Scientists grow mouse embryos in mechanical uterus



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The mouse embryos appeared perfectly normal. All of their organs were developing as expected, as were their limbs and circulatory and nervous systems. Their tiny hearts beat at a normal rate of 170 beats per minute.

But these embryos did not grow in a mother mouse. They were developed inside an artificial uterus, the first time such a feat has been accomplished, scientists reported on Wednesday.

The experiments, conducted at the Weizmann Institute of Science in Israel, aimed to help scientists understand how mammals develop and how genetic mutations, nutrients and environmental conditions can affect the fetus. But the work may one day raise deep questions about whether other animals, even humans, should or could be raised outside of a living womb.

In a study published in the journal Nature, Dr. Jacob Hanna described the removal of embryos from the uterus of mice at five days of gestation and their growth for six more days in artificial uteri.

At this point, the embryos were about halfway through their development; full gestation lasts about 20 days. A human at this stage of development would be called a fetus. To date, Dr Hanna and his colleagues have grown over 1,000 embryos in this way.

“This is truly a remarkable achievement,” said Paul Tesar, developmental biologist at Case Western Reserve University School of Medicine.

Alexander Meissner, director of genome regulation at the Max Planck Institute for Molecular Genetics in Berlin, said “to go this far is incredible” and that the study was “a major milestone”.

But research has already progressed beyond what investigators described in the article. In an interview, Dr Hanna said that he and his colleagues took fertilized eggs from the oviducts of female mice right after fertilization – on day 0 of development – and cultured them in the artificial uterus for 11 days.

Until now, researchers could fertilize mammalian eggs in the lab and grow them for a short time. The embryos needed a living uterus. “Placental mammals grow locked up in the uterus,” Dr. Tesar said.

This has prevented scientists from answering fundamental questions about the early stages of development.

“The holy grail of developmental biology is understanding how a single cell, a fertilized egg, can make all of the specific cell types in the human body and become 40 trillion cells,” said Dr Tesar. “Since the dawn of time, researchers have been trying to develop ways to answer this question.”

The only way to study the development of tissues and organs was to turn to species like worms, frogs and flies that do not need a uterus, or to take embryos from the uterus of laboratory animals at varying times, providing developmental glimpses more like snapshots. than the video.

What was needed was a way to get into the uterus, to observe and adjust the development of mammals as they went. For Dr Hanna, that meant developing an artificial uterus.

He spent seven years developing a two-part system that included incubators, nutrients, and a ventilation system. Mouse embryos are placed in glass vials inside the incubators, where they float in a special nutrient liquid.

The vials are attached to a wheel that spins slowly so that the embryos do not stick to the wall, where they will warp and die. The incubators are connected to a ventilation machine that delivers oxygen and carbon dioxide to the embryos, controlling the concentration of these gases, as well as the pressure and flow of the gas.

On day 11 of development – more than half a pregnancy in mice – Dr Hanna and colleagues examined the embryos, only the size of apple seeds, and compared them to those developing in the uterus of live mice. The lab embryos were identical, the scientists discovered.

By this time, however, the lab-grown embryos had grown too large to survive without a blood supply. They had a placenta and a yolk sac, but the nutrient solution that fed them by diffusion was no longer sufficient.

The next goal is to overcome this obstacle, Dr Hanna said in an interview. He plans to use an enriched nutrient solution or an artificial blood supply that connects to the placentas of the embryos.

In the meantime, experiences await you. The ability to keep embryos alive and to develop midway through pregnancy “is a gold mine for us,” said Dr Hanna.

The artificial uterus may allow researchers to learn more about why pregnancies end in miscarriages or why fertilized eggs fail to implant. This opens a new window on how genetic mutations or deletions affect fetal development. Researchers may be able to see individual cells migrating to their ultimate destinations.

The work is “a breakthrough,” said Magdalena Zernicka-Goetz, professor of biology and bioengineering at Caltech. It “opens the door to a new era of developmental study in the experimental mouse model”.

A recent development offers another opportunity. Researchers directly created mouse embryos from mouse fibroblasts – connective tissue cells – making early embryos without starting with a fertilized egg.

Combine this development with the work of Dr Hanna, and “now you no longer need mice to study the development of mouse embryos,” said Dr Meissner. Scientists may be able to make all the embryos they need from connective tissue.

If scientists could make embryos without fertilizing eggs and could study their development without a uterus, Dr Meissner said: “you can escape the destruction of embryos.” It would not be necessary to fertilize mouse eggs just to destroy them during the study.

But the work could eventually expand beyond mice. Two other papers published in Nature on Wednesday report attempts that come close to creating early human embryos in this way. Of course, said Dr Meissner, the creation of human embryos is years away – if it’s allowed at all. For now, scientists generally refrain from studying human embryos beyond 14 days of fertilization.

In the future, said Dr Tesar, “it is not unreasonable that we may have the ability to develop a human embryo from fertilization to birth entirely outside the womb.”

Of course, even the suggestion of this sci-fi storyline will horrify many. But this is the beginning, with no assurance that human fetuses can develop entirely outside the womb.

Even assuming they could, Dr Tesar noted, “whether this is appropriate is a question for ethicists, regulators and society.”

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