NEWSWEEK: You won the Nobel Prize for uncovering the process of RNA interference. Can you explain to our readers exactly what this entails?
Andrew Z. Fire: Our observations built on previous work by others in plants and fungi. When people tried to put extra copies of a gene into a plant, instead of getting more of the result, they got less. It seemed there was a way that the organism had to sense that there were extra copies—and not just extra copies but some that were also probably somehow messed up. So the organism had to be able to detect unwanted activity. And if it sensed this activity, which is going to come out in the form of some kind of RNA [an intermediary between stable DNA, which stores information in our genes, and proteins, which act on the information] that is unusual, it went ahead and got rid of them. We studied something similar with worms.
What did you find?
We wanted to know how an organism can tell the difference between foreign RNA and what’s inside. It turns out it’s a fairly simple structural distinction. If we took double-stranded RNA and put it into cells, that could shut a gene down pretty efficiently. The organism is looking for RNA where both strands present in the cell (normally, it’s just one strand). That was essentially the result. We could put two strands of an RNA in and it would shut down the corresponding gene…The cell not only gets rid of double-stranded material but looks for anything that looks similar and gets rid of it too.
You studied RNA interference initially in microscopic roundworms. How does the process work in human cells?
Researchers knew that if you put double-stranded RNA into human cells, you don’t get a specific knockdown of corresponding genes. It just shuts down the whole cell. So what other people did based on the knowledge of the double strand is to look for some kind of biochemical intermediate in the process that might be sufficient to give you a specific biologic single gene effect without the whole cell shutdown effect. A few years after our paper was published, Thomas Tuschl [an associate professor at Rockefeller University] figured out something called SiRNA, a specific double-stranded RNA, which could do interference in human cells [to shut down a gene without shutting down the whole cell].
What are the potential applications for humans?
The biggest medium-term application is researchers who are studying a given question. For example, let’s say we’re interested in an individual cancerous tumor—a population of cells that are doing something against our best interest—and want to know what makes it so we can get rid of it. One way is to go on a gene by gene basis through all the thousands of genes and decrease the function of each one at a time to figure out which are needed for the tumor to grow. The hope in that case is to find the gene that is needed for the tumor but not required for normal cell growth. So far, the experiment has been in a lab. If you had that information and really believed RNA to be a gene-silencing tool, though, you could imagine taking double-stranded RNA into a sick person and making them healthy. People are exploring that, but delivering it is very complicated. Some clinical trials are being done in tissues that are very good at receiving the RNA material like the eye and the liver.
What diseases are being targeted in the clinical trials?
One is macular degeneration, which causes blindness. The reason it’s moved so quickly to clinical trials mostly has to do with the ethics of doing clinical trials. No other treatment is approved for macular degeneration. Also, the eye is fairly self-contained. It’s easier to test it in the eye in a clinical trial than injecting it into the bloodstream…
Are there other possible benefits beyond using RNA as a drug?
The other half of it is that once you have a catalogue of genes that are important for a given tumor or virus or disease, you can look in the pharmaceutical guide to known drugs that block that gene product. Then we’re not going to go to RNA interference for a cure, but to the drugstore essentially.
Has this been done already?
Yes, one good example is in Holland, at the Netherlands Cancer Institute, where researchers were looking at a rare cancerous tumor. They discovered some genes in the pathway that they knew could be inhibited by aspirin. They gave the patients a very concentrated form of aspirin to fight the tumor. One hopes that these sort of discoveries will be used not just to make miracle medicines but to guide treatment.
What other diseases could be targeted with this type of treatment?
People are talking about the hepatitis C virus, which is extremely nasty. One can imagine both injecting double stranded RNA into the body and identifying drugs that target certain genes. The other area where there is ongoing work is in respiratory viruses. In any given case, there’s a chance therapy would work and also a chance it wouldn’t be sufficient.
What work are you most excited about now?
I’m excited by all of it. Those of us doing the science are excited about how the process works and what it’s doing there in the cells…
What are you working on now in the lab?
Most of our work is with small roundworms. The basic question is how the RNA honing mechanism is regulated and how it is turned on when it is needed and down when it is not needed, and how the process of targeting specific sequences seems to be set up to benefit the cell.
You will split a $1.37 million prize with Craig Mello. How do you plan to spend the money?
I have no ideas yet. It’s all still a little unreal.
