Scientists Look to Sperm to Improve Reproductive Health and Beyond

Sperm are half of the equation for new life. To date, however, its counterpart, the egg, has been the more frequent gamete of study.

But in several Yale School of Medicine (YSM) laboratories, researchers are diving deep into understanding the structure and physiology of sperm. Unraveling the mysteries of the male reproductive cells—from how they fuse with eggs to how they navigate through the female reproductive tract—could lead to insights into new therapies for infertility and contraception, they say. And it could one day even help scientists better understand the pathology underlying diseases such as cancer.

“Sperm cells do not gain the attention they deserve,” says Jean-Ju Chung, PhD, associate professor of cellular and molecular physiology at YSM. “Studying gametes, especially sperm physiology, is very important not only for reproductive health, but for society overall.”

That it remains unclear how sperm bind and fuse to eggs is remarkable, says Steven Tang, PhD, assistant professor of molecular biophysics and biochemistry at YSM. As many as one in six couples worldwide experience infertility, which in many cases stems from the inability of sperm to recognize or fuse with eggs. Studying how this process is disrupted could help scientists find ways to help many couples struggling with infertility, Tang says.

His team is examining the surface of sperm cells to look for molecules that drive sperm to recognize eggs and ultimately facilitate fusion. Tang hypothesizes that sperm contain unique proteins that play this role.

“We know that sperm only fuse with eggs and not with any of the other 30 trillion cells in the body,” he says. “This is a unique, specific event, which is why we believe it is mediated by proteins that are only on the sperm surface.”

Tang’s team isolates various proteins from sperm cells and examines their molecular structure using high-resolution techniques. They also study how these proteins interact with a simplified model of reproductive cell membranes—striving to recreate sperm-egg fusion in a test tube, Tang explains.

Through this work, his team has discovered unique antibodies that can inhibit fusion. Not only do the findings further scientists’ knowledge of why infertility occurs, but future studies on these antibodies could open new avenues for infertility treatment as well as novel contraceptives. “This leads to new frontiers of understanding of how antibodies block the fertilization process,” Tang says.

During the fertilization process in humans, millions of sperm navigate through the female reproductive tract, but only around a few hundred reach the fallopian tube, and (typically) just one fuses with the egg. To succeed, sperm must move forward through the cervix, uterus, and fallopian tubes and adapt to changes in their environment along the way. When a sperm reaches an egg, it undergoes hyperactivation. Its tail changes from a symmetrical beating pattern to a strong, whip-like motion, which gives the sperm enough power to penetrate the egg.

Throughout the journey, channels on the sperm cell respond to changes in the environment and control the flow of ions that drive movement. Low sperm motility can hinder the sperm’s ability to reach and penetrate the egg, contributing to infertility.

Chung became interested in how ion channels drive motility as a postdoc. The lab where she studied had discovered a calcium channel called CatSper that was unique to the tail of sperm cells and essential for sperm hyperactivation. When CatSper is activated, calcium ions flow into the sperm cell, which enables the tail to switch its motility pattern to the whipping motion seen in hyperactivation. Men who have mutations in the genes for these CatSper channels are completely infertile, Chung says.

Now, at YSM, Chung’s team has been working to characterize the molecular composition of this channel and better understand its structure within the sperm cell. Sperm cells are the smallest cells in the human body. The researchers use techniques such as super-resolution microscopy to see how molecules are arranged in the tails of sperm. “Through this process, much of our current knowledge on CatSper has formed,” she says.

Beyond hyperactivation, Chung’s team discovered that CatSper channels also play a role in a maturation process called capacitation that occurs while sperm are in the female reproductive tract. Capacitation involves significant physiological changes that enable the sperm to fertilize eggs. Through the imaging of sperm cells along the female reproductive tract, Chung’s laboratory discovered distinct molecular differences in the CatSper channels in sperm that reach the egg compared to those that fail. In ongoing research, her team is trying to understand how these differences might alter the maturation process—allowing some sperm to have a higher chance of success than others.

On the male infertility side, understanding how CatSper activates could lead to new therapies, which Chung says could also have significant benefits for women. When couples experience infertility, treatment often requires women to undergo invasive procedures, even when the infertility stems from issues with sperm. “If we can identify how to improve sperm motility or hyperactivation, we can improve the fertilization rate in vitro,” she says. “This can potentially reduce the number of in vitro fertilization cycles for couples who are facing infertility.”

Furthermore, while hormonal contraception is available for women, it can often cause intolerable side effects. New contraceptives for men could help reduce the unequal burden that women currently carry in terms of family planning, Chung says. For male contraceptives, the identification of molecules that block CatSper could support the development of new male contraceptives. She envisions a world where men could one day receive an oral medication or patch that blocks the CatSper activity in their sperm. “In the millennial and Gen Z generations, surveys show that there is more and more willingness among men to try a contraceptive,” Chung says.

Sperm are produced through a process called spermatogenesis. This process occurs in the testes, which contain the precursor cells, or germ cells, for sperm. When most cells in our body divide, they separate completely to create two identical cells, known as daughter cells. However, during the cell division process of a germ cell, the daughter cells do not fully separate and remain clustered together. The laboratory of Lynn Cooley, PhD, C.N.H. Long Professor of Genetics at YSM, is interested in the steps driving the unique cell division process of germ cells.

Scientists have observed that dividing germ cells develop intercellular bridges, known as ring canals, that keep the daughter cells connected. These structures persist throughout the entire spermatogenesis process. Cooley’s team has been investigating ring canals, using live imaging of fruit fly spermatogenesis to capture the process of ring canal formation in real time.

“We wanted to identify the instructions for incomplete cell division to form germ cell clusters, and how ring canals form,” says Kari Price, PhD, a former postdoctoral fellow in Cooley’s laboratory who led much of this research. “We aim to understand why it’s so important for sperm cells to develop this way.”

When somatic (non-sex) cells divide, an organelle called a midbody forms within a narrow membrane tether that connects the two new daughter cells. The midbody recruits proteins that sever this bridge to complete the cell division process, making it a transient structure that disappears once its job is done. Cooley’s team discovered that midbodies also form during germ cell division. Interestingly, the midbodies of these germ cells were significantly bigger than those seen between dividing somatic cells.

Unlike somatic cells, however, when the midbodies form between germ cells, a dramatically different process occurs. Instead of severing the tether connecting the new germ cells, the midbody remodels itself from a sphere shape into a ring, forming a ring canal, which lines the inside of the intercellular bridge, keeping the connection between cells intact. “This is not at all like what happens in cells that completely divide,” Cooley says. “We observed this and said—whoa, this is a huge clue to what’s different about germ cells.”

The researchers found that these processes are also present in female germ cells, as well as in germ cells from other species, including mammals like mice. They even observed this process in a simple freshwater polyp known as Hydra vulgaris. “We’re convinced that what we found is a phenomenon of germ cells that has been conserved for millions and millions of years,” Cooley says.

“If we know how to disrupt a ring canal in an acute way, perhaps we could design drugs and provide new contraceptives,” Price adds. “I think there’s incredible potential.”

And not just for reproductive medicine: Research into the unique way sperm cells divide could also lead to new ways to treat diseases. Researchers have observed incomplete cell division in certain types of cancers and immunodeficiency syndromes.

“We have a lot to learn at the very basic level about how cells divide, and how that might inform what goes wrong in cells that don’t divide properly,” says Cooley. Doing so, she says, could lead to new therapies that target what goes awry in cell division, like that which occurs in disease. “We could learn how to reprogram the cell division machinery to fix cancer.”