Laboratory for the Evolution of Human Development & Traits
We search how the evolution of genetic, cellular and physiological programs
has contributed to the appearance of human traits.
Self-organising stem cells
During evolution, distinctive human traits arose through genetic modifications that reshaped both embryonic development and the maternal uterus, ultimately changing the characteristics of newborns. One important evolutionary transition involved deeper implantation of the embryo into the maternal endometrium. This enabled the nascent placenta to remodel maternal blood vessels more extensively, altering how the embryo is perfused. This mode of implantation is associated with enhanced and prolonged growth of fetuses with larger brains.
However, these evolutionary changes may also have created vulnerabilities. In humans, approximately 20% of conceptions end in miscarriage, largely during the first trimester. These losses are frequently associated with shallow implantation and abnormal blood flow. Chimpanzees, our closest living relatives, appear to experience two- to three-fold fewer first-trimester losses.
These evolutionary changes in our development raise fundamental questions about present human reproduction and traits: Which genetic, molecular, and cellular innovations appeared in human embryos and uteri? How have they shaped both the benefits and vulnerabilities of human pregnancy and the traits of newborns? What have their past and present consequences been for our species?
Until recently, these questions were largely inaccessible because early human pregnancy cannot be directly studied in vivo. Stem-cell-derived models of embryos and endometrium now make mechanistic, scalable investigations possible in vitro. They offer an opportunity to investigate human reproduction by retracing the developmental and evolutionary history of early pregnancy, with a particular focus on implantation and placentation—the vital, yet potentially conflictual, interface between embryonic and maternal tissues.
Mouse & human blastoids. Before implantation in the uterus—around days 3–5 in mice and days 6–9 in humans—the mammalian embryo is known as a blastocyst. We have contributed to identifying conditions that promote the self-organisation of stem cells into structures that closely resemble mouse and human blastocysts, which we termed blastoids (Nature 2018, Protocol.io 2018, Nature 2021, Nature protocol 2023). Blastoids form efficiently, are morphologically and transcriptionally close to the blastocyst (see independent benchmarking of human blastoids here), and contain analogues of all three cell types that normally develop into the complete organism (placenta, yolk sac and fetus). Such blastoids can also be introduced into the uterus (mouse blastoid) or combined with endometrial organoids in vitro (human blastoid) to recapitulate aspects of implantation and development. In contrast to blastocysts, blastoids can be formed in large numbers and are suitable for screenings and genetic manipulations, approaches that underpin scientific and biomedical discoveries. As such, they offer an opportunity to investigate the principles of early pregnancy.
Fundamental research. Using blastoids, we investigate the evolution of gene regulatory networks controlling the cellular programs required for blastocyst implantation. By dissecting the genetic foundations of the distinctively human mode of implantation, our research aims to understand how genomic changes shaped human traits—including vulnerabilities such as early pregnancy loss. Ultimately, this work seeks to uncover the evolutionary origins of human pregnancy and their lasting consequences for our species.
Biomedical research. This research also enables us to disentangle the ineluctable constraints of pregnancy from its manageable vulnerabilities, knowledge that is essential for developing novel therapeutic approaches to global health challenges such as fertility decline, reproductive health and prenatal preventive medicine. To do so, we founded dawn-bio, a biotech company that leverages blastoids for biomedical research.
Ethical research. These advances have ethical implications and we contributed to outlining a roadmap for the gradual and justifiable use of Stem Cell-Based Embryo Models, and for the dissemination of a sensible, accurate picture of contemporary human embryology that aims to maximize societal benefit though public support (see our page on the ethics). This resulted in the inclusion of an ethical framework for Stem Cell-Based Embryo Models in the guidelines of the International Society for Stem Cell Research (2021, revised in 2024), their progressive implementation by European national ethics committees (in the UK, France, the Netherlands, Scandinavia, and Germany; 2021–2024), awareness by the European Union (consultation for the Hybrida project and the ERC Executive Agency), and the creation of a working group in the EMBL Ethics Board (2024–present).
NEWS THREAD
20th of November 2023 We published an article about 'Changing the public perception of human embryology' that calls for sensible public communication about stem cell-based embryo models that is necessary to secure public support and to ultimately achieve societal impact.
17th of August 2023 We published two papers about building an ethical framework for human embryo model research (see here and here). These manuscripts follow up on the previous ones (see here, here, here, and here) and aim to draft a roadmap for a gradual and justified usage of embryo models that maximize benefits to society. Here, we propose a refined legal definition of an embryo, suggest "tipping points" for when embryo models could eventually be afforded similar protection to that of embryos, and then revisit basic ethical principles to guide the research.
25th of January 2023 We published two detailed protocols for generating human blastoids that you can find here and here. To make the embryo model accessible, we employed three different commercially available 96- and 24-well microwell plates with results similar to our custom-made ones, and showed that blastoids also form in clinical in vitro fertilization medium and can be cryopreserved for shipping. We also explained in detail our current understanding of (1) the initial parameters sufficient to form blastocyst stage-like cells (e.g., initial cell state, initial aggregate properties, the mix of molecules necessary and sufficient to stimulate the process) and of (2) the methods to evaluate the results (e.g., obtaining efficient morphogenesis and lineages specification, matching the pace and sequence of blastocyst development, etc…). You can also read here the Twitter thread and here a blog post from Heidar Heidari Khoei.
7th of July 2022 We published our paper on mouse blastoids formed with Trophectoderm Stem Cells (TESCs). Using knowledge of blastoids & blastocysts, we defined an optimal set of molecules secreted by the epiblast (inducers) that captures in vitro stable, highly self-renewing mouse trophectoderm stem cells (TESCs) better resembling the blastocyst stage as compared to Trophoblast Stem Cells (TSCs). TESCs have enhanced capacity to form blastoids that implant more efficiently in utero due to inducers not only maintaining local trophoblast proliferation and self-renewal, but also secreting WNT6/7B that stimulate uterine decidualization. As such, blastocysts & blastoids actively instruct the uterus to create a supporting surrounding. Many of these molecules are also produced by human blastocysts.
26th of December 2021 The labs of Fredrik Lanner (Karolinska Institutet) and Sophie Petropoulos (Université de Montréal) led an independent consortium to benchmark the different 2021 attempts to form models of early human embryos. They included our model which, along with the one of the laboratories of Ge Guo / Austin Smith, formed cells that match well with the human blastocyst. Establishing reference maps including cells originating from pre-blastocyst and post-blastocyst conceptus is crucial to properly evaluate the generated cell types and stages. An appropriate state of the cells constituting the model (e.g., cell types, cell stage) is critical for blastoids to predict in vivo development. We commented on this Biorxiv paper as this preprint repository is wonderful not only for posting papers but also for discussing them. We hope our suggestions are helpful. See also the summarising Tweet thread by Alok Javali et al.
2nd of December 2021 We published our paper on human blastoids (Open access). They form with remarkable efficiency (>70%), recapitulate the temporal sequences of blastocyst development, and form cells transcriptionally similar to the blastocyst (>97% of the cells). Beyond these essential features, we observed that blastoids attach only to hormonally-primed endometrial cells, and do so via the polar trophectoderm as in utero, which increases the confidence in the functionality of the model. This model opens an avenue for mechanistic investigations of early human development. Kim Baumann (Nature Reviews Molecular Biology) wrote a Research Highlight about it entitled A role model of human blastocysts, and Alok Javali from our lab wrote on The Node a story of this scientific journey entitled The making of... human blastoids. See also the summarising Tweet thread, by Alok Javali et al.
8th of June 2021 The International Society for Stem Cell Research updated its ethical guidelines and included a framework for the use of human embryo models. This is the result of 2 years of in-depth and collegial discussions with scientists and ethicists worldwide. We also wrote a summary of the updates that was published in Stem Cell Reports.
1th of May 2021 The journal of the International Society for Stem Cell Research called Stem Cell Reports allowed Jianping Fu (University of Michigan) and I (Nicolas Rivron) to prepare a special edition on embryo models. This was an opportunity to gather experts in the field, summarise the state of the art, pinpoint the potential technical and ethical pitfalls, and think of the future. It will take a village to form embryo models! You can read an editorial that we wrote and download a Snapshot to decorate your lab fridge.
3rd of June 2020 The National Academies of Sciences, Engineering, and Medicine of the U.S.A. published the proceedings of a workshop held in January 2020 in Washington and termed Examining the State of the Science of Mammalian Embryo Model Systems. The scientific and biomedical perspectives opened by stem cell-based embryo models are discussed, including for blastoids.
3rd of March 2020 The lab of Janet Rossant (University of Toronto) and collaborators make a detailed analysis of the single-cell RNA sequencing data from mouse blastoids. They confirm the presence of analogs of the 3 founding cell types (Epi, Tr, PrE), and their transcriptional proximity to the cells of blastocysts. They also (and mainly) question the potential for extended/expanded potential stem cells (EPSCs) to form functional trophoblasts and propose that blastocyst-like structures formed with EPSCs-only form mesoderm-like cells rather than trophectoderm-like cells.
16th of December 2019 The lab of Magdalena Zernicka-Goetz (Caltech) makes use of our blastoid protocol. They confirm the presence of analogs of the 3 founding cell types (Epi, Tr, PrE), the potential to implant in utero, and then replace the embryonic stem cells with extended potential stem cells (EPSCs) to investigate their capacity to form primitive endoderm. Great follow-up!
2nd of May 2018 We published our paper on mouse blastocyst-like structures formed solely from stem cells and called them blastoids. It is exciting for us to see a model of the full conceptus, which comprises analogs of the three founding lineages (epiblast, trophectoderm, primitive endoderm)! Because blastoids model a pre-implantation stage and form an analog of the trophectoderm that normally mediates the interaction with the uterus, we transferred them in utero, where they recapitulated aspects of implantation (decidualization, vascularization). However, no fetus or live mouse could form.
Affiliation
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter (VBC), Vienna, Austria
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Content and statements offered on this website are not representative of statements, opinions, or policy of the IMBA institute, or the Austrian Academy of Science or the Vienna Biocenter. This website is not an official media outlet of the these institutions.
