Test Monkeys' Offspring Pick Up Genetic Modification

By Rob Stein
Washington Post Staff Writer
Thursday, May 28, 2009; A01

Scientists have created the first genetically modified monkeys that can pass their new genetic attributes to their offspring, an advance designed to give researchers new tools for studying human disease but one that raises many thorny ethical questions.

In this case, Japanese researchers added genes that caused the animals to glow green under an ultraviolet light -- and beget offspring with the same spooky trait -- to test a technique they hope to use to produce animals with Parkinson's, Huntington's and other diseases.

The work, described in today's issue of the journal Nature, was hailed by some medical researchers as a long-sought milestone that could lead to crucial insights into many ailments and provide invaluable ways to test new treatments.

But because the work marks the first time members of a species so closely related to humans have had their genetic makeup permanently altered, the research set off alarms that it marked a troubling step toward applying such techniques to people, which would violate a long-standing taboo.

"It would be easy enough for someone to make the leap to trying this on humans," said Lori B. Andrews, who studies reproductive technologies at the Illinois Institute of Technology's Chicago-Kent College of Law. "If you make this kind of change, it's passed on to all future generations. Many people think it's hubris to have people remaking people in this way."

The approach could tempt some to use the technique to try to engineer desirable traits in people, creating a society of genetic haves and have-nots, Andrews said. Others worried that the work could have additional disturbing implications, such as potentially blurring the line between species.

"It's hard to put your finger on what is it about this research that is likely to stimulate ethical debate besides the sort of gut feeling that this is not the right thing to do," said Mark A. Rothstein, a bioethicist at the University of Louisville. "But I think we'd better contemplate where this research is going and develop policies to deal with it before it slaps us in the face."

Scientists have genetically engineered many other species to be research tools. Mice in particular have been created with a wide assortment of characteristics and diseases that mimic human ailments. But because mice are so genetically different from humans, scientists have long sought to breed primates to provide better disease "models." Although scientists have been able to genetically modify individual monkeys, they had never been able to make the new traits hereditary -- a crucial step for breeding large enough numbers of research animals.

In humans, researchers have tried to correct genetic defects in individual patients, but there has always been a strict prohibition against making changes that would be passed on.

In the new work, Erika Sasaki of the Central Institute for Experimental Animals in Kawasaki and her colleagues conducted experiments using marmosets, small monkeys common in South America that mature and reproduce quickly.

The researchers modified a virus called a lentivirus to carry a jellyfish gene known as GFP (green fluorescent protein) into the genetic material of the marmosets' cells. The gene is widely used in research because it is easy to track -- cells in which the gene is active glow green when exposed to ultraviolet light.

The researchers used the genetically engineered virus to insert the jellyfish gene into 80 marmoset embryos, which they then transferred into the wombs of 50 females. Seven pregnancies resulted in five offspring, four of which showed signs of the jellyfish gene in their hair roots, skin, blood cells and other tissues. Under ultraviolet light, the skin on the soles of their feet glowed green.

Most important, eggs from one of the females and sperm from one of the males had the gene, and the researchers reported that the male's sperm was used to produce at least one second-generation offspring with the gene -- a male named Kouichi whose skin glowed green under the light.

In a telephone briefing for reporters yesterday, the researchers said they had produced four offspring -- two from the male and two from the female. Three of the offspring glowed green.

"We believe this is the first case that is ever established in the world that has an introduced gene that is successfully translated to the next generation in a primate," said Hideyuki Okano of Keio University School of Medicine.

Several researchers deemed the research landmark work.

"I think it's a pretty big advancement," said Shoukhrat Mitalipov of the Oregon Health and Science University, who co-authored an article published with the Japanese paper. "Primates are the only species you can faithfully use to make models of some very important human diseases involving higher brain function and neurological functions."

But others criticized the work. Animal rights advocates said it paves the way for producing colonies of primates conceived expressly to suffer cruel illnesses and undergo potentially painful and dangerous medical experiments.

"Instead of manipulating the genes of marmosets or other non-human primates, why aren't scientists harnessing the power of the human genome or any of the other technology that has exploded over the last 10 years?" said Eric Kleiman of In Defense of Animals, an international animal protection organization based in San Rafael, Calif. "This is a step backward, not a step forward."

Even some who do not necessarily oppose the use of animals in research said the work raised other concerns.

"At some point, how many human genes in a marmoset or rhesus monkey or macaque or whatever does it take to form a new species -- a species that is part human at its basis?" bioethicist Rothstein said.

And although there has long been a taboo against making genetic changes in people that could be hereditary, the new work makes that prospect more likely, others said.

"This is proof of concept in a closely related species," Andrews said.

"Some in the future might want to put a gene into humans to give them the running speed of a cheetah, for example, or maybe create the potential for night vision." Andrews noted that reproductive technologies are largely unregulated in the United States.

"This is just another reason why we need to go behind the doors of the [fertility] clinics and create an oversight mechanism that works," Andrews said.

Other researchers dismissed such concerns, saying marmosets were much more distantly related to people than other primates, such as chimpanzees. And although several researchers agreed that animal research should be limited, they said it is impossible to get answers to many key questions any other way. Creating better animal models could reduce the number of animals needed for research, they said.

"In the end, if we have good models, we may end up using less animals and we may end up having better answers," said Anthony Chan, a geneticist at Emory University who helped to create a rhesus monkey with Huntington's disease.

But Chan agreed that steps should be taken to make sure the technology is not used on people.

"We should never do it in humans," Chan said. "We don't want to change our evolutionary path. That would have a profound impact on the next generation."

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