Hans Clevers

Johannes Carolus (Hans) Clevers (born 27 March 1957)[3] is Principal Investigator at the Hubrecht Institute for Developmental Biology and Stem Cell Research (KNAW) and the Princess Máxima Center for Pediatric Oncology, Professor at Utrecht University and Oncode Investigator. Clevers was the first to identify living stem cells in the intestine and is one of the world's leading researchers on adult stem cells, their role in cancer and their potential for regenerative therapy.[4]

Hans Clevers
Clevers in 2012
Born (1957-03-27) 27 March 1957
Eindhoven[1]
NationalityDutch
EducationUniversity of Utrecht
Known forResearch on normal stem cells and their potential for regenerative therapy
AwardsLouis-Jeantet Prize for Medicine (2004)[2]
Breakthrough Prize in Life Sciences (2013)
Scientific career
FieldsMolecular genetics and Cell biology
InstitutionsHubrecht Institute for Developmental Biology and Stem Cell Research – Utrecht University – UMC Utrecht – The Princess Maxima Center for pediatric oncology
Doctoral advisorRudy Ballieux
Websitehttps://www.hubrecht.eu/research-groups/clevers-group/

By culturing living stem cells from the intestinal tract, he developed the first organoids: 3D-mini-organs that behave cellularly and molecularly like the organ the stem cell derived from. Organoids can now be grown from a large number of tissues and are increasingly being used to study the physiology and pathology of many human organs and to develop personalized treatments and new drugs.

Early life and education

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. For his Ph.D. he studied under Rudy Ballieux.[5][6] From 1986 to 1989 he did postdoctoral work under the direction of Cox Terhorst at the Dana-Farber Cancer Institute at Harvard University. After his stay at Harvard, he returned to the Netherlands to start his own research group at the department of Clinical immunology of the UMC Utrecht. 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.”[7][8][9]

Career

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 and Utrecht University. From 2002 to 2012 he was director of the Hubrecht Institute for Developmental Biology and Stem-Cell Research at the Royal Netherlands Academy of Arts and Sciences. In 2008 and 2015 he received ERC Advanced Investigator Grants. In 2013 he was awarded the $3 million Breakthrough Prize in Life Sciences for his work. In March 2012, Clevers, who since 2000 had been a member of the Royal Netherlands Academy of Arts and Sciences, was elected its president, succeeding Robbert Dijkgraaf. In connection with his election to this position, he resigned as director from the Hubrecht Institute but kept his research lab there.[7][8][9][10][11] From 2012–2015 he was President of the Royal Netherlands Academy of Arts and Sciences (KNAW). From 2015–2019 he was director Research of the Princess Maxima Center for paediatric oncology, located on the Utrecht Science Park close to the Hubrecht where he maintains his lab. Presently, Clevers leads research groups, at the Hubrecht Institute as well as at the Princess Maxima Center.

Research

Highlights of research

To summarise his scientific highlights, Hans Clevers identified the crucial downstream component of the Wnt signaling cascade, TCF, and the mechanism by which Wnt signals activate specific TCF target genes. With these insights and in a collaboration with Bert Vogelstein, he proposed that in APC-deficient colon cancer, it is the inappropriate activation of the Wnt pathway that transforms cells. He was the first to link Wnt signaling with adult stem cell biology, when he showed that TCF4 gene disruption leads to the abolition of crypt stem cell compartments of the gut. He went on to show that the Tcf4-driven target gene program in colorectal cancer cells is the malignant counterpart of a physiological crypt stem cell program. Clevers then described the Wnt target Lgr5 as a marker for adult stem cells and wth this, discovered the stem cells of intestinal crypts. By the creation of several ingenious Lgr5-based transgenic mice, he established the intestinal crypt as one of the pre-eminent models to visualize and study adult stem cells in mammals. He described several counter-intuitive characteristics for crypt stem cells: Lgr5 stem cells are abundant, they cycle rapidly, they divide symmetrically, and utilize their Paneth cell-daughters as their niche. He then identified the Wnt signal-enhancing Rspondins as ligands of Lgr5, and exploited the Rspondin/Lgr5 axis to develop a 3D organoid culture system for indefinite expansion of normal intestinal epithelium starting from a single adult Lgr5 stem cell. Similar results were then reported by him for multiple additional human and mouse tissues. This has opened ways to replace animal experimentation to generate disease models directly from patients as well as avenues for regenerative medicine.

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. 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.[7]

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 in a collaboration with Bert Vogelstein 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.

Other activities

Corporate boards

Clevers is inventor on multiple 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. In addition, his corporate roles include:

  • Roche, Non-Executive Member of the Board of Directors (since 2019)[12]
  • Decibel Therapeutics, Member of the Scientific Advisory Board (since 2016)[13]
  • Surrozen, Co-Founder

Editorial boards

He is on the editorial board of several scientific journals, including Cell, Cell Stem Cell, Stem Cell Reports. He is also an honorary professor at Central South University in Changsha, Hunan, China and honorary director of the organoid center of Fudan University, Shanghai.

Non-profit organizations
  • Francis Crick Institute, Member of the Scientific Advisory Board
  • Research Institute of Molecular Pathology (IMP), Member of the Scientific Advisory Board

Honors and awards

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

Publications

Clevers has more than 700 publications to his name and has been cited a total of more than 120,000 times. All his publications can be found on pubmed.

References
  1. Prof.dr. J.C. Clevers (1957 – ) at Catalogus Professorum Academiæ Rheno-Traiectinæ.
  2. Louis-Jeantet Prize
  3. "2016 – Johannes C. Clevers". Ilse & Helmut Wachter Stiftung. Retrieved 18 September 2020.
  4. "Hans Clevers: "Every day new research is showing us that many types of cancers are fed by tumour stem cells"". IRB Barcelona.
  5. Roos Menkhorst (22 June 2013). "Ik leerde het belang van vertrouwen in mezelf". Trouw (in Dutch). Retrieved 20 February 2016.
  6. "Laureates: Hans Clevers". Breakthrough Prize. Retrieved 20 February 2016.
  7. "Hans Clevers on Becoming a Scientist". Oral History Collection.
  8. "Hans Clevers". Hubrecht Institute. Archived from the original on 31 December 2011. Retrieved 15 March 2012.
  9. "prof.dr. Hans Clevers". UMC Utrecht.
  10. "Het spijt ons, maar deze pagina bestaat niet". KNAW. Archived from the original on 6 August 2013.
  11. "Heineken Prize and presidency for Hans Clevers". Netherlands Proteomics Centre.
  12. Board of Directors Roche.
  13. Decibel Therapeutics Assembles World-Class Scientific Advisory Board Decibel Therapeutics, press release of 1 November 2016.
  14. "Hans C. Clevers". European Molecular Biology Organization. Retrieved 16 May 2020.
  15. "Hans Clevers". Royal Netherlands Academy of Arts and Sciences. Archived from the original on 16 August 2019.
  16. "NWO Spinoza Prize 2001". Netherlands Organisation for Scientific Research. 5 September 2014. Retrieved 30 January 2016.
  17. "Hans Clevers". Academia Europaea. Archived from the original on 28 March 2019.
  18. "Laureates 1976 to 2018". Ernst Jung Foundation. Archived from the original on 31 March 2020.
  19. "Professor Dr. Hans Clevers". American Academy of Arts and Sciences. Archived from the original on 24 May 2020.
  20. "Koninklijke onderscheidingen 2012" (in Dutch). Utrecht University. Archived from the original on 9 May 2015.
  21. Clevers, H. (2013). "A gutsy approach to stem cells and signalling: an interview with Hans Clevers". Disease Models & Mechanisms. 6 (5): 1053–1056. doi:10.1242/dmm.013367. PMC 3759325. PMID 24046385.
  22. "Hans Clevers". National Academy of Sciences. Archived from the original on 24 March 2019.
  23. "Hans Clevers, MD, PhD". American Association for Cancer Research. Archived from the original on 24 May 2020.
  24. "Hans Clevers" (in French). French Academy of Sciences. Archived from the original on 24 May 2020.
  25. "Hans Clevers" (in German). orden-pourlemerite.de. Archived from the original on 16 May 2020.
  26. "Academy Professor Prize Awarded to Ineke Sluiter and Hans Clevers". Royal Netherlands Academy of Arts and Sciences. 28 April 2016. Retrieved 10 May 2016.
  27. "Hans Clevers". The Royal Society. Archived from the original on 23 October 2019.
  28. "Professor Johannes Carolus Clevers HonFRSE". The Royal Society of Edinburgh. 15 March 2019. Retrieved 15 March 2019.
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