An Ode to Ian Wilmut, Father of Dolly the Sheep
Ian Wilmut, the British scientist best known as “the father of Dolly, the clone sheep” died on September 10, 2023. He was diagnosed with Parkinson’s disease five years ago, and even though the work of his team accelerated research on many diseases, including his own, he was aware that it would take decades until new treatments became available. He was only being realistic when he said “People like me will probably have died of Parkinson’s disease before then.”
When newspapers from all over the world announced that a Roslin Institute research team has cloned a sheep and named her “Dolly” (after Dolly Parton, for obvious reasons) in 1996, it triggered ethical and moral concerns about the possibility of cloning humans.
However, Ian Wilmut himself was also concerned about human cloning and advocated for strict regulations about this issue. “The overall aim is actually not, primarily, to make copies,” Dr. Wilmut had said in an interview, “It’s to make precise genetic changes in cells.” He worked tirelessly to explain why human cloning should not be attempted.
Despite being a popular theme in science fiction for centuries, the thought of clones with much better characteristics than an average human, no matter how exciting, has always sparkled an element of fear. Still, the cloning of Dolly was a major scientific breakthrough and had a revolutionary impact on a wide range of research areas, including genetic engineering and stem cell studies.
The story of Dr. Wilmut
Ian Wilmut was born in 1944, in the village of Hampton Lucy, England. Both his parents were teachers, and during his young ages, Wilmut attended the school where his father taught. He wanted to pursue a naval career, but his colour blindness got in the way. Working on the farm on weekends, he developed an interest in biology, and he studied agriculture in university. He got married with Vivienne Craven and had three children with her. Two years after Vivienne’s death in 2015, he married his second wife.
In 1971, Wilmut finished his PhD in the University of Cambridge (Darwin College) with a thesis on the cryopreservation of boar semen. He joined the Animal Breeding Research Station in 1973, which later became the Roslin Institute. Dr. Wilmut was also part of the team that created Frostie, the first calf to be born from a frozen embryo. His studies focused mainly on gametes and embryogenesis, which eventually led to the cloning of Dolly the sheep in 1996. The main idea, in fact, was to create genetically modified animals to study human diseases.
Dr. Wilmut became a fellow of the Royal Society in 2002, and the chair of reproductive science at the University of Edinburgh in 2005. One year later, he was made the first director of the MRC Centre for Regenerative Medicine at the University of Edinburgh. He was knighted in 2008 and he retired from the Roslin Institute the same year, although he continued with scientific studies until 2012. In all these years, he continuously conducted studies, published scientific papers in prestigious journals, co-wrote two books on cloning, and received numerous honours and awards for his contributions to science. In 2018, he was diagnosed with Parkinson’s disease, which eventually led to his death.
The story of Dolly
Dolly was not the first cloned animal, nor the first cloned sheep. However, the early cloned animals were all created from embryonic cells by using a technique called “nuclear transplantation”. The technique consists of taking an egg cell, fertilising it in the laboratory, taking its fertilised nucleus (and thus the genetic material) out, and transferring it into an unfertilised egg cell whose nucleus is also removed. Dolly’s significance is that she was the first mammal to be cloned from an adult somatic cell instead of such a fertilised egg cell (or an embryo).
To create Dolly, the research team at the Roslin Institute used a different technique known as somatic cell nuclear transfer. Dr. Wilmut and his colleagues harvested cells from the udder of a 6-year-old Finn Dorset sheep, and transferred the nuclei of these cells into egg cells taken from a Scottish Blackface sheep. The team had to do this hundreds of times –they cloned 277 embryos, but only 13 began to divide normally and could develop sufficiently to be implanted in surrogate mothers, and only one implantation was successful. The researchers slept near the pregnant sheep for weeks, and finally, Dolly was born on 5 July 1996. Dr. Wilmut and his team announced Dolly to the world 7 months later, after making sure she was healthy and that their patent application was handed.
Dolly’s birth was a revolutionary step, proving that cloning studies do not have to be limited to the use of embryonic cells. Instead, it was possible to essentially reprogram an adult cell to develop into an entire organism, creating a genetically identical copy of an animal –even a complex animal like a high mammal. It also marked the peak of Dr. Wilmut’s career. In 2016, he said that without Dolly, stem cell research could be 20 years behind.
Dolly gave birth to six lambs, and lived at the Roslin Institute until she was put to sleep the age of six, due to severe arthritis and a virus-induced lung disease. Dolly’s body was donated to the National Museum of Scotland, where she has been on display since 2003.
…and the story of cloning
A clone defines an organism carrying an (almost) identical DNA to another organism. Clones can be seen in nature quite often, especially in bacteria and fungi, where a cell simply divides to produce two genetically identical copies of itself. Some plants also reproduce asexually through making clones of themselves, and many horticultural plant cultivars are also clones as they are derived from a single “parent” plant. It is also the case when identical twins develop from the same, single, fertilized egg. When genetic engineering techniques are not involved, this is called natural cloning. And things stayed in their “natural” course until the early 1900’s.
The idea of creating clones was an exciting dream for scientists even when no one even knew what genetic material consisted of. A biologist called Hans Driesch was in fact the first to demonstrate in 1885 that it was possible to physically separate the cells of a sea urchin embryo, at the two-cell stage, and have two entire embryos forming from each. Some decades later, another German scientist, Dr. Hans Spemann tried the same with salamander embryos and came up with the first solid idea of nuclear transfer. As technology was not advanced enough around 1920’s, Spemann could only experiment on separating salamander embryo cells at a very early stage.
In 1952, a team of scientists led by Robert Briggs and Thomas J. King succeeded in transferring the nucleus from an early tadpole embryo into a frog egg they had removed the nucleus of, and watched a tadpole develop from this egg. In 1958, John Gurdon took this one step further and used the nucleus of a somatic cell. He harvested the intestinal cells of a frog, and transferred their nuclei to enucleated egg cells to create tadpoles. Frogs were chosen as the first candidates because their eggs were large enough to manipulate. Of course, trial does not necessarily mean absolute success. Although the cloned frog embryos never reached adulthood, the technique used was a milestone, and thus began the nuclear transfer experiments. The same story went on for years, cloned frogs only developed to tadpoles and then died, or developed abnormally. But the researchers never gave up and wanted to try the experiment with other animals, as technology kept advancing.
Nuclear transfer experiments in mammals started in 1975, when J. Derek Bromhall transferred the nucleus of a rabbit embryo cell into an enucleated rabbit egg cell. The first clone sheep came about a decade later, when Steen Willadsen separated cells from a very early stage lamb embryo and fuse these with enucleated egg cells. The trial was successful and the resulting embryos were placed into the womb of surrogate mother sheep, who later gave birth to three live lambs.
Dr. Keith Campbell wanted to create clones from cells that have developed beyond these early embryonic stages. He also thought the key to success was keeping the cell cycles of the donor and recipient cells in synchrony. It would be problematic to catch both cells at the correct moment, so he had to find a way to slow down cellular activity, forcing the cell into a sort of hibernating state.
This was actually done by a group of American scientists when they simply forgot to give the nourishing serum to their embryonic cell batch, unknowingly starving the cells to be cloned. The experiment yielded four calves, but no one realised the significance of this accidental starvation on the experiment’s success.
Two years later, Campbell and Wilmut tried the starvation technique on embryo cells, on purpose, and created two cloned sheep called Megan and Morag. This experiment proved his theory on synchronising the cycles of the donor and the recipient cells. However, they were still working with embryonic cells. Even though embryonic cells have the ability to develop into virtually any type of cell in an organism, working with embryos raised ethical concerns, especially when the number of embryos to obtain one viable clone was considered. For all these reasons, Campbell and Wilmut extended the technique to work with somatic cells and their efforts led to the birth of Dolly, the first mammal cloned via somatic cell nuclear transfer.
What does the future hold?
Since Dolly, a wide range of animals have been cloned from somatic cells. Researchers also used cloning techniques to populate endangered species, and considered recreating extinct animals. Another idea was to insert engineered genes into genomes while creating clones. While this may bring a lot of interesting sci-fi scenarios into mind, the actual idea behind it was to study diseases or to treat them. But for this purpose, the model organism had to be biologically close to humans. The cloning of a Rhesus monkey via somatic cell nuclear transfer in 2007 opened the door to the possibility of creating individual-specific stem cells that could be used to treat certain diseases.
Another important milestone was also reached only a year before that, when Shinya Yamanaka developed a method to reprogram adult cells into the equivalent of an embryonic stem cell. This achievement, which eliminated the need to create and then destruct an embryo in stem cell research, brought him over 30 prizes including the 2012 Nobel Prize in physiology or medicine.
And finally, the scientists succeeded in using cloning to create human embryonic stem cells in 2013. The donor cells were taken from a baby with a rare genetic disorder and the stem cell lines produced were specific to “that” baby. This marked the beginning of person-specific treatments. However, there were still issues.
Stem cells produced this way did not always act exactly like embryonic stem cells, because they retained the biological “memories” of cells they were derived from. This was a killjoy that could limit their therapeutic use, because the old cellular memories could affect the function of stem cells derived from them. In August 2023, Australian scientists developed a new technique to erase the cellular memory and make the resulting stem cells more similar to embryonic stem cells -both molecularly and functionally.
Earlier this year, American scientists created synthetic human embryos using only stem cells, without egg or sperm cells. Then, in September, Israeli scientists announced they have grown the first complete human embryo models that mimic all the key structures that one can see in the early embryo.
So, the focus is now on creating model embryos that may raise less or no ethical concerns. These models resemble actual embryos in the earliest stages of human development. They do not have a beating heart, a gut, or the early development of a brain, but they do have the cells that could form the placenta, yolk sac and the embryo itself.
Such models may provide scientists a means to study and understand certain genetic disorders, even recurrent miscarriages. Mimicking human embryonic development using stem cells can give researchers valuable information about how the embryo develops at early stages and what can go wrong.
One way or the other, studies on cloning and stem cells will continue and advance. Maybe one day scientists will discover a perfectly safe and ethical way to reprogram cells and implant them in people to treat a large variety of diseases. Maybe one day we will all even have our own stem cell libraries, ready to be used at any time. However, one thing is for sure: Even if no actual embryos are used, proper legislation and control on lab-grown entities may make things more reassuring.
REFERENCES
- 1. https://www.washingtonpost.com/obituaries/2023/09/12/ian-wilmut-dolly-sheep-obit/
- 2. https://archive.nytimes.com/www.nytimes.com/books/97/12/28/home/0303cloning-sci.html
- 3. https://www.nytimes.com/2013/05/16/science/scientists-use-cloning-to-create-embryonic-stem-cells.html
- 4. https://www.bbc.com/future/article/20120229-cloning-which-animals-and-when
- 5. https://learn.genetics.utah.edu/content/cloning/clonezone
- 6. https://frontlinegenomics.com/evolution-of-cloning-a-dolly-good-show/