Meet the Scientist Bringing Gene Editing to Life: An Interview With Jennifer Doudna

Emmanuelle Charpentier, left, and Jennifer Doudna pose by a student mural in San Francisco in Octobe 2015. Doudna has been involved in a prolonged patent dispute over a gene-editing technology. Eloy Alonso/Reuters

About 10 years ago, scientists at a yogurt laboratory in Denmark noticed a peculiar feature in a bacterial genome. They spotted repeating patterns of bases—the components of DNA sequences, denoted as A, T, G and C—that were the same backward and forward. Such genetic palindromes had been seen before and had already been given a name: clustered regularly interspaced short palindromic repeats, or CRISPR.

But the yogurt scientists noticed something strange. Sandwiched inside the CRISPR sequences were strings of bases that exactly matched DNA sequences from a virus that had infected their bacteria.

The appearance of viral genome sequences inside the bacteria could mean only one thing: The bacteria had mounted an attack against the virus and was now equipped to recognize such future invaders. The bacteria were doing what humans do, adapting their immune system to survive.

Across the globe, scientists dug into the discovery. Two of them—Jennifer Doudna, a microbiologist at the University of California, Berkeley, and Emmanuelle Charpentier, a microbiologist now at Berlin's Max Planck Institute for Infection Biology—figured out how the adaptive immunity happened. In short, a protein called Cas9 cuts into the viral genome so that the bacteria can integrate a portion into its own DNA.

Doudna and Charpentier found that the CRISPR-Cas9 complex could be fairly easily co-opted to alter the genetics of other organisms. In other words, CRISPR-Cas9 is an entry point for genetic engineering. They published this finding in 2012. But this team wasn't the only one trying to unravel CRISPR-Cas9 and figure out how to capitalize on nature's genius. At the Broad Institute, bioengineer Feng Zhang was doing the same.

A major looming question at the time was whether CRISPR-Cas9 could be used to alter the DNA of eukaryotic cells; that is, cells with a confined nucleus and other distinct parts held inside a membrane. Plants are eukaryotes. So are humans. (Bacteria are not.) If CRISPR-Cas9 were to be used to edit human genes—say, for the purpose of curing a disease rooted in DNA—then finding a way to introduce the technique into eukaryotic cells could be crucial. And the university employing the scientists who succeeded, as well as the scientists, stood to gain both significant prestige and a large amount of money.

Scientists working with CRISPR-Cas9 knew their research could lead to unprecedented commercial developments, but securing ownership of the discovery, and thereby profiting from its commercialization, depended on filing a patent. At the time this work was unfolding, the United States followed a "first to invent" patent system; the individual who first conceived of the idea was entitled to own it. In 2013, under the Leahy-Smith America Invents Act, the U.S. switched to a "first to file" system, followed by nearly every other country, granting ownership to whoever filed the patent first.

Doudna filed a patent for the technology using CRISPR-Cas9 to alter DNA in May 2012, before the patent system changed to first to file. That December, Zhang filed a more specific patent claim for a technique using CRISPR-Cas9 specifically for altering eukaryotic cells. Zhang's application included a request for an expedited review, which requires an extra fee. Zhang was awarded ownership of this intellectual property in 2014 (patent number 8,697,359), and Berkeley filed a "patent interference," a request for the U.S. Patent and Trademark Office to investigate the application for possible overlap with theirs, which was filed earlier.

The interference filing set off a long battle that spurred countless news reports, bitter arguments and professional attacks. On Wednesday, more than a year after the fight began, the patent office gave its ruling: the Broad Institute's patent stands. Doudna's May 2012 patent application, which covers use of the CRISPR-Cas9 technology in other types of cells, is still pending.

Newsweek spoke with Doudna about the ruling, the CRISPR-Cas9 technology and what's next for her.

What do you think about the ruling?
The judges declared that both sets of claims, brought by the Broad on the one hand and by University of California on the other, are separately patentable inventions. That ruling means that the Broad's patent will stand and also that our patent can now be issued, which I'm pleased about.

Many reports of the ruling have characterized it as a big win for the Broad Institute. Do you agree?
I think the decision is more nuanced than that. I think obviously the Broad Institute is happy that their patent didn't get thrown out. We're delighted that our patent can now proceed to be issued.

The Broad has a patent for the use of CRISPR-Cas9 in one type of cell. Our patent claims to cover all types of cells. The analogy I've been using to describe this is that it's as though they have a patent for green tennis balls but we have a patent for all tennis balls. That's where things stand at the moment. From the perspective of companies, people who are using this technology commercially will need to get licensing from both parties to proceed if they're using the technology in plants or animal cells.

Discussions about the patent dispute included concerns that it was holding up commercializing the technology. Is that true? And if so, what work can now proceed that couldn't before the ruling was made?
I don't think we have seen an effect of this patent dispute on that process.

One of the reasons why people think this technology is so promising is that it's very enabling. It's enabling because it's relatively simple to use and access. Over the last four and a half years since we first published our work, many groups have adopted this technology for all sorts of uses and in different kinds of animal and plant systems. The research is proceeding incredibly rapidly in both academic laboratories and in companies.

It's still early days. The technology is evolving, and products are still in the pipeline. I think once there are actual products, the market from this, whether they are human therapeutics or other things, then the question of who holds the patent rights will become an issue. But at least for human therapeutics, that's certainly a ways down the road still.

What kind of developments might we see down that road?
I think on the human therapies side, it's very exciting right now. Clinical trials with the CRISPR-Cas9 technology trials are already proceeding in cancer patients. I think what's coming along in the not-too-distant future will be clinical trials using this technology to treat or even cure genetic disease. I suspect that the first technologies we'll see will be for treating diseases including sickle cell anemia as well as conditions of the eye. Introducing the editing molecules into those cell types is relatively straightforward.

Further down the road, perhaps a decade away, we may see new treatments for muscular dystrophy and cystic fibrosis. I think the challenges for these diseases...have less to do with the gene-editing technology and more to do with figuring out how to deliver the editing molecules into tissues.

We've already seen plant products coming on the market that were generated using CC. A CRISPR mushroom was already created at Penn State University. And many more products are in the pipeline right now, both made by companies and made by academic labs. I think we're going to see much more rapid advances in plant biology than have been possible in the past because of the ease of use of this technology in plant systems.

Has this patent dispute been a frustrating experience for you?
Certainly it's been a learning experience. I see myself as forever a student. I've always been involved in doing fundamental research. We got into this field of gene editing because we were studying the way bacteria fight viral infections and investigating a viral immune system called CRISPR. That was really how we got into this. I was not a genome engineer in the beginning.

It's been a fascinating journey over the past five years, doing research that led to the realization that this system could be harnessed as a powerful technology. And it's been equally fascinating being involved in the development of that technology, applying it in different systems. In my own lab here at Berkeley, we're continuing to do fundamental research on other CRISPR systems as well as understanding how these proteins actually carry out editing.

So I guess I see the patent dispute as part of my education. I've learned a lot about the patent process. I try to take the long view here. I really value the work that scientists are doing to develop a clearly important technology and see it used to solve real-world problems. I try to stay focused on that challenge, which for me, ultimately, is what is rewarding. When there are real solutions that come forward from this, when there are human therapies or solutions to problems in agriculture or what have you, for me that will be very satisfying.

What is next for you in the laboratory?
We're continuing to work on understanding how these gene-editing technologies actually work in cells. We've been able to deal with some of the challenges of the technology, such as figuring out how to deliver it into different kinds of cells.

I've been very active in the Bay Area here, developing an academic institute called the Innovative Genomics Institute that is a partnership between two University of California campuses, Berkeley and San Francisco. The San Francisco campus is a medical school. This institute is offering us a chance to work with clinicians and partner with researchers who are going to be developing gene editing as a therapy. I'm also working with plant geneticists. We are pushing to use gene editing in agriculture and teaming up with colleagues around the Bay Area and at various companies to do that.

Having been through this experience with the business side of discovery, are there aspects of the patent system that you think need to be updated in accordance with where this science is headed?
I think you'll have to ask me that question 10 years from now, when I can look back with more perspective. As challenging as the patenting process is, I respect the fact that it really does enable companies to have protection as they are working on commercial use of the technologies. This need is especially important for human therapies, which require a lot of financial investment and a long time to develop. So as imperfect as the process is, it serves a very important purpose, and I respect that. Ask me a few years from now and maybe I'll have a better sense of how one might be able to improve the system.

Would you work with scientists at the Broad Institute now or in the future?
I already do. I have collaborations with scientists at MIT, Broad Institute, Harvard University and elsewhere. These collaborations don't necessarily come out in the media reports about the dispute. There is a wonderful community of scientists collaborating on projects, working together on things. Over the course of my career, I've found that scientists have become much more collaborative. I would never let the patent dispute inhibit me from working with people that I want to work with at any institution.

So this legal battle has not soured you on commercializing your laboratory discoveries?
Oh, the opposite. It's encouraged me to do that. It's exciting to be involved in all of this.

This technology is a great example of how critical fundamental research is to developing new technologies. Nobody would have expected that a powerful gene-editing tool would come from the study of a bacterial immune system. That's an important message to put out there. How do we get new technologies right now? They really come from all directions.

Do you have any advice for other scientists about navigating the patent system?
I've realized that, at least in my institution and others I've worked at, there isn't very good education of academic scientists about the patenting process. Now I'm working with my students and others here at my university to just explain what the process is.

Many scientists doing the next experiment in the lab, we're not necessarily thinking about whether we should file a patent on this, how do we do that and what does that even mean. I think that that lack of knowledge has really come home to me very clearly. We need to have a better way of educating scientists about that process.

This interview has been edited and condensed.