Raring to go with RNAi research

Highlights from Pioneering Research: the Cancer Research UK annual research publication 2014/15.

Professor Greg Hannon has recently moved to the Cancer Research UK Cambridge Institute after 23 years at Cold Spring Harbor Laboratories in New York. A pioneer in the field of RNA interference (RNAi), Greg’s achievements include defining the key components of the RNAi machinery, designing synthetic RNAs that can silence mammalian genes, and generating comprehensive libraries of these RNAs representing every gene in the human, mouse and rat genomes.

Greg has consistently set himself challenging goals in science. As a PhD student, he exploited the parasitic worm Ascaris to unravel the biochemistry behind trans-splicing of RNA transcripts. More recently, he devised a technique for capturing and sequencing large collections of DNA which he then used, in collaboration with paleogeneticist Svante Pääbo, to compare the human and Neanderthal genomes. Greg’s current interests include applying RNAi-based genetic screens to cancer biology and stem cells.

We caught up with Greg in his lab at the Cambridge Institute, to find out what is currently exciting him in science, why it’s OK to take risks in research, and how his new home will benefit his work.

“It all started for me back in 1997 when I heard Craig Mello talk about this phenomenon called RNAi that he’d discovered in C. elegans — he later (in 2006) won the Nobel Prize for this discovery. I was intrigued, but it wasn’t until I heard another lecture about the use of RNAi to shut down genes in Drosophila embryos that I realised that RNAi, if it was conserved, could be an incredibly powerful tool for studying mammalian cell biology. I left the lecture, called my lab to share my excitement, and that was the beginning of my RNAi research. We redirected essentially all of our research, and within a few weeks we’d shown we could use double-stranded RNA to knock down expression of a LacZ reporter gene. From those early days it has just kept growing and I’ve never looked back.

I loved Cold Spring Harbor, and the environment and colleagues kept me there for more than two decades. It was an outstanding and highly focused environment to work in; however, my lab had grown to over 50 people and I found I had little time actually in the lab anymore. I kept a bench and worked in the lab, periodically at least, until I had more than 30 people, but I came in one day and all my stuff was dumped on a trolley — the lab was really overcrowded and someone else needed the bench. And then they needed the trolley more than they needed me working and my stuff was just boxed up! I hadn’t done what my lab called ‘real’ work for a good while when I started thinking about the need for a change.

I really wanted to get back to being hands on at the bench again, doing research on a day-to-day basis, with time to read, talk to scientists in my group and mentor PhD students. That’s what I’m trying to get back with my move to Cambridge — I’ve really not had a chance to do that over the past decade, and it feels great. If you’re working at the bench you have a much better handle on what’s going on in the lab. It also gives me the opportunity to pilot new things and try new approaches — my time is quite fragmented so it’s more suited to short, discrete projects. Right now, we’ve just started collaborating with Simon Tavare’s lab, and I’m going to be doing the wet lab stuff to begin with — that is until we get someone more qualified.

I really hit it off with Simon Tavaré, the Director of the Cambridge Institute (CI). For me, the personal aspect of a research environment is so important. Science is a very social endeavour, and the relationships you have with your colleagues are what makes time at work so enjoyable and rewarding. We’ve started a lot of new experiments and collaborations in new areas in the few months we’ve been here. They’re all things that are fairly out there, so the environment is impacting us in good ways. You should be introduced to new things by your colleagues, and excited by them — why would you want to work anywhere except at a place where your environment and colleagues influence you in unexpected ways?

The other thing that’s great about the CI is that the support functions and core facilities we’ve used so far have been excellent. Microscopy and genomics are outstanding — James Hadfield in Genomics has really helped refine pipelines for doing high throughput sequencing for us. And Stefanie Reichelt in Microscopy is fantastic — I’ve had a few crazy ideas but I’m not a microscopist and Stefanie’s just leapt on board to help. She can take the kernel of an idea and really help to elaborate it, and set me up with the people I should talk to.

Right now, I’m busy establishing collaborations that will combine our skills with those already established at the institute. For instance, I’m already working closely with Shankar Balasubramanian (chemical biology) and Simon Tavaré (computational biology). We have some pretty cool ideas and the potential to generate some really far-reaching technological advances.

Developing innovative technologies has always been a major strand of my research, as they invariably catalyse an explosion of discoveries in a field — consider the impact of PCR or next generation sequencing — and are vital to keep research at the leading edge. Conventional grant mechanisms don’t tend to reward high-risk strategies, so I’m very enthusiastic about being the Chair of the CRUK Pioneer Award Committee, which aims to support innovative projects at an early stage. There have certainly been points in my career when I’ve benefited from grants awarded for projects that were thought of as high-risk at the time, so anyone with ideas like that will be assured of a hearing!

Being in Cambridge will certainly sharpen our focus on cancer too. We’re pursuing our long-standing interest in breast cancer (with Carlos Caldas) and in pancreatic cancer (with Duncan Jodrell), but I’m also interested in looking at metastasis. It’s an exceptionally hard problem — how do we find dormant tumours? Perhaps if we understand tumour dormancy we can make cancer a chronic disease. We have to understand the difference between cells that progress and those that don’t at the exact moment the tumour process is reinitiated. I’ve got some ideas about this — and the fantastic microscopy facility here is helping — but to be honest, I’m not confident we’ve identified of a good way to do it yet.

With regard to my research philosophy, I’ve always enjoyed solving puzzles; I think that’s what first appealed to me about RNAi — we went from understanding its molecular basis, to building tools that allowed investigators to exploit it to study gene function in mammals. People ask me what themes my lab will have, but I prefer projects to grow organically. I’ve previously described my lab as organised chaos, but that’s the way I like to do science, as you’re more creative and opportunistic. It feels really good to be out on the edge — there’s a certain amount of fear as things may not work, but after a while you get a sense for what’s likely to work and what isn’t. And along with that comes a lot of excitement about what’s possible — what can be done. At Cold Spring Harbor I really felt that anything was possible, and I hope to retain that attitude in my new scientific home in Cambridge.”

This story was originally published in Pioneering Research: Cancer Research UK’s annual research publication for 2014/15. Find more at cruk.org/pioneeringresearch