‘The Joy of the Discovery’: An Interview with Jennifer Doudna

In August 2012, University of California, Berkeley biochemist Jennifer Doudna and colleagues published an article in the journal Science titled “A Programmable Dual-RNA—Guided DNA Endonuclease in Adaptive Bacterial Immunity.” Though the paper’s title was dry, its impact was revolutionary. In it, Doudna announced that her research group had discovered a simple method for editing genes. An enzyme found in bacteria known as CRISPR–Cas9 could be programmed, she reported, to search out and destroy specific genes.

“Our study reveals a family of endonucleases that use dual-RNAs for site-specific DNA cleavage and highlights the potential to exploit the system for RNA-programmable genome editing,” she and her colleagues reported. This—the most significant biological discovery since the double helix—changed everything. 

It certainly changed everything for Jennifer Doudna. Since 2012, she has received just about every significant science award short of a Nobel prize: a Kavli, a Gruber, the Japan prize, and a Howard Hughes Medical Institute investigator award. On the darker side, the researcher also found herself embroiled in a four-year long patent dispute. At stake are tens of millions of dollars in licensing fees for CRISPR–Cas9.

The acrimony surrounding that dispute, however, seemed like a distant battle on a recent evening at New York’s Rockefeller University. Doudna, who is fifty-four, had flown in from California to receive another honor. This time, it was the Pearl Meister Greengard Prize, established by Nobel Laureate Paul Greengard and his wife, the artist Ursula von Rydingsvard, to give recognition to women scientists. (The prize is named for Dr. Greengard’s mother, who died giving birth to him.)

We spoke for two hours before the award ceremony. “That there even is a prize like this one,” Doudna said, “is a sign that people are really beginning to value the contributions of women to science.” An edited and condensed version of the interview follows.

Claudia Dreifus: Where did you grow up?

Jennifer Doudna: Hawaii. I grew up in a small town, Hilo. We were one of the few Caucasian families there in the 1970s, and I certainly felt like a different animal from everybody else in my school.

My formative experience was trying to figure out who I was in the world and how to fit in in some way. I spent a lot of time reading. I can remember lying on my bed a lot, just kind of thinking and wondering about how things worked, especially nature and why the animals and plants in Hilo had evolved the way they had.

How was it that your family lived in Hilo?

Well, my father was a literature professor at the University of Hawaii. He loved reading popular books about science. It was he who gave me Jim Watson’s The Double Helix. That was one of the early ways I got exposed to the kind of science I’d be eventually doing. I thought: “Scientists can really do this? They can do experiments and find out the structure of molecules? Wow.” The book was mind-blowing.

The other thing was that it showed the human side of science, the conflicts, the collaborations. These were aspects of science I had no idea about because the science textbooks we had in school were very dry. Jim Watson’s book was a different vision.

It certainly was. The Double Helix is infamous for Watson’s sexist descriptions of the x-ray crystallographer Rosalind Franklin.

He calls her “Rosy.”

Yes, and he also describes her as neurotic,  uppity, and, in his opinion, unattractive. Watson, as we know, used Franklin’s breakthrough photograph from her London laboratory to solidify his ideas about the double helix. Some researchers have claimed that Franklin’s image was shown to him without her permission. What did you—a young woman interested in science—think as you read Watson’s literary negation of a female scientific peer?

You know, when I first read that, I was too young to understand what goes on in the world. Later, I learned about Rosalind Franklin and how amazing she was and how, in many ways, she was a victim of her time and gender. But my first reaction to The Double Helix was to be fascinated with these people.

I guess, though, I must have internalized some of it because for many years I absolutely did not want to be seen as a “woman” scientist. I did not want to be seen as anything other than how good my ideas were. In school, I stayed away from organizations for women in science. I’m sort of embarrassed to say that now.

And yet, I read somewhere that for a long time, you suffered from “impostor syndrome,” a feeling that you didn’t quite belong at the top tier of the scientific world. Feeling like an impostor is common among women and minority group members working in professions where they’ve long been excluded. Did you ever get over that?

No [laughs]. That’s, at some level, always in the back of my mind. I came from a comparatively humble background. Both my parents were teachers. I didn’t feel in any way special when I was growing up. Nobody said, “you’re gifted,” or “you are going to go far.” It was assumed I’d go to college, but it wasn’t expected that I’d have a particular career, or certainly not this one.

On the other hand, my father really respected my intellect. When I told my father I wanted to go to graduate school, he didn’t even blink. When I told him that I might apply to Harvard, among other places, I asked, “Should I? I’ll never get in.” And he said, “You’ll certainly never get in if you don’t apply.”

And I got in! I was completely shocked.

At Harvard, you were able to work in the laboratory of Jack Szostak, who was later a co-recipient of a Nobel prize for research into the biochemistry of telomeres. Was he a kind of substitute father for you?

I think that’s fair. He’s very different from my Dad, but he respected my intellect. Here I was, in my early twenties, and this brilliant scientist would occasionally come to me and discuss an experiment: “Do you think this is a good idea?” And I was, like, “Why is he asking me?” And I think that the kind of interactions we had helped me enormously. I thought, “If this brilliant scientist respects my intellect, maybe it’s something worth respecting.”

In the scientific community, the word about you is that you have a special talent for asking the right questions of nature and designing experiments that will answer them. Is a good nose one of the elements of a successful scientific career?

I think so. I remember when I was in graduate school, thinking about my adviser, Jack Szostak. I wondered, what made him a great scientist? And the thing that stood out for me was his incredible ability to pick the right problems and go after the right questions.

I don’t know where it comes from. It’s just sort of a sense that one has.

How did this crazy idea to use the immune system of certain bacteria, CRISPR, as a tool to edit genes first come to you?

That goes back to my studies with Jack Szostak. His interest was the origins of life. Once I had my own lab, I often went back to questions like: “Who are we, where did we come from, why is biology the way it is, and how did it evolve this way?”  

In that mode, in the early 2000s, I was studying RNA molecules (thought to be the transmitter of information in early life forms means by which genetic information was transferred). I wondered how bacteria, single-celled organisms, might have produced, over eons, an RNA-guided adaptive immune system.

When I began the research, I wasn’t thinking about gene-editing. I was thinking about the three domains of life—of which bacteria are one. I thought that bacteria might be able to tell us something about why we all had evolved the way they have. I wondered about the immune systems of bacteria and how they worked. And then, around 2006, a colleague at Berkeley named Jillian Banfield told me that there were curious repetitive sequences in the DNA of bacteria that included the DNA of viruses. She wondered if this was some kind of bacterial immune system. That was a key moment.

How did studying the properties of bacterial RNA lead to a revolutionary technique for editing genes in animals and plants?

It’s a long story that unfolded in several stages. The first was probably in 2011 when I had a conversation with Emmanuelle Charpentier, then of Umeå University in Sweden.

This was at a professional meeting in Puerto Rico. We’d both given papers and we had a coffee, and she talked about this adaptive immune system in a bacterium she was studying. This bacterium had a single CRISPR-associated protein that protected bacterial cells from viruses—it would later be called CRISPR–Cas9. I wondered how this single protein achieved that.

In 2011, there were just a few labs studying these CRISPR systems. Mine was one. The systems people were studying required multiple proteins to create a functional immune system. What Emmanuelle was describing was a single protein that somehow provided adaptable protection against different viruses.

I realized that this was quite different from the systems I’d been studying. And that was very exciting. You had a single protein to do something that in other bacteria required many proteins, and it somehow used an RNA-guided mechanism. Wow. I wanted to learn more.

Right then, we talked of working together to figure out how this Cas9 protein worked. I could feel the hairs on my neck kind of standing up because I felt that there was something mysterious and deep about this project.

The second key moment was also in 2011 in my lab. Martin Jinek, my postdoc then, was testing what it might take for the Cas9 protein to work as a DNA cleaver. We’d already done experiments that had shown Cas9 finding DNA molecules and cutting them up. So now Martin wanted see if he could change the RNA molecules used as address codes for Cas9 so that he could send them to specific sequences on the genome. The question was: Could we program Cas9 to find and cut any sequence of DNA?

And we did! In an experiment, Martin discovered that you could give Cas9 an engineered RNA molecule that would direct it toward specific DNA segments and make a cut. Such cuts can trigger DNA-editing in animal and plant cells.

When that happened, I thought, “Holy smokes. This is incredible.”

So, in that moment, you saw that this technique could alter genes and thus gave modern science the chance to re-engineer evolution?

I didn’t say those words to myself. I thought that we now had found a different way to induce changes in genomes because you could easily direct this protein to any place in the genome and it would trigger a change.

Your discovery means that, among other things, the world now has the means to eliminate many genetically related diseases.

Well, potentially. On the horizon, we’re on the verge of solving sickle-cell anemia and muscular dystrophy. In animals, these diseases have been cured through gene-editing. Those are the positive possibilities. On the other hand, there could be a North Korea trying to create a race of humans who fit into their system. But I’m not worried about that happening in my lifetime. That’s far away.

I’m told you’ve had bad dreams about the downside of your discovery.

Yes. There’s one in particular that haunts me. This dream came early on. I had been thinking a lot about the profound tool that genome-editing is, about all of the wonderful things that it enables—cures for genetic diseases and conditions, an increased food supply. But it also brings the potential for eugenics, for state-sponsored alteration of human beings. You even can imagine creating new species of humans.

I’m not talking about immediately. But somehow, these ideas are not so crazy, right? So, one night, I dreamed that a colleague said, “I need to introduce you to someone.” This man turned around and it was Hitler. But you know, the dream really brought home to me the profound nature of what we were doing.

It was one of the things that encouraged me to come out of the lab and start talking about it more openly. I thought, “the only hope for controlling this is to be transparent about it. You want to be alerting everyone to what this is.”

This inevitably brings up a Frankenstein question. In the novel, Dr. Frankenstein feels a lot of regret about having created his monster. Do you relate to that?

Yes! Well, I relate to the issue in the book. But I don’t relate to it personally. The story, it’s a wonderful reflection of someone who has done something he was passionate to do, only to realize that it had repercussions that maybe he couldn’t have anticipated.  

I don’t have any regrets about the science we’ve done. I think that I would regret  not being vocally involved in advocating for the responsible use of it.

Many bioethicists are worried, though. The National Academies of Sciences in the US has urged scientists worldwide to move carefully on how they deploy the technology. What is your take on what seems to be a global rush to embrace CRISPR?

My take is twofold. I think there is a lot of potentially interesting work that can be done in very early human embryos to uncover the genetic basis for early human development. Many questions about human embryo genesis have gone unanswered because, until CRISPR, it hasn’t been possible to manipulate the genes involved. Under appropriate guidelines, there’s value in doing that work.

The flip side is the desire in some areas to rush forward to change human embryos and implant them for actual reproductive use. We have to ask if there’s really a medical need for that and if the technology is safe enough to offer to people.

Some of your fears are materializing already. In November, Dr. He Jiankui of Shenzhen, China, gave a press conference in Hong Kong at which he claimed to have used CRISPR to revise the genetic code of twin embryos implanted into a Chinese woman. Do you worry about how easy the technology is to use and how it provides an opening to entrepreneurs seeking to make a quick reputation for themselves?

Dr. He’s announcement underscored the necessity for international cooperation to ensure responsible use.

We must ask you about the intellectual property controversies surrounding CRISPR. Though you and your University of California team were the first to publish news of the discovery, and while your patent application was still pending, a research group headed by Feng Zhang and based at the Broad Institute, MIT, and Harvard filed multiple CRISPR patent applications of their own. Some have suggested that this patent fight is a modern redux of the Rosalind Franklin story. Do you think so?    

People know when papers were published and who wrote them. You can’t change the reality that Emmanuelle and I published our paper in 2012. There we made a very clear prediction and description of how this would be useful for genome editing. I think arguably that our paper really set off the subsequent work done in many other labs—including those at Harvard and MIT, who actually cited our paper in their own publications in 2013.

Originally, the patent fight was framed around who invented it first. I thought they weren’t going have an easy time winning that argument. More recently, it’s been framed around: Was our technology enabling in the sense that it was envisioned to be the kind of genome-editing tool that it became? Part of the fight has circled around quotes that I made to reporters in the early days where I said that I didn’t know for certain that this would work.

I think the whole patent fight has been such an unfortunate aspect of this whole experience. Because it exemplifies, for me, the worst of scientists and non-collegiality.

How have you dealt with it?

You know, when things like that happen, I always go back to my roots in Hawaii. I had very tough times there. I looked different from everyone else. Children can be so cruel. I didn’t have many friends. I had to build up an internal voice that I would come back to. I told myself then, “There’s an internal part of me they’ll never touch.”

The truth is that no one can ever take away from me the joy of the actual discovery. No one can take away those moments in the lab when we saw something in nature that had never been seen before.  

That’s what I love about science. You go into the lab, do an experiment, and get a little bit of knowledge about the world that unravels another piece of the mystery of nature. I love that.