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ARCIVES Genome Sequencing Technology: Improvement of the Electrophoretic Sequencing Process and Analysis of the Sequencing Tool Industry by Kazunori Maruyama Ph.D

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ARCIVES Genome Sequencing Technology: Improvement of the Electrophoretic Sequencing Process and Analysis of the Sequencing Tool Industry by Kazunori Maruyama Ph.D Genome Sequencing Technology: Improvement of the Electrophoretic Sequencing Process and Analysis of the Sequencing Tool Industry by Kazunori Maruyama Ph.D. in Material Science, Mie University (2001) M.S. in Macromolecular Science, Osaka University (1993) Submitted to the Alfred P. Sloan School of Management and the Department of Chemical Engineering in Partial Fulfillment of the Requirements for the Degrees of Master of BusinessAdministration and Master of Science in Chemical Engineering In Conjunction with the Leaders for Manufacturing Program at the MASSACHUSETTSINSUE Massachusetts Institute of Technology OF TECHNOLOY June 2005 JUN 01 2005 02005 Massachusetts Institute of Technology. All rights reserved. LIBRARIES Signature of Author Alfred P. Sloan School of Management Department of Chemical Engineering May 6, 2005 Certified by -- Roy E. Welsch Professor of Statistics and Management Science Thesis Advisor Certified by r Patrick S. Doyle Assistant-Professor of Chemical Engineering Thesis Advisor Accepted by · - Margaret Andrews Alfred P. Sloan School of Management Executive Director of Masters Program Accepted by - - Daniel Blankschtein Department of Chemical Engineering Graduate Committee Chairman .ARCIVES Genome Sequencing Technology: Improvement of the Electrophoretic Sequencing Process and Analysis of the Sequencing Tool Industry by Kazunori Maruyama Ph.D. in Material Science, Mie University (2001) M.S. in Macromolecular Science, Osaka University (1993) Submitted to the Alfred P. Sloan School of Management and the Department of Chemical Engineering in Partial Fulfillment of the Requirements for the Degrees of Master of Business Administration and Master of Science in Chemical Engineering ABSTRACT A primary bottleneck in DNA-sequencing operations is the capacity of the detection process. Although today's capillary electrophoresis DNA sequencers are faster, more sensitive, and more reliable than their precursors, high purchasing and running costs still make them a limiting factor in most laboratories like those of the Broad Institute. It is important to run those sequencers as efficiently as possible to reduce costs while producing robust assemblies. Polymer media for electrophoresis is the most important determinant for sequencing throughput. This thesis investigates the effect of polymer media on the performance of Applied Biosystems (ABI) 3730xl, the de-facto standard of DNA sequencers and develops analysis procedures for ABI3730xl system and its data. Due to its use in the human genome project (HGP), ABI has established a monopolistic position in the DNA-sequencing tool industry. As the de-facto standard of DNA sequencers ABI3730xl is highly automated, well-optimized, and black-boxed, despite the importance of higher throughput sequencing for diagnostic applications, third parties have found it difficult to improve sequencing methods. This thesis also conducts an analysis of the DNA-sequencing tool industry to discuss how ABI has established current monopolistic status, what kind of business model would be attractive for ABI in the post-HGP period, how new companies can successfully enter this industry, and how they can keep improving DNA-sequencing throughput along the line of "Moore's law". Thesis Supervisors: Roy E. Welsch Professor of Statistics and Management Science Patrick S. Doyle Assistant Professor of Chemical Engineering 2 Table of Contents Acknowledgements 5 1. Introduction 6 2. Background 8 2.1 Broad Institute Overview 8 2.2 Genome-sequencing Operation Overview 11 2.2.1 Operation Process 11 2.2.2 Genome-sequencing Technology 13 3. Improvement of the Electrophoretic Genome-sequencing Process 16 3.1 Introduction 16 3.2 Research History of Polymer Media for DNA-sequencing 18 3.2.1 Linear Water-Soluble Polymers 18 3.2.2 Thermo-Sensitive Polymers and Polymers with Higher-order Structure 22 3.2.3 Summary of Past Polymer Research 24 3.3 Experimental Section 25 3.3.1 Selection of Polymers 25 3.3.2 Capillary Electrophoresis 25 3.3.3 Chemical Analysis 26 3.4 Results and Discussions 28 3.4.1 Establishment of Experimental Protocol for Polymer Research 28 3.4.2 POP7 35 3.4.3 DMA 41 3.4.4 LPA 44 3.4.5 Chemical Analysis of POP7 47 3.4.6 Polymer Mixtures 52 3.5 Possible Approaches for the Future 55 3.6 Summary 57 3 4. Analysis of the Genome-Sequencing Tool Industry 58 4.1 Introduction 58 4.2 History of Genome-Sequencing Technology 58 4.3 Emergence of the Genome-Sequencing Tool Industry 63 4.4 Analysis of the Genome-Sequencing Tool Industry 65 4.4.1 Industry S-curves 65 4.4.2 Uniqueness and Complementary Assets to Create and Capture Value 66 4.4.3 Industry Structure - Present and Future 70 4.4.4 Value Chain and Boundaries 73 4.4.5 Strategy for the Future of ABI 74 4.5 Summary 75 5. Conclusion 76 4 Acknowledgements The author wishes to acknowledge the Leaders for Manufacturing Program for its support of this work. He would also like to thank Robert Nicol, Patrick Cahill, James Meldrim, Karen Foley and the group of Technology Development at the Broad Institute. Finally, he would like to thank his wife, Naoko, for her continuous support during his busy but fun days in Cambridge. 5 1. Introduction Huge technological advancements in information technology and a deeper understanding of biomaterials in the past twenty years have allowed for the discovery of the entire genetic information of humankind. The Whitehead Institute Center for Genomic Research was a primary contributor to this achievement. In the 1990s, during the Human Genome Project, its sequencing operation played a key role in rapidly improving genome-sequencing throughput. The Whitehead Institute has recently combined research efforts with the Massachusetts Institute of Technology (MIT) and Harvard University to form the Broad Institute. Even after the completion of the Human Genome Project in 2003, increased sequencing throughput at an affordable cost is critical to the realization of advanced and economical genomics-based medications. However, without tangible economical returns in the near future, research institutes and related industries in the genome-sequencing arena are evidently frustrated. Not only is the next incremental technological step necessary to move the field forward but also an appreciation for past and potential future balances of power in the arena would be enough to drive such a highly technology-driven industry toward future medical applications. The Broad Institute has improved throughput of genome-sequencing operations with an eye toward future healthcare applications. A primary bottleneck of the current sequencing operation is the capacity of the sequence detection process using the "Genome Sequencer," a key instrument in reading base code sequence for DNA. Many scientists and engineers in the Broad Institute are conducting research not only on multicapillary electrophoresis, the current sequencing technology, but also on next-generation technologies, to increase the capacity of the sequence detection process. This thesis is based on a Leaders for Manufacturing (LFM) internship at the Broad Institute, where the author worked with the genome sequencer in terms of both technological and business aspects. The author investigated polymer media of the current genome sequencer to improve its operation efficiency. He also conducted technology and 6 business analyses for the genome-sequencing tool industry and made attempt to forecast the future of the industry. The thesis proceeds as follows: Chapter 2, "Background," provides information on the Broad Institute as well as modem genome-sequencing technology. It concludes with a discussion of the detection phase of the genome-sequencing process, providing insight into the multicapillary electrophoresis procedure. Chapter 3, "Improvement of Electrophoretic Genome-sequencing Process," consists of the engineering portion of this thesis, investigating possibilities for improving the efficiency of current genome-sequencing. The discussion focuses on the role of polymer media in multicapillary electrophoresis technology. Chapter 4, "Analysis of the Genome-sequencing Tool Industry," examines the business perspective of genome-sequencing technology with an analysis of research history and the emergence of the genome-sequencing tool industry. The discussion includes how the monopoly status of Applied Biosystems, Inc. (ABI) has been successfully established, whether ABI's dominance will continue in the future, and how the industry can be developed in the future. Chapter 5, "Conclusion," ties the discussion of the preceding chapters together and offers some perspectives on how conclusions can be applied outside the field of genomics. 7 2. Background 2.1 Broad Institute Overview The Broad Institute is the collaborative research organization between MIT, Harvard University, and the Whitehead Institute; its official name is "The Eli and Edythe L. Broad Institute of MIT, Harvard University and its affiliated hospitals, and Whitehead Institute." In June 2003, philanthropists Eli & Edythe Broad of Los Angeles gave $100 million to create an institute with MIT, Harvard, and Whitehead to fulfill the genome's promise for medicine. The institute begin its activity later that same year. Figure 1 shows the mission statement of the Broad Institute. o Our scientific mission is: To create tools for genomics medicine and make them broadly available to the scientific community To apply these tools to propel the understanding and treatment of disease o Our organizational mission is: --- To enable collaborative projects
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