The mysteries of why some men can't produce sperm are now closer to being solved by scientists.
The inability to make sperm is one of many reasons why men may be unable to conceive, making up around 10 percent of infertile men. Now, scientists have shed light on what might be going wrong in the process of sperm generation, according to a new study published in the journal Science Advances.
Experimenting on mice, researchers found that the process of meiosis, which is how the body produces haploid sex cells—containing a single set of chromosomes, rather than two as usual—which then develop into sperm.
The synaptonemal complex is a protein structure formed in meiosis, which forms a bridge of sorts between pairs of chromosomes, allowing genes to be swapped around and the chromosomes to successfully split off into haploid cells.
"It is well known from many studies in multiple organisms that the synaptonemal complex is essential for meiosis and chromosome segregation," Katherine Billmyre, a meiotic chromosome biology researcher at the University of Georgia, a former postdoctoral fellow at the Stowers Institute for Medical Research, and co-author of the paper, told Newsweek.
"The synaptonemal complex is a large multiprotein structure that forms early in meiosis between chromosomes and holds them together to allow meiosis to progress normally. When the SC is completely lost, there are high levels of chromosome missegregation that lead to the gametes (eggs or sperm) containing an incorrect number of chromosomes. Having the incorrect number of chromosomes is what can lead to miscarriage and birth defects."
Previous research suggested that mutations in the proteins that make up the synaptonemal complex may contribute to an inability to create sperm, which this study confirms.
"Most of the previous studies have looked at a complete loss of the synaptonemal complex where the entire structure does not form," Billmyre said. We took a different approach where we tried to identify specific regions of the protein that were potentially important. We collaborated with Owen Davies (a structural biologist) to identify a region to examine. We then made specific mutations in a mouse SC protein to test the importance of that region. We found that a single amino acid change resulted in the protein being unable to form a normal SC structure."
The researchers—hailing from the Stowers Institute for Medical Research, in collaboration with the Wellcome Centre for Cell Biology at the University of Edinburgh—used a gene editing technique to mutate specific proteins in the synaptonemal complex protein in mice and found that a single mutation was enough to cause infertility in the rodents.
"We're talking about pinpoint surgery here," Scott Hawley, an investigator at the Stowers Institute for Medical Research, a professor of cell biology and physiology at the University of Kansas School of Medicine, and co-author of the paper, said in a statement. "We focused on a tiny little region of one protein in this gigantic structure that we were pretty sure could be a significant cause of infertility."
Mice are often used as a model species for human conditions, and although they are separate species, the researchers also modeled human protein sequences and found that as the synaptonemal complex is very similar between species, the same mutated protein likely leads to infertility in humans, too.
The researchers hope that these findings will help them to develop ways to treat infertility in men, especially those who do not make enough sperm.
"Nine percent of men and 11 percent of women of reproductive age in the U.S. experience fertility issues," Billmyre said. "Azoospermia is a major cause of male infertility, affecting about 10-15 percent of infertile men."
"While we are not working on treatments for male infertility, our study on the basic biology of the synaptonemal complex improves our understanding of how SC proteins function during meiosis. Having more information on the basic biology of this structure will provide other groups in the future more information to develop treatments," she said.
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Update 10/24/23, 11:52 a.m. ET: This article was updated with comment from Katherine Billmyre.
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