This textbook contains the essential knowledge in modeling, simulation, analysis, and applications in dealing with biological cellular control systems. In particular, the book shows how to use the law of mass balance and the law of mass action to derive an enzyme kinetic model - the Michaelis-Menten function or the Hill function, how to use a current-voltage relation, Nernst potential equilibrium equation, and Hodgkin and Huxley's models to model an ionic channel or pump, and how to use the law of mass balance to integrate these enzyme or channel models into a complete feedback control system. The book also illustrates how to use data to estimate parameters in a model, how to use MATLAB to solve a model numerically, how to do computer simulations, and how to provide model predictions. Furthermore, the book demonstrates how to conduct a stability and sensitivity analysis on a model.

An introduction to the mathematical concepts and techniques needed for the construction and analysis of models in molecular systems biology. Systems techniques are integral to current research in molecular cell biology, and system-level investigations are often accompanied by mathematical models. These models serve as working hypotheses: they help us to understand and predict the behavior of complex systems. This book offers an introduction to mathematical concepts and techniques needed for the construction and interpretation of models in molecular systems biology. It is accessible to upper-level undergraduate or graduate students in life science or engineering who have some familiarity with calculus, and will be a useful reference for researchers at all levels. The first four chapters cover the basics of mathematical modeling in molecular systems biology. The last four chapters address specific biological domains, treating modeling of metabolic networks, of signal transduction pathways, of gene regulatory networks, and of electrophysiology and neuronal action potentials. Chapters 3–8 end with optional sections that address more specialized modeling topics. Exercises, solvable with pen-and-paper calculations, appear throughout the text to encourage interaction with the mathematical techniques. More involved end-of-chapter problem sets require computational software. Appendixes provide a review of basic concepts of molecular biology, additional mathematical background material, and tutorials for two computational software packages (XPPAUT and MATLAB) that can be used for model simulation and analysis.

A survey of how engineering techniques from control and systems theory can be used to help biologists understand the behavior of cellular systems.

I Principles 1 1 Models of Systems 3 1. 1 Systems. Models. and Modeling . . . . . . . . . . . . . . . . . . . . 3 1. 2 Uses of Scientific Models . . . . . . . . . . . . . . . . . . . . . . . . 4 1. 3 Example: Island Biogeography . . . . . . . . . . . . . . . . . . . . . 6 1. 4 Classifications of Models . . . . . . . . . . . . . . . . . . . . . . . . 10 1. 5 Constraints on Model Structure . . . . . . . . . . . . . . . . . . . . . 12 1. 6 Some Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 1. 7 Misuses of Models: The Dark Side . . . . . . . . . . . . . . . . . . . 13 1. 8 Exercises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 2 The Modeling Process 17 2. 1 Models Are Problems . . . . . . . . . . . . . . . . . . . . . . . . . . 17 2. 2 Two Alternative Approaches . . . . . . . . . . . . . . . . . . . . . . 18 2. 3 An Example: Population Doubling Time . . . . . . . . . . . . . . . . 24 2. 4 Model Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 2. 5 Exercises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 3 Qualitative Model Formulation 32 3. 1 How to Eat an Elephant . . . . . . . . . . . . . . . . . . . . . . . . . 32 3. 2 Forrester Diagrams . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 3. 3 Examples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 3. 4 Errors in Forrester Diagrams . . . . . . . . . . . . . . . . . . . . . . 44 3. 5 Advantages and Disadvantages of Forrester Diagrams . . . . . . . . . 44 3. 6 Principles of Qualitative Formulation . . . . . . . . . . . . . . . . . . 45 3. 7 Model Simplification . . . . . . . . . . . . . . . . . . . . . . . . . . 47 3. 8 Other Modeling Problems . . . . . . . . . . . . . . . . . . . . . . . . 49 viii Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. 9 Exercises 53 4 Quantitative Model Formulation: I 4. 1 From Qualitative to Quantitative . . . . . . . . . . . . . . . . . Finite Difference Equations and Differential Equations 4. 2 . . . . . . . . . . . . . . . . 4. 3 Biological Feedback in Quantitative Models . . . . . . . . . . . . . . . . . . . . . . . . . . 4. 4 Example Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. 5 Exercises 5 Quantitative Model Formulation: I1 81 . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. 1 Physical Processes 81 . . . . . . . . . . . . . . . 5. 2 Using the Toolbox of Biological Processes 89 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. 3 Useful Functions 96 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. 4 Examples 102 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. 5 Exercises 104 6 Numerical Techniques 107 . . . . . . . . . . . . . . . . . . . . . . . 6. 1 Mistakes Computers Make 107 . . . . . . . . . . . . . . . . . . . . . . . . . . 6. 2 Numerical Integration 110 . . . . . . . . . . . . . . . . 6. 3 Numerical Instability and Stiff Equations 115 . . . . . . . . . . . . . .

An introduction and overview of system modeling in biology that is accessible to researchers from different fields, including biology, computer science, mathematics, statistics, physics, and biochemistry.

This book provides an accessible introduction to the principles and tools for modeling, analyzing, and synthesizing biomolecular systems. It begins with modeling tools such as reaction-rate equations, reduced-order models, stochastic models, and specific models of important core processes. It then describes in detail the control and dynamical systems tools used to analyze these models. These include tools for analyzing stability of equilibria, limit cycles, robustness, and parameter uncertainty. Modeling and analysis techniques are then applied to design examples from both natural systems and synthetic biomolecular circuits. In addition, this comprehensive book addresses the problem of modular composition of synthetic circuits, the tools for analyzing the extent of modularity, and the design techniques for ensuring modular behavior. It also looks at design trade-offs, focusing on perturbations due to noise and competition for shared cellular resources. Featuring numerous exercises and illustrations throughout, Biomolecular Feedback Systems is the ideal textbook for advanced undergraduates and graduate students. For researchers, it can also serve as a self-contained reference on the feedback control techniques that can be applied to biomolecular systems. Provides a user-friendly introduction to essential concepts, tools, and applications Covers the most commonly used modeling methods Addresses the modular design problem for biomolecular systems Uses design examples from both natural systems and synthetic circuits Solutions manual (available only to professors at press.princeton.edu) An online illustration package is available to professors at press.princeton.edu

Like engineering systems, biological systems must also operate effectively in the presence of internal and external uncertainty—such as genetic mutations or temperature changes, for example. It is not surprising, then, that evolution has resulted in the widespread use of feedback, and research in systems biology over the past decade has shown that feedback control systems are widely found in biology. As an increasing number of researchers in the life sciences become interested in control-theoretic ideas such as feedback, stability, noise and disturbance attenuation, and robustness, there is a need for a text that explains feedback control as it applies to biological systems. Written by established researchers in both control engineering and systems biology, Feedback Control in Systems Biology explains how feedback control concepts can be applied to systems biology. Filling the need for a text on control theory for systems biologists, it provides an overview of relevant ideas and methods from control engineering and illustrates their application to the analysis of biological systems with case studies in cellular and molecular biology. Control Theory for Systems Biologists The book focuses on the fundamental concepts used to analyze the effects of feedback in biological control systems, rather than the control system design methods that form the core of most control textbooks. In addition, the authors do not assume that readers are familiar with control theory. They focus on "control applications" such as metabolic and gene-regulatory networks rather than aircraft, robots, or engines, and on mathematical models derived from classical reaction kinetics rather than classical mechanics. Another significant feature of the book is that it discusses nonlinear systems, an understanding of which is crucial for systems biologists because of the highly nonlinear nature of biological systems. The authors cover tools and techniques for the analysis of linear and nonlinear systems; negative and positive feedback; robustness analysis methods; techniques for the reverse-engineering of biological interaction networks; and the analysis of stochastic biological control systems. They also identify new research directions for control theory inspired by the dynamic characteristics of biological systems. A valuable reference for researchers, this text offers a sound starting point for scientists entering this fascinating and rapidly developing field.

This advanced textbook is tailored for an introductory course in Systems Biology and is well-suited for biologists as well as engineers and computer scientists. It comes with student-friendly reading lists and a companion website featuring a short exam prep version of the book and educational modeling programs. The text is written in an easily accessible style and includes numerous worked examples and study questions in each chapter. For this edition, a section on medical systems biology has been included.

An introduction and overview of system modeling in biology that is accessible to researchers from different fields, including biology, computer science, mathematics, statistics, physics, and biochemistry. Research in systems biology requires the collaboration of researchers from diverse backgrounds, including biology, computer science, mathematics, statistics, physics, and biochemistry. These collaborations, necessary because of the enormous breadth of background needed for research in this field, can be hindered by differing understandings of the limitations and applicability of techniques and concerns from different disciplines. This comprehensive introduction and overview of system modeling in biology makes the relevant background material from all pertinent fields accessible to researchers with different backgrounds. The emerging area of systems level modeling in cellular biology has lacked a critical and thorough overview. This book fills that gap. It is the first to provide the necessary critical comparison of concepts and approaches, with an emphasis on their possible applications. It presents key concepts and their theoretical background, including the concepts of robustness and modularity and their exploitation to study biological systems; the best-known modeling approaches, and their advantages and disadvantages; lessons from the application of mathematical models to the study of cellular biology; and available modeling tools and datasets, along with their computational limitations.

What every neuroscientist should know about the mathematical modeling of excitable cells, presented at an introductory level.