Bespoke genetic circuits rewire human cells
Engineered DNA device could coax cells to differentiate - or die - on demand.
By Ewen Callaway
Biologists have constructed a programmable genetic "circuit" that can rewire cells to respond on demand to just about any signal desired. One version of the circuit makes human cells susceptible to an antiviral drug--but only if they are making abnormal amounts of a protein implicated in cancer.
The technique could have a wide range of uses, for example coaxing stem cells to transform into different tissues once inside the body or making plants activate a defense program in response to low nutrients.
"The broad idea here is being able to control cellular behavior and cellular decisions in response to potentially any protein of interest," says Christina Smolke, a bioengineer at Stanford University in California, who led the new study, published online November 25 in Science.
The main challenge in controlling how cells behave has been how to tap into cellular pathways. To do this, Smolke and her team constructed a stretch of DNA that acts as genetic circuit. When inserted into cells and transcribed into RNA, the circuit encodes its protein product only when it senses the presence or absence of a particular target protein inside the cell.
For example, the team created a circuit containing the gene for an enzyme that renders cells sensitive to the antiviral drug ganciclovir. They inserted a stop signal into the gene sequence, which prevents the cell from using the resulting messenger RNA to produce a working protein. But next to the stop signal they encoded a short stretch of RNA--an aptamer--that recognizes a signaling protein called beta-catenin, which is overproduced by some tumors. When the aptamer binds its target, it causes the cell to splice the messenger RNA in a way that removes the stop signal, allowing enzyme production.
Deadly device
To test their circuit, the researchers stimulated human cells to produce extra beta-catenin--as if they were cancer cells --then treated them with ganciclovir. Cells that contained the circuits were killed by the drug.
"This is very clever, beautiful work," says Wendell Lim, a synthetic biologist at the University of California, San Francisco.
In theory, the circuit could contain any gene, and aptamers can be designed to recognize any protein. By tweaking the "wiring" of such circuits, they could make cells respond to either the presence or absence of a desired protein, says Smolke. Including more than one aptamer sensor on the same circuit could even allow researchers to trigger different responses to different combinations of proteins.
Adam Arkin, a systems and synthetic biologist at Lawrence Berkeley National Laboratory in California, says the new technique is a breakthrough because of its flexibility. Other efforts to commandeer cell signaling have tended to be "one-offs of bespoke engineering", he says, whereas Smolke's circuit can be used to tap into a wide range of biological pathways in different types of cells.
Cell-hacking circuits are years away from the clinic, but Smolke thinks they could eventually be combined with other experimental treatments to control where and when they act within the body. For example, pluripotent stem cells capable of generating a range of tissues could be instructed to respond to protein cues within the body that cause them to differentiate into the desired one. Cancer-killing immune cells could contain circuits that keep them from attacking healthy cells.
"If we got good at gene therapy, then you could imagine these sophisticated sensing systems that would only deliver the kill or the gene when it's in the exact right location," agrees Arkin.
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