In vitro gametogenesis: The case for an anticipatory approach

The Human Fertilisation and Embryology (HFE) Act is more than 35 years old, and – as many have noted – it is showing its age. One concern is whether it can accommodate emerging technologies in assisted reproduction.

I recently worked on a report entitled Modernising Regulatory Pathways for Assisted Reproductive Technologies: A Case Study on IVG, published by the UK's Regulatory Horizons Council (RHC). The report uses in vitro gametogenesis (IVG) as a lens through which to consider whether the UK has a framework capable of assessing new technologies lawfully, safely and credibly as they emerge. Here, I offer a personal reflection on the rationale for the report and its themes.

One useful way to begin is by considering mitochondrial donation, an assisted reproductive technology (ART) that aims to reduce the risk of transmitting mitochondrial diseases from mother to offspring (see BioNews 1298 and 1334). This was a genuine innovation in the clinic, requiring years of painstaking research and supporting legislation. I do not wish to downplay the fiendishly complex science involved, but mitochondrial donation is, in some ways, conceptually simple – it moves parental DNA from an affected egg or embryo to an unaffected, stage-matched egg or embryo.

Now consider IVG, an emerging technology still very much in the research phase. IVG first aims to convert an ordinary cell from the body, such as one found in blood, into a pluripotent stem cell. Then, using methods of cell culture that may require generating a version (an organoid) of the testis or ovary in a dish to support onward development, these cells are directed over time to become functional gametes. In short, sperm or eggs might ultimately be obtained from blood cells.

IVG is already a reality in mice (albeit with low efficiency), but experts estimate around five to ten years before it could be feasible in humans. IVG could revolutionise assisted reproduction, but it also raises profound safety concerns alongside complex ethical and social issues.

The RHC report assesses the UK's preparedness for emerging ARTs such as IVG, where uncertainties abound. It first sets the scene by reviewing the UK fertility sector and its regulation, progress in IVG research, and the international context.

The central question that the report grapples with is how our existing regulatory framework, and broader governance ecosystem, would cope with rapid progress in disruptive new technologies like IVG. How would the safety of IVG be assessed, prior to any clinical use? How would clinical use be trialled initially? How would stakeholder and public opinions, and associated ethical imperatives and 'red lines', be legitimately incorporated into a governance framework?

The HFE Act currently prohibits the use of IVG in the fertility clinic. But if IVG can be made safe, there are people to whom it could matter enormously – including those who cannot produce viable gametes – and demand will surely follow. So what should happen if progress in IVG research is rapid? Rather than making recommendations, the report discusses various options along two dimensions of action – when to act, and what to do.

With regard to the first dimension (when to act), the report makes a compelling case (in my opinion) for preparing now, well in advance of IVG becoming feasible. Acting now includes galvanising a number of organisations to work in a joined-up fashion and begin a process of review and reform. By acting now, there will be time to ensure that the ethical issues raised by IVG are considered well before any clinical use.

However, the report does not assume that IVG will ever be used clinically. Being prepared is not deterministic in this way. The risks associated with reproductive uses of IVG will need to be carefully assessed through preclinical research, using IVG to create human embryos, and this also requires time.

The second dimension (what to do) concerns the design of a future regulatory framework, for emerging ARTs such as IVG. While there may be other legislative mechanisms to support reform, including the Regulating for Growth Bill (see BioNews 1339 and 1341), it is likely that an amended HFE Act will be central to securing legitimacy here. The RHC report outlines a number of options, and I think is most compelling when it discusses a technology-neutral approach to legislation, capturing a number of future technologies (not just IVG).

For example, a future HFE Act could focus more on acceptable outcomes, with technical/methodological details kept to a minimum to support futureproofing. The point is for the UK to be ready to respond to new technologies, rather than playing catch-up on each occasion, which risks reactive and disjointed legislation. Staged approaches to any clinical use would be central in this vision, and safety considerations would be crucial.

The RHC report also outlines the risks of doing nothing. The absence of clear legal routes to clinical use of novel ARTs may inhibit research and lead to loss of inward investment, loss of talent overseas, medical tourism, and – if clinical use proceeds elsewhere – loss of international influence on the design of governance frameworks.

The wider stem cell science context permeates the RHC report, because IVG does not sit in isolation. The report does not aim to resolve the governance of stem cell-based embryo models (SCBEMs), nor does it make the case for revisiting the 14-day limit on human embryo culture. But these topics are neighbours to IVG, not strangers.

For example, the status of IVG-derived embryos will be contested, and some may argue (although the RHC report does not) that such IVG-derived embryos belong with SCBEMs for regulatory purposes. Furthermore, the time limit on embryo culture impacts how thorough any preclinical safety assessments of IVG and other ARTs can be. As the report notes, opening the HFE Act to address the regulation of ARTs is an opportunity to address adjacent research topics.

There are other pressing reasons to reconsider regulation of in vitro technologies. One is progress in the area of fertility preservation, which aims to isolate immature gametes found in prepubertal gonads and mature them in a laboratory setting – a protocol that might take weeks, or months, of culture. These technologies, and other interventions in gametes that raise safety considerations, require both legal clarity and associated regulatory pathways to responsible clinical use.

The importance of public engagement and ethical scrutiny is stressed throughout the RHC report, drawing on the wider ecosystem of research and clinical governance in the UK. Some IVG use cases that have been discussed are contentious, and require careful management to secure trust. The opinions of key stakeholders – including prospective beneficiaries of the technology, and also those who could be disadvantaged – will be vital.

The report feels like a timely publication. Debate about the future of fertility regulation is live across Parliament and the wider policy community. I hope that the report earns its place in that conversation, not by telling anyone what must happen, but by making the case for review and for an anticipatory approach to technologies like IVG... before the science forces our hand.