Embryos, genes & regulation: the impact of scientific progress on future reproductive medicine and the HFEA

This year marks the 30^th anniversary of the HFEA and therefore represents an opportune moment to reflect on how the HFE Act sometimes struggles to cope with scientific progress and its implications for contemporary (and future) assisted reproduction. Here, I will consider how advances in scientific research in the years since the Act was formulated have led to regulatory challenges that the HFEA will face, with three key examples.

Regulating the germline: heritable human genome editing

It is widely accepted that genome editing is not sufficiently precise and controllable to permit its safe and effective use in an IVF clinic, even if such a thing were lawful in the UK. A recent high profile, international report¹ outlines how safety and efficacy might be established and identifies initial uses of heritable human genome editing, for prevention of heritable disease transmission, which might be justified if safety were established on the basis of pre-clinical data. The HFEA, which has licensed the use of genome editing in human research embryos and developed regulation for another germline intervention, mitochondrial donation, will surely play a central role in the wide-ranging (scientific and ethical) debate that will be required before deciding if any such uses have public support.

In vitro-derived gametes and stem cell-derived embryo-like structures: stametes and stembyos?

Decades of research have given scientists a reasonable understanding of how controlled changes in gene expression allow a single-cell zygote, following fertilisation, to give rise to distinct tissues during development. They can now intervene in these processes in order to direct the fate of cells towards a desired end. This research has led to the ability to derive functional gametes (eggs and sperm) from pluripotent stem cells, at least in mice. The potential implications for human reproduction are profound: a near limitless supply of functional gametes from skin cells, and all that would follow from that. Researchers have also exploited the potential of stem cells to derive embryo-like structures directly, without any fertilisation step². These blastoids, or, potentially, gastruloids are likely to be great tools for exploring cell fate control in human embryogenesis, and much more; but they are clearly not embryos and require no regulation by the HFEA. However, what if they were to become more similar to the genuine articles in the years to come?

The HFEA has developed an international reputation for being a trustworthy regulator partly because it takes seriously its responsibilities to patients, diverse stakeholders and the wider public.

The 14-day rule: there to be broken?

Bona fide human embryos can be cultured lawfully for no longer than 14 days (or until the first appearance of the primitive streak), due to a convention that is increasingly being contested. It is time, some have argued³, to consider permitting human research embryos to be cultured beyond 14 days, to shine a bright light on key developmental processes that have hitherto remained obscure, such as gastrulation and the appearance of primordial germ cells. The insight gained could prove important for future reproductive medicine. Culture techniques have developed to the point where this is feasible⁴. 14 days of human development does not mark a bright line in the moral significance attributed to the human embryo; rather, its significance is more practical, offering as it does clarity to the regulator and reminding us of the settlement, devised by the Warnock Committee, that has permitted regulated human embryo research in the UK to proceed unhindered for 30 years. The scientific case for culturing beyond 14 days in certain circumstances appears very strong; but revising the Act will require revisiting all the deliberations that delivered the original settlement, and the outcome of this cannot be guaranteed.

The HFEA has developed an international reputation for being a trustworthy regulator partly because it takes seriously its responsibilities to patients, diverse stakeholders and the wider public. As discussions take place about what a 21^st century HFE Act will look like, and the impacts on it of scientific progress, the HFEA will no doubt again play a central role in promoting debate, listening carefully and using its experience to generate a consensus on key elements.

 

Footnotes:

¹ National Academy of Medicine, National Academy of Sciences and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. https://doi.org/10.17226/25665

² Yu, L. et al. Blastocyst-like structures generated from human pluripotent stem cells. Nature 591, 620–626 (2021); Liu, X. et al. Modelling human blastocysts by reprogramming fibroblasts into iBlastoids. Nature 591, 627–632 (2021)

³ Hyun, I. et al. Human embryo research beyond the primitive streak. Science 371, 998-1000 (2021)

⁴ Shahbazi, M. et al. Self-organization of the human embryo in the absence of maternal tissues. Nat Cell Biol 18, 700–708 (2016); Deglincerti, A. et al. Self-organization of the in vitro attached human embryo. Nature 533, 251–254 (2016)

Andy Greenfield has been a programme leader at MRC Harwell since 1996. His central research focus is the genetics of sex (gonad) development and understanding human differences of sex development (DSD).

Andy has also made contributions to regulation and policy in reproductive medicine. He was a member of the HFEA from 2009-2018 and chaired its License Committee. In 2014 and 2016, he chaired two HFEA-commissioned expert panel assessments of the safety and efficacy of mitochondrial replacement techniques. He was a member of the Nuffield Council on Bioethics (NCoB) from 2014-2020 and chaired its 2016 working group that examined ethical issues associated with genome editing applications in a variety of contexts. He was also a member of the international commission, convened by the National Academies of Sciences and the UK Royal Society, that in 2020 made recommendations on prospective uses of heritable human genome editing. He is currently a member of the UK Regulatory Horizons Council.

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