Thursday, December 10, 2020

As a trained violinist and violist, scientist Debbie Thurmond sees parallels between the orchestra and our body’s endocrine system, with insulin serving as the conductor.

“Sometimes conductors make mistakes, and sometimes the string or wind sections aren’t carefully listening to one another’s cues, and in either case the orchestra fails to execute the performance,” Thurmond says. “When the body starts responding to insulin, your muscle and fat cells start to absorb all the excess sugar from your bloodstream. That sends a message back to the pancreas that you do not need so much insulin anymore. These tissues are constantly responding to one another. Metabolic or autoimmune stress on one's pancreas causes the conductor to make mistakes, combined with the string and/or wind sections not carefully listening to each other, this meticulously precise orchestration falls apart.”

Debbie Thurmond

Thurmond is the new director of City of Hope’s Diabetes & Metabolism Research Institute and a 1997 PhD graduate from the University of Iowa. Her lab specializes on the inner workings of how beta cells in the pancreas release insulin, and how insulin’s target tissues are designed to respond to the insulin signal. Insulin in the bloodstream gives functional directions to a person’s brain, liver, skeletal muscles, fat tissue, and other tissues. Without insulin, the body cannot take up nutrients, leading to high blood sugar.

In type 1 diabetes, these insulin-producing beta cells are attacked by the immune system. Scientists are tasked with using a targeted approach to calm this immune storm while maintaining a functional immune system otherwise.

To achieve this end, researchers under Thurmond’s directorship at City of Hope are preparing to begin a clinical trial for the first type 1 diabetes vaccine to be tested in the United States. Spearheaded by a member of her prestigious faculty, the trial is funded by The Wanek Family Project for Type 1 Diabetes, a $50 million initiative to find a cure for type 1 diabetes. City of Hope is an independent research and treatment center for cancer and diabetes in Duarte, Calif.

Thurmond, the Ruth B. & Robert K Lanman Chair in Gene Regulation & Drug Discovery and the Chair in the Department of Molecular & Cellular Endocrinology at the City of Hope, will not venture a guess when a vaccine could be publicly available.

“This trial was initially conducted in the Netherlands and that looked promising. Now, it will open up in the United States for the first time,” says Thurmond says. “There is unlikely to be a single solution for all patients. As with other diseases, type 1 diabetes has different characteristics for different patients.”

Thurmond has tremendous insight into how type 1 diabetes behaves in individuals with the disease. Having obtained tissue samples from nPOD, a biobank that collects pancreata and related tissues from type 1 diabetics and provides those samples to investigators who submit proposals for experimentation. Thurmond had a remarkable finding upon examining the tissues. More than half of the samples still had insulin positive cells, meaning insulin was present in the pancreas of patients diagnosed with type 1 diabetes and dependent upon injecting insulin to live. The presence of insulin positive cells also indicates that insulin was not being released, because there was no insulin present in the bloodstream.

“Individuals with type 1 diabetes still have the capacity to make their own insulin, but a defect in the system prevents their bodies from releasing the insulin,” Thurmond says. “This changes how we treat and cure type 1 diabetes, because now we are not looking for ways to replace the cells. We are looking for ways to get them to start functioning again.

“I can start evaluating what's present in those beta cells and what's missing from those beta cells, so I might tell a story as to why they're not functioning. Once we know that, we can figure out how to reinvigorate them. They just need to be taught how to function again.”

Academic adventure

Originally training in veterinary medicine, Thurmond, who was not a medical student, challenged herself by taking a medical school course in endocrinology at the University of California, Davis. She quickly became fascinated by the complexity of the endocrine hormone system. Insulin a hormone in this system.

After earning her bachelor’s and master’s degrees, Thurmond set her sights on pursing a doctorate in biochemistry, with a focus on molecular biology and endocrinology in mammalian cell systems. This exact research was being conducted halfway across the country at the University of Iowa by Professor Alan Goodridge, director of the school’s Biochemistry and Molecular Biology Departments. 

“It was just incredibly exciting to go to a place that had the focus precisely in the area in which I was most interested,” Thurmond says. “I was open for an adventure, and my husband was too. We said, ‘We're both native Californians, let us go experience the Midwest.’”

Faculty in the UI’s Biochemistry Program were waiting to challenge her.

“The biochemistry program was excruciatingly rigorous. If you are a person who likes challenges, it was a great place to be,” Thurmond recalls. “It was a very structural biology-based program. For somebody like me who had a strong background in physiology and metabolism, it was a new and different challenge. It also taught me the value of model systems. I was introduced to the power of yeast genetics, Drosophila genetics, NMR spectroscopy, and X-ray crystallography.”

With her doctorate in hand, Thurmond remained at Iowa as a postdoc in the Physiology and Biophysics Department under the mentorship of Dr. Jeffrey Pessin. As a postdoc, she cloned several seminal genes that she ultimately discovered to oversee how beta cells release insulin into the bloodstream.  
With a strong understanding of the endocrine system, Thurmond began her professional career, landing a position as faculty in the Biochemistry Department at Indiana University School of Medicine, rapidly rising through the ranks and becoming associate director of the diabetes group there.

Thurmond then was recruited by the City of Hope in 2015. While it was a tough decision to leave Indiana University, this was an opportunity she could not turn down. Now director of City of Hope’s Diabetes & Metabolism Research Institute, Thurmond oversees 35 faculty members from eight departments. She also continues to maintain her own 12-member laboratory, which includes two new PhD graduate students.

“The City of Hope brings out the inventor in me. That is why I came to the City of Hope,” Thurmond says. “As a scientist, you are driven to better understand the body. I have discovered why these beta insulin-producing cells were not functioning, because so many people had presumed for years that they were not making the insulin or that the cells themselves did not even exist.

“It turned out that there are cells and they do make insulin, but the insulin does not know how to get out. Now it is my challenge to teach them how to do so.”