An NCI-designated Comprehensive Cancer Center
By Wayne Lewis | November 1, 2019
Discovering insulin’s role in processing sugar. Identifying a blood factor that serves as a marker for glucose control. Creating technology leading to the development of synthetic human insulin.
 
For nearly 50 years, scientists who have made major advances in the understanding and treatment of diabetes have called City of Hope home.
 

“I don’t think any other research institution in the country has made as many contributions to diabetes research as we have here at City of Hope,” said Arthur Riggs, Ph.D., the Samuel Rahbar Chair in Diabetes & Drug Discovery who co-led the investigations that resulted in synthetic human insulin.

 
That history is part inspiration and part prelude for today’s City of Hope diabetes researchers. Building on past milestones, as well as the institution’s acute understanding of the role of the immune system in cancer, investigators work on an integrated approach to type 1 diabetes with the support of The Wanek Family Project for Type 1 Diabetes.
 
“Because they gave so generously, the Waneks allowed us to try some approaches that otherwise would not have been funded,” said Bart Roep, Ph.D., the Chan Soon-Shiong Shapiro Distinguished Chair in Diabetes and director of The Wanek Family Project. “What I like most is that they have the same ambition as I, which is to cure diabetes and do it quickly. That focus helps us cut to the chase and be very patient-minded.”
 
City of Hope’s strategies for fighting type 1 diabetes center on three key features of the disease: dysfunction in the insulin-producing beta cells of the pancreas, the immune system’s role in attacking those cells and potentially deadly complications. These efforts span a host of disciplines, uniting basic and clinical science.

Negotiating With the Immune System

City of Hope has been a pioneer of an investigational procedure called islet cell transplantation since 2004. The therapy takes donated beta cells, found in mini-organs known as islets, and implants them in type 1 diabetes patients in a bid to kick-start insulin production.
 
While City of Hope researchers advanced that treatment, the institution built up expertise in other areas.
“As we established the islet cell transplantation platform, it became natural that we look at ways of focusing on immune modulation strategies,” said Fouad Kandeel, M.D., Ph.D., the Arthur D. Riggs Distinguished Chair in Diabetes & Metabolism Research, who directs City of Hope’s Islet Cell Transplantation Program.
 
Today, researchers at City of Hope are hard at work on an array of therapies that tackle the immune component of type 1 diabetes. This direction requires nuance to quiet the immune assault on beta cells without compromising the body’s natural defenses against threats such as invasive microbes.
 
“What we try to do at City of Hope is not bombard the immune system into submission, but negotiate with it,” said Roep, who also is professor and founding chair of the Department of Diabetes Immunology. “We try to teach the immune system to preserve beta cells.”
 
Approaches include a “reverse vaccine” close to being tested in clinical trials, potent designer antibodies and mixed chimerism — a strategy for transplanting blood-forming stem cells from a healthy half-matched family member donor into a patient.
 

Rare Combinations

 
Meanwhile, City of Hope investigators delve into the molecular mechanisms behind beta cell health. They are developing ways to revitalize beta cells and buttress them against immune attack, with efforts that extend to growing new cells in the lab to augment a limited stock of human islets.
 
The signature spirit of collaboration at City of Hope leads to promising combinations such as Roep’s work with Debbie Thurmond, Ph.D., the Ruth B. & Robert K. Lanman Chair in Gene Regulation & Drug Discovery Research.
 
“There aren’t a lot of examples of a beta cell biologist and an immunologist working closely together on a project that has a direction forward,” said Thurmond, who also is professor and founding chair of the Department of Molecular & Cellular Endocrinology. “He and I both recognize that individually our research is unlikely to cure the disease, but together we can probably design some very creative solutions that we hope will be maximally effective.”
 

Moving Side Effects to the Center

 
Many know about the day-to-day burdens faced by type 1 diabetes patients such as the need to monitor blood glucose and inject with insulin. But it is the complications of the disease — including kidney failure and blindness — that endanger lives and erode quality of life.
 
“Once insulin became freely available, nobody really needed to die of diabetes. What kills patients is the complications associated with diabetes,” said Rama Natarajan, Ph.D., who first established the link between complications and epigenetics — that is, changes in gene expression due to external or environmental factors.
 
Natarajan is City of Hope’s National Business Products Industry Professor in Diabetes Research and professor and chair of the Department of Diabetes Complications & Metabolism. She and her colleagues are creating new knowledge about the underlying mechanisms behind complications of the disease while developing potential treatments. Their studies are accelerated by recent advances in technology that allow for unprecedented views into basic processes.
 
“By looking deeper into the genome and epigenome using these amazing technologies, we are seeing so many new aspects of type 1 diabetes that we never did before,” Natarajan said.
 

The Potential of Precision Medicine for Diabetes

 
City of Hope’s integrated approach suggests a vision for the future of type 1 diabetes care — one where there is a therapy appropriate for every patient. The mix of cellular therapies that renew and protect beta cells, immunotherapy, islet cell transplantation and treatments for mitigating complications could be adjusted to the needs of each case.
 
“This is an integrated way to treat,” said Kandeel, who also is associate director of the Diabetes & Metabolism Research Institute at City of Hope and chair of the departments of Clinical Diabetes, Endocrinology & Metabolism and Translational Research & Cellular Therapeutics. “It is also a form of precision medicine, giving the patient exactly what they need.”
 
To realize that vision requires close connections between basic research and clinical science — which also makes the institution a haven for top scientists.
 
“The advantage to working at City of Hope is that I’m encouraged to have intellectual curiosity, but I’m also provided with the means and the colleagues to see that the work comes to fruition in clinical care,” Thurmond said. “It’s the best of both worlds.”
 

Links to Other Diseases

 
Many of the breakthroughs in type 1 diabetes from City of Hope research also represent progress against type 2 diabetes; at the same time, type 2 diabetes is an area of focus for many investigators in the Diabetes & Metabolism Research Institute.
 
“I don’t like saying ‘type 1 diabetes research.’ I prefer the more general ‘diabetes research,’” said Riggs, director of the Diabetes & Metabolism Research Institute. “Insulin is important to both types, the loss of beta cells is a critical aspect in both, and the complications are more or less the same.”
 
Likewise, City of Hope’s excellence in cancer care presents a boon to efforts against type 1 diabetes.
After all, many of the researchers describe the diseases as flip sides of the same coin. Cancers develop after the immune system has failed to root out abnormal cells; in type 1 diabetes, the immune system is overactive in attacking beta cells.
 
“We have a unique opportunity to be at the forefront of investigating the interface between cancer and diabetes,” Riggs said.
 
Indeed, some diabetes investigations take cues from certain aspects of cancer studies, and vice versa. And while City of Hope does not treat a large number of diabetes patients, a small portion of cancer patients develop type 1 diabetes as a side effect of treatment, and they receive high-quality care from City of Hope endocrinologists.
 
With a distinguished history behind and promising projects in progress, City of Hope researchers are cutting a path to type 1 diabetes breakthroughs — and one day, perhaps soon, a cure.

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