Male infertility, here’s why some men don’t produce sperm: the study

2023-10-21 12:16:04

Why do some men not produce sperm? Researchers involved in the fight against infertility have long tried to answer this question, a condition that affects millions of couples around the world and which in half of the cases originates from a male problem. 10% of infertile men, in particular, have little sperm, not enough to fertilize an egg, or none at all. Now a study in ‘Science Advances’, conducted by scientists from the US Stowers Institute for Medical Research in collaboration with colleagues from the Wellcome Center for Cell Biology at the University of Edinburgh in Scotland, has identified the cause of the lack of sperm synthesis: it is the mutation of a small portion within a protein, one of the many ‘building blocks’ that make up a large bridge structure crucial for the production of gametes, the male and female sex cells. The discovery, the authors hope, will pave the way for targeted therapies.

“A significant cause of male infertility is failure to produce sperm.” But “if you know exactly what’s wrong, there are emerging technologies that can potentially solve the problem,” says Stowers Institute researcher Scott Hawley, head of the lab that published the work along with Owen Davies of the Wellcome Centre.

The scholars focused their attention on “a protein structure similar to a reticular bridge”, which is called the synaptonemal complex and which in most species whose reproduction occurs sexually – including humans – must be formed adequately to allow synthesis of sperm and eggs. The team led by Katherine Billmyre of the Hawley Lab understood, thanks to tests on mice, that “modifying a single, very specific point of this bridge causes it to collapse, leading to infertility”.

The process of cell division that gives rise to sperm and eggs is called meiosis and involves several phases, one of which is the formation of the synaptonemal complex. “Like a bridge,” the scientists explain, this protein structure “holds pairs of chromosomes in place, allowing the genetic exchanges necessary for the chromosomes to separate correctly into sperm and eggs to occur.” Because “a significant contributor to infertility is defects in meiosis,” Billmyre clarifies, it is critical to understand how the synaptonemal complex forms and what can go wrong in building this bridge.

Previous research has already examined many proteins that make up the synaptonemal complex and how they interact with each other, identifying various mutations linked to male infertility. The authors of the new study, however, focused on a protein that has the task of forming the networks of this ‘bridge of life’ and which has a portion common to humans, mice and most other vertebrates. An element that suggests how indispensable this area may be for the correct assembly of the synaptonemal complex. Using a genetic editing technique – the ‘cut and paste’ of DNA – the scientists tried to make various mutations to the chosen protein, localized in the very small area that they considered potentially crucial. They did it in mice, thus being able to test the effect of different mutations in live animals for the first time.

“We focused on a tiny region of a single protein within this gigantic structure” that is the synaptonemal complex, because “we were pretty sure” that “a significant cause of infertility” could be there, Hawley points out. Well, “only a single mutation,” among those predicted by the modeling and testing experiments, “has been verified as responsible for infertility,” the authors report. And “the molecule that”, mutated, “caused infertility in mice – they point out – probably works in the same way in humans”. For Billmyre, what’s “really exciting” is that “our research can help us understand a fundamental process necessary for life.” And as Hawley says, knowing what can go wrong will help science avoid it.