Scientists have created the first genetically modified monkey, an advance that could lead to customized primates for medical research and that brings the possibility of genetic manipulation closer than ever to humans.
The researchers made the monkey by splicing jellyfish genes into eggs of rhesus monkeys just to see if their techniques would work. In the future, they hope to produce animals with genes that cause Alzheimer's disease, breast cancer, hereditary blindness and other ailments so they can test new therapies and vaccines.
"There are fantastic discoveries now being made from studies of human diseases in mice," said Gerald P. Schatten, who with Anthony W.S. Chan led the research at the Oregon Regional Primate Research Center in Beaverton. "We're optimistic that genetically modified primates can translate some of those discoveries in mice safely and swiftly to people."
Scientists have made gene-altered fruit flies, rabbits, sheep, goats, cattle, pigs and other animals since the first such animal, a mouse, was created in 1976. The work involves adding genes from one species into eggs or early embryos of another species so the foreign DNA ends up in many or all of the developing animals' cells.
The creation of the monkey -- named ANDi, a backward acronym for "inserted DNA" -- marks the first time anyone has genetically altered a primate, the grouping of animals that includes monkeys, apes and humans. The method did not work perfectly; the genes can be found throughout the monkey but mostly are not working. Nonetheless, the work gives some credence to long-standing fears that scientists may one day use similar techniques to add desirable traits to human embryos, heralding an era of "designer babies."
Already, some fertility clinics offer tests that allow parents to choose embryos free of unwanted traits (such as disease genes) or carrying desirable traits (such as a tissue type that will make the newborn a useful organ donor for a sibling). But although some coveted human genes have been discovered -- such as the gene for human growth hormone, which could help a child grow to otherwise unachievable height -- no one has inserted such a gene into a human embryo. That's because of ethical concerns, and because there has not been a monkey model on which to practice.
The gene-altered monkey, described in today's issue of the journal Science, was born in Oregon in October. The jellyfish DNA in its genes has no medical value but is a popular tool with genetic engineers because it makes animals glow green when they're exposed to blue light, offering quick and dramatic evidence that a gene-transfer method works.
A stillborn monkey in the Oregon experiment did have fluorescent green fingernails and hair. But its live-born counterpart does not glow, even though tests show the jellyfish genes are present throughout its body. That means the foreign genes are functioning poorly or not at all, experts said, and suggests that the technique is not refined enough to make truly useful gene-altered monkeys -- much less genetically enhanced humans.
Indeed, several scientists doubt the method will ever work well, saying that newer techniques under development offer more promise for making genetically altered monkeys.
Some critics, opposed to genetic modification of humankind's close cousins and concerned about a slide down an ethical slope, said that even if the method could be made to work in monkeys, they would oppose its use.
"Before, it was mice. Now, monkeys -- both cloned and gene-altered," said Eric Kleiman, research director of Defense of Animals, an international animal advocacy group based in Mill Valley, Calif. "It's pretty clear who is next. And it will be just as reprehensible when people are manufactured to suit experimenters."
Schatten said he opposes any human applications. "We certainly don't support any extrapolation or extension of this kind of work to human beings," he said.
To engineer the monkey, Schatten's team stuffed copies of a foreign gene, in this case the gene for jellyfish green fluorescent protein (GFP), into specialized viruses called retroviruses. Then they injected those viruses into hundreds of unfertilized monkey eggs. There the viruses did what they do naturally: They inserted their genes, including the GFP gene, into the egg cells' DNA. The researchers fertilized the gene-altered eggs with monkey sperm, then transferred some of the resulting embryos into the wombs of surrogate mother monkeys.
Of 222 gene-altered eggs to which sperm were added, 126 grew into embryos in laboratory dishes. Of 40 embryos that were transferred to 20 surrogate mothers (two embryos per mother), just five pregnancies resulted -- one of them twins. Of those six fetuses, three were born live. And only one of those, ANDi, contained any jellyfish genes.
Several scientists questioned whether key hurdles could be overcome with the method. Retroviruses are notorious for inserting their genes in unpredictable locations, often disrupting useful genes or landing in places where the new genes won't work, said John Gearhart of Johns Hopkins University. Moreover, he said, Schatten has not shown that the jellyfish gene is present in ANDi's sperm cells -- a prerequisite if the new trait is to be passed on to offspring.
Even if the genes are in ANDi's sperm (which can't be known for sure until four years from now, when he becomes sexually mature), those genes would probably be dormant in the next generation, said Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Mass., who made the first "transgenic" mouse. That's because new genes inserted by retroviruses almost always shut down in an animal's offspring -- yet another reason why creators of transgenic animals do not like to use retroviruses.
"That problem has not even been resolved in the mouse after more than 20 years of work, so I'm not very optimistic that it is going to be resolved in the monkey," said Jaenisch, who sees stem cells and cloning as far more promising tools for making useful transgenic animals.
Another problem is that many disease genes, such as those for muscular dystrophy and common hemophilia, are too big to fit inside a retrovirus. "The whole transgenic field has moved away from retroviruses because the packaging size is very limited," said David Ayares, vice president for research at PPL Therapeutics in Blacksburg, Va., which is producing cloned, gene-altered pigs for possible use as organ donors for people.
Schatten acknowledged that the work's ultimate value remains uncertain given the technical drawbacks, the high cost of working with monkeys and the ethical issues raised by genetic engineering.
"This is proof of principle," he said. "The jury is still out as to how or even if nonhuman primates should contribute to the discovery of molecular medical cures."
One thing everyone seemed to agree on is that it's too soon to think about adding genes to human embryos.
"I don't see this in its present state as being anything we'd ever want to do with human beings," said David Baltimore, president of the California Institute of Technology, "although it's another step in that direction."