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The BBC's Christine McGourty
The technique could be used to make cows immune to BSE
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Thursday, 29 June, 2000, 13:53 GMT 14:53 UK
Cloning gets specific
Scientists have finally published details of an advance in cell technology that has resulted in the creation of the first sheep clones whose genes have been selectively modified.

The researchers at the Edinburgh (UK)-based biotech company PPL Therapeutics can now introduce a gene into a specific location in an animal's genome.

Previously, this could only be done randomly. The new technique has several applications, but, primarily, it should make the "pharming" of animals to produce useful drug compounds in their milk far more efficient.

The work was originally disclosed last year but details were held back because of a patent application.

Targeted regions

Those details have now appeared in the journal Nature. They describe the methods that led to the birth of the first genetically modified sheep clones - including two female lambs named Cupid and Diana.

The team at PPL was closely involved in the creation of Dolly the sheep, the first mammal clone created from an adult cell. Their new research has improved the traditional hit-or-miss technique of gene splicing by getting a "foreign" gene to enter a specific region on a chromosome, one of the structures that bundle up DNA in the nuclei of cells.

The researchers, led by Dr Alexander Kind, inserted a gene that coded for a human protein into sheep fibroblast cells - the cells that produce collagen. "Flanking" regions of DNA, which are like bookends, marked the beginning and end of the region of DNA that was to be replaced.

Matching bookends also surrounded the genetic material being inserted - this ensured it only went into the targeted location. Next, using the same method that created Dolly, the modified fibroblast cells were fused with eggs from which the nuclei had been removed. As a result, the eggs acquired the nuclei and genetic instructions of the fibroblasts: they became clones.

Lung disease

Surrogate mothers were used to carry the developing embryos to term, but only three survived.

Among the live births were Diana and Cupid. They now carry a gene that means they produce a human protein called alpha-1-antitrypsin in their milk. Lack of this protein can cause the lung disease familial emphysema and lead to complications for patients with cystic fibrosis.

Dr Alan Coleman, research director at PPL Therapeutics and a member of the team, said: "The significance of this technique is that you can choose exactly where you want to add a gene, or you could disrupt an existing gene.

"You could, in principle, eliminate the kind of genes responsible for BSE and scrapie.

"But cleaning up whole flocks and herds around the world I think would be impossible. There are just too many animals, and you would lose genetic diversity."

Pig to human transplants

Alternatively, he said, the technology could be used to make animal models of human illnesses on which new treatments could be tested.

This is often done in mice but the rodents do not always mimic diseases and symptoms accurately, Dr Coleman said.

"Mice are used if the model they present is a good one, but often you don't get the same symptoms humans have," said Dr Coleman. "Sheep might be a much better model."

Dr Coleman said the scientists also hoped to produce selectively modified pig clones within the next year. PPL Therapeutics announced in February that it had succeeded in creating five pig clones - a much harder task than producing sheep.

Pigs have a gene which triggers a severe rejection response when their tissue is put in humans. If this can be "switch off", it would remove a big obstacle to pig to human transplants, said Dr Coleman.

Ethical issues

There will be many who will oppose the use of animals in this way, whatever the benefits to humans.

Dr Donald Bruce, Director of the Society Religion and Technology Project of the Church of Scotland, said that just because a procedure was technically possible did not mean it was ethically correct.

"The fact that we already eat pigs (some use this as a moral argument to justify xenotransplantation) is irrelevant," he told BBC News Online. "Eating a pig is at least doing no more than happens in nature; switching organs is not. Xenotransplantation represents a completely different way of using animals from anything humans have done before."

He said xenotransplantation would be justified only if the efficacy in quality and length of life was so great that it justified what would otherwise be an unacceptable intervention in "one of God's creatures".

He said science should be allowed to pursue this possibility, but if things did not go well, "then there would eventually come the point when repeated pig research could not be justified".

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14 Mar 00 | Sci/Tech
Scientists produce five pig clones
14 Mar 00 | Sci/Tech
From pig clone to human transplant
21 Jul 99 | Sci/Tech
Cloned animals to treat emphysema
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