building biological systems from standard parts tom knight mit computer science and artificial...
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Building Biological Systems from Standard Parts
Tom Knight
MIT Computer Science andArtificial Intelligence Laboratory
IGEM Headquarters
Ginkgo Bioworks Inc.
A Scientist discovers that which exists;an Engineer creates that which never was.
-- Theodore von Karman
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Maxwell / DarwinPhysics / Biology1900’s / 2000’s
Science ~ 1870
Electrical engr. ~ 1905
Major ideas: modularity, hierarchy, information, black box behavior, feedback, design & synthesis, control of materials, technological substrate
Perfect devices
Science ~ 1960
Synthetic biology ~ 2000
Major ideas: modularity, hierarchy, information, black box behavior, feedback, design & synthesis, control of materials, technological substrate
Perfect behavior
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Major societal problems
• Energy & raw materials
• Environmental protection and cleanup
• Health & aging
• Defense against natural and unnatural events
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Science and Engineering
Natural organisms Engineered organisms
Knowledge & understandingExcellent models
ScienceSystems Biology
EngineeringSynthetic Biology
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Science and Engineering
Engineered organisms
Knowledge & understandingExcellent models
Science &Systems Biologyof natural organisms
Engineering &Synthetic Biology using standard parts
PartsRepository
De novo DNAsynthesis
Revisedknowledgeand newtechniques
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Systems Biologyvs.
Synthetic Biology Based on Standard Parts
Systems Biology- Models of natural systems- New discoveries from data analysis and fusion- Understanding of noise and other effects in natural systems- Success measured in match of the model to nature- Embrace natural complexity
Synthetic Biology Based on Parts- Parts designed for use by others- Engineering design tools- Simulators- Industrial development of good parts and devices- Simple organisms to hold designs- iGEM team success is based on parts- Registry is the primary catalog of parts- Success measured in generality and utility of parts, systems and protocols-Remove natural complexity
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Powerful tools of engineering design
• abstraction• hierarchy• modularity• standardization• isolation, separation of
concerns• flexibility
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Abstraction model
Small core of standard parts
Real world complexity
Constructed complexity
catabolism anabolism
Design information
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Abstraction model
Metabolic intermediates
AAs, NTPs, core metabolites
FoodLiving systems, waste
catabolism anabolism
genome
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Abstraction model
Requirements Implementations
Abstraction barrier
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Abstraction layers
Standard interfaces
Contracts
Abstractions
Part
Abstraction layer
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Abstractions in electronicsUser
Application software
Operating system, user interface
Programming language
Instruction set architecture
Virtual machine
Computer hardware design
Functional computing units
Logic synthesis
Logic gates
Circuit design
Transistors
Mask geometry
Fabrication technologies
Semiconductor physics
Quantum physics
Differential equations: KCL, KVL, device models, network theory
State change, abstract behavior
1E9 components
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Types of designersUser
Application software
Operating system, user interface
Programming language
Instruction set architecture
Virtual machine
Computer hardware design
Functional computing units
Logic synthesis
Logic gates
Circuit design
Transistors
Mask geometry
Fabrication technologies
Semiconductor physics
Quantum physics
Tall, thin designer
Broad, deep designer
Carver Mead, 1980Mead & Conway, Introduction to VLSI Design
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Standards & Design RulesUser
Application software
Operating system, user interface
Programming language
Instruction set architecture
Virtual machine
Computer hardware design
Functional computing units
Logic synthesis
Logic gates
Circuit design
Transistors
Mask geometry
Fabrication technologies
Semiconductor physics
Quantum physics
Carver Mead, 1980Mead & Conway, Introduction to VLSI Design
Spacing rules
Fanout rules
Signal restoration rules
Run Microsoft software
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Complexity ReductionUser
Application software
Operating system, user interface
Programming language
Instruction set architecture
Virtual machine
Computer hardware design
Functional computing units
Logic synthesis
Logic gates
Circuit design
Transistors
Mask geometry
Fabrication technologies
Semiconductor physics
Quantum physics
100’s of OS calls100 statements
100’s of instructions
10’s of units
10’s of gate types
4 types of transistors
15 mask layers
6 materials
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Complexity Reduction
• Good News:
Biology is modular and abstract
Evolution needs modular design as much as we do
We can discover the modular designs, modify them, and use them
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Learn New Engineering Principles from Biology
Coping with errors
Design with unreliable components
Design with evolution
Self organization
Self repair
Molecular scale construction
Biology is the nanotechnology which works
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Role of Standards in Engineering
• Simplified thinking about interfaces: Design rulesComposition: Structural / Functional
• Reusable Parts
• Contracts and commercial access
• Independent evolution of components and technologies
• Facile comparison of results
“The good thing about standards is that there are so many to choose from”
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“In this country, no organized attempt has yet been made to establish any system, each manufacturer having adopted whatever his judgment may have dictated as best, or as most convenient forhimself.”
Williams Sellers “On a Uniform System of Screw Threads”Franklin Institute April 21, 1864
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Several Standards
• Standard components & interfaces
• Standard composition
• Standard function & interfaces
• Standard measurements
• Standard chassis
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Biobricks:Standard Biological Parts
• Snap together Lego block assemblyMechanical compatibility
• Output of one component suitable as input of next componentFunctional compatibility
Input SensorsComputational DevicesOutput Actuators
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Naturally Occurring Sensor and Actuator Parts Catalog
Sensors• Light (various wavelengths)
• Magnetic and electric fields
• pH
• Molecules Autoinducers H2S maltose serine ribose cAMP NO
• Internal State Cell Cycle Heat Shock
• Chemical and ionic membrane potentials
Actuators• Motors
Flagellar Gliding motion
• Light (various wavelengths)• Fluorescence• Autoinducers (intercellular
communications)• Sporulation• Cell Cycle control• Membrane transport• Exported protein product
(enzymes)• Exported small molecules• Cell pressure / osmolarity• Cell death
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Standard Component Form
gca GAATTC gcggccgc t TCTAGA g
cgt CTTAAG cgccggcg a AGATCT c
EcoRI XbaI
t ACTAGT a GCGGCCG CTGCAG gct
a TGATCA t cgccggc GACGTC cga
SpeI PstI
E X S P
No internal sequences of the form
EcoRI: GAATTCXbaI: TCTAGASpeI: ACTAGTPstI: CTGCAG
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Assembly 3-Way
E P
E X St A CTAGA a a TGATC T t SpeI XbaI
t ACTAGA a a TGATCT t mixed
E X S P
X S P
vector origin antibiotic resistance
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DARPA Biocomp PlasmidDistribution 1.0 May 2002
• Standard vectors, components, protocols• Very limited coverage –
Plac, ECFP, EYFP, lacZ, T1 Assembled compound structures
• Enough to get started
• More coming soon Lux systems from V. fischeri and P. luminescens cI, p22-C2, tetR, luxR Antibiotic resistance, pACYC & pSC101 ori Autoinducer systems from V. fischeri, P. aeruginosa
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Some toy experiments
• Plac – ECFP• Plac – EYFP• Plac – ECFP – EYFP• Plac – EYFP – ECFP• Plac – ECFP – T1 – EYFP• Plac – EYFP – T1 – ECFP
• Need standardized measurement techniques
• Need good modeling tools
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Grace Kenney 6/7 2006June-Wha Rhee 6/7 2006Maia Mahoney 6 2005Connie Tao 6 2004Louis Waldman 2/6 2005Alex Wissner-Gross 6/8/18 2003Danny Shen 6 2005Jose Pacheco 10/14 2003Reshma Shetty BE GVinay Mahajan BE GTy Thomson BE GSamantha Sutton BE GNeel Varshney HST GVoichita Marinescu HST GBrian Chow MAS GPeter Carr MAS RS
No prerequisites, no credit, consumes most of January… 13 waitlisted students
Laura Wulf, MIT News Office c.2003
MIT Synthetic Biology, IAP Class 2003
Four project teams, shared componentssixty fabricated components – Blue Heron
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Key Ideas• Build system out of standard parts
Pre-optimized for assembly
• Use standard techniques to assemble themNo surprisesRoutineRobot assembly
• Network effects on the size of the library6 -> 5500
• Couple functional and physical designsParts have a logical function, not random DNA
fragments
• Measured and characterized for modelingFirst time success
• Part collections of similar interchangeable parts
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Standard Plasmids
• pSB1A3 pSB “synthetic Biology” 1 -> high copy number origin (pUC19 e.g.) A -> Ampicillin resistant 3 -> Biobrick cloning site with up and downstream terminators
• Available antibiotics A ampicillin (orange) 100 ug/ml C chloramphencol (green) 35 ug/ml K kanamycin (red) 50 ug/ml T tetracycline (yellow) 15 ug/ml
• Available origins - pSC101, p15A, inducible
• We need parts returned to the Registry in 1 series plasmids if possible
• VF2, VR sequencing primer locations
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Resources
• IGEM home pages: igem.orgPast team project wikis, posters, presentations
• Registry of standard biological parts:Partsregistry.org
• Openwetware: openwetware.orgSearching the literature
• IGEM headquarters [email protected]
• Me: [email protected]
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Synthetic Biology
• An Engineering technology based on biologywhich complements rather than replaces standard
approaches
• Engineering synthetic constructs willEnable quicker and easier experimentsEnable deeper understanding of the basic
mechanismsEnable applications in nanotechnology, medicine
and agricultureBecome the foundational technology of the 21st
centurySimplicity is the ultimate sophistication
-- Leonardo da Vinci