The mouse embryos looked completely normal. All their organs develop as expected, along with their limbs and the circulatory and nervous systems. Their little hearts beat at 170 times per minute.
But these embryos did not grow in a mother mouse. They developed into an artificial uterus, the first time such an achievement has been achieved, scientists reported Wednesday.
The experiments, at the Weizmann Institute of Science in Israel, were intended to help scientists understand how mammals develop and how gene mutations, nutrients, and environmental conditions can affect the fetus. But the work may one day raise deep questions as to whether other animals, even humans, should be cultured outside of a living uterus.
In a study published in the journal Nature, dr. Jacob Hanna removing embryos from the uterus of mice at five days of pregnancy and allowing it to grow for another six days in artificial uterus.
At that time, the embryos were about halfway through their development; full gestation is about 20 days. One is called a fetus at this stage of development. To date, dr. Hanna and his colleagues cultivate more than 1,000 embryos in this way.
“It really is a remarkable achievement,” said Paul Tesar, a 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 that ‘it is far-reaching to get far’ and that the study was ‘an important milestone’.
But the research has already progressed beyond what the researchers described in the article. In an interview, dr. Hanna said he and his colleagues took fertilized eggs from the ovaries of female mice just after fertilization – on Day 0 of development – and cultured them for 11 days in the artificial uterus.
So far, researchers have been able to fertilize mammalian eggs in the laboratory and only grow them for a short time. The embryos needed a living uterus. “Placental mammals develop trapped in the uterus,” said Dr. Tesar.
This has prevented scientists from answering fundamental questions about the earliest stages of development.
“The holy grail of developmental biology is to understand how a single cell, a fertilized egg, can form all the specific cell types in the human body and grow to 40 trillion cells,” said Dr. Tesar said. “Since the beginning 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 such as worms, frogs and flies that do not need a uterus, or to remove embryos from the uterus of experimental animals at different times, which look at the development more like taking screenshots. as video.
What was needed was a way to get inside the womb, to monitor and adapt to the development of mammals. For Dr. Hanna means that an artificial uterus must be developed.
He worked for seven years on the development of a two-part system that includes incubators, nutrients and a ventilation system. The mouse embryos are placed in glass vials in incubators, where they float in a special nutrient fluid.
The vials are attached to a wheel that rotates slowly so that the embryos do not stick to the wall, where they deform and die. The incubators are connected to a ventilation machine that supplies oxygen and carbon dioxide to the embryos, which control the concentration of the gases, as well as the gas pressure and flow rate.
On day 11 of development – more than halfway through a mouse pregnancy – dr. Hanna and his colleagues examine the embryos, as large as apple seeds, and compare them to those that develop in the womb of live mice. The laboratory embryos were identical, the scientists found.
But by that time, the laboratory-grown embryos had become too large to survive without blood supply. They had a placenta and a yolk sac, but the nutrient solution they fed by diffusion was no longer adequate.
Overcoming the obstacle is the next goal, said dr. Hanna said in an interview. He is considering using an enriched nutrient solution or an artificial blood supply that connects to the placentas of the embryos.
Meanwhile, experiment experiments. The ability to keep embryos alive and develop halfway through pregnancy is a goldmine for us, ‘said Dr. Hanna said.
The artificial uterus can enable researchers to learn more about why pregnancies end in miscarriages or why fertilized eggs do not implant. This opens a new window on how gene mutations or deletions affect fetal development. Researchers may be able to see how individual cells migrate to their final destinations.
The work is a “breakthrough,” Magdalena Zernicka-Goetz, a professor of biology and biological engineering, told Caltech. This “opens the door to a new era of development in the experimental mouse model.”
A recent development offers another opportunity. Researchers have directly created mouse embryos from fibroblasts of the mouse – connective tissue cells – which make early embryos without starting with a fertilized egg.
Combine the development with Dr. Hanna’s work, and “now you do not need any mice to study the development of mouse embryos,” said Dr. Meissner said. Scientists may be able to make all the embryos they need from connective tissue.
If scientists could make embryos without fertilizing eggs and study their development without a uterus, dr. Meissner said, “You can get away with destroying the embryo.” It is not necessary to fertilize mouse eggs, but only to destroy them during the study.
But the work may eventually extend beyond mice. Two other articles published in Nature on Wednesday report on efforts attempting to create early human embryos in this way. Of course, dr. Meissner said the creation of human embryos is still years away – if it is allowed at all. And for now, international regulations prohibit the study of human embryos for more than 14 days of fertilization.
In the future, dr. Tesar said, “It is not unreasonable that we have the ability to develop a human embryo from conception to birth, completely outside the womb.”
Of course, even proposing this scenario for science fiction would be very terrifying. But these are early days, without assurance that human fetuses can ever develop completely outside the womb.
Even though he assumes that they could, dr. Tesar remarked, “whether it is appropriate is a question for ethicists, regulators and society.”