Type of Document Dissertation Author Hinkelmann, Franziska Babette Author's Email Address fhinkel@vt.edu URN etd-08032011-113739 Title Algebraic theory for discrete models in systems biology Degree PhD Department Mathematics Advisory Committee

Advisor Name Title Laubenbacher, Reinhard C. Committee Chair Herdman, Terry L. Committee Member Jarrah, Abdul Salam Committee Member Tyler, Brett M. Committee Member Keywords

- systems biology
- discrete models
- Mathematical biology
- finite fields
- reverse-engineering
- polynomial dynamical systems
Date of Defense 2011-08-01 Availability unrestricted AbstractThis dissertation develops algebraic theory for discrete models in systems biology. Many discrete model types can be translated into the framework of polynomial dynamical systems (PDS), that is, time- and state-discrete dynamical systems over a finite field where the transition function for each variable is given as a polynomial. This allows for using a range of theoretical and computational tools from computer algebra, which results in a powerful computational engine for model construction, parameter estimation, and analysis methods. Formal definitions and theorems for PDS and the concept of PDS as models of biological systems are introduced in section 1.3.

Constructing a model for given time-course data is a challenging problem. Several methods for reverse-engineering, the process of inferring a model solely based on experimental data, are described briefly in section 1.3. If the underlying dependencies of the model components are known in addition to experimental data, inferring a "good" model amounts to parameter estimation.

Chapter 2 describes a parameter estimation algorithm that infers a special class of polynomials, so called nested canalyzing functions. Models consisting of nested canalyzing functions have been shown to exhibit desirable biological properties, namely robustness and stability. The algorithm is based on the parametrization of nested canalyzing functions. To demonstrate the feasibility of the method, it is applied to the cell-cycle network of budding yeast.

Several discrete model types, such as Boolean networks, logical models, and bounded Petri nets, can be translated into the framework of PDS. Section 3 describes how to translate agent-based models into polynomial dynamical systems.

Chapter 4, 5, and 6 are concerned with analysis of complex models. Section 4 proposes a new method to identify steady states and limit cycles. The method relies on the fact that attractors correspond to the solutions of a system of polynomials over a finite field, a long-studied problem in algebraic geometry which can be efficiently solved by computing Gröbner bases. Section 5 introduces a bit-wise implementation of a Gröbner basis algorithm for Boolean polynomials. This implementation has been incorporated into the core engine of Macaulay2. Chapter 6 discusses bistability for Boolean models formulated as polynomial dynamical systems.

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