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Cambridge University Science Magazine
Still reeling from a flurry of discussion and soul-searching in the wake of the first attempts at human genome editing in 2015, the world of human embryo research now faces another controversial breakthrough. Two groups of researchers, including several Cambridge scientists, have grown human embryos in culture for an unprecedented 13 days. The researchers were striving to gain a better understanding of the process of implantation, wherein the embryo attaches to the uterine wall to gain access to maternal supplies of oxygen and nutrients. Implantation is critical for normal embryonic development, but very little is known about how it is regulated or the changes that take place within the embryo during the process. This is because embryos at the implantation stage could not be kept alive outside the uterus – until now. In their papers, published this year in the journals Nature and Nature Cell Biology, the researchers describe how they adapted a technique initially developed for culturing mouse embryos to grow human embryos for far longer than was previously possible. The researchers thereby imaged previously unseen stages of human embryonic development. However, by pushing the boundaries of human embryo research, the researchers have also awakened abeyant concerns regarding the ethics underpinning the entire field.

To better understand the issues, let’s take a brief detour into the early development of a human embryo. It all begins with the fusion of a sperm cell and an egg cell in a woman’s fallopian tube, creating a zygote. The freshly minted zygote then starts off on a 4-5 day journey to the uterus. During its journey, the zygote begins to divide to form a ball of cells known as the blastocyst, which is comprised of three cell lineages: the epiblast which will form the foetus, and the trophoectoderm and primitive endoderm, which both support embryonic growth. By around six days after fertilization, the blastocyst begins the process of implanting into the uterine wall, a critical step which is accompanied by profound molecular and cellular changes. By around 14 days after fertilization the blastocyst has developed further, with cells and tissues displaying more complex and clearly visible 3-D organization. One structure that features prominently in bioethical discussions of human embryo research is a cell mass known as the primitive streak.

"Currently, human embryos can legally be grown in culture for no more than 14 days after fertilisation"

The emergence of the primitive streak features prominently in bioethical discussions about the use of human embryos. It is the basis for an internationally recognized ethical standard, known as the 14-day rule, which prohibits keeping human embryos alive in culture for longer than 14 days, or the beginning of primitive-streak formation, whichever comes first. In the UK, the 14-day rule was codified in 1984 by the Warnock Committee of Inquiry into Human Fertilization and Embryology and is now a central tenet of the Human Fertilization and Embryology Authority’s regulations on the use of human embryos in research. Pursuant to this standard, the Nature Cell Biology and Nature studies lasted only 13 days. While this guideline has existed for years – it was first proposed in the US in 1979 by the Ethics Advisory Board of the Department of Health, Education, and Welfare – until very recently it was considered impossible to keep human embryos alive for anywhere near 14 days in culture. The 2008 Cambridge Textbook of Bioethics, for example, notes that “…it is not possible to culture an embryo in vitro for more than five or six days, a limit not likely to be exceeded soon…”

Why is the primitive streak so significant? One common argument is that after the formation of the primitive streak, the blastocyst can no longer divide into two pieces to form twins (as sometimes happens with pre-14 day embryos). Hence, 14 days might be considered to be the approximate time when an embryo becomes, without question, a distinct individual. It is thus a point of ‘moral significance’ at which the embryo becomes worthy of greater respect. The formation of the primitive streak has been a successful public-policy guideline because it is an early enough cut-off to alleviate public concern, while not appearing overly oppressive to researchers – in large part because at its adoption growing embryos in vitro for 14 days seemed a very distant prospect. However, with the recent advancements in human embryo research, scientists can now study human embryos in vitro up to and beyond implantation with potentially large biomedical implications. Longer cultures might help scientists to unravel the process behind miscarriages, increase in vitro fertilization rates, and better understand stem cell differentiation, for example. There is therefore an imperative need to revisit the 14-day rule.

Another reason for re-examining longer experiments is that the argument for the 14-day rule could be considered quite arbitrary. Whilst simultaneously recommending the rule on the grounds described above, the 2002 report of the President’s Council on Bioethics, Human Cloning, and Human Dignity noted that “we are not persuaded by the argument that fourteen days marks a significant difference in moral status.” In fact the repeated offering of this argument inspires more cynicism than confidence, as it seems that legislators are attempting to mask a merely practical standard behind the veneer of a strong ethical argument.

Legislation is of course an amalgam of what is possible and (hopefully, in an ethical society) what is right, and also what it is right to legislate (though few would dispute that human embryo research falls into this latter category). It is unreasonable to expect legislation on something as complicated as the use of human embryos in research to reflect an ethical consensus, just as it is unreasonable to expect a diverse society to ever reach a uniform ethical consensus on such an issue. And there are of course myriad difficulties inherent in the attempt to extract a simple moral tenet from biological facts like the progression of embryo development. However, the fact that the 14-day rule is somewhat arbitrary does not necessarily make it a bad law. Some are concerned that if we admit that the 14-day rule was simply a useful standard - a morality of convenience, if you will - that we open the door to a ‘slippery slope’. There may well be profound medical and scientific justifications for scientific exploration of ever more advanced stages of human embryonic development. On the other hand, there is concern that continuing to push the boundaries of scientific exploration by moving this law further and further back, will we weaken our respect for human life and open the door to, as the President’s Council on Bioethics puts it, “a coarsening of our moral sensibilities”? Yet others might argue that research into human embryonic development is something which, the like the atom bomb, once seen as possible will inevitably be pursued.

From stem cell research, to human genome editing, to new proposals to synthesize from scratch a functional human genome, research is increasingly pushing the bounds of the public’s – and of many scientists’ – comfort. There is an increasing urgency in the need for comprehensive, and preferably international, guidelines on human embryo research. While it is a challenging mandate, hopefully, scientists, ethicists, and policy makers together will be able to address these needs with some sense of finality. Any decision must take into account two main goals: supporting research but, so far as is possible, showing sensitivity towards different ethical views.

Featured image: Vall d'Hebron Research Institute (VHIR)