Dolly, the first cloned animal, didn’t live long. But her clones are doing well. Why?
Four clones of Dolly the sheep known as Nottingham’s Dollies — Debbie, Denise, Dianna and Daisy — have just celebrated their 9th birthdays and, save for a bit of arthritis, are in good health, according to a new study that concludes clones can live long and healthy lives.
Given the apparent success of the sheep cloning project, research on cell reprogramming conducted by scientists around the globe is expected to move forward, with possible applications to human reproduction, health and agriculture.
The new findings, reported in the journal Nature Communications, come during the 20th anniversary year of the birth of Dolly (1996–2003), who was the first mammal to be successfully cloned from an adult cell. She died from a progressive lung disease at the relatively young age of 6; the average lifespan of a sheep is 10–12 years.
The scientists believe that a number of factors help to explain why the quartet of Nottingham’s Dollies is thriving, even though they were derived from the same cell line that produced Dolly.
“Environment will play a big role in longevity and health,” lead author Kevin Sinclair, a professor of developmental biology at the University of Nottingham, told Discovery News. “You could imagine a study where you separated identical twins at birth and placed one in an impoverished environment and the other in an enriched environment. Life expectancy and health will differ considerably. However, Dolly and the other four clones here at Nottingham were all well managed.”
Other possible reasons include the fact that the Nottingham Dollies have the same nuclear DNA as Dolly did, but different mitochondrial DNA because the eggs came from different donors. Epigenetic variations — i.e., modification of gene expression rather than alteration of the genetic code itself — vary between individual animals and could also contribute to health differences.
“Dolly died because she picked up a virus that causes lung tumors,” Sinclair said. He was a close colleague of the late Keith Campbell, also of the University of Nottingham, who was a leader of the initial Dolly cloning project.
For the more recent work led by Sinclair, Notthingham’s Dollies and other cloned sheep at the university last year underwent a barrage of medical tests. The examinations looked for obesity, hypertension, osteoarthritis, glucose tolerance and insulin sensitivity. The researchers also examined the heart rate, blood pressure and entire muscle/bone health of the existent cloned sheep.
The tests found that all of the clones showed no sign of disease or other health problems, save for some mild cases of arthritis as well as, in Debbie’s case, a more moderate form of this degeneration.
The cloning technology that yielded Debbie and her sheep sisters is called somatic cell nuclear transfer (SCNT). For this process, a nucleus is removed from a healthy egg that then becomes the host for a nucleus, which is transplanted from another cell, such as a skin cell.
“SCNT can and is being used in farm animal breeding in North America and Asia,” Sinclair said. “It can be used to increase responses to selection for traits of agricultural importance, such as growth, milk yield, animal health (disease resistance), and environmental impact. If you work with genetically modified donor cells, then you can also produce transgenic (genetically altered) animals by SCNT — again with improved characteristics for the aforementioned traits.”
SCNT has been used to generate human embryonic stem cells. These hold potential for therapeutic purposes and also for research to better understand human health issues.
Although other experts say it is now biologically possible to clone a human, the ethics and legality surrounding such a possibility are a minefield.
Sinclair said, “Human cloning is banned in every country that I am aware of. I can think of no reason why you would want to clone a human and can see no benefit of it.”
Another problem is that the efficiency of SCNT remains low, meaning that a relatively large number of cloned embryos generated in a laboratory are required to produce cloned offspring compared to natural conception or in vitro fertilization.
“As with natural conception and IVF there are losses throughout gestation and in the period shortly after birth; it’s just that these losses are greater with cloned embryos,” Sinclair said.
Embryo loss, pregnancy complications and the deaths of newborns are still high as a result. Ethical concerns then remain concerning the welfare of cloned animals, despite the good health report for the Nottingham Dollies. Anecdotal evidence suggests that cloned cattle can also live long and healthy lives, once past the critical early life risks.
Bruce Whitelaw, a professor of animal biotechnology at the University of Edinburgh’s Roslin Institute, told Discovery News that the new information about the health of the Nottingham Dollies is “another part of the evidence that animal biotechnologies can be successfully used.”
Helen Sang, also with the University of Edinburgh, said that there is no evidence that the cloned sheep have aged prematurely, which was proposed to be an adverse effect of cloning, particularly from cells that were isolated from an adult animal and therefore could have been expected to have aged in some way already.
“It is important to have good data to answer the question of premature aging of cloned animals and to have data that demonstrate that those that survive to adulthood are indistinguishable from equivalent animals,” Sang said. “This has implications for the regulation of the use of cloned animals and their offspring in agriculture.”
The Nottingham Dollies, which are reaching the upper limit of a sheep’s average lifespan, may not have long for this world.
Sinclair explained, “Our clones are getting quite old now and so in the next year or so we will consider euthanasia so that we can, in a controlled manner, harvest tissues and cells post mortem so that we can undertake more detailed molecular assessments of age and health.”
He and his team are more focused now on assisted reproduction by looking at ways to improve embryo culture in the laboratory, which could also benefit cloning methods. His university does not have an active program of research into cloning at present, but he said that there are other groups with such a focus outside of the U.K.