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Conceptual Problems (continued)

By Melissa Hendricks

With that in mind, Evans and PhD student Matt Marcello are studying another step of fertilization, in which the egg and sperm first stick together. In particular, they want to know which proteins on the sperm's surface take part in this process.

There are many potential candidates, since hundreds of different proteins embroider the sperm's surface. Researchers have shown that one, a molecule named IZUMO, is clearly essential for the sperm to stick to the egg. But Evans believes that several others must be involved. As the sperm approaches the egg, "it is still swimming like gangbusters," says Evans. "The sperm needs to slow down, and probably just one molecule might not be enough to slam on the brakes."

So Evans and Marcello are using a method of staining sperm to see if they can identify other molecules. The technique allows them to see—literally—where a protein resides on a sperm. Marcello mixes sperm with an antibody to the protein he wants to study, then adds a special fluorescent label to illuminate the antibody as it bonds to the surface protein. Through a fluorescence microscope, he can trace a protein's location on the surface of the sperm.

The sperm for these studies come from two genetic mouse models of male infertility. The mice produce sperm that look normal and swim fairly normally. But the sperm, says Evans, "have sperm-egg interaction issues." In one case, the sperm appear to bind too weakly to the egg. In the other, the sperm seem to bind too tenaciously. In both cases, the sperm score dismally low fertilization rates.

Marcello and Evans hypothesize that these sperm contain defective proteins that prevent them from binding properly to the egg. It could be, for example, that certain proteins position themselves in the wrong place on the sperm's surface, and this misalignment prevents proper bonding. Although his research is in its early stages, Marcello believes the sperm staining technique could one day reveal abnormalities in surface proteins that could explain infertility in the mouse models, and perhaps in people, too.

Currently, fertility specialists can determine whether a man is making normal numbers of sperm, if the sperm swim normally and if they are shaped normally. But in about one-quarter of cases of male infertility, doctors can find no underlying cause. A diagnostic tool that works at the molecular level might offer more answers, says Marcello. "The hope is that we can bring males into the clinic who are having trouble and say, 'Are these proteins functioning properly in your sperm?'"

"Ten to 20 years from now, I think we will have much better insights into what causes infertility," says Evans. "The next step will be to begin to do something to treat it that is not as massively expensive and invasive as IVF."

"If one day, a doctor could tell a man or a woman, 'You're infertile for Reason Number Seven. Here's a pill you can take,' that would be impressive."

Back in the Evans lab, the requisite two hours have passed and Wo has returned to check on her petri dish of eggs and sperm. Looking again through the microscope, she's reassured to see what appear to be fertilized eggs.

The next day, Wo returns to the lab to take images of the fertilized eggs after performing a step to prevent further development. To prepare the dish for viewing, she removes the culture medium, places a glass cover slip over the embryos and seals the slide in place with nail polish.

And then a mishap occurs. While applying the nail polish, Wo accidentally nudges the cover slip—just a tad, but a tad too much—and she squishes the fertilized eggs. Under the microscope, the cells look twisted.

Wo doesn't take the mishap too hard. After all, Evans reassures her, mistakes happen in the lab, just as they do in vivo. Sometimes two sperm fertilize an egg. Sometimes no sperm do, even when a couple desperately hopes to get pregnant. And sometimes fertilization occurs even when a couple desperately hopes it won't. Ultimately, says Evans, her research aims to help people have more control over those events.

"At the end of the day, our goal is to help people have better options—to be able to not reproduce when they don't want to reproduce and be able to get pregnant when they want to get pregnant," Evans says. "Pretty much everyone in the world can understand that."

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