Twenty years after the birth of Dolly the sheep, cloning remains controversial and little-used. But now a new study, started in the lab that made Dolly famous, may reduce some of that controversy by showing that cloned sheep that make it through early life healthy will likely remain that way indefinitely.
The study followed into late middle age four Dolly clones—Debbie, Denise, Dianna and Daisy, all derived from frozen cells from the same mammary gland as Dolly was—and nine sheep of other species. The 13 sheep are now all over nine years old, the sheep equivalent of a person’s seventh or eighth decade. And they are all indistinguishable from “normal” animals according to scans of their bones, readings of their blood sugar levels and detailed blood pressure monitoring. “We can say these are perfectly normal,” says Kevin Sinclair, first author on the paper, published Tuesday in Nature Communications.
Cloning is still significantly less efficient than normal breeding. Only as few as one or two out of 100 cloned embryos might develop normally into a live animal. But the new study shows that if a cloned animal survives pregnancy and the first few weeks of life, it is likely to be just as healthy as other animals of its breed. “[This study] tells us that it is possible for a small proportion of cells to produce normal offspring which would be indistinguishable from animals that were conceived naturally,” says Sinclair, a developmental biologist at the University of Nottingham, which was involved in Dolly’s creation.
Dolly’s successful birth on July 5, 1996, proved that the DNA of an adult cell could be reset to a different purpose. This led to an explosion of interest in stem cells, and a Nobel-winning discovery that differentiated cells could be turned back into multi-purpose stem cells.
Dolly died prematurely, which gave rise to the impression that cloned animals have shorter lifespans. But Sinclair says she died from a contagious illness that spread through the flock—not because of any weakness inherent in clones. She did have some arthritis in her knees, but geneticist Helen Sang at the Roslin Institute, where Dolly was born, says any sheep who was kept inside as much as Dolly was—and fed as many treats by photographers hoping for a good picture—would be subject to joint problems.
Cloning has not massively taken off in the years since Dolly, largely because of its inefficiency and due to public wariness, researchers say. The practice is used in some countries to retain farm animal traits that are considered particularly useful, like parasite resistance or climate hardiness. In Europe, public concerns over cloning have led to a ban against allowing animals that have been cloned—or their descendants—into the food supply. Some scientists believe cloning could also be used to shore up endangered species, using recovered or stored DNA.
When it was first explored, cloning was also thought to have medical potential—the initial idea was to get cloned animals to produce therapeutic proteins in their milk that could be used to treat human diseases. Now most people think gene editing will be far more useful. Still, several researchers say they hope the new study will help counter the European public’s dim view of cloning.
“Here we have such a negative perception about cloning, so something positive is very welcome,” says Pasqualino Loi, a veterinarian and reproductive biologist at the Università degli Studi di Teramo in Italy, who was on the team that created Dolly. Loi, who says research funding in Europe is a struggle because of the food-supply ban, is trying to improve the efficiency of cloning by making donor cells more closely resemble sperm cells.
Keith Campbell, a key member of the team that cloned Dolly, bred the 13 other sheep back in 2007 at the University of Nottingham. He died in 2012, at age 58, of suicide. Sinclair says the university asked him after Campbell’s death if the sheep had any scientific value and if he wanted to take over their care. “I don’t know what [Keith] had in mind for them,” Sinclair says.
He decided that watching the sheep age would provide the first scientifically rigorous review of the aging of cloned animals, leading to this new study. He now wants to follow the sheep for their last year or so of life and see whether they are as normal at the molecular level as they are in terms of behavior and performance measures. “Even if we pick up minor differences at the molecular or cellular level, the conclusion is, ‘So what?’” Sinclair says. “We’re not picking up any problems that are causing these animals any distress.”
Shoukhrat Mitalipov, a reproductive biologist at Oregon Health Sciences University in Portland, adds that he is glad his friend’s work has survived him. “We learned so much from Keith,” he says. “I’m very happy that there’s still publications coming out from the work he contributed.”