On June 28, 2012, a joint press release went out from the U.S. Department of Energy and the Lawrence Berkeley National Laboratory announcing a new paper in Science from an international team of researchers based there. “Programmable DNA Scissors Found for Bacterial Immune System,” it declared, hinting that the discovery could lead to a new “editing tool for genomes.”
That paper, “A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity,” has now been cited by more than 15,000 publications and downloaded nearly 65,000 times. It laid out the inner workings of a system called CRISPR/Cas9, transformative work for which two of its authors, Jennifer Doudna and Emmanuelle Charpentier, were awarded the Nobel Prize in chemistry just eight years later.
At the time, though, no reporters came calling, no news stories were published. Doudna’s only quote was in that press release. “Although we’ve not yet demonstrated genome editing,” she said, “given the mechanism we describe, it is now a very real possibility.”
A decade later, we know what an understatement that turned out to be. CRISPR has been used to manipulate the genomes of organisms across every branch of the tree of life, including humans. It’s now being tested to treat dozens of inherited diseases, with companies planning to ask regulators for approval of the first CRISPR-based medicine as soon as later this year.
STAT spoke with Doudna, a biochemist at the University of California, Berkeley, where she directs the Innovative Genomics Institute, about the first 10 years of CRISPR genome editing and what comes next. Excerpts from the conversation are below, lightly edited for clarity.
Looking back, are you surprised this paper didn’t make a bigger splash when it was first published?
It’s interesting because it kind of speaks to the way that scientific discoveries happen. This was a case where at the time of that publication, it wasn’t the kind of thing that would generate New York Times headlines because it was still very much in the realm of fundamental, curiosity-driven science. Only in retrospect did it become clear to people who weren’t specialists what an important moment that was.
But within the field there was certainly a feeling of intense excitement — a number of people started reaching out about obtaining materials used in the project so they could use them in their lab, and I started getting invited to meetings to talk about it. There was definitely this sense of opportunity and anticipation about the potential this had to change things in the research world.
Although, I do remember that around that time I was corresponding with a scientific illustrator in Wisconsin [named Adam Steinberg], who was creating a piece of artwork for the article. And at one point he wrote to me saying, “You know this is going to win a Nobel Prize, don’t you?”
Was he the first person to make that prediction to you?
He was, yes. At the time I didn’t even want to think about that or go there, there was just so much to do. But it struck me that here’s this person who’s a professional artist and he got how big of a deal this was.
You and Charpentier won the Nobel in 2020. Has it changed anything for you, in the day-to-day life of a scientist?
If it’s changed anything it’s probably the kinds of meetings I’m invited to now. More and more, I find myself in meetings with people who are not scientists who’ve heard of CRISPR and want to understand what kind of an impact it’s going to be having. And I’ve been excited to engage with these folks, and also I’ve been struggling with the challenge of balancing time. You know, how much should I be devoting to that kind of thing versus advancing the science?
The science has been advancing so fast though! Last summer, we saw data from Intellia showing in vivo CRISPR editing in humans for the first time, which seems to be having a durable effect. And there are now half a dozen clinical trials of CRISPR therapies for sickle cell disease underway. What do you make of that evolution?
Recently I had the opportunity to speak over Zoom with Victoria Gray — the first sickle cell patient in the U.S. to be treated with CRISPR — and to hear about her life before and after the therapy. I’ll just never forget that moment. For a scientist to see the real-world impact of work they were involved in, there’s just nothing like it. To see that real-world impact within 10 years of that original publication? That’s just mind-blowing to me.
To what do you credit the incredible pace of development?
I think it’s a combination of things. CRISPR technology appeared on the scene at an opportune moment in the field; there were increasing numbers of whole genome sequences available. By then, sickle cell disease had been one of the longest studied of all the human genetic disorders. And it was also a time when biotech was booming, so there was a lot of investor money available to start those first CRISPR companies and make it possible to hire really good people.
There was also a hunger, in part because there was so much disappointment in the field when earlier forms of gene therapy didn’t work out. Many people, myself included, were sort of wondering whether it would ever be possible to do genetic therapies in human beings. So CRISPR came along at a time when people were looking to turn that field around. And it didn’t hurt that the technology was so enabling — that just made the science go really quickly.
In 2018, you began a collaboration with Bruce Conklin at the Gladstone Institute at the University of California, San Francisco to push CRISPR toward the clinic. You told me at the time it was out of a need to “step back and figure out how to ensure in the future that this technology is not something only available to the 0.1 percent.” Can you talk about the work you’re doing there to address costs and accessibility?
Recently, we initiated a clinical trial for sickle cell disease with research that was done at the Innovative Genomics Institute. That’s being run by a three-way collaboration between UC Berkeley, UCSF, and UCLA, and as part of that, we’ve been engaging with the patients to better understand their experience with the disease and the health care system. And what that has confirmed for me is the need to advance the technical aspects of CRISPR to the point where we don’t need bone marrow transplantation for this type of therapy.
If we could do more editing in vivo so we don’t have to extract cells, edit them, and replace them — which at least for blood disorders usually requires a bone marrow transplant — I think that would really be transformative. So that’s one example of something we’re now working on.
But I don’t think there’s going to be a one-size-fits-all approach, but different delivery modalities will be more cost-effective than others. We’ve seen a really good example of this recently with the Covid-19 vaccines. One of the reasons the mRNA vaccines have been so successful is not only their efficacy but also the relative ease of manufacturing compared to other types. Making viral vectors, which requires cultivating cells, is just much harder to do on a large scale than something that is completely controllable in vitro in the lab. So I think we’ll see the same thing in the CRISPR world.
What do you think people can expect to see from CRISPR in the next 10 years?
I think in the next decade, at least I hope, that we’re going to see real advances around delivery to the point where we can start to use CRISPR as a standard of care for certain types of diseases. I think that could be possible for sickle cell disease. I don’t want to trivialize the challenges around doing that, but I think there is a lot of motivation in the field and a lot of innovation and creativity that’s going into that effort right now, which gives me hope we may succeed in that goal.
I also think it’s quite possible that we’ll see CRISPR start to be used not just to treat disease but also to prevent disease. Whether it’s preventing it because CRISPR is being used diagnostically, which is already happening. Or whether it’s being used to edit genes which, if left untouched, would predispose people to disorders, especially during aging.
Clearly CRISPR would have to be safe first and foremost, but I think there’s interest in this. And if that were to happen, then we’re going to see a situation where genome editing really has a much more widespread impact across the population.