THE YEAR 2024 - The year of the embryo!
David F. Albertini, PhD, is the Editor-in-Chief of the Journal for Assisted Reproduction and Genetics (JARG), Professor, Bedford Research Foundation, MA, a Visiting Senior Scientist at The Center for Human Reproduction, NY, and a Visiting Researcher at Rockefeller University, NY.
One of the world’s most accomplished reproductive biologists offers his year-end assessment of 2024 with the conclusion that it must be described as the year of the embryo.
In a twisted and somewhat unexpected turn of events, this year has brought out possibly the worst and the best when it comes to the biology and politics of human embryos. Following the recent trend of exploring the potential of pluripotent stem cells to generate equivalents of the peri-implantation stages of human development, a notable and remarkable series of papers appeared this year. Somewhat surprisingly, the latest research extended efforts of previous years by describing “synthetic” embryo models with properties not unlike those expected during or immediately following the time of implantation. Time will tell just how useful these models will be when it comes to deepening our understanding of why so many pregnancies fail at this critical juncture in human development.
A 3D image human embryo model on Day 14, including placenta. Jacob Hanna, Ph.D., Weizmann Institute for Science, Israel
And along with the technological breakthroughs at the heart of producing and characterizing such models, mounting ethical concerns this work delivers to a society already sensitized to the promise and perils this line of research constitutes, the politicization of all things embryos and human ARTs has muddied the conversation that should be occurring between science and society. At stake here could be opportunities to solve the perplexing riddle to explain the successes and failures that contribute naturally to species survival.
What rises to the surface of our collective quest to understand human development within the confines of technological bravado and ethical agency is both the biological and clinical relevance to the earliest stages of human development, and a sense of humility and respect for the emergent complexities inherent to the fateful meeting of egg and sperm.
As articulated by Hopwood recently, the year 2024 in a sense represented a new dawning of human developmental biology, the overarching discipline of the past work on human embryos that now can be viewed in a context of where these advances will bring us into the future (1). This has been a difficult and challenging transition to effect in part because of the unintended mismatch between basic research, clinical ARTs, and ethical implications over the past decade, as elaborated upon by Brivanlou and Gleicher (2). While sorting out a system that achieves balance between these three domains is an ongoing effort of great import, original scientific contributions in 2024 have enlightened all parties as to a number of remarkable behaviors and properties exhibited by human embryos.
Most striking among these features of the human conceptus was the demonstration in 2016 that human embryos could manifest a level of self-organization in culture such that many of the post-implantation lineages emerged with little to no prompting and in the total absence of the female reproductive tract and female contribution (3,4). What has followed these foundational observations is nothing short of a multinational effort that recognized, and exploited experimentally, the possibility that under appropriate conditions, these self-organizing principles were capable of recapitulating specific aspects of human development using pluripotent stem cells.
So it was that the propagation of blastocyst-like structures, or “blastoids” as they came to be known, was demonstrated yielding what appeared to be morphological equivalents of the preimplantation embryo at day 5/6 of development (5,6) (and see Figure 1). The next developmental stage requiring demonstrating took aim at the epiblast itself and the germ layer precursors of endoderm, mesoderm, and ectoderm that would echo emergence of gastrulation-like events (7,8). And finally, that pluripotent stem cells could be coaxed into pursuing fates associated with extraembryonic components was achieved (9,10).
While we cite here only a subset of the papers contributing to this year’s advances with stem cell-based models, we note with a measure of caution that most investigations in this area reveal “likenesses” in the form of morphology and gene expression patterns to human embryos, though conditions resulting in reproducible and efficient production of models have yet to be achieved. Nonetheless, the future is bright for further refinement of model systems that in time will avail their utility for many applications such as media testing, drug screening and the like.
Of the more highly suggested uses for such models are those underscoring the prevalence of miscarriage, in line with ongoing studies that have already been adopted using both placental and embryonic stem cells (11). With mounting interest in deriving stem cells capable of following lineages that specify either embryonic (epiblast) derivatives, or those of extraembryonic nature (yolk sac, placenta), it can be anticipated that more complete and interactive models will result as has been exploited in some of the work reviewed above (10).
Arriving at this point in pursuit of understanding human development comes after a long and storied history using animal models as both guideposts and sentinels for technological implementation and conceptual design and rigor (12). While the mouse has by far been the most experimentally and genetically tractable, the history of developmental biology evidences the casting of a broad net to have included invertebrate and vertebrate models from which fundamental principles of embryogenesis obtain. It is interesting in this light to keep in mind that like all eutherian mammals, the evolution of placentation coincides with the female gamete becoming a “yolkless” entity (13).
While to some the importance of this dimension to development may conjure up an appreciation for how the placenta evolved to sustain and nourish the developing fetus (against the backdrop of the well-known luteo-placental shift for establishment and maintenance of pregnancy), others have come to recognize that while not “yolky” the eggs of humans do depend on the maternal endowment of organelles and informational molecules that drive and support development up to, and possibly beyond, implantation. This unique feature of the human egg, and the remarkable self-organizing capabilities noted previously (3,4), finds its basis in an ever-increasing body of evidence consistent with the idea that building a developmentally competent egg embodies much more than genetic determinants realized during the intraovarian process of oogenesis.
Two recent publications begin to delineate the non-genetic dimension of early development at two critical junctures, zygotic gene activation (ZGA) and compaction, the time when the first lineage allocation takes place whereby fetus and placenta begin to take on their proscribed future identities (14,15).
In conclusion, the year 2024 has more than filled its bill as the year of the embryo, bringing to the forefront the arena of synthetic embryos and all the while raising more questions than ever regarding the mysteries of early development that continue to capture the attention and imagination of all engaged in grasping the meaning of life for our species.
References
1. Hopwood N. Past and future of human developmental biology. Development. 2024;151(17).
2. Brivanlou AH, Gleicher N. The evolution of our understanding of human development over the last 10 years. Nat Commun. 2021;12(1):4615.
3. Deglincerti A, Croft GF, Pietila LN, Zernicka-Goetz M, Siggia ED, Brivanlou AH. Self-organization of the in vitro attached human embryo. Nature. 2016;533(7602):251-4.
4. Shahbazi MN, Jedrusik A, Vuoristo S, Recher G, Hupalowska A, Bolton V, et al. Self-organization of the human embryo in the absence of maternal tissues. Nat Cell Biol. 2016.
5. Sozen B, Jorgensen V, Weatherbee BAT, Chen S, Zhu M, Zernicka-Goetz M. Reconstructing aspects of human embryogenesis with pluripotent stem cells. Nat Commun. 2021;12(1):5550.
6. De Santis R, Brivanlou AH. The treasure inside human naive pluripotency, generation of trophectoderm and blastoids. Cell Stem Cell. 2021;28(6):985-7.
7. Karvas RM, Zemke JE, Ali SS, Upton E, Sane E, Fischer LA, et al. 3D-cultured blastoids model human embryogenesis from pre-implantation to early gastrulation stages. Cell Stem Cell. 2023;30(9):1148-65 e7.
8. De Santis R, Rice E, Croft G, Yang M, Rosado-Olivieri EA, Brivanlou AH. The emergence of human gastrulation upon in vitro attachment. Stem Cell Reports. 2024;19(1):41-53.
9. Weatherbee BAT, Gantner CW, Iwamoto-Stohl LK, Daza RM, Hamazaki N, Shendure J, et al. Pluripotent stem cell-derived model of the post-implantation human embryo. Nature. 2023.
10. Oldak B, Wildschutz E, Bondarenko V, Comar MY, Zhao C, Aguilera-Castrejon A, et al. Complete human day 14 post-implantation embryo models from naive ES cells. Nature. 2023;622(7983):562-73.
11. Puscheck EE, Ruden X, Singh A, Abdulhasan M, Ruden DM, Awonuga AO, et al. Using high throughput screens to predict miscarriages with placental stem cells and long-term stress effects with embryonic stem cells. Birth Defects Res. 2022;114(16):1014-36.
12. Hopwood N. Species Choice and Model Use: Reviving Research on Human Development. J Hist Biol. 2024;57(2):231-79.
13. Rothchild I. The yolkless egg and the evolution of eutherian viviparity. Biol Reprod. 2003;68(2):337-57.
14. Fabreges D, Corominas-Murtra B, Moghe P, Kickuth A, Ichikawa T, Iwatani C, et al. Temporal variability and cell mechanics control robustness in mammalian embryogenesis. Science. 2024;386(6718):eadh1145.
15. Festuccia N, Vandormael-Pournin S, Chervova A, Geiselmann A, Langa-Vives F, Coux RX, et al. Nr5a2 is dispensable for zygotic genome activation but essential for morula development. Science. 2024;386(6717):eadg7325.