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Death Sentence on Cloning

The final curtain is drawn over the controversial Dolly cloning. But that should spell the death for ‘therapeutic’ human cloning as well, say Dr. Mae-Wan Ho and Prof. Joe Cummins.

The complete document with references, is available in the ISIS members site. Full details here

Ian Wilmut, father of Dolly the cloned sheep, had effectively passed the death sentence on cloning in a review published in Nature October 2002. The death sentence was already overdue by then, for cloned animals had been pronounced “a gallery of horrors” the year before.

The review said cloning by present methods is “very inefficient”, due to “inappropriate expression of many genes”, “failure of ‘reprogramming’”. Cloning has so far been accomplished in sheep, cattle, mice, pigs, goats, rabbits and cats; but not in rat, rhesus monkey and dog. And only 0-4% of embryos reconstructed using adult or foetal somatic cells develop to become live young.

In addition to failures during embryonic development, there are high rates of foetal, perinatal and neonatal loss, and production of abnormal offspring. Some effects are attributed to embryo culture.

Typically, at least one third of surrogate mothers confirmed pregnant lose their foetuses during gestation. Abnormal development of the placenta, including reduction of blood vessels is a principal contributing factor during early pregnancy in sheep and cattle. It may also contribute to some of the defects reported in neonates. In cattle the rate of loss is also increased in the second and third trimester (compared with in vitro fertilisation, IVF), with greater losses when adult rather than foetal or embryonic nuclei are used. The over-accumulation of placental fluid occurs rarely in natural pregnancies, but can affect up to 2 and 40% of pregnancies established with IVF and cloned embryos, respectively. In cloned mice, the placenta is often 2-3 times heavier than normal.

Many cloned offspring die within the first 24h of birth, commonly from respiratory distress, increased birth weigh and major cardiovascular abnormalities that can result in gross distension of the liver and dilated major vessels. Oversized offspring are frequent in many species. Prolong gestation, fluid accumulation, enlargement of organs, sluggish onset of labour and difficulty in breathing are also common.

Postnatal abnormalities that have been described include failure of the immune system, structural abnormalities of the brain, digestive dysfunction, enteritis and umbilical infections. Genetic background or donor cell type may play a part. In two independent studies with different strains of mice, those cloned with cumulus cells became obese in adult life, whereas those from Sertoli cells of immature mice died at an unusually early age. By contrast, physiological studies of cloned calves suggest normality, at least for the tests administered. But the eldest was only 4 years when tested. Success also depends on the cell cycle stage of the donor cell.

In sheep, cattle and mice, inappropriate expression of genes, perturbations in the expression of imprinted genes are often observed. Epigenetic instability inherent to embryonic stem cells lines may also be a factor in the failure of cloning from such cells.

Another top cloner Yanagimachi summarized the experience of cloning mammals: “At present, cloning efficiency..…is low regardless of the cell type (including, embryonic stem (ES) cells) and animal species used. In all animals, except Japanese black beef cattle, the vast majority (97%) of cloned embryos perish before full term. Even in the Japanese cattle, less than 20% of cloned embryos reach the adulthood. This low efficiency of cloning seems to be due largely to faulty epigenetic reprogramming of donor cell nuclei after transfer into recipient eggs. Cloned embryos with major epigenetic errors die before or soon after implantation. Those with relatively ‘minor’ epigenetic errors may survive birth and reach adulthood. We found that almost all foetuses of inbred mice die at birth from respiratory problems, while those of hybrid mice do not, suggesting that genomic heterogeneity masks—to some extent—faulty epigenetic errors. So far, the majority of cloned mice that survived birth, had a normal life span and were fertile. However, these animals may not be totally free of health problems. Post pubertal obesity in certain strains of mice is one example.”

Cloned adults show abnormalities including liver damage, tumours and impaired immune systems. And serial cloning of mice to six generations did not improve embryo survival, suggesting that ‘clone-ability’ could not be improved by selection. The fundamental question is, do cloning defects arise from unsolved technical problems or are the deaths and defective phenotypes a fundamental and irreparable consequence of cloning?

A recent study examined the expression of 10 000 genes in developing embryos and placenta of cloned mice, using a micro array gene-chip. Clones were derived from embryos produced using cell nuclei from cultured embryonic stem cells or from freshly isolated cumulus cells (cumulus cells are the maternal cells adhering to the developing egg), and the RNA in placenta and liver cells screened. The results show that for both donor cell types, about 4% of the expressed genes in placenta of the cloned animals differed dramatically from normal embryos, and the majority of abnormally expressed genes were common to both cumulus cell clones and embryonic stem cell clones. But the expression of a smaller set of genes differed between the embryonic stem cell clones and the cumulus cell clones. The livers of the cloned mice also showed abnormal gene expression, although to a lesser extent than the placental cells, and involved a different set of genes. Thus, most abnormalities were common to the cloning operation, with the rest reflecting the particular cloned nuclei (whether from embryonic stem cell culture or fresh cumulus cells).

It is clear that cloning animals is no longer considered a commercially viable option, and there are those of us who have opposed it on ethical grounds long before.

However, many researchers are still arguing for ‘therapeutic’ human cloning, ie, to clone human embryos that will be sacrificed to produce embryonic stem cells for tissue replacement, a procedure that most people find objectionable on ethical grounds. Of course, the abnormalities in gene expression and ‘reprogramming’ that dogs animal cloning will still affect the embryonic stem cells, which raises serious safety concerns. But these concerns are generally ignored.

The overriding concern of most people including ourselves, is that ‘therapeutic’ human cloning is an “unnecessary evil” when evidence dating back to 2001 already shows that adult stem cells, readily obtainable from patients themselves, are a much safer, more effective and affordable treatment.

Research and clinical findings since have amply confirmed the promises of adult stem cells. A new report in the Lancet earlier this year documents how bone marrow cells taken from patients who have suffered myocardial infarction and injected back into the patients, were able to regenerate the damaged heart tissues.

This should spell the death also for ‘therapeutic’ human cloning and human embryonic stem cells research.

The complete document with references, is available in the ISIS members site. Full details here

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