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As Key Data Loom, Nobel Winner Mello Reflects on RNAi “Sci-Fi” Story

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I was on to something big. I just always liked science. I always feel like there’s some major discovery just waiting over the horizon.

X: What were you trying to do with those initial experiments?

CM: We were not directly studying gene silencing. We were trying to use gene silencing just as a tool, and noticed that there were really surprising things going on. And that’s how a lot of discoveries get made, when you notice something unexpected and you decide to pursue it. If you notice something unexpected you might ignore it, too, or think that you made a mistake, but in this case it was obvious there was something interesting going on. It was just a matter of trying to figure out what it was and how the mechanism works. And we’re still working on it today. There’s still a lot to learn.

X: Once the initial discoveries were made, did you get involved in forming a company?

CM: I stayed very centered on the basic research. I don’t think I really appreciated [commercializing discoveries] until my own daughter developed type 1 diabetes back in 2001, when she was 1 year old. It was of course heartbreaking and scary to have a child who is absolutely dependent on science and medicine to stay alive. It really gets brought home to you when someone you love is alive because of molecular or genetic medicine.

X: Once you made your initial discoveries, what did you do with your patents?

CM: We made the decision to license very broadly. We wanted to make it available to researchers at the lowest cost possible. We really didn’t expect there were going to be drugs for a long time anyway, but if they came, then we’d worry about royalty streams at that point. So we made a very cheap license, and frankly didn’t make that much money off of the foundational IP, which is about to expire.

It was a learning curve, because making a patent easy to license isn’t necessarily the best way to commercialize. It actually creates an opportunity for someone to make a follow-on discovery and make a huge amount of money off of what you might call an improvement in an existing technology. That is kind of what MIT was able to do around the technology that Alnylam ended up licensing—essentially they were able to make that the franchise for the company. I don’t know what MIT got, but I bet it’s a lot more than what UMass got for its role in the more foundational IP.

X: Do you regret that?

CM: I don’t regret it personally, because I think there were positive aspects, too, about making the IP easy for people to license. But some folks on the business side of the university probably regret it. I think it could’ve made the university a lot more money than it did. That part I kind of do regret.

X: You did ultimately form one RNAi company, RXi Pharmaceuticals. But it hasn’t distinguished itself in the same way that, say, Alnylam has. Why not, and what did you take from it?

CM: Unfortunately, we didn’t have investors with the vision needed to go through all the ups and downs. We never raised the kind of money that Alnylam raised. The field definitely requires a lot of continued investment and reinvestment. In an academic setting we can make those investments through federally funded and privately funded research. It’s harder for a small company. Unless it can raise a lot of money and run a big research team, it can’t keep pace with what’s being done in academia.

X: Did you think the RNAi field moved too fast?

CM: I can’t blame anybody because hindsight is always much better, 20/20 as they say. But at the time that companies first began to invest directly in RNA interference, they were investing in delivering these natural RNAs that were incredibly unstable. They were almost guaranteed to fail. I think a lot of people underestimated the hurdle that delivery represented. In retrospect it should’ve been pretty clear that a lot of investment in chemistry was going to be necessary to get a potent molecule over the finish line.

In the whole field there was a lot of hyperbole, because it was really cool from a science side that cells could do this and that they had these mechanisms. But everyone I advised, I told them, look: there are obstacles. Maybe that’s why we couldn’t raise much money [at RXi], because I was too honest or something.

X: Are you worried that if Alnylam fails here, it will set the field back once again?

CM: The only thing that would concern me at this point is surprising toxicity or something. That would be very bad, there’s no nice way to put it. But if there are problems, I don’t think it’s going to end this field. One trial failing would just be another one failing. But I think it’s going to be successful—and it’s just the beginning.

X: As gene therapy, CRISPR, and other methods advance, is RNAi being surpassed?

CM: The nice thing about RNAi is you can withdraw the drug and you haven’t permanently modified the individual, whereas with gene therapy [and gene editing technologies] you’re stuck with any kind of negative ramifications. The fact is that the delivery problems have been solved for some target tissues and are being solved for others like the brain. In the meantime we found out that the duration of effect is surprisingly long. So I’d say the upside is much bigger than the downside in all of this.

X: What does the future hold for RNAi?

CM: It’s a whole new ballgame now. The hard work has been done, or a lot of it. It’s time to start making drugs. And that requires a big investment, but now it’s an investment that’s much more likely to see a return.

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