The Diabetes Research Institute (DRI) combines its diabetes cure-focused mission with its open and collaborative philosophy to enable promising research for type 1 diabetes to be translated to patients in the fastest and most efficient way possible.
By: John Parkinson, Clinical Content Coordinator,
Since its inception in the early 1970s, the Diabetes Research Institute at the University of Miami (pictured here) set out to change the international research paradigm. In a world where researchers typically worked in isolation, coveted their findings and were reluctant to share knowledge and information, the DRI did it differently. Camillo Ricordi, MD, DRI Scientific Director and Chief Academic Officer, talks about how the Institute transformed independent investigators into a collaborative, multidisciplinary environment that is focused on one disease, with one goal–finding a cure. And it is in this type of collaborative environment, Dr. Ricordi believes, where a cure for diabetes can be found in the fastest, safest and most efficient way possible by bringing together a wide range of scientific expertise.  

The DRI is a hybrid institution.That is, it combines traditional academic medicine with a cure-focused mission. DRI maintains this mission by conducting clinically-relevant research with an open-door concept of sharing research information. Today, the Institute works with over 30 research centers, both here in the U.S. and internationally. The Institute maintains a cure-driven focus and either modifies research toward that end, or eliminates initiatives and projects that don’t fit that criteria. Simply put, DRI is in the business of finding a cure.
Dr. Ricordi (pictured below) has a highly-respected reputation within the diabetes research field, having developed significant contributions to islet cell transplantation. His revolutionary invention of the automated method of islet isolation, called the “Ricordi Chamber,” made it possible to isolate large numbers of islet cells (insulin-producing cells) from the human pancreas. He was also a key member of the team that performed the first series of successful clinical islet transplants that reversed diabetes in a small group of patients, which was published in the leading peer-reviewed journal, The Lancet.
DRI’s research is aimed at discovering a biological cure—to restore natural insulin production and normalize blood sugar levels in patients. Having already shown that islet transplantation has achieved insulin independence in patients with longstanding diabetes, with some living insulin free for more than a decade, researchers are now focused on overcoming the remaining challenges. These include developing a reliable and plentiful source of insulin-producing cells for transplant and eliminating the need for harsh immunosuppression that transplant recipients must take for life. spoke with Dr. Ricordi about the DRI’s cure driven focus; a number of its cure research initiatives; and the overall environment of diabetes research today. For those out there who may not be familiar with DRI, can you provide an overview of the organization?

Ricordi: We are a hybrid structure in that we are a traditional academic institution, publishing papers and competing for NIH grants, and yet at the same time, we remain true to the mission, which is to only support research that is linked to curing type 1 diabetes.  

We are a considered a center of excellence at the University of Miami, built upon an  agreement with the University that gives us some latitude in terms of strategic planning and objectives. This allows us to remain true to our cure focus.

In doing so, we spend a lot of time with people in industry to learn how to model academic research into the most effective way to find a cure.

If a particular research pathway or initiative will help us reach a cure more quickly and efficiently, it can then fit into our strategic mission, without having to necessarily fulfill the requirements of a traditional academic institution. In those environments, the focus is on bringing back resources to the institution, such as NIH grants, with a sizable indirect cost recovery for the institutions. However, it is very rare that at a traditional academic institution, scientists are asked what they have done over the past three to five years to help us get closer to a cure. The focus is more on bringing money and resources to the institution, improving its NIH ranking, or improving the quality of the papers produced.

In contrast, our entire focus must remain on finding a cure, and those research initiatives that do not meet this requirement are either cut or reformatted to fit something with more promise, independently from the amount of funding that they can generate for the institution. Can you explain what your bench-to-bedside approach for researching a diabetes cure is?
Ricordi: What the term means is bringing a potential breakthrough idea toward its clinical realization. In other words, to translate research from the basic, or bench, level to the clinic, or bedside, where those research breakthroughs can benefit people living with diabetes. At the DRI, we can accomplish this in the fastest and most efficient way possible through our multidisciplinary structure within the Institute and our worldwide collaborations.

We have been through three eras in research, which links to your question.

In the first era, scientists would work in isolation, often secretively, and may stumble upon a discovery.

In the second era of research, you had more of what happened in the Manhattan Project, where we build a center of excellence and bring in experts from all over the world to resolve a specific problem within an ivory tower kind of environment.

Today, we at DRI use the third generation of research. We have our bench-to-bedside strategy, which is where we operate openly, utilizing Internet technology to break geographic barriers and collaborate with multiple teams, both here in the U.S. and internationally.

That is why we formed the Diabetes Research Institute Federation. The DRI Federation now includes over 30 centers worldwide.

And often times, our bench-to-bedside approach may occur across several institutions and on different continents to overcome any obstacles and regulatory constraints that vary by country.

In a traditional university, people might say you should get a five-year grant for NIH-funded animal studies, and eventually get it renewed for another five years on the same animal model system so that you can get tenure. In that model, there are no performance indicators that evaluate a scientist in his/her efforts to bring a concept towards clinical verification or advance it on the path to cure. In traditional academic institutions, the emphasis is more on increasing the bottom line by bringing resources to the institution in the form of grants, indirect cost recovery, donations and high-quality publications. There is very little incentive for collaboration, team work, and the actual development of cures.
Our emphasis is on keeping concepts moving quickly towards relevance in the human setting. When possible, we try to move out of mouse studies into human clinical trials. We cannot do everything at the clinical level, but as soon as we see something has great promise, we move it along in a fast-track mode, towards verification of its clinical potential. The way we operate is through an integrated network of shared resources, or platform technologies, to facilitate the ability for scientists, whether they come from DRI or outside the institution, to test their promising ideas in the most efficient way possible.

The Institute is organized like a moving escalator toward clinical applications. Whenever a pilot project enters, depending upon the level it enters, it is like a translational escalator being brought up to clinical application.

We try to not only support, but develop an infrastructure for worldwide collaborative diabetes research. Can you tell me about the new immunosuppressive drug regimen that has enabled patients to remain insulin-free for five years?

Ricordi: The DRI’s Dr. Rodolfo Alejandro, director of Clinical Cell Transplantation, Dr. Bernhard Hering from the University of Minnesota, and Dr. James Shapiro from University of Alberta in Edmonton, Canada, worked together to improve the effectiveness of the immunosuppressive regimen surrounding an islet transplant, which has led to dramatically-improved results. These efforts were part of the Islet Consortium that is funded by NIH and which just finished the phase III trial.

The consortium is made up of a number of institutions across Europe and North America that are looking at new protocols of islet transplantation beyond the initial Edmonton protocol. The original Edmonton protocol was developed by Dr. James Shapiro and collaborators using Rapamycin, Prograf and anti IL-2 receptor antibody for the induction immunosuppression, without the use of steroids. In these studies, most patients were insulin-independent at one year. However, there was a continuous decline over the years in remaining insulin-free. And by five years, a majority of the patients needed insulin injections.
People thought there was an intrinsic problem with islet transplantation, but what we learned was that this immunosuppression regimen blocked the capability of beta cells to replicate. So the transplanted cells will deplete over the years and not have the ability to replenish themselves. 
Through the collaboration with Drs. Alejandro, Hering and Shapiro, new concepts were introduced. First, the realization that you need to deplete the T-cells at the induction of the treatment, otherwise you will not have long-term survival of the islets. The other has been the introduction of anti-inflammatory agents in the peri-transplant period.
We now know that adding the anti-inflammatory agent in addition to the immunosuppressive regimen dramatically improves the long-term survival of the transplanted islets. What specific agents are you using for T-cell depletion and inflammation?
Ricordi: We are using Thymoglobulin or Campath-1H for the induction and we are also using Enbrel to subside inflammation. When do you begin dosing and how long are you using these two agents?
Ricordi: You begin dosing immediately before the transplant to calm the system. The Thymoglobulin is administered between three to five doses at the time of and post-transplant. The anti-inflammatory drug is given for the first 10 days, post-transplant. How does DRI characterize or define islet transplants in terms of it being a cure today, and what do you think about the future of the procedure?
Ricordi: We believe islet transplantation is a tool and a first step platform for cell-based technology to cure type 1 diabetes. It’s a first step because we don’t have enough islets to cure diabetes. In the context of type 1 diabetes, it cannot be considered a cure because patients require anti-rejection drugs, which can often cause unwanted side effects.
Our definition of a cure is the biological replacement of insulin production that is lost in people with type 1 diabetes, but without introducing any risks to the patients, like those imposed by chronic use of anti-rejection drugs.
That is why all the new strategies we are working on focus on eliminating the need for these harmful drugs and increasing the supply of insulin-producing cells, as well as identifying new sites within the body, other than the liver, to house the transplanted cells. While the liver has been used as an islet transplant site over the years, it has posed a number of challenges and is not an optimal site.
We want to be able to treat all patients with diabetes who might benefit from this procedure. Of course, it is not just those with type 1, but also those with type 2 diabetes who are insulin-dependent and would benefit from cell replacement therapy. One of the things you are looking to do is “Improve Transplant Technology.” Can you talk specifically about how you are doing that, like with your biohybrid device, for example?
Ricordi: We are working on a platform technology to create a mini organ to mimic the native pancreas, in the abdominal cavity of patients, instead of placing insulin producing cells inside the liver, as I mentioned before. In addition, we are studying barrier technologies (new generation micro-encapsulation), to protect the islets with a semi-permeable membrane which can shield the cells from the immune system, but still allow glucose to enter and insulin to be secreted. The encapsulated islet cells will then be distributed within the new site. The newly-created transplant site offers the ability to incorporate other cell types and agents to promote local protection again the immune system and provide transient oxygen until new blood vessels grow that can deliver oxygen and nutrients naturally. DRI has been involved in research to turn stem cells into insulin-producing islet cells. Can you explain the process, including defining what an oxygen sandwich is?

Ricordi: We noticed while growing stem cells in vitro that, as they grow in size, several cells at the center of the cell clusters die because they are not fed enough oxygen. The reason for this is because in traditional culture systems the exchange of air only comes from the surface—between air and fluid.

The sandwich technique uses a semi-permeable membrane of silicone and perflourocarbon to allow oxygen to be delivered from both above and below, at the bottom of the culture dishes or flasks. We found this can also be a platform technology for endocrine cells. Do you have any timeline for starting a clinical trial utilizing stem cells?

Ricordi: The first embryonic stem cell trial will probably be performed by a California biotechnology company in 2013, pending resolution of any regulatory impediments or barriers.

The use of other reprogrammed stem cells will take longer, and we are looking at about three to five years from now.

There will be other stem cell trials in 2013 that will be geared toward tolerance induction to eliminate the use of anti-rejection drugs. We are collaborating with two major networks in this direction. One of the things many laypeople have a hard time understanding is why a cure has not been found yet. Is it because of the complexity in understanding the pathway to the disease?

Ricordi: We have the intrinsic complexity of understanding the immune system, and we are at the last frontier for controlling the immune response to transplants.

But scientific challenges are not the only ones we confront on the path to a cure. We are also deeply aware that there is a domino effect of other impediments and barriers, including regulatory, legal, economic, and even institutional and academic challenges. To address these challenges, we recently started another organization called The Cure Alliance . [The Cure Alliance is also on Facebook under the same name]. The Alliance looks at promoting international collaborative efforts and resolving the impediments on the path to cures, which are shared by cure focused research for all disease conditions, not just diabetes.

It now takes an average of $1.5 billion dollars and seven to 10 years to develop a new treatment molecule. More academic institutions are giving up on translational research, because it is too costly.

If you think about the United States alone, in 2008 we spent $52 billion in research and development for pharmaceuticals that generated less than 20 treatment molecules—which didn’t cure any diseases.

It is like providing band-aids on wounds that never heal.

Industry is focused on a return on investment when developing a new molecule. If it takes years to develop an effective drug, they require a large enough market to recover the costs of development over the 20 years of life of the patent on that molecule. And that is why the strategy is often to develop treatments for improving quality of life for chronic disease conditions.

Diabetes is a perfect example. There are an estimated 350 million people affected worldwide which is projected to grow to over 500 million in the next two decades.

With the Cure Alliance, we have also proposed solutions related to what it would take to develop cures, including allowing selected centers of excellence to perform pilot studies outside of the complex regulatory framework for pharmaceutical drugs. None of the great medical breakthroughs, including transplants or the polio vaccine, would have been developed in last century in the present regulatory environment.

We have developed a call for action and a grassroots campaign to increase public awareness because it is time for people to wake up and realize the time separating us from cures depends also on the number of obstacles that we encounter on the path. We have to take steps to address the impediments blocking innovations and the development of cures. What are a few of the big picture research goals DRI is hoping to achieve by the end of 2013?

Ricordi: We hope to start the process towards obtaining approval of insurance reimbursement for islet cell transplantation for patients with the most severe cases of type 1 diabetes, such as those with hypoglycemic unawareness. We also hope to start two tolerance induction pilot trials, one in collaboration with Dr. Suzanne Ilstad and collaborators in Louisville and Chicago, and the other one with Dr. Richard Burt in Chicago and collaborators in Sao Paulo and Paris. We also hope to have our first pilot clinical trial for the new implantation site for islet transplants. In this trial, we are testing a new biohybrid device and a new implantation site. This includes a collaboration with the University of Alberta and with the National Academy of Science in Tiblisi, Georgia.  We will also conduct trials for the new molecules to block inflammation with collaborating DRI Federation centers in Italy.

I think 2013 will be an important year for translational research and pilot clinical trials in diabetes.

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