My guest today, Jennifer Doudna, made a scientific discovery that just may be one of the most profoundly important advances ever in human history. You’ve no doubt heard of CRISPR, the gene-editing technology for which Doudna shared the 2020 Nobel Prize in Chemistry. It puts a power in the hands of humans that we’ve never had before, and — for better or for worse — the opportunity to play God.
DOUDNA: If you’re studying butterflies or you’re studying rice or you’re a clinician with patients that have rare genetic diseases that you ultimately try to treat or cure, CRISPR is applicable in all of those types of cases.
Welcome to People I (Mostly) Admire, with Steve Levitt.
Jennifer Doudna is scientific royalty. I don’t think it’s an exaggeration to argue that history will put her side by side with Galileo, Newton, Einstein, names like that. CRISPR, that’s an abbreviation for clustered regularly interspaced short palindromic repeats, allows researchers to pick any specific part of an organism’s D.N.A. and replace that segment with a different snippet of D.N.A. of the researchers’ choosing. And the application of them and the applications of this technology are essentially limitless.
LEVITT: So, you’ve published hundreds of academic papers, many incredibly important and well-cited ones. But there’s this one paper of yours published in the journal Science in 2012 that was like a nuclear explosion or a tsunami or a supernova. Did you foresee its impact, the attention it would get?
DOUDNA: I certainly had a feeling it would be an important paper.
LEVITT: But I have to laugh because every academic, every time they publish a paper, they think, oh my God, this is such an important paper.
DOUDNA: That’s true.
LEVITT: Stephen Dubner, my co-author, he calls that “the lull before the lull,” because usually you think there’s going to be a storm, but there is no storm. I absolutely suffer from these delusions that people are going to care about what I do. But of course, I’m not writing papers that are altering the course of human progress. So, let me ask you for a prediction. What probability would you put on CRISPR materially extending your own life?
DOUDNA: Oh, well, I think about it a little bit differently. I think about it more from the perspective of making sure that our lives are healthy. So, rather than extending our lifespan, I’d like to see us focus on healthy aging.
LEVITT: Yeah, quality of life.
DOUDNA: So, for example, if CRISPR could one day be used widely to prevent people who are otherwise genetically susceptible to heart attacks or to Alzheimer’s disease — if we could prevent that, that would be awesome. Victoria Gray, for example, was the first patient here in the United States to be treated with CRISPR for her sickle cell disease. And she’s been willing to talk about how this has really transformed her life.
LEVITT: So, the CRISPR gets into the D.N.A., and it snips it. And then the cell repairs itself. The problem that you’re trying to solve is that among 10,000, 12,000 genes, you need a device that can find the exact gene out of all the D.N.A. And then it can cut the D.N.A. and can put back in whatever you want. And do that in a way that doesn’t interrupt the livelihood of the cell. That sounds like a problem that’s impossible. It sounds incredible that we can do it. And even before you showed it could be done, people didn’t expect it would be possible for decades, right?
DOUDNA: Right. It’s an extraordinary task to be able to identify a single region of the D.N.A. of an entire cell. And to put it in perspective, that’s the script that encodes all of the information necessary to make a human being or a magnolia or a frog or anything else. And that script is typically billions of base pairs in length, if we’re talking about a human or a plant. And to be able to use a tool that will go inside the cell and sift through all of that D.N.A. to find a single target sequence, where we’re going to induce a change to that sequence, that really is — you’re right. It is extraordinary. It still blows my mind actually.
LEVITT: Now, whenever I’m faced with a new problem, my first instinct looking for a solution is always try to come up with something from scratch, a brand-new solution. And then I quickly remember that it’s so much easier to borrow a solution that someone else has already figured out to a different problem and to repurpose it for my needs. And I think it’s fascinating that one of the greatest scientific advances we’ve ever had, the original inventors were the lowly bacteria, and we repurposed what they’d done for our needs.
DOUDNA: That’s right. So, that’s really how the whole field got started was through a handful of scientists that were studying this bacterial immune system and then eventually recognized that it’s fundamental components could be harnessed as a powerful genome-editing technology. And you may know, Steve, that this is not unusual in biology, actually. A number of the most important biotechnologies that have come along over the past few decades have originated in bacteria.
LEVITT: Yeah, bacteria don’t get the respect they deserve, I think, is a fair assessment, right?
DOUDNA: That’s true. But the thing to think about here is that bacteria had a powerful motivator. And that is, they want to live. And the selective pressure for bacteria to find ways to fight viral infection, efficiently and effectively is very strong. There are a number of pathways that we know about, and probably others that we don’t know about yet, that do that. CRISPR is one of them. And CRISPR is particularly powerful because it can be programmed, meaning that the same system can be easily redirected towards different viruses. And once we understood how that worked, we could use it to modify sequences in any kind of cell.
LEVITT: And humans have not succeeded in developing something like this inside our own bodies to fight viruses. It’s a completely different pathway than the ones we use to fight viruses.
DOUDNA: That’s correct. It’s different. to our knowledge, there’s not a CRISPR-type system in human cells. However, our cells and our bodies have other immune mechanisms. But we don’t have this one.
LEVITT: So, let me ask you a couple of practical questions about how CRISPR works, because there are pieces that still evade me. So, I understand in a test tube how this could be done pretty easily, but in living organisms, the D.N.A. is inside the cell. If a scientist is trying to solve sickle cell, how do you get the CRISPR into the cell?
DOUDNA: Great question. That’s kind of the question, in a way, with CRISPR right now. It depends on the particular application. Now, in the case of sickle cell disease, that’s a disease where primarily the blood cells are affected. And so, to use CRISPR therapeutically in patients that have sickle cell disease — the way it’s done right now is that cells are removed from the patient, from the bone marrow. And these are stem cells, though, so they’re cells that can give rise to mature new blood cells. Those stem cells are edited with CRISPR. And so, to get the CRISPR molecules into those blood stem cells, typically it would involve a very slight disruption of the cell membrane so that these molecules can get into the cell. And then they have signals on them that tell them to go into the nucleus where the D.N.A. is located. They make their change. And then the edited cells are replaced back into the patient using a bone-marrow transplant.
LEVITT: That makes sense because obviously, doing it inside the body will be much more difficult. Another question I have: You have to do this at scale too. If you’re trying to deal with sickle cell, you must have to do millions, probably billions of cells. And do you go one-by-one inserting the CRISPR?
DOUDNA: One by one would take a long time, right? So, we can’t really do it that way. The way that it’s done in the laboratory or in a clinic is to take a collection of those cells and treat them in a test tube with a formulation of CRISPR. Often it’s done by either encoding the CRISPR protein and guiding RNA in a piece of D.N.A. that can be introduced into the cells or by doing it through direct introduction of the CRISPR molecules themselves. And again, in both cases it involves just a little bit of disruption of the cell membrane to allow these components of CRISPR to go into the cell.
LEVITT: And so, if you do this en masse, I’m imagining one CRISPR per cell very organized and orderly, but presumably the CRISPRs don’t know what the other CRISPRs are doing. And so, many of them might go for the same cell and undo the work of the one before it. It seems like it wouldn’t be assembly line-like when they go to work.
DOUDNA: Well, you’re right that you could have multiple CRISPR molecules getting into the same cell. But the thing is that once the editing is done, it’s done. So, they can’t really do more.
LEVITT: Oh, they can’t undo it because —
LEVITT: — you’ve changed the code. So, the next one just bangs around —
DOUDNA: That’s it.
LEVITT: — doesn’t find a home, and —
LEVITT: — leaves and goes and does something else. And you’ve sent along a replacement bit of D.N.A. to put into the cell, but the old piece of D.N.A.’s still floating around in the cell, too. Is there a way that you get the replacement to take priority over the old piece of D.N.A., or is it random which one gets repaired when the cell puts itself back together?
DOUDNA: There are ways to favor the desired change. So, for example, one way to do that is just to include a large excess of the piece of D.N.A. that you want to introduce into the cell during editing so that when it comes around to a choice, that’s the molecule most likely to be found for editing.
LEVITT: Oh, I see. So, many of these snippets of D.N.A. can be carried around with it into the cell. An obvious place where you might want to do this would be in a sperm or an egg cell, but they’ve only got a single strand of D.N.A. Does this still work?
DOUDNA: It actually does work in sperm and eggs. And that raises other ethical issues —
DOUDNA: — but this is how people are using CRISPR right now to create new mouse strains, for example, by editing mouse embryos that then gives rise to whole animals that have a modified genome.
LEVITT: People always talk about you in reference to CRISPR, but you were an amazingly accomplished scientist before then — you won the Alan Waterman Prize for your work on R.N.A. Do you ever get annoyed that it’s just “CRISPR, CRISPR, CRISPR?”
DOUDNA: No, I don’t. I don’t. I think of my life as B.C. And A.C., right? Before CRISPR and after. But you’re right. I was doing a lot of other things before CRISPR came along. And in many ways that research led me to CRISPR. So, even though it was seemingly quite different, I might not have ended up where I did if I hadn’t taken that path.
LEVITT: Now, obviously there’s enormous amounts of skill in what you do, but it seems like there was a big dose of luck floating around, too. Would you agree with that?
DOUDNA: I would definitely agree. I think a lot of things in science have an element of serendipity, if we’re honest.
LEVITT: Could you talk about that luck? People might think, “Oh, you had a path.” And you said, “I want to create something like CRISPR. And I’m going to set out and do it.” And you spent 15 years doing it. Not like that at all, right?
DOUDNA: Not like that at all. There was a project that we had started on CRISPR around 2007 or so. And it came about because a colleague at Berkeley, Jillian Banfield, had evidence that bacteria had an adaptive immune system called CRISPR. But at the time there was no experimental evidence for it. The hypothesis came about from studying bacterial D.N.A. sequences. And so, we had started to work on it in my lab just a couple of people doing a few experiments. I thought about it as a little side entertainment project. Then I went to a conference in 2011 where I met Emmanuelle Charpentier. And her laboratory was coming to CRISPR from a very different point of view than mine. I’m a biochemist. And we’ve always studied molecules and mechanisms. Her lab was interested in bacteria that caused human disease. And so, she had come upon a CRISPR system in a type of bacterium that causes a flesh-eating infection in immune-compromised people. And so, she wanted to understand how it might be contributing to the biology of this type of bacteria. When we met at the conference, she wondered whether we might like to collaborate with her laboratory to help figure out the chemistry behind this CRISPR pathway. I thought it sounded like a great project. And so, we started working together — kind of unlikely collaborators, not only because we were coming to the field from very different backgrounds, but also because she was working in Sweden at the time. And I, in my lab, of course were way far away in California. So, geographically, it was not super easy. I also wanted to point out that because Emmanuelle Charpentier’s lab happened to be studying a CRISPR system from this particular bacterium, we focused our research together on that type of CRISPR system. That CRISPR system turned out to be very effective at genome editing later. So, it’s still today, even 10 years after we published our work, the molecule of choice for many people who are just interested in using it as a genome-editing tool because even though lots of other types of CRISPR systems have been studied since then, and many labs have looked for better proteins, this one still is in many ways the best. And talk about serendipity, right? But that’s how it played out.
LEVITT: Yeah, it’s similar in some ways to penicillin, which was equally serendipitous, happened to be exactly the right antibiotic, which turned out to be about the best one we found for a long, long time.
DOUDNA: Exactly. I think a little luck is always a good thing.
LEVITT: Yeah. You talked about Professor Banfield and Charpentier. You’re all women. Do you think that there was something going on here in context with the old boys network — it was the fact that you were women facilitated your collaboration?
DOUDNA: Probably not. I’ve had lots of male collaborators over the years, too, but I think in this instance it’s possible that women — because of our cultural upbringing and things — that there’s a little bit more willingness perhaps to break out of the norm or just do things scientifically, let’s say, that are not in the mainstream. And I know for myself, for example, that I have often felt that because nobody in my family was a scientist, and certainly I don’t feel that my parents were expecting me to become a great scientist or anything like that, that at some level I felt a freedom to pursue things I found interesting and to tell myself, “If I try this thing and it doesn’t work out, what the hell, I’ll do something else with my life.” Nobody will be disappointed because they’re not really expecting anything from me. And I’ve talked to some other women that have said similar things to me. I don’t know if that’s true for Professor Charpentier or Banfield but I think that you’re getting at something that pertains to probably not just women, but people in general who are coming into a field where there’s not really a pre-existing expectation of them. And so, it does give them freedom to do things that are outside of the norm.
You’re listening to People I (Mostly) Admire with Steve Levitt and his conversation with Jennifer Doudna. After this short break, they’ll return to talk about the ethical boundaries of CRISPR technology.
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LEVEY: Hey, Levitt. So, now’s the time when we answer a listener question. And we had a question about E.S.G. or environmental, social and governance investing. These are nonfinancial benchmarks that investors can use to analyze a company’s operations. Our listener Casey works on E.S.G. reporting and he wonders if it could serve as roughly the same function as a carbon tax since carbon emissions are something that a company would share in their E.S.G. report. Casey wonders if it could lead to the market favoring companies that emit less carbon. What do you think?
LEVITT: So, I have to say, I am not a big believer in E.S.G. investing and there are a bunch of reasons, but let me just stick to one important reason, which is that the stock market is a market and ultimately economists believe that the price of a stock is determined by the long-term flow of profits that come to that company. And so, if you have a bunch of well-intentioned E.S.G. investors who refuse to invest in the company because they don’t agree with the activities of that company. Well, that will temporarily cause the price of that stock to fall. But that leaves the opportunity for the meanies, the bad guys, the people who don’t care about E.S.G. to swoop in and drive the price right back up. E.S.G. investing is not likely to change the real incentives of the people who are making decisions in companies. All I think it will do is end up shifting returns away from the E.S.G. investors towards the meanies — the people who don’t care about environmental and social criteria.
LEVEY: What about consumers? Do you think consumers care about E.S.G. criteria?
LEVITT: The power of this kind of reporting comes in getting the information to consumers because companies care whether consumers buy their product or not. So, to the extent that we found good mechanisms to make that information available, I think that could have a much more important impact on how companies behave than by burying it in financial reports where only serious investors are going to see it. But even there, I’d say it’s complicated. Think about eggs, right? Is it cage-free or organic or free range? It’s not obvious what’s good for the chickens. And there are people who claim that if you put free-range chickens out, but you still have a thousand chickens in the yard, that’s actually terrible for the chickens because of the way the pecking order works. And I think there’s enormous amounts of consumer confusion about what those things mean. But still, I’m with you, Morgan. I think that would be an excellent way to try to influence companies’ behavior is by putting information in the hands of consumers.
LEVEY: What if, in a way to standardize how good or bad a product is for the environment, companies had to put on the label of their product the carbon emissions that it took to create that product?
LEVITT: I don’t think companies have any idea how much carbon is going into making their products. It’s not simple. And environmentalists argue back and forth. There’s this debate about plastic bags versus paper bags.
LEVITT: And there was a thought for a long time that plastic bags were the most awful thing that had ever happened, but then some people did analysis and they found that maybe paper bags are worse than plastic bags. So, I do think it would be a good idea to put carbon emissions on consumer packaging, but the amount of lying and cheating that will go into it if it’s not very carefully monitored would be immense.
LEVEY: So, is the standardization the reason that you’re so pro a carbon tax?
LEVITT: The beauty to me of a carbon tax is almost all of the carbon we put into the atmosphere comes from burning fuels that we pull out of the ground. If I pull a barrel of petroleum out of the ground, we know exactly how much carbon that’s going to emit in the long run, so we can tax it really easily at the point.
LEVEY: Well, Casey, thanks so much for writing in. So, sorry that Steve isn’t a bigger supporter of E.S.G. reporting, but keep up the good work. If you have a question for us, we can be reached at firstname.lastname@example.org. That’s P-I-M-A@freakonomics.com. It’s an acronym for our show. Steve and I read every email that’s sent, and we look forward to reading yours.
In the second half of our conversation, I’d like to really dig into the applications of CRISPR. How has it been used so far and what stands in the way of it being applied more broadly? Is it technical limitations or ethical ones? Jennifer is especially well qualified to answer these questions because not only did she discover the technology — she started the Innovation Genomics Institute, which aims both to advance the usage of these tools and also to address the thorny ethical questions that CRISPR raises.
LEVITT: I’d like to talk about the applications of the CRISPR technology. And typically, I think given the incentives of reporters of the popular press, media coverage around CRISPR goes right to the most controversial applications, designer babies and whatnot. But my strong sense is that there’s one domain that has already been completely and totally transformed by CRISPR, and that’s academic biology and biochemistry. Am I right about that?
DOUDNA: I agree. It’s fair to say that CRISPR came along at an opportune time. So, here’s another kind of serendipity, I guess you could call it, because we’ve heard this in other fields too, that when you have a technology or some kind of a breakthrough that comes along at the wrong time, even if it’s very useful in the long-term, it just takes forever to develop because it doesn’t have an immediate impact or there’s just not an immediate problem that it’s solving. In the case of CRISPR, however, it was a technology that came along at, in many ways, exactly the right time. And the reason is that we have sequences now of the whole human genome, the first of which became available around the year 2000. So, having that kind of data was very powerful in one way, but it also could be frustrating for scientists because you could see things in the D.N.A. and you’d like to know, “Gee, what happens if I change that gene? Or what would happen if I added a piece of D.N.A. over there?” And until there was that capability, it was simply a question that couldn’t really be answered. And so, CRISPR offers a tool that is, first of all, widely accessible. It doesn’t require a lot of special technical expertise beyond knowing a little bit about how to work with cells, to be able to use it. And secondly, it can be programmed to interact with any D.N.A. in any type of cell. If you’re studying butterflies or you’re studying rice or you’re a clinician with patients that have rare genetic diseases that you’re trying to determine the cause of and ultimately to try to treat or cure, CRISPR is applicable in all of those types of cases. And so, we’ve just seen a very rapid adoption of this technology across all fields of biology over the last decade, that’s been really exciting.
LEVITT: I think a second area where it’s been pretty impactful already is with plants and agriculture. So, what are some of the biggest wins we’ve had so far in that domain?
DOUDNA: You might’ve seen the news about a CRISPR tomato that’s now being sold in Japan. So, that’s one commercial product that’s come forward. There also are other big commercial crops: corn and rice that are certainly in the pipeline.
LEVITT: The one with rice, if I understand, is some kind of a transformation in yield that’s mind-boggling, many multifold-increase in yield per acre.
DOUDNA: That’s right. That’s right. And I think it’s worth mentioning here that that has brought along with it questions about do we consider an edited plant to be a G.M.O., which has a bad connotation associated with it? There’s been a lot of discussion about this and debate about this. But I think that fundamentally CRISPR offers plant breeders an extraordinary opportunity. Because it has this ability to precisely introduce changes to genomes, plant breeders are no longer subject to having to introduce random changes and then select for plants that have desired traits, which is how —
DOUDNA: — plant breeding has been done forever before this.
LEVITT: And I assume you find the fear of genetically modified plants, of G.M.O., to be largely irrational?
DOUDNA: I think it’s largely irrational. One always has to be careful and cautious. So, I’m not saying that we shouldn’t be thoughtful about how we use a technology like this, for sure. But if you’re making a targeted change to a genome in many ways, that’s actually less risky than introducing lots of random changes that you can’t control.
LEVITT: So, another domain in which CRISPR can be applied is to fight genetic disorders in humans who are born with a bad copy of a gene. And we mentioned already sickle cell anemia, which is a great example. So, there’s been clinical progress in the field with sickle cell anemia. Is that right?
DOUDNA: Yeah, it’s been extraordinary.
LEVITT: What makes sickle cell such a great first application for these technologies?
DOUDNA: A couple of things. It’s one of the genetic diseases that’s best understood at the genetic level. It’s been known for a long time what causes it. Also, it’s one of the more common of the genetic disorders. And because it affects the blood, it’s possible to do the genome editing ex-vivo, meaning outside the body.
LEVITT: So, how have the clinical trials progressed?
DOUDNA: Several companies have run clinical trials or are running them right now for sickle cell disease. And actually, our institute, the Innovative Genomics Institute, has also gotten F.D.A. approval to run a phase I clinical trial. The outcome of the initial trials have been really exciting in the sense that CRISPR is offering these patients an effective cure of their disease. On the other hand, I do want to point out that right now, those therapies are very expensive. We’re talking about on the order of $1 to $2 million a patient. So, what we’re thinking about at the Innovative Genomics Institute is how to reduce the cost. And one of our goals for running our own trial — which is to my knowledge, the only trial for sickle that’s being run out of a non-profit organization — is to focus on how we control the cost of the therapy and make it available to those that need it, regardless of their ability to pay.
LEVITT: One of my friends, Kevin Murphy — he’s an economist at the University of Chicago — he talks about, well, imagine you come up with this amazing technology that cures cancer and it costs $10 million per person. Now you’re in the worst possible situation because you have this cure, but it’s a cure that will be unavailable on a wide basis. It’s in some ways worse than no cure at all. Is it your sense that we’ll get into some really powerful cost savings and these technologies will relatively quickly become widespread?
DOUDNA: I guess it depends on what you mean by relatively quickly, but over time, yes, the cost is going to come down because it will become easier and less expensive to make the molecules that are needed for these therapies. When we think about sickle-cell disease and frankly, anything else that you want to use CRISPR for, for human therapeutics, a big factor there is going to be delivery. How do you get the CRISPR molecules where they’re needed? In the sickle-cell example, the way that this treatment is done right now is using a bone marrow transplant to replace the edited cells back into the patient. But we’re imagining a day when you have a delivery strategy that allows you to give a patient a one-time injection, or maybe someday even they just have to take a pill. And the person has the therapeutic benefit without having to go through the bone-marrow transplant. That would save many weeks of hospitalization, which is extremely expensive. And of course, it would be much more pleasant for the patient —
DOUDNA: — to not have to go through that as well.
LEVITT: So, other than the cost and the difficulty of delivery, are there real risks in say treating sickle cell? Or is it really that the technology’s fine, we just need to figure out a way to scale it?
DOUDNA: Well, the accuracy of the technology is always something to pay attention to. The good news is that so far in these types of trials people have looked very carefully at the accuracy and the news is generally quite good. The level of accuracy is good enough that it’s not a concern. But I think, one always has to remain vigilant there because there’s always a risk for some kind of off-target effect to happen. Beyond that, it really does come down to ensuring that the editing that happens is the editing that you want. Because we talked about the fact that when cells repair D.N.A., they can repair it in different ways. And there are lots of clever things that are happening right now with the technology to do that. So, I’m pretty confident that over time it’ll get easier and easier to make sure that the editing is precise.
LEVITT: So, I understand the cost is one of the main reasons that progress has been slow in terms of getting this out in the field. But I also suspect given what I know about medical ethics, that medical ethics has landed in a strange spot where it’s a tragedy if a single person dies from a CRISPR-based intervention to correct sickle cell, but it’s somehow much less tragic if thousands of people die prematurely each year because we have a paralyzing fear that one person might die from a new treatment. Have you experienced that kind of phenomenon at all? A fear of newness slowing down things that, in a true cost-benefit calculus, shouldn’t be slowed down or prevented?
DOUDNA: It’s a real dilemma, isn’t it? And the way you just phrased it, I think most people would say, “Gosh, yeah, we should absolutely be fast-tracking treatments that have the potential to save thousands, even if it means more risk for a few.” But of course, that’s different if you’re one of the few. It has to be managed carefully. I think many people feel that, on the one hand we’re grateful for the Food and Drug Administration in the U.S. and the regulatory role that they play. At the same time, it can feel that the whole process of testing out new therapies is quite laborious and quite slow. And I think it’s worth continuing to ask: Are there ways to speed that up, that don’t needlessly endanger people, but also ensure that new therapies are really rolled out as quickly as possible?
LEVITT: I love how you stated that so carefully and politically. I can’t control myself. When I get to that issue —
DOUDNA: Let’s hear how you would phrase it.
LEVITT: I think related to Covid, it’s so frustrating to me, for instance, that we knew that hundreds of thousands of people would die. And yet, on the simplest mechanisms of how Covid is spread, when people are contagious, we steadfastly refused to do anything like a challenge trial, which would put a few very well-paid volunteers at risk to save thousands of thousands of lives. But the medical ethicists just said, “No, that’s not even on the table.” And I think that’s just misguided. People don’t usually ask economists for moral guidance on ethics, so maybe I’m just out of step with the world. I’m not sure.
DOUDNA: Well, it’s interesting that you mentioned that example. The one that I think of with regard to Covid actually comes down to testing because I feel that we’ve been so desperately in need of good testing ever since the start of the pandemic. And yet, it’s been very hard. And I’ve experienced this because we run a Covid-testing lab at our institute. And we’ve had a very active academic consortium that’s been working on CRISPR-based Covid diagnostics where we’ve had to coordinate with the F.D.A. regarding the kind of data that would be necessary to get emergency use authorization. And it’s been really challenging to work with them. One could ask: Do you want to make the barriers so high for testing labs and for new testing technologies that it becomes very difficult for these technologies to come online and actually start helping people? And I don’t know what the right answer is, but I’m not sure we’re at the right answer now.
LEVITT: So, the ultimate application of CRISPR is to so-called germline cells or altering the genes of an embryo so that the whole organism’s D.N.A. is altered. And those changes are then passed onto future generations. This, I think, is where the unbelievable power of CRISPR looms largest. Do you agree about that?
DOUDNA: If you think about it, what you just described — it means that human beings can rewrite their own evolution now because we can change our genomes in the germline so that we create heritable changes in future humans that are passed on to their kids, etc. And we have control over that. It’s kind of extraordinary to think about it that way, to me at least.
LEVITT: Kind of?
DOUDNA: I mean, very, very, very extraordinary. Yeah.
LEVITT: So, ethical issues obviously loom large here. And I know you’ve been a pioneer in trying to build scientific consensus around setting the right ethical standards in this domain. Which I find admirable, but also, it’s odd. Do the same traits that make a great scientist make one good at knowing where to draw the line between right and wrong? You trained to be a scientist, not a Supreme Court judge, for a reason, right?
DOUDNA: You’re absolutely right. I don’t think those same traits do necessarily apply in each case. I definitely never had real training in bioethics. So, I really had a lot of reluctance to get into this whole topic when CRISPR was just beginning. But I felt compelled. Because it seemed that there was such a big potential risk for this technology to be used inappropriately, especially in the early days. If I didn’t get out in front of it, who would? A lot of scientists really just don’t want to get into the area of bioethics because they feel they’re either not qualified, or they just want to do their research. They don’t want to spend time focusing on that. So, I had to get over that with myself and just dive into it. And so, I’ve been involved for a number of years now on this topic. How is it going to be affordable in the future? How is it regulated? Who decides who gets to use it? These are all really interesting, really complex questions.
LEVITT: So, right now, there’s essentially a moratorium on doing these kinds of germline experiments in humans. Although it seems to me, morally, there’s at least some cases where I don’t see how anyone could reasonably argue against it. So, for instance, I just had a baby. And when the baby was a fetus, we did a whole series of genetic screens. And I think many parents, when those genetic screens come back positive, abort. So, it seems to me in a world in which parents are going to abort a fetus, can there really be a moral objection to using CRISPR on a sperm or an egg to avoid those kinds of genetic disorders arising? Do you have a stance on that?
DOUDNA: Your question is reminding me of the first meeting that we had on this topic back in early 2015. So, it was really quite early in the development of the technology. And this was a small meeting, sponsored by the Innovative Genomics Institute, in which we had about 20 scientists who were sitting around a table for a couple of days, discussing exactly this question: Would there be circumstances where editing the human germline — meaning eggs or sperm or embryos — would make sense? Lots of opinions, lots of debate. And then at one point, somebody at the meeting leaned in and said, “Wait a minute. Maybe we’re thinking about this all wrong because maybe we’re going to come to a point where we would consider it unethical not to use it in that way.” And that stopped the conversation, and everybody started thinking, “Oh, yeah. What are the situations where that might be true?” So, I think you have a good point. With where the technology is today, I just don’t think scientifically or technically it’s at a point where it would be responsible to use it that way, because it just hasn’t been shown to be safe yet. There needs to be more work done probably on non-human systems to understand it better. But going forward, could we imagine a time when there would be applications where germline editing might make sense? I think, yes. I’m not against that. I just think that we have to be, again, very thoughtful and cautious about it.
LEVITT: So, we’ve done a lot of that on mice and other species.
LEVITT: Do they seem to do fine?
DOUDNA: They do.
LEVITT: Because it seems like, especially if you do it in a sperm or an egg, once you’ve done it, you’ve done it. And it seems like once you’re born, it’s hard to see how that first cell being poked a little bit would have much impact. We poke cells all the time, I think, when we’re doing artificial insemination and stuff like that.
DOUDNA: Well, we poke them, but we don’t change their D.N.A., or at least not on purpose.
It’s almost impossible when you think about the implications of CRISPR not to be a little unsettled. The capability it affords humans goes so far beyond what we’ve been able to do in the past. And consequently, there seems to be a general consensus we want to employ CRISPR only cautiously and in a few particularly compelling use cases. But I’m going to go out on a limb and make a prediction: it won’t be long before the use of CRISPR becomes far more normalized, and that applications that make people squeamish today will be widespread. We’ll ask ourselves, “How did we ever live without CRISPR?” All it will take, I think, is a few successes and familiarity. Many things are viewed as repugnant when they’re new. Take life insurance: It was initially thought to be morally disgraceful. Imagine! Benefiting financially from the death of a loved one? And if you’re old enough, you’ll remember the furor over test-tube babies, a procedure which just a few decades later, is completely commonplace. I suspect the exact same thing will happen with CRISPR, and I just hope I live long enough to reap some of the benefits. Thanks for listening, and we’ll see you next week.
People I (Mostly) Admire is part of the Freakonomics Radio Network, which also includes Freakonomics Radio, No Stupid Questions, and Freakonomics M.D. All our shows are produced by Stitcher and Renbud Radio. Morgan Levey is our producer and Jasmin Klinger is our engineer. We had help on this episode from Alina Kulman. Our staff also includes Alison Craiglow, Greg Rippin, Gabriel Roth, Rebecca Lee Douglas, Zack Lapinski, Julie Kanfer, Eleanor Osborne, Mary Diduch, Ryan Kelley, Emma Tyrrell, Lyric Bowditch, Jacob Clemente, and Stephen Dubner. Our theme music was composed by Luis Guerra. To listen ad-free, subscribe to Stitcher Premium. We can be reached at email@example.com, that’s P-I-M-A@freakonomics.com. Thanks for listening.
LEVITT: And Topher, the tech guy on your end, said that the last time you were in this recording studio was the day you won the Nobel Prize. Does it bring back good memories?
DOUDNA: Yeah. I actually was thinking of that when I was walking in, and I’ll never forget it.
- Jennifer Doudna, professor of biochemistry and molecular biology at U.C. Berkeley
- “First Sickle Cell Patient Treated With CRISPR Gene-Editing Still Thriving,” by Rob Stein (NPR, 2021).
- “GABA-Enriched Tomato Is First CRISPR-Edited Food To Enter Market,” by Emily Waltz (Nature, 2021).
- “Interview with Jennifer A. Doudna,” (The Nobel Prize, 2020).
- “Jennifer Doudna and Emmanuelle Charpentier: Behind the Development of CRISPR Genome Editing,” (I.G.I News, 2020).
- “Expensive Treatments for Genetic Disorders are Arriving. But Who Should Foot the Bill?” (Nature, 2019).
- “Breakthrough DNA Editor Born of Bacteria,” by Carl Zimmer (Quanta Magazine, 2015).
- “A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity,” by Martin Jinek, Krzysztof Chylinski, Ines Fonfara, Michael Hauer, Jennifer A. Doudna, and Emmanuelle Charpentier (Science, 2012).