In this interview, Nobel Laureate Jennifer Doudna, Ph.D., joins AAPS Executive Director Tina Morris, Ph.D., and AAPS Member-at-Large Gopi Shankar, Ph.D., to discuss her roles as scientist, academic, and biotech startup founder. This interview highlights the fascinating agricultural origins of CRISPR, where and how in the world this technology might be taking off, and the influence of CRISPR on pharmaceutical science. Overwhelmingly, AAPS members are passionate about the next generation of scientists, and Dr. Doudna discusses how she continues to support students and offers insight into the mindset of an effective mentor.
What do you think about the timing of the Nobel award in comparison to awards made for breakthrough technologies, like PCR where the award came so much later? Do you think the timing of your award is helpful to the CRISPR field?
The timing is interesting. It speaks to the transformation that the field of biological research is undergoing currently, and that CRISPR is certainly apart of. Other technologies in the field of molecular biology recognized by Nobels took longer to develop. One of the extraordinary things about CRISPR is just how fast it went from a fundamental research discovery to a powerful technology that is now being used in labs and companies around the world.
In terms of how the Nobel affect that development? I’ve wondered about that, too. In the short term, it may be a hinderance to people like me and Emmanuelle Charpentier, because of the things that go along with the prize and the expectation that we will serve as ambassadors for science, which I think is entirely appropriate but does take away from the laboratory.
But in the broader sense, I think the prize will help the field. It elevates the attention paid to CRISPR—or genome editing—more widely. This is a big boost. There has been a flurry of interest since the prize was announced, including from people who maybe were aware of CRISPR but are now thinking about it in practical terms.
When you published your landmark 2012 Science paper, did you imagine how impactful it would be?
From the moment we had the realization that this system could be harnessed for genome editing, we knew that it was going to be impactful, it was just a factor of the scale. There was a lot of excitement in our lab, and among our collaborators and colleagues. As soon as our work was published by many others who quickly appreciated the utility of a tool like this—a technology that would easily allow manipulation of genomes. Even though there was that early feeling that we were onto something big, it would have been very hard for us to imagine just how big and how fast the field would become.
How did your research evolve into the area of microbial genomes and the CRISPR area?
There is an interesting and direct connection between RNA and genome editing that is linked by CRISPR. The reason I started to study CRISPR, which is naturally an immune system in bacteria, is that it works using an RNA-guided system. It is a mechanism that fundamentally relies on a lot of the same properties and chemistries that I had been studying in other contexts.
Over the course of my whole career I focused on understanding the role of RNA molecules in cells—how these molecules control genetic information, both in viruses and in human cells. That is a theme that is linked through different projects that we have worked on over the years. CRISPR comes under this category as well, as an RNA-guided immune system. And frankly, I thought it was very interesting that bacteria would have evolved a system that relied on RNA as the sentinel in the cell that triggers the cell to destroy viruses that are trying to infect.
Did you start off with the hypothesis that living things have to have an immune system to be able to survive and therefore bacteria might also, or did some of your findings then lead into understanding that bacteria also developed an immune mechanism?
Neither, because the discovery of CRISPR as an immune system was really done by others. This was work that originally came out of research that was being done in a handful of microbiology labs around the world. And importantly, a team that was working on food science. These were folks that were in the dairy industry and they were very interested in the possibility of a bacterial immune system because it would have very practical implications for protecting cheese and yogurt cultures from being destroyed by viruses.
I love that aspect of the CRISPR story. It goes back to a very utilitarian reason for doing science. And that work led to the discovery of CRISPR as an immune system, but nobody knew how it worked. And there were really interesting genetics that implicated the CRISPR genes in this pathway, but it wasn't clear how they worked and how the system might function either in bacteria or in a chemical sense, and that's really where we got involved.
What else do you think is necessary to continue CRISPR’s success in the pharmaceutical and therapeutic space?
It's very important first to communicate about what this technology is and what it is not. I think it helps to describe the excitement in the field but also the current challenges. And I would say that one of the current challenges is the cost of using genome editing especially for therapeutic applications. The potential is extraordinary, but the cost right now is high. This is something I think about a lot right now. We have to think about ways to develop it further so that the cost comes down substantially.
And then, in terms of the fundamental understanding of the technology, I don’t think that people have to understand all the details about it. Just like I do not understand every detail about how my cell phone works, but I can still use it and I can use it in ways that are effective and safe, and that protect privacy. The same thing is true with CRISPR technology. People do not need to understand all the details about it. But I do think they do need to know what it does and does not achieve.
The vast majority of clinical uses for CRISPR, in my view, are going to be in individuals, not in embryos. I don’t personally see ethical challenges beyond what we would think about for any kind of therapy where you want to make sure it is safe and effective for people. I don’t think there are ethical concerns beyond that when it is used in individuals.
Are there other safeguards that that should be put in place anyway to protect from misuse?
Well, I certainly think that it is going to be important to know how to do appropriate clinical trials for genome editing. And this is something that the FDA and other regulators are currently grappling with. On the one hand, one wants to ensure safety and effectiveness. On the other hand, it is impractical to do a full-blown clinical trial for every format of CRISPR.
The great thing but also the challenging thing about CRISPR is that it is truly a personalized system. It can be personalized to each individual genetic situation. That’s the great opportunity but we do have to figure out appropriate ways to test it and ensure safety and effectiveness.
In terms of regulation of other uses of CRISPR, let’s say in human embryos or the human genome, I think it is absolutely critical that the topic is discussed openly and that we encourage a global engagement around this. It has to start with the scientific and clinical communities.
A number of organizations have stepped up in this regard. There’s been a lot of interest at the World Health Organization, at UNESCO, and among scientific societies around the world. This has been a good thing. The feeling right now among the scientific community is that many countries need to coordinate and cooperate as the technology continues to advance. A great recent example of that is the report released on human genome editing that focuses specifically on germline editing and called for several criteria to be applied for anyone that wanted to use CRISPR in human embryos.
You have an eminent academic career, but you have also cofounded and are very active in several biotech startup companies. How has this influenced or maybe changed your perspective on research and how you approach what you do, and what you might do in the future?
Great question. I’ve become much more appreciative of the kinds of bottlenecks that projects face in a practical sense, that have less to do with the science per say, and a lot more to do with the direction of technology development; the regulatory challenges ones might face and the legal issues with getting freedom to operate. And then the challenges of putting together the right team of people that are going to be able to advance a technology for a particular application. Those are things that I did not think about in the same way before I started to work directly with companies and be a founder myself in this space. It has been really exciting and fun.
My approach in terms of my involvement with these smaller companies has primarily been to enable former lab members of mine, many of them former graduate students, to be successful entrepreneurs. I get a lot of pleasure out of that. I am very proud of the work that these folks are doing. It is just amazing to see what they’ve been able to do.
I also think it’s the right thing for the field. It is relatively uncommon in biotech for scientific founders to become part of the management of a company, and yet I think that it is not unusual at all to see that in the tech world. There is a bit of a disconnect there, and I’m excited that maybe we are seeing a change in that regard. Especially recently with several biotech companies that are featuring scientists in their leadership teams that are quite successful.
You have talked about your excitement regarding the potential agricultural uses for CRISPR. What makes this particularly interesting for you, and how do you see pharmacrops impacting the future of our world?
The impact globally of CRISPR in the near term is probably more likely to come from applications in agriculture than in the clinic, just for practical reasons. We all need to eat and we all are dealing with climate change. These are two areas where CRISPR can have an almost immediate impact as it starts to be applied in various crops and other areas of agriculture.
There are so many exciting opportunities right now in that area that include being able to manipulate the genomes of plants in unprecedented ways—with a precision and speed that has not been possible previously. This is really, truly extraordinary. What I see right now in the agricultural sector with CRISPR is that it is almost like opening the door to a new world. There are so many things to do be done right now. I almost feel that that if I were starting my career as a scientist right now, I’d be very tempted to focus on agriculture because I think there are so many things to be done currently.
What part of the world might lead this effort?
It is hard to say. We have had a lot of interest from Argentina and Brazil in using and testing CRISPR in various agricultural settings. It has been unfortunately quelled by the current pandemic, but I am hoping we can resurrect those projects once it becomes possible to travel.
In the Bay Area of California where I work, there’s a lot of exciting agricultural work that goes on. I’m hopeful we will be able to have a center of some of this research right here. We have consortium of folks from USDA, universities in the area, and the National Laboratory that are currently working together through the Innovative Genomics Institute to use CRISPR in various agricultural settings. We just had an exciting workshop recently where we had a number of groups presenting their results and their data. There is a lot going on that is very exciting.
We are all excited about CRISPR, but could you share what was your best experiment or study besides CRISPR?
There have been a few, but one that comes to mind that is very relevant here is from when I was graduate student working in a lab where my professor, Jack Szostak, said to us students, “I’m very interested in the origin of life and figuring out how did life evolve to be what it is today.”
I can’t imagine a bigger or more important question in biology. It cuts to the heart of biological science. His genius was that he was able to take a question like that and turn it into practical projects that we could work on in the lab. What I was doing at that time was working on trying to test whether RNA molecules had the ability to replicate themselves in a controlled laboratory setting. The reason that was exciting was that it really got to the heart of how life might have evolved in the first place; that there might have been molecules—and one hypothesis was these might have been RNA molecules—that these could both encode genetic information but also do chemistry.
It was incredibly exciting, and we actually published a series of papers while I was a graduate student that showed that the answer was yes: that you could develop in the lab very simple RNA molecules that have the ability to synthesize copies of themselves. For me, that was the start of my love of RNA. I kind of never left. It set me on the path that eventually led me to CRISPR.
Who were key leadership figures or mentors throughout your career that have had a big impact on your development throughout your career?
It really comes down to a few people that were extremely influential. I have to start with my family. No one in my family was a scientist, but my father was very interested in science. His father had been a civil engineer. My father became a literature professor, but in his spare time he liked to read about science, including authors who wrote about biological sciences. He was very much encouraging of my interest in science when I was quite young. I had several influential teachers and professors, and then lab mentors later, who also encouraged my interest and importantly, helped build my confidence in science.
Something I learned from them is that, as a mentor, one of your important roles—maybe your most important role—is to build the confidence of your trainees so that they trust themselves and ask the right questions. And that is one of the hardest things to do in science. There are lots of experiments one could do, but there’s a relatively smaller number that are really worth doing. How do you make those decisions? That is challenging. But you can build trainees’ confidence over time to trust their judgement and build their confidence to decide: is this question worth going after?
What advice would you give to women who are young in their career?
Currently, there are still challenges and barriers to women in science. I have seen that more as I have gotten father along in my career. At a more senior level, there are not very many women who are CEOs of companies or sitting on boards of directors. And this is changing, but change takes time. I would say, one must appreciate that is the world we live in right now but also not to be daunted by that.
The path forward involves women doing science the way they feel comfortable doing it. Working your family and personal obligations into your professional life is one thing that is important. And confidence building. There is a tendency for women to talk themselves out of things. Advice I got from my dad and later from other mentors was to go for it. If you want that position or to apply for that fellowship, the only one willing to go to bat is yourself, so go for it.