Project Summary The parent grant, 2R35GM119770, (“Multi-cellular and multi-scale systems modeling to understand the dynamics of the human immune system in interdisciplinary applications”) supports my research program, which aims to identify how the immune system can be rewired en masse to elicit higher-order decision-making while still enabling the system to remain otherwise “healthy.” To this end, we are leveraging a highly interdisciplinary research team (computational and experimental immunologists, software engineers, and education researchers) and collaborators to build a Virtual Immune System -- a multi-scale, multi-approach computational framework to understand better the complex dynamical nature of the immune system, identify more accurate multi-dimensional biomarkers, and identify safe and effective treatments within a reasonable time and cost. In addition to expanding the Virtual Immune system, my program continues to develop methods and technologies for data-driven model construction, visualization, computation, real-time simulations, and reproducibility to advance multi-scale modeling of the immune system and beyond, including a cloud-based collaborative modeling software, Cell Collective. Cell Collective is a core technology that enables us to continue to build collaborations and deepen our existing relationships, including with translational partners to advance the impact of our systems work on drug discovery, a large international team modeling COVID-19, and with virologists and immunologists to further validate our computational predictions experimentally. This supplement will enable us to enhance the scalability, robustness, and sustainability of Cell Collective, which is currently used by thousands of scientists and life sciences students, and instructors around the world.