M. Michael Wolfe, M.D., professor of medicine and research professor of physiology and biophysics at Boston University School of Medicine and chief of the Gastroenterology Section at Boston Medical Center, was awarded an Individual Biomedical Research Award by The Hartwell Foundation. Wolfe, considered a premier authority on the biology of GI regulatory peptides, will receive $300,000 direct cost over three years as a Hartwell Investigator for his project, "Peptide Replacement Therapy Using Transgenic Stem Cells Delivered to the Small Intestinal Mucosa".

Wolfe and his colleagues are developing a technique to redress hormone and enzyme deficiencies that cause diseases such as type 1 diabetes. The technique relies on engineering stem cells that produce the missing peptides and implanting them in the small intestine.

Because of their molecular size and susceptibility to degradation by stomach acid and digestive enzymes, insulin and other hormones must currently be administered by injection. The discomfort and inconvenience associated with injections often diminish patient compliance, particularly in children, which increases the risk of long-term complications. This concern is of particular importance for patients with type 1 diabetes, who often require multiple daily insulin injections to maintain stable blood sugar. Type I diabetes is one of the most common severe chronic diseases in children (1/300 in the US) and a major cause of end-stage renal disease, blindness, cardiovascular disease and premature death in the general population.

In a manuscript published in Science in 2000, Wolfe and his collaborators reported that intestinal K-cells of transgenic mice, which normally manufacture a hormone called GIP, could be engineered to express insulin and maintain normal blood glucose levels, even after pancreatic insulin-producing ("islet-beta") cells were destroyed. Employing the same genetic approach, Wolfe plans to transform stem cells that, like pancreatic islet-beta cells, will produce insulin in response to food ingestion. Using endoscopy, he plans to introduce transformed cells into the intestinal lining, where they will be programmed to become K-cells and produce insulin as well as GIP. The relocation of insulin production to the upper small intestine will "hide" it from the autoimmune response that destroys beta-cells in type 1 diabetes. Moreover, because K- and beta-cells are functionally similar, the K-cell appears to represent the ideal candidate for "hosting" the "foreign" insulin gene.

Wolfe is recognized as one of the world's leading authorities on GIP, and he initially cloned the GIP cDNA and ascertained its central role as principal mediator of the "enteroinsular axis". This axis functions as the hormonal connection between the intestine and pancreas following the ingestion of food. He established GIP as the likely mediator of the glycemic index and has theorized that low carbohydrate diets and gastric bypass surgery mediate their beneficial effects in part by suppressing GIP expression. He proved its importance in obesity by demonstrating functional receptors on adipocytes and by showing that GIP, like insulin, suppresses the breakdown of fat, which in essence results in an increase in fat storage.

"Boston University is delighted to have been invited by The Hartwell Foundation to participate in this year's competition and is deeply proud of Dr. Wolfe's selection for this exceptionally competitive Individual Biomedical Research Award," said Karen Antman, MD, dean of Boston University School of Medicine and provost of Boston University Medical Campus. "The award provides strategic funding for remarkably original research that combines genetic engineering, stem cell therapeutics, and gastroenterology, with exciting potential clinical implications. Private funding is vital to advancing such high-risk, high-gain work, and we are very grateful to The Hartwell Foundation for playing that role at BU."

Wolfe is highly regarded for his ability to translate his own research and others' observations into the clinical arena. He has been funded nearly continuously by the National Institutes of Health since the early 1980s and is one of only a very few American academicians with an invention that culminated with a drug currently on the market (Pepcid Complete®).

"The Hartwell Foundation is honored to provide financial support to Dr. Wolfe," said Foundation President Frederick Dombrose, Ph.D. "Participating institutions nominated exceptional individuals, making this year's competition for Investigator awards very tough."

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Each year, The Hartwell Foundation announces its Top Ten Centers of Biomedical Research, inviting each center to hold an internal competition to nominate four candidates for a Hartwell Individual Biomedical Research Award. In August, Boston University was invited to participate as an extraordinary 11th institution and to submit two nominees for consideration.

The Hartwell Foundation seeks to inspire innovation and achievement by providing financial support to individual researchers in the United States for innovative and cutting-edge applied biomedical research that has the potential to benefit children. The general aim is to provide funds for early stage research projects that have not yet qualified for funding from traditional sources.

More information about The Hartwell Foundation is available on their web site, at thehartwellfoundation/.

Source: Michelle Roberts
Boston University

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