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Gene Synthesis Agilent, Darpa to Revamp 20-year-old Process

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Sometimes it pays to dream big. That’s what led to the $6.1 million collaboration among Agilent Laboratories, the University of Colorado, and the Defense Advanced Research Projects Agency to develop a new method of synthesizing DNA.

Principal investigator Doug Dellinger of Agilent Labs recalls the beginning of the partnership: “It started with DARPA having this totally pie-in-the-sky goal.” The agency wanted to be able to rapidly produce 10,000 long sequences of DNA; it also wanted a DNA synthesizer the size of a Pentium microchip with self-contained reagents, Dellinger says. “I kind of beat them up a little bit on some of their assumptions.” His solution: “Well, let’s chop this up into smaller pieces … and maybe in 10 years we’ll get to their pie-in-sky thing.”

First step — improving DNA synthesis, a technology that hasn’t changed since it was published 20 years ago by Marvin Caruthers. Dellinger, who later worked with Caruthers, is now teaming up with his lab at the University of Colorado for the DARPA project. Says he, “Caruthers and I, for many years, have been having discussions about how [we] would … improve the technology.”

The rate-limiting factor was the incompatibility of the four chemical steps required to add each additional base to a sequence, Dellinger explains. That meant lots of washing to separate steps — and it didn’t help that the reagents were noxious, expensive to acquire and dispose of.

So the new synthesis method, still in progress, would use different chemistries to condense four steps into two (relying on a buffered aqueous solution instead of the harmful solvents). “We can synthesize DNA in about half the time you would typically do it,” Dellinger says.

DARPA, which is kicking in $3.7 million, hopes that this technology will bring it one step closer to a micro-synthesizer. Agilent, which contributed the rest, plans to use the technique for its own manufacturing, particularly in Dellinger’s array program.

— Meredith Salisbury

 

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