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African Swine Fever (ASF) disease is caused by infection of susceptible Suidae with African Swine Fever Virus (ASFV). In Eurasian domestic pigs, and closely related wild boar, ASF is characterised by a haemorrhagic fever and a high mortality rate of 95-100%. There are currently no effective treatments for ASF, and as such, ASF is a major threat to pig production worldwide. An outbreak of ASF across Eurasia lead to an estimated global loss of around ¼ of all domestic pigs between 2018 and 2019. By contrast, although native African pig species such as the warthog, red river hog (RRH) and bush pigs are infected by ASFV, they carry a lower viral load and do not show clinical signs of infection. The current gold standard model for the study of ASFV in vitro are primary macrophages harvested from domestic pigs. Primary macrophages have limited proliferative potential in vitro and their use requires a constant supply from sacrificed animals. This is at odds with the 3Rs principal to reduce animal use in research. Moreover, primary macrophages are not readily amenable to genetic modification, making it difficult to interrogate gene function in this cell culture model. There is limited access to primary macrophages from wild suid species, leaving the genetic variation responsible for ASFV tolerance in wild African species largely unexplored. This project aims to produce better in vitro models to study ASFV using induced pluripotent stem cells (iPSCs). IPSCs can be expanded indefinitely in culture and can differentiate into any cell type of the three germ layers. This provides a genetically stable platform for in vitro gene editing and allows for the functional analysis of the genetic variation seen in wild Suidae, including ASFV tolerant RRHs and ASFV susceptible wild boar. This project has used tetracycline regulatable reprogramming factors to produce iPSCs from the domestic pig, RRH, and wild boar. The iPSCs were dependant on exogenous reprograming factor expression for maintenance of the undifferentiated state, but were shown to self-renew and produce derivatives of all three germ layers, including macrophages, after directed differentiation in vitro. Moreover, they were amenable to genetic modification using CRISPR/Cas9 as shown through the generation of REX1-GFP stem cell reporter lines. IPSC-derived macrophages (iPSCdM) exhibited molecular signatures of macrophage identity as determined by RT-qPCR, surface marker expression and RNA-Seq. In addition, they were able to phagocytose foreign particles and could be infected by macrophage specific pathogens including porcine reproductive and respiratory syndrome virus (PRRSV). Domestic pig iPSCdMs supported replication of ASFV to the same level as pig embryonic stem cell derived macrophages and pig ex vivo derived macrophages, making them an appropriate model for the study of ASFV in vitro. Comparison of ASFV infection between domestic pig and RRH iPSCdMs matched the in vivo infection kinetics, with lower levels of viral replication in the ASFV tolerant RRH. RNA-Seq analysis, and confirmatory RT-qPCR, indicated that infection and immunity related genes, including the pattern recognition receptors TLR2, TLR4 and inflammasome regulator CASP1, were downregulated in RRH macrophages. Corresponding differences were also noted in the iPSCdMs in response to immune stimulation. As a proof of principle, TLR2 knock-out domestic pig iPSCs were generated as a model to study the role of this pattern recognition receptor during ASFV infection in future experiments. Taken together, the results in this thesis show that iPSCdMs provide a useful new model for the study of ASFV tolerance in vitro. This also shows the potential of iPSC technology to effectively capture and interrogate biologically interesting and important genetic variation of wild animal species.

This thesis is fundamentally concerned with revealing the complex and nuanced interrelationship between collective and individual interests in health research, and the implications of this for optimising contemporary health research regulation (HRR). This task of optimisation can be characterised as a persistent preoccupation in the heath research arena, in that consideration of these interests can be located both in foundational international instruments that have shaped the course of modern health research regulation, as well as in contemporary instruments and guidelines. Nonetheless, the nature of human health research has been transformed since the post-World War II era, which has impacted both on how health research is conducted, as well as debates about what the regulation of this endeavour ought to look like. In this way, contemporary health research constantly challenges traditional regulatory structures that are underpinned by an increasingly outdated approach to individual and collective interests that are at stake. The regulatory system struggles to keep pace and this is particularly evident in relation to data-intensive health research. This thesis tackles these tensions head on. I propose that a new approach to HRR is required that is capable of engaging with the multiplicity of ways in which decisions about the conduct of health research might impact on our lives. More particularly, I argue that there is something about the quality of human health research that is focused on realising and promoting collective interests that builds on, but also goes beyond, the protection of individuals who contribute to that research, and that this must be reflected in the way that it is regulated. The solution I offer is the concept of 'publicness', as introduced and explored in this thesis. More specifically, publicness reflects the interrelationship between collective and individual interests, thereby drawing attention to the context in which this interplay takes place, as well as the implications of this relationship for HRR, both now and in the future. I identify three interlinked and overlapping facets of publicness: relationality, temporality and accountability. The analysis in this thesis deploys the tripartite framework provided by publicness in order to scrutinise several aspects of HRR. This serves to (i) reveal new insights in relation to existing concepts in HRR, namely the public interest, social value and social licence; (ii) identify how HRR can better account for the full range of interests in play throughout the research and data lifecycle, with a focus on temporal aspects of the research endeavour and the mutability and diversity of and within publics in HRR; and (iii) offer a reconceptualisation of the public interest that is better equipped to meet the realities and challenges of the contemporary health research environment. A case study, in relation to a high-profile and disputed transfer of identifiable NHS patient data from The Royal Free NHS Foundation Trust to Google DeepMind, reintegrates the preceding analysis to the contemporary data use landscape. This illustrates how publicness helps to optimise HRR by both elucidating 'lessons learned', and through the identification of positive steps that can support future data-sharing initiatives to better account for publicness. In these various ways the diagnostic and normative value of publicness helps to provide a new understanding of what is at stake in health research and its regulation, and to provide a basis to move beyond what already exists in the sub-optimal HRR ecosystem.

NHS research ethics committees (RECs) serve as the gatekeepers of health research involving human participants. They have the power to decide, through a regulatory 'event licensing' system, whether or not any given proposed research study is ethical and therefore appropriate to undertake. RECs have several regulatory functions. Their primary function has been to protect the interests of research participants and minimise risk of harm to them. Yet RECs, and other actors connected to them, also provide stewardship for the promotion of ethical and socially valuable research. While this latter function traditionally has been seen as secondary, the 'function hierarchy' is increasingly blurred in regulation. Regulatory bodies charged with managing RECs now emphasise that the functions of RECs are to both protect the interests of research participants, and also promote ethical research that is of potential benefit to participants, science, and society. Though the UK has held in some of its previous regulations (broadly defined) that RECs equally function to facilitate (ethical) health research, I argue that the 'research promotionist' ideology has moved 'up the ladder' in the regulation of RECs and in the regulation of health research, all the way to implementation in law, specifically in the Care Act 2014, and in the regulatory bodies charged with overseeing health research, namely the Health Research Authority. This thesis therefore asks: what impact does this ostensibly twinned regulatory objective then have on the substantive and procedural workings of RECs? I invoke a novel 'anthropology of regulation' as an original methodological contribution, which enables me to study empirically the nature of regulation and the experiences of actors within a regulatory space (or spaces), and the ways in which they themselves are affected by regulation. Anthropology of regulation structures my overall empirical inquiry to query how RECs, with a classic primary mandate to protect research participants, now interact with regulatory bodies charged with promoting health research and reducing perceived regulatory barriers. I further query what this changing environment might do to the bond of research and ethics as seen through REC processes of ethical deliberation and decision-making, by invoking the original concept of 'regulatory stewardship'. I argue that regulatory stewardship is a critical, but hitherto invisible, component of health research regulation, and requires fuller recognition and better integration into the effective functioning of regulatory oversight of research involving human participants.