Jennifer Doudna on CRISPR, One-Time Cures, and Science Communication

Thank you. Real pleasure to be here.

Easy ride. Yes. Pretty good.

So many things have happened as you said and some of it has been on the science front and some of it's been on the frankly larger scale of public policy and where medicine is headed, where agriculture is headed but with these kinds of tools now that we have for manipulating DNA. It's really been very interesting to see all of that unfolding. What am I most excited about? I guess certainly top of mind today is the opportunity to create bespoke CRISPR therapies for patients in real time. I think this is such an interesting moment we're in right now. We've seen the example with baby KJ. We talk about that right here today. And there are so many things going on here at Stanford and in the Bay Area and of course much more broadly across the country and elsewhere that make us think that, you know, there really is an opportunity right now to seize the moment, figure out how we can find those patients that can benefit from CRISPR and create the pathway to helping them in real time and doing it in a cost-effective way. That's what I'm scaling — the thing really interested in doing.

Well, this institute started just over 10 years ago in Berkeley and in San Francisco. We were a joint institute from the very beginning linking UCSF and UC Berkeley and UC San Francisco with the idea that we could bring genome editing to bear on health and climate challenges in ways that would have real world impact. How do we do that? You know, it sounds like a broad grand goal, but you know, how do you actually get there? And what I'm excited about is that over the 10 years of our existence, we've raised a lot of money. We've also invited a lot of partners in. We've just recently signed an agreement with our third campus partner, UC Davis, has become a formal partner of the IGI. And we love the idea that we can leverage expertise that exists on different campuses to focus on big projects and problems that none of us individually would be able to work on or really tackle meaningfully. And what's amazing is that we're really focused now on building collaborative teams, especially with younger scientists who are just starting their careers and with companies that can bring their expertise to bear on these projects and problems and inviting people that are very excited about science but maybe are not scientists. Philanthropy comes to mind. That can meaningfully gather their different capabilities to do things that otherwise wouldn't happen.

That's what we do. The new frontier. I think that's right. Perfect place to do it. And we're excited to be able to collaborate on a few of these things.

It's an incredible story, isn't it? It's so inspiring to see the example of a child who was affected by a metabolic disease diagnosed in real time and treated with a therapy that was created for him, for his disease. And tested first in animals and in collaboration with appropriate regulatory guidelines and his clinical team at the Children's Hospital of Philadelphia figuring out how to actually treat this patient and ensure that he would have a safe path to what we hope will be a permanent cure for the disease. It's really really exciting. You know, it's worth pointing out that this is probably not a one-off case. This is an example of what is now possible to do and it's partly inspiring to see a patient and his family of course treated effectively but what's even bigger and inspiring to all of us is the opportunity to do that for so many more. And the key features of that — this was CPS1 deficiency, so this was a metabolic disease that causes hyperammonemia and that can cause severe brain damage and would even be associated with a 30 to 50% risk of death. So this is not a trivial condition and one that was diagnosed pretty early in life — like two or three months when he was first diagnosed.

Yeah. Yeah.

That's right, three.

It's incredible. Yeah, it's really very exciting. And as you're saying, I think the inspiration is part the effect on this individual, but it's also the idea that we could do this for many others and we now have a pathway. We can see all of the steps that can happen and how to do them in a period of time that's meaningful for the patient. It doesn't take years and years — this was done in a matter of months.

That's what we're seeing. It's really interesting to see this and I think it's partly again that you know the FDA after all is human beings and they can see the potential, they can see the opportunity. I think Fyodor Urnov at the IGI deserves a lot of credit for his role in helping to educate regulators about the science. As you said, it's often hard for them to keep up. There's so many things happening. How do they become experts in every new technology? They really can't. And so it does require scientists to go in and say, 'Look, you know, we'd like you to understand what we're doing. We want to work with you. We want to partner with you. We want to do this in a way that makes sense for everybody. And of course, safety has to come first.'

Yeah, it's very interesting because that partnership existed already — you know, was kind of pre-existing to the diagnosis of KJ. This is a partnership with a company called Danaher that makes molecules among other things. And they are very good at it. They know how to make molecules that are prepared in a way that can be delivered clinically. And so when the baby KJ case came along, they stepped up and said, 'Yes, we're willing to provide the molecules needed for this treatment and we'll do it at our expense.'

Right. So it goes to the liver pretty naturally which is exactly where you need the—

Exactly. And this is what CRISPR has offered from the very beginning, right? — this opportunity to create a targeted approach for each individual mutation. It's just that, you know, if you have a rare disease where for each disease that you're treating, you have to go through a full-blown three-phase clinical trial, it's not realistic, right? I mean you don't even have the patients to do it even if you wanted to, and the expense would be prohibitive. But here, I think the FDA is saying, 'Look, let's take a new lens to this. Let's recognize that this is really a different kind of technology. And we're really talking about a different kind of therapy, aren't we?' This is not something that you're going to be injecting someone with every day or a month. Hopefully, it's a one-and-done.

One and done.

Exactly. So yeah, well talking about scaling — you know, that's talking about an N-of-one therapy, but you also have these ideas to potentially impact the entire population or thinking about the planet by editing the microbiome. And I realize that you recently got a big grant with Jill Banfield to think about microbiome editing. I spent a lot of time thinking about genetics, genomics, and also gene editing. I hadn't spent a lot of time today thinking about microbiome editing. So tell me what's in scope for that. Essentially exciting.

It's on the agenda because — and this involves our wonderful colleagues up at UC Davis who have for a long time been aware that the microbiome in the cow rumen — which is where, you know, they're digesting grass in multiple stomachs and got a lot of microbes that are busily doing that kind of metabolism — the problem is that some of those bugs are also making a lot of methane. And that's one of the most powerful greenhouse gases and it's like a third or something human-produced. Shocking, right? I was astounded to learn that agriculture and in particular cattle farming accounts for almost a third of the methane emitted annually that's human-caused. So, what can we do about that? I don't think it's realistic to ask everybody to stop cattle farming. Right. That's just not going to happen. And so better would be to find a way to actually just reduce the methane emissions at the source. And so this is where we think CRISPR comes in because we know we can manipulate genes in these microbes. Increasingly, we know the genetics of methane production in the cow rumen. And so again, it's sort of an analogy to the baby KJ case where we've got all the pieces, right? We've just got to put them together to make something that's going to have real impact. And that's what we're doing with our BIOM program. So we have a whole team of young investigators. Jill Banfield is the leader, but we've got a lot of scientists now who are really focused on this kind of challenge working both at the Berkeley site of IGI, but also working up at UC Davis where they actually are birthing calves and starting to test. So it's great. The idea is that we would treat individual cows. And again, the idea would be a one-and-done kind of treatment that would then be maintained through adjustments that wouldn't be prohibitively expensive in the diet and would be possible to distribute around the world.

It's an interesting question, right? I mean that's one of the things we're researching right now is to what extent you get that kind of population change.

Sorry — Susan Lynch up at UCSF, you may know her — she has had a longstanding clinical research program on the connection between the human microbiome and asthma. And so we would love to be able to also manipulate the human microbiome to reduce asthma susceptibility. Sounds a bit wild. I thought it was kind of a — it sounded a bit like a long shot when we first discussed it, but I think again the pieces are coming together. We understand the genetics of production of molecules in the human gut that can induce asthma susceptibility. And now again we have the tools to manipulate it. So you can start to see the pieces coming together. I think in many ways the microbiome has been really ignored by human physicians and by the health care system to date partly because we haven't been able to manipulate it very well. Obviously C. diff diarrhea has been one area of great success. But overall, I think we've found it fascinating from a scientific standpoint as we learn more and more ways that the microbiome interacts with the human part of the dual organism and vice versa. Obviously a lot of diet-nutrition work and our GI colleagues have been to the fore. But some of the remarkable impacts that are seen even on psychological conditions and psychiatric conditions, on anxiety from the microbiome — it's just remarkable. And I do think that we're ready for another revolution there where we understand that we can actually manipulate the microbiome in a much more precise way to help with these diseases where it's clearly fundamental. Even responses to chemotherapy and other trials that we've seen — the microbiome could make a significant...

Yeah. But now we have the tools to do it.

Well, it's a great question because I consider myself the most naive person probably out there when it comes to thinking about how to sort of commercialize scientific discoveries. I certainly didn't — that was not on my radar when I started my career and even when we started working on CRISPR it wasn't the thing that was on my mind at all. And I had to learn about it because I realized fairly quickly once we had done the initial work on CRISPR that when you have a technology that's cross-cutting like this and you see opportunities for it to have real impact, some of that can get done in academia. But frankly, you're probably going to need the teams and the financing to do it much more broadly than would be possible in a typical academic laboratory. And so how to do that became top of mind for me at that point. And I was fortunate to have a lot of people, including a number of folks at Stanford — I consider, by the way, I've long considered Stanford a real leader in this. Stanford has had a culture for a long time about how to make that smooth transition between fundamental discoveries and scaling that happens with commercialization and how to do that effectively. It's been a great journey. I can just give a 30-second summary because you alluded to my little foray into the business world and this happened in 2009. So I had a really exciting opportunity to move to Genentech and I decided to do it because I felt that I was sort of mid-career at that point and I'd been at Yale for several years before I moved to UC Berkeley. So I'd been at two wonderful universities. I was starting to worry a little bit that my work although exciting on one hand was not going to have the kind of impact — especially in health — that I would always write about in my NIH grants, you know? And I thought, you know, am I really talking about that? But yes — well — this is part of the story, right? Because I went — I accepted the position at Genentech and it was a bit of a tumultuous time there. They were being purchased by Roche at the time. And so there were lots of changes happening. And I just realized within a few weeks that it was, you know, a little bit like putting a square peg in a round hole or something. You know, I do love the academic setting in the sense that I love the lab. I love working with my students. I really enjoy that interchange. So I ended up going back to Berkeley. I had taken a leave — thankfully they took me back. But you know an interesting thing happened because when I went back, I had cleared my calendar completely as you can imagine. I didn't have any travel. I wasn't going to be there and I didn't have any teaching, you know. And so I had — I suddenly had — you know, I looked at my calendar and I had like these blank days of just being able to hang out in my lab, talk to my students, think about things, work on things that I just found interesting. One of them was CRISPR. Because this was something we were playing around with due to Jill Banfield — right? Her ideas around what it might be doing. And because of that, in part, you know, I think it really gave us the freedom to explore some ideas that might or might not have happened otherwise. And so I really taught myself something interesting in that whole process. And that is that, you know, I think it is important to pursue your scientific interests. I think it's good to keep an eye toward applications and thinking about where could this discovery have impact. But I do think it's important to be true to what you really love to do. And that's kind of what I taught myself in that experience.

As scientists somewhat under attack — and it is a fascinating moment because on the one hand we've got more tools than ever for communication, right? We got all kinds of social media. We've got many people who have stepped forward as spokespeople for science which is great. And a lot of those folks have many followers, right? And they've attracted a lot of attention and a big audience on the one hand. And then on the other hand there's a lot of frankly just false information and disinformation that goes around. Vaccines come to mind for example where unfortunately it does a tremendous disservice to the science and also to people that could otherwise benefit from it. So what do we do? You know, and I think that it's a tough challenge that I'm not sure there's an easy answer to. I do think that scientists need to be better about communicating about their work. I don't mean that all of us need to become national or international lecturers on the topic. It's just that I think all of us need to figure out where can we have an impact. It's as simple as having a one or two sentence non-jargony explanation of what we're doing so that when you sit down on a plane and you're chatting with your seatmate about what you do, you can roll that out. Get in an elevator — you can tell somebody quickly what you're doing and why it matters. Unfortunately, because scientists haven't been effectively doing that over the last few decades, there's been a bit of an erosion of the appreciation of science across our country. And I think some taxpayers at least wonder, 'Yeah, why are we shelling out money for projects on things like bacterial immune systems? And why does that matter?' Right? And so I think it is very important to do this. So this is what I tell my students. I say, 'You know, figure out where you're comfortable. You don’t have to be an author. You don’t have to be a lecturer necessarily if you want to do that. But just being able to tell your grandmother what you're doing and why it matters is really key.'

Exactly. It's those conversations I think can really have an impact on people. And like you say, just being able to understand — I often say this to my students and trainees when they're giving a scientific presentation — you actually want to think about it as if you're explaining it to your grandmother or explaining it to a family member because that will force you into a narrative format to sort of tell a story.

That's right. And I think that we could all be better at that. And I think that in order to gain a little bit of the public's trust — and we have collectively lost some of that, whether it's because of folks who are treating science as something other than the rigorous approach to truth that we know it to be or whether it's because we're less good at communication — we definitely have lost a step. And so either way, I think we all do need to step up a little bit.

Right. Yes. It just seems like — I mean, that's one of — I mean, we've talked about individual humans, we've talked about planets. This is almost like, you know, planetary-scale ideas — like thinking about how life could actually have started. It's such a fascinating question. When I got to graduate school, I really didn't know what I wanted to work on. And my adviser Jack Szostak was brilliant at taking a huge question like that and boiling it down to experiments that we students could actually do in the lab. You know, it was really interesting to me to see how you do that, how you think about — and we try to do this of course in our own research, right? — as we have big questions we want to answer, but you've got to somehow figure out how to turn it into, you know, an experiment that somebody can actually do in a two… you know. And so that was my first real exposure to that type of science. And I've never lost that sense of wonder at, you know, the kinds of capabilities that scientists have when they really put themselves to a task like that. And, you know, in the case of the RNA world — yeah, I think it's still a really interesting question that's not fully answered. I think we have a good sense of the kinds of molecules that clearly had to be around in the prebiotic Earth. Where they came from is a question. I think this asteroid data is fascinating, right? Because it does kind of support the idea that Francis Crick, I think, first proposed, which is that life probably came from elsewhere — or at least the components came from elsewhere — because maybe there wasn't actually time for those molecules to evolve here on the planet. Or to emerge, you know, on the planet — not really known. But I think this new evidence is certainly interesting in terms of thinking about the origins of life. Maybe the components arrived here and were easy fodder for evolution to begin working on.

It's been fun. I mean I can't imagine having done anything else, in a way, because it's been just such a wonderful career to be involved in the process of discovery.

Yeah. No, the toolbox will continue to expand. That's for sure. You know, the capabilities will continue to evolve. That's also for sure. I think it's really a question of how to turn this kind of technology now into a turnkey approach to disease. You know, whether we're talking about planetary disease or human disease, it's really about doing that in a way that becomes scalable. And I still think there's a really important role for academics and for nonprofits here because I think it's pretty clear that — again, I defer to your expertise here on the clinical side — but humans are complicated.

Right. And, you know, this is why — you know, people always wonder why do so many drugs fail in clinical trials? It's just — it's brutally hard. And I admire people that have devoted their careers to drug discovery because it's a really hard problem. It's harder than anything I do, I think. You know, right? It's — you know — our work is the first step, but then you've got to actually show that it works in an actual disease situation and is safe for people to use. And, you know, that's a whole different ballgame. So I do think it's going to require continued technological and scientific discovery to get us at least closer to that goal of being able to quickly come up with therapies that are effective for different types of disease.

Great to be here. Thanks again so much.