One Step Closer to a Cure for Type I Diabetes

The 300-person auditorium was nearly filled to capacity. Students, educators and professional biologists listened intently, so silent you could hear a pin drop. World-renowned Harvard professor Douglas Melton, Ph.D., emphasized the importance of research on cell development in order to use stem cells to create a pancreas and recreate human diabetes. “If you watch something develop, it’s very informative of what goes wrong,” he said in his lecture on Tuesday, March 23, part of the Hope Ritter lecture series offered by the UGA Department of Cellular Biology.

Melton, who established his own laboratory at Harvard and conducts research for the Howard Hughes Medical Institute, became motivated to find a cure for Type I diabetes after two of his children were diagnosed with the autoimmune disease. He has twice been listed as one of the 100 most influential people in the world by TIME magazine and for good reason. His research primarily focuses on ways to make insulin-producing cells, otherwise known as pancreatic beta (b) cells, which Type I diabetics do not have. He cited a statistic that made clear why his research is so important: 0.5 percent of newborns in the United States will be fully insulin-dependent by age 18.

Melton wasted no time delving into the lecture. “I’m going to give you an intro to the pancreas – just for fun,” he said. Snickers echoed throughout the audience as he described early thought on pancreatic function. Scientists in the 16^th century believed the pancreas functioned solely as a cushion for other internal organs such as the stomach. Just 100 years later, scientists knew that pancreatic enzymes were involved in digestion. Today, researchers have divided the pancreas into two main components – exocrine cells and the islets of Langerhans.

The pancreatic beta cells that Melton’s research focuses on are located within the islets of Langerhans. He said that there are two main problems that need to be resolved. There is a loss of beta cells, so researchers must figure out how to make more of them. Researchers must also figure out how to stop the body’s immune system from attacking and killing its own beta cells.

How do scientists create more beta cells? “We should plan for success and try to do this in a way that is clinically relevant by using chemicals that tell cells what to do,” said Melton. The process of creating beta cells began by determining which genes were turned on or off during different stages of cell development. By manipulating these genes with chemicals in a lab, Melton has successfully differentiated cells to create definitive pancreatic cells.

Melton believes that within five years, scientists will have the capability to make “buckets” of any kind of cell. “The nucleus in these cells still has the capacity to go back to the beginning. You can erase it, in a sense, and let it start over,” he said. Using this concept, Melton has been able to “reprogram” pancreatic exocrine cells into expressing genes that are essential in beta cell functioning. These new insulin-producing cells closely resemble beta cells, and insulin expression remains strong and permanent over time. The process is fast and efficient – it takes only three days, and fully 20% of the reprogrammed cells become beta cells.

What does this mean for diabetics? This is when Melton addressed the second problem – how to stop the immune system from attacking beta cells. The body can only make new beta cells by replication. All new beta cells must come from preexisting beta cells, so a Type I diabetic has lost all capability to create new beta cells. The entire audience laughed as Melton “quoted” what the body of a diabetic would say if simply injected with new beta cells. “Thanks! I recognize those cells. I’ve been killing them for a long time. I’m going to keep killing them!”

A major key, then, to cracking the code on Type I diabetes is figuring out why the immune system does not recognize the pancreas as “self” but rather treats it as an invader and tries to kill it. Melton next plans are to study the development of diabetes in mice. These mice are genetically modified so that the cells and tissues are actually human in nature. In this manner, Melton and his research team can find out which type of cell affects the onset of diabetes and how many different ways there are to develop the disease. “If that doesn’t work, I really don’t know what I’ll do,” he said.

Perhaps most relevant to diabetic patients today is finding out what triggers beta cells to divide, however. Melton cited an experiment in which a mouse cured itself of diabetes after having most of its beta cells killed in a laboratory setting. The residual beta cells boosted replication so that the mouse could cure itself.

“We’re very keen on finding signals for beta cell replication that could be useful in newly onset diabetes to boost replication and increase tolerance,” said Melton. Recently diagnosed diabetics often experience a “honeymoon period” in which the body still retains some capability to produce insulin before all of the beta cells have been killed. If scientists can keep the body from killing beta cells and induce replication before the cells are all gone, it is possible that the patient may regain the ability to produce insulin.

Douglas Melton began his lecture with the words, “I wasn’t certain I could do science.” He has clearly proven that not only can he do science, but he can also make a difference and inspire hope in the lives of millions of people.