Harvard Researchers Unlock Sperm Secrets

Two Harvard-affiliated researchers have discovered the function of a unique protein which allows sperm to blast through the tough outer layer of an unfertilized egg and which may be the target of a future 100 percent effective contraceptive.

By measuring the current that flows across the sperm’s plasma membrane for the first time, Yuriy V. Kirichok and Betsy Navarro of the Children’s Hospital in Boston, found that sperm have a unique ion pathway. The discovery allowed Kirichok and Navarro to determine the function of the cation channel of sperm (CatSper) and could potentially lead to the development of new contraceptives designed to block the protein.

According to David Clapham, Castaneda Professor of Cardiovascular Research at Harvard Medical School and the principal investigator of Kirichok’s lab, understanding the function of CatSper can lead to the development of CatSper blockers to serve as contraceptives. Hydra Biosciences, a biotech company co-founded by Clapham, is already developing a drug that would specifically target CatSper.

“CatSper is a wonderful target for contraceptives because it is only in mature sperm,” Clapham wrote in an email. “And blocking its function results in 100 percent infertility…for as long as the drug was in the body”

When sperm are swimming far away from eggs, their flagella beat steadily with sinusoidal motions. However, for fertilization to occur, the sperm need to be hyper-activated. Hyper-activated sperm swim with vigorous, whip-like motions that gives them the force they need to penetrate the protective membrane of the eggs. Prior to Kirichock and Navarro’s research, which was published in the February 9 issue of the scientific journal Nature, the cause of this hyper-activation was unknown.

According to Kirichock, data on sperm physiology has long suggested that ion channels located on the sperm’s plasma membrane played a key role in determining sperm motility and sperm-egg interactions, and scientists have been unsuccessfully trying to measure the activity of those ion channels since 1985.

When Kirichok undertook the challenge in early 2004, “sperm cells had a very bad reputation among physiologists,” he wrote in an email.

The sperm’s constant wriggling and rigid plasma membranes made them difficult targets to study using the traditional patch-clamp technique. The patch-clamp method uses a tiny pipette to delicately rupture the plasma membrane of cells to measure the flow of electrical currents.

According to Clapham, sperm were the last bastion of cells to resist patch-clamping.

Kirichok’s breakthrough came when he noticed a tiny bubble on the sperm’s tail, near the head, which allowed him to patch-clamp the sperm at that bubble.

“For us it was a bit like being the first to enter an ancient sealed pyramid—as soon as you get in you don’t know exactly what you will find, but you know it will be new and interesting,” Clapham wrote.

What they discovered was that sperm hyper-activation requires the current produced by CatSper.

First discovered by Clapham’s lab in 2001, the CatSper protein is activated by the higher pH environment of the female cervix. Activated CatSper allow calcium ions to flow into the sperm’s tail. The calcium influx, measurable as an electrical current, alters the way the flagella bends and hyper-activates the tail’s motor proteins. In experiments, mice altered to lack the CatSper protein had weak swimming sperm and were infertile.

“You could say CatSper is a kind of Viagra at the cellular level,” Clapham wrote.

—Staff writer Xianlin Li can be reached at li3@fas.harvard.edu.