DARPA-BAA-16-17.pdf

Broad Agency Announcement Biological Control

BIOLOGICAL TECHNOLOGIES OFFICE

DARPA-BAA-16-17

February 18, 2016

DARPA-BAA-16-17, Biological Control

TABLE OF CONTENTS

PART I: OVERVIEW INFORMATION

PART II: FULL TEXT OF ANNOUNCEMENT

1. Funding Opportunity Description

1.1. PROGRAM OVERVIEW

1.2. PROGRAM INTRODUCTION AND SCOPE

1.3. PROGRAM STRUCTURE

1.4. PROGRAM OBJECTIVES

1.5. PROGRAM METRICS AND MILESTONES

2. Award Information

3. Eligibility Information

3.1. ELIGIBLE APPLICANTS

3.2. COST SHARING/MATCHING

3.3. OTHER ELIGIBILITY REQUIREMENTS

4. Application and Submission Information

4.1. ADDRESS TO REQUEST APPLICATION PACKAGE

4.2. CONTENT AND FORM OF APPLICATION SUBMISSION

4.3. FORMATTING CHARACTERISTICS

4.4. SUBMISSION DATES AND TIMES

4.5. FUNDING RESTRICTIONS

4.6. OTHER SUBMISSION REQUIREMENTS

5. Application Review Information

5.1. EVALUATION CRITERIA

5.2. REVIEW AND SELECTION PROCESS

6. Award Administration Information

6.1. SELECTION NOTICES

6.2. ADMINISTRATIVE AND NATIONAL POLICY REQUIREMENTS

6.3. REPORTING

6.4. ELECTRONIC SYSTEMS

7. Agency Contacts

8. Other Information

8.1. INTELLECTUAL PROPERTY

8.2. PROPOSERS DAY

PART I: OVERVIEW INFORMATION

Federal Agency Name: Defense Advanced Research Projects Agency (DARPA), Biological Technologies Office (BTO)

Funding Opportunity Title: Biological Control

Announcement Type: Initial Announcement

Funding Opportunity Number: DARPA-BAA-16-17

Catalog of Federal Domestic Assistance Numbers (CFDA): 12.910 Research and Technology Development

Dates (All times listed herein are Eastern Time.)

o Posting Date: February 18,2016 o Proposal Abstract Due Date: Friday, March 18, 2016, 4:00 PM o Proposal Due Date: Friday, April 29, 2016, 4:00 PM o BAA Closing Date: Friday, April 29, 2016, 4:00 PM o Proposers’ Day: February 22, 2016

Anticipated individual awards: Multiple awards are anticipated.

Types of instruments that may be awarded: Procurement contracts, cooperative agreements, or Other Transactions.

Agency contact o Technical POC: Elizabeth Strychalski, Program Manager, DARPA/BTO o BAA Coordinator: DARPA-BAA-16-17@darpa.mil

DARPA/BTO

ATTN: DARPA-BAA-16-17

675 North Randolph Street Arlington, VA 22203-2114

Teaming information: See Section 3.3 and Section 8.2 for further information.

mailto:DARPA-BAA-%23%23-%23%23@darpa.mil

PART II: FULL TEXT OF ANNOUNCEMENT

1. Funding Opportunity Description The Defense Advanced Research Projects Agency (DARPA) often selects its research efforts through the Broad Agency Announcement (BAA) process. This BAA is being issued, and any resultant selection will be made, using procedures under Federal Acquisition Regulation (FAR)

35.016 and the Department of Defense Grant and Agreement Regulatory System (DoDGARS) Part 22 for Grants and Cooperative Agreements. Any negotiations and/or awards will use procedures under FAR 15.4, Contract Pricing, as specified in the BAA (including DoDGARS Part 22 for Grants and Cooperative Agreements). Proposals received as a result of this BAA shall be evaluated in accordance with evaluation criteria specified herein through a scientific review process.

DARPA BAAs are posted on the Federal Business Opportunities (FedBizOpps) website, https://www.fbo.gov/, and, as applicable, the Grants.gov website at http://www.grants.gov/. The following information is for those wishing to respond to this BAA.

DARPA is soliciting innovative research proposals in the area of control of biological systems.

Proposed research should investigate innovative approaches that enable revolutionary advances.

Specifically excluded is research that results primarily in incremental or evolutionary improvements to the existing state of practice.

1.1. PROGRAM OVERVIEW

The objective of the DARPA Biological Control program is to build new capabilities for the control of biological systems across scales—from nanometers to centimeters, seconds to weeks, and biomolecules to populations of organisms—using embedded controllers made of biological parts to program system-level behavior. This program will apply and advance existing control theory to design and implement generalizable biological control strategies analogous to conventional control engineering, for example, for mechanical and electrical systems. The resulting advances in fundamental understanding and capabilities will create new opportunities for engineering biology.

Specifically, the Biological Control program will demonstrate tools to rationally design and implement multiscale, closed-loop control of biological systems, through the development of biological controllers, testbeds to evaluate control of system-level behavior, and theory and models to predict and design effective control strategies. The resulting capabilities will be inherently generalizable to a variety of biological systems. Successful teams will integrate and apply these capabilities to demonstrate a practical proof-of-principle biological solution to a proposer-defined application relevant to the U.S. Department of Defense (DoD).

1.2. PROGRAM INTRODUCTION AND SCOPE

Control is essential to engineer a system of interacting components for a desired behavior.

However, the tools and techniques needed to successfully design and build control into biological systems are prohibitively lacking, when compared with the variety and sophistication of those available for nonbiological systems. The innate control exhibited by biological systems, despite their inherent complexity, indicates that closing this gap is possible. While control of https://www.fbo.gov/ http://www.grants.gov/ biological systems has been a theme in research, most recently in the field of synthetic biology, major technical challenges remain. Efforts to design and implement effective control of biological systems have been hampered by difficulties in applying and adapting established theory from conventional control engineering, as well as a lack of adequate experimental tools to assemble biological parts into controllers with measurable, predictable performance, across the spatial, temporal, and organizational scales relevant to biological systems.

Today, biological control strategies are typically open-loop, use controllers assembled from a limited number of biological parts, and target behavior with minimal or uncharacterized effects across scales. For example, genetic circuits often control the production of small molecules or fluorescent proteins. Although these outputs may result in a system-level behavior—for example, the fluorescence of a cell or cell population—these typically serve as sensors only. To operate as controllers for this program, the resulting optical properties should directly enable the biological system to perform programmable work in a closed-loop manner at system-level spatial, temporal, and organizational scales relevant to meet a practical need. Furthermore, biological controllers today often require considerable ad hoc, empirical optimization, due to an overall lack of generalizability and adequate predictive capabilities for implementation in complex and/or undercharacterized biological systems. This program will leverage empirical measurements into predictive capabilities to inform the design and implementation of broadly-applicable approaches for biological control. Several studies1-5 are representative of promising initial progress.

To advance capabilities beyond the state of the art, the Biological Control program will lay a theoretical and technological foundation for control of biological systems. Looking to control engineering for nonbiological systems, this program will apply and advance existing capabilities for implementation in biological systems. Realizing this vision will require experimentally-validated theories and models to aid the rational design of control strategies and controllers that operate across scales—from nanometers to centimeters, seconds to weeks, and biomolecules to populations of organisms—to target system-level behaviors relevant to practical applications.

Rigorous characterization of the operation and performance of the controllers will further require testbeds consisting of a naturally simple or synthetically simplified biological system, as well as hardware for quantitative measurements and dynamic environmental control. The resulting measurements will enable empirical and unambiguous connection of input stimuli to output effects, to inform the prediction of system-level behavior. The program will leverage innate mechanisms for biological control and ensure reliable, generalizable, closed-loop control of system-level behavior compatible with the distinctive properties of biological systems, such as stochasticity, emergence, and complexity.

Biological systems have considerable economic and strategic impact for national security, and control of those systems has broad practical and intellectual implications, for example, to

1 Ang, J., Bagh, S., Ingalls, B. P. & McMillen, D. R. Considerations for using integral feedback control to construct a perfectly adapting synthetic gene network. J Theor Biol 266, 723–738 (2010).

2 Mishra, D., Rivera, P. M., Lin, A., Del Vecchio, D. & Weiss, R. A load driver device for engineering modularity in biological networks. Nat Biotechnol 32, 1268–1275 (2014).

3 Chandra, F. A., Buzi, G. & Doyle, J. C. Glycolytic oscillations and limits on robust efficiency. Science 333, 187– 192 (2011).

4 Harris, A. W. K., Dolan, J. A., Kelly, C. L., Anderson, J. & Papachristodoulou, A. Designing Genetic Feedback Controllers. IEEE Trans Biomed Circuits Syst (2015). doi:10.1109/TBCAS.2015.2458435.

5 Hsiao, V., de los Santos, E. L. C., Whitaker, W. R., Dueber, J. E. & Murray, R. M. Design and implementation of a biomolecular concentration tracker. ACS Synth. Biol. 4, 150−161 (2015).

advance biotic-abiotic interfaces, control complex systems, develop active materials with life-like properties, understand complexity and life, and harness the tremendous promise of engineered biological systems for human use. Such capabilities and understanding will find initial practical application at the conclusion of this program, in a proof-of-principle demonstration of a biological solution to a proposer-defined application relevant to DoD, such as marine biofouling and biocorrosion on naval vessels or other problems of equivalent biological complexity and significant consequence to national security. To ensure the safe development of capabilities for control of biological systems, work performed in this program will proceed in laboratory settings only.

1.3. PROGRAM STRUCTURE

The Biological Control program is divided into three Phases to deliver increasingly sophisticated, broad, and practical capabilities for control of biological systems, culminating in a demonstration of a proposer-defined, proof-of-concept biological solution to an application of relevance to DoD. During Phase 1 (18 months), teams will develop an initial biological controller, testbed, and predictive models for the controller and its effects on the initial target system-level behavior. During Phase 2 (18 months), teams will develop additional controllers with more stringent performance criteria, target additional system-level behaviors, and demonstrate multiple controllers simultaneously. During Phase 3 (12 months), teams will build a proof-of-concept biological solution to a proposer-defined application of relevance to DoD, such as combating biofouling and/or biocorrosion, fighting antibiotic resistance, improving biomanufacturing platforms, or enabling environmental bioremediation. Phase 3 will emphasize translating capabilities built in Phase 1 and Phase 2 to demonstrate the application of biological control strategies and rational design of biological controllers for a specific practical application.

The ability to predict system-level behavior from high-quality measurements and theoretical models is critical to the success of the Biological Control program and should be emphasized, along with a control theoretic perspective, in the proposed approach.

To accomplish the objectives of each Phase, three Technical Areas (TAs) will be addressed concurrently within each Phase: (TA1) biological controllers; (TA2) testbeds to evaluate controller performance; and,, (TA3) theory and models to support the prediction of system-level behavior and design of biological control strategies. TA1 should consist primarily of wet laboratory research. TA2 should consist of both wet laboratory research and hardware development for measurement and environmental control. TA3 should consist primarily of theory, modeling, and computer simulation, emphasizing control theory, to develop predictive models and design control strategies for biological systems.

Each team must fully address all Phases and TAs. Successful teams will engage both theorists and experimentalists in active collaboration across TAs to meet the goals of the program, with approximately equal emphasis in the proposed approach on theoretical and experimental components. Proposals that address only a subset of Phases or TAs or that do not involve teams with deep expertise across the relevant theoretical and experimental fields of science and technology will be considered non-conforming.

DARPA expects that the proposer-defined, proof-of-concept demonstration in Phase 3 will be based on the capabilities developed in Phase 1 and expanded in Phase 2. For this reason, proposers should focus the technical discussion of their proposals primarily on the concepts and approaches for Phase 1 and Phase 2, while still outlining a clear and credible technical plan for

Phase 3. Experimentally, DARPA anticipates that the biological system comprising the testbed in Phase 1 and Phase 2 should be suited to developing understanding and capabilities for control of biological systems generally and may not be the same as the demonstration system in Phase 3, which should be suited to a specific proof-of-concept application relevant to DoD. However, DARPA expects that the capabilities from Phase 1 and Phase 2 will generalize and transfer readily, with minimal modifications, to the demonstration system in Phase 3. Therefore, strategies for integrating, expanding, and generalizing capabilities for control of biological systems, as well as fully leveraging experimental results and tools against predictive theory and models—and vice versa—should be elaborated throughout. Proposals should also discuss mitigation of technical challenges that may arise within each Phase and TA.

Throughout the program, teams will interact with an independent verification and validation (IV&V) team to test and validate progress. The IV&V team will consist of subject matter experts from Government, Federally Funded Research and Development Centers (FFRDCs), and/or academia and domain experts. This independent team will experimentally test the reproducibility and performance of capabilities for the control of biological systems developed in Phase 1 and Phase 2 for TA1 and TA2 of the Biological Control program. As teams will be expected to collaborate closely with the IV&V team, proposals must budget and include plans for delivering to the IV&V team all materials, protocols, and domain knowledge necessary to experimentally reproduce demonstrated capabilities for control in Phase 1 and Phase 2. Should duplication of the testbed and/or associated specialized equipment present an unreasonable cost, teams should outline a secondary plan to allow the IV&V team access to the team’s laboratory, as necessary, to test and validate progress. IV&V team members will be required to complete appropriate nondisclosure agreements, to protect intellectual property. To avoid potential conflicts of interest, performers for DARPA-BAA-16-17 will not be allowed to compete for the IV&V contract. DARPA-BAA-16-17 is not soliciting proposals for IV&V.

To ensure the safe development of capabilities for control of biological systems, work performed in this program will proceed in laboratory settings only. Efforts to manipulate or study organisms in any context not completely insulated from the natural environment will be deemed non-conforming to this solicitation. Proposers must ensure and demonstrate throughout the program that all methods and demonstrations of capabilities comply with national guidance for manipulation of genes and organisms and follow all guidance for biological safety and biosecurity. Proposals should address any potential safety and security issues that the development of the proposed capabilities might pose and include a discussion of approaches and strategies to monitor, mitigate, and manage these risks during technology development. In addition, all proposed efforts must meet any applicable regulations designed to protect human health and the environment promulgated by the Environmental Protection Agency, the Food and Drug Administration, the Department of Agriculture, the Department of Health and Human Services, and any other cognizant agencies within the Government. Proposers must also comply with any applicable state or municipal regulations or ordinances governing biotechnology practices.

1.4. PROGRAM OBJECTIVES

DARPA anticipates that the Biological Control program will provide predictive, closed-loop, generalizable means for controlling various biological systems and programming diverse system-level behaviors across multiple scales. Examples of potential system-level behaviors to be controlled include, but are not limited to, behaviors that may be decomposed, individually and/or in combination, into growth and reproduction, adaptation and evolution, sensing and responding, and metabolism. Control of these behaviors may be combined to achieve a desired overall system-level behavior for a target practical application. Approaches that emphasize generalizability of control strategies are strongly encouraged; capabilities for control of biological systems should find potential applicability beyond the specific biological system and demonstration application proposed. Regardless of the specific approach, proposed approaches to the Biological Control program must include the following features, with additional details provided in Section 1.5:

Biological Controller(s): Control of system-level functions must be implemented using biological controller(s) comprised of biological parts and embedded in a biological system.

o Must be constructed using natural and/or synthetic biological parts only, to the exclusion of nonbiological technologies, such as nanoparticles and NEMS/MEMS devices.

o Must be consistent with closed-loop control, by providing measurements of the state of the biological system, comparing with and driving to the desired state, and maintaining that desired state within programmed limits.

This control loop may not use nonbiological technologies.

o Must effect output(s) that result ultimately in controlled system-level behaviors, regardless of the scales of the biological controller(s) and their components.

o Must be sufficiently modular to allow simultaneous use of multiple controllers without significant loss of predictability or performance.

o Should be generalizable and transferable to other biological systems with minimal modifications.

o Should, to the extent possible, follow a rational design process based on theory and/or models; therefore, capabilities for control of biological systems developed primarily through screening or similar methods, with no basis in predictive theory and/or models, are inconsistent with the program goals.

Testbed: The performance of the biological controller(s) must be measured and evaluated through the use of a testbed consisting of a biological system and hardware for quantitative measurements and dynamic environmental control.

o Must include a biological system that is sufficiently simple so that predictable connections between input stimuli and output effects may be established with confidence from measurements and models.

o Example biological systems include, but are not limited to, life-like systems (e.g., cell-free systems, protocells, and genetically minimized cells), characterized microbes (e.g., E. coli and S. cerevisiae), or multicellular systems (e.g., roundworms and hydra).

o Must allow for reproducible, quantitative measurements of a variety of system parameters related to the controller inputs and outputs, system state, and target system-level behaviors to be controlled, sufficient to enable predictability across spatial, temporal, and organizational scales relevant to control.

o Must allow time-course measurements of dynamic behavior, in addition to end-point measurements.

o Must include environmental control sufficient to evaluate controller performance reproducibly and for a range of static and dynamic environmental conditions.

o Must be appropriate to study a variety of controllable system-level behaviors, consistent with the innate behaviors of the biological system.

o Must be chosen such that results for control are reasonably generalizable between different biological systems, beyond the specific biological system used for the testbed.

Theory and Models: The rational design of biological controllers and associated control strategies must be grounded in theory and predictive mathematical models.

o Must provide prediction to inform the design and implementation of biological controllers and control strategies, as opposed to merely describing experimental results.

o Must model biological controllers that implement various control strategies that are grounded in and/or advance existing control theory.

o Must provide testable quantitative predictions for testbed behavior and controller performance.

o Should be readily adaptable and generalizable for modeling control for biological systems beyond that chosen for the testbed, including, but not limited to, the proposer-defined application of relevance to DoD.

o Must identify methods of tuning controller output(s), as appropriate to the system-level behaviors targeted for control.

o Should be implemented in computational tools to aid design and implementation of control strategies and biological controllers.

o Should include the development of new control theory and modeling approaches, as appropriate.

Demonstration: The program will culminate with a practical demonstration of biological control addressing a proposer-defined application relevant to DoD.

o Should constitute a proof-of-concept demonstration at the laboratory scale.

o Must proceed in closed laboratory environment only, without release of any kind into the environment.

IV&V: The biological controllers and testbed must be made available for independent verification and validation (IV&V) to assess reproducibility and capabilities for control with respect to the program metrics and milestones.

1.5. PROGRAM METRICS AND MILESTONES

For DARPA to evaluate the effectiveness of a proposed approach to the stated program objectives, DARPA hereby promulgates the following program metrics that may serve as the basis for determining whether satisfactory progress is being made to warrant continued funding of the program. Although the following program metrics are specified, proposers should note that DARPA has identified these goals with the intention of bounding the scope of effort, while affording the maximum flexibility, creativity, and innovation in proposing solutions to the stated problem.

Performer progress will be assessed against the milestones and metrics defined below, as well as end-of-period and intermediate milestones defined by the proposer. Certain specific metrics must be set by the proposers in their proposals (e.g., percent error tolerance on steady-state measurement), based on what is believed to be attainable. Where such ‘proposer-defined metrics’ are expected is made explicit in the metrics and milestones defined below. Proposers are encouraged to provide additional qualitative and quantitative proposer-defined metrics, as appropriate, beyond those requested explicitly below, with a strong preference for quantitative metrics. Proposers should provide a technical and programmatic strategy that conforms to the Biological Control program schedule and presents an aggressive plan to fully address all program metrics and milestones, whether they are specified in this solicitation or proposer-defined. Proposals should cite explicitly the qualitative and quantitative criteria that the proposed effort will achieve in accordance with the metrics and milestones for each Phase and TA.

Proposers must also include a detailed management plan that supports effective communication and collaboration within teams, across relevant fields of science and technology and between theorists and experimentalists. For the purposes of this solicitation, the following additional definitions and clarifications apply:

Complexity:

o Refers to the high degree of interconnectedness of the scales and components of a biological system, in a manner that complicates prediction and control of system-level behavior at the state of the art.

Generalizability:

o Control strategies based on system-agnostic theory and models, once well-understood and implemented in one biological system, should be straightforward to adapt for use in other biological systems.

Control across scales:

o Refers to mechanisms at one or more scales operating in such a way as to control a behavior at one or more different, typically larger, scales.

o For example, for an application of DoD relevance involving marine biofouling, biomolecular mechanisms at nanometer characteristic scales may ultimately control the system-level structural behavior of a biofilm at millimeter scales relevant to preventing biofouling and reducing drag.

System-level behavior:

o Behaviors targeted for control that manifest at the organizational level of a whole biological system, for example, a cellular community, multicellular organism, or ecosystem, given that the whole system is approximately centimeter-scale or smaller and compatible with laboratory scale experiments.

o Examples include, but are not limited to, behaviors that may be decomposed, individually and/or in combination, into growth and reproduction, adaptation and evolution, sensing and responding, and metabolism, to facilitate generalization to other biological systems.

PHASE 1 (BASE) 18 MONTHS

Deliver one or more biological controller(s) and testbed, with associated predictive theory and models, for which one or more system-level behavior(s) are demonstrably controlled in a closed-loop manner.

Phase 1 TA1: Controller(s) Design and build one or more biological controller(s) consistent with Phase 1 TA2 and

Phase 1 TA3 capable of achieving closed-loop control of one or more proposer-defined, system-level behavior(s).

o Compose controller(s) of biological parts only, and include biological mechanisms, such as sensors, for closed-loop control.

Demonstrate input signals, which may take a variety of forms, including, but not limited to, chemical, thermal, mechanical, or optical, to program the controller, while outputs are biological and integral to the biological system in TA2.

Demonstrate control of at least one system-level behavior, by achieving three (3) or more steady-state, proposer-defined outputs associated with the target behavior within proposer-defined tolerances in relevant quantities, such as time to achieve steady-state value and deviation from setpoint value.

Integrate controller(s) into the testbed in TA2, to evaluate controller performance according to proposer-defined metrics, and demonstrate stable integration for a proposer-defined period of two or more times greater than a relevant system-level characteristic timescale (e.g., doubling time for cells, passages for serial batch culture, or life cycle time for multicellular organisms).

For biological controllers developed in Phase 1, provide detailed schematics, protocols, domain knowledge, and other information and/or materials as necessary and relevant to the IV&V team.

Phase 1 TA2: Testbed Develop a testbed, consisting of a biological system and hardware for measurements and environmental control, compatible with the target system-level behavior(s) and controller(s) in TA1.

o Demonstrate a testbed that includes a biological system, which is a naturally simple or synthetically simplified biological system of appropriately reduced complexity to ascertain predictable connections with confidence between inputs and outputs for control from measurements and models in TA3.

Demonstrate application of inputs to program the controller(s).

Demonstrate measurement of one or more parameters at each scale of length, time, and/or organization relevant to control of the target system-level behavior(s).

o Demonstrate measurands and measurement methods consistent with TA3, informative for evaluation of the control strategy and controller, and yielding measurements relevant to proposer-defined metrics.

o Where possible and practical, use of orthogonal measurements is strongly encouraged.

Demonstrate time-course measurements of dynamic behavior, in addition to end-point measurements.

Demonstrate manipulation and measurement of a sufficient variety of proposer-defined environmental conditions (e.g. temperature, pH, salinity, flow rate, etc.) relevant to the biological systems and target system-level behavior(s).

Demonstrate sufficient number and type of sensors to assess the state of the biological system and inform control of the target system-level behavior(s).

Integrate controller(s) designed in TA1 into the testbed, evaluate controller performance according to proposer-defined metrics, and demonstrate stable integration for a proposer-defined period of time two or more times greater than a relevant system-level characteristic timescale (e.g., doubling time for cells, passages for serial batch culture, or life cycle time for multicellular organisms).

For the testbed developed in Phase 1, provide detailed schematics, protocols, domain knowledge, and other information and/or materials as necessary and relevant to the IV&V team.

Phase 1 TA3: Theory and Modeling Produce predictive, mathematical analytical and/or computational model(s) with biological significance grounded in control theory for the controller(s) in TA1 and testbed in TA2.

o Explicitly include experimentally accessible inputs, outputs, biochemical or other relevant interactions between the controller(s) and testbed, and measurands to evaluate controller performance, in a manner interpreted readily by experimentalists in TA1 and TA2.

Describe and predict the target system-level behavior(s) for control in the testbed, both without and with embedded biological controller(s).

Apply theory and models to optimize controller(s) performance, with respect to relevant proposer-defined metrics in TA1.

Demonstrate relevance for informing control strategies, including, but not limited to, those implemented in TA1 and TA2 and compatible with the controller(s), testbed, and target system-level behavior(s).

Demonstrate agreement between predicted and measured controller performance, according to proposer-defined metrics, as well as system-level behavior(s) of the testbed, both without and with the embedded controller(s).

Identify the need for and initiate development of new analytical tools grounded in control theory, as required, for design, analysis, and optimization of control strategies and controllers, with respect to relevant proposer-defined metrics.

For each model or valid approximation thereof, according to proposer-defined metrics:

o Characterize the relevant parameter space (e.g., reaction rates, component concentrations, length and time scales, etc.), indicating the region(s) for which the proposed control strategy is valid for the controller embedded in the testbed.

o Provide stability analysis, as well as analyses of controller robustness and stability margins, as appropriate.

o Characterize sensitivity and show sufficient disturbance attenuation, as appropriate.

o Analyze the response to three or more step input-type perturbations, for example, in terms of overshoot, rise time, settling time, and steady-state error.

o Provide and evaluate additional proposer-defined performance metrics, as appropriate.

PHASE 2 (OPTION 1) 18 MONTHS

For the testbed in Phase 1, develop additional biological controllers that meet more stringent performance criteria, implement additional control strategies, and control additional system-level behaviors.

Phase 2 TA1: Controllers Design and build three or more additional biological controllers to control the same system-level behavior(s) as in Phase 1 using alternative control strategies and/or additional proposer-defined, system-level behaviors.

o Must meet metrics and milestones, as applicable, for Phase 1 TA1.

Demonstrate control of system-level behavior(s) of interest by achieving five or more steady-state, proposer-defined outputs and five or more dynamic, proposer-defined outputs associated with the behavior of interest, within proposer-defined error tolerances in relevant quantities, such as time to achieve steady-state and deviation from the setpoint value.

Demonstrate combinations of up to three or more controllers in the testbed in TA2, for simultaneous control of multiple system-level behaviors, to implement more sophisticated overall control and control strategies, according to proposer-defined metrics, than is possible for each controller operating independently.

For biological controllers developed in Phase 2, provide detailed schematics, protocols, domain knowledge, and other information and/or materials as necessary and relevant the IV&V team.

Phase 2 TA2: Testbed Must meet metrics and milestones, as applicable, for Phase 1 TA2 but with regard to controllers developed in Phase 2 TA1.

Integrate the controllers in TA1 into the testbed, evaluate controller performance according to proposer-defined metrics, and demonstrate stable integration for a proposer-defined period of time five or more times greater than a relevant system-level characteristic timescale (e.g., doubling time for cells, passages for serial batch culture, or life cycle time for multicellular organisms).

For biological control developed in Phase 2, provide detailed schematics, protocols, domain knowledge, and other information and/or materials as necessary and relevant to the IV&V team.

Phase 2 TA3: Theory and Modeling Must meet metrics and milestones, as applicable, for Phase 1 TA3 but with regard to controllers and testbeds developed in Phase 2 TA1 and Phase 2 TA2, respectively.

o Additionally, Phase 2 proposer-defined metrics for controller performance must be more stringent than those in Phase 1 TA3.

Implement models of controllers and testbed in a computational environment that is practical and accessible to experimentalists to aid rational design of control strategies and controllers.

PHASE 3 (OPTION 2) 12 MONTHS

Demonstrate the applicability, generalizability, and predictability of capabilities for control of biological systems developed in Phases 1 and 2.

Phase 3 TA1: Controllers Design and implement controllers to enable a proposer-defined, practical, proof-of-concept demonstration of relevance to DoD.

Demonstrate controllers that build on results from Phase 1 and Phase 2 and meet the metrics and milestones, as applicable, for Phase 2 TA1.

Demonstrate, for the demonstration system in Phase 3 TA2, simultaneous control of multiple system-level behaviors according to proposer-defined metrics, to implement more sophisticated overall control and control strategies than is possible for each controller operating independently.

Phase 3 TA2: Testbed Design and build a demonstration system to serve as an application-specific testbed to evaluate controllers for the proposer-defined, practical, proof-of-concept demonstration relevant to DoD.

Must meet metrics and milestones, as applicable, for Phase 2 TA2, but with regard to controllers developed in Phase 3 TA1.

Phase 3 TA3: Theory and Modeling Must meet metrics and milestones, as applicable, for Phase 2 TA3 but with regard to controllers and testbeds developed in Phase 3 TA1 and Phase 3 TA2, respectively.

Demonstrate rapid transition of capabilities to the demonstration system through rational design of biological control strategies and biological controllers based on theory and modeling in Phase 1 TA3 and Phase 2 TA3.

Participate in tests of the models’ predictive capability. DARPA will determine and announce the details for this test no later than the conclusion of Phase 2.

o Demonstrate correspondence between predictions and measurements obtained by the IV&V team.

o Predictive capability will be evaluated and scored based upon the agreement between predictions and measurements.

2. Award Information

Multiple awards are anticipated. The amount of resources made available under this BAA will depend on the quality of the proposals received and the availability of funds.

The Government reserves the right to select for negotiation all, some, one, or none of the proposals received in response to this solicitation, and to make awards without discussions with proposers. The Government also reserves the right to conduct discussions, if it is later determined to be necessary. If warranted, portions of resulting awards may be segregated into pre-priced options. Additionally, DARPA reserves the right to accept proposals in their entirety or to select only portions of proposals for award. In the event that DARPA desires to award only portions of a proposal, negotiations may be opened with that proposer. The Government reserves the right to fund proposals in Phases with options for continued work at the end of one or more of the Phases.

Awards under this BAA will be made to proposers on the basis of the evaluation criteria listed below (see section labeled “Application Review Information”, Sec. 5.), and program balance to provide overall value to the Government. The Government reserves the right to request any additional, necessary documentation once it makes the award instrument determination. Such additional information may include but is not limited to Representations and Certifications. The Government reserves the right to remove proposers from award consideration should the parties fail to reach agreement on award terms, conditions and cost/price within a reasonable time or the proposer fails to provide requested additional information in a timely manner. Proposals identified for negotiation may result in a procurement contract, cooperative agreement, or other transaction depending upon the nature of the work proposed, the required degree of interaction between parties, whether or not the research is classified as Fundamental Research, and other factors.

In all cases, the Government contracting officer shall have sole discretion to select award instrument type and to negotiate all instrument terms and conditions with selectees. Proposers are advised that if they propose cooperative agreements, DARPA may select other award instruments, as it deems appropriate. DARPA will apply publication or other restrictions, as necessary, if it determines that the research resulting from the proposed effort will present a high likelihood of disclosing performance characteristics of military systems or manufacturing technologies that are unique and critical to defense. Any award resulting from such a determination will include a requirement for DARPA permission before publishing any information or results on the program. For more information on publication restrictions, see the section below on Fundamental Research.

Fundamental Research It is DoD policy that the publication of products of fundamental research will remain unrestricted to the maximum extent possible. National Security Decision Directive (NSDD) 189 established the national policy for controlling the flow of scientific, technical, and engineering information produced in federally funded fundamental research at colleges, universities, and laboratories. The Directive defines fundamental research as follows:

'Fundamental research' means basic and applied research in science and engineering, the results of which ordinarily are published and shared broadly within the scientific community, as distinguished from proprietary research and from industrial development, design, production, and product utilization, the results of which ordinarily are restricted for proprietary or national security reasons.

As of the date of publication of this BAA, the Government expects that program goals as described herein may be met by proposers intending to perform fundamental research. The Government does not anticipate applying publication restrictions of any kind to individual awards for fundamental research that may result from this BAA. Notwithstanding this statement of expectation, the Government is not prohibited from considering and selecting research proposals that, while perhaps not qualifying as fundamental research under the foregoing definition, still meet the BAA criteria for submissions. If proposals are selected for award that offer other than a fundamental research solution, the Government will either work with the proposer to modify the proposed statement of work to bring the research back into line with fundamental research or else the proposer will agree to restrictions in order to receive an award.

Proposers should indicate in their proposal whether they believe the scope of the research included in their proposal is fundamental or not. While proposers should clearly explain the intended results of their research, the Government shall have sole discretion to select award instrument type and to negotiate all instrument terms and conditions with selectees. Appropriate clauses will be included in resultant awards for non-fundamental research to prescribe publication requirements and other restrictions, as appropriate.

For certain research projects, it may be possible that although the research being performed by the prime contractor is restricted research, a subawardee may be conducting fundamental research. In those cases, it is the prime contractor’s responsibility to explain in its proposal why its subawardee’s effort is fundamental research.

The following statement or similar provision will be incorporated into any resultant non-fundamental research procurement contract or other transaction:

There shall be no dissemination or publication, except within and between the contractor and any subawardees, of information developed under this contract or contained in the reports to be furnished pursuant to this contract without prior written approval of DARPA’s Public Release Center (DARPA/PRC). All technical reports will be given proper review by appropriate authority to determine which Distribution Statement is to be applied prior to the initial distribution of these reports by the contractor. With regard to subawardee proposals for Fundamental Research, papers resulting from unclassified fundamental research are exempt from prepublication controls and this review requirement, pursuant to DoD Instruction 5230.27 dated October 6, 1987.

When submitting material for written approval for open publication, the contractor/awardee must submit a request for public release to the DARPA/PRC and include the following information: (1) Document Information: document title, document author, short plain-language description of technology discussed in the material (approx.

30 words), number of pages (or minutes of video) and document type (e.g., briefing, report, abstract, article, or paper); (2) Event Information: event type (conference, principal investigator meeting, article or paper), event date, desired date for DARPA's approval; (3) DARPA Sponsor: DARPA Program Manager, DARPA office, and contract number; and (4) Contractor/Awardee's Information: POC name, email and phone. Allow four weeks for processing; due dates under four weeks require a justification. Unusual electronic file formats may require additional processing time. Requests may be sent either via email to public_release_center@darpa.mil or by mail at 675 North Randolph Street, Arlington VA 22203-2114, telephone (571) 218-4235. Refer to the following for link for information about DARPA’s public release process: http://www.darpa.mil/work-with-us/contract-management/public-release.”

3. Eligibility Information All responsible sources capable of satisfying the Government’s needs may submit a proposal that shall be considered by DARPA.

3.1. ELIGIBLE APPLICANTS

3.1.1. Federally Funded Research and Development Centers (FFRDCs) and Government Entities

Federally Funded Research and Development Centers (FFRDCs) and Government entities (e.g., Government/National laboratories, military educational institutions, etc.) are subject to applicable direct competition limitations and cannot propose to this BAA in any capacity unless they meet the following conditions: (1) FFRDCs must clearly demonstrate that the proposed work is not otherwise available from the private sector; and (2) FFRDCs must provide a letter on official letterhead from their sponsoring organization citing the specific authority establishing their eligibility to propose to Government solicitations and compete with industry, and their compliance with the associated FFRDC sponsor agreement’s terms and conditions. This mailto:public_release_center@darpa.mil information is required for FFRDCs proposing to be prime contractors or subawardees.

Government entities must clearly demonstrate that the work is not otherwise available from the private sector and provide written documentation citing the specific statutory authority and contractual authority, if relevant, establishing their ability to propose to Government solicitations. At the present time, DARPA does not consider 15 U.S.C. § 3710a to be sufficient legal authority to show eligibility. While 10 U.S.C.§ 2539b may be the appropriate statutory starting point for some entities, specific supporting regulatory guidance, together with evidence of agency approval, will still be required to fully establish eligibility. DARPA will consider FFRDC and Government entity eligibility submissions on a case-by-case basis; however, the burden to prove eligibility for all team members rests solely with the proposer.

3.1.2. Non-U.S. Organizations

Non-U.S. organizations and/or individuals may participate to the extent that such participants comply with any necessary nondisclosure agreements, security regulations, export control laws, and other governing statutes applicable under the circumstances. See Section 4.2.1 “Proprietary and Security Information” regarding the proposers capabilities to perform research and development at the classification level they propose.

Procurement Integrity, Standards of Conduct, Ethical Considerations, and Organizational Conflicts of Interest Current federal employees are prohibited from participating in particular matters involving conflicting financial, employment, and representational interests (18 U.S.C. §§ 203, 205, and 208). Once the proposals have been received, and prior to the start of proposal evaluations, the Government will assess potential conflicts of interest and will promptly notify the proposer if any appear to exist. The Government assessment does NOT affect, offset, or mitigate the proposer’s responsibility to give full notice and planned mitigation for all potential organizational conflicts, as discussed below.

Without prior approval or a waiver from the DARPA Director, in accordance with FAR 9.503, a contractor cannot simultaneously provide scientific, engineering, technical assistance (SETA) or similar support and also be a technical performer. As part of the proposal submission, all members of the proposed team (prime proposers, proposed subawardees, and consultants) must affirm whether they (their organizations and individual team members) are providing SETA or similar support to any DARPA technical office(s) through an active contract or subcontract. All affirmations must state which office(s) the proposer, subawardees, consultant, or individual supports and identify the prime contract number(s). All facts relevant to the existence or potential existence of organizational conflicts of interest (FAR 9.5) must be disclosed. The disclosure must include a description of the action the proposer has taken or proposes to take to avoid, neutralize, or mitigate such conflict. If in the sole opinion of the Government after full consideration of the circumstances, a proposal fails to fully disclose potential conflicts of interest and/or any identified conflict situation cannot be effectively mitigated, the proposal will be rejected without technical evaluation and withdrawn from further consideration for award.

If a prospective proposer believes a conflict of interest exists or may exist (whether organizational or otherwise) or has questions on what constitutes a conflict of interest, the proposer should send his/her contact information and a summary of the potential conflict via email to the BAA email address before time and effort are expended in preparing a proposal and mitigation plan.

3.2. COST SHARING/MATCHING

Cost sharing is not required; however, it will be carefully considered where there is an applicable statutory condition relating to the selected funding instrument (e.g., for any Other Transactions under the authority of 10 U.S.C.§2371). Cost sharing is encouraged where there is a reasonable probability of a potential commercial application related to the proposed research and development effort.

3.3. OTHER ELIGIBILITY REQUIREMENTS

While teaming is not required, teaming is strongly encouraged to meet the program goals across all Phases and TAs. DARPA requires teaming to be resolved before proposal submission and, as such, will facilitate the formation of teams with the expertise necessary to meet the goals of the program (see Section 8.2 below).