1. Living Foundries
Alicia Jackson
Program Manager, DARPA
Living Foundries Industry Day
Arlington VA
June 28, 2011
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2. DARPA
Prevent technological surprise and Create technological surprise
• Sponsor revolutionary, high-payoff research
• Driven by the Program Managers
• Capabilities/Mission focused
• Diverse performers—looking for the best people with the best ideas
• No peer review
• Driven by quantitative milestones
• Flexible, rapid review and contracting
The question that all DARPA programs must answer: Is it game changing
and will it have lasting impact on DOD and the warfighter?
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3. Heilmeier's Catechism
1. What are you trying to do? What problem are you trying to solve?
Articulate your objectives using absolutely no jargon.
2. How is it done today, and what are the limits of current practice?
3. What's new in your approach and why do you think it will be
successful?
4. Who cares?
5. If you're successful, what difference will it make?
6. What are the risks and the payoffs?
7. How much will it cost?
8. How long will it take?
9. What are the midterm and final "exams" to check for success?
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4. Living Foundries
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5. Living Foundries: The Vision
Polymers
DNA Catalysts
instructions
Electronic/
optical
Cellulose
materials
Natural gas
Chemicals
Sugar Molecules
Fuels
PET Pharma
Coal “cell-like”
Multi-cellular
factory
constructs
Self-repairing
Custom, distributed, systems
on-demand manufacturing “cell-free” systems
Image adapted from:
Vickers et al., Nature Chemical Biology, 2010 and Keasling, Science, 2010
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6. We’re just scratching the surface of what’s possible
Engineering biology today is a time and money intensive process
minimal bacterium yeast
11
1.00E+11 10
Effort (total $ * yrs to develop) [$*yr]
10
1.00E+10 10 DARPA
annual budget
1.00E+09 109
1.00E+08 108
SOA
1.00E+07 107
1.00E+06 106
5
1.00E+05 10
Where Living Foundries will take us
4
1.00E+04 10 metabolic engineering
complex genetic circuits genome rewrite
1.00E+03 103
1
1 10
10 100
100 1,000
1,000 10,000
10,000 100,000
100,000
Complexity (# genes inserted/modified)
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7. New approach: decouple design from fabrication through
design rules and standardized parts
SOA: ad hoc, empirical, Goal: hierarchical engineering
expensive process Large systems
Standardization and modularity
(def band-detect (s lo hi)
(and (> s lo) (< s hi)))) of genetic parts and chasses
(let ((s (diffuse (aTc)
0.8 0.05)))
(green (band-detect Abstraction of genetic function
s 0.2 1)))
Small to manage complexity
Many iterations systems
X No Decoupling of design and
iteration fabrication
Application Application Example of a possible approach
Program cells in a high-level language
Coupled Design tools and compile to genetic code
Iterate >20x
Design/Fabrication Standardized, well-characterized parts
4 mos
Parts/Devices and devices that are CAD friendly
Automated synthesis and assembly of
~105 attempts Fabrication DNA in standardized cell chassis
7 yrs (SOA) Quick, high-throughput identification
Test/Debug and quantification of the cell state
• Natural parts don’t work as expected
outside of native environment
Coupled design and fabrication DNA Transform+20x
• Not all parts exist
• Design rules are unknown Transform 3 wks
• No reliable design tools
Time (months)
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8. What is needed for Living Foundries
Accelerate the biological design, build, test cycle and
expand the complexity of designs that can be built.
What is needed Technical Challenges
Design tools that span from high-level • Interoperable tools for design, modeling
description to fabrication in cells and fabrication
• Well-characterized, standardized and
Modular genetic parts that allow a orthogonal genetic parts
combination of systems to be • Scalable, low-cost, high-fidelity DNA
designed and reproducibly assembled synthesis processes with rapid turn-times
• Test platforms and chassis that readily and
Rapid construction, evolution and predictably integrate new genetic designs
manipulation of genetic designs
• Locate failures and characterize the whole
cell state
Routine system characterization and This list is not comprehensive: Additional/alternative
debugging that informs the design cycle areas of research and development may be proposed
An open and accessible platform for engineering biology
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9. Structure of Living Foundries
Anticipated BAA #1
Advanced Tools and Demonstrate tools
Capabilities and platform
capabilities
Outcome:
Tools and capabilities to
• Interoperable design tools
accelerate the biological
• New, modular genetic parts,
regulators, and circuits design, build, test cycle
• Standardized test platforms, Proof of concept and expand the
ATC BAA
cell-like systems and chassis complexity of designs
• Low cost, rapid DNA synthesis that can be built.
• Quantitative, high throughput Integrate tools
characterization and and platform
debugging capabilities in full
demonstration
Anticipated BAA #2:
Living Foundries Challenge
Demonstrations 24 Months
Outcome:
BAA Demonstrate
Demonstrate capability to build
multiple complex functionalities, capability to build
on demand, in a “cell-like” multiple complex
system functionalities in a
“cell-like” systems
Integrate the tools and capabilities around a series of challenge demonstrations
to prove-out the Living Foundries goal of rapid biological design and engineering
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10. BAA #1: Example areas of interest
Accelerate the biological design, build, test cycle and
expand the complexity of designs that can be built.
(1) Design tools that span from high-level description to synthetic circuit modeling to
automated fabrication in cells, i.e. interoperable tools and databases for design,
modeling, and fabrication
(2) Modular genetic parts, regulators, devices, and circuits (and the new methods
to develop and refine these) that allow a combination of systems to be designed
and reproducibly assembled increasing the efficiency, sophistication, and scale of
possible designs.
(3) Rapid construction, editing and manipulation of genetic designs, including low
cost DNA synthesis and assembly techniques, facile modification and manipulation of
genetic designs into a system/chassis, and designs engineered to readily translate
between different systems/chassis
(4) Well understood test platforms, ‘cell-like’ systems and chassis that readily integrate
new genetic designs in a predictable fashion
(5) Routine system characterization and debugging of synthetic gene networks that
feeds back and informs the design cycle
This list is not comprehensive: Additional/alternative areas of research and
development may be proposed
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11. Proposed Program Scope & Structure
• Each proposal may address one or more areas of interest
• Proposals must address how the need for future integration will
inform the design and development of tools/capabilities from their
conception
Simultaneously developing multiple interrelated tools, technologies
and/or methodologies in close concert is one way to address this
requirement
• Proposals must ensure tight coupling between any proposed design
tool development and experimental work
• Proposals must include a proof-of-concept to demonstrate utility to
the Living Foundries goals and to aid teaming for BAA#2
• Successful proposals will consist of a multidisciplinary team with
expertise both inside and outside of the biological sciences
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12. A successful proposal will address:
1. Why is the specific tool/capability proposed important and what problem does it solve?
Be quantitative.
2. What is the impact? Be quantitative. If successful, by how much will each tool/capability
speed the biological design, build, test cycle and/or expand the complexity of designs
that can be built?
3. What is the end goal and how does this compare against the current state of the art?
Include quantitative metrics.
4. What is the new technical idea behind the proposed tool/capability and why can it
succeed now? Provide examples of recent scientific advances that will enable success.
5. How will each specific tool/capability be developed to ensure its ability to integrate with
and support other tools/capabilities?
6. What is the proposed proof-of-concept to be demonstrated by the end of Phase I to
demonstrate the utility of the proposed tools/capabilities to the Living Foundries goals?
7. What is your approach/strategy to mitigate any potential safety/security risks during
technology development?
8. Looking ahead to the challenge demonstrations in BAA #2—if successful, what specific
new target applications will be possible that cannot be achieved today?
How will you take Living Foundries from vision to reality?
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13. Living Foundries: Impact Example
>100x
>100x
Living Foundries
Complexity
(#genes)
DNA synth/
Design Identify /modify potential genes and assemble potential pathways assembly
Transform +20x
cycle
time Transform At least 1 order of magnitude decrease in design cycle time
1 2
1 3 4 Time (months)
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14. Evaluation Criteria
1. Overall Scientific and Technical Merit
2. Potential Contribution and Relevance to the DARPA Mission
3. Proposer’s Capabilities and/or Related Experience
4. Realism of Proposed Schedule
5. Cost Realism
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15. Other Considerations
Interoperability
DARPA expects its investment in design tools and databases developed under the Living Foundries
program to be multiplied many-fold by adoption and improvement by researchers throughout the US.
To facilitate interoperability, the goal is to have all applicable design tools and databases developed
under the ATC program be compatible with Synthetic Biology Open Language (SBOL) core data model.
Bio-Safety and Security
Proposers must ensure that all methods and demonstrations of capability comply with any national
guidance for manipulation of genes and organisms and meet all criteria for biological safety and security
Proposals should address any potential bio-safety/security issues that the development of the proposed
tools/capabilities might pose. They should include a discussion of approaches and strategies to
manage, mitigate and monitor these risks during technology development.
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