Biologists often speak of switching genes on and off to give microbes new abilities–like producing biofuels or drugs, or gobbling up environmental toxins. For the most part, though, it’s nearly impossible to turn off a gene without deleting it (which means you can’t turn it on again). This limits biologists’ ability to control how much of a particular protein a microbe produces. It also restricts bioengineers’ ability to design new microbes.
Now researchers at Boston University, led by biomedical engineering professor James Collins, have developed a highly tunable genetic “switch” that offers a greater degree of control over microbes. It makes it possible to stop the production of a protein and restart it again. The switch, which could be used to control any gene, can also act as a “dimmer switch” to finely tune how much protein a microbe would produce over time.
The researchers made a highly effective microbe “kill switch” to demonstrate the precision of the approach. For years, researchers have been trying to develop these self-destruction mechanisms to allay concerns that genetically engineered microbes might prove impossible to eradicate once they’ve outlived their usefulness. But previous kill switches haven’t offered tight enough control to pass governmental regulatory muster because it was difficult to make it turn on in all the cells in a population at the same time.
The field of synthetic biology involves redesigning networks of genes to enable microbes to perform useful functions efficiently. An example of such a function would be the production of a protein that leads to a desired end product, such as a fuel or a drug. But it’s hard for bioengineers to control how a cell will use the gene it’s given, and this makes it difficult to control the organisms en masse. A community of cells inside a biofuel reactor, for example, won’t behave uniformly, even if the cells are genetically identical clones.
“You’re trying to regulate an entire population [of microbes],” says Dan Robinson, senior vice president of biological sciences at Joule Unlimited, a company designing microbes that convert sunlight into fuels. (Joule was not involved with the research, but Collins is a scientific advisor to the company.)
Collins’s switch, described online in the Proceedings of the National Academy of Sciences, turns a modified gene on and off. The switch is created by sequences of DNA that can be added to any gene that a bioengineer wants to regulate. When the cell takes the first step toward expressing that gene–making an intermediate molecule of RNA that can be “read” to make the relevant protein–it also creates the RNA switch. When the first, “off” RNA switch is made, it latches onto the ribosome, preventing it from making a particular protein. When the second, “on” switch is made, it pulls the first RNA switch off of the ribosome and binds to it the switch, freeing the ribosome to resume production.\