Generative Optogenetics - DARPA BTO
Executive Summary:
DARPA’s Biological Technologies Office is awarding $1.7M–$1.99M Phase 1 awards to teams developing optically controlled, template-free DNA or RNA synthesis in living cells under the Generative Optogenetics (GO) program. The program uses a staged process beginning with 5-page abstracts due January 16, 2026, followed by invitation-only oral proposals.
How much funding would I receive?
If selected, you would receive a fixed-price Phase 1 award of $1.7M for Research Objective 1 (RO1) or $1.99M if addressing both RO1 and the optional Research Objective 2 (RO2). DARPA anticipates multiple Phase 2 awards for teams that successfully pass the Phase 1 Concept Design Review at month 9.
What could I use the funding for?
The DARPA GO program aims to develop a protein complex, referred to here as a nucleic acid compiler (NAC), that can be expressed within living cells to allow an end user to program genetic instructions into those cells, template-free, using nothing but light to transfer the genetic information to the cells (Figure 1). The central challenge of developing the NAC involves integrating protein domains / subunits for precise optical responsiveness (i.e., optogenetic domains), substrate binding, and enzymatic activity into a functional complex of proteins (i.e., a holoenzyme). While many of these domains have precedence as either engineered or naturally occurring proteins, the challenge lies in developing the interoperability and seamless integration of these domains into a functional holoenzyme, the NAC. Advances in computational design, which allow for accurate prediction of protein structures and binding interactions, are essential for optimizing substrate binding sites, allosteric interactions, and domain integration. These computational tools are crucial for designing the NAC to respond rapidly and predictably to optical signals, enabling the synthesis of long, accurate nucleic acid sequences that can precisely alter cellular function as intended. Moreover, expression of the NAC itself must not be deleterious to host cell function or viability.
To develop the NAC, the GO program consists of two Research Objectives (ROs):
-
All GO performers MUST address RO1, which focuses on developing the core capability of the NAC for template-free DNA or RNA synthesis, where optical inputs precisely dictate the sequence of the nucleic acid produced by the NAC in a living cell. A NAC can be designed using a variety of architectures, ranging from extremes of a single, monolithic protein comprised of multiple domains to multi-unit complex (Figure 2). To accomplish this, performers will need to solve three critical challenges: achieving multiplexed optogenetic control, ensuring stability and the precise polymerization of the NAC-nucleic acid sequences, and successfully integrating the molecular components into the NAC.
1.3.2.1. Multiplexed Optogenetics
Achieving distinct multiplexed optical programming of the NAC presents a significant challenge, as it requires precise engineering of multiple protein domains capable of responding to distinct wavelengths of light. Currently optogenetic systems have been demonstrated to support up to three distinguishable wavelengths (red, green, and blue) within a cell, but expanding this capability is essential for enabling the NAC to incorporate nucleotides with high precision. This expansion may involve optimizing existing optogenetic domains or developing new ones with improved photophysical properties, such as enhanced spectral separation, faster on/off kinetics, and reduced phototoxicity. By leveraging photons as massless information carriers, these optogenetic domains must facilitate precise molecular motion and interaction, ensuring accurate nucleotide incorporation and enzymatic activity. Computational protein design tools and directed evolution approaches offer potential strategies to overcome these limitations, enabling the multiplexed optical control required for the NAC to function effectively.
1.3.2.2. Stable and Precise Polymerization
The NAC must achieve precise polymerization, including initiating synthesis, maintaining processivity to stabilize elongating nucleic acid sequences, and efficiently releasing the synthesized strand to meet program metrics for length and accuracy. The NAC design may need to include strategies to address the challenge of selectively binding the correct nucleotide substrate at the correct time from the mixture of these substrates that exists within the cellular environment. Overcoming this challenge will be necessary for the NAC to achieve desired sequence accuracy metrics for the GO program. Additionally, the stability of the complex formed between the NAC and the nucleic acid sequence it is synthesizing must be sufficient to avoid unwanted dissociations that will result in truncated sequences. Similarly, NACs that synthesize single-stranded nucleic acids will need to overcome issues associated with secondary structures (e.g., hairpin loops) in the DNA/RNA molecule that could interfere with continued synthesis. Achieving stable NAC-based nucleic acid synthesis may necessitate designs that incorporate accessory subunits/domains to improve processivity by holding on to the newly synthesized strand and/or single-stranded binding proteins/domains that hinder the formation of problematic secondary structure in DNA/RNA molecules. Finally, the performers will need to resolve the challenge of releasing synthesized sequences, which may involve strategies such as natural termination signals or engineering inducible cleavage mechanisms.
1.3.2.3. Integration of Molecular Components
A fully functional NAC must integrate optogenetic, substrate binding, catalytic, and other domains into a cohesive holoenzyme capable of precise and predictable operation. This integration presents significant challenges, as the domains must interact seamlessly to ensure accurate nucleotide incorporation and overall system functionality. For example, optogenetic domains may need to regulate substrate binding to ensure that nucleotide incorporation into the DNA or RNA sequence aligns precisely with the optical illumination pattern. Similarly, designs involving protein subunit binding must coordinate these interactions with substrate binding domains to maintain synchronization and fidelity. Addressing these challenges may involve strategies such as identifying domains that interact effectively to control the NAC, ensuring synchronous activation and deactivation of multiple NACs within a living cell, and optimizing domain interfaces for efficient communication. Potential approaches include leveraging computational tools to map allosteric pathways, modeling molecular motion to predict domain interactions, and employing high-throughput empirical methods to refine and validate integration strategies.
-
OPTIONAL, GO performers may elect to address RO2 in addition to RO1. Note that GO performers shall not pursue RO2 without addressing RO1. RO2 addresses the challenge of achieving high-fidelity synthesis in NACs by incorporating mechanisms to detect and filter out sequence errors. Some applications of GO technology will necessitate NACs capable of synthesizing longer sequences, and it is anticipated that increasing the length of the sequence will increase the likelihood it contains errors. To this end, RO2 aims to investigate the tradeoffs involved in designing a NAC with enhanced error detection capabilities to meet stricter error tolerance requirements, including how these design choices impact overall NAC performance. There are several potential approaches to address RO2 (Figure 3), an example includes developing doublestranded synthesis methods that incorporate components such as mismatch-binding proteins (e.g., MutS homologs). These proteins can either flag errors for downstream correction or be engineered to degrade faulty sequences, ensuring that only high-fidelity nucleic acid strands are retained. Other strategies may include utilizing base editors to identify nucleotide incorporation errors or synthesizing palindromic sequences that fold onto themselves to increase error detection. RO2 provides an opportunity to explore innovative solutions to error mitigation while considering the tradeoffs in performance, complexity, and scalability inherent to these approaches.
Are there any additional benefits I would receive?
Beyond the direct award, companies benefit from:
DARPA Validation & Technical Credibility
Selection by DARPA’s Biological Technologies Office (BTO) signals exceptional technical rigor and alignment with DARPA’s high-risk, high-reward biotechnology priorities. This validation materially strengthens credibility with strategic partners, investors, and future government customers.
Non-Dilutive Advancement of Breakthrough Biotechnology
GO awards enable teams to mature foundational, high-risk biological technologies using non-dilutive capital. Companies can advance technically ambitious platforms without sacrificing equity, increasing both technical readiness and enterprise value.
Access to DARPA Program Leadership & Expert Networks
Awardees engage directly with DARPA program managers, technical reviewers, and advisory working groups throughout the program. This access provides rare insight into government priorities, technical expectations, and future transition considerations.
Commercialization Support & Structured Market Exposure
GO performers receive guidance from an Independent Commercialization and Consulting Group (ICCG) and participate in structured commercialization workshops and pitch events. These activities help teams refine business hypotheses, market positioning, and transition strategies alongside experienced investors and operators.
Enhanced Visibility Across the Biotechnology Ecosystem
Participation in a DARPA flagship biology program elevates company visibility across the defense, academic, and commercial biotech ecosystems—positioning awardees as leaders in next-generation genetic and optogenetic technologies.
Stronger Long-Term Exit & Transition Potential
By maturing core technology under DARPA sponsorship and demonstrating government-backed technical progress, companies strengthen their positioning for follow-on funding, strategic partnerships, and long-term acquisition or licensing opportunities.
What is the timeline to apply and when would I receive funding?
The process begins with a 5-page abstract due January 16, 2026.. Selected teams are invited to present an in-person Oral Proposal Package. Phase 1 awards follow oral presentations, subject to funding availability. Phase 1 runs 12 months, with a major down-selection at month 9. Phase 2, if awarded, runs an additional 30 months
Where does this funding come from?
Funding is provided by the Defense Advanced Research Projects Agency (DARPA) within the Department of Defense, through DARPA’s Biological Technologies Office (BTO), using Other Transaction (OT) for Prototype authority.
Who is eligible to apply?
Eligible applicants include U.S. and non-U.S. companies, startups, universities, nonprofits, and research institutions, including nontraditional defense contractors and small businesses. Federally Funded Research and Development Centers (FFRDCs) and government entities may apply with additional eligibility documentation. All performers must be able to accept an OT agreement and comply with export control and CUI requirements.
What companies and projects are likely to win?
Competitive teams will demonstrate deep expertise in protein engineering, optogenetics, enzymatic nucleic acid synthesis, and computational biology, with a credible plan to integrate these into a functioning system in living cells. DARPA emphasizes technically bold, high-risk approaches that directly address program metrics rather than incremental biology research.
Are there any restrictions I should know about?
Yes. The program excludes human and animal research, embryonic stem cells, bioprospecting for new natural proteins, substantial hardware development, in vitro assembly workflows, and systems that operate outside the central dogma. Phase 2 work involves Controlled Unclassified Information (CUI), requiring NIST 800-171–compliant systems and DARPA security coordination.
How long will it take me to prepare an application?
Most teams should expect 4–6 weeks to prepare a competitive abstract, including technical framing, team formation, and compliance review. Invited teams will need additional time to prepare a detailed Oral Proposal Package, cost models, and milestone plans under DARPA’s OT structure
How can BW&CO help?
Our team specializes in complex federal R&D proposals and can:
Triple your likelihood of success through proven strategy and insider-aligned proposal development
Reduce your time spent on the proposal by 50–80%, letting your team focus on technology and operations
Ensure you are targeting the best opportunity for your project and positioning your company for long-term growth under Federal & State R&D Initiatives.
How much would BW&CO Charge?
$4,000 for Abstract Submission.
Fractional support is $300 per hour.
For startups, we offer a discounted rate of $250 per hour to make top-tier grant consulting more accessible while maintaining the same level of strategic guidance and proposal quality.