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Science Scientists capture most intimate view yet of human conception

A protein called Izumo1 (blue) attached to the surface of a sperm cell, triggers conception when it locks onto a Juno protein emerging from the surface of an egg. Newly published research by Canadian and Japanese scientists has revealed exactly how this link up is achieved. Artist rendering of the first moment the sperm and egg touch by Joy Qu

Joy Qu

Birds do it. Bees do it.

But until now, no one has been entirely sure how humans do it – at least at the molecular level.

Using high-powered X-rays and sophisticated computer algorithms, two teams of researchers – one based in Canada, one in Japan – have revealed the mysterious connection that allows a human sperm to fasten on to an egg and trigger fertilization.

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The result offers a vivid portrait of one of the most important of all biological processes and lays the foundations for further studies that could lead to new forms of contraception.

"It will open up a lot of doors," said Jeffrey Lee, a structural biologist at the University of Toronto who was the senior researcher on the Canadian team. "This is the first time we've identified a protein complex linking a human sperm to a human egg."

While fertilization is the crucial first step to all human life, it has not been easy for scientists to determine precisely what happens when egg and sperm meet. In addition to the technical challenges, experiments that require human fertilization immediately raise ethical issues.

To sidestep these dilemmas, researchers in both groups found ways to separately generate two proteins that are known to be crucial for fertilization and studied their interaction.

The teams were then able to deduce the three-dimensional structures of the proteins and show precisely how they fit together, atom to atom. Their complementary findings were published Wednesday in the journal Nature.

"They've done a great job and arrived at similar answers so it looks like we're getting a consensus on this," said Gavin Wright, a researcher at the Wellcome Trust Sanger Institute in Cambridge, England, who was not a member of either team.

In 2014, Dr. Wright and colleagues showed that a protein nicknamed Juno, which protrudes from the cell membrane of the egg, is the likely docking point for a sperm-related protein called Izumo1, that was identified by researchers at Osaka University in 2005. The two proteins are fittingly named: Juno after the Roman goddess of marriage and Izumo1 after a famous shrine honouring the Japanese Shinto god of good relationships.

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Genetic experiments with mice, which have their own versions of Juno and Izumo 1, demonstrate that interfering with the normal development of either protein causes infertility. But what scientists didn't know was how the all-important coupling of Juno and Izumo1 takes place.

Starting two years ago, Halil Aydin, a doctoral student in Dr. Lee's lab, set out to solve the puzzle using tools and methods that were developed primarily to study how viruses infect their hosts. He put insect cells to work as miniature factories to crank out the Juno and Izumo1 proteins and prepared samples to be blasted by a powerful beam of X-rays at the Canadian Light Source facility in Saskatoon. From the data obtained there, the Toronto group eventually reconstructed what the proteins look like and how they attach. The team members did not realize they were in a race to understand the process until they submitted their findings and learned of the Japanese result.

One intriguing detail is that the Izumo1 protein, which is long and narrow but bent like a boomerang, becomes more extended once it makes contact with Juno.

"It snaps up and locks in place, almost like a Swiss Army knife," said Dr. Lee.

The researchers speculate that this change in shape may allow the structure to bind to other yet-to-be-identified proteins that are then involved in merging the membranes of the two cells so that the genetic material they contain can combine.

The joining of the two proteins appears to help prevent DNA from more than one sperm from entering an egg. As soon as a first connection is made, the egg sheds the remaining Juno proteins from its surface.

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"They might act as decoys" to intercept incoming sperm, Mr. Aydin said.

In a similar way, information about how the proteins attach could potentially be used to design molecules that latch onto and prevent sperm from forming a connection with an egg, providing a form of birth control that does not require hormones to regulate female ovulation.

Mr. Aydin said when he began the study he was shocked by how much is not yet known about the details of fertilization – details that he hopes to continue to uncover after completing his PhD.

"I came up with this project so it's like my baby," he said. "I don't want to give up on this field because there's so much still to do."

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