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TRANSCRIPTOME ANALYSIS in MAMMALIAN CELL CULTURE: APPLICATIONS in PROCESS DEVELOPMENT and CHARACTERIZATION Anne Kantardjieff We

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TRANSCRIPTOME ANALYSIS in MAMMALIAN CELL CULTURE: APPLICATIONS in PROCESS DEVELOPMENT and CHARACTERIZATION Anne Kantardjieff We TRANSCRIPTOME ANALYSIS IN MAMMALIAN CELL CULTURE: APPLICATIONS IN PROCESS DEVELOPMENT AND CHARACTERIZATION A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL OF THE UNIVERSITY OF MINNESOTA BY Anne Kantardjieff IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Wei-Shou Hu August, 2009 © Anne Kantardjieff, August 2009 ACKNOWLEDGMENTS First and foremost, I would like to thank my advisor, Prof. Wei-Shou Hu. He is a consummate teacher, who always puts the best interests of his students first. I am eternally grateful for all the opportunities he has given me and all that I have learned from him. I can only hope to prove as inspriring to others as he has been to me. I would like to thank my thesis committee members, Prof. Kevin Dorfman, Prof. Scott Fahrenkrug, and Prof. Friedrich Srienc, for taking the time to serve on my committee. It goes without saying that what makes the Hu lab a wonderful place to work are the people. I consider myself lucky to have joined what could only be described as a family. Thank you to all the Hu group members, past and present: Jongchan Lee, Wei Lian, Mugdha Gadgil, Sarika Mehra, Marcela de Leon Gatti, Ziomara Gerdtzen, Patrick Hossler, Katie Wlaschin, Gargi Seth, Fernando Ulloa, Joon Chong Yee, C.M. Cameron, David Umulis, Karthik Jayapal, Salim Charaniya, Marlene Castro, Nitya Jacob, Bhanu Mulukutla, Siguang Sui, Kartik Subramanian, Cornelia Bengea, Huong Le, Anushree Chatterjee, Jason Owens, Shikha Sharma, Kathryn Johnson, Eyal Epstein, ze Germans, Kirsten Keefe, Kim Coffee, Katherine Mattews and Jessica Raines-Jones. This work was enabled by the great collaboration we have had with the Bioprocessing Technology Institute in Singapore. I would like to thank Prof. Miranda Yap, Peter Morin Nissom, Robin Philp, Kathy Wong, Song-Hui Chuah, Bernard Loo, Faraaz Yusufi, Eugene Koh and Eric Tan. I am happy to count you as friends. This work was also the result of a number of fruitful industrial collaborations, and I would like to take the opportunity to thank all of the wonderful people I had the chance to collaborate with. Thank you to Scott McIvor and the people of his lab, especially Paul Score, who first taught me how to clone (when I had no idea what cloning was!). I would also like to thank Prof. Jennifer Maynard, who was a great teacher to me in my first few years. I would like to thank all of the people at the Minnesota Supercomputing Institute who were i invaluable to our bioinformatics efforts, including Zheng Jin Tu and Wen Dong. I would also like to thank Kevin Silverstein, for always doing his best to answer my endless questions. I would like to thank all of the wonderful friends I have made during my time here. You are the reason grad school was so much fun. Thank you to Allison, Josh and Alex for a great way to spend Sunday nights! Finally, I would like to thank my family, on whose support I have always been able to count. Thank you for all your love and encouragement. ii ABSTRACT The advent of recombinant protein therapeutics more than two decades ago fundamentally transformed healthcare paradigms and has since improved the quality of life of millions of people. The production of these complex products is typically carried out in cultured mammalian cell lines, with a few cell lines accounting for the majority of production. Chief among these is the Chinese hamster ovary (CHO) cell line. Despite its importance, little genomic information is currently available in the public domain for this cell line. Consequently, our lab has devoted significant efforts to the development of genomic tools for CHO, including custom Affymetrix microarrays. These tools enable the global study of cellular gene expression. This thesis research has applied these transcriptome analysis tools to further understand the process of recombinant protein production. The course of bringing a recombinant protein product to production scale involves a series of complex and often lengthy steps. As demand for these products continues to increase, there is a need to streamline process development efforts. One approach to facilitate this process is to increase our fundamental understanding of cell culture processes. Microarrays are well-suited to this application, and in this work, transcriptome analysis has been use to characterize multiple facets of cell culture process development, including cell line development and modulation of process parameters in fed-batch cultures. We found significant variation amongst clonal gene expression profiles during cell line development, an observation which could be exploited to develop gene expression-based clone screening protocols. We also uncovered the widespread impact process parameters can have on cellular gene expression. In particular, we found that raw material source, namely different hydrolysate lots, has a profound effect on the transcriptional signatures of fed-batch cell culture processes. iii As next-generation sequencing technologies become increasingly mature and cost-effective, they are now being applied to the study of gene expression. We have used ultra high-throughput sequencing to investigate the deep transcriptome of CHO cells. We found that the technology correlated well with microarrays, and displayed a significantly broader detection range. Through this analysis, we also identified a number of transcriptionally-active regions in the CHO genome. The unprecedented depth achievable through next-generation sequencing now allows us to set genome sequencing firmly in our sights. iv TABLE OF CONTENTS ACKNOWLEDGMENTS ............................................................................................................................. I ABSTRACT ................................................................................................................................................ III TABLE OF CONTENTS ............................................................................................................................. V LIST OF TABLES .................................................................................................................................. VIII LIST OF FIGURES ................................................................................................................................... IX 1 INTRODUCTION ............................................................................................................................... 1 1.1 THESIS ORGANIZATION ................................................................................................................. 3 2 BACKGROUND .................................................................................................................................. 4 2.1 RECOMBINANT PROTEIN PRODUCTION IN CULTURED MAMMALIAN CELLS .................................. 4 2.1.1 Host Cell Lines for Recombinant Protein Production ............................................................. 5 2.1.2 Developing Production Cell Lines........................................................................................... 6 2.1.3 Typical Culture Process for Recombinant Protein Production ............................................... 9 2.2 MICROARRAYS FOR TRANSCRIPTOME ANALYSIS ........................................................................ 10 2.2.1 Developing Genomic Tools for Chinese Hamster Ovary Cells ............................................. 14 2.3 NEXT-GENERATION TECHNOLOGIES FOR TRANSCRIPTOME ANALYSIS ....................................... 22 3 TRANSCRIPTOME ANALYSIS OF DHFR AMPLIFICATION ................................................ 24 3.1 SUMMARY ................................................................................................................................... 24 3.2 INTRODUCTION ........................................................................................................................... 25 3.3 MATERIALS AND METHODS ........................................................................................................ 26 3.3.1 Plasmid and Transfection ...................................................................................................... 27 3.3.2 Gene Amplification, Sample Preparation and Array Hybridization ...................................... 27 3.3.3 Microarray Data Processing and Analysis ........................................................................... 28 3.3.4 Functional Analysis ............................................................................................................... 29 3.4 RESULTS ..................................................................................................................................... 29 3.4.1 Experimental Design and Gene Amplification ...................................................................... 29 3.4.2 Global Analysis of Transcriptional Response ....................................................................... 31 3.4.3 Comparison to Host Cell Line ............................................................................................... 32 3.4.4 Transcriptional Response to Amplification ........................................................................... 34 3.4.5 Comparison between Control Population and IgG-Producing Clones ................................. 36 3.5 DISCUSSION ................................................................................................................................ 39 3.6 CONCLUSIONS ............................................................................................................................
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