Tiny Switch Shuts Down Genes

Telling a gene when to turn off has so far required scientists to send in messengers that speak the language of the cell–molecules such as hormones or sugars. Now, researchers have found that by first splicing the right RNA sequences into a gene, they can control it with any small molecule they choose. The technique, reported in today’s issue of Science, might one day help control genes used in gene therapy without interfering with the cell’s other functions.
The new control technique, as designed by biochemists Michael Green and Geoffrey Werstuck, of the University of Massachusetts Medical Center in Worcester, employs two pieces that bind strongly together–a short stretch of RNA called an aptamer that is inserted into the gene and a molecule small enough to enter the cell easily. When the molecule is sent in, it should bind to the RNA and create a blockade that prevents the gene from making protein.
The researchers tested this method by first selecting a small molecule, a dye called H33342, then mixing it with a solution containing hundreds of different RNA pieces until they found several that bound to it tightly. Next they inserted two of these aptamers into a gene taken from a bacterium and slipped that modified gene into a culture of hamster cells. At first, the cell had no trouble making protein from the gene with the aptamer. But when the researchers added the dye, protein levels dropped by up to 90%, depending on the amount of dye used.
Nearly any small molecule might be chosen in place of the dye, if RNA aptamers can be found that bind to it. “It could be almost any innocuous chemical,” Green says.
The researchers say that in the future when genes are sent into a tissue as gene therapy, small molecules may be able to keep them turned off when they’re not needed. Andy Ellington, a biochemist at the University of Texas, Austin, who applauds the new technique, points out that although there are still relatively few opportunities to use gene therapy, “there will come a time when [this technique] will be very important.”
–Kevin Boyd