George Church is known for pushing the boundaries of biology. The Harvard University geneticist played a key role in developing technologies to read and edit genes and has made waves with his proposal to resurrect the extinct woolly mammoth. Now one of his latest projects could have enormous implications for how humans reproduce.
Church’s lab at the Wyss Institute of Harvard is one of a handful around the globe trying to coax adult stem cells, derived from blood or skin, to become human eggs capable of forming an embryo. They haven’t figured out how to do that just yet, but Church and his colleagues say they’ve taken an important step: growing miniature human ovaries in a dish, complete with the vital cells normally needed to support and nourish an egg.
Church and several other scientists are confident that, within the next few years, someone will cross the finish line and create the first lab-grown human egg.
Such an advance would hold numerous possibilities. The eggs and miniature ovaries could spur research into conditions like infertility and ovarian cancer, and help scientists make sure that pharmaceutical drugs don’t impair fertility. Longer-term, lab-grown eggs could help infertile women have children of their own — even during menopause or into older age. With further refinement, the technique may allow same-sex couples to have biological children by making eggs from male stem cells or sperm from female stem cells.
Eggs are arguably the most precious of human cells. While men can produce large numbers of sperm throughout life, women have a finite number of eggs that declines from birth. Collecting eggs is an expensive and uncomfortable procedure. And figuring out how to grow an egg is difficult, in part because it is so hard to get eggs to do research on in the first place.
Church said he wants to “break that Gordian knot” by figuring out how to make eggs en masse. “Our goal is not to make one, it’s to make millions,” he said. “And its utility will be immediate, because as soon as you have millions of eggs, you can do tests on them.”
Lab-grown eggs would open previously unimaginable doors for the millions of couples who want biological children but currently can’t have them. But the technology could also fuel dystopian nightmares, allowing wealthy parents or dictatorial governments to create and screen hundreds of embryos and select only ones with the desired genes for birth. It could also be used to make eggs or sperm from a person’s skin cells without their consent.
“I don’t think we’re ready for any of this,” said Henry Greely, director of the Center for Law and the Biosciences at Stanford, who has studied the ramifications of lab-grown eggs and sperm and outlined these scenarios, and others, in his 2016 book “The End of Sex and the Future of Human Reproduction.” “There are some really complicated political questions.”
While other scientists have made lab-grown eggs and sperm from mice and used them to make mouse pups, applying the technique to human cells is one of the final frontiers for stem cell biologists.
In 2006, the Japanese biologist Shinya Yamanaka discovered how to take cells from the skin or blood of an adult and revert them into a blank slate seemingly capable of becoming any cell in the body — much like an embryonic stem cell, but without the same ethical and political controversy.
Yamanaka’s induced pluripotent stem cells earned him a share of the Nobel Prize in Physiology or Medicine in 2012, and since then, much of stem cell research has centered on concocting molecular recipes to coax those stem cells to become other cells, such as pancreatic cells that scientists are testing as a treatment for type 1 diabetes.
The Church lab’s key discovery was identifying a pair of proteins — known as transcription factors — that reprogram pluripotent stem cells into ovary building blocks in just five days. The team’s recent paper, published in the peer-reviewed scientific journal eLife last month, reveals how they transformed skin cells from a 66-year-old woman into granulosa cells, which produce female sex hormones and form sac-like structures called follicles that nurture and protect a developing egg.
When these granulosa cells were mixed with stem cells that have the potential to become eggs, they formed tiny ovary-like structures in a dish, which the scientists dubbed ovaroids.
Other scientists have made things similar to ovaroids using granulosa cells painstakingly dissected from the ovaries of fetal mice, but Church’s team says their method provides the first quick and easy way to make fully human ovaries in a dish.
“We still don’t have the right culture conditions to actually go all the way to eggs. But we’re working on that,” said Merrick D. Pierson Smela, a graduate student in Church’s lab who was one of the leaders of the study. The lab is also trying to figure out how to get eggs to enter a special form of cell division called meiosis that prepares them for being fertilized. “That will be a big milestone, and probably the hardest one to get,” he added.
The Wyss Institute has licensed the ovaroid technology to the New York biotech startup Gameto, which has raised $40 million from private investors and partly funded the Church lab’s ovaroid studies. The company wants to use the mini organs to help improve the chances of success for women undergoing in vitro fertilization.
IVF normally involves hormonal treatments to help eggs mature and become ready to be fertilized and form an embryo. “Despite that, a number of these eggs come out immature and are just thrown away. And we think that’s insane,” said Christian Kramme, a former graduate student in Church’s lab and coauthor of the eLife paper who is now vice president of cell engineering at Gameto.
Gameto hopes to move that maturation step to the lab bench. A woman undergoing IVF would still need to get her eggs aspirated from her ovary, but perhaps without the burden of hormone treatments. Kramme hopes it could improve the odds of successful IVF too, and other researchers not involved with the company or the Church lab’s work said the idea seems sound.
“That’s not far-fetched, and that may be the easiest direction to take this technology,” said Ramiro Alberio, a professor of developmental biology at the University of Nottingham. But he views the ovaroids as an “incremental” step toward making an egg.
Several researchers took a critical view of the paper and said they were unconvinced by its claims. Many expected the lab to run more thorough tests on the granulosa cells and ovaroids to prove that they’re similar to natural ovaries before publishing.
Church chalks up the disagreements to divisions between biologists who are trying to perfectly recreate what exists in nature versus synthetic biologists, like himself, who just want to make something that works. “We’re not trying to recreate something that we already have. We’re trying to create something new,” he said.
Some researchers question whether lab-grown eggs can ever be thoroughly tested enough for reproductive purposes. “If you’re making an egg to make a baby, the bar for quality is off the charts, because you can’t screw it up,” said Jonathan Tilly, a professor of biology who studies stem cells at Northeastern University.
Church agrees it could be years before medical regulators feel ready for tests to begin in people and longer for it to become widely used. But he believes that tests in larger animals, including pigs and elephants, are not far off, and could provide a steppingstone to doing it in humans.
Society will need time to absorb the ethical implications of the work. But Greely, the Stanford bioethicist, expects it will take another decade of research for medical regulators and doctors to feel comfortable using the egg to make a baby, and longer before the approach becomes widespread. “That’ll give us time to think about [these issues],” he said.