Human lung tissue cultivated in the laboratory helps to better understand respiratory diseases ranging from asthma to pneumonia and enables researchers to find new therapeutics. Moreover, the risk of new pathogens can also be assessed more quickly.
When a new virus such as the coronavirus arises, infectiologists are faced with pressing questions like: How does the virus enter the human body? Does it multiply quickly, does it destroy tissue? Only those who can answer these questions have a chance of systematically searching for countermeasures.
Immunologist Katja Hönzke from Charité's Department of Infectious Diseases and Pneumology is trying to provide answers to precisely these questions. To do so, she cultivates models of human lung tissue in her laboratory. These so-called organoids measure only a maximum of 200 micrometers in diameter. They provide Hönzke with insights into the mechanisms of a respiratory pathogen infecting the lung and the resulting consequences. As these understandings are extremely valuable in the case of new pathogens or new virus strains, the Robert Koch Institute is cooperating with her working group: the federal institute uses her findings to accurately assess the incidence of infection.
Up to now, researchers mostly investigated respiratory diseases with the help of animal experiments. However, as most pathogens do not infect mice or rats, experts first had to modify the germ or animal in order for the infection to occur at all. These steps take time and resources and above all, entail the ethical disadvantage of animal experiments.
Therefore, Hönzke is working intensively on establishing lung organoids as an alternative method to study respiratory diseases. Organoids should be cultivated as effectively as possible and as close to the human original, the lung. First, donor tissue from lung cancer patients provided from various clinics in Berlin is obtained. Through an U.S. organization, researchers occasionally receive healthy donor tissue as well which was categorized as not suitable for transplantation. Hönzke first isolates precursor cells from the tissue samples, which are able to form lung tissue cells. Out of the precursor cells, she is able to cultivate two types of organoids in the laboratory: bronchial organoids simulating secreting bronchi and upper airways, and alveolar organoids resembling human alveoli in their cellular composition. Both organoids can be propagated indefinitely, and can also be frozen and thawed again. "This is a crucial advantage," explains the researcher.
Scientists can use organoids to gain a better understanding of respiratory diseases. Asthma, chronic obstructive pulmonary disease (COPD), pneumonia and lung cancer are common and sometimes even fatal health conditions without adequate treatment options. Hönzke is currently also testing newly developed as well as established drugs against infectious pathogens such as the latest influenza virus strains on the organoids. This enables rapid identification of effective drugs. She is also evaluating the potential of active substances that are currently under development. The results of lung organoids experiments have so far proven to be reliable and as significant as those of fresh human lung tissue, which serves as reference.
The researcher can also use organoids to precisely observe the mechanisms of how a germ attacks the airways and lungs. SARS-CoV-2, for example, mainly takes the ACE2 receptor as a cellular entry route. It was only when Hönzke genetically modified her organoids to produce this receptor in large numbers on the cell surface, the virus successfully multiplied within the lung model. The research group was thus able to demonstrate the direct correlation between the virus entry via the ACE2 receptor excluding other, alternative receptors. Her project showed that the COVID-19 pathogen is only able to directly infect human alveolar cells to a very limited extent. In contrast, the majority of viruses entering the lungs are directly taken up by cells of innate immunity, the alveolar macrophages, and trigger targeted immune activation within. "The interaction between the lung and the immune system is very important," says Hönzke. "It also explains, for example, a particularly severe form of pneumonia: when people get a bacterial infection after a viral infection. The viral immune response prevents a simultaneous response to the bacterial infection. As a result, the bacteria gain an advantage and are able to multiply in the lung and damage the tissue.
In order to take the response of the immune system into account, Hönzke has started to infiltrate her organoids with macrophages. Her aim is to create a more accurate model of the fascinating complexity of the human lung. The respiratory organ with its lobes has a very complex anatomical and functional structure. "We simply don't yet know which substances contribute to a stem cell developing into the various lung-specific cells. We do not yet fully understand the maturation of the lung. Our organoids are currently quite simple in their cellular composition and structure," explains Hönzke.
One could hope that the tiny mini-lungs might one day become plate-sized lungs that can be transplanted. Then donor lungs would no longer be needed. However, Hönzke sees this vision in the very distant future. "Cultivated tissue always has disadvantages. That is definitely not our goal at the moment." For her, a lot is achieved if the organoids reveal more than a mouse in an animal experiment and the mouse no longer has to die for it.
Original text (German): Susanne Donner, December 2022.