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INTERVIEW I’ve always had a fascination with the underlying theme of evolution in biology, and how a lot of biological pathways, systems and organisms are connected by evolution. You can find patterns of similarity even in seemingly very different kinds of cells or molecular pathways. So when I heard about the possibility of an RNA-guided system in bacteria, I was immediately interested. When did you start making the connection that this intriguing bacterial immune system could be used to target and cut particular sequences of DNA? The first three or four years of CRISPR biology in our laboratory were focused on Cas proteins that recognise CRISPR RNA and cut it up into useful, usable segments of RNA. It was very similar to work we had been doing on RNA interference and an enzyme that chops up RNA called Dicer. A graduate student in my lab, Rachel Haurwitz, who had been taking some classes at Berkeley’s Business School, got me thinking about starting a biotechnology company. Rachel and I founded a company called Caribou Biosciences in October 2011 with the purpose of developing these CRISPR-Cas proteins for research or clinical uses – for example, as diagnostic tools that could recognise and signal the presence of viral RNA molecules. This was before our laboratory had completed our work on the class of proteins known as Cas9. Of course, once the CRISPR-Cas9 work was done it was clear this was going to be a very useful way to change DNA sequences and therefore genomes – “As a technology it really cuts across every area of biology. I find that both very, very exciting, and also a bit daunting” Right: Jennifer Doudna using a combination of cryoelectron microscopy and 3D image reconstruction Below: The University of Hawaii in Hilo GROWING UP IN HAWAII “When people think of Hawaii they probably think about beaches, hula girls and grass huts. That was not my Hawaii at all. My Hawaii was a small, rainy, kind of working-class town called Hilo. My dad worked at the branch of the University of Hawaii there. “I would always wonder about certain types of animals and plants on the island and their particular niche, and how they survived. In those days I wasn’t really thinking about DNA – I probably didn't even know what that was – I was just very curious about the natural world. “I came to realise as I was going through school that I loved mathematics and really enjoyed my high-school chemistry class, and I started to think about applying chemical principles to understanding biology. “I found myself increasingly drawn to the kind of questions about the natural world that really boiled down to molecules – figuring out how a molecule controls the way that cells and organisms develop, whether a cell is normal or cancerous, all of those sorts of things.” and that changed lots of things. It certainly changed the goals of Caribou at that point. Was there a single ‘eureka’ moment when the power of the CRISPR-Cas9 system dawned on you? Or was it more stepwise and iterative than that? Martin Jinek, who was a postdoc in the laboratory doing the research on Cas9, did the initial experiments on Cas9. He showed it was programmable – an RNA-programmed protein – and figured out how the DNA targeting and cutting works. Then, very importantly, he figured out that he could simplify the system, relative to the way it works in nature, combining two types of RNA into one RNA to guide Cas9 to its target. When he showed that approach worked very nicely for directing Cas9 to a desired sequence for cutting, that was really when we said “Gosh – this is going to be amazing”. It was just so easy to work with this protein – a lot easier than any of the earlier technologies for gene engineering. In your book, ACrack in Creation, you wrote of having a recurrent dream that a tsunami is approaching you on a beach near where you grew up, representing the overwhelming surge in interest and questions raised by this technology. Do you still have this feeling? Absolutely. The wave has only got bigger. So many things are happening right now on multiple fronts. As a technology it really cuts across every area of ia Torch Brad 12 / The Biologist / Vol 66 No 5
page 15
biology. I find that both very, very exciting, and also a bit daunting. It’s difficult to keep up with the scientific literature, much less stay on top of all the different facets of genome editing such as questions about ethics, safety and the affordability of future geneediting therapies. Going back to that period when things really exploded, around four or five years ago, how did you feel being at the heart of so many concerns and difficult ethical questions everyone suddenly wanted answers to? I was incredibly nervous. I felt poorly equipped to answer any of those concerns and the really big ethical questions. I was hesitant, initially, to dive into any kind of public discussion about these issues, and it was a very intense time for me. Thinking about how genome editing might eventually be deployed, especially in places like the human germline, quickly moved from being science fiction to becoming clearly on the scientific horizon. I started to think very seriously, first of all, about how we alert people to what is happening in this area of science. Then, how would one start to engage with all of the different kinds of stakeholders that could play a role in making decisions around a technology such as this? I felt a real sense of personal responsibility having been involved in the early stages of this whole field. I spent a lot of time in 2014 talking with colleagues of mine at Berkeley and at Below: Doudna holds a model of the Cas9 protein (white) interacting with DNA (orange and blue) the Innovative Genomics Institute, which I started that year. In January 2015 we convened the first meeting on human genome editing in the Napa Valley. That was really the kick-off to those sorts of conversations, because after that the National Academies and the international scientific and clinical organisations got involved. Since then we’ve just seen an incredible uptick in the numbers of meetings, reports and groups that are weighing in on what should be done now that we have access to such a powerful tool. How do you feel that those conversations are going? On the whole I would say that I’m quite pleased. I’m first of all glad that they’re happening at all – I think that’s paramount. It’s also important that they be made open to people who are not specialists in the field, or maybe don’t even have particular scientific training. There’s been a real appreciation across the scientific community that it’s critical for scientists to be involved in [these ethical] discussions, even though for many scientists it’s just not in our DNA – a lot of us would prefer to be in the laboratory doing the next experiment and not talking on a public platform about something that could be quite contentious. Obviously some of the most contentious debate around gene editing involves the human germline. Do you think things are moving too quickly here? Yes, I do, and I don’t think I am alone in having that view. The data that was presented by He Jiankui last year [the Chinese scientist who claimed to have used CRISPR to confer HIV resistance to twin girls] demonstrated two things very clearly. First, that the Vol 66 No 5 / The Biologist / 13

INTERVIEW

I’ve always had a fascination with the underlying theme of evolution in biology, and how a lot of biological pathways, systems and organisms are connected by evolution. You can find patterns of similarity even in seemingly very different kinds of cells or molecular pathways. So when I heard about the possibility of an RNA-guided system in bacteria, I was immediately interested.

When did you start making the connection that this intriguing bacterial immune system could be used to target and cut particular sequences of DNA? The first three or four years of CRISPR biology in our laboratory were focused on Cas proteins that recognise CRISPR RNA and cut it up into useful, usable segments of RNA. It was very similar to work we had been doing on RNA interference and an enzyme that chops up RNA called Dicer.

A graduate student in my lab, Rachel Haurwitz, who had been taking some classes at Berkeley’s Business School, got me thinking about starting a biotechnology company. Rachel and I founded a company called Caribou Biosciences in October 2011 with the purpose of developing these CRISPR-Cas proteins for research or clinical uses – for example, as diagnostic tools that could recognise and signal the presence of viral RNA molecules.

This was before our laboratory had completed our work on the class of proteins known as Cas9. Of course, once the CRISPR-Cas9 work was done it was clear this was going to be a very useful way to change DNA sequences and therefore genomes –

“As a technology it really cuts across every area of biology. I find that both very, very exciting, and also a bit daunting”

Right: Jennifer Doudna using a combination of cryoelectron microscopy and 3D

image reconstruction

Below: The University of

Hawaii in Hilo

GROWING UP IN HAWAII

“When people think of Hawaii they probably think about beaches, hula girls and grass huts. That was not my Hawaii at all. My Hawaii was a small, rainy, kind of working-class town called Hilo. My dad worked at the branch of the University of Hawaii there.

“I would always wonder about certain types of animals and plants on the island and their particular niche, and how they survived. In those days I wasn’t really thinking about DNA – I probably didn't even know what that was – I was just very curious about the natural world.

“I came to realise as I was going through school that I loved mathematics and really enjoyed my high-school chemistry class, and I started to think about applying chemical principles to understanding biology.

“I found myself increasingly drawn to the kind of questions about the natural world that really boiled down to molecules – figuring out how a molecule controls the way that cells and organisms develop, whether a cell is normal or cancerous, all of those sorts of things.”

and that changed lots of things. It certainly changed the goals of Caribou at that point.

Was there a single ‘eureka’ moment when the power of the CRISPR-Cas9 system dawned on you? Or was it more stepwise and iterative than that? Martin Jinek, who was a postdoc in the laboratory doing the research on Cas9, did the initial experiments on Cas9. He showed it was programmable – an RNA-programmed protein – and figured out how the DNA targeting and cutting works. Then, very importantly, he figured out that he could simplify the system, relative to the way it works in nature, combining two types of RNA into one RNA to guide Cas9 to its target. When he showed that approach worked very nicely for directing Cas9 to a desired sequence for cutting, that was really when we said “Gosh – this is going to be amazing”. It was just so easy to work with this protein – a lot easier than any of the earlier technologies for gene engineering.

In your book, ACrack in Creation, you wrote of having a recurrent dream that a tsunami is approaching you on a beach near where you grew up, representing the overwhelming surge in interest and questions raised by this technology. Do you still have this feeling? Absolutely. The wave has only got bigger. So many things are happening right now on multiple fronts. As a technology it really cuts across every area of ia

Torch

Brad

12 / The Biologist / Vol 66 No 5

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