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Efforts to Clone Monkeys Illustrate the Potential Hazards for Humans

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    Efforts to Clone Monkeys Illustrate the Potential Hazards for Humans
    Process proves to be health risk for both fetuses and mothers 
    Rick Weiss, Washington Post 
    Saturday, May 15, 1999 
    1999 San Francisco Chronicle 


    Tanja Dominko focuses her microscope on a glistening egg recently
retrieved from a female rhesus monkey's
    ripened ovary. 

    Nudging a high-tech joystick, she directs a hair-thin glass needle
toward the silvery orb -- touching, dimpling and
    then gently piercing its outer coat. 

    ``We're in,'' says Dominko, as she injects a tiny payload of monkey DNA
to replace the egg's own genes, already
    removed. She backs the needle out of the egg, leaving the new genes in
their yolky home to direct the growth of a
    monkey that will be biologically identical to the one that donated the

    Dominko is part of a team at the Oregon Regional Primate Research
Center -- the only facility in the United
    States, and perhaps the world, trying to clone a monkey. If the
researchers succeed, they will have produced the
    first genetic replicas of these close human relatives for medical

    But if this effort goes as others have, this newly formed cell will
become two cells, then four, then perhaps eight,
    and then die. 

    Cloning, it turns out, is a serious health risk -- usually resulting in
death for the clones themselves and sometimes
    even killing mothers pregnant with those clones. Moreover, as cloners
expand their efforts to a growing variety of
    animals, including cows, goats, sheep and mice, it's becoming clear
that the problem is not simply one of
    beginner's bad luck. 

    ``There are a hell of a lot of fetal and neonatal deaths along the
way,'' said Gerald Schatten, who heads the lab
    that Dominko works in. ``There are placental abnormalities, abnormal
swelling, three to four times the normal
    rate of umbilical cord problems, severe immunological deficiencies.'' 

    The problems offer a sobering perspective on how much remains unknown
about how to make animals from a
    single parent. And they are forcing scientists to focus on one of the
deepest questions in reproductive biology:
    Why is it that most animals need DNA from both a male and a female to
create viable offspring? 

    At Beaverton, no cloned embryos have survived long enough to even count
as a pregnancy. (Two ``cloned''
    monkeys, Netty and Ditto, born here in 1997, were actually made by
splitting two embryos in half and are not
    genetically identical to each other.) 

    In other large mammals such as sheep and cows, researchers are finding
that about half of all clones that develop
    into fetuses harbor serious abnormalities, including peculiar defects
in the heart, lungs and other organs -- many
    of them fatal before birth. Others have succumbed weeks or months after
birth, dying suddenly and mysteriously
    after a seemingly healthy start. 

    The cause of these abnormalities and deaths remains a mystery, but
there is growing evidence that at least some
    are linked to a disruption of a genetic mechanism known as
``imprinting,'' which is nature's way of ensuring that
    every baby has two parents. 

    Imprinting was discovered about a decade ago but still is only vaguely
understood. It works on the molecular
    level inside sperm and eggs, labeling certain genes with genetic
``tags'' that say, in essence, ``this gene's from
    mom,'' or ``this gene's from dad.'' The tags function as tiny molecular
switches, deciding whether mom's genes or
    dad's genes will be active in various parts of a developing embryo. 

    In one recent study of 13 calves cloned by James Robl and colleagues at
the University of Massachusetts at
    Amherst, four fetuses aborted in the last trimester, one died at birth
and two died soon after. In most of those
    animals, the lungs and other organs were grossly abnormal, including
some whose hearts were enlarged and had
    very thin walls. 

    The placentas were oversized and filled with excess fluid. They
resembled the placentas Robl found in a
    previous batch of cloned calves, some of which had as much as 50
gallons of excess fluid stored within them. 

    An imprinted gene involved in placenta development could be at the
center of all those problems, said Jonathan
    Hill, a researcher at Texas A&M University who studied the calves. 

    ``It's very much at the hypothesis stage,'' Hill said. But if an
imprinting problem caused the placenta to develop
    badly, as imprinting imbalances are known to do, that could in turn
cause severe blood pressure problems in the
    developing fetus, he said. Abnormal blood pressure is a known cause of
enlarged, thin- walled hearts and other
    abnormalities seen in the calves. 

    Like Hill, many scientists are coming to believe that imprinting will
be a major hurdle to overcome if cloning is
    to become commercially practical. But imprinting problems probably do
not account for all the problems in
    cloning. Autopsies on three of Robl's cows that succumbed mysteriously
while pregnant with clones revealed
    livers that were filled with fat, suggesting some kind of metabolic
abnormality was induced by the clones they
    were carrying. 

    In another study of cloned animals, reported in last week's issue of
the medical journal The Lancet, researchers in
    France describe a cloned calf that was apparently healthy at birth but
then suffered a sudden decline in immune
    system cells after its seventh week of life. Within a few days, the
calf was dead. 

    An autopsy found that the animal had an underdeveloped thymus gland,
which helps the immune system mature. 

    Some of the abnormalities seen in clones have also been seen in
noncloned animals that were created by standard
    in vitro fertilization techniques. That suggests to some researchers
that at least some problems in clones might be
    caused by damage to embryos in the laboratory, and not by cloning
itself. Some suspect, for instance, that the
    nutrients they feed to the embryos in the lab might lack a key
ingredient, or that the electrical shock that starts a
    cloned embryo dividing can cause genetic damage. 

    Whatever is causing the problems, cloners say, there is hope that the
difficulties can be overcome. After all,
    several cloned animals 

    --including Dolly the sheep -- appear perfectly normal. That suggests
that, if imprinting is the problem, at least
    some adult cells bear the right combination of mom and pop imprints to
support normal embryo growth. Perhaps
    Dolly and other healthy clones were grown from cells that happened to
have that right pattern. If so, perhaps
    scientists can learn how to identify those clonable cells. 

    If nutritional deficiencies or electrical damage turn out to be the
culprit, better laboratory techniques might help. 

    Answers might be years away. Meanwhile, Schatten, Dominko and their
colleagues push ahead, trying this and
    that. Their goal, they emphasize, is not to learn how to clone humans,
but to produce an invaluable tool for testing
    AIDS vaccines and new drugs and studying human illnesses. 

    1999 San Francisco Chronicle  Page A5