Scientists from both campuses of The Scripps Research Institute (TSRI) have been awarded a total of $7.9 million from the Defense Advanced Research Projects Agency (DARPA) of the U.S. Department of Defense. The two teams will build what is, in essence, an artificial immune system, comprising vast “libraries” of different types of molecules from which will emerge individual compounds to detect or neutralize an array of biological and chemical threats.
Under the auspices of DARPA’s new Fold F(x) Program, the Jupiter, Florida team, led by Professor Tom Kodadek and Assistant Professor Brian Paegel, will receive $5.7 million; the La Jolla, California team, led by Professor Floyd Romesberg, will receive $2.2 million.
Developing New Libraries
In Jupiter, Kodadek, Paegel and their colleagues will develop libraries of functional compounds and engineer highly automated strategies for rapid synthesis, screening and production. These libraries will contain molecules each tagged with a DNA “barcode” that uniquely identifies the molecules’ chemical structure. “We hope to create chemical libraries and screening platforms that are truly revolutionary in their capabilities,” Kodadek said.
For Paegel, the DARPA grant will expand his lab’s current program in drug discovery technology development. His team has developed a microfluidic circuit that screens single compounds suspended on artificial beads, processing more than 200,000 compounds in a matter of hours. “We envision next-generation small molecule discovery as a distributed enterprise, not just limited to facilities like our molecular screening center in Jupiter,” Paegel said. “Our ultra-miniaturized approach will make this vision a reality.”
Evolving New Functions
In La Jolla, Romesberg and his colleagues will develop variants of oligonucleotides—short, single-stranded DNA or RNA molecules—modified to be both stable and to have increased functionality. The team will leverage a system known as SELEX (Systematic Evolution of Ligands by Exponential Enrichment) to evolve novel function molecules. “We plan to modify the classical SELEX methodology with two innovations from our previous work,” Romesberg said.
The first innovation, developed by Tingjian Chen, a postdoctoral fellow in the Romesberg lab, is a DNA polymerase evolved to recognize nucleotides with modified sugars, which impart the corresponding oligonucleotide polymers with increased thermal stability and resistance to enzymes that typically degrade oligonucleotides.
The second innovation is an unnatural base pair, developed as part of the team’s recent expansion of the genetic alphabet, which can be modified with linkers to site-specifically attach different functionality to oligonucleotides. The combined technologies should allow for the evolution of novel biopolymers that are both stable and possess virtually any desired binding or catalytic activity.
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