The Ethics of Stem Cell-Based Embryo-Like Structures

Given the policy and tentative aims of our larger qualitative study, we were particularly interested in collecting lay and professional (specifically, legal and ethical) perspectives. Lay participants were considered eligible for inclusion in the focus group study if they had no prior knowledge of hELS research and represented main demographic characteristics (sex, age, and educational level) of the Dutch population. The lay participants considered eligible for the pilot focus group were selected from the personal network of the first author and had not met each other previously. (APD) invited eight participants in total: first, informally via text message and, upon initial confirmation, formally via-email. Three of the selected participants ended up not joining the pilot: one for reasons unknown and two due to personal circumstances. Lay participants that were not part of the pilot were selected and approached by a professional recruitment agency and offered a small amount of financial compensation (fifty euro) for the time and effort they invested in participating in our research study. It is unknown if, and how many, participants rejected the invitation of the professional recruitment agency. Professional participants were considered eligible for inclusion in the focus group study if they had previous professional (scholarly or policy) experience in developing ethical and legal frameworks for emerging biotechnologies. Eligible participants were selected from the professional networks of the authors, and many of them were therefore professionally acquainted with one another. In total, thirteen eligible professionals were approached by (APD) via e-mail. Six of these professionals refused to participate in the focus group study: two for reasons unknown, three due to personal circumstances, and one due to a perceived lack of expertise on the topic of inquiry. Due to the COVID-19 pandemic, recruitment was kept to a minimum and ended as soon as a sufficiently diverse number of participants per focus group had been reached. All participants received the same invitational letter in advance of the interviews, which thoroughly described the topic, aims, methods, confidentiality, and informed consent procedure of the study. Written informed consent was acquired at the beginning of each interview. For an overview of the full research sample and relevant participant characteristics per group type, see table 1 and 2.

In order to enable the discussion of the different topics in a uniform manner whilst still enabling individual participants to raise and divagate into the issues they considered significant, we developed an interview guide (see Supplementary Files) to semi-structure the focus group interviews. The interview guide, which was developed based on the aforementioned agenda-setting input and supplemented by discussions with the research team, contained eighteen questions that aimed to probe the participants’ intuitions about hELS research in general and their perspectives on the conceptual, moral, and legal qualification of hELS in particular.

The interview guide was tested in a pilot and its first question—namely, “When you think of the possibility to create “synthetic embryos”/ “embryo-like structures,” what comes to mind? Do you think it is a positive or negative development?”—was amended later to include auxiliary imagery in order to incentivize greater discussion between participants. In order to do this in a thought-provoking yet simplified way, we used cartoon images to represent “negative” and “positive” associations. In the “negative” image, the scientist was depicted as a man with a malicious grin, wearing Doctor Frankenstein attire, while frowning his eyebrows as he forcefully held the tube in his left hand. In the “positive” image, the scientist was depicted as a woman with a friendly smile, wearing stereotypical laboratory attire, while enthusiastically pointing toward the tube she held in her right hand. This question was of direct relevance to the themes reported in this article (which we further explain below).

Due to the explorative aims of our research study and the COVID-19 restrictions in force at the time, sufficient diversity in views was prioritized over data saturation. In particular, four (in person and semi-structured) focus group interviews were conducted: three with lay participants—one of which was a pilot that consisted therefore of fewer participants (table 1)— and one with health law and health ethics professionals involved in policymaking (table 2). The interviews lasted two hours on average and were held at professional venues between the end of August and the beginning of September 2020. In each interview, only participants and the two first authors were present. (WD), a male professor and doctor with previous experience in qualitative research, moderated the interviews while (APD), a female PhD candidate with no previous experience in qualitative research, attended as an observer and practical facilitator. All interviews were conducted in Dutch, audio recorded, transcribed verbatim, and pseudonymized. The pseudonymized transcripts were not returned to participants for comments or corrections.

The transcripts were analysed thematically. Open codes were generated in Atlas.ti 8 software in an inductive or “bottom up” (rather than deductive or “top down”) manner in order to include findings that lie outside the traditional ethical discourse and that may have otherwise been dismissed prematurely (Braun and Clarke 2006). These codes were formulated as closely as possible to the participants’ own wording in order to avoid interpreting data too soon and subsequently validated by (WD) through a randomized sampling method. After that, the resulting list of open codes was clustered through mind mapping by (APD), which included interpreting individual codes in relation to the topics to which they referred as well as in the context of their respective discussions, and subsequently evaluated and adapted by the research team. This procedure went back and forth using the constant comparative method of analysis (Kolb 2012) until higher order themes could be consistently identified in the data and agreed upon by all members of the research team.

Participants with a positive outlook on hELS research expressed that they believed hELS could contribute to new insights into developmental disorders and fertility problems, while potentially alleviating a great deal of suffering—for example, by minimizing the use of animals and perhaps even altogether replacing the use of human embryos in research (table 3, quotes 1–4). These positive expectations were also explicitly associated with the participants’ confidence in both the researchers and in the ability of society to monitor and control the further development of hELS (table 3, quotes 5–7). For professionals, their positive outlook on hELS research had additionally to do with their confidence in the regulatory systems in which science is already embedded (table 3, quote 8).

Among participants with negative intuitions about hELS research, several expressed scepticism with regard to the utility of the field. For some, this had to do with preferentially allocating scientific efforts to more pressing human needs (table 3, quote 11). For others, it had to do with hELS research being perceived as yet another hubristic attitude toward human life, with some participants stressing that one should learn to accept one’s reproductive (mis)fortune, rather than continuously strive for improvement (table 3, quotes 10 and 12). This conviction that infertility should be accepted was notably shared by an involuntarily childless participant (table 3, quote 9) and led to the sharing of similar understandings in that group, the thrust of which was that scientific efforts to engineer the human condition are not necessarily for the best.

In addition to concerns about the utility of hELS, negative perspectives also arose in view of reservations about scientists. For some, these reservations had to do with a general scepticism about scientific knowledge fed by experiences with contradictory scientific claims (table 3, quote 14). For others, it had to do with the particular fear of hELS researchers feeling inclined to go beyond what is socially acceptable and deliberately pursue unscrupulous aims. The concern about “scientists going rogue” was especially perceptible in lay groups (table 3, quotes 13 and 15), but it was also acknowledged by professionals, one of which referred to Jiankui He, a Chinese scientist who became worldwide news for having prematurely used germline editing in birthed humans, as the epitome of a science cowboy (table 3, quote 16).

Another perceptible reason for hesitancy toward the field was the presumed inability of society to monitor and control the further development of hELS research. In lay groups, general utterances seemed to conceive of emerging biotechnologies as inevitable and uncontrollable forces of disruption (table 3, quotes 17–18), a finding that captures the broad sense of unease we felt during lay discussions and presumably indicates a certain sense of public resignation. While one of these participants expressed that his sense of unease had to do with his cynical outlook on politics in general (table 3, quote 19), most participants seemed more concerned about the practical feasibility of setting limits to scientific developments. This concern had to do with three main challenges: (i) regulative terms and definitions being quickly outdated as a result of new scientific developments (table 3, quotes 20–21), (ii) scientific developments continuously shifting previously set and societally agreed upon norms (table 3, quote 22), and (iii) rules for research with hELS requiring consistent application across international jurisdictions (table 3, quote 23).

The concern that it may not always be feasible to regulate hELS research in view of these challenges was particularly salient with regard to the commercial and (hypothetical) reproductive application of hELS. Participants worried that commercial uses may cause the development of hELS research to be driven by financial interests, such as those of the pharmaceutical industry, rather than by the interests of society and humanity (table 3, quote 24). Moreover, one of the participants in the professional group feared that the commercial application of hELS might lead to or otherwise encourage the commodification of (sensitive) human material (table 3, quote 26). Finally, lay and professional participants were also perceptibly wary of using hELS for reproductive applications, often because this would amount to a form of cloning, which was perceived by many as morally wrong (table 3, quotes 27, 29–31). The reasons for viewing hELS cloning as frightful or fundamentally wrong were not spelled out by these participants, nor were they always immediately clear to others in the group (table 3, quote 28). The categorical nature of these rejections during the discussions, however, lead us to hypothesize that they must relate to fundamental questions about human identity and human existence, rather than about offspring risks.

Several participants also expressed having ambivalent feelings about hELS research, with most of them arguing that, despite being inclined towards a more positive outlook, they would have preferred there to be a “slider” in between the positive and negative images we presented them with (table 3, quote 33). This ambivalence arose due to (i) scientific research being perceived as morally indeterminate, and (ii) (lack of) knowledge about comparable emerging biotechnologies.

On the former, participants explained that they did not immediately have positive or negative associations, because that would depend on how hELS research is used: both lay and professional participants noted that scientific research may be used for good and bad purposes, and that research with hELS can similarly work both ways (table 3, quotes 32–34). The fact that these participants did not conceive of hELS research as an “either/or” but as an “and/and” endeavour, suggests that it is the perceived moral indeterminateness of research that lies at the heart of their mixed feelings towards this particular field.

On the latter, there were notable differences between lay and professional participants. Whereas, in lay groups, participants explicitly indicated that their doubt had to do with not knowing enough about hELS research (table 3, quotes 35–37), the professionals’ immediate contemplation of potentially preferable alternatives (table 3, quotes 38–39) suggests that their hesitation arose instead from their high familiarity with comparable debates and alternative biotechnologies.

The common ground between lay and professional participants was much greater when it came to their requirements for having (more) confidence in hELS research. Differences in expertise levels did not seem to get in the way of reaching a general sense of consensus, with both lay and professional group emphasizing the importance of developing at least some regulation for hELS research and suggesting similar regulatory limits. On the unclear legal status of hELS, for instance, most lay and professional participants agreed that insofar as hELS are incapable of further development they are indeed not human embryos in terms of the Dutch legal definition, which defines the embryo as “a cell or cluster of cells with the potential to develop into a human being” (Embryos Act 2002). Nevertheless, both emphasized that this alone should not preclude them from being due at least some degree of legal protection. How much protection they should be due depended in turn on their different views on the conceptual and moral qualification of hELS (Pereira Daoud, et al. 2022).

The first theme underscored the spectrum of perspectives commonly found in related fields of research, with public views often ranging between positive, ambivalent, and negative perspectives (Pauwels 2009, 2013; Ancillotti, et al. 2016; Avellaneda and Hagen 2016; Gouman, Vogelezang, and Verhoef 2020). The fact that these differences were also prevalent in the focus group with professionals suggests that they are not the product of a knowledge deficit concerning science, supporting the view that scientific knowledge does not necessarily cultivate a more positive attitude toward particular avenues of research (Priest, Bonfadelli, and Rusanen 2003; Akin, et al. 2017). At the same time, this group was notably less prone to cynicism than lay groups were. While professionals worried about the occasional “cowboy” (e.g., Jiankui He) but had consensual confidence in the governance mechanisms already embedded in science, lay participants associated hELS research more often with severe dystopias (e.g., The Boys from Brazil (table 3, quote 27)) and showed greater concern about hostile intentions on both individual (i.e., “mad-scientists,” e.g., Josef Mengele (table 3, quote 15)) and institutional levels (e.g., foreign governments (table 3, quote 15)). The qualitative difference between the professionals’ milder and consensual concern for “misuse” and the lay participants’ more severe and discordant concern for “abuse” may relate to what the literature describes as “deference to scientific authority”, i.e., the “stable, long-term reliance on the scientific process and its application” (Akin, et al. 2017, 291). The professionals’ explicit mention that their confidence in hELS research arose from their familiarity with the broader “processes, norms, and structures of the scientific enterprise” (Scheufele 2013, 14044), of which governance mechanisms (e.g., peer-review, ethics committees) are an intrinsic part, seems to support this thesis. Notwithstanding, there may also be other factors influencing these differences. Educational attainment and trust in other institutional bodies, for instance, have previously been found to play a significant role in the Dutch public’s trust in science (van den Broek-Honingh and de Jonge 2018), which could arguably also help explain the qualitative contrast we found between lay and professional participants. From a policy perspective, these findings suggest that it might be wise (for the Dutch government) to inform people not only about the nature of scientific advancements but also, and perhaps more importantly, about the governance mechanisms in which that scientific enterprise is embedded. Without this knowledge, disproportionate concerns about emerging (bio)technologies are more likely.

The second theme showed that most professional and lay participants are receptive to research with hELS as long as the field is regulated. With the exception of a few participants in lay and professional groups, this applied regardless of the (conceptual and moral) qualification of these structures (Pereira Daoud, et al. 2022). Calls for governance are common in synthetic biology and related fields of research, including organoid research (Boerset al. 2018; Haselager, et al. 2020; Lensink, et al. 2021; Bollinger, et al. 2021), and possibly related to the lay participants’ sense of biotechnological ineluctability that we and others (Ancillotti, et al. 2016) have found. Despite the foregoing differences in confidence between lay and professional groups, both groups ended up proposing similar regulatory criteria for having confidence in (the regulation of) hELS research. First, and as previously found by Pauwels (2009), the domain of application played a decisive role in the acceptability of hELS research. Here, two domains were especially contentious: (i) commercial applications, which are known to affect public attitudes towards related emerging biotechnologies (Critchley 2008; Critchley, Bruce, and Farrugia 2013), including organoid-technology in the Netherlands (Boers, et al. 2018; Lensink, et al. 2021), and (ii) reproductive applications, which we discuss in the next section. Second, and in support of the recommendations of Aach and colleagues (Aach et al. 2017), regulating the development of morally concerning features in hELS was deemed crucial by participants, though it remains to be established whether the features they suggested—i.e., developmental potential and (specific features in) organogenesis—should be considered as such (Pereira Daoud, et al. 2022). Finally, and like in previous studies (Ancillotti, et al. 2016; Boers, et al. 2018; Lensink, et al. 2021), collaborative design through public engagement was considered vital in having public confidence in (the regulation of) hELS research. The participants’ call for increased societal engagement involved the three types of motivation previously demarcated by Stirling (2008): “normative—organizing dialogues are good for reasons of democracy, equality or justice; instrumental—building trust, a positive reputation and support; and substantive—moving towards desirable goals, such as environmental quality, public health and human well-being” (Steen and Nauta 2020, 599). The fact that participants in each group voiced these motivations offers proof-of-concept for RRI frameworks in at least two ways. One, it underscores that societal engagement is not only societally desirable but also desired by society; two, it demonstrates that engaging the public is practically feasible, with our results demonstrating that both lay and professional citizens reach similar conclusions.

Taken together, these findings suggest two kinds of concern specifically raised by hELS: (i) general concerns about the technology, and (ii) specific concerns about the application of the technology. Concerns of the general kind arose in relation to what hELS research was perceived to represent, namely, a further step toward potentially deplorable human dominion over life. The shift in moral focus from mere tinkering to creating de novo is commonly found in intersecting fields of research (de Vriend 2006; Pauwels 2009; Ancillotti, et al. 2016), and often contextualized within the extensively discussed “playing God” framework (van den Belt 2009; Dabrock 2009; Douglas and Savulescu 2010; Dragojlovic and Einsiedel 2012; Link 2013; Kaebnick 2014). This framework essentially conveys the view that it would be wrong for humans to (re-)design and create life because so doing would amount to a certain kind of hubris, i.e., a failure to recognize human limitations (Douglas and Savulescu 2010). This view was echoed in principled lay statements about the relationship between humans and the natural world and of the place humans should have within it (table 3, quotes 9–12), which could help explain the “exceptionally strong moral injunctions—strong enough to generate a view that an activity should be flatly banned” (Kaebnick 2014, 146) we found in these groups. The professionals’ emphasis on the two-sidedness of research and importance of deciding what counts as “good” democratically (table 3, quotes 42, 77–78) suggests that their precautionary stance stemmed instead from “the dilemma arising when (…) the risk of harmful use is sufficiently high that it is no longer clear whether that knowledge should be pursued or disseminated” (Douglas and Savulescu 2010, 689).

Specific concerns revolved around the application of the technology in research and reproductive contexts. The research use of hELS was warmly welcomed by participants insofar as hELS do not possess the features that they considered morally concerning. Prominent examples of such features were a heart(beat), central nervous system, and developmental potential (table 3, quotes 61–72). Whereas a central nervous system is widely accepted as a morally important marker because of how it could denote a capacity to experience pain, the moral relevance of a heart or heartbeat remains contested in the ethical literature (Romanis 2019; Colgrove 2020). It is unclear why a heart(beat) would be morally relevant in itself, apart from indicating an ongoing development towards a new human individual. But if that were the reasoning, then it would not be the heart(beat) but rather the potential to grow into a human being that bears moral relevance. Should certain hELS acquire this potential upon further improvement, the question of whether they are to be regarded as human embryos themselves emerges, which would stand in the way of presenting them as morally less-sensitive types of research material. At this point, there is an interesting parallel with the dilemma emerging in the field of human brain organoids. As one commentator has put it, “If it looks like a human brain and acts like a human brain, at what point do we have to treat it like a human brain—or a human being?” (Greely 2020, 35). In light of our findings, further exploration of public perspectives on common ethical issues in brain organoid and hELS research would thus seem warranted (Sawai, et al. 2022). Even though the moral bearing of the embryo’s (or hELS’) “potential” remains a matter of extensive debate (Stier and Schoene-Seifert 2013; Hyun 2013; Piotrowska 2020; Sawai, et al. 2020; Denker 2021), it is noteworthy that the participants’ discussions of the concept (table 3, quotes 66–72) closely aligned with the different positions taken in that scholarly debate. Whereas some participants viewed that potential as granting some but not absolute protection, others argued that its acquisition should be seen as a categorical cut-off point for research with hELS (Pereira Daoud, et al. 2022). These results seem to support precautionary policy trends that distinguish between hELS based on whether or not they can be reasonably expected to lack developmental potential. This distinction is drawn in the Updated Guidelines of the International Society of Stem Cell Research (ISSCR 2021), which recommend subjecting research with hELS that aim to model the “integrated” development of human embryos to greater regulatory oversight and is beginning to be formalized by law in some jurisdictions, including the Netherlands. At the same time, our results also reflect the lack of consensus in the ethical literature about the degree of moral respect that that potential can confer. This means that, even if research with some (“integrated”) hELS were to be regarded as morally equivalent to research with human embryos based on developmental potential, this would by itself still tell us very little about which regulatory conditions and limits we should draw.

The reproductive application of hELS was an unexpected but major point of concern. In the scientific literature, the reproductive application of hELS is usually regarded as too far-off, if not too far-fetched (Cyranoski 2019; Nicolas, Etoc, and Brivanlou 2021; Posfai, et al. 2021; Popovic, Azpiroz, and Chuva de Sousa Lopes 2021), and explicitly condemned by the scientific community (ISSCR 2021). This lack of theoretical grounding combined with the already broad scope of our discussions led us to focus exclusively on non-reproductive applications of hELS research. However, despite our conscious effort to guide focus group discussions towards non-reproductive applications, the theoretical possibility of using hELS to create offspring later turned out to be a recurring thread, with participants single-handedly asking about and consensually arguing against the use of hELS in reproductive contexts. The particular reasons to consider the use of hELS for human reproduction as “scary” or “unethical” (table 3, quotes 26, 29) remained largely undetermined, but their explicit associations with cloning (table 3, quotes 27–28, 30) and eugenics (table 3, quotes 58–59) provide telling clues. Whereas references to eugenics seem to indicate a familiar anxiety about societally contentious horizons associated with reproductive selection and enhancement, as thoroughly discussed in the past (Evers 1999; Wilkinson 2010a, 2010b), their combination with concerns related to cloning may be taken to refer to the theoretical scenario of producing genetically modified clones with future hELS technologies (table 3, quote 26). While we cannot establish this hypothesis with certainty, the fact that the reproductive application of hELS is discussed so scarcely in the scientific (and ethical) literature while so vividly present in the minds of lay and professional participants makes it certainly worth investigating further.