DOLLY the sheep never looked like a history-maker. True, her celebrity status made her unusually people-friendly, homing in on the merest rustle of a reporter’s notebook, though reputedly prone to turning her back on photographers; otherwise, she looked as much like mutton on the hoof as any other ewe. But, just as the birth of the world’s first mammal to be cloned from the adult body cell of another rewrote the facts of life, so her death leaves issues which will never go away.
Suffering from progressive lung disease, Dolly, a Finn Dorset ewe, was put down on Friday, at the Roslin Institute outside Edinburgh which had created her six and a half years ago. A post mortem has confirmed that she had pulmonary adenomatosis, a viral infection among sheep of three to four years of age. The post mortem also revealed that she was suffering from the arthritis diagnosed a year ago, although the Roslin Institute stresses that while a question mark remains over the vulnerability of cloned animals, there was nothing to suggest that Dolly had succumbed to these diseases because she was cloned.
The life and times of Dolly the sheep have by now entered as much into history, indeed folklore, as into the annals of science. She was cloned from a cell taken from the udder of a six-year-old Finn Dorset ewe, the cell being coupled with an unfertilised egg from a Blackface ewe, an electric current encouraging the fusion of the two. The artificially created embryo was grown for seven days in a culture, then transferred to the womb of another sheep, which became pregnant.
Dolly (yes, she was named after the famously-endowed country and western singer) was born on 5 July 1996, heralding, it seemed, a degree of biological control which some might call God-like. She went on to give birth, conventionally, to two sets of four apparently normal offspring.
World attention immediately focused on the Midlothian laboratory, on Dolly and on Professor Ian Wilmut who led the team responsible for the cloning and who, though not given to hyperbole, suggested that Dolly "might reasonably claim to be the most extraordinary creature ever born".
Dolly may have left us - although the world’s most celebrated sheep will be stuffed and mounted for posterity in the Museum of Scotland in Edinburgh - but she leaves a legacy of aspirations, dilemmas and fears, justified or otherwise, surrounding cloning.
The scientific legacy
Ask Dr Harry Griffin, acting director of the Roslin Institute what his epitaph for Dolly might be, and he replies, after some thought: "A self-confident sheep that gave the Institute a great opportunity to explain the new genetics to the public, an opportunity of which we took full advantage."
So far as Dolly’s legacy is concerned, he points to what so excited the scientific community when her birth was announced. "It wasn’t anything practical; it was the fact that she was created from a cell taken from an adult animal.
"At that time it was thought that all the cells in our body were rather fixed in their ways, that they all developed from a single cell and there was a gradual sophistication of cells so we ended up with something like 200-plus cell types, and this was a one-way process. What Dolly and all the other clones created from single cells have demonstrated is that the cells in our bodies are much more versatile than we previously thought.
"That was why Dolly was voted scientific breakthrough of the year in 1997 and maybe that will be her legacy; that the cells in our bodies are naturally more versatile - bone marrow cells, for example, might help heal muscle or heart injuries."
Bring on the clones
Dolly was not the only cloned animal to emerge from Roslin, before or since. She joined the company of Welsh mountain ewes Megan and Morag , born in 1995, but cloned from cultured embryo cells, rather than adult cells. Since Dolly, the Midlothian research centre has produced other cloned lambs, while in July last year, PPL Therapeutics Inc, a US spin-off of the Institute, successfully cloned four healthy pigs, (a fifth died shortly after birth of unknown causes). The elimination of certain genes associated with organ rejection in the pigs boosted hopes of xenotransplantation, the beneficial transplanting of certain organs from animals into humans.
Back at Roslin, researchers, in conjunction with Florida-based Viragen, have been working on the possibility of cloned, transgenic hens whose eggs would contain genetically introduced human antibodies to combat disease. The institute has already produced a non-cloned but transgenic chicken.
Elsewhere, universities in Hawaii and Japan have cloned mice, while in 2002, the University of Texas fanfared the first cloned cat.
Old before her time?
Dolly was cloned from the cell of a six-year-old ewe, which makes life awkward for obituary writers - was she just six, or really 12? This issue arose again with her premature death; also that of Australia’s first cloned sheep, Matilda, born in 2000, who died unexpectedly in January.
Dr Griffin, however, regards the issue of premature ageing as "a bit of a sub-editors’ invention: the only symptoms we have discovered is that the ends of the chromosomes are a bit shorter than they should be. But this was because she was derived from a six-year old sheep."
He agrees there may be a broader issue on whether cloned animals are less robust, "but you cannot extrapolate any significance from one animal".
However, he points to research in Japan in which ten out of 12 cloned mice survived for a far shorter time than normally bred control mice. "So there is still a question mark there, but our experience with Dolly doesn’t really add or subtract anything from the story."
When Dolly was announced, the cover of the German paper Der Spiegel depicted a regiment of Hitlers, reflecting the widespread preoccupation with - and disquiet at - the prospect of human cloning which now seemed worryingly feasible. Quite apart from the inevitable scare headlines and Frankenstein allusions, a more poignant aspect manifested itself in the distressing phone calls which Professor Wilmut received directly after news of Dolly’s birth broke. As he told this paper in an interview, nothing could have prepared him for the harrowing appeals from heartbroken parents, asking whether he could replicate children they had lost.
Of course, even if it was somehow possible to genetically replicate Hitler, or for that matter someone’s dead offspring, although they might look strikingly similar to the source of their genetic material, environmental factors would ensure they would never found the Fourth Reich, or grow into that much-missed child.
The Roslin Institute has consistently warned against human cloning, pointing out that Dolly was the only survivor from 277 reconstructed embryos, the rest dying before or after birth, and suffering from deformities, large foetus syndrome and other problems. So far, an average of only 1-2 per cent of cloned embryos have resulted in live births.
Yet recent months have seen claims, still unsubstantiated, of successfully cloned human babies. At the beginning of this year in the United States, a company calling itself Clonaid, associated with the decidedly odd Raelian cult, which believes mankind was genetically engineered by aliens, announced that one of their followers had given birth to a baby, cloned from a 31-year-old woman. Other cloned children were due, insisted Clonaid, which has not offered any evidence to back up its claim.
And in Italy, Dr Severino Antinori, a fertility specialist, reported he was supervising the pregnancies of several women bearing cloned babies. Towards the end of last month he went on hunger strike in protest at police and health officials investigating his claims. In the face of such claims, Dr Griffin has stated: "Any attempt to clone a child would be wholly irresponsible given the abundant evidence from experiments in animals that present cloning techniques are inefficient and unsafe."
Griffin doesn’t believe, however, that the creation of Dolly opened a Pandora’s box: "I think a lot of the scenarios people imagine are based on a strong element of science fiction. Yes, if a child was cloned that would go over a barrier that I don’t think society should cross."
The ethical legacy
Dr Donald Bruce, director of the Church of Scotland’s Society, Religion and Technology project, describes Dolly as "an icon for both the promise and the threat of biotechnology. Dolly’s real impact was in making people realise, as never before, the importance of the ethical dimension to advances in biotechnology.
"More than anything else, she represents a limit of technology, that we must not apply reproductive cloning to humans. It is one thing to clone a sheep to find better ways to reproduce pharmaceutical proteins in her milk - the original reason why Roslin and PPL got into sheep cloning, and ethically acceptable as far as it went. It is quite another to use the method to make cloned human babies. Recent cloned baby claims are probably a hoax, but they highlight the need for a universal ban on reproductive human cloning."
Dr Bruce adds that while Dolly’s demise was a one-off, it signalled the need for a wider study of cloning and welfare if the technique was to be used further with livestock. Animal welfare is also a concern of Sheila McLean, Professor of Law and Ethics in Medicine at Glasgow University: "Dolly’s creation certainly pushed back the frontiers of medicine and science dramatically and to that extent it has to be welcomed. Her death will probably be about as important as her life, reaffirming the fact that we are a long way, in technical terms, from even considering human cloning.
"But the question which needs to be asked now, in terms of human but also animal cloning, is that while there are undoubtedly good things coming out of animal cloning, there is also the question of animal welfare. There is a balancing act that needs to be done with animals before we can even start thinking about humans. We don’t need to look to bigger arguments about ethics if we get a very clear message that we are getting unhealthy offspring that is going to suffer, and I think that is the major issue right now."
Goodbye Dolly, hello Polly?
While the world mourns Dolly, it is worth remembering that five months after her arrival, Roslin’s spin-off biotech company PPL Therapeutics announced the birth of Polly, the world’s first "transgenic" lamb - not only cloned, but genetically engineered so her milk contains proteins with potential in treating haemophilia. While Polly’s birth prompted nothing like the level of excitement that greeted Dolly, she was regarded as the way ahead, a major step towards Roslin and PPL’s goal of being able to achieve precise, beneficial genetic modifications in livestock .
Much research still requires to be done, but the creators of Dolly and Polly may turn out to be not so much the new Frankensteins of tabloid hysteria but the creators of livestock which could help banish diseases that have blighted mankind throughout history.
THE POTENTIAL BENEFITS
Precise genetic modification of farm animals: This may suggest producing herds of top-pedigree farm animals; in practice, cloning would probably be confined to cattle and pigs because the high cost can only be justified in these animals - cloned cows have already been auctioned for over $40,000 each in the United States, although the Roslin Institute points out that these prices reflect novelty value rather than economic worth.
Fighting disease: Human proteins are increasingly valued for the treatment of diseases. Some can be extracted from blood, but this is expensive and can risk contamination by AIDS or hepatitis C. At Roslin and elsewhere, research is examining "pharming", introducing certain genes to sheep or other milk-producing animals, cloned or otherwise, so that when they reach adulthood, the beneficial gene product can be extracted from their milk. Thus Polly’s milk contained the blood-clotting factor IX, used in the treatment of haemophilia B. Other diseases which might potentially be treated through pharming include emphysema and cystic fibrosis.
Therapeutic cloning: Also under investigation is "therapeutic cloning" - the direct replacement of dysfunctional tissue with healthy cells which could help sufferers of problems as diverse as Alzheimer’s and Parkinson’s disease, diabetes, heart attacks and strokes.
Xenotransplantation: Research into genetically modified pigs is seeking to eliminate the genes which cause rejection of pigs’ organs which could otherwise function well in humans.
A cure for cancer? Roslin and other research centres are trying to create genetically-modified hens whose eggs would contain complex proteins which may prove effective in fighting lung and skin cancer.