07/29/2016

A Health Check-Up for Dolly’s ‘Sister Clones’

7:17 minutes

Twenty years ago, Dolly the sheep was born, becoming the first mammal cloned from an adult cell. Dolly lived for 6.5 years and developed osteoarthritis late in life. Researchers analyzed her chromosomes and found that she had shortened telomeres, an indication that her genetic age was actually older than her 6.5 years.

Four clones derived from the same cell line as Dolly. Credit: The University of Nottingham
Four clones derived from the same cell line as Dolly. Credit: The University of Nottingham

In a recent study in Nature Communications, scientists report that four of Dolly’s “sister clones” — sheep born from the same cell line as Dolly — had normal cardiovascular, blood pressure, and insulin levels for sheep of their age. Kevin Sinclair, a developmental biologist and author on the paper, says the sister clones, who are now the age equivalent of about 70 human years, actually seem to be in relatively good shape.

“They’re what we would call genomic copies — they share the same nuclear DNA, they’re the same cell line, the same batch of cells in fact that gave rise to Dolly,” Sinclair says. “But of course the eggs in which the nuclei from these cells are injected are from different donors, from different animals, and so they share the same nuclear DNA, but they don’t share the same mitochondrial DNA. … That’s why we refer to them as being genomic copies, rather than as purely identical.”

Pictures of the clone sisters show a healthy-looking group of fluffy white sheep. Only one of them, an ewe named Debbie, seems to be having health problems.

“Their physical health is very good,” Sinclair says. “On x-rays last year she [Debbie] showed the most radiographic evidence of the most advanced osteoarthritis. … in June this year, just a month or so ago, we started to notice that she was getting a little stiff in the mornings. So we’ve since been giving her a little medication.”

Sinclair says scientists who study cloning have changed their focus from where it was 20 years ago, when Dolly was born, and are now concentrating more on IPS cells, or induced pluripotent stem cells.

“The field has kind of moved a little bit away from cloning in some respects towards these IPS cells,” Sinclair says. “I think that’s where most of the activity is likely to be in the future. There are two or three labs that are cloning human embryos with the view of generating human embryonic stem cells for therapeutic purposes.”

“What this particular study shows us, however, is that there’s a population of cells that quite clearly undergo, for all intents and purposes, almost complete reprogramming to be just normal embryos, which give rise to normal pregnancies and then normal offspring, which can live a long time.”

There have been other changes for cloning since Dolly, and Sinclair says that bodes well for the success of future experiments.

“Modern protocols now for cloning animals are much more efficient than they were at the time that Dolly was created,” Sinclair says. You can now take a differentiated cell and restore it to something like an embryonic cell, capable of dividing into many cell types.

“Cloning is still undertaken, particularly in the United States, and the protocols in the news today are much more efficient, are much more effective,” Sinclair says adds. So we can be hopeful, with the research that’s taking place, that in the future we could maybe see more healthy cloned animals like this.”

—Elizabeth Shockman (originally published on PRI.org)

Segment Guests

Kevin Sinclair

Kevin Sinclair is a Professor of Developmental Biology at the University of Nottingham in Nottingham, England.

Segment Transcript

JOHN DANKOSKY: 20 years ago, scientists awaited the birth of an animal that was the first of its kind. Dolly the Sheep was born in Edinburgh, Scotland. She was the first mammal cloned from an adult cell. Dolly lived until nearly seven years old, not too bad for a sheep. Two years before her death, though, she developed osteoarthritis. And when researchers examined her chromosomes, they found that she had shortened telomeres, a possible sign that her DNA was older than her actual biological age.

This week, another team of scientists published a study that looked at the health of Dolly’s sister clones, four sheep that were created from the same cell line. My next guest is here to tell us how that check-up went. Kevin Sinclair is an author on that paper. He’s also professor of developmental biology at the University of Nottingham in Nottingham, England. Welcome to Science Friday.

KEVIN SINCLAIR: Hi, John. Good to be here.

JOHN DANKOSKY: So first of all, these sheep were created from the same cell line. You’ve called them sister clones. Are they exact replicas of Dolly?

KEVIN SINCLAIR: So they’re what we would call genomic copies, John. They share the same nuclear DNA. They’re the same cell line, the same batch of cells, in fact, that gave rise to Dolly. But of course, the eggs in which the nuclei from these cells are injected are from different donors, from different animals.

And so they share the same nuclear DNA, but they don’t share the same mitochondrial DNA. So that’s true for all clones generated by somatic cell nuclear transfer. And that’s why we refer to them as being genomic copies rather than as purely identical.

JOHN DANKOSKY: So these four cloned sheep are now nine years old, and sheep usually live 10, 12 years old or so?

KEVIN SINCLAIR: Yeah. It’s possible. It’s kind of like humans. It’s difficult to do a direct age comparison. But as a rough rule of thumb, you could say one sheep year is equal to eight human years. And of course, humans are capable of living into their 70s and 80s and beyond, but few actually do that. These animals are probably, now at nine years old, they’re probably right about a 70-year mark.

JOHN DANKOSKY: And so how’s their physical health?

KEVIN SINCLAIR: Their physical health is very good. As you probably could see from the pictures being circulated and also the video, every summer they’re out in a paddock, and then we bring them into the barn. One of the clones– her name is Debbie– when we undertook MRI and X-rays last year, she showed the most radiographic evidence of the most advanced osteoarthritis.

But she was showing no clinical signs last year. But in June this year, just a month or so ago, we started to notice that she was getting a little stiff in the morning. So we’ve since been giving her a little medication, not every day, but occasionally through her diet.

JOHN DANKOSKY: So overall, their health is better than Dolly’s health was? I mean, Dolly, of course, didn’t make it to nine years old.

KEVIN SINCLAIR: As far as we can ascertain, that’s probably true. I mean, Dolly– I mean, the only thing that we could say about Dolly was that she developed osteoarthritis at a younger age than these animals and started to show clinical signs at a younger age than these animals.

I mean, Dolly died, unfortunately, because she just picked up a virus that causes lung tumors. It’s prevalent throughout the world. And it’s prevalence in the UK is quite low, and so she and other members of the flock were really unlucky to have picked up that virus. And that was the reason for her early demise.

JOHN DANKOSKY: I’m John Dankosky, and this is Science Friday from PRI, Public Radio International. We’re talking with Kevin Sinclair, who’s a professor of developmental biology at the University of Nottingham in Nottingham, England about sister clones of Dolly the Sheep. So Dolly was a success, but it took about 300 attempts or so to get there. How has cloning technology changed over the course of the last 20 years?

KEVIN SINCLAIR: So it’s moved a long way, in fact. Modern protocols now for cloning animals are much more efficient than they were at the time that Dolly was created. And the level of research isn’t as great as it once was. Because if you were to think about what was cloning’s greatest legacy, it probably was– it demonstrated for the first time that you could induce what we call pluripotency in cells.

You could take a terminally differentiated cell and restore it to something akin to an embryonic cell, which is capable of dividing into many cell types. And that was the impetus for scientists to look at ways of trying to do that in the laboratory. And that led to the discovery that you could induce cells to become pluripotent by using a small number of genes. And so-called induced pluripotent cells, stem cells, is really what’s taken off since.

So cloning is still undertaken, particularly in the United States. And the protocols being used today are much more efficient and much more effective. So we can be hopeful with the research that’s taking place that in the future we could maybe see more healthy, cloned animals like this.

JOHN DANKOSKY: So what do these healthy, cloned animals tell us about what cloning might do for us? I mean, we’ve been thinking about cloning and its use in human medicine for years. Do the next 20 years bring something in which cloning actually helps us live longer, be healthier?

KEVIN SINCLAIR: So I just said the field has kind of moved a little bit away from cloning in some respects towards these IPS cells. And I think that’s where most of the activity is likely to be in future. There are two, three labs that are cloning human embryos with a view of generating human embryonic stem cells for therapeutic purposes. And it’s evident that that process is actually really quite effective in inducing pluripotency.

What this particular study shows us, however, is that there’s a population of cells that quite clearly undergo, for all intents and purposes, almost complete reprogramming to produce normal embryos, which give rise to normal pregnancies, and then normal offspring, which can live a long time.

And so where there are some cells that can undergo effectively complete reprogramming, and that gives us hope that in the future, as we refine our techniques, that we can expect a much larger population of these cells. And so that we can use either cloning or IPS cell technology with more confidence that they will produce cells which are effective and also safe for use.

JOHN DANKOSKY: I just have one last, quick question for you. Are there more Dollys coming from this line of sheep?

KEVIN SINCLAIR: No, it’s not likely that there will be. I mean, this is an opportunity. My former colleague Keith Campbell, who passed away in 2012, he was interested in evaluating his protocols to go back to the original line and to see how far things had progressed. It’s likely in the future that we’re going to move forward with other cell lines.

JOHN DANKOSKY: Kevin Sinclair is a professor of developmental biology at the University of Nottingham in Nottingham, England. Thank you so much for joining us, sir.

KEVIN SINCLAIR: Welcome.

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