The strategic proposal, "Computational Prediction of Intracellular Reactions," proposes research and development (R&D) subjects and promotion strategies for establishing simulation technology that can be practically applied in bioproduction and drug discovery research. Advances in life sciences have enabled chemical and genetic interventions in cells and organisms, leading to modifications of their functions, which have improved disease treatment and the efficiency of producing valuable substances. Here, as an approach to further these advancements of bioproduction and drug discovery research, we propose to establish simulation technology that integrates "intracellular reactions", such as metabolism, signal transduction, and gene expression--triggered by interactions of biomolecules--with cellular function. This involves computationally predicting the effects of interventions, such as drug treatments and genetic modifications, thus providing guides to the exploration of optimal intervention conditions in bioproduction and drug discovery research.

There are various types of intracellular biomolecules, such as proteins and lipids, that interact with each other to facilitate intracellular reactions. The reactions include metabolic processes, signal transduction, and gene expression regulation, leading to the expression of a cellular function. As each cell contributes to the functions and behaviors of cell populations, tissues, organs, and the organism as an individual, exploring optimal intervention conditions based on a deep understanding of these intracellular reactions is crucial to create safe and effective pharmaceuticals and efficient bioproduction technologies. However, the current situation requires numerous experimental trials and errors for these explorations and identifications, leading to significant time and economic cost.

Since the main reactive environment is within living organism, it is required to consider various involved biomolecules, intracellular substances, and interactions with adjacent environments and cells, in bioproduction and drug discovery research. However, experimentally capturing the full scope of intracellular reactions is a huge burden, and the optimization of intervention conditions is often based mainly on the researchers' experience. Enhancing simulation technology is essential for the next-generation R&D approach in bioproduction and drug discovery, but current simulation technologies are often applied under limited conditions and variables, restricting their scope and practical usability.

In this proposal, we suggest addressing the following three R&D subjects to advance simulation technology for practical applications in bioproduction and drug discovery research:

• R&D Subject 1: Cohesively integrate and connect intracellular reactions across spatial and temporal scales.
• R&D Subject 2: Capture and analyze the interactions and underlying relationships between intracellular reactions.
• R&D Subject 3: Accumulate data related to intracellular reactions and improve computational model accuracy.

Implementing this strategic proposal is expected to result in the following societal benefits:

• Improvement in bioproduction efficiency in Japan.
• Enhancement of drug discovery capabilities in Japan.

Additionally, these could contribute to the economic stability and independence from abroad by strengthening Japanese industrial competitiveness and reducing external dependencies on essential ingredients and pharmaceutics production.

Following scientific and technological impacts are also expected:

• Deepened understanding of life science.
• Development of foundational and basic technologies related to the implementation of the subjects above.
• Accumulation of spatiotemporal data related to intracellular reactions and development of data integration platform.
• Formation of interdisciplinary communities and cultivation of next-generation talents.

To efficiently promote the above R&D subjects and maximize the outcomes, the strategic proposal suggests establishing a virtual research institute. This institute would facilitate collaboration across geographical boundaries and encourage long-term team projects. Setting initial, mid-term, and long-term milestones is essential for accelerating the development of simulation technology as a fundamental technology for life science research. It is also important to expand the interdisciplinary community and continuously activate the research as a new research area by sharing outcomes beyond the virtual institute, thereby for achieving collaborative discoveries.

• (in Japanese) Computational Prediction of Intracellular Reactions