This strategic proposal aims to deepen our understanding of the underlying mechanism by which cells, the core unit of life, exert their versatile capabilities upon changing cell types and cell states. In this approach, the seeds for novel molecular modalities and technologies to manipulate the potential of cells (e.g., artificial manipulation of gene expression patterns so as to modify a cell's phenotype) will be created. To build a solid new foundation for promoting original basic and applied research, we propose a organize multidisciplinary research and development founded on the cooperation of life scientists, medical scientists, chemists, engineering scientists, and etc...

Japan is one of the few countries that have discovered and developed new drugs; however, the country's drug discovery capabilities have been in decline. For example, during the COVID-19 pandemic, the development of new vaccines and new therapeutics in Japan lagged behind other nations. While the problem is multifaceted, the weakening of basic research has been identified as a major problem.

In recent years, drug modalities have diversified in response to the identification of novel targets that cannot be easily targeted by conventional drug discovery technologies. In the future, it is thought that the segregation and selection of therapeutics among different modalities will be advanced. In order for Japan to maintain and improve its presence as the world's leading centers of drug discovery, it is critical to improve drug discovery technologies and platforms to create new drug modalities. Thus, in order to accomplish the goal of promoting basic and applied life sciences it becomes essential to integrate heretofore distinct research fields to increase the possibility of establishing drug discovery platform technologies.

The human body consists of tens of billions of cells which can be divided into ca. 500 differentiated cell types. In view of the discovery that differentiated cells can be reprogrammed to become pluripotent, these differentiated cells would also have the potential to be transformed in vitro or in vivo into cells displaying function and properties different from their original cells through manipulation of their gene expression profiles. However, our current understanding is insufficient for fine tuning the regulatory mechanisms of cell differentiation and homeostatic maintenance. In recent years, application of various single-cell analyses and molecular modalities has enabled elucidation for how cells exhibit their unique characteristics and diversity, resulting in the expansion in the scope of target molecules. Japan has particular expertise in the fields needed to manipulate cellular function, such as epigenetic research, iPS, ES cell technology, imaging technology, and omics technologies. By integrating these strengths and through the creation and use of molecular modalities capable of controlling various target molecules, it is possible to further advance our understanding of cellular differentiation, such as elucidation of its specificity points and target molecules for a given cell type, with which to connect to technologies for controlling and using cells in intervention, prevention, and treatment of various diseases. It is expected that this will lead to the creation of new drug discovery platform technologies.

As the following issues are mainly led by life scientists, medical scientists, chemists, and engineering scientists, we propose to promote R&D as an initiative that integrates mutual knowledge and technologies among different fields.

1. Elucidation and understanding of the potential of cells
   • Chemical biology approach
   • Direct reprogramming with molecular modalitys
   • Elucidation of the mechanism of heterogeneity, plasticity and fluctuation of cells
   • Elucidation of quality control mechanism of cells in cellular populations
2. Analytical technologies that enable the evaluation of cells' potential
   • Development of omics measurement technology
   • Development of imaging technology
   • Integration of omics and imaging technologies
3. Creation of new molecular modalities
   • Epigenetic regulation
   • Targeted molecular regulation by chimeric compounds
   • Fine regulation of cell fate and function