In 2018, Melanie Balbach, a postdoctoral scientist at Weill Cornell Medicine, surprised her bosses with a remarkable video of mouse sperm -- just sitting there.
A colleague in the lab had asked for help injecting mice with an experimental drug developed for eye disease, and Balbach agreed, with one condition. She knew that the potential eye drug targeted a molecular pathway that was crucial for male fertility. On a scientific hunch, she wanted to check what happened to normally thrashing, free-swimming sperm.
"She showed the movie of these sperm not moving, just twitching," said Lonny Levin, a professor of pharmacology at Weill Cornell. "I said, 'Oh my God. That's a holy grail. That's a male contraceptive.'"
In a study in Nature Communications, the team demonstrates that an improved version of the drug can stop sperm from maturing and swimming, preventing mouse pregnancies within 30 minutes after an injection. About 2½ hours later, some sperm start to swim and male mice began to regain normal fertility. They were able to father normal offspring.
The approach offers new hope in the decades-long quest for better birth control for men, who have long had two options, each with drawbacks that limit their use: condoms or a vasectomy. For many experts in the field, the Supreme Court decision to overturn Roe vs. Wade has only increased the urgency for more contraceptives, including ones that shift some of the burden from women to men.
"This could be a game changer for a male contraceptive," said Wipawee "Joy" Winuthayanon, an associate professor of obstetrics, gynecology and reproductive health at the University of Missouri School of Medicine, who was not involved in the research.
Many of the drug-based male contraceptives in development, including hormone approaches that are the furthest along, interfere with the creation of sperm, a process that unfolds over 74 days in humans. That means they require a daily pill, or a gel rubbed into the skin. These drugs take weeks or months of treatment to start working - and for the effects to reverse. That may be attractive for some men, but not for others.
"The twist they have with this paper is that ... they're trying to develop an on-demand male contraceptive agent. I think that's a really exciting way of thinking about it," said Gunda Georg, a professor of medicinal chemistry at the University of Minnesota, who is also working on male contraceptives. "If you could just pop a pill right before intercourse, and then be protected."
The new drug, called a soluble adenylyl cyclase (sAC) inhibitor, stops a molecular switch from turning sperm "on" and triggering them to swim and search for an egg.
Jochen Buck, who co-directs the Weill Cornell laboratory with Levin, said it became clear nearly two decades ago that sAC played an essential role in sperm activation, and there had been initial interest from drug companies. But he said that interest waned over the subsequent 15 years.
Pharmaceutical interest in developing new contraceptives has lagged for a variety of reasons, several scientists said. They must be highly effective, easy to tolerate and extremely safe, since they are being given to healthy people. Some have doubted men would take such drugs. And targeting sperm production with a drug has turned out to be tricky because many of the proteins involved are important for other bodily functions.
The initial experiment from Balbach reignited the lab's work on sAC inhibitors as a form of birth control, particularly when a case study published in 2019 described two men who were infertile and lacked the gene that codes for sAC. Aside from infertility, their major health issues from lacking the enzyme were increased risk of kidney stones.
That result gave the New York researchers confidence that blocking sAC on a short-term basis wasn't likely to cause a slew of other health problems, a major concern about contraceptives that could need to be well-tolerated and safe in healthy people.
While the current version of the sAC inhibitor suggests that the approach works in mice and on human sperm in a lab dish, it is still a few years away from even being tested in men. Levin and Buck would like to use chemistry techniques to create the most potent, optimal form of the drug so that it prevents pregnancy for 12 hours and can be taken as a pill rather than an injection. They founded a start-up company, called Sacyl Pharmaceuticals, to help move the research forward once they have settled on the best version.