Personal motivation fuels some scientists' groundbreaking work in halting a disease that interrupts childhood and life
Thomas Delong, PhD, moved to Colorado from Germany two decades ago intent on one thing: understanding the origin of type 1 diabetes (T1D) and finding ways to stop it. Diagnosed at age 12 with the disease that affects 9.5 million people worldwide, Delong's mission was deep-rooted and personal.
So when an opportunity arose to do his post-doctoral work with T-cell pioneer Kathryn Haskins, PhD, at the University of Colorado Anschutz, making the move across the Atlantic was an easy choice for the biochemist. "She was the first to identify T cells that trigger diabetes in mice," Delong said of Haskins' ground-breaking discovery in the 1980s.
Delong spent years searching for what causes those T cells to go rogue and attack the insulin-producing beta cells of the pancreas. In 2016, he had his own breakthrough finding: identifying a likely culprit. Now, his team's most recent research is showing promise in outwitting the instigator he discovered, work that could inform future therapies that delay or prevent the disease.
Search points to hybrid insulin peptides (HIPs)
T1D is an autoimmune disease that often strikes in childhood. By attacking the beta cells in the pancreas, it abolishes the body's ability to produce insulin, a hormone necessary for regulating blood sugar levels. Without treatment, uncontrolled glucose levels result in deadly complications, requiring life-long monitoring and insulin supplementation.
Within eight years of joining the Haskins' lab in the Department of Immunology & Microbiology, Delong made his novel discovery using nonobese diabetic (NOD) mouse models. By "thinking outside the box," he found that it wasn't regular insulin proteins that were switching T cells into attack mode, as most scientists suspected.
"The T cells were recognizing what we call hybrid insulin peptides, or HIPs," Delong said. "With normal proteins - a chain of amino acids of say ABCDE - your immune system sees its own sequence and doesn't touch it." But the hybrid peptides take a fragment of an amino acid sequence of insulin and link it to a fragment of another protein.
"Now, all of a sudden, you get an amino acid sequence that's ABCD-XYZ that is not directly encoded in your DNA. So the immune system sees it as foreign and starts attacking," he said.
How CU Anschutz leads
- CU Anschutz is home to one of the world's largest specialized centers for type 1 and type 2 diabetes (T1D and T2D) - the Barbara Davis Center for Diabetes (BDC) - and one of 16 Diabetes Research Centers in the country supported by the National Institute of Diabetes and Digestive and Kidney Diseases.
- The BDC serves 7,500-plus patients a year, including over 90% of Colorado's children diagnosed with T1D and is a world leader in diabetes research focused on prevention, cutting-edge treatment and the search for a cure.
Teamwork leads to pioneering HIPs discovery
Finding the specific HIPs causing the autoimmune attack wasn't easy, partly because cross-linking proteins in the human genome opens the door to trillions of possible combinations, Delong said. "It was like looking for a needle in a haystack."
Moreover, the mass spectrometry technology used in the search contained only mouse and human proteins in its database - not hybrid peptides he was unknowingly seeking.
But Delong persisted and was the first to define antigens for the diabetogenic T-cell clones developed in the Haskins' lab, despite strong competition from other scientists across the country searching for the T-cell trigger.
Like building a skyscraper, basic science takes teamwork (and a lot longer to complete). Delong emphasized that before his HIPs' finding, the Haskins' lab had done years of groundwork, identifying islet antigens that triggered activity of the pathogenic T cells that attack islet beta-cells.
It was a collaborative research effort that culminated in the important discovery, published in Science in 2016.
Type 1 diabetes facts
- T1D is increasing by 3% a year worldwide for reasons not fully understood.
- Having a family member with T1D makes a person 15 times more likely to develop the disease.
- Many times, people (often children) go too long undiagnosed with symptoms and end up hospitalized with diabetic ketoacidosis, a life-threatening condition.
- Free screening for T1D (along with celiac disease) is available for Colorado children (age 1 through 17) via the ASK (Autoimmunity Screening for Kids) program at CU Anschutz.
Scientists translate findings to humans
For his next phase, Delong moved his lab to the CU Anschutz Skaggs School of Pharmacy and Pharmaceutical Sciences in 2017 and gathered more collaborators from across the CU Anschutz campus to take the science to the next level.
With the help of Peter Gottlieb, MD, of the CU Anschutz School of Medicine's Barbara Davis Center for Diabetes (BDC) and researchers from the Haskins' group, such as Rocky Baker, PharmD, Delong translated the work into humans.
"We were able to show that patients with recent onset type 1 diabetes had significantly elevated levels of these HIP-reactive T cells when comparing them to the non-diabetic control subjects," Delong said.
Maki Nakayama, MD, associate professor of basic research with the BDC, isolated T cells from the residual islets (where beta cells live) of organ donors with type 1 diabetes, he said. "And she showed that some of these T cells also target HIPs. So, we basically caught these HIPs at the crime scene."
Key points:
- In 2016, CU Anschutz researcher Thomas Delong, PhD, discovered that hybrid insulin peptides (HIPs) trigger T cells to mistakenly attack the insulin-producing beta cells in diabetes-induced animal models.
- The breakthrough finding, a result of years of work by a team of researchers, was published in Science.
- With collaborators from across campus, Delong was able to translate the finding to humans, identifying elevated levels of HIP-reactive T cells in people with recent-onset T1D.
- After identifying an enzyme responsible for HIP formation, researchers most recently showed that by blocking the enzyme, they were able to notably reduce HIPs levels and significantly slow disease development in mouse models.
- The work could help inform future treatments to prevent or delay type 1 diabetes.
Studies illustrate promise in slowing disease
Now Delong and team are back to animal models, looking for ways to prevent HIPs from forming. One of his post-doctoral students - Jason Groegler, a Venture Fellow with CU Innovations - is tackling the work with the same personal motivation.
"I have type 1 diabetes, so when I was looking for grad schools, that's where I wanted to focus," said Groegler, who moved into an opening in Delong's lab after his first semester on campus. "I didn't really want to do research outside of that," he said.
"At the time, there was another student (Samantha Crawford, PhD,) who found that the enzyme cathepsin D was involved in forming hybrid insulin peptides that contribute to disease," Groegler said. "So, my project stemmed from that. Since we knew how these were forming, we wanted to identify a way to prevent them from forming."
In a study published in January in the journal Diabetes, Groegler and team showed that by modifying one of two insulin genes in mice models to block cathepsin D, they were able to dramatically reduce HIP-levels in beta cells.
The immune systems in the mouse models were less reactive against insulin, and diabetes developed significantly slower. After one year, 43% of modified mice remained diabetes-free, compared with only 10% of normal mice.
Now the researchers are modifying both insulin genes in mouse models and seeing an 80% to 100% reduction in HIP formation in their preliminary data. "It's really showing us that the enzyme cathepsin D is responsible for exclusively making these hybrid peptides that drive the disease progression in mice," Delong said.
Scientists hold out hope in finding a cure
It's another win in Delong's decades-long mission to unravel a disease that interrupts childhoods and changes lives. With the research resources available at CU Anschutz, Delong is optimistic that he will achieve his goal.
"Science takes time. But everything we need to do this work (from patients and biobanks to cutting-edge technology and experts in diverse fields) is right here on campus," he said. "It's the best place to be to do this research."
For Groegler, just learning about the disease he lives with is his strongest motivator, he said. "But it would be nice to be able to live without having to give myself insulin every day," he added. "If we can cure it, obviously, that's the ultimate goal."
"I agree with that," Delong said. "We are here to understand diabetes and figure out how to stop it, and we will do it."
