Orchestrating a Cure

By Ngoc Nguyen

The success of the Edmonton team brings scientists closer to perfecting islet cell transplantation, which would ultimately free millions from the regimen and ravages of insulin-dependent diabetes.

In June 2000, news of a breakthrough in diabetes research rocked the scientific community.

Researchers at the University of Alberta in Edmonton, Canada made the grand announcement that eight islet cell transplant patients have remained insulin-free for as many as 15 months and counting.

The Edmonton study was so notable that the New England Journal of Medicine couldn't wait to spread the news. "It's the first time that transplants of this type have been successful," said the journal's editor, Dr. Marcia Angell. The NEJM web site published an abbreviated version of the study several weeks ahead of schedule.

The success of the Edmonton team brings scientists closer to perfecting islet cell transplantation (ICT), which would ultimately free millions from the regimen and ravages of insulin-dependent diabetes.

Currently, over one million Americans have Type 1 diabetes, a condition most commonly diagnosed in childhood, in which the body's ability to produce insulin, a substance essential for blood sugar regulation, is impaired.

Therefore, those with insulin-dependent diabetes must endure a lifetime of infinite insulin shots and finger pricks to maintain and monitor blood sugar levels. Early on, they learn that tight glucose control is dogma, when it comes to staving off debilitating diabetes complications including kidney failure and nerve damage that can lead to numbness, pain, and in severe cases, limb loss.

Despite tight glucose control, however, some "brittle" diabetics cannot control their blood sugars with insulin. For people in this fragile state, ICT could be their last recourse.

The idea behind ICT is simple: replace the defunct islet cells with functional ones.

When working normally, pancreatic islet cells produce normal levels of insulin. But in Type 1 diabetics, islet cells are destroyed, insulin production halted and in effect a wrench is thrown into the body's glucose-regulating machinery. The transplantation of new islet cells is necessary to jump-start insulin production again.

In the past, ICT achieved dismal results. The operations offered only a brief glimpse of diabetes-free life to a mere handful of patients. Of the 267 transplant cases, 12.4 percent achieved insulin independence for one week, and less than nine percent remained insulin-free beyond one year.

Dubbed the "Edmonton Protocol," the treatment and drug strategies of the University of Alberta team have surmounted a few of the age-old obstacles that once made ICT more of an experimental dream than anything else.

In terms of the technology, the Edmonton team benefited from being at the right place at the right time.

According to Massimo Trucco, M.D., chief of the division of immunogenetics at Children's Hospital of Pittsburgh, "They finally found the right combination of drug and treatment strategies, which made the difference."

ICT requires a safe, abundant and replenishable tissue source: Hundreds of thousands of islet cells must be extracted from several pancreatic donors.

Advances in islet cell isolation and processing technology enabled the Edmonton researchers to procure many more functional cells from each donor pancreas. They were able to extract enough islets from two pancreases to successfully reverse diabetes in all eight study patients.

Once extracted, the islets are injected via the main (portal) vein into the liver, where they then nest and start producing insulin. Getting the islets in is simple getting them to stay is another matter .

Once transplanted, the new islet cells will immediately be regarded as foreign substances that are then attacked by the body's immune system.

To make matters worse, the body's own remaining islet cells are still under fire as well, a process called autoimmunity. A life-long regimen of immune-suppressant drugs are necessary to stave off problems of rejection and autoimmunity.

Although the Edmonton protocol still required immunosuppressant drugs, the three drugs used were for the first time steroid-free, resulting in fewer side effects, thus improving the post-transplant quality of life.

And, according to Camillo Ricordi, M.D., scientific director of the Diabetes Research Institute in Miami, using fewer donor organs introduces fewer foreign elements, results in fewer complications and decreases the number of anti-rejection drugs neccessary.

Despite these promising results, some in the islet research community say there's still an uphill battle ahead.

With only 3,000 donor pancreases available for transplantation last year, the number of people who could benefit from the procedure has been limited. Even though the Edmonton Protocol called for two pancreases fewer than all previous surgeries that still translates to only about 1,500 patients who could undergo the procedure.

And, currently, an anti-rejection drug regiment is still too harsh for kids.

"The Edmonton protocol is not the best solution for children, says Trucco, delivering bad news to the 13,000 children diagnosed each year with insulin-dependent diabetes. "Children cannot tolerate 40 years of immunosuppression."

Prolonged use of the drugs is potentially toxic to the liver and kidneys. For this reason, a lifetime of anti-rejection medications can significantly increase a child's risk for cancer.

"It's been shown that children who undergo immunosuppression therapy [after a transplant] are at a 60 percent risk of developing lymphoma within a ten year period," says Ricordi.

In fact, Dr. Shapiro, lead researcher on the Edmonton team, is the first to emphasize that the Edmonton protocol "is not for everyone." According to Shapiro, the experimental transplants were performed in patients whose blood sugar levels could not be controlled or those with life-threatening diabetic complications. Children are not likely to be in this camp.

When ICT can be done on a large-scale with minimal, no or "milder" concoctions of anti-rejection drugs, researchers may then be able to safely perform the procedure in children. That way, patients with juvenile onset diabetes could reverse their diabetes earlier, avoiding some of the complications of late-stage diabetes.

While the Edmonton Protocol is an exciting chapter in islet transplantation research, the story is far from over.

"First, we will replicate the brilliant results of the Edmonton Protocol, which requires one to two pancreas(es) per transplant patient, says Ricordi. "Next, we'd progress to be able to do multiple transplants from a single pancreas, and then minimal replication for multiple transplants. Lastly, we'd turn to animals 'cells or genetically engineered cells."

ICT will no doubt capture the spotlight again as researchers attempt to duplicate the success of the Edmonton Protocol in a ten-center worldwide clinical trail set to start this Fall.

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