Pediatrician - Special Surgery Edition
October 9, 2015
In the Hackam lab (l to r), first row: Dorothy Hallberg, Chhinder Sodhi; 2nd row: Thomas Prindle, David Hackam, Peng Lu; 3rd row: William Fulton, Diego Nino, Hongpeng Jia.
Therapy for necrotizing enterocolitis, or NEC, is limited to surgery that leaves patients with insufficient intestine—short bowel syndrome—and at risk of long-term complications. Unable to absorb enough nutrients, these children require feeding support for life—and many transplantation and immune-suppressive therapy that pose long-term risks. If ever a disease needed a lab, Johns Hopkins pediatric surgeon David Hackam felt, NEC was it.
Through simulating NEC in mouse models and employing genetic and pharmacologic approaches to prevent its course, Hackam and his colleagues have made some significant inroads. For NEC to develop, explains Assistant Professor of Surgery Chhinder Sodhi, three factors must come into play—premature birth, hypoxia, and a bacterial infection. In that perfect storm, Hackam’s group identified a specific molecule that attracts gram-negative bacteria in the gut—toll like receptor 4 (TLR4)— which is highly expressed in the initiation of the disease. Expression of TLR4 is necessary for the development of the intestines, Sodhi explains, but high expression of it halts blood flow to the intestines and normal development in its tracks, resulting in NEC. The Hackam lab had its treatment target.
The group has also found that amniotic fluid, which contains the wound-healing protein epidermal growth factor or EGF, inhibits TLR4 signaling, which could lead to development of a drug inhibiting TLR4 activity and preventing NEC inflammation in premature infants. In the womb, Sodhi notes, normal birth babies bathe in and drink amniotic fluid while premature babies do not. Lab members have also found protection against NEC in breast milk, which is not readily available to premature infants. They showed that NEC did not develop in mice fed with infant formula containing sodium nitrate, a compound known to improve blood flow and found in breast milk.
“NEC often develops within the first two weeks of life, usually after milk feeding has begun and the infant’s immature bowels are prone to infection,” says Sodhi. “The premature infant’s difficulty with blood and oxygen circulation also increases their risk of NEC. Without the breast milk and amniotic fluid, you have high levels of TLR4.”
In another preventive strategy, the group is also searching for diagnostic markers in, among other places, the mother’s stool. Another goal is identification of mutations in the TLR4 gene that cause higher signaling and expression. “We’re studying all of the genes in the TLR4 pathway, taking them away and putting them back, to correct the signaling,” says Sodhi.
In yet another approach, what Hackam calls his lab’s “most exciting work,” he and his team are collaborating with Cornell scientist John March to create an artificial intestine for NEC patients. They’ve mastered a way to culture intestinal stem cells but they’ve been unable to create a structure where the cells can grow—but Hackam is determined to find such a scaffold.
“Surgeons can’t operate in silos and by necessity,” says Hackam. “These infants, born with intestines that don’t work, are left without a gut. They can wait for an intestinal transplant, but why not develop an artificial intestine? There’s a clear, unmet need for it.”
This research initiative, funded by a $500,000-plus grant from The Hartwell Foundation, also dovetails with studies by Hopkins pediatric plastic surgeon Anand Kumar in the plastics stem cell lab. There Kumar and his colleagues are investigating muscle stem cell biology for regenerative applications for bone defects of the skull and face for cleft lip and palate, and craniosynostosis patients.
“These children have too much or too little bone and we don’t have great places to get bone grafting materials,” says Kumar. “We’re working constantly to engineer bone.”
In Hackam’s mind, that’s one more illustration of the continuing influence of science on surgery