'm really looking forward to the conversation. I thought that I would start by talking about the science of genome editing a little bit, don't worry, we won't get too far in the weeds. But I want to explain a bit about this technology from my perspective as a biochemist and someone who knew almost nothing about genome editing just a few short years ago. And that's because the story that I want to tell you tonight is really about a technology that came about from a curiosity driven scientific project that started with a very different kind of question than where it ended up. And to me, I've been doing science now for several decades. And what I've always enjoyed about science is that you don't know where it's going. You ask questions and you try to answer them in the laboratory, working with, if you're lucky, smart students and people smarter than you. And the science goes where it will. And your job as a scientist is really just to follow the clues, try to interpret the data, and make sense of what it means about the natural world. And that's what we were doing in the lab back in 2012 when we came across an enzyme that's part of a bacterial adaptive immune system known as CRISPR. That once its mechanism of behavior was uncovered, immediately presented itself as a powerful technology for something very different from what it does in its native host and bacteria. And that is as a technology for genome editing. So let me just start by pointing out that I think very, very typically technologies have come about in the way I'm going to describe tonight where scientists are interested in a question. They're trying to figure something out. And they kind of stumble across something that has already happened in nature that gives a powerful clue to the way that you might be able to do something that you'd like to be able to do or control in the laboratory. And that's absolutely true for CRISPR-based genome editing. And what you're seeing here is just a slide that shows the surface of a bacterial cell under attack from viruses. And when these viruses attack the cell, they're literally injecting their genetic material, their DNA into the cell. And for a bacterium, that event initiates a process where the cell has about 20 minutes to defend itself against the virus before it gets destroyed. And so that's a very powerful selection for ways that the bacterium can fight off these viruses. And that's exactly what the CRISPR system is. It's an adaptive immune system that allows cells to detect an infection, grab a little piece of the viral DNA, and store it in a place in the bacterial DNA, in the bacterial genome called CRISPR. And then use that information to protect cells from future infection. So just to tell you a bit about how I got into this, I was minding my own business working on other problems and looking at how cells control the flow of genetic information. But I was working mostly on mammalian cells at the time, back in around 2005 when a colleague of mine at Berkeley, Jill Banfield, called me one day and told me that she had discovered something potentially very interesting in her research. Now, she's a scientist who, very different from me, she works on bacteria and she studies them not in the laboratory, but in their natural setting. So she goes foraging for interesting microbes that are growing in the wild, in various environments. And rather than trying to cultivate those bugs in the laboratory, she sequences their DNA to find out who they are and, importantly, what kinds of viruses they might be interacting with. And that work had uncovered something that at the time was a real head scratcher. And that was that about half of the bacteria that Banfield's lab was studying had a very distinctive set of DNA sequences in the bacterial chromosome, which is what you're seeing here in the cartoon, that included short snippets of repeated DNA, the black diamonds, flanking unique bits of DNA sequence. And what emerged in those three publications in 2005 was that those unique bits of sequence in these arrays were in fact derived from viruses. So this was the first hint that perhaps what these mysterious sequences were, were some kind of adaptive immune system, a way that cells could store information from viruses. And somehow, by an unknown mechanism, use that information to protect cells from future infection. So I thought that was very interesting. And so we met, we started meeting kind of regularly for coffee. And I started a little side project in my research laboratory to try to figure out how these adaptive immune systems might actually function. And what emerged over the next few years from work that actually was done largely in two different settings, one was in a couple of bioinformatics labs, people that work on DNA sequences and try to make sense of what they mean by comparing different kinds of sequences, as well as scientists working in a yogurt company who were trying to figure out how to protect their cultures that they were using for culturing yogurt and cheese from being destroyed by viruses. And that combination of scientists figured out that these CRISPR immune systems protect cells because they can detect a viral infection, which is cartooned here. And store pieces of viral DNA in the CRISPR array and the chromosome. Importantly, there are adjacent genes called CRISPR associated or CASS genes that encode proteins that work together with these CRISPR arrays. And the way the process unfolds in the cell is that the CRISPR array at the DNA level is copied into molecules of RNA. And so for many of you know what RNA is, but if you don't, it's basically just a chemical cousin of DNA that is a kind of a throw away copy of parts of the genome. So the cell makes a little RNA copy of the CRISPR array. And then those individual RNA molecules each include a single segment of sequence that can match the sequence of the DNA and is derived from a virus. So you can think about it like a little address code that's been produced by the cell that provides an address to a particular virus. And those RNA molecules then combine with proteins encoded by the CASS genes. They form protein RNA surveillance complexes that can search the cell, looking for matching bits of sequence that might match those sequences in these little RNA address labels. And if a match is found, then the cell, these molecules are able to grab on to the matching DNA sequence and allow the CASS proteins to cut up the DNA. So for bacteria, it's a great way to create a genetic vaccination card in the cell that can provide protection from future infection. So it's some really cool biology. Now, one of the things about these systems, these CRISPR systems, is that they're very diverse in biology. So scientists started looking at all of the different kinds of genes that occur in different bacteria that have CRISPR adaptive immune systems. And what they found was that in this cartoon just shows each of those boxes, each colored box corresponds to a different kind of gene that's found in different bacteria with CRISPR immunity. And you can see there's lots of different variability. Some of the boxes are very small. They encode small proteins. Some of the boxes are big. They encode really big proteins. And so for people like me that work on understanding molecular function, we were having a lot of fun starting to get in there and figure out what the functions of these different proteins and their corresponding RNA address labels were doing. And that sort of study started leading me to meetings, scientific meetings, types of meetings that I had never attended before, including in 2011, a scientific conference sponsored by the American Society of Microbiologists. I'm not a microbiologist, but I went to this meeting because they were having a session on CRISPR immunity, which at the time was just, you know, they're really just a handful of labs around the world that had started to pay attention to these things. So at that meeting I met Emmanuel Charpentier, someone that worked in Sweden. She was working on bacteria that infect humans and trying to understand their biology. And in the course of her research she had come across CRISPR systems because she found that one of the bugs she studied had a very interesting and at the time a very distinctive kind of CRISPR immune system that had just a single large protein known as Cas9 that had been shown genetically to be essential for the function of this CRISPR immune system in this particular kind of bacterium. We met at the conference, we started chatting about our work, and we realized that we had complementary expertise. I work on molecules and how they function. She works on bacteria and their biology and how they infect humans. We decided to get together to figure out the function of this adaptive immune system in the bacterium she was studying. In particular, we wanted to understand the molecular function of this protein Cas9, which seemed very interesting because it seemed to be the only requirement for these bugs to protect themselves from viruses using their CRISPR system. And that was the question, how does Cas9 work? What does it do? That's what we set out to figure out. And that started us on a great collaboration that is, I think, very characteristic of the way that science, at least in my experience, is now conducted, where it's often collaborative. It's often international. It often involves professors and academic organizations, at least, who are working together. But really the work is being conducted by the members of their laboratories, and that was true for us. And so we started working together with two fantastic scientists, Martin Yenek, who was a postdoc in my lab at the time, and Chris Chilinski, a graduate student in Emanuel's lab. And these two scientists were working several thousand miles apart, but using the internet and social media and Skype and everything, they were able to get to know each other virtually, at least, and share data and ideas. And they figured out that Cas9 is a very interesting protein that has the ability to recognize molecules of DNA at a 20-letter sequence that matches the letters in the guide RNA, that RNA address code. And that's the molecule, and you can see the end of the molecule is gold in this cartoon. That's the address label that the protein uses to recognize a particular place in a DNA molecule, whether the DNA molecule is small or as big as the human genome. And the way the protein works is it has two active centers that can cut DNA. So remember that DNA is a double helix, and so we have to cut both strands if we're going to actually break it like a rope, and that's what the protein does. And importantly, our studies show that the system to function requires a second kind of RNA molecule, the molecule shown in red, that provides the handle for Cas9 to bind. So it's really a dual RNA-guided system in nature that allows recognition of viral DNA in bacteria and then cutting of that viral DNA, which leads to its degradation. So really fun, really cool biology. But Martin Yenek, in my lab, being sort of a really good biochemist, started trying to minimize the essential parts of this complex of proteins and RNAs, and he was trimming away at the RNA to figure out the minimal parts that would be necessary for this kind of DNA recognition and cutting to work. And he was able to show that you could combine the address label RNA molecule with the handle RNA molecule into a single RNA that we called the single-guide RNA that would provide the address and the means of recruiting the Cas9 protein in the same piece of RNA. And the significance of that was that we then had, this point, had created in the lab a simplified system of providing a sequence of letters to this particular protein that would direct it to any desired place in a DNA molecule and direct Cas9 protein to make a cut in the DNA. And so that was kind of a, you might think, well, that sounds like kind of a cool widget. But the reason that it was really exciting to us at the time was because this was happening in the context of a lot of other research in the field, showing that in animal and plant cells, unlike in bacteria, when DNA is broken like this, the cells can detect broken DNA and repair it. And in the process of repairing it, they can introduce a change to the DNA sequence. And in fact, depending on how this kind of experiment is done, one can control the way that the repair of the DNA happens so that you actually can literally edit a DNA sequence. You can make a precise alteration to the DNA. And so if you imagine being able to do that in a cell, you can actually precisely go into a cell with this kind of a tool, cut the DNA in a particular place and trigger cells to change the sequence as they fix the break in the DNA. And so that sort of realization for us was really kind of the moment, I guess, when this curiosity-driven project metamorphosed into a very different kind of project because we realized, looking at each other in the lab, that we had sort of come across this very interesting molecule that nature had evolved. We had been able to engineer it into a simplified form that could be used as a technology and by using this, that we could trigger genome editing in cell types varying from anything from yeast to human cells to fish to plants to essentially anything because of the fundamental nature of this tool, the way it works. So I thought I would, let's see, I think I have a slide here. Yeah, I wanted to show you a video that illustrates how we imagine this molecule of Cas9 with its guide RNA operates when it gets into the nucleus of a cell like ours. So it goes in where the DNA in our nuclei and cells like ours highly compacted into chromatin and this bacterial enzyme is able to search through the DNA looking for that sequence of 20 letters matching its RNA zip code. And when it finds a match, it is able to hold on to the DNA double helix, it unwinds the DNA and allows a match to be made with the RNA and then the protein cuts the DNA and hands off those broken ends to repair enzymes in the cell that can fix the break by, for example, here inserting a new piece of genetic information in the process. So it's a powerful way that scientists can precisely change DNA sequences and importantly this can be done in a way trivially because it's quite straightforward to use this protein and to design guide RNAs that will direct this protein to a desired place in essentially any genome. Something that very quickly became clear after we published our work in the summer of 2012 by labs that started to adopt this for applications in a wide range of biological settings. So, you know, we've continued in my lab. Again, we're biochemists and structural biologists mostly in my lab. So we're very intrigued to understand how this actually works and we've been working away on understanding how this amazing protein prize apart the DNA double helix to make a break. This is a photograph of a 3D printed model of Cas9 that's based on a crystallographic structure where we can actually see the positions of all the atoms in the protein and the guide RNA and the DNA that it's holding on to. And I'm showing you this here so you get a sort of a sense of the incredible ability of this protein to grasp the DNA duplex and hold on to a particular place where it can trigger a break. So it's a highly, it's an enzyme that we now understand to be adapted to be quite accurate at DNA recognition and cutting. So you can predict how it's gonna work when it gets into cells and we know a lot more about that now because of all of the thousands of experiments that have been done since 2012. And it's an enzyme that has a curious ability to unwind DNA, sort of much like a masseuse, sort of relaxing the DNA duplex. And as scientists, we're curious about this process. We're still trying to answer this question of how it prize apart the strands of the DNA, something that's fundamental to its mechanism because it doesn't have an external energy source. So it doesn't, a lot of enzymes that are well known like enzymes that copy DNA and things are proteins that have a way of harnessing some kind of chemical energy source in cells and this one doesn't do that. So one of the clues that's emerged over the last few years about how it might work is the fact that it undergoes a large change in structure when it binds to RNA and to DNA. And this is a little video that just morphs between different crystallographic structures of the protein and you can see that it undergoes a big rearrangement in its shape when it holds on to the guide RNA. It forms this structure that has a central channel for DNA recognition and we think that's really the structure that's actually searching through a genome. When it finds a matching DNA sequence, it forms an RNA DNA helix in the protein that allows a further change in the protein's shape that may actually help it unwind the DNA strands and then finally there's a chemical cleaver in the enzyme, this yellow part of the enzyme that swings into position so it can actually cut the DNA. We understand now a lot of detail about how this protein actually operates. You can really see in a video like this that it's really a little molecular machine that has been evolved over eons and microbes to have this very particular ability to recognize DNA at one particular position and generate a double-stranded break. So it's great for bacteria, but it's also great as a technology. And so what's happening right now is that it was sort of an incredible experience of going through this time in the lab where we were focused on the fundamental biology and mechanism of something like this and then starting to watch it take off as a technology and we were doing some work in that area too, even though that's not sort of what we do as professionals, but we were so fascinated by the fact that this enzyme provides a capability that hadn't really been possible before for precisely altering sequences in cell types and allowing scientists to do that in a way trivially. It was easy to do it. And so this technology has now advanced to the point where it's really, we're starting to see exciting applications in a wide range of areas including in, of course, fundamental research, but also in healthcare, in therapeutics, in agriculture, and in diagnostics. And I thought I would just, in the last couple of minutes of the talk, I wanted to just highlight some of the things that are happening right now that are, I think, really interesting but also lead us to some fundamental questions about the ethics of a technology like this that's powerful, simple to use, and presents opportunities, but also I think tremendous challenges to all of us as humans. And so just as one example of research that's going on that I think could have exciting implications in the future for clinical medicine is something that we're actually working on with scientists at UC San Francisco. Berkeley doesn't have a medical school, so we have, but fortunately we've got a branch of our university right across the bay with one of the most, one of the best medical schools. So we've been able to work with colleagues there to start asking how could you imagine using genome editing to eventually come up with an effective treatment or even a cure for neurodegenerative disease. And this is an example of experiments done by Brett Stahl in my lab. He was a Stanford graduate student who came to my lab as a postdoc with the idea that he could potentially come up with a way to introduce gene editing molecules like this Cas9 protein into the brain where it could affect changes in the DNA that would have a beneficial effect on patients with neurodegenerative disease. And what he's doing here in this experiment is he makes a modified form of Cas9 that is able to penetrate across cell membranes. And so what he does is to take that modified protein, add the guide RNA so he adds that little address label in the lab in just a purified setting and then we can inject it into the brain. And this we're doing this in a mouse model of a neurodegenerative disease known as Huntington's disease that has a well-known single genetic defect that causes the disease. We can inject this into the brain of these mice and we're doing this in a mouse that has an engineered genome so that when editing occurs in the desired place, the cells actually turn on a red protein and you can actually see the cells that turn red. So it's a very nice visual way to observe where editing is occurring. And you can see that in the experiment, the slice of a mouse brain on the right, we actually get significant amounts of editing on two sides of the brain where these proteins have been injected. So it just gives you a sense of the kind of specificity that we're talking about with something like this. And we're actually now moving towards working with larger animal models and really thinking hard about how we could move this from an experiment in a research laboratory to a setting where you could imagine conducting a clinical trial someday. I also wanna point out that there are other applications in healthcare that I think are really interesting but in my opinion also bring up ethical questions. And one of them is this work that's being done both in academic and commercial labs now to engineer animals to be better organ donors for humans. And this is a picture of some piglets that were generated by CRISPR-Cas9 genome editing that where the genome editor was used to do two things. One was to remove endogenous viral DNA sequences that are naturally integrated into the pig genome and could be problematic for humans if their organs were implanted, transplanted. And the other thing is to use gene editing to create humanized versions of the pig genome that would allow their organs to be better accepted by a patient in a donor kind of setting. So this is going on. Companies wanna make money from this. Doctors are interested. And of course patients are potentially interested in this. What about the pigs? And so we have to think about animal rights, animal welfare, and this is just one example. But I don't know if anyone saw the story in Gizmodo recently, but there's also work going on in monkeys that also I think raises questions about how we're using genome editing in animals and what would be the right way to regulate and control that kind of work. And then I just wanna mention that there's just a lot of really, really exciting work that's being happening right now in agriculture. And I just wanna mention one example of this. And this is a picture from a publication from I think already two summers ago from a lab at Cold Spring Harbor, Zach Lipman. And I was at a meeting a few months ago where Zach was giving a talk, presenting his more even more recent work where he showed that he could use CRISPR-Cas9 in tomatoes to literally change a regulatory sequence in the tomato genome that allowed him to dial up or down the number of fruits that these plants were producing. And they were genetically the same otherwise, right? So it's really an incredible thing. It was a room this size, packed, and he was giving a talk and most of the people in the audience were scientists working on mammalian cells and thinking about biomedical applications. And Zach gave his talk and there was a collective from the audience because well, we all like tomatoes maybe, but it was just an incredible demonstration of the power of a tool like this that allows you to have that kind of genetic control over an organism, something like controlling the number of fruits that are produced. And then finally, I just wanna mention that one of the more recent areas of development using CRISPR enzymes is actually the area of diagnostics because some of the research that we and others have done shows that these enzymes are useful not only for cutting DNA, but also for holding onto DNA and triggering a signal that you can detect easily in a test tube. And this is brought about the idea that you could potentially use these systems not only to make edits inside of cells, but you could also use it to detect DNA and RNA molecules that come from viruses, for example, or bacteria that you might wanna detect in a clinical setting, but do it in a very simple, cost-effective way, point of care kind of diagnostic, almost like you sort of imagine a home pregnancy test kind of test that would allow you to figure out if you have a bacterial infection or a viral infection, or things like that. So that's also an area where there's now very rapid advances that are happening using these kinds of bacterial proteins. So it's triggered a whole sort of field of not only people like me that are understanding fundamental aspects of these proteins, but also a large commercial enterprise of people that are trying to capitalize on different aspects of these enzymes, and that again raises questions about who owns CRISPR and who should own it and who should make money from it and how do we regulate it and all of those sorts of questions that I never thought I would have to think about, but now I do. And I want to just end by mentioning that there are fundamentally two different ways that we could imagine using a genome editing tool like CRISPR to make changes to the DNA of cells. One is doing it in what we call somatic cells. These are fully differentiated cells where the changes that are made are not heritable by future generations, but the other kind of change is doing that kind of editing in what's called the germline. That means in sperm or eggs or embryos where the genetic changes become part of an entire organism and they can be inherited by future generations. And this possibility was clear very early on because of the research done initially in zebrafish and then later in rats and mice and then ultimately in monkeys and then more recently in humans. And this is a picture that just shows the way this is done. So this is actually a mouse embryo, fertilized egg that's being held by a pipette on the left injected with CRISPR-Cas9 molecules by a needle coming in from the right. And these experiments are certainly in mouse embryos and other kinds of fish and worms and those sorts of animals that are worked with in the laboratory. This kind of editing is trivial to do. And it turns out that it's also not that difficult to do it in mammals, in primates and even in humans. And so several years ago now, this was actually a picture that was on the cover of the Economist magazine under the banner Editing Humanity. And at the time, I think many of us working in the field felt that it was a little bit science fiction-y and it was a little bit of hyperbole, right? Because it was sort of imagining all the things you might do with genome editing. And for those of you that know about human genetics, you know that these types of traits that are shown here are traits that for the most part we don't know the genetics of and most likely they have many genes that contribute to these traits. So it's not, it wouldn't be something that one could imagine doing today. But nonetheless, it raised the specter of genome editing in humans and not only in somatic cells but also in the human germline. And as you may know, fast-forwarding now a few years, we had a conference in November of 2018, so just a couple of months ago in Hong Kong at which a scientist in China in fact announced that he had in fact done germline editing in human embryos and not only for research purposes but had actually implanted those embryos and they were those babies that in fact had been born. So this was really I think a wake-up call to the international community that we need to really get serious about thinking about how we talk about this, how we explain it to people, how we imagine regulating it and what can be done to ensure that there is responsible use of what is a very exciting technology but that also has potential for very ethically, I think, challenging kinds of applications like the one that was announced in Hong Kong. And I'm gonna leave it there because we're gonna, I know we have a lot of things to discuss but summarizing, I'm just pointing out that RNA-guided gene editing has become a very powerful tool and many researchers across the world are taking advantage of this technology now in their fundamental work but increasingly we're going to see products coming to market that are generated using this and we have to think about controlling it, we have to think about regulation and the biology is gonna continue to drive the technology I think as it goes forward. And I wanna just thank a fantastic group of people, this is a recent photograph of my research lab at Berkeley, wonderful collaborators, I couldn't possibly list them all but these are just sort of a collection of people that we've been working with recently and then of course we've had wonderful support for the work and I couldn't have done this without trust by agencies that believed in us when we were working on a very obscure system called CRISPR that nobody had ever heard of and I finally I just wanna mention the Innovative Genomics Institute, a partnership between UCSF Berkeley and the Gladstone Institutes, we actually have some faculty here at Stanford who are affiliates of the IGI and we're doing a lot to both advance fundamental research with genome editing but we also really want to be part of the discussion and conversation about education and ethics and I'll leave it there, thank you. Thank you. Why don't you get started Kelly? You know I think you really ended on the keynote to me which is how do we combine some of the exciting parts of this technology while trying to minimize the chance of things like the babies being born when we don't know enough? So the first thing I wanna hear from you is almost a little more about your personal reaction to that news and what it must have been like to be at that Hong Kong summit when this was all coming down, if you don't mind sharing. Right, well I had a little heads up about it because I actually got an email from He Jean-Cui, the scientist who made this announcement a few days ahead of the conference in Hong Kong and you can just imagine getting an email whose subject line was babies born, babies born, kid you not and it explained in just a couple of sentences that this had been done very matter of factly and that he wanted to have a private meeting with me before or during the meeting in Hong Kong where he was an invited speaker. Yeah, it was a real shocker and so I called David Baltimore who was the chair of the organizing committee for that meeting which I was serving on as well and we agreed that we needed to really have a plan in place for how to manage this because we could just only imagine that it would be a big circus around this kind of announcement and I immediately changed my flight, I flew out that night to Hong Kong and I got there in time to have some meetings with not only the organizing committee but also with He Jean-Cui twice we met before the conference actually started and what struck me when I met with him was that and you've seen maybe the pictures of him he's quite a young scientist he actually did his doctoral training here at Stanford in the lab of Steve Quake and he's not an MD, he's not a clinician he's not somebody that runs an in vitro fertilization clinic or something like that and he also seemed, I thought, remarkably naive about what the likely public reaction would be to his work I think he sort of had somehow imagined that he would be embraced internationally that people would celebrate this as a great achievement and that perhaps you might even be awarded big prizes for his work and I think he was quite shocked really that in fact the reaction was quite the opposite Yeah, if you had had the opportunity to talk with him like some of our colleagues have in advance what would you have said to him if he gave you hints this was in the works? Well, you know the thing was that he had actually appeared a couple of times previously in my sort of professional travels I had come across him at a couple of meetings and in fact he had attended a small, very small meeting that we had at Berkeley that was ironically about ethics human-germline editing and he had presented some work but it always appeared to me as though he was doing fundamental research I had no idea that he was actually intending to proceed to the clinic and I think if he had made that known to me certainly I would have advised against it So I'm curious to ask as the non-scientist amongst us here and I'm sure there are some people in the room too maybe many who are aware of the general story but when you get into the details of the science can't follow along so I just wanna try out a couple of ideas that in reaction to this announcement about the birth of babies that had been CRISPR edited to make sure I gather together the kind of big takeaway from it So this is a revolutionary technology because it provides this relatively simple approach to editing genes not just human genes but the genes of any species and as I understand it that relatively low barrier to entry so say people have often talked about analogy say to the Manhattan Project and the nuclear bomb or the nuclear physics where you needed uranium and it wasn't easy for anyone to get their hands on that so it was easier comparatively speaking to regulate research into nuclear energy the barrier to entry here is pretty low maybe you can say like if someone had a whole bunch of advanced classes in high school like Jiwu has like how much money do you need to set up a CRISPR editing lab in your garage I'm kinda curious to answer that It's a lot less than doing something in nuclear physics that's for sure That's for sure and you get to the germ line so it's not just editing the gene of a particular organism but it now gets passed on all the way down the line so it's part of the profound nature of this so the story about the kind of journalistic sensationalist way to put this would be playing God with the genetic sequence itself of course it can have unbelievably important positive therapeutic uses and you gave some examples of those including with plants and not just animals and the like but I wanna get to the potentially less beneficial applications but maybe just set the stage for how easy is it to get access to the technology and the background to that question of course is like as with artificial intelligence and information technology for the people who develop it let's assume are extremely well intended imagine all types of beneficent uses of the technology but when it gets out and circulated they learn that there are people who are not as well intended not so beneficent and can use the same technology for really I mean the kind way to put it would be unhappy ends but an unhappy end in the CRISPR case is germ line editing that then goes through the progeny of all future organisms that's a profound thing so give us a little bit of the detail about what's the barrier to entry for a really sharp 14 year old and the well-meaning scientific community that's imagining all of these powerful applications how does the well-meaning scientific community think about the lessons that in local terms, Facebook has learned about the malevolent uses of connecting people around the world yeah well with respect to access to this is a technology for scientists that you know funk operating scientists in academic labs it's it's very inexpensive to get a hold of of the Cas9 protein and the kinds of you know constructs that you would need to work with it in the lab so for example there's an organization called AdGene which is a non-profit that's operated out of Cambridge, Massachusetts that distributes research reagents to scientists at cost so that means that for sixty five dollars you know essentially the cost of a FedEx shipment you can get a hold of the Cas9 protein and the accompanying molecules that you would need to direct it into cells and start using it for for genome editing so that's one of the things that's actually made this technology so I would say democratizing right it's just become widely available you don't have to have a lot of money you don't have to have special connections you don't have to know somebody who knows somebody you can just you know you can just get a hold of it and then in terms of more sort of DIY do-it-yourself kind of science well you know the indiegogo you know my neighbor down the street three or four years ago actually you know texted me one day and said hey Jennifer did you see that indiegogo was selling a crisper kit I was stunned and actually they do right so then some smart scientists some young people just right out of college at the Innovative Genomics Institute tested it and it didn't work so but they started working with some high school teachers around the Bay Area who wanted to get access to this for their students and they're now working on a kit that actually does work that allows students not to edit embryos but to edit yeast and turn them green and you know things like that so the students can actually learn about how these molecules work and what they enable because we hope that part of the you know we think that part of the path forward with all of this is education it has to be about teaching young people about this what it is how it works and and how to think about using it responsibly all right the that the I'm gonna pick up on that last phrase using it responsibly so I don't wanna in any way minimize these enormous potential beneficent therapeutic uses and we should definitely talk more about them but using it responsibly if it taught we're talking about a couple hundred bucks you know democratizing CRISPR experiments is one way to put it that sounds like great we get lots of people invested in the technology get a bunch of experiments will get quicker innovations but if you were to go back to the Manhattan Project idea like democratizing nuclear weaponry sounds nightmarish so again the the philosopher in me wants to you know make a realist take a take a realist you know picture of human beings and intentions and the professional community that at the moment at least with respect to doctor had in china is can you know roundly condemned the the the CRISPR edited baby if it's fully democratized at low cost in any corner of the world with the you know relatively minimum amount of know-how given the low barrier to entry why rely on the good intentions of people or or better should we rely on the good intentions of people you mean should we will rely on good intentions versus putting in place some kind of legal framework or you know some yeah well this is something that you know many people are discussing this right now and the challenge is that I think even if you wanted to put in place a legal framework the reality is that right now you know with the way that science and and really our societies are global whether we like it or we don't it's it's just a fact and so if we here in the united states for example agreed that you know this is just too dangerous of the technology let's not allow scientists to use it other you know that would have its own issues of you know debate and trying to figure out how you would enforce such a thing but I think the reality is that this kind of use and and various uses of gene editing or any other technology like this would forge ahead in other countries and so with the U.S. want to take a position of a backseat to that or do we want to instead hopefully be playing more of a leadership role and you know that's and again there's no right or wrong answer to it necessarily but I myself think that we're better off being being engaged and and trying to if we can play more of a leadership role so I have a question I'm in a basic science department even though I'm not a basic scientist and and one of the challenges that I see is as much as our scientists colleagues want to sort of think about these ethical issues and the good uh... you said something earlier that really struck me which is you follow the science where it takes you and you don't always know where that's gonna be and I worry a little bit that that in order for our scientists to really take advantage of that they don't always get the training and the support to think about the ethics so I wonder what thoughts you have on that because I feel like you're you've really come out strong about the ethics on this from the very beginning and that is unusual frequently when we have these new technologies I think you're right my my experience in science is that I think many scientists and frankly I would put myself in the same category until very recently uh... was sort of having the opinion that I'm not a bioethicist I'm not professionally trained in that area that somebody else's responsibility I'm just doing my next experiment I'm trying to publish my paper I'm trying to finish my thesis you know right I'm trying to get a job and trying to get tenure and uh... and I think many scientists uh... you know feel that way and I sympathize because I under I understand that that mentality completely I do think that you're right that we actually don't do a good job at least in in in our graduate program it's true and in the programs that I came through as a trainee in exposing students to you know the the realities of thinking about their work in the context of how it might be used uh... how it might impact other people other fields fields that they don't that they aren't expert in and it's it's a big challenge I'm not sure how we how we tackle that I'd love to hear I don't know if you have you know thoughts about better ways that you envision you know educating students that you know because we you know we I think we all you know we all like I'm I'm teaching right now an ethic I'm participating in ethics course at Berkeley you know for our graduate students but it's it's really not about this kind of thing right it's really just about uh... you know who should be a co-author on a paper you know things like that right what you know right it's that kind of thing yeah which is I mean I'm not trying to minimize that it's important but it's a different level from what we're talking about yeah well I am sure you have the same experience when you teach but sometimes it does feel a little bit like being sycophist and always pushing it up the mountain uh... but the challenge is to try to find ways to do that I think that don't make it seem like folks who work in bioethics are just like no you may not do this right I once had someone at our genetics department retreat say to me do you like genetics because you're always talking about the bad parts of it I was like no I love genetics that's the best part so I'm sorry that sometimes bioethics has come across as as being like the the goalkeepers or the people who are supposed to stop something and I want to find a way that we can work better together as a team to move science forward in an ethical way just quick thought on this too I mean the at one level as the resident philosopher here on the stage the person who thinks about ethics professionally you know more or less full-time there's a piece of me that reacts to hearing the story about what scientists are like and and even you know you said until some of the more recent years and the recognition recognition of the power of the technology the scientists are also humans living a human life involves confronting profoundly difficult complex moral questions I'm not sure why that would be balled off from one's professional life so I just always am curious about the division of labor in one's head between being a human and being a scientist that's my own curiosity there but then separately you know since I now am and getting involved in this research effort here at Stanford called human center centered artificial intelligence and I'm teaching a class now on ethics public policy and technology we're not really foregrounding any issues in biotechnology but it is interesting to me to reflect on the fact that in medical schools as a result of a whole variety of things that happen some of them really not happy stories about experimenting on human beings in ways that now we recognize as profoundly wrong and unethical bioethics has become a kind of institutionalized feature within education and you can't you know you wouldn't find a medical school that didn't have a bioethics unit you can't best of my knowledge become a doctor without taking classes in bioethics and there are professional standards that are expected to be upheld there's nothing quite equivalent to that in the school of engineering with respect to computer scientists and so that's an interesting story for me but I'm aware when I you know walk across campus this you know the science quad here that there is a you know a kind of sensibility that the ethicist role is the finger wagging ball it's like to slow down think about it some more maybe not do it at all and the reaction is often just let scientists be scientists let us go full throttle on innovation and discovery because we want to remind you about the revolutionary stuff that often comes out of this and of course I'm not immune to that response but if you feel like is you know pushing the Sisyphean boulder up the hill or you know reacting in a way which the let scientists be scientists is the circle that you're familiar with how then is the challenge for you of bringing these ethical and social dimensions of something as revolutionary and I mean that in the fullest sense of the word with positive and negative uses as as CRISPR right well I think that I'm not I'm not entirely sure what how what your question is fair enough fair enough I counted as a that's maybe my fault that's my fault you got you got me up and running there so let me put it as a question if we recognize the ethical and social dimensions of this technology and you have assumed as you you've said very clearly that you've taken a responsibility to break out of the mold of being merely a scientist accelerating the discovery how's it gone the past couple of years when you've had to Hong Kong and you got the email message as we started it do you feel like it's pushing a boulder up the hill or do you feel like breaking into a public conversation is you know we're making good progress there and the public awareness of the challenges here is going the way you're hoping I think there's been an interesting thing that that well I'll make a few points of relevant to that I think that I mean look at the room here tonight I mean this is really incredibly exciting to me to see all of you here you're interested in the science but I think you're also here because you're really interested in where this technology is going and you're you want to be part of that conversation right so I think that's wonderful that's really really exciting I don't think scientists role is to counter the finger waggers you know right or say you know I know best because I'm a scientist I'll tell you what we should do with this technology but I do think scientists need to be engaged in the conversation and often they aren't and so I think that you know what I see as maybe one of the roles that I can play right now is to encourage more scientists to get engaged and to be part of the discussion and I think they want to I just think they don't know how to you know so I think there's a desire it's just that there's often scientists are you know they I often hear this believe me I often hear this from my colleagues who say but I don't know enough about X and Y to you know I'm not an expert in that I can't really speak to it because I don't really know and I always say well but neither do I you know I may not they're talking about things I really don't know about I'm just trying to I'm trying to learn and I'm really trying to facilitate a broader conversation let me take one more pass I'm just trying to get you to come over on my territory here as the philosopher that's obvious I'll put you back here in a minute there's a sense of personal responsibility that you or any scientist could take there's a sense of professional responsibility you know the various professional societies that you belong to this Hong Kong meeting you're making statements not just as an individual but as a group of scientists and the third you know piece of that potential three-legged stool it seems to me is external regulation of some kind whether it's from a government whether it's from some type of super national body do you see a role for policy regulation or a super national body that's not just a professional group of scientists somehow taking stock of this and regulating it in a way I do I definitely do yeah and I think the question is how to do that whenever you say regulation or rules or laws that immediately to me brings to mind enforcement right how do you enforce it and I think that's a big challenge and right now you know that's being discussed very broadly in the scientific community how do we put in place for example whether you want to call them guidelines or regulations that would govern the use of for example genome editing and human embryos how do we do that in a way where scientists will or anyone that might try to do this would respect it and I think that the what happened in Hong Kong was kind of a to me a really important wake-up call that what had been done up until now wasn't enough right it wasn't enough because when I talked to Hu Zhenkui he said to me I said to him but you know what about this report that was produced by the National Academies and it had very clear criteria for you know proceeding into the clinic with human germline editing did you did you consider that and he said oh but I followed that right he said I followed that and I said how can you how can you claim that and he you know in his mind I think he really had convinced himself that he had followed those criteria so to me that says well we need much clearer criteria for one thing and we also need to have much broader buy-in so I think another you know thing that we talked a little bit about dinner but you know something worth considering is what role do scholarly journals play in this kind of debate or discussion because one of Hu Zhenkui's clear goals I think was to publish a prominent paper in a very high profile journal that would attract a lot of international attention and frankly would provide a lot of you know sort of professional you know stamp of approval and so should journals do that I've also had people say to me why hasn't he published his work I would like to read what he did and be able to evaluate for myself what do I think of what he did right and so I think that's another you know factor in all of this I mean we when we were in Hong Kong and Hu Zhenkui you know was a scheduled speaker there and he was planning to get up and you know give his talk we were sitting in the audience waiting for him to come on stage and there was a lot of security and there's tons of media and it was really really a circus and meanwhile and I was sitting next to someone who was getting real-time you know texting from someone in the US who said did you know that Scott Gottlieb at the FDA who's the head of the FDA has just posted an interview where he is very critical that you folks at the National Academies meeting in Hong Kong are giving a stage to Hu Zhenkui why are you giving him an opportunity to present his work he should be condemned and we literally had to kind of in real-time respond to that to Scott Gottlieb and explain that in our view this person is you know whether you like it or not he is someone who is part of the scientific community he has done something he's claimed something and he's already a scheduled speaker at a meeting he should get up and present his data for evaluation by a group of scientists that's how we viewed it so you know people have different opinions but that was how we we viewed it but then you could you know you could take a different point of view potentially about you know should he be allowed to publish that work in a scholarly journal and believe me I've heard opinions all over the map about that well so I want to ask one last question before I know we need to get to some audience questions you must all have a million we could talk for hours about safety and whether or not this is ready for primetime or if it ever should be but if we can jump forward however many decades or years to imagine that day I want to hear from you about how we decide what medical conditions and we'll stay away from enhancement for now you can all ask about that in a minute what medical conditions are the right ones either for somatic germline treatment or germline and you gave the example of Huntington's disease which I think anyone who works in medicine knows is a quite medically severe really profound condition and that's probably one of the more clear cut examples but there are many more illnesses and disabilities that are going to be less clear so what are your thoughts yeah well I think that you know in my opinion we would certainly want to start with diseases like that that have a clear single genetic cause that's well known and well documented where there are studies that have been done that you know have looked for example in animal models and followed the behavior of animals that where you've been able to you know alter that the gene that's involved and test for safety and and then I think you know you also have to think about the practicalities of doing this for example right now in my opinion probably the major bottleneck to moving forward in the clinic just scientifically not ethically is delivery how do we actually introduce gene editing molecules into the cells where you want to make changes to DNA and not into other cells and that's still something that's very hard to do not just with CRISPR but with you know lots of other things too but you know the technology again it's moving forward very so I think what we're going to see is kind of a you know an evolution of thinking about you know the kinds of diseases that can be treated now and right now you know the easiest ones are going to be things where you could take for example blood cells out of a patient do the editing outside the body and then put the cells back so they can repopulate the blood supply with corrected cells to correct things like sickle cell disease versus something like Huntington's where as I mentioned you know the big challenge there is how do you get it into neurons and ensure that the kind of editing that occurs is safe and effective at treating the disease and I think we're a lot farther away from being able to do that right now so part of it I think will just be decided based on you know where the technology is. How much of it do you think is going to be the scientists picking the diseases either that are kind of technically easier to treat versus really looking to the families and the patients with these conditions and finding out who really wants these therapies to go forward. That is such a good question that is a great question and I think about that a lot because I think right now and again this is my just my view of it I think that right now a lot of it is being driven by frankly just by scientists deciding that this is possible to do that is not so possible to do or at least not possible for me to do and so you know choices are being made based on those kinds of factors rather than what's the most pressing medical need right and the other thing is that and I see this and I suspect that my colleagues in working in the field see it as well is that you know I get approached quite often by family foundations or even wealthy individuals who say to me I would like to sponsor research on you know disease X which is typically you know a rare disease that affects their family and you know some some of them are willing to put in a lot of money and so then you have to decide you know is that what are the ethics of that like is that should that drive our decision should we be working on rare diseases that are sponsored by billionaires you know and but not working on things that might affect many more people you know it's I think these are really there there's a lot of ethical questions there as well we're going to open it up to questions but I want to end we got microphones on either side so if you have a question you can line up now as we get to questions I'll just end with where Kelly prompted us which is this distinction that often gets made between genetic enhancements and therapeutic uses of the uses oh yeah do you think that's the right distinction where the therapeutic stuff is the beneficent good part and the enhancement part is the ethically worrisome part or is there a better distinction to make how do you think about that conventional distinction in the first place I think it's actually a hard distinction to make actually except in sort of the at the extremes because for example there's a well-known gene that affects hyper cholesterol emia right which is you know one of the leading causes of cardiovascular disease in you know in humans so if suppose it became possible to knock out that gene in let's say in embryos so that you would effectively protect people for over their lifetime against heart attacks and strokes they don't have to worry about their diet they don't have to take drugs they just don't have to worry about that right they might have to worry about other things but not that you know is that an enhancement or is that a medically important thing to do it's hard to know how you would quite define that but I think we might not be that far from having those kinds of decisions to make alright let's open up the questions if you could avoid doing the rambling non-question that Aisa comes to that would be great we'll start over here sir first I want to thank you for this enlightening educational and thought provoking forum so thank you for that first question you started to go down a path where you were talking a little bit about the future I want to pull on that thread a little bit more because I frankly feel that we are human 1.0 in Silicon Valley you have brought on through these technologies what I think will become human 2.0 and I think we are the transitional generations that are the folks that are sitting in this room but maybe a hundred years from now the transition will be over and the world will supersede and I haven't heard anyone really talk about what are the ethics and how should society how should we as a you know the last of our kind handle this transition because I think that is really what's at play and I think that's the horror of when you talk about the incident in Hong Kong is that we start to see that this is the thin wedge that will only grow as the century unfolds and I think that's really the reality of what's going to happen because you can't stop human nature if your child has a disease like you talked about you're going to do everything in your power and everything your wallet can afford to fix that and if you don't do it here at Berkeley then they will go and find another lab somewhere else in some other country and get it done and as the technology becomes more precise and more effective in curing diseases to why wouldn't you look at what parents do today to give their child every possible advantage to get into a school like this or get a job at an outstanding company or whatever so this will just be another tool in that toolbox so I think the reality is the human 2.0 is going to happen and what I really want us to talk about is how do we deal with it how do we deal with it and make that transition that's a great point and a great question and I think that the short answer I guess is that we need certainly to have forums like this where we discuss these issues so that people become aware of just what's happening I agree with you 100% that I think we're all living through a fascinating moment right now if you will Hank really who's in the audience has written a bit about this where the whole way we think about for example human reproduction I think is changing I had that profound sense when I was in Hong Kong actually sitting there and listening to this guy's presentation I just I thought oh my god I'm like living through this you know historical moment but I think you're right that in the future it's coming I think we can all see that and the question is not should this happen because I don't think we can prevent it but it's how will it happen and that's important and I you know that's what we need to work on is the how part the questioner described it not as a fascinating moment but we are the transitional generation interesting way of putting it we'll go up to the top and then come over here yes thanks for being here I've heard the word ethics the word ethics has been thrown around about 12 times and regulations have been thrown around about 14 times and it's not very clear to me anything concrete came out of that so let me give you a concrete situation what if North Korea right now since Cas9 is so easily acquireable, CRISPR so easily to be implemented what if North Korea starts making babies out of this technique, designer babies do we treat this the same way as we do them testing nuclear weapons and then how in which case how do we respond so that's a concrete situation next month the New York Times will publish an article where they say 10,000 babies are being in the test bed in North Korea what do we do? Rob? these are the geopolitical questions about science that are profound I'm giving you an actual scenario right? well we got the scenario we understand sir but I think you raise a good point that there are things that can now be imagined at least that are not that far out of what's possible and so we have to start thinking together about how to deal with that in my view no easy answer to that question right? I don't know what the right response is right now to that and I think that we all have to be as best we can engaging in this and working with our regulatory agencies at least here in the US but I really think it has to be an international effort to put in place a set of I would call it regulations that control that but would rogue states follow those? no probably not so it's a very hard question and frankly it does not just pertain to CRISPR-Cas9 does it? it pertains to frankly any technology that can be used for ill intent people speak of an arms race in AI maybe there's an arms race in CRISPR or enhancing humans thank you very much for this great talk today my name is Megan Palmer I'm a bio engineer and now a policy scholar here at Stanford and also work to run part of an international competition in genetic engineering with a lot of these young scientists and engineers and so my question really has to do with thinking about this inspiration and engagement to work proactively on these issues what's deep enough what's enough for some of these scientists and engineers because in this case we saw engagement with ethics we saw even a set of ethical principles being put out that almost served a surface level as justification instead of critique and so how do you begin to think about that sort of surface level ethics engagement sort of performance instead of practice and related to that on some of these security considerations should we think about engaging on those intentional misuse worst case scenarios in the same way well to your first question I've thought about this quite a bit and I've had some really interesting debates about it I think right now my own opinion is that we're better off let's just take human germline editing as an example I think we're better off putting in play sort of detailed criteria that the international community agrees would need to be met for anyone to proceed into the clinic because I think what I sort of took away from what happened in Hong Kong with this announcement was that the sort of the guidelines that were in place were too squishy it was easy for someone to convince themselves that they were actually following those guidelines and so I think we actually need to have very precise criteria for what would need to be done to proceed into the clinic again and I think that has to begin with an international forum of experts but I think that hopefully would then lead to actual governmental level regulations that would be put in place and then your second point was does this differ with some of the really intentional misuse worst case scenarios what do you think about ceding that type of inspiration and information amongst this group? Right, well and again this is just me speaking personally and I'm very interested to hear other people's opinion about this but I often feel very uncomfortable when there's lots of if there's an effort to do kind of a detailed discussion of unethical applications and how one would do that I think maybe that's appropriate for discussion at the meetings of the CIA or whatever the planning for these sorts of things but I just think that doing that publicly or like publishing papers about how to do that is counterproductive myself, that's my opinion Yes sir. Hi. So I want to frame my question around this hypothetical conversation that you might have with a young scientist somewhere in the world that might have come across a technology as powerful as CRISPR maybe in another area what words of advice or what words of comfort or what technical kind of advice would you give to this young scientist if you were having a conversation with him or her? Well I would say that it's important always to be thinking about the broader context of your work and how it could be used or misused and and just you know sort of the just generally kind of the broader impact of work that any of us are doing whether we're working on technologies or fundamental knowledge and so that's one thing and then I think I would also say that I would advise not being afraid to trust your judgment and don't worry about not being an expert in bioethics or law because I think that scientists have to be willing to voice opinions and debate and discuss and learn from other colleagues who know more in those areas and frankly I think it's for me personally it's been a fascinating journey and I've learned more in the last six years and I probably learned my entire life before that so Back up to the top Hello, up here I wanted to say thank you for coming out and also commend your courage for doing this because I'm not going to let you off the hook I think Professor Reich asked some really good questions about what happens when people make weapons basically and this is tremendous weapons technology so you know you're the founder of four companies you're going to be a billionaire I think it's safe to say my med school classmate is working with you at Intellia the CEO he's a very smart guy you guys will be successful and you'll be able to get your constructs into cells and then if that gets married up with something that does it widely I think you've got an ethical problem because you've built a capacity let's say at Intellia where you can do this but you haven't developed an antidote you haven't developed a vaccine so if you're going to release something into the wild that can get into cells and change people's genomes don't you have a responsibility also to prevent that from being weaponized and to work just as hard on the counter excuse me counter technology is on the offensive technology agreed and I'm glad you brought that up because actually that exactly what you just said sort of an antidote to CRISPR or an antichrisper is something that has caught the attention of agencies including the Department of Defense and they have an organization called DARPA and DARPA has put out I think now it's at least two calls for proposals that are aimed at exactly what you just said basically controlling CRISPR making sure that it's done safely and not only that that you could shut it down if you needed to or even reverse its effects if you needed to but you want to outsource it to the government isn't the responsibility of the companies to do this well first of all I would just say if I were king of the FDA I wouldn't let anything on the market unless it had an antidote already in its pocket well so the question is how do you want that research to be done so the government funds people like me academic scientists to do research and they can direct that research by putting out calls for proposals in certain areas as the DARPA agency did in this case and so you know frankly that's one of the major ways that fundamental research gets done in the country companies as you know they're companies like these are publicly traded companies they have shareholders they have fiduciary responsibilities too they actually have to focus on getting products to market you could argue that well part of the product has to be the safety switch for it but they might not agree it just depends on what their priorities are if the FDA were to say we want to prove a therapy unless it has a safety switch you can imagine they would prioritize it then but that hasn't happened yet I'll write my congressman gone a little bit over we started a little bit late with apologies to the many people who still have questions we're going to end with this question and hopefully this will be the start of many such conversations here at Stanford thank you I had several deja vu's discussion of the Asilomar conference and what was happening at that time and I was wondering whether you have studied any of the transcripts I assume you've talked to Paul and I'm sure David has a lot of insights into it but there's so many things you were saying that were seemed like exact conversations that I remember at that time right so he's referring to the Asilomar meeting that happened back in 1975 which is a meeting that kind of historic because it was convened by scientists to discuss something called molecular cloning and this was at a time when it had become possible to make pieces of DNA in the laboratory that encoded particular kinds of proteins you could clone them, you could make copies of them and bacteria and it quickly became obvious to scientists doing this work that that first of all this was very powerful technology was the origin of genetic and arguably kind of the origin of kind of the whole sort of modern biotech industry and modern molecular biology but at the same time it also was potentially very dangerous because of course in the human gut we have bacteria of the type that are grown in the lab and that people were using for this kind of molecular cloning and people started thinking, gosh what if you had human gut bacteria that were suddenly able to make anthrax any kind of dangerous protein that scientists could clone in the lab and so they convened a meeting to discuss this and as you mentioned both Paul Berg and David Baltimore were part of that and so that led to sort of a situation where there was initially kind of self-regulation by the scientific community and it was if you look at how things unfolded it wasn't entirely effective but I think it did provide a model for how we can think about dealing with other technologies like for example CRISPR and so at the Innovative Genomics Institute back in 2015 we actually convened the first meeting of scientists to have sort of an asylum our moment if you will and discuss the future of genome editing especially in humans and in the human germline and that meeting included both Paul Berg and David Baltimore and they were incredibly helpful and they have been all along as I mentioned David Baltimore actually convened the meeting in Hong Kong that we just had they've both been very involved and engaged in this conversation and they provided important perspective because they've seen some of the same questions that were raised back in the 70s are now coming up again 40 years later about a new technology but it raises some of the same kinds of issues and I would argue actually then goes a step beyond because now we're actually talking about you know not engineering bacteria but we're talking about actually engineering humans potentially but it's a great it's been a great sort of blueprint I would say for shaping the conversation now I want to thank you all for coming out tonight would you please join me in thanking Dr. Jennifer Doudman