Hans Clevers

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 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.”[6]

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.”[6]

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.”[6]

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)[11]
• Decibel Therapeutics, Member of the Scientific Advisory Board (since 2016)[12]
• Kallyope, Member of the Scientific Advisory Board (since 2016)
• Surrozen, Co-Founder

He is also on the editorial board of multiple 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.

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