Would Synthetic Embryos Usher in the Era of Artificial Organs?
Scientists have replicated the natural process of mammalian embryonic development in the laboratory up to the point of development of brain and heart. Using stem cells, researchers created synthetic mouse embryos outside uterus that recapitulated natural process of development in the womb up to the day 8.5. This is a milestone in synthetic biology. In the future, this will guide studies on human synthetic embryos, which in turn could usher in development and production of synthetic organs for patients awaiting transplants.
An embryo is usually understood as an intermediate developmental stage in sequential natural phenomenon of reproduction initiated by sperm meeting an ovum to form a zygote, which divides to become an embryo, followed subsequently by development into a foetus and a new-born upon completion of gestation.
Advancements in embryonic cell nuclear transfer saw the instance of skipping the step of fertilisation of an egg by the sperm. In 1984, an embryo was created from an egg in which its original haploid nucleus was removed and replaced by the nucleus of a donor embryonic cell which successfully underwent development in a surrogate to give birth to the first cloned baby sheep. With the perfection of Somatic Cell Nuclear Transfer (SCNT), Dolly the sheep was created in 1996 from a mature adult cell. This was the first case of cloning of a mammal from an adult cell. Dolly’s case also opened up the possibility of development of personalised stem cells. In both the cases, sperm was not used, however it was the egg (with the replaced nucleus) that grew to become embryo. So, as such, these embryos were still natural.
Could embryos be created without involvement of even an egg? If so, such embryos would be synthetic to the extent that no gametes (sex cells) would be used. These days, such embryos (or ‘embryo-like’ or embryoids) are routinely created using Embryonic stem cells (ESC) and cultured in vitro in the lab.
Among mammals, mice take a relatively short period (19–21 days) to procreate which makes mouse embryo a convenient study model. Of the total, pre-implantation period is about 4–5 days while the rest 15 days (about 75% of the total) is post implantation. For post-implantation development, the embryo has to get implanted within the uterus which makes it inaccessible for outside observation. This dependence on maternal uterus imposes a barrier in investigation.
The year 2017 was significant in the history of mammalian embryo culture. Efforts to create synthetic mouse embryos got a fillip when researchers clearly demonstrated that embryonic stem cells have ability to self-assemble and self-organise in vitro to give rise to embryo-like structures that resembled natural embryos in important ways1,2. However, there were limitations arising from uterine barriers. It is routine to culture pre-implantation embryo in vitro but any robust platform for the ex-utero culture of post implantation mouse embryo (from egg cylinder stages until advanced organogenesis) was unavailable. A breakthrough to address this came last year in 2021 when a research team presented a culture platform that was effective for the post-implantation development of mouse embryo outside the maternal uterus. An embryo grown on this platform ex utero was found to precisely recapitulate in utero development3. This development overcame uterine barriers and enabled researchers to better understand post-implantation morphogenesis and has thus helped synthetic embryo project come to an advanced stage.
Now, two research groups have reported growing synthetic mouse embryo for 8.5 days which is the longest so far. This was long enough for distinct organs (such as beating heart, gut tube, neural fold etc) to have developed. This latest progress is truly remarkable.
As reported in Cell on 1st August 2022, the research team generated mouse synthetic embryos using only naïve Embryonic Stem Cells (ESCs) outside maternal uterus. They co-aggregated the stem cells and processed them using the recently developed culture platform for prolonged ex-utero growth to get post-gastrulation synthetic whole embryo with both embryonic and extraembryonic compartments. The synthetic embryo satisfactorily achieved milestones for 8.5 days stage of mouse embryos. This study highlights ability of naive pluripotent cells to self-assemble and self-organize and model the entire mammalian embryo beyond gastrulation4.
In the most recent study published in Nature on 25th August 2022, the researchers used extraembryonic stem cells as well to extend developmental potential of embryonic stem cells (ESC). They assembled synthetic embryos in vitro using mouse ESCs, TSCs and iXEN cells which did recapitulate natural whole embryonic development of mouse in uterus to the day 8.5. This synthetic embryo had defined forebrain and midbrain regions, a beating heart-like structure, a trunk comprising a neural tube, a tail bud containing neuromesodermal progenitors, a gut tube, and primordial germ cells. The whole thing was within an extra-embryonic sac5. Thus, in this study organogenesis was more advanced and remarkable vis-a-vis the study reported in Cell on 1st August 2022. Perhaps, use of two types of extra-embryonic stem cells enhanced developmental potential of embryonic stem cells in this study. Interestingly, only naïve Embryonic Stem Cells (ESCs) were used in the earlier study.
These accomplishments are truly remarkable as this is the farthest point so far in studies on synthetic mammalian embryos. Ability to create a mammalian brain has been a major goal of synthetic biology. Recreating the natural process of post-implantation embryonic development in the laboratory overcomes the uterine barrier and makes it possible for the researchers to study earliest stages of life that is normally hidden in the uterus.
Ethical issues notwithstanding, achievements in studies on mouse synthetic embryo will guide studies on human synthetic embryos in near future which could usher in development and production of synthetic organs for patients awaiting transplants.
- Harrison SE et al 2017. Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro. SCIENCE. 2 Mar 2017. Vol 356, Issue 6334. DOI: https://doi.org/10.1126/science.aal1810
- Warmflash A. 2017. Synthetic Embryos: Windows into Mammalian Development. Cell Stem cell. Volume 20, Issue 5, 4 May 2017, Pages 581–582. DOI: https://doi.org/10.1016/j.stem.2017.04.001
- Aguilera-Castrejon, A., et al. 2021. Ex utero mouse embryogenesis from pre-gastrulation to late organogenesis. Nature 593, 119–124. https://doi.org/10.1038/s41586-021-03416-3
- Tarazi S., et el 2022. Post-gastrulation synthetic embryos generated ex utero from mouse naive ESCs. Cell. Published: August 01, 2022. DOI:https://doi.org/10.1016/j.cell.2022.07.028
- Amadei, G., et al 2022. Synthetic embryos complete gastrulation to neurulation and organogenesis. Published: 25 August 2022. Nature. DOI: https://doi.org/10.1038/s41586-022-05246-3