The following is a brief excerpt from an extended audio interview conducted between Laura L. Kiessling, Editor-in-Chief of ACS Chemical Biology, and CRISPR investigator and former Associate Editor Jennifer A. Doudna. You can listen to the full interview here, or read it in the latest issue of ACS Chemical Biology.
Laura L. Kiessling: How did you make your way from ribozyme structure to CRISPR?
Jennifer A. Doudna: Well, it certainly has not been a straight path, that’s for sure. It’s a good question, and it’s hard to give you a really concrete answer, because I do not think there’s any one way that I think about projects in the lab, necessarily. I think that, for me, science is always a collaborative process, whether it is students I’m working with in lab, or other faculty members or their students that we’re collaborating with, or reading a paper and getting an idea from it and saying, “Gee, that’s something we ought to do,” or listening to a podcast. Anything, right?
I guess if I had to say an idea that maybe links together a lot of the work that we’ve done over the years, it’s probably linked together by this fascination about the role of RNA molecules in molecular evolution. It’s something that I came to as a graduate student with Jack Szostak and then pursued when I was a postdoc from the perspective of, as you said, looking at structures of catalytic RNA molecules called ribozymes. And then that project, which was the area that I started working on when I was a new faculty member at Yale back in the mid-90s, morphed into thinking about structures of RNA in viruses that can influence the way that proteins are made in viruses, and the way that viruses can actually hijack the protein-making machinery in infected cells.
How did I get into that? Well, that really came along because of a postdoc that came to the lab, Jeff Kieft, who was very interested in getting into that area. So I thought, “Wow, that sounds pretty exciting. I don’t know anything about it, but it sounds like it has a lot to do with the kinds of problems that we’re thinking about with ribozymes.” And so we started off in that direction, and then eventually, I moved my lab to UC Berkeley in 2002. Part of my motivation for that move, although I had loved my time at Yale honestly, but I also sensed a really exciting opportunity at Berkeley to take my research in what I thought was a bit more of a biological direction. Thinking really about how to understand molecular structure in the context of a cellular system.
To do that, we started working on small RNAs that are involved in RNA interference, which is a pathway in animal and plant cells that uses very tiny pieces of RNA to control the levels of proteins that are made in those cells. So we were working again on the very fundamental aspects of that. Oddly enough, that’s actually how I got into CRISPR, because it was through that work that a colleague at Berkeley, who works on bacterial communities and does a lot of DNA sequencing in bacteria, Jill Banfield, someone I had only met maybe once or twice—
JAD: She was at Wisconsin, then moved to Berkeley. She was working on these bacterial genome sequences and finding examples of CRISPR arrays. Of course, at that time, nobody knew what they did, and her hypothesis was they might be operating at the level of RNA: copies that would be made in the cell and then somehow deployed to protect cells from future viral infection. And so she Googled, “Who at Berkeley works on little RNAs?” My name popped up, and she called me and said, “I think we need to talk.” And the rest is history.