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The Key Male Fertility Protein (Revealed)

Scientists have discovered the NELL2 gene, which has promising implications for the future of male contraceptives and male fertility treatments.

October 14, 2020
Katie Sabel

We all know the basics of male fertility from biology class: sperm comes from the testes, and then ejaculated during intercourse. You may have heard more from articles about male infertility as well. Mostly, they talk about low sperm count and how different everyday activities affect sperm count and quality. For instance, maybe you’ve heard that less sleep leads to poorer sperm quality, or that laptop heat decreases sperm count.

In fact, a lot of studies have been done on behavioral impact on sperm quality and quantity. However, not much research has been done about sperm maturation- that is, the way that sperm come to be fertile in men’s bodies. 

Until recently, scientists weren’t sure what the exact details of the sperm maturation process was. They knew that sperm had to mature before they could be released, and that this process takes place once the sperm move out of the testes and into the epididymis (a small tube connected to the testes). The exact nature of that process, though? No one knew. Scientists knew it had to do something with proteins, but they didn’t know exactly which proteins were necessary for the maturation process. 

The Discovery


Scientists at Osaka University discovered the NELL2 gene in their lab, represented below by test tubes and pipettes
Osaka University and Baylor College of Medicine worked together to conduct research on male fertility. You can read more about their discovery on the Baylor College of Medicine’s blog.

In a recent research study by Osaka University and Baylor College of Medicine, scientists discovered that key protein in male fertility. This protein factor is called NELL2, and it’s secreted by the NELL2 gene. 

During this study, researchers generated knockout mice - named because they “knocked out”  a gene from them - that were lacking the NELL2 gene. The results were conclusive: the mice without the NELL2 gene were sterile due to a defect in sperm motility.

Plus, the good news doesn’t end with the new discovery of that key protein. Researchers also found that the mice missing the NELL2 gene could be helped. When researchers gave these infertile mice a germ-cell-specific transgene, their infertility was reversed!

So What Does This Mean for Humans?

A pregnant woman holds her husband's hands on her belly, thanks to advancements in male fertility
Thanks to the discovery of this protein, scientists may be able to make greater progress on treating male infertility. Plus, there’s promising implications for hormonal male contraceptives as well!


Thanks to this study, we now know that any disruption in the luminal pathway causes men to be infertile. After all, the sperm need to travel through that pathway and collect all the essential enzymes in order to mature. If that pathway is missing NELL2 or one of the other key proteins, the sperm that travel through it won’t be able to fertilize an egg.

Additionally, this study has very promising implications going forward. Now that we know about NELL2’s importance and the importance of the luminal pathway, we’ll be able to diagnose infertility better. What’s more, we’ll also be able to begin to treat male infertility in new and more effective ways. 

This study also has promising implications for male contraceptives as well! Now that we understand what makes sperm fertile, there’s the potential to develop a form of birth control that targets that protein and shuts it off. 

As it stands, we only have two major forms of male contraception: condoms and vasectomies. Both are imperfect methods of contraception. Condoms, for instance, are only 98% effective at preventing pregnancy (and that rate is likely even lower than we think).

Meanwhile, vasectomies are nearly 100% effective, but they’re not without their flaws either. What’s seldom mentioned about vasectomies is that they can actually take up to three months to begin working as a contraceptive. Plus, vasectomies can be painful. Symptoms such as temporary pain, bruising, and infection are all commonly experienced after the procedure.

Additionally, vasectomies are permanent. While there is some possibility of being able to reverse the procedure, there’s no guarantee that it’ll work. It’s possible that after the procedure, your fertility won’t be able to come back. Because of this, it’s not a very practical form of contraceptive. After all, you never know if you’ll change your mind about wanting kids, or even change your mind about wanting more kids.

So, neither current form of male contraception is without its flaws. This is why the idea of a NELL2-based contraceptive is so exciting- it’s possible that it could be hormone based, like current female contraceptives. That way, males can engage in safe sex, and then turn their fertility back on when they’re ready to conceive.

Nothing’s certain yet, of course, but the possibilities seem to be very promising. Plus, regardless of male contraceptives, this study may be able to help us find treatments for male infertility as well. It’ll be very interesting to see how these practices around fertility develop in the future!

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