Dolly.  Her name is still shorthand for a landmark in the science of cloning.  Born in July 1996, this perfectly normal-looking sheep grabbed headlines around the world.  A team of researchers in Scotland had painstakingly taken the nucleus of an adult mammary cell from a sheep’s udder and placed it into the casing of a developing sheep egg.  The resulting embryo went on to be born as Dolly, who took global stardom in her four-legged stride.  Professor Sir Ian Wilmut, who led the research team at the Roslin Institute in Edinburgh University that produced Dolly, was in QUB last week to deliver the Barcroft Lecture in the School of Medicine, Dentistry and Biomedical Sciences.  Professor Wilmut spoke to a packed audience of more than 300 staff and students about the history of cloning and the need to ensure that patients can access the benefits of new technologies emerging from the field.

While cloning had been used for biomedicine and agriculture since the 1970s and 1980s, the 1990s ushered in Dolly, kick-starting intense media interest. “We were surprised at how quickly public interest developed and lasted,” said Professor Wilmut before his lecture. “I still get asked about it all the time, 20 years on.”  When Dolly was born (after more than 270 attempts at the cloning procedure), she changed the game by opening up new ways to control the genetic makeup of mammals, he noted.  “What we set out to do with Dolly and has been done by other people since the method was established, was to have cells that we could culture, to make the precise [genetic] change that we wanted,” explained Professor Wilmut, who is today Professor Emeritus of the Scottish Centre for Regenerative Medicine at Edinburgh University.  The technique has been used to produce proteins in animal milk that can be isolated to treat disease, explained Prof Wilmut, and it has also underpinned new and useful animal models of human diseases such as multiple sclerosis.

Dolly’s success also had another, conceptual effect on biology, noted Professor Wilmut. “All the evidence was that before Dolly that once a cell became a particular type of cell like skin or blood or muscle that was it, it was fixed for the rest of its life and the mechanisms of being such a cell were fairly rigidly fixed,” he explained. “What Dolly showed was there were factors in the egg, at least, which could change a cell completely so that instead of going on being mammary tissue [it] became embryo tissue. It made people have the confidence to go looking for other methods.”  That train of thought eventually led around a decade later to the development of induced pluripotent cells, or iPS cells, where a cell of a given type can be ‘rebooted’ and encouraged to grow as another cell type.

‌“That is the biggest impact of the Dolly experiment,” said Professor Wilmut. “It made lots of people think about this for the first time.” Induced pluripotent cells have enabled new models of diseases in the lab - so-called ‘diseases in a dish’ - that can provide researchers with insights into mechanisms and potential treatments, but concerns about aspects such as the quality of their DNA and the potential for tumour formation have provided hurdles to overcome.   

Professor Wilmut is optimistic about the future of iPS cells as direct treatments for disease, but he cautions that progress will be slow and needs to be careful. “There is a need to apply rigorous tests to prove they are exactly what we want in terms of their function and DNA and so on,” he said. “The law quite rightly requires extensive preclinical testing before you begin the clinical tests to see whether they have the effect on patients that you hope.”

A handful of labs are starting clinical trials in humans with iPS cells and Professor Wilmut believes that if they show clinical benefit, the field will start to move more rapidly.  In the meantime, he is part of a gobal alliance called GAiT (The Global Alliance for iPSC Therapies (GAiT) that seeks to harmonise procedures for producing pluripotent stem cells, to ensure they can be transferred between countries.  “It is important if you want to move cells from one country to another that they were produced under the same biological and ethical circumstances as they would in the country that you want them to go to,” said Professor Wilmut.  “You could imagine the horror of the situation where you have some cells that would match a particular patient but they can’t be used because there is something different about the culture system.”

While many of the advances in pluripotent stem cell technology could lead to new treatments for disease, Professor Wilmut is keen to put the timelines in context, stressing that the impact could take many years.  “The trials necessary to test cells before they can be put into patients take a long time,” he said.  “So when you see someone like me positive and enthusiastic and optimistic, it is important to include this cautionary remark in, so that people do not get misled.”

Following his lecture at QUB, Professor Wilmut was awarded the Barcroft Medal by Professor Pascal McKeown.

Text by Claire O'Connell

Above: Professor Sir Ian Wilmut (L) receives the Barcroft Medal from Professor Pascal McKeown, Acting Dean & Head of School, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast