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Home , Jennifer Doudna, Kavli Prize

Technology and Innovation, Vol. 20, pp. 475-482, 2019 ISSN 1949-821 • E-ISSN 1949-825X http:// Printed in the USA. All rights reserved. dx.doi.org/10.21300/20.4.2019.475 Copyright © 2019 National Academy of Inventors. www.technologyandinnovation.org

THE NAI FELLOW PROFILE: AN INTERVIEW WITH DR.

Jennifer A. Doudna1-7 and Kimberly A. Macuare8 1Department of Molecular and Cell , University of California, Berkeley, Berkeley, California, USA 2Department of Chemistry, University of California, Berkeley, Berkeley, California, USA 3California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, California, USA 4Innovative Genomics Institute, University of California, Berkeley, Berkeley, California, USA 5Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, California, USA 6MBIB Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA 7Gladstone Institutes, University of California, San Francisco, San Francisco, California, USA 8National Academy of Inventors, Tampa, FL, USA

In a recent interview with Technology and Innovation, Dr. Jennifer A. Doudna, pioneering biochemist and renowned research scientist, discusses the potentials and pitfalls of , the importance of diversity for pushing perspectives, and what Frankenstein might have to teach us about the boundaries of science.

INTRODUCTION This issue’s NAI Fellow Profile features the pio- neering biochemist and renowned research scientist Dr. Jennifer A. Doudna. After starting her career as a research fellow at the University of Colorado, Boulder, Doudna went on to serve as the Henry Ford II of Molecular Biophysics and at before joining the University of California, Berkeley, where she currently serves as a professor of biochemistry, biophysics, and struc- tural biology and is the Li Ka Shing Chancellor’s Chair in Biomedical and Health Sciences. In addi- tion, she heads the Innovative Genomics Institute and is a Howard Hughes Medical Institute Investigator. Doudna received her B.S. in chemistry from and her Ph.D. from in biochemistry. She is the author of over

(Photo courtesy of Jennifer A. Doudna) ______

Accepted: November 1, 2018. Address correspondence to Kimberly A. Macuare, Ph.D., Associate Editor, Technology and Innovation Journal of the National Academy of Inventors® at the USF Research Park, 3702 Spectrum Boulevard, Suite 165, Tampa, FL 33612. E-mail: [email protected]

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200 technical papers and inventor on 24 U.S. pat- stages, CRISPR genome editing promises a revolu- ents with more than 100 published applications. Her tion in our ability to treat everything from fungal pioneering contributions to the life sciences have crop diseases to human cancers. been recognized with numerous honors, including In a recent interview with Technology and fellowship in the National Academy of Inventors, Innovation (T&I), Dr. Jennifer A. Doudna discusses the American Academy of Arts and Sciences, and the potentials and pitfalls of genome editing, the the American Association for the Advancement importance of diversity for pushing perspectives, of Science as well as membership in the National and what Frankenstein might have to teach us about Academy of and National Academy of the boundaries of science. Sciences. Among her many prizes and recognitions, she has received the , the , and INTERVIEW the Medal of Honor of the . T&I: Please tell us a little bit about some of Early on in her career, Doudna became inter- the projects that you are working on currently. ested in RNA, specifically its catalytic activity. Her first efforts in this area were devoted to understand- Doudna: Well, I would say there are really two ing the structure and function of RNA, including major types of projects that we’re pursuing. One her breakthrough discovery revealing the defined is we’re hoping to understand more about the and organized structure of RNA molecules and her fundamental biology of CRISPR systems in na- important work on and how they perform ture. So, we want to know how it is that bacteria their -like roles. In addition to expanding use these kinds of pathways. As you may know, our understanding of these molecules, Doudna’s they evolved as viral defense mechanisms, but we work in this area has had important potential clini- also think they probably help bugs to talk to their cal applications, especially as regards and neighbors in an environment and help regulate other viruses, where her discoveries of how RNA genes, so we’re trying to figure out those pathways. is connected to the production of viral Of course, we’re very excited about opportunities may allow for the development of drugs that target to use genome editing for various applications. We this process and thus treat these conditions. Most have several partnerships with academic colleagues recently, Doudna’s work on RNA led to her work on who are clinically inclined working on two major CRISPR, which serves as a natural defense against focus areas: immune diseases and brain cancer. viral invasions in bacteria. This system evolved as an adaptive immune response in microbes. After T&I: Is this in partnership with clini- exposure to virus, the cell saves a memory of the cians who are working at your universi- viral DNA. —a DNA-cutting protein—patrols ty, or is this a cross-university partnership? the cell, carrying that memory around in the form of a guide RNA molecule. Upon the virus’ reappear- Doudna: This is actually people who work ance, Cas9 checks to see if its guide RNA matches at the University of California, San Fran- the viral DNA, and if it does, Cas9 cuts the DNA cisco, so our neighbors across the bay. in two. The CRISPR-Cas9 system thus eliminates the viral threat while leaving the bacterial cell’s own T&I: Obviously, everybody wants to talk about DNA untouched. Realizing the amazing potential, CRISPR and learn more, so let’s dig in here a little Doudna and fellow scientists showed that Cas9 could bit. What has the discovery of this method done for easily be programmed with a custom guide RNA and both the practice and the applications of genome directed to cut specific DNA sequences. This makes editing in terms of speed and efficacy as com- CRISPR-Cas9 a powerful genome editing tool that pared to the methods that were being used before? lets scientists change the genetic code of any organ- ism. This technology has already revolutionized the Doudna: It’s remarkable. I haven’t really experienced pace of biological discovery. While still in its early anything like this in my career—where a technology, THE NAI PROFILE 477 within just a few short years, has really transformed Doudna: Well, you mentioned one already, which is the kind of science that is going on across different the idea of engineering that would have areas of biology. an impact broadly in the environment. People have I’ll just give you a couple of examples. One of been very excited about the potential to use gene the things I hear quite frequently from colleagues drives, which are a way of using genome editing to who work with animals, and especially with mice, spread a genetic trait quickly through a population, is that it went from taking anywhere from a year or such as the population of mosquitoes or other kinds two, sometimes more than that, to engineer mouse of insects. I’m excited by the possibility of using it to strains that mimic genetic disease in humans so that control the spread of mosquito-borne disease, which they could be studied in the laboratory. Now, with is an amazing opportunity. At the same time, I think CRISPR-based genome editing, it takes a matter of we have to be careful about releasing organisms into four or five weeks. You get a sense of just how the the environment that might have unintended con- pace of science has ramped up incredibly with the sequences, either on their own populations or on ability to manipulate the genome. And this is true species that depend on them. I think that’s one area not just in animals but also in plants, so there are that requires thoughtful consideration. opportunities in plant biology to really understand Another is the potential for human germline edit- the underlying genetic causes of plant traits and sus- ing and the opportunities there. There are really grave ceptibilities to disease and things like that. risks and ethical challenges. We have already seen one It’s really exciting to see how the pace of research scientist in China forging ahead with this and rais- has opened up as well as the ways that people are ing a lot of questions about how to maintain control using genome editing and creative opportunities to over this technology in the future. explore the of organisms that in the past The third would be the tremendous opportunities, would have been intractable. It used to be the case— but potential risks, with using genome editing in agri- certainly when I was a graduate student and learning culture. It’s a great tool that is available now to plant about science and initially as a professional—that we biologists and geneticists for research purposes but were taught that there were just a few types of organ- also to create plants that are adapted better to their isms that most scientists would study because they environments or have other properties that might be were genetically tractable: things like fruit flies or desirable to humans. At the same time, we don’t want tiny worms called nematodes. Now those limitations to inadvertently do things that will introduce plants are taken away. Now people are studying butterflies that will be disruptive to the environment in some and they’re studying all kinds of human cells that way. I think it’s critical for scientists to be thinking come from cancer patients or really anybody else. deeply and engaging very actively in this discussion. For any individual, you can culture cells and study their genetics pretty easily, as well as all kinds of other T&I: In academia, scientific communication organisms that were previously not possible to inves- often means the production of papers for special- tigate. I think it gives you a sense of how the pace of ized journals or books that can be read by other research has increased tremendously since 2012. specialists. When you wrote A Crack in Creation, you were writing to a broader audience. Why T&I: All of that is really amazing, and this tech- was that an important project for you to do? nology is incredible. However, the flip side of that is you’ve also been one of the leading voices advo- Doudna: I was really excited to take that on because cating for a cautious approach to utilizing this tool. I was feeling very strongly that there needed to be a Just this morning, there was a story on NPR about more open and active discussion about genome edit- the creation of mosquitos modified with this tool to ing, not just among scientists and practitioners but quickly spread a lethal mutation—something that also the general public. These are people who are going could have broad impacts. What are the potential to be impacted in the future by the use of genome pitfalls of moving ahead without being cautious? editing, whether it’s in a doctor’s office or the food 478 DOUDNA they might be purchasing at the store or growing in clearly weren’t sufficient to deter its initial use in their gardens. There are also the kinds of insects that embryos that was announced last November. I think they might encounter or any other creatures environ- we’re now at a point where we need more than that. mentally who could be impacted by genome editing. We really need to have very clear requirements for So, I was passionate about working on that project, anyone in the future who would want to do such a and, frankly, it wouldn’t have happened without my thing. The key question is how does one ever enforce coauthor Sam Sternberg, who was a former gradu- such a thing given that science is global and differ- ate student of mine and a terrific scientist who’s now ent countries have different types of restrictions on running his own lab at . After he scientific work. I think that an important way to do finished his Ph.D., he decided that he wanted to take that is to engage not only governments and regula- a year off and really focus his energies on scientific tory agencies, and of course the scientific community writing, namely writing a book that would be for the as well as a lot of the leadership of science in differ- general public about our experience with CRISPR in ent countries, but also scientific journals. We should our lab and where we felt that the technology is going. ensure that journals, journal editors, and the folks I won’t sugarcoat it. It was a hard project for sure. who review journal articles are also aware of these Sam and I had many moments when we would call requirements so that there’s a very clear dedication on the other and say, “This is never happening.” Both the part of those scholarly outlets to not publicize and of us felt very happy that we had sort of fought our publish work that has been conducted unethically. way through the challenges of writing that book and working with a wonderful editor at Houghton Mifflin T&I: You described yourself as a scientist who is to get it out there. The reception overall has been choosing from the buffet of all science has to offer quite good, and I still receive almost daily emails instead of somebody who deeply digs in just one area from people who’ve read the book and have enjoyed the whole time. In your role as a mentor and a pro- it or had questions they wanted to follow up on. That fessor, is that something that you are trying to pass makes me feel happy that I spent the time doing it. on to your students? Do you encourage them to look for those intersections or to take 20% time in the lab T&I: In addition to getting educated about to work on their own projects or things that are going genome editing, what are some other steps to lead them to some kind of unexpected discoveries? that we can take in order to regulate the way that this technology is going to be employed? Doudna: I don’t think I actively do that. I don’t sit down with people in my office and outline it in so Doudna: A couple of personal things that are in the many words. I do think that I set that example for works currently include putting together an interna- them, and I certainly encourage people in my lab to tional forum of experts to review the current state be thinking broadly about their research projects. of the science and applications of genome editing I’ll give you a couple of quick examples. At our and put forward not only what I would call guide- last annual laboratory retreat, we had every single lines for ethical or responsible use, but I would say member of the laboratory give a short talk, but the something like requirements. We’ve created a set of instruction was not to talk about your project, not to guidelines that will form the basis for possible gov- talk about anything that has to do with what you’re ernment regulations or even legislation. I think it’s actually researching in the lab, but to tell us about important that happens because I do feel what’s hap- something else. Tell us about a new idea that you pened up until now is that only the scientific societies have, about an interesting paper you have read that have been involved in this discussion. For exam- stimulated an idea, or just something you think is ple, as you may know, the National Academies of interesting. That is what we want to hear about. It Science put out a report almost two years ago that put was really great. I think everybody really enjoyed it. forward a set of guidelines for use of genome edit- It was very stimulating, and it sort of helped us all get ing, especially in human embryos; however, these those blinders off that we all have and start thinking THE NAI PROFILE 479 about other questions or problems that are interest- As you can imagine, when you have that kind of a ing that we might not be working on currently but melting pot, you really have minds and people who would be fun to pursue. The other thing is that I are united in their intellectual interests. They come also really encourage people in my lab to collaborate from all kinds of backgrounds. They have all sorts both internally in the lab with their coworkers and of perspectives and interests. It just brings a won- outside of the lab with other scientists. We actively derful diversity to our work. I think that the more look for opportunities to work with people who have we can encourage that kind of a diverse set of peo- complementary expertise that are either experts in a ple who are pursuing science as a career, the better. technique that isn’t typically used in our lab or work on a system that we’re not currently studying and T&I: Your early education included broad reading don’t have expertise to work on. We encourage those across disciplines. Given the fact that you grew up kinds of partnerships because I’ve continually found with two humanities in your house, what that’s where a lot of the most interesting and creative are your thoughts on the value that STEM and the discoveries come from: those interfaces between two humanities have for each other? Has your practice of different areas of science. science been informed in any way by the humanities?

Doudna: Absolutely. My practice has been informed by the humanities. You know my father was an English professor and a lover of books. He loved stories of all kinds, and he actually loved science. He read a lot of books by people like Lewis Thomas and John McPhee and others who wrote about scientific subjects. He often enjoyed debating ideas from those books with me or basically anybody else who would listen and talk to him about it. He gave me a copy of Strunk and White when I graduated from college and told me, “This is most important for you for the (Photo courtesy of Jennifer A. Doudna) next two years; it is to really guide you as a writer because no matter what you do, being a good writer T&I: On your lab’s “About Us” page, you have is going to be key.” Boy, was he right. a really direct statement about diversity and its Those are very practical ways that the humanities value, specifically that the more reflective of have influenced me. I would say that, on a broader society’s diversity the lab is, the better you are. level, I find that this is what’s so fascinating about Could you elaborate a little bit on the value of the whole CRISPR field now. The idea and the con- diversity for producing innovative outcomes? cept of genome editing goes far beyond the science. It actually goes into the humanities. It goes into history. Doudna: I’m a big believer in that. I’ve seen this We’re getting into a philosophy and all of the societal over and over again in my career so far. People who sociology. What happens when you have a technology come to research or to the laboratory as scholars like this that takes off very rapidly and the science is from diverse backgrounds bring a perspective to moving faster than people’s conception of it or under- their work that wouldn’t be attainable in any other standing of what it means for our future as humans? way. I’ve seen so many examples of it. I work at a I do find myself referring to a lot of writing. One fabulous public university in California where we great example last year was actually Mary Shelley’s have people coming to our campus from all over Frankenstein and the 200th anniversary of the book. the world. They come from Asia, they come from There was a lot of discussion about this in the media, South America, they come from Europe, they come but also the San Francisco Ballet did a ballet version, from Africa, and they come from all over the U.S. and I took my son to see it. That led us to talk about 480 DOUDNA the story and think about what it means in terms it was really wonderful to see young women who are of what’s happening today, not only with genome looking up to me, but, of course, also to many other editing but also with artificial intelligence. People women who are ahead of them in their careers and are grappling with the ability to do certain things seeing all of the opportunities available. I know that that might have very profound impacts in the future. that meant a lot to me when I was at that stage as well; I had some really important role models.” Perhaps T&I: On a final note, you have been honored by the even more importantly, she serves not just as an aca- National Academy of Inventors, National Academy of demic model but a model for real life, which, as she Science, National Academy of Medicine, Japan Prize, acknowledges, includes more than just science. As etc. You are just an engine of productivity. What keeps she notes, “We all research and try to balance it with you motivated to keep doing all of this? What keeps all the other things that one does in life, including you going back to the lab? Back to the classroom? being a daughter, sister, mother, wife, partner, etc.” As a successful scientist, a respected professor, and Doudna: You know, I think it’s the people that I work as a partner and mother, Doudna has become a role with every day. I just have the pleasure of working model on many levels, and, as she acknowledges, with remarkable people who are stimulating in every “That’s a role that I now see myself playing, and I’m way and keep me on my toes intellectually. They really honored to do it.” keep me honest, and I think it’s that coupled with just the continual curiosity about nature and want- FURTHER READING ing to know more. The further I go in my career, 1. Chen JS, Ma E, Harrington LB, Da Costa the more I realize I don’t know how many questions M, Tian X, Palefsky JM, Doudna JA. are still out there. For me, it really always comes CRISPR-Cas12a target binding unleashes down to thinking about the science, thinking about indiscriminate single-stranded DNase activ- the next question that we want to answer in the lab ity. Science. 2018;360(6387):436-439. as well as the broader implications of what we’re 2. Chen JS, Dagdas YS, Kleinstiver BP, Welch MM, doing. It’s just an incredible joy to have that oppor- Sousa AA, Harrington LB, Sternberg SH, Joung tunity to both do the research and then participate JK, Yildiz A, Doudna JA. Enhanced proofread- in thinking about how it will be used in the future. ing governs CRISPR-Cas9 targeting accuracy. Nature. 2017;550:407-410. CONCLUSION 3. Sternberg SH, Redding S, Jinek M, Greene EC, Despite the amazing success she has achieved, Doudna JA. DNA interrogation by the CRISPR Doudna is remarkably humble and very cognizant RNA-guided endonuclease Cas9. Nature. of her place in the line of scientists who have come 2014;507(7490):62-67. before her and those who are coming up behind 4. Jinek M, East A, Cheng A, Lin S, Ma E, Doudna her. This was especially clear when the conversa- JA. RNA-programmed genome editing in tion turned to her status as a role model for women human cells. Elife. https://elifesciences.org/ in science. When asked if she embraced her status articles/00471. as an exemplar, she says, “I’m so honored; I can’t tell 5. Jinek M, Chylinski K, Fonfara I, Hauer you how it just really catches me, and I have to pinch M, Doudna JA, Charpentier E. A pro- myself. I still think of myself as that struggling stu- grammable dual-RNA-guided DNA dent at some level. It just never kind of leaves you, endonuclease in adaptive bacterial immunity. and it’s probably a good thing.” This ability to remem- Science. 2012;337(6096):816-821. ber what it is like to be a young student allows her to 6. Jinek M, Doudna JA. A three-dimensional view empathize with students, such as the sophomores in of the molecular machinery of RNA interfer- the undergraduate course she taught this spring, sev- ence. Nature. 2009;457(7228):405-412. eral of whom invited her to speak at their sorority 7. MacRae IJ, Zhou K, Li F, Repic A, Brooks AN, speaker series. Doudna recalls, “I was so touched, and Cande WZ, Adams PD, Doudna JA. Structural THE NAI PROFILE 481

basis for double-stranded RNA processing by Dicer. Science. 2006;311(5758):195-198. 8. Batey RT, Rambo R, Doudna JA. Tertiary motifs in RNA structure and folding. Angew Chem Int Ed Engl. 1999;38(16):2327-2343. 9. Cate JH, Gooding A, Podell E, Zhou K, Golden B, Kundrot C, Cech TR, Doudna JA. Crystal structure of a group I domain: principles of RNA packing. Science. 1996;273(5282):1678-1685. 10. Ferré-D’Amaré AR, Zhou K, Doudna JA. Crystal structure of a hepatitis delta virus ribozyme. Nature. 1998;395(6702):567-574.