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DARPA is soliciting innovative research proposals to generate and evaluate novel biological tools and countermeasures that facilitate the safe pursuit of advanced genome editing applications, while reducing the risk of, and providing new protections against potential engineered genetic threats. Proposed research should investigate radically different approaches to integrate biosafety and biosecurity features into new genome editing biotechnologies and their derivative applications (e.g., gene drives) at their inception. Implementation of a “safety first” approach to the development of gene editors and derivative tools will foster, and even accelerate, responsible innovation while mitigating the risk of unintended consequences.
DARPA’s Safe Genes program will address the underlying need for transformative innovation in biosafety and biosecurity in the context of emergent genome editing tools and their derivative technologies, including gene drives (self-perpetuating gene editing systems that bias inheritance in populations through sexual reproduction). The program will deliver novel biological capabilities to facilitate the safe and expedient pursuit of advanced genome editing applications while also providing the tools and methodologies to mitigate the risk of unintentional consequences or intentional misuse of these technologies. The Safe Genes program will support the development of the tools, methodologies, and foundational knowledge that are prerequisite for the safe application of advanced gene editing technologies beyond a research and laboratory setting. The emergence of advanced genome editing tools has created the ability to modify genetic material in a manner that is precise, rapid, cost-effective, and broadly accessible. CRISPR-Cas represents the newest and most widely adopted tool in the genome engineering toolkit, which already consists of a diverse set of molecules including mega nucleases, transposons, recombinases, protein nucleic acids, zinc-finger nucleases, and TAL (transcription activator-like) effector nucleases. These editing tools have not only enabled significant advancements in genetic research, including manipulation of previously inaccessible genomes, but have also set the groundwork for transformative applications.
In order to realize the full potential of genome editing and derivative technologies, new tools and methodologies to safely control activities, limit off-target effects, and reverse unwanted outcomes of these technologies is desirable. In the case of nuclease-based tools, the efficiency of target site modification and the resulting “edited” sequences can vary significantly based on target sequence, location in the genome, and how the intrinsic cellular repair processes resolve the consequent DNA breaks for a given editing event. In addition, the introduction of DNA breaks elsewhere in the genome beyond the intended target site (off-target activity) can exceed on-target modifications1 , posing a significant threat to safety and health of the host organism. New strategies to improve the efficiency, specificity, and overall predictability of gene editing systems have been encouraging2,3,4; however, significant gaps remain before these tools can be applied for practical use.
Safe Genes will encompass a four year effort organized in two phases of two years duration each. During Phase I, performer teams will establish the fundamental tools and in vitro and in vivo proofs-of-concept for their selected Technical Area(s). The Phase II period will focus on in vivo and in situ demonstration of efficacy, safety, specificity, and stability of the selected tools and methodologies. Intermediate and end-of-phase milestones, outlined in this BAA, will be required in each phase to evaluate progress throughout the program. Quantitative metrics to assess technical performance towards milestones will be established by the proposer and agreed upon by DARPA (see Section 1.4 for details). In addition, all proposers are expected to implement and adhere to strict biosafety and biocontainment measures, described below (see Section 1.5 General Requirements).
- Proposal Abstract Due Date, October 6, 2016
- Proposal Due Date, November 17, 2016
Areas of Interest
The program consists of three Technical Areas (TAs) to be addressed concurrently:
- TA1: control of genome editing activity
- TA2: countermeasures and prophylaxis
- TA3: genetic remediation