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The Mystery of Dolly and 3-parent Children

Fortunately—or rather, unfortunately—I didn’t know why the first cloned animal from an adult cell was called Dolly. When her existence made the headlines in Bangladeshi newspapers, I was still in high school and didn’t even know the internet’s existence. Had I known how to use the internet to gather information back then, I probably would have figured it out. Unfortunately, Bengali newspapers and magazine articles weren’t that informative. Even after sifting through all articles I could find on Dolly, I still didn’t know how exactly scientists achieved that amazing feat. I, however, did know what I wanted to do with my life at that point: I wanted to be a geneticist. While I didn’t end up being one, I don’t think I would have chosen biology in college if Dolly hadn’t come along. Recently, I came across another news article that caught my eye: a woman had successfully given birth to a baby with three parents. Reading the article, I couldn’t help but being nostalgic about Dolly because the technique used by the doctors was thematically similar to what was done in Dolly’s case. Even though Dolly was cloned from her mother, she was not an exact genetic replica of her mother. Technically, she had two genetic mothers. Here, I want to explain why and how a child could have three genetic parents.
In human and other complex organisms, DNA mainly resides inside the nucleus, analogous to City Hall that governs a city. Inside the nucleus, an egg or sperm—collectively called germ cells—carries one set of tightly packed DNA or chromosomes (the number of chromosome set, n, is 1). Compared to germ cells, other cells in the body—called somatic cells—carry two sets of chromosomes (n = 2). When a sperm fertilizes an egg, it donates another set of chromosomes to the egg. Hence, a fertilized egg has two sets of chromosomes (n = 2; 1 from father and 1 from mother). That cell would then divide to make 2 daughter cells, and those 2 cells divide to make 4 and so on until the embryonic development completes. In Dolly’s case, Dr. Keith Campbell and his team took a somatic cell (n = 2) from Dolly’s mother and fused it with a donor egg whose nucleus had been removed (n = 0). After fusion, the egg became similar to a fertilized egg because it now had 2 sets of chromosomes (n = 2; both sets came from the mother).
But how do you make this artificial fertilized egg divide so that normal embryonic development can begin? It turns out that an electric pulse could spark the beginning of life: scientists electrically shocked the fused egg to stimulate cell division. When the cell division reached a certain stage, scientists transferred the nascent embryo into a surrogate mother. After several months, that surrogate mother gave birth to the famous sheep we came to know as Dolly. Since Dolly was taken from the mammary gland, scientists thought of the famous singer, Dolly Patron, when they named the sheep.
Dolly on display in Scotland! Photo Courtesy: Bruce Goodwin 
The reason Dolly is not 100% genetically identical to her mother has to do with mitochondrial DNA (mtDNA). If we think of a cell as a city, mitochondria are the power generators for that city. But this organelle also carries DNA, which comes from the mother’s egg only. When a sperm fuses with an egg, the sperm’s mtDNA is actively destroyed by the egg. That leaves the fertilized cells with two sets of chromosomes and mtDNA from the mother. When the cell divides, the daughter cells also get the mother’s mtDNA as well as the nuclear DNA. In Dolly’s case, even though a somatic cell was fused with a nucleus-free donor egg, the mtDNA that came from the somatic cell didn’t survive; all of Dolly’s mtDNA came from the donor’s egg. Dolly, thus, had two genetic parents: one gave her mtDNA and the other, nuclear DNA. She was not exactly her mother’s clone as I thought back in high school.
The mystery of 3-parent children now becomes clearer. We can imagine a scenario where the father gives a child one set of chromosomes, mother another set, and a donor mtDNA. But why would anyone resort to such a complicated procedure?
The mother who gave birth to a healthy boy with 3-parents in Mexico in 2016 had seen her first two children die from Leigh syndrome. This fatal neurological disorder is caused by a mutation in an mtDNA gene. It was necessary in this case to replace the mother’s mtDNA that carried the mutation with a donor’s healthy mtDNA.
The technique used here had several differences compared to what we saw in Dolly’s case. Since scientists were not trying to make a clone of the mother, they used germs cells that came from both parents. Dr. John Zhang, the scientist/doctor whose team helped the couple, had to overcome two difficulties in this case though. One, they had to go to Mexico because such procedure is not allowed in the US. And two, the parents were against discarding a fertilized egg for religious reasons. So in Mexico, Dr. Zhang and his team collected only the nucleus from the mother and transferred it to a nucleus-free donor egg; the donor’s egg now contained the mother’s nucleus and donor’s mtDNA. Scientists then let the father’s sperm fertilize the donor’s egg. The rest of the procedure was similar to Dolly’s, except the scientists planted the ball of divided cells into the mother, not into a surrogate mother.
This technique also has been used to circumvent infertility. On April 9, 2019, a Greek mother gave birth to a healthy boy with the help of this technique. She resorted to this technique because other fertilization procedures didn’t work for her. She had poor egg quality.
In Ukraine, a similar technique has been used on several women with poor egg quality. There, eggs from both mother and donor were fertilized with the father’s sperms. The fertilized nucleus from the donor was then replaced with the fertilized nucleus from the mother. Hence, these babies also have three genetic parents.
Dolly was put to sleep when she less than seven, even though Finn Dorset sheep like Dolly normally lives between 11-12 years. It is possible her shorter life span had to do with the mismatch between donor’s mtDNA and mother’s nuclear DNA. A 2016 study on mice suggested such mismatch could accelerate aging and affect metabolism and obesity. Since it’s unknown whether the findings in mice also hold true in humans, we can only hope that all the children born with the help of this technology would have a long, healthy future ahead of them. Meanwhile, the ethical debates over using these techniques on humans would continue. We can blame—or thank—Dolly for initiating those debates.

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