Legal Facts and Reasons for Action: Between Deflationary and Robust Conceptions of Law’s Reason-Giving Capacity

This chapter considers whether legal requirements can constitute reasons for action independently of the merits of the requirement at hand. While jurisprudential opinion on this question is far from uniform, sceptical views are becoming increasingly dominant. Such views typically contend that, while the law can be indicative of pre-existing reasons, or can trigger pre-existing reasons into operation, it cannot constitute new reasons. This chapter offers support to a somewhat less sceptical position, according to which the fact that a legal requirement has been issued can be a reason for action, yet one that is underpinned by bedrock values which law is apt to serve. Notions discussed here include a value-based conception of reasons as facts ; a distinction between complete and incomplete reasons ; and David Enoch’s idea of triggering reason-giving. Following a discussion of criticism against the view adopted here, the chapter concludes by considering some more ‘robust’ conceptions of law’s reason-giving capacity

Reverse Engineering Legal Reasoning

This chapter describes a novel and valuable approach to the relationship between economic analysis and the law called “reverse engineering legal reasoning”. Social engineering conceives of the law as a means to social ends and of the economist as the technician studying to what extent laws are fit for purpose. Building on this idea, reverse engineering legal reasoning is a way to identify economic concepts that describe—are coherent with or fit—the content of legal reasoning. To do so, alternative economic hypotheses about the content of legal reasoning are formulated. On these grounds, the degree of coherence between economic concepts and legal reasoning can be made explicit. Reverse engineering legal reasoning extends the focus of positive economic analysis from the effects of the law to its content. It is useful for economists to suggest ways to increase the effectiveness of the legal system; to contribute to its functioning; as source of evidence to test economic assumptions; and to solve disagreements among economists, especially in relation to value choices

HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells

Polymorphisms in the human leukocyte antigen (HLA) class I genes can cause the rejection of pluripotent stem cell (PSC)-derived products in allogeneic recipients. Disruption of the Beta-2 Microglobulin (B2M) gene eliminates surface expression of all class I molecules, but leaves the cells vulnerable to lysis by natural killer (NK) cells. Here we show that this 'missing-self' response can be prevented by forced expression of minimally polymorphic HLA-E molecules. We use adeno-associated virus (AAV)-mediated gene editing to knock in HLA-E genes at the B2M locus in human PSCs in a manner that confers inducible, regulated, surface expression of HLA-E single-chain dimers (fused to B2M) or trimers (fused to B2M and a peptide antigen), without surface expression of HLA-A, B or C. These HLA-engineered PSCs and their differentiated derivatives are not recognized as allogeneic by CD8+ T cells, do not bind anti-HLA antibodies and are resistant to NK-mediated lysis. Our approach provides a potential source of universal donor cells for applications where the differentiated derivatives lack HLA class II expression