A Conversation With David E. Clapham: Small Wonders: Understanding The Way Of The Warrior Sperm

CAMBRIDGE, Mass. — The first thing that David E. Clapham of Harvard Medical School wants me to know as we meet for breakfast on a recent morning is that hes not a sperm specialist.

Dr. David E. Clapham of Harvard Medical School is looking into new ideas for male contraception.

Scientists can study the effect of their changes to sperm, above, without destroying them.

Its true that Dr. Claphams résumé is eclectic. At 54, he is a Howard Hughes Medical Institute investigator, has an electrical engineering degree from Georgia Tech and an M.D. and a Ph.D. in cell biology from Emory University, and has worked as a practicing internist.

But while Dr. Claphams laboratory, tucked into the pediatric cardiology department at Bostons Childrens Hospital, studies heart cells and neurons, the most noteworthy topic there really is sperm: how they swim, how they function.

In fact, the Clapham lab is one of the few venues in the world where researchers are looking into new ideas for male contraception.

Q. If youre not, as you say, a sperm specialist, then how did your labs sperm research begin?

A. By accident. I study ion channels, the molecular gates on the membranes of our cells. Within our bodies, whenever they open and close, about a million ions per second flow through them. This is how neurons communicate with one another and how muscles get signals to contract.

Way back in 1999, in my lab, we were rummaging through the database of the Human Genome Project, searching for previously undiscovered ion channels. Once we detected them, we used molecular biology and biochemistry to find where in the body they were.

One day, one of my postdoctoral fellows, Dejian Ren, discovered an ion channel that really was different from any of the hundreds of others that exist in a body: CatSper. It was only found in one tissue type, the testes, and only in the tail of mature sperm.

That got my attention because this meant that it was doing a very specific job. It would turn out that the CatSper gene, which makes the proteins that create the ion channel, held the key to one of the great mysteries of reproduction: how sperm penetrate eggs.

Q. And just how do they do that?

A. As you know, a human sperm needs to swim through the female reproductive tract for something like 15 minutes to get to the egg. They have a kind of built-in motor that permits them to do that. When sperm get to the egg, they need to crash through the ovums membrane to deposit their DNA there.

The way that happens is that at the end of its run, this ion channel brings the sperm calcium, which changes the shape of its tail and turns it into a kind of whip. The sperm is then propelled into hyper drive — pushing it into the egg with 20 times the force of normal swimming. Now, if this ion channel is blocked, there can be no fertilization.

Q. Among biologists, is sperm research very respected?

A. Well, in biology, all the glamour is in neuroscience. The common thing said is: Learning and memory, thats the theoretical physics of biology. In terms of prestige, reproduction is far down the line. Another thing: because reproductive research is about sex and possibly about contraception, it doesnt get a lot of funding. That too has something to do with its low status.

Whenever I speak in some neurobiology department, you always get someone asserting, Sperm arent as interesting as neurons. I then have to say: Sperm have everything neurons have, and more. Sperm can secrete DNA. They move. They have terrific mechanical problems to overcome.

Q. What are some of the underappreciated attributes of sperm?

A. Im fascinated by how determined they are. Sperm — each one seems an individual in the way they move. When they change from one motion to another, its fascinating.

Moreover, they have the ability to do much more than most other human cells: they crawl long distances in a short period of time, they can sense their surroundings. In fact, they have molecules that are much the same as olfactory receptors in our noses.

As you watch them under a microscope, you get the sense that they are going somewhere, or at least think they are. They surround an egg and vigorously try to fuse with it. They dont give up until they run out of energy.

Q. Have you noticed any social behaviors among them?

A. The social behavior of sperm is somewhat like the social behavior of humans. Sperm cluster around an egg. Sperm get more vigorous when theyre around an egg. (Laughs) It remind us of what males are like around females.

Q. Does your research have any practical applications?

A. It might be useful in understanding some aspects of male infertility. Men who have a mutation in this gene are infertile. The research could also lead us to a new form of contraception. If you can find a drug that interferes with the calcium getting to the sperms tail, you can prevent fertilization.

In terms of proof of principle, we absolutely know this will work. The same sort of gene exists in mice. In my lab, weve taken it out in mice and were created infertility 100 percent of the time.

Q. Are you suggesting you may have found a new male contraceptive?

A. Actually, either gender could take it. Its possible to even give a woman a drug that could block the CatSper channel when the sperm entered her body. A man could take the drug any time before ejaculation.

As ideal as this might be, were encountering two huge roadblocks. On a scientific level, we still have to find the exact compound to knock out the CatSper gene. Weve also got a nonscientific problem: there arent any big pharmaceutical companies interested in developing new contraceptives anymore.

One pharmaceutical company — I wont name it here — was ready to make a deal, and then a high-level decision came down to pass. They werent doing reproduction anymore.

Q. Why not take your research to other firms?

A. We have. Theres a general feeling throughout the industry that reproduction is just too risky in terms of potential liability and in terms of controversy. They feel that the estrogen-based birth control pill works fine. As far as they are concerned, the problem is solved.

One major drug manufacturer has recently decided to stop doing contraceptive research altogether. I hear that another will soon make a similar announcement. I see them as doing things to refine the birth control pill, but they are not interested in new approaches.

Im still continuing, though. Im interested in this research because it might do the world some good, but also for its own sake. Whenever you find something that has never been understood before, thats a wonderful feeling. Its what everyone I know in science lives for.

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