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Largely unknown just a few decades ago, computational systems biology is now a central methodology for biological and medical research. This amazing ascent raises the question of what the community should do next. The article outlines our personal vision for the future of computational systems biology, suggesting the need to address both mindsets and methodologies. We present this vision by focusing on current and anticipated research goals, the development of strong computational tools, likely prominent applications, education of the nextgeneration of scientists, and outreach to the public. In our opinion, two classes of broad research goals have emerged in recent years and will guide future efforts. The first goal targets computational models of increasing size and complexity, aimed at solving emerging health-related challenges, such as realistic whole-cell and organ models, disease simulators and digital twins, in silico clinical trials, and clinically translational applications in the context of therapeutic drug development. Such large models will also lead us toward solutions to pressing issues in agriculture and environmental sustainability, including sufficient food availability and life in changing habitats. The second goal is a deep understanding of the essence of system designs and strategies with which nature solves problems. This understanding will help us explain observed biological structures and guide forays into synthetic biological systems. Regarding effective methodologies, we suggest efforts toward automated data pipelines from raw biomedical data all the way to spatiotemporal mechanistic model. These will be supported by dynamic methods of statistics, machine learning, artificial intelligence and streamlined strategies of dynamic model design, striking a fine balance between modeling realistic complexity and abstracted simplicity. Finally, we suggest the need for a concerted, community-wide emphasis on effective education in systems biology, implemented as a combination of formal instruction and hands-on mentoring. The educational efforts should furthermore be extended toward the public through books, blogs, social media, and interactive networking opportunities, with the ultimate goal of training in state-of-the-art technology while recapturing the lost art of synthesis. [ABSTRACT FROM AUTHOR]

Digital twins are computer programs that use real-world data to create simulations that predict the performance of processes, products, and systems. Digital twins may integrate artificial intelligence to improve their outputs. Models for dealing with uncertainties and noise are used to improve the accuracy of digital twins. Most currently used systems aim to reduce noise to improve their outputs. Nevertheless, biological systems are characterized by inherent variability, which is necessary for their proper function. The constrained-disorder principle defines living systems as having a disorder as part of their existence and proper operation while kept within dynamic boundaries. In the present paper, we review the role of noise in complex systems and its use in bioengineering. We describe the use of digital twins for medical applications and current methods for dealing with noise and uncertainties in modeling. The paper presents methods to improve the accuracy and effectiveness of digital twin systems by continuously implementing variability signatures while simultaneously reducing unwanted noise in their inputs and outputs. Accounting for the noisy internal and external environments of complex biological systems is necessary for the future design of improved, more accurate digital twins. [ABSTRACT FROM AUTHOR]