They call it the "Edmonton Protocol," and it could well be the most important breakthrough in diabetes therapy since Drs. Frederick Banting, Charles Best, John MacLeod, and James Bertram Collip discovered insulin in 1922.

Using a deceptively simple and yet effective transplant procedure, researchers at the University of Alberta in Edmonton have achieved a 100 percent success rate in erasing all symptoms of type 1 brittle diabetes-an extremely severe form of the disease-in 11 men and women who were unable to control their condition with insulin shots.

Although the researchers themselves carefully refrain from calling the treatment an outright cure, all 11 patients have remained needle-free and without symptoms for up to 16 months after the procedure was performed.

Affecting an estimated 16 million people in the United States alone, diabetes mellitus results from a lack of insulin, which is produced by islet cells in the pancreas. Insulin enables the body to process fats and sugars derived from food. In type 1 diabetes, affecting about ten percent of the diabetic population, the islet cells are destroyed by the body's immune system. In type 2 diabetes, these cells progressively lose their function. Without adequate insulin, blood sugar levels become elevated, leading to serious complications, including kidney failure, blindness, brain impairment, cardiovascular disease, and a ten to 15 year loss in life expectancy.

Current treatments for patients with diabetes are designed to either replace insulin with regular injections, increase the production of insulin or help insulin act more efficiently. In severe cases where those interventions are inadequate, whole pancreas transplantation may be considered. While successful in 75-90 percent of patients, whole organ transplants are a hugely complicated procedure fraught with considerable risk and morbidity. By contrast, the relatively low risk Edmonton Protocol intervenes in the type 1 diabetic process in two ways: by transplanting healthy islet cells harvested from two donor pancreases into the patient, and by preventing rejection of those cells with a special "cocktail" of anti-rejection drugs (sirolimus [Rapamune®], tacrolimus [Prograf®], and daclizumab [Zenapax®]).

Resembling a simple blood transfusion more than a transplant operation, patients remain fully awake during the procedure. Instead of invasive surgery, the surgeon passes a small needle through the patient's side and into the portal vein, the principle blood vessel that leads to the liver. Carefully purified islet cells are then squirted into the vein, where they are carried by the blood on to the liver. Once there, an amazing thing happens. The cells "nest" in the organ and begin to produce insulin, effectively converting a "neighborhood" of the liver into a healthy pancreas, thus replacing the pancreatic cells that were destroyed by the autoimmunity aspects of the disease. Patients go home about 12 hours later and the turnaround from insulin resistance to a normal state begins almost immediately.

To protect the transplanted cells, the anti-rejection cocktail is taken as two pills-one drug taken once-daily, the other twice-daily-with an antibody given once every two weeks for ten weeks.

According to Dr. John Shapiro, a transplant surgeon and director and head of the Clinical Islet Transplant Program at the University of Alberta (U of A) in Edmonton, who conceived the basics of the new protocol while studying whole pancreas organ transplantation techniques at the University of Maryland in Baltimore, the concept of pancreatic islet cell transplantation is not new, just frustratingly unsuccessful until now, despite the persistent efforts of the best researchers around the world.

In fact, Dr. David Harlan of the US National Institutes of Health (NIH) organ transplant research center, points out scientists like Drs. Camillo Ricordi at the University of Miami, Dr. Bernhard Herring at the University of Minnesota, and Dr. Ray Rajotte at the U of A, among others, have steadfastly kept the concept of islet transplants going for over 30 years, convinced it would work, but meeting with little success.

Compared to the 100 percent success rate achieved so far by the Edmonton Protocol, previous attempts have been only eight percent successful, Dr. Shapiro pointed out, results so disappointing that funding for islet transplant research became increasingly hard to find. He added that work on the new technique might not have continued save for the Alberta Diabetes Research Foundation, a group of parents and volunteers who raised two million dollars for the U of A researchers through garage and bake sales.

What makes the new technique so effective, Dr. Shapiro said, seems to be related to how it is performed. That, in turn, is a direct result of the innovative work his co-developers have contributed to the protocol: namely, Drs. Jonathan Lakey, an assistant professor of surgery at U of A and Director of the Clinical Islet Isolation Laboratory; Greg Korbutt, a cell biologist; Edmond Ryan, a diabetes specialist, and Dr. Rajotte, a biochemical engineer who assembled and heads the U of A team. Dr. Shapiro joined the group in 1993.

In addition to the less invasive needle-based delivery system, Dr. Shapiro and colleagues came up with four new approaches to the islet transplant procedure and tried them all. First, they decided to process two pancreases instead of one so they could put in more islet cells than had been previously used.

That became possible thanks to new harvesting techniques developed by Dr. Lakey. "The goal is to implant enough islet cells to achieve normal blood glucose levels," he explained. "The new process is a rather difficult undertaking that other centers have been unable to do to date. It takes myself and four colleagues about six hours to perform. Unlike a kidney transplant, where the whole organ is placed, we are only isolating and transplanting islet cells, which are notoriously difficult to isolate. They make up only two percent of the pancreas, so we are literally picking needles out of a haystack."

Secondly, instead of keeping the cultured cells in cold storage for a day or more, Dr. Shapiro decided they should be transplanted immediately in an effort to minimize cell death. Individual cells, like whole organs, simply do better inside the body than outside, he reasoned, so why not return them to their proper environment as soon as possible? Thirdly, the researchers decided to abandon the traditional practice of using fetal calf serum to culture islet cells, suspecting that the animal protein might affect the cells in some way that would induce an immune response in the recipient.

Finally, Dr. Shapiro developed a glucocorticoid-free immunosuppressive regimen consisting of three relatively new organ anti-rejection drugs: sirolimus (Rapamune®, Wyeth-Ayerst, approved by the FDA in 1999); tacrolimus (Prograf®, Fujisawa, FDA approved in 1994), and daclizumab (Zenapax®, Roche, approved in 1997 as the first humanized monoclonal antibody to be included in an immunosuppressive regimen).

Previously, as with other organ transplant procedures, islet transplant patients had received steroid-based agents to suppress their immune system, but the Edmonton team noticed these drugs also caused the body to reject the insulin being produced by the transplanted cells. With the new regimen, the insulin became available and based on results to date, has been capable of returning all patients to normal blood sugar levels.

"The main downside of the procedure is the need for patients to remain on anti-rejection drugs, which is also why we can not say this protocol is a cure for type 1 diabetes," Dr. Shapiro said. "But we and others around the world are already working on experiments that suggest the same transplant procedure could be performed with a tolerance strategy that would essentially re-educate the immune system, making immunosuppressive drugs unnecessary. We are still cautious about these strategies, however, because they have not been done in people yet."

Currently, the main candidates for the Edmonton Protocol are adult patients who have had type 1 diabetes for five years or more, who are not well controlled by insulin injections, and have hyperglycemic unawareness and coma, he added. "But in the near future, we also hope to use the technique in children the moment they are diagnosed with diabetes. In doing so, we could head off the long-term risks associated with the disease.

"Unfortunately, the protocol can not yet help type 2 diabetes patients because they would probably require about ten times more islet cells than type 1 individuals," Dr. Shapiro said. "Given the limited supply of donor organs, we first need to develop methods of growing an unlimited supply of these cells to reach this group."

Dr. Lakey estimated the means of establishing a consistent supply is at least five years away, and will require considerable study, probably along three avenues of investigation: cloning islet cells, developing stem cells that can differentiate into islet cells, and xeno-transplantation using animal cells. Fetal pig tissue is considered the most logical source by many researchers, but this raises a number of ethical and immunologic issues that medicine and society at large will have to work out, he added.

For the present, however, the Edmonton Protocol has continued to capture world attention since mid-May, when Dr. Shapiro stood before colleagues attending the meeting of the American Society of Transplant Surgeons in Chicago and stunned them with results of the first eight patients treated with the new technique. Later that month, he and Dr. Lakey flew to London, England, and received a standing ovation when they presented their findings in a special address to the British Royal College of Surgeons.

In June, the New England Journal of Medicine issued an early web bulletin prior to the publication's normal release date because of the trial's importance to public health, and in July, President Clinton announced $5 million would be allocated to ten international centers to see if the Edmonton results can be duplicated. Besides the Edmonton site, researchers in Miami, Minneapolis, Boston, St. Louis, Seattle, Bethesda, MD, Germany, Italy, and Switzerland, will perform the procedure in a total of 40 severe type 1 diabetes patients over the next 18 months.

According to Dr. Harlan, funding will come from the NIH and the International Juvenile Diabetes Foundation through the Immune Tolerance Network (ITN), a collection of 70 international leaders in immune tolerance research headed by Dr. Jeffrey Bluestone.

"We know from past experience that standard anti-rejection agents have not worked in islet transplant procedures, so we are excited by this new protocol," Dr. Harlan said. "If the ITN study reproduces what Edmonton has demonstrated, it changes the whole landscape on islet cell transplantation and gives us an important first step towards a cure."

He added the ITN was set up because animal research suggests the immune system can, under certain circumstances still not completely understood, be re-educated to tolerate 'foreign' implanted tissues without immunosuppressing drugs. Combined with the Edmonton Protocol, a powerful new alternative treatment for type 2 diabetes patients may be on the horizon.

As daunting as that task may seem, said Dr. Harlan, nobody thought humans could fly until the Wright brothers demonstrated it was possible in 1903. In 1969, men flew to the moon. "I think Drs. Shapiro and Lakey have done a Wright Brothers thing," he added. "The minute you demonstrate something is possible, you unleash creative talents all over the world that can make all kinds of major advances in a very short time once they are convinced a principle works. There are still major hurdles to overcome, but the Edmonton group has demonstrated that an islet cell isolation technique is possible."