Monkey Business

By MICHAEL D. LEMONICK

At the end of an inconspicuous two-lane road near the city of Beaverton, Ore., a cluster of modest concrete-and-glass buildings nestles amid ponds, fields and magnificent groves of evergreens--an oasis of natural beauty standing firm against the encroaching suburbs. Only a pair of football-field-size enclosures surrounded by 9-ft.-high sheet-metal walls and monitored from a watchtower give the hint that this is something more than just an unusually idyllic office park. The huge pens suggest a dinosaur paddock from Jurassic Park--an image reinforced when whatever is inside inexplicably starts slamming violently against the metal walls.

But while the creatures housed at the Oregon Regional Primate Research Center are nothing more exotic than monkeys, one experiment performed here and reported in last week's Science had something in common with the Spielberg thriller: an animal, produced by genetic manipulation, like nothing else on Earth. Despite its utterly normal outward appearance, the Rhesus monkey known as ANDi bears an extra gene taken from, of all creatures, a jellyfish. And while so-called transgenic animals have been created before, this is the first time such a species-mixing experiment has been performed on a primate, the class of animals that includes human beings--a point driven eerily home by the monkey's uncannily humanlike hands, expressive features and big round eyes.

It's ANDi's close kinship to humans that makes this experiment at once so promising and so troubling. On one hand, the ability to manipulate the genes of a creature so similar to humans could give researchers an incredibly powerful tool for studying and perhaps someday curing human illnesses--introducing Alzheimer's genes, for example, to test new drugs and vaccines against the disease. For that reason, says Richard Weleber, a professor of ophthalmology at Oregon Health Sciences University who believes the research could help cure the form of blindness known as macular degeneration, "this is a revolutionary achievement."

But the experiment also raises disturbing questions not only about animal rights but also about how far genetic manipulation can be permitted to go. If ANDi's genome has indeed been altered, he'll pass the change on to his offspring, creating an entire line of transgenic descendants. And while this so-called germline gene engineering is routinely done in lower creatures, moving it up to primates brings the technique much closer to being done in humans--a step so troubling that nobody is ready to take it. Says Tom Murray, president of the Hastings Center for Bioethics in Garrison, N.Y.: "You could not morally justify attempting anything like this in humans for a very long time."

Doing it in monkeys, however, could save lives. For more than a decade, researchers have been working with so-called knock-out and knock-in mice--rodents that have had genes added or effectively subtracted from their genome. By observing these custom-made lab animals, researchers have gleaned invaluable information about the workings of hundreds of illnesses, including arteriosclerosis, sickle-cell anemia and nearly every variety of cancer that afflicts people.

But mice are different from people; they aren't perfect laboratory stand-ins. They don't age precisely the way people do, for example. They don't have monthly menstrual cycles, and their neurological and immune systems differ in important ways. Much better to have a more closely related animal with body systems that are more like ours--which is why primate center senior scientist Gerald Schatten and his colleagues decided to try manipulating the genes of the Rhesus monkey, a close cousin to humans and already the mainstay of many medical experiments.

Before they could try transferring a gene, the scientists had to master the technique of in vitro (that is, test-tube) fertilization, which isn't typically used with monkeys. Though the technique wasn't required to create ANDi, the Oregon team had already learned to clone the animals, which in the future will prove important since having identical copies of different monkey strains will be crucial for rigorous scientific experiments. That milestone--the first cloning of a primate by embryo splitting--was achieved by Schatten's group last year.

Finally, Schatten and his team were ready to try a DNA transfer (see diagram). This first effort was meant only to test the technique, so they decided to use a gene that occurs naturally in jellyfish, where it directs the production of a harmless protein that glows with a greenish light under the right illumination. Mice, rabbits and other creatures who have had the same gene inserted actually do shine dimly; while ANDi (his name is a backward acronym for "inserted DNA") does not, the scientists have detected traces of the gene in his muscle, hair, cheek and blood cells. The researchers suspect that the gene may not be expressing its protein--or at least not at detectable levels--and may turn on fully only as ANDi ages.

Even if the new gene has indeed made it into ANDi's reproductive cells--which can't be known until he reaches sexual maturity in four or five years--there are plenty of hurdles to creating useful research monkeys. Scientists still must learn to substitute a malfunctioning gene for the animal's healthy version, then hope the gene expresses its protein at the right time, in the right place and in the right amount to mimic human disease. For diseases involving the misbehavior of several genes, the difficulties will only be compounded. "These techniques are really in their infancy compared to what we can do with the mouse," says Schatten.

For animal-rights activists, the leap from mouse to monkey will be a red flag. More broadly troubling, ANDi's success also raises the specter of human-germline gene engineering--that is, altering people's basic DNA so that any changes are passed on to their offspring. This sort of genetic tinkering, which could ultimately lead to "designer babies," artificially enhanced to be healthier, smarter or even more attractive, is currently far beyond our expertise. Nobody is likely to try to play God with humans in this way for decades.

In part that's because, as ANDi's case proves, it's very difficult and expensive to do, and because the unexpected side effects of gene transfers will be hard to predict. Indeed, even conventional gene therapy, which doesn't change the basic germline, has become controversial since the death of Jesse Gelsinger in a gene-therapy trial at the University of Pennsylvania last year. Besides, scientists have much simpler ways to stave off at least some genetic diseases. Parents whose embryos have the gene for Tay-Sachs disease, for example, can test for that defect and never bring the embryo to term.

But the ability to replace faulty genes directly--or even add enhanced genes--and then have those changes passed on to one's descendants will eventually come. When it does, say ethicists, we'd better have policies in place to deal with it. Germline gene manipulation shouldn't necessarily be banned, says Jeffrey Kahn, director of the Center for Bioethics at the University of Minnesota. But, he adds, "I think it's important to have this discussion now, when we have time to think about the implications."

--Reported by David Bjerklie/New York, Dan Cray/Beaverton and Dick Thompson/Washington

With reporting by David Bjerklie/New York, Dan Cray/Beaverton and Dick Thompson/Washington