Issue 117 Item 12 New Insulin Gene Discovered

Can lead to a new method for making insulin and repair damaged cells Researchers at Boston’s Joslin Diabetes Center have identified a pivotal genetic switching mechanism for making insulin, a major discovery that could lead to a recipe for brewing insulin-making cells or even repairing damaged cells inside patients.

Scientists trying to crack the code of diabetes have known since the early 1990s that the gene responsible for making insulin was turned on by three proteins, like switches on a car’s dashboard. They even came up with names for each of those molecular buttons. But how did the switches get flipped? It wasn’t much good knowing that the buttons were there if the chemical key for turning them on proved elusive.

Seven or eight years ago, researchers identified two of the chemical switching mechanisms. But one remained stubbornly hidden, resisting the efforts of dozens of researchers – until now.

Molecular biologist Arun Sharma and a team of other Joslin scientists used knowledge gleaned from the study of birds and countless hours in a bone-chilling room to pry secrets from the insulin gene.

The discovery dramatically speeds up attempts to take stem cells and convert them into insulin-producers, said specialists familiar with Joslin’s work. However, making such cells available for transplanting is still years away.

"It is very significant what they have done," said Alberto Pugliese, a top scientist at the University of Miami’s Diabetes Research Institute. "This research goes to the bottom of how an insulin-making cell works, which is crucial because we need to understand that in order to produce a cell that makes insulin."

For cells to become beta cells, they need a certain set of genes, and those genes, in turn, must be switched on. That’s where the car dashboard analogy comes in. The genes have three sites, like buttons on a dashboard. For those buttons to be activated, specific proteins must bind with each site. In laboratory parlance, those binding proteins are known as transcription factors. Without transcription factors, the genes cannot be turned on.

Scientists knew two of the transcription factors.

"And then there was the third one," said Dr. Gordon C. Weir, who leads Joslin’s Section on Islet Transplantation and Cell Biology. "They knew that button was important and they knew that there was a transcription factor that went along with it, but they couldn’t find the transcription factor. A lot of people tried and had careers die looking for this thing."

Sharma began hunting for the factor five years ago, collaborating with three other scientists. The research, supported by the Juvenile Diabetes Research Foundation and American Diabetes Association, first received attention in the scientific community three months ago in the journal Proceedings of the National Academy of Sciences.

Sharma performed elaborate biochemical tests to derive the transcription factor, then cloned it, using knowledge harvested from earlier research, into a chemical that leads to the formation of eye lenses in chickens and quail.

The connection to the avian protein was discovered after studies of the human insulin protein showed promise and scientists began searching for a roadmap of how the protein operates. They scanned databases for similar proteins, and their finding proved that they had peeked behind the correct scientific door.

"We knew that if it works in chickens, this protein in humans could be equally important," Sharma said. "It saves you a couple of months’ work to figure out how it really works when you have information from a similar protein in another animal system."

Finding that third factor proved especially daunting because it exists only in small quantities in beta cells, said Dr. Michael German, a diabetes researcher at the University of California-San Francisco. To hunt for it, Sharma and other scientists spent days cloistered in what’s known as a cold room, a sector of the laboratory chilled to roughly 40 degrees Fahrenheit where cells are reduced to their component parts.

"What Arun had to do was a very laborious process," German said. "It really was a difficult task."

Scientists at Joslin and other specialists in the field believe that now that all three of the factors have been identified, they can begin devising strategies for giving birth to insulin-producing cells in the laboratory or developing methods for repairing ailing cells inside diabetics.

"It’s a major advance," said Scott Campbell, national vice president of research programs for the American Diabetes Association. "If you can understand the key to development of beta cells and how they function to produce insulin, you may have the key to curing diabetes one of these days."

The hope is that one day, stem cells – blank molecular slates that become different organs – can be nudged into insulin-making cells in the lab. That would present the best treatment yet for patients with Type 1 diabetes and it could also delay the development of Type 2 diabetes.