Study Highlights the Utility of Organoids in Changing Clinical Management
Investigating the cause of clinical symptoms ordinarily doesn’t involve organoid research. But this was no ordinary patient.
“Sam” was born in 2015 without a pancreas due to a homozygous genetic mutation in PDX1, the gene that is essential for the development of pancreatic exocrine and endocrine cells. He was discharged from the Cincinnati Children’s neonatal intensive care unit on insulin therapy and followed by pediatric endocrinology and pediatric gastroenterology. When his care team could not determine the cause of symptoms such as chronic diarrhea, poor weight gain, and abdominal pain, Mansa Krishnamurthy, MD, MSc, recruited him to a research study for patients with rare genetic forms of diabetes and congenital hyperinsulinism.
Krishnamurthy, a physician-scientist in the Division of Endocrinology, uses basic and translational approaches in the lab to better understand how rare genetic mutations affect insulin production and secretion. Her work is made possible in part by resources from the hospital’s Center for Stem Cell and Organoid Medicine (CuSTOM). The Center specializes in technologies such as patient-derived induced pluripotent stem cells, CRISPR/Cas9 genetic correction, and organoid modeling. Organoid model systems contain all the various cell types one would expect to find in patients, making them an excellent tool for studying disease.
A Surprising Discovery
“Researchers know PDX1 is important for the pancreas, but we don’t know how a mutation in the gene affects the gastrointestinal (GI) tract,” says Krishnamurthy. Hoping to shed light on the pathophysiology and potential source of the child’s symptoms, she worked with her research mentor, James Wells, PhD, to generate organoids from the patient’s stem cell line representing different regions of the GI tract (mainly the stomach and intestine).
What she discovered surprised her. “We found bits of intestine in the stomach organoids and bits of the stomach in the intestinal organoids—a condition referred to as gastric and intestinal metaplasia,” Krishnamurthy says. This prompted a re-examination of recent biopsies from the patient that my gastroenterology colleagues had obtained, which also showed evidence of the metaplasia.”
Krishnamurthy shared her discovery with Joe Palermo, MD, PhD, Sam’s pediatric gastroenterologist at Cincinnati Children’s. Palermo had observed abnormalities in the patient’s previous biopsies and was interested in Krishnamurthy’s more detailed investigation. He suggested that at the child’s next scheduled endoscopy, he would biopsy tissue from the stomach and duodenum, avoiding the transition zone where stomach and intestine cells often coexist. Those biopsy results confirmed Krishnamurthy’s initial findings.
“Our discovery didn’t shed light on what was causing Sam’s GI symptoms, but it did change his treatment plan,” Krishnamurthy says. “The presence of metaplasia raises his risk of getting gastric and intestinal cancers, so we will monitor him over time with an increased number of endoscopies with biopsies. In a sense, the organoids we created were diagnostic and captured valuable information that a biopsy could not.”
Sam, now 8, is taking proton pump inhibitors to alleviate his pain symptoms and is doing well. He continues to be seen by Krishnamurthy and Palermo for ongoing care.
A Possible Alternative to Large Clinical Trials for Very Rare Disorders
Palermo notes that specialized studies like these are critical to understanding rare disorders such as PDX1 mutation. “We’re never going to have enough patients with a PDX1 mutation to do a large clinical trial, so we need good alternatives,” he explains. “Organoids allow us to use the patient’s own tissue to develop very specific types of cells, see them interact with other cell types, understand how certain tissues behave, and test the effect of different therapies. That’s important for both the short- and long-term management of these patients.”
Palermo adds that expert pathologists at Cincinnati Children’s played a key role in Krishnamurthy’s study. “Histological findings can be subtle and challenging to interpret when looking at a rare pathology,” he says. “Dr. Krishnamurthy did an excellent job bringing together a team that shared her enthusiasm for really understanding what was happening at the cellular and molecular levels and applying what we learned to the clinical setting.”
Krishnamurthy’s work is part of a much larger effort at Cincinnati Children’s to use organoids as a revolutionary platform to understand disease, develop new personalized treatments, and, ultimately, generate tissue for transplantation. In just the last 18 months, researchers within CuSTOM have made the following discoveries.
- Michael Helmrath, MD, published a study on May 1, 2023, in the journal Development, reporting that organoids accurately mimic key development stages of the human intestine. The study opens doors to a new wave of disease-origin research.
- Helmrath, a pediatric surgeon and director of CuSTOM, also led a team that successfully developed a complex “next-generation” intestinal organoid that includes key elements of a functional immune system. Co-authors of the five-year study, published online on Jan. 26, 2023, in Nature Biotechnology, say this is the first in vivo organoid of any type to incorporate a functional immune system.
- Masaki Kimura, PhD, a member of the Takebe Research Lab, developed new technology to create liver organoids from human stem cells at a population scale. His findings were published in Cell on October 27, 2022.
Krishnamurthy published the findings from her organoid study in Gastroenterology (October 2022).
(Published October 2023)
