First, your parents had to meet. But another, less celebrated encounter also made your existence possible—one of your father's sperm latched onto one of your mother's eggs. Now, researchers have solved a lingering mystery about this cellular rendezvous by identifying the sugar molecules on human eggs that sperm connect to.
Before fertilization can occur, a sperm must fasten to the zona pellucida, a membrane that encases the egg. The zona pellucida in humans contains four kinds of proteins. In turn, these proteins sport branched sugars, or carbohydrates, that researchers suspect enable the sperm to get a grip. Although scientists have identified mouse carbohydrates that sperm bind to, they haven't been able to do the same for people, largely because of a scarcity of zona pellucida samples to test.
To overcome that hurdle, glycobiologist Gary Clark of the University of Missouri School of Medicine in Columbia and colleagues obtained nearly 200 human eggs that were donated to research after they failed to fertilize during a type of infertility treatment. The researchers then used mass spectrometry to identify the carbohydrates in zona pellucida material from the eggs. As the team reports online today in Science, the sugars from human zona pellucida predominantly carry one kind of carbohydrate branch, a structure known as sialyl-Lewisx. These sialyl-Lewisx branches are much more common on the egg than on any other kind of body cell, Clark says, and they completely coat it.
Next, the researchers tested whether sialyl-Lewisx molecules help bring sperm and egg together. They gave sperm the chance to attach to eggs in a solution that contains added sialyl-Lewisx molecules. The extra carbohydrates distracted the sperm and reduced the number that adhered to eggs, the researchers found. Antibodies that glom onto sialyl-Lewisx molecules also reduced sperm binding.
"The data in this paper clearly demonstrates that sperm primarily bind to a specific sugar molecule ... present on the outer surface of the egg," Clark says. However, he notes, some sperm can attach to the egg even with distracting sialyl-Lewisx molecules nearby, suggesting that binding to the zona pellucida involves another interaction, probably between a protein on the sperm and a protein on the egg.
"Knowing, from a pure science perspective, the events that are occurring at the beginning of human life is pretty amazing," says co-author Anne Dell, an analytical biochemist at Imperial College London. But she adds that the results could have practical benefits as well, such as improved contraceptives and fertility treatments. For example, the discovery of the sperm's target on the egg might help clinics identify infertile men. "There are some men out there who have wonderful sperm, but they don't bind to the egg," Clark says.
Sialyl-Lewisx branches occur on some immune cells, helping direct them to certain locations in the body. Clark says that this immune connection suggests that sialyl-Lewisx sugars don't just promote fertilization. They might also help prevent the immune system from attacking a fertilized egg or embryo, which carries "foreign" molecules from the father and, in theory, should provoke immune cells. Tumor cells often bedeck themselves with sialyl-Lewisx molecules, and the rogue cells could be using them to escape detection by the immune system, he adds.
Experts are impressed. "It's the first time we've had any detailed analysis of the human zona [pellucida]," says Christopher Barratt, a reproductive biologist at the University of Dundee in the United Kingdom. "It's technologically a marvelous paper," adds reproductive biologist Harvey Florman of the University of Massachusetts Medical School at Worcester. "I found it very impressive that these guys could pull it off." An obvious next step, these researchers say, is identifying the protein on sperm that recognizes sialyl-Lewisx branches. "We also need to know what's on the other side" of the sperm-egg bond, says developmental biologist Luca Jovine of the Karolinska Institute in Sweden.