Cloning - The Good, The Bad and The Ugly

Cloning and genetic modification (GM) of organisms, including plants and animals, has enormous therapeutic potential. But what are embryonic stem cells, how are stem cells made (...
14 April 2004


Good news! Cloning can cure genetic diseases! Bad News! You die younger. The scientific press has recently thrown up both good news and bad news for those of us interested in the field of cloning. Work from America has shown that a genetic deficiency can be cured by using cloning techniques, while Japanese scientists tell us that cloned animals tend to die young. So what exactly do these papers say? And what do they mean for the future of cloning research?

The success story comes from the lab of Rudolf Jaenisch, using mice deficient in a gene called Rag2 which is important for the immune system. Without this gene, the animals are highly susceptible to infections. Notably, a similar condition exists in humans defective for the equivalent gene. The American researchers took cells from the tail tips of the mutant mice, and injected them into eggs from which the DNA had previously been removed. These eggs were then allowed to develop to an early stage of development known as a blastocyst. Mouse blastocysts have an intriguing property in that certain cells from these embryos can be maintained indefinitely in culture (in plastic dishes), becoming embryonic stem cells.

These embryonic stem cells (or ES cells, as they are more often known) can be replaced in blastocysts and will develop into normal mice, or they can be treated with various chemicals to turn them into a wide range of other cell types. The researchers took the ES cells from the cloned blastocysts lacking the Rag2 gene, and repaired the mutation using standard genetic engineering techniques. These mended ES cells were then used in two different ways. Firstly, they generated new embryos from the ES cells and allowed them to develop into mice.

These "healed" mice were then used as bone marrow donors, replacing the defective immune cells in the mutant mice with functional repaired cells. Because the donors and the mutants are derived from mice with the same genetic background (apart from the Rag2 mutation), there are no problems with rejection of the donated cells. Analysis of the treated mutants showed a complete restoration of the immune system, making this method a great success.

A second approach involved growing the repaired ES cells in culture with certain factors which convert them into specialised immune system stem cells. These artificially generated immune stem cells could then be transplanted back into the mutant mice. Unfortunately, the mutant mice rejected these transplanted cells, perhaps due to changes which happen to the cells during the culturing process. The transplants were only successful when the Rag2 mutants were given treatment to further damage their already compromised immune systems, as it is the remaining immune components that cause the rejection. But what does this research mean practically? Can we transfer this knowledge to human therapies?

Sadly, it would appear not at the moment. In the successful first experiment, the scientists used the cloned repaired ES cells to generate a whole new donor mouse. If we translate this to humans, this would mean generating an adult clone as a "spare part" donor, an act that most people would view as morally questionable in the extreme. A less extreme but perhaps comparable situation might be the furore that surrounded the announcement that a couples undergoing IVF had genetically selected their embryos to be cell donors for their other child. Although the second approach, growing the cells in culture, had some success when the mutant host animals were treated with immunosuppressants, this is also a far from ideal situation as the whole point of the therapy is to restore immune function.

Another nail in the coffin of this idea is the fact that human ES cells do not have exactly the same properties as mouse ES cells. Indeed, the difficulty of working with these cells (both technically and legally) has meant that researchers know very little about the properties and potential of human ES cells. However, this research does at least give a glimmer of hope that one day cloning and stem cell technology could be used in this way to treat human diseases.

In the other corner of the world, both scientifically and geographically, Japanese scientists led by Atsuo Ogura have demonstrated that cloned mice die significantly sooner than normal mice, or mice generated by artificial injection of sperm into the egg. Over eighty percent of the clones had died after 2 years and 2 months, while the normal mice were still going strong. The clones were found to suffer from severe penumonia and liver failure. Other researchers have also shown clones to have excessive obesity, birth defects and a high rate of death immediately after birth. This is true not just of mice, but of other animals such as cows.

The recent claim in the media by human cloning guru Severino Antinori that at least one woman is currently pregnant with a cloned human is enough in itself to warrant a shiver of fear in the scientific community. As the evidence grows that cloning directly to make whole new individuals (not ES cells, as with the American experiments) leads to defects and problems, the likelihood of generating viable human clones recedes. The attack of the clones, at least as the science fiction writers would have it, seems to be just as far away as ever.


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