The End of Males? Mouse Made to Reproduce Without Sperm

Bijal P. Trivedi
for National Geographic News
April 21, 2004
Dads, in the mammalian branch of the animal kingdom, are often out of the loop when it comes to producing progeny. After that initial contribution of sperm, they are excluded from pregnancy and are all but superfluous even after birth, when nurturing falls to Mom. Now Japanese scientists have streamlined reproduction even further—they have eliminated fathers entirely.

Scientists led by Tomohiro Kono, a biologist at the Tokyo University of Agriculture, have created baby mice without the introduction of sperm. They combined the genetic contents of two mouse eggs—one of which had been genetically altered—to produce a live mouse that reached adulthood and reproduced.

The results are published in the April 22 issue of the journal Nature and could have profound implications for disease and the role of males in reproduction.

Amphibians, fish, and insects are able to reproduce from eggs alone—a process called parthenogenesis. But under normal circumstances mammals, including humans and mice, cannot. They need genetic contributions from mom and dad.

"The goal of our study was to discover why sperm and eggs were required for development in mammals," Kono said.

Imprinting Eggs and Sperm

During normal sexual reproduction, mammals inherit two copies of each gene—one set from mom, the other from dad. It was thought that both components were essential, because a subset of genes, described as "imprinted" genes, behave differently depending on whether they were delivered via sperm or egg. Both are needed to produce healthy offspring.

The Japanese team believed that they could use two eggs to create a viable mouse embryo. The challenge was to get the imprinted genes in one of the eggs to behave as if the genes had come from a sperm.

"Imprints" are chemical additions to the DNA—they don't alter genetic code but block various genes from turning off or on. The critical point is that only one copy of an imprinted gene should be active—if the mother's copy is on, the father's copy is off, or vice versa.

To get genes in one of the two eggs to "act like genes in a sperm," Kono's team had to find a way to switch off the maternal imprints.

Tricking the Embryo

The scientists couldn't use eggs from adult mice since adult eggs are already imprinted. If two such eggs were combined the product would be an embryo with a poorly developed placenta. The embryo would die during early development.

The immature eggs from newborn mice, however, have not yet been given a maternal stamp.

In previously published studies, the Japanese researchers combined a mature egg from an adult with an immature egg from a newborn. They discovered that the embryo lived longer than any previous mouse embryo created without sperm—more than halfway through gestation.

But why could the embryo not make it all the way?

Kono's team speculated that imprinted genes were somehow killing the mice embryos prematurely. The team focused on two such genes. One, called IGF2, is an essential gene for the growth and development of the fetus and is only turned on in the sperm. The other, called H19, turns off the IGF2 gene in eggs.

The scientists kept the mice alive by genetically altering the immature egg. They removed the "off switch" (H19), allowing the IGF2 gene to turn on, just as it would have if it had come from the sperm.

"Combining the mature egg with the immature egg, which had been genetically tweaked to produce IGF2, tricked the embryo into believing it had received genes from both a mother and father," said Marisa Bartolomei, a geneticist specializing in imprinted genes at the University of Pennsylvania in Philadelphia.

Risky Business

Kono and his team believe that just turning on the IGF2 gene may have caused a ripple effect—effectively restoring all the other paternal imprints in the immature egg. This enabled the embryo to complete development and eventually reproduce.

"What is most exciting and unexpected is that turning on a single gene was able to trigger changes in the immature egg that gave all the genetic material a paternal imprint," said Patrick Lam, an embryologist at the University of Sydney in Wentworthville, Australia. Lam co-authored a commentary on Kono's report.

But producing a healthy mouse by this approach was difficult.

Kono and his team produced 457 reconstructed eggs—each containing genetic material from a mature egg and an immature IGF2-producing egg. These hybrid eggs were then grown until each formed a ball of cells, called a blastocyst. Three hundred and seventy-one blastocysts survived, and these were used to impregnate surrogate females.

A total of ten live pups survived gestation. Of these, only two survived outside the womb. One, named Kaguya, lived to adulthood, mated with a male, and produced a litter of pups in the normal way.

This is a technically extraordinary piece of work, Bartolomei said. "It has really pushed the field forward."

No Need for Men?

Could Kono's results be used to render men obsolete?

"Imprinting is pretty complicated," said Randy Jirtle, a geneticist specializing in imprinting at Duke University in Durham, North Carolina. Genes can be imprinted in some tissues but not others. It can also vary from species to species.

There are about 80 to 90 known imprinted genes in mice. Those involved in cognitive processes or nurturing behavior may not have been properly imprinted in Kaguya. These effects may not be obvious just from studying this one mouse.

"There is no doubt that this result is amazing," Jirtle added. "But just because this mouse is walking around on the Earth does not mean that the animal is normal."

What's more, there is no guarantee that what worked in mice will work in humans.

Producing a mouse from two eggs is a very risky and very inefficient procedure—only two embryos survived of 371 that were implanted in surrogate mothers.

"The success rate is less than 1 percent—who knows what went wrong with the other 99 percent," Lam said. "Like cloning, it would be completely unethical to try such experiments in humans."

Until the role of imprinted genes—many of which have been implicated in disease—is better understood, it is safe to say that Dad is still an essential part of reproduction.

For more animal reproduction news, scroll down.

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