Research Magazine 2009
Cells to the Rescue
Necessity is indeed the mother of invention. While limitations on federal funding for embryonic stem cell research—which were partially lifted last March—touched off a series of heated ethical debates nationally, they also sparked new developments in labs like Michael Wolfe’s.
“Researchers know a great deal about embryonic stem cells,” says Wolfe, professor of medicine and chief of gastroenterology at the BU School of Medicine and Boston Medical Center. “But there are other potential sources for obtaining stem cells—all of which can express every gene in a human’s makeup—to investigate and explore. In recent years, we have seen phenomenal progress in these new areas.”
Induced pluripotent stem cells, or iPS cells for short, are adult cells that have been taken from a patient’s skin and then reprogrammed into undifferentiated cells able to develop into any one of the more than 200 types of cells in the human body. Because iPS cells are derived from the patient’s own tissue, they are not susceptible to rejection by the immune system when reintroduced, thereby potentially eliminating the need for immunosuppressants. With support from the Hartwell Foundation, Wolfe is exploring how iPS cells might be used to cure Type 1 diabetes mellitus.
Affecting approximately one in 300 children in the United States, Type 1 diabetes is caused by the immune system attacking pancreatic beta-islet cells, which are responsible for releasing insulin and without which the body is unable to utilize sugars and other nutrients to store and conserve energy. Current treatment options are less than ideal. Insulin replacement therapy requires patients to check their blood sugar levels at regular intervals and to administer painful injections, often multiple times every day. As a result, compliance can be erratic, despite serious long-term health risks, including blindness and renal and cardiovascular disease. Previous efforts to cure the disease by creating artificial beta cells have been unsuccessful.
“What do you think happens?” asks Wolfe. “The body says, ‘I don’t like these cells,’ and destroys them.” Instead, he and his team—including biochemist Michael Boylan and postdoctoral gastroenterology fellow Elisa Valente—are focusing on K-cells, endocrine cells in the upper small intestinal lining (adjacent to the pancreas) that share similarities with beta cells, including the ability to recognize glucose levels in the intestine and to manufacture needed hormones. In other words, says Wolfe, “you have a cell that behaves very much like a beta cell, only it’s not a beta cell,” making K-cells an exciting alternative for Type 1 diabetes research.
Building on results published in Science in 2000, in which Wolfe and his collaborators showed that K-cells can be used to express insulin in genetically altered mice whose beta cells have been destroyed, he is now working to develop a gene therapy treatment that will eliminate Type 1 diabetes in mice by delivering iPS cells to the intestinal lining. These iPS cells are programmed to develop into K-cells capable of producing insulin peptides in response to food ingestion, as well as another peptide that is naturally synthesized by K-cells, called glucose-dependent insulinotropic polypeptide, or GIP. Treatment in humans, a possibility that lies several years down the road, would involve a pain-free, one-time endoscopy and would include a kind of genetic circuit breaker designed to stop the therapy if toxicity develops or if it is no longer required.
To facilitate insulin production in K-cells, Wolfe is collaborating with Gustavo Mostoslavsky, an assistant professor of medicine and an expert in using lentiviruses to modify cells. “The virus we are using in this case has actually been derived from HIV,” says Mostoslavsky. “This sounds scary, but of course the virus has been emptied of its pathogenic qualities while retaining great efficiency at introducing genes into both dividing and nondividing cells.” Many other viruses can introduce genes only into cells that divide.
The peptide replacement technique under development by Wolfe and his colleagues could have far-reaching applications for viral hepatitis, chronic diarrhea, obesity, dwarfism, and other conditions caused by various hereditary and acquired deficiency states.
“We could actually treat anything that has a gene with these little peptide factories,” says Wolfe. “And we could do it with one treatment only, instead of using daily injections. Wouldn’t you rather have one treatment only?”
Gastroenterologist Michael Wolfe uses a delivery truck analogy to explain how K-cells—which normally produce glucose-dependent insulinotropic polypeptide, or GIP—can be made to do the job of beta-cells by producing insulin instead. The structural gene (which contains important information leading to the production of a specific product) is analogous to the trailer containing goods to be delivered, while the promoter (which directs the expression of the gene to the correct cell at the appropriate time) is comparable to the cab and driver. By placing the GIP promoter in front of the insulin gene, Wolfe can “trick” K-cells into delivering a different set of goods—insulin—in diabetic mice.
Schematic courtesy of Michael Wolfe