Israeli-Japanese Collaboration Achieves Breakthrough in Biology of Sex

We knew that sperm and egg come together, but we didn’t know how. Now we do – a discovery that could also shed light on some forms of infertility and, conversely, lead to new contraception methods

Ruth Schuster
Ruth Schuster
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We see an engineered kidney cell expressing Juno and and mouse sperm expressing Izumo1 (red), DNA stained in blue. The pink arrowhead highlights a sperm that is bound but did not fuse, and the white arrowhead points out a sperm fused to the cell and is therefore stained in greenCredit: Technion spokesperson's office
Ruth Schuster
Ruth Schuster

It is the name of one of the oldest, most venerated shrines in Japan. First appearing in the historic record in 950 (though it may have existed before), the shrine formally known as Izumo Oyashiro is dedicated to the Shinto deity of marriage. It is also the inspiration behind the name of Izumo1, the protein behind a breakthrough in the biology of sex by a collaboration of Israeli and Japanese scientists.

The new knowledge could theoretically help both the infertile and the unwillingly fecund among us.

Technically, Izumo1 is a protein. More specifically, it is protein from the immunoglobulin superfamily that was discovered almost two decades ago by Naokazu Inoue and colleagues at Japan’s Genome Information Research Center. Inoue et al. elucidated already back then that Izumo1 was related to male fertility. Mouse studies showed that if you muck with the gene, the male mice are sterile. The mice could produce normal-looking sperm, but they could not do the job.

You too have Izumo1 protein in your sperm if you are a man, and the 2005 team demonstrated that Izumo1 plays a role in attaching man-sperm to she-hamster-egg – but let us not go down that rabbit hole.

Now, a team of scientists at the Technion – Israel Institute of Technology, Haifa, Nagoya University and Tokyo University reports deducing another crucial role, beyond binding the sperm and egg: actually fusing them.

This is a far nicer image of a hamster than the one you will get while reading about experiments in this article.Credit: Vienna Wildlife/Shutterstock

The breakthrough by Nicolas Brukman, Clari Valansi, Kateryna Flyak and Xiaohui Li with Benjamin Podbilewicz from the Technion, Tetsuya Higashiyama of the University of Tokyo and Kohdai Nakajima of Nagoya University was published last week in The Journal of Cell Biology. For the first time, a protein actually causing fusion of sex cells has been identified in vertebrates – specifically mammals, including we.

Which means this: When a sperm and egg bind, they become like a ball with a tail glued to a bigger ball sans tail. They do not become one ball. But at the next stage, when sperm and egg fuse, their envelopes merge, ultimately allowing their content to mix. Later, the genetic material comes together and the two cells become one bigger cell, the zygote, which will become baby. Sex cells that can bind but don’t fuse achieve nothing.

Beforehand, sexual fusogens had only been identified in plants, archaea and other low-ranking life-forms (though they don’t exist in bacteria). Just recently, Podbilewicz and colleagues proposed that sex-cell-fusion-type proteins actually emerged first in archaea three billion years ago, which is a billion years before sex was invented.

He also points out that mammalian fusogen proteins have been identified in the context of the placenta and muscular tissue, as opposed to sex cells, but they are different families of fusogens and we shall now ignore them.

Juno in the house

Back in the present, the researchers found that Izumo1 protein on the sperm cell’s surface interacts with a protein called Juno – named after the Roman goddess of fertility and love – on the egg’s surface.

Anyway, once Izumo1 and Juno bind together, Izumo1’s second role begins. It also operates as a fusogen, joining the two sex cells into one cell that gets half its DNA from mother and half from father.

But is it a solo actor? Maybe. The team did demonstrate that Izumo1 alone can induce fusion with cells expressing Juno. Nice. They found that mutant Izumo1, where the binding domain is impaired, can still fuse; and vice versa. “Finally we found the first gamete fusogen [in vertebrates],” Podbilewicz says. “We are not saying there are no others. We are looking at other candidates – for instance, in the egg. We think there could be more proteins that play a role in fusion.”

In fact, the discovery of the dual role played by Izumo1 was a complete surprise, Podbilewicz reveals. They were on a molecular quest to find the mammalian fusogen and were actually thinking of Izumo1, which had shown a role in binding, in terms of a negative control (i.e., use and it won’t fuse).

Yet there we are: fusion ensued. Of human and hamster kidney cells in culture, and mouse sperm to kidney cells. (Experiments on human sex cells are frowned upon.) The union of the cells was attested by multiple methods, including time-lapse imaging by Kohdai Nakajima.

Kidney cells expressing Izumo1 and a fluorescent protein on the nucleus (magenta) are bound to a mouse oocyte expressing a fluorescent protein on the membrane (green) and a blue staining to see the DNA.Credit: Technion spokesperson's office

How technically can Izumo1 play a dual role? Proteins are generally mega-molecules, aka huge things, and may have more than one “active domain” that does stuff, like binding to the active domain of some other protein. Indeed, Izumo1 turns out to have one domain that handles binding and another that handles fusing, the scientists report. Theoretically, infertility problems could arise in either domain. Or both. Or from mutation in the Juno protein to which Izumo1 locks.

An unfortunate rejection

Finding the first vertebrate sex-cell fusogen is quite the coup for basic research. It could have practical applications too: potentially better, smarter contraception methods – and, on the flip side, personalized infertility treatments, explains “Nico” Brukman.

Research into the protein is young but researchers have lines of evidence suggesting Izumo1 is relevant to human fertility, he says. For instance, it has been reported that some infertile men have lower levels of Izumo1. In other words, it isn’t that their Izumo1 gene mutated; it’s that its expression – gene into protein – is diminished. Though there could be, in addition, mutations that haven’t been identified yet, Brukman adds.

Podbilewicz adds a caveat that doctors at present are not looking for Izumo1 impairment in their frustrated male patients. But meanwhile, Brukman adds, immune-infertile women with antibodies against Izumo1 have been identified. When sperm arrive, their Izumo1 binding and/or fusion domains are blocked by the antibodies; they are technically rejected, and so they can’t merge with the egg.

Any information about Izumo1 is precious in this age of rapidly declining sperm quantity and quality, according to separate research. First identified in the West (and pooh-poohed by some scholars), some research suggests that sperm counts have declined by more than 50 percent in less than half a century – a spectacular rate of decline if true.

Asked if there is any indication that the global woes behind this infertility plague (whatever the causes are – pollution for sure, among other things) is affecting or could affect Izumo1 production (expression of the gene), Brukman says it’s early days and we have no idea about this yet.

Yet hypothetically, this knowledge can be harnessed: if a given infertile male is shown to have Izumo1 impairment, the doctor can refer him straight to assisted reproduction via injection of sperm right into the egg, bypassing the entire bind+fuse mechanism (and also bypassing trials of other methods that wouldn’t work in this case). This knowledge could help create more effective personalized infertility medicine, Brukman sums up.

The research group from the Technion in Haifa (from left): Katerina Flyak, Xiaohui Li, Dr. Nicolas Brukman, Clari Valansi and Prof. Benjamin Podbilewicz.Credit: Technion spokesperson's office

When it comes to birth control possibilities, the theoretical options abound. “One possibility is to find ways to inhibit Izumo1’s fusogenic ability,” Brukman says. “We can try to design drugs to block one function, the other or both [binding & fusing].”

There are any number of ways to deliver a drug, he adds. Podbilewicz points out the charms of ointments. Remember the target molecule, Izumo1, is on their external membrane. Thus, the drug could be applied to either participant in the sex act, in the appropriate area, and ruin the sperm’s day as they emerge.

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