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Causality in Medicine with Particular Reference to the Viral Causation of Cancers

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Causality in Medicine with Particular Reference to the Viral Causation of Cancers Causality in medicine with particular reference to the viral causation of cancers Brendan Owen Clarke A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy of UCL Department of Science and Technology Studies UCL August 20, 2010 Revised version January 24, 2011 I, Brendan Owen Clarke, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. ................................................................ January 24, 2011 2 Acknowledgements This thesis would not have been written without the support and inspiration of Donald Gillies, who not only supervised me, but also introduced me to history and philosophy of science in the first instance. I have been very privileged to be the beneficiary of so much of his clear thinking over the last few years. Donald: thank you for everything, and I hope this thesis lives up to your expectations. I am also extremely grateful to Michela Massimi, who has acted as my second supervisor. She has provided throughout remarkably insightful feedback on this project, no matter how distant it is from her own research interests. I’d also like to thank her for all her help and guidance on teaching matters. I should also thank Vladimir Vonka for supplying many important pieces of both the cervical cancer history, as well as his own work on causality in medicine from the perspective of a real, working medical researcher. Phyllis McKay-Illari provided a critical piece of the story, as well as many interesting and stim- ulating discussions about the more philosophical aspects of this thesis. Similarly, I also wish to thank the other members of the Causality reading group (Jonathan Everett, Toby Friend, David Lagnado, John Pemberton, Christoph Schulz and Adam White) for all the good-natured arguments that we have had. The intellectual environment is incredibly important when producing such an interdisciplinary work. I’d therefore like to thank the students and staff of the department of Science and Technology Studies at UCL for their support and ideas. Particular thanks must go to Joe Cain, for reminding me about biology and teaching, as well as his critical eye on the first parts of the thesis, David Teira for all his acumen, Silvia De Bianchi for her help with Kant, and Chiara Ambrosio for reminding me that there’s more to philosophy than philosophy of science. Here, I might also thank Hasok Chang for show- ing how beautiful integrated history and philosophy of science can be. Finally, I must acknowledge the virtues of Ian James Kidd for showing me how to make specialist research engaging. These acknowledgements would not be complete without vigorously thanking Jon Williamson and Federica Russo for providing the philosophical germ of this thesis, as well as all their helpful comments on my earlier work. I wish to thank Carl Craver for suggesting that the relationship between evidence and mechanism was one worth exploring. I’d also like to thank some individuals who significantly contributed to my medical education, in particular Kevin Brown and his colleagues at the Health Protection Agency, who taught me about the practical difficulties of relating clinical disease to newly discovered viruses, and Alan Bates, who made some important comments about post-mortem causality. Acknowledgements 4 After all these expressions of scholarly gratitude, I cannot conclude without some more personal thanks. To Alex Durell, Neil Forrest, Nick Heath, Ross Howlett, Chris Matcham, Mark Richards, Martin Wallwork: thanks, chaps. Classificatorily fuzzy thanks must also go to Carl Pappenheim, not only for his help with causal graphs, but (much more importantly) everything else over the last two decades. Carl: if I thank you here, will you stop moaning about the wedding? Kelvin Meek should be remembered for helping with the more sophisticated historical aspects of this work, and for his friendship. To my parents, my brother and my grandparents: thank you for absolutely everything over what has been, at times, a troublesome university career. To Peter and Lindie Allen, thank you for all your support. Finally, this thesis is dedicated to my wife Rosemary and my son Thomas. As well as all the practical help with the preparation and production of the thesis itself, I could not have done any of this without you. Thank you. London, August 18, 2010 Abstract In this thesis, I give a metascientific account of causality in medicine. I begin with two historical cases of causal discovery. These are the discovery of the causation of Burkitt’s lymphoma by the Epstein-Barr virus, and of the various viral causes suggested for cervical cancer. These historical cases then support a philosophical discussion of causality in medicine. This begins with an introduction to the Russo- Williamson thesis (RWT), and discussion of a range of counter-arguments against it. Despite these, I argue that the RWT is historically workable, given a small number of modifications. I then expand Russo and Williamson’s account. I first develop their suggestion that causal relationships in medicine require some kind of evidence of mechanism. I begin with a number of accounts of mechanisms and produce a range of consensus features of them. I then develop this consensus position by reference to the two historical case studies with an eye to their operational competence. In particular, I suggest that it is mechanistic models and their representations which we are concerned with in medicine, rather than the mechanism as it exists in the world. I then employ these mechanistic models to give an account of the sorts of evidence used in for- mulating and evaluating causal claims. Again, I use the two human viral oncogenesis cases to give this account. I characterise and distinguish evidence of mechanism from evidence of difference-making, and relate this to mechanistic models. I then suggest the relationship between types of evidence presents us with a means of tackling the reference-class problem. This sets the scene for the final chapter. Here, I suggest the manner in which these two different classes of evidence become integrated is also reflected in the way that developing research programmes change as their associated causal claims develop. Contents Glossary and list of acronyms 12 1 Introduction 13 1.1 Non-human viral oncogenesis............................... 15 1.2 Medical schemes of causality................................ 17 1.3 A note on causal discovery................................. 20 2 Epstein-Barr Virus and Burkitt’s Lymphoma 25 2.1 Introduction......................................... 25 2.2 Suspicion: BL as a tumour syndrome............................ 28 2.3 Domain finding: BL as a geographical disease....................... 33 2.4 Making mechanisms: EBV................................. 42 2.5 Application: prospective epidemiology........................... 51 3 Cervical Cancer 53 3.1 Introduction......................................... 53 3.2 Suspicion: Cervical cancer as a venereal disease...................... 56 3.3 Domain finding: HSV and cervical cancer......................... 60 3.4 Making mechanisms I: HSV (1966-1983)......................... 61 3.5 Application I: HSV..................................... 63 3.6 Making mechanisms II: HPV (1983–)........................... 66 3.7 Application II: HPV..................................... 74 4 The Russo-Williamson Thesis 76 4.1 Introduction......................................... 76 4.2 The Russo-Williamson Thesis............................... 77 4.3 Philosophical counterarguments to the RWT........................ 86 4.4 The RWT as an empirical proposition........................... 92 4.5 Historical counterexamples to the RWT.......................... 95 5 Mechanisms 108 5.1 Introduction......................................... 108 Contents 7 5.2 Mechanistic theories of causality.............................. 109 5.3 Mechanisms in medicine.................................. 126 5.4 Levels and gaps....................................... 133 5.5 Functional definition.................................... 140 5.6 Branching and track-switching............................... 142 5.7 Two kinds of effects..................................... 143 5.8 Preventions and omissions................................. 146 5.9 A definition of mechanisms for the Russo-Williamson Thesis............... 150 6 Evidence for Causality 151 6.1 Introduction......................................... 151 6.2 Two types of types of evidence............................... 152 6.3 Evidence in the cases.................................... 154 6.4 Evidence of mechanism................................... 164 6.5 Evidence of difference-making............................... 170 6.6 Difference-making and the Reference Class Problem................... 174 7 Conclusion: The Russo-Willamson Thesis Redux 179 7.1 The Russo-Williamson Thesis redux............................ 179 7.2 Integration of evidence in practice............................. 181 7.3 Final conclusions...................................... 182 Bibliography 183 List of Figures 2.1 BL cases from the 1961 postal survey........................... 38 2.2 BL cases and climatic conditions.............................. 39 2.3 BL cases and tsetse distribution............................... 40 2.4 BL cases and malaria distribution.............................. 41 2.5 Route of the tumour safari................................. 41 3.1 HPV
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