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The Search for Sperm: Fighting Male Infertility in the Jenkins Men's Reproductive Health Lab

Emerging research from the Jenkins lab takes steps forward in developing tools to help those struggling with infertility.

Infertility is defined as the inability to conceive after one year of regular, unprotected sex. Male infertility is a complex disorder that affects around one in ten men, ages sixteen to 74 years old.

The first step in screening men for infertility is performing a semen analysis, in which sperm quantity and quality are assessed in a man’s ejaculate. Approximately 10 percent of infertile men have no sperm in their ejaculate, a condition called azoospermia. If an azoospermic couple still wants to attempt having biological children, the next step is performing a surgical procedure to identify and extract sperm from the testicles. This procedure is called a micro Testicular Sperm Extraction, or micro TESE.

Picture of the two leaders in the Jenkins lab

“In this procedure, they cut open the testicle and start looking for hot spots where sperm production may be taking place,” says Timothy Jenkins, professor of physiology and researcher of men’s reproductive health. “They biopsy [the hot spots], hopefully find some sperm, and then use the sperm for in vitro fertilization. In vitro fertilization is a medical procedure in which eggs are removed from a woman’s ovaries, fertilized by a man’s sperm in a lab, and transferred to the woman’s uterus to hopefully develop into a baby.

The micro TESE is an invasive, expensive surgery that can cost anywhere from $10-20,000 out of pocket, usually not covered by insurance. The surgery also has a high 40 percent fail rate where no sperm are detected. A large proportion of the individuals who fail the micro TESE do so because of underlying issues with sperm production. In other words, there were no sperm to begin with (as opposed to an obstruction, where sperm are being produced, but are just blocked from being released in the semen).

Is there a better way to screen for individuals that will likely fail the micro TESE? This is where the Jenkins lab comes in.

All cells, to some degree, release little fragments of their own DNA—called cell-free DNA—into their surroundings.

“Even if there are no sperm in the ejaculate, if we can identify sperm cell-free DNA, that means there are sperm somewhere along the reproductive tract,” says Ryan Barney, the third year PhD candidate of cell biology and physiology working on this project as a part of his dissertation research. “This may warrant doing the [micro TESE] surgery, but if there’s absolutely no sperm DNA present, you might not want to move forward with it.”

Picture of the machine used to screen sperm DNA

So how does one identify DNA that comes from sperm as opposed to any other cell? DNA contains instructions for making proteins. Every cell in the body contains the same exact DNA, but what makes sperm different from another cell—for example, a muscle cell—are the genes (regions of DNA) that are active, and therefore, turned into protein. Chemical modifications on the DNA, called methylation, control which genes are turned on and which are turned off. These specific chemical modifications to the DNA molecule are detectable with tests that read the DNA.

The Jenkins lab has been exploring the ability to identify different cells’ DNA by their methylation patterns and found regions of sperm DNA that have extremely unique, sperm-specific patterns. Because of this, they are able to detect and identify even tiny amounts of sperm DNA in a big mixture of DNA with extremely high accuracy.

This process can be put into clinical practice and be used as a preliminary semen analysis screen for the micro TESE surgery. If clinicians can detect sperm cell-free DNA in the ejaculate of azoospermic men, that would indicate a greater likelihood of success for the micro TESE surgery.

According to Jenkins, the number of men this procedure would affect is relatively small, because azoospermia only affects approximately 1 percent of men, or approximately 10 percent of infertile men. However, for those who have struggled with infertility, "I think identification of rare sperm will be very impactful in the clinic for these ... patients."

This technology has other exciting potential applications for forensics such as enhancing the ability to concretely identify sperm in cases of sexual assault and rape, as well as screen for cancer. Cancer cells rapidly grow and release large amounts of cell-free DNA into their surroundings. These techniques are currently being repurposed for developing tests for earlier detection of prostate and other cancers.