I was very happy to attend the BaCell3D 2024, a young and swiss-based conference focusing on the latest advances in 3D cell culture and organoid technologies. The organizers brough together a wide spectrum of reseach topics, from the establishment of novel organoid models to the development of advanced tools to manipulate or readout 3D samples. Here I would like to briefly highlight some of the key takeaways and impressive works that I have seen during the conference.

Organoid 2.0 / 3.0 for better modeling

The first thing that made me jaw-dropping was the vision of the next-generation organoid models presented by Prof. Matthias Lutolf. He mentioned how organoid models can be integrated into customized microfluidic chips to generate “mini-organ” with either good fluidic controls or flexible open-top design. He showed preliminary results on how intestinal epithelials can be co-cultured with mesenchymal cells and reflected the in-vivo-like cell organization along the crypt-villus axis. His team and Nikolche team together also demonstrated applications such as tissue resident immune cell co-culture, microbiome interaction, and even drug-absorption studies. As a remark, he visioned that there might still be tradeoff between complexity and throughput. The key is to use the right model for the right scientific question. There’s no one-size-fits-all solution.

Embryogenesis and developmental biology

The second thing that comes out of the blue is how early embryo models can be built in a bottom-up manner by intricate microenvironment control to provide meaningful biological implicaions. Talk from Dr. Jesse Veenvliet was particularly impressive in this regard. With slides of amazing fluorescent images, he showed how early development can be recapitulated in vitro and how different factors (i.e., ECM, morphogens) influence the fate of cells. I was quite interested in the PIV ECM map he presented and thus asked him about how he think about the dynamic interactions between 3D cell model and the extracellular space. He said it’s important to keep in mind that how cells response to extracellular space does not necessarily reflect the way they do in vivo and is of course not “optimized” and of equilibrium. I like how he practically addressed the question I have been thinking about for a long time.

In addition, there are also many other groups studying “symmetry breaking” events during early development. For example, Prof. Prisca Liberali’s group study how deterministic tissue structure emerges from few cells. Such an event can be explained from a genetic, mechanical, or even lipidomic perspective. Such researches might be very different story-by-story, but I really look forward to seeing them converge to an universal principle in the future.

Creating perturbations

The third thing is about the toolbox for inspecting the genotype-phenotype relationship in 3D models. As Prof. Barbara Treutlein highlighted, the near future of organoid research would be to screen throught different perturbations and to quantify the phenotypic changes in a high-throughput manner via single-cell techniques such as spacial omics and single-cell sequencing. CRISPR screening might be the powerful tool available for this purpose. What really broadened my horizon is what Miriam Wandres, a PhD student from the lab of Nikolaus Rajewsky, presented. She demonstrated the use of optogenetic CRISPRa system together with a Cre-loxP design to stably activate Wnt3A signaling in the early brain organoid. The uniform upregulation of Wnt3A signaling in the organoid led to a hippocampus-like structure after ~40 days of culture. During the networking session, she also shared her personal insights about the tricks and tips of applying optogenetics into 3D models. Such a perturbation toolbox which manage to activate or inhibit genes in a spatiotemporal manner is definitely a game-changer in the field, especially when it comes to assembloids and complex microphysiological systems.

New models from new protocols

Last but not least, taking risk to try out new protocols to differentiate new organoid models is also a main pillar in the field. Prof. Karl Koehler showed how he managed to establish a protocol for inner ear organoid and then unexpectedly discovered clues for the development of skin hair follicles, ending up with hair-bearing skin organoid. Now they are attempting to adapt the system into microfluitics and create a “mini-skin” on the chip. This guy gonna be the next Lutolf in the field (a more biologist one), I guess.

Conclusion

  • Single cell sequencing is the default readout for organoid analysis.
  • 3D imaging is also quite popular and well-adopted in the community.
  • Protocols seem to still be the very bottleneck in the field, the best organoid models are basically owned by the labs who developed them and are not easily reproducible.
  • Synthetic biomaterials seem not to be a blockbuster in the field yet, a lot of study based on Matrigel has yet to be reproduced in other gels.
  • Tools are important, but biological question is even more impactful.

I genuinely enjoyed the conference and hope to have chance to be poster/selected talk presenter in the future. Know that is ambitious but anyway let’s see how it goes.