For couples who can’t seem to get pregnant, one of the more common causes is egg or sperm quality: sperm that never make it to the egg or that can’t fertilize it once they’re there, and eggs that resist fertilization or implantation in the uterine wall. Now, for the first time, scientists have turned adult cells into egg- and sperm-cell precursors, an achievement that could one day help infertile couples conceive a child that shares their DNA.
Amander Clark, a developmental biologist at the University of California, Los Angeles, created the egg and sperm precursors using an existing line of induced pluripotent stem (iPS) cells, so named for their ability to turn into just about any tissue type and lauded for their potential in regenerative medicine. Until now, however, no one had shown that it was possible to prod iPS cells to rewind their internal clocks all the way back to the gamete, or “germ cell,” stage.
Researchers had previously shown that embryonic stem cells could produce egg- and sperm-cell precursors. But infertile couples would need to use donor eggs or sperm obtained from infertility clinics. “The benefit of using an iPS cell is that it has the donor’s own genetics,” Clark says. “Our research is many, many, many years awayam from generating a cell type that would be capable of fertilization and, therefore, making a healthy child. But this is one of the first steps.”
The study also highlights the differences between embryonic stem cells and iPS cells, which have been under study for a much shorter time period. When Clark compared the developmental potential of iPS cells to that of embryonic stem cells, she found that the latter resulted in egg and sperm precursors that were substantially healthier, with fewer chromosomal abnormalities. (This difference could be a major obstacle on the path toward using iPS cells in the infertility clinic.) “Because the [desired] outcome of using these cells is producing a healthy baby, the quality of a germ cell is essential in order to ensure that you have the birth of a healthy child,” Clark says. As a result, she notes, it will be essential to establish tests that can determine the quality of a germ cell before it gets anywhere near the clinic.
“There’s a real danger here: if you make a gamete that’s not right, rather than helping someone, you harm them,” says Peter Donovan, codirector of the Sue and Bill Gross Stem Cell Research Center at the University of California, Irvine. “This points out that we may need to be even more careful about this.”
Clark believes that the quality of iPS cell gametes has much to do with how the original cell line was formed in the first place: two years ago researchers used a method that employs a virus to induce the genetic changes needed to reprogram an adult cell. That virus also inserts itself into the cell’s DNA and can cause cancer. However, newer techniques have created iPS cells without integrating viral DNA. “We’d like to be able to use these more modern, contemporary iPS cells to see if the molecular integrity of the germ cells we derive from them is improved,” Clark says.
“It’s very interesting,” says Renee Reijo Pera, the director of the Stanford University Center for Human Embryonic Stem Cell Research and Education. “I think it’s going to be a marvelous tool for human genetics and for some potential treatments.” But she cautions that it’s a very early step. Scientists have been working with embryonic stem cells for far longer, and are still only able to coax them to develop into germ precursor cells. “The big step is still to come, and that’s getting a mature egg or sperm cell,” she says. “That’s turned out to be a roadblock so far.”
Even with all the caveats, Donovan and Reijo Pera agree that the study represents a big step forward. Studying iPS-induced germ cells in vitro could allow researchers to understand the intricate process through which gametes are formed. “That itself could have a big impact on understanding underlying mechanisms of infertility,” Donovan says. And that, in turn, could help elucidate the effects of toxins on a developing embryo. “If we understand how the embryonic and fetal periods are affected by toxic environments, we can understand how to protect the germ line during development,” he says.