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Grant spurs effort to map biology of Crohn’s disease

Nov. 20, 2019, 4:14 PM


by Bill Snyder

Vanderbilt University Medical Center (VUMC) has been awarded a three-year, $3 million grant from The Leona M. and Harry B. Helmsley Charitable Trust to map — in unprecedented detail — the biology of Crohn’s disease.

Under the terms of the award, which was announced last month, VUMC will work with several other institutions to create a “gut cell atlas” — essentially a catalog of individual cells, gene expression patterns and proteins in the small and large intestines of Crohn’s patients and those without the disease.

From left, Qi Liu, PhD, Lori Coburn, MD, Gregor Neuert, PhD, Keith Wilson, MD, Ken Lau, PhD, and Bennett Landman, PhD, are leading VUMC’s contribution to the “gut cell atlas” program funded by the Leona M. and Harry B. Helmsley Charitable Trust.
From left, Qi Liu, PhD, Lori Coburn, MD, Gregor Neuert, PhD, Keith Wilson, MD, Ken Lau, PhD, and Bennett Landman, PhD, are leading VUMC’s contribution to the “gut cell atlas” program funded by the Leona M. and Harry B. Helmsley Charitable Trust. (photo by Joe Howell)

“There is an urgent need to map the cells of the gut at high resolution,” Garabet Yeretssian, PhD, director of the Helmsley Charitable Trust’s Crohn’s Disease Program, said in a news release. “By creating a Gut Cell Atlas, there is tremendous potential to better understand gut health and Crohn’s disease and develop better treatments for patients.”

Keith Wilson, MD, VUMC’s principal investigator and director of the Vanderbilt Center for Mucosal Inflammation and Cancer, said the effort will help bridge the bench-to-bedside gap between discovery science and improving treatment options for patients. “This is a good beginning,” he said, “the tip of the iceberg.”

Crohn’s disease and ulcerative colitis are the major forms of inflammatory bowel disease (IBD), which is estimated to afflict as many as 3 million Americans. Symptoms include persistent diarrhea and chronic abdominal pain.

Corticosteroids, immunomodulators and cutting-edge biologic therapies can relieve symptoms, but full remission is achieved in only about half of patients. One of the main obstacles to improving treatment is not knowing the etiologies or specific changes in the gastrointestinal tract that lead to Crohn’s disease.

“Each patient is different — that’s what makes it difficult,” said Lori Coburn, MD, co-principal investigator of the Vanderbilt grant. “Determining what’s going on at the cellular level will aid the search for new therapies and help physicians choose treatments that are most likely to work in their patients,” she said.

To that end, the Vanderbilt researchers are applying sophisticated technologies including single-cell RNA sequencing and bioinformatics analyses to measure the RNA, a marker of gene expression, in individual cells that have been separated after being collected via biopsy.

Using this approach, “you actually can end up saying that Crohn’s disease is different from normal because this cluster of cells seems to be expressing these genes,” said Wilson, the Thomas F. Frist Sr., Professor of Medicine in the Vanderbilt University School of Medicine.

Coburn, assistant professor of Medicine, is one of five co-principal investigators. She leads the study’s Clinical Core, which will oversee patient recruitment, sample collection and management of the clinical trial.

Ken Lau, PhD, associate professor of Cell and Developmental Biology and an expert on single-cell approaches to evaluating the gastrointestinal mucosa, directs the Single-Cell RNA Sequencing Core.

Gregor Neuert, PhD, MEng, assistant professor of Molecular Physiology & Biophysics, Pharmacology and Biomedical Engineering, directs the RNA-FISH Core. RNA-FISH is a method for detecting and localizing RNA in cells. When combined with multiplex immunofluorescence, it can quantify RNA and protein expression at the single-cell level.

Qi Liu, PhD, associate professor of Biostatistics and Biomedical Informatics, directs the Bioinformatics/Biostatistics Core. She and her colleagues have developed techniques for analyzing the single-cell RNA sequence data.

Bennett Landman, PhD, who directs the Center for Computational Imaging in the Vanderbilt University Institute of Imaging Science, leads the Computer Imaging Analysis/Machine Learning Core. His group has developed machine-learning applications for integrating microscopic tissue studies with RNA and protein expression data to produce a molecular expression “map.”

The project co-investigator is Elizabeth Scoville, MD, MSCI, assistant professor of Medicine. Collaborators include Yu Shyr, PhD, the Harold L. Moses Professor of Cancer Research and chair of the Department of Biostatistics; David Schwartz, MD, professor of Medicine; and M. Kay Washington, MD, PhD, professor of Pathology, Microbiology & Immunology.

“I’ve been doing IBD research for more than 29 years,” said Wilson, a professor in the Departments of Medicine and Pathology, Microbiology & Immunology, “but there is no way we could have ever submitted this important grant without our Vanderbilt colleagues.”

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