The Role of Large-Scale Genotyping Projects in the Developing World and the Importance of Genomic Sovereignty

Bridging the genomics gap: the role of large-scale genotyping projects in the developing world and the importance of genomic sovereignty by Billie-Jo Hardy A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Sciences University of Toronto © Copyright by Billie-Jo Hardy, 2011 Bridging the genomics gap: the role of large-scale genotyping projects in the developing world and the importance of genomic sovereignty Billie-Jo Hardy Doctorate of Philosophy Institute of Medical Sciences University of Toronto 2011 Abstract In recent years, there have been several proposals for large-scale human genotyping projects in the developing world. The dissertation presented here explores the motivations, opportunities and challenges of initiating locally led, large-scale genotyping projects documenting human genomic variation in the developing world. I analyze two case studies: the Indian Genome Variation Consortium in India and the University of Cape Town, Department of Human Genetics and the African Genomics Education Initiative in South Africa. These case studies, together with similar projects in Mexico and Thailand provide compelling reasons for pursuing these projects: the potential to address local health needs and reduce health care costs; the opportunity to stimulate economic development through investments in genomic sciences, and the availability of unique population resources. In an effort to capture the value of these investments and promote an equal stake in international collaborations, Mexico and India have developed guidelines and laws to protect local human genetic material as a sovereign resource, referred to here as ‘genomic ii sovereignty’. Critics have suggested that it can impede international collaborations and reduce access to external funding. I provide an in depth analysis of genomic sovereignty and how it may contribute to each country’s aim of achieving health equity through investments in genomics, its relation to heritage and patrimony, and its potential limitations. The debate is critical, as the knowledge generated from large-scale human genomic research will need to be interpreted in larger international collaborative efforts before it can lead to health benefits. Qualitative case study methodology is employed and the primary data source consists of interviews conducted with key informants. The research described here provides a source of empirical description and analysis that is informing the framing of policies, principles and practices on how research infrastructure and capacity are being established for human genomic sciences in developing countries. iii Acknowledgments To Waldorf from Statler. Thank you. I am fortunate to have known you. Your curiosity was endless. Your warmth and kindness was infectious. Sara, your friendship is, and forever will be, deeply missed. In life I have learned that ‘it takes a community’ to accomplish anything well. And so, I would like to thank my community for helping me complete this dissertation. Mahsi Cho! I would first like to acknowledge and thank all those who directly contributed to this research – collaborators, co-authors and participants in India, Mexico, South Africa, Thailand and Singapore – without their participation, insight and support this work would not have been realized. Abdallah, as my supervisor, I am grateful that you gave me the opportunity to take this five year journey, during which I have learned so much, made many life long friends and had an incredibly great time. As you well know by now, I am a natural born cynic, but your positive attitude has been a yin to my yang and I am thankful for your leadership and guidance. Beatrice, as a member of my thesis committee and my friend, you have been an incredible mentor and without your excellent advice, support and feedback, I would not have been able to complete this journey. Peter, thank you for your confidence in me – your insight on the early framing of my dissertation and your persistent questions helped propel this work forward. I would like to thank the Canadian Institute for Health Research for awarding me the Canadian Graduate Scholarship and the Douglas Kinsella Award. My fellow graduate students at the McLaughlin-Rotman Centre for Global Health have been a daily source of inspiration and will always be my greatest memory of these years. Sara, Dominique, Monali, Rahim, Ken, Lara, May, Andrew, and Fabio, thank you for the intellectual and emotional support, as well as the many cups of coffee and tea! A special shout out to Halla Thorsteinsdottir whose friendship, support and feedback helped me through the final months and to Jocalyn Clark whose friendship, advice and little gifts boosted my dwindling confidence. iv There have also been a number of individuals on the operational team at the MRC who have all assisted me along the way – Andrew, Leticia, Harjit, Munira, Christine, Tijana, Heather and Joanna and so many others, thank-you! Finally, Simon – thank you for always believing in me. Your love, support and patience are what got me through all these years of late nights on the laptop. v Table of Contents Table of Contents ACKNOWLEDGMENTS IV TABLE OF CONTENTS VI LIST OF TABLES X LIST OF APPENDICES XI CHAPTER 1 INTRODUCTION 1 1 1 1.1 INTRODUCTION 1 1.2 STATEMENT OF THE ISSUE 4 1.3 RESEARCH QUESTIONS 6 1.4 SIGNIFICANCE OF THE RESEARCH 8 1.5 DISSEMINATION OF THE WORK 8 1.6 STRUCTURE OF THE THESIS 12 CHAPTER 2 LITERATURE REVIEW 15 2 15 2.1 INTRODUCTION 15 2.2 GENOMICS AND HUMAN GENOMIC VARIATION 15 2.3 LARGE-SCALE HUMAN GENOMIC VARIATION INITIATIVES 19 2.4 ETHICAL, LEGAL, AND SOCIAL ISSUES 33 2.5 HUMAN GENOMIC VARIATION: HEALTH BENEFITS AND OTHER DRIVING FORCES 47 2.6 HUMAN GENOMIC VARIATION: THE DEVELOPING WORLD 54 2.7 SUMMARY 63 CHAPTER 3 METHODOLOGY 66 3 66 vi 3.1 INTRODUCTION 66 3.2 THEORETICAL FRAMEWORK 67 3.3 RESEARCH DESIGN 69 3.4 DATA COLLECTION AND ANALYSIS 74 3.5 ETHICAL CONSIDERATIONS 78 CHAPTER 4 FROM DIVERSITY TO DELIVERY: THE CASE OF THE INDIAN GENOME VARIATION INITIATIVE 79 4 79 4.1 INTRODUCTION 79 4.2 BACKGROUND 80 4.3 ADOPTION OF GENOMIC MEDICINE IN INDIA 81 4.3.1 KNOWLEDGE-BASED ECONOMY 81 4.3.2 GENOMIC SOVEREIGNTY 84 4.3.3 POLITICAL WILL 85 4.3.4 LOCAL HEALTH BENEFITS 86 4.4 GENOMIC MEDICINE CHALLENGES IN INDIA 88 4.4.1 ACADEMIC LINKS 88 4.4.2 PUBLIC-PRIVATE SECTOR LINKS 88 4.4.3 COMMERCIALIZATION IN THE PUBLIC SECTOR 89 4.4.4 THE NEED FOR REGULATORY FRAMEWORKS 90 4.4.5 DELIVERY REQUIRES INNOVATIVE SOLUTIONS 91 4.4.6 PHYSICIANS’ UNDERSTANDING 92 4.4.7 PUBLIC AWARENESS 92 4.5 CONCLUDING REMARKS 93 CHAPTER 5 SOUTH AFRICA: FROM SPECIES CRADLE TO GENOMIC APPLICATIONS 95 5 95 5.1 INTRODUCTION 95 5.2 BACKGROUND 96 5.3 POLITICAL WILL 97 5.4 GENOMIC SOVEREIGNTY 100 5.5 INSTITUTIONAL LEADERSHIP 101 vii 5.6 LOCAL HEALTH BENEFITS 103 5.7 KNOWLEDGE-BASED ECONOMY 105 5.8 CONCLUDING REMARKS 107 CHAPTER 6 ILLUSTRATING GENOMIC SOVEREIGNTY 110 6 110 6.1 INTRODUCTION 110 6.2 INTERNATIONAL AND NATIONAL GUIDELINES ON GENOMIC RESEARCH 112 6.3 SOVEREIGNTY DEFINED 117 6.4 THE EVOLUTION OF GENOMIC SOVEREIGNTY 121 6.4.1 THE CONVENTION ON BIOLOGICAL DIVERSITY 121 6.4.2 INDIGENOUS PEOPLES AND GENOMIC SOVEREIGNTY 125 6.4.3 INDONESIA AND VIRAL SOVEREIGNTY 130 6.5 GENOMIC SOVEREIGNTY: A WORKING DEFINITION 133 6.5.1 GENOMIC SOVEREIGNTY: AN ECONOMIC ARGUMENT 134 6.5.2 GENOMIC SOVEREIGNTY: A KEY TO PUBLIC SUPPORT 136 6.5.3 GENOMIC SOVEREIGNTY AS PATRIMONY 138 6.6 DISCUSSION 141 6.7 CONCLUSION 150 CHAPTER 7 THE NEXT STEPS FOR GENOMIC MEDICINE – CHALLENGES AND OPPORTUNITIES FOR THE DEVELOPING WORLD 153 7 153 7.1 INTRODUCTION 153 7.2 GENOMIC MEDICINE IN THE DEVELOPING WORLD 155 7.3 EXPLORING POTENTIAL OPPORTUNITIES 158 7.4 CHALLENGES 162 7.5 CONCLUSIONS 167 CHAPTER 8 CONCLUSION 169 8 169 8.1 SUMMARY OF THE RESEARCH FINDINGS 169 8.2 STUDY LIMITATIONS 171 viii 8.3 RECOMMENDATIONS FOR FUTURE WORK 172 REFERENCES 174 APPENDIX 1 208 APPENDIX 2. 209 APPENDIX 3. 210 APPENDIX 4. 217 APPENDIX 5. 220 COPYRIGHT ACKNOWLEDGEMENTS 224 ix List of Tables Chapter 2: Table 1. International Guidelines on Genetic Databases Table 2. National Legislation and Guidelines on Genetic Databases Table 3: Examples of Human Genes Involved in Varying Susceptibility to Communicable Disease Table 4: Some adverse effects of HAART, the drugs presumably involved and the main genetic variants that have been studied Chapter 6: Table 1: Roadmap to investing in large-scale human genomic research in the developing world Table 2: International guidelines on genomic research Table 3: ‘Sovereignty Test’ Table 4: Genomic sovereignty recommendations Chapter 7: Table 1: Challenge faced by developing countries investing in genomic medicine x List of Appendices Appendix 1. Series of Publications related to the Human Genomic Variation: Implications for Global Health Hardy B. and Séguin B., Singer PA., Daar AS. (2008) Genomic medicine and developing countries: creating a room of their own. Nature Reviews Genetics 9:487-493 Genomic Medicine in Developing Countries – October 2008 Nature Reviews Genetics Supplement o Séguin B., Hardy B., Singer PA., Daar AS. (2008) Human genomic variation initiatives in emerging economies and developing countries. Nature Reviews Genetics 10:S3-S4 o Séguin B., Hardy B., Singer PA., Daar AS. (2008) Genomics, public health and developing countries: the case of the Mexican National Institute of Genomic Medicine (INMEGEN). Nature Reviews Genetics 10:S5-S9 o Hardy B., Séguin B., Singer PA., Mukerji M., Brahmachari SK., Daar A.S. (2008) From diversity to delivery: the case of the Indian Genome Variation initiative. Nature Reviews Genetics 10:S9-S14 o Séguin B., Hardy B., Singer PA., Daar AS.

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