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Organoids: Exploring the third dimension



21 October 2016 - For many decades, scientists have been culturing cells in two-dimensional monolayers on flat and rigid substrates. Although researchers have learned a lot from these systems, they also have their limitations. “There is tremendous wisdom in the architecture of a body – the architecture of a prostate, a mammary gland, or a liver,” said Mina Bissell of the Lawrence Berkeley National Laboratory in Berkeley, California. This wisdom is not reflected in two-dimensional cultures. By losing the context in which cells grow, they also lose their normal function.


Back in the 1980s, Bissell stressed the importance of maintaining the cells’ microenvironment and allowing them to grow in three dimensions. But it was only more recently – with the development of stem cell technologies – that the idea of growing three-dimensional ‘organoids’ in a dish picked up momentum. Human stem cells have enormous self-organizing capacity. Under the right conditions, they do in a dish what they do in real life: divide, differentiate and sort into realistic organ-like structures.


On 12–15 October 2016, researchers from different fields met at the EMBO | EMBL Symposium Organoids: Modelling Organ Development and Disease in 3D Culture in Heidelberg to discuss some of the latest discoveries in organoid research. “This is somewhat of a historic meeting, as is the very first conference on organoids,” said Jürgen Knoblich of the Institute of Molecular Biotechnology in Vienna, who, together with Bissell and EMBO reports editor Esther Schnapp, organized the conference.


From bench to bedside 

There are two types of organoids grown from stem cells, depending on whether they are derived from pluripotent or adult stem cells. Hans Clevers of the Hubrecht Institute in Utrecht, The Netherlands, pioneered the latter technology when, in 2007, he started growing organoids from guts. Today, his lab has applied the technology to grow organoids from a number of different tissues – liver, lung, prostate, pancreas and breast tissue – almost anything except brain.


Organoids from an adult cell can be grown very quickly. “You take a rectal biopsy and within a few days, you have a gut organoid,” explained Clevers, who delivered the conference keynote lecture. This makes them ideally suited for a whole array of clinical applications.


The step from bench to bedside has been extraordinarily fast in organoid research. For example, organoids from different patients can be used as ‘avatars’ to test medication. Clevers has set up organoid biobanks from patients for a number of different heritable diseases and cancers. They are used for screening drugs in drug development, or to find the best medication for individual patients in a personalized medicine approach. They serve to test toxicity directly on a functional representation of human organs and may, in the future, serve people in need for organs. In the even more distant future, this may be combined with CRISPR/Cas9 gene editing technologies to correct mutations before autologous transplantation.


Modelling disease

The organoid field combines researchers from different disciplines and with different research styles, and the EMBO | EMBL Symposium brought them together to explore this interdisciplinary field from all angles. “It is high level basic cell and developmental biology meeting the clinic,” said Clevers. Clinicians contribute strongly to the adult organoid area with its many medical application. “Organoids from pluripotent stem cells are more complex and there are many very rigorous basic researchers in the field,” Clevers commented.


Jürgen Knoblich is one of them. “An important part of starting organoid research is providing a detailed description of their normal development. It’s just like establishing a new model organism,” he explained. After studying neural development in flies and mice, brain organoids became a new model system for him in 2011, when his lab pioneered a new protocol for growing them from stem cells.


A thorough knowledge of the normal development, Knoblich explained, is required for the next step towards clinical application, namely investigating the exact causes of developmental abnormalities in disease models. As one example, he has explored brain organoids derived from a patient with microcephaly and found that the phenotype arose because a defect in spindle orientation impeded precursor cells to divide sufficiently. Spindle orientation in early nervous system development has been Knoblich’s field of interest ever since his early fly research. “It has been very rewarding to take the same research question from flies all the ways to humans, and now even starting to work with individual patients,” he said.


“Organoids are really another name for 3D thinking,” said Bissell. They have already contributed to new approaches and discoveries, but there is more to come. Scientists around the world are working on improving organoid complexity to reflect normal organ development in more detail. “We are expanding our repertoire,” said Knoblich. And with that, organoids will continue to open up opportunities to explore new questions.