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Q&A: Jennifer Doudna Talks About Promise and Restraint in Future of CRISPR


NEW YORK (GenomeWeb) – Last week, Cold Spring Harbor Laboratory's meeting on genome engineering was dedicated to the "CRISPR/Cas9 Revolution." Indeed, 2015 has been the breakout year for CRISPR and it has taken off as both a research tool and a cause for public concern.

As CRISPR/Cas9's profile has risen, so has Jennifer Doudna's. She has stepped up as one of the public faces of the technology, drawing attention to both its promise and perils. In January, she made an appearance at the World Economic Forum in Davos, Switzerland to talk about CRISPR. Along the way she has been profiled in The New York Times and named one of Time's 100 Most Influential People. Now, some have predicted she'll end her year with a return trip to Europe in December to collect the Nobel Prize.

Doudna sat down with GenomeWeb at CSHL to talk about the various ways she teaches people about CRISPR/Cas9 and the future of genome editing in research and medicine. The following is an edited version of the transcript.

Thomson Reuters recently predicted that you and Emmanuelle Charpentier would win a Nobel Prize this year. What was your reaction to that?

Someone in my lab texted that to me. [Laughs] Of course, I'm incredibly honored to even be considered for something like that. I try not to think about it too much I guess. It's one of those unpredictable things for me and I want to always remain grounded in the science. I want to remember that there are patients out there that need us as scientists to be working hard to help them, and I really try to remain connected to the values I hold most dear. I think for any scientist it's an incredible honor, and who knows what the future holds.

You teach introductory freshman biology at the University of California, Berkeley. Do you teach CRISPR to your undergrads?

I do. In that course I talk about the components of DNA and the components of proteins, and we talk about the structure of DNA and the structure of RNA. We often talk about how genome sequencing has been influential in the area of biology in the last 15, 20 years, about how mutations give rise to disease, that scientists like to study mutations, and how up until about 10 years ago it was hard to make any precise changes in DNA. [That was when] we started to see engineered nucleases, and we talk a little bit about TALENs and zinc finger nucleases. Then we talk about CRISPR. We talk about how this is a technology that came out of a basic science project to understand how bacteria fight infection and it turns out to be a programmable system for binding and cutting DNA, and that leads into DNA repair, which is what happens after the cut.

I think students enjoy it. Even last year they were starting to read about CRISPR in the media, so they were excited to hear about what was going on on our campus and feel like they were involved in it.

When you first published the paper about Cas9 being an RNA-guided nuclease, what was the first thing you thought of using it for?

We realized it would be a really great way to conduct genome editing that was different from other methods that were out there because it's a programmable enzyme. I'm a researcher and I do sort of basic science, so I was excited about introducing it as a tool for introducing mutations in cells where it would allow you to do biochemistry in cells, where you could make very defined nucleic acids or proteins and study that small change in cells. I also had the idea, as many people did, that if you had a tool for genome editing that was robust, it would also potentially be a great therapy for disease. There's a lot of momentum in that direction and I feel now it's going to happen; it's just a matter of time.

What has changed the most about CRISPR this year?

What's changed the most from a whole field perspective is that the public appreciation of CRISPR is starting to happen now. Scientists have been aware that this is going to be really exciting since three years ago now, but I think the public haven't been very aware until probably this year. We've seen the media attention on it. I get more and more emails from people who want to see this used therapeutically. They have children with defects, they have genetic disorders themselves, they want to see it used ASAP, and they want to know what needs to happen for this to be a therapeutic. They want to know about the science. They want to know how long it will be until it will be useful therapeutically. Sometimes they have family foundations and want to know if they can support it financially. There's a growing appreciation that at some point it will be a therapy.

What do you tell someone affected by a genetic disorder who wants to know more about CRISPR/Cas9?

I have a standard reply to people that explains where we are scientifically with it. I don't want to create false hopes, so I try to tell them it's still early days with the technology, it'll be a while before it'll be approved as a therapy. I try to tell them what some of the current bottlenecks are, what needs to happen.

Occasionally, I meet with them. I had a recent meeting with a young man who is the father of a 6-year-old daughter who has a sporadic mutation that causes an ataxia disease that affects her muscles and her intellect. He said, 'I want to know what needs to happen to turn this into a therapy because I want this for my daughter.' It was so real. It was so earnest. It was an interesting conversation because he's not a scientist, [though] he'd done a lot of reading, but we had a very open discussion about what the steps are to go from where we are to today to when we have a real therapy.

What is the Doudna lab working on right now?

We're working on two broad areas of the CRISPR system. One is basic biology, trying to understand how these molecules work, not only the Cas9 enzyme, but other enzymes that are part of these CRISPR pathways. They're very diverse pathways, and we're interested in the whole biology of how new DNA is acquired from viruses to start the immune system, kick it off in the bacteria. We're working on how cas9 works with DNA and the conformational change of the protein and how we can engineer it do other things.

Another broad area we're working on is applications. The biggest bottlenecks for applications both with therapeutics, but other things, too, are really delivery and the way that DNA is repaired after the cut is made. Those are the two biggest bottlenecks. Those are the areas where we're working to understand the molecular basis for these pathways and how we can manipulate them.

You're participating in an international summit on human germline genome editing in December. Now there's also going to be a meeting related to that in October. What will you be discussing?

These are meetings sponsored by the National Academies, and the goal of the October meeting, it's sort of a pre-meeting ahead of the December meeting to basically get everybody on the same page about the science and where the field really stands right now as well as to decide what should be on the agenda in the December meeting. Of course, we'll have an agenda planned. We want to figure out by talking to scientists and a few other stakeholders, are there other issues that we need to be considering.

The goal is to be a public meeting and we want to invite commentary. I don't quite know what will come of it but I think it's an important start to, frankly, the series of meetings that will happen on these issues. There's this one happening in the US, there are also meetings happening in the UK, the Netherlands, perhaps elsewhere as well. The European parliament is considering this issue in the near future. We'll see an ongoing discussion about this.

The topic is timely and it's not an easy one. It's one where there are many points of view and where people need to have an opportunity to think about the science, and understand it, hopefully, and weigh in with their views on it.

Feng Zhang of the Massachusetts Institute of Technology just presented a new CRISPR-related, RNA-guided, non-Cas9 system that can edit DNA. What are your thoughts on that?

I think it underscores the wonderful diversity of these CRISPR systems. That's something we've appreciated for a long time, is that these CRISPR systems have a fascinating plethora of proteins involved in defense in bacteria. It's early days, it's interesting basic biology. It'll be interesting to see if that turns out to be useful for genome editing. It's unclear at this stage if it will or not. If it is, that's great, then it goes in the toolbox.

Can you tell us anything about the intellectual property dispute over the patent for CRISPR/Cas9?

I think that it'll clearly take time to sort it out. I'm very confident from a scientific perspective on our position. As a scientist, I would really like to see it resolved because I think the science is so exciting, and it would be unfortunate to see the science held back. It may still be a bit of time before it really gets resolved. Getting clarity around it will be important so that it can be commercialized appropriately. For academic labs, it doesn't really matter. All of us that are doing academic work are forging ahead, we're doing our research. As you can see at this meeting, it's not really holding back the companies either, they're forging ahead as well, but at some point it will be important to have clarity around that issue.

What's one thing about CRISPR you think people should be talking more about?

The thing we haven't really seen at this meeting that's huge is synthetic biology. We had a session on model organisms, but really we're talking about being able to do genetics in non-model organisms. I have colleagues at UC Berkeley doing experimentation in industrial strains of yeast that are used for biofuel production. In the past it was impossible to engineer them efficiently, and you couldn't do it with precision. Now you can. This is transforming the speed of that field and the kinds of experiments that can be done.