By Brianna Abbott
March 21, 2019 200 p.m. ET
Grady is an 11-month-old rhesus macaque who lives at the Oregon National Primate Research Center just west of Portland. She spends her days playing and is hitting all of her normal developmental milestones. She’s also the result of a novel reproductive technology that relies on frozen testicular tissue, according to a new study.
Grady’s birth is a breakthrough in the effort to preserve fertility for young boys who undergo cancer treatment, researchers say. The frozen tissue, which came from prepubescent rhesus macaques, produced sperm when reattached to the primates after they grew older. That then led to a successful pregnancy and healthy baby Grady, according to the researchers who described their findings in the journal Science.
“I’m excited about this work because it truly addresses a need in human clinical care,” says Robert Brannigan, a professor of urology at Northwestern University, Feinberg School of Medicine who wasn’t involved in the work, noting that the procedure is still experimental. “The proof of principle is one that’s very encouraging.”
The survival rate for childhood cancers is now over 80%, according to the American Cancer Society. Radiation, chemotherapy and other treatments, however, typically leave 30% of survivors infertile. Many male patients are too young to freeze their sperm in advance for future use, leaving them unable to have a biological family.
Looking for another reproductive avenue, many researchers have turned to tissue freezing, or cryopreservation. For women and girls, ovarian tissue can sometimes be successfully frozen and then transplanted back to produce mature eggs. One analysis found that there have been at least 84 babies born from women who received this sort of transplant since 1999.
For men, however, the practice has yet to reach the clinical level. Despite success in mice and other animals, the procedure had yet to result in an offspring in primates. Nevertheless, young male patients have been opting to freeze their testicular tissue samples for at least a decade, in hopes that a procedure may be available within their lifetimes. Hundreds of samples are scattered in research facilities across the globe.
“Currently, there is no endpoint for that,” says Kutluk Oktay, a professor at Yale University School of Medicine and director of the Innovation Institute for Fertility Preservation and IVF, who has about a dozen samples frozen at his clinic. “So we are in desperate need for progress in that area.”
In the new work, researchers at the Magee-Womens Research Institute of the University of Pittsburgh Medical Center used five rhesus macaques that were close to puberty and removed one testicle from each, freezing the tissue. Once the macaques showed signs of puberty— roughly five to seven months later—the researchers removed the other testis and grafted samples of both fresh and previously frozen tissue fragments onto the monkeys’ backs and under their scrotal skin.
The researchers monitored the macaques for eight to 12 months. Once the macaques hit puberty, they all produced testosterone levels in the normal range despite being castrated. Lumps began to grow in the sample areas. The researchers analyzed the tissue and saw that all samples produced sperm, and there was no difference between the fresh and frozen tissue.
“It was made of tubules that looked just like spaghetti,” says Kyle Orwig, a professor of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh and senior researcher on the study. “That was exactly like a normal testis.”
The researchers sent sperm from one of the cryopreserved tissue grafts to the primate research center at Oregon Health and Science University that houses female monkeys. The sperm were injected into 138 eggs, and 11 embryos were ultimately viable and transferred into six female rhesus macaques. One of the embryos developed into a pregnancy, and Grady (“graft-derived baby”) was born on April 16, 2018, weighing 471 grams, or a little over 1 pound. Dr. Orwig said that he felt like a “proud papa” on the day she was born.
A few procedural tweaks, such as the cryopreservation method or the size of the grafts, may explain why Grady’s birth has been successful when previous attempts have failed, the researchers noted.
Before moving the procedure into humans, scientists want to replicate the procedure in non-castrated primates, and Dr. Orwig and his team recently submitted a grant to try to secure funding for this study. The team chose to fully castrate the animals because previous research indicated that would produce the best results, but they also want to make sure that the process can work without castration.
Future tests in subjects with cancer will also need to make sure that no cancerous cells are included in the tissue samples.
Clinical testing, however, may occur within the next several years. Dr. Orwig says that he may soon start approaching some of his patients with previously frozen tissue to see if they would be interested in the procedure. Some researchers also believe that the results may cause more families to consider freezing testicular tissue.
“A little boy probably doesn’t care at this moment” says Susan Taymans, the program director at the Fertility and Infertility Branch of the National Institute of Child Health and Human Development, which funded the research. “But when he’s an adult and looking to start a family, he’s going to be very grateful that this was offered to him and that it’s available.”