“It may sound like it’s on the scientific fringe, but it’s not a pipe dream. This is actually happening”. When stem-cell researcher Dr. Kyle Orwig, of the University of Pittsburgh Department of Obstetrics, Gynecology, and Reproductive Sciences, made this remark, he was talking about the ground breaking work that is generating eggs and sperm from skin cells.
But he could have been talking about any number of assisted reproductive technologies (ARTs) that are rapidly advancing in research labs around the world and, in some cases, are starting to make their way into the clinic.
Most people are familiar with fertility drugs that induce a woman to produce eggs and with in vitro fertilization (IVF), in which sperm and eggs are combined outside the body and the resulting fertilized eggs are then transplanted into a woman’s reproductive tract. While both are still commonly used in clinics, new technologies are pushing the envelope on just how much science can do to improve men’s and women’s chances of becoming fathers and mothers.
Research is under way to generate eggs and sperm from adult skin cells. It has been accomplished in mice but has yet to be replicated in humans, although several labs are trying. Kyle Orwig of the University of Pittsburgh Department of Obstetrics, Gynecology, and Reproductive Sciences, is collaborating with some of the labs conducting skin-to-gamete research. Here, spermatogenic cells that produce sperm are colored in blue and brown. Elongated spermatids, the immediate precursors of sperm, are the elongated dense blue structures located near the lumen on the inside of the seminiferous tubule. (Image courtesy of Brian Hermann and Dr. Kyle Orwig).
The skin-to-gamete research is perhaps the most sensational of the technologies. In this work, researchers Mitinori Saitou of Kyoto University in Japan and Katsuhiko Hayashi of the University of Cambridge in the United Kingdom announced in 2013 that they had taken mature skin cells from an adult mouse and, from those cells, generated pluripotent stem cells that developed into primordial germ cells, which they implanted into sterile mice.
About a quarter of the male and female mice began producing sperm and eggs, respectively. Hayashi followed up by combining the sperm and eggs in a petri dish and transplanted the subsequently fertilized eggs into female mice, which successfully carried the embryos to term and resulted in baby mice.
“That means that in principal, we could take a biopsy from the skin of either a man or a woman and turn it into eggs or sperm, so he or she could have their own genetic child from their skin cells,” Orwig says.
This work in mice has yet to be replicated in humans, although several labs are trying. Orwig is collaborating with three of them, including the labs of Dr. Gerald Schatten, the director of the Pittsburgh Development Center; Dr. Renee Reijo Pera, the former director of the Center for Human Embryonic Stem Cell Research and Education at Stanford University and now at Montana State University; and Dr. Amander Clark of the University of California, Los Angeles Department of Molecular Cell and Developmental Biology.
Stem cells for the clinic
A bit closer to the clinic is Orwig’s own research designed to allow young male cancer patients to have children someday. Some cancer treatments can cause permanent infertility in men and prepubertal boys. Adult men have the option to freeze a semen sample containing sperm before initiating treatment to preserve their future fertility. This option is not available to prepubertal boys, who are not yet producing sperm, but Orwig hopes to change that by retrieving testicular tissue and using stem cell-based technologies to reinitiate spermatogenesis.
“We and others have developed the technology in a variety of animals, including monkeys, to retrieve sperm-producing stem cells from the testicular tissue,” Orwig explains. The idea is that the testicular tissue can be frozen prior to the initiation of the treatment, thawed at a later date, and processed to produce a suspension of cells, including spermatogonial stem cells, that would be transplanted into the testis of the now cancer-free but infertile individual to regenerate normal spermatogenesis.
“Then he could have a baby the normal way by sexual intercourse, or if he could generate only a fraction of normal sperm rather than normal fertility, we could use ARTs to get the most out of the few sperm that he has,” he says. Based on their success in animals and on several encouraging studies on human cells, Orwig and his collaborators think the technology is almost at the point where it can be used on humans. At present, 500–600 patients have had their testicular tissue frozen, he notes, and he is also recruiting patients to obtain additional biopsied testicular tissue.
While some safety and feasibility studies need to be done, he believes the technology is mature and could be translated to the clinic within the next five years. Perhaps the biggest challenge currently is obtaining a sufficient number of stem cells from the patient. “We anticipate that the number of stem cells in the testis is relatively low, and the number that we can retrieve in a small biopsy from the patient will be even lower, so we need to develop cell-culture technology that will allow us to amplify those cells before we do a transplant,” Orwig says. His and several other labs around the world are working on that issue.
In addition, this line of technology has another consideration: Is it safe to reintroduce tissue that was harvested prior to cancer therapy? “If we’re putting cells back into a patient, there’s a risk of putting a cancer back in too because you got the cells before they started their therapy,” he says. “That’s a critical issue, and we should not be too cavalier about taking these technologies to the clinic if it means putting a patient at risk.”