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May 28, 2021 3:09 pm

Labs Worldwide Seek to Adopt ‘Highly-Sought Grail’ Device Made in Israel to Grow Mouse Embryos Outside Womb

avatar by Sharon Wrobel

Mouse embryos growing outside the uterus. Photo: Jacob Hanna et. al. / Weizmann Institute of Science / YouTube screenshot

A mechanical device system developed by Israeli scientists to grow the embryo of a mammal outside of the womb for an extended period will be used by 14 labs around the world, as a technique to better understand the formation of cells and organs, including the heart.

It took seven years for scientists at Israel’s Weizmann Institute to develop and engineer the mechanical device unit, which was key to the breakthrough success of growing embryos for six days in artificial wombs, after removing them from the uteruses of mice at five days of gestation.

The scientists observed how a hollow tiny ball of 250 identical cells on its way to becoming a mammalian embryo first attached to an awaiting uterine wall, and then developed into nervous system, beating heart, stomach and limbs.

To grow mouse embryos outside the womb until advanced stages “has been a highly-sought grail in the field of embryonic development for nearly 100 years,” Jacob Hanna, Associate Professor at the Weizmann Institute of Science’s Department of Molecular Genetics and head of the study told The Algemeiner. Previous attempts had limited success as the embryos began to show developmental anomalies as early as 24 hours after culture initiation.

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Since the research was published in March in the journal Nature, 14 labs located across the United States, the United Kingdom, Switzerland and Japan have asked to work with the ventilator device, which the Weizmann Institute team used to develop “good quality” embryos, according to Hanna. The institutions include Oxford University, Caltech and an a lab in South Western Texas.

“I believe that if you publish something you need to share it and make it accessible for academia,” said Hanna. “It is an in-house patented unit which we engineer, assemble and try out before we send it to the labs who are interested in using it.”

Over a period of seven years, Hanna and his team developed a two-way system which created an artificial uterus for culturing mouse embryos and included incubators, a ventilation machine and a special nutrient fluid. Researchers started with several-day old mouse embryos — right after they would have implanted in the uterus — and placed them on a special growth medium in a laboratory dish. At this stage, the embryos were balls of identical stem cells, which attached to this medium as they would to the uterine wall and doubled and tripled in size.

For the second developmental stage, the mouse embryos were placed in 3D rotating glass jars floating in a special nutrient fluid inside incubators. The fluid contained high quality human serum. The glass jars were attached to rollers that kept the solutions in motion and continually mixed, which helped keep the embryos, while growing without maternal blood flow to the placenta, bathed in the nutrients without getting deformed. In addition to the careful regulation of the nutrients in the tubes, Hanna and his team connected the incubators to a ventilation system and experimented with controlling the gases, oxygen and carbon dioxide.

“Controlling the temperature and pressure environment showed to be important as the uterus is contracting all the time,” said Hanna.

After a trial and error period, the mouse embryos eventually survived until day 11, about halfway through the animals’ 20-day gestation. Scientists compared the development of the artificially grown embryos to those developing in the uteruses of living mice and found that they were identical.

Hanna added that the scientific window his system has created into the early embryo study could also be used for observing the early development of liver cells, which could then be grown further to see how they could function in transplant medicine. Researchers may be able to study the development of blood cells and bone marrow and how individual cells migrate between organs to their ultimate destinations.

“Like many landmark papers, the work of Hanna has a wide impact for a series of reasons. Being able to grow embryos outside the uterus for an unprecedented time period, will allow to study the assembly of a mammalian organism in unparalleled detail. Moreover, it will significantly advance our possibilities to study of developmental aberrations occurring in humans,” Claude Brodski, Head of the Laboratory for Molecular Neuroscience at the Ben-Gurion University of the Negev, told The Algemeiner.

“Finally, it will increase our ability to grow embryonic cells used for disease modeling, drug screening and cell replacement therapy. Hanna’s work also illustrates that our possibilities to understand and manipulate embryogenesis is progressing at a tremendous pace. Therefore, we as a society, have to engage in a discussion, what we want to allow for human embryos developing outside of the uterus,” Brodski added.

In the next step, Hanna and his team want to see if they can skip the step of removing embryos from pregnant mice. They take fertilized eggs from female mice at day 0 of development and grow them in the artificial uterus to day 13, trying to create artificial embryos made from stem cells — possibly, in the future, even using human cell lines.

“At day 11 we saw the development of organs and buds of arms and legs. At day 13 we would want to observe the extension of lymphs and the separation of fingers and toes,” said Hanna.

The scientists believe that their embryonic development technique will give researchers an “unprecedented” tool for understanding the development of gene mutations, and may provide detailed insight into birth and developmental defects as well as those involved in embryo implantation and miscarriages.

“Our aim is to make a research tool and to show its efficiency,” Hanna said. “We hope that our system of growing normal mouse embryos ex utero will be adopted by many labs around the world, and that culturing mouse embryos in a tube for extended periods of time will become a commonly used technique as culturing cells.”

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