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