Dolly the Sheep: Her life and legacy 25 years on

As the world’s most famous celebrity sheep (to be fair, are there any others?), there was no humble farm life for Dolly, who was reared and cared for at the Roslin Institute where she made the occasional bemused media appearance for photographers.

Her personal life was chronicled in the media such that we know she went on to have a total of six lambs with a Welsh Mountain ram called David, including Bonnie, who was born in April 1998, twins Sally and Rosie in 1999, and triplets Lucy, Darcy and Cotton 2000.

READ MORE: Where next for Covid vaccinations - boosters, children, and lifelong protection?

Her death in 2003 at the tender age of six (like all the greatest celebrities, she died too soon) was also poured over amid speculation that the very cloning technology which had brought her into being may have hastened her end.

The average lifespan of a sheep is 10 to 12 years, but Dolly developed osteoarthritis aged four - the cause of which was never determined - and in February 2003 was put to sleep after CT scans revealed tumours growing in her lungs.

Subsequent research debunked any specific link to cloning, however.

The form of lung cancer she developed is fairly common, particularly among sheep kept indoors, and had been caused by an outbreak of a lung cancer-causing virus called Jaagsiekte sheep retrovirus (JSRV) at the Roslin Institute. A number of other sheep were also infected.

Two-year-old twin Maisie Ferguson from North Berwick meets Dolly the Sheep clone at the National Museum of Scotland in Edinburgh

Research led by Glasgow University concluded that fears cloning had triggered early onset arthritis were “unfounded”and in fact the “prevalence and distribution” of osteoarthritis as detected via radiographic scans of Dolly’s skeleton, which is stored by the National Museums of Scotland, was “similar to that observed in naturally conceived sheep”.

But 25 years on, what significance does Dolly still hold for science?

Her creation may have conjured up headlines likening her to a sort of ovine Frankenstein’s monster, especially in a era gripped by panic that genetically-modified tomatoes were an inevitable precursor to genetically-engineered babies, but her purpose and legacy were more prosaic.

To go back to the beginning, Dolly’s was cloned from a cell taken from the mammary gland of a six-year-old Finn Dorset sheep (hence the name ‘Dolly’ after the famously curvaceous country singer Dolly Parton) which was then transplanted into an egg cell taken from a Scottish Blackface sheep whose own nucleus - and therefore DNA - had been removed.

Dolly the Sheep was famously named after country singer Dolly Parton - who was said to be amused by the honour

The scientists behind that project, led by Ian (now Sir Ian) Wilmut, had carried out 277 of these nucleus transfers, from which only 29 were developed into embryos suitable for implanting and, in the end, only one - Dolly - reached term.

“The technique is very difficult,” Bill Ritchie, who performed the nuclear transfer, told the BBC in 2016.

“I sometimes wonder how it works at all.”

READ MORE: Why the Delta variant has left herd immunity through vaccination alone mathematically impossible

The fact that Dolly was born with the white face, as opposed to her surrogate mother’s black face, was the first visible clue that she was really a genetic duplicate of the original Finn Dorset sheep.

It was the first time that scientists had proven that cloning a mammal was possible.

In America, President Bill Clinton set up a task force to examine the legal and ethical implications of cloning amid fears it might be pursued in future as a way to, for example, bring bereaved parents’ children back from the dead.

Meanwhile, the researchers faced a backlash from some religious groups over accusations that they were “playing God”.

Despite fears that the trajectory was towards human cloning (something most scientists still regards as impossible and of no benefit anyway, except at the level of potentially using stem cells to grow replica organs for transplant), all the Roslin scientists were actually interested in was perfecting genetically modified animals.

Indeed, in the year after Dolly’s birth, Roslin produced several transgenic sheep, all secreting the human blood-clotting factor IX into their milk.

The idea was to harvest this protein for the treatment of haemophiliacs, but even the most productive of these transgenic animals (Polly the sheep) didn’t express it in high enough quantities for it to be commercially viable.

The Dolly cloning breakthrough accelerated stem cell research, including the Nobel prize winning work of Shinya Yamanaka (pictured)

Other biologists around the world set about trying to understand how Dolly was even possible, since cells like heart or skin cells (or mammary gland cells) which had matured from stem cells into their fully specialised function were at that time not thought able to revert back to that immature stem state.

Dolly’s creation suggested otherwise and opened the door to a flurry of stem cell research globally in the hope of finding cures for everything from spinal injuries to degenerative brain or muscle disorders.

Biologist Dr Shinya Yamanaka was among those inspired by Dolly to embark on experiments turning adult cells back into stem cells.

After nearly a decade of research in mice, Yamanaka and his colleagues pinpointed the four factors - now known as the Yamanaka factors - and their underlying genes which reprogramme adult cells back into undifferentiated stem cells.

Some people have turned to cloning to bring dead pets back to life

The discovery won him a Nobel Prize in2012 and paved the way to artificially reprogrammed cells, called induced pluripotent stem cells (iPS), which are now a vital tool in stem cell therapy where the goal is to grow new but genetically identical healthy cells in patients suffering from diseased or injured tissue.

It also avoids painful and invasive procedures such as harvesting stem cells from bone marrow, or from young human embryos where there are huge ethical implications let alone much a higher risk of rejection compared to those grown from a person’s own cells.

Experimental treatments are already underway in the hope that stem cells could be an effective treatment to ease or reverse conditions such as Alzheimer’s, Parkinson’s or Motor Neurone Disease, as well as paralysis caused by spinal cord damage.

READ MORE: Covid 'lab leak' hypothesis no longer just for conspiracy theorists 

There are more bizarre consequences from Dolly’s short and remarkable existence, however: a boom in ‘pet cloning’ for grief-stricken owners willing to pay top dollar to resurrect their beloved pooches and moggies.

Dr Dougie Clarke, an expert in molecular genetics at Huddersfield University, told the Yorkshire Post earlier this year that many people will pay to get a copy - or clone - of their pet.

He said: “Companies in America and South Korea have been specialising in this since 2001. The first dog to be cloned was an Afghan hound.

“But the same technology is also being used for something of real use, in the cloning of sniffer dogs that are used to search out explosives or drugs.

"Only a very small number usually make the grade, but Korean scientists managed to clone a golden Labrador retriever that was renowned for its sniffing abilities, and made several clones of it.”

PROF. IAN WILMUT OF THE ROSLIN INSTITUTE WITH DOLLY THE SHEEP AS SHE TAKES HER PLACE AS A PERMANENT EXHIBIT IN THE ROYAL MUSEUM OF SCOTLAND IN 2003

Meanwhile, Dolly is even tangentially connected to Covid via Angela Scott - one of the pioneering scientists who helped create her - and who is now the chief operating officer for Motherwell-based TC BioPharm (TCB).

The firm has just been granted permission to begin clinical trials testing its gamma-delta T cell (GDT) therapy previously used on cancer patients to determine whether it can also boost Covid patients’ immune systems.

The GDTs - the body’s first line of defence against viral infection - have been collected from healthy donors and genetically-modified by TCB into tailored products which target diseases including melanoma, lung and kidney cancers.

The trial on Covid patients will get underway at Edinburgh Royal Infirmary later this month.

And as for Dolly?

She was feted in life life like no sheep before and, in death, she is memorialised in taxidermy as one of the National Museum of Scotland’s most popular displays in an exhibition all about the ethics of creating transgenic animals

The Roslin Institute has also moved on.

While Dolly remains the centre’s most famous breakthrough, its researchers no longer work in cloning and are instead focused on more efficient technologies such as gene editing and stem cells to “refine and reduce” to use of animals, as well as improving their welfare.