Jon Oatley's name was misspelled in the original version of this story. It has been corrected.
PULLMAN — Around the world, close to half of all pregnancies are unintended. But despite decades passing since the invention of the female birth control pill, male birth control has been largely limited to condoms and vasectomies.
Jon Oatley is the associate dean for research and professor in the School Molecular Biosciences at Washington State University. He’s also the principal investigator for research he says could be an essential first step in developing the first fully reversible, nonhormonal male birth control.
That key, Oatley said, is something he and his eight co-authors discovered while compiling a database of molecules expressed only in the testicular tissue of mammals. Samples included tissue from cattle, sheep, mice, pigs and publicly available data on human tissue. One molecule, a protein-encoding gene called ARRDC5, stood out.
“In the peer-reviewed scientific literature, there had been nothing reported on the function of this gene in any species,” Oatley said.
What they found, Oatley said, was that the gene seemed to play a key role in the final stages of the sperm production process.
To test it, the team used gene-editing technology to make a “knockout” mouse model — changing the DNA sequence that encodes for ARRDC5 to no longer be functional. What they found, he said, was that the gene-edited male mice were infertile, with no other apparent side effects.
“The mice were completely normal, except just the males were infertile,” Oatley said. “The female knockouts are completely fertile, and can reproduce just like normal.”
Though still in early stages, Oatley said, the findings show promise for human application down the line.
ARRDC5 is what scientists call a “one-to-one orthologue.” In simpler terms, it means the gene stays the same — a sort of evolutionary cornerstone — despite a wide range of other genetic differences between species.
“Even going from a lower-order organism like a mouse, all the way up to humans,” Oatley said. “There’s only one copy of the gene in the mouse genome, only one copy in the human.”
Oatley is far from the first researcher interested in finding more male birth control options. But so far, nonhormonal, reliably reversible male contraception has eluded scientists.
While a considerable number of women use hormonal birth control in the form of pills or long-acting, reversible options such as intrauterine devices (IUDs) or implants, the side effects for men have been considered by many early test subjects to be intolerable.
Health care providers have identified a need for male birth control as a step toward health equity, and research shows a growing interest among men in male birth control, especially following the overturn of Roe v. Wade last year.
Oatley said he’s acutely aware that his findings could be more significant than ever as abortion access is limited for many Americans. According to the Guttmacher Institute, a research and policy organization that describes itself as promoting “sexual and reproductive health and rights,” 61% of unintended pregnancies worldwide end in abortion.
“As we change reproductive rights, and different states adopt different laws, trying to stop pregnancies from happening versus trying to terminate pregnancies that are unintended — we have to have a male contraception. I think it’s huge,” Oatley said.
Targeting ARRDC5 holds the potential to circumvent the undesirable side effects that other attempts at male birth control have presented, he said. A medication that targets the gene would offer men a more desirable option for taking charge of their reproductive health care while reducing the burden of birth control on people who can get pregnant.
“It doesn’t interfere with the endocrine system or the hormone system. A lot of hormonal-based male birth control targets testosterone. That has a multitude of problems, including reduction in libido,” Oatley said. “So I guess it works as a contraceptive, if men have really low libido, but most of the time that’s not attractive to men.”
But, how exactly would inhibiting one gene work as birth control without any other side effects?
Sperm production, Oatley said, is a long process he imagines like a car assembly factory. Without ARRDC5, sperm are misshapen, and unable to swim or fertilize an egg.
But unlike hormonal birth control, which affects the system as a whole, disrupting ARRDC5 is like removing a final step in production that makes a car drivable.
“It’s not putting the frame together, that ARRDC5 is having a role in,” Oatley said. “It’s like putting the tires or the doors on at the very end.”
The findings might also have implications for treating male infertility. Clinical descriptions of male infertility often include low sperm counts, abnormally formed sperm and immobile sperm. ARRDC5 seems to play a role in all three, Oatley said, which might potentially mean some men who are infertile have a dysfunction in how ARRDC5 is expressed.
“If that’s the case, then we could start to think about devising strategies to restore the function of that molecule and bring their fertility back to normal,” he said.
The findings also have potential for nonhuman subjects such as companion animals, livestock and even population control in wildlife, Oatley said.
In both domestic and wild animals, neutering or castration can have undesirable health effects. Wild animals may become more susceptible to viral or bacterial diseases, or struggle to compete for resources with intact males.
“I think people generally equate testosterone production to just musculature and aggressive behavior,” Oatley said. “But it’s also really important for the immune system, it’s really important for bone health, similar to estrogen in females. So when you remove testicles, and thereby remove testosterone, there are side effects of that.”
The next step for Oatley and his team will be testing the same model on an intermediate animal, which for them means sheep. But those tests won’t be able to start until the animals’ breeding season begins in the fall.
“If the same effect happens as it did in the mice, and the sheep can no longer produce functional sperm but are otherwise normal healthy, then that gives us a really strong indication,” he said. “(In that case it would be) really strongly likely that the ARRDC5 also plays a key role in sperm production in a human.”
The timeline for developing a drug approved for human use to target ARRDC5 depends largely on biological proof of concept and available resources, Oatley said.
The researchers could potentially move forward even with just the mice studies to start identifying potential drug compounds that would inhibit ARRDC5.
If a drug is produced that’s effective in mice, the next step would be to test on other animals such as sheep, and later down the line, nonhuman primates. If those drug effects remain consistent, they could become eligible for human trials.
Sun may be contacted at rsun@lmtribune.com or on Twitter at @Rachel_M_Sun. This report is made in partnership with Northwest Public Broadcasting, the Lewiston Tribune and the Moscow-Pullman Daily News.
