Proto BioCompiler Jacob Beal October, 2011 Work partially sponsored by DARPA; the views and conclusions contained in this document are those of the authors.

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Proto BioCompiler Jacob Beal October, 2011 Work partially sponsored by DARPA; the views and conclusions contained in this document are those of the authors and not DARPA or the U.S. Government. 1

Vision: WYSIWYG Synthetic Biology Bioengineering should be like document preparation: 2

Vision: WYSIWYG Synthetic Biology Bioengineering should be like document preparation: 3

Why is this important? Breaking the complexity barrier: Multiplication of research impact Reduction of barriers to entry *Sampling of systems in publications with experimental circuits DNA synthesis Circuit size ? 4

Why a tool-chain? Organism Level Description Cells This gap is too big to cross with a single method! 5

The TASBE architecture: Organism Level Description Abstract Genetic Regulatory Network DNA Parts Sequence Assembly Instructions Cells High level simulator Coarse chemical simulator Testing High Level Description If detect explosives: emit signal If signal > threshold: glow red Detailed chemical simulator Modular architecture also open for flexible choice of organisms, protocols, methods, … 6

A Tool-Chain Example (yellow (not (cyan (Dox)))) 7

A Tool-Chain Example (yellow (not (cyan (Dox)))) Doxcyannotyellow 8

A Tool-Chain Example (yellow (not (cyan (Dox)))) Doxcyannotyellow rtTA CFP B B EYFP Dox 9

A Tool-Chain Example (yellow (not (cyan (Dox)))) Doxcyannotyellow rtTA CFP B B EYFP Dox pHef1artTA pTreCFP pTre LacI pHef1a- LacO1Oid EYFP mirff4 4xff4 10

A Tool-Chain Example (yellow (not (cyan (Dox)))) Doxcyannotyellow rtTA CFP B B EYFP Dox pHef1artTA pTreCFP pTre LacI pHef1a- LacO1Oid EYFP mirff4 4xff4 11

A Tool-Chain Example (yellow (not (cyan (Dox)))) Doxcyannotyellow rtTA CFP B B EYFP Dox pHef1artTA pTreCFP pTre LacI pHef1a- LacO1Oid EYFP mirff4 4xff4 12

Today’s focus: BioCompiler Organism Level Description Abstract Genetic Regulatory Network DNA Parts Sequence Assembly Instructions Cells High level simulator Coarse chemical simulator Testing High Level Description If detect explosives: emit signal If signal > threshold: glow red Detailed chemical simulator Compilation & Optimization 13

Transcriptional Logic 14

Motif-Based Compilation High-level primitives map to GRN design motifs –e.g. logical operators: (primitive not (boolean) boolean :grn-motif ((P high R- arg0 value T))) arg0 value 15

High-level primitives map to GRN design motifs e.g. logical operators, actuators: (primitive green (boolean) boolean :side-effect :type-constraints ((= value arg0)) :grn-motif ((P R+ arg0 GFP|arg0 value T))) GFP value arg0 Motif-Based Compilation 16

High-level primitives map to GRN design motifs e.g. logical operators, actuators, sensors: (primitive IPTG () boolean :grn-motif ((P high LacI|boolean T) (RXN (IPTG|boolean) represses LacI) (P high R- LacI value T))) value LacI IPTG Motif-Based Compilation 17

Functional program gives dataflow computation: (green (not (IPTG))) Motif-Based Compilation 18

Functional program gives dataflow computation: (green (not (IPTG))) IPTGnotgreen Motif-Based Compilation 19

Operators translated to motifs: IPTGnotgreen Motif-Based Compilation 20

Operators translated to motifs: IPTGnotgreen LacI A IPTG B GFP outputs arg0 Motif-Based Compilation 21

Operators translated to motifs: IPTGnotgreen LacIA IPTG B GFP LacI A IPTG B GFP outputs arg0 Motif-Based Compilation 22

LacIA IPTG B GFP Optimization 23

LacIA IPTG B GFP LacIA IPTG B GFP Copy Propagation Optimization 24

LacIA IPTG B GFP LacIA IPTG B GFP Copy Propagation LacIA IPTG GFP Dead Code Elimination Optimization 25

LacIA IPTG B GFP LacIA IPTG B GFP Copy Propagation LacIA IPTG GFP Dead Code Elimination LacIA IPTG GFP Dead Code Elimination Optimization 26

(def sr-latch (s r) (letfed+ ((o boolean (not (or r o-bar))) (o-bar boolean (not (or s o)))) o)) (green (sr-latch (aTc) (IPTG))) Complex System: Feedback Latch 27

(def sr-latch (s r) (letfed+ ((o boolean (not (or r o-bar))) (o-bar boolean (not (or s o)))) o)) (green (sr-latch (aTc) (IPTG))) Complex System: Feedback Latch LacI B IPTG IGIFGFPD E1 E2 A aTc JHC J TetR Unoptimized: 15 functional units, 13 transcription factors 28

(def sr-latch (s r) (letfed+ ((o boolean (not (or r o-bar))) (o-bar boolean (not (or s o)))) o)) (green (sr-latch (aTc) (IPTG))) Optimization of Complex Designs LacI B IPTG Unoptimized: 15 functional units, 13 transcription factors IGIFGFPD E1 E2 A aTc JHC J TetR Copy Propagation 29

E1 (def sr-latch (s r) (letfed+ ((o boolean (not (or r o-bar))) (o-bar boolean (not (or s o)))) o)) (green (sr-latch (aTc) (IPTG))) Optimization of Complex Designs LacI B IPTG Unoptimized: 15 functional units, 13 transcription factors I GIF GFP D A aTc J H C J TetR Common Subexp. Elim. 30

E1 (def sr-latch (s r) (letfed+ ((o boolean (not (or r o-bar))) (o-bar boolean (not (or s o)))) o)) (green (sr-latch (aTc) (IPTG))) Optimization of Complex Designs LacI B IPTG Unoptimized: 15 functional units, 13 transcription factors I GIF GFP D A aTc H J C J TetR NOR Compression H 31

E1 (def sr-latch (s r) (letfed+ ((o boolean (not (or r o-bar))) (o-bar boolean (not (or s o)))) o)) (green (sr-latch (aTc) (IPTG))) Optimization of Complex Designs LacI IPTG Unoptimized: 15 functional units, 13 transcription factors I GIF GFP aTc H TetR Dead Code Elimination H 32

E1 (def sr-latch (s r) (letfed+ ((o boolean (not (or r o-bar))) (o-bar boolean (not (or s o)))) o)) (green (sr-latch (aTc) (IPTG))) Optimization of Complex Designs LacI IPTG Unoptimized: 15 functional units, 13 transcription factors I GIF GFP aTc H TetR Copy Propagation H 33

H E1 (def sr-latch (s r) (letfed+ ((o boolean (not (or r o-bar))) (o-bar boolean (not (or s o)))) o)) (green (sr-latch (aTc) (IPTG))) Optimization of Complex Designs LacI IPTG Unoptimized: 15 functional units, 13 transcription factors IG I F GFP aTc TetR Common Subexp. Elim. H 34

H (def sr-latch (s r) (letfed+ ((o boolean (not (or r o-bar))) (o-bar boolean (not (or s o)))) o)) (green (sr-latch (aTc) (IPTG))) Optimization of Complex Designs LacI IPTG Unoptimized: 15 functional units, 13 transcription factors I I F GFP aTc TetR Dead Code Elimination H 35

H (def sr-latch (s r) (letfed+ ((o boolean (not (or r o-bar))) (o-bar boolean (not (or s o)))) o)) (green (sr-latch (aTc) (IPTG))) Optimization of Complex Designs Unoptimized: 15 functional units, 13 transcription factors I F GFP H LacI IPTG TetR aTc I 36

H (def sr-latch (s r) (letfed+ ((o boolean (not (or r o-bar))) (o-bar boolean (not (or s o)))) o)) (green (sr-latch (aTc) (IPTG))) Optimization of Complex Designs Unoptimized: 15 functional units, 13 transcription factors F GFP H LacI IPTG TetR aTc F NOR Compression I I 37

H (def sr-latch (s r) (letfed+ ((o boolean (not (or r o-bar))) (o-bar boolean (not (or s o)))) o)) (green (sr-latch (aTc) (IPTG))) Optimization of Complex Designs Unoptimized: 15 functional units, 13 transcription factors F GFP H LacI IPTG TetR aTc F Dead Code Elimination 38

GFP Optimization of Complex Designs LacI F IPTG TetR H aTc F Final Optimized: 5 functional units 4 transcription factors (def sr-latch (s r) (letfed+ ((o boolean (not (or r o-bar))) (o-bar boolean (not (or s o)))) o)) (green (sr-latch (aTc) (IPTG))) Unoptimized: 15 functional units, 13 transcription factors H 39

Compilation & Optimization Results: Automated GRN design for arbitrary boolean logic and feedback systems –Verification in ODE simulation Optimization competitive with human experts: –Test systems have 25% to 71% complexity reduction –Optimized systems are often homologous with hand designed networks 40

pHef1artTA EYFP Hef1a-LacO1Oid mKateTrepLac Dox EBFPTre Realization with Characterized DNA parts pHef1a 41

Onward Through the Tool-Chain… (yellow (not (cyan (Dox)))) Doxcyannotyellow rtTA CFP B B EYFP Dox pHef1artTA pTreCFP pTre LacI pHef1a- LacO1Oid EYFP mirff4 4xff4 42

Proto is available (or google “MIT Proto”) Includes libraries, compiler, kernel, simulator, platforms Licensed under GPL (w. libc-type exception) BioCompiler is available on request 43

TASBE Project Team: Jacob Beal (PI) Aaron Adler Rick Schantz Fusun Yaman Joseph Loyall (PMs) Ron Weiss (co-PI) Jonathan Babb Noah Davidsohn Douglas Densmore (co-PI) Swapnil Bhatia Traci Haddock Viktor Vasilev Chenkai Liu Sponsored by: 44