Beyond the Blastocyst

Modeling human embryology with stem cells

Success rates for in vitro fertilisation (IVF) continue to hover around 25%, and almost 30% of pregnancies fail shortly after implantation for unknown reasons. The high rate of implantation failure and early pregnancy loss is ascribed to chromosomal abnormalities, as the majority of embryos display chromosomal mosaicism, a mixture of cells with normal and abnormal chromosomal constitutions. While the incidence of mosaicism declines with developmental progression and mosaic embryos can result in healthy live births, chromosomal mosaicism is associated with decreased implantation and pregnancy potential.

Progress in the study of human development and the impact of aneuploidies is slow due to the limited number of embryos available for research and experimental and ethical constraints. Here, we will use newly developed human blastoids, models of the blastocyst-stage embryo generated entirely from stem cells, to analyse the mechanisms of human development at an unprecedented level of cellular and molecular detail. Our multidisciplinary consortium will combine advanced single-cell (epi-)genomic and proteomic technologies, phosphoproteomics, real-time imaging and microfluidics to construct a 4D map of human development and dissect the cellular interactions that guide early cell-fate decisions and morphogenesis. We will then investigate how chromosomal aberrations affect these developmental mechanisms and explore interventions that promote healthy development. In complementary research, we will develop an ethical framework for sound policy-making with regards to human embryo model research and its clinical applications.

Our project on the molecular dissection of human embryonic development will directly impact our understanding of human embryology and the genesis of birth defects. It will lead to a better understanding of implantation failure and improve in vitro reproductive technologies.

 

Our objectives are to use human blastoids:

  1. to study the molecular mechanisms that regulate early human development and to understand how aneuploidies interfere with these mechanisms;
  2. to develop methods to improve IVF success of mosaic embryos;
  3. to develop an ethical framework that facilitates policy-making and acknowledges the need for embryo models, respects their moral value and promotes ethically sound clinical applications.

Team members

More information about: Ina Sonnen

Ina Sonnen

Group Leader, Hubrecht Institute

Ina Sonnen is a group leader at the Hubrecht Institute. Within the Beyond the Blastocyst consortium she investigates how signalling pathways and in particular signalling dynamics regulate early human development. She obtained her PhD in 2012 from the University Basel, Switzerland, for her research in the lab of Erich Nigg at the Max Planck Institute of Biochemistry, Munich, and Biozentrum Basel. Combining cell biological and biochemical techniques with super-resolution microscopy she studied the structure and duplication of centrosomes during cell proliferation. She then performed postdoctoral work at the European Molecular Biology Laboratory (EMBL) in the groups of Alexander Aulehla (developmental biology) and Christoph Merten (microfluidics) to study how signalling pathways control periodic segmentation of the vertebrate embryo (somitogenesis). There she established a microfluidic system, which allows simultaneous perturbations of signalling pathways at high temporal precision with real-time imaging. She has used this to dissect the function of signalling oscillations during somitogenesis. With her own group at the Hubrecht Institute Ina combines these techniques with biochemical and single-cell techniques to study the function and mechanism of how signalling and signalling dynamics control both embryonic development and adult tissue homeostasis. In collaboration with other groups, she has established gastruloids as embryo-like model system of somitogenesis.

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More information about: Lisa Sackmann

Lisa Sackmann

PhD student, Hubrecht Institute

Lisa Sackmann is a PhD student (start 2023) in the group of Dr. Ina Sonnen and Dr. Jop Kind at the Hubrecht Institute in Utrecht. She completed her Bachelor’s degree in Biomedical Sciences in Maastricht where she found her interest in developmental biology and fertility. There, she joined Dr. Masoud Zamani (UMCU) to write her thesis on single-cell technologies in reproductive medicine. To follow up, she completed her Master’s degree (Cancer, Stem Cells and Developmental Biology) in Utrecht. As part of the programme, she developed single-molecule imaging tools for C. elegans in the group of Dr. Suzan Ruijtenberg (UU). As part of the U/Select Honours programme, she went abroad to join the group of Dr. Jérôme Gros at Institut Pasteur in Paris. Here, she explored the role of mechanics in modulating pluripotency during early quail development with spatial transcriptomics technology. Based on her interest in the early embryo, advanced imaging, and the modulating role of mechanics, she applied to join the PSIDER project in the Sonnen and Kind lab. In her PhD, she will explore the role of the mechanical environment and internal forces during early human development as well as implantation through the use of artificial embryo-like structures (blastoids).

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More information about: Jop Kind

Jop Kind

Group Leader, Hubrecht Institute

Jop Kind is a PI of the Blastoid consortium and a group leader at the Hubrecht Institute (since 2018) and Oncode Institute (since 2018). His groups aim is to obtain better understanding of the role of chromatin and epigenetics in gene regulation. More specifically, the work is directed towards understanding the mechanisms that govern the acquisition of new identities and traits in lineage specification events in early mouse development and in cancer. To this end his group employs and develops single-cell genomics technologies to delineate these processes in great detail and with high temporal resolution.

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More information about: Esther Baart

Esther Baart

Head of the laboratory for Reproductive Medicine, Erasmus MC

Esther Baart is head of the laboratory for Reproductive Medicine, Department of Obstetrics and Gynecology, Erasmus MC, University Medical Center Rotterdam. She graduated from Wageningen University in 1998 with an MSc degree in Cell Biology. She continued as a junior researcher, working on both female and male mammalian meiosis, and developed a murine model system for studying fertilization and embryo development after intracytoplasmic sperm injection. She went on to obtain her PhD degree at the Department of Obstetrics and Gynecology, Erasmus MC. Between 2005-2008 she worked as a clinical embryologist and researcher at the University Medical Center, Utrecht. In 2008, she moved back to the Department of Obstetrics and Gynecology at the Erasmus MC, where she is currently working as head of the IVF laboratory and assistant professor. She brings a long standing research interest in embryo aneuploidy and chromosomal mosaicism to the consortium, with several well-cited papers showing that chromosomal abnormalities are the main factor that limits the success of IVF. By successfully establishing a research program at the intersection of clinical embryology and fundamental developmental biology, she aims to understand the origins of these abnormalities and the impact on human development and IVF success. These central questions are addressed using cutting edge stem cell, cell biology and molecular biology techniques and insights, together with leading experts in these fields. Using human embryos donated for research, advanced embryo models, imaging techniques and innovative single cell approaches, we explore embryonic mechanisms to understand chromatin and chromosome behaviour in human embryos and how this impacts development.

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