HR001123S0027-Amendment-01.pdf

The purpose of Amendment 1 to HR001123S0027, Tellus, is to extend the proposal abstract submission deadline, clarify device specifications, and clarify University Funding guidelines.

Changes bolded/highlighted/underlined below.

Part I Overview Information is updated as follows:

o Proposal Abstract Due Date and Time: May 22 2023, 4:00 PM ET

Section 1.3 Program Structure is updated as follows:

PROGRAM STRUCTURE

This BAA solicits proposals which focus on developing (1) an interactive Methodology that enables rapid design of robust, reliable, user-specified microbial sense-and-respond devices in appropriate environments, and (2) fabrication and testing of several such microbial devices (“Tellus devices”). Proposers are required to address both Methodology Development with a user interface and Tellus Device Fabrication. Proposals must describe the technical approach planned to achieve the targeted improvements in Methodology Speed (reduction in time to design, build, and experimentally test devices) and Accuracy (increase in device success at meeting performance criteria), as well as how successive Tellus devices will be fabricated and tested on shortened intervals. Tellus is a 2.5-year, single phase program that will be guided by the SCHEDULE and PROGRAM DELIVERABLES, MILESTONES AND METRICS as described in Sections 1.5 and 1.6, below.

Tellus performers will develop multiple (≥ 6), unique, living microbial sense-and-respond devices based on the parameters provided in Table 1. The Tellus program goals are to ascertain which of the parameters noted in Table 1 can be reliably incorporated to create “Tellus devices” that will function in a range of environments, and to develop the Methodology to enable more facile development of bespoke sensors based on different combinations of these parameters to be reliably designed, built, and tested. To achieve this goal, DARPA aims to “pressure test” the design-build-test-learn cycle for such devices. Note that while Tellus does not aim to have performers experimentally demonstrate stand-off or remote detection using microbial devices, it will be important to determine what is theoretically feasible based on sensitivity toward input stimuli, and/or output signal types and strengths that can be generated.

Section 1.3.1 Tellus Methodology and Device Development is updated as follows:

Tellus Methodology and Device Development

Performers will design, build and test a total of (at least) six unique Tellus devices using parameters selected from Table 1. Proposals should include designs for five unique Tellus devices (see Table 2 for notional examples) with at least two device designs per operational domain. DARPA will choose two initial designs from these five, which will be the first two Tellus devices that selected teams will fabricate (see Section 1.6, Table 4 for completion dates).

Subsequently, after the program commences, DARPA will select and provide to proposers the parameters for the next four devices at periodic intervals designed to “pressure-test” how quickly functional new devices can be designed, built, and tested. For this reason, it is likely that the

DARPA-selected parameters for devices #3-#6 will NOT align with the proposer’s initial designs, and proposers should plan accordingly to be able to address a diverse set of parameters for devices #3-#6. This will allow the Tellus program to cover as many parameters in the table as possible.

For each completed device, it is expected that at least 10 complete ‘variants’ will be tested and made available to DARPA’s Independent Verification and Validation (IV&V) partners per scheduled deliverables (see Sections 1.4 and 1.5.3 for more details). This is to ensure sufficient data is collected to build a robust Methodology. “Variants” should differ from each other so as to attempt to optimize or vary functionality (e.g., increase range of activity, specificity, operating kinetics) or utilize different components (e.g., different ribosome binding sites, regulatory elements, environmental stress response genes, or information processing circuits). Performers should strive to optimize each of these devices in order to make a fair comparison.

Of equal importance to the actual microbial device fabrication and testing will be articulating the plan to use data obtained from these tests to inform the Methodology for designing robust and functional devices. The vision sought for the Methodology is to enable an end user to specify the kind of stimuli they’d like to detect; their preferred output signal; if they want to be able to distinguish between different stimuli or all possible combinations; and their anticipated environmental conditions. The Methodology would then provide guidance on the specific design needed for reliable operation: what chassis to use; which genetic circuits, biomolecular components or pathways to build; and what kind of signal output strength they might expect. It is expected that many iterations of the Tellus device design-build-test-learn cycle (i.e., >10 variants per device for each of six devices) will be necessary to realize the gains sought for Speed and Accuracy of the Methodology. Performers will be encouraged to cooperate/collaborate with each other and DARPA’s IV&V partners to develop an optimized Methodology for Tellus devices.

Proposals should include plans for data sharing with IV&V partners and DARPA. Proposals should also describe all necessary positive and negative controls, and identify anticipated technical challenges and associated risk mitigation strategies.

Key technical challenges that will need to be overcome by the Tellus program:

Sensing and discriminating between different combinations of multiple stimuli.

Lowering limits-of-detection without increasing background.

Employing more sensitive receptors which have inherently smaller dynamic ranges that suffer from saturation at higher concentrations.

Difficulty of use in realistic environmental conditions.

Integration with “receiver” device(s) to collect/measure output signals.

Overcoming genetic burden of added pathways/circuits on cells/efficacy.

Determining whether to use single cells vs. multiple cells or consortia.

Difficulties associated with robust circuitry design and high throughput testing.

Response time needed for processing stimuli.

Developing strategies to record and store stimulus detection events for retrieval at a later time.

Multiplexing sensing modalities.

Operating discriminately in the presence of confounders.

The proposed technical approach is expected to be multidisciplinary in order to address the development of the Methodology for designing the Tellus device, genetic and/or biomolecular engineering of the organism(s), bio-based energy harvesting to enable long endurance, and generation of output signals detectable via a “receiver” (that can potentially translate to stand-off or remote detection). Strategies for optimizing, integrating, and expanding capabilities should be elaborated throughout. Proposals should also discuss mitigation of technical challenges that may arise. Specifically excluded from this opportunity is research that: (1) proposes the use of phage, viruses or plants (although microalgae are acceptable) as a functional component of the microbial device; (2) proposes use of well-established chemical stimuli such as antibiotics, quorum-sensing molecules, inducers like isopropyl β-D-1-thiogalactopyranoside (IPTG) or Β-galactose; or (3) proposes only the use of fluorescent or luminescent proteins for output signals.

Proposals that fail to assemble 5 unique microbial devices will be considered non-conforming and may not be evaluated further. Each proposed microbial device should conform to the specifications listed in Table 1 (i.e., selection of an Environmental Domain, Environmental Condition, at least three Stimuli to be Sensed, at least one Biologically-encoded Information Processing step and at least one Output Signal/Communication Method).

Section 1.3.2 Eligible Organisms is updated as follows:

Eligible Organisms Microbial organisms that are appropriate include living non-pathogenic bacteria, archaea, spores, or single cell eukaryotes (algae, fungi), that ideally have demonstrated functionality in the selected Environmental Domains and Environmental Conditions described in Table 1.

Performers will need to understand growth rates, managing biomass (without environmental release of genetically modified organisms) and how this affects sensor function in different Tellus device configurations. While integrating detection of multiple stimuli, information processing and output signal generation into a single organism could achieve Tellus program goals, use of a microbial consortia approach would also be responsive to this BAA. Should a consortial approach be proposed, it should be clear how the organisms selected work in concert with each other in regard to multiplexed stimuli detection and response (times, output signals).

Device Endurance and Response Time in Section 1.6.2 Tellus Program Metrics is updated as follows:

Device Endurance and Response Time: Performers will have to address endurance and response time goals for their Tellus devices as requested in Table 5. These will ideally be tunable to allow maximum flexibility to adapt to various environmental monitoring applications. It is anticipated that strategies to help the microbes remain fully functional for the entire duration specified in Table 5 may include environmental energy or nutrient scavenging; encapsulation; use of microbial consortia; and stimulus detection modes that reduce reliance on transcription/translation approaches.

Controlled Unclassified Information (CUI) in Section 4.2.5 Additional Proposal Information is updated as follows:

Controlled Unclassified Information (CUI) For unclassified proposals containing CUI, applicants will ensure personnel and information systems processing CUI security requirements are in place.

If an unclassified submission contains CUI or the suspicion of such, as defined by Executive Order 13556 and 32 C.F.R. Part 2002, the information must be appropriately and conspicuously marked CUI in accordance with DoD Instruction (DoDI) 5200.48. Identification of what is CUI about this DARPA program is described in Attachment 1 - CUI Guide.

Unclassified submissions containing CUI may be submitted via DARPA’s BAA Website (https://baa.darpa.mil) in accordance with Section 4.2.7 of this BAA.

Proposers submitting proposals involving the pursuit and protection of DARPA information designated as CUI must have, or be able to acquire prior to contract award, an information system authorized to process CUI information IAW NIST SP 800-171 and DoDI 8582.01.

Section 8.2 University Funding is updated as follows:

In order to ensure that U.S. scientific and engineering students will be able to continue to make strategic technological advances, DARPA is committed to supporting the work and study of Ph.D. students and post-doctoral researchers that began work under a DARPA-funded program awarded through an assistance instrument. Stable and predictable federal funding enables these students to continue their scientific and engineering careers.

To that end, should a DARPA funded program awarded through a grant or cooperative agreement with a university or a Research Other Transaction pursuant to 10 U.S.C. § 4021 where the university is a participant end (due to termination or down-select) before the planned program completion, DARPA may continue to fund, for no more than two semesters (or equivalent), the documented costs to employ or sponsor Ph.D. students and/or post-doctoral researchers. Should such a circumstance arise, the following will take place:

1) The Government will provide appropriate notification to the University participant by the Agreements Office or through the prime performer.

2) The University must make reasonable efforts to find alternative research or employment opportunities for these students and researchers.

3) Before any costs will be paid, the University must submit documentation describing their due diligence efforts in finding alternative arrangements that is certified by a University official.

https://baa.darpa.mil/

4) In addition to this documentation, the affected students and researchers must submit statements of work describing what research activities they will pursue during the period of funding and the final deliverable they will submit when the funding is complete.

5) In determining these costs, DARPA will rely on information from the University's original proposal unless specific circumstances warrant requesting updated proposals. In no circumstances will this funding be provided when the program is ended because of suspected or actual fraud or negligence.

DARPA Down-Select Definition:

DARPA often structures programs in phases or options that include specific objectives and a designated period of performance. This may result in potentially issuing multiple awards to maximize the number of innovative approaches. This approach allows the Government to monitor progress and enables programmatic decision points based, at a minimum, against stated evaluation criteria, metrics, funding availability, and program goals and objectives. As a result, select performers may advance via award of a subsequent phase or through exercise of a planned option period.