Georg Busslinger

Our research group focuses on the epithelial cell biology of human gastrointestinal organs, specifically the esophagus, stomach, and small intestine. These digestive organs perform specialized functions that work in concert to facilitate nutrient uptake and digestion. The esophagus transports ingested food to the stomach. The stomach creates a highly acidic environment to sterilize food, eliminating harmful bacteria and initiating pre-digestion. The small intestine plays a central role in nutrient digestion and absorption.

These essential functions are carried out by highly specialized gastrointestinal epithelial cell types, characterized by rapid turnover and continuous renewal during normal homeostasis. Disruption of gastrointestinal homeostasis is linked to numerous digestive diseases, many of which are common in the human population. Chronic inflammation can lead to conditions such as esophagitis, Barrett’s esophagus, gastritis, or Crohn’s disease, all of which can increase the risk of gastrointestinal cancer. Notably, esophageal and gastric cancers are particularly aggressive, with currently limited treatment options.

Gastrointestinal Organoids

The molecular functions of epithelial cells and corresponding tumor cells in gastrointestinal organs have historically been studied using animal models or, more recently, through single-cell transcriptomics in human tissues. A transformative advancement in this field has been the development of organoid cultures, which are derived from adult human epithelial stem cells and can be maintained indefinitely without the need for immortalization.

These human gastrointestinal organoids, created from either healthy tissue or tumor biopsies, preserve the cellular architecture, differentiation capacity, and epithelial cell diversity found in vivo. When combined with cutting-edge technologies such as single-cell genomics and CRISPR/Cas9 genome editing, these organoid models enable detailed functional analysis of human gastrointestinal cells and cancers at an unprecedented level of resolution.

Function of Gastrointestinal Epithelial Cell Types

Through single-cell RNA sequencing, we have recently uncovered new insights into the cellular composition and gene expression signatures of distinct epithelial cell types in the human esophagus, stomach, and duodenum. Our future research aims to functionally dissect key epithelial cell populations, such as the acid-secreting parietal cells and hormone-producing enteroendocrine cells of the human stomach, as well as newly discovered BCHE-expressing cells in the duodenum.

To achieve this, we will employ CRISPR-based genome editing to insert fluorescent markers into cell type-specific genes, enabling precise identification and isolation of these differentiated cell types within organoid cultures. We will then study their response to extracellular signals, mechanisms of action, and roles in disease pathogenesis.

Moreover, we will explore how nutrients and microbiome-derived signals influence gastric and duodenal epithelial behavior and potentially contribute to carcinogenesis. All of our projects are deeply rooted in the use of organoid technology, genome editing, and next-generation sequencing to advance understanding of human gastrointestinal biology and disease.

Georg Busslinger studied molecular biology at the University of Vienna first and then obtained his master’s degree at the ETH Zurich (Switzerland). Prior to initiating his PhD, he investigated the epigenetic regulation of the interferon response for one year in the laboratory of Alexander Tarakhovsky at the Rockefeller University in New York (USA). He subsequently joined the group of Jan-Michael Peters at the Research Institute of Molecular Pathology (IMP) in Vienna for his PhD studies and investigated the molecular mechanisms that control the localization of cohesin in the mammalian genome of non-proliferating cells. For his postdoctoral study, he joined the laboratory of Hans Clevers at the Hubrecht Institute in Utrecht (the Netherlands), where he became an expert in the field of organoid biology. He characterized the human gastrointestinal epithelia of the esophagus, stomach, and duodenum at single-cell resolution, which resulted in a molecular definition of the different cell types of these organs as well as in the identification of rare cell populations and of a novel hormone produced by enterochromaffin-like cells. Additionally, he investigated the cellular and molecular aspects of different stages of Barrett’s esophagus, a common premalignant state of esophageal adenocarcinoma. Together with doctors at UMC Utrecht, he also initiated a research study to investigate the potential of in vitro esophageal and gastric tumor organoid cultures for predicting the patient’s response in vivo to chemotherapeutic treatments. Since 2021, he has been a group leader at MedUni Vienna with a research focus on the differentiation behavior of human gastric cells, cellular aspects of inflammatory diseases along the gastrointestinal tract, and how microbes interact with the epithelial cells.

Busslinger GA et al. Molecular characterization of Barrett’s esophagus at single-cell resolution. PNAS USA. 2021 Nov 23;118(47):e2113061118. (abstract)

Busslinger GA, Weusten BLA, Bogte A, Begthel H, Brosens LAA, Clevers H. Human gastrointestinal epithelia of the esophagus, stomach, and duodenum resolved at single-cell resolution. Cell Rep. 2021 Mar 9;34(10):108819. (abstract)

Beumer J et al. High Resolution mRNA and secretome atlas of human enteroendocrine cells. Cell. 2020 Aug 20;182(4):1062-1064. (abstract)

Busslinger G.A., Lissendorp F., Franken I., van Hillegersberg R., Ruurda J., Clevers H., de Maat M. The potential and challenges of patient-derived organoids in guiding the multimodality treatment of upper gastrointestinal malignancies. Open Biol. 2020 Apr;10(4):190274. (abstract)

Holzmann J., Politi A.Z., Nagasaka K., Hantsche-Grininger M., Walther N., Koch B., Fuchs J., Dürnberger G., Tang W., Ladurner R., Stocsits R.R., Busslinger G.A., Novak B., Mechtler K., Davidson I.F., Ellenberg J., Peters J.M. Absolute quantification of cohesin, CTCF and their regulators in human cells. Elife. 2019 Jun 17;8:e46269. (abstract)

Busslinger G.A., Stocsits R.R., van der Lelij P., Axelsson E., Tedeschi, A., Galjart N., Peters, J.-M. Cohesin is positioned in mammalian genomes by transcription, CTCF and Wapl. Nature. 2017 Apr 27;544(7651):503-507. (abstract)

Ladurner R, Kreidl E, Ivanov M.P., Ekker H, Idarraga-Amado M.H., Busslinger G.A., Wutz G., Cisneros D.A., Peters J.M. Sororin actively maintans sister chromatid cohesion. EMBO J. (abstract)