Professor Hans CLEVERS
Winner of the 2004 Louis-Jeantet Prize for medecine

The information below refers to the time of the award.

Hans CLEVERS is a professor in molecular genetics at The Academic Biomedical Centre of the University of Utrecht and the director of the Hubrecht Laboratory at the Netherlands Institute for Developmental Biology of the Royal Netherlands Academy of Arts and Sciences in Utrecht. Hans CLEVERS is a citizen of the Netherlands. He was born in 1957.

During the development of an animal and the different tissues that compose it, cells receive continuously messages from neighbouring cells which instruct them to grow and to become specialized. These messages are sent in the form of soluble factors that diffuse from a secreting cell to a responding cell either in close neighbourhood or at distance. Only cells with appropriate receptors will respond by transmitting a signal across their cytoplasm to the nucleus, which then modifies their genetic program. At the centre of Hans CLEVERS’s work is the question of how the Wnt signal is transmitted and how it changes the fate of responding cells. He discovered that Wnt induces nuclear accumulation of a protein known as b-catenin that associates with transcription factors of the Tcf family and consequently activates certain genes. Extending his study to colon cancer cells Hans CLEVERS found excessive levels of b-catenin/Tcf-4 complexes that provoke unrestrained cell proliferation and constitute accomplices in causing cancer. It then became clear that the Wnt signalling pathway plays a central role in the controlled renewal of normal intestinal tissue.

With the Louis-Jeantet Prize for medicine, Hans CLEVERS proposes to investigate the molecular defects in signalling pathways that cause juvenile polyposis. Patients with this disease develop intestinal polyps and cancer at young age. He hypothesizes that the intestinal epithelium misses the correct message from the environment and, therefore, induces additional inappropriate crypts ultimately leading to excessive tissue growth. Hans CLEVERS plans to enlarge his group with two new collaborators.

Short biography

Hans Clevers is a Dutch citizen born in 1957. He studied medicine and biology at the University of Utrecht. He received his M.D. in 1984 and his Ph.D. in 1985 at the same university. For his postdoctoral training, from 1985 to1989, he joined the group of Cox Terhorst at the Dana Farber Cancer Institute at Harvard Medical School in Boston, USA. In 1989 he returned to the Department of Clinical Immunology at the University of Utrecht where, in 1991, he was nominated professor and chairman of the Department of Immunology. In 2002 he became the director of the Hubrecht Laboratory at the Netherlands Institute for Developmental Biology of the Royal Netherlands Academy of Arts and Sciences in Utrecht. Since 2002, Hans Clevers is a professor in molecular genetics at The Academic Biomedical Centre of the University of Utrecht. Since 1999 he is a member of EMBO and, since 2000, a member of the Royal Netherlands Academy of Arts and Sciences. In 2000 Hans Clevers received the Catharijne-prize for medical science, and in 2001 the award of the European Society for Clinical Investigation and the Spinoza-award.

Intestinal development and cancer

The development of a fertilized oocyte into an adult animal or human being involves a bewildering amount of biological events. Over the last decade, developmental biologists studying organisms as diverse as worms, fruit flies, zebrafish or mice have uncovered two very important principles. First, it turns out that individual cells in developing organisms do not follow an autonomous path towards their ultimate destiny. Rather, these cells are in continuous communication with other cells, nearby or at a distance, to decide what should happen next. In order to communicate a message, cells produce and secrete soluble signaling molecules for which the cellular neighbors carry specific receptors. Second, the chemical languages by which cells communicate during development are highly similar throughout the animal kingdom. Evolution has created only a handful of signaling pathways. These pathways are used multiple times in different permutations during the development of an organism. Different organisms can utilize the same signaling pathways to reach very different goals: The same signal can induce the formation of a wing in flies, or help to form a beating heart in mice. Because of this principle of conservation, one can study some esoteric developmental process in worms and from the results make predictions about the molecular pathology of human disease.

Genetic studies in model organisms have helped unravel the signaling pathways into their component genes. One of the prominent signaling pathways subject to intense scrutiny by developmental biologists is the Wnt cascade. Certain cells secrete Wnt factors to relay a message. This triggers a biochemical cascade in the responding neighboring cell, ultimately leading to nuclear accumulation of a protein called b-catenin. In the mid-nineties, it was not understood how accumulated b-catenin could reprogram a cell.

Hans Clevers has molecularly defined the majority of currently known Tcf/Lef transcription factors in flies, frogs and mammals. In 1996, he and others made the seminal finding that these factors constitute the ultimate effectors of the Wnt cascade. Tcf proteins can interact with b-catenin, once the latter protein accumulates in response to Wnt signaling. It is this complex that can activate genes in the nucleus of cells, and thus effectively reprograms the cell that receives a Wnt signal.

The finding that Tcf and b-catenin cooperate made important predictions about the etiology of colon cancer. It was already known that mutations in the APC (Adenomatous Polyposis Coli) gene lead to familial predisposition to colon cancer. Under normal circumstances the APC gene product binds and inactivates b-catenin. Hans Clevers showed that the gut-specific transcription factor Tcf-4 formed a stable complex with free b-catenin present at excessive levels in colon cancer cells. This resulted in the inappropriate reprogramming of the cancer cell by b-catenin/Tcf-4, leading to unrestrained cell proliferation. Thus, b-catenin and Tcf were firmly established as accomplices in causing cancer of the colon and, subsequently, of many other organs. These findings allow new strategies for the development of cancer drugs. Subsequently, it became clear that an intact Wnt cascade plays a central role in the physiological balance between the loss of “old” cells and the production of “young ” cells as replacements in the tissue layer that covers the inside of the intestine (see figure). Hans Clevers and his colleagues have gone on to study various aspects of the role of the Wnt cascade in development and cancer, complementing the study of patient material with those of different animal models including mice, frogs, flies, worms and – most recently – zebrafish.

Figure. The inside of the intestine is covered with a single layer of cells. New cells are produced in specific compartments, termed crypts that harbor the stem cells. The proliferation of the cells in the crypt is activated by Wnt signals. Once the cells leave the crypt and move up the villus, they mature to be actively involved in the digestion and uptake of food substances. After a few days, the cells reach the tip of the villus and die to be replaced by younger cells. Mutations in components of the Wnt cascade disturb this delicate balance of proliferation and death, and ultimately result in cancer of the intestine.

Professor Hans CLEVERS
Hubrecht Laboratory
Uppsalalaan 8

Tel.: +31 30 212 18 26 (secretariat)
Fax: +31 30 212 18 01