Making Primordial Germ Cells

Over the past decade, Mitinori Saitou at Kyoto University in Japan has been teasing apart the genetic cascade that prompts a stem cell to turn into a primordial germ cell (PGC), the cells that generate thousands of eggs in a woman and millions of sperm in a man. He has succeeded, with incredible implications for the future of human reproduction.

Saitou partnered with colleague Katsuhiko Hayashi from the University of Cambridge in the UK to take mature skin cells from an adult mouse and turn them into induced pluripotent stem cells. These pluripotent stem cells could also be turned into PGCs.

Then came the ultimate test of their discovery. They implanted the PGCs into sterile mice. About one mouse in four became fertile again—male mice began producing sperm, and female mice began producing eggs. Hayashi harvested these sperm and eggs and combined them in the lab to produce living embryos, which he placed into surrogate mouse mothers.

Children of Mice

The mouse babies were born fertile and healthy, with a success rate around one-third that of current in-vitro fertilization (IVF) techniques. To illustrate what he’d accomplished, Hayashi took a skin cell from a normally-colored mouse and used it to grow egg cells in an albino mouse. When the babies were born, they had the dark coloring of their genetic parent.

However, their own naturally-occurring PGCs were fragile and misshapen, and any offspring they might have would carry a high risk of genetic diseases.

“While it is exciting that artificial primordial germ cells express the same markers as natural cells, there is much work to be done before we can conclude that the [sperm and eggs] derived from these cells can be considered fully functional,” said Dr. Alan B. Copperman, Director of Reproductive Endocrinology and Infertility at the Icahn School of Medicine at Mount Sinai Medical Center, in an interview with Healthline.

Copperman is worried about certain markers that attach themselves to DNA, called epigenetic markers, which affect how DNA is expressed in cells. These markers become attached to DNA strands as the result of very early experiences in the womb and during childhood. These markers are normally erased and replaced by a new set when a PGC creates a sperm or egg cell, giving offspring a fresh chance to interact with its environment. With artificial PGCs, flawed epigenetics may be causing the high rate of failure.

A Brave New World?

Saitou and Hayashi began their experiment to learn how to create PGCs in the lab, not to revolutionize fertility research. Nonetheless, the implications of their discovery are far-reaching.

Using their techniques, sperm or egg cells could be created from the skin cells of a person of either sex. This could someday offer a way for same-sex couples to have a biological child together. It also gives new hope to couples struggling with infertility and to women who’ve had no luck with IVF.

However, “Our work is still at a purely basic level using the mouse, and it would take many more years to apply this work to humans,” Saitou told Healthline.

Scientists would first have to test the technique in monkeys and other primates and observe their offspring for several generations to see if there are any lasting epigenetic problems. How long would this take? No one knows for sure. 

Simply unlocking the monkeys’ genetic pathway to create PGCs could take another decade. For scientists to establish safety in monkeys and then discover the human genetic pathway, the wait might be more than 50 years.

The new discovery raises a slew of ethical questions as well. In theory, a mouse could be self-fertilized with both sperm and an egg made from its own DNA. Saitou and Hayashi did not attempt this.

“Abuse and misuse of any new technology—such as artificial creation of primordial germ cells—could send us down a slippery slope which could impact society by introducing the possibility of routine cloning, or positive and negative eugenic selection of future generations,” said Copperman. “While I am enthusiastic about the basic science implications of these findings, today’s reproductive biologists have a responsibility unparalleled in our history to act judiciously, transparently, and cautiously, as they pursue germ cell research.”

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