Over the past decade, Phillip Zamore's group at the University of Massachusetts Medical School has done pioneering work in elucidating RNA silencing pathways. His seminal studies on RNA interference (RNAi) led to his involvement in the creation of the Cambridge, MA–based RNAi flagship Alnylam. In 2009, Zamore gave a talk at the Boston SciCafé on allele-specific huntingtin targeting in a rapid-onset mouse model of Huntington disease. And last year, he joined a team working on an adeno-associated virus–based gene therapy company, Voyager Therapeutics. Nature Biotechnology caught up with Zamore to talk about his formative experiences in starting companies.
Nature Biotechnology : How did you first get involved in Alnylam?
Phillip Zamore: Alnylam was conceived right after Tom Tuschl, Phil Sharp, Dave Bartel and I reported that siRNAs were produced from long, double-stranded RNA and acted as the guides for RNAi in animals (flies). The therapeutic implications of a small RNA that could direct the destruction of a complementary mRNA were pretty clear, but from conception to the birth of a funded company took about two years. The scary part for me was how to start a company while simultaneously growing my new lab at UMass Medical School. Phil Sharp solved that problem when he introduced us to Christoph Westphal, who was then with Polaris. Christoph took on the task of organizing the company, securing financing, hiring the right people. In retrospect, we were incredibly lucky to have worked with so many talented people from the very beginning, particularly Christoph.
NBT: What strengths do you feel you have brought to these startups?
PZ: My two mentors who taught me the importance of translational research were Zuoshang Xu and Neil Aronin. Zuoshang recruited me to help him develop allele-specific siRNAs as a potential therapy for ALS [amyotrophic lateral sclerosis]. Neil and I have worked together to develop RNAi-based therapy for Huntington's disease for more than a dozen years. Our current efforts at Voyager Therapeutics to use adeno-associated virus to deliver microRNA-like triggers of RNAi as therapy for neurodegenerative diseases trace their origins to my original collaborations with Zuoshang and Neil. Voyager, a company backed by Third Rock and co-founded by my UMass colleague Guangping Gao, Mark Kay from Stanford University, Krystof Bankiewicz from the University of California, San Francisco, and me, is another example of starting with the right people. I think I add the most value to a company the same way I add value to my own lab: by thinking hard about a problem, testing my ideas against data and not pretending I can multitask. All my attention needs to be on the problem at hand. It's corny, but the hat needed for both translational and basic research is a thinking cap. And I work hard not to pretend I know something about running a business. Just the opposite; the best part of being an academic founder of a company is that you get to learn about managing projects and people from the experts.
NBT: What remaining roadblocks do you see to successful commercialization of RNAi?
PZ: Science and biotech are both subject to the whims of fashion. RNAi is a perfect example of the Heidi principle: one day you're in; the next day you're out—but in reality nothing particularly notable changed between the two days. RNAi chugged along from the very beginning. The perceived 'downs' for RNAi were rarely real setbacks. A setback is when progress is reversed, not when the rate of progress slows. Some problems took longer to solve than others, but there are now many RNAi trials in the clinic, and I'm optimistic that we'll soon see drugs that improve patients' lives. For Alnylam, the drug that is furthest along targets TTR amyloidosis.