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.
Depending on how they’re designed, production of the RNA switches can be regulated by exposing the bacteria to a particular chemical. By controlling how much of the “on” and “off” RNAs are made, it’s also possible to regulate protein production over a continuum, not just turn it totally on or off.
While other gene-expression techniques need to be engineered for a particular gene, Collins says, the RNA-based switch “can be used to control any gene of interest.” Other switches rely on proteins to regulate gene expression. But the use of proteins requires several steps, which means they’re not as fast to make as the RNA switches.
The microbial self-destruction system Collins made to demonstrate the switches uses two genes that, when expressed at the same time, create two proteins that cause the cell to burst. Both genes are set to “off” in all cells by the ribosome-binding RNA component until an external chemical stimulus causes the cells to produce the second piece of RNA, freeing up the ribosome to make the cell-killing proteins.
Such a kill switch could be useful in microbes designed to, for example, break down environmental toxins. Once the microbes have cleaned up a toxin, “you could spray the area with an innocent compound that triggers cells to expire on command,” says Collins. The kill switch could also be coupled to other synthetic biology tools such as genetic clocks in order to design bacteria that live for a given number of days.
These switches make it possible “to do the kinds of things people like me struggle to do,” says Robertson. One of the main challenges for a company like Joule, he says, is complying with regulations about environmental containment of genetically modified organisms, and Collins’s switch could help.
Collins is currently working to combine the switches to make what he calls tunable “switchboards.” “We want to tune genes like a rheostat,” he says. Such a switchboard might be used to control a population of cells so that they first put their energies toward growing their population. Then, when engineers deem it timely, they can administer chemical signals that cause the cells to gradually ramp up production of a fuel, for example.
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