This week, two groups report that they have sustained human embryos in vitro for 12–13 days1, 2, 3. Embryos normally implant in the wall of the uterus at around day seven. Until now, no one had reported culturing human embryos in vitro beyond nine days4, and rarely have they been sustained for more than seven.
This latest advance comes only 21 months after the researchers at the Rockefeller University in New York City (some of whom are involved in the latest embryo-culturing work) announced that, under certain conditions, individual human embryonic stem cells can self-organize into structures akin to the developmental stages of embryos soon after implantation5, 6 (see ‘Two advances in human developmental biology’). The cells were obtained from pre-existing stem-cell lines (derived from 4–5-day-old embryos donated through fertility clinics).
Two advances in human developmental biology
In 2014, researchers at the Rockefeller University in New York City placed human embryonic stem cells on plastic discs with patterned surfaces designed to support cell clustering, and treated the cells with a bone growth factor5. In one or two days, the cells had arranged themselves into radially symmetric patterns. These mirror — in flattened form — the organization of embryos soon after implantation in the uterine wall. From the outside in, concentric circles of cells form each of the three germ layers that give rise to all fetal tissues: the endoderm, mesoderm and ectoderm cells. These in vitro models even show evidence of primitive-streak-like regions.
These self-organizing structures, although embryo-like, are essentially two-dimensional. Other in vitro models have demonstrated some degree of self-organization when human embryonic stem cells are cultured in 3D environments10.
All these differ from implanted human embryos resulting from a fertilized egg in several ways. But it is plausible that researchers could one day create more comprehensive 3D models6.
This week, teams led by researchers at the Rockefeller University and the University of Cambridge, UK, report1, 2 that they cultured intact human embryos in vitro and obtained interpretable images up to day 12–13. Each team stopped its studies by day 14 in accordance with UK law and international guidelines.
The latest work provides compelling insight into how the early human embryo transitions from a floating hollow ball of cells to a three-layered gastrula attached to the uterus. Studies on human embryos sustained in culture could help to clarify whether self-organizing structures truly mimic early human development. Tracking, in real time, the morphological and molecular changes in embryonic cells and the interactions between them during these later days of development, could elucidate the cell-signalling pathways that guide embryo organization and tissue formation.
These techniques could shed light on the disorders that result in early pregnancy losses and birth defects, and facilitate clinical applications of stem-cell research. In conjunction with gene-editing tools, they could even help to determine the role of specific genes in human development.
In principle, these two lines of research could lead to scientists being able to study all aspects of early human development with unprecedented precision. Yet these advances also put human developmental biology on a collision course with the '14-day rule' — a legal and regulatory line in the sand that has for decades limited in vitro human-embryo research to the period before the 'primitive streak' appears. This is a faint band of cells marking the beginning of an embryo's head-to-tail axis.
The 14-day rule has been effective for permitting embryo research within strict constraints — partly because it has been technologically challenging for scientists to break it. Now that the culturing of human embryos beyond 14 days seems feasible, more clarity as to how the rule applies to different types of embryo research in different jurisdictions is crucial. Moreover, in light of the evolving science and its potential benefits, it is important that regulators and concerned citizens reflect on the nature of the restriction and re-evaluate its pros and cons.
The 14-day limit was first proposed in 1979 by the Ethics Advisory Board of the US Department of Health, Education, and Welfare7. It was endorsed in 1984 by the Warnock committee in the United Kingdom8, and in 1994 by the US National Institutes of Health's Human Embryo Research Panel9.
In at least 12 countries, this limit is encoded in laws governing assisted reproduction and embryo research (see 'International agreement'). The rule is also embodied in numerous reports commissioned by governments, and in scientific guidelines for embryo and assisted-reproduction research. These include China's 2003 Ethical Guiding Principles on Human Embryonic Stem Cell Research and India's 2007 Guidelines for Stem Cell Research and Therapy.
Some versions of the rule cover embryos created by any means; others apply only to products of fertilization. Some explicitly refer to gastrulation (when three different cell layers appear) or the formation of the primitive streak; others mention only the 14 consecutive days of development. In most cases, however, what seems to be crucial is the stage of development that the 14th day typically represents, not the consecutive number of days in culture.
The formation of the primitive streak is significant because it represents the earliest point at which an embryo's biological individuation is assured. Before this point, embryos can split in two or fuse together. So some people reason that at this stage a morally significant individual comes into being.
Yet views differ on the moment in development at which a human embryo obtains sufficient moral status that research on it should be prohibited. Some, for instance, believe that the cut-off is the point of fertilization; others argue that it comes much later, when the embryo develops into a fetus that can experience pain, exhibit brain activity or survive outside the womb.
Revisiting the 14-day rule might tempt people to try to rationalize or attack the philosophical coherence of the limit as an ethical tenet grounded in biological facts. This misconstrues the restriction. 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 inquiry and simultaneously show respect for the diverse views on human-embryo research.
In fact, as a public-policy instrument, the 14-day rule has been tremendously successful. It has offered a clear and legally enforceable stopping point for research, because the primitive streak can be visibly identified and it is possible to count the number of days that an embryo has been cultured in a dish. The alternatives at each extreme — banning embryo research altogether or imposing no restrictions on embryo use — would not have made for good public policy in a pluralistic society.
Scientific advances are now prompting re-evaluations of other long-established research policies. For instance, it has proved difficult to maintain a previous consensus among funders, regulators and researchers that genetic engineering of human cells is permissible as long as those cells are not sperm, eggs or embryos. The clinical use of mitochondrial-replacement therapies — which cause heritable changes to future generations — was approved last year by the UK government, and deemed 'ethically permissible' earlier this year by a committee of the US Institute of Medicine.
Some might conclude from such developments that policymakers redefine boundaries expediently when the limits become inconvenient for science. If restrictions such as the 14-day rule are viewed as moral truths, such cynicism would be warranted. But when they are understood to be tools designed to strike a balance between enabling research and maintaining public trust, it becomes clear that, as circumstances and attitudes evolve, limits can be legitimately recalibrated.
Any decision to revise the 14-day rule must depend, however, on how well any proposed changes can uphold the rule's two chief goals: supporting research and accommodating diverse moral concerns.
The rule became a standard part of embryo-research oversight through the convergence of deliberations of various national committees over decades. Hundreds of medical and scientific associations submitted recommendations, and dozens of public forums were held. Any formal changes to this rule should occur through similar processes of consensus-building involving experts, policymakers, patients and concerned citizens.
Ideally, discussion should begin at an international level given the global nature of this research — although taking local cultural and religious differences into account properly would also require national-level debates. A complication is that in many countries, a revision to the 14-day rule would involve a legislative change. Yet the kind of international discourse that we envision could facilitate and inform local decisions to amend law or research policy.
There are precedents for this type of international discourse. In response to the development of powerful gene-editing technologies such as CRISPR–Cas9, the US National Academy of Science, the US National Academy of Medicine, Britain's Royal Society and the Chinese Academy of Sciences jointly hosted an international summit in December last year to discuss scientific, ethical and governance issues raised by the research. The second component of this initiative — a science and policy review and report on human gene editing — is ongoing.
A path forward
Scientists have a crucial part to play in this process. In 1985, when the legality of human-embryo research in the United Kingdom was threatened by a parliamentary bill, Nature editors appealed to embryologists to submit explanations of their research and its importance — to educate policymakers and the public before undue restrictions on research were passed (see Nature 314, 11; 1985).
Today, researchers of human developmental biology should similarly engage with the public about what they are doing and why it matters. And they should consider designing their experiments in a way that, while furthering discovery, also addresses people's moral concerns.
In the immediate future, researchers should work closely with their local research-oversight committees to ensure that they are not at risk of violating current laws or guidelines. There are currently ambiguities around the legal definition of 'human embryo' in some jurisdictions, and uncertainties around the biological potential of self-organizing, embryo-like structures6.
Next week, the International Society for Stem Cell Research (ISSCR) will release its revised guidelines for stem-cell research. These guidelines are the result of a multinational, interdisciplinary task force (which included one of us, I.H.) with input from stakeholders around the world. One of the goals of these guidelines is to provide a framework for those concerned about how research oversight should proceed in light of new forms of embryo research.
In the short term, we think that the ISSCR's recommended approach to oversight of work involving human embryos offers a practical path forward — especially if supplemented with input from representatives of the many advisory committees that have adopted the 14-day rule. Obvious candidates are the UK Human Fertilisation and Embryology Authority, the US National Academies of Sciences, Engineering, and Medicine, and the Chinese Ministry of Science and Technology and Ministry of Health.
Close collaboration between these organizations could help to prevent a public backlash and the implementation of reactive, more restrictive limits on research.
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