Dieter Egli, PhD, is a unique basic scientist with a passion and expertise in translational research – his goal is to apply his work to cure type 1 diabetes. Although early in his career, and a newly recruited Columbia University/Berrie Center faculty member, Dr. Egli is a pioneer in stem cell biology and in the creation of diabetes patient-specific stem cells.
Dr. Egli, Assistant Professor of Developmental Cell Biology in the Department of Pediatrics, is a panelist on the Berrie Center Diabetes Research Panel to be held April 2, 2014 at the University Club. He will speak about the applications of stem cell research for type 1 diabetes—and the hope to ultimately utilize beta cells generated from skin cells obtained from skin biopsies from patients with type 1 diabetes at the Berrie Center in cell therapy strategies. He hopes to, one day, cure type 1 diabetes by replacing insulin deficient beta cells with healthy ones generated from patient-specific stem cells.
Dr. Egli and colleagues published two major discoveries in 2013, both significant advances toward the goal of creating patient-specific beta cells from stem cells. These studies looked at two different monogenic forms of diabetes and demonstrated for the first time, the ability to create patient-specific beta cells that not only secreted insulin, but that also exactly recapitulated the genetic signature and metabolic characteristics of the skin cell donor’s diabetes.
In the first study, Dr. Egli and his team focused on a form of diabetes that is caused by one easily identifiable gene. This form of monogenic diabetes is caused by a mutation in the glucokinase gene and is sometimes called Maturity Onset
Diabetes of Youth (MODY)- 2. There are many other forms of MODY caused by mutations in other genes. MODY-2 is the most common form of MODY.
Dr. Egli and colleagues, including Drs. Robin Goland, Rudolph Leibel, Matthew Freeby, and Wendy Chung, utilized the skin cells of MODY-2 patients at the Berrie Center to produce induced pluripotent stem (iPS) cells. Pancreatic beta cells were then created from these stem cells or iPs cells. The MODY beta cells were transplanted into a mouse, and they secreted abnormally low levels of insulin, similar to the abnormally low levels of insulin secretion that characterizes MODY-2. Researchers then repaired the MODY-2 gene mutation and restored insulin secretion to levels seen in beta cells made from iPS cells from healthy control skin donors. These exciting findings were reported last June in Journal of Clinical Investigation.
The second major discovery focused on a devastating genetic disease called Wolfram Syndrome. Dr. Egli and others hypothesize that findings in this very rare disease may have important implications for all forms of diabetes.
Wolfram Syndrome, a rare disease that causes death in early adulthood, includes dysfunction in multiple organ systems and is associated with hearing loss, visual loss, problems with urinary function, psychiatric illness and insulin deficient diabetes. The underlying problem is an inability at a cellular level to cope with stress so cells die prematurely. The part of the cell that is most involved with the cell’s stress response is called the endoplasmic reticulum (ER) and cellular stress is called “ER stress.” Wolfram Syndrome is a disease in which there is abnormal ER stress.
Dr. Egli and colleagues investigated the role of ER stress in the beta cell in Wolfram Syndrome. They utilized the skin cells of Wolfram Syndrome patients at the Berrie Center to produce induced pluripotent stem (iPS) cells. Pancreatic beta cells were then created from these stem cells or iPs cells.
By creating an in-vitro model of the pancreatic beta cells in Wolfram Syndrome, scientists were able to show that the beta cells failed to secrete insulin normally. In these cells, an abnormal endoplasmic reticulum stress response (ER stress) led to beta cell failure. They also found that a drug, called 4-phenyl butyric acid, relieved this ER stress and improved insulin secretion. The findings were reported last October in the journal Diabetes.
“We think this is worth testing in patients with Wolfram Syndrome and other forms of diabetes,” said Dr. Egli, “because there is no other effective treatment available for these patients, and this drug is already FDA approved for other indications it is given orally and is very safe and well-tolerated.”
The experiment is important, Dr. Egli explained, not just for people with rare genetic disorders, but as a model for how beta cells fail (and can possibly be rejuvenated) in more common forms of diabetes like type 1 diabetes. There is accumulating evidence that protection from ER stress is important in protecting the beta cell from the immune assault in type 1 diabetes.
“The distance between an idea and its implementation is enormous,” added Dr. Egli, “and we have made remarkable progress. But as a scientist, I see more of what’s missing and what we need to do to replace the beta cells of people with diabetes so they are no longer dependent on lifelong medical care. What really matters is curing this disease.”
In addition to Dr. Egli, the April Diabetes Research Panel scientists are Berrie Center and Columbia faculty members, Robin Goland, MD, J. Merrill Eastman Professor of Medicine and Berrie Center Co-Director and Rudolph Leibel, MD, Christopher Murphy Professor of Pediatrics and Berrie Center Co-Director, who will moderate the panel; Domenico Accili, MD, Russell Berrie Foundation Professor of Medicine and an international leader in the field of beta cell biology; Wendy Chung, MD, PhD, Associate Professor of Pediatrics, a renowned clinical and molecular geneticist; Rebecca Haeusler, PhD, an Assistant Professor of Pathology and Cell Biology, who studies the connection between diabetes and cardiovascular diseases; and Michael Rosenbaum, MD, Professor of Pediatrics, and an expert on the physiology of body weight regulation.
To RSVP to the Diabetes Research Panel contact Morgan Tupper at 212-304-7210 or firstname.lastname@example.org