- The Washington Times - Monday, August 13, 2001

LONDON — The doctors responsible for cloning the sheep Dolly say they are outraged by scientists who plan to press ahead with attempts at human cloning, calling any such attempt intolerable.
Dr. Severino Antinori, an Italian gynecologist, and Dr. Panayiotis Zavos, an American "andrologist," announced last week that they would start work on creating the first human clone "in the next 30 to 60 days."
They insisted that the first cloned human baby will be born next year.
But Ian Wilmut, the scientist who stunned the scientific world by leading the effort that produced Dolly, said in an interview: "To try cloning on humans today would be criminally irresponsible. The problems are far too serious."
Dr. Harry Griffin, another scientist at the Roslin Institute near Edinburgh, Scotland, where Dolly was created, dismissed reports that, five years after her birth, Dolly has aged prematurely, is weak, cannot walk properly and suffers from intestinal problems.
"None of that is true," he said. "The truth is that Dolly is physically a normal 5-year-old sheep. She's been pregnant three times and produced six healthy lambs, so no problems there."
But Dr. Griffin utterly rejected any suggestion that Dolly's good health meant the cloning of humans could go ahead safely. "There are dozens of problems," he said tersely.
To understand those problems, you first have to understand a little about "single nuclear transfer," the process by which Dolly was created and which Drs. Antinori and Zavos are proposing to use to clone people.
Cloning is possible because of the strange and surprising fact that each cell in the body has the capacity to make every other cell: It contains a copy of the complete set of instructions needed to build everything.
It used to be thought that once a cell had adopted a particular function — once it had become part of the liver or the brain or the lining of the stomach — it was impossible to "reprogram" it to build anything else. But Dolly proved that it could: She came from a single cell taken from the udder of a 6-year-old Finn Dorset ewe.
The seven steps to a clone are, in theory, relatively simple. First, you need an unfertilized egg — a human one if a human is to be cloned, a sheep's egg if it is to be a Dolly. Second, you have to remove the DNA sequence — that is to say, the set of genetic instructions for building every part of the adult organism — from the nucleus of the egg. The Scottish doctors simply sucked it out with a pipette.
Third, you need another cell, to fuse with the egg. That cell could come from anywhere in the body of the human or animal to be cloned, because practically every cell contains the complete set of chemical instructions needed for creating that particular individual. Step four is the insertion of that single cell into the egg.
Step five requires the fusion of the new cell and the egg. This is the crucial step that "switches on" the cell's DNA — the 30,000 to 40,000 genes which dictate the building of a new body — and persuades it to start the manufacture of an embryo. The process normally requires the application of a small electrical current.
"That's what happened in the creation of Dolly," said Dr. Griffin. "It mimics the changes that happen when sperm fertilizes an egg."
The sixth step is to implant the egg, now flush with genetic material, into the womb of a sheep — or woman. If that implantation is successful, the egg will divide and develop, so that after nine months, in the case of a human, step seven occurs: the birth of a clone.
While the theory is simple, there are practical problems and difficulties with every one of those steps. "There are dozens of unknowns with even sheep," said Dr. Griffin. "There are certainly going to be vastly more with humans."
To begin with, cloning has a success rate of about 1 percent or less.
"We had to implant 277 eggs to get one cloned sheep," said Dr. Griffin. "Other laboratories that have cloned mice and pigs report similarly high rates of failure.
"Now — laying aside the serious ethical problems associated with treating human embryos in this way — where are you going to get that number of human eggs to create them from? There simply isn't a surplus anywhere. I don't see how Drs. Antinori and Zavos could possibly legitimately get hold of the number of eggs they would need even to start."
Step two — the removal of DNA material from an egg — would not in itself be any more difficult with a human cell than it is with one from a sheep. The trouble is not with the technical manipulation, but with its effects — no one knows what they are, except that they are almost certainly likely to be bad. The same is true of steps three to five.
The manipulation of the genetic material certainly has adverse effects on how accurately the cellular machinery works. Dolly may be in good shape, but she seems to be exceptional, more of a lucky fluke than anything else.
The majority of cloned animals have something wrong with them. They die in the womb, or soon after birth. Typical defects are malfunctioning lungs, a heart that doesn't work as it should, an imperfect immune system and abnormal size.
The scientists have theories about why so many clones seem to go wrong. One is that molecules attached to the genetic material which are important in ensuring that only some genes are "switched on" at any given location in the body (so that, for instance, your brain cells are in your head, rather than in your stomach), are scraped off or damaged when the cell to be cloned is manipulated by the experimenters. Manipulation by experimenters is inevitable, not just when DNA is removed from the egg, but also when the new cell is inserted into it.
The process disrupts development in other ways. Kevin Eggan, a professor at the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology, said that even when they look normal, many cloned animals have damaged or imperfectly copied genes, which, in people, could result in serious mental problems.
"Disruption of those genes in humans," he said, "could cause retardation, among other difficulties."
Dr. Rudolph Jaenisch, a colleague of Mr. Eggan's, cautioned that there are between 30,000 and 40,000 genes in the human genome.
"Any one of them is, in principle, a target for faulty programming in the cloning process. We have no idea how many are adversely affected by it, and there's no way at present to find out. Tiny copying errors can have horrible consequences."



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