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Dolly's Legacy

Nuclear transfer--used to clone Dolly and now owned by Geron--may help scientists develop more potent stem-cell therapies
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Image: GERON CORPORATION

NUCLEAR TRANSFER, the first step in creating a clone, involves inserting the nucleus from an adult somatic, or differentiated, cell into the emptied cytoplasm of an egg cell. The egg cell then reprograms the adult cell's genes so that it behaves like an all-purpose stem cell.

Since early May, when Geron Corporation acquired Roslin Bio-Med, there has been nervous speculation about what the marriage might mean. Geron, the biotech wunderkind, last made big news in November 1998 when scientists they funded--James A. Thomson of the University of Wisconsin and John D. Gearhart of Johns Hopkins--independently isolated two sorts of so-called human pluripotent stem cells. These cells that have tremendous therapeutic potential because they can develop into any other type. Roslin Bio-Med is the firm established to commercialize nuclear transfer, the method researchers at Roslin Institute used to clone Dolly the sheep in 1997.

Might not the two be ideal parents for the first human clone? Last week, headlines around the world aired that suspicion: "Science 'weeks from cloning human embryo,'" London's Daily Mail shouted on June 15; "Cloned embryos planned," echoed the Montreal Gazette. Similar stories appeared the same day in the Daily Telegraph and Boston Herald.

But the situation it is not so simple. Geron, which promptly denied the accusation, does have scientists at an undisclosed location conducting experiments in which they transfer the nuclei of adult cells into human eggs already relieved of their own--the first step in creating a clone, Dolly-style. But instead, after five to ten days, the researchers are removing pluripotent stem cells from the resulting ball of 100 or so and analyzing them.

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Image: GERON CORPORATION

PLURIPOTENT STEM CELLS, first isolated in humans last November, can be transformed into any other type of cell, making them the ideal raw material for fashioning replacement parts. By reactivating telomerase, an enzyme that reknits the frayed ends of genes in older cells that have undergone many divisions, scientists can extend the life span of the new parts.

Why is this work not quite human cloning? For one thing, most scientists maintain that a 10-day old embryo is not yet a life because the nervous system hasn't developed, an event that begins around day 14. Less controversial is the argument that creating human embryos for the sake of harvesting stem cells doesn't really serve Geron's purposes. Although such harvested cells could be cultured as say, liver cells for treating hepatitis or dopamine-producing cells for Parkinson's, the resulting transplants would likely be rejected by patients' immune systems.

It is in this regard that Geron's motivation in purchasing Roslin's cloning technique becomes clear. Nuclear transfer hinges on the fact that, somehow, factors in an egg cell's cytoplasm can reactivate all of the genes in adult cells so that they behave like stem cells. All adult cells contain an organism's entire set of genes, but they shut off all save those genes they need to function as hair, blood and so forth.

If Geron can learn what chemicals in an egg cell's cytoplasm reprogram an adult cell's nucleus--the aim of their current experimentation--they can avoid using embryos altogether. In that case, any cell from a patient could be used to whip up perfect tissue matches--histocompatible in the parlance of immunology--for treating a range of conditions.

One possible glitch with using a patient's adult cell to make replacement tissue is that the cells in that tissue may be prematurely aged. In other words, the cells, though new, start life at the age of the cell from which they were derived. Indeed, although stem cells can divide indefinitely, once they are differentiated, they are locked into a limited life-span, counted down by the number of divisions they undergo. With each division, the stretches of DNA at the ends of their chromosomes--regions called telomeres--begin to fray and shorten, leaving the remaining DNA more liable to errors and mutations.

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Image: GERON CORPORATION

STEM CELL-DERIVED TRANSPLANTS can be made in a variety of tissue types. Moreover, when they are created using the genes from a patient's adult cells, they make a perfect tissue match, described by scientists as histocompatible.

A report in the May 27th issue of Nature confirmed that Dolly the clone is in fact chromosomally older than she is chronologically. Her telomeres are shorter than they should be for a three-year old ewe. They are instead the length expected of a six-year old animal, which is the age of the sheep from whom Dolly was cloned. (Otherwise, Dolly--who just completed her second successful pregnancy, delivering triplets in March--is completely healthy.)

It is unclear whether shrinking telomeres will be problematic in culturing human tissue transplants, but if it turns out they are, Geron has an answer for that too. In August, 1997, Nobelist Thomas Cech of the University of Colorado at Boulder and colleagues at Geron isolated the human gene for telomerase reverse transcriptase (hTRT)--an enzyme that reknits loosening telomeres and extends a cell's life. And five months later, Jerry Shay and Woodring Wright of University of Texas Southwestern Medical Center, also working with Geron collaborators, published additional findings, showing that, by introducing the hTRT gene to cells, they could make those cells repair unraveling telomeres. By reactivating telomerase activity in stem-cell derived tissue transplants, Geron could provide patients with a life-time warranty on their new parts.

In the final analysis, it seems clear that Geron is not going for the obvious play, pairing stem cells and nuclear transfer to pursue human clones. Instead, Roslin's technology is just another card they need to shoot the moon in the game of developing a new generation of potent medical therapeutics.

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