If only there were a cure. David Breault, MD, PhD, associate chief of the Division of Endocrinology at Boston Children’s Hospital, was seeing patient after patient with Type I diabetes. Children facing lifetimes of insulin injections, special diets and the threat of long-term complications including blindness, heart disease and kidney failure.
Breault knew that patients with type I diabetes mysteriously destroy their own insulin-producing beta cells. He had read reports of researchers transplanting beta cells to supplement insulin. These transplants, even when successful, required powerful immunosuppressant medications to prevent patients’ immune systems from attacking the donor cells.
But Breault was also aware that investigators had, for a decade, been looking to stem cells as the source of a constantly renewing supply of beta cells. Advancing that promise, he has now found a way to convert patients’ own cells — from the stomach and intestine — into beta cells that produce insulin.
Because the approach gets around the problem of immune rejection and avoids current inefficiencies in other forms of cell-based therapy, it could be a game changer.
Insulin from a mini-stomach
Breault originally pursued the idea of harvesting stem cells from the pancreas, the natural source of beta cells, to treat disease. He used a marker called telomerase to identify and isolate these cells. The problem was that the cells Breault found did not give rise to insulin-producing cells. They turned out to have a mysterious function, probably as a regulator of the nearby insulin-producing cells.
To move forward, Breault went back to the beginning. During fetal development, he knew, the stomach and intestine are formed before the pancreas. Joining forces with scientist Qiao Zhou, PhD, at the Harvard Stem Cell Institute, he began to try to convert stomach and intestinal cells into insulin-producing beta cells.
The team began with mice and then moved to patient biopsies of stomach and intestinal tissue. If grown in dishes under special conditions, the biopsied cells formed hollowed balls, so-called “mini-stomachs” or “mini-intestines.” The researchers then added three reprogramming factors (the products of certain genes that control DNA expression) to convert some of the gastrointestinal cells into beta cells that could secrete insulin. The yellow-green cells in the image are insulin-producing.
The mini-stomachs turned out to work more efficiently than the mini-intestines. When transplanted into “diabetic” mice lacking beta cells, they produced enough insulin to prevent spikes in blood sugar levels. They kept the animals alive for six months, while untreated mice died within eight weeks.
Breault’s team went on to show that the technique could work with human cells, a major step toward the ultimate goal: to take this into the clinic.
A numbers problem
We have robustly shown that you can make insulin from cells in the intestine and stomach.
A challenge remains. For every patient treated, researchers would need to make 1 billion converted beta cells from these mini-stomachs or intestines. That cannot be done with the small numbers of cells from a stomach or intestinal biopsy. Breault’s next step will be to develop strategies to coax the gastrointestinal cells to reproduce in high numbers in a dish. He then can convert these into insulin-producing beta cells.
A group in China recently published an exciting set of related findings. These researchers extracted a patient’s stomach cells and successfully expanded them in dishes by adding small molecules. They also discovered that “feeder cells,” from a different part of the stomach, perform a mysterious support function enabling the stomach’s stem cells to reproduce. But despite these important advances, the Chinese group was unable to develop efficient methods to convert stomach cells into beta cells.
Breault has already proven he can do this conversion. His team now plans further studies with mouse and human cells to advance the results toward clinical treatment.
Organoids for science
As founder and director of the Organoid Core at Boston Children’s, Breault leads an NIH-funded program based jointly in the Divisions of Endocrinology and Gastroenterology at Boston Children’s. In this unit, researchers are growing “mini organs” from gastrointestinal stem cells taken from biopsies of mice and (with their families’ consent) children.
Mini organs are turning out to be crucial research tools to help uncover mechanisms underlying gastrointestinal diseases. Recently, for example, Breault’s team supplied mini-colons to Min Dong, PhD, in the Department of Urology, and helped Dong’s team unravel the mechanism by which the bacterium Clostridium difficile — the most common cause of antibiotic-associated diarrhea — causes such potent and lethal havoc.
As for diabetes, Breault and Zhou recently scored a $1 million NIH grant to further investigate the mechanism of human gastrointestinal stem cell to beta cell conversion. But Breault has another hurdle ahead.
Protecting newly-minted beta cells
Even though the beta cells would be made from diabetic patients’ own cells, the disease itself prods the body to mistakenly attack them. Breault will eventually have to encapsulate them into meshes designed to protect against immune system attack. Other teams are fast working on encapsulation strategies.
“We have robustly shown that you can make insulin from cells in the intestine and stomach,” says Breault. “That gives us two sources of tissue, which are pretty easy to get and very easy to expand. The ultimate goal is to move this work into the clinical realm, within the next five to 10 years.”