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Researchers Find Big Risk of Defect in Cloning Animals

Gina Kolata / New York Times 25mar01

cloning defect

Dr. Ryuzo Yanagimachi, University of Hawaii
Genetically identical mice: the obese one on the right is the clone.

Four years after researchers in Scotland startled the world by announcing that 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.

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.

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.

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. Two infertility specialists recently announced that they wanted to clone humans.

Initial fears that clones 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 the safety of cloning arose. Fewer than 3 percent of all cloning efforts succeed.

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.

"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."

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.

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.

"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.

Dr. Jaenisch said, "It would be reckless and irresponsible," adding, "What do you do with humans who are born with half a kidney or no immune system?" And, he said, what about the possibility of creating children who appear to be normal but whose genes for neurological development work improperly?

Scientists say they see what appear to be genetic problems almost every time they try to clone.

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.

Cloned mice also tend to have developmental abnormalities, taking longer to reach milestones like eye opening and ear twitching, Dr. Yanagimachi has found.

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.

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.

Cloning mice is more efficient, Dr. Yanagimachi said. But even then, only 2 percent to 3 percent of his attempts succeed.

"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.

Dr. Westhusin says that when he thinks about what happens in cloning, "it's a wonder it works at all."

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.

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.

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.

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 clinics for in-vitro fertilization have vast experience in growing human embryos in the laboratory and have perfected the method.

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.

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.

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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