Folio News Story
November 16, 2007

A history of breakthroughs

The U of A remains at the forefront of diabetes research

by Michael Brown
Snubbed by history, U of A biochemistry professor James Bertram Collip discovered a way to isolate and refine insulin.
Snubbed by history, U of A biochemistry professor
James Bertram Collip discovered a way to isolate
and refine insulin.

The Edmonton Protocol's recent heroics in the diabetes treatment, while extraordinary, didn't mark the first time University of Alberta research turned the tide in the fight against diabetes. And, thanks in part to the Alberta Diabetes Institute (ADI), it probably won't be the last.

Nearly 80 years before U of A researcher Dr. James Shapiro performed the world's most successful islet cell transplant, James Bertram Collip discovered a way to isolate and refine insulin.

James Shapiro led the team that achieved success with the Edmonton Protocol treatment of Type 1 diabetes.
James Shapiro led the team that achieved success with
the Edmonton Protocol treatment of Type 1 diabetes.

Although history has chosen to largely overlook Collip's contribution, at least one author has argued Collip's efforts were as important as work done by the three scientists who got most of the credit: Frederick Banting, Charles Best and John MacLeod.

Toronto historian Michael Bliss wrote in his 1982 book The Discovery of Insulin that the team's achievement was clouded by a good deal of petty jealousy and backstabbing, mostly on Banting's part.

In 1915, at the age of 23, Collip was hired by the U of A to lecture in biochemistry and physiology. By 1921, he was head of the new Department of Biochemistry and had established himself as an experienced researcher with 23 academic publications, most concerning problems of blood chemistry.

As a relatively inexperienced scientist, Banting knew he needed Collip's chemical expertise. The crude extract Banting and Best had come up with to treat diabetics was only partially successful in lowering blood sugar in diabetic dogs; the active ingredient or "mysterious something" responsible for aiding in the metabolism of carbohydrates required further purification. Collip accepted an invitation to work with Banting and spent part of a sabbatical with Banting, Best and MacLeod in Toronto.

Banting, on the heels of an ill-advised clinical failure on human patients at Toronto General Hospital, looked on as Collip struck gold.

"I experienced then and there all alone in the top storey of the old Pathology Building perhaps the greatest thrill which has ever been given me to realize," Collip wrote on the night of this crucial discovery.

What soon followed was the now-legendary physical confrontation between Collip and Banting during which Collip, impatient with Banting's competitive attitude, threatened to keep the purification process to himself.

Differences were temporarily ironed out, however, and Collip's new extract was tested on 14-year-old Leonard Thompson, a severely diabetic patient. The results were unambiguously favourable. Although it was still to undergo further refinement, insulin was a success. What had been a painful, devastating disease had become manageable, and MacLeod and Banting were awarded the Nobel Prize for Medicine.

Fast forward nearly 50 years to 1972, when U of A bioengineer Ray Rajotte sat in on a talk by American researcher Paul Lacey, who had cured diabetic rats by transplanting Islet of Langerhans cells from a healthy rat. Rajotte, whose interest at that point had included cryopreservation of stomachs and kidneys, decided then and there that maybe there was a niche for his work.

Rajotte thought Lacey's research wasn't advancing because of problems trying to freeze kidneys. "I thought . . . 'Maybe I should try to learn how to isolate islets and try to freeze them. Maybe they'll have some sort of clinical application down the road.' "

Edmonton Protocol pioneer Ray Rajotte put in years of research to find a way to transplant islet cells.
Edmonton Protocol pioneer Ray Rajotte put in years
of research to find a way to transplant islet cells.

Rajotte spent the next few years in research labs in every corner of the United States learning everything he could about isolating islets before returning to the U of A and piecing together an islet team.

Isolating the insulin-producing islets posed a problem. However, if donor islets could somehow be isolated, it was postulated that they could be injected into the liver. There, the islets would become revascularized and perform their duties as usual, away from the besieged pancreas, the site where the diabetic's immune system inexplicably attacks healthy islets. With any luck, such a transplant - accompanied by a proper anti-rejection drug regimen - could allow a Type 1 diabetic to be free of insulin injections.

In 1989, Rajotte's islet team carried out Canada's first islet transplant.

"The first two patients got an insulin reduction requirement, but they didn't quite get off insulin," said Rajotte, explaining that his team reconfigured the procedure for a third patient to double the number of islets, by using both fresh and cryopreserved samples. The result was short-lived insulin independence.

"From '89 to '99, 269 transplants were carried out worldwide, but only eight per cent got off insulin, so that was a disappointment."

Undeterred, Rajotte continued to build the U of A's islet team. James Shapiro was recruited to the U of A where he worked on his PhD, studying the screening of new anti-rejection drug and steroid combinations for possible testing on islet transplantation. He went on to stops in Vancouver, Japan and the University of Maryland. In 1998, Shapiro was recruited back to the U of A with a mandate to reactivate a stalled Clinical Islet Transplant Program.

Along with Dr. Jonathan Lakey, Shapiro developed what came to be known as the Edmonton Protocol, and on March 11, 1999, Bryon Best, a teacher from the Northwest Territories, was the first person to receive an islet transplant that employed the drugs and novel techniques devised by Lakey and Shapiro. Within a week the patient no longer required insulin injections and was able to maintain a steady glucose count.

"In the initial design, there wasn't a eureka moment because it was built out of absolute desperation; all the previous transplants weren't working, the approach was failing," said Shapiro, explaining that it was not just a single alteration to the previous islet transplant method, but rather a series of steps used to help enhance the success rate.

"I was so busy . . . we didn't quite realize how successful this was until we analyzed the results in the first seven consecutive patients that were treated with this protocol."

"The moment I realized that all seven patients were completely free of insulin at the time that we analyzed them, that was a big, big moment. All of a sudden there was this brand-new protocol. We had 100 per cent of patients off insulin. I think at that moment there really was a eureka moment not only for the team but for the patients involved."

Still, Shapiro says that although his findings have led to more than 100 straight successes at the U of A alone, "one has to be realistic."

"It's remarkable, but it's not enough," said Shapiro, who is introducing the Edmonton Protocol to diabetes treatment programs around the world. "There are 2 million Canadians with diabetes and many more millions worldwide. If we're really going to have an impact on most patients, we're going to have to have something far better than what we have even now. So, you don't get dizzy with the success; you focus on what is needed to take us to the next step."

Although the Edmonton Protocol has lasted on some patients from the moment that the cells were transplanted until now, its impact has faded on some patients, who are now using small amounts of insulin. These relapses and the lifetime of anti-rejection drugs has forced Shapiro back to the drawing board, which now sits in the newly minted ADI.

"The way I like to think of it is we are going to leave no stone unturned until we get to a point where we have a true cure for this terrible disease," said Shapiro who, in 2005, took the Edmonton Protocol a step further by carrying out a transplant from a living donor. "There are many different avenues yet to be explored."

Beyond the Edmonton Protocol, other treatments - like the use of pig islets as a viable alternative to the limited supply of human islets - are now on the horizon, and one day may write a chapter in the U of A's diabetes story.

"What really matters at the end of the day is how people interact and what new ideas come forward to allow one to move forward to the point where you have a cure," said Shapiro. "You can't guarantee that a new building will establish that, but it will certainly help."