The Life and Death of Dolly

Dr Jamie Love 1999 -2009 ©

This page is the Question and Answers following on from The Cloning of Dolly.

Angela asks ...
I was wondering how they came up with the name "Dolly"? Why did they call her that ?

When Dolly was no more than a speck (a zygote) she was given the unexciting name "6LL3". I don't know the exact reason why she was assigned that name but I suspect it was a code based upon the specific conditions and order in which the experiment was done. Remember, they microinjected 277 times before they got a lamb, so each injection got a boring code name.

One of the stockman (person who handles the animals at the farm) who helped with her birth suggested the name "Dolly". Why? Well, he knew that her nucleus had come from cells originally collected from the breast of a sheep. (Breast cells were being studied at the Institute in previous years and had been grown for other experiments.) Later, in an interview, Dr Wilmut admitted that, "Dolly is derived from a mammary gland cell and we couldn't think of a more impressive pair of glands than Dolly Parton's." (Dolly Parton is a singer, well know for her bosom and her voice.)

Hani writes from South Africa ...
Why did the process have to be repeated 276 times? Don't the cells divide or is it because the experiment failed 276 times?

The short answer is that the experiment failed 276 times. To understand the failures we need to know more about the way the researchers did their work.

The Roslin team knew from previous research on embryo transfers (moving embryos into a different mother) that the transfers don't always work. The embryos may die for various reasons. They also knew that the nuclear transfer itself might introduce new ways for things to go wrong. Remember, they had to inject the nucleus through the enucleated oocyte's protective coat (zona pellucida), zap it with electricity and hope that the nucleus would have become quiescent during its time in tissue culture. Any of these new steps might cause the embryo to die or never develop. In order to better understand what might be going on the researchers introduced a step I failed mention.

First a little more background information about developmental biology. A few days after normal fertilisation a zygote would be expect to have divided approximately four times, producing a ball of 16 cells. (Think about the math. That's 1---> 2---> 4---> 8--->16) At this point in its development the embryo looks like a tiny mulberry and is called a morula. ("Morula" is Latin for "mulberry".) Soon after this stage the zona pellucida (the "egg shell") starts to disappear and as the cells continue to divide they allow fluid to enter the center of the mass of cells. This forms a hollow ball, with cells on the outside and fluid inside. This is called a blastocyst. All mammals (including you and me) developed from zygote, to morula and then to blastocyst, before implanting into the wall of mother's uterus. These are very important steps in our development and that of a lamb.

Anyway, a few days after placing the "new cells" into ewes' oviducts, the researchers collected them to see how well they had developed. As you might imagine it is not easy to find a tiny morula or blastocyst in a sheep's oviduct. Of the 277 they put into ewes they recovered only 247. That means over 11% of the embryos were lost in the first few days. Some may have been lost because they are so difficult to find. Others may have died early and decomposed. Unfortunately, when they examined each of them under the microscope only 29 of the 247 recovered were either a morula or a blastocyst. Or to put it another way, 88% of the "new cells" transferred had not developed. That's a significant loss in the experiment.

The researchers then placed the remaining 29 "good embryos" into 13 ewe's. Some ewes got only one embryo, some got two (which is the average number of lambs that ewes have at a time) and some ewes got three embryos. The exact number depended upon availability of the embryos at the time and the availability of "receptive" ewes. Ewes, like all mammals, must have the right balance of hormones in order to "adopt" an embryo at its particular stage of development. If the embryo and ewe are not "synchronized" (the phrase used for this balance) the embryo will not implant in the ewe's uterus. This is not an easy thing to do and the Roslin researchers explain in their paper "Not all recipients were perfectly synchronized." Perhaps that's why only one of those 13 ewes actually became pregnant. Of course, that was the one that gave birth to Dolly!

The difficulty seems to have been in the ability to actually "reprogram" the "new cell" to behave like a zygote. Their success rate for this important step was 12% (29 "good embryos" from 277 "new cells"). There was also a high loss in the last stage, when only one embryo (Dolly) actually "took". This is a much higher rate of embryo loss than expected from a natural mating and is probably due to the manipulations of the morulas and blastocysts as well as the difficulty "synchronizing" the ewes. That means the total success rate was only 0.4% (1 lamb per 277 "new cells" made by nuclear transfer).

Hani goes on to ask ...
If Dolly were to receive a heart or liver from her twin, would her body recognise the new organ as a foreign body or would it accept it as its own?

Dolly doesn't have a living "twin". Her nucleus came from the tissue cultured mammary (breast) cells of a sheep now dead. If any one of those other 276 "new cells" had made it to birth then Dolly would have had a twin.

But I know what you are asking and it's an excellent question! Organ transfers from identical twins are usually accepted as if they had come from the same person. I say "usually" because, as in most of medicine, there are complication and exceptions, but these are fairly small in number. Therefore it would be a safe bet that organs could be swapped among clones without rejection.

Hani concludes her letter asking ...
If we were to clone a Bill Gates, would the clone have the same high IQ and photographic memory as the original? Would the clone have the same tempestuous personality as the original?

Probably not. IQs, photographic memories and personalities are formed by a combination of genes AND environment. Bill Gates' clone would have all the genetic foundation on which to build those traits but it takes many years of environmental influence to shape the final "person". If Mr Gates were to raise his clone in a suitable environment, "Billy-two" might have an even higher IQ, better memory and be even more tempestuous! Or maybe Billy-two would just be an easy-going, stupid kid. Nobody knows which individual genes or environmental factors shape these complex behaviors, but most scientists agree that it is a combination of nature (genes) and nurture (environment). How much does each contribute? Well, that's when you can sink into a heated debate (in the newsgroups, not here!). Opinions are free because that's what they are worth. Data is what makes science valuable and science is the only way to settle such a debate.

I recall one very good study done a few years ago. A researcher at the University of Minnesota compared the IQs of identical twins (clones) and "non-identical" twins (of the same sex). He concluded that genes were responsible for about half the similarity of the IQs of the identical twins, and the rest of their IQ was due to their environment.

Many people have asked the obvious question,
"How hard would it be to clone a human?"

No one knows. Again, there are plenty of opinions. Certainly anyone thinking about trying it would have to find a more efficient method of cloning mammals. S/he would also have to recruit a lot of women willing to donate both oocytes for the nuclear transfer as well as the use of their uterus in order to grow the clone. Also, there's no guarantee that the same technique would work with humans. Maybe it only works with sheep. After all, Gurdon's cloning of frogs (tadpoles) didn't open the door to cloning humans. These same problems would also have to be considered by folks hoping to clone endangered species. Anyone cloning humans would have to tolerate the "moral outrage" (opinions) of those who see this as an evil idea. Anyone cloning an endangered species would probably be praised. (Probably.)

Makala from Arizona wrote to tell me ...
I am getting very confused. Some say Dolly is fake some say she is real. I would really appreciated it if you would tell me, just a simple Yes or No!

Yes, Dolly is a real clone. There are two reasons why people insist she is a fake.
1. Some folks just like to "cause trouble" or refuse to believe certain things that are beyond their ability to understand.
2. Dolly's mitochondria (tiny organelles inside the cell that give it "power") are NOT cloned! This is a very minor detail but an explanation is in order.

Mitochondria contain less that 1% of 1% of the genes in a cell. (They are an interesting part of the cell and you can find lots about them on the web by doing a search.) Dolly's mitochondria are from the enucleated egg from which she was created, not from the original cell. Recall that the folks at the Roslin Institute injected a nucleus (not mitochondria) into the enucleated oocyte. That means all of Dolly's nuclear DNA is cloned but not her mitochondria.

The fact that Dolly's mitochondria are not cloned comes as no surprise to folks who did the experiment or who understand the details. Sadly, some people like to make a big deal out of nothing and they enjoy dismissing the hard work and success of others. People who say Dolly is a "fake clone" either do not know what they are talking about, love conspiracy theories or try to look smug by pointing out this tiny detail about Dolly.

Mitochondria are unusual, genetically speaking. For example, we inherit half our nuclear DNA from our father and half from our mother but we get ALL our mitochondria from our mother! People who call Dolly a "fake" could also claim that a father is less of a parent that a mother because the child has its mother's mitochondria not its father's! They might go on to claim that (for example) Chelsea Clinton is not President Clinton's daughter because she does not have any of Bill Clinton's mitochondria. Obviously that is silly but it is also a great way to get people's attention and to raise a trouble. That is exactly the kind of "logic" being used to claim that Dolly isn't a clone.

I hope I have cleared up the confusion.

Larry commented ...
I heard rumors about Dolly's health. It's said she was unhealthy and very overweight.

Many people have asked about Dolly's weight and I think information may have been confused with other research. Embryo transfers developed using similar techniques can cause the "big calf problem" in cattle. In this condition - which occurs not only with cattle but also other mammals such as pigs - the embryos grow a bit too big and may have a difficult (even fatal) delivery. Recent research shows this is caused by a developmental problem involving a growth receptor that gets a bit "confused" in the early development of a transplanted embryo. The problem is due to embryo transfer, not cloning as such - but you must do an embryo transfer to get a clone. Maybe that is where people get confused and rumors about Dolly began.

That said, Dolly was an average-size lamb that grew a little overweight because she was given lots of treats posing for the camera! And she spent a lot of time indoors. Dolly's health problems were due to her being a "couch potato" and had nothing to do with being a clone.

Her indoor-life was due to her fame. Folks at the Roslin Institute refused to put Dolly in a situation where activist might try to steal or harm her. That said, Dolly actually did have opportunities to frolic with other sheep in the pastures, because, by hiding her among so many other sheep, she was safe. (No one is going to steal or harm the whole flock.) That said, she was not allowed out at night. (In Scotland, whole flocks of sheep have been stolen during the night so they didn't want to chance it with Dolly.) Over the years, even her modest indoor lifestyle and slight weight problem wore on her. Dolly developed a mild arthritis but this was likely due to the fact that she spent part of her life on a hard floor, not the soft land where sheep normally spend all their life. Zoo keepers and veterinarians are well aware of this problem in "normal" animals kept in captivity.

My point is that there is no evidence Dolly's slight weigh problem or arthritis were due to cloning.

Anonymous asked ... Did Dolly herself produce normal offspring without any defects?

Yes. Six lambs - all healthy and normal. Her first, Bonnie, was born in 1998. The following year she had twins (Sally and Rosie) and in 2000 she had triplets (Lucy, Darcy and Cotton).

"High School Student" wrote ...
I heard the clone aged twice as quickly as was supposed to and thus died very early, and I would like to know if this is true.

Dolly did not age unusually rapidly. She aged like any sheep. She was not sickly or "weird". If a trained veterinarian were asked to examine Dolly, without being told she was a clone, the vet would consider her unremarkable.

In a way, this is strange. Dolly was cloned from a nucleus that was already six years old. (I am talking about the breast cell from which Dolly's nucleus came.) You might expect her to have "old" chromosomes - and she did!

By "old chromosomes" I mean that the ends of her chromosomes, called the telomeres, were shortened. As we age, the telomeres on our chromosomes become shorter with each nuclear division. Exactly why that happens is too complicated to get into here. (But I teach it in my course. ) Using sophisticated molecular methods it was confirmed that Dolly had short telomeres. Roughly, they were as short as you might expect for a sheep six years older!

So, Dolly would have been born with six years already on her "clock" and I would expect her to die of "old age" about six years after she was born - because sheep live about 12 years. I would have expected her to age rapidly. But she didn't!

Lots of people ask ...
What became of Dolly?

Early in the year of 2003, Dolly developed a progressive lung disease, common among sheep. There is no evidence this was due to cloning. On 14 February, 2003 veterinarians decided her lung infection was not clearing up so, to avoid Dolly experiencing any pain or suffering, they "put her down" (killed her using a strong pain killer). She died by going into a deep sleep from which she never woke.

Her necropsy (animal autopsy) was unremarkable. Her lung problem was shown to be due to a type of lung cancer, caused by a virus and common among sheep, especially those kept indoors. Indeed, other sheep in Dolly's flock died of the same disease.
Dolly died (was "put down") at age six and a half years, about half the lifetime of a normal sheep - but her common diagnosis and death was unrelated to her uncommon origin.

In her death, as is her life, Dolly appeared to be just a normal sheep. However, her death, like her life, was treated as unusual. Her body was prepared by a taxidermist and now sits in the National Museum of Scotland (Edinburgh)!

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