Bill Ritchie: The man who made Dolly the Sheep
Bill Ritchie, Photo courtesy of Bill Ritchie
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While we’ve heard about some of the ways in which humans are shaping species through our actions on their environments and habitats, or through selective breeding, there are ways in which we’re changing life in the laboratory, through technologies like genetic modification and cloning. And when you mention cloning, one of the first animals that comes to mind is Dolly the Sheep.
Born in 1996, she was the first mammal to be cloned from an adult cell. We’ve previously covered Dolly’s story - and that of Ian Wilmut and Keith Campbell, the researchers who led the project that led to her birth - back in episode 23 of our first series. But there’s another character in this story who tends to be overlooked, and that’s the embryologist who actually carried out the cloning procedure that led to the creation of Dolly.
William Ritchie, known as Bill, started his career in science in 1972 as a hands-on support worker collecting samples and measurements from sheep in an agricultural research facility in Scotland. But his life changed when a new transmitter was installed in the area, bringing young Bill a relatively new TV channel: BBC2.
Bill: BBC Two at that time had loads of very interesting programs to me as I was working at the farm, doing most of the stuff, collection of material, things like collecting the different measurements that we were doing on sheep at the time. So I saw all these Open University programs and started an Open University course. And 10 years after that, I actually managed to gain a degree from the Open University and it kind of snowballed from there.
Kat: Armed with his open university degree, Bill moved to the Roslin Institute in Edinburgh, where he found an opportunity to step closer to the scientific side of things.
Bill: A lot of the work I was doing at Roslin was anaesthetising sheep to remove embryos, and because I had a little bit spare time when I had finished anaesthetising the animals, I then started helping that particular embryologist to select the oocytes and pick up oocytes and move them around, a lot of embryology is actually moving things around and being able to find them again. You're talking about a sheep embryo, about 150 microns, just about visible with the eye without looking through the microscope. But during that time, of course I was gaining experience and looking through microscopes and hand-eye coordination, picking up these embryos and giving them to that particular embryologist.
Bill: I was there maybe three or four years when I was perhaps doing a bit more of that and the equipment that was used for the microscopes micro manipulators and micro injectors, were being used at that time by a PhD student, a guy called Lawrence Smith, and as he finished his PhD, of course, the equipment was then not being used and I was encouraged to actually start using the equipment. In actual fact, that was perhaps one of the things that kind of got me hooked. Initially when I was assisting the embryologist at Roslin, it was looking through the microscope and seeing these golden spots of light, which were the early embryos, the pro-nuclear embryos, and being able to pick these up and move them around and it did kind of get me hooked onto the whole idea of doing this and it really just developed from there.
Kat: Bill took over the embryological machinery, which was being used by the previous PhD student Lawrence Smith, getting to grips with hand-crafting and using the microscopic glass tools that were required to manipulate and inject the tiny embryos. Smith had already been trying to clone sheep by putting the nucleus from a cell, which contains all the DNA, into an unfertilised egg, or oocyte, from which the DNA had been removed. Bill built on Smith’s technical developments, setting the stage for a new scientific idea to finally come to life.
During the late 1980s, scientists were starting to get more and more excited about the possibilities of using new genetic engineering tools to bring benefits for human and animal health. This was in part driven by the problem faced by people with the bleeding disorder haemophilia, who lack a particular protein that helps their blood clot.
The proteins they were getting for treatment had been purified from blood donations, but unfortunately due to a lack of effective blood screening techniques, viruses like hepatitis and HIV were coming along for the ride. So, was it possible to make a genetically modified sheep that could make this molecule instead?
Bill: The idea that there was that the actual protein, which was of interest, would be actually expressed in the milk of these animals. So you could breed them, milk them and remove the protein. Sheep. Of course don't get AIDS or hepatitis and this would be one way of actually producing the blood products without going through a human and being extracted from the blood.
Kat: Conventionally at the time, these kinds of transgenic animals were made by injecting small bits of DNA into an egg cell. But that wasn’t enough for the Roslin team.
Bill: In actual fact, this was going to be, I suppose, a commercial product and of course, if you want to make an animal which is identical to another, if you wanted to make the same animal with the same gene modification, then the only way to actually do that would be to actually clone that animal in some way or to actually add these genes to to an embryo. But if you use cloning, then of course all the cells in the body and that animal are the same. So it's a way of actually replicating an animal with a particular genetic modification.
Kat: While many people have heard of Dolly the Sheep, she wasn’t actually the first successful cloned mammal - although she was the first from an adult cell. Bill first created a cloned animal in 1993, three years before Dolly, by injecting the nucleus from one of the eight or so cells in a newly fertilised embryo back into an unfertilised oocyte But to make the idea of genetically modified animals a reality, the Roslin team had to be able to create clones from cells that could be grown - and therefore genetically manipulated - in the lab.
The real breakthrough came in the form of Megan and Morag, two lambs born in 1995 who Bill cloned from embryonic cells that had been grown in the lab, proving that it was possible to clone from cultured cells. In turn, they set the stage for the 1996 arrival of Dolly, who was cloned from an adult breast cell that had been grown in the lab, and then Polly and Molly, born in 1997, who were the first animals to be cloned from genetically modified cultured cells, finally bringing the team’s original vision to fruition.
Bill: My former boss, professor Keith Campbell. He always said that Morag and Megan were the most important animals because they were the enabling technology. So Dolly was a bit an aside and Polly the following year was really the culmination of a lot of these experiments. But we certainly knew that we could clone from an embryo, which was very early. We didn't know that we could clone from adult cells at that time.
Kat: It’s easy enough to talk about these breakthroughs now as if they were simple or inevitable but I was curious to know if Bill always thought that it would work.
Bill: I do sometimes wonder how it worked with a process, which was so, so difficult in those days, especially. And it's kind of a little bit easier now and that all these things which took so long in the past are now almost instantaneous. You can buy a lot of things as I say, but it was a huge experiment. A huge organisation required to actually get oocytes at the right stage with recipient animals at the right stage and with everything working. I just don't know how it actually worked. Just huge number of people and I've always said that all these experiments from farm staff who were handling the animals to people who are producing the cells to everyone else who was in between, people washing dishes and everyone was very important. And that it's a chain where you're only as good as the weakest link. And we were very successful because we had some very good people.
Kat: While the whole team played their part, bringing Megan, Morag, Dolly, Polly and Molly to life involved hours of painstaking work for Bill, manipulating hundreds of tiny embryos down the microscope. So did he ever get fed up?
Bill: I don't think you ever feel frustrated. You know what's happening, you're aiming for a particular result from an experiment. And my day was very busy, and even if I spent maybe two or three, maybe four hours at a microscope, that was a very, very hard day for me. And as I say, everyone has to do their job from people making medium to people injecting animals, to make them superovulate.
Kat: Eventually the cloning programme at Roslin came to an end, and Bill moved on to take his embryological expertise elsewhere.
Bill: And when I left Roslin, I did go to Dubai and did some work with a camel breeding company there and assisted them in producing the first cloned Camel. Camels are very important animals in the area, for racing mostly, so cloned racing camels were some of the things that happened. And I traveled all over speaking about things like that, helping people start laboratories and all sorts of things like that. One of the most recent ones was to actually go to Africa, to Kenya, and teach people there to carry out the cloning technique. And we produce one of the first clones of a native breed of animal in Kenya. And the idea behind that was of course, to make a transgenic animals, which would be resistant to trypanosomes the parasite that causes sleeping sickness in humans, but also causes massive loss of productivity in cattle in the Sub-Saharan Africa. So yeah, lots of little things like that.
Kat: From cloning sheep to racing camels and African cows, it’s clear to Bill that the development of this technology has left an indelible mark on the world.
Bill: Well, I mean, if you're talking about the real legacy of Dolly, I think it's far more interest in STEM cells and I think we're now seeing things coming through now, which we might say were far more as the result of the law that we broke, If you like, the one that said "once the cell has been differentiated, it couldn't be undifferentiated" and that's what I was taught. So the fact that we found that, that wasn't true, the fact that Yamanaka then discovered other ways of making STEM cells. It all develops, and it's probably resulted in a lot of human diseases which are being looked at through the process of STEM cells and STEM cells are the real thing that seems to come from Dolly and the experiments that we carried out.
Bill Ritchie. And thanks to my other guests, Alex Ball and Helen Pilcher.
