25 years ago this year, the world was introduced to revolutionary cloning research, leading to a ground-breaking approach to transgenics that most people will remember in the form of Dolly the Sheep. Ahead of his official TV interview with Horizon aired in the UK on 8th December 2021, I spoke to Professor Grahame Bulfield, former Director of the Roslin Institute (home of the research programme).
Who is Professor Grahame Bulfield?
Bulfield’s journey through an incredible and extensive career began in 1959 when he started studying BSc Agriculture with Honours at University of Leeds. Being brought up in the country and working on farms, agriculture was the natural and obvious route to take. Genetics was part of this course which Bulfield particularly enjoyed and it was thanks to the encouragement from one of his lecturers that he would pursue this area further.
He went on to enrol for a Diploma in Animal Genetics at the Institute of Animal Genetics (now known as the Roslin Institute) at the University of Edinburgh. Bulfield would also spend some time at the University of Uppsala in Sweden as a Yorkshire Agricultural Society Travelling Fellow.
After achieving his PhD, Bulfield then went on to spend some time in the Department of Genetics at the University of California in 1968, until returning to the UK in 1971. Now at University of Leicester, Bulfield was appointed Lecturer and Medical Convenor of Medical Genetics - here he would play a part in another significant scientific discovery.
A PhD student was working on a mutation (known as mdx) in the X-chromosome of a mouse that was particularly peculiar. With some prior knowledge of the symptoms, Bulfield believed it could be muscular dystrophy. A colleague working on muscular dystrophy in chickens helped to confirm suspicions. Finding this naturally occurring mutant showing non-lethal muscular dystrophy meant that this could be studied effectively. These findings have been a model for human muscular dystrophy ever since.
In 1981, Bulfield returned to Edinburgh as Head of the Genetics Group at the Poultry Research Centre. Following an integration, Bulfield found himself back as part of the team at the Roslin Institute in 1986 until becoming head of the entire station two years later.
Transgenics at the Roslin Institute
In 1988, the level of efficiency in transgenics at the institute remained extremely low - only around 1% and something needed to be done about this. Leading this specific area of research was Sir Ian Wilmut.
Bulfield reflected on Wilmut and his team’s ideas for improving this; the kickstart to the whole cloning project. The idea was to attempt genetic modification of cells in culture and to then transfer these cells into an embryo to make a whole animal.
Bulfield stressed the importance of understanding that Dolly the Sheep was not the beginning nor the end of this particular research programme. It was previously discovered a year earlier with the other subjects, Megan & Morag, that this could be achieved from embryo cells. As an extension to this research, a year later similar experiments would take place, one of which using a mammary gland cell.
Until this point, it was assumed that once a cell had become a mammary gland, it would not go back to an embryo. However in the shape of Dolly the Sheep, Ian Wilmut and his colleagues proved this theory wrong, meaning nearly all the biology textbooks we had, needed to be re-written.
The third stage of the project included adding foreign genes into the cells in culture. These were selected and put into embryos again, producing three more animals, Polly, Holly & Molly, which all had a human gene within them and were cloned at the same time. The important thing about the human gene was that it worked, i.e. produced a human protein.
With this, the whole journey that the institute set out to achieve was successful. Subsequently, genetic cloning in farm animals became incredibly efficient - almost 100%.
Grahame Bulfield with Dolly (front) whose original name was Tuppence but an Animal Technician who was a country and western fan called her Dolly (who is also famous for her mammaries!) and Megan & Morag (back)
The successful research did not come without its share of difficulties. In general, the UK was struggling financially at this time. Funding for such projects was extremely limited.
On the day Dolly’s success was announced to the world, the funding that had been available was withdrawn. “We had the biggest scientific breakthrough of the decade and no money to fund it”, Bulfield explained.
The government informed Bulfield and his colleagues at the Roslin Institute to find funds by themselves. This was achieved by the formation of the company ‘Roslin Biomed’ which culminated in raising £6 million from venture capital company, 3i, and this is how the research was able to continue for a year or so following the initial victories.
Roslin Biomed was eventually bought over by US corporation, Geron, In early 2000 for £30 million. Roslin only owned some of the shares when they were sold and most of the money was put into Roslin Foundation, which would be used exclusively for research at the institute.
Twenty-five years on, the foundation is still running with money available for the current director to use.
There were also some ethical concerns around exactly what this breakthrough meant for the limitations of science. Coming almost out of nowhere, many people did not think this cloning process was possible. It opened the door to possibilities surrounding human cloning and so it was vital for the team at Roslin to be open with the public, journalists and parliament about what exactly the research was to be used for. The law surrounding cloning was later discussed with parliament to make sure that human cloning was made completely illegal.
Bulfield explained, “Science can be used for good or evil, and it’s not necessarily the science but what it’s used for and changing the law meant it couldn’t be for human cloning”.
While some journalists attempted to whip up fear, generally there was a lot of support behind this project from the public and the breakthrough was recognised for all of its positive significance.
Bulfield explained how he believed being open and honest about the work taking place was crucial to this - “You can’t say, ‘let’s not do this work, it looks a bit dangerous or it could be used for dangerous things’, the important thing is to communicate it and explain it so that the regulators, governments, parliaments and so on can bring out the correct regulations to control it”.
I asked Bulfield if he believed, had this research not already taken place, could it still happen in today’s research environment?
The short answer to that was yes.
“Scientists are working on a broad front and anyone who makes a breakthrough is often only a short while ahead of the next person” Bulfield commented. In fact, at the time, there were other labs working on a similar approach. He simply believes Wilmut and his colleagues were particularly clever and had their breakthrough some way ahead of other people.
The breakthroughs with Megan, Morag, Dolly, Polly, Holly and Molly continue to play a vital role in research for genetically engineered animals so we can continue to learn about their development and functions, as well as contributing to a wide range of vaccines and treatments.
The BBC Horizon documentary 'Dolly: The Sheep that changed the world is now available to watch here