How COVID-19 is accelerating the development of alternatives to animal testing: Charité 3R – Replace | Reduce | Refine - Charité

The model dilemma in biomedical research

Since the beginning of the pandemic, research has been trying to find answers to the pressing questions with the highest priority: how does the corona virus SARS-CoV-2 attack human cells, how does it activate the immune system? Which organs are affected and how can the disease be treated?

In a recent comment in Nature Reviews Materials, Prof. Dr. Andreas Hocke, member of the council of spokespersons of Charité 3^R and co-author of the comment explains that animal models are only of very limited use in answering these questions. New human-based models such as micro-engineered multi-organs-on-chip are crucial for combating this, future pandemics and general disease research.

Animal studies play a central role in preclinical research because animals can be used as models for humans to better understand and treat human diseases. However, transferring findings from animals to humans is often difficult because animal models do not always provide the information that is relevant for humans. In addition, establishing an animal model is very expensive and lengthy, so that animal models are not quickly available in a pandemic situation. Although the World Health Organization commissioned an expert panel at the beginning of the Corona pandemic to identify suitable animal models for research and vaccine development, a key finding from the September 2020 summary review is that there is no animal model that fully represents the situation in humans.

Some animal models cover certain aspects of the disease in humans. In hamsters and ferrets, for example, the receptor through which the virus enters the cell is very similar to the human receptor. Therefore, these animals are very suitable for testing, for example, the transmission of the disease or the effectiveness of vaccines. However, these models lack basic analytical capabilities that would be necessary to study disease mechanisms. The otherwise frequently used genetically modified mice are hardly suitable as disease models because they develop completely different disease patterns than humans.

Therefore, cell cultures from human cells play a central role in the investigation of SARS-CoV-2. Even in simple 2D-cell cultures, it was possible to show which molecules are responsible for the uptake of the virus particle into the cells. Three-dimensional organ models, so-called organoids, consist of different cell types and already depict properties of inflammation and disease mechanisms. For example, with the help of a lung organoid, an active substance called imatinib could be identified that blocks the uptake of the virus particle into the cells. This active substance is now being tested in clinical trials on humans. Kidney, heart and brain organoids also provide important contributions to understanding the effect of COVID-19 on the individual organs.

However, to understand the interaction of several organs, more complex models are needed. Here, organ chips ("organ-on-a-chip") allow further progress, as they can be interconnected and thus simulate the interactions between several organs and blood vessels. These models promise very good predictive power, but there are still many challenges to overcome in their application. For example, the establishment of new organ chips requires special technical expertise and is associated with high costs. The authors therefore propose to specifically advance the development of modular organ chips that can be interconnected in a modular system and can be procured ready for use. Such an organ chip construction kit would be very valuable for the investigation of infectious diseases and other research questions. However, some development steps are still necessary for its application. For example, mapping the immune system in the organ model is a major challenge. It is also important to establish a higher-level validation strategy that enables the comparability of organ chips.

As a result, the authors call for the use of models in biomedical research to be continuously critically questioned with regard to their specific predictive power and not to consider animal experiments as the standard for evaluating human-related questions. Regulatory authorities such as the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) support the implementation of human-based models. Especially for diseases with an urgent medical need and a lack of suitable animal models, human-based models can accelerate clinical research, which may ultimately facilitate their acceptance in routine scientific and regulatory practice.