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First Gene-Altered Monkey Created

By Rick Weiss
Washington Post Staff Writer
Thursday, January 11, 2001

Scientists have created the world's first genetically modified monkey, an
advance that suggests the possibility of making customized primates for
medical research and brings the art of genetic manipulation closer than
ever to humans.

Researchers said they hoped the technique would help them produce monkeys
with Alzheimer's disease, breast cancer, hereditary blindness and other
ailments against which new therapies or vaccines could be tested.

"There are fantastic discoveries now being made from studies of human
diseases in mice," said Gerald 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 the
egg or early embryo of another species so the foreign DNA ends up in many
or all of the developing animals' cells.

Although the approach has proven very useful for genetic research, it has
also stirred fears that similar techniques might someday be used to add
desirable traits to human embryos, heralding a new era of "designer babies."

Already, many 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 actually 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, born in Oregon last October and described in
Friday's issue of the journal Science, is endowed with jellyfish genes. The
jellyfish DNA 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 sport 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 in the monkey,
experts said, and suggests that the technique is still not refined enough
to make truly useful gene-altered monkeys -- much less genetically enhanced
babies.

Indeed, several scientists doubted the method would ever work well, saying
newer techniques already under development offered 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 slippery slope, said that even
if the method could be made to work in monkeys they'd 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 opposed 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 cell's 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.

The method is not very efficient. 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 -- named ANDi, a backward
abbreviation for "inserted DNA" -- contained any jellyfish genes.

Several scientists questioned whether key hurdles could be overcome with
the Oregon 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 the 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 so-called 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 today 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, for example, 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 their 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, although it's another step in that direction," said
David Baltimore, president of the California Institute of Technology.

© 2001 The Washington Post