Hirschsprung disease – also known as congenital megacolon – occurs when an infant’s intestinal nerve cells don’t develop properly, which affects the movement of stool.
As a result, the infant’s intestine becomes blocked, causing severe constipation and intestinal obstruction.
One in 5,000 infants are affected by Hirschsprung disease. The only treatment currently available is to remove the affected portion of the intestine through surgery, an invasive procedure with the risk for complications.
Even with surgery, at least half of all children with Hirschsprung disease will have persistent gastrointestinal difficulties throughout life, including life-threatening intestinal inflammation, severe obstruction and soiling accidents.
A Mass General research team led by Allan Goldstein, MD, is determined to change the course for patients with Hirschsprung disease through scientific research and innovations. Goldstein is chief of Pediatric Surgery at Mass General for Children and the Marshall K. Bartlett Professor of Surgery at Harvard Medical School.
The Goldstein Lab uses animal models and tissues obtained from patients with Hirschsprung disease to better understand the disease and identify new strategies for treatment.
The start of a journey in Hirschsprung disease research
Goldstein first encountered Hirschsprung disease during his pediatric surgery fellowship at Columbia University.
He was treating a patient from Ecuador with intestinal pseudo-obstruction – a condition where the intestine cannot contract and push food or waste through the digestive tract. Complications can include bacterial infections, malnutrition, and a reliance on intravenous nutrition, with all of its associated complications.
The patient—a young teenager when Goldstein treated her —suffered significantly from the disease and unfortunately died when she was 25 years old.
This encounter awoke Goldstein’s interest in understanding intestinal motility, leading him to pursue research on the enteric nervous system (the part of the nervous system that controls gastrointestinal function).
For Goldstein, it was clear that Mass General was the ideal place to embark on this journey as a surgeon-scientist. He completed his surgery residency here at the hospital, where he trained under Patricia Donahoe, MD.
Donahoe has been a role model for Goldstein and many others in the field of pediatric surgery, demonstrating that it is possible to perform basic science research while being an outstanding pediatric surgeon.
Stem Cell Therapy as an innovative approach for Hirschsprung disease
One of the primary research areas in the Goldstein lab is to develop neuronal stem cell transplantation as a novel treatment for neurointestinal diseases such as Hirschsprung disease.
The research team hopes to generate new intestinal nerve cells that function normally and can be administered to patients whose nerve cells are either missing or not functioning normally.
“We want to avoid the need for surgery, or at least avoid the need to remove the rectum in babies with Hirschsprung disease. If we can do that, it would make a big difference in their long-term outcomes. These children have a long life ahead of them and we want to optimize their GI function and their quality of life,” says Goldstein.
Goldstein and team have established methods to isolate neuronal stem cells from the intestines and from the subcutaneous fat of mice and human patients and developed methods to culture and expand these cells in the lab.
The cultured cells are then transplanted into mice with Hirschsprung disease and other diseases caused by an absence or abnormality of the intestinal nervous system.
Over the past years, the team has generated various animal models and demonstrated that the transplanted cells can survive, grow and develop into neurons – making functional connections with other cells after they are delivered into the recipient animal’s intestine.
The team hopes to one day generate new intestinal nerve cells that function adequately in humans and can be transplanted into patients to restore intestinal motility without the need for immune-suppressing drugs or surgical removal of the digestive tract.
“I see a lot of children with Hirschsprung disease, and it is a constant inspiration to try to help them and their families. As anyone with children knows, when a child suffers, the whole family suffers,” he adds.
“So I think that combination, the research environment in our lab plus the opportunity to change the lives of these families and their kids is what makes me most excited.”
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