Rewriting DNA for Fun and Profit

CRISPR in the eyes of one of its pioneers, Jennifer Doudna

Matthew Hutson
Jul 20, 2018 · 9 min read
Photo: picture alliance/Getty

CRISPR is fast becoming a household term, with one of the key scientists exploring this gene-editing mechanism following close behind. Jennifer Doudna, PhD, a biochemist at the University of California, Berkeley, co-authored a breakthrough paper in 2012 examining how it works and suggesting how it might be harnessed by humans. Such a tool is already beginning to transform agriculture, medicine, and our understanding of the human species. It’s also dusting up a fair amount of controversy.

With transformative technologies come ethical questions: How should CRISPR be used, for what, and by whom? No surprise, these questions are being debated in boardrooms and in the courts as leading scientists compete for startup funding and face off against their former collaborators in patent disputes about who can use the tech.

“CRISPR is a big deal because this gives scientists, really, for the first time, an easy tool for altering the code of life.”

Doudna’s seminal paper showed that a process by which bacteria build defenses against viruses, called CRISPR-Cas9, could be programmed to manipulate other kinds of DNA. A few months later, two other teams, led by Feng Zhang, PhD, and George Church, PhD, respectively, showed it could be used in eukaryotic cells, the kind in plants and animals. Doudna and Zhang each filed patent applications, with Zhang being granted one for his core finding in 2014 and Berkeley filing a complaint, calling the work derivative of Doudna’s. In 2018, Doudna, her collaborator Emmanuelle Charpentier, and their co-authors were granted a patent. Berkeley’s complaint has not been resolved.

The legal back-and-forth hasn’t slowed the work. In labs and now clinics, this controversial gene-editing technique is being tried and tested. Doudna spoke with Medium about eugenics, patents, scaremongering, and the origin of life.

This interview has been edited for length and clarity.

Medium: Why is CRISPR such a big deal?

Jennifer Doudna: CRISPR is a technology for changing the genome, rewriting DNA. It’s a big deal because this gives scientists, really, for the first time, an easy tool for altering the code of life. We’re able to correct mutations that cause disease and interrogate DNA in ways that until now were either very difficult or impossible.

Photo: The Washington Post/Getty

You’ve been interested in RNA—which carries genetic information and is sometimes referred to as DNA’s less famous cousin—for a long time. Why?

I’m delighted that you asked me that question, because it shows that you appreciate my more esoteric background. I’ve been fascinated by RNA since I was a graduate student. I was studying under a scientist who was interested in the origin of life. One of the theories was that it was actually RNA rather than DNA that provided the genetic information and the chemistry necessary for life to evolve into what it is today. I’ve been amazed and captivated by that question ever since.

Speaking of esoteric, you’ve said that the early work that led to CRISPR—you were working on how bacterial defenses could be used to attack viruses—was one of the most obscure things you’d ever done. When did you realize CRISPR could have wide applications?

When we appreciated that this was a tool in bacteria that has evolved for programmed targeting of viruses, when we understood how that worked, it was immediately clear that this could be a valuable tool for other purposes because of its ability to cut DNA in a precise way.

Does it seem funny that humans are learning lessons from bacteria?

It tickles me, actually. And if we look back over the past few decades in biological research, a lot of the technologies have come about from bacteria. Everything from being able to clone pieces of DNA to sequencing DNA, imaging molecules, these are all technologies that have come along fundamentally from molecules that were found originally in bacteria.

CRISPR is being lauded as a potential tool to cure disease. What is your take on that?

There’s also lots of excitement about the opportunities in clinical medicine. It’s already possible to use the CRISPR-Cas9 gene-editing technology to alter DNA in ways that would correct the disease-causing mutations in Huntington’s disease and sickle cell disease and a number of others. The big question now is how to turn that technology, which is working in the laboratory, into a clinically valid approach. To me, the barriers have more to do with delivery to the right areas of the body and validating the outcomes rather than the editing technology itself.

How far off is that?

Things are clearly moving fast. I think what we’ll see over the next two to three years are clinical trials that involve editing the blood or potentially editing the eye. These are tissues that are easier to get access to with current delivery methods. And time will tell. I would not be surprised, really, to see these treatments coming forward in the next decade and perhaps before that.

With those possibilities comes money. There are lots of startups and companies working on these technologies. What’s your view of the business landscape? Is there too much money? Not enough?

There are lots of commercial interest in this and, I think, for good reason. I think we’ll increasingly see CRISPR-Cas9 technology woven into the fundamentals of the way a lot of companies are operating. The things that affect that will be not only money but also the regulatory climate and public acceptance of CRISPR.

There was a big reaction this year to studies suggesting that CRISPR might increase the risk of cancer. Are you at all worried?

This has been known for a long time, that when DNA is cut in a cell, it leads to DNA repair, which also leads to other kinds of DNA damage. What this latest work highlights is the fact that we need to be cautious as we move forward.

“I think we approach our work with a sense of wonder about the world, trying to understand what’s going on.”

Do you have advice for readers so they don’t get overly excited or fearful?

It seems to me every few weeks a publication comes out that points to some new danger in genome editing, and CRISPR in particular, that causes a temporary flurry of activity and questions and concerns, and the publicly traded CRISPR company stocks typically go down temporarily. I think it’s important to understand that there are literally thousands of researchers around the world working with CRISPR, so it’s being vetted very thoroughly. A lot of these scare stories are, I think, really overhyped.

You’ve pointed out a need for both curiosity and skepticism in the public.

Absolutely. That’s certainly how I was trained as a scientist and one of the reasons I love doing science. I think we approach our work with a sense of wonder about the world, trying to understand what’s going on, and that’s the curiosity piece, as well as healthy skepticism, questioning data, questioning our own assumptions about the world, questioning our own interpretations of data and those of others. We all come to our work—and our lives, really—with various kinds of biases and assumptions, and we always have to be asking, “Am I being misled in some way?”

You were initially against using CRISPR on embryos—which some argue could lead to eugenics. Why did you change your position?

When I first thought about using CRISPR in human embryos, I have to admit I felt really queasy about it, because it did raise the whole specter of eugenics. And one of the unique things about the CRISPR-Cas9 technology is that it’s quite easy to use. Since it doesn’t require incredible funding or long timelines or unusual expertise, I started to think this could be incredibly dangerous to do in human embryos—that it was certainly not something to be offering to parents as a way to edit their kids by clinics. I thought that would be very dangerous, especially before the technology was thoroughly vetted, and especially before there was broad societal consensus about the use of the technology in that way.

But it’s become clear that there may be ways to use CRISPR in the germline—in embryos and in sperm and egg cells—that would remove disease-causing mutations from those cells, and I think that we have to look at that as an opportunity.

Do you hear from parents who want to use the technology for their family?

I do, pretty routinely. It touches me deeply when I see people’s lives and kids affected by genetic diseases.

What are some of the other uses of CRISPR that have impressed you the most?

The ability to make multiple changes in plant genomes in a single experiment—that really is game changing. It makes it possible to introduce traits into plants quickly, which has application in both academic research and, of course, commercial uses.

And I will also mention the use of CRISPR in fundamental research. There’s an experiment underway trying to understand bipedalism. How did that trait evolve, being able to walk on two legs? In a series of experiments, scientists are comparing rodents that walk on four legs to those that are bipedal but are otherwise quite similar. They can introduce genes from the bipedal rodent into the quadrupeds using CRISPR to ask what’s necessary to create an animal that can walk on two legs. It’s an amazing opportunity to use gene editing for inquiring about this very fundamental property of humans that we currently don’t understand at the genetic level.

To get a bit nerdy about bipedalism, it’s surprising that a complex orchestrated behavior like locomotion could be changed by just switching a few genes.

Well, I think that’s the question, right? What really gives rise to a complex trait like that? No one thinks it’s going to be one gene. Will it be a few? Will it be many? Will it be something we call epigenetics, meaning making changes that don’t alter the DNA sequence but affect the way information encoded in the genome is deployed? I think these are now questions that can all be addressed using the CRISPR technology.

I won’t ask about the state of your patent dispute, because I know you’re sick of talking about it. [Ed note: And because her PR handler asked us not to.]

[Laughs.] It’s my favorite topic.

But more generally, do you think it’s too easy for scientists to get burned by the patent system? And how might institutions help them better navigate it?

It doesn’t always work well. It’s difficult to navigate the complexities of the system. I wish I had a simple answer or recommendation. I don’t right now, but I think what I’m experiencing, I consider myself on a very intense learning curve with all of this. We need to ask our universities to do a better job of educating their own employees, people like me, about the way the system operates.

Who would be your dream collaborator?

I had the opportunity to meet Mitchel Berger, who is one of the top neurosurgeons. He works mostly on patients who have brain cancer and was the surgeon who worked on Vice President Joe Biden. We began discussing the opportunities to use genome editing in the brain and to treat a very challenging situation like brain cancer. That has led to a very productive collaboration with multiple scientists at both UC Berkeley and UCSF.

We have everybody from doctors to clinicians who are seeing patients every day to people who are doing fundamental research on the genome editing and those who are more on the engineering side. How do we engineer ways to deliver molecules into the brain? They’re all working in a collaborative partnership that I’m finding to be incredibly exciting.

You started out studying molecules, and now you’re learning about brains, society, and law. What new path has fascinated you the most?

I have to admit that I love fundamental research. I love asking questions about fundamental biology that I imagine have never been answered before. And I also get very jazzed when I think about collaboration with the neurosurgeon and collaboration with colleagues who work in agriculture. Maybe I’m interested in too many things.

What do you see in CRISPR’s future? What excites you?

It’s the combination of understanding fundamental aspects of the human genome, because it’s really still quite mysterious, and the very practical applications of genome editing. I imagine: Would it be possible someday for someone who has a child with a genetic disease to go to the doctor, that child gets their DNA sequenced, and then we understand what the cause of the disease is and can do something about it? That potential is really exciting, and I would love to be part of trying to make it a reality.

Matthew Hutson

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Science writer, fire dancer, guy on the Internet.

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About this Magazine

Three-person babies. Extreme biohacking. Outposts on Mars. Cheating death. The changing nature of life as we know it. The future portends to be amazing (and terrifying), and it's right around the corner. The July issue of Medium's monthly magazine explores the stunning scientific, technological, social and medical advances that are changing where and how we live. Cover Art: Fanny Luor

Three-person babies. Extreme biohacking. Outposts on Mars. Cheating death. The changing nature of life as we know it. The future portends to be amazing (and terrifying), and it's right around the corner. The July issue of Medium's monthly magazine explores the stunning scientific, technological, social and medical advances that are changing where and how we live. Cover Art: Fanny Luor

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