The ethical importance of research

We conduct research to systematically examine and gain insight into the complexities of life and the world around us, and use this knowledge to improve the human condition. Research for such purposes that is conducted in accordance with international standards is therefore an ethically good enterprise.1 Given our ability to systematically examine aspects of human existence that deeply impact our lives, research aimed at promoting human health and well-being is a moral imperative. This imperative also applies to research that has the potential to improve fertility and reproductive health. If we accept that procreation is a moral good, then society has an obligation to support scientific research that is broadly aimed at improving fertility.

This obligation arises from two considerations: first, improving fertility for those segments of the population requiring scientific interventions to procreate enables such individuals to pursue a life that is meaningful to them while at the same time not infringing on others’ fundamental interests2 and second, such scientific research addresses issues relating to the right to fair and reasonable access to healthcare. If we are to consider the instrumental value of procreation, the motivation becomes stronger in countries where major demographic shifts are contributing to ageing populations with decreasing fertility rates that have fallen well below replacement levels.3 4 For example, total fertility rates in 2018 for the USA were 1.7, 1.7 for the UK, 1.4 for Japan and only 1.1 for the Southeast Asian city-state of Singapore.5 With an estimated replacement fertility rate of 2.1,6–8 countries such as these must rely on immigration policies to maintain their current population levels.

We acknowledge that the effects of unchecked population growth in combination with ever-increasing consumption rates impact on environmental degradation and the critical preservation of limited resources.9 However, we do not view the solution to population growth control as being achieved by depriving only some persons from procreating, simply because they face fertility issues. Rather, there are global collective moral obligations that need to be considered in reducing consumption and human impacts on environmental health and climate change, if we are to discuss this complex and confronting problem with issues of justice in mind. In this paper, we are not able to further elaborate on this important aspect of the argument.

While both men and women are living longer in these countries, they are also deciding to have children later, which affects the health and quality of their reproductive tissues.3 10 11 Maternal age is one of the strongest predictors of oocyte quality.12 Therefore, the quality and quantity of ovarian follicles are vital for a woman’s reproductive lifespan. A condition known as premature ovarian insufficiency (POI), where the loss of normal ovarian function is due to the loss of ovarian follicles (ie, loss of quantity) before the age of 40 years, affects approximately 1% of women under 40 years old and 0.1% of women under 30 years of age.13 Hence, this exemplifies that quantity is equally important in a woman’s reproductive lifespan, especially when POI occurs in young women, and ovarian follicles and the oocytes are perceived to be of better quality than in older women. Furthermore, young women who have undergone gonadotoxic treatment and have high numbers of good quality ovarian follicles destroyed can have problems conceiving due to the sheer low number of ovarian follicles and will go into the POI state and be rendered infertile despite the likely presence of low numbers of perceived better-quality oocytes due to her younger age (barring the fact that these oocytes could have been affected by the medical treatment).

During normal ageing in women, the culmination of clinical menopause occurs because of loss of both quality and quantity of ovarian follicles, which signals the end of a woman’s reproductive lifespan. Thus, both quantity and quality of ovarian follicles are equally vital for a woman’s reproductive lifespan. Research on human reproductive cells and tissues can thus improve the fertility of couples and help them conceive healthy babies with less risk of complications in pregnancy. It can also promote the procreative choices of women who want to delay parenthood until later in life when they are likely to be more financially secure.

While technological fixes alone will not resolve diminishing fertility rates, there are social and moral imperatives to support this research because it benefits not only individual parents, but society as well through improved reproductive health and knowledge of the developmental and ageing processes. Given these imperatives, regulation and ethical review of fertility research ought to be constructive and not unreasonably obstructive. In this paper, we draw a philosophical distinction between high-risk and low-risk research with reproductive tissues, especially that which involves human embryos, that can facilitate constructive regulation and ethical review.

Human embryo research

Research with human embryos in most countries is highly regulated. Some countries, including Austria and Italy, have prohibited any research that results in the destruction of human embryos.14 15 Other countries, including Australia, the UK and Singapore, allow destructive embryo research with appropriate ethical review and under certain conditions. For example, some jurisdictions allow embryo research when limited to supernumerary embryos or when there is an absence of an adequate alternative. Following the prohibition on developing human embryos beyond 14 days of fertilisation, most of these countries also mandate the destruction of embryos after this time period.15

There are at least two reasons for this variability. The first is because of different views of the moral status of the embryo. Embryo research often destroys embryos, and some hold the view that embryos have moral status and that it is wrong to destroy them, even as wrong as killing a person.16 17 Other people do not hold such views and believe that embryos do not hold moral status, and therefore, in accordance with this view, it is not wrong to destroy them for scientific research that may benefit future patients.16 18 However, the most common position is the gradualist view of moral status: that is, the fetus gradually acquires increasing moral status during pregnancy, meaning that abortion at advanced gestations requires much stronger justification. This view holds that human embryos have a limited degree of moral status, meaning that their use in research should be balanced against the benefits and that their use in research is only ethically acceptable if the benefits outweigh the presumed ethical violation of destroying them. This view may be true but our distinction is still important. Even if an early embryo has low value on this view, the future person view states it should be accorded higher moral status if it will, or would likely, become a future person.

Second, if the embryo will not become a future person, but still retains some status or value on this view, it is necessary to compare this status or value to other contexts. In most western liberal countries, abortion and contraception are available on demand. This suggests a view of very low moral status. Indeed, in many jurisdictions, embryos surplus to a couple’s needs must be destroyed by law after a certain period of time, even when they could be donated to childless couples who desire them. This again suggests a view of very low status or value. And even if they did have some value or status, this must be considered against the very real value of well-designed research. To treat embryos in research differently to research in in vitro fertilisation (IVF), or reproduction generally, is a form of ‘research exceptionalism’.

Ethics committees must make decisions when national rules are unclear regarding in vitro cultures of viable (surplus) embryos and embryo model research. The International Society for Stem Cell Research leaves it up to each country to decide on the extension of the 14-day rule. However, our distinctions apply to these situations and the 14-day rule is irrelevant. If an embryo is earlier than 14 days, but will turn into a person, then it should be treated as if it were a person, even though it is not. For example, a modification on a blastocyst which would be implanted should be treated in the same way as a modification of an infant.

Research should be treated on a par with clinical practice and termination of pregnancy. Fourteen days does not signify anything of relevance to the future person. Jeff McMahan argued that an individual organism begins at 14 days, when cells begin to co-ordinate to form an organism, just as when tribes begin to co-operate there emerges a nation.19 This argument is dubiously based on claims about the lack of cellular organisation before 14 days. Yet, even if an individual begins to exist at 14 days, rather than being a clump of cells, that individual is not yet a person. According to the future person distinction we have presented, it is implantation (or ectogestation) that matters, not embryonic stage of development. We acknowledge that the issue is complex and we do not attempt to settle the matter here.

Furthermore, in this paper, we only consider jurisdictions that allow fertility treatments through, for example, IVF and the inevitable destruction of embryos that are discarded or surplus for treatment purposes. These jurisdictions have accepted that research with embryos that would otherwise be destroyed is ethically acceptable. In fact, some jurisdictions, such as the UK, even allow the creation of embryos solely for the purposes of research. However, we do not consider this scenario; we focus only on embryos created in clinical contexts for the purposes of fertility treatment.

The second, and more important, reason for the contention surrounding embryo research is that an embryo has the potential to become a future person whose life can be fundamentally changed by what was done at this very vulnerable and profound stage of development. It is essential that anything done to an embryo, or information derived from it, is consistent with the well-being of the future person and does not expose that person to unreasonable risks. This requires minimising risk, ensuring that experimentation is based on the best available evidence and reasoning, and ensuring that risks are proportionate to the expected benefits, either to the future person (or to others, such as other fertility patients).15 Several layers of evaluation can help to achieve these aims: first evaluation by the researchers themselves, then by an ethics committee, then by the parents or producers of the embryo, who must ultimately give their informed consent for the research.

Various ethical review procedures in different countries instantiate these basic requirements in different forms. Our goal is not to question these requirements directly but question the scope. Despite some countries having relatively permissive legislation in relation to embryo research, such as the UK, many countries (such as Australia16 and Singapore) have legislation which imposes onerous requirements on low-risk embryo research, such as observational studies. We will argue it is important ethically to differentiate between two different kinds of embryo research: research on embryos that will foreseeably result in a future person and research on embryos that will not foreseeably result in a future person because of the decision of either the donor/provider or their treating physician not to implant the embryo. Let us call these two kinds of research: Future Person Embryo Research and Non-Future Person Embryo Research.

The nature of the future person embryo research and non-future person embryo research distinction

Future person embryo research includes anything which is done to an embryo that will be or could be implanted into a woman’s uterus. This might include embryo biopsy, preimplantation genetic screening, whole genome analysis, observational research (including using time lapse imaging), embryo culture, media from embryo culture used for non-invasive testing and gene-editing in embryos. Experimentation on gametes (sperm and eggs) is not embryo research per se but may raise the same ethical issues as future person embryo research if those gametes might be used to create an embryo which is transferred to the woman’s uterus.

Non-future person embryo research involves any procedure done to an embryo that will never be implanted because of the decision of the patient or their treating physician. This category includes embryos that are clinically assessed as being unsuitable or nonviable for transfer, as well as embryos that will not form a future person because of independent decisions not to implant or use them for fertility treatment. For example, the donor’s family is complete and they do not wish to donate them to other couples or dispose of them as biological waste. Experimentation on gametes that will not create an embryo for fertility treatment may also fall into this category. The donors must give their informed consent for use of these tissues for research purposes.

There are thus four relevant categories to embryo research:

1. Research on gametes that are not intended to, or will not foreseeably, create an embryo for treatment.

2. Research on non-viable embryos that will not be used for treatment.

3. Research on viable (surplus) embryos that will not foreseeably be used for implantation.

4. Research on viable embryos or gametes that will be used for treatment.

It is category 4 that we argue raises special ethical issues related to future persons.

Why does this distinction matter?

This distinction matters because future person embryo research generally requires high-level scrutiny to protect future persons whereas non-future person embryo research, although embryo research, does not require this level of scrutiny, including risk-benefit evaluation because no sentient person will ever be directly affected. An embryo or fetus does not become a person until after birth.19 20 While some theologians have argued that personhood begins at fertilisation21 22 many others disagree,23 24 and in jurisdictions that allow destructive embryo research, preimplantation embryos are not attributed with legal or moral personhood. Even if human embryos are attributed with some special status, which aligns with the prevailing gradualist view of the moral status of human embryos, it is insufficient to protect them from destructive research. It is only when embryos are to be implanted into a biological womb that they can foreseeably turn into a person. At that time, an embryo should be treated as if it were a person, even though it is not, if there is the intention to gestate that pregnancy to term.

For example, an experimental modification made to an embryo which would be implanted should be treated in the same way if that modification were made to an infant. That would be future person research and warrants high levels of ethical scrutiny. However, if that embryo will not ever be implanted to foreseeably become a person, then it is non-future person research and should require much less scrutiny.

In a nutshell, future person embryo research is contentious and warrants detailed ethical review; non-future person embryo research is not as contentious and requires much lower level, faster review (still conforming to the requirements for ordinary human tissue research and legislation). What matters ethically is whether there could be a future person resulting from this embryo and whether the person subsequently borne out of the research could be adversely affected in the future by what is done now.

However, there are exceptions. Future person embryo research can also be relatively uncontentious, and not require high-level research ethics review. For example, in non-interventional observational research, nothing is done to the embryo and nothing interferes with its growth that could affect the life of a future person. Such research may involve the collection of data on the future person. However, with the informed consent of the future person’s prospective parents and appropriate data protection protocols, such research would ordinarily be considered as no-more-than minimal risk. The research would come under the purview of ethics review, but would not warrant high levels of ethical scrutiny. Similarly, non-future person embryo research can occasionally be contentious for reasons other than the mere fact it destroys an embryo, for example, when research on discarded embryos is potentially discriminatory,17 frivolous or lacks positive social value.18

Application of this distinction to test cases

Table 1 provides examples of test cases that exemplify the distinctions between the categories of embryo research discussed above so as to clarify the appropriate level of ethical oversight required. These cases raise additional ethical issues which are not the focus here, so we refrain from elaborating on ethical concerns such as privacy, confidentiality, consent and deidentification, particularly in case 1. In case 2, there are also issues relating to incidental findings, such as the discovery of chromosomal imbalances in the embryos, for example, chromosome translocations that may be inheritable from the parents and will have implications for the couple to be investigated to confirm their karyotypes and then decide whether there are repercussions for their future plans for conceiving.

An important overarching question not considered here due to the focus of this argument, but certainly important to consider in the broader context, is whether couples only producing chromosomally abnormal embryos should be able to successfully request the transfer of an abnormal embryo, such as one with Trisomy 21 or Down syndrome.

We do not include case 4 (see below) in the Table because it is emerging research that warrants a section of its own for more detailed description.

The most controversial research: future person affecting research

The most controversial kind of research is that which can change the life course of a future person. An obvious example would be gene editing, for example, to correct major genetic abnormalities such as Tay Sach’s disease or less severe conditions such as thalassaemia major, cystic fibrosis or Huntington’s disease. Most jurisdictions in the world forbid this kind of research but there have been calls for a translational pathway to such trials.26 27

To some, it might seem that such research could never be justified. However, for those who will be born with life threatening genetic disorders, it could be literally life-saving.

What seems impossible fast becomes a clinical reality. For example, preimplantation screening is not a standard part of clinical care in many parts of the world. Controversy around the usefulness of preimplantation genetic testing-aneuploidy (A) (PGT-A) for these young female patients remains. However, there is growing evidence that PGT-A improves clinical outcomes in the conditions in which the risk of embryo aneuploidies might increase, such as advanced maternal age, recurrent pregnancy loss, repeated implantation failure, severe male infertility factor.26–32 It involves biopsing the trophectoderm from the day 5 embryo (blastocyst) to determine if the embryo has the correct set of chromosomes (euploid) to deem it chromosomally normal for embryo transfer. Years ago, it might have seemed incomprehensible to remove a part of the embryo to check its genetics. Indeed, in some countries it is still considered ‘experimental’ and can only be done under a research protocol. While such research is the most controversial, if sufficient evidence accrues, the benefits could outweigh the risks and it could, in some circumstances, be ethical to proceed.