Jennifer Doudna PhD, the UC Berkeley biochemist who shared the 2020 Nobel Prize in Chemistry with Emmanuelle Charpentier PhD, was the recent guest of honor for the final episode in the “Women in Science” web series, co-organized by GEN and the Rosalind Franklin Society.
The full video in the Women in Science series can be seen here.
In 2012, the Doudna and Charpentier labs teamed up to publish a landmark paper in which they adapted the CRISPR microbial anti-viral defense system to create a programmable method for genome targeting. The work laid the foundation for CRISPR genome editing, which has become not only a ubiquitous research tool but also applied in clinical gene therapy, diagnostics, agriculture, and many other applications.
In the Women in Science webinar, which originally aired on November 20, 2020, Doudna was joined by several friends and former colleagues, including Martin Jínek PhD (University of Zurich, Switzerland), Dipali Sashital, PhD (Iowa State University), Samuel Sternberg, PhD (Columbia University), Blake Wiedenheft, PhD (Montana State University), Ross Wilson, PhD (Innovative Genomics Institute), and Rodolphe Barrangou, PhD (North Carolina State University; Editor-in-Chief, The CRISPR Journal). Also participating were GEN chief editor John Sterling, Kevin Davies, PhD (GEN/CRISPR Journal), and Karla Shepard Rubinger (Rosalind Franklin Society).
Doudna discussed a broad range of topics, including how to celebrate a Nobel Prize in a pandemic, what the award means for women in science, her views on mentorship, and her decision earlier this year to launch a high-throughput COVID-19 diagnostic lab. (The interview has been lightly edited for length and clarity.)
GEN: Congratulations on the 2020 Nobel Prize for Chemistry. You got the traditional, early-morning wakeup call, but not from Sweden. It was from a reporter?
Doudna: It was from a reporter! How embarrassing, that I miss an important call like that, but that’s what happened. I did get a call from Heidi Ledford at Nature who popped the question. It was quite a moment.
GEN: So, what’s happening with the actual ceremony? It looks like it’s going to be a virtual ceremony this year, which is a part of a damper on it, but hopefully they’re going to make up for it somehow.
Doudna: Well, yes and no. I think the interesting silver lining is that probably means a lot more people can participate, that would normally be the case. I think that’s what we found this year. I think many of us who have been to scientific meetings virtually, we’re finding that there’s just a lot more participation, because of the zoom format.
But you’re right, that’s how it’s happening and all of the Nobel lectures have already been recorded and they’re going to be broadcast on December 8 along with a small, sort of celebratory ceremony in Stockholm.
GEN: Your Nobel Prize is seen as an important moment for women in science. Following the award, Emmanuelle Charpentier said, “I think it’s very important for women to see a clear path. The fact that Jennifer and I were awarded the prize today can provide a very strong message for young girls.” What lasting message do you think that awards can send?
Doudna: Both Emmanuelle and I felt proud of our gender that morning and just happy that we were sending a message collectively to girls and others who have felt excluded from the STEM fields that their work can be recognized. There’s a celebratory feeling about science, no matter where it’s done, or where it comes from. I think that’s a really important message, especially this particular award.
GEN: A year before you met Emmanuelle (in 2011), you actually left UC Berkeley to take a senior position at Genentech. Without the awakening of your return to Berkeley, CRISPR’s history might have been different. Can you talk a little bit about that awakening?
Doudna: It was a very interesting experience because I had an opportunity to join one of the best biotech companies that is famous for its fundamental discovery research. That was a very exciting opportunity for me and I embraced that opportunity. However, once I actually got into the company itself, I realized that I missed my Berkeley colleagues and I really missed the kind of discovery science that we almost take for granted—or at least I’d come to take for granted in the university environment. Very kindly, my colleagues at Berkeley were happy to welcome me back. The lab hadn’t physically moved at the time, so it was easy to go back fairly quickly. My colleagues at Genentech were also understanding. I think many of them had come from academic backgrounds, so they understood the challenges of making that cultural shift.
GEN: Back in 2011 you were already a highly accomplished researcher fielding numerous offers to collaborate. What was it that you saw in Emmanuelle when you first met her that set the stage for your transatlantic collaboration?
Doudna: I loved her sense of adventure, her desire to understand the secrets of the CRISPR pathway. I think that was very, very interesting. We both shared that passion, but we were coming to it from different backgrounds, and I think that really made for a very interesting and exciting collaborative opportunity.
I’ve been involved in almost countless collaborations now over my 26 years of running a lab. And I’d say at least half of them fizzle—they don’t really go anywhere. So, it really speaks to the fact that Emmanuelle and I shared a vision for what we wanted to do together scientifically. [Credit also] to the folks in our labs—Martin Jínek and Krzysztof Chylinski in particular—who were able to forge very quickly a scientific connection across thousands of miles and start doing science together.
GEN: Have you had a chance to speak to Emmanuelle in the past few weeks to compare notes and share congratulations with each other?
Doudna: Yes, a couple of times. She’s been in the same whirlwind that I’ve been in. It’s been really fun to celebrate the science that we did together and discuss what this award means, and how it will be viewed, especially by other up-and-coming scientists.
GEN: The big project that’s dominated your life this year, of course, is COVID-19. What prompted you to take matters in your own hands and get this important COVID-19 testing facility off the ground on your campus?
Doudna: I’m a strong believer that science needs to be needs to be proactive as well as reactive. As scientists, we need to be ready to pivot our expertise where it’s needed. And boy, what a a case-in-point with COVID! Back in March, like many of us, I had the growing feeling that life was about to change. Maybe dramatically. With a group of colleagues at Berkeley. I was astounded at the responses to put together a small meeting that ended up being 60 people. We got together, mostly virtually, to talk about what we could do scientifically as scientists to address this pandemic. Everybody unanimously said the most important immediate thing we can do is set up a test.
None of us had any idea how to run a clinical laboratory, but we figured it out. We got that lab going in three weeks, and now we’re actually doing all of the testing for the UC Berkeley campus, as well as with several important community partners. I’m really proud of the team. It’s been an extraordinary journey. We went from running the lab with volunteer students and postdocs. Initially we did all the R&D to get the test up and running to now a whole professional team including an MD, who runs the clinical aspect of the work that we do.
GEN: Most people know that you co-founded Mammoth Biosciences, which is developing CRISPR diagnostic tests. Are you optimistic that CRISPR technology will eventually be able to provide an at-home test if not for this pandemic, then for the next one?
Doudna: Well, at home is going to be tough. Initially I’m seeing a lot of effort to develop CRISPR as a point-of-care test that would be able to provide real-time surveillance testing. And that’s something that I think is very likely to happen during the current pandemic. It’s pretty clear that we’re going to need robust and widespread testing for at least the next several months, if not longer, for COVID-19 and then obviously having the ability to take a test like CRISPR, which is programmable, and then targeted to other viruses, it will be very valuable for pandemic preparedness in the future.
GEN: What turned you to science growing up in Hawaii that has carried you through all these years to where you are now?
Doudna: It was a combination of things. I grew up in an intellectual family. Nobody was a scientist, but my father loved doing puzzles and reading and talking about science. So we did a lot of that, even though nobody was practicing it professionally.
I loved math. I was highly influenced also by that island environment—being aware of all the plants and animals that evolve in that environment. I couldn’t help wondering how does that work? I’ve always been driven by those how questions, wanting to understand in molecular detail what we observe in biology.
GEN: What’s your advice to women who want to excel in basic science or biotechnology and come from developing countries where there is less science and opportunity. Could they dream of being awarded a Nobel Prize?
Doudna: Absolutely! My experience certainly has been that the people I see who are most successful in science tend to be those who are just laser-focused on their passions—they don’t let anyone dissuade them from what they want to do. People here know I have a stubborn streak. I think that’s sometimes been a strength In science to be absolutely committed to an idea that you have and pursuing it to see if it’ll pan out or not.
I can think of a number of times in my career when that’s been true for me before CRISPR came along. There were questions I had about biological system that I wanted to answer and there were plenty of naysayers saying that’s either a silly idea or that will never work. I did it anyway. I wasn’t always right, but at least I satisfied my question and my passion.
GEN: We talked about the scientific and medical implications of CRISPR but what are the ethical limitations?
Doudna: It’s a very interesting challenge we have right now in this field, because the technology clearly opens the door to many opportunities that include applications in the environment, in agriculture, and of course in medicine that are very exciting, but also brings important questions and challenges.
Ultimately, we’re all affected, but I do think the scientific community in particular needs to step up. I’ve been quite pleased that we’ve really seen that across the spectrum of applications for CRISPR. It’s an ongoing challenge to keep that conversation going and to keep the transparency going. Earlier we talked about international collaboration—that is absolutely critical in terms of managing the use of a technology like CRISPR. It is non-trivial to achieve that kind of cooperation but essential to work at it.
GEN: When did it hit you that CRISPR was going to be a real life-altering world changing technology, not just you and your lab? Was there a moment in time where you realized it was bigger than you thought?
Doudna: We could see that there was a lot of really interesting biochemical activity of this CRISPR-Cas9 protein as an RNA-guided DNA cutter. But for us, the pivotal moment of the project going from a pure curiosity-driven investigation to something that we could see would have much bigger, broader implications was when we were in my office talking about Martin’s [Jínek] biochemical data defining the essential components of the Cas9 DNA-targeting mechanism, especially on the RNA side. That led to the idea that the RNA molecules could be combined into a single-guide format that we thought was really cool and fun. Wow, we understand enough about this to be able to redesign it! And beyond that it would also create a much simpler, two-component system for DNA cutting that would be programmable.
Thinking of my graduate work in the 1980s, I was imagining the New England Biolabs catalogue of all of the available restriction enzymes being compressed into one protein that could be trivially reprogrammed with its RNA guide. It was a profound idea. Going on in the context of all the other work that was beyond our lab, both on DNA repair and on genome engineering with engineered proteins, all the pieces started to come together and I think that was really that proverbial moment.
GEN: What’s your version of [Rosalind Franklin’s] Photograph 51?
Doudna: I think if there is a Photo 51 in my mind, it would be this slide I still show in talks because I love the data. It was one of the experiments Martin did where he designed five different single-guide RNAs that would target parts of a plasmid sequence. He did in a way the simplest experiment in molecular biology of cutting that plasmid DNA with these different single-guide RNA-programmed Cas9 complexes and a separate enzyme to chop out these pieces of DNA. And this beautiful agarose gel shows all of these DNA fragments of different sizes, corresponding to where the guide RNA’s cutting. It just encapsulates what this protein is capable of doing.
GEN: What are some of your big hopes for the technology, not just from your lab, but from the international community that’s using your technology?
Doudna: Certainly thinking about how the technology will be deployed and how it will actually have impact around the world is something that lots of people are thinking about. What really keeps me up at night right now is the idea that we, as a field, need to go from the proof of principle to increasingly thinking about how we actually make the technology widely available to people that need it.
A great example of this is the work that’s been done with sickle-cell disease, a monogenic disorder that CRISPR is perfectly suited to treat or even cure by making corrections to or changes to a specific gene that could mitigate the disease phenotype in affected patients. In fact, that’s been done now by a company called CRISPR Therapeutics, which Emmanuelle co-founded, and other groups are working on this. The question we ask ourselves is how do we ensure that a technology that clearly works for a disease like that, which is extraordinary and very exciting, becomes affordable and available to those that need it right now.
That CRISPR therapy is going to be north of $1 million per patient, which is just not sustainable. So at the Innovative Genomics Institute, where we’re working at UC Berkeley and UCSF, this is front and center in our minds. We’re working on different ways of delivering the CRISPR molecules, coming up with strategies that will avoid having to use a bone marrow transplant for these patients, for example, as well as investigating new CRISPR enzymes that are potentially going to be easier to deliver because they are either smaller or have other advantages in their chemistry that make them easier to get into particular cell types or tissues. So that’s one of the big areas that I am focused on at the moment.
GEN: And what’s going on in your own lab that’s really exciting right now?
Doudna: We’re doing a lot of work currently with Jill Banfield PhD, at Berkeley. She is the person who told me about CRISPR originally and continues to work on the discovery of new CRISPR systems in various microbial communities.
In addition to that discovery work, we’re also very excited about being able to manipulate the genomes of communities of bacteria. This is something that I’ve talked a lot to Sam Sternberg about and he’s also very interested in this. I think this is a very exciting direction for the future because if it were possible to manipulate microbes of specific organisms within their natural communities, whether it’s the human gut, soil, water, or environmental niches, this will absolutely change the way microbiological research is done, where it’s not necessary to cultivate individual organisms in laboratories to study them, but you can actually do investigations or even manipulations in a natural setting. I think that’s very exciting.