Realizing the potential of organoids—an interview with Hans Clevers

Abstract

The past decade has witnessed the development of a powerful new model to study human disease: stem cell–derived organoids. These are 3-dimensional structures recapitulating the architecture of an organ in miniature. Because they can be generated from any patient, organoids offer unprecedented possibilities for medical research, including individualized therapy, toxicology testing, and drug discovery. Given the development of organoids mimicking ever more tissues, including brain, the female reproductive tract, and early embryos, combined with the advance of gene editing technologies, the scientific community and the public are starting to consider the ethical implications of organoid technology. One of the driving forces behind organoid research is Hans Clevers from the Hubrecht Institute in Utrecht, the Netherlands. Here, he discusses the potential of organoids for medicine, the current status of research, and the ethical implications. The interviewer is Sina Bartfeld, a former postdoc of the Clevers lab and now an independent group leader. SB: The development of organoids proceeded incredibly fast, with less than ten years from discovery to the first use in the clinic. Looking back, what was the first breakthrough? HC: First, I think it is important to distinguish two different technologies because they use two different types of stem cells. On the one hand, there are the stem cells that can create a whole organism, the pluripotent stem cells, which are either induced pluripotent stem cells or embryonic stem cells. In short iPS or ES cells. On the other hand, what many people do not realize is that there is a second type of stem cell. These so-called adult stem cells constantly regenerate our tissues. For example, the adult stem cells of the intestine will regenerate the inner lining of the intestine, the epithelial cells. Both fields, the iPS/ES field and the adult stem cell field have each developed organoid technologies. SB: And both fields had their breakthroughs. HC: I think the one for iPS/ES was the establishment of the first organoids by Yoshiki Sasai in 2008. Before that, people who used ES and iPS cells just wanted to make one cell type, like simply more stem cells, or beta cells, or liver cells, or neurons. Sasai was the first to notice that if you first allow the pluripotent stem cells to form clusters of cells, so-called embryoid bodies, you get more than that, you get structures. He did not yet use the word organoid, but he described that you get anatomical representation [1]. This initiated the ES/ iPS organoid field. Our discovery that small intestinal stem cells can build mini-guts then kickstarted the adult stem cellderived organoids field [2]. SB: Can you remember when you realized the medical potential of organoids? HC: I think immediately when I saw them. Toshi, Toshiro Sato, who was then a postdoc in my lab, grew them in culture but had not told anybody. I asked, „How is it going, are you growing gut stem cells yet?“. And he said, „Yeah, they are here“. And he showed them to me. The moment I saw them I realized: well apparently you can expand primary tissue and it is not just a lump of stem cells, which is what we thought we would get, but it is really a small organ. SB: You expected a lump of cells because this is what people had seen in the iPS/ES field? HC: Yes, in iPS and ES, this is what people did back then, start from one andmake a million. Just pure stem cells without any organ-like structure, like a lump of cells. So, our intention was to do the same with adult stem cells. But this is not what they did, the cells organized themselves into these mini guts. When you see them growing, particularly the mouse ones, their vitality is striking. This was very surprising. And when Toshi then also saw that all the cell types of the intestinal epithelium were present in the mini-guts, we realized that if this could be transferred to human stem cells, which Toshi went on to do, you can do everything that people now do in mice in human cells. And you can do it for individual patients. In a personalized fashion. This was not very visionary, I think anybody who saw that experiment would have immediately * Sina Bartfeld [email protected]; [email protected]