A Primer on Embryonic Development and Looking to the Future

Writer: Yumiko Imai ‘26

Editor: David Han ‘25

At the beginning of the developmental path, fertilization creates one zygote: a fertilized egg. From one cell to billions at the time of birth, that cell and its descendants will undergo thousands of divisions. The very first division produces two cells which then divide and produce four cells. Over time, the embryo which starts off at one cell grows to two, four, eight, 16, and so on in an exponential fashion.

Embryonic development consists of cell division and growth in a controlled and sequential series of processes. It is an incredibly elaborate process that necessitates lots of regulation, and lots of communication between cells [1]. To give an overview, the early divisions are regulated by mechanosensation. When two or more cells push up against each other, there are receptor proteins on the outside of the cells that sense the mechanical forces from the pushing between them. Those proteins that recognize the forces transduce signals into the cell that change gene expression and protein activity [2]. Changing the levels of gene expression and protein activity is essential to cell differentiation, the process

that encompasses the progressive specialization of these embryonic cells [3]. After differentiation, cells undergo cell fate determination to start developing unique cell types that will go on to have different functions within a growing embryo and later fetus. A part of this development worth calling attention to is around five days post fertilization (5dpf). At this point, the embryo is called a blastocyst which is composed of two cell types: the inner cell mass and the trophectoderm, better known as the ICM and TE [4]. The cells of the ICM are embryonic stem cells which are the focus of many scientists who study stem cells.

In 2024, over $330 million dollars from the NIH alone will go towards human embryonic stem cell research(5). Why is this? Researchers are studying embryos to understand key processes during early human development. They are attempting to characterize the specific events that are taking place. Of importance to development in the context of a fetus is that researchers are becoming able to identify genetic and chromosomal abnormalities that compromise development [4]; in other words, identifying what leads to miscarriage and birth defects. During the earliest days and phases of development, even before an individual would know that they are pregnant, almost 50% of fertilized eggs die [6]. Such high loss of pregnancy during those stages means that studying those phases could make huge contributions to the field of fertility.

In the past and continuing to the present, in vitro fertilization (IVF) has been used to study embryos. Developed in 1970 by Robert Edwards, IVF made it possible for babies to be born to couples that otherwise would not have had the opportunity [7]. IVF has also had impacts in the lab, allowing for the identification of key morphological processes. The genomic, transcriptional, and epigenetic profiles of the IVF cells have been studied up through every developmental stage possible. However, IVF has its limitations for research because the origin of the cells are from human embryos which are of course not readily available because they are from donated eggs [8]. In a necessary response, a new field called synthetic embryology was developed in which synthetically created in vitro embryo models are used to study embryos instead. Synthetic embryos are laboratory-produced and created from stem cells. They are induced to behave and grow like embryonic stem cells. There is still an issue with these lab-synthesized stem cells, however: they self-terminate before proceeding through the full embryonic developmental process [9]. This prevents further research past a certain stage.

New advancements in embryonic development research in 2023 by two research groups are pushing the field forward and promoting a far greater understanding of the mechanisms behind development. Groups at the Weizmann Institute in Israel and at the University of Cambridge in the UK both showed that they could research and nurture embryo models through and beyond the 14 day mark that is legally allowed as stipulated by International Society for Stem Cell Research, the ISSR [10]. In the past, researchers have had issues with embryo models because certain stages of development aren’t exactly representative of what is happening in a human embryo [11]. It’s just not quite accurate enough, and this is evident by day 14 at which the models lose morphological similarity. The success from last summer is that the research at both institutions has created embryo models that have structural organization and morphological similarity to a real human embryo, even at day 14 [10].

With stem cell research, it always feels like the possibilities of applications of the research are far-reaching. The discoveries in 2023 will contribute to a greater understanding of miscarriages. Between days seven and ten, the embryo implants itself in the uterine lining (see Figure 1). After that point, what contributes to miscarriage hasn’t been researched because the tiny cell “disappears” as it implants itself [12]. Now, with a cell line that allows for observation of development past implantation, more information about the mechanisms of cell death at that point will likely be discovered. An idea floated by the researchers from Israel includes getting a better understanding of the effects of medications on real human embryos to assess risk and potentially widen treatment possibilities for pregnant individuals who get sick [13]. And one last thought that seems far-fetched but not outside of the realm of possibility is taking cells from sick patients, creating model embryos from their cells, and allowing the embryo to start growing and developing organs that can be used as a source of cells for transplantation [13]. The future of research in this field will use the discoveries of the summer as an incredible stepping stone.