TR: Do you think RNA interference arose as a way to combat viruses?
AF: Most people in the field would accept the proposal–by people working in plants initially, not us–that this is an antiviral system. That’s a little less clear in mammalian systems, but I think it’s going to be true as well. One of the functions of the whole [RNAi] system is antiviral, but there are probably other functions too, and we would like to learn about those functions in worms.
TR: Are you involved in any of the startups developing RNA-interference therapeutics?
AF: Only as a cheerleader. I don’t have any direct involvement, but I know a bunch of the people at Alynylam, Sirna, Isis, and a couple other companies involved. I’ve enjoyed watching them. People involved in those companies have been really careful about what they say because it’s not clear whether it’s going to work next year, whether the first trial or the fifteenth trial is going to work, how many times we’ll have to go back into the lab for any given target or any given disease application to really figure out things more. I think both the technical side and the financial people are aware that it’s got to be a long-haul project that might bear fruit in the short term but that likely will be something that will work in the long term.
The principle is very good. If you could get RNA to the target, you could have some really cool therapeutics. Not that you could cure everything, not that everything would work perfectly, but there are some things. Delivery is a major issue in all of it. There’s some good creative work that’s been done, but each time a new delivery system is invented, or even a modification is done, that needs its own clinical testing for efficacy, safety, and specificity. That’s something that makes the work by nature not immediate. That’s not to say that some of the beginning trials that are going on won’t be successful, but I think we’re all hoping that there’s more to come.
TR: What are you working on now?
AF: We’re working on basic mechanisms of silencing in our favorite model, which is still the worm, and how those mechanisms are regulated and what they do for the organism itself. [We are also looking for] gene-silencing events in disease. There are people here [at Stanford] who have a huge knowledge of different details of normal and diseased tissue, and where we might look for specific cases where disease and optimal treatment correlate with the engagement of the gene silencing mechanism. We’re trying to figure out in specific cases how [the characteristics of a tissue] correlate with the engagement of the gene-silencing mechanism. We look forward to trying to find examples where we understand what’s going on and find cases where we can guide therapy or guide intelligent [treatment] decisions, for tumors in particular, based on the molecular character of certain tissues.
TR: Can you give me an example of a disease in which gene silencing is implicated?
AF: Cancer is really the major player in that area. Lots of genes are silenced in cancer; that’s been known for quite a while. Those seem to involve small-RNA-dependent mechanisms. Some of the kinds of genes that are silenced are involved in controlling the cell cycle: if you silence those genes you end up with cells that can become malignant. It’s a multi-hit phenomenon; there are many different changes in the genetic capabilities of cells that go on in cancer. It looks from preliminary results elsewhere that some of the changes likely involve small RNAs.
TR: Does your work on gene silencing in germ cells have any applications to stem-cell research?
AF: Germ cells [which give rise to sperm and eggs] seem to need to keep themselves going based on some intrinsic mechanisms that are similar to stem-cell mechanisms. The RNAi machinery seems to be involved in that, but no one knows how that connection is set up. There are some interesting tie-ins between the RNA regulatory field and stem-cell research. There’s a lot of interest in adult stem cells and how RNAi might be used either to understand them or to begin to take apart the mechanisms that are responsible for their function.