Efforts to make a fluorescent green monkey are not quite a glowing success--yet.
In an attempt to create the first transgenic primate, scientists at the Oregon Regional Primate Research Center in Beaverton have produced a rhesus monkey that carries the gene coding for green fluorescent protein (GFP). This gene, first isolated from glowing jellyfish, has been inserted into a host of experimental species, including plants, frogs, and mice. Although he is not green, the 3-month-old monkey named ANDi, described on page 309 of this issue, is something of a proof of principle. The achievement could lead to valuable experimental models for certain diseases and a better understanding of primate and human development, say other biologists. But the cumbersome technique is not likely to lead to transgenic humans, green or otherwise.
To produce ANDi, reproductive biologists Anthony Chan, Gerald Schatten, and colleagues injected a genetically modified virus into the unfertilized eggs of rhesus monkeys. A few hours later, they injected sperm into the oocytes to fertilize them. As with other in vitro fertilization (IVF) procedures in nonhuman primates, this one was relatively inefficient. Half of the fertilized eggs developed into embryos, and five pregnancies resulted from 20 embryo transfers, including one set of twins, which were miscarried.
Three healthy monkeys were born, but the team has detected the GFP gene only in ANDi. The miscarried twins also carried the GFP gene, but unlike ANDi, their hair follicles and toenails did glow under fluorescent light. Schatten attributes the miscarriage to the fact that rhesus twins are rare, but the team is investigating whether it might be related to the inserted gene. So far, the team doesn't know whether ANDi's cells are expressing the protein. But Schatten says other transgenic animals have delayed producing their transgene for up to a year after birth.
Although the gene transfer techniques the researchers used are routine in other organisms, reproductive biologist Ted Golos of the Wisconsin Regional Primate Research Center in Madison says the birth of ANDi is the first demonstration that a primate egg can develop normally after such manipulations.
"We've made an incremental step from one species to another," Schatten says. And even that small step involved multiple hurdles. Whereas the experiment "is essentially several days' work in transgenic mice," Golos notes, monkey eggs are difficult to collect, and primatologists do not know how to artificially control a monkey's reproductive cycle. That meant the researchers had to time the experiment precisely so that an embryo was ready when a surrogate mother was at the right stage of her reproductive cycle. In fact, ethics considerations aside, the project might have been easier to achieve in humans, for whom IVF technology is much more advanced.
Even so, the work will not inspire fertility doctors to try the technique with human embryos anytime soon, Schatten predicts. Scientists can't control where the modified virus enters the genome, so the risk of an inserted gene interrupting an important gene would be relatively high. "I don't see an immediate therapeutic application," says bioethicist LeRoy Walters of the Kennedy Institute of Ethics at Georgetown University.
And until researchers find more efficient ways to create specific genetic changes, says Schatten, transgenic monkeys will not be common research tools. Even if those techniques were feasible, expense and ethical considerations would limit the use of transgenic monkeys as medical models, he says: "We don't need a knockout monkey for every disease."
But for questions that are difficult to study in rodents, such as those related to aging, neurodegenerative diseases, immunology, and behavior, transgenic primates could prove a plus, Golos says. Schatten predicts that genetically altered monkeys could be a boon to developmental biologists as well. Because monkeys are large enough to fit into magnetic resonance imaging machines, researchers might be able to introduce gene markers and track organ development by noninvasive means. "ANDi and his future cousins and brothers and sisters will help us bridge that gap between what we know in the mouse and what we're keenly interested in in human development," he says.
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