Industry Day Living Foundries DARPA

Living Foundries

Alicia Jackson

Program Manager, DARPA

Living Foundries Industry Day

Arlington VA

June 28, 2011

8/23/2011 1Approved for Public Release, Distribution Unlimited

DARPA


The question that all DARPA programs must answer: Is it game changing and will it have lasting impact on DOD and the warfighter?

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

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?

Living Foundries



Living Foundries: The Vision

Chemicals

Fuels

Pharma

Molecules

“cell-like” factory

Sugar

Natural gas

Cellulose

PET

Coal

Custom, distributed, on-demand manufacturing

DNA instructions

Polymers

Catalysts

Electronic/ optical materials

Multi-cellular constructs

Self-repairing systems

“cell-free” systems

Image adapted from: Vickers et al., Nature Chemical Biology, 2010 and Keasling, Science, 2010

1.00E+03

1.00E+04

1.00E+05

1.00E+06

1.00E+07

1.00E+08

1.00E+09

1.00E+10

1.00E+11

1 10 100 1,000 10,000 100,000


1 10 100 1,000 10,000 100,000

Complexity (# genes inserted/modified)

1010

1011

109

108

107

106

105

104

103

Eff

ort

(to

tal

$ *

yrs

to

de

ve

lop

) [$

*yr]

yeastminimal bacterium

Engineering biology today is a time and money intensive process

DARPA annual budget

We’re just scratching the surface of what’s possible

Where Living Foundries will take us

genome rewritecomplex genetic circuits

metabolic engineering

SOA

SOA: ad hoc, empirical, expensive process


Goal: hierarchical engineering

(def band-detect (s lo hi)

(and (> s lo) (< s hi))))

(let ((s (diffuse (aTc)

0.8 0.05)))

(green (band-detect

s 0.2 1)))

X

Smallsystems

Large systems

Many iterations

No iteration

Application

Itera

te >

20x

Standardization and modularity of genetic parts and chasses

Abstraction of genetic function to manage complexity

Decoupling of design and fabrication

New approach: decouple design from fabrication through design rules and standardized parts

• Natural parts don’t work as expected outside of native environment

• Not all parts exist

• Design rules are unknown

• No reliable design tools

7 yrs (SOA)

Time (months)

Transform

Transform 3 wks

Coupled Design/Fabrication

~105 attempts

4 m

os

DNACoupled design and fabrication +20x

Parts/Devices

Design tools

Fabrication

Test/Debug

Application

Program cells in a high-level language and compile to genetic code

Standardized, well-characterized parts and devices that are CAD friendly

Automated synthesis and assembly of DNA in standardized cell chassis

Quick, high-throughput identification and quantification of the cell state

Example of a possible approach


What is needed for Living Foundries

An open and accessible platform for engineering biology

• Interoperable tools for design, modeling and fabrication

• Well-characterized, standardized and orthogonal genetic parts

• Scalable, low-cost, high-fidelity DNA synthesis processes with rapid turn-times

• Test platforms and chassis that readily and predictably integrate new genetic designs

• Locate failures and characterize the whole cell state

Design tools that span from high-level description to fabrication in cells

Modular genetic parts that allow a combination of systems to be

designed and reproducibly assembled

Rapid construction, evolution and manipulation of genetic designs

Routine system characterization and debugging that informs the design cycle

What is needed Technical Challenges

Accelerate the biological design, build, test cycle and expand the complexity of designs that can be built.

This list is not comprehensive: Additional/alternative areas of research and development may be proposed

Structure of Living Foundries


Anticipated BAA #1Advanced Tools and

Capabilities

Anticipated BAA #2:Living Foundries Challenge

Demonstrations 24 Months

ATC BAA

BAA

Demonstrate tools and platform capabilities

Integrate tools and platform

capabilities in full demonstration

Demonstrate capability to build multiple complex functionalities in a “cell-like” systems

Outcome:

• Interoperable design tools

• New, modular genetic parts, regulators, and circuits

• Standardized test platforms, cell-like systems and chassis

• Low cost, rapid DNA synthesis

• Quantitative, high throughput characterization and debugging

Outcome:

Demonstrate capability to build multiple complex functionalities,

on demand, in a “cell-like” system

Integrate the tools and capabilities around a series of challenge demonstrations to prove-out the Living Foundries goal of rapid biological design and engineering

Tools and capabilities to accelerate the biological design, build, test cycle and expand the complexity of designs that can be built.

Proof of concept

BAA #1: Example areas of interest


(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

Accelerate the biological design, build, test cycle and

expand the complexity of designs that can be built.

This list is not comprehensive: Additional/alternative areas of research and development may be proposed

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

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?

Living Foundries

Living Foundries: Impact Example


Transform

Transform

DNA synth/ assemblyIdentify /modify potential genes and assemble potential pathways +20x

1 1 2 3 4 Time (months)

Design cycle time At least 1 order of magnitude decrease in design cycle time

>100x

Complexity (#genes)

>100x

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

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.

Technology

Industry Day Living Foundries DARPA