Human developmental biology – a global perspective

I believe public interest in human developmental biology is increasing, but the political and regulatory landscape is fraught for scientists. In the USA, the 1995 Dickey-Wicker Amendment prohibits using federal funds for research with human embryos. Therefore, human embryonic stem cells (hESCs) serve as surrogates for studying human development funded by National Institutes of Health (NIH) or other agencies that receive funding from the US Department of Health and Human Services. When I started my lab in 2006, we used State funds to derive new hESC lines from human embryos and, in 2009, President Obama expanded the NIH registry to allow new hESC lines, including the ones we were deriving. It was an exciting time to be in the field. However, our work was affected by the 2010 Shirley versus Sebelius case, when the US District Court for the District of Columbia granted a preliminary injunction halting federal funding of hESC research. My first NIH grant used hESC lines to study human development and, overnight, the NIH no longer funded this research. Furthermore, in 2017, a programme officer indicated concern for the funding of human fetal tissue research. Learning from Shirley versus Sebelius, I removed fetal tissue experiments from my NIH grant renewal – a decision not based on science but practicality; to protect my trainees' and postdocs' salaries. Indeed, in 2018, the Trump Administration's policies restricted NIH funding for fetal tissue research. Although overturned by the Biden Administration in 2019, the situation is still in flux. Concurrently, human stem cell-based embryo models emerged, but the Dickey-Wicker Amendment restricts researchers' freedom in using federal funding in this field because of the legal language on what constitutes an ‘embryo’. In the USA, being a human developmental biologist is challenging. I am grateful for a supportive community that considers this research crucial and where outcomes have real potential to help reproductive diseases and infertility. Ultimately, the research is for them, and this keeps me motivated, especially during the hard times.

In South Africa, the legal framework for research using human embryos and stem cells is governed by a single line in the National Health Act published in 2003, which places local research in this field within the internationally recognised ethical limit, the ‘14-day rule’. With no supporting documentation since this time to outline the usage of human stem cells or stem-cell models, there is very little in the way of a defined legal or political framework to govern the research of the few human developmental biologists in South Africa. However, in South Africa, as it is for much of the continent, human developmental biology is not recognised as a research priority. With limited national funding and significant healthcare priorities, a major portion of funding and infrastructure nationwide has been guided over several decades towards infectious disease research, with a particular focus on HIV, tuberculosis and malaria. With these clear national priorities, there are indeed very few researchers who focus on developmental biology within South Africa, and fewer still making use of stem cell-based embryo models. The few that are in this field depend greatly on self-regulation to draw limits to their work and need to obtain funding and materials from international sources to undertake it. With the recent prevalence of human stem cell models in international research, I hope that there will be an increase in interest in this field across South Africa. Of particular local relevance is the fact that the African population is the most genetically diverse in the world, which contrasts with an almost complete absence of African-origin stem cells used when modelling the human embryo. Therefore, this presents a significant area of potential impact that can be guided by African researchers in the future.

Public support for human stem cell- and embryology-based research continues to be high in Israel. The reasons lie in the high abundance of genetic diseases in Jewish, Arab and Beduin communities, which caused religious and political leaders to swiftly support research to prevent or alleviate such conditions, including pregestational diagnosis, donating excess human embryos for research and embryonic stem cell derivation, as well as stem cell-based embryo modelling. Of course, all such research is conducted under ever-evolving legal regulations that are periodically updated, based on ethical approval. The exciting Perspective by Hopwood describe cycles of enthusiasm for human embryo research and competition between different species and models, but I wish to re-emphasise the parallel view. Although undoubtedly the goal is to develop efficient, flexible and editable platforms of human embryo-like processes, it does ‘take a village’ to achieve this. Each research ‘cycle’ constitutes an essential neighbourhood in this hypothetical village: mouse embryology, human embryology, mechanisms of induced pluripotent stem cell reprogramming, pluripotency in rodents, naïve pluripotency in humans, organoids, synthetic embryology, gastruloids, etc. Although the focus of the research community has drifted over time, this has helped reveal and build each of these neighbourhoods. Such trends may happen because of new hypotheses based on new or emerging knowledge. For example, studying rodent pluripotency was essential to revisit human pluripotency and derive alternative naïve-like conditions, which have been essential for embryo modelling. Moreover, the success of generating bona fide synthetic embryo models with mouse stem cells increases knowledge and motivation for students to succeed with human stem cells in the future (although there is no guarantee). Therefore, I view these systems as complementary. Science is a meritocracy, and Israeli universities and funding agencies continue to maintain broad support across all the different subdomains related to embryology.

How the human body develops and functions is a crucial question in developmental biology and it has been addressed from many different angles over the years. In the UK, we are uniquely positioned to study this from a human perspective, with key investments and infrastructure to enable world-class human embryo and fetal tissue research. One such investment was the establishment of the Human Developmental Biology Resource (https://www.hdbr.org/), which has transformed research in the field by providing access to high quality embryonic and fetal material, not just in the UK but around the world. Further support has come from Development's ‘From Stem Cells to Human Development’ meetings and the Human Developmental Biology Initiative (https://hdbi.org/). Both have brought researchers studying different aspects of human development together to collaborate and share information to achieve the common goal of understanding the mechanisms underlying our own development. This includes researchers across disciplines and fields, using human clinical data, human tissue and cell-based systems and a wide array of animal models. This intersection is one of the reasons for the current momentum of human developmental biology in the UK and it is vital that it remains fully integrated into both fundamental and clinical research. To continue to grow as a field, we need to learn as much as possible from all model systems and enthuse the next generation of scientists about the wonders of studying human development. We also need to maintain transparency with the public about why this research is so important and what we do with the material they have kindly donated for research. One recent example is the HDBI public dialogue on the 14 day rule for human embryo research (https://hdbi.org/public-dialogue#:∼:text=Summary,of%20research%20involving%20human%20embryos). These conversations are crucial for the public support of our work and, in turn, its continued advancement here in the UK.

In 2002, legislation was enacted in Australia to prohibit certain activities relating to human embryos, and to regulate others. Subsequent amendments brought the use of embryos created by a process other than fertilisation for research purposes, and the creation and use of embryos for mitochondrial donation research and clinical purposes, into the regulatory regime. Political, social and religious debates accompanied each legislative change, highlighting how challenging it has been to create an appropriate legal environment that fosters research into human developmental biology while recognising the special status of the human embryo. Some sectors of Australian society remain opposed to any research using cells derived from human embryos. To illustrate, the ‘Research Involving Human Embryos Act 2002’ was passed only after one of the longest debates in Australian parliamentary history. Australian human embryo research focuses on the development and refinement of assisted reproductive technologies, such as in vitro fertilisation (IVF), preimplantation genetic testing and, lately, mitochondrial replacement therapy. There is no prioritised funding for studying human developmental biology. Currently, funding is targeted for research on stem cell-based models of organogenesis (organoids) for the purpose of disease modelling, functional genomics investigation of disease variants and translational research in developing advanced therapeutics. Accessibility to research materials is restricted to IVF embryos donated for research and stem cell-based embryo models of early embryogenesis, such as pluripotent stem cell-derived blastoids. Presently, Australia has no centralised banking of fetal biospecimens for research. The term ‘fetus’ applies to ‘the developing human being from fertilisation to delivery’; therefore, research using human embryos from fertilisation to day 14 or initiation of gastrulation and stem cell-based embryo models requires separate governance under the ‘Research Involving Human Embryos Act’ and ‘Ethical Guidelines on the Use of Assisted Reproductive Technology in Clinical Practice and Research’. Thus, in addition to the technical challenges, there are a range of other factors that will need to be considered if Australia is to participate actively in the human developmental biology renaissance.

Human developmental biology and stem cell research are focal points in Canada, reflecting their crucial importance in advancing our understanding of human health, disease mechanisms and medical innovations, as well as being fuelled by curiosity about our own development. Moreover, these research areas hold substantial potential to positively impact the Canadian economy, given our publicly funded universal healthcare system. I believe research involving in vitro human embryos is rising in Canada, driven by advancements in cutting-edge methodologies, increasing infertility rates and a growing recognition of species differences. Specifically, the increasing reliance on assisted reproductive medicine has facilitated access to supernumerary human preimplantation embryos, enabling researchers such as myself to obtain these valuable tissues for research purposes. Canada has a strong ethical framework for human embryo and stem cell research, which fosters scientific advancement and public trust. Although religious and cultural values influence discussions, regulations are secular and based on scientific and legal principles. The legal and ethical considerations for studies using stem cells and human embryos are governed at the institutional, provincial and federal levels in Canada to ensure compliance with established ethical and legal frameworks, such as the ‘2004 Assisted Human Reproduction Act (AHRA)’. Further, the main federal funding agencies, known as the Tri-Council, are dedicated to promoting ethical standards in stem cell research, as outlined in the Tri-Council Policy Statement (TCPS 2). There is also a dedicated Stem Cell Oversight Committee (SCOC), which ensures that research complies with ethical standards. The SCOC works with organisations, such as the Stem Cell Network and the International Society of Stem Cell Research (ISSCR), to stay updated on best practices and evolving ethical standards. I believe maintaining adherence to these robust ethical and legal frameworks is essential for Canada to sustain its leadership in human development and stem cell research.

Human developmental biology in Japan has a strong foundation, exemplified by the Kyoto Collection of Human Embryos. Founded by Hideo Nishimura in 1961 (Nishimura et al., 1966), this collection comprises over 45,000 specimens, including both normal and diseased specimens, and has been instrumental in understanding the morphological basis of human development (Shiota, 2018). However, in developmental biology, studies elucidating key principles of development using model organisms amenable to various experimentations have been the mainstream. Consequently, the value of the Kyoto Collection and similar investigations may not have been fully appreciated, with human developmental biology remaining as a minor field until recently. Initially, research using hESCs in Japan was very strictly regulated. Yet, the generation of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka (Takahashi et al., 2007) and the pioneering work on brain organoids by Yoshiki Sasai (Eiraku et al., 2011) have laid the groundwork for investigating human development. Furthermore, research using non-human primates (Nakamura et al., 2016) has highlighted significant differences in key developmental mechanisms between primates and mice, the most prevalent mammalian model, underscoring the importance of directly analysing humans or primates for understanding human development. The advent of powerful genome engineering and single-cell omics technologies have promoted such investigations. As a result, human developmental biology is now recognised as a crucial discipline within the broader field of human biology, the basic medicine of this century. Despite these progresses, Japan lacks national guidelines for research involving human embryos or fetuses, and there is no systematic infrastructure to collect and distribute these specimens, unlike the Human Developmental Biology Resource (HDBR) in the UK. Given the growing importance of human developmental biology, it is crucial to establish a practical domestic system to promote this field. Strengthening relevant initiatives and promoting research using non-human primates are also crucial steps. With these measures, Japan can contribute further to human developmental biology and better integrate its research endeavours with global advances.

China is currently confronting a precipitous decline in its population. Concurrently, the prevalence of congenital defects and developmental disorders remains elevated, exerting a substantial impact on public health. These issues of population and reproductive health are intimately associated with embryonic development processes. In response, significant national emphasis has been placed on the disciplines of reproductive biology and developmental biology, particularly in areas concerning embryonic development research. Within the confines of a stringent ethical framework, China actively endorses research pertaining to human embryonic development. This encompasses ethically guided in vitro cultivation of human embryos, developmental studies on non-human primate embryos, research employing stem cell-based embryo models, and investigations involving human natural embryos and extra-embryonic tissues across the full gestational spectrum. Moreover, the Chinese government diligently addresses the ethical implications surrounding human embryonic research, striving to construct a robust ethical and legal regulatory framework at the national level. This framework is designed to ensure that such scientific endeavours adequately address human health needs while strictly adhering to ethical standards.

Development recognises that article length restrictions mean a limited number of countries are represented in this Perspective. We encourage human development and stem cell researchers from other countries to also share their views on the Node; see the related post here: https://thenode.biologists.com/human-dev/discussion/.

A.T.C. thanks lab members past and present, advocates and mentors. M.S. thanks Shigehito Yamada for information on the Kyoto Collection of Human Embryos.