In Fruit Flies, it's not Diabetes, it's 'Flyabetes'

Assistant Professor Eric Rulifson, Ph.D. thinks there’s a lot to learn about diabetes from the humble fruit fly. Never mind that fruit flies have no pancreas - he is convinced that they teach us about how islet cells develop and how they might one day be grown artificially. Rulifson was initially studying wing development in fruit flies (called Drosophila melanogaster) as a post-doctoral fellow at Stanford University. Fruit flies, or Drosophila, are workhorses of the geneticists’ lab – they are small and breed very quickly.

After being diagnosed with type 1 diabetes several years before, Eric’s thoughts turned towards the problem of diabetes. He knew, for example, that insulin-like proteins were present throughout the animal kingdom, even in the smallest of creatures. He also knew that the fruit fly version of insulin was produced in cells located in their brain tissue.

He decided to turn the question of how these endocrine cells develop into his research focus and subject of his future career.

He took the work with him next to the University of Pennsylvania, and three years later, to the Diabetes Center and Institute for Regeneration Medicine at UCSF. Through genetic analysis, cell staining and microscopy, his group was able to figure out how specific cells in the embryo tissue give rise to the cell groups he’s dubbed “flylets.” Like human islets, they produce insulin in their final state.

Rulifson’s research with flylets is one possible path to restoring insulin-producing cells for people with type 1 diabetes, who now rely on daily insulin injections to regulate their uptake of blood sugar. Type 1 diabetes is considered an autoimmune disease, in which the body’s immune system attacks and destroys insulin-producing beta cells in the pancreas. The dream of a long-term cure is to be able to transplant new cells that replace the destroyed ones, restoring the natural ability to produce insulin rather than relying on daily injections and strict lifestyle modification.

Rulifson is also hoping to soon add sea squirts to his menagerie of animal research subjects. With a body plan more similar to higher vertebrates, their larvae are another piece of the evolutionary path from insects to people. Mice are also on his agenda, with some informal collaboration already underway between his group and the laboratory of Diabetes Center associate director Mike German, M.D., who has a mouse model of diabetes.

“Perhaps,” Rulifson says, “we can identify the gene networks that direct cells to the insulin-producing cell fate, and by looking at this in flies, sea squirts and vertebrates, we may see how those networks have come to be used in people.”

He adds, “Probably all multi-cellular animals have insulin – it’s the signal that relates their nutrient status to growth and metabolism. My game plan now is to advance the fly research to generate clues about how this cell’s development works in the formation of tissues and organs in vertebrates. Hopefully, we can begin to understand how the activation of specific gene networks has moved around, from brain to gut, maybe serving as building blocks for beta-cell development.”

Rulifson likes to joke that he wants to cure “flyabetes.” He hopes to quickly achieve in the fly what teams of researchers around the world, including here at UCSF, are hoping to achieve with islet transplantation.

“If the goal is to make buckets of beta cells for transplant to save diabetics,” he says, “there’s a lot to add to the work that has been done in the pancreas with beta cell development, to complement it. People don’t really understand these deep evolutionarily conserved relationships between sets of genes governing tissue development.”

Creating a new source of islets for transplantation, according to Rulifson, involves more than just identifying stem cells that can be coaxed into differentiating themselves into beta cells. First, the genetic controls responsible for this transformation must be fully understood – and his friends the fruit flies are simply the first step.