ICSB3: DRPM Measures

Enabling Technology : Biomaterials Evolution Platform 9:05-9:35 4-Feb-2009 Wyss Institute for Biologically Inspired Engineering Thanks to: 1 Feb 10 8:30-9:00: Jim Collins - Anticipatory Medical Devices 9:05-9:35: George Church - Biomaterial Evolution 9:40-10:10: Joanna Aizenberg - Adaptive Architectures 10:15-10:45: Don Ingber - Programmable Nanomaterials 10:50-11:20: Don Ingber Biomimetic Microsystems 2 Biomaterials Evolution Platform DNA Synthesis, assembly & analysis on chips - VDJ-ome (antibody libraries) 3-D DNA structures: inorganic interfaces In vitro systems: multi-enzyme resistance Microbial systems: multi-virus resistance - Metabolic engineering fuels & chemicals

Human cell systems: combinatorial regulation - Organ self-assembly 3 Sequencing tracked Moores law 2X/2 yr until 2005-9 10,000x/4yr 10 1 0.1 0.01 $/bp 2005 $50M 0.001 0.0001 0.00001 2009 $5K 0.000001 0.0000001

1990 1995 2000 2005 2010 2009 goal of 2% for $200 (coding + regulatory) 4 Open-architecture hardware, software, wetware e.g. 1981 IBM PC $150K - 2 billion beads/run Polonator Rich Terry

Senior Engineer 5 DNA Synthesis, assembly & analysis on chips Digital micromirror & inkjet Nitrobenzyl linkers for selective release of beads or cells 6 Biomaterials Evolution Platform DNA Synthesis, assembly & analysis on chips - VDJ-ome (antibody libraries) 3-D DNA structures: inorganic interfaces In vitro systems: multi-enzyme resistance Microbial systems: multi-virus resistance - Metabolic engineering fuels & chemicals Human cell systems: combinatorial regulation - Organ self-assembly 7

Antibody (& TCR) VDJ regions VH*DH*NH*JH*V*J 46*23*N * 6 * 67* 5 = > 2M combinations , 750 bp, >1E10 cells Roth DB et al Mol Cell Biol. 1989 9:3049 N (1-13): 14 22 13 15 10 4 5 4 2 2 3 2 1 Lefranc, The Immunoglobulin FactsBook; Janeway, Immunobiology 2001 8 Biomaterials Evolution Platform DNA Synthesis, assembly & analysis on chips - VDJ-ome (antibody libraries) 3-D DNA structures: inorganic interfaces In vitro systems: multi-enzyme resistance Microbial systems: multi-virus resistance - Metabolic engineering fuels & chemicals Human cell systems: combinatorial regulation - Organ self-assembly 9 First practical application of DNA nanostructures

Residual NMR dipolar couplings for membrane proteins >15kDa Douglas, et al. PNAS 2007 10 Selection of DNAs enabling selection of CNT structures Material properties change at the sub-nm scale (& sensitive to defects) Carbon Nanotubes Tensile strength: 62,000 MPa vs CNT-rope 3600, silk 1000, steel 800 Thermal conduction: 6000 W/mK vs Cu 385 Electrical current density of 4000 MA/cm2, vs Cu 4 C60 fullerite Bulk Modulus: 491 GPa vs diamond 442, steel 160 11 Biomaterials Evolution Platform DNA Synthesis, assembly & analysis on chips - VDJ-ome (antibody libraries) 3-D DNA structures: inorganic interfaces

In vitro systems: multi-enzyme resistance Microbial systems: multi-virus resistance - Metabolic engineering fuels & chemicals Human cell systems: combinatorial regulation - Organ self-assembly 12 Mirror world : resistant to enzymes, parasites, predators Approach#1: De novo Chemical synthesis (below) #2: Redesigned peptidyl transferase + D-AA-tRNAs (next slide) 352 AA Synthetic Dpo4 Sulfolobus DNA polymerase IV 4 peptide bonds left to construct L-aminoacids D-nucleotides (current biosphere) D-aminoacids L-nucleotides (Mirror-biopolymers) Duhee Bang

13 113 kbp DNA 151 genes Synthetic Life High speed & accuracy Route to mirror proteins Jewett Pure translation: Forster & Church MSB 05 GenomeRes.06 Shimizu, Ueda 01 14 Biomaterials Evolution Platform DNA Synthesis, assembly & analysis on chips - VDJ-ome (antibody libraries)

3-D DNA structures: inorganic interfaces In vitro systems: multi-enzyme resistance Microbial systems: multi-virus resistance - Metabolic engineering fuels & chemicals Human cell systems: combinatorial regulation - Organ self-assembly 15 Genome Engineering Multiplex Automation (GEMA) for multi-viral resistance 16 Genome Engineering Multiplex Automation (GEMASS) in vivo homologous allele replacement (lagging SS mimics) 3 hr Cycle time. Application: 314 change for multivirus resistance 17 Improving process yield, health, safety: What threatens all biological

systems? What do all viruses have in common? or lack? 18 New genetic code: viral-resistance, novel amino acids no functional GMO DNA exchange PEG-pAcPhe-hGH (Ambrx) high serum stability 314 TAG to TAA changes TTT TTC F TTA TTG 4 TCT 11495

TAT 22516 TCC 11720 TAC 18932 TCA 9783 TAA TCG 12166

TAG CTT 15002 CCT 9559 CAT CTC 15077 CCC 7485 CAC CTA

5314 CCA 11471 CAA 71553 CCG 31515 CAG 41309 ACT 12198

AAT 34178 ACC 31796 AAC 5967 ACA 9670 AAA 37915 ACG 19624

AAG GTT 24858 GCT 20762 GAT GTC 20753 GCC 34695 GAC

14822 GCA 27418 GAA 35918 GCG 45741 GAG L ATT ATC I

ATA ATG GTA GTG M V P T A Y STOP S 18602 CTG

L 30362 STOP H Q N K D E 1 21999

TGT 7048 16601 TGC C 8816 2703 TGA STOP 1256 314 TGG

W 20683 17613 CGT 28382 13227 CGC 29898 20888 CGA 39188

CGG 7399 24159 AGT 11970 29385 AGC 45687 AGA 14029 AGG 43719

GGT 33622 25918 GGC 40285 53641 GGA 24254 GGG 4859 R

S R G 3 21862 2 2896 1692 Isaacs Charalel Church Sun Wang Carr Jacobson Kong Sterling 10893

15090 19 Biomaterials Evolution Platform DNA Synthesis, assembly & analysis on chips - VDJ-ome (antibody libraries) 3-D DNA structures: inorganic interfaces In vitro systems: multi-enzyme resistance Microbial systems: multi-virus resistance - Metabolic engineering fuels & chemicals Human cell systems: combinatorial regulation - Organ self-assembly 20 Accelerated evolution for valuable metabolites & biofuels 21 Biomaterials Evolution Platform DNA Synthesis, assembly & analysis on chips - VDJ-ome (antibody libraries) 3-D DNA structures: inorganic interfaces

In vitro systems: multi-enzyme resistance Microbial systems: multi-virus resistance - Metabolic engineering fuels & chemicals Human cell systems: combinatorial regulation - Organ self-assembly 22 Re-programming adult human cells to multiple tissues with combinations of DNAs Hair or skin sample 23 Combinations of regulatory genes Viral delivery: -catenin, Dnmt3l, Dppa2,3,4,5, Ecat1, Eras, Fthl17, Grb21, Ecat8, Fbx15, Gdf3, hTERT, Klf4, Myc, Nanog, Oct4, Rex1, Sall4, Sox2, Sox15, Stat3, Tcl1, Utf1 Signals: Activin, BMP4, Estrogen, FGF, HGF, PDGF, Retinoate, Shh, TGF, VEGF. Skin-derived stem cells Respiratory

epithelium Cartilage & bone Immature Brain 24 Biomaterials Evolution Platform DNA Synthesis, assembly & analysis on chips - VDJ-ome (antibody libraries) 3-D DNA structures: inorganic interfaces In vitro systems: multi-enzyme resistance Microbial systems: multi-virus resistance - Metabolic engineering fuels & chemicals Human cell systems: combinatorial regulation - Organ self-assembly 25 . 26 .

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