Christian Kramme grew up in a big family, the youngest of seven kids raised in California’s Santa Clarita Valley. By the time he moved across the country to do a PhD in George Church’s lab at Harvard, his siblings were already trying to start families of their own. And some of them were struggling. So when Church, the legendary geneticist and cell engineer, asked Kramme what he wanted to work on, he decided to swing big; he wanted to make eggs. Human eggs. From scratch.
“There was really no precedent in his lab,” said Kramme. “When I arrived, not a single person there was working on reproduction.”
But there was something of a blueprint for what he was after.
Starting about a decade ago, scientists in a handful of developmental biology labs around the world began cataloging the complex chemical recipe an embryo uses to make gametes — sperm or egg cells — with the idea that if they could copy it, they could coax any cell along the same path. Working mostly in rodents, these pioneers in so-called in vitro gametogenesis, or IVG, have since turned mice stem cells into sperm and eggs, including a recent success creating eggs from the stem cells of a male mouse.
Key to these breakthroughs is first creating a clump of reproductive tissue to send these would-be-gametes the coordinated signals they need to become sperm or eggs. Kramme spent most of his PhD figuring out how to make the human version of this ovary-in-a-dish, supported by New York City-based biotech Gameto. In February, Kramme and his colleagues revealed in a paper published in eLife how they transmuted the skin cells of a 66-year-old woman into granulosa cells that could secrete reproductive hormones and even form ovarian follicles.
These mini-ovaries, or “ovarioids,” aren’t yet sufficiently like the real thing to produce the worlds’ first lab-grown human egg, a milestone that would open the door to an array of radical new reproductive possibilities. But Gameto licensed the technology for what it sees as a much more near-term (and slightly less sci-fi) application: boosting the odds of success for people seeking in vitro fertilization.
In a pair of preprint studies posted online in late March, the company — which has raised $40 million from private investors including Anne Wojicki, the CEO of 23andMe, and cryptobillionaire Brian Armstrong — unveiled an early look at the science behind its first product. The ready-made reproductive support cells, Fertilo, can mature eggs in a petri dish rather than inside a human body.
In most parts of the world, IVF involves a series of hormonal injections taken to send the ovaries into overdrive, maturing multiple eggs at once rather than the single egg typically developed and released monthly. Approaches vary, with places like Japan, Vietnam and Thailand tending toward a lighter drug regimen, while the American assisted reproductive industry skews toward pumping patients full of as many hormones as their bodies can withstand, to drive the maturation of as many eggs as physically possible. IVF is a numbers game. More shots in the abdomen equal more shots on goal.
But there are downsides to that approach. Synthetic hormones are expensive to manufacture, driving up the cost with each additional shot. They can also cause unpleasant side effects, including a condition called ovarian hyperstimulation syndrome, which leads to symptoms including nausea, depression, and ovarian cysts in one-third of IVF patients, and in rare cases can require hospitalization. And the long-term health impacts of repeated exposures to huge amounts of hormones have not been well-studied.
Those are risks people determined to start families through IVF are usually willing to take. More hormones usually means more mature, high-quality eggs. But many eggs still come out immature, not having developed sufficiently to survive fertilization. In most clinics, those eggs get tossed, a costly loss when truly every egg counts. Gameto is betting that with the help of its ovarioids, they might not have to.
In vitro maturation, or IVM, is not a new idea. Not long after the first test tube baby, Louise Brown, was born in 1978, reproductive endocrinologists began playing around with adding various hormones to the culture medium to nudge eggs into developing further outside the body before implantation. The first IVM baby was born in a hospital in Seoul, Korea in 1991. But there always seemed to be something missing from the cocktail; leading to lower pregnancy rates and higher incidence of miscarriage. For those reasons, it has remained both limited and controversial in its practice.
“The reality is that all the randomized controlled trials done until now do not show an improvement with IVM as compared to IVF,” said Ben Mol, who leads the evidence-based women’s health care research group at Monash University in Melbourne, Australia and is not involved with Gameto.
What makes Gameto’s technology different is that it’s adding not hormones and proteins, but actual cells to the culture medium. The idea is that these organoids will be better at making the necessary chemical cocktail to drive maturation than Gameto’s scientists will be at guessing the ingredient list and the exact order and amount in which they get added.
Early last year, the company began working with clinics in Spain, Peru, and the U.S. to test whether immature eggs donated by IVF patients could be rescued by nestling them next to stem cell-derived granulosa cells. The biggest challenge was figuring out how the two might happily cohabitate. Eggs are extremely sensitive to their surroundings — any kind of spike in carbon dioxide or slight shift in pH can cause an egg to come apart. They are so sensitive that embryologists often don’t wear perfumes or gloves because they emit volatile compounds that can be toxic to an egg.
“It’s like a huge cellular sponge,” said Kramme, who is now Gameto’s vice president of cell engineering. To limit exposure, eggs are kept in tiny volumes of liquid, just 100 microliters of culture media coated in a protective layer of mineral oil to keep anything from getting in or out. Gameto’s scientists had to find a way to make their ovarian support cells also survive in that single droplet of liquid. The result is something that looks less like a mini-ovary and more like a sea of tens of thousands of these cells, ready to support an egg once added.
One of the preprints described those methods as well as the results. After 24 to 28 hours together in an incubator, a majority of the immature eggs now looked like mature ones; both visually and in terms of the genes they expressed and the proteins they produced.
That was with eggs produced from standard, high hormone regimens. The company and its academic collaborators at Harvard and Duke University also tried to mature eggs from people who received a minimal amount of hormonal stimulation — sometimes as little as one or no injections. These, they fertilized and let develop to the blastocyst stage, allowing them to test the resulting embryos for chromosomal abnormalities. Over half — 57% — of the eggs retrieved made it that far and appeared chromosomally normal, compared to 22% in existing in vitro maturation methods.
“It definitely shows the possibility that in IVF the answer is not always more drugs,” said Kramme, a co-author on the two studies. “Maybe with some of these newer techniques we can really decrease the burden on the patient instead of just using them like an incubator.”
The second study was small, with just seven donors, and the research is still at an early stage. Both studies have been submitted for publication, but have not yet been peer-reviewed.
For Mol, the results hint at progress in a field that’s yet to deliver on the promise made more than three decades ago, when early IVM researchers said the technology might one day rid all IVF patients of having to take hormone treatments. But Mol cautioned that without clinical data, it’s hard to make predictions about how well it will work in the real world. “From these surrogate outcomes, this appears to be an improvement on existing IVM technology, but it remains to be seen if this will actually result in more live births,” he said.
Mol also emphasized that most IVF failures happen when embryos don’t survive the move from the lab to the uterus. “This effort is aimed at creating more or better embryos, but that’s not where our biggest problem is,” he said.
Data show that IVF success rates go down with age, with the steepest dropoff occurring around 36 to 40. Dina Radenkovic, Gameto’s CEO told STAT that happens because women “run out of eggs.” “It’s kind of the first problem, and that’s really what we’re solving,” she said.
Gameto plans to first sell its egg maturation product to fertility clinics in the U.S. and Europe — a customer base it’s already quite familiar with. Gameto co-founder and chairman Martin Varsavsky also founded the largest chain of fertility clinics in America, accounting for one-quarter of the IVF cycles performed in the U.S. each year. Gameto also sees opportunities for its tech farther upstream, by making egg freezing — which relies on largely the same procedure as IVF to produce and retrieve eggs — more appealing to younger individuals who could freeze their eggs without such high doses of hormones.
The company declined to give specifics on future pricing, but Radenkovic suggested that Fertilo could knock a few thousand dollars off the average IVF cycle or egg-freezing procedure.
Before that happens though, Gameto plans to run a series of live birth studies in the U.S., Europe, and Japan.
It’s a little fuzzy whether that would actually be required for the company to start selling mass-produced ovarioids to clinics — assisted reproduction is largely unregulated in the U.S. The Food and Drug Administration regulates the hormones used in IVF, but not most other aspects of the process. As such, manufacturers don’t need to show clinical benefits before entering the market. Studies have shown that many of the add-on procedures for IVF, such as preimplantation genetic testing, “embryo glue, and “assisted hatching” , have little to no scientific evidence behind their claims of increasing the odds of having a child.
According to current FDA policy, the culture media that the eggs are kept in is exempt from the pre-market drug approval process. The agency’s definition of culture media allows for supplements such as proteins and antibiotics to be added, but it doesn’t speak specifically to live cells, like Gameto’s organoids. “Unfortunately, there’s not too much precedent,” said Radenkovic. “But you know we really want to be an evidence-based company which is why we do expect to have a live birth rate study, and then go to market.”
This story has been updated with the correct spelling of Dina Radenkovic’s first name.
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