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Marc D. RiedelAssistant Professor, ECE University of Minnesota
EE 5393: Circuits, Computation and BiologyEE 5393: Circuits, Computation and Biology
ORAND AND
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“Minnesota Farmer”
• Most of the cells in his body are not his own!
• Most of the cells in his body are not even human!
• Most of the DNA in his body is alien!
Who is this guy?
“Minnesota Farmer”
• 100 trillion bacterial cells of at least 500 different types inhabit his body.
Who is this guy?
He’s a human-bacteria hybrid:
vs.
• only 1 trillion human cells of 210 different types.
[like all of us]
“Minnesota Farmer”
Who is this guy?What’s in his gut?
• 100 trillion bacterial cells of at least 500 different types inhabit his body.
He’s a human-bacteria hybrid:
vs.
• only 1 trillion human cells of 210 different types.
[like all of us]
About 3 pounds of bacteria!
What’s in his gut?“E. coli, a self-replicating object only a thousandth of a millimeter in size, can swim 35 diameters a second, taste simple chemicals in its environment, and decide whether life is getting better or worse.”
– Howard C. Berg
flagellum
Bacterial Motor
Bacterial Motor
Electron Microscopic Image
“Stimulus, response! Stimulus response! Don’t you ever think!”
We should put these critters to
work…
Synthetic Biology
• Positioned as an engineering discipline.– “Novel functionality through design”.– Repositories of standardized parts.
• Driven by experimental expertise in particular domains of biology.– Gene-regulation, signaling, metabolism,
protein structures …
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
• Quantitative modeling.• Mathematical analysis.• Incremental and iterative design changes.
Engineering Design
Building Digital Circuits
Intel 4004(1971)
Intel “Nehalem”(2008)
~2000 gates
~2 billion gates
inputs outputs
• Design is driven by the input/output specification.• CAD tools are not part of the design process; they are
the design process.
Building Digital Circuits
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1x
2x
mx
digital circuit
…
…
…
...
Synthetic Biology
• Cellulosic ethanol (Nancy Ho, Purdue, ’04)
• Anti-malarial drugs (Jay Keasling, UC Berkeley, ‘06)
• Tumor detection (Chris Voigt, UCSF ‘06)
Feats of synthetic bio-engineering:
Strategy: apply experimental expertise; formulate ad-hoc designs; perform extensive simulations.
From ad hoc to Systematic…
Claude E. Shannon1916 –2001
“A Mathematical Theory of Communication,” Bell System Technical
Journal, 1948.
Basis of information theory, coding theoryand all communication systems.Basis of all digital computation.
“A Symbolic Analysis of Relay and Switching Circuits,”
M.S. Thesis, MIT, 1937
[computational] Synthetic Biology[computational] Analysis
“There are known ‘knowns’; and there are unknown ‘unknowns’; but today I’ll speak of the known ‘unknowns’.”
– Donald Rumsfeld, 2004
BiologicalProcess
Molecular Inputs
Molecular Products
KnownKnown
UnknownKnown /Unknown
UnknownGiven
Artificial Life
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
Going from reading genetic codes to writing them.
Artificial Life
Going from reading genetic codes to write them.
Moderator: “Some people have accused you of playing God.”
J. Craig Venter:“Oh no, we’re not playing.
Biochemistry in a Nutshell
DNA: string of n nucleotides (n ≈ 109)
... ACCGTTGAATGACG...
},,{},,,{ 2013 aaGTCA
Nucleotides:
Amino acid: coded by a sequence of 3 nucleotides.
Proteins: produced from a sequence of m amino
acids (m ≈ 103).
},,,{ GTCA
protein},,{ 201 maa
The (nano) Structural Landscape
“You see things; and you say ‘Why?’ But I dream things that never were; and I say ‘Why not?’"
– George Bernard Shaw, 1925
Novel Materials…
Novel biochemistry…
Novel biological functions…
Jargon vs.Terminology
“Now this end is called the thagomizer, after the late Thag Simmons.”
The Computational Landscape“There are known ‘knowns’; and there are unknown
‘unknowns’; but today I’ll speak of the known ‘unknowns’.”
– Donald Rumsfeld, 2002
Semiconductors:exponentially smaller, faster, cheaper – forever?
1 transistor (1960’s)2000 transistors(Intel 4004, 1971)
800 million transistors(Intel Penryn, 2007)
The Computational Landscape
• Abutting true physical limits.
• Cost and complexity are starting to overwhelm.
“There are known ‘knowns’; and there are unknown ‘unknowns’; but today I’ll speak of the known ‘unknowns’.”
– Donald Rumsfeld, 2002
Semiconductors:exponentially smaller, faster, cheaper – forever?
The Computational Landscape
• Multiple cores?• Parallel Computing?
Potential Solutions:
“There are known ‘knowns’; and there are unknown ‘unknowns’; but today I’ll speak of the known ‘unknowns’.”
– Donald Rumsfeld, 2002
The Computational Landscape
b
a?
• Novel Materials?
Potential Solutions:
• Novel Function?
“There are known ‘knowns’; and there are unknown ‘unknowns’; but today I’ll speak of the known ‘unknowns’.”
– Donald Rumsfeld, 2002
gene
The Computational Landscape“There are known ‘knowns’; and there are unknown
‘unknowns’; but today I’ll speak of the known ‘unknowns’.”
– Donald Rumsfeld, 2002
RNAp outputprotein
repressorprotein
The Computational Landscape
gene
“There are known ‘knowns’; and there are unknown ‘unknowns’; but today I’ll speak of the known ‘unknowns’.”
– Donald Rumsfeld, 2002
RNAp
Biological computation?
nada
Research Activities in my Lab
• The concurrent logical and physical design of nanoscale digital circuitry.• The synthesis of stochastic logic for robust polynomial arithmetic.• Feedback in combinational circuits.• High-performance computing for the stochastic simulation of
biochemical reactions.• The analysis and synthesis of stochasticity in biochemical systems.
Our research activities encompass topics in logic synthesis and verification, as well as in synthetic and computational biology. A broad theme is the application of expertise from the realm of circuit design to the analysis and synthesis of biological systems. Current projects include: ?
Research Activities in my Lab
• We’re studying the mathematical functions for digital circuits. • We’re writing computer programs to automatically design such circuits.
• We’re studying the concepts, mechanisms, and dynamics of intracellular biochemistry.
• We’re writing computer programs for analyzing and synthesizing these dynamics.
CircuitsCircuits
BiologyBiology
Two Made-Up Facts[well, abstractions, really…]
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g
Logic Gates
Biochemical Reactions
+
“AND” gate
0001
1x
2x
g0011
0101
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Logic Gates
“XOR” gate
0011
0101
0110
1x
2x
g
1x 2x g
Logic Gates
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inputs outputs
Digital Circuit
1x
2x
mx
circuit
),,( 1 mn xxf a
),,( 11 mxxf a
),,( 12 mxxf a),,( 1 mxxf a
inputs outputs
1x
2x
mx
circuit gate
Digital Circuit
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NAND
OR
ANDAND
AND
NOR
1
0
0
1
1
1
1
0
1
0
0
1
Digital Circuit
My PhD Dissertation[yes, in one slide…]
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x1
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It’s not a bug, it’s a feature.
circuit0
1
Characterize probability of outcomes.
inputs outputs
Model defects, variations, uncertainty, etc.:
Current Research
circuit
inputs outputs
Model defects, variations, uncertainty, etc.:
0,1,1,0,1,0,1,1,0,1,…
1,0,0,0,1,0,0,0,0,0,…
p1 = Prob(one)
p2 = Prob(one)
Current Research
circuit
inputs outputs
Model defects, variations, uncertainty, etc.:
51
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Current Research
Biochemical Reactions
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cellprotein count
+
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5
9
Biochemical Reactions
+
+
+
slow
medium
fast
Bacteria are engineered to produce an anti-cancer drug:
Design Scenario
drugtriggering compound E. Coli
Bacteria invade the cancerous tissue:
cancerous tissue
Design Scenario
cancerous tissue
The trigger elicits the bacteria to produce the drug:
Design Scenario
Bacteria invade the cancerous tissue:
cancerous tissue
Problem: patient receives too high of a dose of the drug.
Design Scenario
The trigger elicits the bacteria produce the drug:
Design Scenario
• Bacteria are all identical.• Population density is fixed.• Exposure to triggering compound is uniform.
Constraints:
• Control quantity of drug that is produced.
Requirement:
Conceptual design problem.
cancerous tissue
Approach: elicit a fractional response.
Design Scenario
produce drug
triggering compound E. Coli
Approach: engineer a probabilistic response in each bacterium.
with Prob. 0.3
don’t produce drugwith Prob. 0.7
Synthesizing Stochasticity
Engineering vs. Biology vs. Mathematics
Dilbert Beaker Papa
Communicating Ideas
Domains of Expertise
• Vision• Language• Abstract Reasoning• Farming
Human
Circuit
• Number Crunching
• Mining Data• Iterative
Calculations
“A person's mental activities are entirely due to the behavior of nerve cells, glial cells, and the atoms, ions, and molecules that make them up and influence them.”
– Francis Crick, 1982
Astonishing Hypothesis
“That the astonishing hypothesis is astonishing.”
– Christophe Koch, 1995
The Astonishing Part
Circuits & Computers as a Window into our Linguistic Brains
CircuitBrainConceives of circuits and
computation by “applying” language.
Lousy at all the tasks that the brain that
designed it is good at (including language).
?
If You Don’t Know the Answer…
