The mouse embryos looked completely normal. All of their organs developed as expected, as well as their limbs, circulatory and nervous systems. Their little hearts beat at a normal 170 beats per minute.
But these embryos did not grow in a mother mouse. They were developed in an artificial womb, the first time such a feat has been achieved, scientists reported Wednesday.
The experiments, at the Weizmann Institute of Science in Israel, were designed to help scientists understand how mammals evolve and how gene mutations, nutrients and environmental conditions can affect the fetus. But the work may one day raise profound questions about whether other animals, even humans, should or can be grown outside of a living womb.
In a study published in the journal Nature, Dr. Jacob Hanna removing embryos from the womb of mice after five days of pregnancy and growing them in artificial uterus for another six days.
At that point, the embryos were about halfway through their development; full gestation time is approximately 20 days. A human at this stage of development would be called a fetus. To date, Dr. Hanna and his colleagues cultivated more than 1,000 embryos in this way.
“It’s a truly 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 “getting this far is great” and that the study was “an important milestone.”
But the research has already gone beyond what the researchers described in the paper. In an interview, Dr. Hanna said he and his colleagues had taken fertilized eggs from the fallopian tubes of female mice just after fertilization – on day 0 of development – and cultured them in the artificial uterus for 11 days.
Until now, researchers were able to fertilize mammal eggs in the lab and grow them for only a short time. The embryos needed a living uterus. “Placental mammals develop locked in the womb,” said Dr. Tesar.
That kept 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 make all the specific cell types in the human body and grow into 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 such as worms, frogs and flies that do not require a uterus, or to remove embryos from the uterus of laboratory animals at different times, giving a glimpse of the development is more like snapshots. than video.
What was needed was a way to get into the womb, observe and adjust mammalian development as it happened. For Dr. Hanna, that meant developing an artificial womb.
He spent seven years developing a two-part system with 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 spins slowly so that the embryos do not attach to the wall, where they would become deformed and die. The incubators are connected to a ventilation machine that supplies oxygen and carbon dioxide to the embryos and controls the concentration of those gases, as well as the gas pressure and flow.
On day 11 of development – more than halfway through a mouse pregnancy – Dr. Hanna and colleagues took the embryos, just the size of apple seeds, and compared them to the embryos that developed in the wombs of live mice. The lab embryos were identical, the scientists found.
By then, however, the lab-grown embryos had grown too large to survive without a blood supply. They had a placenta and yolk sac, but the nutrient solution that fed them by diffusion was no longer sufficient.
Getting over that hurdle is the next goal, Dr. Hanna said in an interview. He is considering the use of an enriched nutrient solution or an artificial blood supply that connects to the embryo’s placentas.
Meanwhile, the experiments beckon. The ability to keep embryos alive and develop in mid-pregnancy “is a goldmine for us,” said Dr. Hanna.
The artificial womb could allow researchers to learn more about why pregnancies end in miscarriages or why fertilized eggs are not implanted. It opens a new window on how gene mutations or deletions affect fetal development. Researchers may be able to see individual cells migrate to their final destination.
The work is “a breakthrough,” said Magdalena Zernicka-Goetz, professor of biology and biological engineering at Caltech. It “opens the door to a new era of research to development in the experimental mouse model.”
A recent development offers another possibility. Researchers directly created mouse embryos from mouse fibroblasts – connective tissue cells – to create early embryos without starting with a fertilized egg.
Combine that development with the work of Dr. Hanna’s, and “now you don’t need mice to study mouse embryo development,” said Dr. Meissner. Scientists may be able to make all the embryos they need from connective tissue.
If scientists could create embryos without fertilizing the eggs and study their development without a uterus, said Dr. Meissner, “You can escape the destruction of embryos.” It wouldn’t be necessary to fertilize mouse eggs just to destroy them during the study.
But the work could eventually extend beyond mice. Two other papers published in Nature on Wednesday report on efforts 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 is allowed at all. And for now, international regulations prohibit the study of human embryos after 14 days of fertilization.
In the future, Dr. Tesar, “it is not unreasonable that we should have the ability to develop a human embryo from conception to birth, entirely outside the womb.”
Of course, even the suggestion of this science fiction scenario will bore many with horror. But it is still in its infancy and there is no guarantee that human fetuses could ever fully develop outside of the womb.
Even assuming they could, Dr. Tesar, “whether that is appropriate is a question for ethicists, regulators and society.”