Biological uncertainties about reproductive cloning

Abstract

The controversy over human reproductive cloning was brought to the fore again last week with the announcement of plans to create human embryos within the next few months by somatic-cell nuclear transfer (SCNT), and possibly to produce the world's first cloned baby before the end of next year. These plans were announced by Italian gynaecologist Severino Antinori and US-based reproductive physiologist Panayiotis Zavos at a meeting held by the US National Academy of Sciences. What is the justification for rushing into a procedure about which so many scientists have serious reservations? One concern is the inefficiency of the procedure, even though the embryo loss is declining. With Dolly the sheep, the first animal resulting from SCNT, DNA had been transferred into 277 enucleated oocytes, which resulted in 29 embryos, which were implanted into 13 sheep. The single livebirth gave a success rate of about 3% (or 0·4% if based on zygotes created). More worrying, though, are the developmental abnormalities and/or neonatal deaths. The commonest abnormalities are fetal overgrowth, defective placentas, respiratory distress, and cardiac anomalies. Zavos' arguments at last week's meeting and elsewhere (eg, www.reproductivecloning.net) are that success rates have reached 80% (eight livebirths from ten embryos) with calves and that suboptimum design and execution of experiments could have accounted for failure rates and for morbidity among the offspring. Moreover, he calculates that, with systematic pre-implantation and prenatal screening, the 25–50% rate of developmental abnormalities and/or neonatal deaths among the livebirths could be brought down to below the 3% rate associated with natural conceptions. Such arguments may well sound convincing to potential volunteers. However, they take insufficient account of the fact that the problems with cloning are not merely technical but biological. Very little is known of epigenetic reprogramming, the process that regulates the resetting of an adult pattern of cells to an embryonic one. With natural conception, the reprogramming takes place not just postzygotically but also during gametogenesis. With SCNT, the donor nucleus has to be reprogrammed in a very short time and in a very different context from that of maturation of the sperm or ovum. These differences make the process error prone. Since in principle the reprogramming that occurs before fertilisation regulates all genes in the genome, errors can be expected in any gene and in the imprinting of genes, whereas problems are thought to be less likely with X-chromosome inactivation or telomere-length adjustment, the events that are reprogrammed postzygotically. The indications from animal work are that a substantial number of the abnormalities so far detected arise from epigenetic dysregulation. Current methods of preimplantation or prenatal genetic screening pick up chromosomal aberrations and single-gene defects but not epigenetic dysregulation. Nor can current methods of prenatal imaging pick up microscopic effects such as the thickened pulmonary arterioles that have been associated with respiratory distress. Some effects of dysregulation may be subtle and not expressed phenotypically, but with the potential for all 30 000 or so genes to be affected, who knows what the cumulative effect might be and when it might manifest? Another important uncertainty is how the relationship between parent and child (or rather, man and delayed twin) will develop. The child's interest must be a crucial factor in decisions on how far forward reproductive cloning should be taken. Uncertainties and risk assessment are part and parcel of medical practice. The medical need for reproductive cloning is not huge. Other methods of assisted conception exist for the 1% of infertile couples in which the male partner has no usable sperm. Nuclear cloning would thus be the solution only for those men whose desire for a biologically related child is overwhelming, or for those couples who abhor the idea of artificial insemination with a stranger's sperm. For now, and probably for a very long time to come, the uncertainties associated with human reproductive cloning far outweigh the need, and the procedure should not be attempted.