Hypothesis Testing with Evolutionary and Systems Biology Models by Seongho Ryu

" The important thing is not to stop questioning. Curiosity has its own reason for existing. One cannot help but be in awe when he contemplates the mysteries of eternity, of life, of the marvelous structure of reality. It is enough if one tries merely to comprehend a little of this mystery every day. Never lose a holy curiosity. " Albert Einstein v DEDICATION For my mother and family, who have always support me to finish with my research, even during the most difficult times. Finally to my lovely wife, Yoonkyung Do, who helped me make it through these years. Without her help and continuous guidance, this would have never been possible. vi ACKNOWLEDGEMENTS I would like to thank my advisor, Bud Mishra, for his role in inspiring this project, as well as his commitment to introspection, and to reflecting upon and exploring meaningful issues in Bioinformatics. I also thank my co-advisor, David Fitch. This dissertation could not have come to fruition without his help. I am also indebted to committee members, Suse Bryode, Dan Tranchina and Tim Cordozo for their ongoing guidance and support, as well as their frequent feedback at every stage of this project. I am also everlastingly grateful to my wife Yoonkyung Do, for her endless tolerance and her helping me maintain hope that I would indeed finish this project. I would also like to thank my mother, Jungja Kim, who inspired me from the beginning of my life. Finally, many thanks to Samantha and other lab members, who so patiently offered their time. vii PREFACE A new term, systems biology, is very widely used in current bioscience. Systems biology refers to a network of peripheral biological areas rather than a single well-delineated field. Bioinformatics is now an essential tool to fulfil the goal of systems biology. The model checking method, used in this study, is a computational model approach to propose specific testable hypotheses about a biological system with experimental validation. Through this method, it is possible to acquire quantitative description of cells or cell processes. viii ABSTRACT This study focuses on the analysis of dynamic computational models capable of explaining biochemical and evolutionary systems. First, we mathematically modeled the intrinsic apoptosis pathway by using a system of ordinary differential equations (an ODE model) generated by a systems biology tool, Simpathica, which is a simulation and reasoning system developed to study biological pathways. Caspase-9 is …