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The time has come to extend the 14-day limit
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  1. Sophia McCully
  1. Department of Global Health and Social Medicine, King's College London, London, UK
  1. Correspondence to Sophia McCully, Department of Global Health and Social Medicine, King's College London, London WC2R 2LS, UK; sophia.mccully{at}kcl.ac.uk

Abstract

For the past 40 years, the 14-day rule has governed and, by defining a clear boundary, enabled embryo research and the clinical benefits derived from this. It has been both a piece of legislation and a rule of good practice globally. However, methods now allow embryos to be cultured for more than 14 days, something difficult to imagine when the rule was established, and knowledge gained in the intervening years provides robust scientific rationale for why it is now essential to conduct research on later stage human embryos. In this paper, I argue that the current limit for embryo research in vitro should be extended to 28 days to permit research that will illuminate our beginnings as well as provide new therapeutic possibilities to reduce miscarriage and developmental abnormalities. It will also permit validation of potentially useful alternatives. Through consideration of current ethical arguments, I also conclude that there are no coherent or persuasive reasons to deny researchers, and through them humanity, the knowledge and the innovation that this will generate.

  • embryos and fetuses
  • ethics
  • in vitro fertilisation and embryo transfer
  • reproductive medicine
  • policy guidelines/inst. review boards/review cttes

Data availability statement

There are no data in this work.

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Introduction

For the past 40 years, the 14-day rule has both governed and enabled embryo research and therapeutic innovation globally. It has been a piece of legislation and a rule of good practice, defining a clear boundary in which valuable research has been able to proceed against some considerable opposition. Up until now, the 14-day rule has worked and been an effective tool, influencing many jurisdictions.1 For reasons which this paper will set out to illustrate, we can now be confident it is safe to make a policy change and extend the 14-day rule without fear of any moral and regulatory slippery slope, a concern which need not apply to the 14-day rule (as argued by Sarah Chan2 ,i). Many studies suggest that important events taking place during early embryogenesis, prior to 14 days, are likely to have an impact on later development. But without the ability to go further, their real significance will be hard to ascertain. Moreover, the embryo itself, as opposed to the supporting extraembryonic tissues, only starts to develop after 14 days, and how are we to learn about our beginnings if we cannot study them?

I argue that the current limit for embryo research in vitro should be extended to 28 days because there is much research with promising therapeutic applications that would benefit from the ability to explore embryos 15 days and beyond3–7 and no coherent or persuasive reasons to deny researchers, and through them humanity, the knowledge and the innovation that this will generate.

What is the 14-day rule?

Enforced in the UK by the Human Fertilisation and Embryology Authority,8 the ‘14-day rule’ which limits research on intact human embryos ‘prior to 14 days gestation or the beginning of primitive streak formation’ is part of the Human Fertilisation and Embryology Act 1990 (as amended in 2008),9 but was established by the Warnock Committee10 led by Baroness Mary Warnock in 1984. The ‘14-day’ element to the Act was suggested by the renowned developmental biologist Anne McLaren,11 as it is only after this that the central nervous system (CNS) of the developing human begins to develop. This legislation has been successfully implemented in the UK, but also in several other jurisdictions (eg, Australia’s Research Involving Human Embryos Act 200212), and it is followed even in countries without relevant laws or even guidelines 13. Nevertheless, opponents of the rule argue that this was simply an arbitrary time limit that was chosen as a compromise to permit any research at a time when prolife views were strong.

Why extend the 14-day rule?

‘Robert Edwards famously suggested ‘that most of the secrets of the development of life are contained in early embryos, and that we are extremely likely to be able to use what we learn from such embryos to save many lives and ameliorate many conditions which make life miserable’. (This exchange between Robert Edwards and John Harris was reported to me by John Harris in a personal communication.) John Harris concludes: ‘we would not only be crazy but wicked to cut ourselves off from these benefits unless there are the most compelling of moral reasons to do so. I have argued that there are no such compelling reasons.14

Debate on the rule was reopened by the publication of two articles in Nature and Nature Cell Biology in 2016 that demonstrated the ability to culture human embryos up to—and likely beyond—14 days.4 5 Now, more research has further proven this capacity.15 Many researchers have argued3 6 that an extension could lead to greater understanding of normal human development during and just following gastrulation, about which we know little, and of congenital defects that may arise during this period, as well as to potentially improve in vitro fertilisation (IVF) and reduce rates of miscarriage.16 It would also allow better testing of the safety of new techniques, such as mitochondrial replacement therapy (MRT). At the time, the 14-day rule was adopted, it was not possible to get close to culturing embryos for this long. Therefore, the many advances that have been made since the initial compromise was adopted over the 14-day rule now make this threshold less reasonable from a scientific and technological standpoint, and potentially disastrous in terms of research and innovation forgone which promises both to save and prolong lives and also to offer health and scientific rewards.

We can take the development of the heart as an example of the knowledge we are missing. The heart is the first organ to develop, beginning from around 16 days and forming a functional beating structure, although one that is still immature, by day 28.17 Congenital heart disease (CHD) is a problem caused by abnormal formation of the heart that occurs while the fetus is still developing. In the UK, CHD is one of the most common birth defects, affecting around 8 in 1000 babies.18 There are some factors that increase the risk of CHD, such as Down’s syndrome, maternal diabetes (this does not include gestational diabetes) and some drugs.19 Current research in mice is paving the way for understanding heart formation20 and aspects of CHD, and its possible causes,21 but as discussed below, there are differences between human embryos and those of other species.

But due to the 14-day rule, we are not currently able to investigate this crucial period in human embryos from ‘Carnegie stage 9’22 to find answers and possible ways to prevent potentially life-threatening defects like CHD.

Other common birth defects include improper formation of the neural tube. The neural tube is formed between day 18 and day 30 of pregnancy in a process where the early developing CNS, which begins as a flat plate-like structure, folds up and joins along its dorsal (back) aspect.23 This is not to suggest that the primitive streak is the nervous system. It is to highlight that the CNS does begin to develop early in gastrulation from cells that were epiblast as these are induced to form neural ectoderm. That this occurs very early in gastrulation is evident (in the mouse) from looking at the expression of genes that define the CNS.24 Neural tube defects are those where this process malfunctions, leaving an opening in the spinal cord or brain. This will lead to problems such as spina bifida or severe brain abnormalities.25 Many are aware that it is now recommended that those who are attempting to conceive and those who are pregnant should supplement their diet with folic acid to prevent spina bifida, with guidance recommending this at least for the first 12 weeks.26 In the event that spina bifida does occur, there is now the possibility of in utero surgery to correct the defect. While this is an impressive method and has corrected a number of cases,27 it is still dangerous and risky. As such, having the ability to examine further reasons for neural tube defects through embryo research could avoid the need for these surgeries or suffering of individuals born with neural tube disorders.

A miscarriage is the loss of a pregnancy at some point during the first 23 weeks, with the majority occurring in the first 12 weeks, and many women not knowing they were pregnant to begin with. It is estimated that 25% of pregnancies end in miscarriage.28

There has been some progress in assessing women who experience recurrent miscarriage,29 but it is difficult to determine information from their unsuccessful early embryos because it may not be known they were pregnant at an early stage. For the most part, it is possible to have the cause of miscarriage researched only if a woman has experienced miscarriage at least three times in a row.29 This means there are many who have had one or two miscarriages, where no examination is undertaken.

In 2017, the priority setting partnership charity, the James Lind Alliance, and associated charities and organisations, identified 10 questions for miscarriage research.30 Two of the questions determined: ‘what investigations are of true clinical value? (eg, ultrasound, gene sequencing, natural killer cells)’ and ‘to what extent do genetic and chromosomal abnormalities in the fetus cause miscarriage?’ These questions highlight the community’s desire to understand the basis for miscarriage, which, if the 14-day rule is extended, could potentially begin to be answered.

One could loosely define reproductive freedom as individuals having choice and autonomy on issues related to reproduction. As one of the seminal voices on the subject of reproductive freedom, and a notable player in the bioethics field,31 John Robertson’s work1 is a legitimate basis to help frame this paper’s understanding of reproductive freedom. If one is to examine Robertson’s essay on procreative liberty,32 it is clear to see that there are more important and potentially harmful issues2 that may infringe on procreative liberty and reproductive freedom than that of the research use of surplus IVF embryos that were, most likely, never to be implanted in utero; or indeed embryos specifically created for research which were never intended for implantation. However, those other issues are beyond the scope of this paper.

Nevertheless, Robertson highlights just how crucial the collaborative role of the patient and the physician, and in this instance, the researcher is.3 As such, it is critical to research the embryo because, as highlighted recently through early embryo work, we are beginning to develop different methods33 that could contribute to more robust embryo development in culture, and perhaps better IVF outcomes, including reduced rates of miscarriage. This relates to a recent exploration of relational autonomy,34 which is important to consider when discussing the role of the physician and/or the researcher. With regard to the already defined understanding of reproductive freedom, this physician/researcher role could be interpreted as one where they have the obligation to give—or help inform—prospective parents all the options, and, where needed, and based on a health and care ethos, assist in the decision-making processes. The nuances of relational autonomy are well beyond the scope of this essay, but could contribute to this debate and deserve further exploration elsewhere.

While extending the rule may not answer all questions there are about disease, infertility and miscarriage, it will certainly add to the literature and open the ‘black box’ of human development, generally thought of as being up to 28 days, after which it is possible to obtain aborted embryos and use these for research.3

Those who disagree with extending the 14-day limit may argue that we are currently able to use models in place of human embryos, but there are issues with these.35 Any model is only of use if it has been validated against the real thing. For example, current research using embryonic stem (ES) cell models of early gastrulation is incredibly promising, but without breaching the 14-day rule how will we know if any answers reflect reality?

Why extend rather than remove (the limit)?

There is still a lot we don’t know about fertilisation in humans—should we restrict research to the first 24 hours? Of course not, partly because we then learn nothing about the next stages, which are themselves essential for normal embryo development, but also because we will never know whether embryos generated in the first 2 hours are normal or not; whether any problems are intrinsic to the embryos, or due to the way they have been handled in culture. And yes, many would argue that much more happens during the period of 14–28 days36 37 than that between 7 and 14 days, and that this is of great relevance to subsequent development and to what happens when things go wrong; whether this is due to intrinsic (genetic) factors or to extrinsic factors (including the effect of nutrition, toxic substances, infectious diseases, and so on). Development of the embryo is a continuum—surely research needs to understand all aspects of this continuum. The part we cannot currently explore properly is precisely this period of 14–28 days (we can culture embryos up to 14 days and we can access aborted material from 28 days onwards).

Why experiment on embryos at all?

When examining the ‘rule’, one should initially explore the reasons why there are, and should be, experiments on human embryos at all. Many argue that animal models are a sufficient replacement for the use of human embryos. Although IVF and embryo transfer was first established in animals, mainly mice, it was not possible to simply apply the same methods to humans; they had to be adapted, which required research on human eggs and sperm and early embryos. Increasing the efficiency of IVF has also necessitated much research using human embryos. For basic understanding, much work is carried out on animal embryos, which may appear similar to human embryos before implantation. However, the morphology diverges after this, and underlying mechanisms even prior to implantation are now known to be distinct.38

Indeed, recent research suggests that even the morphology of the mammalian blastocyst differs substantially among species.35 As such, while animal models are useful to an extent, after all some mechanisms are similar, this diversity shows there is really no substitute for a human embryo to understand human embryogenesis.

Being closest to humans in evolutionary terms, non-human primates (NHPs) have been suggested as an alternative model, and embryos from macaques have been cultured up to 20 days.39 However, while very worthwhile, we do not know how closely they resemble human embryo biology and cannot answer this question without doing the comparison. Moreover, unlike couples who donate their surplus IVF embryos to research, NHPs are not able to give informed consent. The gratuitous use of NHPs for embryo culture experiments would be wasteful, especially given the large numbers of surplus human embryos that could be used. Perhaps the use of NHP embryos should be restricted to testing new methods that require implantation and subsequent development. Otherwise, they are not an appropriate substitute. This is not to say all research using NHPs as models should be done away with, but surely it is legitimate to argue that when we do use NHPs, we want to be sure they are appropriate models.40 If the limit were to be extended, a comparison between human embryos and those of NHPs could ensure this.

New models of human embryo development rely on the properties of clumps or colonies of human pluripotent stem cells (ES cells or induced pluripotent stem (iPS) cells) to self-organise, together with inducing molecules, into structures that resemble early postimplantation embryos (eg, see Rosado-Olivieri and Brivanlou).41 These can undergo quite extensive and complex development in vitro, but it is very unlikely that they could develop normally if implanted; they currently lack well-organised extraembryonic tissues required for this. Indeed, they should not be implanted, simply on the grounds of safety, let alone ethical issues. It does, however, seem very likely that they will provide useful models for aspects of human development including gastrulation and perhaps even later events. However, again, it would be difficult to prove that they represent normal human development and be valid models, without comparisons with normal human embryos maintained in culture.

Increasingly, for some things, there is no option but to use human embryos for research.38

Fetal tissue research as a comparator

Notwithstanding the importance of the scientific basis for human embryo research, there are ethical and philosophical reasons why this rule is now ready for amendment.

In the UK, in line with the Abortion Act 1967,42 an abortion is legally permitted up to the 24th week of pregnancy. Conventionally, a human embryo is termed a fetus from 9 weeks after fertilisation. It is legal to abort an embryo or fetus substantially ‘older’ than 14 days, and, with appropriate consent, to do research on its tissues, yet it is illegal to experiment on an embryo beyond 14 days that was never to be implanted. With the introduction of tests in the UK, such as non-invasive prenatal screening43 (National Health Service 2020), for three of the most severe chromosomal disorders, there is an increase in selective abortion.44 Surely, if we are able to discover reasons why an embryo might have abnormalities through experiments on intact embryos maintained beyond 14 days, and then use new technologies such as genome editing38 to avoid or correct the problem (bearing in mind the demonstration that these technologies will be both safe and effective may also require tests during the ‘black box’ period), we may be able to reduce the frequency of selective abortion and thus reduce embryo and fetal wastage. Of course, if expectant parents underwent the non-invasive prenatal test (NIPT), a simple test examining fetal DNA in maternal blood, and found the fetus had a chromosomal abnormality, there is no question that it is their choice as to whether they opt for abortion or choose to continue with the pregnancy. The point is there may be ways—in this ‘black box’ period—to ensure a greater proportion of normal embryos as opposed to those with chromosomal abnormalities.

In order for pregnant couples (or singletons using assisted reproductive technology) to achieve appropriate reproductive freedom,45 46 they should have the opportunity and ability to produce, at the very least, a healthy child. While there are many issues that can occur during pregnancy, and birth, with the potential to find reasons why miscarriages occur or why embryos have disease, it seems an infringement on reproductive freedom not to ensure that a healthy baby is the priority.

Location of the embryo

In the Nuffield Council on Bioethics report on human embryo culture,47 Elsejin Kingma considers the idea that the ‘location of an embryo—whether it is in a pregnant woman or in a petri-dish—may affect its moral status and/or value’. She argues that it is not just the stage of the embryo that is relevant to its moral status or value, but whether it is, or will be, in an environment that promotes its further development. She concludes that this means there is (further) good reason for a moral distinction between ‘research’ embryos and ‘reproductive implanted embryos’.47 If they are not used for research, it is not as though they are going to be reimplanted and suddenly become viable ‘potential’ humans. There is no suggestion of the types of research highlighted in this paper, and any other non-clinical experimentation, taking place in utero. Of course, there are some clinical applications going ahead, such as surgery to correct spina bifida referred to earlier which should still be considered research at this stage. However, that is not the same as research on surplus embryos in vitro. The embryos that would be in question are those whose location is, and will remain, in a Petri dish. Therefore, while Kingma is not stating that embryos have no moral status, her arguments give weight to an extension of the 14-day rule.

Role of the public and regulator(s)

Finally, it is of the utmost importance to note, and something that is consistently forgotten by many opponents of embryo research in general, but also challengers of 14-day rule extension, that it is not currently possible in the UK, and many other jurisdictions,48 to do research on human embryos unless you are granted a licence by the appropriate regulatory authority, in the UK the Human Fertilisation and Embryology Authority (HFEA).49 This would be the same if there was an extension to the 14-day statutory limit—which would de facto extend the period over which the HFEA has jurisdiction.

Chan argues, policies and laws are not rigidly stuck fast forever more, never to be revisited, they are meant to be open to alteration.2 Therefore, in terms of fears about a ‘slippery slope’, this very stringent regulation ensures that it would in fact be illegal to enter down one. Openness as well as robust regulation and oversight are the guardians against malpractice and unfettered sliding into any unethical crevasse. This could happen within the 14-day limit as much as beyond it. The 14-day limit may have engendered considerable trust, but this is mostly because bad things have not happened. We just have to make it likely that the same will be true if the limit is extended.

Conclusion

As with any fundamental change that will have a (positive) effect on humanity, it will be important to consider different opinions and consult all parties,50 be that the general public, the religious sector, affected individuals (eg, infertility patients). A consultation of this nature would need to be based on deliberative democracy, where groups of the public are given information in as unbiased a manner as possible and then they can provide their views. This has been done for both MRT51 and genome editing.52

The 14-day rule has become limiting and just because something has once worked does not mean it should stay the same or not strive to improve. As is clear to see, there are a multiplicity of reasons why embryo research beyond 14 days can help us realise the metamorphic potential of healthcare. From this analysis, and that of others,2 there are no substantive ethical reasons for not altering the limit.

Embryo research is a crucial undertaking and will help us to make many transformational discoveries, thus extending this very arbitrary limit is an endeavour that must be achieved.

Data availability statement

There are no data in this work.

Ethics statements

Patient consent for publication

Acknowledgments

The author is very grateful to Professor John Harris for many useful discussions, and the scientists who gave her their time, extensive knowledge and thoughts on the subject matter. The author would also like to thank the reviewers for their useful and thought-provoking comments.

References

Footnotes

  • Twitter @sophiamccully

  • Contributors SM is the sole author of this article.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • The rule can be revised without falling foul of accusations of moral slippery slope-ism: since it was not a moral threshold in the first place.2

  • A characteristic of reproductive freedom is that its limits arise largely at the bearing, birthing and rearing stages rather than at the conceiving stage of reproductive choice.32

  • Scientific advances may also help them plan a healthy child and fit it into their lives with fewer of the burdens that planned parenthood now entails.32

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