Dolly (5 July 1996 – 14 February 2003) was a femaleFinn-Dorset sheep and the firstmammal that wascloned from an adultsomatic cell. She was cloned by associates of theRoslin Institute in Scotland, using the process ofnuclear transfer from a cell taken from amammary gland. Her cloning proved that a cloned organism could be produced from a mature cell from a specific body part.[2] Contrary to popular belief, she was not the first animal to be cloned.[3]
The employment of adult somatic cells in lieu ofembryonic stem cells for cloning emerged from the foundational work ofJohn Gurdon, who clonedAfrican clawed frogs in 1958 with this approach. The successful cloning of Dolly led to widespread advancements within stem cell research, including the discovery ofinduced pluripotent stem cells.[4]
Dolly lived at the Roslin Institute throughout her life and produced several lambs.[5] She was euthanized at the age of six years due to a progressive lung disease. No cause which linked the disease to her cloning was found.[6]
Dolly's body was preserved and donated by the Roslin Institute in Scotland to theNational Museum of Scotland, where it has been regularly exhibited since 2003.
The cell used as the donor for the cloning of Dolly was taken from amammary gland, and the production of a healthy clone, therefore, proved that a cell taken from a specific part of the body could recreate a whole individual. On Dolly's name, Wilmut stated "Dolly is derived from a mammary gland cell and we couldn't think of a more impressive pair of glands thanDolly Parton's."[1]
Birth
Dolly was born on 5 July 1996 and had three mothers: one provided the egg, another the DNA, and a third carried the cloned embryo to term.[10] She was created using the technique ofsomatic cell nuclear transfer, where thecell nucleus from an adult cell is transferred into an unfertilizedoocyte (developing egg cell) that has had its cell nucleus removed. The hybrid cell is then stimulated to divide by an electric shock, and when it develops into ablastocyst it is implanted in a surrogate mother.[11] Dolly was the first clone produced from a cell taken from an adult mammal.[12][13] The production of Dolly showed that genes in the nucleus of such a maturedifferentiated somatic cell are still capable of reverting to an embryonictotipotent state, creating a cell that can then go on to develop into any part of an animal.[2]
Dolly's existence was announced to the public on 22 February 1997.[1] It gained much attention in the media. A commercial with Scottish scientists playing with sheep was aired on TV, and a special report inTime magazine featured Dolly.[7]Science featured Dolly as thebreakthrough of the year. Even though Dolly was not the first animal cloned, she received media attention because she was the first cloned from an adult cell.[14]
Dolly lived her entire life at theRoslin Institute in Midlothian.[15] There she was bred with aWelsh Mountain ram and produced six lambs in total. Her first lamb, named Bonnie, was born in April 1998.[5] The next year, Dolly produced twin lambs Sally and Rosie; further, she gave birth to triplets Lucy, Darcy and Cotton in 2000.[16] In late 2001, at the age of four, Dolly developedarthritis and started to have difficulty walking. This was treated withanti-inflammatory drugs.[17]
Death
On 14 February 2003, Dolly waseuthanised because she had a progressive lung disease and severe arthritis.[6] AFinn Dorset such as Dolly has a life expectancy of around 11 to 12 years, but Dolly lived 6.5 years. A post-mortem examination showed she had a form of lung cancer calledovine pulmonary adenocarcinoma, also known as Jaagsiekte,[18] which is a fairly common disease of sheep and is caused by theretrovirusJSRV.[19] Roslin scientists stated that they did not think there was a connection with Dolly being a clone, and that other sheep in the same flock had died of the same disease.[6] Such lung diseases are a particular danger for sheep kept indoors, and Dolly had to sleep inside for security reasons.[20]
Some in the press speculated that a contributing factor to Dolly's death was that she could have been born with a genetic age of six years, the same age as the sheep from which she was cloned.[21] One basis for this idea was the finding that Dolly'stelomeres were short, which is typically a result of theaging process.[22][23] The Roslin Institute stated that intensive health screening did not reveal any abnormalities in Dolly that could have come from advanced aging.[21]
In 2016, scientists reported no defects in thirteen cloned sheep, including four from the same cell line as Dolly. The first study to review the long-term health outcomes of cloning, the authors found no evidence of late-onset, non-communicable diseases other than some minor examples of osteoarthritis and concluded "We could find no evidence, therefore, of a detrimental long-term effect of cloning by SCNT on the health of aged offspring among our cohort."[24][25]
After her death Dolly's body was preserved via taxidermy and is currently on display at theNational Museum of Scotland in Edinburgh.[26]
After cloning was successfully demonstrated through the production of Dolly, many other large mammals were cloned, including pigs,[27][28]deer,[29] horses[30] and bulls.[31] The attempt to cloneargali (mountain sheep) did not produce viable embryos. The attempt to clone abanteng bull was more successful, as were the attempts to clonemouflon (a form of wild sheep), both resulting in viable offspring.[32] The reprogramming process that cells need to go through during cloning is not perfect and embryos produced by nuclear transfer often show abnormal development.[33][34] Making cloned mammals was highly inefficient back then – in 1996, Dolly was the only lamb that survived to adulthood from 277 attempts. Wilmut, who led the team that created Dolly, announced in 2007 that the nuclear transfer technique may never be sufficiently efficient for use in humans.[35] But by 2014, Chinese scientists were reported to have 70–80% success rates cloning pigs,[28] and in 2016,Sooam Biotech was producing 500 cloned embryos a day.[36] Another Koreancommercial pet cloning company,Viagen, the firm charges $50,000 (£38,000) to clone a dog, $30,000 for a cat, and $85,000 for a horse, showing cloning economy is getting more popular despite the cost.[37]
Cloning may have uses in preserving endangered species, and may become a viable tool for revivingextinct species.[38] In January 2009, scientists from the Centre of Food Technology and Research of Aragon in northern Spain announced the cloning of thePyrenean ibex, a form of wild mountain goat, which was officially declared extinct in 2000. Although the newborn ibex died shortly after birth due to physical defects in its lungs, it is the first time an extinct animal has been cloned, and may open doors for saving endangered and newly extinct species by resurrecting them from frozen tissue.[39][40]
In July 2016, four identical clones of Dolly (Daisy, Debbie, Dianna, and Denise) were alive and healthy at nine years old.[41][42] TheNottingham Dollies, were humanely euthanised following research published in 2017, natural life expectancy of sheep rarely extends beyond nine to 10 years, after re-examine Dolly's case, showing they were all aging normally.[43][44]
Scientific American concluded in 2016 that the main legacy of Dolly has not been cloning of animals but in advances intostem cell research.[45] Gene targeting was added in 2000, when researchers cloned female lamb Diana from sheep DNA altered to contain the human gene foralpha 1-antitrypsin. The human gene was specifically activated in the ewe’s mammary gland, so Diana produced milk containing humanalpha 1-antitrypsin.[46] After Dolly, researchers realised that ordinary cells could be reprogrammed toinduced pluripotent stem cells, which can be grown into any tissue.[47]
The first successful cloning of aprimate species was reported in January 2018, using the same method which produced Dolly. Two identical clones of amacaque monkey,Zhong Zhong and Hua Hua, were created by researchers in China and were born in late 2017.[48][49][50][51]
In January 2019, scientists in China reported the creation of five identical clonedgene-edited monkeys, again using this method, and the gene-editingCRISPR-Cas9 technique allegedly used byHe Jiankui in creating the first ever gene-modified human babiesLulu and Nana. The monkey clones were made in order to study several medical diseases.[52][53]
In popular culture
In 2003, Belgian artistDominique Goblet published a short comic strip about Dolly the cloned sheep with the title: “2004 Apparition de Dolly dans la campagne anglaise”[54]
^Shiels PG; Kind AJ; Campbell KH; et al. (1999). "Analysis of telomere length in Dolly, a sheep derived by nuclear transfer".Cloning.1 (2):119–25.doi:10.1089/15204559950020003.PMID16218837.
