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Reflections and Revolutionary Implications of RNAi


By Allison Proffitt

Sept. 13, 2007 |  BOSTON — Last October, Craig Mello shared the Nobel Prize in Physiology or Medicine for his work on RNA interference (RNAi). In his keynote address at the annual DDT* conference before a standing room only crowd last month, Mello reflected on the ten months since winning the Prize. He discussed a free and open scientific community, funding opportunities, the challenges and changes in medicine, and of course, award-winning worms.

Mello recounted hours spent brainstorming on the phone with fellow laureate Andrew Fire, switching the phone between sore ears. “Those brainstorming sessions are incredibly important,” Mello said. “I don’t think we give enough credit to the importance of those kinds of discussions with your lab group and lab members. It’s important to have people... who think differently than you do that you can bounce ideas off of. I encourage everyone... to be more open and free with their ideas. It’s a little bit risky to share your information, but chances are you’ll advance your understanding much more rapidly.”

Mello sees great potential in the mechanism of RNAi. In lower organisms such as Caenorhabditis elegans, which Mello and Fire worked with, RNAi is a crucial defense against viruses. But RNAi isn’t just an immune response.

“It is the ‘Google’ of the cell,” Mello explained. “You have a cell packed full of information and the cell needs to coordinate expression of those genes... One way you can achieve that coordination is by using information from the gene — small pieces of RNA — to find corresponding sequences elsewhere in the cell, just like you would search Google to find a play by Shakespeare.”

Cell IT
Mello advocated for a shift in the biomedical community’s view of DNA and RNA. “Everybody always thought that DNA was the brain of the cell. That’s where all the information was stored; that’s what controls everything in the cell. But I think that now we can think of RNA as sort of using the DNA as hardware,” he said. “The RNA and proteins are the software inside our cells. After all, all of our differentiated cells have the same DNA, but obviously they do very different things. So the basic idea is that the RNA and proteins can program the DNA to do different things and that can play a role in differentiation of cells.”

RNAi is crucial to improving our understanding of gene regulation, evolution, and drug platform targets, Mello said, and will help speed research on gene pathways. “The implications of RNAi could be revolutionary,” he said.

Mello listed three major challenges to developing RNAi therapeutics — stabilization, delivery, and silencing efficacy — but summed them up as delivery, delivery, delivery. “There’s a lot of promise and progress already in that area,” Mello said, mentioning drug carrier peptides, biopolymers, systemic mechanisms, and nanotechnology as options.

While meeting with Vice President Dick Cheney and other officials after his Nobel Prize, Mello stressed the historic opportunities that exist for lawmakers to further groundbreaking research made possible by the Human Genome Project and discoveries like RNAi. “I tried to explain it to George Bush,” Mello joked. “You drill the well, and the oil is flowing, but we need a pipeline.”

Mello challenged researchers as well. “I think we need, all of us, as we’re out there in our communities, to project to everyone what a wonderful opportunity we have in biomedical research and drug development to really make a difference in people’s lives. With the genome project and all the great tools we have for gene expression profiling, PCR, RNAi, and so forth, we really are advancing medical research at a great pace. I think it’s unethical not to invest more money at every level,” he said.

“We may be on different teams but we all have the same objective. Biomedical research is something that can’t only be done in academia, and it can’t only be done in industry. We need to come together and we need to keep that focus on the big picture.”

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* Drug Discovery and Development of Innovative Therapeutics (DDT), World Trade Center, Boston; August 7-10, 2007

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