Mouse embryos grown without eggs or sperm: why and what’s next?

Amazing stuff! This is huge!

I have speculated here several times before that probably in about 20-30 years from now women will not have to give birth anymore unless they choose otherwise. In the not so distant future, new human life can be born ex utero and God will be smiling.

"Under the right conditions, stem cells can divide and self-organize into an embryo on their own. In studies published in Cell and Nature this month, two groups report that they have grown synthetic mouse embryos for longer than ever before. The embryos grew for 8.5 days, long enough for them to develop distinct organs — a beating heart, a gut tube and even neural folds.
The process is far from perfect. Just a tiny fraction of the cells develop these features and those that do don’t entirely mimic a natural embryo. But the work still represents a major advance that will help scientists to see organ development in unprecedented detail. ...
The two research teams achieved the feat using similar techniques. ... has been working on this problem for a decade. “We started with only embryonic stem cells,” ... “They can mimic early stages of development, but we couldn’t take it any further.” Then, a few years ago, her team discovered that when they added stem cells that give rise to the placenta and yolk sac, their embryos developed further. Last year, they demonstrated that they could use this technique to culture embryos until day 7. ...
team also conducted an experiment in which they knocked out a gene called Pax6, which has a key role in brain development. When they eliminated this gene, the mouse heads didn’t develop correctly, mimicking what occurs in natural embryos that lack that gene. The result demonstrates “that the system is actually functional” ...
For researchers, these synthetic models have many advantages over natural embryos created from eggs and sperm. Because they grow outside of the uterus, they’re much easier to observe. They’re also easier to manipulate using genome-editing tools. ..."

From the first abstract:

"In vitro cultured stem cells with distinct developmental capacities can contribute to embryonic or extraembryonic tissues after microinjection into pre-implantation mammalian embryos. However, whether cultured stem cells can independently give rise to entire gastrulating embryo-like structures with embryonic and extraembryonic compartments remains unknown. Here, we adapt a recently established platform for prolonged ex utero growth of natural embryos to generate mouse post-gastrulation synthetic whole embryo models (sEmbryos), with both embryonic and extraembryonic compartments, starting solely from naive ESCs. This was achieved by co-aggregating non-transduced ESCs, with naive ESCs transiently expressing Cdx2 or Gata4 to promote their priming toward trophectoderm and primitive endoderm lineages, respectively. sEmbryos adequately accomplish gastrulation, advance through key developmental milestones, and develop organ progenitors within complex extraembryonic compartments similar to E8.5 stage mouse embryos. Our findings highlight the plastic potential of naive pluripotent cells to self-organize and functionally reconstitute and model the entire mammalian embryo beyond gastrulation."

From the second abstract:

"Embryonic stem cells (ESC) can undergo many aspects of mammalian embryogenesis in vitro, but their developmental potential is substantially extended by interactions with extraembryonic stem cells, including trophoblast stem cells (TSCs), extraembryonic endoderm stem cells (XEN), and inducible-XEN cells (iXEN). Here, we assembled stem-cell derived embryos in vitro from mouse ESCs, TSCs and iXEN cells and showed that they recapitulate whole natural mouse embryo development in utero to day 8.5. Our embryo model displays head-folds with defined forebrain and midbrain regions and develops a beating heart-like structure, a trunk comprising a neural tube and somites, a tail bud containing neuromesodermal progenitors, a gut tube, and primordial germ cells. This complete embryo model develops within an extra-embryonic yolk sac that initiates blood island development. Importantly, we demonstrate that the neurulating embryo model assembled from Pax6 knockout-ESCs aggregated with wild-type TSCs and iXENs recapitulates the ventral domain expansion of the neural tube that occurs in natural, ubiquitous Pax6 knockout embryos. Thus, these complete embryoids are a powerful in vitro model for dissecting the roles of diverse lineages and genes in development. Our results demonstrate the self-organization ability of embryonic and two types of extra-embryonic stem cells to reconstitute mammalian development through and beyond gastrulation to neurulation and early organogenesis."

Mouse embryos grown without eggs or sperm: why and what’s next? Two research teams grew synthetic embryos using stem cells, long enough to see some organs develop.

Post-gastrulation synthetic embryos generated ex utero from mouse naive ESCs (open access)

Synthetic embryos complete gastrulation to neurulation and organogenesis (no public access)

Without Egg, Sperm or Womb: Synthetic Mouse Embryo Models Created Solely from Stem Cells

This research has caught quite some attention! This is possibly a gamechanger! Imago dei becomes a whole new meaning!

I have predicted here previously that human procreation/reproduction will be very different in about 20-30 years from now. Women (transgender men?) will not have to get pregnant anymore or give birth. Plus, longevity and health will have improved tremendously by then!

"... researchers have grown synthetic embryo models of mice outside the womb by starting solely with stem cells cultured in a petri dish – that is, without the use of fertilized eggs. The method opens new horizons for studying how stem cells form various organs in the developing embryo, and may one day make it possible to grow tissues and organs for transplantation using synthetic embryo models. ...
team built on two previous advances in his lab. One was an efficient method for reprogramming stem cells back to a naïve state – that is, to their earliest stage – when they have the greatest potential to specialize into different cell types. The other, described in a scientific paper in Nature in March 2021, was the electronically controlled device the team had developed over seven years of trial and error for growing natural mouse embryos outside the womb. The device keeps the embryos bathed in a nutrient solution inside of beakers that move continuously, simulating the way nutrients are supplied by material blood flow to the placenta, and closely controls oxygen exchange and atmospheric pressure. In the earlier research, the team had successfully used this device to grow natural mouse embryos from day 5 to day 11. ...
These synthetic models developed normally until day 8.5 – nearly half of the mouse 20-day gestation – at which stage all the early organ progenitors had formed, including a beating heart, blood stem cell circulation, a brain with well-shaped folds, a neural tube and an intestinal tract. ...
n addition to helping reduce the use of animals in research, synthetic embryo models might in the future become a reliable source of cells, tissues and organs for transplantation. ..."

From the abstract:

"In vitro cultured stem cells with distinct developmental capacities can contribute to embryonic or extra-embryonic tissues after microinjection into pre-implantation mammalian embryos. However, whether cultured stem cells can independently give rise to entire gastrulating embryo-like structures with embryonic and extra-embryonic compartments, remains unknown. Here we adapt a recently established platform for prolonged ex utero growth of natural embryos, to generate mouse post-gastrulation synthetic whole embryo models (sEmbryos), with both embryonic and extra-embryonic compartments, starting solely from naïve ESCs. This was achieved by co-aggregating non-transduced ESCs, with naïve ESCs transiently expressing Cdx2- and Gata4- to promote their priming towards trophectoderm and primitive endoderm lineages, respectively. sEmbryos adequately accomplish gastrulation, advance through key developmental milestones, and develop organ progenitors within complex extra-embryonic compartments similar to E8.5 stage mouse embryos. Our findings highlight the plastic potential of naïve pluripotent cells to self-organize and functionally reconstitute and model the entire mammalian embryo beyond gastrulation."

Without Egg, Sperm or Womb: Synthetic Mouse Embryo Models Created Solely from Stem Cells - Life Sciences | Weizmann Wonder Wander - News, Features and Discoveries: he method opens new vistas for studying how stem cells self-organize into organs and may in the future help produce transplantable tissues

¬Post-Gastrulation Synthetic Embryos Generated Ex Utero from Mouse Naïve ESCs (open access)

Development of synthetic embryo models from day 1 (top left) to day 8 (bottom right). All their early organ progenitors had formed, including a beating heart, an emerging blood circulation, a brain, a neural tube and an intestinal tract

Scientists plan to drop the 14-day embryo rule, a key limit on stem cell research

This could be a major game changer if approved! I have blogged e.g. here before about one of the possible future consequences of this research, i.e. women would not have to be pregnant anymore and give birth to new human life.

"In 2016, [a researcher] grew human embryos in a lab dish for longer than anyone had before. ... breaking all prior records. The embryos even attached to the dish as if it were a uterus, sprouting a few placental cells. But on day 13, [the researchers] halted the experiment. ...
For the last 40 years, the [14-day rule for in vitro embryo research], which is law in some countries and a guideline in others, has served as an important stop sign for embryonic research. The 14-day limit arose after the birth of the first test-tube babies in the 1970s. It has provided a clear signal to the public that scientists wouldn’t grow babies in labs. ... Now, however, a key scientific body [International Society for Stem Cell Research] is ready to do away with the 14-day limit. The action would come at a time when scientists are making remarkable progress in growing embryonic cells and watching them develop. Researchers, for example, can now create embryo-like structures starting even from stem cells, and some hope to follow these synthetic embryo models well past the old two-week line.

By allowing both normal and artificial embryos to continue developing after two weeks, the end of the self-imposed limit could unleash impressive but ethically charged new experiments on extending human development outside the womb. ...
Because embryo research doesn’t receive federal funding in the US, and laws differ widely around the world, the ISSCR has taken on outsize importance as the field’s de facto ethics regulator. ...
But such techniques raise the possibility of someday gestating animals outside the womb until birth, a concept called ectogenesis."

Scientists plan to drop limits on how far human embryos are grown in the lab | MIT Technology Review As technology for manipulating embryonic life accelerates, researchers want to get rid of their biggest stop sign.

Here is the link to the official announcement by ISSCR:

The ISSCR Will Release Updated Guidelines for Stem Cell Research and Clinical Translation in May

Balls of cells mimic an unseen stage of human embryo development

How many more years will it take to gestate a human fertilized egg outside of the womb? Perhaps 15-30 years?

"After about 14 days, the embryo elongates and forms layers, revealing a rough plan for the body. But this dramatic transformation, called gastrulation, has never been directly observed in human embryos: Growing them to this stage in a lab is technically difficult and ethically fraught. Now, researchers have made structures from human stem cells that mimic some features of embryos after gastrulation, an advance that could reveal how genetic mutations and chemical exposures can lead to miscarriages and birth defects."

"The structures, created from stem cells and called gastruloids, are the first to form a 3D assembly that lays out how the body will take shape. The gastruloids developed rudimentary components of a heart and nervous system, but lacked the components to form a brain and other cell types that would make them capable of becoming a viable fetus. ... Human embryos take a momentous leap in their third week, when the largely homogeneous ball of cells starts to differentiate and develop specific characteristics of the body parts they will become, a process known as gastrulation. During this process, the embryo elongates and lays down a body plan with a head and tail, often called the head-to-tail axis.
But scientists have never seen this process in action. That is partly because many countries have regulations that stop embryos from being grown in the laboratory for research beyond 14 days after conception. ... Moris says the most thrilling result was the formation of pockets of cells that symmetrically straddle the head-to-tail axis. Genetic analysis showed that the cells were those that would eventually go on to form muscles in the trunk, vertebrae, heart and other organs. ..."

Balls of cells mimic an unseen stage of human embryo development | Science | AAAS

Lab-grown cells mimic crucial moment in embryo development Artificial structures developed the rudimentary components of a heart and nervous system.

Is The Artificial Womb Coming?

Posted: 7/21/2019

For decades, there have been efforts to create artificial wombs, but, in the past, these were rather preliminary, primitive, and not very functional experiments as far as I remember. These past experiments have advanced our knowledge, but not much more.

However, given the latest scientific and technological advances, the outlook has changed dramatically! I think, it is quite possible that in 15-30 years human babies will not be born naturally anymore. How many women died in childbirth in the course of history of humanity?

Be prepared for the intensive moral and religious controversy this prospect may cause!

Sources (S):

1. Israeli Scientists Say They Bio-Engineered Model Of 'Receptive' Human Uterus