synthetic biology: the next generation of biotechnology - christina smolke, stanford engineering
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July 16, 2011 12th Annual eDay
Christina D. Smolke Department of Bioengineering Stanford University
Natural chemicals and materials
Taxus brevifolia (pacific yew) taxol
Papaver somniferum (opium poppy) codeine, morphine
spider silk
Clostridium acetobutylicum butanol
Hevea brasiliensis (rubber tree) rubber
Microbial biofactories
Taxus brevifolia (pacific yew) taxol
Papaver somniferum (opium poppy) codeine, morphine
spider silk
Clostridium acetobutylicum butanol
Hevea brasiliensis (rubber tree) rubber
New chemicals raw materials microbial fermentation
genetic materials,
manipulation & control
materials products
www.neurooncologia.com
Intelligent therapeutics
Apps Tools
c/o D. Endy (Stanford University)
1. Info. theory & signal proc. 2. Device design
7. Control & dyn. systems
5. Fab, CAD & EDA 6. Reverse engineering
3. Languages & grammars 4. Standards & abstraction
c/o D. Endy (Stanford University)
signal processing automated response dynamic control
Circuitry remote control memory communication
Actuators (Outputs) reporting delivery motility
phenotype self-organization synthesis
Sensors (Inputs) chemicals biomolecules temperature light
Engineering systems
Synthetic biology
signal processing automated response dynamic control
Circuitry remote control memory communication
Actuators (Outputs) reporting delivery motility
phenotype self-organization synthesis
Sensors (Inputs) chemicals biomolecules temperature light
Ongoing tools revolution DNA Sequencing
Read Out the Genetic Code
Recombinant DNA
Basic “Cut” & “Paste”
Polymerase Chain Reaction
Amplify & Make Simple Changes
First Gen. Biotech =
...
Next Gen. Biotech Adds New Tools
=
c/o D. Endy (Stanford University)
Transformative advances in fabrication platforms
Cellular assembly Carr PA, Church GM. 2009. Nat Biotech. 27: 1151-1162
genome transplantation
natural
engineered
Gibson DG, et al. 2010. Science. 329: 52-6
Now that we can write in DNA, what
do we say?
Challenge: Design Gap
Molecular computers enable programming of function input
output
input A
outp
ut
sensor1 / transmitter1 / actuator
input A
outp
ut
sensor1 / transmitter2 / actuator
input B
outp
ut
sensor2 / transmitter1 / actuator
input output
Win MN, Smolke CD. 2007. PNAS. 104: 14283-8
Molecular computers enable programming of function input
output
input A
outp
ut
sensor1 / transmitter1 / actuator
input A
outp
ut
sensor1 / transmitter2 / actuator
input B
outp
ut
sensor2 / transmitter1 / actuator
A B output
0 0 1 0 1 1
1 0 1 1 1 0
n sensors / n transmitters / actuator
Win MN, Smolke CD. 2008. Science. 322: 456-60
Decoupling & abstraction lead to powerful technology platforms
Win MN, Liang JC, Smolke CD. 2009. Chem Biol. 16: 298-310
harvesting and refining from nature
rational computer- aided design (CAD)
evolving new functions
Building scalable bio-manufacturing platforms
anti-malarial
analgesics
anticancer
antimicrobial
hair growth
anti-HIV
Integrating into a microbial host
Hawkins KM, Smolke CD. 2008. Nat Chem Biol. 4: 564-73
Harvesting natural diversity
Building a microbial drug factory
Enzymes catalyze reactions:
Morphinan Alkaloids
Sanguinarine / Berberine Alkaloids
Bis-BIAs
Building a microbial drug factory
Morphinan Alkaloids
Sanguinarine / Berberine Alkaloids
Bis-BIAs
Building a microbial drug factory
DNA
protein
metabolite
Morphinan Alkaloids
Sanguinarine / Berberine Alkaloids
Bis-BIAs
Building a microbial drug factory
Morphinan Alkaloids
Sanguinarine / Berberine Alkaloids
Bis-BIAs
Building a microbial drug factory
Morphinan Alkaloids
Sanguinarine / Berberine Alkaloids
Bis-BIAs
Building a microbial drug factory
Integrated systems design of microbial factories
SalR-GFP SalAT-mCherry
Vacuole
Nucleus
ER
Mitochondrion
Golgi
Synthesome
pH 4-5
pH 8-9
degradation
pH 7-8
input A
outp
ut
Targeting biosynthesis to specialized compartments
Noninvasive detection of chemical synthesis
Building autonomous control systems
Culler SJ, Hoff KG, Smolke CD. 2010. Science. 330: 1251-5
Molecular computers can rewire disease pathways
Culler SC, Hoff KG, Smolke CD. 2010. Science. 330: 1251-5
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Chen YY, Jensen MC, Smolke CD. 2010. PNAS. 107: 8531-6
Cellular therapies: engineering the immune system
http://www.discoverymedicine.com/Leslie-E-Huye/files/2010/03/
harvest lymphocytes from patient recover and engineer
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proliferation
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A molecular computer controlling immune response
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Chen YY, Jensen MC, Smolke CD. 2010. PNAS. 107: 8531-6
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Apps
Tools
Device Design
AGGTACAGTTATCA CCCATTGCATGGTA TTCAAAGAAGTCGT GGCCCAGATTCGAC AAATCGTGTAGTAA TGGTCCAGCTGATT GGTTCAAATAACGG
input A
outp
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Languages & Grammar Standardization Abstraction Synthesis
The Smolke Laboratory
Alfred P. Sloan Foundation Arnold and Mabel Beckman Foundation Bill and Melinda Gates Foundation Defense Advanced Research Projects Agency National Institutes of Health (NIGMS, NCI) National Science Foundation (CBET, CCF, CAREER)
Funding Sources Andrew Babiskin Travis Bayer Chase Beisel Yvonne Chen Stephanie Culler Kristy Hawkins Kevin Hoff Maung Nyan Win
Alumni
Let’s design with DNA…
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