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TOWARD A COMPUTATIONAL SOLUTION TO THE INVERSE PROBLEM OF HOW HYPOXIA ARISES IN METABOLICALLY HETEROGENEOUS CANCER CELL POPULATIONS by andrew sundstrom A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Program in Computational Biology New York University September 2013 Bhubaneswar Mishra UMI Number: 3602735 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. UMI 3602735 Published by ProQuest LLC (2013). Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, MI 48106 - 1346 c Andrew Sundstrom All Rights Reserved, 2013 DEDICATION For Tiffany & Wren. iv ACKNOWLEDGEMENTS Let me begin by thanking my advisor, Bud Mishra, for encouraging me to “ask for forgiveness, not for permission” throughout the research process. One of the first things Bud impressed upon me was how computation can bring scale and rigor to biology, a principle from which I’ve derived a deeper understanding of both fields. (I would add that computation can also bring mechanism to biology, but this is ar- guable; that biology can bring humility to computation is beyond dispute.) Bud is one of the few genuine polymaths I’ve known, and he’s frequently astonished me with the deep connections he perceives between seemingly dissociated phenomena and fields of research. We first spoke in his office in the fall of 2006. During that wide-ranging conversation it dawned on me that I must study computational biol- ogy under his supervision. This began in earnest that following summer, with our first collaborative publication with researchers at UCLA, and has continued unbro- ken to the present. I thank him for seven years (and counting) of stimulating inquiry, in an environment of honesty, self-reliance, and risk-taking that he has cultivated in his laboratory. Next, I must thank my co-advisor, Dafna Bar-Sagi, for teaching me how to think like a biologist, and how to respect the staggering, defiant complexity of biological systems, which don’t cleave to our beautiful ideas. When I first attended one of her lab meetings in 2009, I was struck by the candor and the quality of criticism that lab members offered each other in relation to their research—a crucible for asking questions and testing hypotheses. During the period that she supervised my depth v qualifying exam, I grew convinced that she should be my co-advisor. Over the past three years, conducting research in her lab, I’ve developed a keen appreciation for the rigors of laboratory bench work, and I treasure my exposure to an entirely sep- arate intellectual tradition than I’d known prior to that. To bridge the disciplines of computation and biology, one must train an agile mind, and take a humble posture. I thank Dafna for helping me do both. For their time, attention, and guidance during dissertation review, I thank the other members of my thesis committee, Leslie Greengard, Ravi Iyengar, and Ernest Davis. I want to acknowledge past and present members of Dafna’s lab who have helped me. I thank Laura Melis for training me to conduct tissue culture experiments and MTT assays. Only a saint could possess the vast reservoir of patience she had for these fumbling hands. I thank Rengin Soydaner-Azeloglu, for teaching me how to ex- tract, prepare, and section a mouse pancreas. I thank Elda Grabocka for teaching me about hypoxia in a cancer setting, introducing me to pimonidazole staining, and for providing me with the tumor section histology slides I used to characterize hypoxia in this dissertation. My many conversations with Cosimo Commisso have enlight- ened me about genetics and biochemistry in general and cancer cell metabolism in particular. He has also taught me about biology as a career, and generously given his time to advise me on mine, for which I am grateful. I hold Elda and Cosimo up as model experimental biologists. I want to acknowledge past and present members of Bud’s lab who have helped me. I thank Ilya Korsunsky and Justin Jee for their efforts to inject life into the lab culture, including holding weekly student-only lab meetings that were especially productive and useful to me. And injecting culture into the lab life, like when Justin had his piano delivered to the lab and turned Ravel’s Toccata from Le Tombeau de Couperin into vi my writing anthem, and when Ilya graced many a late night in the lab with Latin ballroom dance. I found collaborating with Justin on the problem of the evolution of the genetic code to be a real thrill; I can only hope we have the opportunity to work together again. I thank Andreas Witzel for educating me about logic and game theory. His intense, spread-spectrum intellect, and sense of humor, made the lab an especially good place to be for the three years he inhabited the office next door. Lastly, I want to thank Samantha Kleinberg, whose passion for her research made me want to drop what I was doing and study temporal causality. She brought a vigorous and playful sense of inquiry to the lab, and she always took time to help me, including giving me black-belt time management advice—if only I’d listened! Outside of the two labs, there are several I wish to acknowledge. First, I thank Ed Schonberg, colleague and friend, who always lent me an ear, and a squash racquet, for my tales of woe and triumph, and who consistently gave me sound advice for life inside and outside of the academy. I thank Davi Geiger for conversations related to image processing in my research, starting with my masters thesis analysis of AFM images, and continuing most recently with my gradient analysis of histology images. He impressed upon me the need to be methodical, to grow organically with the prob- lem, learning what each algorithm means and where its limit lie, and to develop new mathematics and new algorithms when necessary. My dear friend Alex Botta, a Courant computer science doctoral veteran, always made himself available for my questions, and to offer sage advice about the Ph.D. process. Alex is another polymath of unfathomable wit, who has shaped me in profound ways. Our thirteen-year friend- ship testifies to this; if he hadn’t brought me to the NYU graduate computer science open house in 2003, I might not be writing these words. He taught me early on that “Art needs constraint.” Ever since, I’ve sought to identify the best constraints within vii which to perform my creative work. My Aussie brother, Damian Conway, provided a steady stream of long-distance, and occasional short-range, encouragement. I met Damian in 2000, and over the course of his teaching me to program at a level I’d not dreamt was possible, I realized I was becoming friends with the Mozart of computer programming and programming language design. His singular creativity in the art is my inspiration to recurrently surpass myself at translating thought into code. It is my failing that this dissertation is implemented in Matlab and not Perl6. Lastly, I want to thank David Mordecai, whose conversations over the last three years, ranging from game theory to Bayesian statistical learning, from economics to sociology, from sentiment analysis to spatiotemporal mapping, have proven instrumental not only in stimulating my current research direction, but in exploring my next one. David coached me in invaluable ways throughout the dissertation writing process, helping me get perspective, formulate scope, and manage my time during “essay crisis.” Let me conclude by acknowledging my family. I thank Tom and Martha Mills for their unfailing support and faith in me, not only for the duration of this five-year enterprise, but for the 25 years I’ve known them. They have instilled in me a sense of honesty, generosity, fairness, and respect for one’s work. In their example I’ve come to realize that nothing can approach or replace the love of family, and the personal strength that issues from it. I am blessed to call them my second parents. Denna Reilly, my sister and friend, continually encouraged me through the doctoral process. As the end approached, she would repeatedly exhort, “Stay on target! Stay on target!” I thank my mom, Martha Sundstrom, for giving me her extraordinary emotional ap- petite for the world, and her Sicilian characteristics through which that’s inflected. Her love and faith in me are unbounded. I thank my dad, Pete Sundstrom, for in- stilling in me from as early as I can remember the value of intellectual curiosity, and viii for cultivating my appreciation of antiquity and the long human conversations that form history, art, philosophy, and literature—emanating from Goethe’s understand- ing that “He who cannot draw on 3,000 years is living from hand to mouth.” Most importantly, he taught me how to approach the world with a sense of awe. Little wonder that he was the first to illuminate for me the beauty, and sanctity, of living things, a sensibility I carry straight into this thesis. His love and pride I can see from here. I thank Tiffany Mills, my wife and best friend, my boon companion for more than a quarter-century, for her love and support.

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