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October 21, 2016

DARPA to Fund Research on Controlling, Inhibiting, and Reversing Genome Editing

  • Agency
  • Genetics/Genomics

GenomeWeb - A new funding program from the US Department of Defense's Defense Advanced Research Projects Agency (DARPA) seeks to develop technologies to control, inhibit, or reverse genome editing in a variety of organisms.

"Automakers install brakes in cars not so that people have to drive slowly, but so that people can drive fast and stop when they need to," Renee Wegrzyn, DARPA program manager for the Safe Genes program, told GenomeWeb in an email. "What have not been sufficiently advanced to date are technologies that position safety at the forefront of genome editing, both to enable innovation from responsible scientists and to guard against irresponsible actors who might accidentally or intentionally release genetically modified organisms."

While technologies for spatio-temporal control of CRISPR/Cas9 genome editing or reversal of so-called "gene drive" technologies have already been reported, Safe Genes is the first to address biosafety from this three-pronged approach.

Proposals could address genome editing at any level, from the design of genome editing nucleases like Cas9, to the regulatory circuitry in the cell that controls them, to constructs that deploy gene editors like gene drives.

The program has no specified budget, Wegrzyn said, and DARPA will evaluate each proposal independently, rather than weigh them against other perhaps similar proposals. "DARPA may elect to fund all or part of qualified proposals," she said.

The Safe Genes program launched Sept. 7, and while the deadline for DARPA to provide feedback on proposal abstracts has passed, it will be accepting proposals until Nov. 17. The program will fund projects in three categories: control of gene editing, countermeasures and prophylaxis, and genetic remediation.

DARPA's interest in genome editing stems from both an interest in staying out in front of potential biosecurity threats as well as developing applications useful for the US military.

"Our focus is on the creation and prevention of strategic technological surprise, operating as first movers in areas of science and engineering that are ripe with possibility," Wegrzyn said. "The field of genome editing is clearly one such powerful area, but it's advancing mostly independently of DARPA investments."

Safe Genes is designed to address risks from both bio-terror — intentional misuse of biotechnologies — and unintended consequences, what Wegrzyn dubbed "bio-error."

"The steep drop in the costs of genomic sequencing and gene editing toolkits, along with the increasing accessibility of this technology, translates into greater opportunity to experiment with genetic modifications," she said. "This convergence of low cost and high availability means that applications for gene editing—both positive and negative—could arise from people or states operating outside of the traditional scientific community. Safe Genes technologies will provide the foundational knowledge and new platform capabilities to broadly address bio(t)error threats."

The program has three technical objectives: developing technologies that provide spatial, temporal, and reversible control of genome editors in living systems; novel small molecule and molecular countermeasures that provide prophylactic and treatment options to prevent or limit genome editing in organisms and protect genome integrity in populations; and the capability to eliminate unwanted engineered genes from environments and restore systems to their genetic baseline state.

Multiple research groups have pursued spatiotemporal control of genome editing, especially with CRISPR/Cas9, using a variety of controls like light and small molecules to tightly manage the editing window. Studies have suggested that those technologies could help reduce off-target effects. Some work has also been done on inhibiting CRISPR/Cas9, drawing on viral counter-measures against CRISPR, which evolved as an innate bacterial immune system against phage attack.

And in November 2015, researchers from Harvard University led by George Church and Kevin Esvelt published a method to reverse a gene drive using another gene drive.

While that idea has been demonstrated in yeast, completely erasing the existence of gene drive activity could be trickier. Last week, in an interview with Xconomy, Esvelt said, "No current CRISPR-[Cas9]-based system can return the population to its baseline state the way they are requesting."

Wegrzyn noted that genome editing has the potential to affect several fields DARPA has historically funded. The ability to finely study infectious pathogen, host, and vector biology is attractive. But the agency has hope the technologies developed under Safe Genes could one day be used in more nascent fields.

"DARPA views the field of organism engineering for biomanufacture as an area that could deliver significant benefits to the Defense Department in terms of producing novel chemicals, materials, and coatings," Wegrzyn said. "Reliable control of genome editing is critical to realizing those benefits."

According to the DoD's Fiscal Year 2016 budget, it will spend more than $30 million this year to develop "living foundries," or biologically-based manufacturing, and another $142.1 million over the next four years.

The DoD also launched this year a new $10 million program entitled "Applying Biological Complexity at Scale," which seeks to "enhance global-scale stability, transform hostile environments, and ensure human well-being." Among that program's research goals is to "investigate dynamics and thresholds for transgene stability/instability in systems of infectious disease vectors."

The reason DARPA has not set a total funding amount for the Safe Genes program is to "maximize the quality and creativity of proposed solutions," Wegrzyn said. And while the agency does not cap funding, "cost realism is an important evaluation criterion for proposers to include," she said.