Biology subjects

Geiger, J.

Publications and source records attributed to Geiger, J..

2 recordsLinked to original sources

bioRxiv2026

Modeling Risk Group 4 virus infection and antiviral treatment in microfluidic lung organ-on-chips in maximum containment laboratories

Development of candidate countermeasures against human pathogens frequently includes nonhuman animal experimentation. Preclinical animal pathogen exposure studies are conducted to model diseases and accumulate preliminary and hypothetically translatable data to inform and justify the design of clinical trial evaluation of countermeasure safety and efficacy. In addition to frequent ethical critiques, challenges associated with animal experimentation include considerable resources needed to achieve statistical power and robustness, replicability and reproducibility concerns, potentially compromised objectivity through lack of blinding, fundamental species-specific biological differences, and risk of unpredictable pathogen adaptation to the experimental animal. Recent U.S. and U.K. government initiatives aim to reduce animal experimentation by complementing or potentially replacing them with new approach methodologies (NAMs), i.e., increasingly sophisticated in silico, in chemico, and in vitro approaches. We piloted development of one type of NAM, organ-on-chips (OOCs), in the highly challenging environment of a maximum (biosafety level 4) containment laboratory. Using a Risk Group 4 virus, Nipah virus (NiV), and two types of lung OOCs seeded with human or porcine cells, we demonstrated the recapitulation of key features of NiV lung infection, including viral infection, replication, and translocation, that are associated with proinflammatory cytokine secretion, immune cell recruitment, and disruption of the air-liquid interface barrier. We reproduced the known anti-NiV activity of remdesivir and evaluated that of another potential antiviral, zotatifin. Our results pave the way for similar applications of advanced microphysiological systems for modeling infections caused by high-consequence viruses.

microbiology↗

bioRxiv2025

Stochasticity contributes to explaining minority and majority MOMP during apoptosis

Apoptosis dysfunction is linked to diseases like cancer and neurodegenerative disorders. A key event during apoptosis is mitochondrial outer membrane permeabilization (MOMP), which typically proceeds in a rapid all-or-none fashion. If MOMP occurs only in a subset of mitochondria (minority MOMP), it can be sublethal and contribute to tumorigenesis and cancer progression. Similarly, individual mitochondria escaping widespread MOMP (majority MOMP) can allow cancer cells to recover if apoptosis execution fails. How such heterogeneities in mitochondrial MOMP responsiveness arise within cells is incompletely understood. In particular, whether stochasticity in subcellular protein distributions and interactions across cytosol and mitochondria can realistically contribute to mitochondrial MOMP heterogeneity has not yet been studied. To assess this, we sequentially built and experimentally parameterized a particle-based, cell-sized model including cytosolic and mitochondrial compartments, and that featured a reduced interactome of MCL-1, BAK and tBID. High-performance computing enabled cell-scale simulations of protein distributions and interactions to understand how and under which conditions stochasticity could contribute to heterogeneity in MOMP susceptibility. Our results show that stochastic effects strongly predispose sub-pools of fragmented mitochondria to MOMP under low apoptotic stress. At higher apoptotic stress, fractions of small mitochondria were more likely to escape MOMP than large mitochondria. Retrospective quantification of mitochondrial sizes in experimental scenarios of minority and majority MOMP confirmed these findings. We therefore conclude that stochasticity substantially contributes to enabling small or fragmented mitochondria to undergo MOMP in minority MOMP scenarios and to escape MOMP in majority MOMP scenarios.

cell biology↗