Organoids are of significant interest due to their frequent portrayal as a potential substitute for animal testing. However, there is currently a lack of uniform, well-established quality standards for these organ models.
Tiny thunderclouds the size of a pinhead floating in a petri dish – this is what most organoids, three-dimensional tissue models grown from stem cells, look like. Stem cells are defined as cells that lack or are in the early stages of differentiation. They can develop into any cell type, such as heart or kidney cells, muscle cells or neurons. Researchers can use organoids in order to study organ differentiation, disease development and drug efficiency. As they can be produced from human cells, these mini-organ models in some aspects closer to human organs than animal models.
Research on organoids has enormous potential to reduce or replace certain animal experiments. At the Einstein Center 3R (EC3R), several research groups are studying 3D tissue culture models, such as brain, intestinal and lung organoids or artificial heart tissue. Improving the quality of in vitro model research is the goal of the cross-sectional project "6R - Robustness, Registration, Reporting of 3R Projects" by Prof. Dr. Ulrich Dirnagl, Dr. Ulf Tölch and Prof. Dr. Daniel Strech from the QUEST Center of the Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin. The mission is to make biomedical research more trustworthy, useful and ethically responsible.
"Trust is the key," says Dr. Maren Hülsemann, research associate in this EC3R cross-sectional project at the QUEST Center. This trust is closely linked to the robustness of the experiments. "For researchers who are used to doing in vivo experiments, to even consider replacing their animal models with organ models, we have to ensure that these alternative models are robust." This means that both, the results of organoid research and the organ models themselves must be reproducible. However, this is by not always the case: "If a model works in one laboratory, this does not mean that it will be the same in another laboratory," says Hülsemann. One of the reasons for this the lack of uniform quality standards for in vitro research and therefore no clear guidelines as to what information study protocols have to provide. "A study is robust if the researchers exactly document their experimental set-up, their research hypothesis and whether they have cultivated the organ models from stem cells, cell lines or tissue samples from patients," explains the scientist.
Seamless knowledge transfer is therefore the key to success. In order to ensure that all laboratories within the EC3R have access to the knowledge of the other research groups, scientific protocols are shared via a research data platform. For example, if scientists of one laboratory want to replicate an organ model developed by colleagues from another laboratory, they can access their protocols via this platform. This allows standardized conditions for the organoid development. "In some cases, it is also necessary for a scientist to work in the other lab for three weeks in order to acquire the know-how," explains Hülsemann. "Not everything can be recorded on paper."
Researchers can use the platform to share their knowledge not only within their own institution, but also with colleagues around the world. The teams led by Dr. Mirjana Kessler from the Ludwig Maximilian University of Munich (LMU) and Dr. Katja Hönzke from Charité have also published their protocols there. They work on lung models at the EC3R and were able to show, among other things, how lung organoids can be infected with the coronavirus. "By documenting their methods in detail, they enable other laboratories to replicate their lung models and infect them with other pathogens in the event of another pandemic," explains Hülsemann. A compilation of these protocols was published in the scientific journal "Plos One". "The advantage: the publication refers to protocols that are continuously updated," says Hülsemann. "In that way, the accessible protocols are always up to date."
The 6R group is currently preparing a review of the use of organoids in Covid-19 research. The researchers are analyzing more than 300 studies. On the one hand, they are interested in which organ models were used, how the coronavirus entered the cells and how it was able to multiply within the organoid. On the other hand, they want to check for the robustness of the studies, i.e. precise the authors documented their methods and experiments, and whether other scientists can reproduce the results.
Another review paper is currently being prepared for the project "3D bioprinting of human organ models" by Prof. Jens Kurreck and Dr. Johanna Berg from the Technical University of Berlin and Prof. Dr. Albert Braeuning from the Federal Institute for Risk Assessment (BfR). The scientists want to know what the current state of knowledge is for liver models: What technologies are available for 3D bioprinting of liver models, what types of bioink are being used and what questions are being answered with the help of these liver models? "There is currently a huge amount of literature on this. Even absolute experts can lose track of things," says Hülsemann.
Creating an overview, ensuring clarity and reliability – that is what the 6R project is all about. "There are currently no binding rules," says Maren Hülsemann. "It starts with the nomenclature. Organoid, organ model, 3D tissue model – anything is possible. Finding a standardized terminology would be a first step towards more quality."
Original text (German): Jana Ehrhardt-Joswig, January 2023.