For all its medical potential, cloning is still an unknown quantity, report Clare Mills and Jaap de Roode.
Once the very symbol of cloning, Dolly the sheep is suffering from premature arthritis in her left hind leg. Although, due to treatment, she is not in pain, the progressive disease might lead to her being put down. But Ian Wilmut, leader of the scientific team that produced the clone in 1996, thinks it is impossible to tell if Dolly's arthritis is a direct result of the cloning process. "Some colleagues would say it is possible," he says, "but others would say that Dolly has had an exceptional life. She has been on hard floors most of the time, and far more than a normal sheep she has stood on her hind legs."
Nevertheless, Wilmut, who works at Edinburgh's Roslin Institute, is not convinced cloning is healthy or safe. He argues that human cloning would be dangerous and irresponsible at this stage. He knows what he is talking about. For although Dolly shows no other signs of illness and has produced three healthy litters, the list of aberrations in other cloned animals seems endless. Sheep, cows, pigs, goats, mice, rabbits and cats have been cloned and the evidence is overwhelming: immune-system deficiencies, spontaneous abortions, high birth weights, respiratory and circulatory problems, kidney or brain malformation, diabetes, enlarged tongues, squashed faces, intestinal blockages, twisted feet, premature death due to pneumonia, liver disease and cancer - the list goes on.
In addition, cloning is immensely inefficient. To produce Dolly, 7 embryos had to be created. Only 29 of these developed enough to be implanted in 13 ewes, and just one took her pregnancy to term. With a cloning success rate of 1 to 2 per cent, Wilmut says: "If humans were to be cloned, the likely outcome would be late abortions, still births and, worse, the birth of abnormal children who survived." He mentions a cloned lamb at Roslin that had an abnormality in the blood vessels of the lung. The condition, which could not be detected in utero , left the animal panting continuously. It became so debilitated after a few days that it was put down. "What do you do if it is a child?" Wilmut asks.
He has other ethical concerns about human cloning. "There will be pressure on David Beckham's son to be a football player just because he is David's son," he says. "But if he was his clone, there would be enormous pressures. I understand parents' wish to have children. But as a principle it seems possible to me that some things could do so much harm to the child that it would not be appropriate for the parents to be allowed to have children under those circumstances. Cloning is probably one of those."
Wilmut is sceptical about claims by Italian doctor Severino Antinori, who says he has cloned human beings. Wilmut says none of Antinori's clones has been seen and none of his research has appeared in peer-reviewed journals.
He also doubts the recent claims of Brigitte Boisselier, the scientific director of cloning company Clonaid, that she has the genetic tests to screen for the health of cloned human embryos. Wilmut says that we do not know what is going on during the process of cloning and so we could never test for the process to proceed healthily.
He says even he does not fully understand how transferring a mammary cell from a six-year-old Finn-Dorset ewe into the egg of a Scottish Blackface, from which the DNA had been removed, produced Dolly. But he thinks such processes of exploration are no bad thing. "Until you see what you can achieve, you have no idea of what is there. Then you can think what to use it for."
Only a year after Dolly, Wilmut created Polly, a sheep that was not only cloned, but also carried the human gene for blood-clotting factor IX. Polly shows the advantage of cloning: cells can be grown in culture and manipulated genetically. Successfully transformed cells can then be cloned to produce animals that can, like Polly, produce therapeutic substances in their milk. The advantage is in the culturing of cells: rather than manipulating one embryo, millions of cells can be targeted with a specific gene, and the success rate increases dramatically. With genetic manipulation, numbers matter.
Wilmut says that before Dolly it was unthinkable to clone embryos from which stem cells could be isolated for the purpose of growing specific tissues, such as insulin-producing cells to treat diabetes or nerve cells to treat Alzheimer's disease.
Dolly showed that adult cells can be fully reprogrammed to give rise to an embryo that can develop into a complete individual again. That insight might one day lead to transdifferentiation of cells: the ability to change any cell into a cell of another type, perhaps by changing its environment or the chemical messages within the cell. Again, these cells could then be used to grow specific tissues. Wilmut recently made public his intention to apply for the right to derive stem cells from human embryos for therapeutic applications. One day he may apply for permission to create those embryos himself. In defence of his work, he argues: "Being human in the important or meaningful sense to me means some sense of individuality or personality. I am not sure when that occurs, but I am convinced it occurs way after a six or seven-day embryo, when there is not even the rudiments of a nervous system. At this stage, it is not a human in that different sense of the word. To me, that is the reason why it would be an acceptable thing to do."
But there is a long way to go. A few months ago the American company Advanced Cell Technology announced that it had produced cloned human embryos. Wilmut is sceptical, saying ACT never reached the embryonic stage of about 100 cells, from which stem cells can be isolated. To many scientists, this means therapeutic cloning is a dead end. Wilmut does not agree. He says: "We cannot make that judgement yet." He argues that we should try everything to produce tissues that could be used for treating diseases. Later we could see which technology would be best for which purpose.
Another implication of the Dolly experiment is the possibility of correcting a mutation in a gene that can cause disease. Wilmut thinks this is admirable and not to do it might even be immoral. As with all advances, he says, there is a negative side. "The first time a person put a sharp stone into a stick and made an axe, you could use that (axe) to chop firewood, to kill animals to eatI or to kill someone. Even simple technology can be used in different ways."
But Wilmut firmly believes that 100 years from now the benefits derived from the technology that produced Dolly will outweigh the disadvantages and the potential misuse.
Jaap de Roode and Clare Mills are PhD students working on malaria at the Institute of Cell, Animal and Population Biology, University of Edinburgh.