The Hartwell Foundation

 
     

Second 2011 Biomedical Research Collaboration Award

Memphis, TN, October 15, 2011 --The Hartwell Foundation announced its second Biomedical Research Collaboration Award in 2011, providing funding to expand the frontiers of early-stage, innovative and cutting-edge applied biomedical research through special collaboration. It is the fifth such award made by the foundation since 2008. David Hackam, MD, Ph.D., 2008 Hartwell Investigator and Professor of Surgery, Physiology and Cell Biology at the University of Pittsburgh, together with John March, Ph.D., 2007 Hartwell Investigator and Associate Professor of Biological and Environmental Engineering at Cornell University, will receive $543,571 in direct costs over three years to pursue their proposal for “Generation of an Artificial Intestine for the Treatment of Short Bowel Syndrome in Children.”

The clinical condition in which the body is unable to absorb food after significant loss of the intestine is called short bowel syndrome (SBS). While its true incidence is unknown, in the United States the condition affects over 5000 children, with an estimated 15,000 older patients requiring long-term home parenteral nutrition. SBS can be caused by loss of large portions of functioning intestine – such as occurs typically as a consequence of necrotizing enterocolitis (NEC), Crohn's disease, or as a result of a birth defect in which the intestines do not develop normally. Because food cannot be adequately absorbed by the shortened intestine, nutrients must be administered directly into the circulation through a vein. Although this approach can supply adequate calories, children who receive nutrition directly into the circulation commonly suffer from intravenous catheter infections and severe liver toxicity, with mortality around 30%. Only about one third of patients with SBS can expect to be weaned from parenteral nutrition. The majority of children with short bowel syndrome require intestinal transplantation and if toxicity from the administered nutrition is severe enough, liver transplantation, as well. While the outcome after intestinal transplantation is improving, this procedure is limited by a lack of suitable donors and complications from immunosuppressive therapy. To address the difficulty of managing short bowel syndrome in children, Hackam and March propose constructing an artificial intestine using cultured intestinal stem cells from the recipient’s intestine that can grow on a synthetic 3-dimensional bioscaffold.

Based upon his discovery that expression and signaling activity of a molecular “switch” called toll-like receptor 4 (TLR4) was elevated in the intestine of human infants with NEC and that mice lacking TLR4 were protected from the development of NEC,  Hackam proposed as a 2008 Hartwell Investigator to identify novel chemical compounds for the treatment of the disorder. He deployed a strategy to identify specific inhibitors of TLR4 signaling in the intestine utilizing high throughput computer-aided screening of chemical libraries, combined with whole animal screening. He successfully identified 67 novel TLR4 inhibitors, with one compound particularly effective in reducing the severity of experimentally induced NEC in mice. He is now focused on confirming the mechanism of action of the compound, while performing chemical modification to improve it as a powerful new treatment for the management of NEC in neonates.

As a 2007Hartwell Investigator, March proposed to engineer ordinary, consumer-grade commensal (probiotic) bacteria that live in the human GI tract, to produce a protein that would stimulate the epithelial cells that line the intestine to secrete insulin into the blood circulation. He reasoned that his approach would effectively "hide" the insulin production site from the autoantibodies that destroy insulin-producing β-cells in type 1 diabetes. He successfully demonstrated with a modified probiotic in experimentally-induced diabetic mice clear reductions in blood glucose levels as well as increases in blood insulin. He also demonstrated the effectiveness of this approach in non-obese diabetic mice. Implementation of his innovation for treating type-1 diabetes would move the center of glucose response from the pancreas to the gut, which could result in a therapy that avoids repeated insulin injections and might cost as little as $100 per year.

In their Collaboration, Hackam and March propose to generate and optimize a novel bioscaffold to support the growth and differentiation of intestinal stem cells; optimizing cell growth conditions in a three-dimensional “gut tube” reactor or artificial intestine. They will subsequently implant the gut tube into mice with surgically-created short bowel syndrome and perfuse the intestine with a nutritional formula to assess the ability of the host to absorb nutrients through the artificial intestine. The collaborators will also examine the safety and efficacy of implantation of the artificial intestine in a pig model of short bowel syndrome. The rationale for the use of pigs is that they share greater similarity with humans and the larger abdominal cavity in pigs will facilitate the scale up of the artificial intestine to a size appropriate for humans.

The Hackam-March collaboration brings together a pediatric surgeon and clinical scientist specializing in the intensive care of neonates with intestinal disorders and a bioengineer familiar with the creation of artificial tissue matrices. While Hackam had successfully isolated and grown intestinal stem cells in culture, he lacked an appropriate collaborator with knowledge about construction of a suitable artificial matrix that could be used to support cell growth for an artificial intestine. By contrast, March had developed a novel artificial matrix (bioscaffold) to construct what he called a gut tube reactor, but lacked access to the intestinal stem cells and the expertise in stem cell biology required for it to become a functional intestine.

"The generation of a novel matrix with the ability to absorb nutrients while supporting the growth of intestinal stem cells is highly complex, thus we will use innovative statistical design of experiments software for response surface optimization of the bioscaffold, which will guide us in the development of the artificial intestine," said Dr. March.

“John and I have already generated a structure that bears remarkable similarity to the normal intestine, providing a sense of excitement, conviction and hope that we can overcome the overwhelming skepticism to develop an artificial intestine – a novel translational therapeutic for children with short bowel syndrome,” related David Hackam.

“The generation of artificial organs represents an absolute holy grail in medical research; a transformative approach for children with short bowel syndrome that could benefit thousands of children by reducing morbidity and mortality,” said Frederick Dombrose, President of The Hartwell Foundation.

Fostering collaboration between investigators of complementary scientific strengths is a primary objective of The Hartwell Foundation Mission to fund innovative, early-stage applied biomedical research with the potential to benefit children.

 

2008 Hartwell Investigator David Hackam, MD, Ph.D., University of Pittsburgh

 

2007 Hartwell Investigator John March, Ph.D., Cornell University

Biomedical Research Collaboration Awards

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