Biological Resilience Initiative

Antimicrobial resistance (AMR) is a pressing issue threatening our ability to combat infections caused by bacteria, parasites, viruses, and fungi. The World Health Organization has flagged AMR as a top global public health concern, as it not only leads to severe illness and death but also imposes significant economic burdens due to prolonged treatments and increased healthcare costs. LSI researchers are actively tackling this challenge by investigating the mechanisms behind AMR and developing new strategies to overcome it. Using cutting-edge techniques such as advanced structural biology in the ASTRID core, high-throughput screening in the Biofactorial core, and microbial genetics analyzed in the Bioinformatics core, they aim to understand how pathogens evade our immune system and identify potential targets for new antimicrobial drugs.

Collaborative efforts within and beyond the LSI have led to promising discoveries, including novel therapies like host-directed therapies (HDTs) that target human cells to circumvent AMR. Through multidisciplinary approaches spanning different scales of research, LSI scientists are at the forefront of finding innovative solutions to combat AMR and develop new treatments for drug-resistant infections.

Cancer, a leading cause of global mortality, arises from disruptions across various biological levels, including genes, cells, and tissues. LSI researchers specialize in uncovering the fundamental mechanisms behind cancer development, utilizing core services like the Bioinformatics core for genome-level studies and the LSI IMAGING core for cellular investigations. Their focus extends to understanding how environmental factors, such as diet and aging, impact gene regulation through epigenetic changes, with the aim of identifying new therapeutic targets.

LSI's interdisciplinary approach extends to systems-level inquiries, exploring topics such as cancer metabolism and the resilience of the immune system against tumor formation. Collaborative efforts, including therapeutic strategies like immuno-oncology through the ubcFLOW core, aim to translate these findings into effective treatments. By addressing fundamental questions and leveraging advanced technologies, LSI researchers strive to improve cancer outcomes and advance our understanding of this complex disease.

The immune system acts as our body's defense mechanism against infections and diseases like cancer. However, when this system is thrown off balance, it can lead to autoimmune disorders or severe inflammatory responses, as seen in conditions like COVID-19. To better understand and harness the immune system for therapeutic purposes, LSI researchers utilize advanced tools and technologies provided by core services like the ubcFLOW core, LSI IMAGING core, Proteomics and Metabolomics core, and the Bioinformatics core. These analyses are crucial for developing vaccines and immunomodulatory treatments, particularly in the context of diseases like COVID-19, where understanding immune responses is vital for tailoring effective interventions.

Through collaborations and interdisciplinary approaches, LSI researchers aim to unravel the complexities of immune responses at different scales, from atomic to systems levels. This includes studying how factors like age, sex, genetics, and environmental influences impact immune equilibrium and responses. By employing cutting-edge techniques such as single-cell RNA sequencing and protein profiling, researchers can delve into the intricacies of immune function and develop novel strategies for treating autoimmune disorders and enhancing vaccine efficacy. These efforts are essential for addressing the grand challenge of understanding and manipulating immune resilience for improved health outcomes.

Common chronic diseases such as cardiovascular diseases, neurodegenerative disorders, osteoporosis, and metabolic diseases like diabetes and obesity often stem from an age-related decline in the body's ability to maintain balance. These conditions, which frequently overlap and exacerbate each other, currently lack effective treatments targeting their underlying metabolic defects. LSI researchers are dedicated to laying the groundwork for future therapies that modify the course of these diseases by addressing metabolic dysfunctions. Leveraging core services like the ubcFLOW core for diagnosing immune senescence and the Bioinformatics core for data analysis, they investigate the intricate connections between metabolism, aging, and immunity, aiming to uncover novel therapeutic targets.

Through interdisciplinary collaborations and utilizing advanced techniques such as transcriptomics and proteomics, LSI researchers delve into the underlying mechanisms of aging-related diseases across various model systems, including fruit flies, worms, genetically engineered mice, and human tissue organoids. By comparing molecular aging pathways across these models and correlating findings with human genomic data, they strive to identify conserved targets for intervention. Additionally, Stem Cell and Genome Engineering facilitates the creation of human cell-derived models to test specific pathways involved in aging. LSI researchers are at the forefront of developing cell replacement and gene therapies for these diseases, from foundational research to leading clinical trials. Through these concerted efforts, LSI aims to advance our understanding of age-related diseases and develop innovative therapies to improve health outcomes.

Human resilience on Earth relies on sustainable methods of extracting energy and materials from our environment while minimizing environmental impact. To achieve this, LSI researchers tap into the vast genomic diversity found in microbial communities, facilitated by the powerful tools of the Bioinformatics core. These microbial genomes, containing an immense amount of information accumulated over billions of years, provide the foundation for biological resilience in bacterial populations and drive energy and material transformations crucial for sustainability.

The Grand Challenge ahead involves leveraging this genomic diversity to engineer microbial strains and communities for various applications, from lignin valorization to carbon capture, with the aim of developing innovative biotechnologies. Using advanced techniques offered by the Biofactorial core and LSI IMAGING core, researchers design, build, and test engineered microbial systems to address environmental, industrial, and health-related challenges. By reconstructing microbial networks and understanding complex microbial communities, predictive models and monitoring tools can be developed, paving the way for sustainable solutions to pressing global issues like climate change.

LSI researchers, spanning diverse areas from environmental genomics to bacterial metabolism, collaborate to unlock the potential of microbial systems. Through characterizing enzymes, understanding microbial communities, and studying bacterial behaviors, they aim to deepen our understanding of Earth's biogeochemical cycles and develop resilient solutions for a circular bio-economy. Utilizing core services like the Proteomics and Metabolomics Core, researchers harness the power of microbial biology to drive sustainable innovation and address the challenges of the 21st century.

Researchers are delving into the intricate world of molecular resilience, particularly in proteins and other fundamental life components. Understanding this resilience is crucial for designing effective drugs and grasping the mechanics of adaptation and evolution at the tiniest scale. Cutting-edge core facilities like ASTRID core and Protein and Vector Engineering play a vital role in achieving atomic-level clarity of these structures. They enable the study of proteins implicated in human diseases and those exploited by pathogens, offering new targets for precise therapies. Techniques such as cryo-electron microscopy, X-ray crystallography, and nuclear magnetic resonance are employed to decipher these structures. Biophysical studies, including electrophysiology, provide insights into the functions of individual proteins, bridging the gap to cellular-level understanding. Laboratories operating at this level collaborate on various scientific challenges, with a special focus on Grand Challenges that encompass understanding diseases and developing treatments.

Genetic, genomic, and epigenetic resilience are crucial for cells, organisms, and communities to adapt quickly and pass on information between generations for long-term evolution. Researchers at the LSI are exploring these mechanisms to turn human stem cells into organoids, which mimic organs in the body. Understanding how cancer cells evolve within their environment could lead to ways to prevent and treat cancer. This research contributes to our understanding of genetics and epigenetics and helps develop treatments for various diseases. LSI's Core Facilities, like Bioinformatics and Proteomics and Metabolomics, provide tools for researchers to analyze genetic data and understand how it translates into proteins and metabolites. The Stem Cell and Genome Engineering Core enables researchers to manipulate genetic information, while the Biofactorial core facilitates genome-wide screening. Labs working at this level collaborate on various scientific challenges, particularly focusing on understanding diseases and developing treatments.

Cellular resilience refers to how individual cells and groups of cells adapt and persist in performing their functions within an organism. For instance, resilience in immune cells contributes to the overall immunity of the body. Our memories, fears, and resilience to trauma are influenced by the continuous formation and elimination of connections between neurons throughout life. Research at this level delves into various aspects of cell biology, including cell division, maintaining cell structure, cell signaling, morphology, and how cells respond to different environments. These insights are relevant across different cell types, such as immune cells, neurons, and cancer cells. To conduct this research, scientists use techniques like flow cytometry, high-resolution imaging, and electrophysiology, supported by resources like the Bioinformatics core. The Stem Cell and Genome Engineering Core is essential for creating human cell and tissue models relevant to clinical research. Labs working at this level contribute significantly to addressing major scientific challenges, particularly focusing on understanding diseases and developing treatments.

Organism and system resilience illustrate how humans, animals, and microorganisms withstand and adjust to internal and external pressures. This includes maintaining balance in bodily functions and metabolism across all life stages and genders. Research at this scale examines animal physiology, adaptation to stress, tissue regeneration, and behavior. The BRI benefits from advanced facilities like the Centre for Disease Modelling and various cores, such as the Stem Cell and Genome Engineering core, ubcFLOW, and the LSI IMAGING core. The BRI offers a unique opportunity to study resilience using simple model systems like Drosophila and C. elegans, as well as more complex mammalian models like mice and rats, translating findings to human physiology through patient studies and engineered organoids. Understanding disease mechanisms involves studying resilience using integrated physiological approaches, considering all cells and organ systems in the body, including the impact of biological sex differences. This holistic approach is essential as it captures individual variations, crucial for population-level resilience. Labs working at this scale are pivotal in advancing our understanding of organismal resilience and disease mechanisms.

Ecosystem resilience involves how groups of organisms adapt and thrive while interacting with each other, like the intricate balance between human health and the microbiome both inside and outside our bodies. LSI researchers focus on understanding the resilience of microbial communities in various environments, such as the gut and in interactions with pathogens, including studying antimicrobial resistance. Their work sheds light on host-pathogen dynamics and informs strategies for managing infections. They also explore technologies like single-cell genome sequencing and biosensors for environmental monitoring, supported by resources like the Bioinformatics core and the Biofactorial core. To understand these interactions better, researchers utilize facilities like ASTRID and the Proteomics and Metabolomics core. Labs working at this level contribute significantly to addressing major scientific challenges, particularly focusing on understanding diseases and developing treatments.