Fundamentals of Systems Biology

For decades biology has focused on decoding cellular processes one gene at a time, but many of the most pressing biological questions, as well as diseases such as cancer and heart disease, are related to complex systems involving the interaction of hundreds, or even thousands, of gene products and other factors. How do we begin to understand this complexity? Fundamentals of Systems Biology: From Synthetic Circuits to Whole-cell Models introduces students to methods they can use to tackle complex systems head-on, carefully walking them through studies that comprise the foundation and frontier of systems biology. The first section of the book focuses on bringing students quickly up to speed with a variety of modeling methods in the context of a synthetic biological circuit. This innovative approach builds intuition about the strengths and weaknesses of each method and becomes critical in the book's second half, where much more complicated network models are addressed-including transcriptional, signaling, metabolic, and even integrated multi-network models.The approach makes the work much more accessible to novices (undergraduates, medical students, and biologists new to mathematical modeling) while still having much to offer experienced modelers--whether their interests are microbes, organs, whole organisms, diseases, synthetic biology, or just about any field that investigates living systems.

BUILDING INTUITION Variations on a Theme of Control Learning Objectives Variations Autoregulation Our Theme: A Typical Negative Autoregulatory Circuit Summary Recommended Reading Variation: Boolean Representations Learning Objectives Boolean Logic and Rules State Matrices State Transitions Dynamics Timescales Advantages and Disadvantages of Boolean Analysis Summary Recommended Reading Problems Variation: Analytical Solutions of Ordinary Differential Equations Learning Objectives Synthetic Biological Circuits From Compartment Models to ODEs Specifying and Simplifying ODEs with Assumptions The Steady-State Assumption Solving the System without Feedback: Removal of Activator Key Properties of the System Dynamics Solving the System without Feedback: Addition of Activator Comparison of Modeling to Experimental Measurements Addition of Autoregulatory Feedback Comparison of the Regulated and Unregulated Systems Summary Recommended Reading Problems Variation: Graphical Analysis Learning Objectives Revisiting the Protein Synthesis ODEs Plotting X versus dX/dt Fixed Points and Vector Fields From Vector Fields to Time-Course Plots Nonlinearity Bifurcation Analysis Adding Feedback Two-Equation Systems Summary Recommended Reading Problems Variation: Numerical Integration Learning Objectives The Euler Method Accuracy and Error The Midpoint Method The Runge-Kutta Method Summary Recommended Reading Problems Variation: Stochastic Simulation Learning Objectives Single Cells and Low Molecule Numbers Stochastic Simulations The Probability that Two Molecules Interact and React in a Given Time Interval The Probability of a Given Molecular Reaction Occurring over Time The Relationship between Kinetic and Stochastic Constants Gillespie's Stochastic Simulation Algorithm Stochastic Simulation of Unregulated Gene Expression Stochastic Simulations versus Other Modeling Approaches Summary Recommended Reading Problems FROM CIRCUITS TO NETWORKS Transcriptional Regulation Learning Objectives Transcriptional Regulation and Complexity More Complex Transcriptional Circuits The Transcriptional Regulatory Feed-Forward Motif Boolean Analysis of the Most Common Internally Consistent Feed-Forward Motif Identified in E. coli An ODE-Based Approach to Analyzing the Coherent Feed-Forward Loop Robustness of the Coherent Feed-Forward Loop Experimental Interrogation of the Coherent Feed-Forward Loop Changing the Interaction from an AND to an OR Relationship The Single-Input Module Just-in-Time Gene Expression Generalization of the Feed-Forward Loop An Example of a Multigene Feed-Forward Loop: Flagellar Biosynthesis in E. coli Other Regulatory Motifs Summary Recommended Reading Problems Signal Transduction Learning Objectives Receptor-Ligand Binding to Form a Complex Application to Real Receptor-Ligand Pairs Formation of Larger Complexes Protein Localization The NF-kB Signaling Network A Detailed Model of NF-kB Activity Alternative Representations for the Same Process Specifying Parameter Values from Data Bounding Parameter Values Model Sensitivity to Parameter Values Reducing Complexity by Eliminating Parameters Parameter Interactions Summary Recommended Reading Problems Metabolism Learning Objectives Cellular Metabolism Metabolic Reactions Compartment Models of Metabolite Concentration The Michaelis-Menten Equation for Enzyme Kinetics Determining Kinetic Parameters for the Michaelis-Menten System Incorporating Enzyme Inhibitory Effects Flux Balance Analysis Steady-State Assumption and Exchange Fluxes Solution Spaces The Objective Function Defining the Optimization Problem Solving FBA Problems Using MATLAB Applications of FBA to Large-Scale Metabolic Models Using FBA for Metabolic Engineering Summary Recommended Reading Problems Integrated Models Learning Objectives Dynamic FBA: External versus Internal Concentrations Environmental Constraints Integration of FBA Simulations over Time Comparing Dynamic FBA to Experimental Data FBA and Transcriptional Regulation Transcriptional Regulatory Constraints Regulatory FBA: Method REGULATORY FBA: Application Toward Whole-Cell Modeling Summary Recommended Reading Problems Glossary