Honey, I Shrunk the Organs

(June 8th, 2016) This year’s Körber European Science Prize goes to Dutch professor of molecular genetics, Hans Clevers, for developing a procedure to grow miniature guts and livers from adult stem cells.

In 2013, The Scientist called it one of the “big advances in science” – up there with CRISPR/Cas and a hydrogel implant for optogenetic cell manipulations. The organoids, or three-dimensional organ buds, are grown from stem cells in vitro, and have been heralded as one of the breakthrough technologies in medicine. These mini-organs could be a valuable tool for preclinical drug discovery and validation and they can also be used in precision medicine.

Hans Clevers is one of the pioneers of this technology. In 2007, he discovered that adult stem cells in the small intestine and colon possess a unique marker gene, Lgr5. In an interview with Disease Models & Mechanisms, he remembers the moment of discovery: “We made numerous mouse strains, including Lgr5-GFP tagged mice. The moment we saw tiny cells lighting up under the microscope, I started writing our next ten big papers in my head. It was a remarkable moment – the cells exist, and we could visualise them using these mice.”

But what’s so special about this gene? Clevers explains: “Lgr5 is unique in that it – on its own – specifically marks homogenous populations of stem cells, but not their progenitors, unlike most other markers. We now know that this is because it is a cell-surface receptor protein in the Wnt pathway, and only stem cells require Wnt. In the gut, the stem cells are particularly active – in mice, they divide every day for 2.5 years, so they go through a thousand cell divisions”.

The unique expression pattern of Lgr5 enabled Clevers and his colleagues to isolate these particular adult stem cells and cultivate them. With the right cocktail of growth factors and a suitable 3-dimensional scaffold, Clevers and Japanese guest scientist, Toshiro Sato, eventually generated a long-term culture system of a gut organoid. “We showed that normal tissue can be generated from a single stem cell and it can survive in a mouse for as long as you want. Based on this finding, our lab evolved and now we’re culturing prostate, liver, pancreas, kidney, lung and breast tissue, all for prolonged periods of time, all from humans. There are no changes in chromosomal structure in the cultured cells, and deep sequencing reveals very few mutations,” Clevers said.

Based at the Princess Máxima Center in Utrecht, Clevers is also the founding director of the Hubrecht Organoid Technology (The HUB), a not-for-profit organization founded by the Hubrecht Institute, KNAW and University Medical Center Utrecht. The HUB host “The Living Biobank” which “consists of a rapidly growing collection of organoids from patients with various forms of cancer (colon, prostrate, lung, pancreas) and cystic fibrosis”.

Back in 2012, Clevers was also among the first winners of the lucrative Breakthrough Prize in Life Sciences, the only European winner, by the way. What’s his secret for scientific success? Don’t speculate too much. “In my lab, I try to establish a reproducible, quantitative system, like GFP mice and arrays. Then I throw something at the system and look, without formulating a hypothesis. This is difficult because our brains like to produce causal relationships, even though these are often wrong. I’m constantly telling my group members that they should keep their minds open and make observations without assuming that they know what’s going on. In molecular biology, we can go anywhere we want and there are billions of effects to discover. You cannot do this in a hypothesis-driven way because you’re essentially retracing evolution. There are many solutions to a particular problem but evolution picked one – it’s very arrogant to think we can reconstruct this in our minds”.

Clevers wants to use the €750,000 prize money to advance his gene therapy research. Recently, he successfully eliminated the mutation causing cystic fibrosis in one of his organoid cultures.

In 2014, Norwegian neuroscientists, May-Britt and Edvard Moser, won the Körber Prize and the Nobel Prize. Can Clevers repeat that feat?

Kathleen Gransalke

Photo: Körber Foundation/Friedrun Reinhold

Last Changes: 08.02.2016