The birth of Dolly the sheep in 1996 elicited a tsunami of commentaries, both in the popular media and academic journals, including responses to the prospect of human reproductive cloning. Much of the anxiety expressed over this imagined consequence of Dolly’s genesis revealed fundamental concerns about us losing our commitments to certain ethical goods, such as human dignity, or even ‘what it means to be human’. Over the last 25 years, the focus of much of the ethical debate over human biotechnology has slowly shifted towards other genetic technologies that aim to influence inheritance, such as mitochondrial replacement techniques (MRT) and heritable genome editing. Genome editing, in particular, is a technology with multiple fields of application, actual and potential, in research and innovation. This review suggests that many of the fundamental concerns about the possibility of human reproductive cloning that were precipitated by Dolly persist today in the arguments of those who oppose MRT and any use of heritable human genome editing (HHGE). Whilst it is not accepted here that an understanding of human nature and dignity alone can demonstrate the ethical unacceptability of such assisted reproductive technologies, there are themes of justice, which extend into our relationships with animals, that demand continued wide-ranging examination and public dialogue. While Dolly has cast a long shadow over such discussions, this review suggests that the general existential angst over human uses of biotechnology that she came to symbolise is neither compulsory nor a reliable guide for how to think about biotechnologies today.
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Nick Warr, Pam Siggers, Joel May, Nicolas Chalon, Madeleine Pope, Sara Wells, Marie-Christine Chaboissier, and Andy Greenfield
Sex determination in mammals is controlled by the dominance of either pro-testis (SRY-SOX9-FGF9) or pro-ovary (RSPO1-WNT4-FOXL2) genetic pathways during early gonad development in XY and XX embryos, respectively. We have previously shown that early, robust expression of mouse Sry is dependent on the nuclear protein GADD45g. In the absence of GADD45g, XY gonadal sex reversal occurs, associated with a major reduction of Sry levels at 11.5 dpc. Here, we probe the relationship between Gadd45g and Sry further, using gain- and loss-of-function genetics. First, we show that transgenic Gadd45g overexpression can elevate Sry expression levels at 11.5 dpc in the B6.YPOS model of sex reversal, resulting in phenotypic rescue. We then show that the zygosity of pro-ovarian Rspo1 is critical for the degree of gonadal sex reversal observed in both B6.YPOS and Gadd45g-deficient XY gonads, in contrast to that of Foxl2. Phenotypic rescue of sex reversal is observed in XY gonads lacking both Gadd45g and Rspo1, but this is not associated with rescue of Sry expression levels at 11.5 dpc. Instead, Sox9 levels are rescued by around 12.5 dpc. We conclude that Gadd45g is absolutely required for timely expression of Sry in XY gonads, independently of RSPO1-mediated WNT signalling, and discuss these data in light of our understanding of antagonistic interactions between the pro-testis and pro-ovary pathways.