Congenital disorders often develop early during a crucial stage in embryo development–gastrulation–when cell fates are determined. Studying this in humans, however, is challenging for several reasons:
Thus, there is a need for a model system that can accurately reconstruct the 3D morphology of a human embryo and may overcome the practical, technical, ethical, social and legal limitations. GREAT, along with international collaborators, has made significant progress in the development of so-called ‘gastruloids’; in vitro embryo-like structures made from human pluripotent stem cells. They successfully generated 3D gastruloids from mouse stem cells, which mimic the process of gastrulation. In a recent groundbreaking study, they also achieved the creation of human gastruloids from human embryonic stem cells (hESCs). These innovations provide new tools for studying early development and congenital disorders and may decrease the need for using human embryos for research.
GREAT is taking a comprehensive approach to its research, involving both laboratory work, ethical analysis, and science communication. There will be a focus on creating advanced models of early human development using both hESCs and hiPSCs while exploring the ethical considerations surrounding these models.
The aim of GREAT is to create and utilize human in vitro 3D gastruloids derived from induced pluripotent stem cells (hiPSCs) that faithfully mimic early human development while establishing a comprehensive ethical framework for their use. The primary scientific question is: Can we create an in vitro model system based on human induced pluripotent stem cells that accurately and ethically replicates the early stages of human development?
Specifically, the team will leverage these models to look into the early development of heart-, muscle- and blood tissue. In the future these models can potentially be used to gain understanding of congenital heart, muscle and blood disorders and improve diagnostics and therapeutic approaches. GREAT builds upon their experience in improving the 3D gastruloid protocol in mice and the development of 3D gastruloids using human hESCs. The focus now is to optimize the 3D gastruloid system based on hESCs and also to develop versions of this model system using hiPSCs.
In addition to the scientific research, ethical issues take center stage in GREAT. The ethical issues that will be reflected upon include:
(1) The ontological and moral status of gastruloids: The project delves into the nature of these gastruloids, essentially asking, “What are they?” This involves exploring the fundamental (morally relevant) characteristics of these lab-created structures. Linked to this, the project aims to reflect on the moral status of gastruloids. In essence, it seeks to understand how these structures should be treated.
(2) An ethical framework that addresses questions related to responsible research with gastruloids. For example, one significant question pertains to the duration of culture. Traditional guidelines often limit the culture of embryos to a maximum of 14 days. However, since gastruloids do not start from fertilization, it raises the question of whether the 14-day rule is still applicable, and if not, what other morally relevant features should govern the permissibility of gastruloid research.
Moreover, GREAT has started a campaign for societal outreach in order to ensure that both the scientific results and ethical considerations reach and are discussed with a broad audience. For this purpose, NEMO Kennislink has launched the theme page ‘Embryo’s uit het lab’ (Embryo’s from the lab). On this page, NEMO publishes articles that are meant to inform and entice the general public regarding embryo model research.
With these articles, an environment is created that highlights questions that society might have regarding embryo-like structures, for instance: What kind of entities are these, how should we look at this? What can and should we do with these ‘embryo-like’ models? Besides these informative articles NEMO also facilitates dialogues to openly discuss the perspectives of various groups (including the general public, elderly people, students, and patients) towards gastruloids.
Regie/camera: Maarten Boers (Zeebenen Film)
Scenario: Maarten Boers (Zeebenen Film), Marcia van Woensel (Praat Producties)
Voice Over: Jair Stein
Ana's research focusses on exploring the ethical ramifications of stem cell-derived gametes (SCDGs) and contributing to the development of tangible guidelines, capable of harnessing the potential of SCDGs as valuable research tools, whilst remaining conscientious of morally and legally acceptable practices.
Joost is full professor and head of the department of Developmental Biology at the Erasmus MC. He also founded the Erasmus MC iPS core facility in 2010, which has so far generated more than 250 patient iPS cell lines providing the basis for a wealth of research at the Erasmus MC. In addition, the Gribnau laboratory has established technology to readout epigenomic, transcriptomic and enhancer changes directing cell fate decisions, that is currently applied to define better culture conditions for directed iPSC differentiation. Joost has a longstanding interest in understanding regulation of gene expression in relation to cell fate decisions in development and cell differentiation. Initial studies focused on different aspects of the X-chromosome inactivation (XCI) process, that inactivates one X chromosome in every female cell. The Gribnau laboratory unravelled many key steps of the mechanism directing initiation of XCI (Monkhorst et al., Cell 2008, Jonkers et al., Cell 2009, Barakat et al., Mol Cell 2015,Gontan et al., Nature 2012 and Nature comm. 2018). Recent work focusses on the identification of new XCI regulatory factors (van Bemmel et al. Nat Genet. 2019). To study epigenetic changes in development, the Gribnau laboratory developed several new technologies including MeD-seq and DCM-TM to determine genome wide DNA methylation profiles (MeDseq) and retrieve gene and enhancer activity maps of past expression (DCM-TM) (Boers Genome Res. 2018, submitted). These form the basis for more than 50 collaborations worldwide. The technology has been licensed to Methylomics B.V., that applies the MeD-seq for marker discovery studies in cancer. The Gribnau laboratory has published many papers on human disease modelling using iPSCs, and knowledge obtained is translated and implemented into the iPS facility. At present the group focuses on understanding cell signalling directing cell fate decisions to be translated to improved iPSC differentiation protocols.
