Corona could drive paradigm shift: Charité 3R – Replace | Reduce | Refine - Charité

Some aspects of human disease are best studied in human models. The Corona pandemic is making this very clear right now. The deputy spokesperson of Charité 3^R, Prof. Andreas Thiel, sees this situation as a huge opportunity to drive the shift towards human-based models in research.

When the Corona pandemic rolled in from China at the beginning of 2020, it was immediately clear to Prof. Dr. Andreas Thiel: the mysterious lung disease will be an important topic. Thiel works at the Berlin-Brandenburg Center for Regenerative Therapies (BCRT) on the human immune system, especially the ageing immune system. At the same time, he is one of the initiators of the new research building "the Simulated Human" (Si-M), a joint project of Charité and Technical University (TU) Berlin, in which human model systems such as organ-on-a-chip or organoids will be developed from 2023 on. But that's not all: the researchers also want to use human cells from the blood directly to better understand diseases and develop new therapies. "The methods are there," says Thiel, "and they are proving themselves right now in the pandemic."

The time has come ripe animal-free methods
That direct cell analysis or human lung models are taking the place of animal testing in some areas of biomedical research is a gradual development. But Corona could be the pacemaker for a real paradigm shift, Thiel hopes. "The time has come for these methods to become established now," he says. Indeed, researchers can obtain very detailed information about how the human immune system responds to SARS COV-2 from cells in a person's blood. In a mouse model, this is only possible to a limited extent. The deputy spokesperson of Charité 3^R is currently using these human methods in the "Charité Corona Cross" study, which he launched in spring 2020 together with colleagues from Charité, TU Berlin, the Max Planck Institute for Molecular Genetics and the Robert Koch Institute.

The important question here is the cross-reactivity between SARS COV-2 and the four "harmless" corona viruses. Experts estimate that these viruses cause about 30 percent of seasonal colds in this country. But are people who have had contact with corona viruses in the past also better protected against SARS COV-2 and possibly do not fall ill as severely?

Charité Corona Cross detects cross-reactions
Analyses of reactive T-helper cells from the blood of 900 study participants from Berlin show: Everyone has a certain proportion of memory cells in their blood that can remember at least one native coronavirus. And: Even if the test persons have demonstrably never come into contact with SARS-COV-2, the immune cells can sometimes recognise the new virus. Thus, in every third case, the memory cells were activated when the T-helper cells were presented with fragments of the spike protein of SARS-CoV-2.

"One property of T-helper cells is that they can be activated not only by an exactly 'matching' pathogen, but also by 'sufficiently similar' invaders," Thiel explains. The finding that the memory cells reacted to SARS-CoV-2, although they did not yet know this pathogen, fits this. "By definition, we are dealing with a cross-reaction here," says the immunologist.

Memory cells do not seem to be a risk factor
Further analyses will show the effects the cross-reaction detected in the laboratory has on the course of the disease. In the meantime, some of the test persons have become infected with SARS-COV-2. The disease has not been really severe in any of them. This at least indicates that the cross-reaction is not a risk factor for a severe course of the disease. Thiel does not want to reveal more at the moment, because the evaluation is not yet completely finished.

In the study, the participants - day-care centre staff as well as residents and staff from nursing homes - were given blood samples to determine immune cells and antibodies, as well as throat swabs and saliva samples, which were then analysed using PCR tests. If any of them developed symptoms typical of COVID-19, the tests were repeated. This allows the researchers to retrospectively correlate the immunological parameters with the course of the disease.

The examinations of blood, serum, saliva and pharyngeal secretions are complex. But with the help of new technologies, samples from 20 test persons can be analysed in just one day, even in complex tests, and the data can then even be evaluated. Usually, no normal laboratory can achieve this throughput. The groundbreaking possibilities have also been recognised by the Federal Ministry of Health. The ministry is funding "Charité Corona Cross" with 2.3 million euros.

New study with vaccinated people
"Before Corona, funding like this would have been unthinkable," Andreas Thiel emphasises. But now that cell analyses have gained attention, they can develop their full potential thanks to follow-up funding. Since the beginning of 2021, the study has been continued with vaccinated test persons. The research group wants to analyse whether an existing partial immunity strengthens the vaccination response to the COVID-19 vaccination. However, the reverse case or even an erroneous reaction of the immune system would also be conceivable. "It is important that we do the accompanying research immediately and not wait until half the population has been vaccinated," says Thiel.

At the same time, he is also involved in immunological projects of the National Research Network COVID-19 - an association of German university hospitals funded by the BMBF. The fact that human lung models and organoids are now being used here to study the pathological mechanisms of SARS-COV-2 is a good thing. "It simply doesn't make sense to study it in mice because they have different receptors," says Thiel. In this respect, the pandemic even has a good side. "We can now show the whole world the importance of human models in researching human diseases. That's a huge opportunity."

(Text: Beatrice Hamberger)