BioDesign Automation

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Bio-Design Automation
EE5393 University of Minnesota
Brians Automated Modular Biochemical Instantiator
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ECE Expense Reports
What, How, Why,
What are we doing?

• Investigating design strategies for generating
  netlists of protein-protein biochemical
  reactions.

How are we going about it?

• Applying circuit CAD methodologies modularity /
  abstractions / hierarchical designs.

Why are we bothering?

• Such tools and methods will revolutionize the way
  synthetic biology is done.

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Playing by the Rules
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Playing by the Rules
Rules for integrated circuits
amplifier v1 1 0 rin1 1 0 9e12 rjump 1 4
1e-12 rin2 4 0 9e12 e1 3 0 1 2 999k e2 6 0 4
5 999k e3 9 0 8 7 999k rload 9 0 10k r1 2 3
10k rgain 2 5 10k r2 5 6 10k r3 3
7 10k r4 7 9 10k r5 6 8 10k r6
8 0 10k .dc v1 0 10 1 .print dc v(9)
.end
circuitnetlist
waveforms
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Playing by the Rules
Rules for biochemistry
GillespiesSSA
histogram resulting quantities of proteins
biochemical reactions
and initial quantities of proteins
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Playing by the Rules
Rules for biochemistry
GillespiesSSA
data structures (Gibson Bruck, Fett Riedel)
approximation methods (Petzold) hybrid
discrete/continuous methods (Kaznessis)
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dynamics well studied
mathematics (Tyson, Khammash, Doyle, )
biology (Arkin, Endy, Brent)
computation (Winfree, Shapiro)
GillespiesSSA
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Biochemical Netlists
Netlists found in nature

• Elucidated by biologists.

New Netlists

• Designed by skilled experimentalists(by
  tinkering with existing mechanisms).

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Synthetic Biology

• Positioned as an engineering discipline.
• Novel functionality through design.
• Repositories of standardized parts.

• Driven by experimental expertise in particular
  domains of biology.
• Modify gene regulation, signaling pathways,
  metabolic pathways

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Building Bridges
"Think of how engineers build bridges. They
design quantitative models to help them
understand what sorts of pressure and weight the
bridge can withstand, and then use these
equations to improve the actual physical model.
In our work on memory in yeast cells we really
did the same thing.
Pam Silver, Harvard 2007
Engineering Design

• Quantitative modeling.
• Mathematical analysis.
• Incremental and iterative design changes.

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Synthetic Biology
Feats of synthetic bio-engineering

• Cellulosic ethanol (Nancy Ho, Purdue, 04)
• Anti-malarial drugs (Jay Keasling, UC Berkeley,
  06)
• Tumor detection (Chris Voigt, UCSF 06)

Strategy apply experimental expertise formulate
ad-hoc designs perform extensive simulations.
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Building Digital Circuits

• Design is driven by the input/output
  specification.
• CAD tools are not part of the design process
  they are the design process.

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computational Synthetic Biology
computational Analysis
There are known knowns and there are unknown
unknowns but today Ill speak of the known
unknowns. Donald
Rumsfeld, 2004
Molecular Inputs
Molecular Products
Known /Unknown
Given
Known
Unknown
Unknown
Known
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Gene Regulation
Hard to tinker with this but its the way
computation is done
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Biochemistry in a Nutshell
Nucleotides
DNA string of n nucleotides (n 109)
... ACCGTTGAATGACG...
Amino acid coded by a sequence of 3 nucleotides.
Proteins produced from a sequence of m amino
acids (m 103) called a gene.
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Custom Gene Synthesis
Going from reading genetic codes to writing them.
US Patent 20070122826 (pending)The present
invention relates to a minimal set of
protein-coding genes which provides the
information required for replication of a
free-living organism in a rich bacterial culture
medium. J. Craig
Venter Institute
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Custom Gene Synthesis
Going from reading genetic codes to writing them.
Moderator Some people have accused you of
playing God. J. Craig VenterOh no, were not
playing.
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Biochemical Netlists
What are we doing?

• Figuring out how to design netlists in terms of
  abstract protein types so that we meet desired
  specs.

Why?

• Implement computation signal processing on
  protein quantities.

Ok, but how?
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Playing by the Rules
Biochemical Reactions how types of molecules
combine.
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Biochemical Reactions
cell
species
count
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8
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5
7
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Discrete chemical kinetics spatial homogeneity.
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Biochemical Reactions
Relative rates or (reaction propensities)
slow
medium
fast
Discrete chemical kinetics spatial homogeneity.
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Stochastic Kinetics
The probability that a given reaction is the next
to fire is proportional to

• Its rate.
• The number of ways that the reactants can combine.

See D. Gillespie, Stochastic Chemical Kinetics,
2006.
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Stochastic Kinetics
For each reaction
let
Choose the next reaction according to
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Design Automation for
Integrated Circuits
Behavioral Specification(e.g., DSP function)
Structural Description (e.g., memory and
functional units)
Circuit-Level Description (e.g., NAND2 and D
flip-flops)
waveforms
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Design Automation for
Biochemistry
Integrated Circuits
Behavioral Specification(e.g., DSP function)
Structural Description (e.g., memory and
functional units)
Biochemical Netlist (e.g., Proteins, Enzymes)
Biochemical Synthesis
STA Engine
waveforms
PSB 2009 Stochastic Transient Analysis
Biochemical Systems
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Design Automation for
Biochemistry
Integrated Circuits
Behavioral Specification(e.g., DSP function)
Structural Description (e.g., memory and
functional units)
Biochemical Netlist (e.g., Proteins, Enzymes)
Biochemical Synthesis
STA Engine
DAC 07, SB 3.0 The Synthesisof Stochastic
Biochemical Systems
waveforms
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Design Automation for
Biochemistry
Integrated Circuits
Behavioral Specification(e.g., DSP function)
Joint work with Keshab Parhis group.
Structural Description (e.g., memory and
functional units)
Biochemical Netlist (e.g., Proteins, Enzymes)
STA Engine
Brians Automated Modular Biochemical Instantiator
waveforms