Great article from Fusion.net re: Ovascience

Great article from Fusion.net re: Ovascience. Read the entire article here.

Why an incredible new method to extend fertility is off limits in the U.S.

It’s become a cliché that once a woman hits a certain age, she enters a race against the clock—have kids now, or forgo being a biological parent forever. Fertility comes with a deadline. It’s just one of those cold, hard truths that no amount of Botox can change.

But what if it wasn’t? What if doctors could seriously slow down the clock?

The premise might sound like playing God, but scientists and researchers around the world are already doing this. Leading the charge is OvaScience, a Cambridge-based research company attempting to do nothing less than rewire the building blocks of human life. Question is, are their techniques revolutionary or too good to be true?

OvaScience made headlines in May after its breakthrough method, which involves “revitalizing” older eggs before they are fertilized in vitro, helped a previously infertile couple in Canada give birth to a healthy baby boy—marking the first time a baby was born using the method. But the coverage only scratched the surface of what the company is planning.

OvaScience’s technique is currently being used in countries from Europe to the Middle East, but the FDA has yet to green light it here, in part because it raises some confounding ethical questions. In the meantime, we spoke with fertility experts both inside and outside of the company, who walked us through the tech—and what’s at stake.

The technique

OvaScience’s method boils down to making older eggs—well, young again.

Women are born with a set number of eggs, and as we age, these eggs dwindle. Meanwhile, the quality of the remaining eggs declines over time as well, making it harder to get pregnant. OvaScience’s practitioners aim to basically “perk up” these older eggs through a treatment called AUGMENT.

Here’s how it works. Many reproductive endocrinologists believe that poor egg quality occurs when the mitochondria in an egg cell break down. “We believe this is an energy issue,” said Robert Casper, the Toronto reproductive endocrinologist who helped create the first baby born from AUGMENT. “All of our cells have mitochondria, which provide the energy for all the cell’s functions.”

As the mitochondria degenerate, so do a woman’s chances of getting pregnant. “Our thinking is that, as eggs age, the mitochondria get run down. They start to get mutations in their DNA and they can’t produce enough energy to create a blastocyst,” he told me, referring to the stage an embryo reaches five days after fertilization. (Doctors have found that a woman’s chances of getting pregnant are higher when they implant blastocysts, as opposed to embryos less than five days old.)

The AUGMENT treatment seeks to improve egg health by injecting healthy mitochondria from the patient’s own body into the egg to boost its energy so it can reach the implantation stage without developing chromosomal abnormalities along the way, said Casper. It’s a process that occurs prior to in vitro fertilization, to basically make IVF more successful. And Casper says it’s working.
In his presentation, Casper described 34 women (with an average age of 36) who had previously undergone standard IVF, with very little success—among them, only 10 percent were able to get pregnant with standard IVF, and only one live birth occurred.Casper has been offering AUGMENT for over a year out of the Toronto Center for Advanced Reproductive Technology, and recently presented some of his results at theControversies in Obstetrics, Gynecology & Infertility conferencein Frankfurt, Germany.

After just one cycle of AUGMENT, however, the women experienced 12 clinical pregnancies and nine ongoing pregnancies, according to Casper, plus the live birth that made headlines earlier this year. (Note that a “clinical pregnancy” refers to a pregnancy in which an ultrasound scan has detected at least one fetal heartbeat, but not all clinical pregnancies result in live births.)

Casper is excited about the results, calling the treatment “extremely promising” for women in their late 30s. He’s still working on developing the technique for women 40 and older.

And Casper isn’t the only reproductive endocrinologist practicing AUGMENT who’s hopeful. At the European Society for Human Reproduction and Embryology’s annual meeting in June, other clinicians reported equally impressive results.

Michael Fakih, founder of Fakih IVF, a leading fertility clinic in the United Arab Emirates, discussed 59 women (with an average age of 37.3) who had also unsuccessfully undergone IVF. After undergoing one cycle of AUGMENT, he says their clinical pregnancy rate increased five-fold, jumping from 4 percent to 22 percent.

Likewise, in June, a Turkish clinic using AUGMENT reported the first birthin Turkey by a woman who had previously undergone seven cycles of IVF without pregnancy. While the conference results have yet to be independently verified, so far, OvaScience says AUGMENT has led to six live births.

Of course, the technology doesn’t come cheap. It’s hard to pin down an exact price for the treatment, but according to OvaScience, they set a global price range of $15,000 to $25,000 per cycle, which can mean paying almost twice the cost of regular IVF.

The science

The scientific concept behind AUGMENT isn’t entirely new. Back in the mid 1990s, Dutch embryologist Jaques Cohen and his colleagues at the Institute for Reproductive Medicine in New Jersey experimented with a technique called “cytoplasmic transfer,” in which the cytoplasm from a donor egg was injected into a patient’s eggs. Cytoplasm is the gel-like substance inside a cell where mitochondria are located—the Jell-O part in your 5th grade cell project. This method, like AUGMENT, was used to reenergize an egg via the healthy mitochondria found in the cytoplasm.

Problem is, mitochondria contains DNA, passed from mothers to their children. And while it doesn’t code for things like hair color, eye color, personality, intelligence, or tangible features the way nuclear DNA does, mutations in mitochondrial DNA can lead to various genetic diseases. Thus, tinkering with DNA in the mitochondria is approached with extreme caution in the medical community.

Even though the method helped women get pregnant, the FDA essentiallyput the kibosh on the procedure in the early 2000s, since it was considered gene therapy and technically resulted in children with traces of DNA from three people: the birth mother and father, plus a donor female. (Fun fact: Cytoplasmic transfer, better known as “three-parent babies,” was just approved for use in the U.K., making that country the first to allow it.)

Around the same time that the FDA was outlawing cytoplasmic transfer, researchers at Harvard University were making an incredible discovery. In the early aughts, biologist Jonathan Tilly and his colleagues discovered egg “precursor cells“—basically, egg stem cells—in the ovaries of female mice, which they found were capable of generating entirely new eggs.

Tilly’s findings, published in the journal Nature in 2004, were met with a ton of skepticism. Some scientists questioned whether the precursor cells were real, and a 2014 briefing document from the FDA on cellular tissue stated “there is disagreement” over their existence. The document cites papers in which researchers question the science, in part because no one could replicate the findings.

After all, scientists had long believed that female mammals are born with a set number of eggs—so the ability to grow new eggs from stem cells would be revolutionary. If Tilly could find the same precursor cells in humans, the fundamentals of fertility could change forever.

More than eight years later, Tilly and his team at Harvard claimed to have found them—sitting in the outer layer of the ovarian cortex. “These cells are not exposed to metabolic activity, so they don’t seem to age like eggs do in the rest of the ovary,” Casper told me. He’s confident they’re real.

Armed with newly discovered precursor cells, Tilly cofounded OvaScience in 2011 with businessman Rich Aldrich, a biotech entrepreneur, and David Sinclair, a professor of genetics at Harvard Medical School. The team created AUGMENT as their flagship treatment. As Casper explained it, the cells are in what seems to be suspended animation. “It appears they’re still there even after menopause,” he told me. “They’re not really doing anything, they’re just sitting there. We extract them, rip them apart, and can then use the mitochondria.”

Now, rather than using the mitochondria from a donor, Tilly determined that he could use “younger” mitochondria from a woman’s own precursor cells, thus eliminating the problem of mixing mitochondrial DNA from an third party donor. An ingenious idea, in theory—but the longterm impact on children born from the treatment is still unknown.

The controversy

When a family wants a child, they are often willing to do—and pay—whatever is necessary to boost their odds of conceiving. So with Casper and doctors around the world offering AUGMENT, it’s no surprise that women are signing up for the treatment, despite the fact that the method hasn’t been subject to any clinical trials or longterm testing.

It’s also no surprise that the FDA has not yet approved AUGMENT. Until a few years ago, OvaScience was setting up shop in the U.S., reasoning that AUGMENT qualified as a type of “medical device,” and thus wouldn’t be subject to federal regulation.

But in 2013, the FDA stepped in and informed the company that AUGMENT did, in fact, fall under its purview—arguing that it had jurisdiction over procedures involving gene therapy and human tissue transfer. The FDA wanted OvaScience to file AUGMENT as a new drug, which might have taken years to approve. In response, the company simply stopped practicing the procedure in the U.S., instead focusing on international facilities—and thus bypassing the feds entirely.

“I think the FDA did the right thing,” said Carolyn Givens, a reproductive endocrinologist who practices out of Pacific Fertility Center in the Bay Area, echoing what other experts in the field told me. “I don’t like the government coming down on the regulation of human medical treatments—but when it involves something that might affect future generations, we need to stop and pause.”

Indeed, the question remains: Could mitochondrial DNA extracted from a precursor cell—which will then be passed from mother to child, generation after generation—possibly lead to genetic disease or mutations? That’s the question that Givens, the FDA, and others in the field want answered before embracing the technology. Since the effects of possible mitochondrial DNA mutations may not be apparent until long after birth, skeptics argue more research is needed before approving anything.

“No regulatory agency has yet to determine if gene therapy is safe and effective,” said Alan Copperman, a reproductive endocrinologist at Mount Sinai Hospital in New York. He’s all for helping women have healthy babies, he told me, and he supports exploring new paths to pregnancy—but this type of technology needs to be brought to clinical practice “in a safe and thoughtful manner.”

Givens also raised the question: At what point do we draw the line when it comes to pushing back the biological clock? “Are we going to get menopausal eggs out? Can we? Are we going to allow menopausal women to have babies with their own eggs? Then we’re making human beings from DNA that’s 50 years old,” she said. “We’re at the frontier of really trying to take one of nature’s natural end points and push it.”

Many fertility doctors in the U.S. have high hopes for AUGMENT. “We’re already working with OvaScience to do it here in Encino,” said Michael Feinman, a reproductive endocrinologist at HRC Fertility in Southern California. That is, he’s laying the groundwork so the moment the FDA theoretically gives the green light, his clinic is ready to go.

“The FDA simply does not have rationale here,” Feinman told me, adding that the group has been “close-minded” about reproductive procedures. “There’s no DNA transfer, we’re using the woman’s own genetic material.”

Most of the FDA’s qualms do appear to focus on mitochondrial transfer from a donor to a patient, not from a patient to herself. But the group warns that the effects of gene therapy and mitochondria transfer generally are still a big unknown—hence their request for regulation.

The FDA would not comment on the current status of AUGMENT, or even if it’s under review. A spokesperson but did tell me that “Biological products that also meet the definition of human cells, tissues, and cellular and tissue-based products are subject to additional regulations to prevent the introduction, transmission, and spread of communicable diseases.”

OvaScience would not comment on AUGMENT’s status with the FDA, either, simply telling me that “no decisions have been made”—but they do plan to continue to offer the procedure commercially around the world.

Casper, the doctor who is putting AUGMENT into practice in Toronto, stands by its soundness. “This is a completely safe procedure,” he told me. “We’re putting in the woman’s own mitochondria. We’re not changing anything in the embryo.”

The future

AUGMENT is currently being offered in at least three countries, and Japan is scheduled to start practicing it soon, according to a rep for OvaScience. And several more babies created through the technique are on track to be born within the year.

But AUGMENT’s power, while seemingly formidable, is still limited. One potential issue comes down to the fact that, even though AUGMENT can help reenergize old eggs, the patient still needs to be able to produce at least one otherwise healthy egg—i.e., one free of chromosomal abnormalities—for the treatment to work, which can be difficult for a woman in her early 40s.

“By the time we retrieve the eggs [in older women], they have already gone through the first cell division,” said Casper. Which means they could already be exposed to chromosomal abnormalities, in which case the problem is no longer an energy issue. Without a normal healthy egg to inject the mitochondria into, AUGMENT can’t work.

But what about the concept of growing new eggs? After all, Tilly was able to use the precursor cells in mice to grow eggs—could this technique work in humans as well? OvaScience is working on it, Casper told me, in a procedure they’re calling OvaPrime. He said this treatment is what he’s “most excited about.”

OvaPrime would work by transferring a patient’s egg precursor cells to her ovaries, where “they may mature into fertilizable eggs during the IVF process,” as the website describes it. OvaScience hopes to begin putting it into practice by the end of this year—somewhere other than the U.S.

If scientists figure out how to successfully grow new, viable human eggs out of precursor cells, the procedure would nearly eliminate the biological clock. “Then it might be possible for someone who is 48 to get pregnant,” said Casper—thanks to her brand new, healthy egg.