Transparency in controversial research: A review of human embryo research publication ethical disclosure statements

Summary

In 2021, the International Society for Stem Cell Research (ISSCR) released updated guidelines that included human embryo research guidance. Requiring ethics statements in publications using human embryos is one way to verify adherence to these guidelines. A review of top-tier biomedical journal requirements identified only one publisher that requires a human embryo statement. A review of articles using human embryos from top-tier biomedical journals found that all contain some form of ethics statement, but they differ in content and location. Requiring ethics statements with specific elements could improve transparency and adherence to research guidelines.

In this article, Matthews et al. describe how ethics statements in publications can increase research transparency. Although few biomedical research journals require a human embryo research ethics statement, all human embryo papers in top-tier journals (from 2016 to 2022) had one. These statements varied in content and location in manuscripts. Standardized guidelines on what they contain are needed.

Introduction

Scientists traditionally define a human embryo as the stage of development from fertilization through the first trimester or 8 weeks, after which time it is a fetus (Schoenwolf et al., 2015). Research on human embryos can reveal knowledge about the early stages of human development and differentiation that allows us to broaden our understanding of these processes. It can also identify issues causing and potential treatment for infertility. Before 2016, embryo research was focused on development within the first few days postfertilization (dpf) or later in development, when tissue samples can be collected following elective abortions. However, in 2016, two research groups demonstrated technology that allowed human embryos to be grown to later stages up to 14 dpf (Deglincerti et al., 2016; Shahbazi et al., 2016). In addition, in 2014, researchers began developing cell culture models, which we refer to here as embryoids, that recapitulate stages of early embryo development (Warmflash et al., 2014). These embryoids have extended our understanding of embryo development beyond 14 dpf and include both nonintegrated (simple models with limited cell types) and integrated embryoids (sophisticated models that try to more accurately mimic an embryo) (Amadei et al., 2022; Clark et al., 2021; Weatherbee et al., 2023).

Policies and guidelines for human embryo research exist. Until recently, one important guideline was the 14-day limit, which many countries, but not the United States, have embedded into law (Matthews and Morali, 2020). The 14-day limit only permits research using human embryos until they reach 14 dpf and/or the presence of a primitive streak, at which point work should stop (Matthews et al., 2021a). In the United States, this limit was an informal guideline, which has no formal limit on research using human embryos beyond a ban on federal funding (Matthews and Morali, 2020).

This research presents several ethical challenges. Some view life as starting at conception and thus object to research that uses or destroys human embryos (George and Tollefsen, 2023; Matthews et al., 2021a, 2021b). Additional concerns include the sources of the embryos, particularly as they relate to informed consent, potential risks to egg donors when embryos are created specifically for research purposes, the use of tissues from aborted embryos, and the oversight required for embryo research. There are also scholars who believe that embryos have “special status,” which limits what ought to be done with them or the purposes for which they may be used in research. After the advancements in human embryo research in 2016, new calls emerged suggesting the limit be moved or dropped entirely (Hyun et al. 2016, 2021). Some scholars object to removing the 14-day limit entirely or without another limit to research demonstrating to the public that scientists can respect the compromise. (Hurlbut et al., 2017; Matthews et al., 2021a). The 14-dpf limit was based on a compromise to permit research to an extent, but also ensured that the human embryo was treated as “special” and deserving of additional rights not granted to other cell sources. In addition, this compromise was based on the rationale that (1) it is the first sign of complex differentiation; (2) approximately half of all embryos are believed to fail to thrive past this point; (3) it is believed to be the point at which twinning no longer can occur and as a result, individuality is granted; and (4) the primitive streak (which occurs at approximately 14 dpf) is an easily observable feature (Matthews et al., 2021a).

Research using human embryos and embryoids has become complex scientifically, politically, and ethically. As a result, scientists recently started promoting that the term embryo itself be redefined to ensure different categories of research; embryos, integrated embryoids, and nonintegrated embryoids are treated differently politically and for regulatory or oversight purposes. To address changes in the field, in 2021, the International Society for Stem Cell Research (ISSCR) published updated stem cell research guidelines that included recommendations for human embryo research (Clark et al., 2021; ISSCR, 2021). The revised guidelines no longer categorically prohibit research on embryos beyond 14 dpf. The previous set of guidelines, published in 2016, placed culturing human embryos “beyond 14 days or formation of the primitive streak, whichever occurs first” in the prohibited research category (ISSCR, 2016). Instead of a straight prohibition, the 2021 ISSCR guidelines suggested that scientists and regulators “lead public conversations on the scientific significance as well as the societal, moral, and ethical issues of allowing such research” (Clark et al., 2021). Allowing embryos to be cultured for longer periods if local laws and communities support this work is a significant change. In addition, the 2021 guidelines recommend that human embryo research “be subject to review, approval, and ongoing monitoring, as appropriate, through a specialized oversight process” (ISSCR, 2021).

Calls for public discussion and research oversight are part of broader calls for transparency in science reporting (Clark et al., 2021; Johnston et al., 2022; Lovell-Badge et al., 2021; Matthews et al., 2021a; Ormand et al., 2017; Office of Science and Technology Policy, 2022). One method for increasing transparency in human embryo research is to provide details in published manuscripts regarding features pertinent to the ethical conduct of research, such as how the embryos were obtained and the ethical oversight that was provided.

This paper reviews the transparency of human embryo research published in the peer-reviewed primary literature from 2016 to 2022. We studied human embryo research publication guidelines and primary articles from the top 100 journals, based on 5-year impact factors. The majority of top-tier biomedical journals had human subjects and animal research reporting guidelines, but only one required a statement for papers using human embryos. From these journals, we identified primary research papers that used human embryos and identified statements in their text that included information related to ethical conduct. All 46 articles using human embryos had some form of an ethics statement, regardless of whether the publishing group required it. They were predominantly located in the Methods section (n = 39) and contained information about the consent (n = 44) and oversight (n = 43) processes. Fewer articles described how many embryos were used (n = 10) and the developmental age of the embryos (n = 27).

Based on these findings, we recommended that statements should be included and standardized to include guidelines or laws followed, how long the embryos were grown developmentally, whether consent was obtained from the embryo donors and what information they were given, and whether the research was subject to oversight and approval, and, if so, by whom. Requiring greater transparency regarding the ethical conduct of human embryo research is one way to respond to calls for more transparency in science reporting, emphasizes the importance of the ethical conduct of such research, and increases the likelihood of adherence to existing regulations and guidelines.

Review of journal policies

In the first phase of this work, we reviewed human subjects, animal subjects, and human embryo research policies in top-tier biomedical journals. We chose to look at all three policies, since research on early human embryos was limited prior to 2016, due to technical challenges. Many nations have laws requiring oversight for animal and human subjects, and, as result, we postulated that journals were more likely to include these requirements than human embryo requirements. Furthermore, human subjects requirements could overlap with details that a human embryo research requirement would have, such as donor consent, and serve the same purpose. We believe it is valuable to compare the level of transparency in reporting for each type of research.

From the list of 100 top-tier journals, based on 5-year citation rates, 32 journals were identified as publishing biomedical research. Several of the journals were from the same publisher with the same policies; therefore, only 15 journal policies were reviewed (see Table 1, supplemental materials experimental procedures, Figure S1, and Table S1 for journals included and excluded).

Table 1.

Journals included in assessment of policy statements from top 100 cited journals (Clarivate)

JCR rank	Journal	Policies for research with animals, human subjects, and embryos
3	NEJM	https://www.nejm.org/about-nejm/editorial-policies
6	The Lancet	https://els-jbs-prod-cdn.jbs.elsevierhealth.com/pb/assets/raw/Lancet/authors/tl-info-for-authors-1659004940517.pdf
13	JAMA	https://jamanetwork.com/journals/jama/pages/instructions-for-authors#SecEthicalApprovalofStudiesandInformedConsent
15	Nature	https://www.nature.com/nature-portfolio/editorial-policies/ethics-and-biosecurity#studies-involving-animals-and-human-research-participants
21	Science	https://www.science.org/content/page/science-journals-editorial-policies#guidelines-for-specific-types-of-studies
22	Nature Biotechnology	Subsidiary journal of Nature; see Nature policy
23	Nature Medicine	Subsidiary journal of Nature; see Nature policy
25	Cell	https://www.cell.com/pb-assets/journals/research/cell/methods/Methods_Guide_Cell-1622124325393.pdf
26	Nature Methods	Subsidiary journal of Nature; see Nature policy
27	The Lancet Oncology	Subsidiary journal of The Lancet; see The Lancet policy
32	The Lancet Neurology	Subsidiary journal of The Lancet; see The Lancet policy
36	Cancer Discovery	https://aacrjournals.org/pages/editorial-policies
38	BMJ British Medical Journal	https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/publication-ethics
46	Nature Genetics	Subsidiary journal of Nature; see Nature policy
49	Cancer Cell	Subsidiary journal of Cell; see Cell policy
53	Journal of Clinical Oncology	https://ascopubs.org/jco/authors/journal-policies
58	Immunity	Subsidiary journal of Cell; see Cell policy
62	Cell Metabolism	Subsidiary journal of Cell; see Cell policy
65	JAMA Oncology	Subsidiary journal of JAMA; see JAMA policy
66	The Lancet Diabetes and Endocrinology	Subsidiary journal of The Lancet; see The Lancet policy
67	European Heart Journal	https://academic.oup.com/eurheartj/pages/general_instructions#Journal-Policies
68	The Lancet Respiratory Medicine	https://els-jbs-prod-cdn.jbs.elsevierhealth.com/pb/assets/raw/Lancet/authors/tlrm-info-for-authors-1659004961843.pdf
78	Circulation	https://www.ahajournals.org/research-guidelines
79	Nature Immunology	Subsidiary journal of Nature; see Nature policy
84	Nature Cell Biology	Subsidiary journal of Nature; see Nature policy
85	Journal of Extracellular Vesicles	https://onlinelibrary.wiley.com/page/journal/20013078/homepage/author-guidelines
89	Cell Stem Cell	Subsidiary journal of Cell; see Cell policy
90	Cell Research	https://www.nature.com/documents/cr-gta.pdf
91	Nature Neuroscience	Subsidiary journal of Nature; see Nature policy
93	Annals of Internal Medicine	https://www.acpjournals.org/pb-assets/pdf/AnnalsAuthorInfo-1622139458027.pdf
96	The Lancet Infectious Diseases	Subsidiary journal of The Lancet; see The Lancet policy
98	The Lancet Digital Health	Subsidiary journal of The Lancet; see The Lancet policy

JAMA, Journal of the American Medical Association; JCR, Journal Citation Report; NEJM, New England Journal of Medicine.

All 15 journals reviewed had some form of human subjects policy and referenced guidelines from professional organizations, such as the International Committee of Medical Journal Editors, the Committee on Publication Ethics, or the World Health Organization (Table 2). With the exception of the New England Journal of Medicine (NEJM), all of the other journals required a human subjects statement in the text and mention of an external ethics oversight committee. Thirteen journals referenced specific guidelines to follow, such as Consolidated Standards of Reporting Trials, Animal Research: Reporting of In Vivo Experiments, or the Declaration of Helsinki (from NEJM and the Journal of Extracellular Vesicles). The Lancet Respiratory Medicine has a shorter policy on consent than other Lancet journals. Its policy is missing the following statements: “Appropriate written consents, permissions, and releases must be obtained where you wish to include any case details, personal information, and/or images of patients or other individuals in The Lancet journals in order to comply with all applicable laws and regulations concerning privacy and/or security of personal information” (Lancet, 2023). There is no explanation regarding why the statement is missing.

Table 2.

Human, animal and embryo policies from top-tier biomedical journal publishers

Journal publisher	Policies for			Inclusion of statement for			Mention of
	Human subjects/clinical trials	Animal subjects	Human embryos	Human subjects/clinical trials	Animal subjects	Human embryo	Professional organizations	Regulatory guidelines	Ethics committee approval
NEJM	Y	N	N	N	N	N	Y	N	N
The Lancet	Y	N	N	Y	N	N	Y	Y	Y
JAMA	Y	Y	N	Y	Y	N	Y	Y	Y
Nature	Y	Y	Y	Y	Y	Y	Y	Y	Y
Science	Y	Y	N	Y	Y	N	Y	Y	Y
Cell	Y	Y	N	Y	Y	N	Y	Y	Y
Cancer Discovery	Y	Y	N	Y	Y	N	Y	Y	Y
BMJ	Y	Y	N	Y	Y	N	Y	Y	Y
Journal of Clinical Oncology	Y	N	N	Y	N	N	Y	Y	Y
European Heart Journal	Y	Y	N	Y	N	N	Y	Y	Y
The Lancet Respiratory Medicine	Y	Y	N	Y	N	N	Y	Y	Y
Circulation	Y	Y	N	Y	Y	N	Y	Y	Y
Journal of Extracellular Vesicles	Y	Y	N	Y	Y	N	Y	N	Y
Cell Research	Y	Y	N	Y	Y	N	Y	Y	Y
Annals of Internal Medicine	Y	N	N	Y	N	N	Y	Y	Y
Totals	15	11	1	14	9	1	15	13	14

Only 10 journals had animal research policies. The 5 journals without policies—NEJM, The Lancet, Journal of Clinical Oncology, The Lancet Respiratory Medicine, and Annals of Internal Medicine—focus on clinical human research. Therefore, an animal research policy may have been deemed unnecessary.

Different journals required different content to be placed within their human subjects and animal research statements. For human and animal subjects’ research, Cell Press requires that the authors include the name of the ethics committee that approved the work and a statement “that all experiments conform to the relevant regulatory standards” (Cell, 2023). In contrast, the Science magazine animal research statement required research “adherence to the NIH Guide for the Care and Use of Laboratory Animals or the equivalent, and that they obtained the appropriate Animal Care and Use approvals from their institution” as well as details on the animal “species, strain, sex, age, origin, care (including pain reduction and humane euthanasia procedures), and housing of laboratory animals” (Science, 2023).

Of note, Cell Press changed their requirements for reporting methods in 2016 (Cell, 2023). The journal standardized their methods format, calling it STAR, or “Structured, Transparent, Accessible Reporting,” Methods. This change streamlined methods sections and encouraged consistency in the information reported in the Methods to improve reproducibility. In addition, it increases oversight transparency.

Only one publisher, Nature Portfolio, which published 8 journals in our sample (Table 2), had an explicit human embryo research policy and required an ethics statement. The Nature Portfolio guidelines states: “Manuscripts that report experiments involving the use of human embryos and gametes, human embryonic stem cells and related materials, and clinical applications of stem cells must include confirmation that all experiments were performed in accordance with relevant guidelines and regulations” (Nature, 2023). Furthermore, the publisher requires “an ethics statement identifying the institutional and/or licensing committees approving the experiments and describing any relevant details” and “confirm that informed consent was obtained from all recipients and/or donors of cells or tissues, where necessary, and describe the conditions of donation of materials for research, such as human embryos or gametes” (Nature, 2023). However, the subsidiary Nature journal Cell Research, does not have a human embryo policy or require an ethics statement, although Nature’s other subsidiary journals did. Cell Research is a collaboration between the National People’s Congress and the Chinese Academy of Sciences. It is unclear whether excluding this policy was an oversight or intentional.

Published ethics statements

In phase 2 of our work, we searched PubMed primary research articles for publications reporting on research that (1) used or created human embryos, (2) were published in any of the 32 top-tier biomedical journals included in this review, and (3) were published from 2016 to 2022 (for more information, see the supplemental experimental procedures). The goal of this analysis was to determine how well researchers reported following human embryo research guidelines and what information was given in the ethics statements showing that the work was conducted with ethical oversight.

The search was focused on 7 years that included 2 important changes regarding human research: the release of the 2016 ISSCR guidelines for stem cell research (which contained a ban on human embryo research beyond 14 dpf) and the first publications observing in vitro human embryos for up to 14 days and continued beyond the release of the 2021 ISSCR guidelines (Deglincerti et al., 2016; ISSCR, 2016; Reardon, 2016; Shahbazi et al., 2016). This range allowed us to see the impact of both the 2016 and 2021 guidelines on research reporting.

We used the traditional scientific definition of an embryo, from fertilization to 8 weeks (Schoenwolf et al., 2015). For the purposes of this paper, we have defined ethics statements as any declarations in primary research articles in which authors mention adherence to guidelines, policies, laws, or regulations for research using specific organisms (humans, animals, or human embryos), clinical trial registration, informed consent, or oversight by a committee. We specifically focused on publications that described the use, creation, or destruction of human embryos that were developed from fertilization. This work includes observing human embryos, obtaining embryonic tissues (from an elective abortion), or using human embryos to develop pluripotent stem cell lines. We did not include publications that described the use of human embryonic stem cells previously created, nor did we include ones that developed or used embryoid models unless the authors used human embryos as a control or to develop a cell line.

We identified 46 articles that specifically described research using, creating, or destroying human embryos created via fertilization; we did not include in our analysis embryoids created from pluripotent cell lines unless the research involved embryos as controls or embryos were used to develop the line (Table S2). These articles were published in 9 different journals: Cell (n = 6), Cell Research (n = 3), Cell Stem Cell (n = 11), Immunity (n = 1), Nature (n = 13), Nature Cell Biology (n = 7), Nature Genetics (n = 3), NEJM (n = 1), and Science (n = 1). No articles were found in the other 23 journals (see Table 1 for a full list of journals).

All 46 articles had some form of an ethics statement. Ethics statements ranged from 35 words to 752 words in length. The content and organization of the statements varied immensely. The ethics statements were found in the Methods section most often (n = 39). Seven articles had their ethics statements spread out in multiple parts. Several papers had a second ethics statement located in the Results (n = 3), Discussion (n = 1), or supplementary materials (n = 1) sections. One article, published in Nature Cell Biology, had ethics statements in three sections: the Methods, Results, and Discussion (Shahbazi et al., 2016).

Almost all of the ethics statements contained information on the consent process (n = 44)—usually general notes about using informed consent and often referencing an oversight committee (national board, institutional review board, and/or stem cell research oversight committee). A few provided additional details related to what donating couples were told during the process such as “goals of the research, clinical procedures used in the study, potential benefits and risks to research participants, and steps taken to ensure that the privacy of each embryo donor was well protected” (Deglincerti et al., 2016). In addition, 13 articles discussed financial incentives to donors (oocyte, gamete, and/or embryo). The majority (n = 12) were declarations that no one was paid. Only 1 paper noted payment of “£500 per [egg] donation cycle” (Cavazza et al., 2021).

Many articles (n = 43) mentioned a review board or ethics committee in their statements (Table 3). Twenty-six statements mentioned a national oversight committee, such as the UK Human Embryology and Fertilization Authority (n = 9), Agence de la Biomédecine (n = 5), or the Chinese Ministry of Science and Technology (n = 5). Other references were to other United Kingdom and Chinese authorities and Austrian, Swedish, Belgian, Danish, and Israeli oversight authorities. Articles also mentioned local oversight boards such as the Rockefeller University institutional review board or the Medicine Ethics Committee of the First People’s Hospital of Yunnan Province, and 1 mentioned California state law.

Table 3.

Different themes and content identified in human embryo ethics statements

Themes	Definitions	No. of articles
Oversight
Local review board or ethics committees	Institutional, university, or regional research oversight committee	42
Laws and regulations	Laws, regulations, or state/national oversight authorities	26
Society guidelines	Scientific or medical societies guidelines	14
Time limit	Reference to 14-day limit or other similar restriction	8
Information on embryos used
Source	Location samples were obtained from	41
Number	How many embryos were used in experiments	10
Time stage	Developmental stage or age of embryos used in experiments	27
Other features
Consent	Information on consent procedure and how research was explained to patients	44
Financial compensation	Information on whether or not participants were given compensation for embryo donation	13

Scientific societies were referenced in 14 articles, with ISSCR guidelines being the most common (n = 12). The articles were published in Cell Press journals (n = 3) and Nature journals (n = 9), referencing both the 2016 and 2021 guidelines. Seven papers that referenced the ISSCR guidelines also noted that the embryos used were <14 dpf, including in papers referencing the 2021 guidelines. In addition, 3 articles mentioned the US National Academies of Science, Engineering, and Medicine and 1 mentioned the American Society for Reproductive Medicine guidelines.

The ethics statements frequently described the source of embryos (n = 41), but less often gave the developmental age of the embryo (n = 27) or the number of embryos used (n = 10). We used the traditional scientific definition of an embryo, from fertilization through 8 weeks (Schoenwolf et al., 2015). Researchers described work throughout this range. One set of articles (n = 18) focused on early development (within the first 14 dpf). These embryos were created for research purposes or leftover embryos were obtained from in vitro fertilization clinics. Other papers used samples obtained from tissue banks or from elective abortions (n = 8), which represented older samples up to 8 weeks. A few papers also included fetal tissue samples with the embryonic tissues studied. One paper had both early embryos (day 6) and later embryo samples at Carnegie stage 12, or approximately 30 dpf (Floros et al., 2018).

The 14-day limit was mentioned in only 8 articles, usually in reference to stopping research in advance of it. Only 1 paper was based in the United States; the other 7 were based in China (n = 3), the United Kingdom (n = 2), France and Austria (n = 1), and France and Belgium (n = 1), which have 14-day limits written into their national policies (Matthews and Morali, 2020). However, there were other papers with research based in these countries that did not mention the limit and other papers that used embryo tissues older than 14 dpf.

Conclusion

Over the past decade there has been a strong push toward increasing public engagement with and transparency of scientific research. One aspect of this is to promote open access to publications and data sharing. In 2022, the White House Office of Science and Technology Policy (OSTP) issued a notice requiring all taxpayer-funded research to be open source across various fields by 2025 (Office of Science and Technology Policy, 2022). The European Commission has created the European Open Science Cloud, which allows for data sharing in an already established platform, as well as specific guidelines encouraging open access research (European Commission, 2023). However, for controversial areas of research, such as human embryo development, opening access to research could increase criticism about the work. To avoid this, scientists should be prepared to explain their work as well as show that it was conducted with sufficient ethical oversight and in accordance with established relevant guidelines, regulations, and laws. One way to ensure this is to have ethics statements within manuscripts that describe this process.

Despite finding that only one publisher, Nature Portfolio, required an ethics statement related to human embryo research, our research found that all of the articles contained some relevant information, although at times a bit brief and with limited detail and in different locations. Another publisher, Cell Press, required an ethics statement in their STAR Methods, but did not specifically require information about embryos. The other journal publishers required statements about human subjects, but left it to the authors’ discretion as to what to include within the ethics statement. As a result, statements varied in length, the information presented, and the location within manuscripts, although most statements were included in the Methods section. Placing the ethics statement within the Methods allowed for authors to discuss the oversight while describing its use. Some articles even placed the ethics statements in its own titled subsection, making it easier to locate.

Interestingly, more than half of the articles were published by Nature Portfolio (n = 26), with 13 articles in their flagship journal Nature. Nature Portfolio was the only publisher that explicitly required a human embryo ethics statement. In contrast, the peer-reviewed journal Science only published 1 article using human embryos during this time. There are many reasons for choosing a particular journal, and why articles were published in each journal is beyond the scope of this project; however, transparency requirements did not seem to dissuade research from submitting articles to Nature Portfolio.

The majority of ethics statements contain information related to the donation consent, ethical review committee that approved the work, and the source of embryos. This could have been because the information was similar to information required by journals for human subjects research. Many also noted guidelines, such as ISSCR, or national laws or regulatory authorities. However, we found only a few articles that described the developmental stage of the embryos used and the number of embryos or mentioned the 14-day limit.

Based on these findings, we suggest that more journals require ethics statements when human embryos are used. Ideally, these statements should be contained within the Methods section and include guidelines or laws followed, how long the embryos were grown developmentally, how many embryos were used, the consent process for donations, and whether the research was subject to oversight and approval, and, if so, by whom (Table 4).

Table 4.

Recommendations for ethics statements in journals

(1) Journals that publish human embryos research should require an ethics statement in the paper
(2) The ethics statement should be placed within the Methods section alongside any human subjects or animal subjects statements
(3) The ethics statement should:
✓	Identify guidelines and/or laws adhered to
✓	Describe the consent process for donations of embryos and/or gametes
✓	Specify the oversight committee or authority that reviewed the work
✓	Define the number of embryos used
✓	Characterize the developmental stage(s) studied

Ethics statements are one way to improve transparency within research and to respond to calls for more transparency in science reporting. Requiring these statements, along with open access articles and data sharing, could increase the likelihood that researchers have considered and consulted necessary oversight authorities and guidelines. In addition, it will provide more information to the public, providing insight regarding research review and oversight. Because many in society question science, it is up to researchers to help justify their work and demonstrate that scientists are indeed working ethically and that they follow rules and guidelines, especially when conducting research in controversial areas.