Clark, who only last year succeeded Bulfield as director of the Roslin, had been a transforming influence on the institute since its creation in 1993, Bulfield told The Scientist. Clark was found hanged in his holiday home earlier this month.
During its early years, "Roslin moved from being a bog-standard 'feed-em and weigh-em' farm animal research institute to a world-famous biotechnology institute," said Bulfield, now head of the University of Edinburgh College of Science and Engineering. "Now really it's become a mainstream biotech lab using things like embryonic stem cells. With myself and Ian Wilmut, Clark was the one molecular [biologist] driving force that aided that transition."
Roslin became a favorite of the mass media in 1996 when Ian Wilmut's team created the cloned sheep Dolly, but before her, in 1990, came Tracy the genetically modified sheep. Tracy was the result of Clark's work with Alan Archibald, now head of the division of genetics at Roslin.
"To lose such a talented individual… It's a huge loss, especially so early after his appointment as director," Archibald told The Scientist.
The two first started working together in 1985 in the Animal Breeding Research Organization, where they were trying to produce human proteins in the milk of transgenic animals.
"It began in 1982, when one of the very first transgenic mouse papers appeared in Nature, with a cover picture of a small mouse alongside what looked like a rat in terms of size, but they were brother and sister," said Archibald. The larger animal carried an inserted growth hormone gene.
"Agricultural people then tried to do the same experiment in pigs and sheep, but it didn't go exactly as planned," Archibald said. But he and Clark took their cue from the closing paragraph of that paper, which noted there was a lot of growth hormone circulating in the plasma of these animals. "John and I took that as our inspiration, and rather than producing the proteins in blood where if it's an active protein it can have all sorts of effects on the entire animal, we looked to produce it in milk, partially external to the body," he said.
The protein they got furthest with was alpha-1 antitrypsin, using a promoter from the beta lactoglobulin gene. "John isolated the beta lactoglobulin gene from sheep and characterized it, and expressed it in mice," said Archibald, who said he "was responsible for putting the alpha-1 antitrypsin bit together with it." Clark and Archibald then gave Ian Wilmut and others the construct, and the result was Tracy.
Success with Tracy then drove the creation of Dolly. Only 1% of injected eggs produced germline transgenic sheep, and production costs were far higher than for mice, said Bulfield. "So they decided to see if they could get the cells going in culture, make the transformation, select the right cell, and make an animal out of it." This necessity was a spark that led to Dolly.
"Like many scientists, John was a very driven individual and very committed to his research," said Archibald. "But I guess the thing that made him particularly unique was his recognition of the possibilities for exploiting research—the entrepreneurial dimension to his character. So although the idea for a spin-off company—Pharmaceutical Proteins Ltd, PPL—was around from the beginning, it was John who turned it into reality."
The company has recently folded, but it has been independent of Roslin for some years. Archibald would not be drawn into speculation on the reasons for its failure.
When Ian Wilmut and his team produced Dolly, Clark was pivotal in putting together another company—Roslin Bio-Med—and was involved in its conversion, with the US company Geron, into Geron Bio-Med, which now works on human embryonic stem cells. "A significant part of his personal research program latterly [to develop embryonic stem cells into stem hepatocytes and brain cells] was funded out of Geron funds," said Archibald.
Barry Gusterson, from Glasgow University, confirmed Clark's deep interest in the medical applications of science. He met Clark some 14 years ago when he was interested in making systems of targeted cell ablation, as mechanisms for trying to work out lineage pathways. The two were linking together with researchers at the Institute of Cancer Research to work on model systems for prodrugs.
"He was a very broad thinker," said Gusterson. "Another area he was working on was the possibility of doing xenotransplants by humanizing animal tissues—a completely new area."
Clark studied natural sciences at Christ's College, Cambridge, before gaining an MSc at the University of Western Ontario in Canada and a PhD in genetics at the University of Edinburgh. In 1997, he was awarded the Order of the British Empire—an honor bestowed by the queen—for services to the biotechnology industry. He was elected a Fellow of the Royal Society of Edinburgh in 1999.
"John was a brilliant scientist," said Gusterson. "And he was so generous with sharing his ideas. That all came through with his friendliness. Most people who met him considered him as a friend."
Archibald noted that as director of Roslin, a project Clark was beginning to focus on was how the institute might work more closely with other local institutions.
"Clark really saw the merits in collaborating, and the discussions we've been having since his death show we've got a very clear sense of where he was planning to go, and it's a direction that we are more than content to follow," said Archibald. "We hope we can make that a reality."
BioMed Central
September 8, 2004
Original web page at BioMed Central
