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Ethical, legal, regulatory, and policy issues concerning embryoids: a systematic review of the literature

Abstract

Recent advances in methods to culture pluripotent stem cells to model human development have resulted in entities that increasingly have recapitulated advanced stages of early embryo development. These entities, referred to by numerous terms such as embryoids, are becoming more sophisticated and could resemble human embryos ever more closely as research progresses. This paper reports a systematic review of the ethical, legal, regulatory, and policy questions and concerns found in the literature concerning human embryoid research published from 2016 to 2022. We identified 56 papers that use 53 distinct names or terms to refer to embryoids and four broad categories of ethical, legal, regulatory, or policy considerations in the literature: research justifications/benefits, ethical significance or moral status, permissible use, and regulatory and oversight challenges. Analyzing the full range of issues is a critical step toward fostering more robust ethical, legal, and social implications research in this emerging area and toward developing appropriate oversight.

Background

Methods to culture stem cells to model early human development have been reported since 2014 [1, 2]. Recent advances have resulted in entities that model different stages of early embryo development—from the blastocyst stage at 5 days post-fertilization (dpf), to gastrulation at 17 dpf, to later stages of organogenesis [3,4,5,6,7,8]. These entities are referred to by numerous terms, including embryoids, synthetic embryos, gastruloids, and blastoids [9]. For ease, we will refer to them as embryoids, a general name for all types of cell models of early development.

As science and technology advance, researchers anticipate embryoids will become more sophisticated and resemble human embryos ever more closely [8, 9]. In 2022, researchers were able to grow a mouse embryoid in culture from a cell line to a synthetic embryo that had the early formation of organs and limbs [10]. This new technology, which has only been used on mouse cells, raises concerns regarding how far scientists can and should grow human embryos and embryoids in culture [8, 9].

Embryoid, embryo, and human–animal chimera research raise a number of sometimes-overlapping ethical, regulatory, and policy issues, though they merit separate attention. Numerous scholars have written about ethical questions or concerns associated with embryoid research or that might arise as the science of embryoids advances [11, 12]. Others have highlighted policy or regulatory issues that such research prompts both regarding the status of embryoid research and the relationship between such research and human embryo research. Two recent systematic reviews examined ethical issues associated with organoids [11, 12]. We know of no systematic review regarding ethical, legal, regulatory, and policy issues regarding embryoids. Analyzing the full range of issues identified in the literature pertaining to research on human embryoids (or any stem cell-based models of early human development, regardless of the names used to describe them) is an important step toward fostering more robust ethical, legal, and social implications research in this area and developing appropriate oversight.

Methods

This systematic review followed PRISMA reporting guidelines [13, 14]. The protocol for this paper was published in Open Science Forum and registered on June 16, 2022. In consultation with reference librarians from the Z. Smith Reynolds Library at Wake Forest University, J. Denice Lewis and Kathy Shields, we designed a search strategy that included three databases: PubMed, Embase, and Web of Science. The search strategy for each database is in Appendix 1. No date limits were used. Language limits were applied to restrict publications to English. All searches were completed on January 10, 2022. Searches were imported into Rayyan for de-duplication and then imported to Zotero. Through consultation with authors and review of reference sections of included publications, additional possible publications were identified.

To be eligible, publications had to:

  1. (1)

    Be discoverable using our search strategy or identified by an author;

  2. (2)

    Be published in English;

  3. (3)

    Be accessible via full text to us either online, through the Wake Forest University or Rice University Library, or through Interlibrary Loan; and

  4. (4)

    Identify at least one ethical, regulatory, or policy question or issue related to research involving embryoids (or any term used to describe a stem cell-based model of human embryos).

Consistent with published recommendations for systematic reviews, we included abstracts and dissertations [15, 16]. We also included commentaries, editorials, and other types of publications to maximize data collection.

Selection

Following PRISMA reporting guidelines, Fig. 1 presents the selection process [13, 14]. Initial screening of titles and abstracts was done by one author (ASI) using Rayyan web-based systematic review software. If the abstract did not clearly indicate that an article should be excluded, it was tagged as a “Maybe” and advanced to the next round. In the second phase, three authors (ASI, GK, ER) screened 20 of the same publications to promote consistency and inter-rater reliability. Assessments were compared after screening 10 entries and differences discussed. The same process was repeated with 10 more entries. After that, two authors (either ASI and GK or ASI and ER) screened all remaining titles and abstracts. All articles were excluded based on the highest ranking exclusion criterion in our exclusion hierarchy (see Table 1), included, or tagged “Maybe” for full-text screening. We obtained full texts for all publications marked “Maybe” or “Include.” Full texts were stored and reviewed in Zotero. Two authors (either ASI and GK or ASI and ER) reviewed all full-text publications and either included or excluded each one. Where necessary, we consulted with other authors to make inclusion and exclusion decisions. At each stage, all differences were resolved through discussion and review of the material, allowing us to have 100% consensus. Two duplicates that had not been previously detected were found during the screening process and removed manually.

Fig. 1
figure 1

PRISMA flow diagram [92]

Table 1 Exclusion hierarchy

The reference section of each included publication was reviewed for additional publications to assess. Authors were invited to recommend additional reports or publications for screening. These were screened by two authors (either ASI and GK or ASI and ER), and often in consultation with KRWM, they were marked for inclusion or exclusion.

Data extraction and synthesis

For each included publication, data were extracted independently by two authors (either ASI and GK or ASI and ER) and entered into a data extraction form created using Google Sheets. Data items extracted were:

  • Complete citation

  • Publication type

  • Year published

  • Terms used to refer to embryoids

  • Background information

  • Ethical issues identified

  • Commentary on ethical issues

  • Policy or Regulatory issues identified

  • Commentary on policy or ethical issues

Three authors (ASI, GK, and ER) reviewed the extracted data to combine information, resulting in one comprehensive data sheet. The results were shared with all authors. Through qualitative content analysis, authors identified the themes and identified categories and sub-categories reported here [17].

Results

The initial search yielded 6536 publications. These were imported into Rayyan for de-duplication. After removing 1794 duplicates, 4472 records were screened. After screening titles and abstracts, 4623 publications were excluded because they did not address human embryoids or synthetic embryos. These articles concerned animal models or addressed only “embryoid bodies,” “organoids,” or other models that were not models of human embryos. Full texts were retrieved for the remaining 119 publications. Two additional duplicates were found and removed manually, leaving 117 publications for full-text screening. These were added to Zotero, and full texts were obtained. Of those 117 publications, 83 were excluded because they were not about human models (n = 2), they were not about embryoids (n = 65) or they did not address any ethical, regulatory, oversight, or policy issues (n = 16), and 34 were included. The references of the 34 included publications were reviewed for additional publications to screen, and all authors were invited to share information regarding other possible publications or reports to consider. An additional 22 publications were identified this way and screened. All 22 met our inclusion criteria. A total of 56 publications were included in the review. One of these was an erratum for another included publication [18, 19]. Included publications are listed in Table 2.

Table 2 Included publications

We identified 53 distinct names or terms used to refer to embryoids (see Table 3). There are three different types of terms used to identify embryoids previously described: general, time-based, and cell-based [9]. Some terms, such as embryoid or cell-based embryo model, describe the field as a whole. Other terms, such as blastoid or gastruloid, identify a subset of entities at a specific biological moment that they are recapitulating, the blastocyst or gastrulation, respectively. Still other terms identify the cell types used in the model, for example, ETX embryos which describe embryoids using embryonic, trophoblast, and extra-embryonic endoderm stem cells [20].

Table 3 Names identified

Through an iterative inductive process, we identified four broad categories of ethical, legal, regulatory, or policy considerations found in the literature, each of which is discussed in more detail below: research justifications/potential benefits, ethical significance or moral status, permissible use, and regulatory and oversight challenges. As depicted in Fig. 2, the majority of papers included discussions about oversight, policies and regulations (Policies, n = 45), and the ethical significance or moral status of embryoids (Status, n = 40). Fewer publications discussed potential benefits (Benefits, n = 28) and uses and applications of embryoid research (Uses, n = 25). One publication stated that embryoid research raises no ethical or regulatory considerations (None, n = 1).

Fig. 2
figure 2

Major themes identified

Justifications and potential benefits of embryoid research

Some authors noted that embryoid research requires justification and many indicated that potential benefits associated with the research could justify it (n = 28) [9, 21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47]. Over one-third of the publications (n = 19) noted that embryoid research could avoid some of the ethical concerns or practical problems associated with human embryo research [9, 21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37, 47]. Several scholars also believed that embryoid research could offer an ethical alternative to animal research and reduce reliance on animals (n = 8) [22, 26, 30, 31, 35, 38, 39, 47]. A third potential benefit noted is that embryoid research could improve scientific knowledge in ways that advance human health (n = 12) [9, 21, 22, 24, 26, 30, 36, 40,41,42, 45, 46]. Specific examples of potential health benefits include knowledge that could improve understanding of early pregnancy loss, management of early pregnancy, and treating early developmental disorders [22]. Although embryoid research can raise concerns over the destruction of human embryos, it was suggested that when scientists use induced pluripotent stem cells (which are derived from adult cells) rather than embryonic stem cells, they can avoid these issues (n = 3) [9, 29, 33]. Interestingly, the view that embryoid research requires justification based on potential benefits might suggest that such research raises ethical considerations. This contrasts with the view expressed in one publication that embryoid research raises no ethical considerations: “iBlastoids [embryo-like structures] do not pose any serious ethical concern for several reasons and would not need a robust ethical framework that thoughtfully foresees unintended and unanticipated consequences” [48]. The full list of potential benefits that could justify embryoid research are also summarized in Table 4.

Table 4 Main ethical, legal, regulatory, and policy issues and themes identified in journal articles

Ethical significance or moral status of embryoids

Several authors mentioned issues related to assessing the ethical significance or moral status of embryoids (summarized in Table 4). At the most general level, some authors (n = 5) noted that the possibility of creating synthetic human life raises concerns and suggested that embryoids are or could become sufficiently complex that they constitute synthetic human life [38, 49,50,51,52]. Three publications noted the importance of determining the features of an entity that are morally relevant and how those features relate to an entity’s moral status [49, 53, 54]. A related claim was that there could be ethically significant differences among different types of embryoids based on their features (n = 4) [9, 47, 49, 55]. Many other publications addressed the issue of morally relevant features in more detail by addressing specific features. Some authors noted that the level of complexity of embryoids would affect the ethical issues such research raises (n = 9) [41, 49, 51, 54, 56,57,58,59,60]. Specific morally relevant or potentially morally relevant features identified in the publications reviewed included the possibility of experiencing pain (n = 7) [18, 36, 43, 44, 53, 57, 61], the possibility of sentience (n = 5) [18, 36, 43, 57, 62], and human organismic potential (n = 22) [9, 18, 21, 23, 26, 35,36,37, 41, 49, 50, 52,53,54, 59,60,61,62,63,64,65,66].

In addition, authors discussed the ethical significance or status of embryoids in relation to human embryos and clones. According to some authors, the ethical significance or status of embryoids could be assessed by first determining which features of embryos are morally relevant and then determining which of those features also appear in embryoids (n = 9) [18, 30, 31, 37, 41, 44, 57, 63, 64]. Many publications addressed the relationship between ethical assessments of embryos and embryoids. Some suggested that different accounts of the moral significance of human embryos likely would result in different assessments of embryoids (n = 9) [18, 21, 28, 38, 41, 55, 61, 62, 67]. Several publications raised the question of whether embryos and embryoids should be treated the same or differently (n = 7) [9, 37, 41, 55, 57, 60, 61]. Two publications noted that embryoid research might lead to reconsideration of the question of what respect is owed to embryos [54, 63]. Another issue that draws on the connection between embryo and embryoid research was the observation that embryoid research could raise the same concerns that human embryonic stem cell (hESC) research raises insofar as both involve embryo destruction (n = 2) [28, 68]. A final set of issues regarding the ethical significance of embryoids was the question of whether they are clones and, if so, what concerns that might raise (n = 10) [21, 39, 45, 48, 52, 53, 61, 62, 65, 69].

Permissible uses of embryoid research

A third category of ethical issues concerns permissible uses or applications of embryoid research (summarized in Table 4). While several publications noted the need to set some limits on the use of embryoids (n = 3) [34, 50, 51], one publication questioned whether it would be possible to effectively draw lines limiting such research [49]. Three publications noted that while much attention is paid to the uncertain moral status of embryoids, resolving those questions will not necessarily resolve the question of whether embryoid research is permissible and, if so, which research is permissible (n = 3) [41, 55, 62]. Other articles questioned whether the intentions of researchers, such as the absence of reproductive intentions, were relevant to assessing the permissibility of embryoid research (n = 7) [21, 35, 37, 41, 48, 57, 61]. One publication raised concerns regarding the commercialization of human tissue [40]. Finally, some authors raised questions about banning the use embryoids for reproduction (n = 10) [22, 37, 39, 47, 48, 52, 53, 60, 67, 69] or to create chimeras (n = 3) [18, 52, 53].

Regulatory, and policy considerations regarding embryoid research

A significant number of publications addressed issues related to regulations, oversight mechanisms, guidelines, or policies pertaining to embryoid research (Table 4). These fell into three sub-categories. The first sub-category concerns the relationship between regulation or oversight of embryoid research and previously existing guidelines for human embryo and hESC research. A large group of publications acknowledge that existing human embryo research and cloning laws, policies, and regulations have unclear implications for embryoid research (n = 23) [9, 18, 21, 23, 27, 28, 33, 34, 41, 44, 50,51,52, 55, 57, 60, 62, 64, 66, 67, 70,71,72]. Some stated that the regulations do not apply directly, creating a regulatory gap (n = 3) [41, 60, 62]. Scholars suggest that the major reason for a regulatory gap is that embryoids do not follow canonical embryogenesis, making references to the 14-day rule or appearance of the primitive streak irrelevant (n = 13) [9, 18, 27, 31, 34, 37, 47, 53, 60, 66, 67, 69, 70].

Others were concerned with how embryoid research impacts for regulations, guidelines, policies, or oversight practices of human embryo and hESC research. Several publications indicated that embryoid research motivates revisiting the 14-day rule (n = 6) [18, 41, 49, 54, 62, 64] or has implications for the 14-day rule (n = 4) [18, 27, 41, 54] that has governed human embryo research for more than 40 years. Two publications noted that future decisions regarding embryoid research oversight or regulation could have implications for other types of stem cell research [65, 67]. Finally, several publications noted the many different definitions of embryos and fetuses used in existing policies, guidelines, laws, and regulations, and authors suggested that embryoid research points to the need to revisit those definitions (n = 9) [41, 45, 46, 55, 57, 60, 62, 64, 67].

The second sub-category concerns development of new guidelines, policies, regulations, or oversight mechanisms for embryoid research. A group of publications raised questions regarding the need for separate ethical guidelines, oversight procedures, or regulatory framework for embryoid research (n = 12) [18, 21, 26,27,28,29, 34, 44, 47, 52, 55, 67]. Insofar as separate ethical and regulatory frameworks are necessary, several publications addressed the overall goals and priorities that should inform them (n = 9) [9, 18, 21, 41, 51, 59,60,61, 66]. Some noted that an ethical framework for embryoid research should first be developed and then appropriate regulations and oversight procedures should be based on that framework (n = 6) [18, 22, 39, 47, 54, 67]. One publication raised the question of whether and how judgments about the moral status of embryoids should shape a regulatory framework and of how policies, guidelines, and regulations should treat entities whose ontological status is unclear [53]. One raised the question of how differences among embryoid types should inform regulation [41]. Another questioned the appropriate role of the precautionary principle in shaping policy and practice [39]. Several possible overarching goals or concerns regarding the development of guidelines, policies, regulations, or oversight practices were noted. One concern was that implementing new policies or applying existing rules and regulations to embryoid research could undermine important research (n = 3) [39, 41, 70]. Several publications noted the importance of maintaining public trust in science and scientific institutions (n = 3) [43, 52, 55], or promoting transparency about science (n = 4) [21, 27, 41, 69].

The third sub-category concerns the scope of any new policies, guidelines, regulations, or oversight mechanisms that might developed. Various publications addressed questions of how they should be developed and who should be involved (n = 9) [21, 27, 42, 52, 55, 57, 59, 60, 66]. In particular, one publication noted the importance of including different perspectives and securing international collaboration to avoid disrupting science [53]. Many publications indicated that public consultation, engagement, and deliberation were necessary for the process to be legitimate (n = 11) [18, 21, 27, 36, 39, 42, 45, 46, 53, 60, 70].

There were also several publications that addressed the scope of new guidelines, policies, oversight mechanisms, or regulations. According to some authors, they should address donor rights and interests such as informed consent for gamete or embryo donors (n = 4) [43, 51, 64, 73]; privacy (n = 3) [51, 61, 73]; and benefit sharing (n = 1) [73]. Publications also noted that given the evolving nature of embryoid research, any regulations, guidelines, or policies would need to be sufficiently flexible to adapt to changes in science (n = 8) [21, 23, 39, 41, 56, 59, 60, 67].

Discussion

Systematic review of ethical concerns, questions, reasons, and arguments regarding emerging technologies and practices often reveals additional questions for investigation and can help to advance ethical research, guideline development, and practice by providing an overview of the relevant issues [11, 12, 74, 75]. Our findings reveal several areas for further assessment regarding embryoid research.

Names and definitions

There is no consensus regarding the term that should be used to identify these new entities [9]. Scientists have used both broad and specific names in their publications. Some use complicated jargon-laden names that refer to what these entities are scientifically and what they are derived from. For example, a 2019 paper created a system to make entities that “recapitulate developmental events reflecting epiblast and amniotic ectoderm development in the post-implantation human embryo” [6]. This approach raises at least two concerns. First, it likely makes it more challenging for non-experts to understand what was created, rendering science less rather than more transparent. Second, similar general names are used often for both two- and three-dimensional embryoids, which have significantly different potential to recapitulate an embryo faithfully and precisely.

Decisions about what to call embryoids are important for multiple reasons. First, names and descriptions can affect ethical perceptions of embryoids, a point that others have made regarding organoids [76]. For instance, the term “synthetic human embryo” could immediately generate concerns about destruction of these entities or the possibility of gestating these entities to live birth. In contrast, a term such as gastruloid is much less likely to generate those questions, particularly among the lay public that would not associate it with gastrulation or an early embryo. Second, names can have implications for funding, oversight, and ethical assessment. For instance, if they are referred to in terms of their stem cell origin, oversight of such research might be delegated to stem cell research oversight committees. Using the term synthetic human embryos might trigger review by a committee overseeing embryo research. Depending on how they are described and treated, embryoid research could face different funding or other restrictions. For instance, ISSCR categorizes embryoids into two types: “integrated” embryoids that include all cell or tissue types (and which are to receive full reviews) and “non-integrated” embryoids, which are missing extra-embryonic cells or tissues (which do not require full reviews and instead only needed to be reported to an oversight committee) [47]. Researchers can ensure that their work is viewed as non-integrated and receives reduced oversight by specifying the lack of a cell-type.

There is also no consistent definition of embryoids [9]. No criteria that an entity must meet to be considered an embryoid have been established. There are no shared mechanisms for differentiating between simpler models and more sophisticated models that have greater capacity to develop more fully. Other than the distinction between “integrated” and “non-integrated” embryoids that some scientists use, no additional work to understand what embryoids are has been conducted [9, 47].

It may be helpful to think of questions regarding which entities should be classified as embryoids in terms of long-standing debates in the philosophy of science regarding essentialist, pluralist, and cluster concept approaches to classifying species. One possibility is that we must identify a list of necessary and sufficient conditions an entity must meet to be an embryoid. Attempting to articulate the essence of what is an embryoid could prove impossible, much as essentialist approaches to defining species have faced serious challenges and fallen out of favor [77, 78]. Alternatively, there might be multiple different ways to think about when an entity is an embryoid. Although this still would require identifying the plurality of ways such entities might be classified, it would alleviate the need to identify a single set of criteria, which is what the many varieties of pluralist accounts of species definition offer biologists [77,78,79]. Finally, borrowing from Wittgenstein, “embryoid” might be a cluster concept [80]. The entities share a family resemblance because of various properties that they have without having to possess all of the properties to “count,” much as some philosophers of science have suggested is the case for the concept “species” [81]. Defining the “complicated network of similarities overlapping and criss-crossing” (Wittgenstein §66) that are pertinent to embryoids requires further analysis and re-assessment as research advances.

In establishing criteria for embryoids, important questions related to embryos likely will surface. These include questions about when an embryoid is sufficiently similar to an embryo to be treated as such and, in turn, how embryos ought to be treated, issues we address below.

Fundamental philosophical questions

Numerous metaphysical, epistemological, and ethical questions associated with human embryo research continue to be debated [27]. Embryoids raise many questions similar to those associated with embryo research as well as new ones. We expect disagreements and uncertainties comparable to the human embryo and hESC research debates to ensue and likely to be unsolved as embryoid research advances.

Our answers to these and other fundamental questions likely will lead to different judgments about what research may and may not be done using embryoids. If we were to assume that embryoids are or ought to be treated as if they were equivalent to human embryos, ongoing disagreements about the permissibility of embryo research would apply here as well, with some advocating for different limits or restrictions and others advocating to expand such research.

Public trust, engagement, transparency and research hype

Many publications mention the importance of trust, public or stakeholder engagement, and/or transparency. However, they rarely define engagement or transparency or indicate how it could be achieved. Often, they include little or no discussion of who counts as a stakeholder and how they understand “the public” with whom they recommend engagement. There is no clarity about the type and scope of engagement they recommend nor the purpose of engagement. In addition, there is little to no discussion on how such engagement should inform research and policy decisions. For instance, Lovell-Badge et al. describe new guidelines banning genetic editing of embryos and note that “[i]t will also require meaningful public engagement, political support, and proper oversight within the relevant jurisdiction” [69]. However, neither the paper nor the ISSCR guidelines it references offers any details regarding who this public engagement should include, what it should address, the approach, methods, or models for such engagement, or how it should be used. It is also unclear how researchers would respond if public engagement results in recommendations for limiting or even restricting research.

Identifying stakeholders is an important first step toward a more robust account of public engagement regarding embryoid research. Stakeholders might include scientists, public and private funders of research, donors, patients and their families, patient advocacy organizations, policy makers, and regulators. At a broader level, members of the public in general are stakeholders since a large portion of biomedical research, especially in the USA, is publicly funded [28]. As a result, many believe that this research should be accountable to the public and that researchers should justify the use of limited resources for their work [28, 82]. For example, in the USA there is no stated priority list for research. However, the fact that the federal government invests significant resources into biomedical research, compared to other area of science, suggests that it is a major research priority. In contrast, human embryo research is not a public funding priority area in the USA and federal funding has been explicitly banned for several decades on all human embryo research [28]. The goals of public and stakeholder engagement often are not articulated, yet engagement goals should guide the methods and scope for such engagement [82].

Goals for stakeholder engagement regarding embryoid research remain unclear. ISSCR promotes public engagement for human embryo and embryoid research and has a Public Engagement Task Force [69, 83]. While ISSCR had limited stakeholder engagement when developing their guidelines, others, such as the American College of Obstetric and Gynecology, removed their 14-day limit recommendation without public comment [84]. However, engagement implies two-way communication—all parties both express their views and listen to others. If public input was not an important part of establishing policies, guidelines, or recommendations, it seems that they may be using the term “engagement” to refer to what might best be described as “public outreach.” Outreach involves scientists informing the public about the new policies and research, not listening to and considering various views [82]. True public engagement could help uncover broader social concerns related to research and ways to address them. These discussions, in turn, could play a key role in guiding future research or fostering public acceptance of new research.

As the science of embryoid research advances and these entities become more sophisticated, new questions likely will emerge. Recent work using mouse cells to create embryoids that grew in culture to the point limbs and organs was developing, including a beating primitive heart structure [10]. This work could challenge claims that embryoids will not be able to further develop in culture [10].

Overall, the process of assessing embryoid research should be iterative and therefore public and stakeholder engagement should be iterative. Scientists should consider engaging the public before the work becomes discussed extensively in the public forum, including the lay press, to foster an informed narrative. Ongoing engagement is important, particularly in light of recent significant changes to human embryo research guidelines that were adopted without robust public engagement [27, 57].

One possible explanation for the failure to engage the public is fear. Transparency, while often hailed as an important factor in building and maintaining public trust, could undermine scientists’ interest in garnering public support for embryoid research. Transparency about the significant uncertainty regarding potential future benefits of the research and whether it will yield knowledge that transforms and saves lives could dampen public support for the research. Perhaps to secure support for their work, scientists sometimes “overpromise” or hype as some scholars have suggested happened with hESC research [85]. Transparency, rather than inflated speculation, could weaken rather than strengthen public support. Similarly, transparency about the potential to develop sophisticated entities that could be models of later stage embryos as well as fetuses could interfere with public support or result in unwanted regulatory oversight.

Thus far, scientists have emphasized that embryoids do not have the potential to develop and model later stage human embryos and fetuses [47]. These remarks might be meant, in part, to assuage fears or concerns about this research that could undermine support for it. However, we do not know the true potential of many models until their limits are tested. Significant developments in the area of human embryo research as well as developments in mouse embryoid research suggest that these entities will continue to become more sophisticated [10]. There is no mechanism of accountability in place to avoid the creation of embryoids that mimic later developmental stages or with advanced neurological systems. ISSCR’s recent decision to remove the 14-day limit on human embryo and embryoid research in its guidelines results in having no developmental or time limit for such work. Given the recent incident developing humans with permanent germline edits prior to public or scientific acceptance of this work, guidelines without enforcement are likely to do little to limit researchers interested in expanding to new areas [86]. It is therefore plausible that scientists would see no reason to set a firm limit on the developmental stages or features of embryoids.

Despite numerous calls for public and stakeholder engagement and transparency regarding embryoid research in the publications we reviewed, very little substantive work has been done in this area.

Guidance, oversight, or regulation

Many (n = 21, 37%) publications called for “something” to guide embryoid research. Some authors suggest that ethical guidance will suffice, while others indicate that oversight is or will become necessary as science advances and embryoids resemble embryos more closely. Although some scholars offered recommendations for how embryoid research should be conducted, the scope of any possible guidance remains largely undefined. Existing stem cell research guidelines either do not mention embryoids [87] or provide significant flexibility regarding recommended oversight [69]. One’s understanding of what embryoids are and the values and goals one prioritizes likely will shape the kind of guidance, oversight, or regulation one deems appropriate.

To determine whether and how embryoid research should be regulated or overseen and what such oversight or regulation should require, permit, or prohibit requires, clarity regarding the purpose of regulation and oversight as well as clear definition of what is and is not acceptable will be necessary. Oversight could aim at building and maintaining trust, avoiding wrongdoing, facilitating research, or avoiding liability and ensuring compliance with funders’ and publishers’ policies. Many unanswered questions remain about who should develop regulations or policies, what they should permit and prohibit, how they should be enforced, and who should oversee such research and how.

Understandings of what kinds of entities embryoids are and their moral significance could shape assessments of appropriate regulatory and oversight mechanisms. Someone who sees them as no different from any other collection of cells or biological tissue will answer these questions differently from someone who views sophisticated embryoids as human embryos. Among the latter, views about oversight and limits will turn on their understanding of permissible research on human embryos.

Lack of consensus

Research in this field has been rapidly expanding and the number of publications increased over time. Different areas of concerns were addressed, and recommendations were made by various authors on how to respond to concerns. We did not see any consensus-building efforts, nor did we see any consensus emerging within the field. Authors associated with the 2021 ISSCR guidelines promoted specific recommendations by ISSCR, including how to name and regulate embryoids [69]. However, several of these recommendations were challenged in subsequent literature, including what to call embryoids and how to define them [9, 88,89,90]. For example, a 2023 ISSCR statement expressed concern over the use of terms that suggest that embryo models are embryos [91].This lack of consensus suggests that scientists working in this area themselves do not agree on standards or how to move forward in uncertain regulatory climates.

Limitations

There are several ways in which this systematic review did not capture every relevant publication on this topic. First, we searched only for publications in English, missing conversations on the subject, especially by Chinese researchers who are conducting embryo and embryoid research. Second, embryoid research is developing rapidly and this review reflects a snapshot of the literature up to the date on which we closed our search. Newer material that addresses more recent developments is not represented here. Finally, although the search was carefully designed by a multidisciplinary team that included research librarians, it is possible that we failed to locate some relevant publications. This is due in part to the wide range of terms that have been used to describe embryoids. Due to the nature of this review, we could not assess the quality or significance of the publications reviewed.

Conclusion

Much work remains to be done to address the ethical, legal, regulatory, and policy considerations relevant to embryoid research. As this review revealed, thus far discussion of the risks or potential harms associated with this research has been quite limited and very little attention has been given to this topic from various religious perspectives. As this work becomes more widely known, it will be important to engage people of various faiths to understand how various religious frameworks view embryoids and to expand our understanding of the full range of relevant considerations. At this time, a critical question is how to operate with respect to embryoid research in the face of uncertainty and ongoing scientific developments.

Availability of data and materials

Datasets generated and analyzed during the current study are available from the first author upon request.

Abbreviations

dpf:

Days post-fertilization

hER:

Human embryo research

hESC:

Human embryonic stem cell research

ISSCR:

International Society for Stem Cell Research

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Acknowledgements

We would like to acknowledge and thank Denice Lewis and Kathy Shields, librarians in the Z. Smith Reynolds Library at Wake Forest University, for their assistance in designing the search strategy. We also acknowledge Sally Anglin for help with preparing figures.

Funding

KRWM’s work on this manuscript was supported by the State of Qatar Endowment for International Stem Cell Policy.

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Contributions

ASI contributed to all aspects of data collection, screening, analysis, and writing. ASI, together with KRWM, wrote the first draft of the manuscript. GK contributed to all aspects of data collection, screening, analysis, and manuscript revision. ER contributed to all aspects of data collection, screening, analysis, and manuscript revision. KRWM supported the data screening process and participated fully in analysis and writing. She, together with ASI, wrote the first draft of the manuscript.

Corresponding author

Correspondence to Kirstin R. W. Matthews.

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Appendix 1: search strategy

Appendix 1: search strategy

PubMed

(“Artificial embryo” OR embryoid OR “embryonic organoid” OR “SHEEF” OR “synthetic human entity with embryo-life features” OR “SHEEFs” OR “Synthetic embryo” OR “Blastoid” OR “Gastruloid” OR “PASE” OR “post-implantation amniotic sac embryoid” OR “Micropatterned hESC colony” OR “Micropatterned hESC colonies” OR “ETS Embryo” OR “ETX Embryo” OR “human cell-culture models of early development” OR “hCCMED”) AND (Ethics OR ethic OR ethical OR moral OR Policy OR policies OR Guideline OR Guidelines OR.

Recommendation OR Recommendations OR Law OR Legal OR Regulation OR Regulatory OR.

Oversight OR Governance).

Limits: English.

Embase

(“Artificial embryo” OR embryoid OR “embryonic organoid” OR “SHEEF” OR “synthetic human entity with embryo-life features” OR “SHEEFs” OR “Synthetic embryo” OR “Blastoid” OR “Gastruloid” OR “PASE” OR “post-implantation amniotic sac embryoid” OR “Micropatterned hESC colony” OR “Micropatterned hESC colonies” OR “ETS Embryo” OR “ETX Embryo” OR “human cell-culture models of early development” OR “hCCMED”) AND (Ethics OR ethic OR ethical OR moral OR Policy OR policies OR Guideline OR Guidelines OR.

Recommendation OR Recommendations OR Law OR Legal OR Regulation OR Regulatory OR.

Oversight OR Governance).

Limits: English.

Web of Science

(“Artificial embryo” OR embryoid OR “embryonic organoid” OR “SHEEF” OR “synthetic human entity with embryo-life features” OR “SHEEFs” OR “Synthetic embryo” OR “Blastoid” OR “Gastruloid” OR “PASE” OR “post-implantation amniotic sac embryoid” OR “Micropatterned hESC colony” OR “Micropatterned hESC colonies” OR “ETS Embryo” OR “ETX Embryo” OR “human cell-culture models of early development” OR “hCCMED”) AND (Ethics OR ethic OR ethical OR moral OR Policy OR policies OR Guideline OR Guidelines OR.

Recommendation OR Recommendations OR Law OR Legal OR Regulation OR Regulatory OR.

Oversight OR Governance).

Limits: English.

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Iltis, A.S., Koster, G., Reeves, E. et al. Ethical, legal, regulatory, and policy issues concerning embryoids: a systematic review of the literature. Stem Cell Res Ther 14, 209 (2023). https://doi.org/10.1186/s13287-023-03448-8

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Keywords

  • Embryoids
  • Embryos
  • Ethics
  • Pluripotent stem cells
  • Social implications
  • Synthetic embryos