Navigating Complexity - Multiscale Models of Responses to Environmental Exposures : Towards a One Health Paradigm
del Giudice, Giusy (2024)
Tampere University
2024
Lääketieteen ja biotieteiden tohtoriohjelma - Doctoral Programme in Medicine and Life Sciences
Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology
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Väitöspäivä
2024-10-04
Julkaisun pysyvä osoite on
https://urn.fi/URN:ISBN:978-952-03-3550-2
https://urn.fi/URN:ISBN:978-952-03-3550-2
Tiivistelmä
Interpreting and predicting the response of biological systems to external stimuli is a pivotal aim in pathology, pharmacology and toxicology. The result of this interaction, the phenotype, is the nexus between external environmental pressures and internal genetic and epigenetic forces. Biological systems interact with the “outer world” via three systems: the sensory system, the immune system and cellular mechanisms of molecular sensing. While these evolved in different moments, the immune system and the molecular sensing are widely spread across the domains of life. Despite differences across species, both the immune system and the molecular sensing ensure continuous reception and processing of information about the environment and the inner state of a system. Their role is to produce a response to preserve homeostasis, while priming future responses.
Significant progress has been made to identify genes and pathways involved in the response to specific environmental stimuli. However, little has been discovered about how these factors are linked between each other to produce functional responses in humans, as well as other species. Discovering these links requires a transition that conceptualises biological systems as complex systems, instead of lists of components. Network models explicate these links as edges between entities. Multiscale models rep- resent biological phenomena integrating information across different spatial, temporal, or hierarchical scales. In this respect, multiscale modelling allows a representation of biological systems as consecutive biological layers of organisation (from genes to entire ecosystems), with connection within and across the scales. In this holistic view, the phenotype is an emergent phenomenon of the system, which can be observed at any scale. Interpreting the response to exogenous stimuli as an emerging phenotype can be challenging, especially for long-term responses. This thesis characterises the molecular responses of biological systems to chemical and viral stimuli through multiscale and network models. The approaches developed here allow mechanistic interpretation of molecular alterations as multiscale responses, and can explain the emergent phenotype whether contemporary of the alteration, or predicted as a long-term response. In Study I and II, I used a multiscale conceptual framework and a network approach, respectively, to characterise the long-term consequences of SARS-CoV-2 infections in the lung.
The emergent response arises from the relationships between layers, namely functional connections. While the individual layers can be extremely different across species, the function is often evolutionary conserved, because it is related to the system’s purpose of survival and homeostasis. This conservation allows the definition of models that extend beyond human validity, in line with the emerging concept of “One Health”, that promotes the interconnectedness of humans, animals and the environment. In this thesis, I explore the immune system and the epigenome as the dimensions coordinating functional responses to environmental cues. Both the immune system and the epigenome span across time scales, from evolutionary conserved elements to priming long-term responses, and space scales, from molecules to species. In this respect, the biological function helps to predict long-term responses, as well as to define multi-species models of chemical stimuli response. In Study IV, I define the first One Health model of response to nanoparticulate, by identifying a shared gene regulatory mechanism orchestrated by C2 H2 zinc finger transcription factors.
Complex systems approaches like the ones described in this thesis lead to more generalizable models: the observed phenotype, whether a disease, therapeutic or toxic effect, is an epi-phenomenon emerging from the alterations of the biological system’s molecular network with the environment. In Study V, I present a novel computational framework able to interpret patterns of molecular alterations into a multiscale mechanism leading to an apical phenotype. This thesis advances the understanding of these responses exploiting the complexity of biological systems. The core idea is simple: biological responses need to be interpreted as systemic functional outputs. In Study III and V, I exploit biological differences, untangling the complex immunological landscape response to nanoparticles in the lung, and presenting the impact of selecting test systems when testing chemicals. Through the definition of multiscale models, this thesis highlights the role of immunity and epigenetics as the pivotal elements at the interface with the environment. While orchestrating responses across scales, these systems help to define models that are one step closer to One Health.
Significant progress has been made to identify genes and pathways involved in the response to specific environmental stimuli. However, little has been discovered about how these factors are linked between each other to produce functional responses in humans, as well as other species. Discovering these links requires a transition that conceptualises biological systems as complex systems, instead of lists of components. Network models explicate these links as edges between entities. Multiscale models rep- resent biological phenomena integrating information across different spatial, temporal, or hierarchical scales. In this respect, multiscale modelling allows a representation of biological systems as consecutive biological layers of organisation (from genes to entire ecosystems), with connection within and across the scales. In this holistic view, the phenotype is an emergent phenomenon of the system, which can be observed at any scale. Interpreting the response to exogenous stimuli as an emerging phenotype can be challenging, especially for long-term responses. This thesis characterises the molecular responses of biological systems to chemical and viral stimuli through multiscale and network models. The approaches developed here allow mechanistic interpretation of molecular alterations as multiscale responses, and can explain the emergent phenotype whether contemporary of the alteration, or predicted as a long-term response. In Study I and II, I used a multiscale conceptual framework and a network approach, respectively, to characterise the long-term consequences of SARS-CoV-2 infections in the lung.
The emergent response arises from the relationships between layers, namely functional connections. While the individual layers can be extremely different across species, the function is often evolutionary conserved, because it is related to the system’s purpose of survival and homeostasis. This conservation allows the definition of models that extend beyond human validity, in line with the emerging concept of “One Health”, that promotes the interconnectedness of humans, animals and the environment. In this thesis, I explore the immune system and the epigenome as the dimensions coordinating functional responses to environmental cues. Both the immune system and the epigenome span across time scales, from evolutionary conserved elements to priming long-term responses, and space scales, from molecules to species. In this respect, the biological function helps to predict long-term responses, as well as to define multi-species models of chemical stimuli response. In Study IV, I define the first One Health model of response to nanoparticulate, by identifying a shared gene regulatory mechanism orchestrated by C2 H2 zinc finger transcription factors.
Complex systems approaches like the ones described in this thesis lead to more generalizable models: the observed phenotype, whether a disease, therapeutic or toxic effect, is an epi-phenomenon emerging from the alterations of the biological system’s molecular network with the environment. In Study V, I present a novel computational framework able to interpret patterns of molecular alterations into a multiscale mechanism leading to an apical phenotype. This thesis advances the understanding of these responses exploiting the complexity of biological systems. The core idea is simple: biological responses need to be interpreted as systemic functional outputs. In Study III and V, I exploit biological differences, untangling the complex immunological landscape response to nanoparticles in the lung, and presenting the impact of selecting test systems when testing chemicals. Through the definition of multiscale models, this thesis highlights the role of immunity and epigenetics as the pivotal elements at the interface with the environment. While orchestrating responses across scales, these systems help to define models that are one step closer to One Health.
Kokoelmat
- Väitöskirjat [4901]