Dana-Farber scientist provides early evidence for a male contraceptive

The half-century-long quest to develop a male birth control pill has just gotten a boost from an unexpected corner: a Boston laboratory working to craft potent anti-cancer drugs.

Scientists found that by injecting mice with a compound originally used in cancer research they could interfere with normal sperm development, decreasing their number and ability to move, rendering male mice infertile. But, importantly, when the mice were taken off the regimen, they could sire normal offspring.

Researchers are working now to tweak the substance so that it will target only a specific protein found in the testicles, in the hope the work could advance toward an experimental drug that could one day be tested in men.

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Stopping sperm would seem to have little in common with shrinking tumors. Indeed, unplanned pregnancies were far from Dr. James Bradner’s mind when the Dana-Farber Cancer Institute oncologist led an effort two years ago to craft a molecule that researchers hoped would help spawn cancer-fighting drugs. But in a turn of events that illustrates the serendipity often underlying scientific progress, Bradner and collaborators reported Thursday in the journal Cell evidence that the experimental drug could prevent mice from conceiving offspring but that fertility returned when the regimen was stopped and offspring were normal.

The work is early and still far from even being tested in men, but it provides a powerful starting point for efforts to develop a drug that could give men more responsibility and control over family planning.

With a slew of new efforts launched to interrupt the normal course of sperm development, or block their ability to fertilize the egg—driven by incidental findings from scientists studying cancer or neurobiology and by the revival of drugs designed for other reasons—scientists said a number of solid leads exist that could finally provide new options and shift more responsibility for family planning to men.

“Everybody would like a better solution than condoms and birth control pills,” said Dr. David Clapham, a professor of pediatric cardiology at Children’s Hospital Boston.

But the hurdles to male contraceptive development remain high. Because the drugs would be given to healthy men, researchers have to focus on safety and ensure that any eventual birth control medication doesn’t have side effects. In the case of JQ1, that will be especially important, Clapham said, considering the molecule they are starting with was initially of interest for its chemotherapeutic effects.

Female birth control pills, which transformed women’s control over their reproductive abilities when developed some five decades ago, with key research done by scientists in central Massachusetts, were in some ways tackling a simpler problem.

Dr. John Amory, a professor at the University of Washington School of Medicine who has worked on hormonal treatments for men and a drug that interferes with the maturation of sperm, said that in some ways it’s a numbers game.

A birth control method for women must prevent just one egg a month from being fertilized. Men, though, with every heartbeat generate roughly 1,000 sperm, whose numbers would have to be reduced by 99 percent for a contraceptive to be effective.

“I was thrilled to see this work,” Amory said of the new study. “It’s a really good lead in terms of the non-hormonal approach to male contraception.”

Bradner normally sees patients with blood cancers and runs a laboratory aimed at cancer drug discovery. Two years ago, his laboratory created a molecule that targeted a particular gene that appeared to help cancer cells remember their identity. They called the compound JQ1, named after the scientist, Jun Qi, who developed the compound.

JQ1 seemed to be living up to its promise as a tool that could lead to eventual therapy. The research team found JQ1 could interfere with the activity of a particularly important cancer-causing gene. But when the scientists were examining the drug, they saw a glimmer of activity against a protein similar to the one they were trying to disrupt in cancer. But this protein appeared only in the testicles.

Bradner began scouring the scientific literature to learn what he could about the protein and found that other researchers had uncovered hints that it was profoundly involved in male fertility. A scientist at Columbia University Medical Center, Debra Wolgemuth, had found that deleting a portion of instructions for the protein caused mice to become sterile. Bradner teamed up with Dr. Martin Matzuk, a reproductive biologist at the Baylor College of Medicine, to rigorously test whether the compound could interfere with the development of sperm.

It’s only one of a handful of approaches being used. Wolgemuth and Amory are both working on different approaches to disrupt sperm development. Clapham is working on a technique that stops mature sperm in their tracks, by impeding what he calls the “turbo-thruster stage”—the hyperactive movement sperm’s tails use to move and fertilize the egg. Hormonal approaches are the furthest along, but they don’t work in all men, and there has been worry about the long-term safety of taking such drugs.

“I don't think there’s been a lot of resources poured into it, quite frankly,” said Diana Blithe, director of the male contraceptive development program at the National Institute of Child Health and Human Development. “I think that a lot of companies feel it’s a zero-sum game, if they already have a lot at stake in female contraceptives, they’re just going to lose.”

Some of the hesitation to male birth control has focused on social questions. Would men take such a pill if it existed? Would women trust their sexual partners?

Steve Owens, a 40-year-old middle school teacher from Seattle, has participated in more than half-a-dozen trials over the last 11 years, doing everything from rubbing testosterone gel onto his shoulders to getting a hormonal implant in his arm. Periodically, he took time off from the studies, and he and his wife had two daughters, now 5 years old and 5 months old.

“My wife had been on the pill before our first daughter for 15 to 16 years; we didn’t want to have to go back on the pill,” Owens said. But condoms weren’t particularly convenient, and a vasectomy would have been permanent.

But Owens said his own experience suggests that both men and women would be interested in more options.

“I got to tell my friends about it—I’m a guinea pig,” Owens said, noting he always gets a lot of attention at parties. “Some of the dudes would be like, ‘There’s no way I would do that.’ And all the girls are like, ‘When is this thing going to be on the market?’ ”