20 August 2010

Controlling Microbial Genes: Beyond Synthetic Biology

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. _TR
Kill switch: From top left to bottom right, these images show bacteria dying over the course of a few minutes. Researchers flip a genetic switch that causes the bacteria to make proteins that cause them to burst.
Credit: PNAS

Scientists at Boston University have developed the ability to control the activity of any microbial gene -- reducing or even stopping any gene's protein synthesis activity.
...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.

...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.

...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. _TechnologyReview

By starting with a gene-packed bacterium, the scientists could conceivably "tune" the cell to behave just like a wide range of other bacterial species -- depending upon which genes were "switched on or off" at the time. The only thing missing would be a means to generate new controllable genes on the fly.

This type of development will actually be blended into the field of synthetic biology -- but it will extend the field significantly. Now, instead of simply designing new life forms which will behave as designed, synthetic biologists can design "programmable life forms" which can serve as flexible test beds for a wide range of genetic experiments.

The possibility for the transfer of such techniques to mammalian cells should be setting off warning klaxons among the dieoff.orgy lefty-Luddites from Berkeley to Manhattan to Brussels. And to think they're worried about genetically modified foods!


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