Design and Analysis of Biomolecular Circuits : Engineering Approaches to Systems and Synthetic Biology

This book is devoted to the design and analysis of biomolecular circuits as considered in systems biology and synthetic biology.¡ The aim of the book is to present in a coherent framework some of the most recent work on the analysis, simulation and design of biomolecular circuits and systems, reflecting the interdisciplinary and collaborative nature of the field. The results discussed range from how these systems should be modeled and analyzed, to how they should be physically designed and implemented. ¡ Drawing parallels to electronic circuit design, this book's contents are organized to reflect what the editors believe are the important, necessary steps to build complex synthetic circuits.¡ Coverage includes analysis and simulation, modularity and abstraction, design and standardization, and enabling technologies. Each of these themes is organized in different chapters that are self-contained so that they can be read individually by experts but also read sequentially by someone wanting to get an overview of the field. This book is intended for computational scientists, e.g. mathematicians, physicists, computer scientist or engineers as well as for researchers from the life sciences. Every effort has been made to make the presentation accessible to a broad, multi-disciplinary audience Cover......Page 1 Fluorescent Proteins......Page 5 Applications......Page 9 Microscopy Samples and Microfluidic Devices......Page 11 Design and Analysis of Biomolecular Circuits......Page 2 Single Cell Measurements......Page 4 Preface......Page 6 SLIC......Page 7 Image Analysis......Page 13 Applications......Page 14 DNA Synthesis, RNA Replication, Protein Synthesis......Page 15 Part I Analysis and Simulation......Page 16 Chapter 1: Continuous Time Markov Chain Models for Chemical Reaction Networks......Page 17 Fluorescence Correlation Spectroscopy......Page 19 Equivalence of Stochastic Equations and Martingale Problems......Page 23 Thinning of Counting Processes......Page 25 Concluding Remarks......Page 26 Scaling Species Numbers and Rate Constants......Page 28 Simulation......Page 29 Rates for the Law of Mass Action......Page 31 Hybrid Limits......Page 34 First Order Reaction Networks......Page 35 References......Page 38 Cellular Noise......Page 3 Instrumentation......Page 8 Contributors......Page 12 Introduction......Page 18 Poisson Processes......Page 20 Contents......Page 10 Biophysical Aspects of Minimal Cell Construction......Page 24 Outlook......Page 21 Continuous Time Markov Chains......Page 22 The Martingale Problem and Forward Equation for Markov Chains......Page 27 Stationary Distributions......Page 30 General Form for the Classical Scaling......Page 32 Diffusion/Langevin Approximations......Page 33 Product Form Stationary Distributions......Page 39 Models with Delay......Page 41 Derivation of the Michaelis-Menten Equation......Page 42 Scaling Species Numbers and Rate Constants......Page 44 Determining the Scaling Exponents......Page 45 An Application of the Balance Conditions......Page 47 Hybrid Limits......Page 50 Central Limit Theorems and Diffusion Approximations......Page 51 References......Page 54 Why Do We Need Spatial Models of a Cell?......Page 57 Why Do We Need Stochastic Models?......Page 58 Simulation Toolkits......Page 59 Temporal Models of Chemical Kinetics......Page 60 Monte-Carlo Approaches......Page 62 Lattice Versus Off-Lattice Methods......Page 64 The Next Subvolume Method and Its Coarse-Grained Version, Bτ-SSSA......Page 67 Capturing Spatial Attributes......Page 68 Spatial Simulation Software......Page 69 RDME-Based Methods......Page 70 Methods Based on Microscopic Lattices......Page 71 Off-Lattice Particle Methods......Page 72 Greens-Function Reaction Dynamics (GFRD) Methods......Page 73 Introduction......Page 77 Dynamical Systems Derived from Chemical Reaction Networks......Page 78 The Main Results......Page 81 Discussion......Page 84 References......Page 85 Introduction......Page 87 Qualitative Models from Biology......Page 88 Interaction Networks......Page 90 Jacobian Factorisations and Generalised Graphs......Page 91 Qualitative Classes and Qualitative Rules......Page 93 Mathematical Background......Page 94 Generalised Mass-Action Kinetics......Page 97 Structural Conditions for Local Stability of Equilibria......Page 99 Monotonicity in General CRNs......Page 100 Conclusions......Page 104 References......Page 105 Introduction......Page 107 Basic Results......Page 108 Outline......Page 110 Entrainment of Transcriptional Modules......Page 112 Synchronization of Biological Systems......Page 113 Generic Quorum Sensing Networks......Page 117 Controlling Synchronization of Genetic Oscillators......Page 120 Conclusions......Page 126 Part II Modularity and Abstraction......Page 129 Introduction......Page 130 Modules as Physically Interacting Molecules......Page 131 Modules as Temporally Interacting Genes......Page 132 Modules as Design Patterns......Page 133 Modules in Synthetic Systems......Page 135 Mapping Between a MIP and an RC-Circuit......Page 136 Gene Circuit Fan-Out......Page 140 Gene Circuit Fan-Out in more General Interfaces......Page 142 Noise Correlation Time......Page 144 Fan-Out/Retroactivity Estimation......Page 148 Summary......Page 149 Introduction......Page 152 The Absence of Retroactivity as a Criterion to Demarcate Modules......Page 154 Network Theory and Retroactivity......Page 155 An Algorithm to Identify Modules Minimizing Retroactivity......Page 159 Domain Oriented Modeling and Retroactivity......Page 164 Thermodynamic Constraints......Page 166 Thermodynamic Restrictions on Process Interactions......Page 167 Unidirectionality and Futile Cycles......Page 168 Conclusion......Page 170 References......Page 171 Introduction......Page 173 Modeling Retroactivity......Page 175 Example: A Transcriptional System......Page 176 Quantification of the Retroactivity to the Output......Page 178 Retroactivity and Noise......Page 179 Model......Page 180 Steady State Effects......Page 181 Dynamic Effects......Page 185 Experimental Results......Page 189 Discussion and Conclusion......Page 191 Introduction......Page 194 Precise Problem Formulation......Page 198 Mathematical Details......Page 200 Retroactivity at Steady States......Page 205 Appendix: Chemical Reaction Network Formalism......Page 210 References......Page 211 Part III Design and Standardization......Page 212 Chapter 10: Computer-Aided Design for Synthetic Biology......Page 213 Introduction......Page 214 Methodology......Page 215 Design: Stage 2......Page 219 The Role of Modularity in Design......Page 220 Mathematical Analysis: Stage 3......Page 222 Programming Languages for Mathematical Analysis......Page 223 Systems Biology Software Applications......Page 224 Biological Part Composition: Stage 4......Page 226 Sequence Refinement......Page 228 Design by Evolution......Page 229 Education......Page 231 References......Page 232 Overview......Page 235 Formal Language & Syntactic Model......Page 237 GenoCAD Web Service......Page 240 Eugene......Page 241 Eugene Constructs......Page 242 Eugene Rules......Page 243 XOR Design Example......Page 244 GEC......Page 246 Amorphous Medium and Proto......Page 251 Motif-Based Compilation and Optimization......Page 254 Other High-Level Design Tools for Biological Computation......Page 258 Summary......Page 260 Introduction......Page 263 Robustness of Biological Systems......Page 264 Methods for Robustness Analysis......Page 266 Inverse Problems......Page 267 Formal Specification Languages......Page 269 Parameter Sampling......Page 274 Regularizing the Design Problem......Page 279 Optimizing Robustness......Page 280 Two Cyanobacterial Clock Models......Page 282 Specified Systemic Properties......Page 283 Robustness Results......Page 284 Conclusion......Page 285 References......Page 286 Chapter 13: Data Model Standardization for Synthetic Biomolecular Circuits and Systems......Page 290 Introduction......Page 291 Early Examples of Success: PDB......Page 292 Standards for Models – SBML and CellML......Page 293 Standards for Synthetic Biology......Page 294 The Registry of Standard Biological Parts......Page 295 Software Data Models......Page 296 References......Page 300 The DNA Assembly Challenge......Page 303 The Traditional Multiple Cloning Site Approach......Page 304 The BioBrick Approach......Page 306 BioBrick Limitations and Obstacles......Page 308 SLIC......Page 309 Gibson......Page 310 CPEC......Page 311 SLIC, Gibson, and CPEC Similarities......Page 312 SLIC, Gibson, and CPEC Limitations and Obstacles......Page 313 The Golden Gate Assembly Method......Page 314 Golden Gate Limitations and Obstacles......Page 317 Conclusion......Page 318 Glossary......Page 320 References......Page 321 Part IV Enabling Technologies......Page 323 Chapter 15: Gene Synthesis ... Enabling Technologies for Synthetic Biology......Page 324 Several Technological Developments Enabled Gene Synthesis......Page 325 Historical Overview of Gene Synthesis Milestones......Page 327 Development of Commercial Services Providing Synthetic Genes......Page 328 Technological Background of de novo Gene Synthesis......Page 331 Fields of Application for Synthetic Genes......Page 337 Origin and Reliability......Page 338 Cost, Capacity and Speed......Page 339 Flexibility of Design: Artificial Genes, Operons and Genomes......Page 340 Why Minimal Cells?......Page 343 Autopoiesis and Minimal Life......Page 345 Self-reproduction of Liposomes......Page 348 Vesicle-Based Minimal Synthetic Cells: From the Origins of Life to Synthetic Biology......Page 351 Relevance in Basic Science, Biotechnology, Drug Delivery......Page 353 Enzyme Reactions Inside Liposomes......Page 355 Multi-enzyme Reactions Inside Liposomes......Page 356 DNA Synthesis, RNA Replication, Protein Synthesis......Page 357 Two Selected Cases of Pioneering Research......Page 358 Working for the Production of Nucleic Acids and Proteins Inside Liposomes......Page 361 Toward Self-reproduction of Core and Shell Components......Page 364 What Next?......Page 365 Biophysical Aspects of Minimal Cell Construction......Page 366 Concluding Remarks......Page 368 Abbreviations......Page 369 Introduction......Page 375 Single Cell Analysis......Page 376 Cellular Noise......Page 377 Single Cell Measurements......Page 378 Fluorescent Proteins......Page 379 Budding Yeast As a Model Organism......Page 380 Instrumentation......Page 382 Applications......Page 383 Microscopy Samples and Microfluidic Devices......Page 385 Microscope Light-Path......Page 387 Applications......Page 388 Functional Microscopy......Page 390 Förster Resonance Energy Transfer......Page 391 Fluorescence Correlation Spectroscopy......Page 393 Outlook......Page 395 References......Page 396 Index......Page 400 The book deals with engineering aspects of the two emerging and intertwined fields of synthetic and systems biology. Both fields hold promise to revolutionize the way molecular biology research is done, the way today's drug discovery works and the way bio-engineering is done. Both fields stress the importance of building and characterizing small bio-molecular networks in order to synthesize incrementally and understand large complex networks inside living cells. Reminiscent of computer-aided design (CAD) of electronic circuits, abstraction is believed to be the key concept to achieve this goal. It allows hiding the overwhelming complexity of cellular processes by encapsulating network parts into abstract modules. This book provides a unique perspective on how concepts and methods from CAD of electronic circuits can be leveraged to overcome complexity barrier perceived in synthetic and systems biology.