Remembering the sheep that changed the world

It has been 15 years since the birth of Dolly the sheep, an event which changed perceptions towards genetic science.

Ian Wilmut and his team created Dolly, the first living mammal to be cloned from the cell of an adult animal [GALLO/GETTY]

Stanford, CA – On February 27, 1997, Nature, one of the world’s leading scientific journals, published an article with the title: “Viable Offspring Derived from Fetal and Adult Mammalian Cells”. It doesn’t sound that exciting, but Dolly, the cloned female lamb that was the star of the piece, amazed the world. 

Since the announcement of her birth, millions of words have been written about Dolly, and more broadly about cloning. But why was this one lamb so startling? With 15 years of perspective, what did Dolly really mean? I suggest her story holds four lessons about our societies’ interactions with bioscience: lessons about how the media handles science, how science makes progress, how complicated biology is, and most importantly, how new knowledge in the life sciences will challenge our societies. 

Dolly was a sensation, covered on front pages and leading newscasts around the world. Conversation jumped immediately from cloned sheep to cloned humans. And yet almost no one tried to explain to the general public the incremental steps that had led to her birth. The coverage typically acknowledged that Dolly did not mean that human cloning would necessarily work, but this warning was like fine print in advertising for loans – intended to be ignored as people plunged ahead into the exciting part of the story. The media message? The clones are coming – which was a gross overreaction.

The media likes exciting and controversial stories, because the public likes exciting and controversial stories – and the media makes money by giving the public what it wants. Stories will be goosed to sound as exciting as possible, often without regard for the scientific integrity of the attention-grabbing assertions. Dolly was not, in fact, the harbinger of armies of human clones, though the news coverage might have led credulous readers to think so.

“Dolly was not, in fact, the harbinger of armies of human clones, though the news coverage might have led credulous readers to think so.”

– Hank Greely

The lesson is to be sceptical. Never believe any scientific “breakthrough” when it first appears on the front page of a newspaper (or a website). Wait until other scientists have repeated it, several times. If it really interests you, look beyond the popular press to see what experienced science journalists say about it, including those who write for the weekly journals Nature and Science. They have a level of sophistication and scepticism, about science, based often on decades of observation, that general writers rarely match. 

How science makes progress

Dolly was not the first clone, or cloned mammal, or even cloned sheep. Clones are simply organisms that share exactly the same versions of their genes. Human clones have been around as long as humans have – we call them identical twins – but these are two offspring who are clones of each other. Most forms of life, from bacteria to many plants to various animals (but no mammals) naturally reproduce by making offspring who are clones of themselves.

Early in the 1950s, scientists succeeded in cloning animals that didn’t naturally reproduce that way. Researchers surgically extracted the nuclei (the parts of the cells containing DNA) from frog eggs. They then put a nucleus from the cell of another frog into each of the “empty” eggs. Sometimes these reconstructed eggs started dividing and eventually developed into frogs. Oddly, when they used nuclei from adult frogs, the clones never became adults; they remained in the tadpole stage. Only when they used nuclei from immature frogs did the clones develop into adult frogs. 

Frogs were easy; their eggs are large, easy to get and easy to work with. Eggs from mammals are none of the above, but eventually, in the mid-1980s, Steen Willadsen used this “nuclear transfer” method to produce the first cloned mammals – sheep. Willadsen’s sheep did not get cute names, or any names at all. His work, and that of others who produced cloned cattle, got a little attention, but no controversy. This was at least partially because of an important limitation in their results: they only had success when they used cells from embryos. They could not succeed in cloning when they used nuclei from sheep and cattle that had already been born. When combined with the frog results, this led scientists to conclude that only DNA from cells from immature animals could lead of successful cloning.

This is an important limitation. If you can only clone with nuclei from embryos, you cannot clone an adult dairy cow that you know gives lots of milk. And you cannot clone living people. The scientific conventional wisdom became “no cloned mammals from living animals”.

Ian Wilmut, Keith Campbell and other researchers at the Roslin Institute in Scotland challenged that view. In June 1995, they moved past embryonic cells for the first time in mammals, through the successful birth of two lambs, Megan and Morag, using cells from foetal sheep. These were cells that, unlike those previously used for cloning, had already become a differentiated type of cell. Thirteen months later, on July 5, 1996, they took the next step when Dolly was born – the first living mammal to be cloned from the cell of an adult animal. Sort of. Dolly was actually cloned from a cell thawed from a frozen cell line. Several years earlier, cells had been taken from the mammary glands of an adult ewe, grown in the laboratory, and frozen. One of those cells was Dolly’s “progenitor” – and the sheep it was taken from had been slaughtered several years before Dolly’s birth.

The lesson from this story is that science usually does not proceed by major leaps. Most science is based on incremental improvements on previous techniques or experiments. Dolly was an important step, but she was only one step in a long chain, stretching both before Dolly and after her.  

How biology is complicated

Since Dolly, living clones have been born in at least 17 other species of mammals. Mice, rats, rabbits, ferrets and pigs have been cloned. So have camels, cattle, wild oxen, water buffalo, deer, goats and a wild sheep, as well as cats, dogs and wolves. Among the most interesting species to be cloned were mules, hybrids produced from a male donkey and a female horse that are themselves sterile, and the Pyrenean ibex, a subspecies of mountain goat that had become extinct eight years before it was cloned. 

Since Dolly, living clones have been born in at least 17 other species of mammals [GALLO/GETTY]

But this apparent success is deceptive. Some of these species have been cloned, but without yielding healthy offspring. Neither the Pyrenean ibex nor the wild ox survived for more than a few days. Some species were easy – like mice and cats – while close relatives, like rats and dogs, took many years of work. 

And many species have yet to be cloned successfully. Despite extensive efforts, no one has been able to clone even one primate, the group that includes monkeys, apes and humans. The closest anyone has come, after years of trying, is to keep cloned embryos of rhesus monkeys alive for a few days, but long enough to derive embryonic stem cells from them. No cloned monkeys have been born. And, of course, in spite of some early claims as of the direction of the science, no cloned humans have ever been born. No normal cloned human embryos have survived long enough to yield stem cells, about five days.

In short, biology is complicated. Things that work in one species often don’t work in other species. Pharmaceutical and biotech companies know this only too well. Drugs that work in other animals and that really should work in humans often don’t, sometimes after a billion dollars of effort.

Even when science can do something, it can be frustratingly difficult to translate that into a workable technology. Science tells us how things work and what can be done, but to change the world, we need technologies that achieve the desired result safely, effectively and economically. There is no great mystery about what an artificial heart would need to do – the heart is fundamentally just a pump. But making a safe and effective heart has evaded bioengineers for decades. 

The lesson here is that bioscience may not take us where we expect. Things in biology often do not work as predicted and even when they do, making them work routinely can pose new challenges. The 15 years since Dolly’s birth have not brought us a single human clone or any common uses of cloned non-human animals. The future impacts of biological discoveries are hard to predict.

How biology will challenge our societies

Dolly did not change our world. And yet the processes that led to Dolly are changing our world, in unpredictable ways and at an accelerating pace. We are in the middle of a series of overlapping revolutions in our understanding of how life works. 

Our improved knowledge of biology may allow us to find and destroy viruses that cause disease – or to modify viruses to use disease as a weapon. Neuroscience will allow us to read minds, to help the disabled, but also to determine whether someone is lying, is feeling pain, or truly loves the Big Brother TV show. Stem cell technology may combine with genetic testing or synthetic biology to allow us to choose the genes, and thus some of the characteristics, of our children, transforming our species itself. And, eventually, Dolly may lead to widespread production of cloned livestock, cloned pets and, perhaps, cloned people. 

“Dangerous practices must be regulated, but trying to regulate biology before we know what we’re dealing with can be futile.”

Hank Greely

Advances in biology will affect our societies most profoundly. But exactly what advances are coming, when and how their effects will be felt cannot be confidently predicted. Dangerous practices must be regulated, but trying to regulate biology before we know what we’re dealing with can be futile. After Dolly was announced, the British smugly noted that they already banned human cloning – but not through the method used to make Dolly, which hadn’t been envisioned when that regulation was passed. Premature regulation could also stifle progress in medicine; 20 years before Dolly, some people tried to stop recombinant DNA, a process that has given us scores of effective drugs. 

So what is to be done? We need to watch and study; think and discuss. Any given advance in biology may be world-changing or irrelevant, incredibly beneficial or catastrophic – or, simultaneously, all of the above. We need to keep an eye on what is going in the labs, and in governments and civil society, talk about what it may mean. That won’t guarantee that we will maximise the benefits of new technologies while minimising their harms, but it will, at least, give us a fighting chance.

Sadly, Dolly is not alive to help commemorate her debut. She was euthanised in February 2003 as a result of both lung disease and painful arthritis in her hips, which may or may not have stemmed from her birth as a clone. But Dolly does live on, as a stuffed museum display and, more importantly, as a symbol, though of just what is as murky today as it was in 1997 – of human mastery or of continuing mystery? Of hubris, of hope, or of hype? 

All of the above, I think, but one thing is clear. Dolly was one small example of the revolutions that are deepening our understandings of life. Those revolutions, driven by our desire to relieve human suffering, are accelerating and will affect our world beyond medicine. But what those effects would be will not be obvious from the headlines about any “breakthrough”. Understanding the effects will take time, patience and hard work, work that will be essential for our hopes to use these advances and not to let them use us. That may be Dolly’s most important lesson. 

Hank Greely is Director, Centre for Law and the Biosciences; Professor (by courtesy) of Genetics, Stanford School of Medicine; Chair, Steering Committee of the Centre for Biomedical Ethics; and Director, Stanford Interdisciplinary Group on Neuroscience and Society. He specialises in the ethical, legal and social implications of new biomedical technologies, particularly those related to neuroscience, genetics or stem cell research. He frequently serves as an adviser on California, national and international policy issues.