Dropping the Rope, Ending the War: The Diabetes Research Institute Advances toward a Cure

September 13th 2012   ·   1 Comment

By Richard Morell

The world of contemporary research into medical adversities offers quite a heady journey into the body’s mechanisms for health and well-being, and one of the more promising areas for research is in the hunt for the cure to Type 1 Diabetes (T1D).

The Diabetes Research Institute

In 1971, a group of concerned parents of children diagnosed with Type 1 Diabetes decided to pool their efforts and energies to form the Diabetes Research Institute (DRI) which has been in the forefront of seeking out a cure, and thus eventually put itself out of business.

Barbara Singer, DRI’s Director of Special Projects and one of the founding members of DRI (her daughter was diagnosed with T1D at age 2), described the early history of the organization to have been toward basic needs to keep the research going and growing.  The originating five families felt a concern that there was little impetus or research toward cure.  Back then, only one researcher, Dr. Daniel Mintz at the University of Miami, explored this idea.  Mintz observed that the disease could probably be reversed if insulin-producing cells were somehow reintroduced into the system.  The DRI began its fundraising efforts toward supporting Mintz’s research, and their humble beginnings only yielded $1,500.  Then, in 1972, the government funding for his program was cut off in budget cuts.  The urgency increased, and the DRI had to find the funds to put $50,000 together to keep the research going, even on a shoestring.  That they were able to do so seemed miraculous at the time.

Over the decades following, the quest for the cure continued unabated.  In the 1980s, prominent families in southern Florida started to take notice and this led eventually to connections being made with the Buildings and Trades Department within the AFL-CIO union, which took a look at DRI’s organization and decided to put its energies and fundraising capabilities toward building a state-of-the-art research facility in Florida, which was dedicated in 1992.  Since then, the focus on research has only deepened.

Dr. Mintz recognized too that the directions of possibilities were opening up and that the research probably required some new perspectives to move forward.  After careful consideration, Dr. Mintz led a team to recruit Dr. Camillo Ricordi to guide the direction of research toward its patient-centered and patient-directed, collaborative and interdisciplinary approach which operates still to this day.

Senior Director of Medical Development Dr. Gary Kleiman noted that DRI’s focus is still on “biologic replacement of the insulin producing cells.”  The research however, has gone in mindboggling new directions.  “Nothing can replace the mechanisms of these cells.  But there are other issues that reintroducing the cells need to be addressed.  It’s not like we can knock a bottle off a shelf and the presto it’s cured.”

The Directions of Research

Back in 1994, when the researchers moved into the new building, Kleiman noted that researchers were aware they required the flexibility to face a future that was undefined.  For example, back then they thought they could put all of their cell-processing research and capacities on one floor.  Today, pre-clinical research is conducted in a different part of the facility from the research into human cells.  “We’ve had to go through many incarnations, many renovations,” Dr. Kleiman added.

To give a sense of the evolution of treatment possibilities that have been explored, at one point patients received a donor beta-cell operative pancreas to piggy-back onto the patient’s own beta-cell deficient pancreas which was in all other respects normal.  The possibility created other problems with the regulation of the other pancreatic functions which then were getting double-duty and creating other problems along the way as basically the patient in effect had two pancreases at his or her disposal.  Other more promising avenues are now being explored.

Under Dr. Ricordi’s leadership, DRI has shifted its research approach from basic science to be more patient-centered.  As has been noted in previous articles in The Phoenix, diabetes is a disease that requires the patient to be the pivotal partner in the vigilant management of care.  DRI’s model fosters collaboration and information-sharing across disciplines with the intent of seeking out what works best.  Singer noted that some countries allow greater flexibility in research practice than the United States.  “Research is all about being able to duplicate results, and if someone finds a possibility in one area, and no one else can replicate it, then we move on.  In some cases, scientists can take a process that someone has been researching and tweak it based on their own procedures so that it can be improved.”  The time spent to research, develop and clinically implement treatments shortens as the ability to replicate results becomes more efficient.  A side benefit to DRI’s approach is that the research into cells benefits research into other conditions.  There has also been collaboration between cancer researchers and the DRI.  “The question with cancer is why do the cells multiply to such a large extent? And DRI would like to find this out to see if it can be applied positively to the conditions associated with Diabetes.”

Personal Focus

Just as Ms. Singer brings a personal interest into her work with DRI, so too does Dr. Kleiman, who was diagnosed with Type 1 Diabetes as a child.  “Back in 1960, which was only 38 years after the discovery of insulin, I was really living in the dark ages of diabetes management.  Glass syringes, needles, cutting—it was really archaic.  Kids with diabetes have to grow up fast.”  Over the 42 years since, he has been a part of an upsurge of possibility and hope for those with the disease.  Not only is Kleiman researching different treatments for the cure, he has experienced firsthand some of the possibilities himself, having volunteered to get the islet transplantation surgery when it became possible to do so.  (One can even view his procedure on-line at the DRI’s website.)

Islet transplant surgery involves an extensive process that is still being researched and explored.  Currently, stem cells originating in the pancreas, liver or kidneys undergo a process called “transdifferentiation” in which they are stimulated into becoming insulin-producing cells. The islet cells need to be placed in the body, and are currently transplanted into the liver which is not the most ideal site.  Kleiman labels the liver “the Grand Central Station of the body, because everything goes through the organ.”  Islet cells become exposed to not only nutrients but the toxins that our liver is responsible for catching up and sending through the excretory system and out of the body.  Also, the liver does not get quite the amount of oxygen that the islet cells need, as they are the most metabolically active cells in a healthy organism.  Kleiman added that cells cannot be transplanted into the pancreas because that organ is quite delicate, and the risk for causing pancreatitis is too great to make any attempt.

The issue of transplant rejection also looms, and this aspect complicates matters.  Islet cells are quite sensitive to the anti-rejection medications the body requires to accept the new organs.

Hence, one direction of exploration at DRI has been toward more localized, low-dose anti-rejection regimens, so that the rest of the body does not have to deal with the toxins that a more general usage has caused in patients who have, for example, undergone kidney transplants.  Their brochure ‘leaving the World Toward a Cure” even suggests that the treatment becomes a sort of “sprinkler system” to work with the body to promote acceptance of the transplanted tissue.  In effect, by assisting the body to accept implanted beta cells, researchers are also helping those suffering other conditions but who have to face similar possible consequences, with the focused work on diabetes.

Still, other problems exist around the notion of transplants, not the least of which include both the body’s natural rejection of transplanted material as well as the memory cell aspect of immunity.  Current research operates from the understanding that T1D is an autoimmune disorder.  While Type 2 Diabetes can be reversed through diet and exercise to recalibrate the insulin-glucose balance in the bloodstream, T1D cannot be reversed so easily as the insulin-producing capacity has been obliterated.  The mechanism of that destruction seems to involve genetic predisposition toward the autoimmune response coupled with an environmental trigger.  That trigger often comes in the form of a normal childhood disease such as German measles or mumps that somehow causes the body to misrecognize the beta cells as “alien.”

This understanding of T1D as having autoimmune origins complicates treatment issues.  Barbara Singer discussed this in relation to her own family.  “It’s unusual for families to have more than one child with Type 1 Diabetes, but it’s starting to happen more often now.  My own son was diagnosed when he was 25.  It seems that there is a predisposition in some individuals, and that there is a trigger that causes the mechanism of the body to attack the beta cells.  In my family’s case, I was found to be the predisposed parent, but the trigger never happened in my life.”

A group called TrialMed has been doing research into the HLA markers of the human population to discern which genetic groups are more likely than others to be predisposed to T1D development.  They, like other researchers also seek to discover the process of the autoimmune actions to find where intervention can prevent the destruction of the islet cells to begin with.

Kleiman said “the idea behind vaccinations is that a shot helps to retrain the body to recognize a toxin and to create the antibodies necessary to fight it off.  It creates memory cells that will remember when measles infects the body, so it will go to work to fight the infection.  However, [this also applies to] the body’s recognition of transplanted beta cells.”  In other words, the T1D-impared immune system will still experience replacement islet cells as invaders and attack them once again, and this is in addition to the common problem with all transplant patients of requiring antirejection drugs to keep the donor organ functioning.

One avenue of exploration, with the help of bioengineering, is the creation of a “mini-organ” that will serve as a platform for the islet cells so that they will have access to the bloodstream, as well as supporting other types of assisting cells that can be grafted onto the structure of the artificial organ and integrated into the body.  A good deal of potential exists in the idea of creating a sac for this platform organ from patient-originating venous tissue, and placing it near the liver and pancreas to be a part of the digestive flow.

Regardless of whatever problems can be anticipated or observed, the promise of transplantation of islet cells beckons the research forward, and Kleiman serves as an exemplar of the possibilities.  “People with the disease are under such stress.  [We have to constantly monitor our blood sugar,] and I used to say that there was a tug-of-war going on and I was the rope.  I also said I knew where every coke machine was on the East Coast.  After the surgery, my blood sugars became normal, and for the first time in my life, I did not have those stresses like I used to.  It was like that rope just dropped.”

Recently, the DRI was awarded $4.6 million to continue its work on beta islet transplantations.  The Juvenile Diabetes Research Foundation (JDRF) and The Leona M. and Harry B. Helmsley Charitable Trust both awarded grants totaling $4.6 million in August, 2012.  The focus of the research is on finding suitable sites for beta cell transplants and for the long-term survival of the cells in the body and for decreasing the need for immunosuppression drugs to ward off rejection of the cells.

Other research possibilities include the recent discovery of a “super-islets” that exist in certain individuals whose pancreases have 1000% higher potency and result in the need for 98% of a patient’s pancreas to be removed.  Dr. Juan Dominguez-Bendala in Malaga, Spain has been working with Dr. Antonio Cuesta on this exciting direction.  Dr. Kleiman also mentioned other vectors of possibility:  shrink-wrapping islets with polymers that would repel the immune attacks while letting oxygen and required nutrients in; uses of chimerism to facilitate the reeducation of the body; self-tolerance of insulin in T1D sufferers.

It’s important that this work continue, as both T1D and T2D are on the rise throughout the world.  It appears that whatever environmental In recognition of the value of this incredible work, Louis T. Brindisi sponsors a fundraiser this Saturday, September 15th at the Fort Schuyler Club, 254 Genessee Street, at 6 p.m.

 

By Richard