This document provides information about DARPA's Living Foundries: 1000 Molecules program. The program aims to develop scalable infrastructure for engineering biology that can rapidly prototype genetic designs and produce over 1000 new molecules. Proposals are due in September 2013 and can focus on developing comprehensive infrastructure facilities or innovative component technologies. The facilities will work to produce over 350 unique molecules across three challenge areas within a five year period, demonstrating scalability and capabilities. Requirements include producing molecules that are improved, currently inaccessible, or novel.

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1000 Molecules Proposers’ Day
Alicia Jackson
DARPA/MTO
July 24, 2013

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Engineering Biology
Design and construct genetic pathways, networks
and systems to harness the powerful synthetic and
functional capabilities of biology.

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What You Need to Know

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Proposals Due September 17, 2013

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Vision
Requirements
Proposal Instructions
Evaluation Criteria
Read the BAA

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Enable transformative and currently inaccessible
projects across chemicals, materials, sensing
capabilities and therapeutics
Vision

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Key Technical Components and Capabilities—p. 8
Teaming and Partnerships—pp. 11 and 12
Intermediate Milestones—pp. 14 and 15
Requirements

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Follow Them
Proposal Instructions

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• Overall Scientific and Technical Merit
• Potential Contribution and Relevance to the DARPA Mission
• Proposer’s Capabilities and/or Related Experience
• Cost Realism
• Realism of Proposed Schedule
• Plans and Capability to Accomplish Technology Transition
Evaluation Criteria: p. 47 of BAA

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If you have Questions: DARPA-BAA-13-37@darpa.mil

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Living Foundries: 1000 Molecules
The Details

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Building a new technology base to enable transformative
applications
Living Foundries: ATCG
Foundries
Demo New Capability
New tools to enable rapid
engineering of biology
Enable scale and rapid
prototyping of genetic designs
never before accessible
1000 Molecules
1000 new chemical building
blocks for new materials100x faster DBT cycle for
engineering biology
Fundamental shift in
chemical/materials industry
. . .Enable Impossible Projects
Living Foundries: 1000 Molecules
IMPACT:
Engage and Seed industrial/academic partnerships
Open up new avenues for innovation
Enable access/new entrants
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Petro-materials paradigm dominates today
Inputs Commodity
Chemicals
Materials Products
MATERIEL/INFRASTRUCTURE
FIELD GEAR
Today’s materials are built from a limited set of building blocks

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Petrochemical starting molecules are limited
Finished Motor
Gasoline (42.0%)
Distillate Fuel
Oil (27.0%)
Kerosene-
type Jet Fuel
(8.8%)
Petroleum
Coke (5.1%)
Still Gas (4.1%)
Liquefied Refinery
Gases (3.7%)
Naphtha – bp ≤ 401º
F (1.2%)
Oils – bp ≥ 401º F
(0.7%)
Special Naphthas
(0.2%)
US Petroleum
Refinery Yield
42 US Gallons
Olefins: alkenes including those
with 2, 3, 4, and >4 carbons
Aromatics: conjugated,
planar, cyclic compounds
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Biology provides a far richer palette of starting points
Olefins: alkenes including those
with 2, 3, 4, and >4 carbons
Aromatics: conjugated,
planar, cyclic compounds
Caprolactam
LadderanesFluorocarbons
1,3-Propanediol
Farnesene
Riboflavin
Phosphatidylinositol
Heme
Creatine Coniine
Shikimic acid
Adenine
Biotin

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New materials produced using engineered biosystems
can enhance DoD capabilities
New chemical structures and functions enable new avenues for innovation
MaterialsCommodity
Chemicals
ProductsProducts
Speed DoD
Technology
Development
Commodity
Chemicals
>103 increase in
intermediates
(from 10’s to 10,000’s)
Expanded
Chemical Palette
InputsInputs
Carbon sources:
Corn, Sugarcane,
Biomass, CO2,
Nat Gas, etc.
Chemical Factories:
Yeast, Algae, new
exotic microorganisms
and in-vitro systems
Inherently Flexible,
Adaptable Platform
Materials
New
Materials
with new
properties

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Engineering biology could enable the next advance
Biology Petroleum & Natural Gas Engineering Biology
Inflection
point
2040
Inflection
point
Source: Morgan Stanley Research
Genetically
Encoded Materials

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Infrastructure: Scaled, rapid prototyping of genetic designs
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19. GOAL: Scalable and accessible technology base
• Bridge the gap from initial, laboratory-level, proof-of-concept
experimentation to industrial pilot production.
• Enable scale and sophistication of engineering orders of
magnitude > SOA
• Automated, integrated processes across design, fabrication,
testing, and analysis.
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Key elements/expectations

20. GOAL: Scalable and accessible technology base
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Key elements/expectations (2)
Successful proposals:
• Advanced process design utilizing best industrial
manufacturing practices,
• Integration and modularization of component technologies,
• Identification of driving technical and scientific challenges.

21. Key tech components/challenges
1. Design Innovation: Enable
forward engineering of new systems
• Novel biosynthetic pathway prediction
• Gene cluster discovery
• Chemical structure prediction
• Tools for design and control of
complex networked systems
2. Scalable, Automated Construction:
Parallelized construction of combinatorial
genetic designs
• Large-scale DNA construction
• Optimized genetic chassis
• Genome-scale, parallel editing tools
• Flexible across organisms/designs
3. Design Evaluation: Massively
parallel test and QC of designs
• Integrated, high-
throughput detection and
analysis
• Automated QC of parts,
assembly, and integration
• Validation/verification of
engineered systems
4. Integrated Feedback: Harness
massive data generation to inform future
design
• Analysis of all data, including failure modes
• Machine learning and data mining algorithms
• Generate design rules
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Meta-elements/expectations
Beyond the technology and process infrastructure
Infrastructure should:
• Be applicable to addressing diverse applications beyond
biosynthesis of new molecules
e.g. synthetic biological circuits and networks, creation of libraries,
recoding and refactoring of genomes, etc.
• Readily import, test, and integrate new methods and tech
• Engage and partner with end users, technology developers
and infrastructure providers

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Teams
• Mix of Institutions/Partners – academic, non-profit, and industrial
collaborations
• Multidisciplinary - computer science, engineering, automation, industrial
process development, chemistry/chemical engineering, biological sciences, etc
• Core team members and researchers are expected to be co-located with the
centralized rapid design and prototyping infrastructure maximize
interactions and project focus.
Leadership
• Teams may be led by industrial, academic, or non-profit entities
• Leadership Team should have significant experience and expertise in:
• Directing operations and technology development,
• Leading large and diverse teams with both academic and industrial
partners, and
• Industrial process design
Teaming and management expectations
Commitment: Expect significant time commitment from core team

24. Overview/Purpose: Provides a measure of capabilities
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1000 Molecules
• Generate >350 unique molecules demonstrating a breadth of
structural and functional diversity
• >1000 unique molecules in total generated across all facilities
• Demonstrate infrastructure capabilities in
• throughput,
• rapid product generation, and
• platform flexibility and generalizability
Across numerous designs, pathways, and products

25. 3 Challenge Areas:
1. Rapid, improved prototyping of known molecules.
• Known biosynthetic pathways.
• Includes: molecules previously synthesized biologically and natural products.
• Demonstrate improved production (e.g., yield, cost, purity, etc.) relative to
state-of-the-art production methods by using a biosynthetic route.
2. Prototyping of known, but currently inaccessible, molecules.
• Not routinely synthesized biologically
• Includes synthetic pathways constructed from multiple, unique organisms.
• Of particular interest to DARPA: molecules that are currently very difficult,
impossible, or prohibitively expensive to synthesize chemically.
3. Prototyping of novel molecules.
•Effectively unattainable through synthetic chemistry and cannot be synthesized
using existing biological chemistry.
•Examples: novel enzymes to enable inaccessible pathways, incorporation of
novel elements from the periodic table, or high-efficiency incorporation of non-
natural amino acids into products
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1000 Molecules challenge areas

26. Task Area 2: Demonstration of capabilities
Phase I Phase II
FY15
18 mos 18 mos
Phase III
24 mos
FY18
Challenge Area 1: Rapid, improved
prototyping of known molecules
Super absorbent materials – Polyitaconic acid
Insecticides – Spinocyn
Coating/Fibers – Muconic acid
Natural Products – Artmesinin
Challenge Area 3: Prototyping of
novel materials from new chemistries
Sequence defined, nonnatural polymers –
New nanomaterials –
Novel Catalysts –
Hybrid materials systems
Electro/Optical molecules–
Anti-corrosive coatings –
Thermopolymers –
High-strength polymers –
Challenge Area 2: Prototyping of
known, but currently inaccessible,
molecules
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• Phase 1: >10 molecules from Areas 1 or 2
• Phase 2: >60 molecules, including >15
molecules from Area 2.
• Phase 3: >10 molecules from Area 3 and
> 200 additional molecules from Challenge
Areas 1 and 2.
>350 unique molecules total by end of Phase III

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Anticipated program structure
Phase I Phase II
FY14
18 mos 18 mos
Phase III
24 mos
FY18
Task Area 1
6 mos
Task Area 2
Task Area 1 (TA1): Initial infrastructure and technical design exploration
• Infrastructure plan and technical path are refined
• Culminates in a technical report detailing the proposed technical approach, physical
capabilities, and management structure.
Task Area 2 (TA2): Require centers to develop/demonstrate capabilities
Consists of three phases:
• Phase 1: “pressure test” - produce at least 10 molecules by the end of Phase 1.
• Phase 2 - Produce > 60 molecules, including > 15 known, but currently inaccessible,
molecules (i.e. Challenge Area 2).
• Phase 3 – Produce > 10 completely novel molecules (i.e. Challenge Area 3) and > 200
additional molecules from Challenge Areas 1 and 2.
Performers that complete Task Area 1 may submit proposals to Task Area 2

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Proposing to Task Area 1: Design and study phase
Provide: Brief and concise overview of anticipated project plan and approach to meet
the goals and milestones of the Living Foundries: 1000 Molecules program.
Task Area 1 Study: Identify anticipated technical elements, milestones and metrics
to be refined and/or generated during the Task Area 1 design and study phase of the
program.
Technical Rationale and Approach: Outline of the anticipated technical approach
and plan for Task Area 2, including how the Task Area 1 study work fits into the
overall project plan.
Technical approach and plan must address:
• Description of the proposed infrastructure to be developed
• Overview of and timeline for the technical approach
• Description of and justification for the types of molecules that will be targeted
during each phase of Task Area 2
• Initial steps/proof-of-concept experiments toward developing the proposed
infrastructure
• Anticipated academic and industrial partners
DARPA requires proposers to submit all initial proposals to TA1

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Task Area 2 proposals must address:
(1) Complete Technical approach and plan that addresses the following:
• Description of proposed infrastructure
• Overview of the technical approach, milestones, and timeline both related to infrastructure
capabilities and to the 1000 molecules goal
• Major Technical Risk Elements
• Description of and justification for the types/classes of molecules that will be targeted
during each phase of TA2
• How the proposed infrastructure can be used to address applications beyond the
biosynthesis of new molecules.
• Proposed intermediate and end-of-project demos and proofs-of-concept
(2) Program Plan: A plan with clear timelines, milestones and risks identified for
demonstrating the functional capabilities and performance of the proposed rapid design and
prototyping facility as a whole, as well as for individual components
(3) Teaming and Management plan
(5) Tech Transition Plan: How the infrastructure facility will maintain viability following
cessation of DARPA funding?

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Task Area 2 proposals must address: (cont’d)
(6) SOW
• A general description of the objective
• A brief and concise description of the approach
• Identification of the primary organization responsible for task execution
• The completion criteria for each task/activity - a product, event or milestone that defines
its completion;
• Define all deliverables (reporting, data, reports, software, etc.) to be provided to the
Government in support of the proposed research tasks/activities; and
• An estimate of cost
(7) Discussion of proposer team’s previous accomplishments and work in closely
related research areas.
(8) Description of the facilities and capabilities that would be used for the proposed
effort.

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TA Phase Timeline Milestones
TA1 Up to 6 mo
• Project plan
• Proof of concept (option)
• Initiate infrastructure (option)
TA2
Phase I
Up to 18 mo
• Produce 10 target molecules (Areas 1/2)
• Demonstrate infrastructure capabilities (2 proposer-
defined milestones)
TA2
Phase II
Up to 18 mo
• Produce 60 target molecules, including at least
• 15 previously inaccessible target molecules (Area 2)
• Further demonstration of infrastructure capabilities
(2 proposer-defined milestones)
TA2
Phase III
Up to 24 mo
• Produce 200 target molecules, including at least
• 30 previously inaccessible target molecules (Area 2)
• 10 novel target molecules (Area 3)
• Further demonstration of infrastructure capabilities
(3 proposer-defined milestones)
Program
End
Up to 60 mo
• Produce 350 target molecules, including at least
• 45 previously inaccessible target molecules (Area 2)
• 10 novel target molecules (Area 3)
Anticipated program milestones

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Comprehensive Efforts vs. Advanced Studies
2 categories of proposals for this solicitation:
(1) Comprehensive proposals
(2) Advanced Studies: Innovative component technologies
• Markedly improve the performance of the rapid design and
prototyping infrastructure
• Can be readily automated, parallelized, scaled-up, and/or
utilized in reduced reaction volumes
• Limited to a maximum of 24 months in length
• Only a limited number is expected be funded
The Government strongly prefers an integrated approach to
systematically address all program goals in their entirety

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• Advanced studies: address one or more novel component technologies targeted
as part of infrastructure development.
• Clearly indicate Advanced Studies proposal submission on title page
• Explain the relevance of the work to the overall program goals, as well as propose
detailed objectives and quantitative metrics.
• Groups proposing advanced studies are encouraged to identify teams proposing
rapid design and prototyping centers that may be able to leverage the tools and
technologies resulting from such a study.
Advanced Studies
Phase I Phase II
FY14
18 mos 18 mos
Phase III
24 mos
FY18
TA1
6 mos
TA2
Phase I Phase II
FY14
12 mos
Advanced Studies
12 mos
FY16
Duration: maximum of 24 months and
should consist of 2 phases, each no longer
than 12 months.

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Proposers should focus on 3 aspects:
• Designing and demonstrating a rapid design and prototyping
infrastructure that will enable a radical improvement in capabilities
over SOA
• Outlining the technical approach(es) to be pursued to meet the
infrastructure and DARPA 1000 goals
• Identifying and justifying the molecules and chemical building blocks
proposed for each DARPA 1000 Challenge Area
Key points
The Government expects to fund several types of rapid design and
prototyping infrastructure, spanning a range of approaches, foci, and users
All proposed infrastructure should be generalizable in that it can address a
range of designs, pathways, organisms/systems and/or products

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Key dates
BAA Released 10 July 2013
BAA Process and Proposal
Preparation/Submission Overview Webinar
31 July 2013
Proposals for TA1 and Advanced Studies
Due
17 Sept 2013
Estimated Start date for TA1 and Advanced
Studies
17 March 2014
Note: BAA will remain open until 21 Oct 2014

36. www.darpa.mil
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