Stories about: David Breault

Intestine chip models gut function, in disease and in health

villus-like projections growing in gut chip
Villus-like extensions formed by small intestinal cells from patient biopsies, protruding into the Intestine Chip’s luminal channel. (Credit: Wyss Institute at Harvard University)

The small intestine is much more than a digestive organ. It’s a major home to our microbiome, it’s a key site where mucosal immunity develops and it provides a protective barrier against a variety of infections. Animal models don’t do justice to the human intestine in all its complexity.

Attempts to better model human intestinal function began with intestinal “organoids,” created from intestinal stem cells. The cells, from human biopsy samples, form hollowed balls or “mini-intestines” bearing all the cell types of the intestinal lining, or epithelium. Recently, intestinal organoids helped reveal how Clostridium difficile causes such devastating gastrointestinal infections.

But while organoids have all the right cells, they don’t fully replicate the environment of a real small intestine. Real intestines are awash in bacteria and nutrients, are fed by blood vessels and are stretched and compressed by peristalsis, the intestines’ cyclical muscular contractions that push nutrients forward.

Efforts to recreate that environment led to the Intestine Chip. An early version, created by the Wyss Institute for Biologically Inspired Engineering, cultured cells from a human intestinal tumor cell line.

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Potential cure for diabetes may be in the stomach

diabetes stomach beta cells
The yellow-green cells in this “mini-stomach” are capable of making insulin. The mini-organ was made from biopsied cells from mouse stomachs, with reprogramming factors added.

If only there were a cure. David Breault, MD, PhD, associate chief of the Division of Endocrinology at Boston Children’s Hospital, was seeing patient after patient with Type I diabetes. Children facing lifetimes of insulin injections, special diets and the threat of long-term complications including blindness, heart disease and kidney failure.

Breault knew that patients with type I diabetes mysteriously destroy their own insulin-producing beta cells. He had read reports of researchers transplanting beta cells to supplement insulin. These transplants, even when successful, required powerful immunosuppressant medications to prevent patients’ immune systems from attacking the donor cells.

But Breault was also aware that investigators had, for a decade, been looking to stem cells as the source of a constantly renewing supply of beta cells. Advancing that promise, he has now found a way to convert patients’ own cells — from the stomach and intestine — into beta cells that produce insulin.

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Entry door for deadly C. difficile toxin suggests new mode of protection

Clostridium difficile
C. difficile (Wikimedia Commons)

Clostridium difficile, also called “C. diff,” tops the CDC’s list of urgent drug-resistant threats. Marked by severe diarrhea and intestinal inflammation, C. diff has become a leading cause of death from gastrointestinal illness, causing half a million infections a year in the U.S. alone.

C. diff flourishes best in hospitals and long-term care facilities where people are on long-term antibiotic treatment. “Antibiotics clear out the normal intestinal bacteria and create a space for C. diff to colonize and grow in the colon,” says Min Dong, PhD, who researches bacterial toxins in the Department of Urology at Boston Children’s Hospital.

In today’s Nature, Dong and postdoctoral fellow Liang Tao, PhD, together with researchers at University of Massachusetts Medical School, reveal how C. diff’s most potent toxin gets into cells. The toxin’s entryway, a receptor called Frizzled, provides an important and interesting clue to fighting the hard-to-eradicate infection.

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