THE discovery that genes can be 鈥渟ilenced鈥� using a technique called RNA interference is creating a stir in medicine. And now it seems the technique is even more powerful than thought, able to switch off genes permanently by physically altering our DNA.
This could open up new avenues for fighting diseases, and perhaps even explain the workings of our cells. 鈥淪o far we have only shown this for one gene, for cells in a test tube,鈥� says Kevin Morris at the Beckman Research Institute in Duarte, California. 鈥淏ut I鈥檓 optimistic that it has wider implications.鈥� His team is already planning to adapt the technique to shut down the CCR5 gene that HIV needs to enter cells.
When genes are switched on, they are copied into messenger RNA, which is then used to make the protein. RNA interference, or RNAi, relies small pieces of RNA called siRNAs which either trigger the destruction of matching messenger RNA, or prevent it being turned into a protein.
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But this works only as long as siRNAs are present, so repeated doses would be needed for most therapies. In plants and yeast, however, RNAi can also work via a third, less transient mechanism 鈥� triggering chemical changes in DNA. siRNAs that target the 鈥減romoter鈥� sequence at the start of a gene cause methyl groups to be added to the promoter DNA, switching the gene off permanently.
No one had ever shown that this happens in mammalian cells. 鈥淚f it wasn鈥檛 for a couple of tricks, we also might not have found it,鈥� says Morris. Because of his interest in HIV, Morris used a related virus called feline immunodeficiency virus (FIV) to add an extra gene to human cells. Then he tried targeting its promoter sequence with siRNAs. The team found that the promoter sequence did become methylated, turning off the gene permanently.
However, if an existing gene was targeted, rather than one delivered by FIV, the promoter sequence did not become methylated. Additional studies suggest that FIV plays a crucial role, opening up the cell nucleus so the siRNAs can reach the promoter sequence (Science, DOI: 10.1126/science.1101372).
鈥淚t鈥檚 a very exciting result to find this same mechanism shared by plants, yeast and now humans. The therapeutic implications are huge,鈥� says Robert Martienssen, an RNAi researcher at Cold Spring Harbor Laboratory, New York.
Methylation plays a key role in reproduction and development; it may be one reason why cloning is so difficult, for instance. No one understands how the process is controlled, but Martienssen suggests that our cells might control methylation by producing their own siRNA-like molecules.
Some researchers are sceptical. If this type of silencing does not work without FIV, they point out, it probably does not normally take place in cells. And many labs have failed to see similar results despite massive efforts.
These issues should be resolved quickly. Several attempts to replicate these experiments are already under way. 鈥淭here are a lot of people working on this,鈥� says Morris.