Infectiologists of the Charité were pioneers in the development of alternatives to animal testing by virtue of their lung tissue models. They now work on stem cell-based organoids. This endeavour is a further step towards replacement of animal testing and servicing patients sooner with therapies won from basic research.
When Professor Andreas Hocke began his scientific career at the Charité in 2001, hardly anyone was talking about alternatives to animal testing. He then developed a mouse model, which aimed to reflect pneumonia contracted by out-patients through pneumococci. But soon ethical concerns caught up with the young researcher of lung infections: why should so many animals suffer and die, especially when the scientific relevance of these models is in doubt? “I was almost ready to quit research and look for employment in a clinic,” Professor Andreas Hocke recalls. That the professional physician did stick to research is largely owed to his strong convictions and encouraging discussions with both his superiors and colleagues. “I came to the conclusion that I needed to find a new approach and establish it as a niche,” Hocke says.
From niche to success
In the beginning it was not easy to put into practice the idea of cultivating human lung tissue and using it in infectiology. He lacked the necessary tissue material but much more so the acceptance of his plans in the scientific community. This changed when he was able to present first successes with his co-researcher Professor Stefan Hippenstiel (today, they both are members of Charité 3R’s Speakers’ Council). A sponsored project gave them the chance to examine pneumococci and influenza viruses on human lung tissue; in 2011, Hocke received the first Berlin research award for alternatives to animal testing awarded by the federal state of Berlin and the Verband forschender Arzneimittelhersteller (vfa, Association of Drugmakers in Research); in 2012, he published his first scientific paper.
Today, lung tissue models are standard in the research department of the Medical Clinic m.S. for Infectiology and Pneumology a the Charité. Of course, a small piece of tissue does not make up a human being, but it is closer to the target tissue – the human lung – than a mouse. A great advantage, Hocke thinks, that puts the tissue model on par with the animal model, or even ranks it above. “Either one is a model. But the question is which one is better suited to reflect human medical conditions.”
Andreas Hocke and Stefan Hippenstiel managed to prove for the first time on cultivated lung tissue that all influenza viruses multiply in only one cell type, the type2 cells. A number of further studies also offered remarkable results for basic research and beyond. Despite initial rejections, eventually all papers were published. This is a remarkable success for something that was “niche research” at first.
Testing new therapies without animal testing
At present, both infectiologists together with Dr. Katja Hönzke are examining new anti-viral substances. The project is sponsored by Charité 3R and it is not only expected to bring about new anti-virals, but also to confirm that living human tissue can serve as models for testing new therapies. Living human tissue also serves to research alternatives to antibiotics as is shown by the novel therapy through bacteriophages, developed by Professor Martin Witzenrath, the deputy clinic director. Phages are a distinct microbiological life form that lives off certain bacterial strains and is also capable of destroying them. The aspiration is that this potential can be weaponized against bacterial lung infections.
Lung tissue is limited, organoids can be multiplied at will
The lung model, however, faces limits for purely logistical reasons: human lung tissue is scarce – although all tissue garnered from surgeries Berlin-wide is already being delivered to the lung infectiologists at the Charité. But it is not nearly enough to be broadly used in scientific research. For this reason, the scientists pursue a different path and through organoids they are developing an alternative 2.0. These miniature lungs are won from (adult) human stem cells and they carry the big advantage that they can be multiplied at will. Quite different than original lung tissue, they do not die after approximately one week, but remain vital for many months. It is thus conceivable that they can be broadly used even beyond the Charité.
“Our alternative methods are high-tech and they will help us to bring results from basic research from the lab to the patient much more quickly and also replace a large number of animal testing,” says Stefan Hippenstiel, describing the common goal. “And if it isn’t possible today, it will surely be possible tomorrow.” Stem cell – based organoids are expected to function like a real lung one day, having an immune system and blood circulation and even be able to breathe. But there is still a long way to go. Especially the connection of blood vessels is an unsolved problem in all the research done on organoids. “Science is only starting on this now and we are now finding out, how organoids function, both physiologically and pathophysiologically,” explains Hocke the current state of affairs.
Focusing on a distinct goal
Preliminary findings are promising, however. It is now known that these miniature organs possess various cell types of lung tissue and that they can be infected with influenza viruses. What is more, stem cell biologists at the clinic have already succeeded to isolate a first type of important immune cells of the lung, the so called alveolarmacrophages, from the primary tissue and combine them with organoids. This lung-organoid model is even closer to clinical reality as both immune and stem cells come from the same patient.
“We have shown for many years that reliable scientific results can be produced even without animal testing,” Hocke emphasizes. “I am convinced that we can manage to do this with organoids as well. ”Comparative tests are now expected to determine how miniature lungs differ from primary tissue and whether they are suited as models for the testing of new therapies. The probation phase begins in January, when new anti-viral and anti-bacterial substances are also tested on organoids to produce parallel findings.
By the way, the alternative approach of relinquishing animal testing is no longer a scientific niche today. In the mean time, a large global scientific community has formed that does research on tissues and organoids and it is increasingly successful. The founding of Charité 3R has been made possible, a paradigm shift has set in – and pioneers like Andreas Hocke and Stefan Hippenstiel have no small claim in this.
(Author: Beatrice Hamberger)
Charité - Universitätsmedizin Berlin
Medizinische Klinik m.S. Infektiologie & Pneumologie
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