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Hans Clevers is Head of pharma Research and Early Development (pRED) of Roche, Basel Switzerland, since March 2022. He was group leader at the Hubrecht Institute from 2002 until March 2022 and currently he is advisor/guest researcher at the Hubrecht Institute.
The Organoid group, previously Clevers group, studies the molecular mechanisms of tissue development and cancer of various organs using organoids made from adult Lgr5 stem cells.
In 1991, we reported the cloning of a T cell specific transcription factor that we termed TCF1 (1). Related genes exist in genomes throughout the animal kingdom. We have shown in frogs (4), flies (7) and worms (11) that the TCF proteins constitute the effectors of the canonical Wnt pathway. Upon Wnt signaling, ß-catenin binds and activates nuclear TCFs by providing a trans-activation domain. For these studies, we designed the widely used pTOPFLASH Wnt reporters. In the absence of Wnt signaling, we found that Tcf factors associate with proteins of the Groucho family of transcriptional repressors to repress target gene transcription (9).
The tumor suppressor protein APC forms the core of a cytoplasmic complex which binds ß-catenin and targets it for degradation in the proteasome. In APC-deficient colon carcinoma cells, we demonstrated that ß-catenin accumulates and is constitutively complexed with the TCF family member TCF4, providing a molecular explanation for the initiation of colon cancer (5).
In mammals, physiological Wnt signaling is intimately involved with the biology of adult stem cells and self-renewing tissues (18,19). We were the first to link Wnt signaling with adult stem cell biology, when we showed that TCF4 gene disruption leads to the abolition of crypts of the small intestine (8), and that TCF1 gene knockout severely disables the stem cell compartment of the thymus (2). The Tcf4-driven target gene program in colorectal cancer cells is the malignant counterpart of a physiological gene program in selfrenewing crypts (13, 14).
Amongst the intestinal Wnt target genes (13), we found the Gpr49/Lgr5 gene to be unique in that it marks small cycling cells at crypt bottoms. These cells represent the epithelial stem cells of the small intestine and colon (23), the hair follicle (24), the stomach (28) and many other tissue stem cell types. The cells also represent the cells-of-origin of adenomas in the gut (25) and within adenomas Lgr5 stem cells act as adenoma stem cells (36). Lgr6 marks multipotent skin stem cells (29).
The Wnt target gene encoding the transcription factor Achaete scute-like 2 controls intestinal stem cell state (26). Lgr5 crypt stem cells behave in unanticipated ways: Against common belief, they divide constantly and in a symmetric fashion. Stem cells numbers remain fixed because stem cells compete ‘neutrally’ for niche space (30). This phenomenon was confirmed by in vivo imaging (44). Daughters of the small intestinal stem cells, the Paneth cells, serve as crypt niche cells by providing Wnt, Notch and EGF signals (33). The transcriptional hierarchy of the various enteroendocrine lineages was mapped in mouse and man (58, 66).
Lgr5 resides in Wnt receptor complexes and mediates signaling of the Wnt-agonistic R-spondins (31), explaining the unique dependence of Lgr5 stem cells on secreted R-spondins in vivo and in vitro. Two other Wnt target genes, RNF43 and ZNRF3, encode stem cell-specific E3 ligases that downregulate Wnt receptors in a negative feedback loop (35). Independent work by the Feng Cong lab has first shown that R-spondin, when bound to Lgr5, captures and inactivates RNF43/ZNRF3.
Wnt signaling intimately interacts with the BMP and Notch cascades to drive proliferation and inhibit differentiation in intestinal crypts and adenomas (17, 20). Based on these combined insights, we have established Lgr5/R-spondin-based culture systems that allow the outgrowth of single mouse or human Lgr5 stem cells into ever-expanding organoids. Some examples are mini-guts (27, 32), mini-stomachs (28), colon cancer organoids (32, 47), liver organoids (39, 46, 55), prostate organoids (45), breast cancer organoids (53), ovarian cancer organoids (59), pancreas cancer organoids (48), and even snake venom gland organoids (61). These epithelial organoid cultures are genetically and phenotypically extremely stable, allowing transplantation of the cultured offspring of a single stem cell, as well as disease modeling by growing organoids directly from diseased patient tissues (32, 47, 53). The direct cloning of multiple individual cells from primary tumors allows molecular and functional analysis of tumor heterogeneity with unprecedented resolution (54).
Human organoids allow functional analyses of rare cell types, such as enteroendocrine cells (66). They are readily amenable to CRISPR-mediated genome modification to model for instance malignant transformation (49) and mutagenesis upon faulty DNA repair (52), or to rapidly create knock-in alleles of genes of interest (62, 66). Human rectal organoids model the hereditary disease Cystic Fibrosis, are now routinely used to predict drug response in CF patients. In 2013, we have provided the first proof-of-concept for CRISPR-mediated repair of a hereditary mutation in patient stem cells (43, 64). Human organoids also model infectious disease, as demonstrated for instance for Cryptosporidium (55), a mutagenic E. coli strain (63) and for SARS-CoV-2 (65).
In a collaboration with the Cystic Fibrosis clinic in Utrecht, a functional assay was established for the CFTR channel using rectal organoids. Forskolin opens the CFTR channel, resulting in rapid swelling of normal organoids. As proof-of-concept, the CFTR locus was repaired in single gut stem cells from two Cystic Fibrosis patients, using CRISPR/Cas9 technology in conjunction with homologous recombination. Repaired stem cells were clonally expanded into mini-guts and shown -in a swelling assay- to contain a functional CFTR channel (43). The organoid-based swelling assay has meanwhile become clinical practice in the Netherlands to identify and treat patient with rare mutations that respond to the Vertex drugs (“Cystic Fibrosis Patients benefit from Mini Guts”. A. Saini, Cell Stem Cell 2016). To this end, we founded the non-for-profit HUB foundation which currently builds a biobank of all 1500 Dutch CF patients funded by our national insurance companies. The HUB also maintains large biobanks of colon-, breast-, lung- and pancreas cancer organoids, accessible by academia and industry.
Finally, organoids (as first described by Sasai for pluripotent stem cells and by us for adult stem cells) are rapidly gaining ground as research tools in a wide range of scientific disciplines including basic developmental and cell biology, infectiology, toxicology and research on hereditary diseases and cancer.
In this video, Hans Clevers summarizes the use of organoids in cancer research.
Lohmussaar K, Oka R, Espejo Valle-Inclan J, Veersema S, [...] van Boxtel R, Clevers H
Bannier-Hélaouët M, Post Y, Korving J [...] Imhoff S, Clevers H
Lamers MM, Beumer J, van der Vaart J [...] Haagmans, BL, Clevers H
Post Y, Puschhof J, Beumer B [...] Casewell NR, Clevers H
Beumer J, Puschhof J, Bauzá-Martinez [...] Wu, W and Clevers H
Artegiani B, Hendriks D, Beumer J [...] Tans, S and Clevers, H
Geurts, MH de Poel E, Amatngalim, GD [...}, Beekman, JM and Clevers, H
Pleguezuelos-Manzano C, Puschhof J, Rosendahl A [...] van Boxtel R, Clevers H
Kopper O, de Witte, CJ [...] Kloosterman WP, Clevers H
Schutgens F, Rookmaaker MB [...] Verhaar MC, Clevers H
Gehart H, van Es J, [...] Rios A, and Clevers H
Hu H, Gehart H [...] de Jong YP, Clevers H
Roerink SF, Sasaki N [...] Stratton MR, Clevers H
Sachs N, de Ligt J [...] Cuppen E, Clevers H
Drost J, van Boxtel R [...] Cuppen E, Clevers H
Drost, J, van Jaarsveld, R.H., Ponsioen, B., Zimberlin, C., van Boxtel, R., Buijs, A.,Sachs, N., Overmeer, R.M., Offerhaus, G.J., Begthel, H. Korving, J., van de Wetering, M., Schwank, G. Logtenberg, M., Cuppen, E., Snippert, H.J., Medema, J.P., Kops, G. J. P. L., Clevers, H.
Farin, H.F., Jordens, I., Mosa, M.H., Basak, O., Korving, J., Tauriello, D.V.F., de Punder, K., Angers, S., Peters, P.J. Maurice, M.M. and Clevers, H.
van de Wetering, M., Francies, H.E., Francis, J.M., Bounova, G., Iorio, F., Pronk, A., ... Garnett, M.J., Clevers, H.
Boj, S.F., Hwang, C.I., Baker, L.A., Chio, I.I., Engle, D.D., ..., Clevers, H, Tuveson, D.A.
Huch, M., Gehart, H., van Boxtel, R., Hamer, K., Blokzijl, F., Verstegen, M.A., Ellis, E., van Wenum, M., Fuchs, S., de Ligt, S., van de Wetering, M., Sasaki, N., Boers, S.J., Kemperman, H., de Jonge, J., Ijzermans, J.N.M., Niewenhuis, E.E.S., Hoekstra, R., Strom, S., Vries, R.G.J., van der Laan, L.J.W., Cuppen, E., Clevers, H.
Karthaus, W.R., Iaquinta, P.J., Drost, J., Gracanin, A.., van Boxtel, R., Wongvipat, J., Dowling, C.M., Gao, D., Begthel, H., Sachs, N., Vries, R.G., Cuppen, E., Chen, Y., Sawyers, C.L., Clevers, H.
Ritsma, L., Ellenbroek, S.I., Zomer, A., Snippert, H.J., de Sauvage, F.J., Simons, B.D., Clevers, H., van Rheenen, J.
Schwank, G., Koo, B.K., Sasselli, V., Dekkers, J.F., Heo, I., Demircan, T., Sasaki, N., Boymans, S., Cuppen, E., van der Ent, C.K., Nieuwenhuis, E.E., Beekman, J.M. and Clevers, H.
Stange, D.E., Koo, B.K., Huch, M., Sibbel, G., Basak, O., Lyubimova, A.,Kujalla, P., Bartfeld, S., Koster, J., Geahlen, J.H., Peters, P.J., van Es, J., van de Wetering, M., Mills, J.C., Clevers, H.
Sato, T., Clevers, H.
Huch M., Dorell, C., Boj, S.F., van Es, J.H., van de Wetering, M., Li, V.S.W., Hamer, K., Sasaki, N., Finegold, M.J., Haft, A., Grompe, M., Clevers, H.
Boj, S,F., van Es, J.H.,Huch. M., Li, V.S., Jose, A., Hatzis, P., Mokry, M., Haegebarth, A., van den Born, M., Chambon, P., Voshol, P., Dor, Y., Cuppenm E., Fillat, C., Clevers, H.
van Es, J.H., Sato, T., van de Wetering, M., Lyubimova, A., Yee Nee, A.N., Gregorieff, A., Sasaki, N., Zeinstra, L., van de Born, M., Korving, J., Martens, A.C., Barker, N., van Oudenaarden, A., Clevers, H.
Schepers, A.G., Snippert, H.J., Stange, D.E., van den Born, M., van Es, J.H., van de Wetering, M., Clevers, H.
Koo, B-K., Spit, M. Jordens, I., Low, T.Y., Stange, D.E., van de Wetering, M., van Es, J.H., Mohammed, S., Heck, A.J.R., Maurice, M.M. and Clevers, H.
de Lau, W., Barker, N., … and Clevers, H.
Li, V.S., Ng, S.S., Boersema, P.J., Low, T.Y., Karthaus, W.R., Gerlach, J.P., Mohammed, S., Heck, A.J., Maurice, M.M., Mahmoudi, T. and Clevers, H.
Snippert, .J., van der Flier, L.G., Sato, T., van Es, J.H., van den Born, M., Kroon-Veenboer, C., Barker, N.,Klein, A.M., van Rheenen, J. Benjamin D. Simons, B.D. and Clevers, H.
Sato, T., van Es, J.H., Snippert, H.J., Stange, D.E., Vries, R.G., van den Born, M., Barker, N., Shroyer, N.F., van de Wetering, M., Clevers, H.
Snippert, H.J., Haegebarth, A., Kasper, M., Jaks, V., van Es, J.H., Barker, N., van de Wetering,
M., van den Born, M., Begthel, H., Vries, R.G., Stange, D.E., Toftgård, R., Clevers, H.
Barker, N, Huch, M., …, and Clevers, H.
Sato, T., Vries, R., Snippert, H., van de Wetering, M., Barker, N., Stange, D., van Es, J., Abo, A., Kujala, P., Peters, P., and Clevers, H.
van der Flier, L.G., van Gijn, M.E., .., and Clevers, H.
Barker N., Ridgway R.A., van Es J.H.,van de Wetering M., Begthel H., van den Born M., Danenberg E., Clarke A.R., Sansom O.J., Clevers, H.
Jaks V., Barker N., Kasper M., van Es J.H., Snippert H.J., Clevers H., Toftgård, R.
Barker, N, van Es, J.H., Kuipers, J., Kujala P., van den Born, M., Cozijnsen, M., Korving, J., Begthel, H., Peters, P.C., and Clevers, H.
Batlle E., Bacani J., Begthel H., Jonkheer S., Gregorieff A., Van de Born M., Malats N., Sancho E., Boon E., Pawson T., Gallinger S., Pals S., Clevers, H.
Van Es J.H., Van Gijn M.E., Riccio O., Van den Born M., Vooijs M., Begthel H., Cozijnsen M., Robine S., Winton D.J., Radtke F., Clevers, H.
Reya T., Clevers H.
Radtke, F and Clevers, H.
Haramis A.P., Begthel H., van den Born M., van Es J., Jonkheer S., Offerhaus G.J., Clevers H.
Baas A.F., Kuipers J., van der Wel N.N., Batlle E., Koerten H.K., Peters P.J., Clevers H.C.
Hurlstone A.F., Haramis A.P., Wienholds E., Begthel H., Korving J., Van Eeden F., Cuppen E., Zivkovic D., Plasterk R.H., Clevers H.
Battle, E., Henderson, J.T., Beghtel, H., van den Born, M., Sancho, E., Huls, G., Meeldijk, J., Robertson, J., van de Wetering, M., Pawson, T., Clevers, H.
Van de Wetering, M., Sancho, E., Verweij, C., de Lau, W., Oving, I., Hurlstone, A., Van der Horn, K., Batlle, E., Coudreuse, D., Haramis, A-P., Tjon-Pon-Fong, M., Moerer, P., Van den Born, M., Soete, G., Pals, S., Eilers, M., Medema, R., Clevers, H.
Bienz, M., and Clevers, H.
Korswagen, R., Herman, M. and Clevers, H.
Roose, J., Huls, G., van Beest, M., Moerer, P., van der Horn, K., Goldschmeding, R., Logtenberg, T., and Clevers, H.
Roose, J., Molenaar, M., Peterson, J., Hurenkamp, J., Brantjes, H., Moerer, P., van de Wetering, M., Destree, O., and Clevers, H.
Korinek, V., Barker, N., Moerer, P., van Donselaar, E., Huls, G., Peters, P.J. and Clevers, H.
Van de Wetering, M., Cavallo, R., Dooijes, D., Van Beest, M., Van Es, J., Loureiro, J., Ypma, A., Hursh, D., Jones, T., Bejsovec, A., Peifer, M., Mortin, M., and Clevers, H.
Morin, P.J., Sparks, A., Korinek, V., Barker, N., Clevers, H., Vogelstein, B., and Kinzler, K.
Korinek, V, Barker, N., Morin, P.J., van Wichen, D., de Weger, R., Kinzler, K.W., Vogelstein, B., and Clevers, H.
Molenaar, M., Van de Wetering, M., Oosterwegel, M., Peterson-Maduro, J., Godsave, S., Korinek, V., Roose, J., Destrée, O. And Clevers, H.
Schilham, M., Oosterwegel, M., Moerer, P., Jing Ya, de Boer, P., van de Wetering, M., Verbeek, S., S., Lamers, W., Kruisbeek, A., Cumano, A., and Clevers, H .
Verbeek, J.S., Ison, D., Hofhuis, F., Robanus-Maandag, E., te Riele, H., van de Wetering, M., Oosterwegel, M., Wilson, A., MacDonald, H.R. and Clevers, H.C.
van de Wetering, M., Oosterwegel, M., Dooijes, D., and Clevers, H.C
The Organoid group, previously Clevers group, studies the biology of Wnt signaling in tissue turnover and in cancer. The discovery of Lgr5 as a generic marker of Wnt-dependent stem cells within multiple adult tissues has led to the development of technology to grow these stem cells into ever-expanding epithelial organoids. These organoids recapitulate many aspects of their tissue of origin and allow the study of a multitude of physiological and pathological processes. Patient-derived organoids hold promise to predict drug response in a personalized fashion and open up new avenues for regenerative medicine and, in combination with genome editing technology, for gene therapy.
Scientific training and positions
1985 – 1989 Postdoctoral Fellow, Cox Terhorst Lab at the Dana-Farber Cancer Institute, Boston MA, USA
1989 – 1991 Assistant Professor, Department of Clinical Immunology, University of Utrecht
1991 – 2002 Professor and Chairman, Dept. of Immunology, Faculty of Medicine, University of Utrecht
2002 – 2012 Director Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences
2002 – 2020 Professor in Molecular Genetics at University Medical Center Utrecht
2002 – present Principal Investigator of a research group of ~40 scientists at Hubrecht Institute, Utrecht
2012 – 2015 President of the Royal Netherlands Academy of Sciences (KNAW), Amsterdam
2014 – 2020 Chief Scientific Officer of HUB Organoids Technology, Utrecht
2015 – 2019 Chief Scientific Officer/Director Research of the Princess Máxima Center, Utrecht
2015 – present Principal Investigator at the Princess Máxima Center, Utrecht
2017 – present Oncode Investigator
2020 – present University Professor at University Utrecht
2000 Catharijne prize for medical research
2001 Award from the European Society for Clinical Investigation
2001 Spinoza Award of the Netherlands Research Council (NWO)
2004 Louis-Jeantet Prize for Medicine, Geneva, Switzerland
2005 The Science and Society Prize, Amsterdam
2005 The French honor of “Chevalier de la Legion d’Honneur”
2005 Katharine Berkan Judd Award, New York
2006 Rabbi Shai Shacknai Memorial Prize for Immunology and Cancer Research, Jerusalem
2008 Josephine Nefkens Prize for Cancer Research (Erasmus MC, Rotterdam)
2008 Meyenburg Cancer Research Award, Germany
2009 The Queen Wilhelmina Dutch Cancer Society Award, Amsterdam
2010 The United European Gastroenterology Federation (UEGF) Research Prize
2011 The Ernst Jung Medical Award, Germany
2011 Kolff prize, Amsterdam
2012 Association pour la Recherche sur le Cancer (ARC) Léopold Griffuel Prize, Paris
2012 William Beaumont prize of the American Gastroenterology Association
2012 The Heineken Prize for Medicine
2012 Knight in the Order of the Netherlands’ Lion
2013 The Breakthrough Prize in Life Sciences
2013 International Dream Team (with Hans Bos) by Dutch Cancer Society (KWF)
2014 Massachusetts General Hospital Award in Cancer Research
2014 TEFAF Oncology Chair 2014, Maastricht
2014 Fellow of the AACR Academy
2014 Struyvenberg European Society for Clinical Investigation (ESCI) medal
2014 National Icon of the Netherlands
2015 ISSCR-McEwen Award for Innovation
2016 The Academy Professor Prize of the Royal Netherlands Academy
2016 Kazemi Award for Research Excellence in Bio-Medicine
2016 The Körber European Science Prize, Germany
2016 Swammerdam medal, Amsterdam
2016 The Ilse & Helmut Wachter award, Hamburg, Germany
2017 Princess Takamatsu Award of Merit, Tokyo
2018 Großes Verdienstkreuz mit Stern, Germany
2018 Academia Europaea Erasmus Medal, Barcelona, Spain
2019 Honorary Fellow of the Royal Society of Edinburgh (UK)
2019 Keio Medical Science Prize of the Keio University (Japan)
2019 Citation Laureate, Web of Science Group
2008 – 2015 Louis Jeantet Prize, Geneva
2013 – 2015 Canada Gairdner Award, Toronto
2014 – present Breakthrough Prize in Life Sciences, San Francisco
2015 Pezcoller Foundation – AACR International Award for Cancer Research, Italy
2015 Dr. Paul Janssen Award, Bruxelles
2017 – present Francqui Prize, Bruxelles
2017 – present Shaw Prize, Hong Kong
2017 Kovalenko Medal, National Academy of Sciences Washington
2002 – present Central South University, Chang Sha, China
2014 – 2015 TEFAF Oncology Chair, Maastricht
2015 – 2016 Visiting professor, Weizmann Institute, Rehovoth, Israel
2016 – present Distinguished Visiting Professor, University of Hong Kong
2015 – present Visiting professor, University of Melbourne, Australia
2019 – present Honorary Director, Fudan Organoid Center, Fudan University, Shanghai
2019 – present Foreign Advisory Board Member of Consortium for Neogenetic Medicine, Tokyo
1999 Member European Molecular Biology Organisation (EMBO)
2000 Member of the Royal Netherlands Academy of Sciences (KNAW)
2009 Member of the Academia Europaea
2012 Member of the American Academy of Arts and Sciences
2012 Member of the Royal Netherlands Society of Sciences and Humanities
2014 Member of the National Academy of Sciences of the USA
2016 Member of the Academie des Sciences de I’Institut de France
2017 Member of the Orden Pour le Mérite für Wissenschaften und Künste, Germany
2019 Foreign Member of the Royal Society, London, United Kingdom
2019 Honorary Fellow of the Royal Society of Edinburgh, Scotland
2005 – 2015 Member Scientific Advisory Board of Swiss Institute for Experimental Cancer Research, Lausanne
2006 – 2008 President of the International Society of Differentiation (ISD)
2007 – 2010 Member of the National Scientific Advisory Board NKI-AVL, Amsterdam
2012 – 2015 Member of the Board of the American Association of Cancer Research
2015 – 2021 Member of the Scientific Advisory Board of the Institute of Molecular Pathology, Vienna
2016 – 2020 Member of the Scientific Advisory Board of Kallyope, New York
2016 – present Member of the Scientific Advisory Board of the Francis Crick Institute, London
2016 – 2021 Member of the Scientific Advisory Board of Decibel Therapeutics, Boston
2016 – present Member of the Scientific Advisory Board of Surrozen, San Francisco
2017 – 2018 President of the International Society for Stem Cell Research (ISSCR)
2018 – 2021 Member of the Scientific Advisory Board of Merus, Utrecht
2018 – present Scientific advisor Life Science Partners, Amsterdam
2019 – present Non-executive member of the Board of Directors of Roche Holding Ltd, Basel
2020 – 2021 Member of the Scientific Advisory Board of Volestra Therapeutic Inc., New York
2020 – present Chair of the Scientific Advisory Board DImed Inc., Shanghai
2020 – present Chair of the Scientific Advisory Board of Xilis, at Duke University (NC)
Unsalaried advisory positions
Hans Clevers is advisor/guest researcher at the Hubrecht Institute and the Princess Máxima Center for Pediatric Oncology and Oncode Investigator. He was group leader at the Hubrecht Institute from 2002 until March 2022. Clevers’s research group has spun out a non-profit CRO organization, HUB, with roughly 50 employees. Hans Clevers was scientific advisor to the HUB from 2013-2020. He also fills rotating positions in international ‘Learned Societies’ (e.g. ISSCR, AACR), Award Juries (e.g. Francqui Prize, Brussels; Breakthrough Prize, San Francisco) and in Scientific Advisory Boards (SABs) of various academic institutions (e.g. Crick Institute, London).
Hans Clevers is Head of pharma Research and Early Development (pRED) of Roche, Basel Switzerland.
Acting group leader
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