Hans Clevers

Hans Clevers
Clevers in 2013
Born (1957-03-27) March 27, 1957
Eindhoven [1]
Nationality Dutch
Fields Molecular genetics
Institutions The Princess Maxima Center for pediatric oncology
Education University of Utrecht
Doctoral advisor Cox Terhorst
Known for Research on normal stem cells and their potential for regenerative therapy
Notable awards Breakthrough Prize in Life Sciences

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.[2] Clevers obtained his M.D. in 1984 and his Ph.D. in 1985 at Utrecht University and was a professor in immunology there between 1991 and 2002. Since then, he is Professor in Molecular Genetics at the same university. He received the Spinoza Prize in 2001 and became director of the Hubrecht Institute in 2002. He was elected as the president of the Royal Netherlands Academy of Arts and Sciencest(KNAW)o succeed Robbert Dijkgraaf from 2012-2015.[3] Since June 1, 2015 he is director Research of the Princess Maxima Center for pediatric oncology. In 2013 he was awarded the $3 million Breakthrough Prize in Life Sciences for his work [4]

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 PhD 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. 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.”[7][8][9][10][11]

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. Also in 2002 he became director of the Hubrecht Institute for Developmental Biology and Stem-Cell Research at the Royal Dutch Academy of Sciences. 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 Dutch Cancer Society (KWF) to study the function of stem cells in the normal intestines and in colon cancer, and in 2008 and 2015 he received ERC Advanced Investigator Grants. 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 as director from the Hubrecht Institute but kept his research lab there.[7][8][9][10][12] From 2012-2015 he was President of the Royal Netherlands Academy of Arts and Sciences (KNAW). Since June 1, 2015 he is director Research of the Princess Maxima Center for paediatric oncology, located on the Utrecht campus close to the Hubrecht where he maintains his lab.

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.

He then described the Wnt target Lgr5 as a marker for adult stem cells including those of 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 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, 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 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 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.”[7]

Other professional activities

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.

He is on the editorial board Cell, Cell Stem Cell, Stem Cell Reports, EMBO Reports, Gastroenterology, amongst others.[7][8][9][10][12]

He is a Scientific Advisory Board member for IMP in Vienna; the Institute for Research in Biomedicine in Barcelona and the Netherlands Cancer Institute (NKI) [9] He is also an honorary professor at Central South University in Changsha, Hunan, China.[10]

He is member of the American Academy of Arts and Sciences (Boston), and foreign associate of the National Academy of Sciences (Washington) and the Academy des Sciences de l'Institut de France (Paris).

Honors and awards

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

Major publications

Clevers has more than 540 publications to his name and has been cited a total of more than 62,000 times. His h-index is 127. Some of his most important publications are:

References

  1. ↑ Prof.dr. J.C. Clevers (1957 - ) at Catalogus Professorum Academiæ Rheno-Traiectinæ.
  2. ↑ "Hans Clevers: "Every day new research is showing us that many types of cancers are fed by tumour stem cells"". IRB Barcelona.
  3. ↑ "Hans Clevers volgt Robbert Dijkgraaf op als president KNAW". NRC Handelsblad. 2012-03-26. Retrieved 2012-03-28.
  4. ↑ "A gutsy approach to stem cells and signalling: an interview with Hans Clevers". Disease Models & Mechanisms.
  5. ↑ Roos Menkhorst (22 June 2013). "'Ik leerde het belang van vertrouwen in mezelf'" (in Dutch). Trouw. Retrieved 20 February 2016.
  6. ↑ "Laureates: Hans Clevers". Breakthrough Prize. Retrieved 20 February 2016.
  7. 1 2 3 4 "Hans Clevers on Becoming a Scientist". Oral History Collection.
  8. 1 2 3 4 "Hans Clevers". Hubrecht Institute.
  9. 1 2 3 4 5 "prof.dr. Hans Clevers". UMC Utrecht.
  10. 1 2 3 4 "Het spijt ons, maar deze pagina bestaat niet". KNAW.
  11. ↑ "ACR Special: Interview with Professor Hans Clevers". proteintech.
  12. 1 2 "Heineken Prize and presidency for Hans Clevers". Netherlands Proteomics Centre.
  13. ↑ "Hans Clevers". Royal Netherlands Academy of Arts and Sciences. Retrieved 17 July 2015.
  14. ↑ "NWO Spinoza Prize 2001". Netherlands Organisation for Scientific Research. 5 September 2014. Retrieved 30 January 2016.

External links

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