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September 22, 2015

Protein-Based Sensors Expand Synthetic Biology Repertoire

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    Model of zinc finger proteins binding to their target DNA (orange). [Thomas Splettstoesser (www.scistyle.com),via Wikimedia Commons]

    Engineering proteins to detect specific DNA, RNA, or peptide sequences may not be a new idea, but a new approach taken by synthetic biology engineers at the Massachusetts Institute of Technology (MIT) is as interesting as it is elegant. 

    The MIT researchers developed a flexible system of proteins that sense particular sequences of DNA, triggering cells to undergo a designed molecular response. The responses have the potential to range from switching cell proliferation genes on or off, to activating apoptotic pathways in targeted cancer cells.

    "There is a range of applications for which this could be important," explained senior author James Collins, Ph.D., professor of medical engineering and science in MIT's Department of Biological Engineering and Institute of Medical Engineering and Science (IMES). "This allows you to readily design constructs that enable a programmed cell to both detect DNA and act on that detection, with a report system and/or a respond system."

    The findings from this study were published recently in Nature Methods through an article entitled “DNA sense-and-respond protein modules for mammalian cells.”

    The investigators utilized specialized types of DNA-binding proteins known as zinc-fingers (ZFs), which have the capacity to be programmed to recognize any DNA sequence.  

    "The technologies are out there to engineer proteins to bind to virtually any DNA sequence that you want," noted lead author Shimyn Slomovic, Ph.D., postdoctoral fellow in Dr. Collins laboratory. "This is used in many ways, but not so much for detection. We felt that there was a lot of potential in harnessing this designable DNA-binding technology for detection."

    To create their new system, the researchers coupled the ZFs DNA-binding abilities to a cellular consequence—in this case, production of fluorescent GFP when the ZFs recognized a DNA sequence from an adenovirus. The research team achieved this by exploiting a type of protein known as an intein—a short protein that can be inserted into a larger protein, splitting it into two pieces. The split protein pieces, known as exteins, only become functional once the intein removes itself while rejoining the two halves.

    In this study, the researchers divided an intein in two and then attached each portion to a split extein half and a zinc finger protein. The zinc finger proteins are engineered to recognize adjacent DNA sequences within the targeted gene, so if they both find their sequences, the inteins line up and are then cut out, allowing the extein halves to rejoin and form a functional protein. The extein protein was a transcription factor designed to turn on the GFP gene.

    "Since this is modular, you can potentially evoke any response that you want," Dr. Slomovic stated. "You could program the cell to kill itself, or to secrete proteins that would allow the immune system to identify it as an enemy cell so the immune system would take care of it."

    The researchers are currently adapting this system to detect latent HIV proviruses, which remain dormant in some infected cells even after treatment. Understanding more about how proviruses function could help scientists find ways to permanently eliminate them.

    "Latent HIV provirus is pretty much the final barrier to curing AIDS, which currently is incurable simply because the provirus sequence is there, dormant, and there aren't any ways to eradicate it," said Dr. Slomovic.

    The researchers were excited by their findings and noted that while treating diseases using this system is likely many years away, it could be used much sooner as a research tool. For example, scientists could use it to test whether genetic material has been successfully delivered to cells that they are trying to alter genetically. Cells that did not receive the new gene could be induced to undergo cell death, creating a pure population of the desired cells.

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