Introduction. ECE/CS/BioEn 6760 Modeling and Analysis of Biological Networks. Adventures in Synthetic Biology. Synthetic Biology.
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1 Introduction ECE/CS/BioEn 6760 Modeling and Analysis of Biological Networks Chris J. Myers Lecture 17: Genetic Circuit Design Electrical engineering principles can be applied to understand the behavior of genetic circuits. Can synthetic genetic circuits be designed that behave like electrical circuits such as switches, oscillators, and sequential state machines? This lecture presents principles involved in engineering synthetic genetic circuits as well as some examples. Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 1 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 2 / 48 Synthetic Biology Adventures in Synthetic Biology Genetic engineering (last 30 years): ecombinant DNA - constructing artificial DNA through combinations. Polymerase Chain eaction (PC) - making many copies of this new DNA. Automated sequencing - checking the resulting DNA sequence. Synthetic biology adds: Automated construction - separate design from construction. Standards - create repositories of parts that can be easily composed. Abstraction - high-level models to facilitate design. Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 3 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 4 / 48 Synthetic Genetic Circuits Challenges Increasing number of labs are designing more ambitious and mission critical synthetic biology projects: esearchers are using synthetic biology to better understand how microorganisms function by examining differences in vivo as compared to in silico (Sprinzak/Elowitz). The Gates foundation is funding research on the design of pathways for the production of antimalarial drugs (o et al.). Bacteria are being designed to break down toxic PCB in contaminated soils (Brazil et al.). A number of labs are designing bacteria to kill tumors (Anderson et al.). Natural genetic circuits may not agree with our models because they are not designed well, so we should design better genetic circuits which agree with our models (Drew Endy). Genetic circuits have no signal isolation. Circuit products may interfere with each other and the host cell. Gates in a genetic circuit library usually can only be used once. Behavior of circuits are non-deterministic in nature. No global clock, so timing is difficult to characterize. QUESTION: Can asynchronous synthesis tools be adapted to requirements for a genetic circuit technology? Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 5 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 6 / 48
2 Genetic Circuit Synthesis Genetic Gate Library Set of Experiments Genetic Circuit Perform Experiments Experimental Data Insert into Host Biological Knowledge Learn Model SBML Model Models Construct Experiments Abstraction/ Simulation Simulation Data Plasmid Construct Plasmid DNA Sequence TechMap Logic Equations ATACS Library HDL Set of Experiments Genetic Circuit Perform Experiments Experimental Data Insert into Host Biological Knowledge Learn Model SBML Model Models Construct Experiments Abstraction/ Simulation Simulation Data Plasmid Construct Plasmid DNA Sequence TechMap Logic Equations ATACS Library HDL Modeling Analysis Synthesis Modeling Analysis Synthesis Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 7 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 8 / 48 Genetic Inverter Genetic Inverter (From Adventures in Synthetic Biology - Endy et al.) Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 9 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 10 / 48 Genetic Inverter Genetic Inverter Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 10 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 10 / 48
3 epressilator Genetic Oscillator Elowitz/Leibler (2000) Oscillations used as central clocks to synchronize behavior. Circadian rhythms manifest as periodic variations of concentrations of particular proteins in the cell. Though precise mechanism is unknown can generate a network that has a similar behavior. Note that not all parameter choices lead to oscillations. High protein synthesis and degradation rates, large cooperative binding effects, and efficient repression are all necessary. As a result, strong and tightly repressible promoters are selected, and proteins are modified to make easy targets for proteases. ci laci tet Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 11 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 12 / 48 Genetic NAND Genetic NAND Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 13 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 13 / 48 Genetic NAND Genetic NAND Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 13 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 13 / 48
4 Genetic NO Gate Genetic AND Gate ci ci Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 14 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 15 / 48 Genetic O Gate Genetic AND Gate using Chemical Inducers Cro atc atc ci Cro atc ci P 1 laci tet P 2 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 16 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 17 / 48 Genetic O Gate using Chemical Inducers Genetic AND Gate using One Gene atc atc LuxI Complex LuxI atc P2 LuxI P1 laci tet P3 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 18 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 19 / 48
5 Genetic AND Gate using One Gene Genetic AND Gate using One Gene LuxI LuxI LuxI LuxI Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 19 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 19 / 48 Genetic AND Gate using One Gene PoPS - Polymerases Per Second LuxI LuxI POBLEM: Connecting gates can be difficult because each gate uses different proteins as inputs and outputs. SOLUTION: Use rate of gene expression as the signal much like electrical current. Complex ate of gene expression is the number of NA polymerases that move across a DNA strand per second (i.e., PoPS). LuxI Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 19 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 20 / 48 Genetic Inverter - PoPS Genetic O Gate - PoPS Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 21 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 22 / 48
6 Genetic NO Gate - PoPS Genetic AND Gate - PoPS Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 23 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 24 / 48 Genetic NAND Gate - PoPS Genetic Sender - PoPS Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 25 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 26 / 48 Genetic eceiver - PoPS egistry of Standard Biological Parts Found at: Includes descriptions of numerous BioBricks TM : Part types include: terminators, ribosome binding sites, protein coding regions, reporters, signalling parts, regulatory regions, gates, etc. BioBricks TM aan be assembled into more complex devices and systems: Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 27 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 28 / 48
7 BioBrick TM Assembly Sequential Logic Circuits The output of sequential circuits depend not only on the current input, but also on the recent history of inputs. This history is recorded in the state of the circuit. State is maintained through the use of feedback. Feedback loops are important for stability in control systems. In autoregulation, protein modifies own rate of production. Feedback can be either positive or negative. Genes regulated by negative feedback should be more stable than those unregulated or regulated by positive feedback. Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 29 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 30 / 48 Negative Feedback and Stability Positive Feedback and Bistability Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 31 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 32 / 48 Genetic AND Gate with Memory Genetic Toggle Switch atc atc S Q dimer atc Gene P1 laci tet P2 ci Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 33 / 48
8 Genetic Toggle Switch Genetic Toggle Switch S Q S Q dimer dimer Gene Gene Genetic Toggle Switch Genetic Toggle Switch S Q S Q dimer dimer Gene Gene Genetic Toggle Switch Genetic Toggle Switch S Q S Q dimer Gene Gene
9 Genetic Toggle Switch Genetic Muller C-Element S Q A Muller C-element is a state holding gate common in many asynchronous design methods that is used to synchronize multiple independent processes. A genetic Muller C-element would allow for the design of any asynchronous FSM. C X Y Z Gene Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 35 / 48 Genetic Majority Muller C-Element Genetic Majority Muller C-Element Light ed Light Gene Light Gene Gene Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 36 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 37 / 48 Genetic Majority Muller C-Element Genetic Majority Muller C-Element Gene Light Gene Light Gene Gene Gene Gene Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 37 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 37 / 48
10 Genetic Majority Muller C-Element Genetic Majority Muller C-Element ed Light Gene Light ed Light Gene Light Gene Gene Gene Gene Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 37 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 37 / 48 Genetic Majority Muller C-Element Genetic Majority Muller C-Element ed Light Gene Light Gene Light Gene Gene Gene Gene Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 37 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 37 / 48 Genetic Toggle Muller C-Element Genetic Toggle Muller C-Element Light S Q Gene luxi ed Light LuxI Light Complex Gene lux Light Complex Gene Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 38 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 39 / 48
11 Genetic Toggle Muller C-Element Genetic Toggle Muller C-Element Gene luxi LuxI Light Gene luxi Light Gene lux Gene lux Complex Gene Gene Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 39 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 39 / 48 Genetic Toggle Muller C-Element Genetic Toggle Muller C-Element Gene luxi ed Light Light Gene luxi ed Light Light Gene lux Gene lux Gene Gene Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 39 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 39 / 48 Genetic Toggle Muller C-Element Genetic Toggle Muller C-Element Gene luxi ed Light LuxI Light Gene luxi LuxI Light Gene lux Gene lux Complex Gene Gene Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 39 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 39 / 48
12 Ordinary Differential Equation Analysis ODE Analysis: Toggle Design Use Law of Mass Action to derive ODE model. Study behavior of our model at steady state. Analyze nullclines to characterize the gate. da dt = k a K eqh K eqh +(H H 0 ) d a a + k cr c k c ab db = k bk eql dt K eql + L d b b+ k cr c k c ab dc dt = k c ab k cr c d c c dx = k a e H0 H + k b K eql K eql + L d x x dt dy = k y1k eqx dt K eqx + x + k m y2keqz KeqZ m + zm d y y ( dz c = k z1 dt K eqc + c ) + k z2 K eqy K n eqy + y n d z z Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 40 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 41 / 48 ODE Analysis: Toggle Design ODE: Nullcline Analysis dy dt dz dt = f (H,L)+ k y2 K m eqz K m eqz + zm k y y = g(h,l)+ k z2 K n eqy K n eqy + y n k z z where 0, if H,L = (0,0) f (H,L) = f M, if H,L = (0,1)or (1,0) f H, if H,L = (1,1) and { gh, if H,L = (0,0) g(h,l) = 0, if otherwise Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 42 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 43 / 48 ODE: Nullcline Analysis ODE: Nullcline Analysis Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 43 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 43 / 48
13 ODE: Nullcline Analysis Stochastic Analysis: State Change from Low to High Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 43 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 44 / 48 Stochastic Analysis: State Change from Low to High Stochastic Analysis: State Change from High to Low ToggleC, add light MajorityC, add light ToggleC, add heat MajorityC, add heat Probability of state change Time (sec) Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 44 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 45 / 48 Stochastic Analysis: State Change from High to Low Biologically Inspired Circuit Design Probability of state change ToggleC, remove light MajorityC, remove light ToggleC, remove heat MajorityC, remove heat Human inner ear performs the equivalent of one billion floating point operations per second and consumes only 14 µw while a game console with similar performance burns about 50 W (Sarpeshkar, 2006). We believe this difference is due to over designing components in order to achieve an extremely low probability of failure in every device. Biological systems constructed from very noisy and unreliable devices. Future silicon and nano-devices will also be much less reliable. For Moore s law to continue, future design methods should support the design of reliable systems using unreliable components Time (sec) Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 45 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 46 / 48
14 Biologically Inspired Circuit Design Sources Since the engineering principles by which such circuitry is constructed in cells comprise a super-set of that used in electrical engineering, it is, in turn, possible that we will learn more about how to design asynchronous, robust electronic circuitry as well. Adam Arkin Elowitz/Leibler, Nature Hasty/McMillen/Collins, Nature Gardner/Cantor/Collins, Nature Nguyen/Kuwahara/Myers/Keener, Async 2007 (best paper). Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 47 / 48 Chris J. Myers (Lecture 17: Genetic Design) ECE/CS/BioEn 6760: Modeling Bio Networks 48 / 48
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