By Dr Zoe Bolton, published 15th November 2023

The 14-day rule, which limits the cultivation of human embryos in vitro for research purposes, has been enshrined in UK law for more than three decades. However, the Human Fertilisation and Embryology Authority (HFEA) has just announced proposals to change the law on the regulation of research involving human embryos, and a new report, published by the Human Developmental Biology Initiative (HDBI), suggests that there is also public support for extending the 14-day rule. This blog explores the origins of the 14-day rule in the UK and considers the arguments for and against extending the current limit.

Origins of the 14-day rule

In 1982, the Committee of Inquiry into Human Fertilisation and Embryology, more commonly known as the Warnock Committee, was established. This was in response to advances in in vitro fertilisation (IVF), which four years previously had led to the birth of the UK’s first ‘test tube baby’ Louise Brown. A key aspect of the Committee’s remit was to debate the conditions under which surplus human embryos, created during IVF procedures and which would otherwise have been destroyed, should be permitted for use in research.

As Giulia Cavaliere notes in an article in BMC Medical Ethics, The Warnock Committee had the difficult task of trying to find a policy solution that appeased both those who wanted an outright ban on embryo research for moral reasons, and those lobbying for the scientific contribution it could make to advancing IVF treatment and to understanding the development of the early human embryo. The compromise proposed by the Committee was a 14-day limit on the cultivation of embryos for research, which became law in the UK in 1990 as part of the Human Fertilisation and Embryology (HFE) Act.

The 14-day cut-off point was identified because it is around this time when the primitive streak emerges marking the start of gastrulation: a critical stage in human embryo development where the primary cell layers are formed and the process of developing organs and tissues begins. It is also the point at which the embryo is individuated and can no longer cleave into twins. The 14-day rule in UK law offers both a chronological and biological limit because it permits the use and storage of embryos up to 14 days or until the emergence of the primitive streak depending on which point is reached first. A variation of this rule has been adopted in many jurisdictions across the world and it has become the internationally accepted standard for ethical human embryo research.

When the Warnock Committee made its recommendation, it was only technically possible to sustain a human embryo in vitro for a few days and so the 14-day rule wasn’t prohibitive in terms of scientific development. In fact, it allowed for progress while, at the same time, reassuring those who opposed the use of human embryos for research that there would be a limit. In fact, Insoo Hyun et. al. argue in a comment piece for Nature that, ‘The 14-day rule was never intended to be a bright line denoting the onset of moral status in human embryos. Rather, it is a public policy tool designed to carve out a space for scientific enquiry and simultaneously show respect for the diverse views on human embryo research’.

Most scientists agree that the 14-day rule was an effective policy tool when it was introduced. However, there have since been significant advances in human embryo research that have led to calls for a revision to the rule. The most notable of these came in 2016 when two research groups in the UK and US reported sustaining human embryos in vitro for 12-13 days when previously this had only been feasible for seven days. These embryos could have been sustained in vitro for longer, but they had to be destroyed because of the current law. This breakthrough meant that, for the first time, it was technically, though not legally, possible to research embryos in a laboratory beyond the 14-day limit.

Arguments for extending the 14-day rule

Now that studying human embryos beyond 14-days is technically feasible, the scientific community has been making a case for the research benefits of extending the limit. One of the core arguments for changing the law centres around what is sometimes referred to as the ‘black box’ of human development. The black box denotes the period from day 14-28 of embryo development and it exists because of a gap in access to research materials: no human embryos can be used after day 14 and tissue derived from aborted or miscarried fetuses, which is permitted for use in research in the UK under specific conditions, is not available until after 28 days. Two key developmental stages occur between 14-28 days: gastrulation (see above) and neurulation, which marks the beginning of the process of forming the brain and spinal cord. Not enough is known about this crucial phase and it is significant because this is when many miscarriages and birth defects occur.

Statistics show that the probability of a pregnancy ending in miscarriage in the UK is 25% at four weeks; while the latest NHS data on birth defects in England show that one baby for every 45 births is diagnosed with a congenital anomaly. For those in favour of extending the 14-day rule to 28-days there is a compelling scientific rationale because doing so could lead to medical advances that have the potential to reduce the number of early miscarriages and enable the early identification, treatment or prevention of certain types of birth defects such as congenital cardiac anomalies and neural tube defects like spina bifida. There is also the possibility that early human embryo research might lead to further insights about genetic conditions, such as cystic fibrosis, Down syndrome, and certain cancers.

Understanding more about the black box of human development also has the potential to improve success rates for IVF. Data from the HFEA shows that, in 2021, average IVF birth rates were 33% for patients aged 18-34 and 4% for patients aged 43-50. As Hyun argues in an article in Nature, further research into the current black box of human development could improve understanding of ‘how to predict which early-stage in vitro fertilisation (IVF) embryos are most likely to produce successful pregnancy’. It could also achieve related benefits such as cost reduction, due to the need for fewer rounds of treatment.

Those who support extending the 14-day rule also point to the benefits it could have for other areas of scientific research. For example, research on the development of human embryonic stem cells has already advanced due to the 14-day rule and further progress might be possible in this field if there is access to human embryos for up to 28-days. In an opinion piece for EMBO Molecular Medicine, John Appleby and Annelien Bredenoord argue that increasing the limit to 28-days will also help with establishing the safety and efficacy of techniques for creating in vitro-derived gametes, for the use of CRISPR-cas9 genome editing to treat genetic diseases, and for testing and verifying organoid (miniature models of organ tissue) research findings.

Arguments against extending the 14-day rule

While there is a convincing scientific benefit case for extending the 14-day rule, human embryo research is a controversial topic and there is opposition to making changes to the regulation. In particular, there are concerns that increasing the limit is morally problematic.

There are diverse views on the moral status of the early human embryo and these are summarised in the Nuffield Council on Bioethics report Human Embryo Culture (pp. 17-20). It is clear from that report that the moral status of the embryo is a contested area. For some, the early embryo is just a collection of cells with little or no moral status; for others, particularly those with certain religious beliefs, life begins with fertilisation because it is at that point when there is the potential for a human being to be born even if it is never fully realised; and for others still it is the emergence of the primitive streak, the point at which the embryo becomes fully biologically individuated, that marks the moment when a potential human being exists. Whether or not we accept the argument that the 14-day rule was never meant to represent a moral red line, it has nonetheless come to be interpreted by some as a moral as well as legal cut-off point.

Also of concern to those who oppose extending the 14-day rule is the risk of pain and suffering for the embryo. As Appleby and Bredenoord note, ‘concerns relating to pain and suffering should be taken seriously’ but it is ‘impossible’ for embryos at 28-days to experience sentience, pain or suffering because ‘no functional neural connections exist in the embryo’. In fact, the ability for awareness and pain does not occur until after 40 days of development so, while the sentience, pain and suffering argument has been employed to advocate for retaining the current limit, it does not hold as a reason to oppose extending it to 28-days.

In addition to moral objections, there are those who argue that increasing the limit could be a ‘slippery slope’ opening up the possibilities of further extending the window for embryo research and paving the way for other controversial reproductive technologies, such as genome editing, to progress with less rigorous regulation. On the flip side, is the risk of a backlash which could, in the worst-case scenario, result in an outright ban on human embryo research. Both of these concerns were identified by participants in the HDBI study (pp. 43-44) as well as worries about ‘eugenic’ practices designed to eradicate certain conditions and disabilities from the population (p. 29).

Finally, there are considerations of whether alternatives to human embryo research should be explored further before making changes to the current regulation. One such possibility is using human stem cell based embryo models (SCBEMs). These models mimic the early stages of human embryo development but are not considered as embryos in the biological definition of the term because they are not currently able to develop into the equivalent of fetuses. However, as Nicholas Rivron et. al. note in an article in Cell, these models also raise ethical and regulatory questions which do need to be addressed.

Where do we go from here?

There are compelling research reasons for extending the 14-day rule to 28-days but doing so is likely to be met with fierce opposition from those who object to human embryo research and for whom the 14-day limit was already a step too far. While it is important to be respectful of the diverse views on embryo research, the current rule has been in place for over 30 years so it is time for a formal review and a debate about whether it is still fit for purpose.

In fact, the latest HFEA recommendations propose that, while any possible amendment to the HFE Act will need to contain a clear time limit for embryo research, a new mechanism should be introduced in law to allow for parliamentary consideration of issues, like the 14-day rule, outside of reopening the HFE Act. This is in-line with recommendations that have been made elsewhere. The International Society for Stem Cell Research (ISSCR) has already proposed guidelines to remove the 14 day limit and replace it with a rigorous scientific and ethical oversight process to establish whether the scientific objectives necessitate and justify the time in culture beyond 14 days; while the Health Council of the Netherlands has just recommended extending the 14-day rule to 28-days.

If the UK Government accepts the HFEA’s recommendations, there will need to be widespread public consultation and informed engagement, of the kind that the HDBI has already started, before any changes are made to the HFE Act.