Biomedicine

Green Genes

The first transgenic primates able to pass on their foreign genes are both a stunning medical advance and a troubling peek into the future.

This spring, news of a biological breakthrough arrived in the form of baby marmosets whose feet glowed green under ultraviolet light. Researchers at the Central Institute for Experimental Animals in Kawasaki, Japan, had genetically engineered the monkeys to incorporate a gene, derived from jellyfish, that produces green fluorescent protein. It was the first time scientists had added a gene to a primate in such a way that a new trait could be passed to a second generation.

The feat heralds an exciting possibility: if the genes associated with some cases of human illnesses such as Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease were introduced into primates, colonies of the genetically altered animals could be used to test therapies for these disorders. This would probably be far more effective than studying the effects of the genes in, say, mice or rats, because primates’ brains are much closer to humans’ in terms of complex motor functions and cognition. “We’ve been waiting a long time for [disease] models like these,” says John Morrison, a professor of neuroscience at Mount Sinai School of Medicine in New York.

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For years, researchers have created animal models for the study of disease by transferring new genes into less advanced animals such as mice. In 2001, scientists at Oregon Health and Science University reported the first transgenic primate, a rhesus monkey that produced green fluorescent protein. But the Japanese researchers broke new ground. Erika Sasaki and her colleagues introduced the jellyfish gene into early-stage marmoset embryos. Then they transplanted the embryos into adult female monkeys, resulting in several pregnancies and a few offspring that carried the gene. Sperm and egg cells from monkeys with the gene were then used to produce additional offspring in vitro, some of which also carried the gene and produced the fluorescent protein.

Of course, creating a few transgenic marmosets is a long way from creating colonies available for testing disease-specific treatments. For one thing, Sasaki and her colleagues used a virus to introduce the new gene, which means that they could not control how many copies would be inserted into the monkeys’ genome or exactly where they would be incorporated. Researchers will probably need to develop a more precise, consistent way to introduce new genes, especially if they want to simulate diseases.

Besides, marmosets may not be an ideal research model. They were a good choice for the Japanese team because they reach sexual maturity relatively quickly, and females may produce 40 to 80 offspring in a lifetime. They’re also less expensive and more efficient to work with at the colony level than larger primates that reproduce less copiously. Still, they have yet to prove themselves as models for neurodegenerative diseases. That’s because their brains differ more from humans’ than the brains of Old World monkeys like rhesus macaques do. And less is known about their normal cognitive function, because it has not been studied as actively. So for studying disruptions of higher-order processes like memory, which can be central to neurodegenerative diseases such as Alzheimer’s, they may not be good enough.

Still, the possibility of transgenic primate models could revolutionize medical research. Such primates could offer a proving ground for new therapies that look promising in mice but seem too risky to try in humans. This is especially true for disorders that involve the brain and nervous system. Morrison says the lack of good primate models has been a “major obstacle” in developing and testing new treatments for several neurodegenerative diseases.

Huntington’s disease is a case in point. Current rodent models do not capture key aspects of the disorder, in part because of differences between their brains and those of humans. People with Huntington’s typically display abnormal movement, especially the writhing movements called chorea; they also tend to develop dementia or even psychosis. But rodents don’t have the types of neurons, the number of synapses, or the types of neural relay centers that are crucial to human motor control, so researchers can’t see exactly how potential treatments will affect these systems. A team led by Steve Goldman, a professor of neurology and neuro­surgery at the University of Rochester Medical Center, has developed a possible therapy that uses stem cells to regenerate a type of neuron lost in Huntington’s disease. It works in mice, he says. But it’s not something that’s going to be tested in humans until the researchers can try it out in primates first, because the relevant anatomy in mice is just too different.

Transgenic primates could also prove extremely helpful as disease models for ALS and Alzheimer’s. By using them instead of mice, Morrison predicts, “we’d get a much more faithful model of the degeneration you see in humans.” For instance, efforts to develop antibodies against amyloids–protein deposits that typically develop in the brains of Alzheimer’s patients–seemed promising in mice but failed in humans. “My guess is that if we’d had a really good primate intermediate, we would’ve been better informed,” he says.

To be sure, creating transgenic primates raises tricky ethical issues, especially if the new genes come from humans. The concern is that researchers might challenge the boundaries between humans and other species by inadvertently creating an animal with cognitive abilities such as rational thinking or moral reflection–a creature that would necessarily deserve a greater degree of respect than a typical lab animal, says Robert Streiffer, a bioethicist at the University of Wisconsin at Madison. The idea of experimenting on such an animal would probably strike both researchers and the public as unacceptable.

That situation seems like a distant possibility at the moment, Streiffer says. Still, monkeying with the germlines of primates does cross a new line and deserves careful scrutiny. For one thing, it could open the door to similar engineering in humans. Historically, ethicists have distinguished between introducing new genes into tissues like the liver or pancreas and altering egg cells, sperm cells, or embryos; the latter type of modification, which could be passed on to a recipient’s offspring, has not been performed in humans. Critics typically point to the more frivolous possibilities–say, parents who might wish to give future generations a gene for strength or height. Still, when it comes to some serious diseases like Huntington’s or certain mitochondrial disorders, germline genetic treatment could turn out to be the best or even the only option. “Are we willing to delay the possible discovery of treatments for terrible illnesses because we want to draw a line in the sand?” asks Mark Rothstein, a bioethicist at the University of Louisville. “I’m not willing to do that.”

It is worth keeping in mind that these disorders are devastating. And for the most part, they are currently untreatable. Given that reality, the promise represented by the baby marmosets should be given ample opportunity to grow up.

Amanda Schaffer is a science and medical columnist for Slate and a contributor to the New York Times.

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