Dolly the sheep

Dolly started her life, as with all other cloned animals, in a test tube. Once normal development was confirmed at six days, the embryo, that was eventually to become Dolly, was transferred into a surrogate mother. The pregnancy went without a problem and Dolly was born on 5 July 1996.

Unlike many cloned animals, who often have neonatal problems at birth, Dolly was a normal vigorous lamb and was standing and sucking unaided within minutes.

The animal technicians were aware that this was an important lamb and critical to the research team that had produced her but they were completely unaware of the impact she would finally have.

The birth of Dolly was kept under wraps until the publication of the results could be prepared. Once these results were released, the full impact of the discovery became plain to all the animal carers, as the world’s press descended on Roslin.

Most staff thought that this initial interest would be brief and quickly fade, but that was not the case and the press, in all shapes and forms, regularly visited Dolly for one reason or other for the rest of her life with interest peaking every time there was any concern over her health.

In an attempt to allow Dolly to have as normal as life as possible it was decided that she should be allowed to breed. A small welsh mountain ram was selected as her mate and between them they successfully produced six lambs.

Their first, Bonny, was born in the spring of 1998. Twins followed the next year and triplets the year after that.

Press interest in Dolly had quietened down for a while until, in the autumn of 2001, Dolly was seen to be walking stiffly. X-rays confirmed that Dolly did indeed have arthritis.

This was a blow to everyone and again fuelled the suspicion that cloned animals were destined to age prematurely. The cause of the arthritis was never established but daily anti-inflammatory treatment resolved the clinical signs within a few months.

Although the arthritis was a concern for the animal carers at Roslin, a much more serious problem was feared. In January 2000, one of the cloned sheep, Cedric, died. The post mortem revealed that Cedric had died of sheep pulmonary adenomatosis (SPA). This disease is caused by a virus that induces tumours to grow in the lungs of affected animals. The disease is incurable. SPA was a difficult disease to cope with: there were no blood tests available to confirm the diagnosis and no effective vaccines or treatments.

The most important task was to ensure that, if Dolly did develop the disease, she should not be allowed to suffer. In addition to her regular daily health checks by the animal care staff, veterinary examinations were increased and her weight was measured weekly. Dolly was as far as could be established perfectly well.

She remained healthy until Monday 10 February 2003, when an animal care worker reported that he had noted Dolly coughing. Full veterinary examinations and blood tests were conducted but failed to establish a diagnosis. A CT scan was carried out on 14 February 2003. The scan confirmed the team's worst fears: tumours were growing in Dolly’s chest.

Since a general anaesthetic had been necessary to perform the CT scan it was decided that it would be best if Dolly did not regain consciousness and an overdose of an anaesthetic agent was administered to end her life.

The development of the cloning technology was an extension of Roslin Institute's interest in the application of transgenic technology to farm animals. Transgenic mice have been available since early 1980s produced by a very sophisticated method of genetic modification through a technology using embryonic stem cells.

Cells in culture can be genetically modified in very precise ways: removing genes, substituting one gene for another, introducing a single base pair change in the genetic code. Cloning was therefore a potential alternative way of achieving the same end.

Since the mid-1980s there has been a research interest in developing new uses for farm animals and one of the research ideas being pursued since the early days was the idea of producing human proteins in the milk of transgenic cattle or sheep. Those experiments used a very simple technique for genetic modification called pro-nuclear injection.

This involved introducing the DNA construct, the human gene coding for the protein of interest, into a recently fertilised egg and taking that early embryo to term. A very small proportion of animals produced in this way carried the gene and a proportion of this small proportion expressed the gene so that human protein was produced in the milk.

This was a very inefficient means of genetic modification. There was no control over where gene was inserted or indeed how many genes were inserted and it was only possible to add genes. As part of the developing interest in this area there was a need to improve the efficiency of genetic modification, to control gene expression more reliably and ensure it was expressed in particular tissues only.

The birth of Dolly overturned the assumption among scientists that the whole process of differentiation was irreversible. We all start life as a single cell, the fertilised egg. The cell divides and multiplies and by the time we are born, there are maybe 200 different cell types, each containing the same DNA, the same  30,000 or so genes, but each has differentiated into a particular role.

That role is determined by the proportion of active genes within the cell that determines whether the cell is for example a liver cell or a nerve cell. A presumption among cell biologists was that this was a one way process of progressive and permanent change.

What Dolly demonstrated was that it is possible to take a differentiated cell and essentially turn its clock back; to reactivate all its silent genes and make the cell behave as though it was a recently fertilised egg.

Dolly was also important because she captured the public imagination. A clone, a copy, has been a very discernible strand within science fiction. The idea that there might be an exact copy of oneself somewhere in the world is a theme that has been pursued in science fiction and the prospect that it might be possible to clone a human being excited a lot of speculation and interest.

The likelihood is that the longer lasting benefit will be in the change in perception about biology. Our understanding now is that the cells in our bodies are a lot more plastic than we previously thought and it may be that as we understand more about repair processes, for various organs and tissues, we might find that this understanding informs research that is able to augment the body's normal repair mechanisms.

It may well prove to be an important factor in stem cell research and allow the derivation of stem cells from tissues other than early human embryos. This would alleviate the reservations that many people have about the use of human embryos for research or therapeutic purposes.