Creating life without egg or sperm cells—or a womb

Having previously demonstrated in November 2021 that a mouse embryo can be grown in a synthetic environment outside the womb, Prof. Jacob Hanna and his team in the Weizmann Institute’s Department of Molecular Genetics made headlines again in the summer of 2022 by creating a viable mouse embryo using only stem cells.

In a study published in Cell in August 2022 , the team set out to grow a synthetic embryo model solely from naïve mouse stem cells that had been cultured in a Petri dish, dispensing with the need for starting with a fertilized egg. This approach could, to a large extent, bypass the technical and ethical issues involved in the use of natural embryos in research and biotechnology. Synthetic embryo models might become a reliable source of cells, tissues, and organs for transplantation.

“The embryo is the best organ-making machine and the best 3D bioprinter – we tried to emulate what it does,” says Prof. Hanna.

Before placing the stem cells into the device, the researchers separated them into three groups. In one, which contained cells intended to develop into embryonic organs themselves, the cells were left as they were. Cells in the other two groups were pretreated for only 48 hours to overexpress one of two types of genes: master regulators of either the placenta or the yolk sac.

Soon after being mixed together inside the device, the three groups of cells grouped into aggregates, the vast majority of which failed to develop properly. But about 0.5 percent – 50 of around 10,000 – went on to form spheres, each of which later became an elongated, embryo-like structure. Since the researchers had labeled each group of cells with a different color, they were able to observe the placenta and yolk sacs forming outside the embryos and the model’s development proceeding as in a natural embryo.

These synthetic models developed normally until day 8.5 – nearly half of a mouse’s 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. When compared to natural mouse embryos, the synthetic models displayed a 95 percent similarity in both the shape of internal structures and the gene expression patterns of different cell types. The organs seen in the models gave every indication of being functional.

Both of these breakthroughs from the Hanna lab have received extensive coverage in scientific literature, as well as in leading mainstream media outlets such as The New York Times and The Economist.

For Prof. Hanna and other stem cell and embryonic development researchers, the study presents a new arena: “Our next challenge is to understand how stem cells know what to do – how they self-assemble into organs and find their way to their assigned spots inside an embryo. And because our system, unlike a womb, is transparent, it may prove useful for modeling birth and implantation defects of human embryos.”

Prof. Jacob Hanna’s research is supported by the Helen and Martin Kimmel Institute for Stem Cell Research; Pascal and Ilana Mantoux; and the Dr. Barry Sherman Institute for Medicinal Chemistry.