Heart, brain, pancreas, kidneys: the organs in our body grow into unique, complex shapes during embryonic development. While their outer surface is easy to observe, their internal architecture – curves and chambers and grooves and tubes – is hard to image in a living organism.
Organoids provide a possible solution to this challenge: small, simplified versions of real organs grown from stem cells in the lab. The study of organoids is revolutionising our understanding of how organs develop and work in health and disease.
For a ground-breaking study now published in the journal Nature Physics, an international group of scientists at the IMP, the Max Planck Institute of Molecular Cell Biology and Genetics, and the Max Planck Institute for the Physics of Complex Systems both in Dresden, Germany, have developed novel imaging techniques that allowed them to see what happens inside organoids as they grow, leading them to a conceptual framework to describe and measure the internal anatomy of three-dimensional tissues.
Neuroepithelial organoids, derived from cells that form the neural tube, replicate the early developmental stages of the central nervous system. These organoids are particularly easy to grow and to control in the lab, making them an ideal system to investigate the three-dimensional anatomy of organs.
Keisuke Ishihara, postdoc with Elly Tanaka and first author, tracked the shape of organoids over the course of their development. “The neuroepithelial tissue forms small lobes that fuse into a network of long tubes, which connect into a structure that looks like a wiffle ball,” he explains. “Our aim was to understand how these fusions occur, how we can control them, and how they affect the organoids’ connectivity.”
A growing neuroepithelial organoid from left to right and top to bottom, from small cell clusters and lobes to a ‘wiffle ball’ (Credit: Keisuke Ishihara)
The researchers identified two types of fusion: trans fusion where two separate lobes merge, and cis fusion, where a single lobe is long enough that it loops back and fuses with itself. They found a way to alter the frequency of these fusions, showing how organoid shape and anatomy can be controlled artificially.
Shaping the future of organoid research
“This study takes a physicist’s approach to a biological question: how does form emerge from clumps of cells? In this field, we think of tissues as living materials,” Ishihara says. “So far, we had no precise way of describing the internal structures of organoids. My collaborator Arghyadip Mukherjee, a theoretical physicist now at École Normale Supérieure in Paris, brought in the theoretical framework to describe internal shapes and predict how they change over time.”
By studying the architecture of organoids, scientists aim to uncover general rules that dictate how cells interact and form three-dimensional structures. The applications are not limited to neuroepithelial organoids: in his future lab at the University of Pittsburgh, Ishihara will use the study’s findings to engineer brain and cardiac organoids. By bridging the gap between organoid research, physics, and bioengineering, he wants to develop new chemical and genetic tools to sculpt organoids matched to specific applications.
Keisuke Ishihara, Arghyadip Mukherjee, Elena Gromberg, Jan Brugués, Elly M. Tanaka, Frank Jülicher: “Topological morphogenesis of neuroepithelial organoids”. Nature Physics (2022), DOI: 10.1038/s41567-022-01822-6.
IMPloyable talent: the experience and future plans of Keisuke Ishihara for his lab
About the IMP at the Vienna BioCenter
The Research Institute of Molecular Pathology (IMP) in Vienna is a basic life science research institute largely sponsored by Boehringer Ingelheim. With over 200 scientists from 40 countries, the IMP is committed to scientific discovery of fundamental molecular and cellular mechanisms underlying complex biological phenomena. The IMP is part of the Vienna BioCenter, one of Europe’s most dynamic life science hubs with 2,650 people from over 80 countries in six research institutions, three universities, and 40 biotech companies. www.imp.ac.at, www.viennabiocenter.org
About the MPI-CBG
The Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), located in Dresden, is one of more than 80 institutes of the Max Planck Society, an independent, non-profit organization in Germany. 550 curiosity-driven scientists from over 50 countries ask: How do cells form tissues? The basic research programs of the MPI-CBG span multiple scales of magnitude, from molecular assemblies to organelles, cells, tissues, organs, and organisms. The MPI-CBG invests extensively in Services and Facilities to allow research scientists shared access to sophisticated and expensive technologies. www.mpi-cbg.de
About the MPI-PKS
The goal of the Max Planck Institute for the Physics of Complex Systems (MPI-PKS) is to contribute to the research in the field of complex systems in a globally visible way and to promote it as a subject. Furthermore, the MPI-PKS invests into passing on the innovation generated in the field of complex systems as quickly and efficiently as possible to the young generation of scientists at universities. This requires a high degree of creativity, flexibility, and communication with universities. The concept rests on two pillars: in-house research and a program for visiting scientists. The latter not only covers individual scholarships for guest scientists at the institute, but also 20 international workshops and seminars per year. https://www.pks.mpg.de/
The research lab of Jan Brugués and Frank Jülicher is also affiliated with the Center for Systems Biology Dresden (CSBD) and the Cluster of Excellence “Physics of Life” (PoL) at the TU Dresden. The CSBD is a cooperation between the MPI-CBG, the MPI-PKS and the TU Dresden. In the interdisciplinary centre, physicists, computer scientists, mathematicians, and biologists work together to understand how cells coordinate their behaviour to form tissues and organs of a given form or function. PoL is focusing on fundamental organizational principles of living matter through a close interaction of experiment and theory combined with computational modelling, simulation, and interactive microscopy. https://www.csbdresden.de/