For reproductive rights advocates, the Supreme Court’s decision to overturn Roe v. Wade in June made the need for safe, reliable contraception all the more urgent.

One of the most common forms of birth control is the oral contraceptive pill. Yet for all its popularity, the pill has not changed much since it was first introduced in the 1950s, according to Paula Cohen, professor of genetics at the College of Veterinary Medicine. It is still hormone-driven. It can still induce a host of physiological problems, from blood clots and cardiovascular issues to increased breast cancer rates. And it also still places the responsibility of family planning solely on women.

That’s why Cohen is pioneering an innovative alternative: a form of male contraception that targets a mechanism in the early stage of sperm cell production.

Credit: Ryan Young/Cornell University

“Male contraception is not an area that’s been investigated much,” said Cohen, the director of the Cornell Reproductive Sciences Center and associate vice provost for life sciences at Cornell. “We just passed the 70th anniversary of the contraceptive pill. And the pill is dangerous for women. There’s no prettying that up. It probably wouldn’t have been approved in today’s world, but 70 years ago, it was the liberation that women needed. And in 70 years, we’ve had no innovation in the pill. So I get my lab really riled up about the idea of non-hormonal contraception.”

Cohen’s research seeks to exploit a basic tenet of human procreation: we’re pretty lousy at it.

“Humans are particularly error prone in the way they make the eggs and sperm,” Cohen said. “We’re actually not very good at being reproductively competent, although you wouldn’t ever guess it from the overpopulation issue in this world.”

Cohen has long been interested in human fertility disorders, from pregnancy loss to the conditions, such as Down syndrome and Klinefelter syndrome, that arise from faulty egg and sperm production.

The specific biological process she has targeted for a potential male contraceptive is meiosis, a stage in early spermatogenesis in which a cell undergoes two rounds of division, resulting in four non-identical sperm cells, each of which contains half the number of chromosomes of the original “mom and pop” cell. Should the sperm fertilize an egg, this halved DNA content would pair up with an egg containing an equal amount of DNA to create an embryo with a full set of chromosomes. The first round of meiotic cell division is where “all hell breaks loose” in human procreation, according to Cohen.

To get a sense of just how fraught the process is in people, look at yeast. Approximately 1 in 10,000 yeast cells will mis-segregate their chromosomes during meiosis, Cohen said. That number increases to roughly 1 in 1,000 errors for mice. For human men, about 1 in a 100 of their sperm have the wrong number of chromosomes. And the numbers are exponentially worse for women.

“If you look in women, about 1 out of every 2 of their eggs has a wrong number of chromosomes,” Cohen said. “So that’s like, holy crap, what went wrong? We really don’t understand much about it. And that keeps me awake at night.”

The reason female meiosis is so much more error prone than male meiosis is that men have a built-in “monitoring system” that eradicates any erroneous cell, so those sperm never get produced. Cohen and her lab intend to use that knowledge to identify genes that control meiosis in mouse models, so the researchers can install “a big on/off switch” on the mice genes via genome-editing technology, and then control spermatogenesis. The insights they gain into that mechanism could ultimately inform the development of a form of contraception for human males that is not only reliable, but also reversible.

“If you could hit these cells as they enter meiosis, or stop them entering meiosis, then that would be your off switch, and the spermatogonia would sit there very happily, just waiting,” Cohen said. “Because you don’t want to damage the stem cells, you want to keep the spermatogonia happy, you don’t want to mess them up. You want to get them primed and ready so that when you turn the switch on, then they just enter meiosis. And if any cells happen to squeak through, they would get eradicated through the robust meiotic monitoring system.”

A second, and equally crucial, step is finding a way to experiment with spermatogenesis in a culture system. That’s necessary because meiosis is too complicated to study in vivo, i.e., in multicellular organisms, where there’s so many other ongoing biological processes that get in the way. Until now, a robust culture system for spermatogenesis has been impossible to create.

Credit: Ryan Young/Cornell University

“The conditions for each stage are very specific,” Cohen said. “But I just want to culture them from spermatogonia into meiosis, a small fraction of the overall process. And if I could get that happening robustly, again and again and again, then I can look for genes, and from genes I can find targets. And from targets, I can develop drugs.”

The problem is, with so many unknowns, most funding agencies consider the research too risky to support. But in 2017 the Bill & Melinda Gates Foundation awarded her project a $100,000 Grand Challenges Explorations grant. The resulting research showed so much promise that the foundation awarded the team a $1 million Grand Challenges Explorations Phase II grant in 2019. That award was renewed in 2021.

In addition to her own projects, Cohen is hoping to generate interdisciplinary collaborations through the Cornell Reproductive Sciences Center (CoRe) – formerly the Cornell Center for Reproductive Genomics – which she founded in 2006 to promote state-of-the-art research in reproductive health and fertility. The center, which in 2021 received its second five-year, $8 million, multi-institution grant from the National Institutes of Health’s National Institute of Child Health and Human Development, aims to bring together geneticists, social scientists, humanities experts and others to leverage Cornell’s strong history in reproductive biology. That history has included everything from the development of the pap smear test at Weill Cornell Medicine to groundbreaking faculty research into large animal reproduction.

“We want to emphasize reproductive biology as a strength here on campus and think about reproductive health generally, not just the basic science and basic biology of it, but thinking about social sciences, thinking about transgender issues, thinking about gender identity, thinking about the Roe v. Wade decision and how that impacts our community,” Cohen said. “A lot of social scientists are working on these areas across the campus, but they’ve never really spoken to the biologists, and vice versa. Why is it important for a woman to have autonomy over her own body and her own reproductive decisions? How can scientists help to inform that debate? Every area of society that we look at has a reproductive issue in which we can participate.”