tag:theconversation.com,2011:/us/topics/dolly-the-sheep-35866/articlesDolly the sheep – The Conversation2018-03-01T09:37:38Ztag:theconversation.com,2011:article/926562018-03-01T09:37:38Z2018-03-01T09:37:38ZWhy Barbra Streisand’s cloned dogs aren’t identical to the original pet<p>Wouldn’t it be wonderful if we could bring back a deceased loved one? Such ideas used to be pure science fiction, but recent advances in biotechnology seem to have brought this possibility within reach (at least for the wealthy). </p>
<p>When American singer-actress Barbra Streisand lost her beloved dog Sammie last year, she decided to have her cloned. She’s now raising <a href="https://www.vanityfair.com/style/2018/02/barbra-streisand-cloned-her-dogs">Miss Scarlet and Miss Violet</a>, both of whom are exact genetic replicas of Sammie. (You’ll be glad to know that any pet owner can do the same: for a mere <a href="http://fortune.com/2018/02/28/cost-to-clone-pet-barbra-streisand/">US$100,000 or so</a>, you too could have a genetic replica of your favourite cat or dog.) </p>
<p>But Miss Scarlett and Miss Violet almost certainly won’t turn out to be identical, mini versions of Sammie. </p>
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Read more:
<a href="https://theconversation.com/dolly-the-sheep-didnt-develop-premature-arthritis-after-all-and-thats-good-news-for-cloning-87978">Dolly the sheep didn't develop premature arthritis after all – and that's good news for cloning</a>
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<h2>Well hello Dolly</h2>
<p>Research on cloning started in the 1960s, when British
biologist <a href="http://dev.biologists.org/content/140/12/2446#ref-5">John Gurdon</a> showed that a frog egg’s nucleus (which contains the DNA) could be swapped for another nucleus extracted from an intestinal cell, and that such eggs could develop into tadpoles. This technique makes it possible to create individuals that share every single one of the thousands of genes in the original genome. By comparison, you share only about 50% of your genes with your mother. </p>
<p>The same nucleus-swapping technique can be used with mammals. In 1996, <a href="https://theconversation.com/20-years-after-dolly-everything-you-always-wanted-to-know-about-the-cloned-sheep-and-what-came-next-72655">Dolly the sheep</a> became the first cloned mammal, and today the technology is available to clone a human being – if we wanted to. </p>
<p>But what does it actually mean to be cloned? And can it bring back Sammie?</p>
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<img alt="" src="https://images.theconversation.com/files/208440/original/file-20180301-152587-17nw0q4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/208440/original/file-20180301-152587-17nw0q4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=401&fit=crop&dpr=1 600w, https://images.theconversation.com/files/208440/original/file-20180301-152587-17nw0q4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=401&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/208440/original/file-20180301-152587-17nw0q4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=401&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/208440/original/file-20180301-152587-17nw0q4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=504&fit=crop&dpr=1 754w, https://images.theconversation.com/files/208440/original/file-20180301-152587-17nw0q4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=504&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/208440/original/file-20180301-152587-17nw0q4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=504&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Streisand’s dogs are the Coton de Tulear breed, known for a cotton-like coat.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/coton-de-tulear-dog-nature-background-1031750137?src=ItHRcW7g0jKn_E0JrOG9Sg-1-4">from www.shutterstock.com</a></span>
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<p>Popular culture is permeated by the belief that the features of a plant or animal (including a human being) are fully determined by its genes. Newspaper articles regularly announce the (often dubious) discovery of a “gene for” some physical feature or personality trait. So it’s hardly surprising that the production of exact genetic replicas through cloning is seen as a way to recreate individuals with all their features intact. That’s certainly how it works in the movies. </p>
<p>The reality is far more complicated. </p>
<p>In a recent <a href="http://variety.com/2018/film/news/barbra-streisand-oscars-sexism-in-hollywood-clone-dogs-1202710585/">interview with Variety</a>, Streisand noted that Miss Scarlet and Miss Violet “have different personalities” and “I’m waiting for them to get older so I can see if they have {Sammie’s} brown eyes and her seriousness”. </p>
<p>Streisand’s observations are consistent with evidence that human identical twins (who also share all their genes) often <a href="https://theconversation.com/how-does-genetics-explain-non-identical-identical-twins-55479">diverge markedly</a> in personality, health and even physical features. </p>
<h2>Same genes, but different</h2>
<p>How could genetically identical individuals have different features? </p>
<p>The answer is that genes are not the whole story. Scientists have long been aware that environmental factors also play an important role in shaping an individual’s development and adult traits. Such developmental responses to environment are called plasticity.</p>
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<img alt="" src="https://images.theconversation.com/files/208439/original/file-20180301-152584-h815q5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/208439/original/file-20180301-152584-h815q5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/208439/original/file-20180301-152584-h815q5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/208439/original/file-20180301-152584-h815q5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/208439/original/file-20180301-152584-h815q5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/208439/original/file-20180301-152584-h815q5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/208439/original/file-20180301-152584-h815q5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Yes, identical twins have the same genes – but the environments they experience are different.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/twin-brothers-man-outdoor-sunset-relations-1033564267?src=zKexVhOElezlFvpj08JWbg-1-70">from www.shutterstock.com</a></span>
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<p>Over the past two decades, biologists have learned a great deal about how plasticity works at the molecular and cellular level. It turns out that many features are shaped by <a href="https://theconversation.com/explainer-what-is-epigenetics-13877">epigenetic</a> factors – molecules that are associated with the DNA (examples include methyl-groups and small RNAs), and structural features of chromosomes (such as how tightly the DNA is bound up). </p>
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Read more:
<a href="https://theconversation.com/how-does-genetics-explain-non-identical-identical-twins-55479">How does genetics explain non-identical identical twins?</a>
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<p>Epigenetic factors function like on/off (or dimmer) switches for genes throughout the genome. Environmental factors, such as diet, stress and even social interactions, can flip those switches. </p>
<p>Some of these environmental effects can occur in the womb, which is why maternal malnutrition, smoking and drinking can have such dire consequences for children. Of course, development after birth is also affected by factors such as diet and interactions with parents, siblings or other individuals. </p>
<h2>We still don’t know a lot</h2>
<p>Intriguingly, there is now a great deal of evidence that some epigenetic factors, and other factors that are also influenced by the environment, can be <a href="https://theconversation.com/flies-give-another-twist-in-the-evolving-story-of-heredity-32509">passed down to children</a>, and sometimes grandchildren and beyond. In other words, some of your traits may be determined by environmental switches that were flipped in your parents’ eggs or sperm even before you were conceived, or even flipped in your more remote ancestors. Such <a href="https://press.princeton.edu/titles/11278.html">nongenetic inheritance</a> is becoming an important area of research in the health sciences as well as evolutionary ecology. </p>
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<strong>
Read more:
<a href="https://theconversation.com/kids-learning-and-health-is-shaped-by-genes-they-dont-inherit-as-well-as-genes-they-do-90852">Kids' learning and health is shaped by genes they don't inherit, as well as genes they do</a>
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<p>What this means is that Miss Scarlet and Miss Violet will surely differ from Sammie in many traits, despite having a genome identical to hers. They developed from different eggs (which brings a range of differing factors), were carried inside a different womb to the one Sammie grew in, and were raised by a different mother. They had different experiences and social interactions. Their personalities and physical features bear the imprint of all these prenatal and postnatal factors. </p>
<p>So, sad to say, cloning will not bring back Sammie, nor your own beloved pet. But, on the bright side, this also means that all of us, identical twins included, are truly unique and irreproducible individuals.</p><img src="https://counter.theconversation.com/content/92656/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Russell Bonduriansky receives funding from the Australian Research Council. </span></em></p>Humans, and indeed pet dogs, are more than just products of genes – even before the moment of conception, environments play a vital role in shaping us.Russell Bonduriansky, Evolutionary Biologist, UNSW SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/921432018-02-22T08:10:24Z2018-02-22T08:10:24ZThe ban on human cloning is stupid – Brexit is UK’s chance to get rid of it<figure><img src="https://images.theconversation.com/files/207285/original/file-20180221-132647-xfzym0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/background-many-peoples-crowd-utopia-city-537950647?src=HeoL-_A0VXoOzBc-kj7m9Q-3-35">Barandash Karandashich</a></span></figcaption></figure><p>According to the <a href="https://ec.europa.eu/info/aid-development-cooperation-fundamental-rights/your-rights-eu/eu-charter-fundamental-rights_en">EU Charter of Fundamental Rights</a>, human cloning should be illegal because “everyone has the right to respect for his or her physical and mental integrity”. The UK’s laws have to be in line with this – but only until Brexit. Fifteen years to the month since the <a href="http://news.bbc.co.uk/1/hi/sci/tech/2764039.stm">death of</a> Dolly the sheep in Edinburgh, it’s time to take this opportunity to reconsider the law. </p>
<p>The relevant UK legislation is the <a href="https://www.legislation.gov.uk/ukpga/2008/22/contents">Human Fertilisation and Embryology Act (2008)</a>. Section three stipulates that it is a crime to place a human embryo in a woman unless it was created by the fertilisation of an egg from the ovaries of a woman by sperm from the testes of a man. Since human cloning creates embryos in a different way – replacing the nucleus of a human egg cell by DNA from a somatic cell, for instance – it is outlawed. </p>
<p>The EU charter’s concerns about people’s mental and physical integrity are not the only supposed justifications for criminalising human cloning. The <a href="http://www.europarl.europa.eu/sides/getDoc.do?pubRef=-//EP//TEXT+TA+P5-TA-2000-0376+0+DOC+XML+V0//EN">European parliamentary resolution</a> on human cloning from 1997 says it must be outlawed for being:</p>
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<p>… contrary to the principle of equality of human beings as it permits a eugenic and racist selection of the human race, it offends against human dignity … [And] each individual has a right to his or her own genetic identity …</p>
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<p>There is a common misunderstanding that human cloning is the replication of people. This goes to the heart of why it is seen as abhorrent. Rather, cloning is the replication of gene sets. It is analogous to when people produce twins, where the fertilised egg splits to create two embryos with the same, or virtually the same, DNA. </p>
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<a href="https://images.theconversation.com/files/207287/original/file-20180221-132647-1bj56ag.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/207287/original/file-20180221-132647-1bj56ag.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/207287/original/file-20180221-132647-1bj56ag.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/207287/original/file-20180221-132647-1bj56ag.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/207287/original/file-20180221-132647-1bj56ag.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/207287/original/file-20180221-132647-1bj56ag.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/207287/original/file-20180221-132647-1bj56ag.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/207287/original/file-20180221-132647-1bj56ag.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Twin towers.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Marian_and_Vivian_Brown.jpg#/media/File:Marian_and_Vivian_Brown.jpg">Wikimedia</a></span>
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<p>Just as “identical twins” have more or less identical gene sets, so would a clone.</p>
<p>Identical twins are not identical people. Each twin is unique, just like any other person. In the same way, the bodies and faces of human clones would not be precisely the same – and nor would their minds, personalities, opinions, tastes, appetites or preferences. </p>
<p>Like twins, clones would often make different choices when they were placed in similar circumstances. The only added difference would be that they would usually be younger than the person from whose body they were cloned by much more than the minutes or hours characteristic of twins. </p>
<h2>Not Nazi</h2>
<p>When you see things in this light, it is harder to understand how this would violate the “physical and mental integrity” of anyone involved. It seems obvious that twins have no more or less physical and mental integrity than people who are not twins. Why would it be different with clones? </p>
<p>Similarly, there seems no reason to suppose that we have a right to genetic uniqueness. It would be absurd to say that the existence of one member of a pair of twins is a violation of the right of the other one to genetic uniqueness. </p>
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<a href="https://images.theconversation.com/files/207291/original/file-20180221-132663-ammcip.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/207291/original/file-20180221-132663-ammcip.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/207291/original/file-20180221-132663-ammcip.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=416&fit=crop&dpr=1 600w, https://images.theconversation.com/files/207291/original/file-20180221-132663-ammcip.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=416&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/207291/original/file-20180221-132663-ammcip.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=416&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/207291/original/file-20180221-132663-ammcip.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=522&fit=crop&dpr=1 754w, https://images.theconversation.com/files/207291/original/file-20180221-132663-ammcip.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=522&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/207291/original/file-20180221-132663-ammcip.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=522&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">‘Meh.’</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Hello_Dolly.jpg">Wikimedia</a></span>
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<p>Neither is there any reason to suppose cloning would facilitate a “eugenic” or “racist” selection of offspring any more than normal human reproduction with a chosen partner. It certainly need not do so. To ban it on this suggested ground seems whimsical and irrational. </p>
<p>I would say the same about the idea that it “offends human dignity”. Whose human dignity would be protected by such a ban? The human dignity of people who want and permit their bodies to be cloned? The human dignity of people who would not be born was it not for cloning?</p>
<p>People should be respected as people regardless of the biological derivation history of their embryos. We should repeal the UK legislation against human cloning and think very carefully about whether, how and why we should replace it.</p><img src="https://counter.theconversation.com/content/92143/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Hugh McLachlan does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>What might first seem unarguable starts to look shaky when you bring twins into the equation.Hugh McLachlan, Professor Emeritus of Applied Philosophy, Glasgow Caledonian UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/879782017-11-23T14:00:27Z2017-11-23T14:00:27ZDolly the sheep didn’t develop premature arthritis after all – and that’s good news for cloning<p>Dolly the sheep was just six and a half years old when she died, over half the age most sheep live to. Yet despite her relative youth, she was also thought to be suffering from osteoarthritis, a disease usually found in much older sheep. Dolly was the first animal to be cloned from a fully grown adult, and some speculated that this meant her biological age (how old her DNA was) was effectively older than her chronological age (how long she had been alive). </p>
<p><a href="https://www.ncbi.nlm.nih.gov/pubmed/10360570">Evidence that</a> Dolly’s DNA was indeed older than that of similarly aged non-cloned sheep, and <a href="http://www.sciencemag.org/news/2002/01/dolly-has-arthritis">her diagnosis</a> with early onset osteoarthritis at the age of five and a half seemed to confirm this.</p>
<p>But my colleagues and I have <a href="http://nature.com/articles/doi:10.1038/s41598-017-15902-8">published new research</a> that reveals Dolly, and other clones born around that time, showed no abnormal pattern of osteoarthritis after all. This is important because it means it should be possible to reprogram adult cells to be used for cloning without carrying over the legacy of ageing from the original organism. In short, clones may be like brand new organisms rather than copies of old ones.</p>
<p>Since <a href="https://www.nature.com/articles/385810a0">Dolly’s birth in 1997</a>, more than 20 animal species have been cloned using somatic cell nuclear transfer (SCNT), the process of turning adult cells into new embryos. A <a href="https://rnd.edpsciences.org/articles/rnd/abs/2005/03/r5312/r5312.html">number of studies</a> have investigated the health of cloned offspring but mostly looking at the loss of embryos during pregnancy and complications that occur around and shortly after the time of birth. Few studies were able to assess the long-term health implications of cloning and so we didn’t know whether or not clones suffered disproportionately from common, age-related diseases such as diabetes, heart disease and osteoarthritis.</p>
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<img alt="" src="https://images.theconversation.com/files/196154/original/file-20171123-18001-j4bt8f.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/196154/original/file-20171123-18001-j4bt8f.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/196154/original/file-20171123-18001-j4bt8f.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/196154/original/file-20171123-18001-j4bt8f.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/196154/original/file-20171123-18001-j4bt8f.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/196154/original/file-20171123-18001-j4bt8f.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/196154/original/file-20171123-18001-j4bt8f.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Professor David Gardner setting up radiographs.</span>
<span class="attribution"><span class="source">University of Nottingham</span></span>
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<p>Then in 2016, my colleagues and I assessed a group of 13 aged cloned sheep (eight to nine years of age), four of which were cloned from the mammary-gland cell line that gave rise to Dolly. These animals therefore were effectively clones of Dolly. <a href="https://www.nature.com/articles/ncomms12359">We found</a> only mild, and in one case moderate, evidence of osteoarthritis in these sheep following X-ray and MRI analyses.</p>
<p>None of these animals presented clinical symptoms of this disease and they were otherwise perfectly healthy. This led us to question the nature and extent of osteoarthritis in Dolly and whether or not cloning by SCNT contributed to this disease in Dolly.</p>
<h2>New evidence</h2>
<p>Unfortunately, X-ray records of Dolly’s osteoarthritis (taken some 16 years ago) were not preserved. They were limited, in any case, to records of just the left and right knee. Fortunately, Dolly’s skeleton and that of two other important cloned sheep (<a href="https://www.nature.com/articles/380064a0">Megan and Morag</a>) created at the University of Edinburgh’s Roslin Institute are kept by National Museums Scotland, which has an <a href="https://www.nms.ac.uk/explore-our-collections/stories/natural-world/dolly-the-sheep/">exhibit on Dolly</a>. Dolly and Morag died prematurely after contracting a virus that causes lung tumours in sheep.</p>
<p>We made detailed X-ray analyses of the skeletons and that of Dolly’s first lamb (Bonnie) who was conceived naturally and lived for nine and a half years. We found that the nature and extent of osteoarthritis in Dolly was no different to that of the cloned sheep at Nottingham, nor was it different from similarly aged sheep conceived naturally.</p>
<p>X-ray evidence of osteoarthritis was greatest for Megan, who lived to 13 and a half (equivalent in human terms to someone in their 90s). In contrast, there was no evidence of osteoarthritis in her clone Morag, who died at four and a half.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/196151/original/file-20171123-18001-1j9kdnk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/196151/original/file-20171123-18001-1j9kdnk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/196151/original/file-20171123-18001-1j9kdnk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/196151/original/file-20171123-18001-1j9kdnk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/196151/original/file-20171123-18001-1j9kdnk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/196151/original/file-20171123-18001-1j9kdnk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/196151/original/file-20171123-18001-1j9kdnk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Professor Sandra Corr checking radiographs.</span>
<span class="attribution"><span class="source">University of Nottingham</span></span>
</figcaption>
</figure>
<p>From this evidence, we conclude the original concerns that cloning by SCNT had caused early-onset osteoarthritis in Dolly were unfounded. There are many other naturally occurring factors that could explain why Dolly, and not the Nottingham-Dolly clones, showed clinical signs of arthritis. Not least of which is the fact that Dolly produced six lambs in her lifetime, including a pair of twins and a set of triplets, whereas the cloned sheep at Nottingham were not bred.</p>
<p>This study, and the one <a href="https://theconversation.com/dollys-sisters-show-cloned-animals-dont-grow-old-before-their-time-63090">we published</a> last year on the health of the cloned animals, indicate you can produce perfectly normal and healthy animals using advanced breeding technologies such as SCNT. Although the number of animals we have produced in this way is small, they prove it is possible and so many more could follow.</p>
<p>Since the birth of Dolly, there has been considerable improvements in the overall efficiency of cloning by SCNT. Work in several countries continues to seek further improvements and it’s likely that issues associated with pregnancy losses and complications around the time of birth will be reduced further. Improvements of this nature could open up the possibility to, for example, use SCNT to create genetically modified animals that are resistant to certain diseases such as swine flu. This would help minimise the need for antibiotics and reduce the risk of transmission to humans.</p><img src="https://counter.theconversation.com/content/87978/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kevin Sinclair does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>New research suggests Dolly’s cloning process didn’t create health problems.Kevin Sinclair, Professor of Developmental Biology, University of NottinghamLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/726552017-02-17T16:34:08Z2017-02-17T16:34:08Z20 years after Dolly: Everything you always wanted to know about the cloned sheep and what came next<figure><img src="https://images.theconversation.com/files/156672/original/image-20170213-18085-j4tnpf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Well hello, Dolly.</span> <span class="attribution"><a class="source" href="http://dolly.roslin.ed.ac.uk/media/creative-commons-images/">Photo courtesy of The Roslin Institute, The University of Edinburgh.</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span></figcaption></figure><p>It’s been 20 years since scientists in Scotland told the world about <a href="http://dolly.roslin.ed.ac.uk/facts/the-life-of-dolly/">Dolly the sheep</a>, the first mammal successfully <a href="http://dx.doi.org/10.1038/385810a0">cloned from an adult body cell</a>. What was special about Dolly is that her “parents” were actually a single cell originating from mammary tissue of an adult ewe. Dolly was an exact genetic copy of that sheep – a clone.</p>
<p>Dolly captured people’s imaginations, but those of us in the field had seen her coming through <a href="http://doi.org/10.1038/380064a0">previous research</a>. I’ve been working with <a href="http://doi.org/10.1002/jez.1402280217">mammalian embryos for over 40 years</a>, with some work in my lab specifically focusing on various methods of cloning cattle and other livestock species. In fact, one of the coauthors of the paper announcing Dolly worked in our laboratory for three years prior to going to Scotland to help create the famous clone. </p>
<p>Dolly was an important milestone, inspiring scientists to continue improving cloning technology as well as to pursue new concepts in stem cell research. The endgame was never meant to be armies of genetically identical livestock: Rather, researchers continue to refine the techniques and combine them with other methods to turbocharge traditional animal breeding methods as well as gain insights into aging and disease.</p>
<h2>Not the usual sperm + egg</h2>
<p>Dolly was a perfectly normal sheep who became the mother of numerous normal lambs. She lived to six and a half years, when she <a href="http://www.nature.com/news/1998/030217/full/news030217-6.html">was eventually put down</a> after a contagious disease spread through her flock, infecting cloned and normally reproduced sheep alike. Her life wasn’t unusual; it’s her origin that made her unique.</p>
<p>Before the decades of experiments that led to Dolly, it was thought that normal animals could be produced only by fertilization of an egg by a sperm. That’s how things naturally work. These germ cells are the only ones in the body that have their genetic material all jumbled up and in half the quantity of every other kind of cell. That way when these so-called haploid cells come together at fertilization, they produce one cell with the full complement of DNA. Joined together, the cell is termed diploid, for twice, or double. Two halves make a whole.</p>
<p>From that moment forward, nearly all cells in that body have the same genetic makeup. When the one-cell embryo duplicates its genetic material, both cells of the now two-cell embryo are genetically identical. When they in turn duplicate their genetic material, each cell at the four-cell stage is genetically identical. This pattern goes on so that each of the trillions of cells in an adult is genetically exactly the same – whether it’s in a lung or a bone or the blood.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/157065/original/image-20170216-27406-dqe9xp.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/157065/original/image-20170216-27406-dqe9xp.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/157065/original/image-20170216-27406-dqe9xp.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=273&fit=crop&dpr=1 600w, https://images.theconversation.com/files/157065/original/image-20170216-27406-dqe9xp.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=273&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/157065/original/image-20170216-27406-dqe9xp.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=273&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/157065/original/image-20170216-27406-dqe9xp.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=343&fit=crop&dpr=1 754w, https://images.theconversation.com/files/157065/original/image-20170216-27406-dqe9xp.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=343&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/157065/original/image-20170216-27406-dqe9xp.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=343&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">In somatic cell nuclear transfer, all the DNA comes from a single adult cell.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Cloning_diagram_english.svg">Belkorin</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>In contrast, Dolly was produced by what’s called <a href="http://doi.org/10.1146/annurev-animal-031412-103709">somatic cell nuclear transfer</a>. In this process, researchers remove the genetic material from an egg and replace it with the nucleus of some other body cell. The resulting egg becomes a factory to produce an embryo that develops into an offspring. No sperm is in the picture; instead of half the genetic material coming from a sperm and half from an egg, it all comes from a single cell. It’s diploid from the start.</p>
<h2>Long research path led to Dolly</h2>
<p>Dolly was the culmination of hundreds of cloning experiments that, for example, showed diploid embryonic and fetal cells could be parents of offspring. But there was no way to easily know all the characteristics of the animal that would result from a cloned embryo or fetus. Researchers could freeze a few of the cells of a 16-cell embryo, while going on to produce clones from the other cells; if a desirable animal was produced, they could thaw the frozen cells and make more copies. But this was impractical because of low success rates.</p>
<p>Dolly demonstrated that adult somatic cells also could be used as parents. Thus, one could know the characteristics of the animal being cloned.</p>
<p>By my calculations, Dolly was the single success from 277 tries at somatic cell nuclear transfer. Sometimes the process of cloning by somatic cell nuclear transfer still produces abnormal embryos, most of which die. But the process has greatly improved so success rates <a href="http://www.fda.gov/AnimalVeterinary/SafetyHealth/AnimalCloning/ucm124840.htm">now are more like 10 percent</a>; it’s highly variable, though, depending on the cell type used and the species.</p>
<p>More than 10 different cell types have been used successfully as “parents” for cloning. These days most cloning is done using cells obtained by <a href="http://assets.redangus.org/media/Documents/ARA_Magazine/Archived_Issues/2006/11-November/An_Update_On_The_Science_And_Commercialization_Of_Cloning_Cattle.pdf">biopsying skin</a>. </p>
<h2>More than genes can affect a clone</h2>
<p>Genetics is only part of the story. Even while clones are genetically identical, their phenotypes – the characteristics they express – will be different. It’s like naturally occurring identical twins: They share all their genes <a href="http://doi.org/10.1016/b978-012174597-4.50012-0">but they’re not really exactly alike</a>, especially if reared in different settings.</p>
<p>Environment plays a huge role for some characteristics. Food availability can influence weight. Diseases can stunt growth. These kinds of lifestyle, nutrition or disease effects can influence which genes are turned on or off in an individual; these are called <a href="http://learn.genetics.utah.edu/content/epigenetics/">epigenetic effects</a>. Even though all the genetic material may be the same in two identical clones, they might not be expressing all the same genes.</p>
<figure class="align-center zoomable">
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<figcaption>
<span class="caption">Cloning a winner doesn’t guarantee success for the next generation.</span>
<span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/CORRECTION-Kentucky-Derby-Horse-Racing/29aa09fe40e94a58ad4bd7be60b0fe36/27/1">AP Photo/Darron Cummings</a></span>
</figcaption>
</figure>
<p>Consider the <a href="http://doi.org/10.1530/REP-07-0069">practice of cloning winning racehorses</a>. Clones of winners sometimes also will be winners – but most of the time they’re not. This is because winners are outliers; they need to have the right genetics, but also the right epigenetics and the right environment to reach that winning potential. For example, one can never exactly duplicate the uterine conditions a winning racehorse experienced when it was a developing fetus. Thus, cloning champions usually leads to disappointment. On the other hand, <a href="http://www.wiley.com/WileyCDA/WileyTitle/productCd-0813819717.html">cloning a stallion</a> that sires a high proportion of race-winning horses will result very reliably in a clone that similarly sires winners. This is a genetic rather than a phenotypic situation.</p>
<p>Even though the genetics are reliable, there are aspects of the cloning procedure that mean the epigenetics and environment are suboptimal. For example, sperm have <a href="http://doi.org/10.1016/j.rbmo.2010.02.015">elegant ways of activating the eggs they fertilize</a>, which will die unless activated properly; with cloning, activation usually is accomplished by a strong electric shock. Many of the steps of cloning and subsequent embryonic development are done in test tubes in incubators. These conditions are not perfect substitutes for the female reproductive tract where fertilization and early embryonic development normally occur. </p>
<p><a href="http://doi.org/10.1038/nbt0102-13">Sometimes abnormal fetuses develop to term</a>, resulting in <a href="http://doi.org/10.1530/REP-07-0069">abnormalities at birth</a>. The most striking abnormal phenotype of some clones is termed “<a href="http://doi.org/10.1530/ror.0.0030155">large offspring syndrome</a>,” in which calves or lambs are 30 or 40 percent larger than normal, resulting in difficult birth. The problems stem from <a href="http://dx.doi.org/10.1016/j.theriogenology.2016.05.017">an abnormal placenta</a>. At birth, these clones are genetically normal, but are overly large, and tend to be hyperinsulinemic and hypoglycemic. (The conditions normalize over time once the offspring is no longer influenced by the abnormal placenta.)</p>
<p>Recent improvements in cloning procedures have greatly reduced these abnormalities, which also occur with natural reproduction, but at a much lower incidence.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/157068/original/image-20170216-27402-5jux98.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/157068/original/image-20170216-27402-5jux98.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/157068/original/image-20170216-27402-5jux98.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=483&fit=crop&dpr=1 600w, https://images.theconversation.com/files/157068/original/image-20170216-27402-5jux98.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=483&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/157068/original/image-20170216-27402-5jux98.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=483&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/157068/original/image-20170216-27402-5jux98.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=607&fit=crop&dpr=1 754w, https://images.theconversation.com/files/157068/original/image-20170216-27402-5jux98.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=607&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/157068/original/image-20170216-27402-5jux98.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=607&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Removing genetic material from the nucleus of a cell.</span>
<span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/Associated-Press-Finance-amp-Business-Texas-U-/7d64afe751e1da11af9f0014c2589dfb/124/0">AP Photo/Thomas Terry</a></span>
</figcaption>
</figure>
<h2>Continuing onward with cloning</h2>
<p>Many thousands of cloned mammals have been produced in nearly two dozen species. Very few of these concern practical applications, such as cloning a famous Angus bull named Final Answer (who recently died at an old age) in order to produce more high-quality cattle via his clone’s sperm. </p>
<p>But the cloning research landscape is changing fast. The driving force for producing Dolly was not to <a href="http://doi.org/10.1126/science.280.5368.1400">produce genetically identical animals</a>. Rather researchers want to combine cloning techniques with other methods in order to efficiently change animals genetically – much quicker than traditional animal breeding methods that take decades to make changes in populations of species such as cattle.</p>
<p>One recent example is <a href="http://doi.org/10.1038/nbt.3560">introducing the polled (no horns) gene into dairy cattle</a>, thus eliminating the need for the painful process of dehorning. An even more striking application has been to produce a strain of pigs that is <a href="http://doi.org/10.1038/nbt.3434">incapable of being infected</a> by the very contagious and debilitating PRRS virus. Researchers have even made cattle that <a href="http://doi.org/10.1038/nbt1271">cannot develop Mad Cow Disease</a>. For each of these procedures, somatic cell nuclear transplantation is an essential part of the process.</p>
<p>To date, the most valuable contribution of these somatic cell nuclear transplantation experiments has been the scientific information and insights gained. They’ve enhanced our understanding of normal and abnormal embryonic development, including aspects of aging, and more. <a href="http://doi.org/10.17226/24623">This information is already helping</a> reduce birth defects, improve methods of circumventing infertility, develop tools to fight certain cancers and even decrease some of the negative consequences of aging – in livestock and even in people. Two decades since Dolly, important applications are still evolving.</p><img src="https://counter.theconversation.com/content/72655/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>George Seidel receives funding from various sources, but not recently for cloning research. In 1996, he received a small grant from the Colorado State University Agricultural Experiment Station to study gene expression in cloned embryos. Seidel has been affiliated with Colorado State University since 1971.</span></em></p>In 1997, scientists announced they’d created a healthy sheep cloned from another ewe’s mammary gland cell. Two decades on, the technique is being refined and applied to new challenges.George Seidel, Professor of Biomedical Sciences, Colorado State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/730312017-02-17T16:34:05Z2017-02-17T16:34:05ZMore lessons from Dolly the sheep: Is a clone really born at age zero?<figure><img src="https://images.theconversation.com/files/157348/original/image-20170217-10195-zo9i2d.png?ixlib=rb-1.1.0&rect=4%2C1527%2C3275%2C2965&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">More Dollies, cloned from the same cell line.</span> <span class="attribution"><span class="source">Courtesy of Kevin Sinclair, University of Nottingham</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span></figcaption></figure><p>In 1997 <a href="http://doi.org/10.1038/385810a0">Dolly the sheep was introduced</a> to the world by biologists Keith Campbell, Ian Wilmut and colleagues. Not just any lamb, Dolly was a clone. Rather than being made from a sperm and an egg, she originated from a mammary gland cell of another, no-longer-living, six-year-old Fynn Dorset ewe. </p>
<p>With her birth, a scientific and societal revolution was also born.</p>
<p>Some prominent scientists <a href="http://www.nytimes.com/1998/01/30/us/with-no-other-dollys-cloning-report-draws-critics.html">raised doubts</a>; it was too good to be true. But more animals were cloned: first the <a href="http://doi.org/10.1038/28615">laboratory mouse</a>, then <a href="http://doi.org/10.1126/science.280.5367.1256">cows</a>, <a href="http://doi.org/10.1038/8632">goats</a>, <a href="http://doi.org/10.1038/35024082">pigs</a>, <a href="http://doi.org/10.1038/424635a">horses</a>, even <a href="http://doi.org/10.1038/436641a">dogs</a>, <a href="http://doi.org/10.1016/j.ydbio.2006.02.016">ferrets</a> and <a href="http://doi.org/10.1095/biolreprod.109.081083">camels</a>. By early 2000, the issue was settled: Dolly was real and cloning adults was possible.</p>
<p>The implications of cloning animals in our society were self-evident from the start. Our advancing ability to reprogram adult, already specialized cells and start them over as something new may one day be the key to creating cells and organs that match the immune system of each individual patient in need of replacements.</p>
<p>But what somehow got lost was the fact that a clone was born – at day zero – created from the cell of another animal that was six years old. Researchers have spent the past 20 years trying to untangle the mysteries of how clones age. How old, biologically, are these animals born from other adult animals’ cells?</p>
<h2>Decades of cloning research</h2>
<p>Dolly became an international celebrity, but she was not the first vertebrate to be cloned from a cell taken from the body of another animal. In 1962, developmental biologist <a href="http://doi.org/10.1083/jcb.1812pi">John Gurdon</a> <a href="http://dev.biologists.org/content/develop/10/4/622.full.pdf">cloned the first adult animal</a> by taking a cell from the intestine of one frog and injecting it into an egg of another. Gurdon’s work did not go unnoticed – he went on to share the <a href="https://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/popular-medicineprize2012.pdf">2012 Nobel Prize</a> in Physiology or Medicine. But it was Dolly who had captured our imagination. Was it because she was a warm-blooded animal, a mammal, much closer to human? If you could do it in a sheep, you could do it on us!</p>
<p>Dolly, along with Gurdon’s frogs from 35 years earlier and all the other experiments in between, redirected our scientific studies. It was amazing to see a differentiated cell – an adult cell specialized to do its particular job – transform into an embryonic one that could go on to give rise to all the other cells of a normal body. We researchers wondered if we could go further: Could we in the lab make an adult cell once again undifferentiated, without needing to make a cloned embryo?</p>
<p>A decade after Dolly was announced, stem cell researcher <a href="https://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/yamanaka-facts.html">Shynia Yamanaka’s team</a> did just that. He went on to be the Nobel corecipient with Gurdon for showing that mature cells could be <a href="http://doi.org/10.1016/j.cell.2006.07.024">reprogrammed to become pluripotent</a>: able to develop into any specialized adult cell.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/157263/original/image-20170217-4280-lo3qhr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/157263/original/image-20170217-4280-lo3qhr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/157263/original/image-20170217-4280-lo3qhr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=390&fit=crop&dpr=1 600w, https://images.theconversation.com/files/157263/original/image-20170217-4280-lo3qhr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=390&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/157263/original/image-20170217-4280-lo3qhr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=390&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/157263/original/image-20170217-4280-lo3qhr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=490&fit=crop&dpr=1 754w, https://images.theconversation.com/files/157263/original/image-20170217-4280-lo3qhr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=490&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/157263/original/image-20170217-4280-lo3qhr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=490&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">An adult body cell can be made into an induced pluripotent stem cell that in turn can develop into any kind of differentiated cell.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/induced-pluripotent-stem-cell-ips-regenerative-363797669?src=2eqGFx-_3l5j5NslRYdyYA-1-17">Regenerative medicine image via www.shutterstock.com.</a></span>
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<p>Now we have the possibility of making individualized replacement cells – potentially any kind – to replace tissue damaged due to injury, genetic disorders and degeneration. Not only cells; we may soon be able to have <a href="http://doi.org/10.1016/j.cell.2016.12.036">our own organs grown in a nonhuman host</a>, ready to be transplanted when needed.</p>
<p>If Dolly was responsible for unleashing the events that culminate with new methods of making fully compatible cells and organs, then her legacy would be to improve the health of practically all human beings on this planet. And yet, I am convinced that there are even better things to come.</p>
<h2>Dolly’s secrets still unfolding</h2>
<p>In the winter of 2013, I found myself driving on the wrong side of the road through the Nottingham countryside. In contrast to the luscious landscape, I was in a state gloom; I was on my way to see Keith Campbell’s family after his sudden death a few weeks earlier. Keith was a smart, fun, loving friend who, along with Ian Wilmut and <a href="http://dolly.roslin.ed.ac.uk/facts/the-life-of-dolly/">colleagues at the Roslin Institute</a>, had brought us Dolly 15 years earlier. We had met at a conference in the early 1990s, when we were both budding scientists playing around with cloning, Keith with sheep, me with cows. An extrovert by nature, he quickly dazzled me with his wit, self-deprecating humor and nonstop chat, all delivered in a thick West Midlands accent. Our friendship that began then continued until his death. </p>
<p>When I knocked at the door of his quaint farmhouse, my plan was to stay just a few minutes, pay my respects to his wife and leave. Five hours and several Guinnesses later, I left feeling grateful. Keith could do that to you, but this time it wasn’t him, it was his latest work speaking for him. That’s because his wife very generously told me the project Keith was working on at the time of his death. I couldn’t hide my excitement: Could it be possible that after 20 years, the most striking aspect of Dolly’s legacy was not yet revealed?</p>
<p>See, when Dolly was cloned, she was created using a cell from a six-year-old sheep. And <a href="http://dolly.roslin.ed.ac.uk/facts/the-life-of-dolly/">she died at age six and a half</a>, a premature death for a breed that lives an average of nine years or more. People assumed that an offspring cloned from an adult was starting at an age disadvantage; rather than truly being a “newborn,” it seemed like a clone’s internal age would be more advanced that the length of its own life would suggest. Thus the notion that clones’ biological age and their chronological one were out of sync, and that “cloned animals will die young.” </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/157265/original/image-20170217-4236-1ur3act.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/157265/original/image-20170217-4236-1ur3act.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/157265/original/image-20170217-4236-1ur3act.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=558&fit=crop&dpr=1 600w, https://images.theconversation.com/files/157265/original/image-20170217-4236-1ur3act.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=558&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/157265/original/image-20170217-4236-1ur3act.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=558&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/157265/original/image-20170217-4236-1ur3act.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=701&fit=crop&dpr=1 754w, https://images.theconversation.com/files/157265/original/image-20170217-4236-1ur3act.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=701&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/157265/original/image-20170217-4236-1ur3act.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=701&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Telomeres get clipped with each cell division, limiting how many times a cell can copy itself.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/telomere-cell-division-488807065">Chromosome image via www.shutterstock.com.</a></span>
</figcaption>
</figure>
<p>Some of us were convinced that if the cloning procedure was done properly, the biological clock should be reset – a newborn clone would truly start at zero. We worked very hard to prove our point. We were not convinced by a single DNA analysis done in Dolly showing slightly shorter <a href="http://learn.genetics.utah.edu/content/basics/telomeres/">telomeres</a> – the repetitive DNA sequences at the end of chromosomes that “count” how many times a cell divides. We presented strong scientific evidence showing that cloned cows had all the <a href="http://doi.org/10.1126/science.288.5466.665">same molecular signs of aging</a> as a nonclone, predicting a normal lifespan. Others <a href="http://doi.org/10.1038/35030301">showed the same in cloned mice</a>. But we couldn’t ignore reports from colleagues interpreting <a href="http://doi.org/10.1038/20580">biological signs in cloned animals</a> that they attributed to <a href="http://dx.doi.org/10.1095/biolreprod66.6.1649">incomplete resetting of the biological clock</a>. So the jury was out. </p>
<p>Aging studies are very hard to do because there are only two data points that really count: date of birth and date of death. If you want to know the lifespan of an individual you have to wait until its natural death. Little did I know, that is what Keith was doing back in 2012.</p>
<p>That Saturday afternoon I spent in Keith’s house in Nottingham, I saw a photo of the animals in Keith’s latest study: several cloned Dollies, all much older than Dolly at the time she had died, and they looked terrific. I was in awe.</p>
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<a href="https://images.theconversation.com/files/157344/original/image-20170217-10223-1ot826b.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/157344/original/image-20170217-10223-1ot826b.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/157344/original/image-20170217-10223-1ot826b.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=327&fit=crop&dpr=1 600w, https://images.theconversation.com/files/157344/original/image-20170217-10223-1ot826b.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=327&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/157344/original/image-20170217-10223-1ot826b.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=327&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/157344/original/image-20170217-10223-1ot826b.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=410&fit=crop&dpr=1 754w, https://images.theconversation.com/files/157344/original/image-20170217-10223-1ot826b.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=410&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/157344/original/image-20170217-10223-1ot826b.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=410&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Four 8-year-old Finn-Dorset clones born in July 2007 and derived from the mammary gland cell line that gave rise to Dolly.</span>
<span class="attribution"><a class="source" href="http://www.nature.com/articles/ncomms12359">K. D. Sinclair, S. A. Corr, C. G. Gutierrez, P. A. Fisher, J.-H. Lee et al. doi:10.1038/ncomms12359</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>The data were confidential, so I had to remain silent until late last year when <a href="http://dx.doi.org/10.1038/ncomms12359">the work was posthumously published</a>. Keith’s coauthors humbly said: “For those clones that survive beyond the perinatal period […] the emerging consensus, supported by the current data, is that they are healthy and seem to age normally.” </p>
<p>These findings became even more relevant when last December researchers at the <a href="http://www.scripps.edu">Scripps Research Institute</a> found that induced pluripotent stem cells reprogrammed using the “Yamanaka factors” <a href="http://dx.doi.org/10.1038/nbt.3749">retain the aging epigenetic signature of the donor individual</a>. In other words, using these four genes to attempt to reprogram the cells does not seem to reset the biological clock. </p>
<p>The new Dollies are now telling us that if we take a cell from an animal of any age, and we introduce its nucleus into a nonfertilized mature egg, we can have an individual born with its lifespan fully restored. They confirmed that all signs of biological and chronological age matched between cloned and noncloned sheep. </p>
<p>There seems to be a natural built-in mechanism in the eggs that can rejuvenate a cell. We don’t know what it is yet, but it is there. Our group as well as others are hard at work, and as soon as someone finds it, the most astonishing legacy of Dolly will be realized.</p><img src="https://counter.theconversation.com/content/73031/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>José Cibelli does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>It took years of attempts before scientists were able to clone a mammal from an adult cell. And with that success came plenty more questions.José Cibelli, Scientific Director LARCEL-BIONAND, Spain and Professor of Animal Biotechnology, Michigan State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/630902016-07-26T15:27:21Z2016-07-26T15:27:21ZDolly’s ‘sisters’ show cloned animals don’t grow old before their time<figure><img src="https://images.theconversation.com/files/132031/original/image-20160726-7037-1ah3taz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">University of Nottingham</span></span></figcaption></figure><p>It’s now 20 years since the birth of <a href="http://www.roslin.ed.ac.uk/public-interest/dolly-the-sheep/a-life-of-dolly/">Dolly the sheep</a>, the first mammal to be cloned. This groundbreaking scientific achievement was accompanied by warnings that Dolly might age prematurely because she had been cloned from adult sheep cells, whose “biological clock” had not been reset. Fears were heightened in 2001 when Dolly was <a href="http://www.sciencedirect.com/science/article/pii/S0960982203001489">diagnosed with osteoarthritis</a> at five years of age (she died two years later). This was heralded as evidence of premature ageing, although the condition is actually very poorly described in sheep. </p>
<p>We wanted to better understand how the cloning process affected the health of the animals produced and so <a href="http://nature.com/articles/doi:10.1038/ncomms12359">we’ve been studying</a> a group of cloned sheep, including four of Dolly’s “identical sisters”. We found that most of the animals are actually in good health for their age. There was little sign of blood glucose problems, high blood pressure or osteoarthritis, all of which were highlighted as potential problems. This suggests that the cloning technique can, after all, produce perfectly normal and viable offspring that don’t grow old before their time.</p>
<p>The technique used to produce Dolly is called somatic-cell nuclear transfer (SCNT) and involves reprogramming normal sheep cells into embryonic cells that can turn into any other specific type of cell in the body. This is done by effectively inserting the nucleus of an ordinary cell into an empty egg. The transformed eggs were then used to create embryos that were then implanted in a number of surrogate ewes, eventually leading to the birth of Dolly in July 1996.</p>
<p>But the <a href="http://www.nature.com/nature/journal/v385/n6619/abs/385810a0.html">Nature paper of 1997</a> announcing the creation of Dolly also highlighted inefficiencies with SCNT. It took 277 reconstructed embryos to produce one sheep. Analysing Dolly’s DNA also suggested that her cells were biologically older than her chronological age. It’s as if the cells still thought they were part of the original, older sheep from which she was cloned.</p>
<h2>Health check</h2>
<p>It was against this background that in 2015 we sought to formally assess the health of a group of <a href="http://nature.com/articles/doi:10.1038/ncomms12359">13 cloned sheep</a> ranging from seven to nine years of age. Four of them were effectively clones of Dolly and shared the same DNA in the nuclei of their cells. We investigated three common age-related diseases in sheep: metabolic syndrome (problems associated with obesity), hypertension (high blood pressure) and osteoarthritis (joint pain and stiffness).</p>
<p>There had been <a href="http://www.nature.com/nm/journal/v8/n3/full/nm0302-262.html">some reports</a> of diabetes in cloned mice, and kidney defects among previously cloned lambs that didn’t survive birth, which we thought could lead to increased blood pressure in adults. Dolly herself was diagnosed with osteoarthritis at the relatively young age of five.</p>
<p>Despite their advanced age (sheep rarely live beyond ten years), our animals had normal blood glucose levels and found to be insulin sensitive, meaning they weren’t suffering metabolic syndrome. Blood pressure was also normal and, although there was radiographic evidence of mild osteoarthritis in one or two joints in most sheep, no animal was lame and none required treatment. In the 12 months that followed these assessments, our sheep have remained largely healthy. Recently, one of the now nine-year-old Dolly clones has started to show clinical signs of osteoarthritis (being a little stiff in the morning).</p>
<p>Our findings suggest that cloning long-lived species such as sheep by SCNT generally produces no age-related detrimental health effects in the animals that are successfully born and survive beyond the first week or two. But what about the other embryos that didn’t survive? What can their health teach us about the cell reprogramming process? </p>
<p>During natural conception, the sperm’s DNA and associated proteins are packaged in such a way that the egg can easily dismantle and reassemble it. With SCNT cloning, the egg finds it much harder to reprogram the genetic material inserted from the original animal cell and has just a few hours in which to get it right.</p>
<p>So perhaps it is not surprising that in the majority of cases the egg is only partially reprogrammed. Part of the success of the team behind Dolly was in reducing the likelihood of DNA damage and <a href="http://www.nature.com/nature/journal/v380/n6569/abs/380064a0.html">abnormalities that can occur</a> during reprogramming.</p>
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<img alt="" src="https://images.theconversation.com/files/131947/original/image-20160726-7033-p858n0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/131947/original/image-20160726-7033-p858n0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=474&fit=crop&dpr=1 600w, https://images.theconversation.com/files/131947/original/image-20160726-7033-p858n0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=474&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/131947/original/image-20160726-7033-p858n0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=474&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/131947/original/image-20160726-7033-p858n0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=596&fit=crop&dpr=1 754w, https://images.theconversation.com/files/131947/original/image-20160726-7033-p858n0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=596&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/131947/original/image-20160726-7033-p858n0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=596&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Professor Keith Campbell.</span>
<span class="attribution"><span class="source">University of Nottingham</span></span>
</figcaption>
</figure>
<h2>Making cloning more efficient</h2>
<p>However, in the 20 years since Dolly’s birth there have been significant advances in molecular genetics and cell biology that have greatly advanced our understanding of these early developmental processes. Professor Keith Campbell, who was part of the Dolly team, went on to improve the efficiency of SCNT so that 20% of cloned embryos developed to become live offspring, as opposed to the original 3% in the Dolly experiment. This work produced ten further Dolly clones in July 2007, seven of which lived beyond one week of age and four of which are alive today (and were part of our study).</p>
<p>Many embryos were still lost during pregnancy but, as with natural conception, the vast majority of these losses occurred before they were successfully implanted in the womb. Those clones that failed to survive much beyond the first week of life typically had defects in the heart, lungs or kidneys. However, these losses were of enough concern to the European Parliament that they contributed to its decision to <a href="http://www.sciencemag.org/news/2015/09/eu-parliament-votes-ban-cloning-farm-animals">ban farm-animal cloning</a> for food production in September 2015.</p>
<p>Now that we know cloning can produce normal, healthy animals, we need to increase the survival rate of the embryos to levels similar to those of natural conception. There is reason to be optimistic that this is achievable. We now have a better understanding of the underlying molecular mechanisms involved in the remodelling of the clones’ genetic material.</p>
<p><a href="http://www.sciencedirect.com/science/article/pii/S0167779916300038">Scientists are attempting</a> to do part of this reprogramming before the material is transferred to the empty egg so that it looks more like the genetic material delivered by a sperm during natural conception. If successful, this would allow the egg to more easily complete the reprogramming process, increasing the number of embryos that survive and hopefully reducing the related animal welfare concerns.</p><img src="https://counter.theconversation.com/content/63090/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kevin Sinclair receives funding from University of Nottingham.</span></em></p>Dolly the sheep died young with osteoarthritis, but new evidence shows early-onset diseases aren’t inevitable for clones.Kevin Sinclair, Professor of Developmental Biology, University of NottinghamLicensed as Creative Commons – attribution, no derivatives.