- Four years after researchers in Scotland startled the
world by announcing they had cloned a sheep named Dolly, scientists say
evidence is mounting that creating healthy animals through cloning is more
difficult than they had expected.
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- The clones that have been produced, they say, often have
problems severe enough developmental delays, heart defects, lung problems
and malfunctioning immune systems to give pause to anyone thinking of cloning
a human being. In one example that seems like science fiction come true,
some cloned mice that appeared normal suddenly, as young adults, grew grotesquely
fat.
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- It is not that one particular thing goes wrong or one
specific aspect of development goes awry, researchers say. Rather, leading
cloning experts and developmental biologists said in recent interviews,
the cloning process seems to create random errors in the expression of
individual genes. Those errors can produce any number of unpredictable
problems, at any time in life.
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- Before Dolly's debut in 1997, scientists thought mammals
could not be cloned. But now they have cloned not only sheep but also mice,
cows, pigs and goats. With mice, they have even made clones of clones on
down for six generations. Dolly is apparently normal. And two infertility
specialists recently announced that they wanted to clone humans.
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- Initial fears raised about clones that they would age
rapidly or develop cancer turned out to be unfounded, scientists said.
But as scientists gained more experience, and tried to discern why efforts
so often ended in failure, new questions about its safety arose. Fewer
than 3 percent of all cloning efforts succeed.
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- In cloning, scientists slip a cell from an adult into
an egg with its genetic material removed. The egg then reprograms the adult
cell's genes so that they are ready to direct the development of an embryo,
then a fetus, then a newborn that is genetically identical to the adult
whose cell was used to start the process. No one knows how the egg reprograms
an adult cell's genes, but that, scientists think, is the source of the
cloning calamities that can occur. The problem, they say, seems to be that
an egg must do a task in minutes or hours that normally takes months or
years. In the months it takes sperm to mature, their genes are being reprogrammed.
The same thing happens in eggs, where over years they slowly mature in
the ovaries. And this reprogramming must be perfect, scientists say, or
individual genes can go amiss at any time in development or later life.
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- "With cloning, you are asking an egg to reprogram
in minutes or, at most, in hours," said Dr. Rudolph Jaenisch, a professor
of biology at the Whitehead Institute at the Massachusetts Institute of
Technology. "That's where the major problem is," he said.
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- All the evidence so far, scientists say, indicates that
the breathtakingly rapid reprogramming in cloning can introduce random
errors into the clone's DNA, subtly altering individual genes with consequences
that can halt embryo or fetal development, killing the clone. Or the gene
alterations may be fatal soon after birth or lead to major medical problems
later in life.
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- Some scientists say they shudder to think what might
happen if human beings are cloned with today's techniques. While arguments
over the ethics of human cloning have dominated the debate, these scientists
say the real issue is the likelihood that clones would have genetic abnormalities
that could be fatal or subtle but devastating. Until that problem is solved,
they say, human cloning should be out of the question.
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- "It would be morally indefensible," said Dr.
Brigid Hogan, a professor of cell biology at Vanderbilt University Medical
Center in Nashville and an investigator with the Howard Hughes Medical
Institute.
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- "It would be reckless and irresponsible," Dr.
Jaenisch said. "What do you do with humans who are born with half
a kidney or no immune system?" And, he said, what about the real possibility
of creating children who appear to be normal but whose genes for neurological
development work improperly?
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- Scientists say they see what appear to be genetic problems
almost every time they try to clone.
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- For example, some mouse clones grow fat, sometimes enormously
obese, even though they are given exactly the same amount of food as otherwise
identical mice that are not the products of cloning. The fat mice seem
fine until an age that would be the equivalent of 30 for a person, when
their weight starts to soar, said Dr. Ryuzo Yanagimachi, a University of
Hawaii researcher who first cloned these animals and has studied cloning's
consequences in them.
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- Cloned mice also tend to have developmental abnormalities,
taking longer to reach milestones like eye opening and ear twitching, Dr.
Yanagimachi has found.
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- Cow clones are often born with enlarged hearts or lungs
that do not develop properly, said Dr. Mark E. Westhusin, a cloning expert
at Texas A & M University in College Station, Tex. Dolly herself, while
apparently healthy, grew fat and had to be separated from the other sheep
and put on a diet. But her experience is difficult to interpret since it
is hard to draw conclusions about a propensity to obesity from one animal.
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- The genetic effects most often seem to be fatal at the
very start of life, researchers say. With cattle, for example, 100 attempts
to create a clone typically result in a single live calf, Dr. Westhusin
said.
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- Cloning mice is more efficient, Dr. Yanagimachi said.
But even then, only 2 percent to 3 percent of his attempts succeed.
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- "Cloned embryos have serious developmental and genetic
problems," Dr. Yanagimachi said, which usually kill them before birth.
Just after birth, he said, more die, usually of lung problems. He added
that inbred strains are much harder to clone than hybrid strains of mice,
which makes sense, he said. Inbred animals have much less genetic diversity
and so less opportunity to bypass genetic errors than hybrid animals.
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- Dr. Westhusin says that when he thinks about what happens
in cloning, "it's a wonder it works at all."
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- Scientists knew that every cell in the body has the same
genes so, in theory, all the instructions for making a new copy of an adult
are present in every cell. But most of the genes in an adult cell, like
a skin cell or a brain cell or a liver cell, are silenced. That is why
those cells, which have reached their final stage of development, never
change. A skin cell does not turn into a heart cell. A brain cell does
not turn into a liver cell. And no one expected an egg cell to be able
to reprogram such an adult cell, somehow stripping its genes bare of their
chemical masks.
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- Dr. Jaenisch and Dr. Westhusin say that from preliminary
molecular biology experiments they are starting to see confirmation of
their belief that reprogramming can go awry. They are looking at molecular
patterns of gene expression in embryos created by cloning and comparing
them to the patterns in embryos created by normal fertilization. Their
results so far are consistent with their hypothesis that reprogramming
can result in random errors in almost any gene.
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- But scientists say that every species is different, and
it remains possible that it will be easier and safer to clone humans than
it is to clone other species.
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- Mouse eggs are fragile, Dr. Jaenisch said, which may
complicate efforts to clone. The solutions used to bathe cattle embryos
while they are grown in the laboratory seem to create a large-calf syndrome,
resulting in large placentas and huge calves that often die around the
time of birth. But fertility clinics that do in- vitro fertilization have
vast experience in growing human embryos in the laboratory and have perfected
the method.
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- Some like Dr. Richard Rawlins, who directs the in-vitro
fertilization laboratory for the Rush Health System in Chicago say it is
only a matter of time before someone announces that a human has been cloned.
"In my opinion," he said, "all it takes right now is time,
money and talent." The only question is who will do it first, he added.
It may be the two fertility experts who recently announced that they wanted
to clone a human, Dr. Panayiotis Zavos of the Andrology Institute in Lexington,
Ky., and Dr. Severino Antinori, a fertility doctor in Rome. Or it may be
a relative unknown.
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- Academic scientists say they would not dare to think
of cloning a human at this time. The very experiment would be so controversial
that they would become scientific pariahs, said Dr. Alan H. DeCherney,
chairman of the department of obstetrics and gynecology at the University
of California in Los Angeles. "You'd ruin your career," he said.
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- In the meantime, the House Energy and Commerce Subcommittee
on Oversight Investigations will hold hearings on human cloning on Wednesday,
with a witness list including ethicists and scientists.
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