Rejuvenating The Chance of Motherhood?

An article by Karen Weintraub about a start-up company (OvaScience) giving women over 40 new hope provided by MIT Technology Review. 

Last April, Omar and Natasha Rajani rented a hall, invited 130 guests, and hired a magician to entertain the little ones. In Natasha’s family, first birthday parties are major celebrations. And the Rajanis, who live in Toronto, felt particularly enthusiastic because for a long time they weren’t sure they’d ever be able to throw one.

Natasha, 35, struggled for four years to get pregnant. She and Omar, 40, tried naturally at first; then they used hormones, which led to an ectopic pregnancy, in which the fertilized egg implants outside the uterus—usually in the narrow fallopian tube—and must be removed. Then more hormones. Then in vitro fertilization (IVF). Nothing worked.

Natasha’s obstetrician next offered an unusual option: the couple could try a new method meant to improve the odds of IVF, provided by a Boston-area company called OvaScience. The approach called Augment (for Autologous Germline Mitochondrial Energy Transfer), is so far available only in Canada and Japan.

(OvaScience hasn’t yet sought approval from U.S. regulators). It required the doctor to gather cells from one of Natasha’s ovaries and harvest their mitochondria—the tiny power plants that fuel our cells. These extracted mitochondria would then be injected into one of her eggs along with her husband’s sperm, and the embryo would be transferred to her uterus during a standard IVF procedure. According to OvaScience, the extra energy from the ovarian mitochondria would give her egg a boost, promoting fertilization.

“What Natasha and I liked it was it was kind of like self-treatment,” says Omar. “We thought that it was something that was safe, and it was almost like the body treating and healing itself. We were very, very excited about the opportunity to try it.”

In the round of IVF that Natasha had after trying the new procedure, she got pregnant with a boy, Zain, now almost two. It doesn’t matter, the ­Rajanis say, whether Augment was the reason for the successful pregnancy. All they know is that it felt like a miracle. They have a toddler with an always-sunny disposition—“He’s just an absolute joy of a child,” Natasha says—and two more frozen embryos that might one day become his siblings.

Whether Augment made the difference in Zain’s conception could have far-reaching implications for how we think about both infertility and aging. Infertility affects more than 10 percent of American women—a number that is rising as many women wait longer before considering parenthood. Female fertility starts to decline after age 35. Among women who turn to assisted reproduction techniques such as IVF, only 40 percent of attempts by those under 35 result in a live birth, while 2 percent of those among women over 44 do—largely because of a dwindling number of eggs and a decline in their quality.

Not only could OvaScience’s procedure help many women whose fertility has declined with age, but it would be one of the first successful efforts to slow the body’s relentlessly ticking clock, providing tantalizing clues for ways to halt aging more generally.

Company co-founder and Harvard University genetics professor David Sinclair says conquering the overall aging process is a matter of when not if. “We are at a point where we know how to extend lifespan in mammals, and now there’s a race to see who can prove that we can do this in humans,” Sinclair says. Female fertility, he says, is one of the first bodily systems to break down with age, and he sees reversing infertility as a gateway to reversing aging itself. The goal, Sinclair proclaims, is “to have revolutionary technologies like OvaScience available to everybody—and not to just treat fertility, but another 2,000 age-related diseases, from diabetes through Alzheimer’s.”

Despite Sinclair’s enthusiasm, it’s possible—even likely, some scientists say—that OvaScience’s procedure did nothing at all. For one thing, IVF is notoriously unpredictable. The Rajanis might have just gotten lucky the second time, just as they were unlucky the first.

More than a dozen interviews with experts in fertility and early development reveal little scientific justification for what was done to Natasha Rajani’s eggs and those of the 300 other women who have gone through the procedure, which costs an IVF clinic from $6,000 to $7,000. (The fee that clinics charge patients will vary.) The company harvests the mitochondria from what it believes are immature egg cells found in the ovarian lining; the idea is that these so-called egg precursor cells have fresher mitochondria than the aging, mature eggs. But there is little convincing evidence that they are what ­OvaScience says they are: cells with the power to turn into eggs. And even if such egg-­precursor cells exist and their mitochondria are more youthful than those in a woman’s eggs, does it prove that such an energy boost can improve fertility?

“There is very little data supporting the benefit of these procedures, and often the biological rationale is incoherent,” says Jacob Hanna, an expert in embryonic stem cells at the Weizmann Institute of Science in Israel, who reviewed ­OvaScience’s information at the request of MIT Technology Review. “I hope the company can provide robust data and experimentation on these approaches… It sounds more at the moment like voodoo, or alchemy.”

So is OvaScience leading a breakthrough in battling one of the most fundamental processes of aging, or selling false hopes with little scientific justification?

Youthful Marriage
The founding of OvaScience came about as a marriage of two of medicine’s most audacious and often controversial areas: anti-aging research and infertility research. The company accurately traces its precise origins to the work of the reproductive biologist Jonathan Tilly, now at Northeastern University in Boston. Beginning with a 2004 paper, Tilly has been challenging decades of scientific dogma that girls are born with their whole life’s supply of “primordial” egg cells, which will eventually mature into eggs. After puberty, this stock of eggs develops at the rate of about one a month, and it never renews. The decline in female fertility around 35 occurs as this supply dries up, and menopause strikes when the eggs run out. But Tilly’s research suggested—first in mice and then in people—that the lining of the ovary contains the makings of new supply. If Tilly is right about his conclusions, solving infertility might be just a matter of finding these egg precursor cells and triggering them to mature.

Sinclair says it was natural for him to collaborate with Tilly, who was then at Harvard. Tilly’s work touched on subjects that fascinated Sinclair: how the body ages and what might be done to slow that process. “I’d been trying to figure out what are the primary reasons we grow old and why don’t cells function the older we get,” Sinclair says.

Sinclair introduced Tilly to two biotech entrepreneurs, Rich Aldrich and Michelle Dipp, with whom Sinclair had previously run an anti-aging company called Sirtris Pharmaceuticals. That company was based on Sinclair’s research into sirtuins, proteins that may slow the aging process and can be activated by resveratrol, a compound most found in red wine. Sirtris was sold to GlaxoSmithKline in 2008 for $720 million (GSK closed down its Sirtris facility in 2013, absorbing the sirtuin work into its research efforts), and the biotech investors were looking for their next big play. When the potential partners asked Tilly how he might commercialize his research, ­Sinclair says, Tilly came up with the idea of Augment, using the precursor cells to rejuvenate aging eggs. (Tilly declined to comment for this story.) That was enough for the group to create ­OvaScience, where Dipp served as CEO until last summer.

Sinclair hypothesizes that mitochondria are crucial to aging. The idea is simple. Aging cells have old, slow mitochondria; young mitochondria equal young cells. Hence the Augment program to rejuvenate eggs with mitochondria from cells that are younger and more energetic. Sinclair has also cofounded two other companies, MetroBiotech of Boston and CohBar of Menlo Park, California, to develop drugs related to mitochondrial functions. CohBar hopes peptides made by mitochondria could be useful against diabetes, obesity, and Alzheimer’s, among other diseases, while MetroBiotech is pursuing a therapy to treat diseases associated with malfunctioning mitochondria. It is testing a drug that boosts levels of nicotinamide adenine dinucleotide, NAD, a compound involved in energy metabolism in the mitochondria. “The same molecules [in the drug] we think will treat aging itself,” Sinclair says, citing a 2013 paper his team published in Cell.

Sinclair’s interest in aging has become personal. Now 47 and working in a high-stress job at Harvard, he has time to exercise “barely more than once a week.” In addition to his academic and commercial duties, he also sits on the advisory board of InsideTracker, a company based in Cambridge, Massachusetts; that uses levels of glucose, vitamin D, and other blood factors to determine a client’s “inner age,” as opposed to the historical one. In 2011, Sinclair says, he clocked in at 57, a decade and a half beyond his actual age. In July 2015, convinced he was going to die young, he upped his daily doses of resveratrol. He also added MetroBiotech’s NAD precursor, which has yet to be tested in people and is too expensive for anyone who’s not making it use.

Sinclair says InsideTracker’s aging markers now put him at 31. He’s lost the weight he’d been carrying since college and has been allowing himself to eat dessert again because his body can handle it. (Weight loss isn’t his goal, he says, but mitochondria are also responsible for burning fat, so weight loss “might be a side effect” of the treatment.) “The results in mice and my single-person experiment indicate that aging is more reversible than we thought,” he says.

Too Early
In a pristine lab overlooking a busy highway in the Boston suburbs, OvaScience researchers identify and count what they believe are egg precursor cells. This constitute, OvaScience says, about 6 percent of the cells on the surface of the ovarian cortex. In the Augment procedure, an IVF surgeon laparoscopically removes a section of this layer about half the size of a dime. The tissue is shipped to an OvaScience lab, where the mitochondria are extracted and sent back to the fertility clinic. Just before fertilization, the mitochondria are inserted into the egg alongside the sperm. Then IVF proceeds as usual.

Preliminary data suggests that the procedure improves fertility. In its latest study, released at a conference in November, OvaScience reported a 31 percent success rate among 75 patients who had undergone at least one previous round of IVF before trying Augment. It’s notoriously difficult to get right data on fertility clinic results, but in a 2015 study in the Journal of the American Medical Association, British researchers found that about 30 percent of women are successful in their first round of IVF and 16 to 25 percent are successful in each subsequent round (without Augment). So if the results for Augment prove to be real, it increases success rates from about 20 percent to 30 percent per round—a significant, if modest, improvement.

However, those results only record the experience of Augment patients. As is the case in many early research studies, they were not compared with controls, so there’s no convincing evidence that the procedure made the difference. OvaScience expects to get data from two more trials, including about 300 patients, in the second half of 2017. However, ­OvaScience’s patents on the cells and procedures protect the company’s business interests and prevent outsiders from testing its protocol. So there have been no independent trials. I asked one scientist to examine and comment on OvaScience’s Augment research. After looking at the material the company had presented to me, he declined to say anything. There wasn’t any science to review, he said—just anecdotes.

OvaScience plans two other projects for these egg precursor cells. In a program it’s calling OvaPrime, the cells are extracted from the outer rind of the ovary, isolated, and then reimplanted into the main part of the ovary, where they are projected to mature into healthy, viable eggs. The procedure is designed to help women who don’t make enough eggs—about 30 percent of infertile women, according to the Centers for Disease Control and Prevention. The company is doing safety and feasibility trials now and expects to decide soon whether to pursue this approach commercially.

In another program, called ­OvaTure, OvaScience hopes eventually to perform IVF without hormones. Hormones are now needed to stimulate a woman’s body to release as many eggs as possible. But for many women, hormone injections are the worst part of IVF, with the potential to cause mood swings, nausea, vomiting, abdominal pain, and a slight risk of death. With OvaTure, the woman would have some precursor cells removed, and they would be coaxed in a lab dish to mature into fully functional eggs, all without hormones. The company, however, is still studying whether this technique will work.

These projects will largely determine just how significant OvaScience’s contribution to fertility and anti-aging science will be. Augment might have a limited effect even if the precursor egg cells are not actually capable of turning into eggs, as many scientists believe. And Stock says at around $7,000 per treatment, Augment is a good deal if it saves families from another round of IVF, which can easily run $10,000 to $15,000 per cycle. But the two more ambitious efforts, OvaPrime and OvaTure, will never work unless ­Tilly’s conclusions are right. His research was roundly criticized by colleagues in 2004, and his later publications did not erase the skepticism. Mice may very well have these egg precursor cells, several scientists say. But large, long-lived animals are quite different from mice regarding reproduction—and Tilly hasn’t yet convinced other researchers that women carry around cells capable of extending their fertility.

Still, more scientists are coming around to the possibility that egg precursor cells exist, says Evelyn Telfer, a reproductive biologist at the University of Edinburgh. Initially quite dubious of Tilly’s findings, she changed her mind after touring his lab, welcoming him into her own, and working with the egg-­precursor cells herself. “As with all things that are new, it takes the time to get into the consciousness of people,” says Telfer, who now collaborates with ­OvaScience. A small study she has recently finished suggests that egg precursor cells may help women regenerate their egg supply after experiencing a catastrophe, like chemotherapy for cancer. “It’s an observation we’ve made, and we have to do a lot more work to find out what these cells are doing to the ovary and why we see an increased number of eggs,” she says.

Regardless of what these cells are, the dozen scientists interviewed—most of whom didn’t want their names associated with the company—questioned the idea of using them to “rejuvenate” older eggs. It’s not scientifically obvious that adding extra energy to egg cells would make them more fertile.

Carol Hanna, a staff scientist at the Assisted Reproductive Technology Core Laboratory at the Oregon Health & Science University in Portland, says she and others in the field sincerely hope that Tilly’s science is accurate, but they feel it shouldn’t have moved so quickly to commercialization. “I think a lot of people fall in that middle—they want to believe it but haven’t seen that one piece of information that convinces them,” she says. Renee Reijo Pera, a reproductive and stem-cell biologist at Montana State University, is even blunter: “Almost everybody thinks that the commercial side of the whole enterprise got way out ahead of the science.”

In most areas of medicine other than fertility, it’s standard practice to prove that something works before offering it to patients. Regulations in many countries, however, allow fertility clinics to try a procedure first and test it years later. As a result, dozens of so-called add-on systems to IVF are available to women with very little scientific justification. Industry leaders defend this approach; the first test-tube baby would never have been born if there had been more regulations. But this lack of rigorous oversight also makes patients vulnerable to abuse, says Carl Heneghan, director of the University of Oxford’s Centre for Evidence-Based Medicine. “The sheer number of treatments that are available tells you they all can’t work,” suggests Heneghan. “People will try anything. That’s where the problem starts.”

But there aren’t many alternatives available to infertile couples, says Jake Anderson-Bialis, a venture capitalist turned fertility advocate who cofounded the patient community FertilityIQ. International adoptions have become much more challenging; IVF is costly and puts women on a hormonal roller coaster, and buying another woman’s eggs if their own are too old can add $30,000 or more to that cost.

Anderson-Bialis says he doesn’t blame OvaScience for taking its products to market before the science is firmly established. The infertility business has always been that way. And in his view, the problem of infertility is so big that it justifies some risk-taking.

Improving the odds
This has been a busy few months for ­OvaScience. In 2016, the company signed on seven new clinics in Canada and Japan, bringing its total to nine worldwide. Harald Stock, who jumped from the board into the CEO’s chair in July, says company officials have begun speaking with the U.S. Food and Drug Administration to explore what it would take to bring Augment to the market in the United States. He will soon decide whether to proceed with the OvaPrime and OvaTure programs. And the company, which had more than $130 million in cash as of September 30, decided to move away from its initial business plan of installing small labs in each of the clinics that use its products, instead relying on a centralized lab, which is cheaper and easier for quality control.

Launching a product and a company takes time and personnel, so Stock says he’s committed to moving slowly and deliberately. “We need to stay disciplined not to get overwhelmed,” he says. “We’re still a 100-some-person company and can’t be everywhere.” The company has chosen to build its business in Canada first because it can cover most of the country from just a few cities, Stock says, meaning there’s no need for a massive sales force. He’s waiting to start marketing until enough clinics have been trained so that anyone who wants Augment can get it.

IVF is a growing business. It’s projected to expand from about $10 billion today to $22 billion globally by 2020. Augment, he says, could help women who fail to get pregnant in the first round of IVF. A bigger prize for the company could be on its other projects. OvaPrime could make it possible for women who lack viable eggs to have biological children, he says. And anyone undergoing IVF would prefer to skip the hormones.

In the end, though, OvaScience’s market may not turn out to be colossal. IVF has been getting markedly better over the last few years. And freezing embryos and even eggs, which costs about the same as IVF plus an annual storage fee of $500 to $1,000, has recently made it much easier for women to preserve high-­quality eggs into their late 30s and 40s. It’s the age of the egg—not the woman—that seems to matter: women in their 40s fare just as well as younger women if the quality of their frozen eggs is high, says Hal ­Danzer, co-founder of the Southern California Reproductive Center, a fertility clinic in Beverly Hills, California. Freezing embryos, meanwhile, allows labs to select those that are most likely to succeed, and transfer them after the hormones needed to stimulate egg production have left the body.

Improved IVF success rates leave less room for Augment to shine. Still, boosting the odds even somewhat will entice some prospective parents. Danzer says his patients, many of whom put off parenthood for their careers, are desperate to get pregnant. He has referred several patients to clinics in Canada so they can try Augment, though when asked whether he’d use it in his clinic, he says: “I think it’s a little too early to tell.”

More Articles on Fertility News: 

Age-Related Infertility Caused by scarred ovaries

Women Freezing Eggs To Boost Chances Of Pregnancy Later

Could assisted reproduction reduce birth defects for older women?