HARVARD GAZETTE ARCHIVES

As a sperm wiggles along, an electrode measures how much electric current is generated by the activity. The orange color marks a protein that provides the hyperactivity needed to swim to an egg.

To produce this all-important fertility sprint, sperm tails must switch from an easy, symmetrical beating to a frenetic whiplike lashing. This switching slows down sperm cells but gives them the extra force they need to penetrate an egg's protective coating.

Researchers at Harvard Medical School and Children's Hospital in Boston actually measured the tiny, tiny current in sperm tails that triggers this hyperactivity. The experiments were done with mice, but David Clapham, the Harvard professor of cardiology and neurobiology who supervised the research, says, "I expect that what's true in mice is true in humans. Their genes are very similar to ours."

The key to this seminal stamina is a protein known as CatSper, which both men and mice possess. The protein forms a channel in the middle of the sperm's relatively long tail, allowing electrically charged calcium molecules called cations to flow from body fluids into the sperm. (The name CatSper is short for cation channel in sperm.) These cations cause other fiberlike proteins to contract rapidly and incite the energetic tail whipping.

Although they display normal mating behavior, male mice without CatSper are totally ineffective at impregnating females.

You might guess that knocking out CatSper with a drug would make a great contraceptive. "Yes, it would," agrees Clapham. "It would block the channel that makes males fertile. What's more, it would only be temporary. And, since CatSper is confined to mature sperm, a drug targeted specifically for it would have no side effects."

What you probably wouldn't guess is that such a pill could also work for women. "Sperm swim in the female reproductive tract for at least 15 minutes before they reach an egg." Clapham notes. "Ideally it should be taken just before sex, but it might be made to work after sex."

Such a contraceptive might satisfy the concerns of anti-abortionists, because it would prevent sperm from ever uniting with an egg. Children's Hospital has negotiated a license with a Boston biotech company, Hydra Biosciences, to pursue this approach to pulling the tails of sperm.

David Clapham monitors the movements of mice sperm whose tails boast a protein responsible for a frenetic burst of speed. (Staff file photo Jon Chase/Harvard News Office)

Tale of a tail

The discovery of CatSper was serendipitous in the sense that Clapham and his colleagues weren't looking for it. They were mainly concerned about studying the biological basics of protein channels, pores that open and close to let various ingredients into different kinds of cells.

About six years ago, the researchers found a channel protein for which there did not seem to be any use. It was like a gate to nowhere.

"It was frustrating," Clapham recalls. "We searched 50 separate types of cells, including heart, brain, lung, and kidney cells from both humans and mice, to try to determine where the protein did its job. Finally, a former postdoctoral student, Dejian Ren, found what we later named CatSper in the testes. "

Entrance and exit of calcium into such channels causes all muscles in the human body to contract or relax. The fibers inside sperm cells act in a similar way. Without CatSper, sperm cells move only a third as fast as they do with it, and they travel in a less deliberate direction toward eggs. They don't need CatSper for normal swimming, but it must be turned on for the hyperactive sprint to fertilization.

Discovering all these things about sperm was not easy. Their tails are a hundred times thinner than a human hair and were in constant motion while researchers tried to measure the electric currents that drive them.

Using microscopes, postdocs Yuriy Kirichok and Betsy Navarro, in Clapham's lab, manipulated tiny clamps to hold the wiggling tails and record electric flow along them. They describe the procedure in detail in the Feb. 9 issue of the scientific journal Nature.

CatSper stands to become better known in the future. Its relatives are part of a large family of proteins that close and open many parts of the body to electrically charged molecules like calcium cations. "Such CatSper relatives might provide targets for drugs that treat problems in many different organs, including the heart and brain," Clapham notes. "They open up a whole new area of possibilities to pursue."

Clapham cautions not to take the results of calcium channel research too literally. People have contacted him to inquire about taking calcium pills to solve infertility problems. One woman asked if her son-in-law's fertility would increase if he soaked his testicles in milk daily. Clapham answers, "it's not yet known whether defects in this sperm channel cause male infertility."

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