The mouse embryos looked completely normal. All of her organs developed as expected, along with her limbs, as well as the circulatory and nervous systems. Their tiny 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 uterus, the first time such a feat has been accomplished, scientists reported on Wednesday.
The experiments at the Weizmann Institute of Science in Israel should help scientists understand how mammals develop and how gene mutations, nutrients and environmental conditions can affect the fetus. But the work might one day raise profound questions as to whether other animals, even humans, should or could be cultivated outside of a living womb.
In a study published in the journal Nature, Dr. Jacob Hanna, how embryos are removed from the uterus of mice on five days of pregnancy and cultured in an artificial uterus for a further six days.
At this point the embryos were about in the middle of their development; The full gestation is about 20 days. A person at this stage of development would be called a fetus. To date, Dr. Hanna and his colleagues bred more than 1,000 embryos in this way.
“It really is a remarkable achievement,” said Paul Tesar, developmental biologist at Case Western Reserve University’s medical school.
Alexander Meissner, Director for Genome Regulation at the Max Planck Institute for Molecular Genetics in Berlin, said that “it is amazing to get this far” and that the study is “an important milestone”.
However, the research has already gone beyond what investigators described in the paper. In an interview, Dr. Hanna, he and his colleagues took fertilized eggs from the fallopian tubes of female mice immediately after fertilization – on day 0 of development – and bred them in the artificial uterus for 11 days.
Until now, researchers in the laboratory have been able to fertilize mammalian eggs and only breed them for a short time. The embryos needed a living womb. “Placental mammals develop trapped in the uterus,” said Dr. Tesar.
This prevented scientists from answering basic questions about the earliest stages of development.
“The holy grail of developmental biology is understanding how a single cell, a fertilized egg, can create all of the specific cell types in the human body and grow into 40 trillion cells,” said Dr. Tesar. “Researchers have always tried to find 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 remove embryos from the uterus of laboratory animals at different times for insight into development that are more like snapshots than video.
What was needed was a way to get inside the uterus and watch and optimize mammalian development as it happened. For Dr. For Hanna this meant the development of an artificial uterus.
He spent seven years designing a two-part system that included incubators, nutrients, and a ventilation system. The mouse embryos are placed in glass vials in incubators, where they swim in a special nutrient fluid.
The vials are attached to a wheel that rotates slowly to prevent the embryos from sticking to the wall, where they would deform and die. The incubators are connected to a ventilator that supplies oxygen and carbon dioxide to the embryos and controls the concentration of these gases, as well as the gas pressure and flow rate.
On day 11 of development – more than in the middle of a mouse pregnancy – Dr. Hanna and his colleagues took the embryos, only the size of apple seeds, and compared them with those that developed in the uterus of living mice. The scientists found that the laboratory embryos were identical.
At this point, however, the embryos grown in the laboratory had become too large to survive without a blood supply. They had a placenta and a yolk sac, but the nutrient solution that was diffusing to feed them was no longer enough.
Overcoming this hurdle is the next goal, said Dr. Hanna in an interview. He is considering using a fortified nutrient solution or an artificial blood supply that is attached to the embryo’s placenta.
In the meantime, experiments are due. The ability to keep embryos alive and develop mid-pregnancy “is a gold mine for us,” said Dr. Hanna.
The artificial uterus can allow researchers to learn more about why pregnancies lead to miscarriages or why fertilized eggs cannot be implanted. It opens a new window about how gene mutations or deletions affect the development of the fetus. Researchers may be able to watch individual cells migrate towards their ultimate destinations.
The work is “a breakthrough,” said Magdalena Zernicka-Goetz, professor of biology and biotechnology at Caltech. It “opens the door to a new era in the study of development in the experimental mouse model.”
A recent development offers another possibility. Researchers created mouse embryos directly from mouse fibroblasts – connective tissue cells – to create early embryos without starting with a fertilized egg.
Combine this development with Dr. Hanna’s work and “now you don’t need mice to study mouse embryo development,” said Dr. Meissner. Scientists can potentially make all the embryos they need from connective tissue.
If scientists could make embryos without fertilizing eggs and study their development without a uterus, said Dr. Meissner: “You can escape the destruction of embryos.” It would not be necessary to fertilize mouse eggs in order to destroy them in the course of the study.
But the work could eventually go beyond mice. Two other articles published in Nature on Wednesday report attempts that are close to creating early human embryos in this way. Of course, said Dr. Meissner, the creation of human embryos is years away – if at all allowed. At present, scientists generally fail to examine human embryos after 14 days of fertilization.
In the future, Dr. Tesar: “It is not unreasonable that we might have the ability to develop a human embryo completely outside of the uterus from conception to birth.”
Of course, even the suggestion of this science fiction scenario will horrify many. But it is still early days with no certainty that human fetuses could ever develop completely outside of the womb.
Even if they could, Dr. Tesar: “Whether this is appropriate is a question for ethicists, regulators, and society.”