Ibec Seminar: Hans Clevers
Human organoids model disease in 3D and in 2D
Hans Clevers, MD, PhD , Professor of Molecular Genetics, Utrecht University
The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We originally defined Lgr5 as a Wnt target gene, transcribed in colon cancer cells. Two knock-in alleles revealed exclusive expression of Lgr5 in cycling, columnar cells at the crypt base. Using lineage tracing experiments in adult mice, we found that these Lgr5+ve crypt base columnar cells (CBC) generated all epithelial lineages throughout life, implying that they represent the stem cell of the small intestine and colon. Lgr5 was subsequently found to represent an exquisitely specific, yet ‘generic’ marker for active epithelial stem cells, including in hair follicles, kidney, liver, mammary gland, inner ear tongue and stomach epithelium.
Single sorted Lgr5+ve stem cells can initiate ever-expanding crypt-villus organoids, or so called ‘mini-guts’ in 3D culture. The technology is based on the observation that Lgr5 is the receptor for a potent stem cell growth factor, R-spondin. Similar 3D cultures systems have been developed for the Lgr5+ve stem cells of human stomach, liver, pancreas, prostate and kidney. Using CRISPR/Cas9 technology, genes can be efficiently modified in organoids of various origins. Organoid technology opens a range of avenues for the study of development, physiology and disease, for drug development and for personalized medicine. In the long run, cultured mini-organs may replace transplant organs from donors and hold promise in gene therapy.
About Hans Clevers:
Hans Clevers characterized the molecular effectors of the Wnt pathway: the TCF transcription factors. His group described the role of Wnt in (intestinal) stem cell biology and cancer, eventually leading to the discovery of LGR5 as a novel stem cell marker. This eventually led him to pioneer tissue stem cell based organoids, 3-dimensional in vitro structures that behave anatomically and molecularly like the organ from which they are derived. Organoid biology has revolutionized the way we approach human biology.
Hans Clevers obtained his MD and PhD degrees from the University of Utrecht, the Netherlands. He holds a professorship in Molecular Genetics from the University of Utrecht. He previously held directorship/president positions at the Hubrecht Institute, the Royal Netherlands Academy of Arts and Sciences and the Princess Maxima Center for pediatric oncology. He has served in the Supervisory Board (2019-2022) and as head of Roche’s Pharma Research & Early Development (pRED; 2022-2025). During this time, he oversaw the establishment of Roche’s Institute of Human Biology (IHB) in Basel. He currently supervises his research groups at the Hubrecht Institute and the Princess Máxima Center.
He is the recipient of multiple international scientific awards, including the Breakthrough Prize in Life Science. Hans Clevers is a member of the Royal Netherlands Academy of Arts and Sciences (NL), the National Academy of Sciences (USA), the Royal Society (UK) and the Academie des Sciences (France). He is also Chevalier de la Légion d’Honneur and Knight in the Order of the Netherlands Lion, among many other international accolades.
