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The Big, The Small, and The Complex
CRISPR in Context: The New World of Human Genetic Engineering

It’s happened. The first children genetically engineered with the powerful DNA-editing tool called CRISPR-Cas9 have been born to a woman in China. Their altered genes will be passed to their children, and their children’s children. Join CRISPR’s co-discoverer, microbiologist Jennifer Doudna, as we explore the perils and the promise of this powerful technology. It is not the first time human ingenuity has created something capable of doing us great good and great harm. Are we up to the challenge of guiding how CRISPR will shape the future? The Kavli Prize recognizes scientists for their seminal advances in astrophysics, nanoscience, and neuroscience. The series, “The Big, the Small, and the Complex,” is sponsored by The Kavli Foundation and The Norwegian Academy of Science and Letters.Learn More

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NARRATOR: Since the first humans harnessed fire, our big brains have been presenting us with challenges. Innovations that can bring us great good, and also great harm. In the 15th century, the printing press allowed people to share knowledge, sparking the age of reason and also upending the established order and authority of the church. Learning to master the winds and navigate the seas, humans conquered the globe, and spread deadly microbes to populations with no resistance. In the 20th century, we split the atom, unleashing a power hitherto unimagined and for the first time introducing the possibility of our own annihilation.

NARRATOR: The speed with which our machines can learn has raised the prospect of the so called singularity, the moment artificial intelligence bolts beyond us, creating a world in which we are no longer masters. And now, twin girls have been born in China who were genetically engineered with the powerful gene editing tool called CRISPR CAS-9. Their altered genes will be passed to their children, and to their children’s children. We have discovered a tool that bypasses natural selection, giving us direct control over the levers of evolution. And again, we are challenged. This tool can bring us great good – more food, less disease, or great harm. Can we learn to use it wisely?

GUY MCKHANN: It’s my honor to introduce to you a scientist who has contributed to one of the most significant discoveries in the history of biology, professor of chemistry and of molecular and cell biology at the University of California at Berkeley, the recipient of numerous prizes including last year, the Kavli prize in Nanoscience. Please welcome Jennifer Doudna. You’re welcome.


GUY MCKHANN: So let’s start with the question from the end of the film. So how do we figure out how to use this technology wisely and who actually gets to make those decisions?

JENNIFER DOUDNA: Well, I think it certainly starts with venues like this, honestly, where we, uh, talk about it, we describe the, what the science is, what it means, where it’s going, and we invite participation from all of us who will be affected by it in the future.

GUY MCKHANN: And so as we go forward, is that the scientific community? Is it politicians? Is it global groups? How are we going to decide technology and guidance of it?

JENNIFER DOUDNA: Well, I think it’s all of the above. I favor a the work of the World Health Organization and the National Academies of science right now that have put together international groups to look into the technology and make recommendations. But I think we may also need a group such as the UN to get involved as well.

GUY MCKHANN: So that obviously requires knowledge and understanding the technology and really the basic fundamentals of it. So let’s start with that. So tell us about it.

JENNIFER DOUDNA: Well, uh, I have right here a 3D printed model of a molecule. This is a protein. The white part of this is a protein called CRISPR CAS-9 and it’s a molecular scalpel. It’s literally a tool that scientists can use to cut DNA and trigger targeted changes to genomes. And the way it works is that it has another molecule in it called RNA, this orange piece that provides a script. It’s a set of letters that match the DNA code in a genome. And when that match occurs, this protein is able to make a cut in the DNA. And that triggers the cell to make a change at that precise position in, out of all of the, the DNA inside the cell.

GUY MCKHANN: So this process, even though you and your collaborator Emmanuelle Charpentier, were the, were the discoverers of it in the modern sense, I mean, it evolved. So it actually existed in bacteria?

JENNIFER DOUDNA: That’s right. It evolved over, over eons in microbes because of the need to use it to protect themselves from viruses. So in bacteria, this protein is programmed to find and destroy viral DNA. But when Emmanuelle Charpentier and I did research to understand how that works, we recognized that this tool could be this, uh, this, uh, ability of the protein could be harnessed as a technology for genome editing in other kinds of cells.

GUY MCKHANN: So the technology, as everybody now knows as is CRISPR. So what actually is CRISPR? What does that stand for?

JENNIFER DOUDNA: Clustered regularly interspaced short palindromic repeats. Whew. Don’t make me say it again.

GUY MCKHANN: I promise. So, so, so, so what does that mean? The palindromic part of it means what? Well, the palindromic part of it is the, a, is the repetitive elements. And the way this part of DNA in bacteria was first recognized was actually by a Japanese group in 1987. They didn’t know what it did, but it was distinctive because it had these repeated sequences that flanked other DNA sequences that were at the time of unknown origin. And later in the mid 2000s, three different research groups that were studying these figured out that these sections of DNA between the palindromes were actually coming from viruses. And so these CRISPR elements are in fact, um, a molecular vaccination card for bacteria. It’s a way that bacteria can store pieces of DNA from viruses that have infected them over time.

GUY MCKHANN: So that’s at least two points for jeopardy or trivial pursuit. CRISPR and palindrome.


GUY MCKHANN: Excellent. So, uh, so, but people have been manipulating genes for a very long time, right? So we have a brief film talking about that as well as how CRISPR really has changed the game.

NARRATOR: Humans have been engineering genes for centuries. The vegetables in a modern supermarket and the staple grains that sustain us, bear little resemblance to the ancient plants they derive from. Our domestic animals too have been transformed through generations of breeding. The variety of dogs is a testament to our power. Long before modern biology to transform genes. Beginning in the 1970s we learned to directly manipulate the genetic code stored in the cells of every living thing. But for decades the technology remained cumbersome, expensive and imprecise. Then came CRISPR. In 2012 Emmanuelle Charpentier and Jennifer Doudna discovered they could hijack a mechanism that bacteria use to protect themselves from viruses. With a piece of RNA acting as a guide and a protein called CAS-9 acting as the scissors. Scientists can now target, remove and replace any stretch of the double stranded DNA molecule in any living thing. Easy, quick, inexpensive. And so precise, scientists can switch out a single base pair in the more than 3 billion base pairs that make up the human genome.

GUY MCKHANN: So let’s move now to why there’s so much excitement about this technology as well as frankly speaking, why there’s a little bit of trepidation. So some of the things that it can do and also in your opinion, some of the things that maybe it can’t do. So, uh, starting off, food. So how can CRISPR help the worldwide food chain?

JENNIFER DOUDNA: Imagine being able to make changes to the DNA of plants that introduce traits that can protect them from drought, um, protect them from infection by pests, make them potentially more nutritious. In the past, these kinds of traits would’ve had to be introduced by random mutations to seeds and then many years of selection for plants that have desired traits, often bringing along undesired properties along with them. And then, uh, going through the whole process of, of getting, getting that plant into a market where it can be useful. Now with CRISPR, there’s the opportunity to make targeted changes to the DNA, only manipulating genes that have, uh, the power to control the traits that we’re interested in, in changing and doing it much faster.

GUY MCKHANN: So obviously great agricultural potential benefits, uh, maybe not in Berkeley, but once in a while in New York, you still find somebody who eats meat or fish. Uh, are animals, fish are those populations potentially advantaged?

JENNIFER DOUDNA: Absolutely. Yeah. Yeah. Same kind of manipulations happening in animals that are used agriculturally as well. Making hornless cattle for example and other, other ways of protecting livestock from pests and, and probably in the future, making other manipulations that will be useful as well.

GUY MCKHANN: And are there, are there risks in terms of changing genes that we’re putting out into the agricultural world and the biological world?

JENNIFER DOUDNA: Well, I think we always have to be careful, you know, thoughtful about how we’re manipulating animals that we’re using in our, in the environment. Animal welfare of course is an issue, but also thinking about, uh, the human health risks that might come along with that.

GUY MCKHANN: And what about, so let’s move on now because obviously this is a genetic manipulation. So what about the possibility of genetic diseases? So what are some of the genetic diseases that come to mind that most readily lend themselves to this type of technology?

JENNIFER DOUDNA: Well, there are a number of human diseases that are known to be caused by a single genetic mutation, a single gene that has gone awry. And so these are I think the first targets for something like CRISPR because we can imagine how to alter those individual genes now to have an impact on a patient’s health.

GUY MCKHANN: So some of those would be in terms of-

JENNIFER DOUDNA: Well sickle cell disease is a, is an obvious one. Muscular dystrophy is another, cystic fibrosis. These are all uh, examples, Huntington’s disease is a neurological disorder. And there’s a large number of relatively rare genetic diseases that result from individual changes that happen sporadically that right now we really don’t have any, anything to offer patients. And in the future, hopefully we will have a tool that can actually correct those disease-causing mutations.

GUY MCKHANN: So the single gene disorders being prevalent. I mean we all remember from struggling through university biochemistry that people have sickle cell where they don’t have both genes, where they have one gene, it provides some protection against malaria. So how do we make sure we understand the genetic conditions well enough to know when to intervene?

JENNIFER DOUDNA: Well, I think we have to take it step by step. So it’s great to start with diseases like sickle cell that are fairly well understood. But as you point out, you know, I think we have to be cautious because genes typically don’t have a single role in our health. They have, you know, they interact with lots of other genes. So we do need to be thoughtful about how we manipulate them.

GUY MCKHANN: So what about, so say you’ve got a gene, you’ve got a patient population and you have a manipulation. So what are the ways that, how do we introduce that into human patients who we’re trying to treat? What are the, what are the ways that we can go about doing in terms of doing it in-vivo, ex-vivo and what that means?

JENNIFER DOUDNA: Right. Well there’s really two ways. I think it’s shown on this slide here where, where you can introduce the gene editing molecules in cells that are taken out of a patient. So it’s done ex-vivo, outside the body, and the edited cells are then replaced. And that would be, for example, to treat sickle cell disease. That’s how it would be done. Or we can do it in-vivo where you use something like a virus to deliver the gene editors and then the virus can hone into the tissue where the editing is needed.

GUY MCKHANN: Any thoughts on whether one of those will be particularly more effective or efficient or is it going to depend on different diseases?

JENNIFER DOUDNA: Well today, you know, we’re at a point where the ex-vivo type of delivery is really, I think almost there. It’s really a feasible thing to actually do. And there are trials, clinical trials that are on deck to move ahead using that kind of strategy. In-vivo delivery, however, as you can imagine, it’s a lot harder and to be sure that it’s done right and safely. So I think that’s still a ways off. But in the end, you know, that’s going to be obviously the more powerful way to be able to do gene editing.

GUY MCKHANN: So, but most traits that we deal with and you know in medical centers are not monogenic, they’re polygenic. They’re very, very complicated. I mean, some of the most common things we deal with are things like HIV and all sorts of different forms of cancer. So how can you take an approach like this and think about how you target it for more complex polygenic conditions like that?

JENNIFER DOUDNA: Well for something like cancer I think the, the uh, excitement there is about being able to manipulate the immune system. Imagine we could edit immune cells so that they are, they have the right, uh, properties so that they can target tumors. I think that would be a very exciting way to treat cancer. And then for, uh, for HIV infection there is the potential to, rather than targeting the virus itself, actually target the molecule that is necessary on t cells, the immune cells that get infected by HIV so that HIV can’t get in.

GUY MCKHANN: So there’s been lots and lots of speculation about what CRISPR technology maybe can do, what are prospects for the future? So if we’re going to break things down into, yeah, I think this is probably going to happen relatively soon. Yeah. You know, it’s going to take a lot more work, but this is realistic or this has kind of Harry Potter fantasy world probably Never gonna happen. So let’s just run through a few. So how about life? So the thought that humans have, most humans, we all think I have, we have an age span. I take care of a lot of patients in their eighties and nineties and I’ve kind of figured I’m okay with the eighties, nineties I’m not so sure. But lobsters supposedly don’t age like humans. They’re resistant to a lot of the aging effects. So are you going to be able to help me want them? I want to hit my nineties. Well, I hope so.

JENNIFER DOUDNA: I mean, I think, I think, uh, you know, the potential for gene editing to be impactful in terms of quality of life, I think that that potential is high, whether it, you know, I, I get asked regularly, can, can gene editing extend the length of my life? And uh, I think we’re a lot farther from that.

GUY MCKHANN: So, but so how, when you look, think about it, and you say, okay, how’s, how is it gonna improve the quality of life of somebody who’s 50 in the third row now, where they’ve got an average life expectancy of 35 more years?

JENNIFER DOUDNA: Well, I would say, uh, yeah, I think there’s potential to improve quality of life by protecting us from, uh, from infections by, again, back to the cancer example, being able to provide a way of tuning up the immune system so that it’s more effective at fighting cancer. So I would say those are probably the things that I think are not, you know, they’re not here today, but they’re not completely science fiction either. But being able to, you know, tweak a gene or two and add another, uh, 50 years, I think that’s, that’s probably Sci-fi.

GUY MCKHANN: What about a designer babies? So not fixing medical problems or genetically predisposed conditions, but you know, I want my kid smarter. I want my kid taller, I want my kid to be able to jump like Zion Williamson. I mean, so what about designer babies?

JENNIFER DOUDNA: Well, you know the thing about designer babies is that for the traits like the ones that you mentioned, they’re, they’re all, they’re all going to be things that result from most likely, you know, hundreds or thousands of genes and, um, we don’t for the most part know what those are. So I think the reality of being able to do that kind of manipulation in human embryos is quite a ways off.

GUY MCKHANN: And what about, uh, soldiers? So improving memory, improving endurance, uh, just being used for purposes of things like building armies or making your armies more efficient.

JENNIFER DOUDNA: Again, I think that’s, that’s a, you know, in the future maybe, but it’s certainly not coming anytime soon. There are easier ways to improve your army’s than using CRISPR right now.

GUY MCKHANN: I think that’s probably a relief to all of us. What about the concept of, uh, either maintaining very endangered species, improving on their viability or even the possibility of rejuvenating a species that’s been lost?

JENNIFER DOUDNA: Yeah, I think that’s a really interesting idea. I mean, there’s a number of people I know in academic research who are interested in using CRISPR to bring back extinct species. They’re not talking about bringing back velociraptors by the way, but, um, but, but thinking about bringing back things like the carrier pigeon, you know, which isn’t that different genetically from birds that are alive now and where you could have the potential to rebuild genomes for organisms that have gone extinct in recent times.

GUY MCKHANN: So, uh, help us understand the concept and what the term means of a gene drive. So if you talk about trying to find a way to, for instance, a eradicate malaria, how would you go about that and what does that gene drive term mean?

JENNIFER DOUDNA: Well, you know, the idea of a gene drive has actually been around for quite awhile. I can remember, uh, 30 years ago or so when I was in graduate school, people talking about the possibility of using technology to drive a genetic trait through a population quickly, faster than it would ever happen by Mendelien inheritance. But in those days it was, it really was a fantasy. We didn’t have any way of actually doing that. And the thing about CRISPR is that this, this provides the, the means of doing that. Because if you, if you couple a trait, a gene that you’re interested in introducing across a population to the, uh, the tool that does the insertion, then you, you have a way to introduce it very quickly and very broadly across a population of organisms that are reproducing rapidly, such as mosquitoes. And so this has attracted a lot of attention because we now have a tool that could do things like maybe genetically prevent mosquitoes from spreading diseases through human populations,

GUY MCKHANN: Which recognizing that obviously one of the greatest vectors worldwide of disease, that would be a huge accomplishment.

JENNIFER DOUDNA: Tremendous accomplishment. Yeah.

GUY MCKHANN: In terms of the global health. So let’s move, let’s talk a little bit about how you got to where you are now. So as mentioned before, so 2012, new and professor Charpentier came up with this realization that bacteria were using this strategy. So, but, but after that discovery, and along the way, there were times when you were haunted by it a little bit. And so you wrote a, an article in nature in 2015 called “My Whirlwind Year”. And I’ll just quote, you said by the spring of 2014, I was regularly lying awake at night wondering whether I could justifiably stay out of an ethical storm that was brewing around a technology that I had helped to create. So talk about what that was like initially as well as, you know, scientists, PhDs, even physicians with all our interactions, we’re not really trained for that kind of limelight. So maybe you could address both of those issues a little bit.

JENNIFER DOUDNA: Yeah, I think, you know, many people, me included go into science partly because we’re not going to be in the limelight, you know, so we can sort of work away in our laboratories and work with students, but, but really not, uh, not received public attention for that for the most part. And, uh, and so for me, going through this kind of realization that, you know, this technology was going to be, uh, impactful not only in, in research labs, but also for the kinds of applications that we’re discussing here and, and for things that, you know, might really have ethical issues and challenges such as human embryo editing. So in 2014, early in 2014 I was sitting in my office at Berkeley, I got a call from a reporter who said, have you seen the latest paper out in the journal Cell, which is one of the top science journals in our field.

JENNIFER DOUDNA: And I said, no. And he said, well, it’s from a group that has used CRISPR in monkey embryos and has created CRISPR edited monkeys. And they seem to be fine. They just have a, you know, they have one gene tweaked. And, and I think it was that, that event, that article, reading that paper that made me realize, oh my gosh, I mean, if people are doing this already in monkeys, um, there’s no reason to think that somebody won’t try to do it in human embryos. And that’s when I started thinking about this a lot and really struggling with the, the, you know, debate within myself about, you know, do I really, do I really want to get involved in this kind of discussion? No, I don’t, but I didn’t really feel that it would be responsible not to.

GUY MCKHANN: So how do you make that day to day just cognitive shift from being, you know, an, an eminent scientist who is really focusing on, on one little part of the, uh, of the plant kingdom and animal kingdom, and then all of a sudden you’re looking at, at, at global topics of massive ethical proportions. I mean, how do you make peace with that?

JENNIFER DOUDNA: Well, the first thing I did was, I, I had founded a, an organization that was kind of virtual at the time called the Innovative Genomics Institute at Berkeley and UCSF and um, so through that organization we convened a meeting that was held in the early part of, I think it was January of 2015 with scientists, some of whom had been involved in the 1970s discussions around the ethics of molecular cloning. And, uh, we had a conversation for a day about human genome editing and human germline editing in which we debated, you know, is it, would it be right for anyone to do that? And if they did, you know, what would the issues be? And the upshot of that was that I think everybody felt that, you know, this was a very important topic that needed to be brought to the public attention. So we wrote a perspective that was published in April of that year in Science, very, very shortly before the first publication in a scientific journal of human germline editing in human embryos that was published in a, in a, you know, in a science paper using, using CRISPR.

JENNIFER DOUDNA: And, um, and then, you know, what happened next, which is that, you know, there were a series of meetings that were held by different groups, including the national academies, a report that was issued in the spring of 2017. And these all were essentially calling for moratoria on any clinical use of CRISPR in human embryos, meaning any use to implant a, an edited embryo for the purpose of creating a pregnancy. And yet, uh, that clearly didn’t stop He Jiankui from his work.

GUY MCKHANN: So we’ll have, fortunately, plenty of time to talk about that a little more with other, our other guests in a bit. So you’ve been at some of the most amazing academic hotspots in the country, Harvard, Yale, Berkeley. But you actually, it all started for you in Hawaii, right? So you grew up on the big island in one of the most beautiful places in the world. Unbelievable biological diversity. So how did that impact you as you were moving forward in your career and then also with this discovery?

JENNIFER DOUDNA: Well, I grew up in a very rainy part of Hawaii, a town called Hilo. It’s not what people usually think of when they think of sunny beaches and all that. It was, we had a very rainy, a very rainy town. And I was, you know, I didn’t, I didn’t think too much about it at the time, but I was really influenced by the native environment there. And I was fascinated by all of the plants and animals that I encountered growing up that had clearly evolved to adapt to that island environment. You know, it helped that I had moved there when I was seven, so I had lived in Michigan before that. So that’s kind of a big change between Michigan and Hawaii.

JENNIFER DOUDNA: And, uh, I didn’t, I didn’t think about DNA in those days, but I, I definitely wondered about the chemistry. I always, you know, I had a great chemistry teacher in high school and so I started to wonder about the chemistry of these plants and animals and what had to be different to allow them to adapt to those environments. So I, I really credit that with my early interest in biochemistry.

GUY MCKHANN: So in an environment like that, I mean, you see the natural diversity of animal, plant life in particular that’s there. So when you think about that now and you think about, okay, how much do we understand how evolution came about to generate that world and how do we make decisions about, okay, now we have the possibility to manipulate that.

JENNIFER DOUDNA: Yeah, it’s a, it’s kind of profound, you know, and I think that, but I guess it’s important to point out to everyone here that this isn’t something that happened suddenly in a way, you know, I mean, I think scientists have been thinking about manipulating DNA and manipulating the code of life for, for a very long time. And certainly in agriculture you can go back millennia, right? People plant breeders have been working for a long time. They didn’t necessarily know they were manipulating DNA, but that’s exactly what they were doing. Um more recently, of course there have been technologies previous to CRISPR that gave scientists tools to manipulate DNA. The challenge was that these tools, although very effective and they got a lot of people excited, they were hard enough to use that most labs didn’t have access. And that’s really what CRISPR does. It brings a powerful technology to a point where it’s, you know, it’s just a, it’s democratizing because it’s available to people. You don’t have to have particular expertise to use it and it’s, it’s inexpensive and it works well.

GUY MCKHANN: So, uh, you’ve written about how you’ve had some pretty crazy dreams along the way when you realize the power of this technique, dreaming that you met Hitler, dreaming that you were inundated by a tsunami. So obviously you’re thinking about the fact that there is incredible potential, but also the other side of this a little bit. So talk a little bit about that aspect.

JENNIFER DOUDNA: Yeah, I think uh, you know, I’ve written about this dream I had about Hitler. It was, you know, I was walking into a, into a dark room with a figure, kind of silhouetted, and a colleague of mine said, I want to, I want to introduce you to someone and they want to learn about CRISPR from you. And the person turned around and as they turned around, I realized that it was Hitler and he had sort of a pig face. It was almost like this horror of someone who maybe had already been sort of CRISPR’d, you know, and um, it was, it was just, uh, it was really, it sounds funny now, but it was, it was one of those terrifying, you know, wake up, sweating kind of, kind of dreams. And I think for me it really stuck out in my mind because it, um, it’s really highlighted, you know, sort of brought to a head a lot of the thoughts I had had about my responsibility and made me think, yeah, I really need to start, um, publicizing this. People need to know about this technology and they need to think about how we are going to be responsible using it.

GUY MCKHANN: So before we move on to that a lot more in particularly talking about the, uh, the Chinese children and things. So, you know, you’ve been involved in a fairly extensive, and not just you, cause we all work for universities and universities have a lot of the intellectual property rights to any work we do in those universities. So obviously you’re at Berkeley, it’s a very strong state school. This is a, this is an amazing technology and a lot of people are looking, saying, okay, a technology like this is going to form big companies. There’s a lot of intellectual property here. So I don’t really want to get into the, the whole issue of whose, who’s on what side with all this because it’s all written plenty of places people can find it. But it kind of, there’s a fundamental conflict there because as a scientist, you’re going and you’re trying to make discoveries and you want to share those discoveries in a way that makes the world better, the academic community stronger, everybody’s knowledge. By all of us sharing we all grow and we all come up with ideas off of each other. And yet on the other side, you’ve got patents and potential profits and huge amounts of money. I mean, when I first came to Columbia, the medical school was being supported by a single patent over many, many years it was generating so much royalties. And so, I mean, how do you balance that in terms of saying, look, this is my obligation to share scientifically, but at the same time, okay, now maybe somebody is going to scoop me. So what do you do with that?

JENNIFER DOUDNA: Well, it gets down to, you know, why do we have patents, right? Why, why do we have a patent system? And, um, you know, if you’d asked me question if few years ago I would’ve said, I don’t know. But, um, you know, the purpose of patents is really to provide protection for companies that are going to invest, investors, you know, who are going to invest a lot of money in products that will take potentially years to come to market, such as therapeutics is a great example where it might take, you know, it might take 10 years to develop a therapeutic. And so the company wants to know that they’ve got some protection around that so when they bring their drug to market, they can actually recoup money from what was invested and make a profit and so that’s the purpose of patents. I think, you know, the challenge for patent, the patent system with something like CRISPR and this, you know, CRISPR is not unique in this way, right?

JENNIFER DOUDNA: It’s true for any technology that’s kind of broadly enabling is that on the one hand, as you said, you know, you want to, you want to provide protection for those companies because you want, you know, you want those companies to get involved in commercializing the actual application of the technology. But on the flip side, you want to make sure that the technology is widely available and in as many hands as possible so that it can be made better and that it can be used to do all sorts of, of new things. And I think, you know, the good thing about the university system right now is that, you know, the, the universities really do make these technologies available to researchers and that’s always been true. So right now, even though, yes, there’s a patent dispute going on and, and uh, with CRISPR the good news is that it hasn’t, I don’t think really impinged on anybody’s ability to use the technology. Certainly for academics, they can get it very easily from a nonprofit organization called Addgene. And that’s been one of the reasons why it’s taken off the way it has.

GUY MCKHANN: But it also brings up a topic that we’ll come back to a little later, which is that, you know, you’re running a high powered lab, you have unbelievably talented grad students who are working like dogs in an environment where, and not just your lot, I’m saying globally where it’s an incredibly competitive environment. And you know, it’s very rare that people remember somebody who went first but wasn’t a hundred percent accurate. They remember who went first. And that in and of itself in the scientific environment is fostering some of this need to be the first to be ahead. And I mean, how do you, even with your own students, how do you get the message across to them? Yeah, you know, it’s, it’s really important to be early, but it’s more important to be accurate.

JENNIFER DOUDNA: Well, I say exactly that, basically. I tell them that, you know, it’s most important that we are correct in our work, that we’re scholarly in our work and we work as efficiently as we can but you know, the primary purpose of what we do is to, is to double and triple check ourselves and, and, and be scholars about what we’re doing.

GUY MCKHANN: So, uh, one last point before we move on to the topic of gene editing and particularly human gene editing. Can you help us understand a little more about, in humans, germ cells versus somatic cells? What happens when you apply gene editing technologies to one set versus the other and the ramifications of that?

JENNIFER DOUDNA: Yeah that’s important to understand. So somatic cells are cells that are fully developed and when edits are made to the DNA of those kinds of cells, then they have only effect that one tissue or that one individual. Um, or that could be, it could be stem cells in an individual that develop into a certain tissue type. But uh, but, but it’s quite distinct from germ cell editing. That’s where we’re editing the DNA of eggs or sperm or embryos where the genetic changes become part of the entire organism. And those changes are heritable. They can pass, be passed to offspring, and that can be done in plants, it can be done in animals and it can be done in humans.

GUY MCKHANN: So, so germ cell things are going to be passed on generation to generation. So, so looking at some of the things we talked about before, so single gene disorders, sickle cell, muscular dystrophy, you would want to target what?

JENNIFER DOUDNA: Well, there we would want to target a, we would do somatic cell editing, but we would do it in germ cells, in not germ cells, but uh, stem cells taken from an individual but they wouldn’t be creating heritable changes.

GUY MCKHANN: And in a cancer or HIV type setting?


GUY MCKHANN: Right. Because you’re just looking to target something in a somatic cell population.


GUY MCKHANN: Right. Whereas if you’re trying to, for instance, we’ll talk more about in a minute, but what was actually done in China was to do what?

JENNIFER DOUDNA: Well to do germ cell editing. So that was editing in embryos where the genetic changes become part of the entire organism, the entire person in that case.

GUY MCKHANN: So when you’re using this technique, is it perfect? What’s the fidelity? How often are there genetic mistakes that happen when you’re trying for a result? And what are the potential ramifications of imperfection in the biological system?

JENNIFER DOUDNA: Right. Well, uh, you know, the remarkable thing about this, this, uh, this tool is that it’s, it’s had to evolve to be pretty good at what it does because it can, if it makes a mistake in a bacterium, then it can kill the bacterium. So that’s a pretty strong selective pressure for accuracy. But that being said, of course it’s not perfect. And uh, there are definitely are, uh, um, potential opportunities for it to make mistakes and make, create off-target edits. And that’s been quite thoroughly investigated by, by scientists. I think one of the interesting things that’s happened over the last few years is that people have gotten better and better at using the technology. And today it’s possible to do things like limit the length of time that CAS-9 is in cells and the uh, the amount of it in cells and also to select the target sites in DNA carefully so that they don’t closely match anywhere else in the genome. And by doing those kinds of things, it’s now possible to make really very accurate, uh, genome edits using this tool as well as by using versions of this protein that have been engineered in the lab to be even more accurate. So I, I currently, I think that I, the way I think about off-target editing as something that needs to be monitored carefully, but it’s probably not one of the major bottlenecks for using it in the future. Even in the clinic.

GUY MCKHANN: So let’s move on now to a topic that many people are familiar with through the popular press as a video. Earlier said November, 2018 I think it’s fair to say that a lot of the world was shocked to hear and see the news of He Jiankui’s work in China with, as you were saying, with germline gene editing in two children. And so first, let’s have a short video describing that

NARRATOR: It was a birth announcement that shocked the world.

HE JIANKUI: Two Beautiful little Chinese guard named the Lulu and Nana came crying into the ward as healthy as any other babies a few weeks ago.

NARRATOR: Chinese biophysicist He Jiankui, working largely in secret, had used CRISPR to knock out a gene called CCR5 in two early human embryos, then returned to the embryos to their mother’s womb. CCR5 plays a key role in HIV infection, and the girls’ father was HIV positive. He said his motive was noble.

HE JIANKUI: As a father of two girls, I can’t think of a gift more beautiful and wholesome for the society than giving another couple a chance to start a loving family.

NARRATOR: But the scientific community did not cheer. At the international summit on human genome editing that He attended shortly after the announcement, the reaction was shock and condemnation.

HE JIANKUI: I understand my work will be controversial, but I believe families need this technology and I’m waiting to take the criticism for them.

GUY MCKHANN: So joining us now for this part of the discussion is a bioethicist, physician and research scholar from Stanford University who also happens to be a friend of He Jiankui from his time at Stanford. Please welcome William Hurlbut. Also joining us is a futurist and a member of the World Health Organization Advisory Committee on human gene editing. He’s author of the recently released book Hacking Darwin: Genetic Engineering and the Future of Humanity. Please welcome Jamie Metzl. So Bill, let’s start with you. So, uh, her He Jiankui goes by JK so we’ll just refer to him as that cause it’s a lot easier for me. Uh, and he left Stanford, went to China where he was carrying on this work. Uh, you guys were friends there while you were there and you’re been in communication with him. So how much either directly or indirectly did the scientific community know about what he was actually doing?

WILLIAM HURLBUT: Well I actually first met JK at the meeting that Jennifer and I organized in January, 2017. Subsequently, he emailed me two months later and said, I’m coming through Stanford, could I talk with you? So I, I had nothing on my calendar that afternoon, fortunately So we met for lunch and talked much of the afternoon and then subsequently came back several more times and we talked in great depth, but I, I did not understand that he was pushing quite so fast. Now he’s, I think to back up a little bit, he was under a lot of pressure in the environment he was in. And he, he, he works in Shenzhen, and there’s this concept called Shenzhen speed. Everything’s happening fast, there’s lots of push for scientific discoveries and young scientists in China are under pressure as they are elsewhere.

WILLIAM HURLBUT: But I realized very quickly that he did not have much of a background of thought on ethical issues. So I was trying to get to know him a little better, seed in ideas and concerns, but in the end he went faster than I realized and I did not know that he had implanted embryos, although the last time I met him I strongly suspected it.

GUY MCKHANN: And Jamie, you’ve written a book on genetic engineering which obviously covers gene editing as part of that. So CRISPR, it’s easy relatively speaking for talented scientists. It’s inexpensive. Is that what makes it dangerous?

JAMIE METZL: Well, it’s dangerous and it’s incredibly exciting. You’re right. My book is on the future of human genetic engineering and when you think of, if you think of genetic engineering as a pie, gene editing is a slice of that pie and

CRISPR is a sliver of that slice and CRISPR is incredibly important and revolutionary and it’s going to change a lot of things. But we are part of this process of, really of a genetics revolution that other people have mentioned. It’s going to change a lot about our lives is going to change the way we do healthcare from moving from a world of generalized medicine based on population averages to precision healthcare, to predictive healthcare and life and it’s going to change a lot of things and including the way we make babies and the nature of the babies we make. That’s going to bring real dangers and we need to be mindful of that and it’s going to bring real wonders and we have to be open to curing a lot of these afflictions that have plagued us for millennia.

GUY MCKHANN: But using your pie analogy, it’s kind of a pie in an oven that’s cooking with uneven temperature, right? Because I mean CRISPR is a pretty good piece of pie and the rest of the pie may not be as readily applicable or as broadly applicable.

JAMIE METZL: I would disagree with that because as we understand and increasingly unlock the secrets of the genome, we’re going to be able to make a lot of interventions. And one I talked about, predictive healthcare, and that’s going to touch everybody here in many more significant ways than CRISPR, at least in the near term, will touch us. Um, it’s going to change the way we procreate moving increasingly and over time towards a procreation in vitro rather than, uh, than through sex. And so there are a lot of pieces, a lot of them are moving quickly and they’re going to touch us in a very intimate way and CRISPR is incredibly important example of that.

GUY MCKHANN: I’m going to back us up a little bit. Yeah. So, um, obviously Jennifer, you know more about this technique than probably anybody in the world. JK is a biophysicist not a geneticist. He was able to learn the technique to get the technique to work. So how hard is it? How hard is it to learn for one of your average students? How much would, how difficult would it be for any one of them if they weren’t, they weren’t working in your lab. They’re working in something totally far field may say, you know what, this would really help me. I’m going to go learn this technique, what’s it going to take?

JENNIFER DOUDNA: Well, I mean today you can go to Amazon and you can buy a CRISPR kit to use it in bacteria, not in human embryos, but, um, right. So it’s, you know, it’s something that, uh, we, you know, in my lab at Berkeley, we have every summer we have summer students that come in for 10 weeks. And you know, nowadays, you know, and they come in there, they’re typically editing human cells that are cultured in the lab within a few, you know, a few weeks. So they, you know, they can learn it very fast. I think with respect to JK what I would say there is that, you know, I was sitting, uh, after, you know, this announcement was made in Hong Kong. We were all there. Bill was, was there, you know, we were at this meeting and, and uh, I was sitting with one of the, the, uh, meeting organizers and he said to me, well, you know, two things are clear from this announcement.

JENNIFER DOUDNA: One is that it’s really not very hard to do this because JK is not a, you know, he’s not a specialist. He doesn’t work in an IVF clinic. He doesn’t work with human embryos himself but if, like you said, he figured out how to do it, he got collaborators to help him. And the other thing is it’s really very hard to do it well. And that was true because the, when you look at the details of how the editing was actually done in these girls, um, you know, the changes that were made were in fact not changes that have ever been seen before in the human population and have not even been tested in animals. So that’s kind of what makes it very dangerous is that it’s a tool that’s relatively easy to use, very hard to do it well.

GUY MCKHANN: So that brings up a logical question for all three of you coming from very different perspectives. You’ve got a relatively easy tool where somebody can say I got this, without, as you say, really being expert in it. So even if the global science community decides you know what, we’re going to regulate that. How do you ever enforce a regulation where somebody can go learn it through Amazon?

JENNIFER DOUDNA: Well, maybe Jamie wants to comment on that because the World Health Organization was actually the first to step up with an international team, right?

JAMIE METZL: Yeah, so it’s such an important question and the scientists, actually led by Jennifer and Bill and others have done an incredibly great job of being responsible. But what we are talking about is the future of life and as wonderful as the scientists are, it can’t be just up to the scientists. This has to be regulated in many ways on a national level and on an international level. On a national level, every country needs to have a, a robust regulatory infrastructure and the US is pretty good. We have a dysfunctional healthcare system more broadly, which makes things more complicated. The UK I think is in my mind, the gold standard or a gold standard. Every country needs to have something. But then how do we think about global regulations and we need to come together. The World Health Organization is trying to do that. And as important as that is, it’s really a drop in the bucket.

JAMIE METZL: And we’ve seen how, even with the high level of attention we have on issues like climate change, it’s been really difficult to get international consensus. We’re going to need that kind of big international push to bring everybody to the table, including the scientists to say, how do we have a regulatory infrastructure that at least sets some limitations? It can’t be a genetic free for all. And we can’t have restrictions that impede the very beneficial development of these technologies. How do we find that balance and how do we bring everybody together to try to get there?

GUY MCKHANN: So Bill, obviously you’re, you’re a bioethicist in one of your many skills and talents. So if we think of the analogy of the WHO kind of like the United Nations, countries can opt out. So how do you think about this problem as a bioethicist in terms of how do we tackle it?

WILLIAM HURLBUT: Well, I think the first thing to say for that, and, and this is one of the reasons that Jennifer and I started the programs that we initiated, is that we have to, we have to have a sensible approach to this that doesn’t undermine the great positive good that can come from it. There are perhaps as many as 10,000 known genetic diseases, single gene genetic diseases, 95% of them have no treatments, no cure whatsoever. It’s an amazing opportunity for medicine, but if we, if we hype this and frighten people, maybe that gets the dialogue going, but what we have to do is approach it very sensibly. CRISPR and related technologies are really more revolution in the lab than they are germline genetic engineering, which I think will ultimately be moderately a fringe application. The, the real revolution is in understanding biological process and this provides fantastic tools. The 20th century was about molecular biology, the ingredients that, that make up the organism. In the 21st century it’s shifting to developmental biology, and this tool gives us a chance to probe and alter and examine how natural development takes place both healthy and, and pathological development. And then we need to very sensibly assess what are the potential tools, including the potential dangers of this. And I think that’s the way to go carefully, not hyping it but also taking seriously the way it might be misapplied.

GUY MCKHANN: What about the concept, so you all have touched on it a little bit differently between you, but Jennifer brought up the concept that here in the United States, you could never do a human trial unless you had a pretty good idea of what you predict is going to happen, what the genetic changes are going to do, preferably with an animal model first. Very strict guidelines in terms of institutional review boards for human trials, informed consent, all of those issues that are such mainstays in our scientific community, but maybe a little more lax and when you combine that with scientific pressure and competition to succeed, it seems like it’s a setup for a maelstrom, I mean what do you, what do you do to dampen that and, and to take that on globally?

JAMIE METZL: Maybe if I can just say, uh, the, the first thing that our World Health Organization committee did was call for the WHO to establish a global registry for anyone doing germline edits or edits to any germline cell. So the very first step that we need to do is to try to make sure that nothing or as little as possible is happening in the, in the shadows. But then we need to try to build norms. I mean there are a lot of things that could happen that don’t happen. And one of the reasons is that there are global norms of what is and isn’t okay. And this is so new, the challenge we’re facing is that the science is advancing exponentially, but all of the systems that we’re going to need to regulate it wisely don’t yet exist. And that’s, that’s the race that we’re in.

GUY MCKHANN: Bill, what are your thoughts on that? And also particularly in relation to JK cause you know him. And so, you know, I think it’s easy for somebody to look back and from afar and say, oh well, you know what, this, there must be an element of bad science here. Or because of the fact that it’s not the way we would do it. But I mean, what was his reputation at Stanford as a scientist when he was there as a Grad student?

WILLIAM HURLBUT: Oh very intense. He was focused in the lab. But one time when we were having lunch together, he was talking about how he had to move forward because there’s so much suffering in the world. And I said yes JK, but carefully. And I, I said, there’s a lot of good in nature, a lot of harmony, a lot of beauty. And I mentioned the redwood trees that are in the back, my backyard, isn’t that cool? I have redwood trees in my backyard. And he, he looked kind of blank and I, I said, have you never seen a redwood tree? And he said, no. And so I said, well, come on, we’re going to go look at a redwood tree. I took him for a walk in the redwoods. He just loved it, but you know what it indicated to me was that while he was at Stanford, he, the redwood trees are five minutes behind Stanford and he was in the lab the whole time working, working, working, and we need a broad view of, of life, of nature, a reverend and and respectful appreciation.

WILLIAM HURLBUT: John Muir said that when we try to pick out anything by itself we find it hitched to everything else in the universe, and that’s a really crucial concept because none of this is going to be as easy as it’s portrayed in the journalistic accounts. It’s going to be, require great subtlety, great care, we don’t want to do any harm either materially, physically, but we also don’t want to upset the balance of normal human life. One of the things Jennifer and I realized right away was we need to address this to the, to the whole human species, the whole human family and all of its individual diversity and cultural diversity. That way we can appreciate what it is we’re operating on. We don’t want to turn procreation into production. We don’t want to radically alter the meaning of medicine. We don’t want to create social problems in the process and we don’t want to do ecological disturbances that are damaging to the setting in which we live. And you know, a deep appreciation scientifically for who we are and where we’ve come from includes the fact that, that we are fine-tuned and complimentary to an existing natural world. And if we change that whole natural world so dramatically that we don’t recognize our place in it, we’ll be losers existentially, even if we gain medically.

GUY MCKHANN: So, but that brings up an interesting point. You’re training obviously top notch, hyper competitive students. I’m sure postdocs in your lab must be highly sought after. So are people coming after your post docs saying, hey, you know, bacteria aren’t really that much fun. Why don’t you move up the food chain a little bit? I mean, what are you noticing and what’s the ear to the ground now on that?

JENNIFER DOUDNA: Well, a few years ago I wrote a book called A Crack in Creation with a former graduate student, Sam Sternberg, who is actually now a colleague of yours at Columbia. And, um, and, and Sam, um, you know, we, we, one of the things that we talked about when we were starting that book was a meeting that I had had with somebody who came to me in Berkeley and, and was, actually had approached initially people in my lab and then eventually got to me, but wanted to, was asking people in my lab if they could help her to have a CRISPR baby because she wanted to start a company and she wanted to be the first person to, to bear a CRISPR, CRISPR’d uh, baby. And, um, and, and this is, this is not, this is one sort of isolated example, but you know, we, we pretty regularly are approached by people, maybe not quite that extreme, but people who want to have access to CRISPR, they want to know how to get into clinical trials. They want to understand better the technology. So it’s a challenge. And I think, you know, uh, I try to work with my students to not only, you know, focus on doing great, great science, but as Bill said, you know, I think it’s really critical, especially now that people, uh, take a take a more holistic view of their work, and especially the kind of work that we’re involved with that does have these much, much broader implications.

GUY MCKHANN: Bill, do you remain in touch with JK and do you have any idea where he is right now? Because at least you know the word in the popular press is that he’s lost his job and nobody’s heard from him for a while and China has now passed new rules just came out recently in the news. And do you have any continued contact with him?

WILLIAM HURLBUT: After the gene summit He emailed me and asked if we could talk and over, through January through December and January we had numerous long conversations, two or three hours. I heard the whole story, I confronted him on all the questions about which he was being criticized and I have had some contact with JK as to your specific question. I, I’m just really not at liberty to say what the situation is for JK right now, but I’m worried about him and hoping that he doesn’t suffer more opprobrium than he actually deserves because he is to a certain extent, a product of, of, uh, of, uh, global scientific culture. He did not do what he did alone. People knew about it. It, it wasn’t in secret. It was, you know, like it was sort of in line with what people do except the seriousness of it demanded that he’d be more careful. But quite a few people in the United States and people in China knew what he was doing and yet he did not stay in, in conversation with a larger scientific community, which I think was a mistake. One time when we were talking, I said to him, I felt like he was using his own judgment too much. And so I said, well JK, um, the strength of American society and Western society is the, is the dialogue that we conduct together that we compliment and correct one another’s understanding. And I cited for him the Gettysburg address of the people, by the people, for the people.

WILLIAM HURLBUT: And, and after, after that I sent the Gettysburg address in an email. I sort of wonder what the Chinese sororities thought about that, but uh,

JAMIE METZL: Yeah that’s why he’s been arrested.

WILLIAM HURLBUT: Yeah, maybe I’m a problem, but you know, I was saying to John Cohen, a writer at Science magazine that I think the biggest problem was not JK’s, he wasn’t just seeking fame and fortune. I mean that may be part of it, but it’s part of it for a lot of scientists. But he was also very well-intended when the full story comes out, people are going to be amazed by what he actually wanted to have happen here. But the biggest problem, as I said to John Cohen was it, it was kind of a failure of democratic process. He needed to stay in conversation. He needed to, to be more transparent. And, and this is such a monumental moment that it needed to be one that was adjudicated by the deepest wisdom of the human species.

GUY MCKHANN: So building on that, Jennifer, you’ve obviously been very involved, uh, since 2015 and then 2018 with the global response to this. So can you comment on both, at the earlier introduction, there was a slide showing that I think there were 18 scientists in nature who, uh, all were backing a moratorium in this area. And can you talk about what your feeling is on how we best handle that is a moratorium an answer?

JENNIFER DOUDNA: Well, you know, we, uh, we called for effectively a moratorium, although we didn’t use that word back in the spring of 2015 and that really, you know, started the, the, uh, process of these international groups, uh, triggered by the National Academy team putting together international summits on this topic and a report that was released in the spring of 2017 by that group, which again, without using the word moratorium, effectively called on scientists globally, not to use genome editing in the human, uh, germline in human embryos clinically until and unless it had been thoroughly vetted both scientifically and, and societally. And uh, here’s where we are today. So to me to call for another moratorium, uh, sounds kind of to me a little bit ineffectual and I think it would be better to actually, uh, invite a more open discussion. I think that um, many people think that there are going to be opportunities at least on the research front and maybe someday in the future clinically as well to learn from this experience and the kind of research that a few labs are conducting in human embryos as well as in obviously many other kinds of, of embryo systems in animals.

JENNIFER DOUDNA: So for I would, I would rather not see that conversation shut down, and when you call for a moratorium effectively you’re saying, ah, we’re not going to do that. And it’s very hard to then continue an open conversation I feel and I don’t, I would like to not see that conversation shut down.

GUY MCKHANN: Jamie, your thoughts cause you may have written about this.

JAMIE METZL: I agree, I had a piece on this in the Financial Times. I, I totally understand why people are concerned and I think we all need to be prudent, we all need to be careful. But to create a moratorium that first creates a set of stakeholders, that you’re going to have to convince people to end the moratorium. And so that’s going to be really difficult. And what we need to do is to apply our best values in making decisions in cost benefit analysis. And so one of the reasons why I differ from Bill, I actually think that He Jiankui is quite a villain. And the reason is because the first step in applying genetic, gene editing to a human embryo of a child taken to term needed to be totally defensible. It needed to be transparent. It needed to, you needed to explain why the intervention was made. And by doing that in a race for glory and there’s in his IRB application, which wasn’t even to his primary hospital, there was all of this, this garbage about bringing glory to China. And so in this race he didn’t just potentially harm these two, these two now little girls, he undermined global confidence in using this incredibly powerful tool to actually do good. If the first step had been extremely careful, well thought out, public, transparent with a target that everybody agreed made sense, most likely to eliminate a potentially deadly risk, that would have been a much better first step. And I think He Jiankui has harmed us. On the other hand, he’s raised the alarm that we have a big problem and certainly the WHO committee that I’m on probably wouldn’t exist had this step not been taken.

GUY MCKHANN: So let me ask a hypothetical for any of you. I mean, he did this in November of 2018, given the global climate, scientific pressures and everything else, without a worldwide moratorium, how long you think it would have taken somebody else to do it?

WILLIAM HURLBUT: Let me just respond to the idea that he’s a villain. Okay. I agree with all your criticisms, but he was 34 years old. He was under a lot of encouragement from other forces around him and he believed, I mean, let me tell you, this is a humble guy. He grew up in a very poor village. He told me that when he wanted to invite the girl out that later became his wife, he was embarrassed to invite her out because her family owned the restaurant. So this is a guy who’s come up all the way from the very most rural poverty up to the highest reaches of global science. And I think that’s why he needed to stay in conversation. But I would not label him a villain. But having said that, I, I also talked with him about where he was going and afterwards why once so fast. And it was clear to me that as one after another, the statements that were being made publicly, for example, the Nuffield Council issued a report and I sent it to him through a popular article and the reference to the report and the, the popular article said, Nuffield Council approves germline genetic engineering, including possibly enhancements someday. And JK wrote me back, excellent, in an email, excellent. He saw the global society coming into keeping with what had been called for in the national academy’s moratorium. And one after another he felt that he was checking off the boxes. And I think he was wrong and I tried to tell him he wasn’t doing it adequately. But having said that, after the fact, I asked him if he would have done what he did if there had been a moratorium and he said no, he wouldn’t have done that. It was a mistake. And I’m not, I’m not taking a position on the moratorium. I’d like to hear the arguments more thoroughly. I’m not a political scientist, I’m a physician and a and a scientist and ethicist. But I, I still think that there are reasons why we might consider a moratorium and that’s because JK’s not the only person out there who would use these technologies inappropriately.

GUY MCKHANN: Well, that’s why I was asking the question, right, because they’re, it’s, somebody told me a long time ago, if you walk around with a really good scientific idea, four other people in the world minimum have it, it’s just who’s working on it. And if you go to the Society for Neuroscience and the first time you go there and there’s 25,000 posters and you’re like, I got it. And you walk up and four people have the exact same poster at the exact same time, none of whom you’ve ever met. And so in a situation like this, the response to this as you all are saying, you can call him whatever you want, but the response is what’s raised awareness. And maybe in some ways caused everybody to take a step back and say, hey, wait a minute. We as a world, we need to be looking at this. And the question is whether or not as a global community we’re going to be able to enforce that. And I think that still remains. But I do, I want to, before we move on, I want to ask you, any of you all, do you think he did any harm? What do you think, what do you think are the chances? So two questions. First off because Jamie in speculating and, and saying your opinion on him, you said, you know, he didn’t tackle a big enough problem, but a lot of people would say, well he was trying to keep his, keep daughters in a family with an HIV positive dad from getting HIV. So what’s a big enough problem?

JAMIE METZL: Yeah, so that’s wrong actually. So certainly they were parents where the father had HIV and the Mother didn’t. Um, there are lots of ways, uh, to have that scenario and not have a child who is born with, with HIV. So there’s washing the sperm, there’s a lot of things. So he, what he was doing even by his own admission was an enhancement. And that’s, so certainly if the divide between therapy and enhancement and we’re talking about revolutionary gender genetic technologies is not always as clear as people would like it to be, but this was a pure enhancement and the chances that it did harm, nobody really knows yet. And there’s been very little transparency. So there’s a chance it helped something. There’s a chance that it did nothing. And if there’s a chance that it did considerable harm and that, that this first step into gene editing human embryos is so unknown. That’s why I think that this was such a, an unfortunate first step.

WILLIAM HURLBUT: You, you might show the slide that I, I have of the picture I have of the message he got from an infertility clinic.

GUY MCKHANN: Yeah, that’d be great. If you could.

WILLIAM HURLBUT: I thank that really opens up the…

GUY MCKHANN: I’m going to read the texts.


GUY MCKHANN: So congratulations on your recent achievement of the first gene editing baby delivered by your application. I am the business director’s assistant at fertility and gynecology center in Dubai. Our embryologist is interested in partaking in a course regarding CRISPR gene editing for embryology lab application. Does your facility offer this type of course?

JENNIFER DOUDNA: I sort of think that there is momentum in that direction, you know, I mean I’ve been approached by people in the US who are interested, not, you know, with sort of the same sentiment as you just heard in that, in that email. So that that person is certainly not alone. And, and I think there, there is a lot of, um, interest in human embryo and human germline editing. And it’s not always for the right reasons in my view. You know, it’s a for you know, clinics that would like to make money selling this to people and, and uh, I don’t know how we stop that. I think that, um, it’s very important to have groups like the, the WHO and the national academy’s forum put together that will put forward what I think ought to be very, very specific and very restrictive criteria for anyone that in the future wants to use or even contemplate using genome editing in, in for the clinical use of, of editing human embryos.

JENNIFER DOUDNA: And then, you know, how you enforce that is it’s a very difficult challenge. I’m not sure how you do that. I think it has to be, it has to begin with, um, inviting, I think an open global discussion. I think it has to engage with not, as you said Jamie, not just scientists and clinicians, clinicians, but also other stakeholders. And you know, I think we probably all, certainly Bill and I, hear from people almost daily who have a genetic disease in their families who are desperate and they want, are trying to get help, uh, any way that they can, including with CRISPR. So we need to be, um, also respectful of that. And as you said, the desire to see the technology advancing as quickly as possible but without doing harm. And that’s, you know, that’s the medical oath and it’s always, I think the challenge that we face.

JAMIE METZL: Yeah. And we need to be honest of where this is going. More and more humans forever are going to have kids through IVF. More of us, uh, forever are going to be screening our embryos prior to implantation and we as a species are going to be gene editing our embryos prior to implantation. And maybe that’s in 10 years, maybe that’s in 20 years, but it’s unimaginable that a hundred years from now we’re going to be making babies the way that we, that we do it now. And so we can argue about what the timeframes are going to be. But what would I think we need to do is one, have an inclusive really as a global species wide dialogue on these technologies because they are going to touch all of us. We need to try to build norms and standards and regulations and frameworks so that we can do the cost benefit analysis because if we just say we’re holding the line that these technologies can’t be applied in human procreation, that line will increasingly be, increasingly be indefensible. It has to be is what are the better applications and what are the worst applications and how can we create an infrastructure that facilitates the good stuff and minimizes the bad stuff.

WILLIAM HURLBUT: I assume when you speak of the normalization of IVF and the commercialization of reproduction that you’re thinking in terms of more than, than disease treatment, but in terms of human enhancements, right?

JAMIE METZL: Well, as I, as I said in my remarks, I think it will be very, very difficult to keep a clean divide between what is a therapy and what is an enhancement because it all exists within the context of us.

WILLIAM HURLBUT: Well, I certainly, it’s hard sometimes to even define diseases. There is a disease in the textbooks of the antebellum south called Drapetomania, which meant the a slave that was had a tendency to run away. So there’s cultural construction of disease categories. Having said that, um, you may be right, people may buy into efforts to enhance their children, but I think they’re making a terrible mistake. Every time I speak publicly, somebody asks me if we’re not heading toward a great divide, the rich on the one hand, biologically enhanced and the poor on the other side, and I, my comment is that at least for the next few decades, it’s going to be the children of the poor that are the fortunate ones because their parents won’t experiment on them.

GUY MCKHANN: Well, so let’s, let’s take it back a step from that. Not quite all the way on that extreme because we do have a healthcare system that, let’s face it, it is a two-tier system and we have a huge amount of our GDP we’re spending on healthcare. When you start talking about screening embryos for genetic traits that may predispose to disease, whether or not they enhance, these are gonna be expensive technologies. Companies are going to invest not millions, billions of dollars to make this technology work. So how do we keep it from becoming something like becoming a five foot two volleyball player at USC that you can only do that if you have a lot of resources? How do we actually, because I think saying oh well you know people are going to sign up for experimentation. You know, there’s a lot of cultural aspects where people don’t seek health care in a system where they either can’t afford it or they’re confused by it. So how do we make this if it becomes a technology that we find a globally accepted use, how do we make it a technology that becomes accessible?

JENNIFER DOUDNA: Well, I think, I think uh, to me it’s important to address that question with respect to somatic cell editing because that’s honestly, at least for any kind of applications in humans, that’s the one that’s going to be, you know, here and in a reality much sooner than any broad use of, of human germline editing. And for somatic cell editing that, and again, that just means making changes to an individual that are not heritable. Uh, there, you know, I think these questions of, of, of access cost, you know, sustainability, um, they all come into play because then we all read in the media now about, you know, new treatments and they’re not gene therapies necessarily, but other kinds of drugs that are just, you know, so expensive that you think, you know, who is really going to be benefiting from this except for the very, very wealthy. And um, and so I increasingly am asking myself, you know, how do we ensure that this technology, as it does move forward in the clinic, especially for somatic cell use for rare diseases and things like that, how do we ensure that it is accessible and affordable? And it’s gonna, again, it’s going to require a lot of, you know, pulling together of different interest groups to get that to happen.

JAMIE METZL: Yeah, and it’s, it’s a really, it’s a question of values and systems. If we have the values that have the incredible health disparities that we either have here in this country or between everybody in this room and average person in Central African Republic, those are, if those are our values now, those are the values that we’re going to bring into the future. If we want to have better values realized through our systems, let’s articulate what those values are and look critically at our systems so they can be realized.

WILLIAM HURLBUT: I agree with the significance of the values and by the way, suffering is not the only value that goes into ethical equations. There are other principles involved. It’s, it’s not like, the argument from suffering has no bottom. You can argue for anything. A complement to that sense of values as a realistic scientific appraisal of what goes on at the level of genetics. I was very good friends with Nobel laureate Baruch Blumberg. I taught a course with him and he used to tell our students over and over, except for very obvious disease genes there, it isn’t like there are good genes and bad genes. Genetics is a very, very fragile balance. We’re a species that has millions and millions of years of field-testing. We’re packed for all kinds of weather, all sorts of circumstances that we can’t see in this current environment. There’s lots of reasons to be cautious here. It’s not like genes are like Legos or Mr. Potatohead where you just change a trait by changing a couple of genes. Genes interact with one another. So we need to have a very realistic scientific appraisal of what we’re doing. Certainly there’s plenty of work to do for the next half a century or century before we even ponder anything with regard to genetic enhancements.

GUY MCKHANN: So that brings up an interesting point. You bring up the point that natural selection’s been doing this for as long as we can count time, maybe even back in Brian Greene’s black holes. And so in the situation here you’ve got a, you can call it survival of the fittest, you can call whatever you want, but these things are being biologically tested in a system where you don’t have to know all the answers, the system figures out the answers. But now we’re talking about an ability to perturb based on what we know about the answers. And so how do you balance that?

JAMIE METZL: Yeah, so, so we are as a species for the first time taking these powers that in the past we have attributed to our gods, the ability to recast life, and our knowledge of these unbelievably complex biological systems is miniscule. And yet now we have the ability to go and, and muck around. And that’s why we need a, just an enormous level of humility. And if we had that humility we would follow the timeline that bill just articulated. Let’s wait a century and see how we apply things. But we are this crazy group of monkeys who climbed down from the trees and we’re not going to wait. We’re this hubristic species that grabs onto these technologies. And now it’s not like in the old days where you have your nuclear power and you need a small group of people supported by the state. I mean, Jennifer, I’m certain we’ll win a Nobel Prize for developing the CRISPR CAS-9 system.

WILLIAM HURLBUT: Don’t say that, you’ll jinx it.

JAMIE METZL: I don’t want to jinx it, but the people who are the people who are applying it. You just get an A minus in your high school biology class. So these technologies are out. They are out in the world and this crazy group of, of primates, us, we are going to start using it. We need to be cautious. We need to build systems, we need to try to build norms that can make sure these technologies are used in the most helpful and positive ways possible. But this, this is, it’s out of the bag and that’s, that’s the challenge that we face.

GUY MCKHANN: But, but it’s such a challenge. I mean, Jennifer, you’re working in bacteria. You find out that a system that the only thing on the planet lower in life than a bacteria, which is a virus, has been using to try to take over bacteria and bacteria have a defense mechanism that’s been there for probably a million years and you find it in 2012 and we say, Aha, we can figure out how to use it. But it reminds me of when I went to medical school and my dad said, the great thing about is you’re going to learn all this wonderful stuff. The bad thing is two thirds of it’s going to be proven to be wrong. You just don’t know which two thirds so you gotta learn it all. And the assumption that we have the knowledge, I mean it’s, it’s, it almost defies logic. And so, so, so, so what do we do with that? I mean you’re talking about that in 10 or 20 years everybody’s going to be making designer embryos and bill is saying we’ve got a half a century of hard science left to do. I mean, what do we do Jennifer?

JENNIFER DOUDNA: Maybe I’m going to split the baby here.

GUY MCKHANN: What are we going to, what did we do with this?

JENNIFER DOUDNA: Um, well I think what we’ll see is a, this is my prediction, is that I think over the next couple of years we’ll see a few clinical trials getting going for things like sickle cell anemia and we’ll see how those play out. Hopefully they do no harm first and that they actually are beneficial to patients. And I think with that kind of, of progress, uh, that we’ll, you know, we’ll start to see that we’ll start to see other diseases of that type that are monogenic, caused by a single gene, you know, being treated increasingly using genome editing and, um, and it’ll largely, you know, kind of build from there. And, uh, with respect to human embryo editing, it’s hard to know. Honestly, I can’t really predict how that’s going to play out at this at this moment. There certainly is a lot of interest in it, that’s for sure. And, um, you know, I think that research, uh, on, on embryos will of course continue.

JENNIFER DOUDNA: One thing that I said earlier, but I just want to point it out again, and that is that in my opinion, the technology is just not suitable right now for use in embryos. And I think, uh, He Jiankui’s experiments actually showed that, you know, very clearly it’s just not ready for use in embryos. And I couldn’t tell you when it will be, but certainly more research is needed. And I know, I don’t think it needs to be done on human embryos. I think it could be done on other kinds of, of embryos to understand how DNA manipulation works in those settings. So to me, I think a lot more research needs to happen for that kind of use. And in the meantime we should focus on where it’s really going to have an impact clinically, which is in somatic cell editing as well as in all the other kinds of applications, like in a, you know, controlling mosquito borne diseases and, and uh, improving agricultural products around the world where it’s going to have frankly a much broader impact than any kinds of the applications we’ve been discussing in biomedicine.

GUY MCKHANN: So we’re going to, because we’re running a little bit short on time, so we’re going to finish up with one question that Brian brought up at the very start. These editorials in New York Times that are looking 25, 50 years down the road and writing back. So each of you, you each get to have your editorial 25 years down the road saying this technology, CRISPR technology, so A, as big an impact as we’re predicting now even bigger, smaller and in the overall huge spectrum of where we are, is it going to give us a better future, a more complicated future or a more dangerous future? So let’s start with you first Jamie.

JAMIE METZL: So first we have CRISPR as this, it’s our best gene editing tool. It may not be the last word in gene editing. So gene editing is going to be an increasingly important part of our lives and I think it’s going to be bigger in many ways, but it won’t be all the ways that we are predicting. I mean that. And it’s going to change a lot and our culture will change because we introduce new ideas and everything. I mean, when the first IVF baby, everybody was so stunned. This is not natural. And then things normalized. So this is going to normalize. The technology is going to continue to get better as it has. It’s hard to imagine that it was six years from Jennifer’s discovery to He Jiankui. I mean that’s really nothing. And given that we’re, that technological change is often happening onto this J curve, 25 years from now, that’s a long, long time. So I think we’re going to be using it. It will be new ways. It will be profoundly altering the world within and around us. Um, but it’ll be different from what we’re imagining now.

GUY MCKHANN: And the potential for nefarious uses? Global terrorism?

JAMIE METZL: The potential is huge for nefarious uses and it’s even greater for positive uses. I am an optimist. We certainly have some bad humans, no one in this room. But I think in general we have a drive to use technology to do good things. I think the smartest people in the world are not terrorists. They are people who are thinking, how can we use this technology to do good? And I think that we will, but if we don’t have an honest conversation now about the downsides, then it’s, the rest of the world is going to have that conversation and it’s going to dominate our discourse and we can’t let that happen and we need to do it by talking about this, by having an engaged global dialogue and by being honest about the harms and the dangers and working to minimize them.

GUY MCKHANN: So I would just like to note, you are a futurist and being a pessimist futurist might be a short career path.

JAMIE METZL: You know, you just get depressed and crawl into a hole and that ruins your career.


WILLIAM HURLBUT: So the, the great physicist Neils Bohr said, we are both spectators and actors in the drama of existence. And the way this program opened was to speak of the, the emergence of human intelligence operating over and against nature. Really amazing considerations. Um, the Roman physician Galen said, the physician is only nature’s assistant. And I think we need to pay attention to that. Nonetheless, John Stuart Mill said, if nature and man are both the works of the being of perfect goodness, that being intended nature as a scheme to be amended, not imitated by man. So we have to find our way, who we are and what of a species we are. That’s not just a simple matter of scientific prowess and possibility. It’s a, it requires a broad fundamental examination of the source and significance of the natural world, the meaning of our individual lives and our collective lives as a society and as a species and in that process when we blend those two, I think we will over the next 25 years come to a far deeper understanding, one might even say reverence for that order of that amazing natural world that Jennifer grew up in, that we as physicians see operating in the imminent powers of health that emerged from the natural human body. I think over this course of time, this fantastic new tool will be applied for a great deal of good and the complexity of the, of the misuses of it, or most of the misuses of it will prevent us from misusing it. Nonetheless, I think we’re going to have to have a very comprehensive view that goes beyond science to include ethics and broad social discussion. And I think the watchword there is that in every way we should, we should follow CS Lewis’s admonition that we should answer all of our problems with more love, not less love.

GUY MCKHANN: So Jennifer, first off, I’m not going to jinx you by saying you’re going to win the Nobel Prize, but I will speak on all of our behalf for thanking you together with Professor Charpentier for this discovery and we all do hope you win it. And you do get the last word.

JENNIFER DOUDNA: Do I still get a last word?

GUY MCKHANN: You still get a last word. 25 years from now, you’re writing your editorial.

JENNIFER DOUDNA: All right. Uh, well, 25 years from now, I have to say, I think what will happen is that we are going to have technologies that support genome editing in ways that currently, uh, we find to be bottlenecks. And I’m talking here about delivery. We spoke a little bit about that, how we introduce these gene editors into cells and tissues. Right now that’s a big challenge, whether it’s in humans or plants or anything else. So I think that’s an area where I suspect over the next 25 years, there will be breakthroughs that will also be incredibly enabling for genome editing. Um, and the other thing is that, that, uh, you know, I think we’re going to continue, you know, you just, looking at the rate of advancing, advancements made in the technology of genome editing just over the last few years. I think that pace of that is not slowing down.

JENNIFER DOUDNA: So, you know, we’re going to see incredible opportunities to do things even better than we can do them today. And that does raise this challenge of how we’re going to use this in a way that is maximizing good and minimizing any, any, uh, dangerous or unethical uses. And I keep coming back to the only way that I think there’s a, an opportunity there is we have to be really proactive about catalyzing these discussions and inviting people to get involved. And frankly, you know, over the time that I’ve been a scientist, a practicing scientist, I’ve seen increasing distrust of science and scientists. And I think it’s, it’s frankly, it’s at least in part scientists’ fault. You know, I think a lot of people I know and I, I, you know, certainly with this way and most of my career too focused on our work and talking to our colleagues and not explaining why we do what we do to anybody else. And I think that the more we can get scientists to engage and participate in conversations like this, the better. I’d love to see science become more integral to our society, and people understand how it works and what its limitations are, so that we can grapple with these really big challenges that are coming not only with genome editing, but also artificial intelligence and other rapidly advancing tools that have great potential, but also have great risk.

GUY MCKHANN: All three of you for your viewpoints, your intelligence, your opinions, your differing thoughts on where we may end up. Thank all of you, very much.

The Big, The Small, and The Complex
CRISPR in Context: The New World of Human Genetic Engineering

It’s happened. The first children genetically engineered with the powerful DNA-editing tool called CRISPR-Cas9 have been born to a woman in China. Their altered genes will be passed to their children, and their children’s children. Join CRISPR’s co-discoverer, microbiologist Jennifer Doudna, as we explore the perils and the promise of this powerful technology. It is not the first time human ingenuity has created something capable of doing us great good and great harm. Are we up to the challenge of guiding how CRISPR will shape the future? The Kavli Prize recognizes scientists for their seminal advances in astrophysics, nanoscience, and neuroscience. The series, “The Big, the Small, and the Complex,” is sponsored by The Kavli Foundation and The Norwegian Academy of Science and Letters.Learn More

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