Cara Gormally’s pregnancy was shadowed by grief. As a queer woman wanting to have a baby, the biology professor had figured finding a sperm donor would be the only obstacle she and her partner faced. But thanks to Gormally’s organizational skills and love of making lists, the couple landed on a donor with relative ease.
Then, Gormally struggled to conceive. Each month brought fresh disappointment and loss.
“So much of the process depended on random, heart-breaking chance,” she says. The emotional and financial roller coaster was exhausting.
But it wasn’t the hardest part. The couple had accepted that, as much as they wanted a baby, their child wouldn’t be biologically related to Gormally’s spouse.
“I grieved that our child wouldn’t be genetically related to both of us,” Gormally says. “I longed for the biologically impossible.”
But now, a new set of technologies have the potential to change what’s possible — allowing same-sex partners to have kids who share their genetic material, just like straight couples.
In mammals, pretty much every cell in the body carries two sets of genetic material. One set comes from mom and the other from dad. Eggs and sperm are the only exceptions; they have just one set. Then, when a sperm fertilizes an egg, those two sets combine, restoring the usual number to two sets per cell.
Gormally and other same-sex partners are currently barred from their dreams by a phenomenon called genomic imprinting. It uses a distinct tag from each parent to mark the DNA that mammals pass on to their offspring. The process ensures that, for a small percentage of genes, we only express the copy of genetic material provided by our mother or our father. When this imprinting process goes awry, kids can end up with inactive gene regions that cause miscarriages, developmental defects and cancer.
(Credit: Jay Smith/Discover)
During this genomic imprinting, mom’s distinct collection of tags typically turns off certain genes, so that just dad’s copy is expressed. And dad imparts his own marks that leave only the maternal copy on. (Most imprints silence gene expression, but some activate it.) That’s a problem for same-sex couples who want to have a baby. If both sets of an offspring’s genes come from maternal DNA, for example, then both copies of imprinted genes will be off. So, the embryo can’t make any of the genes’ products.
“We don’t get the full set of [gene] products that we need to undergo proper development unless we have both a maternal and paternal contribution to a fertilized egg,” says Marisa Bartolomei, a geneticist at the University of Pennsylvania in Philadelphia, who discovered one of the first imprinted genes in mice.
Scientists discovered genomic imprinting in mammals about 30 years ago. During experiments in the mid-1980s, researchers removed either the maternal or paternal genetic contributions from newly fertilized mouse eggs. Then, they transferred in a second set of genes from another mouse to create embryos with either two sets of female genetic material or two sets of male genetic material. A surrogate mouse was able to gestate the embryos, but none survived. The finding showed normal development requires genetic material from both a father and the mother. More than that, the outcomes revealed that maternal and paternal genetic material differ from each other in meaningful ways.
Later experiments revealed mice developed differently depending on whether they happened to receive both copies of certain regions of DNA from one parent (rather than one copy from each parent).
Mice with hairpin-shaped tails were telling examples. When researchers deleted the gene region responsible for a hairpin tail from a mother’s genome, mice embryos grew large and died partway through gestation. In contrast, deleting the same region from the paternal genome had no effect on the rodents’ growth or development.
In the three decades since, researchers have found more imprinted genes (they suspect there are between 100 and 200 such genes) and the molecular tags that silence them. Scientists have also taken strides connecting imprinting defects to developmental disorders in humans. But all along, researchers have known that imprinting prevents same-sex parents from having children.
Editing Out Impossibility
In October 2018, researchers overcame this impossibility in mice. By deleting imprinted regions, Wei Li and a team at the Chinese Academy of Sciences in Beijing produced healthy mice from two moms. The researchers also created mouse pups from two dads for the first time. However, the offspring died just a few days after birth.
Despite the loss, Li is optimistic. “This research shows us what is possible,” he says.
To overcome the imprinting barrier, Li and his fellow researchers turned to CRISPR, a gene-editing technique that’s made altering genomes easier than ever. They used the tool to delete gene regions from embryonic stem cells from mice mothers. The researchers then injected these modified stem cells into the egg of a female mouse and then used a third surrogate female mouse to carry the fetus to term.
The team had already seen some success two years earlier when they created mouse pups with two genetic mothers by deleting two imprinted regions. Although these bimaternal mice also grew to adulthood and produced pups of their own, they developed growth defects. On average, the bimaternal mice were 20 percent lighter than their hetero-parental counterparts. In their latest study, Li and his team also deleted a third region from the mothers’ genes, which restored the animals’ growth to normal.
But the scientists had to clear a few more hurdles to generate mice with two genetic fathers. They found, through a process of trial and error, that they needed to remove twice as many imprinted regions in the bipaternal mice as the bimaternal mice. In total, the team deleted seven imprinted regions to successfully create mice from two dads.
Still, the numbers were not in their favor. Only two and a half percent of embryos made it to term and less than half of one percent lived for two days. None made it to adulthood.
“The produced bipaternal mice are not viable, which implies more obstacles are needed to cross to support their postnatal survival, if possible,” Li says. “The lower birth rate, on the other hand, implies the existence of an unknown barrier hindering the development of bipaternal embryos.”
In contrast, the bimaternal mice fared much better. These mice grew to adulthood and were healthy enough to have pups of their own by mating with typical male mice. They also behaved the same as the control mice. As far as the researchers could tell, the bimaternal mice appear as healthy and normal as any other laboratory mice.
“It does not mean that they are normal in every aspect,” Li cautions. “One cannot investigate all the aspects under restricted experimental conditions with a limited number of animals.”
Despite the researchers’ success, Li says the technique is not ready for use in humans. “It is never too much to emphasize the risks and the importance of safety before any human experiment,” he says, particularly in regard to the bipaternal offspring, which currently “are severely abnormal and cannot survive to adulthood.”
The bimaternal offspring hold more promise. The team is now working to translate their findings to monkeys. And that work could bring the impossible one step closer to feasible for humans.
Li’s research is encouraging but it’s a long way from helping Gormally and her spouse. However, it’s also not the only shot for same-sex couples. Another new technology called in vitro gametogenesis, or IVG, may be an alternative potential path for same-sex couples to have their own kids.
Scientists use the technique to make eggs and sperm from other cells in the body. To do so, biologists first reprogram adult skin cells to become stem cells. Then, they stimulate the skin-derived stem cells to develop into eggs or sperm.
Researchers from Japan have now perfected the technique in mice. And in groundbreaking work, Katsuhiko Hayashi and Mitinori Saitou and their team generated functional eggs from mice tail cells.
The researchers then fertilized the eggs with sperm from male mice and implanted the embryos into surrogate mothers. The offspring grew up healthy and fertile. In principle, this approach could allow a woman’s skin cells to be engineered into sperm and used to fertilize her partner’s egg.
IVG could transform same-sex couples’ ability to have their own children. “If it had been possible at the time, we definitely would’ve have tried to do it,” says Gormally, who is now a proud parent to a toddler thanks to her and her spouses’ sperm donor. “[It’s] a total game-changer.”
This story is part of “The Future of Fertility” a new series on Discover exploring the frontiers of reproduction.
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Source : Discovermagazine