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Year in Review: 1997

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Princess Diana's death stuns the world

Weld steps out -
Cellucci steps forward

Mother Teresa is laid
to rest at age 87

Chinese rule returns
to Hong Kong

Supreme Court strikes
down 'Net decency act

UPS strike disrupts thousands of firms

Heaven's Gate cult commits mass suicide

Mars Pathfinder explores Red Planet

Ellen comes out, marking a first in TV

For the first time, a mammal is cloned


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Views split on ability to clone humans

By Richard Saltus, Globe Staff, 03/02/97

No one is saying publicly that cloning a human being is a good idea, but scientists do have conflicting views on a more practical question -- is it now feasible?

Some researchers say that in principle, the technique developed by Scottish scientists to produce a carbon copy of a grown sheep should work in humans.

"I think it's probably possible in humans," said Rudolph Jaenisch, a scientist at the Whitehead Institute for Biomedical Research in Cambridge.

He noted that no one has yet succeeded in cloning a mouse, the most ubiquitous of lab animals, but "there's no reason to think that humans are more like mice than sheep. I think the technology would work."

But others argued that cloning a person would be far from straightforward, and maybe impossible, using the methods that produced the cloned lamb called Dolly.

Although sheep, mice and other mammals have many similarities, there are differences -- perhaps critical ones -- in the details of how their embryos develop. These differences might enable one species to be cloned by transferring the nucleus from a mature adult -- as was done to create Dolly -- while the same method might fail in another species.

Many other questions remain, as well. The Scottish scientists reported that they created 277 embryos but got only one living, cloned lamb for their efforts. Unless they can make vast improvements in the technology, it would be unacceptable for humans, said a scientist who wrote a commentary accompanying the Scottish report.

"How are you going to get nearly 300 eggs from women" to achieve a single cloned human, asked researcher Colin Stewart, who directs the Cancer and Developmental Biology Laboratory in Frederick, Md.

The researchers at the Roslin Institute in Scotland achieved what many had thought biologically impossible. They took a mature, fully developed cell from a six-year-old ewe and combined it with an unfertilized egg from another ewe.

Most remarkably, they managed to reset the genetic program of the six-year-old cell"s nucleus so that it behaved like the nucleus of a just-fertilized embryo, guiding development from just the single cell into a new sheep identical to the older one.

"That is the most amazing thing: You can take the nucleus of a differentiated cell and have it start the whole animal all over again," marveled Kathryn Go, a reproductive biologist with Pennsylvania Reproductive Associates in Philadelphia.

The Scottish researchers used a mammary cell from the adult sheep, which, like every other cell in its body, contained all the DNA instructions to make a complete sheep.

But most of the genes that constitute that DNA had been turned off early in the sheep's development, leaving active only the genes necessary to produce and operate a mammary cell.

The trick was somehow to turn back the clock, biologically speaking, so the genes in the nucleus could revert to a primitive state in which all of them were again able to be activated to produce the panoply of cells that make up a sheep.

To make this work, the donor nucleus (which goes through regular cycles of growth, division and rest) had to be synchronized with the unfertilized egg into which it was placed, just as two gears of a transmission must be turning at the same speed to mesh. In past cloning experiments, the timing was off, and the match produced embryos with abnormal chromosomes.

The synchronization was critically important because the signals for an embryo to begin dividing into progressively more specialized cells come not from the nucleus itself but from the surrounding cell material, called cytoplasm.

In the cloning that led to "Dolly," it was the unfertilized egg into which the nucleus was placed that sent the crucial chemical signals to "reprogram" the nucleus "back to time zero," said Jaenisch, a pioneer in making genetically modified animals for research.

The Scottish researchers set the stage for this to work by starving the ewe's donated mammary cells into a dormant state, so that the nucleus was not going through the normal cycles that trigger cell division.

That way, when the donor nucleus was inserted into the recipient egg, the nucleus was more receptive to the egg's "start" signals, Jaenisch explained.

Why did it work in sheep, when similar experiments in mice, for example, have totally failed? Jaenisch said that in sheep the genes in the embryo don"t turn on until the embryo has already divided into six or eight cells. It doesn't need the nucleus" genetic program right away.

Stewart, of the lab in Frederick, said, "It's possible it works in sheep because the transplanted nucleus has another two rounds of cell division before it's asked to be switched on. This provides enough time for the nucleus to be reprogrammed."

In a mouse, the genetic program in the nucleus has to be up and running in the short time it takes for the embryo to divide into two cells. "The genes in the human embryo get switched on at the four-cell stage," Stewart said. "It's right in between the mouse and the sheep; that's what's so intriguing."


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