Global S&T Development Trend Analysis Platform of Resources and Environment
| DOI | 10.1126/science.abf3751 |
| Human embryo research beyond the primitive streak | |
| Insoo Hyun; Annelien L. Bredenoord; James Briscoe; Sigal Klipstein; Tao Tan | |
| 2021-03-05 | |
| 发表期刊 | Science
 |
| 出版年 | 2021 |
| 英文摘要 | Since the first successful birth resulting from in vitro fertilization (IVF) in the late 1970s, human embryo research has been subject to limits of time and developmental benchmarks. National guidelines, laws, and international norms have prohibited scientists from culturing embryos for research beyond 14 consecutive days, or beyond the appearance of a structure called the “primitive streak,” which defines the beginning of the formation of the principal tissues of the body and the end of the period when an embryo can divide into identical twins ([ 1 ][1]). At the time this limit was put in place 40 years ago, there were no methods to culture embryos in a dish for anywhere close to 14 days. But research since 2016 ([ 2 ][2], [ 3 ][3]) shows that it is likely possible to culture human research embryos past the 2-week limit and suggests that doing so will yield scientific insights that could prove important for human health and fertility ([ 4 ][4]). We thus urge policy-makers and the International Society for Stem Cell Research (ISSCR), which will soon release updated guidelines for stem cell and embryo research, to consider a cautious, stepwise approach to scientific exploration beyond the 14-day limit.
The first articulation of the 14-day limit appeared in the Ethics Advisory Board's report for the U.S. Department of Health, Education, and Welfare in 1979. It was popularized by the United Kingdom's Warnock Committee in 1984 and was echoed in the Human Embryo Research Panel's report for the U.S. National Institutes of Health (NIH) in 1994 ([ 5 ][5]–[ 7 ][6]). Each of these committees advocated that, although embryos in vitro warrant special consideration by virtue of their human developmental potential, they lack the full moral status accorded to persons. As such, it was deemed acceptable to use embryos for scientifically meritorious research whose goal was to benefit human health and improve reproduction.
Having made these key ethical determinations, the committees' remaining task was to provide recommendations for national governance, which the United Kingdom succeeded in doing. Seen in its original light, the 14-day limit is best viewed as a policy decision for science regulation in a pluralistic society, not as a rigid moral principle. The 14-day limit never stood as a philosophical position that the embryo gained an inviolable degree of moral status at that developmental point.
History supports this interpretation. The U.S. Ethics Advisory Board recommended the 14-day limit as part of a national policy for the acceptable uses of IVF-derived embryos. It was important for this policy not to clash with 16 state laws that based fetal research restrictions in utero upon a definition of the fetus as a product of conception that has implanted in the womb. To avoid possible conflict between their recommendations and state laws, the Board declared that in vitro research should conclude 14 days after fertilization, around the time that implantation in the womb would normally be completed.
The NIH Human Embryo Research Panel had a similar policy consideration to weigh. U.S. Federal regulations, based on the recommendations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, set requirements for federal research funding involving post-implantation embryos and fetuses. The Panel wanted to draft guidelines that would allow federal funding for embryo research in vitro. But they realized that this could trigger extant funding constraints around post-implantation embryos, so setting the limit at 14 days made good policy sense. The Panel also said that in vitro research should be limited to the shortest time period consistent with the goals of each research proposal and “for the present” should not go past primitive streak formation. Thus, the Panel's 14-day limit was not offered as an immutable stopping point, as further evidenced by their suggestion that the study of embryos slightly longer than 14 days would be permissible if the goal of the research was to study the primitive streak itself.
Recently, Mary Warnock, who chaired the United Kingdom's Warnock Committee, has acknowledged that the 14-day limit was a somewhat arbitrary number that helped get the bill through Parliament ([ 8 ][7]). In light of these original rationales, we believe it is time to reevaluate the 14-day limit and offer recommendations for a cautious path forward. But first, one must appreciate the scientific reasons for doing so.
Researchers' access to early-stage embryos from natural pregnancy losses is extremely limited. Most women do not know that they are pregnant in the first weeks after implantation, such that the acquisition of embryonic tissue from this early stage of development is extremely difficult. Thus, many scientific questions of both fundamental and practical importance can be answered only by studying IVF-derived human embryos in culture beyond primitive streak formation (see the box).
The difficulty of accessing embryos means that the 2 weeks between the 14th and 28th day after fertilization have been called the “black box” of human development. It covers gastrulation (around days 13 to 20), when cells are allocated into the principal tissues and the body plan is developed. Most of what researchers now know comes from the Carnegie Embryo Series ([ 9 ][8]) and the Kyoto Collection ([ 10 ][9]). The descriptions of these embryos, which were collected over a long span of time, have been limited to histology, and no modern methods of analysis have been possible. Consequently, researchers have little if any direct molecular, cellular, or other data about dynamics or cell fate relationships during this crucial black box period. Yet, it is during this window of development that many congenital anomalies arise, implantations fail, and miscarriages occur. Together, these affect many women and their families. For example, in one study of women presenting for delivery, 43% reported having had at least one early spontaneous abortion ([ 11 ][10]).
People may wonder if there are alternative ways to study these questions. One of us (T.T.) has demonstrated that monkey embryos can be cultured past 14 days, which allows monkey embryos in extended culture to be compared point by point with monkey embryos in utero ([ 12 ][11], [ 13 ][12]). But, although there are many advantages to using monkey embryos in lieu of human embryos, differences between early human and monkey development should not be ignored. For example, monkey embryos implant on the surface of the endometrium, whereas human embryos (as well as those of apes) implant within the endometrium, and this process might be relevant for disorders such as intrauterine growth restriction, which keeps babies from reaching a healthy birth weight. Only through the direct study of human embryos in extended culture systems can researchers fully understand the mechanisms underpinning human development. Rather than monkey embryo culture standing as an alternative, it is likely to fuel the feasibility of, and further scientific interest in, extended human embryo culture.
Another technique for studying human embryo development involves constructing three-dimensional embryo-like models from pluripotent stem cells rather than using actual human embryos ([ 14 ][13]). But to know whether observations from such models are meaningful, it is essential to compare in vitro embryo model systems with IVF-derived embryos. Indeed, comparisons could provide a benchmark to calibrate and validate these new approaches, making stem cell–based human embryo model systems more useful and allowing them to answer questions that currently could only be addressed with IVF-derived human embryos. Once such validation and benchmarking are done, researchers might be able to use embryo model systems more broadly, thereby reducing the number of IVF-derived embryos needed in the future.
#### Scientific goals
There are five categories of questions to be addressed by studies of human embryos beyond primitive streak formation.
##### Fundamental Knowledge
What are the similarities and differences between development in humans and other mammals?
##### Understanding Disease
What are the origins and mechanisms of developmental disorders that arise early in development?
##### Clinical Utility
Can we develop therapeutic interventions that address causes of infertility, developmental disorders, and failed pregnancy?
##### Scientific Validation
How closely do nonhuman primate and stem cell–derived embryo models of human development compare to IVF-derived embryos?
##### Preclinical Safety Assessment
If human sperm and eggs are derived from stem cells or are genetically edited, will embryos created from them develop normally? Will mitochondrial transfer (a process already under consideration for clinical use) affect embryo development?
Perhaps the most compelling questions fall into the category of understanding disease. For example, around 3% of births show some form of congenital anomaly, and many pregnancies fail prior to birth. For instance, approximately 1 in 250 conceptions result in holoprosencephaly, a defect in the formation of the embryonic midline that affects the development of the brain and face. It can be mild or severe and can cause miscarriage or early death. Genetic mutations that contribute to the disease have been identified, but predicting their exact effects—and disease severity—has been elusive. Embryo research might provide answers. Embryo research past 14 days might also explain why many embryos fail to implant and others subsequently spontaneously abort. It might help identify ways to distinguish between viable and nonviable IVF embryos and so might lead to fewer lost pregnancies and implantation failures—and the concomitant suffering and health risks—in fertility patients. It might also help evaluate whether other cutting-edge infertility treatments can produce viable embryos, including gene editing or mitochondrial replacement, and also assess whether embryos made using sperm or egg derived from stem cells develop normally.
If research on human embryos is to be permitted beyond the primitive streak, it should proceed in incremental, measured steps. Here we propose six principles that can be used to weigh whether these extensions are permissible. These apply for extending the 14-day limit, as well as for other complex research, and show how regulations can be shaped to support and promote good scientific practice and beneficial research, not just limit harmful or unethical research.
### Scientific justification
Researchers should adhere to the 14-day limit, unless a strong scientific justification can be offered to culture human embryos longer in locales where it would be legally permissible to do so. Any such proposed research must serve important goals that cannot be adequately met by other means.
### Well-defined increments
Extended embryo culture should commence in small steps, with frequent interim evaluations and reassessments by regulators. For instance, it would first be necessary to assess feasibility of culture past 14 days and, if so, to assess whether those newly permitted experiments were informative enough to justify the use of human embryos. Any research teams proposing to move beyond the 14-day mark would need to seek regulatory permission for each subsequent experiment. Even if the 14-day limit were lifted today, technical limitations mean that experiments could not go far beyond it.
### Independent peer review
Research proposals should be peer reviewed by qualified science and ethics committees that are independent of the researchers. Some countries, such as the United Kingdom, have a robust national system in place for such review. For countries that lack a centralized and consistent system for embryo research review, the ISSCR should provide an ad hoc review panel composed of independent scientific and ethics experts to provide advice for local review committees.
### Public dialogue
Any incremental step in embryo culture should be preceded by public dialogue at the local institutional level and, if feasible, more broadly. Responsible embryo research can only take place if scientific, ethical, and societal concerns and opportunities are explored and discussed in inclusive and deliberative forums hosted by regulators who are empowered to approve the research. Through such forums, researchers involved in these studies should be actively engaged in dialogues with the broader public, which should include nonscientific forms of knowledge, drawing on culture, philosophy, and experience. These should follow what science communicators call a “dialogue model” rather than the “deficit model” ([ 15 ][14]). That is, conversations should be interactive, not instructive, and aim for a bilateral exchange of ideas, such that science-based societal questions benefit from broad input.
### Informed consent
Anyone with dispositional authority over IVF embryos, and any donors whose gametes are used to create embryos that are donated, must give specific consent for extended embryo culture and research. Given people's diverse views around human embryo research, including the views of gamete donors recruited in assisted reproductive contexts, broad consent for any unspecified embryo research would not be ethically acceptable. Those donating embryos or gametes should be told the purpose and length of time that embryos will be studied and whether embryos will be preserved or discarded once the study is concluded. Donors should be informed that the embryos will not be used for reproduction.
### Separation of clinical care and research
The process of obtaining consent for embryo research must be kept separate from any clinical decisions for fertility treatments. Physicians who are treating patients or gamete donors should not be involved in informed consent interviews, nor should people who are involved in the research program. To avoid undue incentives or coercion of embryo donors, nondirective counseling should be provided to donors by people independent of both the research and clinical teams.
Each of these principles will be familiar to many scientists, ethicists, and policy-makers. With singular emphasis, or in combination, they are widely called into action in many other contexts where unconventional research is proposed and weighed. Taken together, this principled approach allows room for collaborative deliberation and compromise between researchers and citizens about what experiments are acceptable or which merit being prioritized.
Allowing some exceptions to the 14-day limit will depend on the technical feasibility of being able to culture embryos beyond this point, a process that will take time and deliberate study. Both scientific and regulatory considerations will prevent the science from advancing too far, too fast. First, a few progressive steps would be necessary to optimize culture conditions to see if human embryos can be sustained a day or two past the 14-day period. Next, one would have to see what data can be collected at these new time points and whether the experiments are informative. Concretely, increments of 2 or 3 days linked to defined developmental milestones seem appropriate.
For example, if reliable conditions for the culture of embryos beyond the 14-day time point are established, the next permissible endpoint could be day 16 to 17 (Carnegie stage 7) with morphological and molecular evidence of the extension of the primitive streak. If achieved, it would then be possible to propose extending culture an additional ∼2 days until the equivalent of day 18 (Carnegie stage 8) corresponding to the formation of the neural groove. Stipulating both a time and an embryological constraint for each increment ensures that limits agreed through debate and public dialogue are not inadvertently breached because of our relatively scant knowledge of exact developmental timing at these stages of human development in vitro or because there is a mismatch between the tempo of in vitro and in vivo development.
The process also makes clear the rationale for an incremental approach. Each increment can be viewed as a hypothesis of the developmental progress expected in a particular time frame. If an experiment fails to support the hypothesis, it will help revise our understanding of human development. If it holds, the next increment may be proposed. Unlike the 14-day limit, this approach can accommodate the possibility that days in culture may not always match up to milestones in embryonic development.
Together with scientists, ethicists, patient groups, and policy-makers, public input will help inform decisions regarding the relative merits of continuing down this path and trying to culture a few days beyond this new point. Many countries have their own national traditions for dealing with difficult discussions like these, for example, in allowing preimplantation genetic testing or mitochondrial replacement strategies. We believe the pace of human embryo culture research should be determined by measured scientific progress and societal openness to moving forward. Realistically, an incremental approach seems to be our only path forward, both from a scientific and a policy standpoint.
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| 领域 | 气候变化 ; 资源环境 |
| URL | 查看原文 |
| 引用统计 | |
| 文献类型 | 期刊论文 |
| 条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/316984 |
| 专题 | 气候变化 资源环境科学 |
| 推荐引用方式 GB/T 7714 | Insoo Hyun,Annelien L. Bredenoord,James Briscoe,et al. Human embryo research beyond the primitive streak[J]. Science,2021. |
| APA | Insoo Hyun,Annelien L. Bredenoord,James Briscoe,Sigal Klipstein,&Tao Tan.(2021).Human embryo research beyond the primitive streak.Science. |
| MLA | Insoo Hyun,et al."Human embryo research beyond the primitive streak".Science (2021). |
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