Hans Clevers

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Johannes Carolus (Hans) Clevers (born 27 March 1957) is a professor in molecular genetics, a geneticist, physician, medical researcher who was the first to identify stem cells in the intestine and is one of the world's leading researchers on normal stem cells and their potential for regenerative therapy.[1] Clevers obtained his Ph.D. in 1985 at Utrecht University and was a professor in immunology there between 1991 and 2002. He received the Spinoza Prize in 2001 and became director of the Hubrecht Institute in 2002. In March 2012, he was elected as is the president of the Royal Netherlands Academy of Arts and Sciences and succeeded Robbert Dijkgraaf in June 2012.[2] In 2013 he was awarded the $3 million Breakthrough Prize in Life Sciences for his work. In a subsequent interview, he said it was a 'great honour' to be the only researcher in Europe awarded.[3]

Early life and education[edit]

Hans Clevers began studying biology at the University of Utrecht in 1975, then began studying medicine as well. He spent part of his seven years of biological study in Nairobi, Kenya, and also, in his words, “did some rotations” at the National Institutes of Health in Bethesda. He received an M.Sc. in Biology in 1982, an M.D. in 1984 and a Ph.D. in 1985. From 1986 to 1989 he did postdoctoral work under the direction of Cox Terhorst at the Dana-Farber Cancer Institute at Harvard University. It was there that Clevers cloned the T-cell gene CD3 epsilon. After his stint at Harvard, he returned to the Netherlands. Describing his path to his career as a medical researcher, Clevers said the following: “There was a bit of an awkward route. I actually studied biology first, and then took up medical school at about the same time....Did two separate studies, graduated from both, was going to be a pediatrician, then decided to spend a year in science, liked it so much more that I realized I didn’t – I shouldn’t become a real doctor. I was not good with – I liked patients, but I was a little bit impatient with them. I then decided to go for a post-doc at Boston to Dana Farber, where I really learned the trade.”[4][5][6][7][8]

Career[edit]

In 1991 Clevers became a professor of immunology at the University Medical Center in Utrecht. Since 2002 he has been a professor of molecular genetics at UMC Utrecht. Also in 2002 he became director of the Hubrecht Institute for Developmental Biology and Stem-Cell Research at the Royal Dutch Academy of Sciences, where until May 2012 he led the WNT Signaling and Cancer research group and was project leader of the Netherlands Proteomics Centre and Cancer Genomics Centre. Clevers discovered similarities between the normal renewal of intestinal tissue and the onset of colon cancer. In 2007 he received a grant of two million euros from the KWF Cancer Society to study the function of stem cells in the normal intestines and in colon cancer, and in 2008 he received an ERC Advanced Investigator Grant. In March 2012, Clevers, who since 2000 had been a member of the Royal Netherlands Academy of Arts and Sciences, was elected its president, a position he assumed on June 1 of that year, succeeding Robbert Dijkgraaf. In connection with his election to this position, he resigned from the Hubrecht Institute and began to carry out research two days a week at the UMC-U.[4][5][6][7][9]

Research[edit]

Highlights of research[edit]

Asked in a 2008 interview what had been the highlights of his research up to that point, Clevers said “there would probably be three. There was a first one, when I just started my lab, within the first few months we cloned the gene that they call TCF1, t-cell factor 1, I used to be a t-cell embryologist when we first started out. And that paper was published in EMBO in ’91, first author. So in that paper we described cloning of this vector, which at that time maybe on the world scale was not great but for my own lab to clone this gene was my first thing I ever did alone. This gene then in ’96 we found to be the crucial missing component of what’s called the Wnt signaling pathway, and this [was] generally seen as a major breakthrough we had. There were papers in ’96 and ’97 in Cell, and we had two papers in Science in the same two years.”

Clevers and his team thus showed that “there is that this TCF transcription factor, there is a small family of them, they occur in every animal on the planet, they are the end point of the signal transcription cascade, and they control virtually every decision in a developing animal. When we realized this we started changing our model systems, we used to work on lymphocytes, and we changed it, first to frogs and flies, drosophila, where the Wnt pathway had been studied by many other people that way we could use assays of those people. We then realized that in mammals Wnt signaling...was not only important in embryos but also crucial in adults, which is novel. And we switched to the gut, we found that one of our knockouts, the TCF4 knockout, one of the four members of that family had no stem cells in the gut. And this is the first link in the literature, this was also a ’97 paper in Nature Genetics, between Wnt signaling and stem cells in adults. And in that same year we found that colon cancer comes about by the disregulation of TCF4, and those two phenomena are really linked. So stem cells need TCF4, cancers disregulate TCF4 by mutating a gene upstream in that pathway called APC.”

After this Clevers's team “continued to work on the intestine and on the physiology of the intestine, which was essentially an unstudied field, much to my surprise. May I emphasize, there are thousands of very competent embryologists, and they work on tiny details, and they fight over the smallest details, are extremely competent. In this intestinal field there are thousands of gastroentromologists that study cancer or colitis or Crohn’s Disease, but there are very few, if any, labs studying normal tissue, which is amazing because that is a tissue that we use every five days. It’s the most rapidly proliferating tissue in a normal body. So my lab actually build up a lot of mouse models and we learn a lot about how that’s being done, and then finally...last year we finally identified the stem cells in the gut. And we now can purify them in large numbers and study their characteristics.”[4]

A recent posting at the website of the Royal Netherlands Academy of Arts and Sciences provides a capsule summary of Clevers's research to date: “His research deals with the intestine, in both its healthy and diseased state. He has discovered that there are numerous similarities between the normal process whereby intestinal tissue is renewed and the development of intestinal cancer. Improved understanding of these processes is crucial to developing new ways of treating cancer. Hans Clevers has described the molecular signalling pathways that are disrupted by cancer and has identified a protein that is specific to stem cells in the intestine. He has then been able to grow 'mini-intestines' from individual stem cells. These are the first steps on the road to regenerative medicine, in this case the regeneration of intestinal tissue.”[7]

Barrett's esophagus[edit]

In 2008, Clevers described his work on Barret's esophagus as follows: “Barret’s Esophagus is a disease ...where stomach contents move back into the esophagus. They are very acidic, they have lots of enzymes, and they will cause erosion of the epithelium, and this epithelium slowly converts, for unknown reasons, into a lining that looks much colon epithelium. And this is the large intestine, which is what my lab studies. And we know exactly how to drive these proliferating cells so they ultimately become cancer cells. We know exactly how to drive them out of [their] stem cell state into a differentiated state.” This involved the use of a drug that has been developed by many pharmaceutical companies for Alzheimer's but that invariably fails in Alzheimer's treatments “because of problems in the gut.”

Clevers's team investigated this process and discovered “that these inhibitors of an enzyme called Gamma Secretase which produces the plaque in Alzheimer’s, the very same enzyme is active as a key component of an arch pathway, so when you try to block the Alzheimer’s process you also block arch signal. And the only tissue in an adult organism of mammal that’s sensitive to blocking arch signals is the intestinal epithelium. So with these Alzheimer’s drugs you cure Alzheimer, at least it works well for Alzheimer, but you drive all the stem cells in the gut to become goblet cells, mucus producing cells. Which is a side effect that probably will not allow these drugs to ever be commercially exploited for Alzheimer’s. But we are applying them locally now in the esophagus to these Barret’s lesions and there we have the same effect. So all proliferative stem cells of the bad tissues, of the Barret’s tissue, converts into goblet cells and they basically disappear in one big glob of slime. And then what’s left is the normal epithelium.”[4]

Other professional activities[edit]

Clevers holds a dozen patents and was involved in the establishment of the biotech firm Ubisys, which, with Ton Logtenberg as CEO, later merged with Introgene to become Crucell. Clevers also played a key role in the founding of Semaia Pharmaceuticals, which was later acquired by Hybrigenics SA. Until taking up his position as president of the Royal Netherlands Academy of Arts and Sciences, he resigned his positions as scientific adviser to two Dutch biotechnology investment firms, Aglaia Biomedical Ventures B.V. and Life Sciences Partners B.V. He also resigned his position as director of Agamyxis, his own start-up company; his founder’s shares are now being administered by a trust office.

He is an editor of EMBO Journal, EMBO Reports, Cell, Gastroenterology, and other journals.[4][5][6][7][9]

He is an official advisor to the ISREC Foundation in Lausanne, Switzerland; the Max Delbrück Center for Molecular Medicine in Berlin; the Institute for Research in Biomedicine in Barcelona; the Netherlands Cancer Institute (NKI); Cancer Research Centre of Lyon; and the Vesalius Research Center in Leuven.[6] He is also an honorary professor at Central South University in Changsha, Hunan, China.[7]

With Eduard Batlle of IRB Barcelona, Clevers co-organized the Barcelona BioMed Conference on “Normal and Tumour Stem Cells” in November 2012, where the function of stem cells in cancer was discussed by 21 world experts and 130 other participants. “In 2007 we held the first Barcelona BioMed Conference on this topic,” said Clevers. “At the time there was only very preliminary data on the relationship between stem cells and cancer. Five years on, many convincing data have emerged to indicate that the majority of tumours are indeed fed by tumour stem cells.”[1]

Honors and awards[edit]

Clevers has been recognized on a number of occasions for his research:

  • 1999: Elected EMBO member
  • 2000: Elected Royal Netherlands Academy of Arts and Sciences member
    • Catharijne-prize for medical science
  • 2001: Award from the European Society for Clinical Investigation
    • Spinoza Award (Netherlands)
  • 2004: Louis-Jeantet Prize for Medicine (Switzerland)
    • Named Chevalier of the Legion d'Honneur (France)
  • 2005: Memorial Sloan-Kettering Katharine Berkan Judd Award (U.S.)
    • Science and Society Prize
  • 2006: Rabbi Shai Shacknai Memorial Prize for Immunology and Cancer Research (Israel)
  • 2008: Josephine Nefkens Prize for Cancer Research from Erasmus MC Rotterdam (Netherlands)
    • Meyenburg Cancer Research Award (Germany)
  • 2009: Dutch Cancer Society Award
  • 2010: United European Gastroenterology Federation (UEGF) Research Prize
  • 2011: Ernst Jung Prize for Medicine from the Jung Foundation for Science and Research (Germany)
  • 2012: Léopold Griffuel Prize from Association pour la Recherche sur le Cancer (France)
  • 2013: Breakthrough Prize in Life Sciences
  • 2014: Massachusetts General Hospital Award in Cancer Research
  • 2014: TEFAF Oncology Chair 2014
  • 2014: Fellow of the AACR Academy
  • 2014: Struyvenberg European Society for Clinical Investigation (ESCI) medal

The Dr. A.H. Heineken Prize for Medicine, awarded by the Royal Netherlands Academy of Arts and Sciences, was presented to Clevers “for his unique understanding of how tissue growth is regulated, both in normal development and in cancer.”[9]

Major publications[edit]

Clevers has more than 415 publications to his name and has been cited a total of more than 47,000 times. His h-index is 104. Some of his most important publications are:

  • van de Wetering, M., Oosterwegel, M., Dooijes, D., and Clevers, H.C. Identification and cloning of TCF-1, a T cell-specific transcription factor containing a sequence-specific HMG box. EMBO J. 10:123-132 (1991)
  • 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. An HMG box containing T-cell factor required for thymocyte differentiation. Nature 374: 70-74 (1995)
  • 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.Sox-4 gene is required for cardiac outflow tract formation and pro-B lymphocyte expansion. Nature 380: 711-714 (1996)
  • Molenaar, M., Van de Wetering, M., Oosterwegel, M., Peterson-Maduro, J., Godsave, S., Korinek, V., Roose, J., Destrée, O. And Clevers, H. Xtcf-3 Transcription factor mediates beta-catenin-induced axis formation in xenopus embryos. Cell 86: 391-399 (1996)
  • Korinek, V, Barker, N., Morin, P.J., van Wichen, D., de Weger, R., Kinzler, K.W., Vogelstein, B., and Clevers, H. Constitutive Transcriptional Activation by a beta-catenin-Tcf complex in APC-/- Colon Carcinoma. Science 275: 1784-1787 (1997)
  • Morin, P.J., Sparks, A., Korinek, V., Barker, N., Clevers, H., Vogelstein, B., and Kinzler, K. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275: 1787-1790 (1997)
  • 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. Armadillo co-activates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell 88, 789-799 (1997)
  • Korinek, V., Barker, N., Moerer, P., van Donselaar, E., Huls, G., Peters, P.J. and Clevers, H. Depletion of epithelial stem cell compartments in the small intestine of mice lacking Tcf 4. Nat Genet 19: 379 383 (1998)
  • Roose, J., Molenaar, M., Peterson, J., Hurenkamp, J., Brantjes, H., Moerer, P., van de Wetering, M., Destree, O., and Clevers, H. The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors. Nature 395: 608-612 (1998)
  • Roose, J., Huls, G., van Beest, M., Moerer, P., van der Horn, K., Goldschmeding, R., Logtenberg, T., and Clevers, H. Synergie between tumor suppressor APC and the beta-catenin/Tcf4 target gene Tcf1. Science 285: 1923-1926 (1999)
  • Korswagen, R., Herman, M. and Clevers, H. Separate beta-catenins mediate Wnt signaling and cadherin adhesion in C. elegans. Nature 406: 527-532 (2000)
  • Bienz, M., and Clevers, H. Linking colorectal cancer to Wnt signaling. Review Cell 103: 311-320 (2000)
  • 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. The beta catenin/TCF4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111: 241-250 (2002)
  • Batlle, 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. Beta- catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 111: 251-263 (2002)
  • Hurlstone, A.F., Haramis, A.P., Wienholds, E., Begthel, H., Korving, J., van Eeden, F., Cuppen, E., Zivkovic, D., Plasterk, R.H., Clevers, H. The Wnt/beta-catenin pathway regulates cardiac valve formation. Nature 425: 633-637 (2003)

References[edit]

External links[edit]