Mechanistic Modeling of Bacterial Nutrient Uptake Strategies by Noele Rosalie Norris B.S., California Institute of Technology (2010) M.A., Queen Mary, University of London (2011) M.S., Massachusetts Institute of Technology (2013) Submitted to the Department of Electrical Engineering and Computer Science in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY September 2019 c Massachusetts Institute of Technology 2019. All rights reserved. Author ............................................................................ Department of Electrical Engineering and Computer Science August 30, 2019 Certified by ....................................................................... Emilio Frazzoli Professor, Mechanical and Process Engineering, ETH Z¨urich Thesis Supervisor Certified by ....................................................................... Roman Stocker Professor, Civil, Environmental, and Geomatic Engineering, ETH Z¨urich Thesis Supervisor Accepted by ....................................................................... Leslie A. Kolodziejski Professor of Electrical Engineering and Computer Science Chair, Department Committee on Graduate Students Mechanistic Modeling of Bacterial Nutrient Uptake Strategies by Noele Rosalie Norris Submitted to the Department of Electrical Engineering and Computer Science on August 30, 2019 in partial fulfillment of the requirements for the degree of Doctor of Philosophy Abstract Bacteria have developed a variety of strategies to find and consume the substrates nec- essary for both the cell's energy-consuming processes and for the additional biomass needed to replicate. A greater understanding of the diversity and regulation of these strategies can provide us with a number of insights relevant for a variety of applications, from predicting bacterial population dynamics and thus carbon-cycling rates in the ocean to bio-engineering bacteria into microscale robots. Here I use toy, mechanistic models of single-cell metabolism that allow me to quantify the costs and benefits of various nutrient uptake strategies. I find that: (i) a sensing-uptake trade-off governs E. coli's regulation of maltose uptake and chemotaxis to maltose; (ii) a rate-affinity trade-off in nutrient trans- port systems governs the speciation of marine oligotrophic and copiotrophic heterotrophs; and (iii) an exploration-conservation trade-off governs the prevalence of motility in the marine microbial world. This work thus provides new understanding of how both pheno- typic diversity and cellular regulation are governed by trade-offs for maximizing growth rate in different environments. Thesis Supervisor: Emilio Frazzoli Title: Professor, Mechanical and Process Engineering, ETH Z¨urich Thesis Supervisor: Roman Stocker Title: Professor, Civil, Environmental, and Geomatic Engineering, ETH Z¨urich In memory of my dad, my hero. \The best thing for being sad," replied Merlyn, beginning to puff and blow, \is to learn something. That is the only thing that never fails. You may grow old and trembling in your anatomies, you may lie awake at night listening to the disorder of your veins, you may miss your only love, you may see the world about you devastated by evil lunatics, or know your honour trampled in the sewers of baser minds. There is only one thing for it then|to learn. Learn why the world wags and what wags it. That is the only thing which the mind can never exhaust, never alienate, never be tortured by, never fear or distrust, and never dream of regretting. Learning is the thing for you...." T.H. White, The Once and Future King Acknowledgements I think I have had an atypical graduate student career. It took me from MIT to ETH Z¨urich and USC. It provided me with the opportunity to gain different perspectives to research, to pique and satisfy my curiosity in a variety of topics, and even to experience different worldviews. It was additionally a journey of self-discovery. There were moments I was banging my head against the wall, wishing I were just a bit smarter, and others| though I will admit more rare|in which I felt the distinct joy of having brilliantly figured something out. I have learned that this is what doing science is all about, and I would like to acknowledge and thank my three thesis supervisors for giving me the opportunity to learn what it means to be a scientist. Foremost, I would like to thank Professors Emilio Frazzoli and Roman Stocker. They both ensured that I always had a pay-check each month. They gave me countless re- sources and opportunities, and they also gave me an incredibly rare gift: the freedom to develop my intellectual curiosity nearly wherever it took me|from taking classes to learn functional analysis to donning a lab coat and learning how to culture E. coli. I would like to thank Emilio for teaching me to be open-minded and curious, whether it be about robotic cars, unmanned aerial vehicles, locusts, zebras, or bacteria; and for never once faltering in his support and for ensuring I made it out with a doctoral degree. And I would like to thank Roman for taking me in and integrating a novice experimentalist into his welcoming lab; and for giving me the wonderfully inspiring opportunity to participate in the Simons collaborative grant for Principles of Microbial Ecology. I would also like to thank my third thesis supervisor, Professor Naomi Levine, for providing me with an intellectual home in Los Angeles. She allowed me to feel part of a close-knit team tackling big problems. She always found the time to talk to me about my work, being both sounding-board and mentor and infusing positivity into my research whenever it was lacking. I would also like to thank my other two thesis committee members, Professors Munther Dahleh and George Verghese. Munzer convinced me to attend MIT and join Emilio's group and advised me about the practicalities of academia, even though he may just well be the busiest person on campus. And George came to my rescue at a time of great need and took the time to learn about my research and offer useful feedback. My success is due to the help of many other people. First of all, I would like to thank the following former and current members of the Stocker lab: Vicente Fernandez for his guidance and for ensuring I was on task and on target; Filippo Menolascina for introducing me to the world of the experimentalist and for convincing me I could succeed; Yutaka Yawata for showing me his awe-inspiring experimental wizardry, which finally gave me the insight that allowed me to get my own experiments working; Ela Burmeister for being the most efficient and brilliant lab manager in the universe and also for being a great friend; Jen Nguyen for being a wonderful labmate, for her friendship and guidance 9 when I was getting started, and for her optimism and cheer that helped me overcome my struggles in the lab; Uria Alcolombri for sharing his enthusiasm and curiosity with me, for spending so much time helping me produce beautiful Western blots, and for showing me that experimental work could be fun; Zachary Landry for opening my eyes to the wonders of the little oligotroph; Mehdi Salek for taking the time and care to help me fabricate my first microfluidic devices; Becky Schilling for being so unbelievably supportive of such a klutzy, experimental novice; Jeanette Wheeler for her camaraderie in the office; Cherry Gao for her help and cheerleading as I reached the finish line; Kwangmin Son for teaching me about the ways of Vibrio; Russ Naisbit for being a thoughtful and careful editor; and Jo¨elleRobinson for her kindness and for ensuring my paychecks made it across the ocean each and every month. I would also like to acknowledge the help I received from current and former members of the Levine lab, in particular: Emily Zakem for her inspiring work, guidance, and mentorship; and Erin McParland for the sunny disposition that helped me start each day and for continually sending useful papers relevant to my research over my way. I would also like to thank the staff at LIDS and the EECS headquarters who saved me from much headache, especially: Janet Fischer, the master wizard of the EECS de- partment, without whose tremendous help I would have been unable to make the move to ETH; Alicia Duarte for being always cheerful and ready to help and for so quickly setting everything right; and Jennifer Donovan for her speedy efficiency and for making LIDS a warm and welcoming place to work. I would also like to thank EECS departmental chair Leslie Kolodziejski for taking the time to provide me with both guidance and moral support. I would also like to thank: Professor Terry Hwa, at UCSD, for his encouragement and feedback on my work; and Professor Cameron Thrash, at USC, for giving me many useful insights into the workings of SAR11. I am also very grateful to have had the support of the following people, who were there for me when I most needed them: Mitra Osqui for teaching me how the pros do control theory, for her friendship and hugs, and for always taking such good care of me whenever I am in town; Omer Tanovic for being the best officemate ever and for inspiring me with his brilliance and also engaging conversations; Sandhya Ramakrishnan for inspiring me to excel in mathematics and for always checking up on me; Barbara Gee, my Caltech academic grandmother, whose support helped me succeed and whose encouragement keeps me going; and Nancy Sulahian for her understanding and for her encouragement to keep singing. Finally, I would like to acknowledge and thank my family for their love and support. To my mom, for always being there for me to listen and to advise and for teaching me grit and perseverance and continually reminding me to \just keep swimming". To my sister, Kelsey Norris, whose hard work and enthusiasm for history has inspired me to be ambitious with my own career and whose thoughtfulness and support is constantly 10 inspiring me to be a better sister.